Pending Policies - Surgery
Hematopoietic Stem-Cell Transplantation for Acute Myelogenous Leukemia (AML)
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Allogeneic hematopoietic stem-cell transplantation (HSCT) using a myeloablative conditioning regimen may be considered medically necessary to treat:
• Poor- to intermediate-risk acute myelogenous leukemia (AML) in first complete remission (CR1) (Refer to Table 1 - Risk Status of AML Based on Cytogenetic and Molecular Factors below); or
• AML that is refractory to standard induction chemotherapy but can be brought into complete remission (CR) with intensified induction chemotherapy; or
• AML that relapses following chemotherapy-induced CR1 but can be brought into second complete remission (CR2) or beyond with intensified induction chemotherapy; or
• AML in patients who have relapsed following a prior autologous HSCT, but can be brought into CR with intensified induction chemotherapy and are medically able to tolerate the procedure.
Allogeneic HSCT using a reduced-intensity conditioning (RIC) 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 (Refer to Special Comment on AML Remission below).
Autologous HSCT may be considered medically necessary to treat AML in CR1 or beyond, or relapsed AML, if responsive to intensified induction chemotherapy.
For conditions not listed above, allogeneic or autologous HSCT is considered experimental, investigational and/or unproven.
Table 1. Risk Status of AML Based on Cytogenetic and Molecular Factors:
Inv(16), t(8;21), t(16;16)
Normal cytogenetics with isolated NPM1 mutation
+8 only, t(9;11) only
Other abnormalities not listed with better-risk and poor-risk cytogenetics
c-KIT mutation in patients with t(8;21) or inv(16)
Complex (3 or more 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 mutations
AML: acute myeloid leukemia;
ITD: internal tandem duplication.
Special Comment on AML Remission: Primary refractory AML is defined as leukemia that does not achieve a complete remission (CR) after conventionally dosed (non-marrow ablative) chemotherapy.
NOTE 1: See Medical Policy SUR703.002 Hematopoietic Stem-Cell Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information) for detailed, descriptive information on HSCT related services.
Hematopoietic Stem-Cell Transplantation (HSCT)
HSCT refers to a procedure in which hematopoietic stem-cells are infused to restore bone marrow function in patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole body radiation therapy. Hematopoietic stem-cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem-cells in it are antigenically “naive” and thus, are associated with a lower incidence of rejection or graft-versus-host disease (GVHD).
Immunologic compatibility between infused hematopoietic stem-cells and the recipient is not an issue in autologous HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the class I and class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).
Acute myeloid leukemia (AML)
AML, also called acute nonlymphocytic leukemia (ANLL), refers to a set of leukemias that arise from a myeloid precursor in the bone marrow. AML is characterized by proliferation of myeloblasts, coupled with low production of mature red blood cells, platelets, and often non-lymphocytic white blood cells (granulocytes, monocytes). Clinical signs and symptoms are associated with neutropenia, thrombocytopenia, and anemia. The incidence of AML increases with age, with a median of 67 years. Approximately 13,000 new cases are diagnosed annually.
The pathogenesis of AML is unclear. It can be subdivided by similarity to different subtypes of normal myeloid precursors using the French-American-British (FAB) classification system. This system classifies leukemias from M0 to M7, based on morphology and cytochemical staining, with immunophenotypic data in some instances. The World Health Organization (WHO) subsequently incorporated clinical, immunophenotypic, and a wide variety of cytogenetic abnormalities that occur in 50% to 60% of AML cases into a classification system that can be used to guide treatment according to prognostic risk categories. The WHO system was adapted by National Comprehensive Cancer Network to estimate individual patient prognosis to guide management, as shown in Table 1 in the Coverage Section.
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 (CR) with standard chemotherapy; and
• Leukemias with monocytoid differentiation (FAB classification M4 or M5).
The WHO system recognizes 5 major subcategories of AML: 1) AML with recurrent genetic abnormalities; 2) AML with multilineage dysplasia; 3) therapy-related AML and myelodysplasia; 4) AML not otherwise categorized; and 5) acute leukemia of ambiguous lineage. AML with recurrent genetic abnormalities includes AML with t(8;21) (q22;q22), inv(16) (p13:q22) or t(16;16) (p13;q22), t(15;17) (q22;q12), or translocations or structural abnormalities involving 11q23. Younger patients may exhibit t(8;21) and inv16 or t(16;16). AML patients with 11q23 translocations include 2 subgroups: AML in infants and therapy-related leukemia. Multilineage dysplasia AML must exhibit dysplasia in 50% or more of the cells of 2 lineages or more, which is associated with cytogenetic findings that include --5, 5q-, -7, 7q-, +8, +9, +11, 11q-, 12p-, -18, +19, 20q-, +21, and other translocations. AML not otherwise categorized includes disease that does not fulfill criteria for the other groups and essentially reflects the morphologic and cytochemical features and maturation level criteria used in the FAB classification, except for the definition of AML as having a minimum of 20% (as opposed to 30%) blasts in the marrow. AML of ambiguous lineage is diagnosed when blasts lack sufficient lineage-specific antigen expression to classify as myeloid or lymphoid.
Molecular studies have identified a number of genetic abnormalities that also can be used to guide prognosis and management of AML. Cytogenetically normal AML is the largest defined subgroup of AML, comprising approximately 45% of all AML cases. Despite the absence of cytogenetic abnormalities, these cases often have genetic variants that affect outcomes, 6 of which have been identified. The FLT3 gene that encodes FMS-like receptor tyrosine kinase 3, a growth factor active in hematopoiesis, is mutated in 33% to 49% of cytogenetically normal AML cases; among those, 28% to 33% consist of internal tandem duplications, 5% to 14% are missense variants in exon 20 of the tyrosine kinase activation loop, and the rest are single nucleotide variants (SNVs) in the juxta-membrane domain. All FLT3 variants result in a constitutively activated protein and confer a poor prognosis. Several pharmaceutic agents that inhibit the FLT3 tyrosine kinase are under investigation.
The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, parts 1270 and 1271. (39) Hematopoietic stem-cells are included in these regulations.
This policy was originally created in 1990 and moved as a separate policy in 2010. The policy has been updated with reviews of the MedLine database. The most recent literature review was performed through October 6, 2017. While the coverage of this policy does not address myeloablative (MA) or reduced intensity conditioning (RIC) prior to hematopoietic stem-cell transplantation (HSCT), discussion of HSCT outcomes maybe influenced by the type of preparative conditioning completed prior to the transplantation.
HSCT has been investigated as consolidation therapy for patients whose disease enters complete remission (CR) following initial induction treatment. It also is used as salvage therapy in patients who experience disease relapse or have disease refractory to induction chemotherapy. This policy discusses the following uses and conditions of HSCT: consolidation therapy with allogeneic HSCT (allo-HSCT) during first complete remission (CR1), salvage therapy for refractory acute myeloid leukemia (AML), therapy for relapsed AML, RIC, and consolidation therapy with autologous HSCT (auto-HSCT).
A 2015 literature review in the New England Journal of Medicine authored by Dohner et al., has summarized recent advances in the classification of AML, the genomics of AML and prognostic factors, and current and new treatments, including outcomes. (1) According to this review of 7053 articles, the primary outcomes were relapse-free survival (RFS) and overall survival (OS), while the secondary outcomes were treatment-related mortality (TRM) and relapse rate (RR). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for each outcome. The primary outcomes were RFS and OS, while the secondary outcomes were TRM and RR. The authors included 9 prospective controlled studies including 1950 adult patients. Patients with intermediate-risk AML in CR1 who received either allo-HSCT or non-allo-HSCT were considered eligible. Allo-HSCT was found to be associated with significantly better RFS, OS, and RR than non-allo-HSCT (HR, 0.684 [95% CI: 0.48, 0.95]; HR, 0.76 [95% CI: 0.61, 0.95]; and HR, 0.58 [95% CI: 0.45, 0.75], respectively). TRM was significantly higher following allo-HSCT than non-allo-HSCT (HR, 3.09 [95% CI: 1.38, 6.92]). However, subgroup analysis showed no OS benefit for allo-HSCT over auto-HSCT (HR, 0.99 [95% CI: 0.70, 1.39]). In conclusion, allo-HSCT is associated with more favorable RFS, OS, and RR benefits (but not TRM outcomes) than non-allo-HSCT generally, but does not have an OS advantage over auto-HSCT specifically, in patients with intermediate-risk AML in CR1.
Allo-HSCT for Chemotherapy-Responsive Consolidation
Systematic Reviews and Meta-Analysis
A 2015 meta-analysis examined prospective trials of adults with intermediate-risk AML in CR1 who underwent HSCT. (2) The analysis included 9 prospective, controlled studies that enrolled 1950 patients between the years 1987 and 2011 (size range, 32-713 patients). Allo-HSCT was associated with significantly better RFS, OS, and RR than auto-HSCT and/or chemotherapy (HR 0.68; 95% CI, 0.48 to 0.95; HR=0.76; 95% CI, 0.61 to 0.95; HR=0.58; 95% CI, 0.45 to 0.75, respectively). Treatment related mortality (TRM) was significantly higher following allo-HSCT than auto-HSCT (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-HSCT over auto-HSCT (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-HSCT in CR1. (3) 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 auto-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); and 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 disease-free survival (DFS) were very similar to those for OS in this analysis. These results concur with those from another meta-analysis on the use of allo-HSCT as consolidation therapy for AML.
A 2005 meta-analysis of allo-HSCT in patients with AML in CR1 pooled data from 5 studies (total N=3100 patients). (4) Among those patients, 1151 received allo-HSCT, and 1949 were given alternative therapies including chemotherapy and auto-HSCT. 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-HSCT in terms of OS for the entire cohort (fixed-effects model HR=1.17; 95% CI, 1.06 to 1.30; p=0.003; random-effects model HR=1.15; 95% CI, 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 allo-HSCT 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), indeterminate benefit for intermediate-risk cases, and no benefit in better-risk patients compared with alternative approaches. Reviewers cautioned that the compiled studies used different definitions of risk categories than other groups (e.g., SWOG, Medical Research Council, European Organisation for Research and Treatment of Cancer, Gruppo Italiano Malattie Ematologiche dell’ Adulto), but examination showed cytogenetic categories in those definitions are very similar to recent guidelines from the National Comprehensive Cancer Network (NCCN). (5) 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. (6-9)
Evidence from the meta-analysis suggests patients with better prognosis (as defined by cytogenetics) may not realize a significant survival benefit with allo-HSCT in CR1 that outweighs the risk of associated morbidity and non-relapse mortality (NRM). 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. (10) For example, patients with better prognosis disease (e.g., corebinding factor AML) based on cytogenetics, and a variant in the c-KIT gene of leukemic blast cells, do just as poorly with post-remission standard chemotherapy as patients with cytogenetically poor-risk AML. (11) 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, as defined in the Background section, 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. (12) These examples highlight the rapidly growing body of evidence for genetic variants 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 on the role of allo-HSCT in different patient risk groups.
A meta-analysis by Buckley et al. (2017) evaluated the relation between minimal residual disease (MRD) at the time of HSCT and post-transplantation outcomes. (13) The literature search, conducted through June 2016, identified 19 studies (total N=1431 patients) for inclusion. Risk of bias was assessed using a modified version of 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, nine were at moderate risk, and five 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 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.
A 2014 study compared outcomes of 185 matched pairs from a large multicenter trial (AMLCG99). (14) Patients younger than 60 years of age who underwent allo-HSCT 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 the allo-HSCT and 46% for the conventional post-remission treatment group (p=0.037). RFS was 52% in the allo-HSCT group and 33% in the control group (p<0.001). OS was significantly longer for allo-HSCT patient subgroups with non-favorable chromosomal aberrations, patients older than 45 years, and patients with secondary AML or high-risk myelodysplastic syndrome (MDS). 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-HSCT versus conventional chemotherapy) among age, cytogenetics, and bone marrow blasts after the first induction cycle.
Section Summary: Allo-HSCT for Chemotherapy-Responsive Consolidation
Evidence for the use of allo-HSCT for patients with AML in CR1 consists randomized controlled trials (RCTs) and matched cohort studies. Some studies have compared allo-HSCT with auto-HSCT or with post-remission chemotherapy. OS rates and DFS rates were favorable for allo-HSCT compared with conventional chemotherapy. In a paired comparison with patients receiving chemotherapy, patients receiving allo-HSCT experienced significantly higher RFS rates. Survival rates appear to be associated with presence of minimal residual disease and cytogenetic prognosis group.
Allo-HSCT for AML Refractory to Chemotherapy
Conventional dose induction chemotherapy will not produce remission in 20% to 40% of patients with AML, connoting refractory AML. (5) An allo-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. (6) 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 (e.g., gemtuzumab ozogamicin), multidrug resistance modulators, and other investigational agents (e.g., FLT3 antagonists). (15) Because it is likely that stem-cell preparations will be contaminated with malignant cells in patients whose disease is not in remission, upfront auto-HSCT has no role in patients who fail induction therapy. (16)
Section Summary: Allo-HSCT for AML Refractory to Chemotherapy
Evidence for the use of allo-HSCT for individuals with primary AML refractory to chemotherapy consists of retrospective studies compiled from data from phase 3 trials and registries. OS rate estimates are 13% at 5 years and 30% at 3 years; however, the procedure is accompanied by high rates of NRM (estimates range, 25%-62%). Nonetheless, these results may provide clinically meaningful benefit for such patients who do not have other treatment options. Auto-HSCT is not recommended for patients who have failed induction therapy, because malignant cells may be included in the stem-cell preparation process.
Allo- or Auto-HSCT for Relapsed AML after Chemotherapy
Most patients with AML will experience disease relapse after attaining a CR1. (5) Conventional chemotherapy is not curative in most patients following disease relapse, even if a second complete remission (CR2) can be achieved.
A 2005 study by Breems et al. evaluated retrospective data from 667 patients who had relapsed, among a total of 1540 patients entered in 3 phase III trials who had received HSCT during CR1. (17) The analysis suggested that use of allo-HSCT among relapsed patients can produce 5-year OS rates of 26% to 88%, depending on cytogenetic risk stratification. Because reinduction chemotherapy may be associated with substantial morbidity and mortality, patients whose disease has relapsed and who have a suitable donor may proceed directly to allo-HSCT.
In patients without an allogeneic donor or who are not candidates for allo-HSCT due to age or other factors, auto-HSCT may achieve prolonged DFS in 9% to 55% of patients in CR2 depending on risk category. (16, 18) 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, auto-HSCT in this setting is usually limited to patients who have a sufficient stem-cell preparation remaining from collection in CR1. (16)
Allo-HSCT is often performed as salvage therapy for patients who have relapsed after conventional chemotherapy or auto-HSCT. (16) The decision to attempt reinduction or proceed directly to allo-HSCT 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 MUD allografts at 5 years for patients transplanted in CR2, and DFS rates of 35% to 40% using sibling transplants and 10% with MUD transplants for patients with induction failure or in relapse following HSCT.
In a 2017 retrospective chart review, Frazer et al. assessed characteristics that might predict OS, RR, and NRM of HSCT in patients with relapsed AML. (19) Data were abstracted from 55 consecutive patients who underwent allo-HSCT for AML in CR2. OS rates at 1, 3, and 5 years post-transplant were 60%, 45%, and 37%, respectively. None of the following pre-transplant variables was significantly associated with OS, RR, or NRM: duration of first remission, patient age, cytogenetic risk category, post MDS, conditioning regimen, or donor type. Limitations of the study were its small sample size and selection parameters that included transplantations conducted across 21 years.
Section Summary: Allo- or Auto-HSCT for Relapsed AML After Chemotherapy
Evidence for the use of HSCT for individuals with relapsed AML consists of retrospective chart reviews compiling data from phase 3 trials and registries. DFS rates ranged from 30% to 44% depending on 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, HSCT may be considered.
A body of evidence is accruing from clinical studies that RIC with allo-HSCT may be used for consolidation therapy in patients with AML. (20-32)
A 2016 systematic review and meta-analysis by Rashidi et al. calculated OS and RFS for patients older than 60 years of age with AML who underwent RIC HSCT. (33) This literature search, conducted through September 2015, identified 13 studies (total 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 and MA regimens for allo-HSCT in patients with AML. (34) The analysis included 23 clinical trials reported between 1990 and 2013, with approximately 15,000 adults. Eleven studies included AML and MDS, and 5 included AML only. A sub-analysis from 13 trials in patients with AML or MDS revealed that OS was comparable in patients who received either RIC or MA transplants, and the 2 years or less and 2 years or greater OS rates were equivalent between the 2 groups. The 2 to 6 year PFS, NRM, and acute and chronic graft-versus-host disease (GVHD) rates were reduced after RIC HSCT, but RR 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.
A randomized comparative trial in matched patient groups compared the net health benefit of allo-HSCT with RIC to MA conditioning. (35-37) In this study, patients (18-60 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 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%] versus 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 or 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 published in 2013 compared MA conditioning and RIC in patients who received allo-HSCT to treat AML. (38) Adults 60 years of age or younger with AML were randomized (1:1) to treatment with RIC (n=18) or MA conditioning (n=19) for allo-HSCT. A maximum median mucositis grade of 1 was observed in the RIC group compared with grade 4 in the MA conditioning group (p<0.001). Hemorrhagic cystitis occurred in 8 (42%) of the patients in the MA conditioning group and none (0%) in the RIC group (p<0.01). Results of renal and hepatic tests did not differ significantly between the 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 MA conditioning (p<0.01). Cytomegalovirus infection was more common in the MA conditioning group (14/19) than in the RIC group (6/18) (p=0.02). Donor chimerism was similar in the 2 groups for CD19 and CD33 but was delayed for CD3 in the RIC group. Five-year TRM was approximately 11% in both groups, and rates of relapse and survival did not differ significantly. Patients in the MA conditioning group with intermediate cytogenetic AML had a 3-year survival rate of 73% compared with 90% among those in the RIC group.
In a 2016 comparative study by the European Group for Blood and Marrow Transplantation, long-term survival was evaluated among patients with AML who underwent allo-HSCT with RIC or with MAC regimens. (39) Data from 701 patients receiving MAC and 722 patients receiving RIC were analyzed. Survival, relapse, and GVHD rates are summarized in Table 2. In a multivariate analysis, the following factors predicted NRM: 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 2. Comparison of RIC and MA Conditioning Regimens in Patients Undergoing Allo-HSCT (39)
Outcomes at 10-Year Follow-Up
RIC (n=722) Rate (95% CI), %
MA Conditioning (n=701) Rate (95% CI), %
20 (17 to 24)
35 (31 to 39)
48 (44 to 52)
34 (31 to 38)
32 (28 to 35)
31 (27 to 35)
• Age 50-55 y
40 (33 to 46)
36 (32 to 41)
• Age >55 y
20 (14 to 26)
28 (24 to 32)
35 (32 to 39)
33 (29 to 37)
21 (18 to 24)
22 (18 to 25)
Allo-HSCT: allogeneic hematopoietic stem-cell transplantation;
NRM: non-relapse mortality;
OS: overall survival;
CI: confidence interval;
GVHD: graft-versus-host disease;
RIC: reduced-intensity conditioning
In a comparative study by Bitan et al. (2014), outcomes were compared for children with AML who underwent allo-HSCT using RIC regimens or MA conditioning regimens. (40) A total of 180 patients were evaluated; 39 underwent RIC and 141 received MA conditioning 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 MA conditioning regimens were 45% and 48%, respectively (p=0.99). Moreover, relapse rates were similar for RIC (39%) and MA conditioning regimens (39%; p=0.95), and recipients of MA conditioning regimens were not at a higher risk for transplant-related mortality (16%) than recipients of RIC regimens (16%; p=0.73).
In a 2015 phase 2 study by Devine et al., 114 patients ages 60 to 74 years with AML in CR1 were treated with RIC and allo-HSCT. (41) Patients were followed for 2 years. The primary end-point was DFS, and secondary end-points were NRM, GVHD, relapse, and OS. Two years post-transplantation, the following rates were recorded: DFS, 42% (95% CI, 33% to 52%); OS, 48% (95% CI, 39% to 58%); NRM, 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: RIC Allo-HSCT
Evidence for the use of RIC and allo-HSCT to treat patients with AML consists of a meta-analysis, 2 RCTs, and numerous comparative and noncomparative studies. In general, compared with MA conditioning, RIC has comparable survival estimates (leukemia-free, overall), though RRs appear higher among patients receiving RIC in some studies.
Auto-HSCT for Chemotherapy-Responsive Consolidation
Systematic Reviews and Meta-Analyses
A meta-analysis published in 2004 by Nathan et al. compared survival outcomes for auto-HSCT in CR1 with standard chemotherapy or no further treatment in AML patients ages 15 to 55 years. (42) Two types of studies were eligible: 1) prospective cohort studies in which patients with an available sibling donor were offered allo-HSCT (biologic randomization) with random assignment of all others to auto-HSCT or chemotherapy (or no further treatment); and 2) randomized trials that compared auto-HSCT with chemotherapy in all patients. Among a total of 4058 patients included in 6 studies, 2989 (74%) achieved CR1; 1044 (26%) were randomized to HSCT (n=524) or to chemotherapy (n=520). Of the 5 studies for which OS data were available, outcomes with auto-HSCT 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=0.86). In all 6 studies, DFS was numerically superior with auto-HSCT compared with chemotherapy (or no further treatment), but only 1 reported a statistically significant DFS probability associated with auto-HSCT. However, the pooled estimate for DFS showed a statistically significant probability in favor of auto-HSCT at 48 months post-transplant (fixed-effects model survival probability ratio, 1.24; 95% CI, 1.06 to 1.44; p=0.006).
There are several reasons why this meta-analysis did not demonstrate a statistically significant OS advantage for auto-HSCT compared with chemotherapy given the significant estimate for DFS benefit. First, the pooled data showed a 6.45% greater NRM rate in auto-HSCT recipients compared with chemotherapy recipients. Second, 14% of chemotherapy recipients whose disease relapsed ultimately achieved a sustained CR2 after undergoing an allo- or auto-HSCT. The intention-to-treat analysis in the studies, which included the latter cases in the chemotherapy group, may have inappropriately inflated OS rates favoring chemotherapy. Furthermore, this analysis did not take into account the potential effects of cytogenetic or molecular genetic differences among patients that are known to affect response to treatment. Finally, the dataset 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 in 2010 by Wang et al., evaluated auto-HSCT plus further chemotherapy or no further treatment for patients with AML in CR1. (43) Nine randomized trials involving 1104 adults who underwent auto-HSCT and 1118 patients who received additional chemotherapy or no additional treatment were identified. Analyses suggested that auto-HSCT in CR1 is associated with statistically significant reduction of relapse risk (RR=0.56; 95% CI, 0.44 to 0.71; p=0.001) and significant improvement in DFS (HR=0.89; 95% CI, 0.80 to 0.98), but at the cost of an increased NRM rate (RR=1.90; 95% CI, 1.34 to 2.70; p=0.23). There were more deaths during the first remission among patients assigned to auto-HSCT than among the chemotherapy recipients or further untreated patients. As a consequence of the increased NRM rate, no statistical difference in OS (HR=1.05; 95% CI, 0.91 to 1.21) was associated with the use of auto-HSCT, compared with further chemotherapy or no further therapy. These results are concordant with the earlier meta-analysis.
A prospective, randomized phase 3 trial by Vellenga et al. (2011) compared auto-HSCT plus intensive consolidation chemotherapy among patients (range, 16-60 years) with newly diagnosed AML of similar risk profiles in CR1. (44) After 2 cycles of intensive chemotherapy (etoposide and mitoxantrone), patients in CR1--who were not candidates for allo-HSCT--were randomized to a third consolidation cycle of the same chemotherapy (n=259) or auto-HSCT (n=258). The HSCT group experienced an upward trend toward superior RFS compared with the chemotherapy group at 5 years (38% versus 29%, respectively, p=0.065). HSCT patients also had a lower relapse rate at 5 years (58%) compared with chemotherapy recipients (70%; p=0.02). OS did not differ between the HSCT group (44%) and the chemotherapy group (41%; p=0.86). NRM rates were higher in the auto-HSCT group (4%) than in the chemotherapy consolidation group (1%; p=0.02). Despite this difference in NRM, the relative equality of OS rates was attributed by the investigators to a higher proportion of successful salvage treatments--second-line chemotherapy, auto- or allo-HSCT--in the chemotherapy consolidation recipients that were not available to the auto-HSCT patients. This large trial has shown an advantage for post-remission auto-HSCT in reducing relapse, but similar OS rates secondary to better salvage of chemotherapy-consolidated patients.
Section Summary: Auto-HSCT for Chemotherapy-Responsive Consolidation
Evidence for the use of auto-HSCT for patients with AML who do not have a suitable allogeneic donor or who cannot tolerate an allogeneic procedure consists of several RCTs comparing auto-HSCT 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 NRM experienced by patients in the transplantation group.
Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
In 2009, Blue Cross Blue Shield Association (BCBSA) requested and received clinical input from various physician specialty societies and academic medical centers. Results of clinical input from 3 reviewers revealed strong consensus among reviewers that RIC allo-HSCT was of value in patients who were in CR. There was general support for the policy statements.
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
Prospective Controlled Clinical Study of Allogeneic Stem-Cell Transplantation with Reduced Conditioning versus Best Standard
Care in Acute Myeloid Leukemia in First Complete Remission
Randomized Phase III Study Comparing Conventional Chemotherapy to Low Dose Total Body Irradiation-Based Conditioning and HSCT from Related and Unrelated Donors as Consolidation Therapy for
Older Patients with AML in 1st Complete Remission
A Phase II Study of Myeloablative and Reduced-Intensity Conditioning Regimens for Children with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Stem-Cell Transplantation
Allogeneic Hematopoietic Stem-Cell Transplantation as Initial Salvage Therapy for Patients with Primary Induction Failure Acute Myeloid Leukemia Refractory to High-Dose Cytarabine-Based Induction Chemotherapy
NCT: National Clinical Trial;
HSCT: hematopoietic stem-cell transplantation.
Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN)
The NCCN clinical guidelines (v.3.2017) for AML is consistent with this policy review. (45) The NCCN guidelines state that HSCT in the context of a clinical trial or best supportive care is recommended for patients with induction failure. Also, a MUD search, including umbilical cord blood, should be initiated for high-risk patients who are eligible for HSCT in CR1, or considered at first relapse in appropriate patients concomitant with reinduction therapy. Recommendations also include auto-HSCT in patients who achieve second molecular remission and to reserve allogeneic transplant for those patients who have persistent disease, despite therapy for relapsed disease.
Summary of Evidence
For individuals who have cytogenetic or molecular intermediate- or poor-risk acute myeloid leukemia (AML) in first complete remission (CR1) who receive allogeneic hematopoietic stem-cell transplantation (allo-HSCT) with myeloablative (MA) conditioning, the evidence includes randomized controlled trials (RCTs) and matched cohort studies. Relevant outcomes are overall survival (OS) and disease-free survival (DFS). The evidence has revealed that allo-HSCT is better at improving OS and DFS rates in patients with AML in CR1 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 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-HSCT with MA conditioning, the evidence includes retrospective data compiled from patients entered in phase 3 trials and registry data. Relevant outcomes are OS and DFS. The evidence would suggest that allo-HSCT improves OS and DFS rates in patients with refractory 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 such 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 CR1 who receive allo-HSCT or auto-HSCT with MA conditioning, the evidence includes retrospective data compiled from patients entered in phase 3 trials and registry data. Relevant outcomes are OS and DFS. The evidence has shown that allo-HSCT 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 a meaningful 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 MA conditioning who receive allo-HSCT with reduced-intensity (RIC), the evidence includes 2 RCTs and other comparative and noncomparative studies. Relevant outcomes are OS, DFS, and treatment-related morbidity (TRM). The RCTs compared RIC with MA conditioning and reported similar rates in non-relapse mortality (NRM), relapse, and OS though one of the trials was stopped prematurely due to a 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 is likely 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 CR1 or beyond without a suitable allo-HSCT donor who receive auto-HSCT, the evidence includes prospective cohort studies in which patients with an available sibling donor were offered allo-HSCT (biologic randomization) with random assignment of all others to auto-HSCT or chemotherapy (or no further treatment); and RCTs comparing auto-HSCT with chemotherapy in all patients. Relevant outcomes are OS and DFS. Compared with chemotherapy, patients undergoing auto-HSCT experienced reduced relapse and improved DFS rates. OS 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.
Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.
Disclaimer for coding information on Medical Policies
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.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.
The following codes may be applicable to this Medical policy and may not be all inclusive.
36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38222, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241
S2140, S2142, S2150
ICD-9 Diagnosis Codes
Refer to the ICD-9-CM manual
ICD-9 Procedure Codes
Refer to the ICD-9-CM manual
ICD-10 Diagnosis Codes
Refer to the ICD-10-CM manual
ICD-10 Procedure Codes
Refer to the ICD-10-CM manual
The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.
The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.
A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
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|4/15/2018||Reviewed. No changes.|
|12/1/2017||Document updated with literature review. Coverage unchanged.|
|6/1/2016||Reviewed. No changes.|
|11/15/2015||Document updated with literature review. The following was added: 1) This wording was added to the acute myelogenous leukemia (AML) that is refractory to standard induction chemotherapy criterion - “but can be brought into complete remission (CR) with intensified induction chemotherapy”; 2) This wording was added to individual medically necessary criterion as it had been previously considered experimental, investigational and/or unproven - “AML that relapses following chemotherapy-induced first CR but can be brought into second complete remission or beyond with intensified induction chemotherapy”; 3) This wording was added to AML in patients who have relapsed following a prior autologous HSCT criterion - “but can be brought into CR with intensified induction chemotherapy”; and 4) This coverage statement was added – “For conditions not listed above, allogeneic or autologous hematopoietic stem-cell transplantation is considered experimental, investigational and/or unproven”. Title changed from Stem-Cell Transplant for Acute Myelogenous Leukemia.|
|6/1/2014||Document updated with literature review. The following was changed: 1) expanded coverage to consider Allogeneic stem-cell support (AlloSCS) may be medically necessary for • poor- to intermediate-risk AML in remission, • AML that is refractory to, or relapses following, standard induction chemotherapy, or • AML in patients who have relapsed following a prior autologous stem-cell support (AuSCS) and are medically able to tolerate the procedure; 2) expanded coverage to consider AlloSCS may be medically necessary when reduced conditioning is used as a treatment of AML in patients who are in complete marrow and extramedullary remission, and who for medical reasons would be unable to tolerate a myeloablative conditioning regimen; 3) expanded coverage to consider: a) donor leukocyte infusion (DLI) and hematopoietic progenitor cell (HPC) boost as medically necessary for AML that has relapsed or is refractory following an AlloSCS procedure, to prevent relapse in the setting of a high-risk relapse, or to convert a patient from mixed to full chimerism; b) DLI and HPC boost are considered experimental, investigational and/or unproven following an AlloSCS treatment for AML that was originally considered experimental, investigational and/or unproven for the treatment of AML; and 4) expanded coverage to consider a) short tandem repeat (STR) markers medically necessary when used in pre- or post-stem-cell support testing of the donor and recipient DNA profiles as a way to assess the status of donor cell engraftment following AlloSCS for AML; b) all other uses of STR markers experimental, investigational and/or unproven, if not listed in the coverage section. Description and Rationale substantially revised.|
|4/1/2010||New medical document originating from: SUR703.017, Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem-cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem-cell Support for Malignancies. Stem-cell transplant continues to be medically necessary when stated criteria are met. [NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information): • Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Non-Malignancies; • Peripheral/Bone Marrow Stem-cell Transplantation (PSCT/BMT) for Malignancies; • Cord Blood as a Source of Stem-cells; • Donor Leukocyte Infusion (DLI); and • Tandem/Triple High-Dose Chemoradiotherapy with Stem-cell Support for Malignancies.|
|Title:||Effective Date:||End Date:|
|Hematopoietic Stem-Cell Transplantation for Acute Myelogenous Leukemia (AML)||04-15-2018||07-14-2019|
|Hematopoietic Stem-Cell Transplantation for Acute Myelogenous Leukemia (AML)||12-01-2017||04-14-2018|
|Hematopoietic Stem-Cell Transplantation for Acute Myelogenous Leukemia (AML)||06-01-2016||11-30-2017|
|Hematopoietic Stem-Cell Transplantation for Acute Myelogenous Leukemia (AML)||11-15-2015||05-31-2016|
|Stem-Cell Transplant for Acute Myelogenous Leukemia||06-01-2014||11-14-2015|
|Stem-Cell Transplant for Acute Myelogenous Leukemia||04-01-2010||05-31-2014|