Stem-Cell Transplant for Leukemia

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MP 8.01.26

Hematopoietic Stem-cell Transplantation for Acute Myeloid Leukemia

Medical Policy
Section Therapy	Original Policy Date 12/1/99	Last Review Status/Date Reviewed with literature search/5:2009
Issue 5:2009		Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

Description

Hematopoietic Stem-Cell Transplantation
Hematopoietic stem-cell transplantation (SCT) 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 radiation therapy. Bone-marrow stem cells may be obtained from the transplant recipient (autologous SCT) or from a donor (allogeneic SCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta 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 vs. host disease. Cord blood is discussed in greater detail in policy No. 7.01.50.

Immunologic incompatibility between infused stem cells and the recipient is not an issue in autologous SCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic SCT. 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 HLA A, B, and DR loci on each leg 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 susceptibility of the patient 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 prior to undergoing bone marrow ablation. As a consequence, autologous HSCT is typically 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.

Reduced-Intensity Conditioning for Allogeneic HSCT

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 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.

Acute Myelogenous Leukemia (AML)
Acute myeloid leukemia (sometimes called acute non-lymphocytic 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, low production of mature red blood cells, platelets, and often non-lymphocytic white blood cells (granulocytes, monocytes). The incidence of AML increases with age, with a median of 67 years. About 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 French-American-British (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 50-60% 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 5 major subcategories of AML: 1) AML with recurrent genetic abnormalities; 2) AML with multilineage dysplasia; 3) therapy-related AML and myelodysplasia (MDS); 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)(p 13;q22), t( 15;17)(q22;aq12), 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 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 about 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 33–49% of CN-AML cases; among those, 28–33% consist of internal tandem duplications (ITD), 5–14% 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 pharmaceutical 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.

Policy

Allogeneic 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 regimen may be considered medically necessary 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 (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.

Policy Guidelines

Primary refractory 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 upon 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, currently 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 the following table:
Risk Status of AML Based on Cytogenetic and Molecular Factors

Risk Status	Cytogenetic Factors	Molecular Abnormalities
Better	Inv(16), t(8;21), t(16;16)	Normal cytogenetics with isolated NPM1 mutation
Intermediate	Normal, +8 only, t(9;11) Other abnormalities not listed with better-risk and poor-risk cytogenetics	c-KIT mutation in patients with t(8;21) or inv(16)
Poor	-5, -7, 5q-, 7q-, +8, Inv3, t(3;3), t(6;9), t(9;22) Abnormalities of 11123, 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.

Some patients for whom a conventional myeloablative allotransplant could be curative may be considered candidates for RIC allogeneic HSCT. These include those whose age (typically older than 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 his or her 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, where usually there is sharing of only 3 of the 6 major histocompatibility antigens. The majority of 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.

In 2003, CPT centralized codes describing allogeneic and autologous hematopoietic stem-cell support services to the hematology section (CPT 38204-38242). Not all codes are applicable for each stem-cell support procedure. For example, Plans should determine if cryopreservation is performed. A range of codes describe services associated with cryopreservation, storage, and thawing of cells (38208-38215).

CPT 38208 and 38209 describe thawing and washing of cryopreserved cells
CPT 38210-38214 describe certain cell types being depleted
CPT 38215 describes plasma cell concentration

Benefit Application

BlueCard/National Account Issues

For indications considered investigational, the following considerations may supersede this policy:

State mandates requiring coverage for autologous SCT offered as part of NIH-approved clinical trials of autologous bone marrow transplantation.
Some plans may participate in voluntary programs offering coverage for patients participating in NIH-approved clinical trials of cancer chemotherapies, including autologous SCT.
Some contracts or certificates of coverage (e.g., FEP) may include specific conditions in which autologous SCT would be considered eligible for coverage.

Rationale

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 AML in first complete remission (CR1) pooled data from 5 studies that included a total of 3,100 patients. (1) Among those patients, 1,151 received allogeneic HSCT, 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 HR =1.17 95% CI: 1.06-1.30; p =0.003; random-effects model HR =1.15, 95% CI: 1.01–1.32; p =0.037) even though none of the individual studies did so. Meta-regression analysis showed 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 to 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 NCCN outlined in the Policy Guidelines, above. (2) 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. (3-6) Together, the body of evidence in the context of clinical review of this policy clearly supports the conclusion that myeloablative allogeneic HSCT may be considered medically necessary for patients with poor- to intermediate-risk AML in CR1. Because better-risk AML typically responds well to conventional induction chemotherapy, allogeneic HSCT may be reserved for treatment of relapsed disease in these patients.

Evidence from the meta-analysis cited above 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 NRM. However, there is considerable genotypic heterogeneity within the 3 WHO cytogenetic prognostic groups that complicates generalization of clinical results based only on cytogenetics. (7) 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 postremission standard chemotherapy as patients with cytogenetically poor-risk AML. (8) Similarly, individuals 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 above in the policy Description). Thus, patients with mutations in NPM1 but without FLT3-ITD 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. (9) 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 above 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.

Autologous HSCT
A meta-analysis examined survival outcomes of autologous HSCT in CR1 versus standard chemotherapy or no further treatment in AML patients age 15-55 years. (10) 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); 2) randomized trials that compared autologous HSCT with chemotherapy in all patients. Among a total of 4,058 patients included in 6 studies, 2,989 (74%) achieved CR1; 1,044 (26%) were randomly allocated to HSCT (n =524) or chemotherapy (n =520). Of the 5 studies for which OS data were available, outcomes with autologous HSCT were better in 3, and outcomes with chemotherapy were better in 2. 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: 0.89-1.15, p =0.86). In all 6 studies, DFS was numerically superior with autologous HSCT compared to chemotherapy (or no further treatment), but only 1 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 posttransplant (fixed-effects model survival probability ratio =1.24, 95% CI: 1.06-1.44, p =0.006).

There are several possible reasons this meta-analysis did not demonstrate a statistically significant OS advantage for autologous HSCT compared to chemotherapy given the significant estimate for DFSbenefit. First, the pooled data showed a 6.45% greater NRM rate in autologous HSCT recipients compared to 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 overall survival 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 to current care. Nonetheless, the evidence suggests the use of autologous HSCT to treat AML in CR1 is feasible and offers improved survival and a chance for cure compared to postremission chemotherapy in patients who lack a suitable stem cell donor.

Primary Refractory AML
Conventional-dose induction chemotherapy will not produce remission in 20–40% of patients with AML, connoting refractory AML.(2) An allogeneic HSCT using a matched related donor (MRD) or matched unrelated donor (MUD) represents the only potentially curative option for these individuals. In several retrospective studies OS rates have ranged form 13% at 5 years to 30% at 3 years, although this procedure is accompanied by NRM rates of 25-62% in this setting. (3) 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 such as FLT3 antagonists. (11) 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. (12)

Relapsed AML
Most patients with AML will experience disease relapse after attaining a first complete remission. (2) 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 3 phase III trials suggest allogeneic HSCT in CR2 can produce 5-years OS rates of 26% to 88%, depending on cytogenetic risk stratification. (13) Because reinduction chemotherapy treatment may beassociated 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. (12, 14) 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 individuals who have a sufficient stem-cell preparation remaining from collection in CR1. (12)

Allogeneic HSCT is often performed as salvage for patients who have relapsed after conventional chemotherapy or autologous HSCT. (12) 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 35–40% using sibling transplants and 10% with MUD transplants for patients with induction failure or in relapse following HSCT. (12)

Reduced-Intensity Allogeneic HSCT
A growing body of evidence is accruing from clinical studies of RIC with allogeneic HSCT for AML. (15-19) Overall, these data suggest 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. No direct comparative studies with sufficiently long follow-up in matched patient groups are available to define the relative net health benefit of allogeneic HSCT with RIC versus myeloablative treatments. Indirect comparison of 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.

RIC allogeneic HSCT may have many of the same limitations as standard-intensity conditioning HSCT: relapse, GVHD (particularly chronic GVHD), and mortality from treatment-related causes other thanmyelotoxicity. However, this approach is increasingly being used in many centers, comprising an estimated 34% of all allogeneic transplantations in 2005. (20) RIC procedures will continue to evolve and will likely supplant myeloablative conditioning regimens for large numbers of patients.

Allogeneic HSCT with RIC is one of many therapeutic approaches that can be used for which some evidence exists to show improved health outcomes in patients who could be expected to benefit from an allogeneic HSCT. Thus, based on currently available data and clinical input as noted in the following section, RIC allogeneic HSCT may be considered medically necessary in patients who demonstrate complete marrow and extramedullary remission, could be expected to benefit from a myeloablative allogeneic HSCT, and who, for medical reasons, would be unable to tolerate a myeloablative conditioning regimen. Additional data are necessary to determine whether some patients with AML and residual disease may benefit from RIC allogeneic HSCT.

Physician Specialty Society and Academic Medical Center Input
In response to requests, input was received from one Physician Specialty Society (2 reviewers) and one 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.

2009 National Comprehensive Cancer Network Guidelines
The National Comprehensive Cancer Network clinical practice guidelines (v.1.2009) for acute myeloid leukemia are generally consistent with this policy.
National Cancer Institute (NCI) Clinical Trial Database (PDQ®)

A search of the NCI PDQ® in April 2009 identified 11 active or approved Phase II or III trials in the U.S. that involve stem-cell support for patients with AML. Trials include allo- and autografting, using various HDC regimens. The role of immunotherapy using gemtuzumab ozogamicin at induction is under investigation in 1 trial (SWOG-S0106).

References:

Yanada M, Matsuo K, Emi N et al. Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission: a metaanalysis. Cancer 2005; 103(8):1652-8.
Baer MR, Greer JP. Acute myeloid leukemia in adults. In: Greer JP, Foerster J, Rodgers GM et al. (eds.). Wintrobe’s Clinical Hematology. Philadelphia, Lippincott Williams & Wilkins, 2009.
Hamadani M, Awan FT, Copelan EA. Hematopoietic stem cell transplantation in adults with acute myeloid leukemia. Biol Blood Marrow Transplant 2008; 14(5):556-67.
Deschler B, de Witte T, Mertelsman R et al. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica 2006; 91(11):1513-22.
Craddock CF. Full-intensity and reduced-intensity allogeneic stem cell transplantation in AML. Bone Marrow Transplant 2008; 41(5):415-23.
Cornelissen JJ, van Putten WL, Verdonck LF et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood 2007; 109(9):3658-66.
Mrozek K, Bloomfield CD. Chromosome aberrations, gene mutations and expression changes, and prognosis in adult acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 2006; 169-77.
Paschka P, Marcucci G, Ruppert AS et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B study. J Clin Oncol 2006; 24(24):3904-11.
Schlenk RF, Dohner K, Krauter J et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358(18):1909-18.
Nathan PC, Sung L, Crump M et al. Consolidation therapy with autologous bone marrow transplantation in adults with acute myeloid leukemia: a meta-analysis. J Natl Cancer Inst 2004; 96(1):38-45.
Estey EH. Treatment of acute myeloid leukemia. Haematologica 2009; 94(1): 10-16.
Stone RM, O’Donnell MR, Sekeres MA. Acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 2004; 98-117
Breems DA, van Putten WL, Huijgens PC et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol 2005; 23(9):1969-78.
Breems DA, Lowenberg B. Acute myeloid leukemia and the position of autologous stem cell transplantation. Semin Hematol 2007; 44(4):259-66.
Blaise D, Vey N, Faucher C et al. Current status of reduced intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica 2007; 92(4):533-41.
Huisman C, Meijer E, Petersen EJ et al. Hematopoietic stem cell transplantation after reduced intensity conditioning in acute myelogenous leukemia patients older than 40 years. Biol Blood Marrow Transplant 2008; 14(2):181-6.
Valcarcel D, Martino R. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and acute myelogenous leukemia. Current Opin Oncol 2007; 19(6):660-6.
Valcarcel D, Martino R, Caballero D et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008; 26(4):577-84.
Oliansky DM, Appelbaum F, Cassileth PA et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in adults: an evidence-based review. Biol Blood Marrow Transplant 2008; 14(2):137-80
Gratwohl A, Baldomero H, Frauendorfer K et al. Results of the EBMT activity survey 2005 on haematopoietic stem cell transplantation: focus on increasing use of unrelated donors. Bone Marrow Transplant 2007; 39(2):71-87.
Acute Myeloid Leukemia. National Comprehensive Cancer Network Clinical Practice Guidelines
in Oncology. v.1.2009 http://www.nccn.org/professionals/physician_gls/PDF/aml.pdf (accessed April 2009)

Codes	Number	Description
CPT	38204	Management of recipient hematopoietic cell donor search and cell acquisition
	38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic
	38206	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, autologous
	38208	Thawing of previously frozen harvest
	38209	Washing of harvest
	38210	Specific cell depletion with harvest, T-cell depletion
	38211	Tumor cell depletion
	38212	Red blood cell removal
	38213	Platelet depletion
	38214	Plasma (volume) depletion
	38215	Cell concentration in plasma, mononuclear, or buffy coat layer
	38220	Bone marrow, aspiration only
	38221	Biopsy, needle or trocar
	38230	Bone marrow harvesting for transplantation
	38240	Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic
	38241	Bone marrow or blood-derived peripheral stem-cell transplantation; autologous
	38242	Allogeneic donor lymphocyte infusions
ICD-9 Procedure	41.00	Bone marrow transplant, not otherwise specified
	41.01	Autologous bone marrow transplant
	41.02	Allogeneic bone marrow transplant with purging
	41.03	Allogeneic bone marrow transplant without purging
	41.04	Autologous hematopoietic stem-cell transplant
	41.05	Allogeneic hematopoietic stem-cell transplant
	41.07	Autologous hematopoietic stem-cell transplant with purging
	41.08	Allogeneic hematopoietic stem-cell transplant with purging
	41.09	Autologous bone marrow transplant with purging
	41.91	Aspiration of bone marrow from donor for transplant
	99.79	Other therapeutic apheresis (includes harvest of stem cells)
ICD-9 Diagnosis	205.00–205.01	Acute myeloid leukemia code range
HCPCS	G0265	Cryopreservation, freezing and storage of cells for therapeutic use, each cell line
	G0266	Thawing and expansion of frozen cells for therapeutic use, each cell line
	G0267	Bone marrow or peripheral stem-cell harvest, modification or treatment to eliminate cell type(s) (e.g., T cells, metastatic carcinoma)
	Q0083, Q0084, Q0085	Chemotherapy administration code range
	J9000, J9001, J9010, J9015, J9017, J9020, J9025, J9027, J9031, J9035, J9040, J9041, J9045, J9050, J9055, J9060, J9062, J9065, J9070, J9080, J9090, J9091, J9092, J9093, J9094, J9095, J9096, J9097, J9098, J9100, J9110, J9120, J9130, J9140, J9150, J9151, J9160, J9165, J9170, J9175, J9178, J9181, J9182, J9185, J9190, J9200, J9201, J9202, J9206, J9208, J9209, J9211, J9212, J9213, J9214, J9215, J9216, J9217, J9218, J9219, J9225, J9226, J9230, J9245, J9250, J9260, J9261, J9263, J9264, J9265, J9266, J9268, J9270, J9280, J9290, J9291, J9293, J9300, J9303, J9305, J9310, J9320, J9340, J9350, J9355, J9357, J9360, J9370, J9375, J9380, J9395, J9600, J9999	Chemotherapy drug code range
	S2140	Cord blood harvesting for transplantation, allogeneic
	S2142	Cord blood derived stem-cell transplantation, allogeneic
	S2150	Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic, and emergency services)
Type of Service	Therapy
Place of Service	Inpatient/Outpatient

Index

Bone Marrow Transplant
High-dose Chemotherapy; Acute Myeloid Leukemia
Stem- cell Transplant; Acute Myeloid Leukemia

Policy History

Date	Action	Reason
12/01/99	Add to Therapy section	New policy represents revision of original policy No. 8.01.15 to focus entirely on AML; policy statement unchanged
08/18/00	Replace policy	Policy statement revised to state that allogeneic transplant after a prior failed autotransplant is considered investigational, based on 2000 TEC Assessment
12/18/02	Replace policy	Literature review update conducted in October 2002, references added; no change in policy statement. Updated CPT codes
11/9/04	Replace policy	Literature review update conducted in August 2004; policy updated with references, NCCN guidelines, and NCI clinical trials information. Policy statement unchanged
09/27/05	Replace policy	Literature review update for the period of August 2004 through August 2005; policy statement unchanged. NCI clinical trials and reference number 9 updated
06/12/08	Replace policy	Policy updated with literature review; terminology in policy statements modified but materially unchanged. NCI clinical trials updated, and reference numbers 12-17 added. “High-dose chemotherapy” removed from title and policy statement.
2/12/09	Replace policy	Clinical input reviewed; policy statement changed to indicate that, Reduced-intensity conditioning allogeneic SCT may be considered medically necessary as a treatment of AML in patients who are in complete marrow and extramedullary first or second remission, and who for medical reasons, would be unable to tolerate a myeloablative conditioning regimen.
05/14/09	Replace policy	Policy updated with literature review; clinical input reviewed, rationale revised extensively. While all policy statements were revised, the two major changes are indicating that allogeneic HSCT may be used in those with poor- to intermediate-risk AML in remission and that allogeneic HSCT may be used after failed autologous HSCT. New references 1, 3, 5-14 added

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