The effects of graft or donor characteristics in haploidentical hematopoietic cell transplantation (HCT) using post-transplant cyclophosphamide (PT-Cy) are largely unknown. In this multicenter retrospective study we analyzed the correlations between graft cell composition (CD34+, CD3+) and donor features on transplant outcomes in 234 patients who underwent HCT between 2010 and 2016. On multivariate analysis, the use of peripheral blood stem cells (PBSC) was associated with an increased incidence of grade 2–4 acute GVHD [HR 1.94, 95% confidence Interval (CI) = 1.01–3.98, p = 0.05]. An elevated CD3+ graft content was associated with an increased incidence of all-grade chronic GVHD [HR 1.36 (95% CI = 1.06–1.74), p = 0.01]. This effect was confirmed only for the PBSC graft group. A higher CD34+ graft content had a protective role on non-relapse mortality [HR 0.78 (95% CI = 0.62–0.96), p = 0.02] but this was confirmed only for the bone marrow (BM)-derived graft cohort. Donor characteristics did not influence any outcomes. GVHD prophylaxis should be modulated accordingly to CD3+ graft content, especially when a PBSC graft is used. These results need further validation in prospective trials.
At first, haploidentical alloHCT (haploHCT) was characterized by a very high mortality due to lethal graft vs. host-disease (GVHD) and graft failure . Later on, the use of T cell depletion reduced GVHD incidence but graft failure, disease relapse and infections remained critical issues . CD34+ cell positive selection and infusion of stem cells megadoses by the Perugia group overcame the graft failure, but the procedure itself was characterized by a high infectious mortality and relapse rate . The introduction of post-transplant cyclophosphamide (PT-Cy) by the Baltimore group has improved the safety and efficacy of haploHCT [4,5,6]. The use of a T cell replete graft followed by PT-Cy with the addition of mycophenolate and tacrolimus led to better survival outcomes in the haploHCT setting. In retrospective studies, these results were similar to those obtained when using a matched unrelated or related donor in both myeloid  and lymphoid diseases . Despite recent reports regarding outcome differences based upon graft source  or conditioning regimen intensity , there are still several areas of uncertainty in this setting. In particular, there is a current interest in defining the influence of donor characteristics and graft cell composition on survival outcomes. Our study addresses these two issues in a large cohort of patients who received haplo-HCT with a PT-Cy-based GVHD prophylaxis.
Patients and methods
Data sources and patients
We retrospectively studied 234 patients who underwent haploHCT as first transplant using a PT-Cy-based GVHD prophylaxis from five European hematological centers. Procedures were performed between March 2010 and December 2016. Data were locked for analysis on 1st June 2017. All the patients were ≥18 years old and affected by hematological malignancies. Donors were mismatched by at least two or more HLA-loci to recipients. GVHD prophylaxis was always PT-Cy 50 mg/kg days +3 and +4 plus mycophenolate 15 mg/kg TID from day +5 to +35 plus the addition of cyclosporine (n = 97)  or tacrolimus (n = 60)  or sirolimus (n = 77)  as already reported. In the last case, GVHD prophylaxis was performed in the context of a clinical trial  or per protocol. Patients, transplant and donors characteristics are described in Table 1. The Institutional Review Boards of the participating institutions approved this study and patients provided informed consent or a waiver for data collection depending on institutional policies.
Graft cell composition analysis
Graft contents were analyzed by flow cytometry and number of CD34+ hematopoietic stem cells and total CD3+ lymphocytes was determined using Trucount tubes containing fluorescent beads as internal standard (BD Biosciences) and the appropriate monoclonal antibodies. Staining of cells was performed at 4 °C for 20 min in the dark in FACS staining buffer (1× PBS supplemented with 2% fetal bovine serum—FBS). Cells acquisition and analysis were performed on a FacsCalibur cytometer using CellQuest software (BD Biosciences). A minimum of 5 × 105 events were collected for accurate data acquisition.
Definitions and endpoints
Response to therapy and disease status were defined accordingly to conventional standard criteria. Conditioning regimen intensity was classified as per consensus criteria . Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and disease risk index (DRI) were defined as already reported [14, 15]. The primary endpoint was overall survival (OS). Death from any cause was considered an event and surviving patients were censored at last follow-up. Secondary outcomes included neutrophil and platelet engraftment, non-relapse mortality (NRM), disease progression/relapse incidence (PD/RI), progression-free survival (PFS) and GVHD-free/relapse-free survival (GRFS) and defined as already reported [16, 17]. Acute and chronic GVHD were graded using established criteria [18, 19].
OS, PFS, GFRS were performed with Kaplan–Meier method. Cumulative incidences of neutrophil and platelet engraftment, acute GVHD, chronic GVHD, NRM and PD/RI were obtained with competing risk analysis. Only covariates with a p < 0.10 in the univariate analysis were incorporated in the multivariate models. A full list of the variables analyzed is reported in table S1.
Since there is not a predefined cutpoint for graft cell components, each subset was considered as a continuous variable and incorporated into the multivariate model. Regarding the definition of a CD3+ threshold in relation to chronic GVHD incidence (only for the PBSC subgroup analysis), we compared quartiles referring to CD3+ graft content and reported the most significant result (1st + 2nd vs. 3rd + 4th quartile), which corresponds to the use of the median value of CD3+ graft content. Other studies used the quartiles to stratify graft cell content [20, 21]. However, since CD3+ was considered as a continuous variable in the context of a multivariate model, a CD3+ threshold alone should not be considered as a precise risk factor. Associations between patient, donor, disease and transplant-related variables and outcomes of interest were evaluated using Cox proportional hazards or competing risks regression models. Results are expressed as hazard ratios (HR). None of the covariates violated the proportional hazards assumptions. Variables with a p < 0.05 in the multivariate analysis were considered significant. A full description of multivariate models is reported in Table 2. A separate analysis considering only the BM or the peripheral blood stem cells (PBSC) cohort was performed using the same methods (table S2).
The proportional hazards assumption for Cox regression was tested for all multivariate models. A center effect was tested for all multivariate models and found none. Kaplan–Meier method, Cox proportional hazards regression analysis and Fine and Gray method were performed using STATA version 13 . Competing risk analysis was performed with R statistical software .
Patients and graft characteristics
Our study cohort comprised both patients who received peripheral blood stem cells (PBSC) and bone marrow (BM) grafts (Table 1). As compared to the BM cohort, the PBSC cohort contained more myeloid diseases (57 vs. 20%, p < 0.01), less patients with a high/very high DRI (62 vs. 81%, p < 0.01), more patients treated with a myeloablative conditioning regimen (81 vs. 52%, p < 0.01). Sirolimus use was more common for the PBSC group (62%) while tacrolimus was mostly used for the BM group (51%). No differences were reported between the two groups in terms of donor age, donor-recipient gender and relationship. Graft cell content was compared as well. We documented a higher cell content for the PBSC cohort for all cell subsets analyzed, as previously reported [24, 25].
The cumulative incidence of neutrophil recovery at day +30 and +90 was 92% (95% CI:89–95) and 95% (95% CI: 92–98), respectively, with no differences between PBSC and BM (day+ 30: 94 vs. 89%, day +90: 97 vs. 95%, p = 0.09). Platelet engraftment at day +30 and +90 was 61% (95% CI: 55–67) and 81% (95% CI: 76–86), respectively. Again, no differences were reported between PBSC and BM (day +30: 62 vs. 61%, day +90: 90 vs. 81%, p = 0.17). Only five patients had primary graft failure, three in the BM and two in the PBSC group, respectively. All of these patients died, four of infectious complications and one of disease relapse.
Overall survival, PFS and GRFS
Median follow-up was 18 months (range 3–62 months) for surviving patients. The 18-month OS was 60% (CI95%: 53–67) with no differences between PBSC and BM (58% vs. 62%, p = 0.96, Fig. 1). On multivariate analysis (Table 2) patient age >50 years (HR 1.61, p = 0.02) and HCT-CI >2 (HR 1.86, p < 0.01) negatively affected OS. As expected, complete remission (CR) before transplant positively influenced OS (HR 0.46, p < 0.01). PFS at 18 months was 46% (CI 95%: 39–53) and again, PBSC and BM were equivalent (48 vs. 45%, p = 0.43, Fig. 1). A detrimental effect on PFS was found for high/very high DRI (HR1.63, p = 0.04). Again, CR before transplant (HR 0.52, p < 0.01) correlated with a better PFS. GRFS at 18 months was found to be negatively influenced by HCT-CI >2 (HR 1.53, p = 0.02) and positively by CR before transplant (HR 0.59, p < 0.01).
NRM and relapse, causes of death
Overall, NRM at 18 months was 18% (CI 95%: 13–23). Interestingly, NRM was not influenced by graft source (PBSC 19% vs. BM 18%, p = 0.98, Fig. 1). Age >50 years (HR 1.84, p = 0.05) and HCT-CI >2 (HR 2.03, p = 0.02) increased NRM. A higher CD34+ graft content (HR 0.78, p = 0.02) had a protective effect. In the subgroup analysis (table S2), a higher CD34+ count was associated only with a statistical trend in the BM group (HR 0.71, p = 0.19) but not in the PBSC cohort. To further evaluate a possible relation between CD34+ graft content and deaths due to infections when using a BM graft, we performed a logistic regression analysis. In this test, a higher CD34+ dose was related to a decreased incidence of death due to infections (OR 0.54, p = 0.03). Moreover, infection-related deaths were more common in those patients who received a BM graft content <2 × 106 CD34+/kg: 45% vs. 11% (χ2 test, p < 0.01). A cut-off of 2 × 106 CD34+/kg was chosen as it is considered a safe threshold cell dose by international guidelines .
Relapse incidence at 18 months was 35% (95% CI: 28–42). In our study cohort there were no differences between PBSC and BM (33% vs. 37%, p = 0.48, Fig. 1). Patients with a DRI high/very high (HR 1.76, p = 0.06) had a statistical trend toward higher relapse. CR before transplant (HR 0.59, p = 0.03) had a protective effect.
A full description of causes of death is reported in Table S3.
Acute and chronic GVHD
Cumulative incidence of grade 2–4 acute GVHD at day +100 was 34% (95% CI: 28–40) with a higher incidence for PBSC vs. BM (41 vs. 26%, p < 0.01, Fig. 1). Grade 3–4 acute GVHD incidence was 11% (95% CI: 7–15). Again, PBSC graft was associated to a higher risk compared to BM (17% vs. 4%, p < 0.01). On multivariate analysis (Table 2), the use of PBSC was the only factor associated with a higher incidence of grade 2–4 acute GVHD (HR 1.94, p = 0.05) while a higher CD34+ graft content was associated with a lower incidence of grade 3–4 acute GVHD (HR 0.69, p = 0.03).
All-grade chronic GVHD at 18 months was 19% (95%CI: 14–24). Also in this setting, patients who received a PBSC graft were more likely to develop GVHD compared to those receiving BM graft (33% vs. 6%, p < 0.01, Fig. 1). The same was true for extensive chronic GVHD incidence of 10% (95% CI: 6–14), with a striking difference between PBSC and BM (20% vs. 1%, p < 0.01). In the multivariate model adjusted for graft cell composition, only CD3+ graft content was associated with a higher risk of all grade chronic GVHD (HR 1.36, p = 0.01). However, when looking at the graft type subgroup analysis (table S2), a statistical trend toward a protective role of higher CD34+ graft content and grade 3–4 acute GVHD was found only in the PBSC group (HR 0.77, p = 0.10). The negative effect of a higher CD3+ graft content and increased all grade chronic GVHD was confirmed only in the PBSC group (HR 1.26, p = 0.04). In fact, using the median value of CD3+ graft content in of the PBSC group (2.3 × 108 CD3+/kg) as a threshold, we were able to stratify patients at higher risk of chronic GVHD incidence at 18 months (44% vs. 20%, p < 0.01)(Fig. 2). Curiously, a higher CD34+ graft content was associated with a higher all-grade (HR 1.58, p = 0.01) and extensive (HR 1.94, p < 0.01) chronic GVHD only for the BM group.
Herein, we report for the first time the effects of graft composition and donor characteristics on a large cohort of patients receiving haploHCT with PT-Cy-based GVHD prophylaxis.
Our survival outcomes are in line with those reported by previous studies [7,8,9]. Moreover, GRFS of our study cohort is superimposable to other current studies [9, 27]. In fact, we reported 18-month GRFS of 41% (BM) and 30% (PBSC) which is very similar to the 12-month GRFS of 41% (BM) and 27% (PBSC) reported by Bashey and colleagues . Relapse was the most frequent cause for a low GRFS for the BM group (58%) while GVHD was the most common one for the PBSC group (46%). Moreover, we confirmed a strong prognostic role for DRI, age at transplant, disease status at transplant and HCT-CI in the PT-Cy setting [7,8,9, 28].
Our first important observation is that donor characteristics did not influence any of the study outcomes. These results are in contrast with those regarding transplants from HLA-identical donors and HLA-matched unrelated donors, where donor age and gender correlated with outcomes [29, 30]. In the haploidentical setting, a protective role for young and male donors has been observed for ATG-based GVHD prophylaxis . As opposed to ATG-based haploHCT strategies, in vivo T repletion with PT-Cy may effectively abrogate alloreactivity thus neutralizing differences related to donor characteristics. PT-Cy is already known to neutralize HLA-mismatch disparities in the haploidentical setting , and probably differences between donors . However, it is also possible that our study was underpowered to detect a significant influence of donor characteristics on outcomes.
Our second aim was to evaluate the role of graft type and composition in the PT-Cy setting. As recently reported by Bashey and colleagues , we did not observe differences in terms of OS, PFS, neutrophil and platelet engraftment between BM and PBSC. On the contrary, in our study disease relapse was not influenced by graft source. This discrepancy could be explained by the lower prevalence of myeloid diseases in our BM group. In fact, in the above study, a higher incidence of relapse with BM graft was shown only for the myeloid diseases subset. However, a recent study by Ruggeri and colleagues did not report significant differences in acute leukemia relapse between BM and PBSC . This is in line with our study. Regarding immunological complications, we confirmed a higher incidence of both acute and chronic GVHD when using PBSC. Also in the multivariate analysis, PBSC was associated with a higher grade 2–4 acute GVHD and grade 3–4 acute GVHD incidence (statistical trend) with HR similar to the Ruggeri study. However, when considering chronic GVHD incidence in the context of a multivariate model, only CD3+ content was associated to a higher risk. Considering the different study population and the different CD3+ phenotype between the PBSC and BM groups, a subgroup analysis related to graft type was performed (table S2). This further study showed that a higher CD3+ graft count has a significant role only in the PBSC context. Taking into account the correlation between CD34+ and CD3+ graft counts (Spearman correlation rank coefficient ρ = 0.65, p < 0.01), it is probable that a graft with a high CD3+ content has also a high CD34+ concentration, in particular for PBSC. From a clinical perspective, only a fraction of the graft could be infused in order to reduce the number of CD3+ cells while maintaining an adequate CD34+ count. Another option would be to perform a pharmacological in vivo CD3+ depletion (e.g., ATG) only for those patients with a higher CD3+ graft count sparing the CD34+ population. If confirmed on clinical trials, these simple strategies could further reduce the chronic GVHD incidence associated with PBSC grafts while avoiding donor procedure risks and logistic issues related to the use of BM grafts. The second clinical implication of our findings is related to the early identification of patients at higher risk of developing chronic GVHD based on CD3+ cells graft content (in the setting of PBSC). This could be helpful in the creation of clinical trials aiming at chronic GVHD prevention for high-risk patients based on graft composition. Interestingly, PBSC graft was associated to a higher risk of acute GVHD occurrence also in multivariate analysis while CD3+ graft count had no influence on this outcome in either the multivaraiable model or the subgroup analysis. This is probably explained by an insufficient power of our study or by other CD3+ cell subpopulations that we did not analyze and might have a pivotal role in acute GVHD incidence . Recently, a study by McCurdy and colleagues, reported an association between a higher CD3+ graft count with higher grade 2–4 acute GVHD and decreased NRM but not increased chronic GVHD in the PT-Cy setting . However, population characteristics differ from our study: PBSC grafts and MAC regimens were not included. Our PBSC cohort has a higher CD3+ content (23 × 107/kg) compared to the BM grafts of the McCurdy study (4 × 107/kg). The higher CD3+ content, mostly related to PBSC grafts, could explain the higher incidence of chronic GVHD in our study population. Regarding the effects of CD3+ on NRM and acute GVHD incidence, it is possible that our study is not powered enough to evaluate this effect (234 vs. 340 patients).
Finally, we confirmed a protective role of CD34+ graft content on NRM as previously reported in the HLA-identical setting [37, 38], probably due to a reduction in the number of infection-related deaths. However, a subgroup analysis showed that this protective effect was evident only when a BM graft was used at doses of >2 × 106 CD34+/kg. Curiously, a higher CD34+ graft content was protective against grade 3–4 acute GVHD (HR 0.69, p = 0.03). McCurdy and colleagues reported similar results showing that a higher dose of total nucleated dose in the graft is associated to a lower acute grade 3–4 GVHD incidence (HR 0.66, p = 0.03) .
Our study considered two different PT-Cy-based strategies (sirolimus/MMF or cyclosporine/MMF) other than the original Baltimore protocol. However, separate studies using these alternative PT-Cy schemes have already shown similar results to the original PT-Cy+MMF+ tacrolimus approach. Thus, we expect that the effect of PT-Cy complementary drugs was minimal on study outcomes. In fact, the use of sirolimus or cyclosporine instead of tacrolimus did not influence any of the study outcomes in both univariate and multivariate models. However, specific comparison studies are needed to truly state that these approaches are equivalent to the original Baltimore protocol.
In conclusion, we confirmed the good results obtained with haploHCT using PT-Cy, especially the very low rate of chronic GVHD. As opposed to ATG-based haploHCT, donor characteristics did not seem to influence study outcomes. We showed that there are no differences in terms of OS and PFS between BM or PBSC derived graft. When using a PBSC graft, a higher CD3+ graft content was strictly associated with a higher incidence of chronic GVHD. The clinician should consider this readily available information in order to perform a risk-adapted surveillance for patients at high risk for GVHD or to design clinical studies aimed to reduce CD3+ cells in high-risk patients. When using a BM graft, the clinician should care about an optimal marrow harvest since a lower CD34+ graft count is possibly associated to higher infection-related deaths. These data should be evaluated in the context of prospective clinical trials.
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All patients and their families. Supported in part by Associazione Italiana contro le Leucemia-Linfomi e Mielomi (AIL).
Conception and design: A.M.; Financial support: none; Collection and assembly of data: All authors. Data analysis: A.M.; Interpretation: All authors. Manuscript writing: First draft prepared by A.M.; All authors helped in revising the manuscript. Final approval of manuscript: All authors
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The authors declare that they have no conflict of interest.
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Mussetti, A., De Philippis, C., Carniti, C. et al. CD3+ graft cell count influence on chronic GVHD in haploidentical allogeneic transplantation using post-transplant cyclophosphamide. Bone Marrow Transplant 53, 1522–1531 (2018). https://doi.org/10.1038/s41409-018-0183-8
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