Nonmyeloablative Allogeneic Stem Cell Transplantation (Reduced Intensity Stem Cell Transplant) for Treatment of Malignancy
DESCRIPTION
Transplantation of allogeneic hematopoietic stem cells derived from bone marrow or peripheral blood, in conjunction with myeloablative chemotherapy, is an established therapy for various malignancies, including acute and chronic leukemias, Hodgkin’s disease, and non-Hodgkin’s lymphomas. The treatment effect results from chemotherapeutic ablation of malignant cells, as well as an associated immune-mediated graft versus malignancy effect. The conventional practice of allogeneic stem-cell transplants (allo-SCT) involves administration of myelotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at high enough doses to cause bone marrow failure in most patients. While such treatment may eradicate the malignant cells, patients are as likely to die from opportunistic infections, graft-versus-host disease, and organ failure as from the underlying malignancy.
Recently, regimens have been developed that seek to reduce treatment-related adverse effects while retaining beneficial (i.e., graft versus malignancy) effects. So-called nonmyeloablative regimens have been tentatively defined as those that do not eradicate the patient’s hematopoietic ability, allowing for relatively prompt hematopoietic recovery (e.g., 28 days or less) without a transplant. Examples of such regimens include fludarabine-cyclophosphamide and fludarabine-idarubicin-cytarabine combinations. On engraftment, patients treated with nonmyeloablative regimens will demonstrate mixed chimerism initially. Most will subsequently convert to full-donor chimerism and may be supplemented with donor lymphocyte infusions to further eradicate malignant cells. Nonmyeloablative chemotherapy is now commonly referred to as reduced-intensity conditioning (RIC), with patients also receiving allogeneic stem-cell support. This procedure also has been called “mini-transplant”.
Two general categories of individuals have been considered to determine who is a candidate for nonmyeloablative transplants. One category includes individuals who are considered candidates for a conventional, myeloablative transplant. For these individuals, conditioning with milder nonmyeloablative regimens represents a technical modification of an established procedure. The other category includes individuals who would not be considered candidates for a conventional, myeloablative transplant. For these individuals, nonmyeloablative transplants would be considered a novel approach. This is because co-morbidities preclude a standard myeloablative-conditioning regimen, or studies have not shown that conventional myeloablative allogeneic transplants have effectively treated malignancies.
POLICY
Nonmyeloablative allogeneic stem cell transplantation for individuals who are candidates for conventional high dose chemotherapy with allogenic stem cell transplantation for the treatment of malignancy is considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
Repeated labs and procedures to address changes in condition and for continued transplant listing are considered medically necessary.
Multiple labs and work-up procedures for the sole purpose of repeat evaluation at multiple transplant centers are considered not medically necessary.
Nonmyeloablative allogeneic stem cell transplantation for individuals who are not candidates for conventional high dose chemotherapy with allogeneic stem cell transplantation as treatment of malignancy is considered investigational.
Other applications of nonmyeloablative allogeneic stem-cell transplantation are considered investigational, including its use in patients who do not meet criteria for high-dose chemotherapy and allogenic stem-cell transplantation due to either age or comorbidities, or as treatment of other malignancies, including, but not limited to, multiple myeloma, renal cell carcinoma, other solid tumors, or autoimmune disease.
See also:
MEDICAL APPROPRIATENESS
Please refer to the Milliman Care Guidelines - Bone Marrow and Peripheral Blood Stem Cell Transplantations for specific disease guidelines.
Note: Medical Appropriateness Criteria below is to match that contained in the medical policy entitled High Dose (Myeloablative) Chemotherapy with Bone Marrow, Peripheral Stem Cell, or Cord Blood Transplant for Hematopoietic Stem Cell Support
Nonmyeloablative allogeneic stem cell transplantation (reduced intensity stem cell transplant) for the treatment of malignancy is considered medically appropriate if ALL of the following criteria are met:
Clinical information submitted for determination of medical appropriateness criteria is dated within the last 7 months
Presence of a disease or condition where hematopoietic stem cell transplant provides improved outcomes over standard therapy
Presence of a good performance status based on the Karnofsky Performance Scale or equivalent measurement scale
Have no serious, uncontrolled psychiatric illness that would hinder compliance with any stage of the transplant process
Have no neurologic illness independent of the disease process being treated
Have completed a full psychosocial evaluation including evaluation of support systems, etc.
Have no active drug or alcohol abuse (documented six month abstinence from drug or alcohol use and ongoing participation in a formal treatment program)
Documentation of the current status for the following: Hepatitis, Cytomegalovirus (CMV), Herpes Simplex Virus (HSV) profiling
Have no active infection (must be afebrile for greater than 48 hours and off antibiotics)
Pulmonary function tests: FVC, FEV1, DLco must all be greater than or equal to 60% of predicted (Young children may be unable to comply and may be evaluated using age appropriate testing)
Left ventricular (LV) ejection fraction must be greater than or equal to 50% of the institutional lower limit of normal
Estimated creatinine clearance must be greater than or equal to 60 ml/min
Serum bilirubin and SGOT must be less than or equal to 1.5 times the institutional upper limit of normal
If hepatitis C RNA positive, individual is ineligible for transplant if liver function tests are elevated
Willingness and ability of the individual or legal guardian to give signed consent and to comply with regular follow-up requirements
ADDITIONAL INFORMATION
Reduced intensity conditioning regimes with allogeneic stem-cell support are increasingly being used in many centers, and it is clear they will continue to evolve and will likely supplant myeloablative condition regimens for select patients. However, the scientific evidence available to date does not provide direct comparison of health outcomes with sufficiently long follow-up in similar patient groups to draw sound conclusions about the net health benefit of this therapeutic approach.
Published data in peer-reviewed literature is insufficient to permit scientific conclusions regarding the use of nonmyeloablative allogeneic stem cell transplantation for individuals who are not candidates for conventional high dose chemotherapy with allogeneic stem cell transplantation as treatment of malignancy.
SOURCES
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American Cancer Society. (2004). Issues related to stem cell transplants. Retrieved July 19, 2006 from http://www.cancer.org/docroot/ETO/content/ETO_1_4X_Stem_Cell_Transplant_and_Having_Children.asp?sitearea=ETO.
Artz, A. S., Van Besien, K., Zimmerman, T., Gajawski, T. F., Rini, B. I., Hu, H. S., et al. (2004). Long-term follow-up of nonmyeloablative allogeneic stem cell transplantation for renal cell carcinoma: The University of Chicago experience. Bone Marrow Transplant, November 15, 2004 (Epub ahead of print). Abstract retrieved December 3, 2004 from PubMed database.
BlueCross BlueShield Association. Medical Policy Reference Manual. (5:2008). Nonmyeloablative Allogeneic Stem-Cell Transplantation for Treatment of Malignancy. (8.01.38). Retrieved June 16, 2008 from BlueWeb. (24 articles and/or guidelines reviewed)
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Childs, R., Clave, E., Contentin, N., Jayasekera, D., Hensel, N., Leitman, S. et al. (1999). Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood, 94 (9), 3234-3242. Abstract retrieved July 6, 2001 from MDConsult Database.
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Feinstein, L., Sandmaier, B., Maloney, D., McSweeney, P. A., Maris, M., Flowers, C. et al. (2001). Nonmyeloablative hematopoietic cell transplantation. Replacing high-dose cytotoxic therapy by the graft-versus-tumor effect. Annals of New York Academy of Science, 938: 328-337. Abstract retrieved August 8, 2001 from PubMed database.
Giralt, S., Khouri, I., & Champlin, R. (1999). Nonmyeloablative mini-transplants. Cancer Treatment and Research, 101, 97-108. Abstract retrieved July 6, 2001 from MDConsult database.
Gomez-Almaguer, D., Ruiz-Arguelles, G. J., Ruiz-Arguelles, A., Gonzalez-Llano, O., Cantu, O. E., & Hernandex, N. E. (2000). Hematopoietic stem cell allografts using a non-myeloablative conditioning regimen can be safely performed on an outpatient basis: report of four cases. Bone Marrow Transplantation, 25 (2), 131-133. Abstract retrieved July 6, 2001 from MDConsult database.
Grigg, A., Seymour, J. F., Roberts, A., & Szer, J. (1999). Mini-allografts' for haematological malignancies: An alternative to conventional myeloablative marrow transplantation. Australian and New Zealand Journal of Medicine, 20 (3), 308-314. Abstract retrieved July 30, 2001 from PubMed database.
Health Technology Assessment Information Service. Windows on medical technology. (2001, November). Allogeneic stem cell transplantation for treatment of metastatic renal cell carcinoma. Retrieved March 24, 2003 from ECRI HTAIS.
Khouri, I. F., Lee, M. S., Romaguere, J., Mirza, N., Kantarjian, H., Karbling, M. et al. (1999). Allogeneic hematopoietic transplantation for mantle-cell lymphoma: Molecular remissions and evidence of graft-versus-malignancy. Annals of Oncology, 10 (11), 1293-1299. Abstract retrieved February 16, 2000 from PubMed database.
McSweeney, P. A., & Storb, R. (1999). Mixed chimerism: Preclinical studies and clinical applications. Biology of Blood and Marrow Transplantation. 5 (4), 192-201. Abstract retrieved July 6, 2001 from MDConsult database.
McSweeney, P. A., Niederwieser, D., Shizuru, J. A., Sandmaier, B. M., Molina, A. J., Maloney, D. G., et al. (2001). Hematopoietic cell transplantation in older patients with hematologic malignancies: Replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood, 97 (11), 3390-3400. Abstract retrieved August 8, 2001 from PubMed database.
Michallet, M., Bilger, K., Garban, F., Attal, M., Huyn, A., Blaise, D., et al. (2001). Allogeneic hematopoietic stem-cell transplantation after nonmyeloablative preparative regimens: Impact of pretransplantation and posttransplantation factors on outcome. Journal of Clinical Oncology, 19 (14), 3340-3349.
Radich, J. P., Olavarria, E., & Apperley, J. F. (2004). Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia. Hematology / Oncology Clinics North America, 18 (3), 685-702.
Sandmaier, B. M., McSweeney, P., Yu, C., & Storb, R. (2000). Nonmyeloablative transplants: preclinical and clinical results. Seminars in Oncology, 27(Suppl. 5) 78-81. Abstract retrieved July 30, 2001 from PubMed database.
Shimoni, A., Giralt, S., Khouri, I., & Champlin, R. (2000) Allogeneic hematopoietic transplantation for acute and chronic myeloid leukemia: non-myeloablative preparative regimens and induction of the graft-versus-leukemia effect. Current Oncology Reports, 2 (2), 132-139. Abstract retrieved July 30, 2001 from PubMed database.
Slavin, S., Nagler, A., Shapira, M., Panigrahi, S., Samuel, S., & Or, A. (2001). Non-myeloablative allogeneic stem cell transplantation focusing on immunotherapy of life-threatening malignant and non-malignant diseases. Critical Reviews in Oncology/Hematology, 39 (1-2), 25-29. Abstract retrieved August 8, 2001 from PubMed database.
The Technology Evaluation Center. (2001, May). Nonmyeloablative allogeneic stem-cell transplantation for malignancy (Vol.16, No. 3). Chicago: BlueCross BlueShield Association.
ORIGINAL EFFECTIVE DATE: 1/1/2002
MOST RECENT REVIEW DATE: 8/14/2008
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