The number of allogeneic transplants from unrelated donors has grown in the past decade in part because of the expansion of the donor registry size. Patient survival has improved due to the selection of more closely matched donors and the development of effective infection prophylaxis. Relapse-free survival remains limited in patients with a large tumor burden at the time of transplantation. A higher marrow cell dose is the major factor to minimize transplant-related death. Future studies of peripheral blood stem cell transplants should be considered for patients with acute leukemia with the goal of enhancing the stem cell dose and improving survival.
Between 1500 and 2000 marrow or blood stem cell transplants are performed nationwide each year for the treatment of acute myelogenous leukemia (AML), according to the International Bone Marrow Transplant Registry (IBMTR).1 Approximately 20% of those transplants are autologous, 60% are from an allogeneic related donor, and 20% are from an allogeneic unrelated donor. In the last decade, the expansion in the pool of volunteer donors has led to an increased probability of finding a match and to a progressive increase in the number of unrelated donor transplants. Globally, there are now more than five million donors typed for HLA-A and B, and 40% of those are also typed for DR.2 In the US, the probability of finding at least one HLA-A, B, and DR matched donor averages 80%, but varies for minorities: there is a 55% probability of finding a match for African–Americans compared to 85% for Caucasians (National Marrow Donor Program (NMDP) data).
Data from the IBMTR on patients with AML transplanted from sibling or unrelated donors have shown that the stage of disease at transplant affects survival.1 Unrelated donor transplants are associated with slightly less survival than HLA-identical sibling transplants for the same stage of disease. However, patients with AML in first remission who are selected for transplants from unrelated donors have high risk features that are usually not demanded for patients that are selected for first remission transplant from an HLA-identical sibling donor.
The Seattle experience
The Seattle marrow transplant team has performed marrow transplantation from unrelated donors in 16 patients with AML in first remission (unpublished data and Ref. 3). These patients had one of three features: (1) high risk cytogenetics, including abnormalities of chromosomes 5 and 7 or complex abnormalities; (2) requirement for more than one cycle to induce a first complete remission (CR); (3) minimal residual disease by molecular probes or flow cytometry. Eight of the 16 patients have remained in first complete remission for 1–7 years. Despite high risk AML, only 3/16 patients have relapsed, suggesting that unrelated donor transplants may have a potent antileukemic effect. Nevertheless, the primary indication for referral of patients with AML for an unrelated donor transplant is failure to induce or maintain remission with chemotherapy.
The probability of relapse-free survival is less in patients transplanted for more advanced disease, 35–40% for patients in second remission, and 10–15% for patients transplanted with relapsed leukemia. The primary factor leading to treatment failure in patients with overt leukemia at transplant is occurrence of post-transplant relapse.3 The cumulative incidence of relapse exceeded 50% for patients transplanted after primary induction failure, and was 44% for those patients with leukemia in relapse. In contrast, the post-transplant relapse was 20% for patients transplanted in either first or second remission. We reported that tumor burden at the time of transplant affects the probability of relapse-free survival.3 For those patients with relapsed leukemia who had circulating blasts, the probability of disease-free survival was less than 2%. For those patients transplanted with less than 30% marrow blasts but no circulating blasts, the probability of disease-free survival was similar to those transplanted in second remission.
A major problem of unrelated donor transplantation is the high incidence of transplant-related mortality, mostly within the first year from transplantation.3 Transplant-related mortality was 25–30% for patients in first remission or primary induction failure, and up to 50% in patients with more advanced disease.3 Transplant-related mortality is age-dependent, with patients below 20 years doing better than older patients.
Role of marrow cell dose
The dominant factor associated with improved disease-free survival and less transplant-related mortality in acute leukemia patients is marrow cell dose.3 This finding was originally reported in a study of patients with AML or acute lymphocytic leukemia (ALL) transplanted in Seattle up to 1994.3 We have recently confirmed that relapse-free survival is associated with marrow cell dose in patients with AML (n = 35) transplanted in first or subsequent remission between 1995 and 1998 (Sierra and Anasetti, manuscript in preparation). The median value of nucleated marrow cells transplanted was 4.0 × 108 cells/kg of recipient body weight. Relapse-free survival at 2 years was 61% and 26%, respectively, for patients that received a cell dose above the median compared to those who received a cell dose below the median (P = 0.02). The effect of cell dose on relapse-free survival was mediated by a decreased incidence of transplant-related mortality and was independent of patient age. A higher cell dose had a very slight effect on shortening the time of granulocyte recovery. There was a significant association of lower marrow cell dose with episodes of neutropenia after initial engraftment (P = 0.008). Most patients who experienced neutropenia died of infectious complications, predominantly pneumonia.3
In a prospective study of 121 consecutive transplants from unrelated donors performed for a variety of diseases at the Fred Hutchinson Cancer Research Center, we tested the hypothesis that the CD34 cell count was responsible for the effects attributed to a high marrow cell dose.14 We found that a CD34 cell dose above the median of 2.5 × 106 cells/kg was associated with a significant improvement in disease-free survival at 1 year (66% vs 44%, P = 0.03). Fifty patients on the study were transplanted for chronic myelogenous leukemia (CML) in chronic phase and 36 patients had AML or ALL. The CD34 cell dose was associated with improved relapse-free survival in both subsets of patients.
There was no evidence that the cell dose of CD14, CD20, CD56, CD8, or CD4 subsets was associated with improved outcome. Taken together, our data suggest that the beneficial effects of higher marrow cell dose on outcome are related to the stem cell inoculum, which we can measure with the CD34 marker. These data also make a strong case for increasing the inoculum of CD34+ cells. One way to achieve this goal, given that bone marrow is a limited source of stem cells, is to use peripheral blood from growth factor-treated donors.4
Cord blood transplantation
Given the importance of the stem cell dose in alternative donor transplants, and the observation that the cell dose is extremely limited in cord blood transplants, one would expect an extreme impairment in outcome when a low cord blood cell dose is transplanted. Data from two studies show very clearly that survival is better in patients transplanted with a higher dose of cord blood cells.56 The probability of treatment failure, including death, a second transplant, or autologous reconstitution, is increased by a lower cord blood cell dose.6 Since there is an inverse correlation between cell dose and patient age, there will be a clear limitation of cord blood transplants for older patients.
The role of T cell depletion
The concept that a higher stem cell dose can improve outcome relates also to the use of marrow T cell depletion after allogeneic transplants.7 So far, there has been no improvement in survival with T cell-depleted compared to T cell-replete marrow transplants. One of the possibilities that may explain the lack of improved survival despite the decreased incidence of graft-versus-host disease (GVHD), is that the ex vivo marrow manipulation has led to the loss of stem cells. Data have shown that after T cell depletion, the CD34 cell dose in the graft was correlated with better outcome.7 A recent analysis from the NMDP also showed that T cell depletion has not improved outcome in unrelated donor transplantation.8 However, in the NMDP analysis, patients with AML in second remission had improved outcome after a T cell-depleted marrow graft.
AML patients in first remission transplanted with T cell-depleted marrow have had excellent survival rates after an intensive pretransplant regimen and no immune suppression post-transplant.9 A similar approach has been reported by Aversa et al,10 who used donor blood mobilized stem cells so carefully depleted of T cells that they did not cause GVHD after transplantation across a whole HLA incompatible haplotype despite no postgrafting immune suppression. With an intensified conditioning regimen and a peripheral blood T cell-depleted graft, the authors reported a 36% disease-free survival at 1 year for AML patients.10 These data are intriguing because they showed that graft failure is no longer a problem if an intensified conditioning regimen and an increased cell dose are used. However, early post-transplant mortality is a complication of using an intensified regimen, and long-term immunodeficiency is a complication of ex vivo T cell depletion.
HLA-compatible, unrelated donors can now be found for 50–85% of patients in need of an allogeneic transplant. Selection of a closer match and better infection prophylaxis have improved survival after unrelated donor transplantation.111213 The outcome of patients with AML is better in remission or after transplant with a low tumor burden. We believe that phase II studies of unrelated donor transplants in patients with high-risk AML in first CR are now justified. The dose of CD34 cells in the graft correlates with more robust engraftment and better patient survival providing the rationale to develop the use of mobilized blood instead of marrow stem cells. The effectiveness of T cell depletion in improving survival after allogeneic transplantation might have not been fully realized because of the limiting number of the stem cells in the graft. Results of initial clinical trials of T cell-depleted blood progenitor cells are intriguing.
Horowitz MM, Rowlings PA . An update from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry on current activity in hematopoietic stem cell transplantation Curr Opin Hematol 1997 4: 395–400
Anonymous . Bone Marrow Donors Worldwide Internet address: http://www.bmdw.org
Sierra J, Storer B, Hansen JA, Bjerke JW, Martin PJ, Petersdorf EW, Appelbaum FR, Bryant E, Chauncey TR, Sale G, Sanders JE, Storb R, Sullivan KM, Anasetti C . Transplantation of marrow cells from unrelated donors for treatment of high-risk acute leukemia: the effect of leukemic burden, donor HLA-matching, and marrow cell dose Blood 1997 89: 4226–4235
Ringden O, Remberger M, Runde V, Bornhauser M, Blau IW, Basara N, Holig K, Beelen DW, Hagglund H, Basu O, Ehninger G, Fauser AA . Peripheral blood stem cell transplantation from unrelated donors: a comparison with marrow transplantation Blood 1999 94: 455–464
Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R, Ortega J, Souillet G, Ferreira E, Laporte JP, Fernandez M, Chastang C . Outcome of cord-blood transplantation from related and unrelated donors New Engl J Med 1997 337: 373–381
Rubinstein P, Carrier C, Scaradavou A, Kurtzberg J, Adamson J, Migliaccio AR, Berkowitz RL, Cabbad M, Dobrila NL, Taylor PE, Rosenfield RE, Stevens CE . Outcomes among 562 recipients ofplacental-blood transplants from unrelated donors New Engl J Med 1998 339: 1565–1577
Mavroudis D, Read E, Cottler-Fox M, Couriel D, Molldrem J, Carter C, Yu M, Dunbar C, Barrett J . CD34+ cell dose predicts survival, posttransplant morbidity, and rate of hematologic recovery after allogeneic marrow transplants for hematologic malignancies Blood 1996 88: 3223–3229
Wagner JE, King R, Kollman K, Anasetti C, Antin J, Casper J, Champlin R, Davies SM, Drobyski W, Fay J, Filipovich A, Heslop H, Karanes C, Kernan N, Nademanee A, Schmeckpeper B, Howe C . Unrelated donor bone marrow transplantation in 5075 patients with malignant and nonmalignant disorders: impact of marrow T cell depletion Blood 1998 92: 686a (Abstr.)
Papadopoulos EB, Carabasi MH, Castro-Malaspina H, Childs BH, Mackinnon S, Boulad F, Gillio AP, Kernan NA, Small TN, Szabolcs P, Taylor J, Yahalom J, Collins NH, Bleau SA, Black PM, Heller G, O'Reilly RJ, Young JW . T-cell-depleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: freedom from relapse in the absence of graft-versus-host disease Blood 1998 91: 1083–1090
Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, Ruggeri L, Barbabietola G, Aristei C, Latini P, Reisner Y, Martelli MF . Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with on fully mismatched HLA haplotype New Engl J Med 1998 339: 1186–1193
Hansen JA, Gooley TA, Martin PJ, Appelbaum F, Chauncey TR, Clift RA, Petersdorf EW, Radich J, Sanders JE, Storb RF, Sullivan KM, Anasetti C . Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia New Engl J Med 1998 338: 962–968
Petersdorf EW, Gooley TA, Anasetti C, Martin PJ, Smith AG, Mickelson EM, Woolfrey AE, Hansen JA . Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient Blood 1998 92: 3515–3520
Sasazuki T, Juji T, Morishima Y, Kinukawa N, Kashiwabara H, Inoki H, Yoskida T, Kimura A, Akaza T, Kamikawaji N, Kodera Y, Takaku R . Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program New Engl J Med 1998 339: 1177–1185
Anasetti C, Heimfeld S, Rowley S, Martin P, Petersdorf EW, Woolfrey A, Hansen JA . Higher CD34 cell dose is associated with improved survival after marrow transplantation from unrelated donors Blood 1999 94: (in press)
About this article
Cite this article
Anasetti, C. Transplantation of hematopoietic stem cells from alternate donors in acute myelogenous leukemia. Leukemia 14, 502–504 (2000). https://doi.org/10.1038/sj.leu.2401648
ISBT Science Series (2015)
Cost and outcome in stem cell collections in HLA-haplo identical/mismatched related transplantation with combined granulocyte-colony stimulating factor-mobilized blood and bone marrow for patients with hematologic malignancies
Transfusion and Apheresis Science (2010)
Journal of Hematology & Oncology (2008)
Bone Marrow Transplantation (2008)
Nonmyeloablative allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors: A review
Blood Cells, Molecules, and Diseases (2008)