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

Number 8.01.21

Effective Date January 21, 2014

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

Replaces N/A

Policy

Myeloablative allogeneic HSCT may be considered medically necessary as a treatment of

Reduced-intensity conditioning allogeneic HSCT may be considered medically necessary as a treatment of

  • Myelodysplastic syndromes or
  • Myeloproliferative neoplasms in patients who for medical reasons would be unable to tolerate a myeloablative conditioning regimen. (see Policy Guidelines)
  • Myeloablative allogeneic HSCT or reduced-intensity conditioning allogeneic HSCT for myelodysplastic syndromes and myeloproliferative neoplasms that does not meet the criteria in the Policy Guidelines is considered investigational.

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

8.01.22

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

8.01.26

Hematopoietic Stem-Cell Transplantation for Acute Myeloid Leukemia

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 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

8.01.54

Hematopoietic Stem-Cell Transplantation for Waldenstrom Macroglobulinemia

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

The myeloid neoplasms are categorized according to criteria developed by the World Health Organization. They are risk-stratified according to the International Prognostic Scoring System (IPSS).

2008 WHO Classification Scheme for Myeloid Neoplasms

  1. Acute myeloid leukemia
  2. Myelodysplastic syndromes (MDS)
  3. Myeloproliferative neoplasms (MPN)
  4. Chronic myelogenous leukemia
  1. Polycythemia vera
  2. Essential thrombocythemia
  3. Primary myelofibrosis
  4. Chronic neutrophilic leukemia
  5. Chronic eosinophilic leukemia, not otherwise categorized
  6. Hypereosinophilic leukemia
  7. Mast cell disease
  8. MPNs, unclassifiable
  1. MDS/MPN
  1. Chronic myelomonocytic leukemia
  2. Juvenile myelomonocytic leukemia
  3. Atypical chronic myeloid leukemia
  4. MDS/MPN, unclassifiable
  1. Myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1
  1. Myeloid neoplasms associate with PDGFRA rearrangement
  2. Myeloid neoplasms associate with PDGFRB rearrangement
  3. Myeloid neoplasms associate with FGFR1 rearrangement (8p11 myeloproliferative syndrome)

2008 WHO Classification of MDS

  1. Refractory anemia (RA)
  2. RA with ring sideroblasts (RARS)
  3. Refractory cytopenia with multilineage dysplasia (RCMD)
  4. RCMD with ring sideroblasts
  5. RA with excess blasts 1 and 2 (RAEB 1 and 2)
  6. del 5q syndrome
  7. unclassified MDS

Risk Stratification of MDS

Risk stratification for MDS is performed using the IPSS. This system was developed after pooling data from 7 previous studies that used independent, risk-based prognostic factors. The prognostic model and the scoring system were built based on blast count, degree of cytopenia, and blast percentage. Risk scores were weighted relative to their statistical power. This system is widely used to divide patients into two categories: (1) low -risk and (2) high-risk groups. The low-risk group includes low -risk and Int-1 IPSS groups; the goals in low-risk MDS patients are to improve quality of life and achieve transfusion independence. In the high-risk groupwhich includes Int-2 and high-risk IPSS groups the goals are slowing the progression of disease to AML and improving survival. The IPSS is usually calculated on diagnosis. The role of lactate dehydrogenase, marrow fibrosis, and beta 2-microglobulin also should be considered after establishing the IPSS. If elevated, the prognostic category becomes worse by one category change.

IPSS: MDS Prognostic Variables

Variable

0

0.5

1.0

1.5

2.0

Marrow blasts (5)

<5

5-10

-

11-20

21-30

Karyotype

Good

Intermediate

Poor

   

Cytopenias

0/1

2/3

-

-

-

IPSS: MDS Clinical Outcomes

Risk Group

Total Score

Median Survival, yrs.

Time for 25% to progress to AML, yrs.

Low

0

5.7

9.4

Intermediate-1

0.5-1.0

3.5

3.3

Intermediate-2

1.5-2.0

1.2

1.12

High

2.5 or more

0.4

0.2

Given the long natural history of MDS, allogeneic HSCT is typically considered in those with increasing numbers of blasts, signaling a possible transformation to acute myeloid leukemia. Subtypes falling into this category include refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or chronic myelomonocytic leukemia.

Patients with refractory anemia with or without ringed sideroblasts may be considered candidates for allogeneic HSCT when chromosomal abnormalities are present or the disorder is associated with the development of significant cytopenias (e.g., neutrophils less 500/mm3, platelets less than 20,000/mm3).

Patients with MPNs may be considered candidates for allogeneic HSCT when there is progression to myelofibrosis or when there is evolution toward acute leukemia. In addition, allogeneic HSCT may be considered in patients with essential thrombocythemia with an associated thrombotic or hemorrhagic disorder. There are no suitable U.S. Food and Drug Administration (FDA)-approved therapies for these patients, only supportive care. The use of allogeneic HSCT should be based on cytopenias, transfusion dependence, increasing blast percentage over 5%, and age.

Some patients for whom a conventional myeloablative allogeneic HSCT could be curative may be considered candidates for RIC allogeneic HSCT. These include those 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. 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 (MUD) 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.

Clinical input suggests RIC allogeneic HSCT may be considered for patients as follows:

  • MDS
  • IPSS intermediate-2 or high risk
  • RBC transfusion dependence
  • Neutropenia
  • Thrombocytopenia
  • High -risk cytogenetics
  • Increasing blast percentage

MPN

  • Cytopenias
  • Transfusion dependence
  • Increasing blast percentage over 5%
  • Age 60-65 years

Description

Myelodysplastic syndromes and myeloproliferative neoplasms refer to a heterogeneous group of clonal hematopoietic disorders with the potential to transform into acute myelocytic leukemia. Allogeneic Hematopoietic stem-cell transplantation (HSCT) has been proposed as a curative treatment option for patients with these disorders.

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 “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 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 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 pre-transplant 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.

Reduced-Intensity Conditioning for Allogeneic HSCT

Reduced-intensity conditioning (RIC) refers to the pre-transplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in conventional full-dose myeloablative (MA) 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 MA to minimally MA 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 MA (conventional) regimens.

Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) can occur as a primary (idiopathic) disease or can be secondary to cytotoxic therapy, ionizing radiation, or other environmental insult. Chromosomal abnormalities are seen in 4060% of patients, frequently involving deletions of chromosome 5 or 7, or an extra chromosome as in trisomy 8. Signs and symptoms of anemia, often complicated by infections or bleeding, are common in MDS; some patients exhibit systemic symptoms or features of autoimmunity that may be indicative of their disease pathogenesis. The vast majority of MDS diagnoses occur in individuals older than age 55–60 years, with an age-adjusted incidence of approximately 62% among individuals older than age 70 years. Patients either succumb to disease progression to acute myelocytic leukemia (AML) or to complications of pancytopenias. Patients with higher blast counts or complex cytogenetic abnormalities have a greater likelihood of progressing to AML than do other patients.

For the past 20 years, the French-American-British (FAB) system has been used to classify MDS into 5 subtypes as follows: (1) refractory anemia (RA); (2) refractory anemia with ringed sideroblasts (RARS); (3) refractory anemia with excess blasts (RAEB); (4) refractory anemia with excess blasts in transformation (RAEBT); and, (5) chronic myelomonocytic leukemia (CMML). However, the FAB system has been supplanted by that of the World Health Organization (WHO), which records the number of lineages in which dysplasia is seen (unilineage vs. multilineage), separates the 5q- syndrome, and reduces the threshold maximum blast percentage for the diagnosis of MDS from 30% to 20% (see Policy Guidelines for WHO classification scheme for myeloid neoplasms).

Several prognostic scoring systems for MDS have been proposed; the most commonly used is the International Prognostic Scoring System (IPSS). The IPSS groups patients into one of four prognostic categories based on the number of cytopenias, cytogenetic profile, and the percentage of blasts in the bone marrow (see Policy Guidelines). This system underweights the clinical importance of severe, life-threatening neutropenia and thrombocytopenia in therapeutic decisions and does not account for the rate of change in critical parameters, such as peripheral blood counts or blast percentage. However, the IPSS has been useful in comparative analysis of clinical trial results and its utility confirmed at many institutions. A second prognostic scoring system incorporates the WHO subgroup classification that accounts for blast percentage, cytogenetics, and severity of cytopenias as assessed by transfusion requirements. The WHO Classification-based Prognostic scoring system (WPSS) uses a 6-category system, which allows more precise prognostication of overall survival (OS) duration, as well as risk for progression to AML. This system, however, is not yet in widespread use in clinical trials.

Treatment of smoldering or non-progressing MDS has in the past involved best supportive care including red blood cell (RBC) and platelet transfusions and antibiotics. Active therapy was given only when MDS progressed to AML or resembled AML with severe cytopenias. A diverse array of therapies are now available to treat MDS, including hematopoietic growth factors (e.g., erythropoietin, darbepoetin, granulocyte colony-stimulating factor), transcriptional-modifying therapy (e.g., U.S. Food and Drug Administration-approved hypomethylating agents, nonapproved histone deacetylase inhibitors), immunomodulators (e.g., lenalidomide, thalidomide, antithymocyte globulin, cyclosporine A), low-dose chemotherapy (e.g., cytarabine), and allogeneic HSCT. Given the spectrum of treatments available, the goal of therapy must be decided upfront, whether it is to improve anemia; thrombocytopenia; or neutropenia, eliminate the need for RBC transfusion, achieve complete remission (CR), or cure the disease. Allogeneic HSCT is the only approach with curative potential, but its use is governed by patient age, performance status, medical comorbidities, the patient’s risk preference, and severity of MDS at presentation.

Chronic Myeloproliferative Neoplasms

In 2008, a new WHO classification scheme replaced the term chronic myeloproliferative disorder (CMPD) with the term myeloproliferative neoplasms (MPN). These are a subdivision of myeloid neoplasms that includes the four classic disorders: chronic myeloid leukemia (CML), polycythemia vera (PCV), essential thrombocytopenia (ET), and primary myelofibrosis (PMF); the WHO classification also includes chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES), mast cell disease (MCD), and MPNs unclassifiable (see Policy Guidelines).

The MPNs are characterized by the slow but relentless expansion of a clone of cells with the potential evolution into a blast crisis similar to AML. They share a common stem cell-derived clonal heritage, with phenotypic diversity attributed to abnormal variations in signal transduction as the result of a spectrum of mutations that affect protein tyrosine kinases or related molecules. The unifying characteristic common to all MPNs is effective clonal myeloproliferation resulting in peripheral granulocytosis, thrombocytosis, or erythrocytosis that is devoid of dyserythropoiesis, granulocytic dysplasia, or monocytosis.

As a group, approximately 8400 MPNs are diagnosed annually in the U.S. Like MDS, MPNs primarily occur in older individuals, with approximately 67% reported in patients aged 60 years and older. In indolent, nonprogressing cases, therapeutic approaches are based on relief of symptoms. MA allogeneic HSCT has been considered the only potentially curative therapy, but because most patients are of advanced age with attendant comorbidities, its use is limited to those who can tolerate the often severe treatment-related adverse effects of this procedure. However, the use of RIC of conditioning regimens for allogeneic HSCT has extended the potential benefits of this procedure to selected individuals with these disorders.

Chronic myeloid leukemia is considered separately in another medical policy. (See Related Policies)

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 December 1999 and was updated regularly with searches of the MEDLINE database. The most recent literature search was performed through October 8, 2013. Following is the summary of the key literature to date.

Myelodysplastic Syndromes (MDS)

Despite the successes seen with new drugs now available to treat MDS (e.g., decitabine, azacitidine, lenalidomide), allogeneic hematopoietic stem-cell transplantation (HSCT) is the only treatment capable of complete and permanent eradication of the MDS clone. (1) A review of allogeneic HSCT using myeloablative (MA) conditioning for MDS included 24 studies (prospective and retrospective) published between 2000 and 2008 that included a total 1,378 cases with age range of 32 to 59 years. A majority of patients (n=885) received matched related donor (MRD) allogeneic HSCT, with other donor types including syngeneic, matched, unrelated donor (MUD), mismatched unrelated donor (URD), and umbilical cord blood. Most studies included de novo and secondary MDS, chronic myelomonocytic leukemia, myeloproliferative neoplasms (MPNs), de novo and secondary acute myelocytic leukemia (AML), and transformed AML. Peripheral blood and bone marrow stem-cell grafts were allowed in most studies. The most commonly used conditioning regimens were busulfan plus cyclophosphamide (BU/CY) and CY plus total -body irradiation (CY/TBI), with cyclosporine A (CYA) used for graft-versus-host disease (GVHD) prophylaxis. Length of follow-up ranged from 5 months to approximately 8 years. Grades II-IV acute GVHD varied from 18% to 100%. Relapse risk ranged from a low of 24% at 1 year to 36% at 5 years. Overall survival (OS) ranged from 25% at 2 years to 52% at 4 years, with nonrelapse mortality (NRM) ranging from 19% at day 100 to 61% at 5 years.

Evidence from a number of largely heterogeneous, uncontrolled studies of reduced-intensity conditioning (RIC) with allogeneic HSCT shows long-term remissions (i.e., longer than 4 years) can be achieved, often with reduced treatment-related morbidity and mortality, in patients with myelodysplastic syndromes/acute myelocytic leukemia (MDS/AML) who otherwise would not be candidates for MA conditioning regimens. (2-13) These prospective and retrospective studies included cohorts of 16 to 215 patients similar to those in the MA allogeneic HSCT studies. The most common conditioning regimens used were fludarabine -based, with cyclopamine (CYA) and tacrolimus used for GVHD prophylaxis. The reported incidence of grades II–IV GVHD was 9 to 63%, with relapse risk of 6 to 61%. The OS rates ranged between 44% at 1 year to 46% at 5 years, with a median follow-up range of 14 months to over 4 years.

In 2013, Kim et al. published a randomized Phase III trial to compare the toxicities of 2 different conditioning regimens (reduced cyclophosphamide [Cy], fludarabine, and antithymocyte globulin [ATG]; standard Cy-ATG). (14) Four (of 83) patients had MDS, and the remaining study patients had severe aplastic anemia. Overall, the incidence of toxicities were reported to be lower in patients receiving the reduced-conditioning regimen (23% vs. 55%; p=0.003). Subgroup analyses showed no differences in the overall results based on differential diagnosis.(14)

In general, these RIC trials showed a low rate of engraftment failure and low non-relapse mortality (NRM) but at the cost of a higher relapse rate than with MA allogeneic HSCT. However, in the absence of prospective, comparative, randomized trials, only indirect comparisons can be made between the relative clinical benefits and harms associated with myeloablative (MA) and RIC regimens with allogeneic HSCT. Furthermore, no randomized trials have been published in which RIC with allogeneic HSCT has been compared with conventional chemotherapy alone, which has been the standard of care in patients with MDS/AML for whom MA chemotherapy and allogeneic HSCT are contraindicated. Nonetheless, given the absence of curative therapies for these patients, coupled with clinical input (see below), RIC allogeneic HSCT may be considered medically necessary for patients with MDS who could benefit from allogeneic HSCT but who for medical reasons (see Policy Guidelines) would be unable to tolerate a MA conditioning regimen.

The recommendations of a systematic review of the role of allogeneic HSCT in patients with MDS prepared by the American Society for Blood and Marrow Transplantation (ASBMT) agree with the present policy statements. (15) Other recent reviews concur with the ASBMT recommendations.(16-21)

Myeloproliferative Neoplasms (MPN)

Data on therapy for MPN remain sparse. (10,22,23) As outlined previously in this policy, with the exception of MA chemotherapy and allogeneic HSCT, no therapy has yet been proven to be curative or to prolong survival of patients with MPN. However, the significant toxicity of MA conditioning and allogeneic HSCT in MPN has led to study of RIC regimens for these diseases. One recent series included 27 patients (mean age, 59 years) with MPN who underwent allogeneic HSCT using an RIC regimen of low-dose (2 Gy) total -body irradiation alone or with the addition of fludarabine.(8) At a median follow-up of 47 months, the 3-year relapse-free survival was 37%, and OS was 43%, with a 3-year NRM of 32%. In a second series, 103 patients (median age, 55 years; range, 32-68 years) with intermediate to high risk (86% of total patients) primary myelofibrosis (PMF) or post- essential thrombocythemia (PT) and polycythemia vera myelofibrosis (PVM) were included on a prospective multicenter Phase II trial to determine efficacy of a busulfan plus fludarabine-based RIC regimen followed by allogeneic HSCT from related (n=33) or unrelated (n=70) donors. (24) Acute grade II-IV GVHD occurred in 27%, and chronic GVHD in 43% of patients. The cumulative incidence of NRM at one year in all patients was 16% (95% confidence interval [CI], 9 to 23%) but reached 38% (95% CI: 15 to 61%) among those with a mismatched donor versus 12% (95% CI: 5 to 19%) among cases with a matched donor (p=0.003). The cumulative relapse rate at 3 and 5 years was 22% (95% CI: 13 to 31%) and 29% (95% CI: 16 to 42%), respectively. After a median follow-up of 33 months (range, 12-76 months) 5-year estimated disease-free survival (DFS) and OS was 51% (95% CI: 38 to 64%) and 67% (95% CI: 55%-79%), respectively.

The largest study of allogeneic HSCT for primary myelofibrosis comes from analysis of the outcomes of 289 patients treated between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). (25) The median age was 47 years (range: 18-73 years). Donors were HLA-identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA non-identical family members in 26 patients. Patients were treated with a variety of conditioning regimens and GVHD prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day treatment-related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5-year OS rates were 37%, 30%, and 40%, respectively. DFS rates were 33%, 27%, and 22%, respectively. DFS for patients receiving reduced-intensity transplants was comparable: 39% for HLA identical sibling donors and 17% for unrelated donors at 3 years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival (RFS) in about one-third of patients.

Data from direct, prospective comparison of outcomes of MA conditioning and allogeneic HSCT versus RIC and allogeneic stem-cell support in MPN are not available. However, a recent retrospective study analyzed the impact of conditioning intensity on outcomes of allogeneic HSCT in patients with myelofibrosis (MF) .(26) This multicenter trial included 46 consecutive patients treated at three Canadian and four European transplant centers between 1998 and 2005. Twenty-three patients (median age, 47 years; range, 31-60 years) underwent MA conditioning, and 23 patients (median age, 54 years; range, 38-74 years) underwent RIC. The majority in both groups (85%) were deemed intermediate- or high-risk. At a median follow-up of 50 months (range, 20-89), there was a trend for better progression-free survival (PFS) at 3 years in RIC patients compared to MA-conditioned patients (58%; range, 23-62 vs 43%; range, 35-76, respectively; p=0.11); there was a similar trend in 3-year OS (68%; range, 45-84 vs 48%; range, 27-66, respectively; p=0.08). NRM rates at 3 years trended higher in MA-conditioned cases than RIC cases (48%; range, 31-74 vs 27%; range, 14-55, respectively; p=0.08). The results of this study suggest that both types of conditioning regimens have curative potential in patients with MF. Despite the RIC patients being significantly older with longer disease duration and poorer performance status than those who received conventional conditioning, the groups had similar outcomes, supporting the use of RIC allogeneic HSCT in this population.

In a retrospective study in 9 Nordic transplant centers, a total of 92 patients with MF in chronic phase underwent allogeneic HSCT. (27) MA -conditioning was given to 40 patients, and RIC was used in 52 patients. The mean age in the 2 groups at transplantation was 46±12 and 55±8 years, respectively (p<0.001). When adjustment for age differences was made, the survival of the patients treated with RIC was significantly better (p=0.003). Among the RIC patients, survival was significantly (p=0.003) greater for patients younger than age 60 years (a 10-year survival close to 80%) than for patients older than 60 years. The stem-cell source did not significantly affect the survival. No significant difference was found in NRM at 100 days between the MA- and the RIC-treated patients. The probability of survival at 5 years was 49% for the MA-treated patients and 59% in the RIC group (p=0.125). Patients treated with RIC experienced significantly less acute GVHD compared with patients treated with MA conditioning (p<0.001). The OS at 5 years was 70%, 59% and 41% for patients with Lille score 0, 1 and 2, respectively (p=0.038, when age adjustment was made). Twenty-one percent of the patients in the RIC group were given donor lymphocyte infusion because of incomplete donor chimerism, compared with none of the MA-treated patients (p<0.002). Nine percent of the patients needed a second transplant because of graft failure, progressive disease or transformation to AML, with no significant difference between the groups.

Ongoing Clinical Trials

A search of the National Cancer Institute (NCI) Clinical Trials Database in October 2013 identified 8 active Phase III trials that involve stem-cell support for patients with MDS/AML or MPN. Information on these trials can be accessed via the following link, available online at: http://www.cancer.gov/clinicaltrials/search/results?protocolsearchid=9718439. In addition, a search of online site ClinicalTrials.gov identified numerous Phase II trials of various treatments for these diseases which are actively recruiting patients.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers

In response to requests, input was received from 2 Academic Medical Center specialists prior to review for May 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 consensus among reviewers that RIC allogeneic HSCT was of value in patients with MDS or MPN who would be medically unable to tolerate a MA HSCT.

Summary

Hematopoietic stem-cell transplantation (HSCT) is at present the only potentially curative treatment option for patients with myelodysplastic syndromes and myeloproliferative neoplasms. The absence of other curative therapies coupled with clinical data and input permit the conclusion that allogeneic HSCT using either a myeloablative or reduced-intensity conditioning regimen is medically necessary in appropriately selected patients with these conditions. Patient selection is guided by age and disease risk factors, as outlined in the .

Practice Guidelines and Policy Statements

National Comprehensive Cancer Network Guidelines

The 2014 National Comprehensive Cancer Network (NCCN) treatment guidelines (v.2.2014) for the use of allogeneic HSCT indicate this procedure is preferred at diagnosis in patients who are candidates for high-intensity therapy, have a suitable donor, and have de novo MDS classified as IPSS Int-2 and High, or those who have de novo MDS classified as Int-1 with severe cytopenias unresponsive to standard therapies (available online at: http://www.nccn.org/professionals/physician_gls/pdf/mds.pdf). Reduced-intensity or MA-conditioning may be used based on patient age, performance status, comorbid conditions, psychosocial status, patient preference, and availability of caregiver. MRD cells are preferred, but MUD cells are an option at some centers. The role of pretransplant remission induction using intensive chemotherapy has not been established.

References

  1. Kasner MT, Luger SM. Update on the therapy for myelodysplastic syndrome. Am J Hematol 2009; 84(3):177-86.
  2. Barrett AJ, Savani BN. Allogeneic stem cell transplantation for myelodysplastic syndrome. Semin Hematol 2008; 45(1):49-59.
  3. 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.
  4. 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.
  5. 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.
  6. Kindwall-Keller T, Isola LM. The evolution of hematopoietic SCT in myelodysplastic syndrome. Bone Marrow Transplant 2009; 43(8):597-609.
  7. Kroger N, Bornhauser M, Ehninger G et al. Allogeneic stem cell transplantation after a fludarabine/busulfan -based reduced -intensity conditioning in patients with myelodysplastic syndrome or secondary acute myeloid leukemia. Ann Hematol 2003; 82(6):336-42.
  8. Laport GG, Sandmaier BM, Storer BE et al. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biol Blood Marrow Transplant 2008; 14(2):246-55.
  9. Martino R, Caballero MD, Perez-Simon JA et al. Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes. Blood 2002; 100(6):2243-5.
  10. Mesa RA. Navigating the evolving paradigms in the diagnosis and treatment of myeloproliferative disorders. Hematology Am Soc Hematol Educ Program 2007:355-62.
  11. Tauro S, Craddock C, Peggs K et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005; 23(36):9387-93.
  12. 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.
  13. 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.
  14. Kim H, Lee JH, Joo YD et al. A randomized comparison of cyclophosphamide vs. reduced dose cyclophosphamide plus fludarabine for allogeneic hematopoietic cell transplantation in patients with aplastic anemia and hypoplastic myelodysplastic syndrome. Ann Hematol 2012; 91(9):1459-69.
  15. Oliansky DM, Antin JH, Bennett JM et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes: an evidence-based review. Biol Blood Marrow Transplant 2009; 15(2):137-72.
  16. Akhtari M. When to treat myelodysplastic syndromes. Oncology (Williston Park) 2011; 25(6):480-6.
  17. Deeg HJ, Sandmaier BM. Who is fit for allogeneic transplantation? Blood 2010; 116(23):4762-70.
  18. Giralt SA, Horowitz M, Weisdorf D et al. Review of stem-cell transplantation for myelodysplastic syndromes in older patients in the context of the Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome emanating from the Centers for Medicare and Medicaid Services. J Clin Oncol 2011; 29(5):566-72.
  19. Deeg HJ, Bartenstein M. Allogeneic hematopoietic cell transplantation for myelodysplastic syndrome: current status. Arch Immunol Ther Exp (Warsz) 2012; 60(1):31-41.
  20. Garcia-Manero G. Myelodysplastic syndromes: 2012 update on diagnosis, risk-stratification, and management. Am J Hematol 2012; 87(7):692-701.
  21. Kroger N. Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome. Blood 2012; 119(24):5632-9.
  22. Tefferi A, Vainchenker W. Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol 2011; 29(5):573-82.
  23. McLornan DP, Mead AJ, Jackson G et al. Allogeneic stem cell transplantation for myelofibrosis in 2012. Br J Haematol 2012; 157(4):413-25.
  24. Kroger N, Holler E, Kobbe G et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood 2009; 114(26):5264-70.
  25. Ballen KK, Shrestha S, Sobocinski KA et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant 2010; 16(3):358-67.
  26. Gupta V, Kroger N, Aschan J et al. A retrospective comparison of conventional intensity conditioning and reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in myelofibrosis. Bone Marrow Transplant 2009; 44(5):317-20.
  27. Abelsson J, Merup M, Birgegard G et al. The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries. Bone Marrow Transplant 2012; 47(3):380-6.

Coding

Codes

Number

Description

CPT

38205

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

 

38208

Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest

 

38209

thawing of previously frozen harvest with washing

 

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

 

38231

Blood-derived peripheral stem cell harvesting for transplantation, per collection

 

38232

Bone marrow harvesting for transplantation; autologous

 

38240

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

 

86812

HLA typing; A, B, or C (e.g., A10, B7, B27), single antigen

 

86813

A, B, or C, multiple antigens

 

86816

DR/DQ, single antigen

 

86817

HLA typing; DR/DQ, multiple antigens

 

86821

Lymphocyte culture, mixed (MLC)

 

86822

Lymphocyte culture, primed (PLC)

 

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)

 

86915

Bone marrow, modification or treatment to eliminate cells (i.e., T-cell depletion)

ICD-9 Procedure

41.02

Allogeneic bone marrow transplant with purging

 

41.03

Allogeneic bone marrow transplant without purging

 

41.05

Allogeneic hematopoietic stem cell transplant

 

41.91

Aspiration of bone marrow from donor for transplant

 

99.79

Other therapeutic apheresis (includes harvest of stem cells)

ICD-9 Diagnosis

238.72

Low grade myelodysplastic syndrome lesions

 

238.73

High grade myelodysplastic syndrome lesions

 

238.74

Myelodysplastic syndrome with 5q deletion

 

238.75

Myelodysplastic syndrome, unspecified

 

238.76

Myelofibrosis with myeloid metaplasia

 

238.79

Other lymphatic and hematopoietic tissues

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

C92.10 – C92.12

Chronic myeloid leukemia, BCR/ABL-positive code range

 

C92.20 – C92.22

Atypical chronic myeloid leukemia, BCR/ABL-negative code range

 

C94.6

Myelodysplastic disease, not classified
Myeloproliferative disease, not classified

 

D45

Polycythemia vera

 

D46.0 – D46.9

Myelodysplastic syndromes code range

 

D47.0 – D47.9

Other neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue code range

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

30243G1, 30243X1, 30243Y1

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

 

07DQ0ZZ, 07DQ3ZZ, 07DR0ZZ, 07DR3ZZ, 07DS0ZZ, 07DS3ZZ

Surgical, lymphatic and hemic systems, extraction, bone marrow, code list

HCPCS

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

 

Appendix

N/A

History

Date

Reason

02/01/00

Add to Therapy Section - New Policy. Policy represents revision of 7.03.10 to focus on myelodysplasia and myelofibrosis. New policy statement on HDC for myelofibrosis.

11/12/02

Replace policy - Policy reviewed with no criteria changes.

07/13/04

Replace policy - Policy reviewed with literature; policy statement also now includes “mini-transplant.” References added; cross-reference to BC.8.01.38 on mini-transplants added.

07/12/05

Replace policy - Policy reviewed with literature search; no change in policy statement. No further review scheduled.

02/06/06

Codes updated - No other changes.

06/02/06

Disclaimer and Scope Updates - No other changes.

10/09/07

Replace policy - Policy updated with literature review. Status changed from AR to BC. References added. No change in policy statement.

11/12/07

Codes updated - CPT code 86817 deleted as directed by RPIW.

05/13/08

Cross Reference Update - No other changes

03/10/09

Replace policy - Policy updated with literature search. Minor terminology changes to policy statements; the intent of the policy statements remain unchanged. Additional policy statements include Reduced intensity conditioning allogeneic SCT is considered investigational as a treatment of myeloproliferative disorders and myelodysplastic syndrome. References and codes added. “High-Dose Chemotherapy” removed from the title and throughout the body of the policy and “myeloproliferative” diseases added to the policy title.

12/08/09

Code Update - 86817 code added back to the policy.

02/09/10

Code Update - New 2010 codes added.

03/08/11

Replace policy - Policy updated with literature search, reference numbers 14-17 added. Myeloproliferative Disorders” replaced with “Myeloproliferative Neoplasms” in title and text. Policy statements revised to indicate that RIC HSCT, previously investigational, may now be considered medically necessary as a treatment of myelodysplastic syndrome and myeloproliferative neoplasms in patients who for medical reasons would be unable to tolerate a myeloablative conditioning regimen. Reviewed and recommended by OAP in February 2011.

10/19/11

Related Policies updated; links refreshed.

01/06/12

Replace policy – Policy updated with literature search; references 15-18 and 20 added. Policy statements unchanged. ICD-10 codes added.

01/24/12

Code 38232 added.

02/09/12

CPT code 38204 was removed from the policy.

06/20/12

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

08/01/12

Update Related Policies Titles: 8.01.17, 8.01.22, 8.01.30, 8.01.35, and 8.01.520. Removed Related Policy 8.01.38 as it was archived.

10/01/12

Update Coding Section – ICD-10 codes are now effective 10/01/2014.

01/29/13

Replace policy. Title revised with addition of the word “Hematopoietic”. Policy rationale updated based on a literature review through September 2012. Reference 26 added; others renumbered or removed. Policy statements unchanged.

09/30/13

Update Related Policies. Change title to 8.01.31.

10/18/13

Update Related Policies. Change title to 8.01.17.

01/21/14

Replace policy. Policy updated with literature search through October 8, 2013; reference 14 added. Policy statements unchanged. CPT code 38230 removed from policy; it does not apply.

02/27/14

Update Related Policies. Change title to 8.01.30.


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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