Dec. 9, 2010 Results from four innovative studies help answer outstanding questions about stem cell transplant procedures in treating various hematologic malignancies. Research recently presented at the 52nd Annual Meeting of the American Society of Hematology reveals that there is no increase in overall cancer risk in people who donate stem cells and that the utilization of a double cord blood stem cell transplant is associated with better overall outcomes when used early in the treatment of acute leukemias. While research shows that the use of an allogeneic stem cell transplant following an autologous stem cell transplant does not improve progression-free survival in patients with standard risk multiple myeloma, scientists have found a promising new treatment that may help prevent chronic graft-versus-host disease, a serious complication of stem cell transplantation.
"Major advances have been made in stem cell transplantation, and studies such as these provide further understanding of the many questions and unknowns that remain in this rapidly evolving field of research," said moderator of the press conference Armand Keating, MD, Vice President of ASH and Professor of Medicine, Director of the Division of Hematology, and Epstein Chair in Cell Therapy and Transplantation at the University of Toronto. "Results from these studies allow us to continuously improve treatment regimens and manage complications for our patients with multiple blood cancers who require stem cell transplants."
Follow-Up of 12,559 Unrelated Donors of Peripheral Blood Stem Cells or Bone Marrow
Donation of peripheral blood stem cells (PBSCs), which are stem cells found in the bloodstream, requires the application of filgrastim or similar drugs in order to mobilize the stem cells from the bone marrow to the bloodstream. Some long-term safety issues related to the use of filgrastim, including a potentially increased risk to the donor of developing leukemia, have previously been raised in the scientific literature. Past research has not extensively addressed long-term bone marrow donor safety issues. In order to further minimize risks for volunteer donors, it is therefore extremely important to determine whether the procedures in which both PBSCs and bone marrow are collected are safe.
Researchers from the DKMS German Bone Marrow Donor Center, the largest bone marrow donation center in the world, set out to determine if there were any long-term risks of developing cancer following the donation of PBSCs or bone marrow through a follow-up questionnaire sent to 15,456 donors. In the survey, four main questions were asked about the overall general health of the donor: whether the donor underwent hospitalization or long-term medical treatment for any condition following the donation, whether the donor needed to take any prescription drugs for more than four weeks after the donation, and whether the donor would be interested in donating PBSCs or bone marrow again.
Results from this retrospective study, the largest ever in terms of length of cumulative observation years, revealed that unrelated PBSC and bone marrow donation are safe procedures that do not carry any increased risk to the donor of developing cancer as compared with the general population. A total of 81.3 percent of the contacted donors sent back completed surveys (12,559 out of 15,456), translating into a total of 55,228 observation years (30,777 observation years for 8,730 PBSC donors, 23,037 observation years for 3,556 bone marrow donors, and 1,414 observation years for 273 donors of both PBSCs and bone marrow). A large majority of donors indicated that their overall health was very good or good (95.1 percent of PBSC donors, 96 percent of bone marrow donors, and 92.2 percent of dual donors). Furthermore, an overwhelming majority also indicated that they would undergo the donation procedure again, with 95.4 percent of PBSC donors and 95.9 percent of bone marrow donors indicating willingness.
Regarding the incidence of cancer in these donors, a total of 85 malignancies were reported, which included 50 cases in 8,730 PBSC donors, 31 cases in 23,037 bone marrow donors, and four cases in 1,414 dual donors. With regard to hematologic malignancies, only six cases were reported, including two cases of Hodgkin disease and one case of plasmocytoma in PBSC donors, one case of acute myeloid leukemia and one case of non-Hodgkin lymphoma in bone marrow donors, and one case of chronic lymphocytic leukemia in dual donors.
"Results of this study provide the best evidence we have so far that there is not a higher incidence of cancer associated with the donation of unrelated peripheral blood stem cells and bone marrow as compared with the general population," said lead study author Alexander H. Schmidt, MD, PhD, DKMS German Bone Marrow Donor Center. "We hope that these results underscore the fact that these donation procedures are extremely safe and will encourage more people to become donors."
Tandem Autologous Hematopoietic Stem Cell Transplants (AuHCT) With or Without Maintenance Therapy (auto-auto) Versus Single AuHCT Followed by HLA Matched Sibling Non-Myeloablative Allogeneic HCT (auto-allo) for Patients With Standard Risk (SR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial
Multiple myeloma is a form of blood cancer characterized by the overproduction of plasma cells in the bone marrow. Research has demonstrated that autologous stem cell transplantation, a procedure in which a patient is treated with high-dose chemotherapy followed by an infusion of his or her own stem cells, is associated with improved overall survival. However, relapse and progression of the disease still occur following this procedure.
Tandem autologous stem cell transplantation, a procedure in which a patient receives two sequential autologous stem cell transplants, may improve survival beyond that seen after a single transplant. Additionally, donor (allogeneic) stem cell transplantation has potential for replacement of the malignant bone marrow with healthy donor cells as well as a potentially beneficial immune-mediated graft-versus-myeloma-effect. Past studies of allogeneic transplantation for multiple myeloma with full-intensity conditioning demonstrated long-term remission in a group of patients; however, side effects and mortality were high. Non-myeloablative conditioning allogeneic stem cell transplantation (also known as a reduced-intensity transplant), in which a patient receives lower doses of chemotherapy or irradiation followed by an infusion of stem cells from a HLA-matched sibling, has been shown to reduce toxicity,while maintaining the beneficial immunologic effects of allogeneic transplantation. The use of autologous followed by reduced-intensity allogeneic transplant has been shown to be feasible, and preliminary results suggest this approach may potentially be superior to tandem autologous transplant.
Researchers from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) sought to determine if a tandem autologous stem cell transplant (auto-auto) with or without maintenance therapy improves overall survival in patients with standard risk multiple myeloma as compared with a regimen of an autologous stem cell transplant followed by non-myeloablative allogeneic stem cell transplant (auto-allo). The BMT CTN is funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute of the National Institutes of Health and has the objective of conducting phase II and III clinical trials in transplantation in the United States. This large, multicenter phase III clinical trial (BMT CTM 0102) assigned 710 patients from 43 institutions to one of two treatment arms. Patients without a matched sibling stem cell donor were enrolled in the auto-auto arm, in which a tandem autologous stem cell transplant was performed using a chemotherapy conditioning regimen of melphalan 200 mg/m2. Patients in this arm were further randomized to receive maintenance therapy of thalidomide and dexamethasone, which are active anti-myeloma drugs, or observation for one year. Patients with a matched sibling stem cell donor were enrolled in the experimental arm, referred to as the auto-allo arm, in which patients underwent an autologous stem cell transplant using a chemotherapy conditioning regimen of melphalan 200 mg/m2 followed by an allogeneic stem cell transplant using a total body irradiation (2 Gy) conditioning regimen. All patients in the study received cyclosporine and mycophenolate mofetil for prevention of graft-versus-host disease. This is a common complication of bone marrow transplantation in which the transplanted donor cells attack the cells in the recipient's body. The primary endpoint of the study was three-year progression-free survival.
The study demonstrated that after three years of follow-up, progression-free survival was 46 percent for the standard auto-auto arm compared with 43 percent for the experimental auto-allo arm, demonstrating that the experimental auto-allo approach was not significantly better than the standard auto-auto approach. Overall survival was 80 percent and 77 percent for the auto-auto and auto-allo arms, respectively. The progression/relapse rates were 50 percent and 46 percent, and treatment-related mortality was 4 percent and 11 percent for the auto-auto arm and auto-allo arm, respectively. In those patients who received the assigned second transplant (82 percent in each arm), the three-year progression-free survival rate was 47 percent for the auto-auto arm and 44 percent for the auto-allo arm. Results of this study show that, in patients with standard risk multiple myeloma, an autologous stem cell transplant followed by reduced insensity allogeneic transplant did not differ from a tandem autologous stem cell transplant in terms of progression-free or overall survival.
The investigators reported that there was poor overall compliance with the maintenance therapy of thalidomide and dexamethasone in the auto-auto arm, with 84 percent of patients not completing the therapy due to overall poor tolerability of this regimen. Progression-free survival and overall survival between the maintenance and observation groups were not significantly different, perhaps due to the high rate of discontinuation of maintenance therapy.
"Research has shown that allogeneic stem cell transplantation can be a curative procedure for certain groups of patients with multiple myeloma; however, it can be associated with increased morbidity and mortality over autologous transplant. Therefore, it is still unknown if this procedure is better in some patients than in others or if it should be the standard of care for all myeloma patients," said lead study author Amrita Krishnan, MD, Director of the Multiple Myeloma Program at the City of Hope Cancer Center in Duarte, CA. "Our study addresses this unanswered question and shows that the toxicity of allogeneic transplantation outweighed the benefits of the reduced relapse risk in patients with standard-risk myeloma."
Outcomes After Double Unit Unrelated Cord Blood Transplantation (UCBT) Compared With Single UCBT in Adults With Acute Leukemia in Remission. An Eurocord and ALWP Collaboration Study
One of the most significant limitations of cord blood transplantation, a procedure in which stem cells are collected from the umbilical cord and placenta after a baby is born, is that each cord blood unit contains limited volumes of blood, which translates into limited stem cells available for transplantation. The number of stem cells needed for a successful cord blood transplant is largely dependent on the size and weight of the patient. Often times hematopoietic stem cells from one cord blood donor are not sufficient to transplant one adult patient. In order to increase the number of cells, adult patients may need to receive two units of cord blood from two different donors.
Previous research from the University of Minnesota has shown that patients with acute leukemia who receive a double infusion of stem cells through an unrelated cord blood transplant have a lower incidence of relapse and a similar rate of leukemia-free survival, but a higher incidence of acute graft-versus-host disease than patients who receive a single cord blood stem cell transplant.
In order to confirm these findings, an analysis of outcomes from a larger population of patient outcomes was conducted to evaluate the benefits of a double unrelated versus a single unrelated cord blood transplant. Researchers from Eurocord, an international registry that collects and validates data from cord blood transplants, and the Acute Leukemia Working Party (ALWP), one of the specialized working groups of the European Group for Blood and Marrow Transplantation (EBMT), collaborated to retrospectively analyze data. This study compared outcomes from 230 double unrelated cord blood stem cell transplants with 377 single unrelated cord blood stem cell transplants in adults with acute myeloid or lymphoblastic leukemia in remission. The study examined separately outcomes in patients who received a cord blood transplant while in first remission compared with those in second or third remission.
At three years, in patients still in first remission, the unadjusted cumulative relapse incidence was significantly less in patients who received a double as compared to a single transplant (15 percent and 25 percent, respectively). The rates of leukemia-free survival were also higher in those receiving a double versus a single transplant (53 percent and 39 percent, respectively). Additionally, the incidence of non-relapse mortality was 32 percent in those receiving a double cord blood transplant compared with 36 percent in those who received a single cord blood transplant. There was a significant difference in acute graft-versus-host disease incidence between the two treatment groups, with 45 percent experiencing the complication after a double transplant compared with 27 percent following a single transplant. For those patients in a second or third complete remission, outcomes following the double transplant were not statistically different from those receiving a single transplant.
"Results from this analysis demonstrate that not only is a double cord blood transplant feasible, but the procedure is associated with better overall outcomes, especially when it is used early in the treatment of acute leukemias," said Vanderson Rocha, MD, PhD, Scientific Director of Eurocord Registry, Hopital Saint Louis, Paris. "Prospective clinical trials are currently underway in Europe and the United States in order to confirm the results seen in this study."
Prophylactic Rituximab After Allogeneic Stem Cell Transplantation Prevents Steroid-Requiring Chronic Graft-Versus-Host Disease
Approximately 50 to 60 percent of adults who receive an allogeneic stem cell transplant experience a complication called chronic graft-versus-host disease (GVHD) that occurs because of the genetic differences between the patient and the donor stem cells. In essence, the donor cells recognize the recipient's own cells as foreign and react by trying to attack and destroy the cells in the patient's body, causing debilitating and sometimes life-threatening symptoms such as skin rashes, blisters, joint pain, stiffness, dry mouth, and dry eyes. Chronic GVHD is the leading cause of mortality among people who survive two or more years following a stem cell transplant, and currently there are no effective treatment options to aid in preventing this complication.
Recent research has indicated that dysregulation of B cells, a type of white blood cell that produces antibodies to fight infection, may play a role in the development of chronic GVHD. Studies have shown that rituximab, a monoclonal antibody that works by depleting B cells, may play a role in the treatment of the condition. The purpose of this exploratory phase II study was to determine if the use of rituximab following an allogeneic stem cell transplant could help prevent chronic GVHD.
Researchers from the Dana-Farber Cancer Institute in Boston enrolled a total of 64 patients who were in remission following an allogeneic stem cell transplant to receive rituximab once every three months for one year (three, six, nine, and 12 months post-transplant). The primary endpoint of the study was to determine the incidence of steroid-requiring chronic GVHD at one year following an allogeneic stem cell transplant. Historically, researchers at Dana-Farber have found that 60 percent of all cases of chronic GVHD require treatment with corticosteroids within one year following transplant. However, treatment with corticosteroids is not optimal as these therapies are known to cause severe and unfavorable side effects.
To date, a total of 54 patients have been evaluated at 12 months after receiving all prescribed courses of rituximab. The study found that the cumulative incidence of any chronic GVHD was 44.6 percent with only 31.2 percent of patients requiring treatment with corticosteroids. Additionally, only 22.4 percent of patients were on corticosteroids at 12 months, and 50 percent were able to discontinue immunosuppressant therapy. Relapse-free survival was 71.1 percent, and overall survival was 88.6 percent.
"Results of this study indicate that rituximab is a promising therapy for the prevention of chronic graft-versus-host disease following an allogeneic stem cell transplant," said lead study author Corey Cutler, MD, MPH, FRCPC, Assistant Professor of Medicine, Harvard Medical School and Dana-Farber Cancer Institute in Boston. "It appears that the use of rituximab may reduce the need to use corticosteroids by up to 50 percent when compared with what we have used historically. However, these results need to be confirmed in a larger randomized clinical trial."
Other social bookmarking and sharing tools:
Note: If no author is given, the source is cited instead.