Therapy

Effect of graft source on mismatched unrelated donor hemopoietic stem cell transplantation after reduced intensity conditioning

Abstract

This retrospective report compared the results of graft source on outcome after allogeneic stem cell transplantation (allo-SCT) in patients with hematologic malignancies receiving a reduced intensity conditioning (RIC) regimen. A total of 152 patients received either a RIC allo-SCT using a 9/10 mismatched unrelated donor (MisMUD, n=42) or a double unrelated umbilical cord blood (dUCB, n=110) graft. With a median follow-up of 30.3 months, the cumulative incidence of non-relapse mortality was 26% in the dUCB group versus 24% in the MisMUD group (P=0.95). Grade 3–4 acute graft-versus-host disease (GVHD) incidence was 19.7% in the dUCB group versus 21.4% in the MisMUD group (P=0.83). The cumulative incidence of extensive chronic GVHD at 2 years was 6.4% in the dUCB group versus 21.4% in the MisMUD group (P=0.02). The Kaplan–Meier estimate of overall survival at 2 years was comparable between both groups (52.3% (95% confidence interval (CI), 42.1–61.5%) in the dUCB group versus 47.9% (95% CI, 31.6–62.4%) in the MisMUD group, P=0.55). Progression-free survival at 2 years was 43.3% (95% CI, 33.7–52.5%) in the dUCB group versus 38.3% (95% CI, 23.2–53.3%) in the MisMUD group (P=0.55). These data suggest that dUCB is a valid alternative graft source with significantly less chronic GVHD compared with MisMUD in the setting of RIC allo-SCT.

Introduction

Unrelated umbilical cord blood (UCB) has emerged as an effective stem cell source for allogeneic hematopoietic stem cell transplantation (allo-SCT) in patients who lack a matched related or unrelated donor available.1, 2, 3 Several studies found similar outcomes between human leucocyte antigen (HLA) 4-6/6-matched UCB and HLA 8/8 matched and 7/8 mismatched unrelated donors (MisMUD), mainly in the setting of standard myeloablative conditioning (MAC) regimen.4, 5 However, because of the high incidence of non-relapse mortality (NRM), MAC regimens are limited to younger patients and to patients in good medical condition.6 Reduced intensity conditioning (RIC) regimens were developed with the aim to decrease NRM in elderly patients, in heavily pretreated patients or in those with medical comorbidities precluding the use of standard MAC regimens.7, 8, 9 RIC regimens aim to take advantage of the graft-versus-malignancy effect mediated by immunocompetent cells of donor origin.10, 11 However, one risk of RIC regimens is that of graft failure because of the low intensity of the conditioning, especially in the context UCB transplantation where the number of hematopoietic stem cells in the graft is low, compared with transplants using bone marrow or peripheral blood stem cells. However, it has been demonstrated that the use of a single partially matched UCB unit sufficiently rich (>3.0 × 107 nucleated cells/kg) or of two partially matched UCB units (dUCB) is feasible and allows satisfactory engraftment, which contributed to the development of RIC regimens in UCB transplantation.12 Thus, several studies compared the outcome between HLA 4-6/6-matched UCB transplantation and grafts from HLA 8/8 matched and MisMUDs after RIC regimen. As for MAC regimens, the outcome of patients was similar regardless of the donor.13, 14 In many European centres, the ‘gold standard’ of unrelated donor choice is a 10/10-matched volunteer donor when there is no HLA identical-related donor available. Several studies showed similar outcomes in this setting.15 Things become more complicated if there is no HLA identical donor available: should a one mismatch volunteer donor be preferred to a single or double UCB graft? Decision is often made according to the urgency of the transplant, but also depends on the patient’s underlying disease. Thus far, no study comparing 9/10-matched unrelated donor and dUCB transplantation have been undertaken. The aim of this report was to compare the outcome after 4-6/6-matched dUCB and 9/10-matched unrelated donor allo-SCT in the setting of RIC.

Patients and methods

Study design

This retrospective study included 152 patients diagnosed with hematologic malignancies who underwent allo-SCT either at the University Hospital of Nantes (CHU de Nantes, France) or at the Institut Paoli-Calmettes (Marseille, France) between August 2005 and July 2011. These two centres have been applying common transplant approaches and procedures during the study period. For the purpose of this analysis, all patients who were at least 16 years of age at the time of transplantation and who received a dUCB (dUCB group) or a one allele or antigen-MisMUD (MisMUD group) transplantation after a RIC were included. Patients without a suitable HLA 10/10-matched related or unrelated donor were considered for a 9/10 MisMUD. However, if there was no sufficient time for an unrelated donor search because of a high-risk disease, or if the preliminary search indicated a lower likelihood of finding an unrelated donor within a reasonable time frame, the use of dUCB was preferred.

The primary end point of the study was overall survival (OS). In this common transplant program, eligibility criteria for RIC allo-SCT included: (1) patient age older than 50 years; (2) heavily pretreated patients who received an autologous hematopoietic stem cell transplantation or with more than two lines of chemotherapy before allo-SCT; and (3) patients with poor performance status because of significant medical comorbidities as described by Sorror et al.6 Written informed consent was obtained from each patient and donor. The study was approved by the local institutional review boards.

Transplant procedures

All donor/recipient pairs were typed at the allelic level. They were first typed at the two-digit level for HLA class I (HLA-A, HLA-B and HLA-Cw) and class II (HLA-DRB1 and HLA-DQB1) using published HLA class I PCR sequence-specific oligonucleotide and/or PCR sequence-specific primers typing protocols. Per study definition, all donor/recipient pairs presented a single HLA mismatch (HLA-A, HLA-B, HLA-C, HLA-DR and HLA-DQ-matched donors) at HLA-A for 7 patients (17%), HLA-B for 2 patients (5%), HLA-Cw for 25 patients (59%), HLA-DR for 1 patient (2%) and HLA-DQ for 7 patients (17%). HLA-DP typing was not routinely performed at the time of this analysis. HLA typing was performed according to the current protocol of the European Federation for Immunogenetics Histocompatibility Laboratory standards. HLA typing in cord blood recipients was performed at antigen level for MHC class I A and B loci and at allelic level with high-resolution typing for MHC class II DRB1 locus. All UCB units were HLA 4-6/6 matched with the patient, and between each other. In all, 61% of dUCB transplants were mismatched at 2 HLA-loci. Patients’ characteristics for the whole study population and for each group are detailed in Table 1. All patients received the preparative regimen as inpatients in private rooms, and remained hospitalized until hematopoietic and clinical recovery. In the MisMUD group, the stem cell source was bone marrow in 7 cases (17%) and granulocyte colony-stimulating factor-mobilized peripheral blood stem cells in the remaining 35 cases (83%). In this series, the median age was 53 (range, 16–69) years. In the dUCB group, the RIC regimen consisted of 200 mg/m2 fludarabine (Flu), 50 mg/kg cyclophosphamide (Cy) and low-dose total body irradiation (2 Gy) for 106 patients and of 150 mg/m2 Flu and 100 mg/kg Cy for 4 patients. In the MisMUD group, the RIC regimen consisted of 30 mg/m2 Flu for 5 consecutive days and 3.2 mg/kg intravenous busulfan for 2 or 3 consecutive days for 36 patients (busulfan substituted with melphalan in 1 case), 90 mg/m2 Flu and 2 Gy total body irradiation for 2 patients. Three patients received a so-called sequential regimen with 30 mg/m2 clofarabine and 1000 mg/m2 cytarabine for 5 consecutive days and, after a 4-day break, 60 mg/kg Cy and 6.4 mg/kg busulfan. Finally, one patient received a modified sequential regimen including 400 mg/m2 amsacrine, 8 g/m2 cytarabine, 80 mg/kg Cy and 2 Gy total body irradiation. Eleven patients (17%), who were not heavily pre-treated, in the dUCB group received anti-thymocyte globulin (ATG) (thymoglobulin; Genzyme, Lyon, France) 5 mg/kg total dose, whereas 39 patients (93%) received ATG in the MisMUD group because of the expected higher risk of graft-versus-host disease (GVHD) in this group. For GVHD prophylaxis, all patients in the dUCB group received cyclosporine A (CsA) and mycophenolate mofetil (MMF).16 In the MisMUD group, GVHD prophylaxis consisted of CsA and MMF,17 but two patients received CsA alone and two patients received CsA and a short course of methotrexate (15 mg/m2 at day +1, 10 mg/m2 at day +3 and +6). In both cohorts, CsA was administered at a dose of 3 mg/kg/day by continuous intravenous infusion starting from day −3 or −2, and changed to twice daily oral dosing as soon as tolerated.18 MMF was given at a fixed oral dose of 2 g/day. No treatment adjustment was performed for MMF. MMF was tapered over 4 weeks starting from day 60 and CsA from day 90 if no GVHD appeared. Supportive care and antimicrobial prophylaxis were reported previously.19 Of note, supportive care was the same during the whole study period. CMV infection management was also homogeneous. All blood products were filtered, irradiated and screened for CMV. In the first 100 days post allo-SCT, patients were assessed at least once per week for CMV reactivation in order to initiate preemptive ganciclovir therapy. Acute GVHD (aGVHD) was evaluated according to the Seattle standard criteria.20

Table 1 Study population characteristics

Statistical methods

OS and progression-free survival were calculated by the Kaplan–Meier method and subgroups were compared using the Log-Rank test. For categorical variables, comparison between the cord blood and the MisMUD group was carried out using the χ2 test for patient gender and CMV serologic status, whereas the Fisher’s exact test was used for diagnosis, disease status at transplantation, conditioning regimen, use of ATG, GVHD prophylaxis, graft failure and cause of death. For continuous data, comparison between regimens was performed using the Mann–Whitney test for patient age, median follow-up, cell doses and median time to neutrophils >0.5 g/l. Probabilities of relapse, NRM, GVHD and neutrophil recovery were calculated using the cumulative incidence procedure and comparisons were performed using the Gray test. Association between graft type and OS were evaluated using the Cox proportional hazard regression model. Association between graft type and cumulative incidence of grade 3–4 aGVHD and extensive chronic GVHD (cGVHD) were calculated using the Fine and Gray regression model for competing risk model. The variables considered were the patient’s age at transplantation (greater or younger than 50 years), patient’s sex, diagnosis (myeloid malignancies versus lymphoid malignancies), disease status at transplantation (standard risk versus high risk), the CMV status, conditioning regimen and the use of ATG. Data were computed using the R package (R Development Core Team, 2006. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-project.org) and GraphPad Prism 5.0 (GraphPad Software, San Diego, CA, USA).

Results

The overall median follow-up was 30.3 (range, 6.0–72.4) months among surviving patients. Transplant-related events are summarized in Table 2. Patients from the dUCB group engrafted at a median of 17 (range, 4–66) days after allo-SCT, whereas patients from the MisMUD group engrafted at a median of 16 (range, 6–46) days (P=0.62). The day 28 cumulative incidences of neutrophils recovery were 80.2% and 97.4% in the dUCB and the MisMUD groups, respectively (P=0.17), with the corresponding probabilities of 94.0% and 97.4% at day 42 after transplantation (P=0.17). Ten (9.1%) patients in the dUCB group and three (7.1%) in the MisMUD group had a spontaneous autologous reconstitution subsequent to primary graft failure. Of the 152 patients included in this study, 78 died during the follow-up period and 74 are still alive at last follow-up (2-year OS of 50.9% (95% confidence interval (CI), 42.3–61.5%)). The 2-year OS was comparable between both groups: 52.3% (95% CI, 42.1–61.5%) in the dUCB versus 47.9% (95% CI, 31.6–62.4%) in the MisMUD group, P=0.55 (Figure 1a). In multivariable analysis, the stem cell source (dUCB versus MisMUD) did not have any significant impact on OS (hazard ratio (HR)=1.14 (95% CI, 0.52–2.49); P=0.74). In all, 37 deaths were directly attributed to disease progression or relapse, whereas death was related to allo-SCT in 41 cases, of which 12 were attributed to aGVHD or cGVHD and 18 to infections. At 2 years, the overall cumulative incidence of NRM was 25.6%, being 26.0% in the dUCB and 24.2% in the MisMUD group (P=0.95; Figure 1c). The cumulative incidence of severe grade 3–4 aGVHD was 19.1% (n=21) in the dUCB group and 21.4% (n=9) in the MisMUD group (P=0.83) (Figure 1e). The cumulative incidence of extensive cGVHD was 6.4% (n=7) in the dUCB group versus 21.4% (n=8) in the MisMUD group (P=0.02; Figure 1f). In multivariable analysis, the risk of developing grade 3–4 aGVHD was not influenced by the type of graft used (MisMUD versus dUCB: HR=2.5; 95% CI, 0.5–12.4, P=0.27) or by the use of ATG (ATG versus no ATG: HR=0.38; 95% CI, 0.08–1.91, P=0.20), whereas the risk of developing extensive cGVHD was higher in the MisMUD group compared with the dUCB group (HR=11.7; 95% CI, 3.8–36.1, P<0.0001). Furthermore, the risk of developing extensive cGVHD was lower in the patients who did not receive ATG (ATG versus no ATG: HR=0.21; 95% CI, 0.06–0.77, P=0.02). Relapse or progression occurred in 55 patients at a median time of 97 (range, 0–1017) days after RIC allo-SCT. At 2 years, the cumulative incidence of relapse or progression from allo-SCT was comparable between both groups (34.3% in the dUCB group versus 37.6% in the MisMUD group, P=0.63; Figure 1d). The Kaplan–Meier estimate of progression-free survival at 2 years was 43.3% (95% CI, 33.7–52.5%) in the dUCB group versus 38.3% (95% CI, 23.2–53.3%) in the MisMUD group (P=0.55; Figure 1b).

Table 2 Transplant-related events
Figure 1
figure1

Outcome after allo-HSCT of the dUCB group (red line) and the MisMUD group (black line). (a) Two-year OS; (b) 2-years progression-free survival; (c) cumulative incidence of TRM; (d) cumulative incidence of relapse; (e) cumulative incidence of grade 3–4 acute GVHD; and (f) cumulative incidence of extensive chronic GVHD.

Discussion

The use of RIC regimens before allo-SCT has widely expanded over the past decade, allowing patients with hematologic diseases and comorbidities or older age to benefit from a potential immune graft-versus-tumor effect. The primary objective of this retrospective study was to assess the relative efficacy of dUCB compared with MisMUD HLA-MisMUD in adults with hematologic malignancies treated with RIC.

In this study, dUCB was a suitable alternative to the use of a 9/10 HLA-MisMUD: OS, progression-free survival and NRM were comparable between the two groups. The main difference between the two groups was the significantly higher cumulative incidence of extensive cGVHD in the MisMUD group. Surprisingly, this did not translate into a decrease of the cumulative incidence of relapse nor increase of the NRM, which may be explained by a slightly shorter follow-up in this group. On the other hand, extensive cGVHD is well known to be responsible for a worsened quality of life.21 Therefore, one would expect that the higher incidence of extensive cGVHD in the MisMUD group would be likely associated with an impaired quality of life in these patients. Unfortunately, quality of life could not be evaluated, because of the retrospective nature of the study. This difference in cGVHD incidence was expected, especially as we have used mostly peripheral blood stem cells (83% of the patients in the MisMUD group). Nevertheless, the large use of ATG in this group (93% of patients received ATG), which is increasingly proven to exert a protective effect against severe cGVHD,22, 23, 24 probably limited the increased rate of cGVHD. Finally, the use of ATG did not result in an increase in relapse, in contrast to the study by Soiffer et al.25 This difference may be explained by the lower dose of ATG used in our study (5 mg/kg total dose).

In terms of engraftment, although the rate of primary graft failure was similar between groups, there was a trend toward a lower cumulative incidence of neutrophil recovery after dUCB transplantation, consistent with most previous reports.13, 14 However, the latter may rather reflect more a slower rather than a failure of hematopoietic recovery, since at day 42, the differences between both groups were very low (94% in the dUCB group versus 97% in the MisMUD group). This slower recovery translated into an increase in death related to infections in this group, which remained the principal complication after cord blood transplantation.26 However, it did not translate into an increase of NRM, although there were more deaths because of GVHD in the MisMUD group.

Obviously, it would be very interesting to analyze the impact of the type of mismatch in the MisMUD group, because the results in the literature are very discordant. Some reports confirmed that mismatches at HLA-B or -Cw level were better tolerated than those at HLA-A or -DRB1 level, whereas others suggested worse survival for HLA-Cw but not HLA-A mismatches.27, 28 In our study, we had a majority of mismatches at the Cw level, but the small number of patients in the MisMUD group precluded an analysis of the type of allelic mismatch.

In conclusion, our results suggest that dUCB is a valid alternative to the use of single-allele MisMUD in the setting of RIC. This should be now investigated in prospective comparative studies.

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Acknowledgements

We thank the nursing staff for providing excellent care for our patients, and the following physicians for their dedicated patient care: N Blin, A Clavert, V Dubruille, T Gastinne, B Mahe, F Mechinaud and F Rialland. MM thanks Pr JV de Melo (Adelaide, Australia) for critical reading of the manuscript. FM was supported by educational grants from the ‘Association for Training, Education and Research in Hematology, Immunology and Transplantation’ (ATERHIT). We also thank the ‘Région Pays de Loire’, the ‘Association pour la Recherche sur le Cancer (ARC; grant #3175 to MM and BG)’, the ‘Fondation de France’, the ‘Fondation contre la Leucémie’, the ‘Agence de Biomédecine’, the ‘Association Cent pour Sang la Vie’, the ‘Association Laurette Fuguain’ and the IRGHET for their generous and continuous support for our clinical and basic research work. Our group is supported by several grants from the French national cancer institute (PHRC, INCa to MM). We acknowledge the continuous support of the cell banking facility (‘tumurotheque’) of the CHU de Nantes.

Author contributions

F Malard: collected, assembled and analyzed data, performed statistical analysis and wrote the manuscript; S Fürst and M Loirat: collected data and commented on the manuscript; P Chevallier, T Guillaume, J Delaunay, Jean El-Cheikh, S. Le Gouill, P Moreau and Didier Blaise: recruited patients and commented on the manuscript; M Mohty: recruited patients, supervised research, analyzed data and wrote the manuscript; all authors approved submission of the manuscript for publication purposes.

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Malard, F., Fürst, S., Loirat, M. et al. Effect of graft source on mismatched unrelated donor hemopoietic stem cell transplantation after reduced intensity conditioning. Leukemia 27, 2113–2117 (2013). https://doi.org/10.1038/leu.2013.170

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Keywords

  • allogeneic stem cell transplantation
  • reduce intensity conditioning
  • umbilical cord blood
  • 9/10 mismatched unrelated donor

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