Hematopoietic Stem -Cell Transplantation for Acute Myeloid Leukemia

Number 8.01.26

Effective Date November 20, 2014

Revision Date(s) 11/10/14; 10/14/13; 10/09/12;10/11/11; 09/14/10; 09/15/09; 11/11/08; 06/12/07; 01/10/06; 12/14/04; 08/12/03; 05/13/03; 12/21/00; 02/01/00

Replaces N/A


Allogeneic hematopoietic stem-cell transplantation (HSCT) using a myeloablative conditioning regimen may be considered medically necessary to treat:

  • Poor- to intermediate-risk AML in remission (see Policy Guidelines for information on risk stratification), or
  • AML that is refractory to, or relapses following, standard induction chemotherapy, or
  • AML in patients who have relapsed following a prior autologous HSCT 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, especially for those that for medical reasons would be unable to tolerate a myeloablative conditioning regimen (see Policy Guidelines).

Autologous HSCT may be considered medically necessary to treat AML in first or second remission or relapsed AML if responsive to intensified induction chemotherapy.

Related Policies


Placental and Umbilical Cord Blood as a Source of Stem Cells


Hematopoietic Stem-Cell Transplantation for Miscellaneous Solid Tumors in Adults


Hematopoietic Stem-Cell Transplantation for Treatment of Chronic Myelogenous Leukemia


Hematopoietic Stem-Cell Transplantation for Acute Lymphoblastic Leukemia

Policy Guidelines

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

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

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

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

The newer preferred World Health Organization (WHO) classification of AML incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers in an attempt to construct a classification that is universally applicable and prognostically valid. The WHO system was adapted by the National Comprehensive Cancer Network (NCCN) to estimate individual patient prognosis to guide management, as shown in Table 1.

Table 1. Risk Status of AML Based on Cytogenetic and Molecular Factors

Risk Status

Cytogenetic Factors

Molecular Abnormalities


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

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

Patients for whom a conventional myeloablative allotransplant could be curative may be considered candidates for reduced-intensity conditioning (RIC), or non-myeloablative conditioning allogeneic HSCT. It is important to recognize that the myeloablative intensity of different conditioning regimens varies substantially and that the distinction between myeloablative regimens and RIC regimens has not been defined. (2) In this setting, patient selection is critical, and variations exist in the criteria used by transplant centers in the United States and worldwide. In general, candidates for RIC or non-myeloablative conditioning regimen allogeneic HSCT include patients whose age (typically >60 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status) preclude use of a standard myeloablative conditioning regimen. A patient whose disease relapses following a conventional myeloablative allogeneic HSCT could undergo a second myeloablative procedure if a suitable donor is available and the patient’s medical status would permit it. However, this type of patient would likely undergo RIC prior to a second allogeneic HSCT if a complete remission could be re-induced with chemotherapy.

Autologous HSCT is used for consolidation treatment of intermediate- to poor-risk disease in complete remission, among patients for whom a suitable donor is not available. Better-risk AML often responds well to chemotherapy with prolonged remission if not cure.

The ideal allogeneic donors are HLA-identical siblings, matched at the HLA-A, -B, and DR loci (6 of 6). Related donors mismatched at one locus are also considered suitable donors. A matched, unrelated donor identified through the National Marrow Donor Registry is typically the next option considered. Recently, there has been interest in haploidentical donors, typically a parent or a child of the patient, for which there usually is sharing of only 3 of the 6 major histocompatibility antigens. Most patients will have such a donor; however, the risk of GVHD and overall morbidity of the procedure may be severe, and experience with these donors is not as extensive as that with matched donors.


Acute myeloid leukemia (AML) (also called acute nonlymphocytic leukemia [ANLL]) refers to a set of leukemias that arise from a myeloid precursor in the bone marrow. There is a high incidence of relapse, which has prompted research into a variety of post-remission strategies using either allogeneic or autologous hematopoietic stem-cell transplantation (HSCT). HSCT refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow 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 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 “naïve” and thus are associated with a lower incidence of rejection or graft-versus-host disease (GVHD). Cord blood is discussed in greater detail in a separate policy. (See Related Policies.)

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 HLAs using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA A, B, and DR loci on each arm of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci.

Conventional Preparative Conditioning for HSCT

The conventional (“classical”) practice of allogeneic HSCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect in this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy (GVM) effect that develops after engraftment of allogeneic stem cells within the patient’s bone marrow space. While the slower GVM effect is considered to be the potentially curative component, it may be overwhelmed by extant disease without the use of pretransplant conditioning. However, intense conditioning regimens are limited to patients who are sufficiently fit medically to tolerate substantial adverse effects that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allogeneic HSCT, immune suppressant drugs are required to minimize graft rejection and GVHD, which also increases the patient’s susceptibility to opportunistic infections.

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

RIC for Allogeneic HSCT

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 non-relapse 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. For the purposes of this policy, the term “reduced-intensity conditioning” will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.

AML (also called 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 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. (See Policy Guidelines)

The WHO system recognizes five 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
  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 two subgroups: AML in infants and therapy-related leukemia. Multilineage dysplasia AML must exhibit dysplasia in 50% or more of the cells of two 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, of which six 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 post-remission strategies using either allogeneic or autologous HSCT.


Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application



This policy was originally created in 1999 and has been regularly updated with searches of the MEDLINE database. The most recent MEDLINE search was performed through June 18, 2014.

Hematopoietic stem-cell transplantation (HSCT) has been investigated as consolidation therapy for patients whose disease enters complete remission following initial induction treatment or as salvage therapy in patients who experience disease relapse or have disease that is refractory to induction chemotherapy.

Consolidation Therapy in Remission

Allogeneic HSCT

A meta-analysis of allogeneic HSCT in patients with acute myeloid leukemia (AML) in first complete remission (CR1) pooled data from five studies that included a total of 3,100 patients. (3) Among those patients, 1,151 received allogeneic HSCT and 1,949 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 (e.g., 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) outlined in the Policy Guidelines (4) 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. (5-8)

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 non-relapse 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. (9) For example, patients with better-prognosis disease (for example, core-binding factor AML) based on cytogenetics, and a mutation 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. (10) 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 post-remission 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. (11) 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 6,007 patients who underwent allogeneic HSCT in first complete remission [CR1]. (12) Among the total, 3,638 patients were stratified and analyzed according to cytogenetic risk (547 good-, 2,499 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 (3) 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). (13) 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 (p=037; log-rank test). 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.

Autologous HSCT

A meta-analysis published in 2004 examined survival outcomes of autologous HSCT in CR1 versus standard chemotherapy or no further treatment in AML patients aged 15 to 55 years. (14) Two types of studies were eligible: 1) prospective cohort studies in which patients with an available sibling donor were offered allogeneic HSCT (biologic randomization) with random assignment of all others to autologous HSCT or chemotherapy (or no further treatment); and 2) randomized trials that compared autologous HSCT with chemotherapy in all patients. Among a total of 4,058 patients included in six studies, 2,989 (74%) achieved CR1; 1,044 (26%) were randomly allocated to HSCT (n=524) or chemotherapy (n=520). Of the five studies for which OS data were available, outcomes with autologous HSCT were better in three, and outcomes with chemotherapy were better in two. None of the differences reached statistical significance, nor did the pooled estimate reach statistical significance (fixed-effects model survival probability ratio=1.01; 95% CI: 0.89 to 1.15, p=0.86). In all six studies, DFS was numerically superior with autologous HSCT compared with chemotherapy (or no further treatment), but only one reported a statistically significant DFS probability associated with autologous HSCT. However, the pooled estimate for DFS showed a statistically significant probability in favor of autologous 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 possible reasons this meta-analysis did not demonstrate a statistically significant OS advantage for autologous HSCT compared with chemotherapy given the significant estimate for DFS benefit. First, the pooled data showed a 6.45% greater NRM rate in autologous HSCT recipients compared with chemotherapy recipients. Second, 14% of chemotherapy recipients whose disease relapsed ultimately achieved a sustained second remission after undergoing an allogeneic or autologous HSCT. The intent-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 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 evaluated autologous HSCT versus further chemotherapy or no further treatment for AML in CR1. (15) A total of 9 randomized trials involving 1,104 adults who underwent autologous HSCT and 1,118 who received additional chemotherapy or no additional treatment were identified. The analyses suggest that autologous HSCT in CR1 was 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 significantly increased NRM (RR=1.90, 95% CI: 0.72 to 0.87, p=0.001). There were more deaths during the first remission among patients assigned to autologous HSCT than among the chemotherapy recipients or further untreated patients. As a consequence of increased NRM, no statistical difference in OS (HR=1.05, 95% CI: 0.91 to 1.21) was associated with the use of autologous HSCT, compared with further chemotherapy or no further therapy. These results were concordant with those of the earlier meta-analysis cited earlier.

A prospective, randomized Phase III trial compared autologous HSCT with intensive consolidation chemotherapy among patients (16-60 years-old) with newly diagnosed AML of similar risk profiles in complete remission (CR1). (16) Patients in CR1 after 2 cycles of intensive chemotherapy (etoposide and mitoxantrone), who were not candidates for allogeneic HSCT, were randomly allocated between a third consolidation cycle of the same chemotherapy (n=259) or autologous HSCT (n=258). The HSCT group showed a trend toward superior relapse-free survival, the primary outcome, compared with chemotherapy recipients (38% vs. 29%, respectively at 5 years, p=0.065, 95% CI: 0.66 to 1.1). HSCT patients had a lower relapse rate at 5 years compared with chemotherapy recipients (58% vs. 70%, respectively, p=0.02). Overall survival did not differ between HSCT and chemotherapy recipients, respectively (44% vs. 41%, p=0.86). NRM was more frequent in the autologous HSCT group than in the chemotherapy consolidation group (4% vs. 1%, respectively, 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, autologous or allogeneic HSCT–in the chemotherapy consolidation recipients that were not available to the autologous HSCT patients. This large study shows an advantage for post-remission autologous HSCT in reducing relapse, but similar OS rates secondary to better salvage of chemotherapy-consolidated patients.

The body of evidence summarized in the 2 meta-analyses and randomized controlled trial (RCT) referenced earlier suggests autologous HSCT to treat AML in CR1 is feasible and potentially offers improved DFS, compared with post-remission chemotherapy in patients who lack a suitable stem-cell donor. However, this procedure is not considered as first-line post-remission therapy for AML patients who are candidates for allogeneic HSCT and for whom a suitable matched donor is available.

Primary Refractory AML

Conventional-dose induction chemotherapy will not produce remission in 20% to 40% of patients with AML, connoting refractory AML. (4) 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 five years to 30% at three years, although this procedure is accompanied by NRM rates of 25% to 62% in this setting. (5) For patients who lack a suitable donor (MRD or MUD), alternative treatments include salvage chemotherapy with high-dose cytarabine or etoposide-based regimens, multidrug resistance modulators, and other investigational agents such as FLT3 antagonists. (17) Because it is likely that stem-cell preparations will be contaminated with malignant cells in patients whose disease is not in remission, autologous HSCT has no role in patients who fail induction therapy. (18)

Relapsed AML

Most patients with AML will experience disease relapse after attaining a CR1. (4) 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 1,540 patients entered in three 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.

In patients without an allogeneic donor, or those who are not candidates for allogeneic HSCT due to age or other factors, autologous HSCT may achieve prolonged DFS in 9% to 55% of patients in CR2 depending on risk category. (18,20) However, because it is likely that stem-cell preparations will be contaminated with malignant cells in patients whose disease is not in remission, and it is often difficult to achieve CR2 in these patients, autologous HSCT in this setting is usually limited to patients who have a sufficient stem-cell preparation remaining from collection in CR1. (18)

Allogeneic HSCT is often performed as salvage for patients who have relapsed after conventional chemotherapy or autologous HSCT. (18) 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 five 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. (18)

Reduced-Intensity Allogeneic HSCT

Evidence continues to accrue from clinical studies of RIC with allogeneic HSCT for AML. (2,21-32) Overall, these data suggest that long-term remissions (24 years) can be achieved in patients with AML, especially those who, because of age or underlying comorbidities are not 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. (33-35) 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 cyclosporine and methotrexate as prophylaxis against GVHD. The primary endpoint 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 three years 13% [95% CI: 6 to 21] versus 18% [10 to 26]; HR=0.62 [95% CI: 0.30 to 1.31], respectively). Relapse cumulative incidence at three 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 three 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 three years was 61% (95% CI: 50 to 74) and 58% (47 to 70); HR=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. (36) 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 II single-center, randomized toxicity study compared MAC and RIC in allogeneic HSCT to treat AML. (37) 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.

Indirect comparison of nonrandomized or otherwise comparative study results is compromised by heterogeneity among patients, treatments, outcome measures, and insufficient follow-up. Further, RIC with allogeneic HSCT has not been directly compared with conventional chemotherapy alone, which has been the standard of care in patients with AML for whom myeloablative chemotherapy and allogeneic HSCT are contraindicated.

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. Thus, based on currently available data and clinical input as noted in the following sections, RIC allogeneic HSCT may be considered medically necessary in patients who demonstrate complete marrow and extramedullary remission, who could be expected to benefit from a myeloablative allogeneic HSCT, especially those who, for medical reasons, would be unable to tolerate a myeloablative conditioning regimen.

Ongoing Clinical Trials

A search of the NCI PDQ® in July 2013 identified 37 active or approved Phase III trials in the United States that involve stem-cell support for patients with AML. Trials include allo- and autografting, using various high-dose chemotherapy regimens

Clinical Input Received from Physician Specialty Societies and Academic Medical Centers

In response to requests, input was received from 1 physician specialty society (2 reviewers) and 1 academic medical center while this policy was under review for February 2009. While the various Physician Specialty Societies and Academic Medical Centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the Physician Specialty Societies or Academic Medical Centers, unless otherwise noted. There was strong consensus among reviewers that RIC allogeneic HSCT was of value in patients who were in complete remission. There was general support for the policy statements.


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; however, 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 back into remission with intensified chemotherapy and who have a donor. For patients who are in remission but don’t have a suitable donor, evidence supports the use of autologous HSCT in consolidation; this procedure is not an option for those who are not in remission. Allogeneic HSCT using reduced-intensity conditioning is supported by evidence for use especially 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 (EBMT), the American Society for Blood and Marrow Transplantation (ASBMT), the British Committee for Standards in Hematology (BCSH), the National Comprehensive Cancer Network, (NCCN), and the specific databases of the National Guideline Clearinghouse and the Guideline International Network database. (1)

Practice Guidelines and Position Statements

The National Comprehensive Cancer Network clinical practice guidelines (V.2.2014) for acute myeloid leukemia are generally consistent with this policy. (38)

U.S. Preventive Services Task Force Recommendations

Hematopoietic stem-cell transplantation is not a preventive service.

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.


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  38. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines: Acute myeloid leukemia V2.2014. 2014; Accessed September, 2014.
  39. Reviewed and recommended for approval by the Oncology Advisory Panel: May 24, 2007; May 22, 2008; August 19, 2010.







Blood derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic



Blood derived hematopoietic progenitor cell harvesting for transplantation, per collection autologous



Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing



Thawing of previously frozen harvest, washing of harvest



Specific cell depletion with harvest, T cell depletion



Tumor cell depletion



Red blood cell removal



Platelet depletion



Plasma (volume) depletion



Cell concentration in plasma, mononuclear, or buffy coat layer



Bone marrow harvesting for transplantation; allogeneic



Bone marrow harvesting for transplantation; autologous



Bone marrow or blood-derived peripheral stem cell transplantation: allogeneic



Bone marrow or blood-derived peripheral stem cell transplantation; autologous



Allogeneic donor lymphocyte infusions



Human leukocyte antigen (HLA) crossmatch, non-cytotoxic (e.g., using flow cytometry); first serum sample or dilution



Human leukocyte antigen (HLA) crossmatch, non-cytotoxic (e.g., using flow cytometry); each additional serum sample or sample dilution (List separately in addition to primary procedure)



Cord blood harvesting for transplantation, allogeneic



Cord blood derived stem cell transplantation, allogeneic



Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition

Type of Service



Place of Service









Add to Therapy Section - New Policy — replaces 8.01.15, original master policy on HDC for miscellaneous malignancies. However, policy statement is unchanged.


Replace Policy - Policy statement revised to state that allogeneic transplant after a prior failed autotransplant is considered investigational, based on 2000 TEC Assessment.


Replace Policy - Policy updated, references added; no change in policy statement. Updated CPT codes.


Replace Policy - Policy reviewed and recommended for approval by OAP July 22, 2003; no change in policy statement.


Replace Policy - Policy updated with references, NCCN guidelines, and NCI clinical trials information. Policy statement unchanged.


Replace Policy - Policy updated with literature search; NCI information updated; no change to policy statement.


Disclaimer and Scope update - No other changes


Replace Policy - Policy updated with literature review; references added. No change in policy statement. Reviewed by OAP on May 24, 2007.


Cross References Updated - No other changes.


Replace Policy - Policy extensively updated with literature search. Policy statement updated to remove “HDC” from statement and replaced with “stem-cell transplantation”. This update also reflected in the title and throughout the policy. Investigational statement was added to include Allogeneic SCT to treat AML relapsing after prior therapy. Reviewed by OAP on May 22, 2008.


Replace Policy - Policy extensively updated with literature search. Policy statements updated to include allogeneic HSCT used in patients with poor to intermediate risk AML in remission and that allogeneic HSCT may be used after failed autologous HSCT. References added. Reviewed by OAP on August 20, 2009.


Code Update - New 2010 codes added.


Replace Policy - Policy updated with literature review; references 10, 21-23 added. No change in policy statements.


Replace Policy – Policy updated with literature search; reference 12 added. No change to policy statements. ICD-9 and HCPCS codes updated; ICD-10 codes added. Title changed from “myelogenous” to “myeloid” leukemia. Codes 38220 and 38221 removed from policy.


Code 38232 added.


The CPT code 38204 was removed from the policy, as it is not specific to transplant.


Minor update: Related Policies updated; 8.01.17 replaced 8.01.507 effective June 12, 2012.


Related Policies title updates: 8.01.21, 8.01.22, 8.01.29, 8.01.30, 8.01.31, 8.01.35, 8.01.514, and 8.01.520


Replace policy. Policy updated with literature search; reference 14 added. No change in policy statements.


Update Related Policies, change title of policy 8.01.21.


The following codes were removed from the policy, as they were not suspending and just informational: HCPCS J9000-J9999 and Q0083 – Q0085.


Replace policy. Rationale updated based on a literature review through July 1, 2013. Reference 27 added; others renumbered/removed. Policy statements unchanged. Code 38204 removed; this is not reviewed.


Update Related Policies. Remove 8.01.31 as it was archived.


Update Related Policies. Remove 8.01.514 as it was deleted.


Update Related Policies. Remove 8.01.20 and add 8.01.529.


Update Related Policies. Remove 8.01.35 and 8.01.42, then add 8.01.530 and 8.01.532.


Annual Review. Policy updated with literature review through June 18, 2014; references 13, and 35-36 added. No change to policy statements. ICD-9 and ICD-10 diagnosis and procedure codes removed; they do not relate to adjudication of the policy.

Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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