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Long-term outcomes of HLA-haploidentical stem cell transplantation based on an FBCA conditioning regimen compared with those of HLA-identical sibling stem cell transplantation for haematologic malignancies

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Abstract

A comparison was conducted of 213 patients with haematologic malignancies who underwent HLA-identical sibling (n=108) or HLA-haploidentical (n=105) haematopoietic cell transplantation (haplo-HCT) at our centre. The conditioning regimen included fludarabine, busulphan, cyclophosphamide and antilymphocyte globulin (ATG) (FBCA). The total dose of ATG differed between identical and haploidentical groups (3.75 mg/kg versus 12.5 mg/kg). The cumulative incidences of grade II–IV acute GvHD in the identical and haploidentical groups were 20.4% and 21.9% (P=0.73), and 2-year cumulative incidences of chronic GvHD were 36.4% and 24.1% (P=0.17), respectively. The 3-year probabilities of non-relapse mortality for identical and haploidentical groups were 20.5% and 34.9% (P=0.048), and for relapse were 22.2% and 21.0% (P=0.85), respectively. The 3-year overall survivals in the identical and haploidentical groups were 62.6% and 52.6% (P=0.054), whereas the 3-year disease-free survivals were 54.7% and 43.1% (P=0.14), respectively. In the multivariate analysis, patients in the high-risk group exhibited reduced survival, and the higher dose of mononuclear or CD34+ cells resulted in an increase in the likelihood of survival. In conclusion, haplo-HCT based on an FBCA conditioning regimen could achieve nearly comparable outcomes to HLA-identical sibling HCT.

Introduction

More than three decades have passed since the first successful allogeneic haematopoietic cell transplantation (allo-HCT) from a haploidentical donor was reported in 1981 in a 10-month-old infant using an ex vivo T cell-depleted bone marrow graft from her father.1 After 35 years of experience, transplanters are now better at overcoming the histoincompatibility barrier between the recipient and the haploidentical donor. Different haploidentical ‘transplant platforms’ have been established by either intensive myeloablative conditioning or reduced intensity conditioning using either T cell-depleted or T cell-replete grafts. The outcomes of HLA-haploidentical haematopoietic cell transplantation (haplo-HCT) have improved notably. The 2-year probability of leukaemia-free survival is 68% for standard-risk patients and 42% for high-risk patients who received haplo-HCT with a T-cell-replete transplantation protocol, as reported by Huang et al.2 The 18-month probabilities of disease-free survival (DFS) are 68% for patients in remission and 37% for patients grafted with active disease, with the use of the post-transplantation cyclophosphamide transplant protocol, according to the study of Bacigalupo et al.3 No significant differences have been identified in the rates of relapse, treatment-related mortality, overall survival (OS) or leukaemia-free survival between HLA-identical sibling transplants and mismatched/haploidentical HCT, as reported by Lu et al.4 HLA-haploidentical bone marrow transplantation with reduced intensity conditioning regimens achieved comparable results to HLA-matched unrelated donor transplantation in a parallel multicentre clinical trial conducted by the Bone Marrow Transplant Clinical Trials Network.5, 6

We have established an approach based on a conditioning regimen that includes fludarabine, busulphan, cyclophosphamide and antilymphocyte globulin (ATG) (FBCA) with G-CSF-primed PBSCs for haplo-HCT without in vitro T-cell depletion. The 3-year probabilities of OS and DFS for intermediate-risk groups with leukaemia were 63.2% and 61.2%, respectively, and for high-risk groups with leukaemia were 39.8% and 32.2%, respectively.7 However, the results for haplo-HCT and HLA-identical sibling HCT have not been compared at our centre. The aim of the present study was to compare the outcomes of 213 consecutive patients undergoing haplo-HCT (based on the FBCA conditioning regimen at our centre) with those of all contemporaneous HLA-identical sibling HCT.

Materials and methods

Patients

This retrospective comparison included 213 consecutive patients undergoing HCT for haematologic malignancies between January 2000 and December 2013 at the Department of Hematology, Zhujiang Hospital, Southern Medical University, using HLA-identical siblings (n=108) and haploidentical donors (n=105). Patients underwent transplantation using a haploidentical donor from our centre if no matched related/unrelated donor was available. When multiple HLA-haploidentical donors were available, we chose the donor whose HLA loci were the closest to those of the patient. If similarly HLA loci-matched donors (for example, multiple 5/10 haplo donors) were available, a male and/or younger donor was chosen. The board of ethics of our hospital approved this study, and all of the patients and their donors provided written informed consent.

Procedures

HLA-A, -B, -C, -DRB1 and -DQB1 were detected with high-resolution DNA typing. The patients underwent HCT that included an FBCA conditioning regimen consisting of fludarabine (25 mg/m2/day, IV) on days −9 to −5, busulphan (3.2 mg/kg/day, IV) on days −8 to −5, cyclophosphamide (60 mg/kg/day, IV) on days −3 to −2 and rabbit ATG (Sanofi Company, Paris, France, IV). The dose of ATG depended on the donor type. If the donor was HLA mismatched with the patient, ATG was administered at a dose of 2.5 mg/kg/day on days −5 to −1; if the donor HLA was identical to that of the patient, ATG was administered at a dose of 1.25 mg/kg/day on days −3 to −1. The day of stem cell infusion was designated as day 0. G-CSF-mobilised peripheral blood stem cells were infused. GvHD prophylaxis included cyclosporine A and a short course of methotrexate. Cyclosporine A was administered (3 mg/kg/day) by continuous IV infusion on day −1 and was switched to oral cyclosporine A as soon as the patients completed IV therapy. Cyclosporine A was tapered gradually and stopped after 180–270 days without GvHD. The transplantation was performed in HEPA-filtered rooms. Other supportive care included blood transfusion and gamma globulin infusion. CMV reactivation prophylaxis was performed conventionally using ganciclovir. Before 2008, itraconazole was administered for fungal prophylaxis; after 2008, voriconazole was administered instead to prevent fungal infection from days −10 to +90.

Routine blood tests were performed once per week for the first 6 months following transplantation. A bone marrow smear and leukaemia fusion genes were checked monthly for minimal residual disease monitoring. Chimerism was detected once a month by DNA fingerprinting of short tandem repeats with PCR or by sex chromosomal FISH.

Definitions

The end point of the last follow-up for all surviving patients was 31 August 2014. The primary outcomes analysed were as follows: OS, DFS (malignancies relapsing during any time of the follow-up or death after transplant), relapse of malignancy, non-relapse mortality (NRM), acute GvHD (aGvHD) and chronic GvHD (cGvHD). Neutrophil engraftment was defined as a blood ANC exceeding 0.5 × 109/L for 3 consecutive days after transplantation. Platelet engraftment was defined as a platelet count exceeding 20 × 109/L for 7 continuous days without transfusion.

Patients were classified as low risk, intermediate risk or high risk in accordance with cytogenetic abnormalities, WBC count at diagnosis, response to induction chemotherapy and relapse after CR1. High risk was defined by the presence of adverse cytogenetics, and/or failure to achieve CR after two cycles of induction chemotherapy, and/or patients in CR2 or beyond.8 Low risk was defined by the presence of favourable cytogenetics and achievement of CR after one cycle of induction chemotherapy. Patients categorised as low risk were not eligible for HCT at our centre. Cytogenetic abnormalities were graded using established criteria.9, 10 For ALL patients, high risk was also defined by a WBC count of >30 × 109/L for B-lineage ALL or >100 × 109/L for T-lineage ALL at diagnosis; and/or central nervous system leukaemia at diagnosis.11 The high-risk group also included CML with a phase other than chronic phase and myelodysplastic syndrome with International Prognostic Scoring System scores of >2.5. Patients who did not meet the low- and high-risk criteria were categorised as intermediate risk. The diagnosis and grading of GvHD were conducted based on published criteria.12, 13 The cumulative incidence of aGvHD was assessed within 100 days after transplantation, and the incidence of cGvHD was evaluated in patients who survived for >100 days after transplantation with allogeneic engraftment. Relapse was described as morphologic, cytogenetic or molecular leukaemia recurrence after transplantation.

Statistical analysis

Comparisons of patient-, disease-, and transplant-related variables between the groups were performed using the Mann–Whitney U-test for continuous variable and the χ2 test for categorical data. The distributions of OS and DFS were computed using the Kaplan–Meier method. Kaplan–Meier curves were compared using the log-rank test. The cumulative incidences of aGvHD, cGvHD, NRM and relapse were calculated using cumulative incidence curves to accommodate competing risks.14 Death was the competing risk for aGvHD and cGvHD. Relapse of malignancy was the competing risk for NRM. The Cox proportional hazards regression model was used for the multivariate analyses. The variables tested included donor type, age, disease status at transplant, risk stratification, HLA disparity and dose of infused mononuclear and CD34+ cells. A forward stepwise model selection approach was used to identify the variables that retained a P-value of 0.05 that was considered significant. The P-values were two sided, and analyses were performed using SPSS version 17.0 (Boston, MA, USA).

Results

Patient and donor characteristics

The characteristics of the patients examined in this analysis are listed in Table 1. The patient and disease characteristics including age, sex, diagnosis, ABO match, donor–patient relationship and risk classification between the identical and haploidentical groups were well matched, except that the patients in haploidentical transplant group had a more advanced disease stage (P=0.001), a higher risk stratification (P=0.007) and were younger (P<0.001) than those in the identical transplant group.

Table 1 Patient characteristics

Engraftment

A mean of 7.20 (2.40–14.70) × 108/kg versus 8.20 (1.50–16.70) × 108/kg (P=0.19) G-CSF-mobilised mononuclear cells and 6.63 (1.22–15.58) × 106/kg versus 6.68 (1.10–17.23) × 106/kg (P=0.31) CD34+ cells were infused in the identical and haploidentical groups, respectively. The median time for neutrophil engraftment were 14 days (range, 9–37 days) for HLA-identical HCT and 14 days (range, 10–25 days) for haplo-HCT (P=0.51). The median times for platelet engraftment were 14 days (range, 7–43 days) and 13 days (range, 9–38 days) in the identical and haploidentical cohorts, respectively (P=0.91). Donor-cell engraftment occurred in 105 patients using HLA-identical siblings (97.2%) and in 103 patients using haploidentical donors (98.1%). One haploidentical patient experienced secondary graft failure, received a second transplant from the original donor and experienced complete haematopoietic recovery. No significant differences were observed for either neutrophil or platelet engraftment between the groups.

GvHD

The cumulative incidences of grade II–IV aGvHD in the identical and haploidentical transplantation groups were 20.4±7.6% and 21.9±7.8% (P=0.73), respectively; the cumulative incidences of grade III–IV aGvHD were 8.3±5.3% and 14.3±6.7% (P=0.17), respectively (Figure 1). A total of 167 patients survived for >100 days after transplantation and were eligible to be analysed for the incidence of cGvHD. In all, 33 identical patients and 18 haploidentical patients developed limited cGvHD. Four haploidentical patients developed extensive cGvHD. The 2-year cumulative incidences of cGvHD in the two cohorts were 36.4±10.0% and 24.1±9.4%, respectively (P=0.17; Figure 2).

Figure 1
figure1

Cumulative incidences of aGvHD by donor type: (a) grade II–IV aGvHD and (b) grade III–IV aGvHD. Haplo, haploidentical donor; MSD, matched related donor.

Figure 2
figure2

Cumulative incidences of cGvHD by donor type. Haplo, haploidentical donor; MSD, matched related donor.

Relapse and NRM

The cumulative incidences of relapse were not significantly different between patients in terms of the two donor types. For transplantation using HLA-identical siblings and haploidentical donors, the 3-year probabilities of relapse were 22.2±7.8% and 21.0±7.8% (P=0.85; Figure 3), respectively. In the multivariate analysis, advanced disease status at transplant was related to a higher risk of relapse (CR2: relative risk=4.09, 95% confidence interval 2.16–7.74, P<0.001; NR: relative risk=4.16, 95% confidence interval 1.81–9.58, P=0.001; Table 2). The 3-year probabilities of NRM were 20.5±8.4% and 34.9±10.2% (P=0.048) in the identical and haploidentical groups, respectively (Figure 3). Multivariate analysis indicated that the high-risk stratification of disease at transplant was a significant risk factor for NRM (relative risk=3.23, 95% confidence interval 1.63–6.40, P<0.001).

Figure 3
figure3

Cumulative incidences of (a) relapse and (b) NRM by donor type. Haplo, haploidentical donor; MSD, matched related donor.

Table 2 Multivariate analysis for relapse, DFS, NRM and OS

OS DFS

The median follow-up for surviving patients were 51.7 months (range, 8.5–160.8 months) in the identical group and 38.4 months (range, 8.2–157.6 months) in the haploidentical group. The 3-year probabilities of OS in the identical and haploidentical groups were 62.6±10.4% and 52.6±10.4% (P=0.054), respectively, whereas the 3-year cumulative incidences of DFS were 54.7±10.4% and 43.1±11.8% (P=0.14), respectively (Figure 4). Between 2000 and 2007, the 3-year cumulative incidence of OS in the identical and haploidentical groups was 59.4±17.1% and 30.0±20.0% (P=0.08), respectively, and the 3-year DFS was 56.3±17.1% and 30.0±20.0% (P=0.12), respectively; whereas in 2008–2013, the 3-year OS in the identical and haploidentical groups was 63.0±13.5% and 60.6±11.2% (P=0.16), respectively, and the 3-year DFS was 53.5±13.3% and 45.5±15.1% (P=0.37), respectively. Multivariate analysis suggested that the patients infused with a higher dose of mononuclear or CD34+ cells had a longer survival time, whereas those in the high-risk group had a shorter survival time (Table 2).

Figure 4
figure4

Probability of (a) OS and (b) DFS by donor type. Haplo, haploidentical donor; MSD, matched related donor.

Causes of death

Of the 108 patients, 38 (35%) with HLA-identical siblings and 48 of 105 (46%) patients with haploidentical donors died during the follow-up. Relapse was the primary cause (n=15, 39%) of death in HLA-identical transplantation, whereas infection (n=19, 40%) was the primary cause of death in HLA-haploidentical transplantation. In the HLA-identical group, 14 patients died of infection (37%), 5 patients died of severe aGvHD (13%) and 2 patients died of organ failure (5%). In the haploidentical group, 15 patients died of relapse (31%), 7 patients died of severe aGvHD (15%) and 3 patients died of organ failure (6%). Infection and relapse were the main causes of death using this transplantation approach based on the FBCA conditioning regimen.

The most likely time to develop infection was during the first 6 months post transplantation. Fungi and bacteria were the main pathologies and causes of death. The rates of CMV reactivation detected by PCR (>103 copies) were 26.9% and 49.5% in the identical and haploidentical patients (P =0.001), whereas the rates of EBV viraemia were 31.5% and 50.5% (P=0.005), respectively. No CMV disease or post-transplant lymphoproliferative disease occurred in any patient. The most common time for relapse was during the first year post transplantation. Although the rate of infection in the haploidentical group was higher than that in the identical group, no significant differences were observed between the groups (P=0.86). The identical situation was found for the rate of relapse. GvHD was not the main cause of death between different types of donor transplantation.

Discussion

This study conducted a retrospective analysis of a contemporaneous population of patients who were treated at a single transplantation centre with an FBCA conditioning regimen and identical supportive care measures. The dose of ATG in the FBCA conditioning regimen was adjusted depending on the HLA disparity between the patient and donor.

The results showed that the 3-year probability of OS and DFS was not statistically significantly different among patients who underwent haplo-HCT or HLA-identical sibling HCT using this approach. Our results were consistent with those reported by Lu et al.,4 who compared the outcomes of T cell-replete haplo-HCT for haematologic malignancies with ATG to the outcomes of HLA-identical HCT. The OS and leukaemia-free survival rates did not significantly differ by donor type. The probability of OS at 2 years was 72% and 71% for patients undergoing transplantation using HLA-identical and haploidentical donors, respectively; the probabilities of leukaemia-free survival at 2 years were 71% and 64%, respectively. In the multicentre, prospective study reported by Wang et al.,15 survival was not significantly different between identical and haploidentical transplants for AML in CR1, with 3-year OS rates of 79% and 82% and 3-year DFS rates of 74% and 78%, respectively. Survival in our study was seemingly inferior to that reported by Lu et al.4 and Wang et al.15 This might be caused by more advanced patients in our cohort, especially in the haploidentical group.

The incidence and severity of clinical aGvHD and cGvHD were not significantly different between HLA-identical sibling transplantation and HLA-haploidentical transplantation with this approach. Compared with 43% grade II–IV aGvHD and 53% cGvHD in HLA-haploidentical transplantation using the GIAC (G-CSF induce donor immune tolerance, intensified immunologic suppression, ATG for the prophylaxis of GvHD in conditioning regimen) approach of Huang and colleagues,16 the incidence of grade II–IV aGvHD and cGvHD in our study was lower. The incidence of GvHD with our approach differed from that reported by Wang et al.15 In the comparative study of HLA-identical sibling and haploidentical transplants reported by Wang et al.,15 the cumulative incidences of grade II–IV aGvHD for identical and haploidentical patients at 100 days were 13% and 36%, respectively, and cGvHD at 1 year were 15% and 42%, respectively.

The 3-year probabilities of NRM were 20.5% and 34.9% in the identical and haploidentical groups, respectively, in this study. Our analysis suggests that the incidence of NRM after haploidentical donor transplantation was higher than that after HLA-identical transplantation using the FBCA conditioning regimen. The NRM in our results are consistent with those reported by Luo et al.,17 who compared the outcomes of T cell-replete HLA-haploidentical transplantation for haematologic malignancies with low-dose ATG with HLA-identical sibling HCT. In the research of Luo et al.,17 patients undergoing haplo-HCT suffer significantly higher incidences of NRM, with cumulative incidences of 4.7% and 30.5% in the HLA-identical and haploidentical cohorts, respectively.

The 3-year probabilities of relapse for HLA-identical and haplo-HCT in our study were 22.2% and 21.0%, respectively. The 3-year probabilities of relapse were not higher than those reported by Luo et al.17 and Huang et al.18 Although the incidences of CMV reactivation and EBV viraemia were still high in this study, we frequently monitored the copies of CMV and EBV DNA, infused gamma globulin monthly and pre-emptively treated patients when there were >103 CMV DNA copies after transplantation, and no CMV-related disease or post-transplant lymphoproliferative disease was observed in this cohort.

Many studies have demonstrated that the addition of ATG to conditioning regimens could not only significantly reduce the incidences of aGvHD and cGvHD,19, 20, 21, 22 but could also facilitate engraftment in allo-HCT. However, the optimal dose of ATG is undefined. A low dose of ATG can result in the loss of immunosuppressive effects, whereas very high doses of ATG can aggravate the delay in immune recovery and increase the risk of relapse and infections. Huang and colleagues15, 16 used a total dose of 10 mg/kg ATG in patients undergoing haplo-HCT, and Luo et al.17 used a total dose of 4.5–6 mg/kg ATG. Our results indicated that the lower incidence of GvHD and higher NRM in haploidentical cohort might be attributed to the use of more intensity of ATG and fludarabine in the conditioning regimen.

In summary, this comparison study suggests that outcomes following haploidentical transplantation, based on the FBCA conditioning regimen, were nearly comparable to those following HLA-identical transplantation using the FBCA regimen. Transplantation with our approach using haploidentical donors should be considered a valid alternative for patients who require allo-HCT but for whom no matched related/unrelated donor is available.

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Acknowledgements

We acknowledge the great contributions of the nurses, physicians and laboratory staff from the Department of Hematology, Zhujiang Hospital, Southern Medical University, China, for their patient care. This work was supported by the Scientific and Technology Programs of Guangzhou, China (No.: 2011Y1-00033-3).

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Correspondence to B Y Wu.

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Long, H., Lu, Z., Song, C. et al. Long-term outcomes of HLA-haploidentical stem cell transplantation based on an FBCA conditioning regimen compared with those of HLA-identical sibling stem cell transplantation for haematologic malignancies. Bone Marrow Transplant 51, 1470–1475 (2016) doi:10.1038/bmt.2016.170

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