Coverage Policy Manual
Policy #: 2001021
Category: Medicine
Initiated: January 1993
Last Review: July 2018
  HDC & Allogeneic Stem &/or Progenitor Cell Support-Acute Myelogenous Leukemia

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:
    • Allogeneic cells can be harvested from bone marrow or peripheral circulation of matched, often unrelated, donors. These cells are not contaminated by tumor and offer the possibility of a beneficial graft vs. tumor effect.
    • Blood harvested from the umbilical cord and placenta shortly after delivery of neonates contain stem cells that antigenically “naïve” and thus are associated with a lower incidence of rejection or graft vs. host disease.
Non-myeloablative or reduced intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in conventional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden but also to minimize as much as possible associated treatment-related morbidity and nonrelapse mortality (NRM) in the period during which the beneficial GVM effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of NRM and relapse due to residual disease. RIC regimens can be viewed as a continuum in effects, from nearly totally myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allogeneic HSCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells.
Acute myelogenous leukemia (AML) (sometimes called acute non-lymphocytic leukemia) refers to a malignancy arising from a myeloid precursor in the bone marrow. Unlike acute lymphocytic leukemia (ALL), AML is relatively rare in childhood, with a median age of onset at 55 years. AMLs can be further subdivided according to the cells' resemblance to different subtypes of normal myeloid precursors according to the FAB classification. This system classifies leukemias from M0-M7. AMLs may be classified on the basis of cytogenetic abnormalities, or on the basis of immunotyping. Initial complete remissions using combination chemotherapy can be achieved in up to 80% of patients. However, high incidence of relapse has prompted research into a variety of post-remission strategies, all focusing on methods of increasing dose intensity. Strategies have included high dose Ara-C, or high dose therapy using either allogeneic or autologous stem cell support.
Primary refractory AML is defined as leukemia that does not achieve a complete remission after conventional dose (i.e.., non-marrow ablative) chemotherapy.
The pathogenesis of AML is unclear. It can be subdivided according to resemblance to different subtypes of normal myeloid precursors using the FAB classification. This system classifies leukemias from M0–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 (detailed in the Policy/Coverage section of this policy).
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 inv(16) 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. It is associated with cytogenetic findings that include -7/del(7q), -5/del(5q), +8, +9, +11, del(11q), del(12p), -18, +19, del(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 (CN-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 mutations that affect outcomes, 6 of which have been identified. The FLT3 gene that encodes FMS-like receptor tyrosine kinase (TK) 3, a growth factor active in hematopoiesis, is mutated in 33% to 49% of CN-AML cases; among those, 28% to 33% consist of internal tandem duplications (ITD), 5% to 14% are missense mutations in exon 20 of the TK activation loop, and the rest are point mutations in the juxtamembrane domain. All FLT3 mutations result in a constitutively activated protein and confer a poor prognosis. Several pharmaceutic agents that inhibit the FLT3 TK are under investigation.
Complete remissions can be achieved initially using combination chemotherapy in up to 80% of AML patients. However, the high incidence of relapse has prompted research into a variety of postremission strategies using either allogeneic or autologous HSCT.
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.

EFFECTIVE October 2014
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:
    • Poor- to intermediate-risk* AML in remission  
    • Primary refractory AML;
    • Relapsed AML.
*Risk Status of AML Based on Cytogenetic and Molecular Factors
Cytogenetic Factors- Inv(16), t(8;21), t(16;16)
Molecular Abnormalities- Normal cytogenetics with isolated NPM1 mutation
Cytogenetic Factors- Normal +8 only, t(9;11) only. Other abnormalities not listed  with better-risk and poor-risk cytogenetics.
 Molecular Abnormalities- c-KIT mutation in patients with t(8;21) or inv(16)
Cytogenetic Factors- 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)
Molecular Abnormalities- Normal cytogenetics with isolated FLT3-ITD mutations
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:
    • AML in first complete remission at high risk for relapse;
    • Primary refractory AML;
    • Relapsed AML.
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.

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.
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.
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.
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).

References: 2000 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Tab 11.

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Bitan M, He W, Zhang MJ, et al.(2014) Transplantation for children with acute myeloid leukemia: a comparison of outcomes with reduced intensity and myeloablative regimens. Blood. Mar 6 2014;123(10):1615-1620. PMID 24435046

Blaise D, Vey N, Faucher C et al.(2007) Current status of reduced-intensity-conditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica 2007; 92(4):533-41.

Bornhauser M, Kienast J, Trenschel R et al.(2012) Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol 2012; 13(10):1035-44.

Brandwein JM, Zhu N, Kumar R, et al.(2017) Treatment of older patients with acute myeloid leukemia (AML): revised Canadian consensus guidelines. Am J Blood Res. Jul 2017;7(4):30-40. PMID 28804680

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