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Originally published as JCO Early Release 10.1200/JCO.2005.09.117 on March 7 2005 © 2005 American Society of Clinical Oncology. Full Haplotype-Mismatched Hematopoietic Stem-Cell Transplantation: A Phase II Study in Patients With Acute Leukemia at High Risk of RelapseFrom the Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Italy; the Department of Immunology, Weizmann Institute, Rehovot, Israel Address reprint requests to Franco Aversa, MD, HSCT Unit, Hematology Section, University of Perugia, 06100 Perugia, Italy; e-mail: aversa{at}unipg.it
PURPOSE: Establishment of hematopoietic stem-cell (HSC) transplantation from mismatched relatives is feasible for patients with acute leukemia. As our original method of graft processing was unsuitable for large-scale clinical studies, we use automated devices for CD34+ cell purification. PATIENTS AND METHODS: Sixty-seven patients with acute myeloid leukemia (AML; 19 complete remission [CR] 1, 14 CR 2, nine CR > 2, 25 in relapse) and 37 with acute lymphoid leukemia (ALL; 14 CR 1, eight CR 2, two CR > 2, 13 in relapse) were conditioned with total-body irradiation, thiotepa, fludarabine, and antithymocyte globulin. Peripheral-blood progenitor cells were mobilized with recombinant human granulocyte colony-stimulating factor and depleted of T-cells using CD34+ cell immunoselection. No post-transplantation graft-versus-host disease (GvHD) prophylaxis was administered. RESULTS: Primary engraftment was achieved in 94 of 101 assessable patients. Six of the seven patients who rejected the primary graft, engrafted after a second transplantation. Overall, 100 of 101 patients engrafted. Acute GvHD developed in eight of 100 patients, and chronic GvHD, in five of 70 assessable patients. Thirty-eight patients died of nonleukemic causes. Relapse occurred in nine of 66 patients receiving transplantation in remission and in 17 of 38 receiving transplantation in relapse. Median follow-up of the 40 patients who survived event-free was 22 months (range, 1 to 65 months). Event-free survival (± standard deviation) rate was 48% ± 8% and 46% ± 10%, respectively, for the 42 AML and 24 ALL patients receiving transplantation in remission. CONCLUSION: Our transplantation procedure provides reliable, reproducible CD34+ cell purification, high engraftment rates, and prevention of GvHD. The mismatched-related transplant emerges as a viable, alternative source of stem cells for acute leukemia patients without matched donors and/or those who urgently need transplantation.
Despite advances in chemotherapy, most adults with acute leukemia relapse, with few surviving, when they have unfavorable prognostic features at diagnosis, when they do not achieve complete remission (CR) after the first induction cycle, and when they are in second or later CR.1,2 Under these circumstances, allogeneic hematopoietic stem cell (HSC) transplantation is preferred as the postremission therapy. Only 25% of patients have a human leukocyte antigen (HLA) –identical sibling. Alternative sources of HSCs are matched unrelated donors (MUD), unrelated umbilical cord blood (UD-UCB), and HLA haplotype-mismatched relatives (HLA-haploidentical). Success in a MUD search depends on HLA diversity, ranging from 60% to 70% in white individuals to around 10% in ethnic minorities. Although molecular analysis achieves closer matches, it reduces the probability of finding a donor, and many patients relapse while awaiting transplantation.3 UD-UCB transplantation patients accept minor antigen mismatches, thus enlarging the pool of potential donors, but UCB units are not always suitable for adult transplantation because of insufficient cell doses.4,5 HLA-haploidentical transplantation offers an immediate source of HSC to almost all patients. Until the early 1990s, HLA-haploidentical bone marrow transplantation was largely unsuccessful in acute leukemia patients because of the high incidence of lethal graft-versus-host disease (GvHD) in unmanipulated transplants6 and graft rejection in T-cell–depleted transplants.7 Extensively T-cell–depleted HLA-haploidentical HSC transplants engrafted successfully once recombinant human granulocyte colony-stimulating factor (G-CSF) –mobilized peripheral-blood progenitor cells were used instead of bone marrow alone.8,9 This approach increased donor CD34+ cells 10-fold, reaching the equivalent of what had crossed the murine histoincompatibility barrier.10 Ex vivo T-cell depletion of the inoculum was the only prophylaxis for GvHD. This is the first phase II study involving a large-scale series of HLA-haploidentical HSC transplants for (prevalently) adults with acute leukemia at high risk of relapse. Our results confirm that infusion of large numbers of highly purified CD34+ cells is associated with high engraftment rates and a low incidence of GvHD, despite no post-transplantation immunosuppression. Above all, we show that survival rates, with an excellent quality of life, are good in patients who had transplantation in remission. Consequently, the results of the present study indicate that transplantation from HLA-haploidentical relatives is a viable strategy for the cure of acute leukemia in hematologic remission at high risk of relapse, when candidates do not have an unrelated donor and/or urgently need transplantation.
Between January 1999 and April 2004, 104 patients with acute leukemia received HLA-haploidentical transplants. Thirty-three patients (19 acute myeloid leukemia [AML], 14 acute lymphoid leukemia [ALL]) in first CR were at high risk of relapse because of unfavorable prognostic features (Table 1). The 22 patients (14 AML, eight ALL) in second CR were also at high risk of relapse because they had already relapsed while on therapy (n = 11) or after autologous transplantation (n = 3), relapsed in the CNS (n = 3), or had unfavorable prognostic features at diagnosis (n = 5). Eleven patients (nine AML, two ALL) were in third or fourth CR. Mean remission times to transplantation were 2 months (range, 1 to 5 months). The other 38 patients (25 AML, 13 ALL) were in chemoresistant relapse. In 15 of 67 AML patients, autologous transplantations had failed. All 44 patients referred to us after MUD search failure (mean search time, 6 months; range, 2 to 90 months) had transplantation. The other 60 patients were ineligible for MUD searches because they were older than the age-limit or because transplantation was urgently needed.
Donor-selection criteria were as previously described.9,11 Family members were assessed for HLA compatibility by serologic methods (HLA-A, -B) or by high-resolution molecular analysis (HLA-DR, -DP, -DQ). Donor-versus-recipient natural killer (NK) cell alloreactivity, determined by HLA-C high-resolution molecular typing and KIR genotyping, and functional assessment of donor NK clonal repertoire in cytotoxicity assays was sought in each donor-recipient pair.12 Transplantations were performed immediately after patient and donor work-ups and stem-cell collection (mean [± standard deviation] time between decision making and transplantation, 20 ± 5 days). All patients and donors provided informed consent. The study was approved by the Umbrian Regional Ethics Committee and by the Perugia University institutional review board (DHHS IRB Registration Number: 0000 3450).
Graft Processing and Transplantation Procedures Conditioning consisted of 8 Gy total-body irradiation on day –9 (transplantation took place on day 0) in a single fraction at an instantaneous dose-rate of 0.16 Gy per minute; lungs shielded to receive 4 Gy; thiotepa (5 mg/kg daily) on days –8 and –7; fludarabine (40 mg/m2 daily) from day –7 to day –3; rabbit antithymocyte globulin (ATG) at 5 mg/kg daily from days –5 to –2 was administered to 78 patients; and 15 received thymoglobuline at a total dose of 10 mg/kg over 4 days, later reduced to 6 mg/kg in 11 patients to lessen immune suppression. Source of ATG varied with drug availability. No immune suppression was given after transplantation as GvHD prophylaxis; no G-CSF was administered post-transplantation. Antifungal prophylaxis included liposomal amphotericine-B (1 mg/kg daily) from day –5 until neutropenia ended. Cytomegalovirus (CMV) prophylaxis was ganciclovir (10 mg/kg) from day –9 to day –2 and foscarnet (90 mg/kg) from day +4 to day +20 followed by pre-emptive therapy.
Outcome Assessment
Statistical Analysis
Donors All donors (45 siblings, 32 parents, 11 children, 12 cousins, two nephews, and two uncles) were identical for one haplotype and incompatible at three loci (HLA-A, -B, -DR) of the other, except for two who were two-loci (HLA-B, -DR) mismatched on the unshared haplotype. Potential donor-versus-recipient NK cell alloreactivity was due to missing expression of HLA-C groups 1 or 2 in 23 AML patients and of HLA-Bw4 group alleles in eight patients. The stem-cell dose was achieved with a median of four leukaphereses (range, three to five). Three donors were poor mobilizers and were substituted with other three-loci mismatched family members.
Grafts Median recovery of CD34+ cells using the Miltenyi and Isolex procedures was 79% and 71%, respectively, and purity was 90% and 95%, respectively. Median T- and B-cell depletion was 4.5 log and 3.2 log, respectively.
Engraftment
Mean (± standard deviation) CD4+ cell counts ranged from 100 ± 40/mm3 to 200 ± 20/mm3 for 10 months post-transplantation, and then started rising. The CD8+ cell count reached 230 ± 80/mm3 on day +60, followed by a steady rise to 570 ± 125/mm3 on day +300. CD16+ NK cells reached 400/mm3 stably by day +30.
GvHD
Non-Leukemic Mortality
Leukemia Relapse Twenty-six patients (16 of 67 AML; 10 of 37 ALL) relapsed at a median of 6 months post-transplantation (range, one to 29 months). Relapse occurred in 17 of 38 patients who were in relapse at transplantation and in nine of 66 patients in remission (Table 2). The cumulative-incidence estimate of relapse was 0.16 (95% CI, 0.08 to 0.30) in patients transplanted in remission and 0.51 (95% CI, 0.36 to 0.72) in those transplanted in relapse (P = .001), with the last event occurring 29 months post-transplantation (Table 2; Fig 2).
In AML patients transplanted in remission, the cumulative incidence of relapse was 0.14 (95% CI, 0.06 to 0.29) in 22 patients whose donor was NK-alloreactive, and 0.28 (95% CI, 0.12 to 0.66) in 18 whose donor was not (P = .11). In AML patients receiving transplantation in relapse, the cumulative incidence of relapse was 0.33 (95% CI, 0.13 to 0.84) for nine patients with NK-alloreactive donors, and 0.45 (95% CI, 0.26 to 0.79) for 17 without (P = .47). Rescue therapy for 26 relapses included: donor lymphocyte infusions (DLI) in five patients, DLI and imatinib in one, haploidentical transplants from the same donors in two, and no treatment in 18 because of rapid aggressive relapse. Twenty-five patients died (23 of leukemia; two of TRM after second transplantation). The patient with Ph+ ALL responded to imatinib (600 mg/d) and DLI (2.2 x 106 CD3+ cells/kg over six doses) and is still in hematologic and cytogenetic remission 6 months later.
Survival Two-year probability of EFS in 42 AML patients and 24 ALL patients receiving transplantation in any CR was 48% ± 8% and 46% ± 10%, respectively. Disease status at transplantation was the only significant factor in both univariate and multivariate analysis (P < .0001; relapse v remission hazard risk, 2.84; 95% CI, 1.72 to 4.69). Figure 3 illustrates probability of EFS according to disease status at transplantation.
The present strategy ensures rapid, sustained engraftment of one-haplotype HLA-mismatched transplants in almost all patients, with a low incidence of GvHD. The few patients who reject have the advantage of another, immediately available haploidentical donor, and all but one transplant in the present series engrafted successfully after a second transplantation. Approximately half of our leukemia patients at very high risk of relapse, who were transplanted in first or later remission, survive with excellent performance status. Consequently, haploidentical transplants emerge as a viable option when matched donors are unavailable. The megadose of highly purified CD34+ cells is crucial for promoting engraftment across the histoincompatibility barrier.8-10 The immune regulatory role of CD34+ cells is supported by observations that cells within the CD34 population are endowed with veto activity.15,16 In bulk mixed leukocyte reaction, the cells neutralize specific cytotoxic T lymphocyte precursors directed against their antigens but not against a third party.15 Early myeloid CD33+ cells are also endowed with marked veto activity.17 Therefore, after transplantation, not only infused CD34+ cells, but also their CD33+ progeny, could inhibit residual antidonor cytotoxic T lymphocyte precursors in recipients. Automated peripheral blood CD34+ cell immunoselection is time- and labor-saving, biologically safe, and reliably ensures a high CD34+ cell recovery rate and medianly 4.5 log T-cell depletion. Infusing a mean of 1 x 104 CD3+ cells/kg prevents GvHD without any post-transplantation immune suppression. ATG in the conditioning, which antagonizes donor T cells in vivo, may also reduce potential GvHD. Similar considerations can be applied to OKT3, which has been used in children.18 On the other hand, 1 to 2 log T-cell depletion still requires post-transplantation immunosuppression. Our overall TRM of 40% needs to be viewed in light of the clinical characteristics of this cohort of patients. Most were at high risk of TRM because of advanced disease status at transplantation (38 in relapse, 11 in third or fourth remission); the majority of the 22 patients in second remission were heavily pretreated adults, and autologous transplants had failed in three; 11 of 33 patients in first remission ranged from age 40 to 62 years. Although TRM was mainly infection-related, no fatal infection occurred after the first year post-transplantation, indicating that there is no risk of late infection-related deaths in the absence of chronic GvHD and immunosuppressive therapy. In adult recipients of UD-UCB, TRM at day 100 ranged from 39% to 54%,4,5,19,20 and MUD transplants rendered a similar incidence.21,22,23 The high TRM in transplants from alternative sources is mainly linked to delayed recovery of immune response against pathogens. In adults, T-cell repertoire reconstitution depends for months on peripheral expansion of mature T-cells in the graft because thymic output is poor.24 After MUD and UD-UCB transplantations, GvHD itself and its prophylaxis and therapy antagonize T-cell expansion and function. Additionally, in UD-UCB transplantations, slow neutrophil recovery increases susceptibility to infections.20,25 In haploidentical transplants, extensive T-cell depletion is required to prevent GvHD, so the T-cell repertoire is very narrow, and ATG in conditioning could delay T-cell homeostatic expansion. When previously investigating immune reconstitution,26 we observed that dendritic-cell interleukin-12 production is largely restored within 1 month of transplantation; most post-transplantation CD4+ cell clones exhibit Th1-Th0 features and pathogen-specific T-cell responses (eg, anti-Aspergillus and anti-Candida) appear 9 to 10 months post-transplantation. Research is focusing on strategies to hasten post-transplantation immune reconstitution by adding back broad-repertoire or pathogen-specific mature donor T lymphocytes after ex vivo depletion of antidonor alloreactivity.27,28 One concern in T-cell–depleted transplants is a higher risk of acute leukemia relapse due to lack of the GvHD-related graft-versus-leukemia effect. Only 16% of the present haploidentical recipients relapsed when transplanted in remission after total-body irradiation and thiotepa-based conditioning and no post-transplantation immunosuppression. The antileukemic strength of this myeloablative conditioning could have compensated for loss of the T-cell–related graft-versus-leukemia effect, as has been demonstrated in T-cell–depleted bone marrow transplantation from HLA-identical siblings.29,30 Furthermore, although donor-versus-recipient NK cell alloreactivity also affects relapse in patients with AML,12,31 it did not reach significance (P = .89) in the present series. Increasing the number of patients and prolonging the follow-up might yield results similar to those observed when all HLA-haploidentical transplantations from 1993 onwards are analyzed.31 In end-stage patients, EFS is extremely disappointing, thus raising the question of whether these patients should be accepted as candidates. However, although success rates are low even after transplantation from HLA-identical siblings and from other sources of HSC,22,32 refusing transplantation is hard, particularly in young patients. Indeed, almost all reports include many advanced-stage recipients even when donors are volunteers.32 When our patients in any remission received haploidentical transplants, EFS was a remarkable 48% ± 8% for AML and 46% ± 10% for ALL. In adult recipients of MUD and UD-UCB transplants at the same stages of disease, EFS ranges from 20% to 50%.5,20,23,32 However, MUD results refer only to patients who undergo transplantation, without taking into account those who do not find a donor or those who relapse and die while awaiting transplantation.33 One must remember that haploidentical donors are found for almost all patients, with no undue delay between decision making and transplantation, which is crucial in urgent cases. As the panel of HLA-mismatched relatives is usually large, one can select the optimal donor first, by avoiding a CMV-negative donor for a CMV-positive recipient, and then, for AML patients, by identifying the NK cell alloreactive donor, if available. The choice of the best alternative source of stem cells for individual patients without matched sibling donors is hampered by lack of randomized studies supplying data on outcomes after MUD, UD-UCB, and haploidentical transplants. It is hoped that guidelines will emerge from the ongoing European Bone Marrow Transplant (EBMT) Registration Study, which will report outcomes after each form of transplantation and after each intention-to-treat decision. In any case, for acute leukemia patients in any remission (even third or fourth) who are at high risk of relapse and who lack an HLA-matched donor, the HLA-haploidentical transplant today emerges as a viable, alternative source of stem cells and is indeed, their only transplant option.
The authors indicated no potential conflicts of interest.
We thank biologists and laboratory technicians Tiziana Zei, Roberta Jacucci Ostini, Marusca Capanni, Feliciana Beattelli, and Antonella Mancusi for their technical assistance in graft processing and immunologic monitoring; Drs Simona Iacobelli (Statistics Centre, GIMEMA Group, Rome, Italy), Vanderson Rocha and Myriam Labopin (Statistics Centre, EBMT Group, Paris, France) for their contribution to the statistical analysis, and Dr Geraldine Anne Boyd, Lecturer in English, University of Perugia, for assistance in preparing this article.
Supported in part from AIRC (Italian Cancer Association), Perugia Section of the AIL (Italian Leukaemia Association), AULL (Umbrian Leukaemia and Lymphoma Association), the Daniele Chianelli Foundation and the Perugia Cassa di Risparmio Foundation. Presented at the Tandem Meeting 2003, Keystone Symposia, Keystone, CO, January 30-Feb 3, 2003; 19th Meeting of the Belgian Hematological Society, Brussels, Belgium, January 30-31, 2004; 4th International Workshop on Haploidentical Transplants. Naples, Italy, July 8-10, 2004. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Burnett AK, Wheatley K, Goldstone AH, et al: The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: Results of the UK MRC AML 10 trial. Br J Haematol 118:385-400, 2002[CrossRef][Medline] 2. Hoelzer D, Gokbuget N, Ottmann O, et al: Acute lymphoblastic leukemia. Hematology (Am Soc Hematol Educ Program) 162-192, 2002 3. Schipper RF, D'Amaro J, Bakker JT, et al: HLA gene haplotype frequencies in bone marrow donors worldwide registries. Hum Immunol 52:54-71, 1997[CrossRef][Medline] 4. Gluckman E, Rocha V, Chevret S: Results of unrelated umbilical cord blood hematopoietic stem cell transplantation. Rev Clin Exp Hematol 5:87-99, 2001[CrossRef][Medline] 5. Sanz MA, Sanz GF: Unrelated donor umbelical cord blood transplantation in adults. Leukemia 16:1984-1991, 2002[CrossRef][Medline] 6. Anasetti C, Beatty PG, Storb R, et al: Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol 29:79-91, 1990[CrossRef][Medline] 7. Kernan NA, Flomemberg N, Dupont B, et al: Graft rejection in recipients of T cell depleted HLA-nonidentical marrow transplants for leukemia: Identification of host derived anti-donor allocytotoxic T lymphocytes. Transplantation 43:482-487, 1987
8. Aversa F, Tabilio A, Terenzi A, et al: Successful engraftment of T-cell-depleted haploidentical "three-loci" incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood 84:3948-3955, 1994
9. Aversa F, Tabilio A, Velardi A, et al: Treatment of high risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 339:1186-1193, 1998 10. Bachar-Lusting E, Rachamim N, Li HW, et al: Megadose of T cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice. Nat Med 1:1268-1273, 1995[CrossRef][Medline] 11. Tabilio A, Falzetti F, Giannoni C, et al: Stem cell mobilization in normal donors. J Hematother 6:227-234, 1997[Medline]
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17. Gur H, Krauthgamer R, Berrebi A, et al: Tolerance induction by megadose hematopoietic progenitor cells: Expansion of veto cells by short-term culture of purified human CD34(+) cells. Blood 99:4174-4181, 2002 18. Handgretinger R, Klingebiel T, Lang P, et al: Megadose transplantation of purified peripheral blood CD34+ progenitor cells from HLA-mismatched parental donors in children. Bone Marrow Transplant 27:777-783, 2001[CrossRef][Medline] 19. Gluckman E, Rocha V, Arcese W, et al: Factors associated with outcomes of unrelated cord blood transplant: Guidelines for donor choice. Exp Hematol 32:397-407, 2004[CrossRef][Medline]
20. Rocha V, Labopin M, Sanz G, et al: Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 351:2276-2285, 2004 21. Weisdorf D, Bishop M, Dharan B, et al: Autologous versus allogeneic unrelated donor transplantation for acute lymphoblastic leukemia: Comparative toxicity and outcomes. Biol Blood Marrow Transplant 8:213-220, 2002[CrossRef][Medline] 22. Petersdorf EW. Hematopoietic cell transplantation from unrelated donors, in Blume KG, Forman SJ, Appelbaum FR (eds): Thomas' Hematopoietic Cell Transplantation Blackwell Publishers. Malden, MA, Blackwell Publishers, 2004, pp 1132-1149 23. Sierra J, Storer B, Hansen JA, et al: Unrelated donor marrow transplantation for acute myeloid leukemia: An update of the Seattle experience. Bone Marrow Transplant 26:397-404, 2000[CrossRef][Medline] 24. Heitger A, Greinix H, Mannhalter C, et al: Requirement of residual thymus to restore normal T-cell subsets after human allogeneic bone marrow transplantation. Transplantation 69:2366-2373, 2000[CrossRef][Medline]
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26. Volpi I, Perruccio K, Tosti A, et al: Post-grafting granulocyte colony-stimulating factor administration impairs functional immune recovery in recipients of HLA haplotype-mismatched hematopoietic transplants. Blood 97:2514-2521, 2001 27. Andre-Schmutz I, Le Deist F, Hacein-Bey S, et al: Donor T lymphocyte infusion following ex vivo depletion of donor anti-host reactivity by a specific anti-interleukin-2 receptor P55 chain immunotoxin. Transplant Proc 34:2927-2928, 2002[CrossRef][Medline]
28. Rauser G, Einsele H, Sinzger C, et al: Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants. Blood 103:3565-3572, 2004
29. Aversa F, Terenzi A, Carotti A, et al: Improved outcome with T-cell-depleted bone marrow transplantation for acute leukemia. J Clin Oncol 17:1545-1550, 1999
30. Papadopoulos E, Carabasi MH, Castro-Malaspina H, et al: T-cell-depleted allogeneic bone marrow transplantation as post-remission therapy for acute myelogenous leukemia: Freedom from relapse in the absence of graft versus host disease. Blood 91:1083-1090, 1998 31. Velardi A, Ruggeri L, Capanni M, et al: Impact of NK Cell Alloreactivity on Mismatched Hematopoietic Transplantation: An Update on Donor Selection Criteria and on Transplantation Outcomes. Blood 102, 2003 (abstr 527)
32. Laughlin MJ, Eapen M, Rubinstein P, et al: Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 351:2265-2275, 2004 33. Kollman C, Weis T, Switzer GE, et al: Non-HLA barriers to unrelated donor stem cell transplantation. Bone Marrow Transplant 27:581-587, 2001[CrossRef][Medline] Submitted September 28, 2004; accepted February 1, 2005. This article has been cited by other articles:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
40 years), pretransplant donor-recipient pair CMV serology (positive/positive, negative/positive, positive/negative, negative/negative), and, in AML, donor-recipient NK cell alloreactivity (yes v no). The impact of these factors on engraftment, nonleukemic mortality, and EFS was also investigated in multivariate analysis (Cox regression model). Two-sided P values less than .05 were considered significant. 
