Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukemia

Overview

Patients with chronic myeloid leukemia (CML) are treated initially with tyrosine kinase inhibitors such as Gleevec® (imatinib), Sprycel® (dasatinib), or Tasigna® (nilotinib). Patients who are resistant or intolerant of these agents are potential candidates for allogeneic stem cell transplantation. Prior to the development of Gleevec, allogeneic stem cell transplants were the only potentially curative therapy for patients with CML, and early transplants were recommended for younger patients. Since the development of effective oral drug treatment of CML, allogeneic stem cell transplantation has been predominately reserved for second-line therapy.[1] In this setting allogeneic stem cell transplantation remains a potentially curative treatment.

A variety of factors ultimately influence a patient's decision to receive treatment for cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient's chance of cure, or prolong a patient's survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of the treatment in question.

The following is a general overview of allogeneic stem cell transplantation for treatment of CML. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.

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For a general overview of the process of allogeneic stem cell transplantation, select Allogeneic Stem Cell Transplant.

Selection of Donors

The first choice for a donor of stem cells is a human leukocyte antigen (HLA)-matched relative; however, such an ideal donor is only available for a minority of patients, resulting in the need to expand the donor pool. It has been determined that related donors who are mismatched for only one HLA antigen are also suitable stem cell donors. Over the past two decades, there has been a marked increase in the number of unrelated donor transplants, with outcomes similar to those achieved with related donor transplants. However, because of genetic disparity, unrelated matched donors cannot be found for many patients, especially for those with unusual HLA types, such as those found in many minority populations. In addition to the genetic problem, many patients die while seeking an unrelated donor, which can be a lengthy process. This has led to the successful development of umbilical cord blood transplantation, which allows for a greater degree of HLA mismatching.

Pretransplant Treatment Regimens

Younger healthy patients with CML are usually treated with intensive chemotherapy with or without total body irradiation prior to stem cell infusion. Such intensive treatment is called myeloablative therapy. Older patients and those with other significant medical conditions are treated with a reduced intensity transplant regimen in order to decrease toxicities.

The following sections will deal predominantly with CML patients who are not responding to Gleevec or who are intolerant to Gleevec and/or other tyrosine kinase inhibitors.

Allogeneic Stem Cell Transplantation

Most of the data concerning the outcomes of allogeneic stem cell transplants has been in patients receiving intensive chemotherapy with or without total body irradiation prior to the Gleevec era. However, recent studies have focused on the impact of prior Gleevec therapy on the results of allogeneic stem cell transplants for patients who are not responding to Gleevec or who are intolerant to Gleevec.

It is generally thought that the best time to perform an allogeneic stem cell transplant is while patients are still in the chronic phase of CML but have developed resistance or intolerance to Gleevec. Transplant results are much worse if delayed until later stages.

Researchers from the Fred Hutchinson Cancer Research Center have reported the outcomes of patients with CML in chronic phase who had received at least three months of Gleevec prior to a conventional myeloablative allogeneic stem cell transplant.[2]They compared the outcomes of patients transplanted in chronic phase who had not received Gleevec with comparable patients who had received Gleevec. The median time from diagnosis to transplant was 1.7 years for the Gleevec group and approximately one year for the comparison group. The three-year survival was 74% for both groups, which may be less than has been observed previously for patients transplanted within one year of diagnosis in the pre-Gleevec era. Among patients in the Gleevec group, three-year overall survival of patients who had a major or complete cytogenetic remission to Gleevec was 97%, while the survival of patients with minor or minimal cytogenetic response or loss of response was 58%. These data suggest that patients who have a poor response to Gleevec have aggressive disease that may be difficult to eradicate with an allogeneic stem cell transplant.

Reduced-intensity Allogeneic Stem Cell Transplants

Traditionally, the radiation and chemotherapy regimens used in allogeneic stem cell transplants are very toxic and involve complete destruction of the bone marrow. Recently, several transplant centers have evaluated less toxic regimens for preparation of patients prior to an allogeneic transplant. The concept is to suppress the patient’s immune system enough for the body to receive a graft of donor stem cells and then induce the graft to fight the leukemia by the infusion of donor lymphocytes. The cancer is attacked both by the immune system and by the chemotherapy drugs.

Researchers from M.D. Anderson have reported results of reduced-intensity allogeneic stem cell transplantation in 64 patients with advanced CML who were not candidates for a standard myeloablative transplant.[3] Half the patients received stem cells from related and half from unrelated donors. With a median follow-up of seven years, overall survival was 33% and progression-free survival was 20%.

Umbilical Cord Blood Transplants

Umbilical cord blood transplants have become an integral part of the management of pediatric and adult patients with hematologic diseases who do not have a suitable related or unrelated stem cell donor. There is increasing evidence that the outcomes of patients with hematologic malignancies receiving umbilical cord blood transplants are comparable to those achieved with related and unrelated donors.One of the main advantages of cord blood transplantation is that stem cells are available without delay, which is a decided advantage because many patients worsen or die before an unrelated donor is found. There is also evidence that the degree of mismatching for HLA antigens is not as important for umbilical cord blood as it is for marrow or blood stem cells. The major limitation of umbilical cord blood transplants is the low cell number with delayed or absent engraftment. There has been skepticism that single units of cord blood would be adequate for full engraftment in adults.

Researchers from the University of Minnesota have reported that adults with hematological diseases have a three-year survival of almost 50% following umbilical cord blood transplantation after a reduced-intensity treatment regimen.[4]It was also suggested that adult patients have better outcomes when two separate cord blood collections are infused together. One of the two cord blood collections is selected on the basis of being a partial rather than a full HLA match. The theory is that stem cells from the mismatched umbilical cord blood collection will contribute to initial engraftment but will ultimately be rejected by a graft-versus-graft reaction.

Researchers from Japan have reported that patients with hematologic malignancies treated with umbilical cord blood transplants have similar outcomes to patients receiving HLA-matched related transplants.[5] This study included patients with CML.

  • The three-year disease-free survival was 70% for cord blood and 60% for bone marrow and peripheral blood transplants.
  • The three-year disease-free survival for standard-risk patients was 93% for cord blood and 85% for bone marrow and peripheral blood transplants.
  • The 3-year disease-free survival for high-risk patients was 56% for cord blood and 45% for bone marrow and peripheral blood transplants.
  • Graft-versus-host disease was less frequent after cord blood transplantation.

These authors concluded that unrelated umbilical cord blood transplants were as safe and as effective as related bone marrow or peripheral blood stem cell transplants.

Treatment of Patients Who Relapse After Allogeneic Stem Cell Transplantation

There are a variety of treatments available for patients with CML who relapse after an allogeneic stem cell transplant. These include Gleevec or other tyrosine kinase inhibitors, interferon alfa, donor lymphocyte infusions, and even a second transplant.

Gleevec has become the first treatment of choice for relapses following allogeneic stem cell transplants. Patients who relapse after an allogeneic stem cell transplant can also receive Sprycel® (dasatinib) or Tasigna® (nilotinib) if they have already shown resistance to Gleevec.

Strategies to Improve Results of Allogeneic Stem Cell Transplantation for CML

The main reasons patients with CML do not respond to treatment with an allogeneic stem cell transplant are relapse and treatment-related mortality. Relapse of leukemia occurs because the high-dose treatment is unable to kill all of the cancer cells. Treatment-related deaths are due to regimen-related side effects, infections, and graft-versus-host disease.

Most transplant centers have research programs to evaluate:

  • New pre-transplant treatment regimens
  • New treatments for graft–versus-host disease
  • Novel post-transplant treatments to prevent relapse

References


[1] Giralt SA, Areora M, Goldman JM, et al. Impact of imatinib therapy on the use of allogeneic progenitor cell transplantation for the treatment of chronic myeloid leukemia. British Journal of Cancer. 2007;137:461-467.

[2] Oehler VG, Gooley T, Snyder DS, et al. The effects of imatinib mesylate treatment before allogeneic stem cell transplant for chronic myeloid leukemia. Blood. 2007;109:1782-9.

[3] Kebriaci P, Detry MA, Giralt S, et al. Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia. Blood. 2007;110:3456-3462.

[4] Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood. 2005;105:1343-1347.

[5] Takahashi S, Ooi J, Tomonari A, et al. Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen. Blood 2007;109:1322-1330.