Comparison of outcomes following transplantation with T-replete HLA-haploidentical donors using post-transplant cyclophosphamide to matched related and unrelated donors for patients with AML and MDS aged 60 years or older

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Abstract

Allografting from HLA-haploidentical donors (HID) is being increasingly utilized worldwide for patients lacking a conventional matched donor. However, its efficacy in older patients with AML and MDS is unclear. We analyzed 127 consecutive allografts for AML/MDS patients aged ≥ 60 years at our center to compare outcomes using HID to those of contemporaneous transplants using matched sibling (MRD) or matched unrelated (MUD) donors. Patient characteristics were similar except HID transplants were more likely in non-white patients and were more commonly performed with reduced intensity conditioning and a marrow graft. For MRD, MUD and HID transplants respectively, 2-year estimates of non-relapse mortality (17, 23, and 9%), relapse (32, 34, and 33%), overall survival (OS) (62, 55, and 67%) and disease-free survival (DFS) (51, 43, and 58%) were not significantly different. Maximum cumulative incidences of grade 2–4 acute GVHD were not different (27, 37, 39%), but incidences of NIH grade moderate to severe (39, 35, 15%, p = 0.028 MUD vs. HID, p = 0.026 MRD vs. HID) and severe chronic GVHD (9, 12, 0%, p = 0.030 MUD vs. HID, p = 0.009 MRD vs. HID) were significantly higher in MRD and MUD than in HID transplants. On multivariable analysis, donor type was not a significant determinant of OS, DFS, TRM, or relapse. However, male gender and high/very high Disease Risk Index (DRI) were associated with significantly higher rates of relapse (HR 1.94, p = 0.047 for male gender, HR 2.48, p = 0.004 for high/very high DRI) and lower OS (HR 1.94, p = 0.018 for male gender, HR 1.80, p = 0.025 for high/very high DRI). HIDs are an acceptable alternative to matched donors in older patients with AML and MDS.

Introduction

Outcomes for non-transplant therapy in older adults (age ≥ 60 years) with AML or high-grade MDS have historically been poor [1, 2]. Allogeneic hematopoietic cell transplantation (allo-HCT) is associated with lower relapse rates and may improve these outcomes. Recent studies have suggested that allo-HCT using reduced-intensity conditioning (RIC) and optimally HLA-matched related or unrelated donors may be effective in this population [3,4,5,6]. However, many older patients will lack suitably healthy and available HLA-matched sibling donors (MRD). Furthermore, many patients, particularly those from ethnic minorities will lack an adequately matched unrelated donor (MUD) [7] and the greater incidence and severity of chronic GVHD typically seen following MUD transplants may be difficult to tolerate in older patients. T-replete haploidentical donor (HID) transplantation using post-transplant cyclophosphamide (ptCy) to mitigate alloreactivity may provide a suitable alternative option for some older patients and may be associated with lower rates of chronic GVHD compared to other donor sources such as MRD and MUD [8,9,10,11,12,13,14,15]. In this analysis, we compare outcomes by donor type (HID, MRD, and MUD) for allo-HCT performed contemporaneously at our center.

Patients and methods

Patients and regimens

All consecutive patients aged ≥ 60 years, who underwent first allo-HCT for AML or MDS at our institution between August 2005 and December 2015, were included in this analysis. This period was chosen to commence when the first HID were performed at our center and extend to a time point that enabled a minimum follow-up of 1-year post transplant. Patients undergoing umbilical cord blood transplants were excluded. Donors were selected at our institution using an algorithm that selection-prioritized an MRD followed by an 8-of-8 HLA A, B, C and DRB1-matched MUD. If such donors could not be accessed within an acceptable timeframe based on the patient’s disease, an HID was used. Patient data were entered prospectively into our institutional database from which they were retrospectively extracted for this analysis. As is our institutional standard, all phases of the allo-HCT, including administration of the preparative regimen and post-transplant care, were administered in the outpatient setting, when feasible, with inpatient admission reserved for complications not manageable as outpatient. Supportive care was per institutional standard and was identical between donor types except that HID transplant patients received fluoroquinolone drug prophylaxis to prevent BK virus cystitis through day +100. Preparative regimens were classified as myeloablative, reduced-intensity or non-myeloablative based upon established criteria [16, 17]. All patients received a T-cell replete graft. All HID transplants received standard GVHD prophylaxis with ptCy (50 mg/kg/d on days +3 and +4 with tacrolimus (to maintain level 5–15 ng/mL from days +5 to +180) and mycophenolate mofetil from days +5 to +35). MRD and MUD patients received standard GVHD prophylaxis with tacrolimus and methotrexate. ATG 4.5 mg/kg rabbit ATG (Thymoglobulin) was added pre-transplant to MUD patients receiving a 9 of 10 HLA matched graft.

Endpoints

Primary outcomes analyzed were overall survival (OS), disease-free survival (DFS; survival without evidence of active malignancy after transplantation), non-relapse mortality (TRM), relapse/progression of malignancy, acute GVHD, and chronic GVHD. Acute GVHD was graded based on the modified Keystone criteria and sub-classified as clinically significant (grades 2−4) and severe (grades 3−4). Because of the possibility of delayed onset of clinical acute GVHD after transplantation was performed using RICT/NST regimens, maximum cumulative incidence of acute GVHD was assessed at 6 months after transplantation. Chronic GVHD was classified as mild, moderate, or severe by National Institutes of Health consensus criteria. Acute and chronic GVHD were prospectively evaluated, graded, and documented by a single dedicated and specialized practitioner.

Covariates

Patient, disease, and transplant-related variables were prospectively documented and obtained for this analysis from our comprehensive institutional database. Disease risk index was retrospectively assigned to each patient using the criteria published by Armand et al. [18].

Statistical analysis

Demographic and clinical characteristics were compared between donor groups by using the Fisher’s exact test for categorical variables and Kruskal−Wallis test for continuous variables. OS and DFS were estimated by the Kaplan−Meier method. Cumulative incidences of TRM, relapse, acute GVHD, and chronic GVHD were calculated to accommodate competing risks. TRM is defined as death in remission. TRM and relapse are competing risks. Death without acute (or chronic) GVHD is the competing risk of acute (or chronic) GVHD. Associations of demographic and clinical factors to survival outcomes were evaluated by using the log-rank test for OS and DFS, and Gray’s test for TRM and relapse. The Wald test was used to compare survival outcomes between donor groups at selected time points [19]. Multivariate Cox models were constructed on OS, DFS, TRM, and relapse. Donor type was included in all four models regardless of significance. For each outcome, a forward stepwise selection procedure was conducted to search for the factors significantly associated with the outcome at the 5% threshold. The following factors were considered and evaluated in the model building procedure: patient age (60–64, ≥65), gender, race (black, white), diagnosis, conditioning intensity, cell source, donor-recipient CMV status, HCT-CI (0–2, ≥3), CIMBTR risk (low, intermediate, and high), DRI risk (low/intermediate, high), HLA matching (full matching, other), donor age (<40, ≥40) and year of transplant (2006–2010, 2011–2015). The final models on OS, DFS, TRM, and relapse included donor type and the variables significantly associated with any of the four outcomes in multivariate Cox analysis. All p values are two-sided and p values less than 5% are considered as significant. All statistical analyses were performed by SAS (version 9.4, SAS Institute Inc.) and R cmprsk package (cran.r-project.org).

Results

Patient characteristics

Patient characteristics are shown in Table 1. MUD transplant patients were more likely to be white than MRD and HID transplants. HID transplants were less likely to receive myeloablative conditioning regimen than MRD and MUD donor transplants (6 vs. 32 and 30% respectively, p = 0.016) and were more likely to have a BM graft (52 vs. 0 and 21%, p < 0.001). However, HCT-CI, DRI, and year of transplant were not statistically different between transplants from the three donor types. Median HLA match was 5 of 10 HLA-A, B, C, DRB1 and DQB1 loci for HID transplants. Two of 57 MUD transplant patients received a 9 of 10 HLA matched graft and 55 were matched at 10 of 10 loci. All HID transplant patients were negative for donor-specific antibodies as defined by a negative anti-donor WBC crossmatch pre-transplant.

Table 1 Patients characteristics

Hematopoietic recovery and donor chimerism

Median times to neutrophil recovery (ANC > 500/mm3) were 15 [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26], 15 (0–22), and 17 [14,15,16,17,18,19,20,21,22,23,24] days for MRD, MUD, and HID transplants respectively (p < 0.01). Times to platelet recovery (platelets > 20,000/mm3) were 19 (0–295), 20(0–196), and 33(20–156) days respectively (p < 0.01). Peripheral blood T-cell (CD3+ cell) donor chimerism at days +30 was significantly higher for HID (median 100%) than MRD (median 86%) and MUD (median 91%) (p < 0.001). Myeloid (CD33+ cell) donor chimerism at days +30 was not significantly different between the donor types (median 100% for each).

GVHD

Cumulative incidences (CI) of GVHD are shown in Fig. 1. The CI of acute GVHD grades 2–4 at 180 days (Fig. 1a) were 35% for the entire population and 27, 37, and 39% for MRD, MUD, and HID transplants respectively (p = NS for all comparisons). CI of acute GVHD grades 3–4 at 180 days (Fig. 1b) were 14% for the entire population and 8, 18, and 15% for the three donor types respectively (p = NS). CI of all grade chronic GVHD at 2 years were 43% for the entire population and 43, 45, and 39% for the three donor types (p = NS on pointwise comparison and Grays test). CI of NIH grade moderate to severe GVHD (Fig. 1c) at 2 years were 31% for the entire population and were significantly higher for MRD (39%) and MUD (35%) than HID transplants (15%) (p = 0.026 MRD vs. HID, p = 0.028 MUD vs. HID on pointwise comparison and p = 0.027 MRD vs. HID, p = 0.043 MUD vs. HID on Grays test). CI of NIH grade severe chronic GVHD (Fig. 1d) were also significantly higher in MRD and MUD than HID transplants (2-year CI 9, 12, and 0% respectively, p = 0.009 MRD vs. HID, p = 0.030 for MUD vs. HID on pointwise comparison and p = 0.047 MRD vs. HID, p = 0.07 MUD vs. HID on Grays test).

Fig. 1
figure1

Cumulative incidences of GVHD by donor type. a Acute GVHD grades 2–4. b Acute GVHD grades 3–4. c Chronic GVHD NIH grade moderate to severe. d Chronic GVHD NIH grade severe

TRM and relapse

The rates of non-relapse mortality (TRM) and relapse are shown in Fig. 2. CI of TRM at 2 years (Fig. 2a) were 18% for the entire population and 17, 23, and 9% for the MRD, MUD, and HID transplants respectively (p = NS for all comparisons). CI of relapse at 2 years (Fig. 2b) were 33% for the entire population and 32, 34, and 33% for the three donor types (p = NS for all comparisons). Donor lymphocyte infusion was used in the treatment of relapse disease in 23% of the relapsed patients (10 out of 43 relapses). None of the Haploidentical recipients who relapsed received DLI.

Fig. 2
figure2

Cumulative incidences of a TRM and b Relapse by donor type

Overall survival, disease-free survival, and GRFS

Estimated OS and DFS are shown in Fig. 3a, b respectively. The estimated OS at 2 years was 60% for the entire population and 62, 55, and 67% for MRD, MUD, and HID transplants respectively (p = NS for all comparisons). The corresponding values for DFS were 49, 51, 43, and 58% respectively (p = NS). The 1-year and 2-year estimates for GVHD free, relapse-free survival (GRFS) were 34 and 26% respectively. Comparison of GRFS over whole study period using log-rank test showed no difference between MRD, MUD, and HID (p = NS for all comparisons).

Fig. 3
figure3

Kaplan−Meier estimates of overall survival (a), disease-free survival (b) and GRFS (c) by donor type

Multivariable analysis

Donor type was not a significant factor on any outcome parameter on multivariable analysis (Table 2). Male gender was associated with a higher risk for relapse (HR 1.94, p = 0.047) and a poorer DFS (HR 1.83, p = 0.024) and OS (HR 1.94, p = 0.018). DRI high was associated with a higher risk of relapse (HR 2.48, p = 0.004) and poorer DFS (HR 2.13, p = 0.003) and OS (HR 1.80, p = 0.025) than patients with DRI low/intermediate risk.

Table 2 Multivariable analysis of OS, DFS, TRM, and relapse

Discussion

This study assesses the outcomes of older patients (≥60 years old) with AML and MDS transplanted in a single center during a 10-year period between 2005 and 2015. The strengths of this analysis include a relatively large number of patients transplanted using HID with a T-replete graft and ptCy, a consistent algorithm for donor allocation at our center, consistent supportive care protocols, prospective documentation of covariates and outcome data and standardized prospective grading and documentation of acute and chronic GVHD in all patients by a single dedicated practitioner. However, the study is limited by its retrospective nature that results in some imbalances between the donor groups with respect to covariates and length of follow-up. Other limitations include a small overall number of patients in each donor arm that can limit the power to detect differences between the donor groups. The use of more bone marrow grafts in HID compared to MUD and MRD can affect the cGVHD and relapse rates in the HID group as has been shown previously where PBSC as stem cell source in HID can lead to lower relapse rates and higher cGVHD [20].

Our data demonstrate that in this population of consecutively transplanted patients with a DRI that was high and intermediate risk in 97% (39% high risk) and an HCT-CMI score ≥3 in 58%, that a 2-year OS of 60%, a DFS of approximately 50% with a TRM of less than 20% can be achieved. Relapse of malignancy was the predominant cause of treatment failure affecting approximately one-third of patients. DRI and patient gender were significant predictors for relapse, DFS and OS on multivariable analysis. The post-relapse survival in this patient population was similar between the three different donor sources, unlike a prior publication from our center showing HID recipients to have worse post-relapse survival than MRD and MUD [21]. This difference between the two reports is likely due to the small number of relapsing patients in each group in this study and limiting this analysis to AML/MDS as opposed to all disease groups.

Compared to other published data in similar patient population, our results show comparable survival and disease control rates [3,4,5,6, 22,23,24]. For example, a recent study of 187 patients with AML and MDS by Pohlen et al. [4] showed a 3-year OS of 35% with a relapse-free survival (RFS) of 32%. However, TRM mortality at 1 year was 37% (compared to 13% at 1 year and 18% at 2 years in our study). Another single institution analysis of 51 patients age > 55 years, HID resulted in 2-year OS of 34% (age 55–65 years) and 15% (age > 65 years) [14]. Similarly, in a recent meta-analysis of 13 studies (749 patients) undergoing allogeneic transplants for AML patients aged > 60, Rashidi et al. [5] observed a 2-year OS and RFS of 45 and 44% respectively with a TRM of 29%. Relatively few prospective studies have been reported. In a relatively large phase II study performed by the CALGB in AML patients in first CR only who were aged 60–75, Devine et al. [3] reported 2-year OS, DFS, relapse rate, and TRM of 48, 42, 44, and 15% respectively. In this study, TRM rates were similar to those observed in our analysis although relapse rates seemed higher despite the fact that all patients were transplanted in CR1. In the CALGB study all patients received a RIC preparative regimen based on low dose busulfan and fludarabine. That may have contributed to the relapse rate of 42% at 2 years. Although the role of intensity of the preparative in preventing relapse following allotransplants for AML remains controversial, a recently published randomized trial conducted by the BMTCTN was terminated early because of a significantly higher relapse rate and lower RFS in the arm receiving RIC [25]. In the present study, MAC was used in approximately 30% of MRD and MUD patients while keeping the overall TRM to 17 and 23% respectively. These data demonstrate that myeloablative conditioning can be successfully used in a significant minority of patients older than 60 years who are selected for lack of comorbidities. MAC was used in only two of our HID patients. This was because MAC transplants on HID patients at our center were mostly restricted to institutionally developed clinical trials where the highest allowable age was 60. Another prospective study by Wang et al. showed that HID transplant can yield similar OS, DFS, and non-relapse mortality to HLA-identical sibling transplant among AML patients transplant in CR 1 [26].

An important finding of our analysis was that HID transplants had similar OS, DFS, TRM, and relapse rates to patients with fully matched donors (MRD and MUD). Indeed donor type (HID vs. MRD or MUD) was not a significant predictor of any of these outcome parameters on multivariable analysis. HID recipients had delayed hematologic recovery and were more likely to have mixed chimerism at day 30 than MRD and MUD. Delayed hematologic recovery has been consistently reported with post-transplant cyclophosphamide and in particular with using bone marrow grafts [27,28,29]. We have previously demonstrated equivalent outcomes for HID transplants compared to MRD and MUD transplants in patients with all age groups with a variety of hematologic malignancies [12, 27]. In the present study we demonstrate that this is also the case for patients aged 60 or greater transplanted for AML and MDS. This study population differs from our prior reports in that it is limited to age > 60 years, AML and MDS disease and included a more recent cohort of patients where our haploidentical program became more focused on PBSC as a graft type.

Whereas the CI of grades 2–4 and 3–4 acute GVHD were not significantly different between patients transplanted from the three types of donor, the CI of moderate to severe and severe chronic GVHD were significantly lower in HID patients than those transplanted from matched donors. Lower rates of chronic GVHD have consistently been seen following T-replete HID transplants using ptCy when compared to matched donor transplants using conventional GVHD prophylaxis based on a calcineurin inhibitor and methotrexate [12, 27, 28, 30]. It remains unclear whether this difference is predominantly due to the effect of ptCy alone or the combination of ptCy with an HID. This question will be answered once larger numbers of matched donor transplants have been performed using GVHD prophylaxis based on ptCy. Nevertheless, since severe chronic GVHD can be particularly difficult to tolerate for older patients, the findings of our study suggest that replete HID transplantation using ptCy may be an attractive alternative to MUD transplants in patients where prevention of chronic GVHD is a priority.

In summary, the findings of this study of relatively recently treated patients from a single center demonstrate that allogeneic transplantation is an effective therapeutic strategy for appropriately selected patients aged 60 and older with AML and MDS. Furthermore, lack of an optimally HLA-matched donor should no longer be considered an obstacle to transplantation for this age group.

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Correspondence to Melhem Solh.

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Bashey, Z.A., Zhang, X., Brown, S. et al. Comparison of outcomes following transplantation with T-replete HLA-haploidentical donors using post-transplant cyclophosphamide to matched related and unrelated donors for patients with AML and MDS aged 60 years or older. Bone Marrow Transplant 53, 756–763 (2018) doi:10.1038/s41409-018-0126-4

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