Advances in Stem Cell Transplantation for AML

Advances in Stem Cell Transplantation for AML.

Advances in Stem Cell Transplantation for AMLDecember 7-11, 2001Orlando, FloridaC. D. Buckner M.D.

Scientific Editor: Charles H. Weaver M.D.

HLA Matched Peripheral Blood Stem Cells (PBSC) Are Superior To Bone Marrow

Researchers from the Royal Marsden Hospital compared outcomes of 40 patients receiving allogeneic bone marrow transplants (BMT) with the outcomes of 19 who received Neupogen®-stimulated PBSC. The actuarial probability of acute graft-versus-host-disease (GVHD) (any grade) was 82% following BMT and 79% following PBSC transplants. Relapse occurred in 19% of bone marrow recipients and 0% of peripheral blood recipients. Non-relapse mortality was 33% for bone marrow recipients and 28% for peripheral blood recipients. Overall survival was 57% following bone marrow and 72% following PBSC transplantation. Disease-free survival was 54% following bone marrow and 72% following peripheral blood transplantation.

Chronic GVHD occurred in 46% of bone marrow and 48% of PBSC recipients. The authors concluded that chronic GVHD rates are comparable with bone marrow or PBSC transplants when the stem cell donor is an HLA-identical sibling and GVHD prophylaxis is rigorous. More powerful graft-versus-tumor effects associated with PBSC transplants may be associated with lower relapse rates. The authors concluded that PBSCs should replace bone marrow as the preferred source of stem cells for transplantation of HLA-identical siblings in conjunction with rigorous GVHD prophylaxis. 1

Striking Survival Advantage of Bad-Risk AML Patients Transplanted from Haploidentical Donors with KIR Epitope Incompatibility in the GvH Direction.

Researchers from Perugia have had success with haplo-mismatched transplants. Since these transplants are T-cell depleted, they have been investigating ways to improve the immunotherapeutic potential of these grafts. They have been evaluating the expression of inhibitory receptors (KIR) for major histocompatibility complex (MHC) class I allotypes. They have found that a persons natural killer (NK) cells will not recognize and will, therefore, kill cells from individuals lacking his/her KIR epitopes. Transplants from these KIR epitope incompatible donors have higher engraftment rates. Therefore, a GVL effector and engraftment facilitating mechanism, which is independent of T-cell-mediated GVH reactions, may be operational in HLA-mismatched hematopoietic cell transplants. They have previously reported that in HLA haplotype-mismatched stem cell transplants (Aversa et al, NEJM 1998), when KIR epitope incompatibility is in the GVH direction, the post-grafting NK repertoire contains high-frequency donor-vs-recipient alloreactive NK clones, which kill pre-transplant cryo-preserved host targets, including myeloid leukemia cells (Ruggeri et al, Blood 1999).

The clinical impact of this phenomenon was evaluated in 92 transplanted bad-risk acute leukemia patients with a minimum follow-up of one year (1-8 years). Transplants were divided into two groups. In the first (n=58), there was no (HLA-C group 1, HLA-C group 2, HLA-Bw4 alleles) KIR epitope incompatibility in the GVH direction and, indeed, only 1/58 donors possessed anti-recipient NK clones. In the second (n=34), there was KIR epitope incompatibility in GVH direction, and all 34 donors possessed NK clones alloreactive against recipient target cells. In the absence of KIR epitope incompatibility in the GVH direction, rejection and GVHD rates were 15.5% and 13.7%, respectively. In the presence of KIR epitope incompatibility in the GVH direction, graft rejection and GVHD rates were both 0% (P<0.01). Moreover, while in the absence of GVH KIR epitope disparity relapses occurred in 10/37 AML patients (with a probability of relapse at 5 years of 0.6), zero relapses occurred in 20 AML patients transplanted from donors with KIR epitope incompatibility in the GVH direction (P<0.002). Evidence from mouse models shows alloreactive NK cells kill myeloid leukemia, ablate the host immune system, and eliminate host APCs, triggering GVHD (Ruggeri et al, ASH 2001).

The combined action of these effects impacts dramatically on the event-free survival (EFS) of AML patients, which was 10% in the absence of KIR epitope incompatibility in the GVH direction, vs 60% in its presence. Consequently, the probability of EFS at 8.5 years is 0.1 in the first group vs 0.6 in the second (P<0.001). Donors with KIR epitope incompatibility in the GVH direction can be found for up to 2/3 of patients. Choosing them may offer a striking advantage for survival. 2

HLA Matched Peripheral Blood Stem Cells (PBSC) Are Superior To Bone Marrow

Researchers from the Royal Marsden Hospital compared outcomes of 40 patients receiving allogeneic bone marrow transplants (BMT) with the outcomes of 19 who received Neupogen®-stimulated PBSC. The actuarial probability of acute graft-versus-host-disease (GVHD) (any grade) was 82% following BMT and 79% following PBSC transplants. Relapse occurred in 19% of bone marrow recipients and 0% of peripheral blood recipients. Non-relapse mortality was 33% for bone marrow recipients and 28% for peripheral blood recipients. Overall survival was 57% following bone marrow and 72% following PBSC transplantation. Disease-free survival was 54% following bone marrow and 72% following peripheral blood transplantation.

Chronic GVHD occurred in 46% of bone marrow and 48% of PBSC recipients. The authors concluded that chronic GVHD rates are comparable with bone marrow or PBSC transplants when the stem cell donor is an HLA-identical sibling and GVHD prophylaxis is rigorous. More powerful graft-versus-tumor effects associated with PBSC transplants may be associated with lower relapse rates. 3

The European Bone Marrow Transplant Group also compared allogeneic peripheral blood stem cells (PBSC) to bone marrow (BM) in adult patients with AML (n=2294) and ALL (n=1171). The source was BM in 2,563 patients and PBSC in 1,102 patients. They also found faster engraftment with PBSC. Acute GVHD did not differ in patients receiving BM or PBSC. However, chronic GVHD occurred in 32% of the AML patients receiving BM vs. 46% among those receiving PBSC (p<0.0001). For ALL patients, chronic GVHD appeared in 40% vs. 49% in the two groups, respectively (p<0.008). Treatment related mortality, relapse, LFS and survival did not differ in AML or ALL patients receiving BM or PBSC. They concluded that patients receiving PBSC compared to BM had a significantly faster engraftment of ANC and platelets and an increased risk of chronic GVHD. However, acute GVHD, TRM, relapse, LFS and survival did not differ in AML or ALL patients receiving BM or PBSC from HLA-identical sibling donors. 4

Both studies support the initial report by Bensinger et al7 that PBSCs should replace bone marrow as the preferred source of stem cells for transplantation of HLA-identical siblings in conjunction with rigorous GVHD prophylaxis.

EBMT Reports 5-Year 60% LFS in Children Receiving Autografts for AML in First CR.

The European Bone Marrow Transplant Group (EBMT) evaluated factors influencing outcomes of autologous transplants for AML in 387 children. All children were in first complete remission and had a median age at transplantation of 7.8 years (range 0.5 16.0). The source of stem cells was bone marrow for 318 and peripheral blood for 69. One hundred and twenty patients received marrow cells purged in vitro with an active cyclophosphamide derivative. In 157 patients, a radiotherapy-containing preparative regimen was employed, whereas the 230 remaining children received a chemotherapy-based myeloablative therapy. Among these latter children, 37 were treated with the BAVC preparative regimen and 138 were given busulfan in combination with other cytotoxic drugs.

In multivariate analysis, they found that use of PBSC as stem-cell source and use of BAVC as preparative regimen were associated with faster neutrophil recovery. Infusion of PBSC, young age, use of BAVC as preparative regimen and no marrow purging were predictive of an accelerated platelet reconstitution. The 5-year Kaplan-Meier estimates of TRM, relapse and LFS were 3%, 39% and 60%, respectively. No factor influenced TRM, whereas in multivariate analysis relapse, probability was increased in children given the BAVC regimen and decreased after in vitro purging, as well as in children with FAB M3 and a time interval between CR and transplant greater than 170 days. These 2 latter variables favorably influenced the probability of LFS, which was, by contrast, reduced with BAVC regimen. In multivariate analysis, a trend for a favorable effect of purging on the probability of LFS was also observed (p= 0.07).< /SPAN>

The authors concluded that this study proved that autologous stem cell transplants in children with AML in 1st CR is a safe procedure, able to cure a relevant proportion of patients and the results obtained can be of help in designing further prospective studies. 5

REFERENCES

  1. Sirohi, B., Powles, R., Singhal, S., et al. Melphalan-Total Body Irradiaiton and Allogeneic Transplantation from HLA-Identical Siblings for Acute Myeloid Leukemia in First Remission: Higher Relapse after Marrow-Derived Stem Cell Grafts Compared to Blood Despite Similar Chronic Graft-Versus-Host Disease. American Society of Hematology: 43 rd Annual Meeting Program and Abstracts. Blood. Vol. 98, No. 11, Part 2. 2001. Abstract 5305.
  2. Ruggeri, L., Capanni, M., Urbani, E., et al. Striking Survival Advantage of Bad-Risk Acute Myeloid Leukemia Patients Transplanted from Haploidentical Donors with KIR Epitope Incompatibility in the GvH Direction. American Society of Hematology: 43 rd Annual Meeting Program and Abstracts. Blood. Vol. 98, No. 11, Part 1. 2001. Abstract 3553.
  3. Sirohi, B., Powles, R., Singhal, S., et al. Melphalan-Total Body Irradiaiton and Allogeneic Transplantation from HLA-Identical Siblings for Acute Myeloid Leukemia in First Remission: Higher Relapse after Marrow-Derived Stem Cell Grafts Compared to Blood Despite Similar Chronic Graft-Versus-Host Disease. American Society of Hematology: 43 rd Annual Meeting Program and Abstracts. Blood. Vol. 98, No. 11, Part 2. 2001. Abstract 5305.
  4. Ringden, O., Labopin, M., Bacigalupo, A., et al. Transplantation of Peripheral Blood Stem Cells as Compared with Bone Marrow from HLA-Identical Siblings in Patients with Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia. American Society of Hematology: 43 rd Annual Meeting Program and Abstracts. Blood. Vol. 98, No. 11, Part 1. 2001. Abstract 2012.
  5. Locatelli, F., Labopin, M., Ortega, J., et al. Factors Influencing Outcome and Incidence of Long-Term Complications in Children Given Autologous Stem Cell Transplantation for Acute Myeloid Leukemia in 1st Complete Remission. American Society of Hematology: 43 rd Annual Meeting Program and Abstracts. Blood. Vol. 98, No. 11, Part 1. 2001. Abstract 3564.
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