Abstract
Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with relatively low incidence of GVHD. Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haploHCT) using PTCy.
Data from the Center for International Blood and Marrow Transplant Research on adult patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (2013–2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced intensity (RIC) conditioning and bone marrow (BM) or peripheral blood (PB) graft source.
646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2–4 aGVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (p=0.002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (p<0.001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2–4 acute GVHD; however, older donor age (30–49 versus <29 years) was significantly associated with higher rates of grade 2–4 acute GVHD (HR 1.53, 95% CI 1.11–2.12, p=0.01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR 1.70, 95% CI 1.11–2.62, p=0.01) in the RIC setting. There were no differences in relapse or overall survival between groups.
Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haploHCT. Our results indicate that in RIC haploHCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
Introduction
For adults with advanced hematologic malignancies, haploidentical donors allow patients without a matched related or unrelated donor the opportunity to proceed with a potentially curative allogeneic hematopoietic cell transplant (HCT).(1–3) The use of post-transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has significantly improved outcomes for haploidentical HCT, approaching those in the matched related and unrelated donor setting.(4, 5) Studies evaluating T-cell replete haploidentical HCT using PTCy have demonstrated rates of acute GVHD in the range of 14–41% and chronic GVHD rates of 0–31%, compared to historical rates of 20–80% and 30–70%, respectively, in matched related and matched unrelated donor transplants.(6–8) The majority of these haplo-transplants were done using reduced-intensity conditioning (RIC) regimens with bone marrow (BM) as a graft source.(3–5, 9–21)
Peripheral blood (PB) grafts have also been increasingly used in the haploidentical setting, and there have been two retrospective analyses comparing BM and PB. A small study by O’Donnell et al., demonstrated no differences in acute GVHD at 100 days, chronic GVHD at 2 years, or OS at 2 years between BM (33%, 23%, 58%, respectively) and PB (40%, 19%, 66%, respectively). However, the rate of relapse was higher with BM compared to PB (19% vs 49%).(14) In contrast, a large CIBMTR analysis by Bashey et al. demonstrated a significantly lower incidence of grades II-IV acute GVHD (HR 0.45, p<0.001) and chronic GVHD (HR 0.35, p<0.001) in BM compared to PB.(9) Relapse was also higher with BM compared to PB (HR 1.49, p=0.009) specifically in patients with leukemia, however there were no differences in OS or non-relapse mortality (NRM).
Although the incidences of GVHD after haploidentical HCT have been described, there is little data describing risk factors for GVHD in this setting. The aim of this study is to describe the incidence, characteristics, and risk factors for acute and chronic GVHD in adult patients with hematologic malignancies who underwent a PTCy-based haploidentical HCT from 2013–2016.
Materials and Methods
Data Source
This was a retrospective analysis using data from the CIBMTR. The CIBMTR is a combined research program of the Medical College of Wisconsin and the National Marrow Donor Program. The CIBMTR comprises a voluntary network of more than 420 transplantation centers worldwide that contribute data on consecutive allogeneic and autologous HCTs to a centralized statistical center. Observational studies conducted by the CIBMTR are performed in compliance with all applicable federal regulations pertaining to the protection of human research participants. Protected health information used in the performance of such research is collected and maintained in the capacity of the CIBMTR as a public health authority under HIPPAA regulations. The CIBMTR collects data at two levels, Transplant-Essential Data (TED) and Comprehensive Report Form (CRF). The TED level data is an internationally accepted standard of data that contains key variables for all consecutive transplant recipients in the United States. When a transplant is registered with the CIBMTR, a subset of patients are selected for the CRF level of data collection. The CRF level data capture additional data related to the patient, disease, and transplant. Thus, a greater number of patients contribute to TED level data compared to CRF data. Additional details regarding the CIBMTR registry have been previously described.(22)
Patients
Eligible patients were ≥18 years with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). All patients underwent HCT from a haploidentical donor (defined in the CIBMTR registry as 1 or more antigen-level mismatch among HLA-A, -B, -C, and –DRB1) using BM or PB as a graft source and GVHD prophylaxis with PTCy, tacrolimus, and mycophenolate mofetil; other PTCy-based prophylaxis regimens were excluded to limit heterogeneity and due to low numbers of these regimens. Conditioning regimens included myeloablative (MAC) or RIC, with or without total body irradiation (TBI).(23, 24) An RIC regimen was defined as a) TBI does of ≤500 cGy as a single fraction or ≤ 800 cGy if fractionated, b) <9 mg/kg of oral busulfan or intravenous equivalent, or c) <140 mg/m2 of melphalan. Transplants using ex-vivo T-cell depletion, antithymocyte globulin (ATG), or alemtuzumab were excluded.
Study Endpoints and definitions
The primary endpoints of this study were incidence of grade II-IV acute GVHD and chronic GVHD. Secondary endpoints included grade III-IV acute GVHD, relapse, OS, non-relapse mortality (NRM), as well as the composite endpoints of GVHD-relapse-free survival (GRFS) (including survival without grade 3–4 acute GVHD, chronic GVHD requiring systemic treatment, relapse or death); and chronic-GVHD relapse-free survival (CRFS) (including survival without chronic GVHD requiring systemic treatment, relapse or death).(25) GVHD was graded according to consensus criteria.(7, 26, 27) Disease status was categorized into early, intermediate, and advanced(28), and the revised Disease Risk Index (DRI) was used to categorize patients into low, intermediate, and high/very high groups.(29) Relapse was defined by hematologic criteria by submitting centers with non-relapse mortality as a competing event. NRM was defined as death without evidence of disease recurrence, relapse was considered a competing event. For relapse, and NRM, patients alive in continuous complete remission were censored at last follow-up. For GVHD, death without the event was considered a competing event. HLA matching was defined as described previously.(30)
Statistical methods
Patient, disease, and transplant-related variables for donor types were compared using chi-square statistics for categorical variables and the Kruskal-Wallis test for continuous variables. Univariate analysis with Gray’s test and log-rank test was used for cumulative incidence and survival, respectively. Variables tested included: patient and gender, Karnofsky performance score, hematopoietic cell transplantation comorbidity index (HCT-CI)(31), DRI, time from diagnosis to HCT, donor age and relation (parent, offspring, sibling), donor/recipient gender, donor/recipient CMV status, use of TBI, and year of transplant. Patients were categorized into 4 groups based on conditioning intensity (myeloablative or reduced intensity) and graft source (bone marrow or peripheral blood). Graft source and conditioning intensity were included in all models. The primary comparisons were RIC-BM versus RIC-PB, and MAC-BM versus MAC-PB.
Multivariable models were built using the Cox’s proportional hazards model. All variables were tested to affirm the assumption of proportional hazards and no variables violated the proportional hazards assumption. A stepwise model building procedure was used to select the adjusted factors for each outcome with a threshold of 0.05 for both entry and stay in the model. The ‘center’ effect was adjusted for all endpoints. Two-way interactions between ‘donor type’ and the adjusted clinical variables in the models were tested, and no significant interactions were detected. A threshold p-value 0.05 for the primary endpoint of chronic GVHD, and of 0.01 otherwise was used for significance of the main testing variable. A threshold of p-value 0.01/2=0.005 (or 0.05/2=0.025 for the primary endpoint of chronic GVHD) was recommended for the significance of pairwise comparisons when the main variable is significant. The impact of cGVHD on relapse was analyzed by treating cGVHD as a time-dependent covariate in the model for relapse. Results were expressed as a hazard ratio with 95% confidence intervals. SAS software version 9.4 (SAS Institute, Cary, NC) was used in the analysis.
Results
Patients, disease and transplant characteristics
Table 1 shows the characteristics of the study population (N=646) grouped by graft source and conditioning intensity. As expected, the median age of patients undergoing MAC conditioning (45 and 42 years for MAC-BM and MAC-PB, respectively) was younger than those undergoing RIC (60 and 62 years for RIC-BM and RIC-PB, respectively). More patients receiving PB grafts had a higher HCT-CI (score ≥3) than those receiving BM: (52% MAC-PB compared to 43% MAC-BM, and 62% RIC-PB compared to 42% RIC-BM). Likewise, more patients with a low HCT-CI (score 0) received BM (25% MAC-BM compared to 12% MAC-PB and 24% RIC-BM compared to 14% RIC-PB). As expected, patients receiving PB had overall higher CD34 and CD3 cell doses compared to BM. 47% in the MAC groups received TBI as part of conditioning, with a median dose of 1200 (range 550–1350) while 89% in the RIC groups received TBI, median dose 200 (range 200–400). Median follow-up was longer in the RIC groups compared to the MAC groups: 24 (range 2–53) and 21 (range 6–50) months in RIC-BM and RIC-PB, respectively, versus 13 (range 4–49) and 14 (range 6–50) months in MAC-BM and MAC-PB, respectively.
Table 1.
Baseline characteristics
| Variable | MAC-BM | MAC-PB | RIC-BM | RIC-PB | P-Value |
|---|---|---|---|---|---|
| Number of patients | 79 | 183 | 192 | 192 | |
| Recipient age at transplant, years | <0.0001a | ||||
| Median (range) | 45 (18–72) | 42 (18–71) | 60 (18–77) | 62 (18–76) | <0.0001b |
| 18–39 | 35 (44) | 78 (43) | 36 (19) | 21 (11) | |
| 40–59 | 24 (30) | 77 (42) | 56 (29) | 55 (28) | |
| 60+ | 20 (26) | 28 (16) | 100 (52) | 116 (60) | |
| Recipient gender | 0.82b | ||||
| Male | 46 (58) | 108 (59) | 121 (63) | 114 (59) | |
| Female | 33 (42) | 75 (41) | 71 (37) | 78 (41) | |
| Recipient gender | 0.03b | ||||
| Caucasian | 57 (72) | 116 (63) | 138 (72) | 139 (72) | |
| African-American | 13 (16) | 56 (31) | 34 (18) | 38 (20) | |
| Asian/Pacific Islander | 3 (4) | 4 (2) | 12 (6) | 12 (6) | |
| Other/Missing | 6 (8) | 7 (3) | 8 (4) | 3 (1) | |
| Karnofsky performance score prior to transplant | 0.002b | ||||
| < 90 | 30 (38) | 96 (52) | 77 (40) | 101 (53) | |
| 90–100 | 43 (54) | 85 (46) | 112 (58) | 87 (45) | |
| Missing | 6 (8) | 2 (1) | 3 (2) | 4 (2) | |
| Sorror HCT-CI | <0.0001b | ||||
| 0 | 20 (25) | 22 (12) | 46 (24) | 26 (14) | |
| 1–2 | 25 (32) | 64 (35) | 62 (32) | 43 (22) | |
| 3+ | 34 (43) | 95 (52) | 81 (42) | 119 (62) | |
| Missing | 0 | 2 (1) | 3 (2) | 4 (2) | |
| Disease | <0.0001b | ||||
| AML | 39 (49) | 115 (63) | 94 (49) | 111 (58) | |
| ALL | 22 (28) | 46 (25) | 34 (18) | 22 (11) | |
| CML | 4 (5) | 10 (5) | 12 (6) | 3 (2) | |
| MDS | 14 (18) | 12 (7) | 52 (27) | 56 (29) | |
| Disease Risk Index | |||||
| AML | 39 | 115 | 94 | 111 | 0.10b |
| Low | 2 (3) | 11 (6) | 7 (4) | 7 (4) | |
| Intermediate | 20 (25) | 57 (31) | 66 (34) | 69 (36) | |
| High/Very high | 15 (19) | 44 (24) | 18 (9) | 29 (15) | |
| Missing | 2 (3) | 3 (2) | 3 (2) | 6 (3) | |
| ALL | 22 | 46 | 34 | 22 | 0.49b |
| Intermediate | 15 (19) | 23 (13) | 20 (10) | 14 (7) | |
| High/Very high | 7 (9) | 23 (13) | 14 (7) | 8 (4) | |
| CML | 4 | 10 | 12 | 3 | 0.03b |
| Low | 4 (5) | 9 (5) | 12 (6) | 1 (1) | |
| Intermediate | 0 | 1 (1) | 0 | 1 (1) | |
| High/Very high | 0 | 0 | 0 | 1 (1) | |
| MDS | 14 | 12 | 52 | 56 | 0.15b |
| Intermediate | 7 (9) | 4 (2) | 27 (14) | 14 (7) | |
| High/Very high | 6 (8) | 7 (4) | 23 (12) | 37 (19) | |
| Missing | 1 (1) | 1 (1) | 2 (1) | 5 (3) | |
| HLA matching | 0.19b | ||||
| Haploidentical (1-antigen mismatch) | 5 (6) | 8 (4) | 6 (3) | 10 (5) | |
| Haploidentical (≥2-antigen mismatches) | 74 (94) | 173 (95) | 181 (94) | 182 (95) | |
| Haploidentical (mismatch number unknown) | 0 | 2 (1) | 5 (3) | 0 | |
| Donor type | < 0.001b | ||||
| Parent donor | 11 (14) | 37 (20) | 14 (7) | 9 (5) | |
| Offspring donor | 30 (38) | 58 (32) | 120 (63) | 124 (65) | |
| Sibling donor | 34 (43) | 88 (48) | 56 (29) | 54 (28) | |
| Missing | 4 (5) | 0 | 2 (1) | 5 (3) | |
| Donor age, years | < 0.001b | ||||
| Median (range) | 38 (12–65) | 37 (9–68) | 37 (8–73) | 39 (8–71) | 0.44a |
| < 29 | 25 (32) | 52 (28) | 55 (29) | 43 (22) | |
| 30–49 | 38 (48) | 70 (38) | 98 (51) | 112 (58) | |
| ≥50 | 12 (15) | 60 (33) | 35 (18) | 34 (18) | |
| Missing | 4 (5) | 1 (1) | 4 (2) | 3 (2) | |
| Time from diagnosis to transplant, months | 0.13b | ||||
| Median (range) | 6 (3–180) | 8 (2–144) | 9 (<1–291) | 8 (2–171) | 0.16a |
| < 6 | 38 (48) | 75 (41) | 58 (30) | 77 (40) | |
| 6 – <12 | 18 (23) | 47 (26) | 64 (33) | 52 (27) | |
| ≥ 12 | 23 (29) | 61 (33) | 70 (36) | 63 (33) | |
| CD34 cell dose, × 106/kg | <0.001b | ||||
| Median (range) | 3 (0–8) | 5 (0–21) | 3 (0–13) | 6 (0–20) | <0.001a |
| < 2 | 28 (35) | 4 (2) | 49 (26) | 8 (4) | |
| 2 – <4 | 31 (39) | 24 (13) | 91 (47) | 20 (10) | |
| 4 – <8 | 17 (22) | 96 (52) | 37 (19) | 107 (56) | |
| ≥ 8 | 0 | 33 (18) | 4 (2) | 44 (23) | |
| Missing | 3 (4) | 26 (14) | 11 (6) | 13 (7) | |
| CD3 cell dose, × 106/kg | <0.001b | ||||
| Median (range) | 0 (0–1) | 2 (0–11) | 0 (0–12) | 2 (0–14) | <0.001a |
| < 2 | 55 (70) | 48 (26) | 120 (63) | 70 (36) | |
| 2 – <4 | 0 | 54 (30) | 0 | 73 (38) | |
| 4 – <8 | 0 | 18 (10) | 0 | 12 (6) | |
| ≥ 8 | 0 | 2 (1) | 1 (1) | 1 (1) | |
| Missing | 24 (30) | 61 (33) | 71 (37) | 36 (19) | |
| D-R gender mismatch | 0.69b | ||||
| M/M | 34 (43) | 62 (34) | 82 (43) | 74 (39) | |
| M/F | 21 (27) | 47 (26) | 46 (24) | 45 (23) | |
| F/M | 12 (15) | 46 (25) | 39 (20) | 40 (21) | |
| F/F | 12 (15) | 28 (15) | 25 (13) | 33 (17) | |
| D-R CMV status | 0.03b | ||||
| −/− | 16 (20) | 31 (17) | 48 (25) | 37 (19) | |
| −/+ | 27 (34) | 41 (22) | 66 (34) | 62 (32) | |
| +/− | 7 (9) | 16 (9) | 16 (8) | 14 (7) | |
| +/+ | 29 (37) | 90 (49) | 61 (32) | 78 (41) | |
| Missing | 0 | 5 (3) | 1 (1) | 1 (1) | |
| Conditioning regimen | N/A | ||||
| BU+FLU/CY (MAC) | 35 (44) | 80 (44) | 0 | 0 | |
| TBI±FLU/CY (MAC) | 24 (30) | 100 (55) | 0 | 0 | |
| TBI±FLU/CY (RIC) | 0 | 0 | 159 (83) | 167 (87) | |
| FLU+MEL (RIC) | 0 | 0 | 29 (15) | 19 (10) | |
| Others | 20 (25) | 3 (2) | 4 (2) | 6 (3) | |
| TBI dose, cGy | |||||
| Median (range) | 1200 (200–1350) | 1200 (200–1200) | 200 (200–300) | 200 (200–400) | <0.001a |
| Year of transplant | < 0.001b | ||||
| 2013 | 6 (8) | 11 (6) | 52 (27) | 13 (7) | |
| 2014 | 16 (20) | 38 (21) | 48 (25) | 39 (20) | |
| 2015 | 20 (25) | 61 (33) | 40 (21) | 69 (36) | |
| 2016 | 37 (47) | 73 (40) | 52 (27) | 71 (37) | |
| Follow-up of survivors, months, median (range) | 13 (4–49) | 14 (6–50) | 24 (2–53) | 21 (6–50) | |
Abbreviations: MAC = Myeloablative, BM = Bone Marrow, PB = Peripheral Blood, RIC = Reduced Intensity Conditioning, HCT-CI = Hematopoietic stem cell transplant comorbidity index, AML = Acute myelogenous leukemia, ALL = Acute lymphoblastic leukemia, CML = Chronic myelogenous leukemia, MDS = Myelodysplastic syndromes, N/A = Not applicable, BU = Busulfan, FLU = Fludarabine, CY = Cyclophosphamide, MEL = Melphalan.
The P-Values were obtained by the following statistical hypothesis tests:
Kruskal-Wallis test
Pearson Chi-Square test
GVHD and Engraftment
In univariate analysis, the incidence of grade 2–4 acute GVHD at 100 days was highest in MAC-PB at 46% (95% CI 39–54), followed by RIC-PB at 36% (95% CI 29–43), MAC-BM at 33% (95% CI 23–44), and RIC-BM at 27% (95% CI 21–33) (p=0.002). A similar pattern was observed for chronic GVHD, where the incidence at 1 year was highest in MAC-PB at 40% (95% CI 32–47), followed by RIC-PB at 34% (95% CI 27–41), MAC-BM at 24% (95% CI 15–35) and RIC-BM at 20% (95% CI 14–26) (p<0.001) (Table 2).
Table 2.
Univariate analysis of transplant outcomes by stem cell source and conditioning regimen intensity
| MAC-BM (N = 79) | MAC-PB (N = 183) | RIC-BM (N = 192) | RIC-PB (N = 192) | ||
|---|---|---|---|---|---|
| Outcomes | N (95% CI) | N (95% CI) | N (95% CI) | N (95% CI) | p-value |
| Grade 2–4 acute GVHD at 6 months | 36 (25–46)% | 46 (39–54)% | 30 (23–36)% | 36 (30–43)% | 0.002 |
| Chronic GVHD at 1 years | 24 (15–35)% | 40 (32–47)% | 20 (14–26)% | 34 (27–41)% | <0.001 |
| Grade 3–4 acute GVHD | 13 (6–21)% | 14 (10–20)% | 5 (3–9)% | 9 (6–14)% | 0.06 |
| Relapse at 1 years | 28 (18–39)% | 26 (20–33)% | 37 (30–44)% | 36 (29–43)% | 0.16 |
| Non-relapse mortality at 1 years | 14 (7–23)% | 18 (12–24)% | 9 (5–13)% | 18 (13–24)% | 0.01 |
| GVHD-free, relapse-free survival at 1 years | 38 (28–49)% | 23 (17–30)% | 41 (34–49)% | 25 (19–32)% | 0.002 |
| cGVHD-free, relapse-free survival at 1 years | 42 (31–53)% | 26 (20–33)% | 43 (36–50)% | 26 (19–32)% | 0.002 |
| Overall survival at 1 years | 67 (56–77-)% | 64 (57–71)% | 70 (63–76)% | 58(51–65)% | 0.07 |
| Neutrophil recovery at 100 days* | 92 (85–97)% | 95 (91–98)% | 94 (90–97)% | 93 (89–96)% | 0.004 |
| Platelet recovery at 100 days | 78 (67–86)% | 85 (79–90)% | 90 (85–94)% | 89 (84–93)% | 0.10 |
Number of graft failures: MAC-BM (n=1), MAC-PB (n=4), RIC-BM (n=4), RIC-PB (n=6).
In multivariable analysis, there were no significant difference in grade 2–4 acute GVHD or grade 3–4 acute GVHD between conditioning and graft source groups (Table 3). Adjusted cumulative incidence of grade 2–4 acute GVHD between all four conditioning and graft source groups is shown in Figure 1. The only significant factor for grade 2–4 acute GVHD in multivariable analysis was donor age 30–49 versus <29 years (HR 1.53, 95% CI 1.11–2.12, p=0.01). For grade 3–4 acute GVHD, older donor age was also the only significant factor (≥50 versus <29 years, HR 3.89, 95% CI 1.81–8.35, p=0.0005). Despite the impact of donor age, donor relation was not a significant factor for acute GVHD. There was a significantly higher risk for chronic GVHD in the RIC-PB group compared to RIC-BM (HR 1.70, 95% CI 1.11–2.62, p=0.01). There was no difference in chronic GVHD between MAC-PB and MAC-BM (Table 3). Adjusted cumulative incidence curves for chronic GVHD are shown in Figure 2. There were also no differences in chronic GVHD severity among any of the groups; overall, 59% were categorized as mild, 28% were moderate, and 13% were severe (Table 4).
Table 3.
Multivariate analysis of transplant outcomes by stem cell source and conditioning regimen intensity
| Outcome | Variable | HR (95% CI) | P-value |
|---|---|---|---|
| Primary Endpoints | |||
| Acute GVHD grade II-IV | |||
| MAC-PB vs MAC-BM | 1.10 (0.66–1.82) | 0.73 | |
| RIC-PB vs RIC-BM | 1.24 (0.84–1.82) | 0.28 | |
| Chronic GVHD | |||
| MAC-PB vs MAC-BM | 1.56 (0.86–2.82) | 0.14 | |
| RIC-PB vs RIC-BM | 1.70 (1.11–2.62) | 0.01 | |
| Secondary Endpoints | |||
| Acute GVHD grade III-IV | |||
| MAC-PB vs MAC-BM | 0.78 (0.38–1.60) | 0.49 | |
| RIC-PB vs RIC-BM | 1.93 (0.94–3.96) | 0.07 | |
| Relapse | |||
| MAC-PB vs MAC-BM | 0.95 (0.59–1.52) | 0.82 | |
| RIC-PB vs RIC-BM | 0.90 (0.65–1.26) | 0.55 | |
| Non-relapse mortality | |||
| MAC-PB vs MAC-BM | 1.31 (0.62–2.78) | 0.48 | |
| RIC-PB vs RIC-BM | 2.06 (1.15–3.68) | 0.01 | |
| GVHD-free, relapse-free survival | |||
| MAC-PB vs MAC-BM | 1.32 (0.94–1.85) | 0.11 | |
| RIC-PB vs RIC-BM | 1.31 (1.02–1.69) | 0.03 | |
| Chronic GVHD-free, relapse-free survival | |||
| MAC-PB vs MAC-BM | 1.36 (0.94–1.98) | 0.10 | |
| RIC-PB vs RIC-BM | 1.23 (0.94–1.61) | 0.12 | |
| Overall survival | |||
| MAC-PB vs MAC-BM | 1.02 (0.64–1.62) | 0.93 | |
| RIC-PB vs RIC-BM | 1.17 (0.86–1.61) | 0.32 |
Figure 1.
Incidence of Acute GVHD II-IV by conditioning intensity and graft source.
Figure 2.
Incidence of Chronic GVHD by conditioning intensity and graft source.
Table 4.
Chronic GVHD severity by stem cell source and conditioning regimen
| Characteristic | MAC-BM | MAC-PB | RIC-BM | RIC-PB | P-value |
| Number of patients with chronic GVHD | 19 | 70 | 43 | 65 | |
| N (%) | N (%) | N (%) | N (%) | ||
| Chronic GVHD severity | 0.44 | ||||
| Mild | 13 (68) | 33 (47) | 26 (60) | 44 (68) | |
| Moderate | 5 (26) | 25 (36) | 12 (28) | 13 (20) | |
| Severe | 1 (5) | 11 (16) | 5 (12) | 8 (12) | |
| Missing | 1 (1) | ||||
To further determine the significance of graft source on chronic GVHD, subset analyses of MAC (N=262) and RIC (N=384) cohorts were performed. This confirmed an increased incidence of chronic GVHD with PB compared to BM in both MAC (HR 1.81,95% CI 1.00–3.28, p=0.05) and RIC (HR 1.72, 95% CI 1.10–2.70, p=0.02) groups, however this only met the predetermined significance level in the RIC group. Due to the known differences in age between MAC and RIC groups, an age-adjusted analysis for chronic GVHD was also performed and demonstrated similar results (data not shown). We further analyzed chronic GVHD in a larger cohort of CIBMTR patients receiving a haplo-identical transplant (N=1401) using TED level data, and confirmed that in the RIC setting, PB was associated with higher rates of chronic GVHD (p=0.0015). (Table 5).
Table 5.
Multivariate analysis of chronic GVHD by stem cell source and conditioning regimen intensity based on TED level data
| Outcome | Variable | HR (95% CI) | P-value |
|---|---|---|---|
| Chronic GVHD | |||
| MAC-PB vs MAC-BM | 1.44 (0.96–2.16) | 0.08 | |
| RIC-PB vs RIC-BM | 1.75 (1.24–2.47) | 0.0015 | |
Regarding hematopoietic recovery, neutrophil recovery at 28 days was highest in MAC-PB (95%), followed by RIC-BM (94%), RIC-PB (93%), and MAC-BM (92%) (p=0.004). Time to neutrophil recovery was comparable across the groups:19 days in MAC-BM (range 5–125), 16 days in MAC-PB (range 1–90), 18 days in RIC-BM (range 2–48), and 17 days in RIC-PB (range 1–105). There was no difference in platelet recovery at 100 days between groups (Table 2). Given the small numbers, there was no notable trend regarding graft failure: 6 in RIC-PB, 4 in RIC-BM, 4 in MAC-PB, and 1 in MAC-BM.
Relapse and Survival Outcomes
Relapse at 1 year was similar among the groups (Table 2, adjusted cumulative incidence shown in Figure 3). In multivariable analysis, revised DRI high/very high versus low (HR 2.11, 95% CI 1.21–3.68, p=0.008) was the only significant factor for relapse. We further analyzed the impact of chronic GVHD on relapse, and found no significant associations between chronic GVHD and relapse in the entire cohort (HR 1.00, 95% CI 0.70–1.44, p=0.99); nor in subset analysis of MA (p=0.80) and RIC (p=0.75) cohorts.
Figure 3.
Incidence of Relapse by conditioning intensity and graft source.
NRM at 1 year was highest in RIC-PB at 18% (95% CI 13–24) and MAC-PB at 18% (95% CI 12–24%), followed by 14% (95% CI 7–23) in MAC-BM, and 9% (95% CI 5–13) in RIC-BM (p=0.01) (Table 2). In multivariable analysis, there was a higher risk of NRM in RIC-PB compared to RIC-BM (HR 2.06, 95% CI 1.15–3.68, p=0.01). There was no difference in NRM between MAC-PB and MAC-BM. Adjusted cumulative incidence of NRM between groups (p=0.0292) is shown in Figure 4. The other significant factors for NRM were older patient age ≥60 versus 18–29 years (HR 2.31, 95% CI 1.18–4.54, p=0.015) and higher HCT-CI ≥3 versus 0 (HR 3.32, 95% CI 1.50–7.35, p=0.003).
Figure 4.
Incidence of Non-relapse mortality by conditioning intensity and graft source.
GRFS and CRFS at 1 year were lowest in the PB groups for both RIC (25% and 26% respectively, compared to 41 and 43% in BM groups) and MAC (23% and 26%, compared to 38% and 42%) (Table 2), but in multivariable analysis, these outcomes were not significantly impacted by graft source or conditioning regimen (adjusted probability, Figure 5). Donor age ≥50 versus <29 years (HR 1.43, 95% CI 1.08–1.88, p=0.012) and Karnofsky performance score 90–100 versus <90 (HR 0.74, 95% CI 0.61–0.90, p=0.003) were significant factors for GRFS, whereas patient age 50–59 versus 18–29 years (HR 1.53, 95% CI 1.09–1.96, p=0.013) and patient race Non-Caucasian versus Caucasian (HR 1.33, 95% CI 1.07–1.65, p=0.010) were significant factors for CRFS.
Figure 5.
GVHD-free, relapse free survival by conditioning intensity and graft source.
OS at 1 year in univariate analysis was similar among all groups (Table 2). In multivariable analysis, patient age 50–59 (HR 1.73, 95% CI 1.12–2.68, p=0.013) or ≥60 years (HR 1.84, 95% CI 1.20–2.82, p=0.005) versus 18–29 years, donor age ≥50 versus <29 years (HR 1.77, 95% CI 1.24–2.52, p=0.002), and revised DRI high/very high versus low (HR 2.68, 95% CI 1.46–4.90, p=0.001) were significant factors contributing to OS. Relapse was the leading cause of death in all groups (Table 6).
Table 6.
Causes of death
| MAC-BM (N = 79) | MAC-PB (N = 183) | RIC-BM (N = 192) | RIC-PB (N = 192) | |
|---|---|---|---|---|
| No. of dead patients | 32 | 75 | 84 | 99 |
| Cause of death - no. (%) | ||||
| Primary disease | 16 (50) | 35 (47) | 60 (71) | 45 (45) |
| Graft failure | 1 (3) | 1 (1) | 2 (2) | 0 |
| GVHD | 1 (3) | 7 (9) | 4 (5) | 3 (3) |
| Infection | 3 (9) | 6 (8) | 3 (4) | 2 (2) |
| IPn/ARD | 6 (19) | 12 (16) | 8 (10) | 16 (16) |
| Organ failure | 2 (6) | 6 (8) | 3 (4) | 17 (17) |
| Secondary malignancy | 1 (3) | 8 (11) | 3 (4) | 14 (14) |
| Others | 2 (6) | 0 | 1 (1) | 2 (2) |
Discussion
This study demonstrates that donor age and graft source are important risk factors for acute and chronic GVHD, respectively, after PTCy-based haploidentical HCT. Similar to previous findings in both matched (32–34) and alternative (35) donor settings, PB grafts in RIC haplo-transplant were found to be significantly associated with chronic GVHD of any severity. Although the impact of specific components of transplant are historically studied as distinct entities (36), we report a significant association of graft source and conditioning (RIC-PB) on chronic GVHD.
Previous studies have reported incidences of acute and chronic GVHD after PTCy-based haploidentical HCT with varying combinations of stem cell sources and conditioning regimens, but only 2 prior studies have compared BM and PB grafts. O’Donnell et al. reported no difference in GVHD or OS but lower relapse with PB, whereas Bashey et al. demonstrated higher incidences of acute and chronic GVHD, as well as lower relapse with PB without a difference in OS.(9, 14) Our study confirms the finding of increased chronic GVHD with PB grafts, however, only in the reduced intensity conditioning setting. Despite the incidence of chronic GVHD at 1 years being highest in the MAC-PB cohort, there was no difference confirmed in multivariable analysis in the myeloablative setting. While GRFS and CGFRS were inferior in the PB groups in both RIC and MAC groups, there was no difference in risk of relapse or overall survival between any of the groups. These results suggest that PTCy does not fully negate the risk of chronic GVHD using PB in the RIC setting. Moreover, no other factors emerged as significant risk factors for development of chronic GVHD after haploidentical HCT with PTCy. Notably, the higher risk of chronic GVHD with the use of PB was not offset by a lower relapse rate nor difference in overall survival. The ability to detect these differences in relapse and survival is likely to be limited by power. There was also no increase in graft failure with BM compared to PB grafts, with a similar time to neutrophil engraftment in all groups.
The effect of both graft source and conditioning was also confirmed in our analyses of a larger cohort of CIBMTR patients using TED level data receiving haplo-transplant. Thus although conditioning intensity is usually determined by a patient’s age, co-morbidities and other non-modifiable factors, graft source is a potentially modifiable variable.
It is also notable that overall incidence of grade 3–4 acute GVHD was low, especially in the RIC setting, a similar finding to what has been recently reported by McCurdy et al. suggesting that PTCy immunomodulation decreases the risk of severe acute GVHD without reduction of grade 2 GVHD, which was significantly associated with higher progression-free survival.(37) In contrast to this recent analysis, we demonstrate older donor age as a significant risk factor for both grade 2–4 and grade 3–4 acute GVHD, as opposed to donor relation which did not have an impact. We were unable to evaluate cell doses for this analysis. Of note, the distribution of donor age between RIC and MAC were similar. This may have implications on donor selection when there is more than one haploidentical donor available (e.g. older sibling versus younger offspring). Other studies have also shown donor age to be a factor in outcomes after haploidentical transplant, and our findings support this as a recommended consideration in donor selection.(38–40)
There are several limitations that should be considered in interpreting these results. First, this was a retrospective analysis based on data submitted to a registry, and thus factors that led to decisions regarding stem cell source and conditioning regimen cannot be determined. We did restrict the analysis to select conditioning and prophylaxis regimens to limit heterogeneity. In addition, although the use of the registry data allowed for a large study population, it is possible that we did not have the power to elicit other risk factors contributing to GVHD, or significant relationships in the observed trends. The power to detect significant differences in chronic GVHD in our subset analysis of MAC and RIC groups was just 48% and 66%, respectively, and this may be why we were unable to detect significant differences in graft source in the MAC setting for GVHD. Nevertheless, our findings of increased chronic GVHD in the RIC groups were further confirmed by a larger cohort using TED level data. This was one of the largest analyses of this type, allowing the ability to evaluate conditioning regimen and graft source as specific risk factors for GVHD after haploidentical HCT. Another limitation includes the duration of follow up for the MAC groups, which were only 13 and 14 months, compared to the RIC groups who had 24 and 21 months of follow up. Notably, the follow up was similar between the BM and the PB groups, thus the subset analyses within the MAC and the RIC groups were not impacted by different follow up periods. Although most relapse and chronic GVHD occur within 1 year of transplant, longer follow up particularly in the MAC groups are necessary, especially given that there was not a difference in chronic GVHD between the MAC groups. In addition, we excluded patients (N=24) who received in-vivo T-cell depletion with ATG or alemtuzumab, as it is known that these agents decrease the incidence of chronic GVHD.(41, 42) Patients who received both PTCy and in-vivo T-cell depletion may potentially have had lower risks of chronic GVHD, although this was overall a small number of patients. Finally, we included only patients with AML, ALL, CML, and MDS, and thus our findings are applicable to only this patient population.
In sum, our results show that PB stem cells contribute to an increased risk of chronic GVHD and NRM in RIC PTCy-based haploidentical HCT, and that other outcomes such as relapse and overall survival are similar. These results aid in decision making regarding graft source in RIC PTCy-based haploidentical HCT. Prospective evaluation of PB versus BM using PTCy platforms is needed to confirm these findings.
Highlights.
In haploidentical HCT with PTCy, conditioning intensity and graft source impact GVHD.
In RIC, PB compared to BM is significantly associated with chronic GVHD.
Older donor age was associated with higher risk of acute GVHD and NRM.
Acknowledgement
The CIBMTR is supported primarily by Public Health Service grant/cooperative agreement U24CA076518 with the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); grant/cooperative agreement U24HL138660 with NHLBI and NCI; grant U24CA233032 from the NCI; grants OT3HL147741, R21HL140314 and U01HL128568 from the NHLBI; contract HHSH250201700006C with Health Resources and Services Administration (HRSA); grants N00014-18-1-2888 and N00014-17-1-2850 from the Office of Naval Research; subaward from prime contract award SC1MC31881-01-00 with HRSA; subawards from prime grant awards R01HL131731 and R01HL126589 from NHLBI; subawards from prime grant awards 5P01CA111412, 5R01HL129472, R01CA152108, 1R01HL131731, 1U01AI126612 and 1R01CA231141 from the NIH; and commercial funds from Actinium Pharmaceuticals, Inc.; Adaptive Biotechnologies; Allovir, Inc.; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Anthem, Inc.; Astellas Pharma US; Atara Biotherapeutics, Inc.; BARDA; Be the Match Foundation; bluebird bio, Inc.; Boston Children’s Hospital; Bristol Myers Squibb Co.; Celgene Corp.; Children’s Hospital of Los Angeles; Chimerix, Inc.; City of Hope Medical Center; CSL Behring; CytoSen Therapeutics, Inc.; Daiichi Sankyo Co., Ltd.; Dana Farber Cancer Institute; Enterprise Science and Computing, Inc.; Fred Hutchinson Cancer Research Center; Gamida-Cell, Ltd.; Genzyme; Gilead Sciences, Inc.; GlaxoSmithKline (GSK); HistoGenetics, Inc.; Immucor; Incyte Corporation; Janssen Biotech, Inc.; Janssen Pharmaceuticals, Inc.; Janssen Research & Development, LLC; Janssen Scientific Affairs, LLC; Japan Hematopoietic Cell Transplantation Data Center; Jazz Pharmaceuticals, Inc.; Karius, Inc.; Karyopharm Therapeutics, Inc.; Kite, a Gilead Company; Kyowa Kirin; Magenta Therapeutics; Mayo Clinic and Foundation Rochester; Medac GmbH; Mediware; Memorial Sloan Kettering Cancer Center; Merck & Company, Inc.; Mesoblast; MesoScale Diagnostics, Inc.; Millennium, the Takeda Oncology Co.; Miltenyi Biotec, Inc.; Mundipharma EDO; National Marrow Donor Program; Novartis Oncology; Novartis Pharmaceuticals Corporation; Omeros Corporation; Oncoimmune, Inc.; OptumHealth; Orca Biosystems, Inc.; PCORI; Pfizer, Inc.; Phamacyclics, LLC; PIRCHE AG; Regeneron Pharmaceuticals, Inc.; REGiMMUNE Corp.; Sanofi Genzyme; Seattle Genetics; Shire; Sobi, Inc.; Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; The Medical College of Wisconsin; University of Minnesota; University of Pittsburgh; University of Texas-MD Anderson; University of Wisconsin - Madison; Viracor Eurofins and Xenikos BV. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government.
Footnotes
Conflict-of-interest disclosure: The authors declare no competing interests.
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