MEDICAL POLICY

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Hematopoietic Stem -Cell Transplantation for Acute Myeloid Leukemia

Number 8.01.26

Effective Date October 14, 2013

Revision Date(s) 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

Policy

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

  • Poor- to intermediate-risk acute myelogenous leukemia (AML) in 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, 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.

Related Policies

7.01.50

Placental and Umbilical Cord Blood as a Source of Stem Cells

8.01.17

Hematopoietic Stem-Cell Transplantation for Plasma Cell Dyscrasias, Including Multiple Myeloma and POEMS Syndrome

8.01.20

Hematopoietic Stem-Cell Transplantation for Non-Hodgkin Lymphomas

8.01.21

Allogeneic Hematopoietic Stem-Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms

8.01.22

Allogeneic Hematopoietic Stem-Cell Transplantation for Genetic Diseases and Acquired Anemias

8.01.23

Hematopoietic Stem-Cell Transplantation for Epithelial Ovarian Cancer

8.01.24

Hematopoietic Stem-Cell Transplantation for Miscellaneous Solid Tumors in Adults

8.01.25

Hematopoietic Stem-Cell Transplantation for Autoimmune Diseases

8.01.27

Hematopoietic Stem-Cell Transplantation for Breast Cancer

8.01.28

Hematopoietic Stem-Cell Transplantation for CNS Embryonal Tumors and Ependymoma

8.01.29

Hematopoietic Stem-Cell Transplantation for Hodgkin Lymphoma

8.01.30

Hematopoietic Stem-Cell Transplantation for Treatment of Chronic Myelogenous Leukemia

8.01.35

Hematopoietic Stem-Cell Transplantation in the Treatment of Germ Cell Tumors

8.01.42

Hematopoietic Stem-Cell Transplantation for Primary Amyloidosis

8.01.511

Hematopoietic Stem-Cell Transplantation for Solid Tumors of Childhood

8.01.514

Hematopoietic Stem-Cell Support for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

8.01.520

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, 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) only

Other abnormalities not listed with better-risk and poor-risk cytogenetics

c-KIT mutation in patients with t(8;21) or inv(16)

Poor

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.

Some 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. (1) 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 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 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. 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.

Coding

In 2003, CPT centralized codes describing allogeneic and autologous hematopoietic stem-cell support services to the hematology section. The code range is 38204-38242. (See Coding section).

A range of CPT codes describe services associated with cryopreservation, storage, and thawing of cells. The code range is 38208-38215. (See Coding section)

Description

Acute myeloid leukemia (AML) (also called acute nonlymphocytic leukemia) 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 radiation therapy.

Background

Hematopoietic Stem-Cell Transplantation

Hematopoietic stem cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naive” and thus are associated with a lower incidence of rejection or graft-versus-host disease (GVHD). 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 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 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 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 Myeloid Leukemia

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. 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 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% 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 (MDS);
  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 33–49% 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.

Scope

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.

Benefit Application

N/A

Rationale

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 July 1, 2013.

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. (2) 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]: 1.06-1.30; 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 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 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 National Comprehensive Cancer Network (NCCN) outlined in the Policy Guidelines (3) 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. (4-7) 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 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. (8) 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. (9) 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 (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. (10) 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]. (11) 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: 0.59–0.90; p<0.01); among intermediate-risk patients across 14 trials, the HR for OS was 0.83 (95% CI: 0.74–0.93; p<0.01); among good-risk patients across 16 trials, the HR for OS was 1.07 (95% CI: 0.83–1.38; 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 (2) and the current Policy Statements for use of allogeneic HSCT as consolidation therapy for AML.

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 1555 years. (12) 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: 0.89-1.15, p=0.86). In all six studies, DFS was numerically superior with autologous HSCT compared to 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: 1.06-1.44, 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 DFS benefit. 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.

A second meta-analysis published in 2010 evaluated autologous HSCT versus further chemotherapy or no further treatment for AML in CR1. (13) A total of 9 randomized trials involving 1,104 adults who underwent autologous HSCT and 1,118 who received additional chemotherapy or no additional treatments were identified. The analyses suggest that autologous HSCT in CR1 was associated with statistically significant reduction of relapse risk (relative risk [RR]: 0.56, 95% CI: 0.44, 0.71, p=0.0004) and significant improvement in DFS (HR: 0.89, 95% CI: 0.80, 0.98), but at the cost of significantly increased NRM (RR: 1.90, 95% CI: 0.72, 0.87, p=0.0002). 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, 1.21) was associated with the use of autologous HSCT, compared to further chemotherapy or no further therapy. These results were concordant with those of the earlier meta-analysis cited above.

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). (14) 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 to chemotherapy recipients (38% vs. 29%, respectively at 5 years, p=0.065, 95% CI: 0.66, 1.1). HSCT patients had a lower relapse rate at 5 years compared to 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 above suggests autologous HSCT to treat AML in CR1 is feasible and potentially offers improved DFS, compared to 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 20–40% of patients with acute myeloid leukemia (AML), connoting refractory AML. (3) 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 from 13% at five years to 30% at three years, although this procedure is accompanied by NRM rates of 2562% in this setting. (4) 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. (15) 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. (16)

Relapsed AML

Most patients with AML will experience disease relapse after attaining a first complete remission. (3) 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. (17) 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 955% of patients in CR2 depending on risk category. (16,18) However, because it is likely that stem-cell preparations will be contaminated with malignant cells in patients whose disease is not in remission, and it is often difficult to achieve CR2 in these patients, autologous HSCT in this setting is usually limited to individuals who have a sufficient stem-cell preparation remaining from collection in CR1. (16)

Allogeneic HSCT is often performed as salvage for patients who have relapsed after conventional chemotherapy or autologous HSCT. (16) 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 35–40% using sibling transplants and 10% with MUD transplants for patients with induction failure or in relapse following HSCT. (16)

Reduced-Intensity Allogeneic HSCT

A growing body of evidence is accruing from clinical studies of RIC with allogeneic HSCT for AML. (1, 19-26) Overall, these data suggest that long-term remissions (24 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. (27) 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 graft-versus-host disease. The primary endpoint was the incidence of non-relapse mortality (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: 6-21] versus 18% [10-26]; HR: 0.62 [95% CI: 0.30-1.31], respectively). Relapse cumulative incidence at three years was 28% [95% CI: 19-38] in the RIC group and 26% [17-36]; HR: 1.10 [95% CI: 0.63-1.90]) in the standard conditioning group. Disease-free survival at three years was 58% (95% CI: 49-70) in the RIC group and 56% ([46-67]; HR 0.85 [95% CI: 0.55-1.32]) in the standard conditioning group. Overall survival at three years was 61% (95% CI: 50-74) and 58% (47-70); HR: 0.77 (95% CI: 0.48-1.25) in the RIC and standard conditioning groups, respectively. No outcomes differed significantly between groups. Grade 3-4 of oral mucositis was less common in the RIC group than in the standard conditioning group (50 patients in the reduced-intensity conditioning group vs. 73 patients in the standard conditioning group); the frequency of other side-effects such as graft-versus-host disease (GVHD) and increased concentrations of bilirubin and creatinine did not differ significantly between groups.

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, 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.

Summary

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. 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 (RIC) 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 (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. (28)

Physician Specialty Society and Academic Medical Center Input

In response to requests, input was received from one Physician Specialty Society (two 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.

2013 National Comprehensive Cancer Network Guidelines

The National Comprehensive Cancer Network clinical practice guidelines (V.2.2013) for acute myeloid leukemia are generally consistent with this policy. Available online at: http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Last accessed September, 2013.

National Cancer Institute (NCI) Clinical Trial Database (PDQ®)

A search of the NCI PDQÒ in September 2013 identified several active or approved Phase III trials in the U.S. that involve stem-cell support for patients with AML. Trials include allo- and autografting, using various high-dose chemotherapy (HDC) regimens (http://www.cancer.gov/clinicaltrials/search).

References

  1. Hamadani M, Mohty M, Kharfan-Dabaja MA. Reduced-intensity conditioning allogeneic hematopoietic cell transplantation in adults with acute myeloid leukemia. Cancer Control 2011; 18(4):237-45.
  2. 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.
  3. Greer JP FJ, Rodgers GM, et al., ed Acute myeloid leukemia in adults. Philadelphia: Lippincott Williams & Wilkins; 2009. Wintrobe's Cliniacl Hematology.
  4. 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.
  5. Deschler B, de Witte T, Mertelsmann 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.
  6. Craddock CF. Full-intensity and reduced-intensity allogeneic stem cell transplantation in AML. Bone Marrow Transplant 2008; 41(5):415-23.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. Koreth J, Schlenk R, Kopecky KJ et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 2009; 301(22):2349-61.
  12. 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.
  13. Wang J, Ouyang J, Zhou R et al. Autologous hematopoietic stem cell transplantation for acute myeloid leukemia in first complete remission: a meta-analysis of randomized trials. Acta Haematol 2010; 124(2):61-71.
  14. Vellenga E, van Putten W, Ossenkoppele GJ et al. Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood 2011; 118(23):6037-42.
  15. Estey EH. Treatment of acute myeloid leukemia. Haematologica 2009; 94(1): 10-6.
  16. Stone RM, O'Donnell MR, Sekeres MA. Acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 2004:98-117.
  17. 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.
  18. Breems DA, Lowenberg B. Acute myeloid leukemia and the position of autologous stem cell transplantation. Semin Hematol 2007; 44(4):259-66.
  19. Oliansky DM, Appelbaum F, Cassileth PA et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myelogenous leukemia in adults: an evidence-based review. Biol Blood Marrow Transplant 2008; 14(2):137-80.
  20. 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.
  21. 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.
  22. Valcarcel D, Martino R. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and acute myelogenous leukemia. Curr Opin Oncol 2007; 19(6):660-6.
  23. 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.
  24. Gyurkocza B, Storb R, Storer BE et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol 2010; 28(17):2859-67.
  25. McClune Bl, Weisdorf DJ, Pedersen TL et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol 2010; 28(11):1878-87.
  26. Lim Z, Brand R, Martino R et al. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol 2010; 28(3):405-11.
  27. Bornhauser M, Kienast J, Trenschel R et al. 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.
  28. Hubel K, Weingart O, Naumann F et al. Allogeneic stem cell transplant in adult patients with acute myelogenous leukemia: a systematic analysis of international guidelines and recommendations. Leuk Lymphoma 2011; 52(3):444-57.
  29. Reviewed and recommended for approval by the Oncology Advisory Panel: May 24, 2007; May 22, 2008; August 19, 2010.

Coding

Codes

Number

Description

CPT

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

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

 

38209

Thawing of previously frozen harvest, 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

 

38230

Bone marrow harvesting for transplantation; allogeneic

 

38232

Bone marrow harvesting for transplantation; autologous

 

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

 

86825

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

 

86826

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)

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 without purging

 

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

Acute myeloid leukemia, without mention of having achieved remission

 

205.01

Acute myeloid leukemia in remission

ICD-10-CM
(effective 10/01/14)

C92.00 - C92.02

Acute myeloblastic leukemia code rang

 

C92.40 - C92.42

Acute promyelocytic leukemia code range

 

C92.50 - C92.52

Acute myelomonocytic leukemia code range

ICD-10-PCS
(effective 10/01/14)

30243G0, 30243G1, 30243X0, 30243X1, 30243Y0, 30243Y1 

Percutaneous transfusion, central vein, bone marrow or stem cells, autologous or nonautologous, code list

HCPCS

S2140

Cord blood harvesting for transplantation, allogeneic

 

S2142

Cord blood derived stem cell transplantation, allogeneic

 

S2150

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

Therapy

 

Place of Service

Inpatient
Outpatient

 

Appendix

N/A

History

Date

Reason

02/01/00

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

12/21/00

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

05/13/03

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

08/12/03

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

12/14/04

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

01/10/06

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

06/02/06

Disclaimer and Scope update - No other changes

06/12/07

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

10/9/07

Cross References Updated - No other changes.

11/11/08

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.

9/15/09

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.

02/09/10

Code Update - New 2010 codes added.

09/14/10

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

10/11/11

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.

01/24/12

Code 38232 added.

02/10/12

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

06/20/12

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

07/30/12

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

10/26/12

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

02/01/13

Update Related Policies, change title of policy 8.01.21.

03/20/13

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

10/14/13

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.

12/06/13

Update Related Policies. Remove 8.01.31 as it was archived.


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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