MP 8.01.21

Allogeneic Stem-Cell Transplantation for Myelodysplastic and Myeloproliferative Diseases

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Medical Policy
Section Therapy	Original Policy Date 12/1/99	Last Review Status/Date Reviewed with literature search/6:2008
Issue 6:2008		Return to Medical Policy Index

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Disclaimer

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

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Description

Hematopoietic Stem Cell Transplantation
Hematopoietic stem-cell transplantation (SCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone marrow toxic doses of cytotoxic drugs with or without whole body radiation therapy. Allogeneic SCT refers to the use of hematopoietic progenitor cells obtained from a donor. They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft vs. host disease. Cord blood is discussed in greater detail in policy No. 7.01.50.
Immunologic incompatibility between infused stem cells and the recipient is a critical factor for achieving a good outcome of allogeneic SCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA A, B, and DR loci on each leg of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci.
Conventional Preparative Conditioning for Hematopoietic Stem Cell Transplantation

The conventional practice of allogeneic SCT involves administration of myelotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow failure. The beneficial treatment effect in this procedure results from chemotherapeutic eradication of malignant cells with an associated immune-mediated graft-versus-malignancy effect. While such treatment may eliminate the malignant cells, patients are as likely to die from opportunistic infections, graft-versus-host disease, and organ failure as from the underlying malignancy.
Reduced-Intensity Conditioning for Allogeneic Stem Cell Transplantation
Reduced-intensity conditioning (RIC) refers to chemotherapy regimens that seek to reduce adverse effects secondary to bone marrow toxicity while retaining the beneficial graft-versus-malignancy effect of allogeneic transplantation. These regimens do not eradicate the patient’s hematopoietic ability, thereby allowing for relatively prompt hematopoietic recovery (e.g., 28 days or less) even without a transplant. Patients who undergo RIC with allogeneic SCT 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. A number of different cytotoxic regimens, with or without radiotherapy, may be used for RIC allotransplantation. They represent a continuum in their intensity, from nearly totally myeloablative, to minimally myeloablative with lymphoablation.
Myelodysplastic Syndrome
Myelodysplastic syndrome (MDS) refers to a heterogeneous group of clonal hematopoietic disorders characterized by impaired maturation of hematopoietic cells and a tendency to transform into acute myelocytic leukemia (AML). MDS can occur as a primary (i.e., idiopathic form), or be secondary to cytotoxic therapy, ionizing radiation, or other environmental insult. Chromosomal abnormalities are seen in 40–60% of patients, frequently involving deletions of chromosome 5 or 7, or an extra chromosome (i.e., trisomy 8). The most widely accepted classification system for MDS is the French-American-British (FAB) system that identifies 5 types of MDS with increasing numbers of circulating blast cells as follows:
Refractory anemia (RA)
Refractory anemia with ringed sideroblasts (RARS)

Refractory anemia with excess blasts (RAEB)
Refractory anemia with excess blasts in transformation (RAEBT)
Chronic myelomonocytic leukemia (CMML)
Patients either succumb to disease progression to 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.
Myeloproliferative Disorders
The myeloproliferative disorders are characterized by the slow but relentless expansion of a clone of cells with the potential evolution into a blast crisis similar to AML. Myeloproliferative disorders include the following:

• Polycythemia vera (PV) is characterized by an expansion of the total red cell mass. Initial treatment focuses on phlebotomy to reduce red cell mass and viscosity. However, the disease inevitably progresses and after a medial survival of 15 years, patients typically succumb to thrombotic complications or leukemic evolution.
• Essential thrombocythemia (ET) is characterized by an isolated expansion of the megakaryocytic lineage. The median survival is 10 years with most deaths due to thrombotic complications
• Agnogenic myeloid metaplasia with myelofibrosis, also known as primary myelofibrosis is characterized by marrow fibrosis, splenomegaly, and extramedullary hematopoiesis.

Chronic myeloid leukemia is considered separately in policy No. 8.01.30

Policy

Benefit Application

Rationale

Myelodysplastic Syndrome (MDS)

This policy on MDS was originally based in part on a 1992 TEC Assessment that focused on allogeneic SCT as a treatment of myelodysplastic syndrome (MDS). (1) The following conclusions were offered:

The 1992 TEC Assessment did not address myeloproliferative disorders.

Myeloproliferative Disorders (MPD)
 
Due to the prolonged natural history of both polycythemia vera or essential thrombocythemia disorders and older average age of onset (60 years), allogeneic SCT has not been extensively studied in these patients. A 1998 review reported only 9 patients with PV had been treated with allogeneic SCT. (2) However, considering that PV represents an emerging malignant clone of cells, and the success of high-dose chemotherapy in other hematopoietic disorders, it seems reasonable to extrapolate the results of high-dose chemotherapy for myelodysplastic syndrome to PV. There has been more research in agnogenic myeloid metaplasia (AMM, also called myelofibrosis) since this disorder may also occur in children. In addition, the short median survival of AMM compared to other myeloproliferative disorders has prompted earlier consideration of high-dose chemotherapy. In one review of a total of 29 patients reported in the literature at the time, 16 patients were alive without evidence of relapsed disease between 7 months and 15 years after transplant. (2)

2004-2007 Update
Recent literature focuses primarily on different RIC regimens and allogeneic SCT for MDS in an attempt to reduce toxicity. (3-6) The specific conditioning regimen used is not a focus of this policy, and thus the policy statement is unchanged. Numerous reports of RIC regimens with allogeneic SCT in patients with MDS have also been published. (7-9) However, properly designed, specific randomized trials are not yet available in this area.
2007National Comprehensive Cancer Network Guidelines
The 2007 National Comprehensive Cancer Network treatment guidelines (V.1.2007) for MDS suggest HDC with allogeneic SCT from an HLA-matched sibling donor is a preferred approach, in particular for those with high-risk disease. (10) The guidelines also suggest RIC regimens and matched unrelated donor stem-cell transplants are becoming options at some centers. However, the NCCN states that comparative clinical trials are needed to determine the role of these approaches.
2007 National Cancer Institute (NCI) Clinical Trials Database (PDQ®)
A search of the NCI PDQ database in March 2007 identified the following active trials that involve stem-cell support for patients with MDS:

• Phase II/III Combination Chemotherapy and Bone Marrow Transplant in Treating Patients With Aplastic Anemia or Hematologic Cancer (RPCI-RP-9815)
• Phase II/III Stem Cell Transplantation for Hematological Malignancies (0005M52481)
• Phase II/III Stem Cell Transplant for Bone Marrow Failures (9504M09637)
• Phase III Filgrastim-Mobilized Peripheral Stem Cell Transplantation Compared With Bone Marrow Transplantation From Unrelated Donors in Treating Patients With Hematologic Malignancies (BMTCTN-0201)
• Phase III Treatment of Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplasia (AMLO2)
• Phase III Biology and Treatment Strategy of AML in Its Subgroups: Multicenter Randomized Trial by the German Acute Myeloid Leukemia Cooperative Group (AMLCG) (AMLCG 99)

2008 Update
No randomized, clinical trials have been identified subsequent to the last update on the use of myeloablative chemotherapy with allogeneic SCT for MDS/AML. However, a growing body of evidence from largely heterogeneous uncontrolled studies of RIC with allogeneic SCT shows long-term remissions (greater than 4 years) can be achieved, often with reduced treatment-related morbidity and mortality, in patients with MDS/AML who otherwise would not be candidates for myeloablative conditioning regimens. (11-15) In the absence of prospective, comparative, randomized trials, only indirect comparisons can be made between the relative clinical benefits and harms associated with myeloablative and RIC regimens with allogeneic SCT. Furthermore, no randomized trials have been published in which RIC with allogeneic SCT has been compared with conventional chemotherapy alone, which has been the standard of care in patients with MDS/AML for whom myeloablative chemotherapy and allogeneic SCT is contraindicated.
Data on therapy for MPD remain sparse. As outlined previously in this Policy, with the exception of myeloablative chemotherapy and allogeneic SCT, no therapy has yet been proven to be curative or to prolong survival of patients with MPD. (16) However, the significant toxicity of myeloablative conditioning and allogeneic SCT in MPD has led to study of the use of RIC regimens for these diseases. A recent series included 27 patients (mean age: 59 years) with MPD who underwent allogeneic SCT using a RIC regimen of low-dose (2 Gy) total body irradiation alone or with the addition of fludarabine. (17) At a median follow-up of 47 months, the 3-year relapse-free survival was 37% and overall survival was 43%, with a 3-year nonrelapse mortality of 32%. While this approach has promise, data comparing outcomes of potentially curative myeloablative conditioning and allogeneic stem-cell transplantation versus RIC and allogeneic stem-cell support are not available.

Based on these findings, the policy statements are unchanged.
2008 National Comprehensive Cancer Network Guidelines
The 2008 National Comprehensive Cancer Network treatment guidelines (V.2.2008) for myelodysplastic syndromes are unchanged from the 2007 version. (18)
2008 National Cancer Institute (NCI) Clinical Trials Database (PDQ®)
A search of the NCI PDQ database in April 2008 identified 7 new active phase III trials that involve stem-cell support for patients with MDS/AML or MPD besides those outlined above in the previous update of this Policy. At least 12 phase II trials of various treatments for these diseases are actively recruiting patients. Information on these trials can be accessed via the following link (http://www.cancer.gov/search/psrv.aspx?cid=111158&protocolsearchid=4415677).

 

References:

1. 1992 TEC Assessment, p. 421
2. Anderson JE. Allogeneic hematopoietic cell transplantation for myelodysplastic and myeloproliferative disorders. In: Thomas ED, Blume KG, Forman SJ, eds. Hematopoietic Cell Transplantation. Malden, MA, Blackwell Science, Inc, 1999.
3. Virchis A, Koh M, Rankin P et al. Fludarabine, cytosine, arabinoside, granulocyte-stimulating factor with or without idarubicin in the treatment of high risk acute leukaemia or myelodysplastic syndromes. Br J Haematol 2004;124(1):26-32.
4. Deeg HJ, Storer B, Slattery JT et al. Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood 2002;100(4):1201-7.
5. Woods WG, Barnard DR, Alonzo TA et al. Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndromes: a report from the Children’s Cancer Group. J Clin Oncol 2002; 20(2):434-40.
6. 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.
7. Kroger N, Bornhauser M, Ehninger G et al. Allogeneic stem cell transplantation after a fludarabine/busulfan based reduced intensity conditioning inpatients with myelodysplastic syndromes or secondary acute myeloid leukemia. Ann Hematol 2003; 82(6):336-42.
8. Martino R, Caballero R, 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.
9. 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.
10. Myelodysplastic Syndromes. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. v.1.2007; http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf
11. 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.
12. Barrett AJ, Savani BN. Allogeneic stem cell transplantation for myelodysplastic syndrome. Semin Hematol 2008; 45(1):49-59
13. 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.
14. Valcarcel D, Martino R. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and acute myelogenous leukemia. Current Opin Oncol 2007; 19(6):660-6.
15. 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.
16. Mesa RA. Navigating the evolving paradigms in the diagnosis and treatment of myeloproliferative disorders. Hematology (Am Soc Hematol Educ Program) 2007; 2007:355-62.
17. 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.
18. Myelodysplastic Syndromes. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. v.2.2008; http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf

Index

Policy History

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