Description 
Hodgkin lymphoma (HL) results from a clonal expansion of a B-cell lineage, characterized by the presence of Reed-Sternberg cells on pathology. Standard treatment is based on the stage at presentation and may involve chemotherapy with or without radiotherapy. Hematopoietic cell transplantation (HCT) has been used for HL, particularly in the setting of relapse or refractory disease.

Summary of Evidence
Autologous Hematopoietic Cell Transplantation
For individuals who have Hodgkin lymphoma (HL) who receive autologous hematopoietic cell transplantation (HCT) as first-line therapy, the evidence includes randomized controlled trials (RCTs). Relevant outcomes are overall survival (OS), disease-specific survival (DSS), change in disease status, morbid events, and treatment-related mortality and morbidity. Randomized controlled trials of autologous HCT as first-line treatment have reported that this therapy does not provide additional benefit compared with conventional chemotherapy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have relapsed or refractory HL who receive autologous HCT, the evidence includes RCTs, a meta-analysis, nonrandomized studies, and case series. Relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. Two RCTs in patients with relapsed or refractory disease have reported a benefit in PFS and a trend toward a benefit in OS. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have relapsed HL after an autologous HCT who receive a second autologous HCT, the evidence includes case series. Relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. No RCTs or nonrandomized comparative studies were identified. In a case series, treatment-related mortality at 100 days was 11%; at a median follow-up of 72 months, the mortality rate was 73%. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Allogeneic Hematopoietic Cell Transplantation
For individuals who have HL who receive allogeneic HCT (allo-HCT) as first-line therapy, the evidence includes no published studies. Relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. No studies specifically addressing allo-HCT as first-line treatment for HL were identified. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have relapsed or refractory HL who receive allo-HCT, the evidence includes a number of case series and a meta-analysis. Relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. A 2016 meta-analysis identified 38 case series evaluating allo-HCT for relapsed or refractory HL. The pooled analysis found a 6-month OS rate of 83% and a 3-year OS of 50%. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have relapsed HL after autologous HCT who receive allo-HCT, the evidence includes case series and a meta-analysis. Relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. A 2016 meta-analysis of 38 case series found that a previous autologous HCT followed by allo-HCT was significantly associated with higher 1- and 2-year OS rates and significantly higher recurrence-free survival rates at 1 year compared with no previous autologous HCT. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have relapsed or refractory HL who receive reduced-intensity conditioning (RIC) with allo-HCT, the evidence includes case series, cohort studies, and a systematic review. Relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. A 2015 systematic review cited a number of studies, including some with comparison groups, showing acceptable outcomes after RIC with allo-HCT in patients with relapsed or refractory HL. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Tandem Autologous Hematopoietic Cell Transplantation
For individuals who have HL who receive tandem autologous HCT, the evidence includes nonrandomized comparative studies and case series. Relevant outcomes are OS, DSS, change in disease status, morbid events, and treatment-related mortality and morbidity. One prospective, nonrandomized study reported that, in patients with poor prognostic markers, response to tandem autologous HCT might be higher than for single autologous HCT. This study was not definitive due to potential selection bias; RCTs are needed to determine the impact of tandem autologous HCT on health outcomes in this population. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information
2020 Input
Clinical input was sought to help determine whether the use of either second autologous HCT for relapsed HL or tandem autologous HCT for HL would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice. In response to requests, clinical input was received from 4 respondents, including 3 complete responses including 2 physician-level responses identified through specialty societies and 1 physician-level response identified through an academic medical center.

For individuals with relapsed HL after an autologous HCT who receive second autologous HCT, clinical input does not support a clinically meaningful improvement in net health outcome and does not indicate this use is consistent with generally accepted medical practice.

For individuals with HL who receive tandem autologous HCT, clinical input does not support a clinically meaningful improvement in net health outcome and does not indicate this use is consistent with generally accepted medical practice.

Further details from clinical input are included in the Appendix.

Background
Acute Myeloid Leukemia Treatment
Complete remission of acute myeloid leukemia (AML) can be achieved initially using induction therapy, consisting of conventional doses of combination chemotherapy. A complete response is achieved in 60% to 80% of adults younger than 60 years of age and 40% to 60% in patients older than 60 years of age. However, the high incidence of disease relapse has prompted research into a variety of post-remission (consolidation) strategies, typically using high-dose chemotherapy with autologous hematopoietic cell transplantation (HCT) or high-dose or reduced-intensity chemotherapy with allogeneic HCT (allo-HCT). The 2 treatments, autologous HCT and allo-HCT, represent 2 different strategies. The first, autologous HCT, is a “rescue,” but not a therapeutic procedure; the second, allo-HCT, is a “rescue” plus a therapeutic procedure.

Hematopoietic Cell Transplantation
Hematopoietic cell transplantation is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune function in patients with cancer who receive bone marrow-toxic doses of cytotoxic drugs with or without whole-body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allo-HCT). These cells can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Cord blood transplantation is discussed in detail in evidence review 7.01.50.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allo-HCT, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. Human leukocyte antigen refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for Hematopoietic Cell Transplantation
Conventional Conditioning
The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease (GVHD), which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not GVHD.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation
Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning (MAC) treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and nonrelapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and nonrelapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. Reduced-intensity conditioning regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this review, the term RIC will refer to all conditioning regimens intended to be nonmyeloablative.

A 2015 review in the New England Journal of Medicine summarized advances in the classification of AML, the genomics of AML and prognostic factors, and current and new treatments.¹ The National Comprehensive Cancer Network guidelines provide updated information on genetic markers for risk stratification, and additional recent reviews summarize information on novel therapies for AML.^2,3,4

Regulatory Status
The  U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, Title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

Policy 
Autologous hematopoietic cell transplantation (HCT) may be considered MEDICALLY NECESSARY in patients with primary refractory or relapsed Hodgkin lymphoma.   

Allogeneic HCT, using either myeloablative or reduced-intensity conditioning regimens, may be considered MEDICALLY NECESSARY in patients with primary refractory or relapsed Hodgkin lymphoma.   

Tandem autologous HCT may be considered MEDICALLY NECESSARY:

• In patients with primary refractory Hodgkin lymphoma.

• In patients with relapsed disease with poor risk features who do not attain a complete remission after cytoreductive chemotherapy prior to transplantation (see Policy Guidelines section).

Second autologous HCT for relapsed lymphoma after a prior autologous HCT is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY .

Other uses of HCT in patients with Hodgkin lymphoma are investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY, including, but not limited to, initial therapy for newly diagnosed disease to consolidate a first complete remission. .

Policy Guidelines 
In the Morschhauser et al. (2008) study of risk-adapted salvage treatment with single or tandem autologous hematopoietic cell transplantation (HCT) for first relapse or refractory Hodgkin lymphoma, poor-risk relapsed Hodgkin lymphoma was defined as 2 or more of the following risk factors at first relapse: time to relapse less than 12 months, stage III or IV at relapse, and relapse within previously irradiated sites. Primary refractory disease was defined as disease regression less than 50% after 4 to 6 cycles of doxorubicin-containing chemotherapy or disease progression during induction or within 90 days after the end of first-line treatment.

Some patients for whom a conventional myeloablative allotransplant could be curative may be considered candidates for reduced-intensity conditioning allogeneic HCT (allo-HCT). They include those with malignancies that are effectively treated with myeloablative allogeneic transplantation, but whose age (typically > 55 or > 60 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status score) preclude use of a standard myeloablative conditioning regimen.

The ideal allogeneic donors are human leukocyte antigen-identical matched siblings. Related donors mismatched at 1 locus are also considered suitable donors. A matched, unrelated donor identified through the National Marrow Donor Program is typically the next option considered. Recently, there has been interest in haploidentical donors, typically a parent or a child of the patient, with whom usually there is sharing of only 3 of the 6 major histocompatibility antigens. Most patients will have such a donor; however, the risk of graft-versus-host disease and overall morbidity of the procedure may be severe, and experience with these donors is not as extensive as that with matched donors.

CODING
In 2003, CPT centralized codes describing allogeneic and autologous hematopoietic cell support services to the hematology section (CPT 38204 – 38242). Not all codes are applicable for each high-dose chemotherapy with stem cell support procedure. For example, Plans should determine if cryopreservation is performed. A range of codes describes services associated with cryopreservation, storage, and thawing of cells (38207 – 38215).

CPT 38208 and 38209 describe thawing and washing of cryopreserved cells
CPT 38210-38214 describe certain cell types being depleted
CPT 38215 describes plasma cell concentration. 

Benefit Application
The following considerations may supersede this policy:

• State mandates requiring coverage for autologous bone marrow transplantation offered as part of clinical trials of autologous bone marrow transplantation approved by the National Institutes of Health (NIH).

• Some plans may participate in voluntary programs offering coverage for patients participating in NIH-approved clinical trials of cancer chemotherapies, including autologous bone marrow transplantation.

• Some contracts or certificates of coverage (e.g., FEP) may include specific conditions in which autologous bone marrow transplantation would be considered eligible for coverage.

Rationale 
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Allogeneic Hematopoietic Stem Cell Transplant with Myeloablative Conditioning for Cytogenetic or Molecular Intermediate- or Poor-Risk Acute Myeloid Leukemia in Complete Remission
Clinical Context and Therapy Purpose
The purpose of allogeneic (allo-) hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in individuals who have cytogenetic or molecular intermediate- or poor-risk acute myeloid leukemia (AML) in first complete remission (CR1) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with cytogenetic or molecular intermediate- or poor-risk AML in CR1.

Interventions
The therapy being considered is allo-HCT with MAC. Allogeneic HCT with MAC is an option for post-remission or consolidation therapy in cytogenetic or molecular intermediate- or poor-risk AML. The purpose of post-remission therapy is to destroy undetectable leukemia cells remaining after induction chemotherapy.

Comparators
The following therapies are currently being used to make decisions about cytogenetic or molecular intermediate- or poor-risk AML in CR1: conventional chemotherapy.

Outcomes
The general outcomes of interest are survival outcomes (overall survival [OS], disease-specific survival [DSS], and disease-free survival [DFS]), relapse rates, and treatment-related morbidity. The median survival of individuals with AML varies with several known prognostic factors related to individual and tumor characteristics such as age, performance status, and karyotype. Overall, the median survival for individuals with AML without chemotherapy or HCT is less than 10 months; the median survival in individuals with chemotherapy but without HCT is approximately 20 months.⁵ Individuals are followed up throughout their lifespan.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Masetti et al (2022) conducted a meta-analysis of allo-HCT for pediatric patients with AML in CR1.⁶ Both prospective and retrospective studies comparing allo-HCT to chemotherapy in higher-risk patients were considered. A total of 9 studies (5 prospective, 4 retrospective) were included; none of the prospective studies were randomized. The meta-analysis showed that OS was improved with allo-HCT compared with chemotherapy (risk ratio, 1.15; 95% confidence interval [CI], 1.06 to 1.24; I²=0%). Similarly, DFS was improved with allo-HCT compared to chemotherapy (risk ratio, 1.31; 95% CI, 1.17 to 1.47; I²=1%). Risk of relapse was higher among patients who received chemotherapy (risk ratio, 1.26; 95% CI, 1.07 to 1.49; I²=23%).

A 2015 meta-analysis examined prospective trials of adults with intermediate-risk AML in CR1 who underwent HCT.⁷ The analysis included 9 prospective, controlled studies that enrolled 1950 patients between the years 1987 and 2011 (sample range, 32 to 713 patients). In this meta-analysis, allo-HCT was associated with significantly better relapse-free survival (RFS), OS, and relapse rate than autologous HCT and/or chemotherapy (hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.95; HR, 0.76; 95% CI, 0.61 to 0.95; HR, 0.58; 95% CI, 0.45 to 0.75, respectively). Treatment-related mortality was significantly higher following allo-HCT than autologous HCT (HR, 3.09; 95% CI, 1.38 to 6.92). However, a subgroup analysis, which used updated criteria to define intermediate-risk AML, showed no OS benefit for allo-HCT over autologous HCT (HR, 0.99; 95% CI, 0.70 to 1.39).

A 2009 systematic review incorporated data from 24 trials involving 6007 patients who underwent allo-HCT in CR1.⁸ Among the total, 3638 patients were stratified and analyzed according to cytogenetic risk (547 good-, 2499 intermediate-, 592 poor-risk patients with AML) using a fixed-effects model. Compared with either autologous HCT or additional consolidation chemotherapy, the HR for OS among poor-risk patients across 14 trials was 0.73 (95% CI, 0.59 to 0.90; p<.01); among intermediate-risk patients across 14 trials, the HR for OS was 0.83 (95% CI, 0.74 to 0.93; p<.01); and among good-risk patients across 16 trials, the HR for OS was 1.07 (95% CI, 0.83 to 1.38; p=.59). Interstudy heterogeneity was not significant in any of these analyses. Results for DFS were very similar to those for OS in this analysis. These results are in line with those from another meta-analysis⁹ on the use of allo-HCT as consolidation therapy for AML.

A 2005 meta-analysis of allo-HCT in patients with AML in CR1 pooled data from 5 studies (N=3100 patients).⁹ Among those patients, 1151 received allo-HCT, and 1949 were given alternative therapies including chemotherapy and autologous HCT. All studies employed natural randomization based on donor availability and intention-to-treat analysis, with OS and DFS as outcomes of interest. This analysis showed a significant advantage for allo-HCT regarding OS for the entire cohort (fixed-effects model HR, 1.17; 95% CI, 1.06 to 1.30; p=.003; random-effects model HR, 1.15; 95% CI, 1.01 to 1.32; p=.037) even though none of the individual studies did so. Meta-regression analysis showed the effect of allo-HCT on OS differed depending on the cytogenetic risk groups of patients, suggesting a significant benefit for poor-risk patients (HR, 1.39, 95% CI not reported), an indeterminate benefit for intermediate-risk cases, and no benefit in better-risk patients compared with alternative approaches. Reviewers cautioned the compiled studies used different definitions of risk categories than other groups (eg, SWOG, Medical Research Council, European Organisation for Research and Treatment of Cancer, Gruppo Italiano Malattie Ematologiche dell’ Adulto).¹⁰ Although the statistical power of the meta-regression analysis was limited by small numbers of cases, the results of this meta-analysis are supported in general by data from other reviews.^11,12,13,14

Evidence from the meta-analysis suggests patients with better prognosis (as defined by cytogenetics) may not realize a significant survival benefit with allo-HCT in CR1 that outweighs the risk of associated morbidity and nonrelapse mortality. However, there is considerable genotypic heterogeneity within the 3 World Health Organization cytogenetic prognostic groups that complicates generalization of clinical results based only on cytogenetics.¹⁵ For example, patients with better prognosis disease (eg, core-binding factor AML) based on cytogenetics, and a variant in the KIT gene of leukemic blast cells, do just as poorly with post-remission standard chemotherapy as patients with cytogenetically poor-risk AML.¹⁶Similarly, patients with cytogenetically normal AML (intermediate prognosis disease) can be subcategorized into groups with better or worse prognosis based on the mutational status of the nucleophosmin gene (NPM1) and the FLT3 gene (the FLT3 gene is a gene that encodes FMS-like receptor tyrosine kinase 3, a growth factor active in hematopoiesis). Thus, patients with variants in NPM1 but without FLT3 internal tandem duplications have post-remission outcomes with standard chemotherapy that are similar to those with better prognosis cytogenetics. In contrast, patients with any other combination of variants in those genes have outcomes similar to those with poor prognosis cytogenetics.¹⁷ It follows that, because the earlier clinical trials compiled in the meta-analysis described here did not account for genotypic differences that affect prognosis and alter outcomes, it is difficult to use the primary trial results to draw conclusions on the role of allo-HCT in different patient risk groups.

A meta-analysis by Buckley et al (2017) evaluated the relationship between minimal residual disease (MRD) at the time of HCT and posttransplantation outcomes.¹⁸ The literature search, conducted through June 2016, identified 19 studies (N=1431 patients) for inclusion. Risk of bias was assessed using a modified version of the Quality of Prognostic Studies instrument, which focused on: prognostic factor measurement, study confounding, and statistical analysis and reporting. Five studies were considered at high-risk for bias, 9 were at moderate-risk, and 5 were at low-risk. The following variables were collected from each study: age, follow-up, adverse-risk cytogenetics, conditioning type (myeloablative or reduced-intensity), MRD detection method, and survival. Reviewers reported that the presence of MRD at the time of transplantation was associated with higher relapse and mortality. This association was seen regardless of patient age and type of conditioning, which suggests that an intense conditioning regimen may not be able to overcome the adverse impact of MRD.

Prospective Studies
Bornhäuser et al (2023) conducted an open-label, 2-arm, multicenter RCT in Germany to assess the ideal postremission strategy in intermediate-risk AML in CR1.¹⁹ Adults with AML (age 18 to 60 years) in CR1 or CR with incomplete blood cell count recovery after conventional induction therapy who had availability of a human leukocyte antigen-matched sibling or unrelated donor were included and randomized 1:1 to receive allo-HCT or high-dose cytarabine (HiDAC) for consolidation and salvage HCT only in cases of relapse. The primary outcome was OS; DFS, incidence of relapse, treatment-related mortality, and quality of life measures according to the Medical Outcomes Study 36-Item Short-Form Health Survey were secondary outcomes. One hundred forty-three patients (mean age, 48.2 years, standard deviation, 9.8 years; 57% male) with AML were randomized. At 2 years, the probability of survival was 74% (95% CI, 62% to 83%) after primary allo-HCT and 84% (95% CI, 73% to 92%) after HiDAC (p=.22). Disease-free survival at 2 years was 69% (95% CI, 57% to 80%) after HCT compared with 40% (95% CI, 28% to 53%) after HiDAC (p=.001). The cumulative incidence of relapse at 2 years with allo-HCT was 20% (95% CI, 13% to 31%) compared with 58% (95% CI, 47% to 71%; p<.001) with HiDAC and nonrelapse mortality after allo-HCT was 9% (95% CI, 5% to 19%) versus 2% (95% CI, 0% to 11%) after HiDAC (p=.005). All 41 participants who relapsed after HiDAC proceeded to receive allo-HCT. There were no differences in quality of life measures between groups. Of note, this trial was closed earlier than anticipated due to slow patient accrual, which was a limitation. Additional limitations included the lack of stratification based on MRD and the use of a cytogenetic classifier at trial initiation (2012) which led to inclusion of some favorable-risk patients, which current guidelines would not recommend allo-HCT in CR1. In conclusion, primary allo-HCT during CR1 was not associated with superior OS compared to HiDAC in adults with intermediate-risk AML <60 years, although some secondary endpoints had promising results and were hypothesis generating.

A 2014 study compared outcomes of 185 matched pairs from a large multicenter trial (AMLCG99).²⁰ Patients younger than 60 years of age who underwent allo-HCT in CR1 were matched to patients who received conventional post-remission chemotherapy. The main matching criteria were AML type, cytogenetic risk group, patient age, and time in CR1. In the overall pairwise-compared AML population, the projected 7-year OS rate was 58% for allo-HCT and 46% for the conventional post-remission treatment group (p=.037). The RFS rate was 52% in the allo-HCT group and 33% in the control group (p<.001). The OS was significantly longer for allo-HCT patient subgroups with unfavorable chromosomal aberrations, patients older than 45 years, and patients with secondary AML or high-risk myelodysplastic syndrome. For the entire patient cohort, post-remission therapy was an independent factor for OS (HR, 0.66; 95% CI, 0.49 to 0.89 for allo-HCT vs. conventional chemotherapy) among age, cytogenetics, and bone marrow blasts after the first induction cycle.

Retrospective Studies
Heidrich et al (2017) conducted retrospective analyses of subgroups from 2 prospective clinical trials, including 497 patients with intermediate-risk AML who did not present with NPM1, CEBPA, or FLT3 internal tandem duplication variants.²¹During the initial analysis (donor vs. no-donor), RFS rates were better for patients who had an available sibling donor (n=83) than for those who lacked a matched sibling donor (49% vs. 26%; HR, 0.5; 95% CI, 0.3 to 0.9; p=.02). A similar improvement was seen for OS, although not statistically significant (p=.08). The authors also conducted a time-dependent multivariate analysis to account for the significantly longer time-from-CR1 observed in patients treated with allo-HCT (median, 115 days) compared with those treated with post-remission chemotherapy (median, 78 days; p<.001). Rates of OS after 5 years were superior for the group who received allo-HCT than for those receiving chemotherapy (OS, 66% vs. 46%, respectively; HR, 0.58; 95% CI, 0.37 to 0.9; p=.02), as were rates of RFS (5-year RFS, 55% vs. 31%; HR, 0.51; 95% CI, 0.34 to 0.76; p=.001). The investigators acknowledged that 38% of the group assigned to post-remission chemotherapy received allo-HCT following a relapse, which might have contributed to a crossover effect.

Section Summary: Allogeneic Hematopoietic Cell Transplant with Myeloablative Conditioning for Cytogenetic or Molecular Intermediate- or Poor-Risk Acute Myeloid Leukemia in Complete Remission
Evidence for the use of allo-HCT for patients with AML in CR1 consists of systematic reviews, RCTs, and matched cohort studies. Some studies have compared allo-HCT with autologous HCT or with post-remission chemotherapy. In some studies, the OS and DFS rates were favorable for allo-HCT compared with conventional chemotherapy. In a paired comparison with patients receiving chemotherapy, patients receiving allo-HCT experienced significantly higher RFS rates. However, in a more recent RCT, there was no difference in OS between allo-HCT and HiDAC, although there were many limitations associated with this study. Two retrospective studies analyzed subgroups of allo-HCT patients who did not present with several common genetic variants or who presented with hyperleukocytosis. Survival rates appear to be associated with the presence of MRD and cytogenetic prognosis groups.

Allogeneic Hematopoietic Cell Transplant with Myeloablative Conditioning for Acute Myeloid Leukemia Refractory to Standard Induction Chemotherapy
Clinical Context and Therapy Purpose
The purpose of allo-HCT with MAC in individuals who have AML refractory to standard induction chemotherapy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population(s) of interest is individuals with AML refractory to standard induction chemotherapy.

Interventions
The therapy being considered is allo-HCT with MAC. Allogeneic HCT is an option for AML refractory to standard induction chemotherapy. The purpose is to destroy leukemia cells remaining after induction chemotherapy.

Comparators
The following therapies are currently being used to make decisions about AML refractory to standard induction chemotherapy: conventional chemotherapy.

Outcomes
The general outcomes of interest are survival outcomes (OS, DSS, and DFS), relapse rates, and treatment-related morbidity. The median survival of individuals with AML varies with several known prognostic factors related to individual and tumor characteristics such as age, performance status, and karyotype. Overall, the median survival for individuals with AML without chemotherapy or HCT is less than 10 months; the median survival in individuals with chemotherapy but without HCT is approximately 20 months.⁵ Individuals are followed up throughout their lifespan.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Retrospective Studies
Conventional dose induction chemotherapy will not produce remission in 20% to 40% of patients with AML, connoting refractory AML.¹⁰ An allo-HCT using a matched related donor or matched unrelated donor represents the only potentially curative option for these patients. In several retrospective studies, OS rates have ranged from 30% at 3 years to 13% at 5 years, although this procedure is accompanied by nonrelapse mortality rates of 25% to 62% in this setting.¹¹ A 2022 observational study reported higher 3-year and 5-year OS (38% and 33%, respectively), but these rates may lack precision due to a small sample size (N=12).²² Another small study reported 4-year OS of 51.0±10.6% among 29 patients who received allo-HCT and 46.2±9.0% among 34 patients who received salvage chemotherapy followed by allo-HCT, both for refractory AML.²³ For patients who lack a suitable donor (matched related donor or matched unrelated donor), alternative treatments include salvage chemotherapy with HiDAC or etoposide-based regimens, monoclonal antibodies (eg, gemtuzumab ozogamicin), FLT3 antagonists, IDH1/IDH2 inhibitors, and clinical trial enrollment.² Because it is likely that stem cell preparations will be contaminated with malignant cells in patients whose disease is not in remission, upfront autologous HCT has no role in patients who fail induction therapy.²⁴

Section Summary: Allogeneic Hematopoietic Cell Transplant with Myeloablative Conditioning for Acute Myeloid Leukemia Refractory to Standard Induction Chemotherapy
Evidence for the use of allo-HCT for individuals with primary AML refractory to chemotherapy consists of retrospective studies compiled from data from phase 3 trials and registries. The OS rate estimates range from 30% to 38% at 3 years and 13% to 51% at 4 to 5 years; however, the procedure is accompanied by high rates of nonrelapse mortality (estimated range, 25% to 62%). Nonetheless, these results may provide a clinically meaningful benefit for such patients who do not have other treatment options. Autologous HCT is not recommended for patients who have failed induction therapy, because malignant cells may be included in the stem cell preparation process.

Allogeneic or Autologous Hematopoietic Cell Transplant with Myeloablative Conditioning for Relapsed Acute Myeloid Leukemia After Chemotherapy-Induced Remission
Clinical Context and Therapy Purpose
The purpose of allogeneic or autologous HCT with MAC in individuals who have relapsed AML after standard induction chemotherapy-induced CR1 is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population(s) of interest is individuals with AML who relapsed after standard induction chemotherapy-induced CR1.

Interventions
The therapy being considered is allo-HCT or autologous HCT. Allogeneic or autologous HCT are options for treatment of relapsed AML after chemotherapy-induced remission. The purpose of HCT is to destroy leukemia cells associated with recurrent AML.

Comparators
The following therapies are currently being used to make decisions about relapsed AML after chemotherapy-induced remission: conventional chemotherapy.

Outcomes
The general outcomes of interest are survival outcomes (OS, DSS, and DFS), relapse rates, and treatment-related morbidity. The median survival of individauls with AML varies with several known prognostic factors related to individual and tumor characteristics such as age, performance status, and karyotype. Overall, the median survival for individuals with AML without chemotherapy or HCT is less than 10 months; the median survival in individuals with chemotherapy but without HCT is approximately 20 months.⁵ Individuals are followed up throughout their lifespan.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Retrospective Studies
Most patients with AML will experience disease relapse after attaining a CR1.¹⁰ Conventional chemotherapy is not curative in most patients following disease relapse, even if a second complete remission (CR2) can be achieved.

A study by Breems et al (2005) evaluated retrospective data from 667 patients who had relapsed, among a total of 1540 patients entered in 3, phase 3 trials who had received HCT during CR1. The analysis suggested that use of allo-HCT among relapsed patients can produce 5-year OS rates of 26% to 88%, depending on cytogenetic risk stratification.²⁵

Allo-HCT is often performed as salvage therapy for patients who have relapsed after conventional chemotherapy or autologous HCT.²⁴ The decision to attempt reinduction to allo-HCT is based on the availability of a suitable stem cell donor and the likelihood of achieving remission, the latter being a function of cytogenetic risk group, duration of CR1, and the patient’s health status. Registry data have shown DFS rates of 44% using sibling allografts and 30% with matched unrelated donor allografts at 5 years for patients transplanted in CR2, and DFS rates of 35% to 40% using sibling transplants and 10% with matched unrelated donor transplants for patients with induction failure or in relapse following HCT.²⁴

In a retrospective chart review, Frazer et al (2017) assessed characteristics that might predict OS, relapse rate, and nonrelapse mortality of HCT in patients with relapsed AML.²⁶ Data were abstracted from 55 consecutive patients who underwent allo-HCT for AML in CR2. The OS rates at 1, 3, and 5 years posttransplant were 60%, 45%, and 37%, respectively. None of the following pretransplant variables were significantly associated with OS, relapse rate, or nonrelapse mortality: duration of first remission, patient age, cytogenetic risk category, post myelodysplastic syndrome, conditioning regimen, or donor type. Limitations of the study were its small sample size and selection parameters that included transplantations conducted across 21 years.

In patients in CR2 without an allogeneic donor or who are not candidates for allo-HCT due to age or other factors, autologous HCT may achieve prolonged DFS in 9% to 55% of patients in CR2 depending on risk category.^24,27 However, because it is likely that stem cell preparations will be contaminated with malignant cells in patients whose disease is not in remission, and it is often difficult to achieve CR2 in these patients, autologous HCT in this setting is usually limited to patients who have a sufficient stem cell preparation remaining from the collection in CR1.²⁴

Section Summary: Allogeneic or Autologous Hematopoietic Cell Transplant with Myeloablative Conditioning for Relapsed Acute Myeloid Leukemia After Chemotherapy-Induced Remission
Evidence on the use of HCT for individuals with relapsed AML includes retrospective chart reviews compiling data from phase 3 trials and registries. The DFS rates ranged from 30% to 44% depending on the source of transplantation cells, and OS rates ranged from 26% to 88% depending on risk stratification. Because reinduction chemotherapy may be associated with high morbidity and mortality, HCT may be considered.

Allogeneic Hematopoietic Cell Transplant With Reduced-Intensity Conditioning for Cytogenetic or Molecular Intermediate- or Poor-Risk Acute Myeloid Leukemia in Remission
Clinical Context and Therapy Purpose
The purpose of allo-HCT with reduced-intensity conditioning (RIC) in individuals who have cytogenetic or molecular intermediate- or poor-risk AML in CR1 who cannot tolerate MAC is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population(s) of interest is individuals with cytogenetic or molecular intermediate- or poor-risk AML in CR1 who cannot tolerate MAC.

Interventions

The therapy being considered is allo-HCT with RIC. Allogeneic HCT with RIC is an option for post-remission therapy for cytogenetic or molecular intermediate- or poor-risk AML. The purpose of post-remission therapy is to destroy undetectable leukemia cells remaining after induction chemotherapy.

Comparators

The following therapies are currently being used to make decisions about cytogenetic or molecular intermediate- or poor-risk AML in CR1: conventional chemotherapy and allo-HCT with MAC.

Outcomes

The general outcomes of interest are survival outcomes (OS, DSS, and DFS), relapse rates, and treatment-related morbidity. The median survival of individuals with AML varies with several known prognostic factors related to individual and tumor characteristics such as age, performance status, and karyotype. Overall, the median survival for individuals with AML without chemotherapy or HCT is less than 10 months; the median survival in individuals with chemotherapy but without HCT is approximately 20 months.⁵ Individuals are followed up throughout their lifespan.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

A body of evidence is accruing from clinical studies that RIC with allo-HCT may be used for consolidation therapy in patients with AML.^{28,29,30,31,32,33,34,35,36,37,38,39}

Systematic Reviews

Song et al (2021) evaluated the efficacy of RIC followed by allo-HCT in patients with AML and myelodysplastic syndrome via a meta-analysis of 6 RCTs (N=1413).⁴⁰ The 6 RCTs compared RIC to MAC before first allo-HCT in patients with AML in complete remission or myelodysplastic syndrome. The primary endpoint was OS. Results revealed that OS was not significantly different between RIC and MAC (HR, 0.95; 95% CI, 0.64 to 1.4; p=.80). The cumulative incidence of relapse was also similar between the groups (HR, 1.18; 95% CI, 0.88 to 1.49; p=.28). Nonrelapse mortality was significantly improved with RIC as compared to total body irradiation/busulfan-based MAC (HR, 0.53; 95% CI, 0.36 to 0.8; p=.002); however, treosulfan-based MAC significantly reduced nonrelapse mortality as compared to RIC (HR, 1.67; 95% CI, 1.02 to 2.72; p=.04). Reduced-intensity conditioning was associated with a trend of increasing graft failure (p=.06); however, graft failure in both arms was rare. The authors concluded that RIC is recommended as an adequate option of preparative treatment before allo-HCT for patients with AML in complete remission or myelodysplastic syndrome. Limitations of the meta-analysis included the small number of included clinical trials, significant heterogeneity between included studies for some outcomes, and lack of blinding in some studies.

A systematic review and meta-analysis by Rashidi et al (2016) calculated OS and RFS for patients older than 60 years of age with AML who underwent RIC HCT.⁴¹ A literature search, conducted through September 2015, identified 13 studies (N=749 patients) for inclusion. Pooled estimates for RFS at 6 months, 1 year, 2 years, and 3 years were 62% (95% CI, 54% to 69%), 47% (95% CI, 42% to 53%), 44% (95% CI, 33% to 55%), and 35% (95% CI, 26% to 45%), respectively. Pooled estimates for OS at 6 months, 1 year, 2 years, and 3 years were 73% (95% CI, 66% to 79%), 58% (95% CI, 50% to 65%), 45% (95% CI, 35% to 54%), and 38% (95% CI, 29% to 48%), respectively.

A 2014 meta-analysis compared RIC with MAC regimens for allo-HCT in patients with AML.⁴² The analysis included 23 clinical trials reported between 1990 and 2013, with approximately 15,000 adults. Eleven studies included AML and myelodysplastic syndrome, and 5 included AML only. A subanalysis from 13 trials in patients with AML or myelodysplastic syndrome revealed that OS was comparable in patients who received either RIC or MAC transplants, and the 2-year or less and 2-year or greater OS rates were equivalent between both conditioning groups. The 2- to 6-year progression-free survival, nonrelapse mortality, and acute and chronic graft-versus-host disease (GVHD) rates were reduced after RIC HCT, but the relapse rate was increased. Similar outcomes were observed regardless of disease status at transplantation. Among the RIC HCT recipients, survival rates were superior if patients were in CR at transplantation.

Randomized Controlled Trials

A randomized comparative trial in matched patient groups compared the net health benefit of allo-HCT with RIC or with MAC.^43,44,45 In this phase 3 trial, patients (18 to 60 years) were randomized to 4 doses of RIC (n=99) at 2 gray of total body irradiation plus fludarabine 150 mg/m², or to 6 doses of standard conditioning (n=96) at 2 gray of total body irradiation plus cyclophosphamide 120 mg/kg. All patients received cyclosporine and methotrexate as prophylaxis against GVHD. The primary endpoint was the incidence of nonrelapse mortality analyzed in the intention-to-treat population. This unblinded trial was stopped early because of slow accrual of patients. The incidence of nonrelapse mortality did not differ between the RIC and standard conditioning groups (cumulative incidence at 3 years, 13% [95% CI, 6% to 21%] vs. 18% [95% CI, 10% to 26%]; HR, 0.62; 95% CI, 0.30 to 1.31, respectively). Relapse cumulative incidence at 3 years was 28% (95% CI, 19% to 38%) in the RIC group and 26% (95% CI, 17% to 36%; HR, 1.10; 95% CI, 0.63 to 1.90) in the standard conditioning group. The DFS rates at 3 years were 58% (95% CI, 49% to 70%) in the RIC group and 56% (95% CI, 46% to 67%; HR, 0.85; 95% CI, 0.55 to 1.32) in the standard conditioning group. The OS rates at 3 years were 61% (95% CI, 50% to 74%) in the RIC group and 58% (95% CI, 47% to 70%; HR, 0.77; 95% CI, 0.48 to 1.25) in the standard conditioning group. No outcomes differed significantly between groups. Grade 3 and 4 oral mucositis was less common in the RIC group (50 patients) than in the standard conditioning group (73 patients); the frequency of other adverse events such as GVHD and increased concentrations of bilirubin and creatinine did not differ significantly between groups.

A phase 2 single-center, randomized toxicity study (2013) compared MAC with RIC in patients who received allo-HCT to treat AML.⁴⁶ Adults 60 years of age or younger with AML were randomized (1:1) to treatment with RIC (n=18) or MAC (n=19) for allo-HCT. A maximum median mucositis grade of 1 was observed in the RIC group compared with grade 4 in the MAC group (p<.001). Hemorrhagic cystitis occurred in 8 (42%) of the patients in the MAC group and none (0%) in the RIC group (p<.01). Results of renal and hepatic tests did not differ significantly between groups. The RIC-treated patients had faster platelet engraftment (p<.01) and required fewer erythrocyte and platelet transfusions (p<.001) and less total parenteral nutrition than those treated with MAC (p<.01). Cytomegalovirus infection was more common in the MAC group (14/19) than in the RIC group (6/18; p=.02). Donor chimerism was similar in the 2 groups for CD19 and CD33 but was delayed for CD3 in the RIC group. Five-year treatment-related morbidity was approximately 11% in both groups, and rates of relapse and survival did not differ significantly. Patients in the MAC group with intermediate cytogenetic AML had a 3-year survival rate of 73% compared with 90% among those in the RIC group.

Comparative Trials

Russell et al (2022) published the results of an observational study of adults aged 60 to 70 years who underwent allo-HCT with RIC compared to patients who received only chemotherapy and did not undergo transplant.⁴⁷ A total of 932 patients with AML (not favorable risk) in remission were followed for 60 months, and 144 received allo-HCT with RIC. Five-year OS was 37% among transplant recipients. Allo-HCT with RIC led to improved OS compared to no transplant (37% vs. 20%, respectively; HR, 0.67; 95% CI, 0.53 to 0.84). Relapse-free survival was also improved with allo-HCT with RIC (32% vs. 13%, respectively).

In a 2016 comparative study by the European Society for Blood and Marrow Transplantation, long-term survival was evaluated among patients with AML who underwent allo-HCT with RIC or with MAC regimens.⁴⁸ Data from 701 patients receiving MAC and 722 patients receiving RIC were analyzed. Survival, relapse, and GVHD rates are summarized in Table 1. In a multivariate analysis, the following factors predicted nonrelapse mortality: RIC, age older than 55 years, advanced disease, and female donor to male recipient. Factors predicting chronic GVHD (a surrogate outcome for quality of life) were in vivo T-cell depletion, advanced disease, and peripheral blood cell transplantation.

Table 1. Comparison of 10-Year Outcomes for Reduced-Intensity Conditioning and Myeloablative Conditioning Regimens in Patients Undergoing Allogeneic Hematopoietic Cell Transplant

Outcomes	RIC (n=722) Rate (95% CI), %	MAC (n=701) Rate (95% CI), %	p
Nonrelapse mortality	20 (17 to 24)	35 (31 to 39)	<.001
Relapse	48 (44 to 52)	34 (31 to 38)	<.001
Leukemia-free survival, overall	32 (28 to 35)	31 (27 to 35)	.57
Age 50 to 55 y	40 (33 to 46)	36 (32 to 41)	.32
Age >55 y	20 (14 to 26)	28 (24 to 32)	.02
Overall survival	35 (32 to 39)	33 (29 to 37)	.57
GVHD-free, relapse-free survival	21 (18 to 24)	22 (18 to 25)	.79

Adapted from Shimoni et al (2016).48
 CI: confidence interval; GVHD: graft-versus-host disease; MAC: myeloablative conditioning; RIC: reduced-intensity conditioning.

In a comparative study by Bitan et al (2014), outcomes were compared for children with AML who underwent allo-HCT using RIC or MAC regimens.⁴⁹ A total of 180 patients were evaluated; 39 underwent RIC and 141 received MAC regimens. Univariate and multivariate analyses showed no significant differences in the rates of acute and chronic GVHD, leukemia-free survival, and OS between treatment groups. The 5-year probabilities of OS with RIC and MAC regimens were 45% and 48%, respectively (p=.99). Moreover, relapse rates were similar for RIC (39%) and MAC regimens (39%; p=.95), and recipients of MAC regimens were not at a higher risk for transplant-related mortality (16%) than recipients of RIC regimens (16%; p=.73).

Noncomparative Studies

In a phase 2 study by Devine et al (2015), 114 patients ages 60 to 74 years with AML in CR1 were treated with RIC and allo-HCT.⁵⁰ Patients were followed for 2 years. The primary endpoint was DFS, and secondary endpoints were nonrelapse mortality, GVHD, relapse, and OS. Two years after transplantation, the following rates were recorded: DFS, 42% (95% CI, 33% to 52%); OS, 48% (95% CI, 39% to 58%); nonrelapse mortality, 15% (95% CI, 8% to 21%); grades 2, 3, or 4 acute GVHD, 10% (95% CI, 4% to 15%); grades 2, 3, or 4 chronic GVHD, 28% (95% CI, 19% to 36%); and cumulative incidence of relapse, 44% (95% CI, 35% to 53%).

Section Summary: Allogeneic Hematopoietic Cell Transplant With Reduced-Intensity Conditioning for Cytogenetic or Molecular Intermediate- or Poor-Risk Acute Myeloid Leukemia in Remission

Evidence for the use of RIC and allo-HCT to treat patients with AML consists of 2 RCTs, 3 meta-analyses, and numerous comparative and noncomparative studies. In general, compared with MAC, RIC has comparable survival estimates (leukemia-free, overall), though relapse rates appear higher among patients receiving RIC in some studies.

Autologous Hematopoietic Cell Transplant for Acute Myeloid Leukemia in Remission With Chemotherapy-Responsive Consolidation

Clinical Context and Therapy Purpose

The purpose of autologous HCT in individuals with AML in remission who do not have a suitable allo-HCT donor is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with AML in remission who do not have a suitable allo-HCT donor.

Interventions

The therapy being considered is autologous HCT. For individuals with AML in remission without an acceptable allo-HCT donor, autologous HCT is an option for consolidation therapy.

Comparators

The following therapies are currently being used to make decisions about the treatment of AML in remission when no suitable allo-HCT donor is available: conventional chemotherapy.

Outcomes

The general outcomes of interest are survival outcomes (OS, DSS, and DFS), relapse rates, and treatment-related morbidity. The median survival of individuals with AML varies with several known prognostic factors related to individual and tumor characteristics such as age, performance status, and karyotype. Overall, the median survival for individuals with AML without chemotherapy or HCT is less than 10 months; the median survival in individuals with chemotherapy but without HCT is approximately 20 months.⁵ Individuals are followed up throughout their lifespan.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A meta-analysis published by Nathan et al (2004) compared survival outcomes for autologous HCT in CR1 with standard chemotherapy or no further treatment in AML patients ages 15 to 55 years.⁵¹Two types of studies were eligible: (1) prospective cohort studies in which patients with an available sibling donor were offered allo-HCT (biologic randomization) with random assignment of all others to autologous HCT or chemotherapy (or no further treatment); and (2) randomized trials that compared autologous HCT with chemotherapy in all patients. Among a total of 4058 patients included in 6 studies, 2989 (74%) achieved CR1; 1044 (26%) were randomized to HCT (n=524) or to chemotherapy (n=520). Of the 5 studies for which OS data were available, outcomes with autologous HCT were better in 3, and outcomes with chemotherapy were better in 2. None of the differences were statistically significant, nor was the pooled estimate (fixed-effects model survival probability ratio, 1.01; 95% CI, 0.89 to 1.15; p=.86). In all 6 studies, DFS was numerically superior using autologous HCT compared with chemotherapy (or no further treatment), but only 1 reported a statistically significant DFS probability associated with autologous HCT. The pooled estimate for DFS showed a statistically significant probability in favor of autologous HCT at 48 months posttransplant (fixed-effects model survival probability ratio, 1.24; 95% CI, 1.06 to 1.44; p=.006). This review comprised studies performed between 1984 and 1995, during which transplant protocols and patient management evolved significantly, particularly compared with current care.

A second meta-analysis, published by Wang et al (2010), evaluated autologous HCT plus further chemotherapy or no further treatment for patients with AML in CR1.⁵² Nine randomized trials involving 1104 adults who underwent autologous HCT and 1118 patients who received additional chemotherapy or no additional treatment were identified. Analyses suggested that autologous HCT in CR1 is associated with a statistically significant reduction of relapse risk (relative risk, 0.56; 95% CI, 0.44 to 0.71; p=.001) and significant improvement in DFS (HR, 0.89; 95% CI, 0.80 to 0.98), but at the cost of an increased nonrelapse mortality rate (relative risk, 1.90; 95% CI, 1.34 to 2.70; p=.23). There were more deaths during the first remission among patients assigned to autologous HCT than among the chemotherapy recipients or further untreated patients. As a consequence of the increased nonrelapse mortality rate, no statistical difference in OS (HR, 1.05; 95% CI, 0.91 to 1.21) was associated with the use of autologous HCT, compared with further chemotherapy or no further therapy. These results are concordant with the earlier meta-analysis.

Randomized Controlled Trials

The RCTs published after the meta-analyses will be reviewed here.

A prospective, randomized phase 3 trial by Vellenga et al (2011) compared autologous HCT with intensive consolidation chemotherapy among patients (range, 16 to 60 years) with newly diagnosed AML of similar risk profiles in CR1.⁵³After 2 cycles of intensive chemotherapy (etoposide and mitoxantrone), patients in CR1 who were not candidates for allo-HCT were randomized to a third consolidation cycle of the same chemotherapy (n=259) or autologous HCT (n=258). The HCT group experienced an upward trend toward superior RFS (38%) compared with the chemotherapy group at 5 years (29%; p=.065). The HCT patients also had a lower relapse rate at 5 years (58%) compared with chemotherapy recipients (70%; p=.02). The OS did not differ between the HCT group (44%) and the chemotherapy group (41%; p=.86). Nonrelapse mortality rates were higher in the autologous HCT group (4%) than in the chemotherapy consolidation group (1%; p=.02). Despite this difference in nonrelapse mortality, the relative equality of OS rates was attributed by the investigators to a higher proportion of successful salvage treatments (second-line chemotherapy, autologous or allo-HCT) in the chemotherapy consolidation recipients that were not available to the autologous HCT patients. This large trial has shown an advantage for post-remission autologous HCT in reducing relapse, but similar OS rates secondary to better salvage of chemotherapy-consolidated patients.

Miyamoto et al (2018) reported results of a randomized, multicenter phase 3 trial conducted in 24 centers in Japan from 2003 to 2011 that compared autologous HCT versus HiDAC consolidation as post-remission therapy in AML.⁵⁴ This trial enrolled 240 patients between 15 and 64 years of age with newly diagnosed favorable- and intermediate-risk AML and Eastern Cooperative Oncology Group (ECOG) performance status of <3; 87 of those who achieved CR1 were randomized to autologous HCT or HiDAC. The study was powered to include 122 patients with 5 years of accrual and 3 years of post-accrual follow-up to detect a difference in DFS at 3 years of 40% versus 65%. Approximately one-third of the patients had favorable risk AML and the remaining two-thirds had intermediate-risk AML. The median age was 48 years. Median follow-up was approximately 4.5 to 5 years. Three-year DFS rate was 41% (95% CI, 27% to 55%) in the HiDAC group and 55% (95% CI, 38% to 68%) in the autologous HCT group (p=.25). Three-year OS was 77% (95% CI, 61% to 87%) versus 68% (95% CI, 52% to 80%) (p=.67). Cumulative incidence of relapse was 54% versus 41% (p=.22). There were no differences between the HiDAC and autologous HCT groups in the incidence of liver or renal dysfunction. The incidence of life-threatening infectious complications (p=.003) and mucositis/diarrhea (p=.002) was significantly higher in the autologous HCT group.

Section Summary: Autologous Hematopoietic Cell Transplant for Acute Myeloid Leukemia in Remission With Chemotherapy-Responsive Consolidation

Evidence for the use of autologous HCT for patients with AML who do not have a suitable allogeneic donor or who cannot tolerate an allogeneic procedure consists of RCTs comparing autologous HCT with chemotherapy and prospective cohort studies. Meta-analyses of these studies and trials reported improved DFS and relapse but did not find a significant improvement in OS. A potential explanation for this discrepancy between DFS and OS is the increased nonrelapse mortality rate experienced by patients in the transplantation group.

Summary of Evidence

For individuals who have cytogenetic or molecular intermediate- or poor-risk acute myeloid leukemia (AML) in first complete remission (CR1) who receive allogeneic (allo-) hematopoietic cell transplant (HCT) with myeloablative conditioning (MAC), the evidence includes systematic reviews, randomized controlled trials (RCTs), and matched cohort studies. Relevant outcomes are overall survival (OS) and disease-specific survival (DSS). The majority of the evidence has revealed that allo-HCT is better at improving OS and DSS rates in patients with AML in CR1 than conventional chemotherapy. One RCT found no difference in OS between allo-HCT and high-dose cytarabine, although the study had many limitations. All trials employed natural randomization based on donor availability and intention-to-treat analysis. Survival rates appear to be associated with the presence of minimal residual disease and risk category. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have AML refractory to standard induction chemotherapy who receive allo-HCT with MAC, the evidence includes retrospective data compiled from patients entered in phase 3 trials and registry data. Relevant outcomes are OS and DSS. The evidence would suggest that allo-HCT improves OS and DSS rates in patients who are refractory to induction chemotherapy better than conventional chemotherapy. While there are some limitations to the evidence, which include its retrospective nature, lack of rigorous randomization, and general pitfalls of registry data, these results may provide a clinically meaningful benefit for patients who do not have other treatment options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have AML who relapsed after standard induction chemotherapy-induced CR1 who receive allo-HCT or autologous HCT with MAC, the evidence includes retrospective data compiled from patients entered in phase 3 trials and registry data. Relevant outcomes are OS and DSS. The evidence has shown that allo-HCT improves OS rates in patients with relapsed AML better than conventional chemotherapy. Limitations of the evidence include its retrospective nature, lack of rigorous randomization, and pitfalls of registry data. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have cytogenetic or molecular intermediate- or poor-risk AML in CR1 and for medical reasons cannot tolerate MAC who receive allo-HCT with reduced-intensity conditioning (RIC), the evidence includes 2 RCTs, 3 meta-analyses, and other comparative and noncomparative studies. Relevant outcomes are OS, DSS, and treatment-related morbidity. The RCTs compared RIC with MAC and reported similar rates in nonrelapse mortality, relapse, and OS, though 1 of the trials was stopped prematurely due to slow accrual of patients. Two retrospective comparative studies found no difference in OS or leukemia-free survival between the conditioning regimens. It appears unlikely that additional comparative evidence will be generated. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have AML in CR1 or beyond without a suitable allo-HCT donor who receive autologous HCT, the evidence includes prospective cohort studies in which patients with an available sibling donor were offered allo-HCT (biologic randomization) with random assignment of all others to autologous HCT or chemotherapy (or no further treatment); and randomized trials comparing autologous HCT with chemotherapy in all patients. Relevant outcomes are OS and DSS. Compared with chemotherapy, patients undergoing autologous HCT experienced reduced relapse and improved disease-free survival (DFS) rates. The OS did not differ between the groups. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society for Transplantation and Cellular Therapy

In 2020, the American Society for Transplantation and Cellular Therapy published expert panel recommendations on the role of hematopoietic cell transplant (HCT) in newly-diagnosed adult acute myeloid leukemia (AML).⁵⁵ Recommendations were generated based on findings from a systematic review and graded based on prespecified criteria. Expert panel recommendations regarding allogeneic HCT (allo-HCT) and autologous HCT and the grades of the recommendations are as follows:

• Patients with unfavorable-risk in first remission (CR1) should undergo allo-HCT. (Grade A)

• Patients with intermediate-risk in CR1 should undergo allo-HCT. (Grade B)

• Patients with favorable-risk in CR1 should not undergo allo-HCT. (Grade C)

• The role of secondary mutational abnormalities in selecting a patient for allo-HCT is unclear. (Grade N/A [not applicable])

• The presence of measurable residual disease at the end of induction therapy should be considered an indication to offer allo-HCT. (Grade C)

• The role of allo-HCT is unclear in patients with induction failure. (Grade N/A )

• Patients with secondary acute myeloid leukemia in CR1 should undergo allo-HCT. (Grade D)

• Patients with therapy-related acute myeloid leukemia in CR1 should undergo allo-HCT. (Grade D)

• Patients ≥ 60 years in CR1 should undergo allo-HCT. (Grade B)

• Autologous HCT is a good alternative to chemotherapy consolidation in patients who are not eligible for allo-HCT. (Grade B)

• Myeloablative conditioning should be the preferred type of conditioning in patients who are fit for myeloablative conditioning, but reduced-intensity conditioning is an acceptable alternative in unfit patients. (Grade D)

In 2015, the American Society for Transplantation and Cellular Therapy (formerly The American Society for Blood and Marrow Transplantation) published guidelines on indications for autologous HCT and allo-HCT.⁵⁶ An updated guideline was published in 2020.⁵⁷ Table 2 summarizes recommendations for HCT in AML from the most recent guideline iteration.

Table 2. Recommendations for the Use of Hematopoietic Cell Transplantation to Treat Acute Myeloid Leukemia

Indication	Allo-HCTa	Autologous HCTa
AML, age <18 years
First CR, low risk	N	N
First CR, intermediate risk	C	N
First CR, high risk	S	N
Second or greater CR	S	N
Not in remission	S	N
AML, age ≥18 years
First CR, low risk	N	C
First CR, intermediate risk	S	C
First CR, high risk	S	N
Second CR	S	C
Third or greater CR	S	N
Not in remission	S	N

a Recommendations were classified as follows: S, standard of care 
(well-defined and generally supported by evidence in the form of high quality clinical trials and/or observational studies); C, standard of care, 
clinical evidence available (large clinical trials are not available; however, sufficiently large cohort studies have shown efficacy with acceptable risk of 
morbidity and mortality); N, not generally recommended allo-HCT: allogeneic hematopoietic cell transplantation; AML: acute myeloid leukemia; 
CR: complete remission ; HCT: hematopoietic cell transplantation

In 2022, the American Society of Transplantation and Cellular Therapy published guidance on the role of HCT in pediatric AML and myelodysplastic syndrome.⁵⁸ The guidelines state that HCT is recommended for patients in CR1 with unfavorable mutations/cytomolecular abnormalities but not for patients with favorable-risk lesions. HCT should also be considered for patients with primary induction failure, refractory disease after 2 to 3 cycles of chemotherapy, and relapse.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network clinical guidelines (v. 3.2026 ) ² for AML state that allo-HCT is recommended for patients aged <60 years after standard-dose cytarabine induction with induction failure or significant residual disease without a hypocellular marrow. It is also recommended after high-dose cytarabine induction with induction failure, or as post-remission therapy in those with intermediate-risk or poor-risk cytogenetics. Allo-HCT is identified as a "reasonable option" for patients aged ≥60 years after standard-dose cytarabine induction with residual disease or induction failure or following complete response (preferably in a clinical trial). In addition, allo-HCT is recommended for relapsed or refractory disease. Autologous HCT is recommended as another option in patients with AML after standard induction chemotherapy-induced first complete remission, although allo-HCT is preferred.

In patients with acute promyelocytic leukemia, a subtype of AML, patients who achieve a molecular remission after second-line therapy should be considered for autologous HCT if they do not have contraindications to high-dose therapy. Allogeneic HCT should be reserved for patients who have persistent disease despite therapy for relapsed disease.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT06643195	Immediate Allogeneic Hematopoietic Stem Cell Transplantation Versus Re-treatment for Patients With High-Risk Acute Myeloid Leukemia: a Randomised, Open-label, Phase 2 Clinical Trial.	358	Sep 2027

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Autologous Hematopoietic Cell Transplantation for Hodgkin Lymphoma
First-Line Therapy for Hodgkin Lymphoma
Clinical Context and Therapy Purpose
The purpose of autologous hematopoietic cell transplantation (HCT) as first-line therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with Hodgkin lymphoma (HL).

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with HL.

Interventions
The therapy being considered is autologous HCT as first-line therapy.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are overall survival (OS), disease-specific survival (DSS), change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.

Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
Federico et al (2003) published results from an RCT of 163 patients with unfavorable HL who had received autologous HCT or additional standard chemotherapy for consolidation after initial conventional chemotherapy.¹³ Patients were randomized to high-dose chemotherapy (HDC) followed by autologous HCT (n=83) or to 4 additional courses of the same standard chemotherapy used in the induction phase (n=80). After treatment, complete remission (CR) was achieved in 92% of patients in the autologous HCT arm and 89% in the standard chemotherapy arm (p=.6). Five-year survival rates (overall, failure-free, and relapse-free) did not differ between the treatment groups, and the authors concluded that HDC with autologous HCT offered no benefit in outcomes over conventional chemotherapy as first-line therapy for patients with advanced HL.

Carella et al (2009) published 10-year follow-up results for the Federico study.¹⁴Ten-year OS rates were 85% (95% confidence interval [CI], 78% to 90%) for the HDC autologous HCT group and 84% (95% CI, 77% to 89%; p=.7) for the standard chemotherapy group. Ten-year failure-free survival rates were 79% (95% CI, 72% to 85%) for the HDC autologous HCT group and 75% (95% CI, 67% to 82%; p=.8) for the standard chemotherapy group. The authors concluded that, after a median follow-up of 107 months, their data suggested patients who respond to induction therapy with conventional chemotherapy do not achieve superior outcomes with consolidation with HDC and autologous HCT.

Section Summary: Autologous Hematopoietic Cell Transplantation as First-Line Therapy for Hodgkin Lymphoma
A small number of RCTs have evaluated the use of autologous HCT as first-line treatment for HL, and these trials have reported no benefit above that of conventional chemotherapy.

Relapsed or Refractory Hodgkin Lymphoma
Clinical Context and Therapy Purpose
The purpose of autologous HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with relapsed or refractory HL.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with relapsed or refractory HL.

Interventions
The therapy being considered is autologous HCT.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are OS, DSS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.

Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A systematic review and meta-analysis of the available RCTs on HCT for patients with relapsed or refractory HL were published by Rancea et al (2014).¹⁵ Reviewers included 3 RCTs, 2 (1993, 2002) of which compared HDC plus autologous HCT with conventional treatment.^16,17 Both trials (described below) were judged to be at moderate risk of bias using the Cochrane criteria. Combined analysis for the outcome of OS demonstrated a hazard ratio of 0.67 for patients treated with autologous HCT, which was not statistically significant (95% CI, 0.41 to 1.07). For the outcome of progression-free survival (PFS), there was a significant improvement for autologous HCT treatment, with a hazard ratio of 0.55 (95% CI, 0.35 to 0.86).

Randomized Controlled Trials
The British National Lymphoma Investigation study (1993) was the first to show that autologous HCT offered patients with relapsed or refractory HL a PFS benefit over conventional chemotherapy.¹⁸ Forty patients with relapsed or refractory HL were given chemotherapy without a transplant (n=20) or autologous HCT after HDC (n=20).¹⁶ A significantly better event-free survival rate at 3 years (53%) was reported for patients who underwent HCT than for those who did not (10%).

Subsequently, these findings were confirmed in a larger 2002 trial by the German Hodgkin Study Group and European Group for Blood and Marrow Transplantation.¹⁷ Patients relapsing after initial chemotherapy were randomized to chemotherapy without a transplant or to autologous HCT. In the final analysis of 144 patients, freedom from treatment failure at 3 years was 55% in the transplanted group versus 34% in the nontransplanted group. This benefit was maintained in a 2007 subgroup analysis, regardless of early or late relapse, and the results were confirmed in follow-up data at 7 years.¹⁹

Nonrandomized Studies
In addition to the RCTs, several large retrospective studies identified in a systematic review have reported event-free survival rates ranging from 25% to 60%, with OS rates from 35% to 66%, showing that disease status before autologous HCT was the most important prognostic factor for the final outcome.⁶

A retrospective observational cohort study by Merryman et al (2021) evaluated autologous HCT after anti-programmed death-1 (PD-1) therapy for patients with relapsed or refractory HL. ²⁰ Seventy-eight patients were identified who underwent autologous HCT as a third-line (or later) treatment; 74% of patients underwent autologous HCT after anti-PD-1 treatment and 26% of patients received anti-PD-1 treatment along with additional therapy prior to autologous HCT. The 18-month PFS and OS after autologous HCT were 81% (95% CI, 69 to 89) and 96% (95% CI, 87 to 99), respectively. Favorable outcomes were reported for patients who had received greater than 4 systemic therapies before autologous HCT (18-month PFS, 73%), who were refractory to 2 consecutive therapies immediately prior to anti-PD-1 treatment (18-month PFS, 78%), and who had positive pre-HCT positron emission tomography (PET) (18-month PFS, 75%); patients who were non-responders to anti-PD-1 treatment had inferior outcomes (18-month PFS, 51%).

Section Summary: Autologous Hematopoietic Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma
Randomized controlled trials and a meta-analysis have evaluated the use of autologous HCT for relapsed or refractory HL. The studies reported no difference in OS, but a significant improvement in PFS, for patients treated with autologous HCT.

Second Autologous Hematopoietic Cell Transplantation for Relapsed Hodgkin Lymphoma After Prior Autologous Hematopoietic Cell Transplantation
Clinical Context and Therapy Purpose
The purpose of a second autologous HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with relapsed HL after an autologous HCT.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with relapsed HL after an autologous HCT.

Interventions
The therapy being considered is a second autologous HCT.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are OS, DSS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.

Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Few treatment options exist for patients who relapse following an autologous HCT. These include single-agent palliative chemotherapy or occasionally, localized radiotherapy.¹⁹ If further remission is attained with conventional-dose chemotherapy, it is rarely durable, with a median OS of less than 1 year.²¹

Case Series
There is limited experience with second autologous HCT, and treatment-related mortality is high (25% to 40%).¹⁶ Smith et al (2008) reported on the outcomes of 40 patients (21 with HL, 19 with non-HL) who underwent a second autologous HCT for relapsed lymphoma.²² Reported results were combined for the 2 populations, but the authors stated the outcomes for both patient groups were similar. Median age at second HCT was 38 years (range, 16 to 61 years). In 82% of patients, the second HCT was performed more than 1 year after the first. The treatment-related mortality at day 100 posttransplant was 11% (95% CI, 3% to 22%). At a median follow-up of 72 months (range, 12 to 124 months) after the second HCT, 73% of patients had died, 62% due to relapsed lymphoma. One-, 3-, and 5-year PFS estimates were 50% (95% CI, 34% to 66%), 36% (95% CI, 21% to 52%), and 30% (95% CI, 16% to 46%), respectively. Corresponding OS estimates were 65% (95% CI, 50% to 79%), 36% (95% CI, 22% to 52%), and 30% (95% CI, 17% to 46%), respectively. Study limitations included the absence of an appropriate comparison group and lack of data on how many patients were considered for a second HCT but were unable to mobilize sufficient stem cells or were otherwise unable to proceed to the second transplant. Finally, heterogeneity of the preparative regimens used in this population precluded comparison of efficacy.

Section Summary: Second Autologous Hematopoietic Cell Transplantation for Relapsed Hodgkin Lymphoma After Prior Autologous Hematopoietic Cell Transplantation
The evidence is limited to case series; no RCTs or nonrandomized comparative studies were identified. In 1 series, treatment-related mortality at 100 days was 11%, and the mortality rate was 73% at a median follow-up of 72 months.

Allogeneic Hematopoietic Cell Transplantation for Hodgkin Lymphoma
First-Line Therapy for Hodgkin Lymphoma
Clinical Context and Therapy Purpose
The purpose of allogeneic (allo)-HCT as first-line therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with HL.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with HL.

Interventions
The therapy being considered is allo-HCT as first-line therapy.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are OS, DSS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.

Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
The application of allo-HCT to the treatment of patients with HL appears limited, due to high procedure-related mortality. No controlled trials evaluating allo-HCT as first-line treatment for HL were identified. In addition, 2015 and 2016 systematic reviews of HCT for HL did not discuss studies using allo-HCT as first-line therapy.^23,24

Section Summary: Allogeneic Hematopoietic Cell Transplantation as First-Line Therapy for Hodgkin Lymphoma
No studies specifically addressing allo-HCT as first-line treatment for HL were identified.

Relapsed or Refractory Hodgkin Lymphoma
Clinical Context and Therapy Purpose
The purpose of allo-HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with relapsed or refractory HL.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with relapsed or refractory HL.

Interventions
The therapy being considered is allo-HCT.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are OS, DSS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.

Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Rashidi et al (2016) published a systematic review and meta-analysis of studies evaluating allo-HCT in HL.²⁴ Thirty-eight studies were selected. Three studies included more than 1 series and were divided into more than 1 group; a total of 42 series were included in the meta-analysis. Sample sizes of included studies ranged from 5 to 285 patients (N=1850 patients). Twenty-eight studies were retrospective and 14 prospective. None was an RCT. Median follow-up in the studies ranged from 11 to 104 months. Results of the meta-analyses are shown in Table 3.

Table 3. Meta-Analytic Outcomes

Follow-Up	Relapse-Free Survival (95% CI), %	Overall Survival (95% CI), %
6 months	77 (59 to 91)	83 (75 to 91)
1 year	50 (42 to 57)	68 (62 to 74)
2 years	37 (31 to 43)	58 (52 to 64)
3 years	31 (25 to 37)	50 (41 to 58)

Adapted from Rashidi et al (2016).²⁴
CI: confidence interval.

In multivariate analysis, more recent studies (ie, those that started to accrue patients in 2000 or later) had significantly higher 6-month and 1-year survival rates than older studies.

Section Summary: Allogeneic Hematopoietic Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma
A 2016 meta-analysis identified 38 case series evaluating allo-HCT for relapsed or refractory HL. The pooled analysis found a 6-month OS rate of 83% and a 3-year OS rate of 50%.

Allogeneic Hematopoietic Cell Transplantation for Relapsed Hodgkin lymphoma After Prior Autologous Hematopoietic Cell Transplantation
Clinical Context and Therapy Purpose
The purpose of allo-HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with relapsed HL after an autologous HCT.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with relapsed HL after an autologous HCT.

Interventions
The therapy being considered is allo-HCT.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are OS, DSS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.

Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
The Rashidi et al (2016) meta-analysis (described above) included 38 case series assessing patients who underwent allo-HCT after a prior failed autologous HCT.²⁴ In a multivariate analysis of factors associated with survival outcomes, reviewers found that a previous autologous HCT was significantly associated with higher 1-year (p=.012) and 2-year (p=.040) OS rates and significantly higher relapse-free survival at 1 year (p=.005) compared with no previous autologous HCT.

Section Summary: Allogeneic Hematopoietic Cell Transplantation for Relapsed Hodgkin Lymphoma After Prior Autologous Hematopoietic Cell Transplantation
A 2016 meta-analysis found that a previous autologous HCT was significantly associated with higher OS rates and significantly higher relapse-free survival rates compared with no previous autologous HCT.

Reduced-Intensity Conditioning with Allogeneic Hematopoietic Cell Transplantation
Clinical Context and Therapy Purpose
The purpose of reduced-intensity conditioning (RIC) with allo-HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with relapsed or refractory HL.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with relapsed or refractory HL.

Interventions
The therapy being considered is RIC with allo-HCT.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are OS, DSS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.

Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Perales et al (2015) conducted an evidence review as part of the development of clinical guidelines on HCT for HL.²³ Reviewers evaluated a number of studies that showed better outcomes with RIC than with myeloablative conditioning regimens. For example, reviewers cited a 2008 study by the European Group for Blood and Marrow Transplantation reporting outcomes in 89 HL patients with relapsed or refractory disease who received an RIC with allo-HCT and were compared with 79 patients who received myeloablative conditioning (ie, conventional group).²⁵ Sixty-two percent of the RIC group had undergone a previous autologous HCT versus 41% of the myeloablative group. Although the incidence of relapse was nearly double in the RIC group (57% v.s 30%), after a median follow-up for surviving patients of 75 months (range, 12 to 120 months), 24 in the RIC group (26.9%) and 18 in the conventional group (22.8%) were alive. Five-year OS rates were 28% (95% CI, 18% to 38%) for the RIC group and 22% (95% CI, 13% to 31%) for the conventional group. Independent adverse prognostic factors for OS were a previously failed autologous HCT (relative risk [RR], 1.59; 95% CI, 1.07 to 2.35; p=.02), the use of myeloablative conditioning (RR, 1.62; 95% CI, 1.27 to 3.29; p=.04), and the presence of refractory disease (RR, 1.51; 95% CI, 1.03 to 2.21; p=.003). Perales et al (2015) concluded: “As a result, the preferred conditioning intensity in adult patients with relapsed/refractory HL is RIC, which results in acceptable treatment-related mortality including in patients who have had a prior ASCT [autologous stem cell transplant].”

Nonrandomized Study
Sureda et al (2012) published a phase II study (HDR-ALLO) of allo-HCT after RIC for patients with relapsed or refractory HL.²⁶ Ninety-two patients were included, of which 90% had received more than 2 lines of therapy, 87% prior radiotherapy, and 86% had failed a previous autologous HCT. Fourteen individuals (15%) progressed under salvage therapy and were excluded from further study treatment. The remaining 78 patients proceeded to allograft (50 were in complete or partial remission and 29 in stable disease). Non-relapse mortality was 8% at 100 days and 15% at 1 year; OS was 71% at 1 year and 43% at 4 years from trial entry. For those who received allo-HCT, PFS was 48% at 1 year and 24% at 4 years. The study was limited by its small sample size and by the non-relapse mortality being adversely influenced by older age, poor performance score, and by the presence of refractory disease.

Section Summary: Reduced-Intensity Conditioning with Allogeneic Hematopoietic Cell Transplantation
A 2015 systematic review assessed a number of studies, including some with comparison groups, showing acceptable outcomes after RIC with allo-HCT in patients with relapsed or refractory HL. A phase II study found slightly improved results for patients receiving RIC and allo-HCT.

Tandem Autologous Hematopoietic Cell Transplantation for Hodgkin Lymphoma
Clinical Context and Therapy Purpose
The purpose of tandem autologous HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with HL.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with HL.

Interventions
The therapy being considered is tandem autologous HCT.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are OS, DSS, change in disease status, morbid events, treatment-related mortality, and treatment-related morbidity.

Follow-up over years is of interest for relevant outcomes.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Nonrandomized Studies
No RCTs have compared tandem autologous HCT with other standard of care therapies. One prospective, nonrandomized study has compared tandem to single autologous HCT for HL. Morschhauser et al (2008) and Sibon et al (2016) reported on the results of a prospective multicenter trial that evaluated a risk-adapted salvage treatment with single or tandem autologous HCT in 245 patients with relapsed or refractory HL.^27,28 Median follow-up time in the initial publication by Morschhauser et al (2008) was 51 months (range, 20 to 110 months). Sibon et al (2016) reported on the 10-year follow-up. Patients categorized as poor-risk (n=150), had primary refractory disease (n=77), or 2 or more of the following risk factors at first relapse: time to relapse less than 12 months, stage III or IV disease at the time of relapse, or relapse in previously irradiated sites (n=73). In this trial, these poor-risk patients were eligible for tandem autologous transplants. Intermediate-risk (n=95) patients, defined as 1 risk factor at relapse, were eligible for a single transplant. Overall, 70% of the poor-risk patients received tandem transplants, and 97% of the intermediate-risk patients received a single transplant.

Ninety-four poor-risk patients responded to cytoreductive chemotherapy (partial response or CR), whereas 55 patients had chemotherapy-resistant disease. A total of 137 patients (including the 94 patients with chemotherapy-sensitive disease and 43 of 55 with chemotherapy-resistant disease) received the first autologous HCT. Among 121 patients who were fully restaged, 64 patients had achieved a CR, 37 a partial response, and 4 had stable disease. These 105 patients then underwent a second autologous HCT after a median of 65 days. Among them, 80 patients achieved a CR, including 17 patients who had achieved partial response and 3 patients with stable disease after the first transplant. Among the 55 patients who had cytoreduction failure, 30 responded to the first transplant (9 with CR), and 17 achieved a CR after the second transplant. Outcome analysis based on the intention-to-treat sample revealed the 5-year freedom from the second failure and OS estimates were 73% and 85% for the intermediate-risk group and 46% and 57% for the poor-risk group, all respectively. At the 10-year follow-up reported by Sibon et al (2016),²⁸ freedom from second failure and OS rates were 64% (95% CI, 54% to 74%) and 70% (95% CI, 61% to 80%) for the intermediate-risk group, and 41% (95% CI, 33% to 49%) and 47% (95% CI, 39% to 55%) for the poor-risk group.

In the poor-risk group, patients who underwent tandem transplant and had a CR to cytoreduction chemotherapy did not have superior outcomes compared with complete responders receiving a single transplant in previous studies by the same group.²⁹ However, in this 2002 study, poor-risk patients who were partial responders and underwent tandem transplants did better compared with partial responders who received a single transplant in previous studies. In this study, 5-year OS rates for poor-risk patients who completed the tandem transplant were 79% and 73% for complete and partial responders, whereas, in a previous trial of single autologous HCT, 5-year OS rates were 86% and 37% for complete and partial responders, all respectively.²⁹ The findings suggested that a single autologous HCT would be appropriate for intermediate-risk patients and for poor-risk patients who are complete responders to cytoreductive chemotherapy, but that tandem autologous HCT showed a benefit in patients with chemotherapy-resistant disease and in partial responders to cytoreductive conditioning. The authors concluded that a trial, randomizing patients to single versus tandem autologous HCT was unrealistic, given the low yearly incidence of poor-risk patients. In their estimation, the best possible comparisons would be with data from previous findings with single transplants.

Tandem autologous HCT for HL has also been evaluated in single-arm studies. Fung et al (2007) reported results from a pilot study on HL that evaluated the toxicities and efficacy of tandem autologous HCT in patients with primary refractory or poor-risk recurrent HL.³⁰ The study involved 28 patients with primary progressive and 18 with recurrent HL who were enrolled in the study between 1998 and 2000. Patients had at least 1 of the following poor prognostic factors: first CR less than 12 months, extranodal disease, or B symptoms (presence of systemic symptoms) at relapse. Forty-one (89%) patients received the second transplant. With a median follow-up of 5.3 years (range, 1.6 to 8.1 years), the 5-year OS and PFS rates were 54% (95% CI, 40% to 69%) and 49% (95% CI, 34% to 63%), respectively. Additionally, Smith et al (2018) reported results from a more recent Phase II trial of 89 patients with primary progressive or recurrent HL conducted by the Southwest Oncology Group (SWOG) Clinical Trials Network.¹¹ This single-arm trial was conducted at 10 centers and enrolled patients between 2006 and 2009. Key patient characteristics included that 53% had induction failure, 18% had an initial response ≤12 months, 83% were stage III or IV at the time of trial enrollment, and 48% previously irradiated patients relapsed in an irradiated site. Eighty-two patients (92%) received the second transplant. With a median follow-up of 6.2 years, the 5-year PFS and OS rates were 55% (95% CI, 44% to 64%) and 84% (95% CI, 74% to 90%).

Section Summary: Tandem Autologous Hematopoietic Cell Transplantation for Hodgkin Lymphoma
There are no RCTs comparing tandem autologous HCT with alternatives for treating HL. One prospective, nonrandomized study reported that patients who had not achieved a CR after conventional chemotherapy had better outcomes with tandem HCT than with single HCT. However, the results of this trial were not definitive, and RCTs are needed to determine the efficacy of tandem transplants.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2020 Input
Clinical input was sought to help determine whether the use of either second autologous hematopoietic cell transplantation (HCT) for relapsed Hodgkin lymphoma (HL) or tandem autologous HCT for HL would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice. In response to requests, clinical input was received from 4 respondents, including 3 complete responses with 2 physician-level responses identified through specialty societies and 1 physician-level response identified through an academic medical center.

For individuals with relapsed HL after an autologous HCT who receive a second autologous HCT, clinical input does not support a clinically meaningful improvement in net health outcome and does not indicate this use is consistent with generally accepted medical practice.

For individuals with HL who receive tandem autologous HCT, clinical input does not support a clinically meaningful improvement in net health outcome and does not indicate this use is consistent with generally accepted medical practice.

Further details from clinical input are included in the Appendix.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Radiology
In 2016, the American College of Radiology issued an Appropriateness Criteria on recurrent HL.³¹ The criteria stated that while salvage therapy followed by autologous HCT is standard of care for relapsed HL, alternative therapies may be considered in select patients. For example, there is evidence that in patients with small isolated relapses occurring more than 3 years after initial presentation, a course of radiotherapy or combined modality therapy without autologous HCT may be considered. Also, radiotherapy may be considered as part of combined modality therapy for patients with local relapse after treatment with chemotherapy alone or for relapses outside of the original site of disease.

American Society for Transplantation and Cellular Therapy
In 2015, guidelines were published by the American Society for Blood and Marrow Transplantation (now referred to as the American Society for Transplantation and Cellular Therapy) on indications for autologous and allogeneic HCT.³² These guidelines were updated in 2020.³³ Recommendations described the current consensus on the use of HCT in and out of the clinical trial setting. The 2015 and 2020 Society recommendations on HL are provided in Table 4.

Table 4. Recommendations for Use of HCT to Treat Hodgkin Lymphoma

Indication	Allogeneic HCT (2015 recommendation)	Allogeneic HCT (2020 recommendation)	Autologous HCT (2015 recommendation)	Autologous HCT (2020 recommendation)
Adult
First complete response (PET negative)	Not generally recommended	Not generally recommended	Not generally recommended	Not generally recommended
First complete response (PET positive)	Not generally recommended	Subsection removeda	Standard of care, clinical evidence available	Subsection removeda
Primary refractory, sensitive	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Standard of care	Standard of care
Primary refractory, resistant	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Not generally recommended	Not generally recommended
First relapse, sensitive	Standard of care	Standard of care	Standard of care	Standard of care
First relapse, resistant	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Not generally recommended	Not generally recommended
Second or greater relapse	Standard of care, clinical evidence available	Standard of care	Standard of care	Standard of care
Relapse after autologous transplant	Standard of care, clinical evidence available	Standard of care	Not generally recommended	Not generally recommended
Pediatric
First complete response	Not generally recommended	Not generally recommended	Not generally recommended	Not generally recommended
Primary refractory, sensitive	Standard of care, clinical evidence available	Not generally recommended	Standard of care, clinical evidence available	Standard of care, clinical evidence available
Primary refractory, resistant	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Not generally recommended	Not generally recommended
First relapse, sensitive	Standard of care, clinical evidence available	Not generally recommended	Standard of care, clinical evidence available	Standard of care
First relapse, resistant	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Not generally recommended	Not generally recommended
Second or greater relapse	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Standard of care, clinical evidence available	Standard of care, clinical evidence available

HCT: hematopoietic cell transplantation; PET: positron emission tomography.
^aSubsection on positron emission tomography positive complete remission was removed because updated response criteria for these lymphoma essentially require normalization of [¹⁸F]2-fluoro-2-deoxy-D-glucose positron emission tomography to be assessed as a first complete remission.

In 2015, the Society also published guidelines on the role of cytotoxic therapy with HCT in patients with HL.²³ Select recommendations are shown in Table 5.

Table 5. Recommendations on Use of Cytotoxic Therapy with HCT to Treat Hodgkin Lymphoma

Recommendation	GOR	Highest LOE
Autologous HCT
Autologous HCT should not be offered as first-line therapy for advanced disease	A	1+
Autologous HCT should be offered as first-line therapy for patients who fail to achieve CR	B	2++
Autologous HCT should be offered as salvage therapy over nontransplantation (except localized disease or in patients with low-stage disease)	A	1+
Autologous HCT should be offered to pediatric patients with primary refractory disease or high-risk relapse who respond to salvage therapy	B	2++
Tandem autologous HCT is not routinely recommended in standard-risk patients	C	2+
Allogeneic HCT
Allo-HCT should be used for relapse after ASCT instead of conventional therapy	B	2++
RIC is the recommended regimen intensity	B	2++
All donor sources can be considered	A	1+
There are limited data for tandem autologous HCT/allo-HCT	D	4
Allo-HCT is preferred over autologous HCT as second HCT (except in late relapse)	C	2+

allo: allogeneic; ASCT: autologous stem cell transplantation; CR: complete response; GOR: grade of recommendation; HCT: hematopoietic cell transplantation; LOE: level of evidence; RIC: reduced-intensity conditioning.

National Comprehensive Cancer Network Guidelines
Current National Comprehensive Cancer Network (NCCN) guidelines for HL (v.1.2026) ⁴ include a recommendation for autologous or allogeneic HCT in patients with biopsy-proven refractory disease who have undergone second-line systemic therapy and are Deauville stage 5 according to restaging based on findings from positron emission tomography or computed tomography. Additionally, in patients with biopsy-proven refractory disease who have undergone second-line systemic therapy and are Deauville stage 1 to 3 according to restaging based on findings from positron emission tomography or computed tomography, high-dose therapy and autologous stem cell rescue plus either observation or brentuximab vendotin for 1 year is recommended for patients with high-risk of relapse.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 6.

Table 6. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
Unpublished
NCT00574496	An Intention-to-Treat Study of Salvage Chemotherapy Followed by Allogeneic Hematopoietic Stem Cell Transplant for the Treatment of High-Risk or Relapsed Hodgkin Lymphoma	25	Aug 2022
NCT01203020	Once Daily Intravenous Busulfex as Part of Reduced-toxicity Conditioning for Patients With Relapsed/Refractory Hodgkin's and Non-Hodgkin's Lymphomas Undergoing Allogeneic Hematopoietic Progenitor Cell Transplantation - A Multicenter Phase II Study	22	Sep 2021
NCT03200977a	Observational Cohort Study to Characterize the Safety of Allogeneic Hematopoietic Cell Transplantation (HCT) For Patients With Classical Hodgkin Lymphoma (CHL) Treated With Nivolumab	95	Dec 2022

NCT: national clinical trial.
^a Denotes an industry sponsored or cosponsored study

References  

1. National Cancer Institute (NCI). Adult Hodgkin Lymphoma Treatment (PDQ) - Health Professional Version. Updated February 12, 2025; http://www.cancer.gov/cancertopics/pdq/treatment/adulthodgkins/healthprofessional. Accessed December 9, 2025.
2. Swerdlow S, Campo E, Harris N, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4 ed. Lyon France: IARC; 2008.
3. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. Jul 2022; 36(7): 1720-1748. PMID 35732829
4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Hodgkin lymphoma. Version 1.2026. https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed December 9, 2025.
5. American Cancer Society (ACS). Hodgkin Lymphoma Stages. Updated October 6, 2025. https://www.cancer.org/cancer/hodgkin-lymphoma/detection-diagnosis-staging/staging.html. Accessed December 9, 2025.
6. Brice P. Managing relapsed and refractory Hodgkin lymphoma. Br J Haematol. Apr 2008; 141(1): 3-13. PMID 18279457
7. Schmitz N, Sureda A, Robinson S. Allogeneic transplantation of hematopoietic stem cells after nonmyeloablative conditioning for Hodgkin's disease: indications and results. Semin Oncol. Feb 2004; 31(1): 27-32. PMID 14970934
8. Schmitz N, Dreger P, Glass B, et al. Allogeneic transplantation in lymphoma: current status. Haematologica. Nov 2007; 92(11): 1533-48. PMID 18024402
9. Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. May 09 2015; 385(9980): 1853-62. PMID 25796459
10. Moskowitz CH, Walewski J, Nademanee A, et al. Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse. Blood. Dec 20 2018; 132(25): 2639-2642. PMID 30266774
11. Smith EP, Li H, Friedberg JW, et al. Tandem Autologous Hematopoietic Cell Transplantation for Patients with Primary Progressive or Recurrent Hodgkin Lymphoma: A SWOG and Blood and Marrow Transplant Clinical Trials Network Phase II Trial (SWOG S0410/BMT CTN 0703). Biol Blood Marrow Transplant. Apr 2018; 24(4): 700-707. PMID 29289757
12. Bair SM, Strelec L, Nagle SJ, et al. Outcomes of patients with relapsed/refractory Hodgkin lymphoma progressing after autologous stem cell transplant in the current era of novel therapeutics: A retrospective analysis. Am J Hematol. Sep 2017; 92(9): 879-884. PMID 28512788
13. Federico M, Bellei M, Brice P, et al. High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy. J Clin Oncol. Jun 15 2003; 21(12): 2320-5. PMID 12805333
14. Carella AM, Bellei M, Brice P, et al. High-dose therapy and autologous stem cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy: long-term results. Haematologica. Jan 2009; 94(1): 146-8. PMID 19001284
15. Rancea M, von Tresckow B, Monsef I, et al. High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed or refractory Hodgkin lymphoma: a systematic review with meta-analysis. Crit Rev Oncol Hematol. Oct 2014; 92(1): 1-10. PMID 24855908
16. Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet. Apr 24 1993; 341(8852): 1051-4. PMID 8096958
17. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet. Jun 15 2002; 359(9323): 2065-71. PMID 12086759
18. Seftel M, Rubinger M. The role of hematopoietic stem cell transplantation in advanced Hodgkin Lymphoma. Transfus Apher Sci. Aug 2007; 37(1): 49-56. PMID 17716946
19. Murphy F, Sirohi B, Cunningham D. Stem cell transplantation in Hodgkin lymphoma. Expert Rev Anticancer Ther. Mar 2007; 7(3): 297-306. PMID 17338650
20. Merryman RW, Redd RA, Nishihori T, et al. Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma. Blood Adv. Mar 23 2021; 5(6): 1648-1659. PMID 33710337
21. Todisco E, Castagna L, Sarina B, et al. Reduced-intensity allogeneic transplantation in patients with refractory or progressive Hodgkin's disease after high-dose chemotherapy and autologous stem cell infusion. Eur J Haematol. Apr 2007; 78(4): 322-9. PMID 17253967
22. Smith SM, van Besien K, Carreras J, et al. Second autologous stem cell transplantation for relapsed lymphoma after a prior autologous transplant. Biol Blood Marrow Transplant. Aug 2008; 14(8): 904-12. PMID 18640574
23. Perales MA, Ceberio I, Armand P, et al. Role of cytotoxic therapy with hematopoietic cell transplantation in the treatment of Hodgkin lymphoma: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Jun 2015; 21(6): 971-83. PMID 25773017
24. Rashidi A, Ebadi M, Cashen AF. Allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma: a systematic review and meta-analysis. Bone Marrow Transplant. Apr 2016; 51(4): 521-8. PMID 26726948
25. Sureda A, Robinson S, Canals C, et al. Reduced-intensity conditioning compared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. Jan 20 2008; 26(3): 455-62. PMID 18086796
26. Sureda A, Canals C, Arranz R, et al. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma. Results of the HDR-ALLO study - a prospective clinical trial by the Grupo Español de Linfomas/Trasplante de Médula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. Feb 2012; 97(2): 310-7. PMID 21993674
27. Morschhauser F, Brice P, Fermé C, et al. Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkin's lymphoma: results of the prospective multicenter H96 trial by the GELA/SFGM study group. J Clin Oncol. Dec 20 2008; 26(36): 5980-7. PMID 19018090
28. Sibon D, Morschhauser F, Resche-Rigon M, et al. Single or tandem autologous stem-cell transplantation for first-relapsed or refractory Hodgkin lymphoma: 10-year follow-up of the prospective H96 trial by the LYSA/SFGM-TC study group. Haematologica. Apr 2016; 101(4): 474-81. PMID 26721893
29. Fermé C, Mounier N, Diviné M, et al. Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin's disease in relapse or failure after initial chemotherapy: results of the Groupe d'Etudes des Lymphomes de l'Adulte H89 Trial. J Clin Oncol. Jan 15 2002; 20(2): 467-75. PMID 11786576
30. Fung HC, Stiff P, Schriber J, et al. Tandem autologous stem cell transplantation for patients with primary refractory or poor risk recurrent Hodgkin lymphoma. Biol Blood Marrow Transplant. May 2007; 13(5): 594-600. PMID 17448919
31. Winkfield KM, Advani RH, Ballas LK, et al. ACR Appropriateness Criteria® Recurrent Hodgkin Lymphoma. Oncology (Williston Park). Dec 15 2016; 30(12): 1099-103, 1106-8. PMID 27987203
32. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Nov 2015; 21(11): 1863-1869. PMID 26256941
33. Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. Jul 2020; 26(7): 1247-1256. PMID 32165328
34. Centers for Medicare & Medicaid Services. 110.23 - Stem Cell Transplantation (Formerly 110.8.1). 2024; https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?ncdid=366. Accessed December 9, 2025.

Coding Section

Codes	Number	Description
CPT	38204	Management of recipient hematopoietic cell donor search and cell acquisition
	38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic
	38206	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, autologous
	38207	Transplant preparation of hematopoietic progenitor cells; cryopreservation and storage
	38208	; thawing of previously frozen harvest, without washing, per donor
	38209	; thawing of previously frozen harvest, with washing, per donor
	38210	; specific cell depletion within harvest, T cell depletion
	38211	; tumor cell depletion
	38212	; red blood cell removal
	38213	; platelet depletion
	38214	; plasma (volume) depletion
	38215	; cell concentration in plasma, mononuclear, or buffy coat layer
	38230	Bone marrow harvesting for transplantation; allogeneic
	38232	Bone marrow harvesting for transplantation; autologous
	38240	Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic
	38241	; autologous
	86812	HLA typing; A, B, or C (eg, A10, B7, B27), single antigen
	86813	HLA typing; A, B, or C, multiple antigens
	86816	HLA typing; DR/DQ, single antigen
	86817	HLA typing; DR/DQ, multiple antigens
	86821	HLA typing; lymphocyte culture, mixed (MLC)
HCPCS	Q0083	Chemotherapy administration by other than infusion technique only e.g., subcutaneous, intramuscular, push), per visit
	Q0084	Chemotherapy administration by infusion technique only, per visit
	Q0085	Chemotherapy administration by both infusion technique and other technique(s) e.g., subcutaneous, intramuscular, push), per visit
	S2140	Cord blood harvesting for transplantation, allogeneic
	S2142	Cord blood-derived stem-cell transplantation, allogeneic
	S2150	Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of posttransplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic and emergency services)
ICD-10-CM	C81.00	Hodgkin lymphoma code range
	C81.01	Nodular lymphocyte predominant Hodgkin lymphoma, lymph nodes of head, face, and neck
	C81.02	Nodular lymphocyte predominant Hodgkin lymphoma, intrathoracic lymph nodes
	C81.03	Nodular lymphocyte predominant Hodgkin lymphoma, intra-abdominal lymph nodes
	C81.04	Nodular lymphocyte predominant Hodgkin lymphoma, lymph nodes of axilla and upper limb
	C81.05	Nodular lymphocyte predominant Hodgkin lymphoma, lymph nodes of inguinal region and lower limb
	C81.06	Nodular lymphocyte predominant Hodgkin lymphoma, intrapelvic lymph nodes
	C81.07	Nodular lymphocyte predominant Hodgkin lymphoma, spleen
	C81.08	Nodular lymphocyte predominant Hodgkin lymphoma, lymph nodes of multiple sites
	C81.09	Nodular lymphocyte predominant Hodgkin lymphoma, extranodal and solid organ sites
	C81.0A	Nodular lymphocyte predominant Hodgkin lymphoma, in remission
	C81.10	Nodular sclerosis Hodgkin lymphoma, unspecified site
	C81.11	Nodular sclerosis Hodgkin lymphoma, lymph nodes of head, face, and neck
	C81.12	Nodular sclerosis Hodgkin lymphoma, intrathoracic lymph nodes
	C81.13	Nodular sclerosis Hodgkin lymphoma, intra-abdominal lymph nodes
	C81.14	Nodular sclerosis Hodgkin lymphoma, lymph nodes of axilla and upper limb
	C81.15	Nodular sclerosis Hodgkin lymphoma, lymph nodes of inguinal region and lower limb
	C81.16	Nodular sclerosis Hodgkin lymphoma, intrapelvic lymph nodes
	C81.17	Nodular sclerosis Hodgkin lymphoma, spleen
	C81.18	Nodular sclerosis Hodgkin lymphoma, lymph nodes of multiple sites
	C81.19	Nodular sclerosis Hodgkin lymphoma, extranodal and solid organ sites
	C81.1A	Nodular sclerosis Hodgkin lymphoma, in remission
	C81.20	Mixed cellularity Hodgkin lymphoma, unspecified site
	C81.21	Mixed cellularity Hodgkin lymphoma, lymph nodes of head, face, and neck
	C81.22	Mixed cellularity Hodgkin lymphoma, intrathoracic lymph nodes
	C81.23	Mixed cellularity Hodgkin lymphoma, intra-abdominal lymph nodes
	C81.24	Mixed cellularity Hodgkin lymphoma, lymph nodes of axilla and upper limb
	C81.25	Mixed cellularity Hodgkin lymphoma, lymph nodes of inguinal region and lower limb
	C81.26	Mixed cellularity Hodgkin lymphoma, intrapelvic lymph nodes
	C81.27	Mixed cellularity Hodgkin lymphoma, spleen
	C81.28	Mixed cellularity Hodgkin lymphoma, lymph nodes of multiple sites
	C81.29	Mixed cellularity Hodgkin lymphoma, extranodal and solid organ sites
	C81.2A	Mixed cellularity Hodgkin lymphoma, in remission
	C81.30	Lymphocyte depleted Hodgkin lymphoma, unspecified site
	C81.31	Lymphocyte depleted Hodgkin lymphoma, lymph nodes of head, face, and neck
	C81.32	Lymphocyte depleted Hodgkin lymphoma, intrathoracic lymph nodes
	C81.33	Lymphocyte depleted Hodgkin lymphoma, intra-abdominal lymph nodes
	C81.34	Lymphocyte depleted Hodgkin lymphoma, lymph nodes of axilla and upper limb
	C81.35	Lymphocyte depleted Hodgkin lymphoma, lymph nodes of inguinal region and lower limb
	C81.36	Lymphocyte depleted Hodgkin lymphoma, intrapelvic lymph nodes
	C81.37	Lymphocyte depleted Hodgkin lymphoma, spleen
	C81.38	Lymphocyte depleted Hodgkin lymphoma, lymph nodes of multiple sites
	C81.39	Lymphocyte depleted Hodgkin lymphoma, extranodal and solid organ sites
	C81.3A	Lymphocyte depleted Hodgkin lymphoma, in remission
	C81.40	Lymphocyte-rich Hodgkin lymphoma, unspecified site
	C81.41	Lymphocyte-rich Hodgkin lymphoma, lymph nodes of head, face, and neck
	C81.42	Lymphocyte-rich Hodgkin lymphoma, intrathoracic lymph nodes
	C81.43	Lymphocyte-rich Hodgkin lymphoma, intra-abdominal lymph nodes
	C81.44	Lymphocyte-rich Hodgkin lymphoma, lymph nodes of axilla and upper limb
	C81.45	Lymphocyte-rich Hodgkin lymphoma, lymph nodes of inguinal region and lower limb
	C81.46	Lymphocyte-rich Hodgkin lymphoma, intrapelvic lymph nodes
	C81.47	Lymphocyte-rich Hodgkin lymphoma, spleen
	C81.48	Lymphocyte-rich Hodgkin lymphoma, lymph nodes of multiple sites
	C81.49	Lymphocyte-rich Hodgkin lymphoma, extranodal and solid organ sites
	C81.4A	Lymphocyte-rich Hodgkin lymphoma, in remission
	C81.70	Other Hodgkin lymphoma, unspecified site
	C81.71	Other Hodgkin lymphoma, lymph nodes of head, face, and neck
	C81.72	Other Hodgkin lymphoma, intrathoracic lymph nodes
	C81.73	Other Hodgkin lymphoma, intra-abdominal lymph nodes
	C81.74	Other Hodgkin lymphoma, lymph nodes of axilla and upper limb
	C81.75	Other Hodgkin lymphoma, lymph nodes of inguinal region and lower limb
	C81.76	Other Hodgkin lymphoma, intrapelvic lymph nodes
	C81.77	Other Hodgkin lymphoma, spleen
	C81.78	Other Hodgkin lymphoma, lymph nodes of multiple sites
	C81.79	Other Hodgkin lymphoma, extranodal and solid organ sites
	C81.7A	Other Hodgkin lymphoma, in remission
	C81.90	Hodgkin lymphoma, unspecified, unspecified site
	C81.91	Hodgkin lymphoma, unspecified, lymph nodes of head, face, and neck
	C81.92	Hodgkin lymphoma, unspecified, intrathoracic lymph nodes
	C81.93	Hodgkin lymphoma, unspecified, intra-abdominal lymph nodes
	C81.94	Hodgkin lymphoma, unspecified, lymph nodes of axilla and upper limb
	C81.95	Hodgkin lymphoma, unspecified, lymph nodes of inguinal region and lower limb
	C81.96	Hodgkin lymphoma, unspecified, intrapelvic lymph nodes
	C81.97	Hodgkin lymphoma, unspecified, spleen
	C81.98	Hodgkin lymphoma, unspecified, lymph nodes of multiple sites
	C81.99	Hodgkin lymphoma, unspecified, extranodal and solid organ sites
	C81.9A	Hodgkin lymphoma, unspecified, in remission
ICD-10-PCS		ICD-10-PCS codes are only used for inpatient services.
	30243G0, 30243X0,30243Y0	Administration, circulatory, transfusion, central vein, percutaneous, autologous, code by substance (bone marrow, cord blood or stem cells, hematopoietic) code list
	30243G2, 30243X2, 30243Y2	Administration, circulatory, transfusion, central vein, percutaneous, allogeneic related, code by substance (bone marrow, cord blood or stem cells, hematopoietic) code list
	30243G3, 30243X3, 30243Y3	Administration, circulatory, transfusion, central vein, percutaneous, allogeneic unrelated, code by substance (bone marrow, cord blood or stem cells, hematopoietic) code list
	30243G4, 30243X4, 30243Y4	Administration, circulatory, transfusion, central vein, percutaneous, allogeneic unspecified, code by substance (bone marrow, cord blood or stem cells, hematopoietic) code list
	07DQ0ZZ, 07DQ3ZZ, 07DR0ZZ, 07DR3ZZ, 07DS0ZZ, 07DS3ZZ	Surgical, lymphatic and hemic systems, extraction, bone marrow, code list
Type of service	Therapy
Place of service	Inpatient/Outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2024 Forward     

07/01/2026	Annual review, no change to policy intent. Updating background, rationale, references, and coding.
07/01/2025	Annual review, updating summary of evidence, background, rationale and references.
07/12/2024	Annual review, no change to policy intent.
01/01/2024	New Policy.