| Coverage Policy Manual | |
| Policy #: | 2001021 |
| Category: | Medicine |
| Initiated: | January 1993 |
| Last Review: | February 2024 |
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| HDC & Allogeneic Stem &/or Progenitor Cell Support-Acute Myelogenous Leukemia | |
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| Description: |
High dose chemotherapy (HDC) involves the administration of cytotoxic agents using several times greater than the standard therapeutic dose. In some cases, whole body or localized radiotherapy is also given and is included in the term HDC when applicable. HDC results in marrow ablation and thus HDC is accompanied by a reinfusion of stem and or progenitor cells in order to repopulate the bone marrow.
Sources of Stem Cells:
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 post-remission strategies using either allogeneic (allo-) or autologous hematopoietic cell transplantation (HCT). Hematopoietic cell transplantation 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.
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
Hematopoietic cell transplantation 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). These cells can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates.
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 acute myeloid leukemia (AML), the genomics of AML and prognostic factors, and current and new treatments (Dohner, 2015). 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 (NCCN, 2022; Blum, 2020; Koenig, 2020).
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.
Reimbursement for high dose chemotherapy (HDC) with stem and/or progenitor cell transplant that has been pre-authorized is made as a global fee limited to the lesser of billed charges or the average allowable charge authorized by the Blue Quality Centers for Transplant in the geographic region where the transplant is performed. This global payment includes all related transplant services including institutional, professional, ancillary, and organ procurement. The global period begins one day prior to the date of the transplant and continues for 48 days after the transplant. This covers the inpatient/outpatient stay and provides a per diem outlier payment if necessary. This global fee also includes the cost of complications arising from the original procedure when services are rendered within the global postoperative period for the particular transplant.
This policy does not address autologous stem cell transplant for Acute Myelogenous Leukemia. High Dose Chemotherapy and Autologous Stem Cell Support is addressed separately in policy #2000044.
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Policy/ Coverage: |
Effective June 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
High dose chemotherapy with allogeneic bone marrow, stem cell, or progenitor cell support meets primary coverage criteria for effectiveness and is covered as a treatment of:
Donor leukocyte infusion for relapse following allogeneic transplant for AML meets primary coverage criteria for effectiveness.
Non myeloablative or reduced-intensity allogeneic transplant as primary treatment of AML or following primary therapy relapse meets primary coverage criteria for effectiveness.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
High dose chemotherapy with allogeneic stem cell support to treat AML relapsing after prior therapy with high dose chemotherapy and autologous stem cell support does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For contracts without primary coverage criteria, high dose chemotherapy with allogeneic stem cell support to treat AML relapsing after prior therapy with high dose chemotherapy and autologous stem cell support is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
EFFECTIVE October 2014 through May 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
High dose chemotherapy with allogeneic bone marrow, stem cell, or progenitor cell support meets primary coverage criteria for effectiveness and is covered as a treatment of:
Donor leukocyte infusion for relapse following allogeneic transplant for AML meets primary coverage criteria for effectiveness.
Non myeloablative or reduced-intensity allogeneic transplant as primary treatment of AML or following primary therapy relapse meets primary coverage criteria for effectiveness.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
High dose chemotherapy with allogeneic stem cell support to treat AML relapsing after prior therapy with high dose chemotherapy and autologous stem cell support does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For contracts without primary coverage criteria, high dose chemotherapy with allogeneic stem cell support to treat AML relapsing after prior therapy with high dose chemotherapy and autologous stem cell support is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
EFFECTIVE prior to October 2014
High dose chemotherapy with allogeneic bone marrow, stem cell, or progenitor cell support meets primary coverage criteria for effectiveness and is covered as a treatment of:
Donor leukocyte infusion for relapse following allogeneic transplant for AML meets primary coverage criteria for effectiveness and is covered.
High dose chemotherapy with allogeneic stem cell support to treat AML relapsing after prior therapy with high dose chemotherapy and autologous stem cell support is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For contracts without primary coverage criteria, high dose chemotherapy with allogeneic stem cell support to treat AML relapsing after prior therapy with high dose chemotherapy and autologous stem cell support is considered investigational, and is not covered. Investigational services are an exclusion in the member certificate of coverage.
Non myoablative allogeneic "mini" transplant as primary treatment of AML or following primary therapy relapse is covered.
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| Rationale: |
This policy was originally created in 1993 and has been regularly updated with searches of the MEDLINE database. The most recent MEDLINE search was performed through September, 2014.
Consolidation Therapy in Remission
A meta-analysis of allogeneic HSCT in patients with acute myeloid leukemia (AML) in first complete remission (CR1) pooled data from 5 studies that included a total of 3100 patients (Yanada, 2005). Among those patients, 1151 received allogeneic HSCT and 1949 were given alternative therapies including chemotherapy and autologous HSCT. All of the studies employed natural randomization based on donor availability, and an intention-to-treat analysis, with overall survival (OS) and disease-free survival (DFS) as outcomes of interest. This analysis showed a significant advantage of allogeneic HSCT in terms of OS for the entire cohort (fixed-effects model hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.06 to 1.30; p=0.003; random-effects model HR=1.15, 95% C, 1.01 to 1.32; p=0.037) even though none of the individual studies did so. Meta-regression analysis showed that the effect of allogeneic HSCT on OS differed depending on the cytogenetic risk groups of patients, suggesting significant benefit for poor-risk patients (HR=1.39, 95% CI not reported), indeterminate benefit for intermediate-risk cases, and no benefit in better-risk patients compared with alternative approaches. The authors caution that the compiled studies used different definitions of risk categories (eg, SWOG, MRC, EORTC/GIMEMA), but examination shows cytogenetic categories in those definitions are very similar to the recent guidelines from the National Comprehensive Cancer Network (NCCN) (Greer, 2009). Furthermore, the statistical power of the meta-regression analysis is limited by small numbers of cases. However, the results of this meta-analysis are supported in general by data compiled in other reviews (Hamadani, 2008; Deschler, 2006; Craddock, 2008; Cornelissen, 2007).
Evidence from the meta-analysis cited here suggests patients with cytogenetically defined better-prognosis disease may not realize a significant survival benefit with allogeneic HSCT in CR1 that outweighs the risk of associated morbidity and nonrelapse mortality (NRM). However, there is considerable genotypic heterogeneity within the 3 World Health Organization (WHO) cytogenetic prognostic groups that complicates generalization of clinical results based only on cytogenetics (Mrozek, 2006). For example, patients with better-prognosis disease (eg, core-binding factor AML) based on cytogenetics, and a mutation in the c-kit gene of leukemic blast cells, do just as poorly with postremission standard chemotherapy as patients with cytogenetically poor-risk AML (Paschka, 2006). 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 (defined earlier in the policy Description). Thus, patients with mutations in NPM1 but without FLT3-ITD (internal tandem duplications) have postremission outcomes with standard chemotherapy that are similar to those with better-prognosis cytogenetics; in contrast, patients with any other combination of mutations in those genes have outcomes similar to those with poor-prognosis cytogenetics (Schlenk, 2008). These examples highlight the rapidly growing body of evidence for genetic mutations as additional predictors of prognosis and differential disease response to different treatments. 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 concerning the role of allogeneic HSCT in different patient risk groups.
A second meta-analysis has been published that incorporated data from 24 trials involving a total of 6007 patients who underwent allogeneic HSCT in first complete remission [CR1] (Koreth, 2009). Among the total, 3638 patients were stratified and analyzed according to cytogenetic risk (547 good-, 2499 intermediate-, 592 poor-risk AML, respectively) using a fixed-effects model. Compared with either autologous HSCT 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<0.01); among intermediate-risk patients across 14 trials, the HR for OS was 0.83 (95% CI, 0.74 to 0.93; p<0.01); among good-risk patients across 16 trials, the HR for OS was 1.07 (95% CI, 0.83 to 1.38; p=0.59). 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 concur with those from the previously cited meta-analysis (Yanada, 2005) and the current Policy Statements for use of allogeneic HSCT as consolidation therapy for AML.
A recent study compared the outcome of 185 matched pairs of patients from a large multicenter clinical trial (AMLCG99) (Stelljes, 2014). Patients younger than 60 years who underwent allogeneic HSCT in CR1 were matched to patients who received conventional postremission chemotherapy. The main matching criteria were AML type, cytogenetic risk group, patient age, and time inCR1. In the overall pairwise-compared AML population, the projected 7-year OS rate was 58% for the allogeneic HSCT and 46% for the conventional postremission treatment group (log-rank test, p=0.037). Relapse-free survival was 52% in the allogeneic HSCT group compared with 33% in the control group (p<0.001). OS was significantly better for allogeneic HSCT in patient subgroups with nonfavorable chromosomal aberrations, patients older than 45 years, and patients with secondary AML or high-risk myelodysplastic syndrome. For the entire patient cohort, postremission therapy was an independent factor for OS (HR=0.66; 95% CI, 0.49 to 0.89 for allogeneic HSCT versus conventional chemotherapy), among age, cytogenetics, and bone marrow blasts after the first induction cycle.
Primary Refractory AML
Conventional-dose induction chemotherapy will not produce remission in 20% to 40% of patients with AML, connoting refractory AML (Greer, 2009). An allogeneic HSCT using a matched related donor (MRD) or matched unrelated donor (MUD) represents the only potentially curative option for these patients. In several retrospective studies, OS rates have ranged from 13% at 5 years to 30% at 3 years, although this procedure is accompanied by NRM rates of 25% to 62% in this setting (Hamadani, 2008). For patients who lack a suitable donor (MRD or MUD), alternative treatments include salvage chemotherapy with high-dose cytarabine or etoposide-based regimens, monoclonal antibodies (eg, gemtuzumab ozogamicin), multidrug resistance modulators, and other investigational agents such as FLT3 antagonists (Estey, 2009).
Relapsed AML
Most patients with AML will experience disease relapse after attaining a CR1 (Greer, 2009). Conventional chemotherapy is not curative in most patients following disease relapse, even if a second complete remission (CR2) can be achieved. Retrospective data compiled from 667 of 1540 patients entered in 3 phase III trials suggest allogeneic HSCT in CR2 can produce 5-year OS rates of 26% to 88%, depending on cytogenetic risk stratification.19 Because reinduction chemotherapy treatment may be associated with substantial morbidity and mortality, patients whose disease has relapsed and who have a suitable donor may proceed directly to allogeneic HSCT.
Allogeneic HSCT is often performed as salvage for patients who have relapsed after conventional chemotherapy or autologous HSCT (Stone, 2004). The decision to attempt reinduction or proceed directly to allogeneic HSCT is based on the availability of a suitable stem-cell donor and the likelihood of achieving a remission, the latter being a function of cytogenetic risk group, duration of CR1 and the patient’s health status. Registry data show DFS rates of 44% using sibling allografts and 30% with MUD allografts at 5 years for patients transplanted in CR2, and DFS of 35% to 40% using sibling transplants and 10% with MUD transplants for patients with induction failure or in relapse following HSCT (Stone, 2004).
Non-myeloablative or Reduced-Intensity Allogeneic HSCT
A growing body of evidence is accruing from clinical studies of RIC with allogeneic HSCT for AML (Hamadani, 2011; Oliansky, 2008; Huisman, 2008; Valcarcel, 2007; Valcarcel, 2008; Gyurkocza, 2010; McClune, 2010; De Latour, 2013; Hamidieh, 2013; Lim, 2010; Peffault, 2013; Pemmaraju, 2013). Overall, these data suggest that long-term remissions (2-4 years) can be achieved in patients with AML who, because of age or underlying comorbidities would not be candidates for myeloablative conditioning regimens.
A randomized comparative trial in matched patient groups compared the net health benefit of allogeneic HSCT with reduced-intensity conditioning (RIC) versus myeloablative conditioning (Bornhauser, 2012; Scherwath, 2013; Shayegi, 2013). In this study, patients (age, 18-60 years) were randomly assigned to receive either RIC (n=99) of 4 doses of 2 Gy of total body irradiation and 150 mg/m2 fludarabine or standard conditioning (n=96) of 6 doses of 2 Gy of total body irradiation and 120 mg/kg cyclophosphamide. All patients received cyclosporin and methotrexate as prophylaxis against GVHD. The primary end point was the incidence of NRM analyzed in the intention-to-treat population. This unblinded trial was stopped early because of slow accrual of patients. The incidence of NRM did not differ between the RIC and standard conditioning groups (cumulative incidence at 3 years, 13% [95% CI, 6 to 21] vs 18% [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% (17 to 36; HR=1.10 [95% CI, 0.63 to 1.90]) in the standard conditioning group. DFS at 3 years was 58% (95% CI, 49 to 70) in the RIC group and 56% (46 to 67; HR=0.85 [95% CI, 0.55 to 1.32]) in the standard conditioning group. OS at 3 years was 61% (95% CI, 50 to 74) and 58% (47 to 70); HR was 0.77 (95% CI, 0.48 to 1.25) in the RIC and standard conditioning groups, respectively. No outcomes differed significantly between groups. Grade 3 to 4 of oral mucositis was less common in the RIC group than in the standard conditioning group (50 patients in the RIC group vs 73 patients in the standard conditioning group); the frequency of other adverse effects such as GVHD and increased concentrations of bilirubin and creatinine did not differ significantly between groups.
In a recent study, outcomes were compared in children with AML who underwent allogeneic HSCT using RIC regimens or myeloablative conditioning regimens (Bitan, 2014). A total of 180 patients were evaluated, 39 who underwent RIC and 141 who received myeloablative 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 myeloablative regimens were 45% and 48%, respectively (p=0.99). Moreover, relapse rates were not higher with RIC compared with myeloablative conditioning (MAC) regimens (39% vs 39%; p=0.95), and recipients of MAC regimens were not at higher risk for transplant-related mortality compared with recipients of RIC regimens (16% vs 16%; p=0.73).
A phase 2 single-center, randomized toxicity study compared MAC and RIC in allogeneic HSCT to treat AML (Ringden, 2013). Adult patients 60 years of age or younger with AML were randomly assigned (1:1) to treatment with RIC (n=18) or MAC (n=19) for allogeneic HSCT. A maximum median mucositis grade of 1 was observed in the RIC group compared with 4 in the MAC group (p<0.001). Hemorrhagic cystitis occurred in 8 (42%) of the patients in the MAC group and none (0%) in the RIC group (p<0.01). Results of renal and hepatic tests did not differ significantly between the 2 groups. RIC-treated patients had faster platelet engraftment (p<0.01) and required fewer erythrocyte and platelet transfusions (p<0.001) and less total parenteral nutrition than those treated with MAC (p<0.01). Cytomegalovirus infection was more common in the MAC group (14/19) than in the RIC group (6/18) (p=0.02). Donor chimerism was similar in the 2 groups with regard to 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 were not significantly different. Patients in the MAC group with intermediate cytogenetic AML had a 3-year survival of 73%, compared with 90% among those in the RIC group.
Allogeneic HSCT with RIC is one of several therapeutic approaches for which evidence exists to show improved health outcomes in patients who could expect to benefit from an allogeneic HSCT.
Summary of Evidence
A substantial body of published evidence supports the use of allogeneic hematopoietic stem-cell transplantation (HSCT) as consolidation treatment for acute myeloid leukemia (AML) patients in first complete remission (CR1) who have intermediate- or high-risk disease and a suitable donor; this procedure is not indicated for patients in CR1 with good-risk AML.
Data also support the use of allogeneic HSCT for patients in second complete remission (CR2) and beyond who are in chemotherapy-induced remission and for whom a donor is available. Allogeneic HSCT is a consolidation option for those with primary refractory or relapsed disease who can be brought into remission once more with intensified chemotherapy and who have a donor.
Allogeneic HSCT using reduced-intensity conditioning is supported by evidence for use in patients who otherwise would be candidates for an allogeneic transplant, but who have comorbidities that preclude use of a myeloablative procedure. These conclusions are generally affirmed in a recent systematic review and analysis of published international guidelines and recommendations, including those of the European Group for Blood and Marrow Transplantation, the American Society for Blood and Marrow Transplantation, the British Committee for Standards in Hematology, the National Comprehensive Cancer Network (NCCN), and the specific databases of the National Guideline Clearinghouse and the Guideline International Network database (Hubel, 2011).
2015 Update
A literature search conducted through September 2015 did not reveal any new information that would prompt a change in the coverage statement.
2016 Update
A literature search conducted through June 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
A 2015 review in the New England Journal of Medicine summarizes recent advances in the classification of acute myeloid leukemia (AML), the genomics of AML and prognostic factors, and current and new treatments (Dohner, 2015).
Allogeneic HSCT for Chemotherapy Responsive Consolidation
Systematic Reviews and Meta-Analyses
A 2015 meta-analysis examined prospective trials of adult patients with intermediate risk AML in first complete remission (CR1) who underwent HSCT (Li, 2015). The analysis included 9 prospective, controlled studies that enrolled a total of 1950 patients between the years 1987 and 2011, with study sizes ranging from 32 patients to 713. Allogeneic HSCT was associated with significantly better relapse-free survival (RFS), overall survival (OS), and relapse rate (RR) than autologous HSCT and/or chemotherapy (hazard ratio [HR],0.684; 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 (TRM) was significantly higher following allogeneic HSCT than autologous HSCT (HR=3.09; 95% CI, 1.38 to 6.92). However, a subgroup analysis showed no OS benefit for allogeneic HSCT over autologous HSCT (HR=0.99; 95% CI, 0.70 to 1.39).
Reduced-Intensity Conditioning Allogeneic HSCT
A 2014 meta-analysis compared reduced-intensity and myeloablative conditioning regimens for allogeneic HSCT in patients with AML (and acute lymphoblastic leukemia) (Abdul, 2014). The analysis included 23 clinical trials that were reported between 1990 and 2013, with approximately 15,000 adult patients. Eleven studies included AML and myelodysplastic syndrome (MDS) and 5 included AML only. A subanalysis from 13 trials in patients with AML or MDS showed that OS was comparable in patients who received either reduced-intensity or myeloablative transplants, and the 2-year or less and 2-year or greater OS rates were equivalent between the 2 groups. The 2- to 6-year PFS, non-relapse mortality, and acute and chronic graft-versus-host disease (GVHD) rates were reduced after RIC-HCT, but relapse rate was increased. Similar outcomes were observed regardless of disease status at transplantation. Among the RIC-HSCT recipients, survival rates were superior if patients were in CR at transplantation.
2018 Update
A literature search was conducted through June 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
ALLO-HCT FOR CHEMOTHERAPY-RESPONSIVE CONSOLIDATION
Retrospective Studies
Heidrich et al 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 (ITD) variants (Heidrich, 2017). During 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=0.02); a similar improvement was seen for OS, although not statistically significant (p=0.08). 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<0.001). 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=0.02), as were rates of RFS (5-year RFS, 55% vs 31%; HR=0.51; 95% CI, 0.34 to 0.76; p=0.001). 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.
Canaani et al published a retrospective analysis of 1275 patients who underwent HCT; of these, 918 patients had normal white blood cell (WBC) counts, and the rest presented with abnormally high WBC (hyperleukocytosis) (Canaani, 2017). For 159 patients in the latter group, WBC counts were between 50,000 and 100,000/μL; for 198 patients, WBC counts were greater than 100,000. By comparing end points such as relapse incidence, leukemia-free survival, nonrelapse mortality, and the occurrence of acute or chronic graft-versus-host disease (GVHD) between groups, the authors evaluated hyperleukocytosis as a potential prognostic indicator of outcomes following transplantation. At baseline, patients in the intermediate- and high-WBC groups had younger median ages (49.1 years and 48.8 years, respectively) than patients without hyperleukocytosis (median age, 52.2 years); additionally, patients with high WBC were associated with the presence of FLT3-ITD and NPM1 variants (p<0.001), and there were significant differences between groups regarding cytogenetic risk category (p<0.001) and the choice of conditioning regimen, whether myeloablative or reduced-intensity (p=0.02). In multivariate analysis, patients with hyperleukocityosis (intermediate and high WBC) were more likely to experience relapse than patients with less than 50,000/μL WBC (29% and 30% vs 22%, respectively); the HR was 1.55 (95% CI, 1.14 to 2.12; p=0.004). Negative outcomes were again linked to patients with hyperleukocytosis for leukemia-free survival and OS, which were favorable for non-hyperleukocytosis patients (respective HRs were as follows: 1.38 [95% CI, 1.07 to 1.78], p=0.013; and 1.4 [95% CI, 1.07 to 1.87], p=0.013). Such findings were statistically significant when different types of transplantation sources (a matched sibling vs an unrelated donor) were accounted for, leading investigators to recommend the use of hyperleukocytosis as a predictor of clinical outcomes following allogeneic HCT.
PRACTICE GUIDELINES AND POSITION STATEMENTS
European Society for Blood and Marrow Transplantation
As part of the position statement published in 2017 on behalf of the European Society for Blood and Marrow Transplantation, Lee et al summarized the current literature regarding allogeneic HCT (allo-HCT) in patients with AML (EBMT, 2017). For patients who lack a matched related or unrelated donor, recent retrospective and registry studies have suggested that allogeneic HCT is an option using a donor who is haploidentical to the patient or in whom all but 1 or 2 human leukocyte antigen loci match that of the patient. While the EBMT did not determine a superior method for haploidentical HCT, it was noted that the preliminary evidence suggests patient outcomes similar to those observed following single or double umbilical cord blood transplantation. The review of the literature did not include pooled analyses of the results, but the EBMT advocates that more prospective studies be conducted, given the potential benefit for AML patients who do not have eligible donors under standard guidelines.
Canadian Consensus Guidelines
Brandwein et al updated evidence-based consensus guidelines from a group of Canadian leukemia experts on the appropriate induction regimens for AML patients who are older; the group considered both candidates for allo-HCT and patients ineligible for transplant (Brandwein, 2017). The consensus group expanded the indication for induction therapy to any patient younger than 80 years old who is eligible for HCT and who does not present with high comorbidities or adverse risk cytogenetics. As potential induction regimens for individuals with intermediate-to-favorable risk cytogenetics, the consensus group recommended the 3+7 regimen (which may include daunorubicin, idarubicin, or mitoxantrone, followed by cytarabine) or, if unable to receive anthracyclines, the FLAG regimen, which consists of fludarabine, cytarabine, and filgrastim. Midostaurin may be administered to patients younger than 70 years in whom a FLT3 internal tandem duplication or tyrosine kinase domain variant is detected; if no such variant (FLT3) is present, gemtuzumab ozogamicin may be administered. Concerning HCT, the consensus group confirmed that haploidentical donors may be selected for patients who lack a matched donor (whether a relative or unrelated); and HCT may be considered in patients younger than 75 years of age and in patients whose disease is in second complete remission.
MEDICARE NATIONAL COVERAGE
The Centers for Medicare & Medicaid Services have the following national coverage determination on use of autologous cell transplantation for AML: “Acute leukemia in remission who have a high probability of relapse and who have no human leucocyte antigens (HLA)-matched” (CMMS, 2017).
2019 Update
A literature search was conducted through June 2019. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
National Comprehensive Cancer Network
The National Comprehensive Cancer Network clinical guidelines (v.2.2018),for acute myeloid leukemia state that allogeneic HCT is recommended for patients aged<60 years after standard-dose cytarabine induction with induction failure or significant residual disease without a hypocellular marrow or as post-remission therapy in those with intermediate-risk or poor-risk cytogenetics (NCCN, 2018). It is also recommended for patients aged ≥60 years after standard-dose cytarabine induction with residual disease or induction failure or following complete response (reduced-intensity HCT).
2020 Update
A literature search was conducted through June 2020. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
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 (Dholaria, 2020). 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:
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 (Majhail, 2015). 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.
Recommendations for the Use of Hematopoietic Cell Transplantation to Treat Acute Myeloid Leukemia:
AML, age <18 years
AML, age ≥18 years
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Song et al 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) (Song, 2021). 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.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Masetti et al conducted a meta-analysis of allo-HCT for pediatric patients with AML in CR1 (Masetti, 2022). 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 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) (Begna, 2022). 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 (Wang, 2022).
Russell et al 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 (Russell, 2022). 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 2022, the American Society of Transplantation and Cellular Therapy published guidance on the role of HCT in pediatric AML and myelodysplastic syndrome (Tarlock, 2022). 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.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
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 patients with chemotherapy but without HCT is approximately 20 months (Master, 2016). Individuals are followed up throughout their lifespan.
Conventional dose induction chemotherapy will not produce remission in 20% to 40% of patients with AML, connoting refractory AML (Baer, 2009).
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 (Mrózek, 2006).
A meta-analysis evaluated the relationship between minimal residual disease (MRD) at the time of HCT and posttransplantation outcomes (Buckley, 2017). 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.
An open-label, 2-arm, multicenter RCT was conducted in Germany to assess the ideal postremission strategy in intermediate-risk AML in CR1 (Bornhäuser, 2023). 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.
In a retrospective chart review assessed characteristics that might predict OS, relapse rate, and nonrelapse mortality of HCT in patients with relapsed AML (Frazer,2017). 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.
A systematic review and meta-analysis calculated OS and RFS for patients older than 60 years of age with AML who underwent RIC HCT (Rashidi, 2016). 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 randomized comparative trial in matched patient groups compared the net health benefit of allo-HCT with RIC or with MAC (Bornhäuser, 2012; Scherwath, 2013; Shayegi, 2013). 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 compared MAC with RIC in patients who received allo-HCT to treat AML (Ringdén, 2013). 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.
The results of an observational study was published 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 (Russell, 2022). 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 (Shimoni, 2016). 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.
In a phase 2, patients ages 60 to 74 years with AML in CR1 were treated with RIC and allo-HCT (Devine, 2015). 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%).
A meta-analysis compared survival outcomes for autologous HCT in CR1 with standard chemotherapy or no further treatment in AML patients ages 15 to 55 years (Nathan, 2004). Two 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 evaluated autologous HCT plus further chemotherapy or no further treatment for patients with AML in CR1 (Wang, 2010). 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.
A prospective, randomized phase 3 trial compared autologous HCT with intensive consolidation chemotherapy among patients (range, 16 to 60 years) with newly diagnosed AML of similar risk profiles in CR1 (Vellenga, 2011). 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.
Results were reported 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 (Miyamoto, 2018). 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.
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