Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia - CAM 80126

Description　
Acute myeloid leukemia (AML) refers to leukemias that arise from a myeloid precursor in the bone marrow. There is a high incidence of relapse, which has prompted research into various postremission strategies using either allogeneic (allo-) or autologous hematopoietic cell transplantation (HCT). HCT refers to a procedure that infuses hematopoietic stem cells to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of drugs with or without whole-body radiotherapy.

For individuals who have cytogenetic or molecular intermediate- or poor-risk AML in first complete remission who receive allo-HCT with myeloablative conditioning (MAC), the evidence includes randomized controlled trials and matched cohort studies. Relevant outcomes are overall survival and disease-specific survival. The evidence has revealed that allo-HCT is better at improving overall and disease-specific survival rates in patients with AML in first complete remission than conventional chemotherapy. All trials employed natural randomization based on donor availability and an 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 a meaningful 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 overall survival and disease-specific survival. The evidence would suggest that allo-HCT improves overall and disease-specific survival 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 clinically meaningful benefit for patients who do not have other treatment options. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have AML who relapsed after standard induction chemotherapy-induced first complete remission 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 overall survival and disease-specific survival. The evidence has shown that allo-HCT improves overall survival 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 a meaningful improvement in the net health outcome.

For individuals who have cytogenetic or molecular intermediate- or poor-risk AML in first complete remission and for medical reasons cannot tolerate MAC who receive allo-HCT with reduced-intensity conditioning, the evidence includes 2 randomized controlled trials, 2 meta-analyses, and other comparative and noncomparative studies. Relevant outcomes are overall survival, disease-specific survival, and treatment-related morbidity. The randomized controlled trials compared reduced-intensity conditioning with MAC and reported similar rates in nonrelapse mortality, relapse, and overall survival though one of the trials was stopped prematurely due to a slow accrual of patients. Two retrospective comparative studies found no difference in overall survival 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 a meaningful improvement in the net health outcome.

For individuals who have AML in first complete remission 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 overall and disease-specific survival. Compared with chemotherapy, patients undergoing autologous HCT experienced reduced relapse and improved disease-free survival rates. Overall survival did not differ between the groups. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Background
Treatment
Complete remission 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
HCT is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune function in cancer patients 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). They 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 allogeneic stem cell transplantation, 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. HLA 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, 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 graft-versus-host disease.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation
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 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 non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. RIC 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 reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative.

A 2015 review in the New England Journal of Medicine summarized recent advances in the classification of acute myeloid leukemia, the genomics of acute myeloid leukemia and prognostic factors, and current and new treatments.¹

Regulatory Status
The FDA 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.

Related Policies
70150 Placental and Umbilical Cord Blood as a Source of Stem Cells

Policy
Allogeneic hematopoietic cell transplantation (HCT) using a myeloablative conditioning regimen may be considered MEDICALLY NECESSARY to treat:

Poor- to intermediate-risk acute myeloid leukemia (AML) in first complete remission (CR1) (see Policy Guidelines section for information on risk stratification); or
AML that is refractory to standard induction chemotherapy but can be brought into CR with intensified induction chemotherapy; or
AML that relapses following chemotherapy-induced CR1 but can be brought into CR2 or beyond with intensified induction chemotherapy; or
AML in patients who have relapsed following a prior autologous HCT, but can be brought into CR with intensified induction chemotherapy and are medically able to tolerate the procedure.

Allogeneic HCT using a reduced-intensity conditioning regimen may be considered MEDICALLY NECESSARY as a treatment of AML in patients who are in complete marrow and extramedullary remission (CR1 or beyond), and who for medical reasons would be unable to tolerate a myeloablative conditioning regimen (see Policy Guidelines section).

Autologous HCT may be considered MEDICALLY NECESSARY to treat AML in CR1 or beyond, or relapsed AML, if responsive to intensified induction chemotherapy in patients who are not candidates for allogeneic HCT.

Allogeneic and autologous HCT are investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY in patients not meeting any of the above criteria.

Policy Guidelines
Primary refractory acute myeloid leukemia (AML) is defined as leukemia that does not achieve a complete remission after conventionally dosed (nonmarrow ablative) chemotherapy.

In the French-American-British criteria, the classification of AML is solely based on morphology as determined by the degree of differentiation along different cell lines and the extent of cell maturation.

Clinical features that predict poor outcomes of AML therapy include, but are not limited to, the following:

Treatment-related AML (secondary to prior chemotherapy and/or radiotherapy for another malignancy)
AML with antecedent hematologic disease (e.g., myelodysplasia)
Presence of circulating blasts at the time of diagnosis
Difficulty in obtaining first complete remission with standard chemotherapy
Leukemias with monocytoid differentiation (French-American-British classification M4 or M5)

The newer, currently preferred, World Health Organization classification of AML incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers. It attempts to construct a classification that is universally applicable and prognostically valid. The World Health Organization system was adapted by National Comprehensive Cancer Network to estimate individual patient prognosis to guide management, as shown in Table PG1.

Table PG1. Risk Status of AML Based on Cytogenetic and Molecular Factors

Risk Status	Cytogenetic Factors	Molecular Abnormalities
Favorable	Inv16, t(8;21), t(16;16)	Normal cytogenetics with isolated NPM1 variant
Intermediate	Normal +8 only, t(9;11) only Other abnormalities not listed with better-risk and poor-risk cytogenetics	c-KIT variant in patients with t(8;21) or inv16
Poor	Complex (³3 abnormalities) -5, -7, 5q-, 7q-, +8, inv3, t(3;3), t(6;9), t(9;22) Abnormalities of 11q23, excluding t(9;11)	Normal cytogenetics with isolated FLT3-ITD variant

AML: acute myeloid leukemia; ITD: internal tandem duplication.

The relative importance of cytogenetic and molecular abnormalities in determining prognosis and guiding therapy is under investigation.

The ideal allogeneic donors are human leukocyte antigen identical siblings, matched at the human leukocyte antigen-A, -B, and -DR loci (6 of 6). Related donors mismatched at 1 locus are also considered suitable donors. A matched, unrelated donor identified through the National Marrow Donor Registry is typically the next option considered. Recently, there has been interest in haploidentical donors, typically a parent or a child of the patient, for which there usually 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
Please see the Codes table for details.

Benefit Application
BlueCard/National Account Issues
For indications considered investigational, the following considerations may supersede this policy:

State mandates requiring coverage for autologous HSCT 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 HSCT.

Some contracts or certificates of coverage (e.g., the Federal Employee Program) may include specific conditions in which autologous HSCT 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 hematopoietic cell transplantation (allo-HCT) with myeloablative conditioning (MAC) in patients 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 question addressed in this evidence review is: Does allo-HCT with MAC improve net health outcomes in patients who have cytogenetic or molecular intermediate- or poor-risk AML in CR1?

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

Populations
The relevant population of interest is patients 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 patients with AML varies with several known prognostic factors related to patient and tumor characteristics such as age, performance status, and karyotype. Overall, the median survival for patients with AML without chemotherapy or HCT is less than 10 months; the median survival in patients with chemotherapy but without HCT is approximately 20 months.⁵ Patients 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 2015 meta-analysis examined prospective trials of adults with intermediate-risk AML in CR1 who underwent HCT.⁶ 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% confidence interval [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 CR1.⁷ 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-analysis^8, 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).⁸ 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).⁹ 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.^10,11,12,13

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.¹⁴ For example, patients with better prognosis disease (e.g., 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.¹⁵ Similarly, 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.¹⁶ 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.¹⁷ 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
A 2014 study compared outcomes of 185 matched pairs from a large multicenter trial (AMLCG99).¹⁸ 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.¹⁹During 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 RCTs and matched cohort studies. Some studies have compared allo-HCT with autologous HCT or with post-remission chemotherapy. 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. 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 patients 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 question addressed in this evidence review is: Does allo-HCT with MAC improve net health outcomes in patients with AML refractory to standard induction chemotherapy?

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

Populations
The relevant population(s) of interest is patients 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 patients with AML varies with several known prognostic factors related to patient and tumor characteristics such as age, performance status, and karyotype. Overall, the median survival for patients with AML without chemotherapy or HCT is less than 10 months; the median survival in patients with chemotherapy but without HCT is approximately 20 months.⁵ Patients 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.⁹ 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.¹⁰ For patients who lack a suitable donor (matched related donor or matched unrelated donor), alternative treatments include salvage chemotherapy with high-dose cytarabine or etoposide-based regimens, monoclonal antibodies (e.g., 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.²⁰

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 are 30% at 3 years and 13% at 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 patients 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 question addressed in this evidence review is: Does allo-HCT or autologous HCT with MAC improve net health outcomes in patients with relapsed AML after standard induction chemotherapy-induced CR1?

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

Populations
The relevant population(s) of interest is patients 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.

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 CR1.⁹ 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.²¹

Allo-HCT is often performed as salvage therapy for patients who have relapsed after conventional chemotherapy or autologous HCT.²⁰ 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.²⁰

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.²² 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.^20,23 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 CR1.²⁰

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 patients 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 question addressed in this evidence review is: Does allo-HCT with RIC improve net health outcomes in patients with cytogenetic or molecular intermediate- or poor-risk AML in CR1 who cannot tolerate MAC?

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

Populations
The relevant population(s) of interest is patients 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.

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.^{24,25,26,27,28,29,30,31,32,33,34,35}

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).³⁶ 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.³⁷ 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.³⁸ 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.^39,40,41 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.⁴² 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
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.⁴³ 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 – 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).⁴³
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.⁴⁴ 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.45, 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 patients 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 question addressed in this evidence review is: Does autologous HCT improve net health outcomes in patients with AML in remission who do not have a suitable allo-HCT donor?

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

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

Interventions
The therapy being considered is autologous HCT. For patients 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.

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.⁴⁶Two 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 CR1.⁴⁷ Nine randomized trials involving 1,104 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 CR1.⁴⁸ After 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 high-dose cytarabine (HiDAC) consolidation as post-remission therapy in AML.⁴⁹ 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 AML in first CR1 who receive allo-HCT with MAC, the evidence includes RCTs and matched cohort studies. Relevant outcomes are OS and DSS. The evidence has revealed that allo-HCT is better at improving OS and DSS rates in patients with AML in CR1 than conventional chemotherapy. 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 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 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.

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 U.S. professional society, an international society with U.S. 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.⁵⁰ 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)
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.⁵¹ Although a formal systematic review was not conducted, evidence was partly used as the basis for the recommendations. The publication reported that none of the authors had any relevant financial conflicts of interest to declare. Table 2 summarizes recommendations for HCT in acute myeloid leukemia.

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

Indication	Allo-HCT^a	Autologous HCT^a
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	C	N
AML, age ≥ 18 years
First CR, low risk	N	C
First CR, intermediate risk	S	C
First CR, high risk	S	C
Second CR	S	C
Third or greater CR	C	C
Not in remission	C	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 response; HCT: hematopoietic cell transplantation

National Comprehensive Cancer Network
The National Comprehensive Cancer Network clinical guidelines (v.3.2021)² for acute myeloid leukemia 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.

According to the guidelines, the role of autologous HCT is diminishing due to improvements in allo-HCT that have expanded the pool of potential donors outside the family setting. Autologous HCT should not be a recommended consolidation therapy outside the setting of a clinical trial.

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
*Unpublished*
NCT00342316	Prospective Controlled Clinical Study of Allogeneic Stem Cell Transplantation with Reduced Conditioning versus Best Standard Care in Acute Myeloid Leukemia in First Complete Remission	340	Jul 2018 (Completed)

NCT: national clinical trial.

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Huisman C, Meijer E, Petersen EJ, et al. Hematopoietic stem cell transplantation after reduced intensity conditioning in acute myelogenous leukemia patients older than 40 years. Biol Blood Marrow Transplant. Feb 2008; 14(2): 181-6. PMID 18215778
Valcarcel D, Martino R. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and acute myelogenous leukemia. Curr Opin Oncol. Nov 2007; 19(6): 660-6. PMID 17906468
Valcarcel D, Martino R, Caballero D, et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol. Feb 01 2008; 26(4): 577-84. PMID 18086801
Gyurkocza B, Storb R, Storer BE, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. Jun 10 2010; 28(17): 2859-67. PMID 20439626
McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol. Apr 10 2010; 28(11): 1878-87. PMID 20212255
Peffault de Latour R, Porcher R, Dalle JH, et al. Allogeneic hematopoietic stem cell transplantation in Fanconi anemia: the European Group for Blood and Marrow Transplantation experience. Blood. Dec 19 2013; 122(26): 4279-86. PMID 24144640
Hamidieh AA, Alimoghaddam K, Jahani M, et al. Non-TBI hematopoietic stem cell transplantation in pediatric AML patients: a single-center experience. J Pediatr Hematol Oncol. Aug 2013; 35(6): e239-45. PMID 23042019
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Pemmaraju N, Tanaka MF, Ravandi F, et al. Outcomes in patients with relapsed or refractory acute promyelocytic leukemia treated with or without autologous or allogeneic hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk. Aug 2013; 13(4): 485-92. PMID 23769669
Song Y, Yin Z, Ding J, et al. Reduced Intensity Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation Is a Good Choice for Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Meta-Analysis of Randomized Controlled Trials. Front Oncol. 2021; 11: 708727. PMID 34692485
Rashidi A, Ebadi M, Colditz GA, et al. Outcomes of Allogeneic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-analysis. Biol Blood Marrow Transplant. Apr 2016; 22(4): 651-657. PMID 26529178
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Ringden O, Erkers T, Aschan J, et al. A prospective randomized toxicity study to compare reduced-intensity and myeloablative conditioning in patients with myeloid leukaemia undergoing allogeneic haematopoietic stem cell transplantation. J Intern Med. Aug 2013; 274(2): 153-62. PMID 23432209
Shimoni A, Labopin M, Savani B, et al. Long-term survival and late events after allogeneic stem cell transplantation from HLA-matched siblings for acute myeloid leukemia with myeloablative compared to reduced-intensity conditioning: a report on behalf of the acute leukemia working party of European group for blood and marrow transplantation. J Hematol Oncol. Nov 08 2016; 9(1): 118. PMID 27821187
Bitan M, He W, Zhang MJ, et al. Transplantation for children with acute myeloid leukemia: a comparison of outcomes with reduced intensity and myeloablative regimens. Blood. Mar 06 2014; 123(10): 1615-20. PMID 24435046
Devine SM, Owzar K, Blum W, et al. Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. Dec 10 2015; 33(35): 4167-75. PMID 26527780
Nathan PC, Sung L, Crump M, et al. Consolidation therapy with autologous bone marrow transplantation in adults with acute myeloid leukemia: a meta-analysis. J Natl Cancer Inst. Jan 07 2004; 96(1): 38-45. PMID 14709737
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Miyamoto T, Nagafuji K, Fujisaki T, et al. Prospective randomization of post-remission therapy comparing autologous peripheral blood stem cell transplantation versus high-dose cytarabine consolidation for acute myelogenous leukemia in first remission. Int J Hematol. Apr 2018; 107(4): 468-477. PMID 29243031
Dholaria B, Savani BN, Hamilton BK, et al. Hematopoietic Cell Transplantation in the Treatment of Newly Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from the American Society of Transplantation and Cellular Therapy. Transplant Cell Ther. Jan 2021; 27(1): 6-20. PMID 32966881
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
Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Stem Cell Transplantation (Formerly 110.8.1) (110.23). 2016; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId = 366&ncdver = 1&DocID = 110.23&bc = gAAAAAgAAAAAAA%3D%3D&. Accessed November 29, 2021.

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	Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing
	38209	; thawing of previously frozen harvest, with washing
	38210	; specific cell depletion with 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	Bone marrow or blood-derived peripheral stem-cell transplantation; autologous
	38242	Allogeneic donor lymphocyte infusions
HCPCS	Q0083-Q0085	Chemotherapy administration code range
	J9000-J9999	Chemotherapy drug code range
	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 post-transplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic and emergency services)
ICD-10-CM (effective 10/01/15)	C92.00-C92.02	Acute myeloblastic leukemia code range
	C92.40-C92.42	Acute promyelocytic leukemia code range
	C92.50-C92.52	Acute myelomonocytic leukemia code range
ICD-10-PCS (effective 10/01/15)	30243G0, 30243G1, 30243X0, 30243X1, 30243Y0, 30243Y1	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
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.

History From 2014 Forward

07/01/2022	Annual review, no change to policy intent. Updating rationale and references.
07/01/2021	Annual review, no change to policy intent. Updating rationale and references.
07/28/2020	Annual review, no change to policy intent. Updating background, guidelines, coding, rationale and references.
07/01/2019	Annual review, updating policy to include a medical necessity statement for auto-HCT and an investigational statement added for patients not meeting medical necessity criteria. Also updating guidelines, rationale and references.
07/31/2018	Annual review, no change to policy intent. Updating background, description, rationale and references.
12/6/2017	Updating policy with 2018 coding. No other changes.
07/03/2017	Annual review, updating title, no change to policy intent.
08/19/2016	Annual review, no change to policy intent. Updating background, description, rationale and references.
08/04/2015	Annual review, no change to policy intent. Updated background, description, rationale, references, guidelines. Added coding.
07/09/2014	Annual review. Added description and related policies. Updated rationale and reference. No change to policy intent.

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Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia - CAM 80126