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1.
Post-Transplant Cyclophosphamide (PTCy) is Associated with Increased Cytomegalovirus Infection: A CIBMTR Analysis
Goldsmith, S. R., Abid, M. B., Auletta, J. J., Bashey, A., Beitinjaneh, A., Castillo, P., Chemaly, R. F., Chen, M., Ciurea, S. O., Dandoy, C. E., et al
Blood. 2021
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Editor's Choice
Abstract
Prior studies suggest increased CMV infection following haploidentical donor transplantation with post-transplant cyclophosphamide (HaploCy). The role of allograft source and PTCy in CMV infection and disease is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection as well as transplant outcomes as it relates to CMV serostatus and occurrence of CMV infection by d180. We examined patients reported to CIBMTR between 2012-2017 who had received HaploCy (n = 757), Sib with PTCy (SibCy, n=403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n=1605) for AML/ALL/MDS. Cumulative incidences of CMV infection by d180 were 42% (99% CI, 37-46), 37% (31 - 43), and 23% (20 - 26), respectively [p<0.001]. CMV end-organ disease was statistically comparable. CMV infection risk was highest for CMV-Seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor [HaploCy (n=545): HR 50.3 (14.4 - 175.2); SibCy (n=279): HR 47.7 (13.3 - 171.4); SibCNI (n=1065): HR 24.4 (7.2 - 83.1); p<0.001]. D+/R- patients also had increased risk for CMV infection. Among seropositive recipients or those developing CMV infection, HaploCy had worse OS and NRM. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic GVHD overall, but CMV infection in PTCy recipients was associated with higher cGVHD (p=0.006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally CMV infection may negate the cGVHD protection of PTCy. This study supports aggressive prevention strategies in all patients receiving PTCy.
PICO Summary
Population
Patients with acute myeloid leukaemia, acute lymphoblastic leukaemia or myelodysplastic synrome (n=2765)
Intervention
Haploidentical transplantation with post-transplant cyclophosphamide (HaploCy, n=757),
Comparison
Sibling donor with post-transplant cyclophosphamide (SibCy, n=403), or Sibling donor with calcineurin inhibitor-based prophylaxis (SibCNI, n=1605)
Outcome
Cumulative incidences of CMV infection by day 180 were 42% (HaploCy), 37% (SibCy), and 23% (SibCNI), respectively. CMV end-organ disease was statistically comparable. CMV infection risk was highest for CMV-Seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor [HaploCy (n=545): HR 50.3; SibCy (n=279): HR 47.7; SibCNI (n=1065): HR 24.4. D+/R- patients also had increased risk for CMV infection. Among seropositive recipients or those developing CMV infection, HaploCy had worse OS and NRM. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic GVHD overall, but CMV infection in PTCy recipients was associated with higher cGVHD. PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally CMV infection may negate the cGVHD protection of PTCy.
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2.
Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide
Im, A., Rashidi, A., Wang, T., Hemmer, M., MacMillan, M. L., Pidala, J., Jagasia, M., Pavletic, S., Majhail, N. S., Weisdorf, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
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.
PICO Summary
Population
Adult patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (n=646)
Intervention
Myeloablative conditioning with a bone marrow graft source (MA-BM, n=79), Myeloablative conditioning with a peripheral blood graft source (MA-PB, n=183)
Comparison
Reduced intensity conditioning with a bone marrow graft source, (RIC-BM, n=192) Reduced intensity conditioning with a peripheral blood graft source, (RIC-PB, n=192).
Outcome
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%). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively. 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. In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD in the RIC setting. There were no differences in relapse or overall survival between groups.
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3.
Superior Survival of Black Versus White Patients Following Post-Transplant Cyclophosphamide-Based Haploidentical Transplantation for Adults with Hematologic Malignancy
Solomon, S. R., Zhang, X., Holland, H. K., Morris, L. E., Solh, M., Bashey, A.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Available evidence from large registry studies has shown inferior survival for black adult patients following both unrelated donor and cord blood transplantation. Post-transplant cyclophosphamide (PTCy)-based haploidentical donor transplantation (HIDT) is being increasingly used in ethnic minorities. However, no studies of the impact of race on outcomes following HIDT have been reported. We analyzed 203 consecutive patients (123 white, 80 black) who underwent first HIDT using PTCy for hematologic malignancy at a single institution. Median recipient age was 53 (19-75) years. PBSC was used as the stem cell source in 66% of patients, and conditioning intensity was myeloablative (MA) in 41%. After a median follow-up of 36 months, the estimated 3-year overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) [95% CI] were significantly better in black patients, compared with white patients (72% [60-81], 65% [52-75] and 25% [16-35] vs. 50% [40-59], 45% [36-54] and 39% [31-47] respectively, p<0.001 for OS, DFS, p=0.015 for CIR). In contrast, 3-yr NRM was similar between black (11%) and white (16%) patients, as were the incidences of acute graft-versus-host disease (GVHD) and moderate-to-severe chronic GVHD. Improved survival was noted in all subgroups of black patients - younger vs. older, male vs female, lower vs. higher DRI, MA vs. non-MA conditioning, or PBSC vs. marrow stem cell source. In multivariate analysis, black race was independently associated with better OS (HR 0.47, p=0.003), DFS (HR 0.49, p=0.003) and relapse (HR 0.49, p=0.01). Black patients achieve superior outcomes to their white counterparts following PTCy-based HIDT due to a decreased incidence of disease relapse.
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4.
Related donor transplants: has posttransplantation cyclophosphamide nullified the detrimental effect of HLA mismatch?
Robinson, T. M., Fuchs, E. J., Zhang, M. J., St Martin, A., Labopin, M., Keesler, D. A., Blaise, D., Bashey, A., Bourhis, J. H., Ciceri, F., et al
Blood advances. 2018;2(11):1180-1186
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Abstract
We sought to identify whether posttransplantation cyclophosphamide (PT-Cy) reduces or eliminates the detrimental impact of HLA mismatching on outcomes of HLA-haploidentical related donor transplantation for acute leukemia. Data from 2143 donor-recipient pairs (n = 218 haploidentical sibling; n = 218 offspring; n = 1707 HLA-matched sibling) with acute myeloid or lymphoblastic leukemia were studied. All received a calcineurin inhibitor for graft-versus-host disease (GVHD) prophylaxis while high-dose PT-Cy was also given to recipients of haploidentical transplant. Patient age correlated with donor-recipient relationship: haploidentical siblings donated to patients aged 18 to 54 years whereas offspring donated to patients aged 55 to 76 years. Therefore, transplant outcomes were examined separately in the 2 patient age groups. In patients aged 18 to 54 years, there were no significant differences in outcomes except chronic GVHD, which was lower after haploidentical sibling compared to HLA-matched sibling transplant (hazard ratio [HR], 0.63; P < .001). In patients aged 55 to 76 years, despite lower chronic GVHD (HR, 0.42; P < .001), graft failure (14% vs 6%; P = .003), nonrelapse mortality (HR, 1.48; P = .02), and overall mortality (HR, 1.32; P = .003) were higher after transplant from offspring compared with an HLA-matched sibling. These data demonstrate a superior outcome in older recipients when using an HLA-matched sibling instead of offspring, although there were differences in transplant platforms (GVHD prophylaxis and graft type) between the 2 groups. Validation of these findings requires a prospective randomized trial wherein the transplant platforms can be closely matched.
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5.
Effect of donor characteristics on haploidentical transplantation with posttransplantation cyclophosphamide
McCurdy, S. R., Zhang, M. J., St Martin, A., Al Malki, M. M., Bashey, A., Gaballa, S., Keesler, D. A., Hamadani, M., Norkin, M., Perales, M. A., et al
Blood advances. 2018;2(3):299-307
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Abstract
We studied the association between non-HLA donor characteristics (age, sex, donor-recipient relationship, blood group [ABO] match, and cytomegalovirus [CMV] serostatus) and transplant outcomes after T-cell-replete HLA-haploidentical transplantation using posttransplantation cyclophosphamide (PT-Cy) in 928 adults with hematologic malignancy transplanted between 2008 and 2015. Siblings (n = 358) and offspring (n = 450) were the predominant donors, with only 120 patients having received grafts from parents. Although mortality risks were higher with donors aged 30 years or older (hazard ratio, 1.39; P < .0001), the introduction of patient age to the Cox regression model negated the effect of donor age. Two-year survival adjusted for CMV seropositivity, disease, and disease risk index was lower in patients aged 55 to 78 years after transplantation of grafts from donors younger than 30 years (53%) or aged at least 30 years (46%) compared with younger patients who received grafts from donors younger than 30 years (61%) and at least 30 years (60%; P < .0001). Similarly, 2-year survival in patients aged 55 to 78 years was lower after transplantation of grafts from siblings (45%) or offspring (48%) compared with patients aged 18 to 54 years after transplantation of grafts from siblings (62%), offspring (58%), and parents (61%; P < .0001). Graft failure was higher after transplantation of grafts from parents (14%) compared with siblings (6%) or offspring (7%; P = .02). Other non-HLA donor characteristics were not associated with survival or graft failure. The current analyses suggest patient and disease, rather than non-HLA donor characteristics, predominantly influence survival in adults.
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6.
Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for High-Risk Acute Lymphoblastic Leukemia
Srour, S. A., Milton, D. R., Bashey, A., Karduss-Urueta, A., Al Malki, M. M., Romee, R., Solomon, S., Nademanee, A., Brown, S., Slade, M., et al
Biology of Blood & Marrow Transplantation. 2017;23(2):318-324
Abstract
Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL.