Browsing by Author "Castillo, Paul"

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    Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study
    (Elsevier, 2020-03) Myers, Kasiani C.; Furutani, Elissa; Weller, Edie; Siegele, Bradford; Galvin, Ashley; Arsenault, Valerie; Alter, Blanche P.; Boulad, Farid; Bueso-Ramos, Carlos; Burroughs, Lauri; Castillo, Paul; Connelly, James; Davies, Stella M.; DiNardo, Courtney D.; Hanif, Iftikhar; Ho, Richard H.; Karras, Nicole; Manalang, Michelle; McReynolds, Lisa J.; Nakano, Taizo A.; Nalepa, Grzegorz; Norkin, Maxim; Oberley, Matthew J.; Orgel, Etan; Pastore, Yves D.; Rosenthal, Joseph; Walkovich, Kelly; Larson, Jordan; Malsch, Maggie; Elghetany, M. Tarek; Fleming, Mark D.; Shimamura, Akiko; Pediatrics, School of Medicine
    Background: Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies. Methods: We did a multicentre, retrospective, cohort study in collaboration with the North American Shwachman-Diamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients. Findings: We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 [56%] cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9-8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8-not reached) and 0·99 years (95% CI 0·2-2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1-39) for patients with leukaemia and 51% (29-68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia-including the two patients initially diagnosed with myelodysplastic who progressed- two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32-82; n=14) compared with 28% (95% CI 10-50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts. Interpretation: Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome.
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    Impact of T Cell Dose on Outcome of T Cell-Replete HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation
    (Elsevier, 2019) Saad, Ayman; Lamb, Lawrence; Wang, Tao; Hemmer, Michael T.; Spellman, Stephen; Couriel, Daniel; Alousi, Amin; Pidala, Joseph; Abdel-Azim, Hisham; Agrawal, Vaibhav; Aljurf, Mahmoud; Beitinjaneh, Amer M.; Bhatt, Vijaya Raj; Buchbinder, David; Byrne, Michael; Cahn, Jean-Yves; Cairo, Mitchell; Castillo, Paul; Chhabra, Saurabh; Diaz, Miguel Angel; Farhan, Shatha; Floisand, Yngvar; Frangoul, Hadar A.; Gadalla, Shahinaz M.; Gajewski, James; Gale, Robert Peter; Gandhi, Manish; Gergis, Usama; Hamilton, Betty Ky; Hematti, Peiman; Hildebrandt, Gerhard C.; Kamble, Rammurti T.; Kanate, Abraham S.; Khandelwal, Pooja; Lazaryn, Aleksandr; MacMillan, Margaret; Marks, David I.; Martino, Rodrigo; Mehta, Parinda A.; Nishihori, Taiga; Olsson, Richard F.; Patel, Sagar S.; Qayed, Muna; Rangarajan, Hemalatha G.; Reshef, Ran; Ringden, Olle; Savani, Bipin N.; Schouten, Harry C.; Schultz, Kirk R.; Seo, Sachiko; Shaffer, Brian C.; Solh, Melhem; Teshima, Takanori; Urbano-Ispizua, Alvaro; Verdonck, Leo F.; Vij, Ravi; Waller, Edmund K.; William, Basem; Wirk, Baldeep; Yared, Jean A.; Yu, Lolie C.; Arora, Mukta; Hashmi, Shahrukh; Medicine, School of Medicine
    Data on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3+ T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3+ T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3+ T cell dose cutoff of 14 × 107 cells/kg identified MSD/low CD3+ (n = 223) and MSD/high CD3+ (n = 1214), and a dose of 15 × 107 cells/kg identified MUD/low CD3+ (n = 197) and MUD/high CD3+ (n = 1102). On univariate analysis, the MSD/high CD3+ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3+ group (33% versus 25%; P = .009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3+ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3+ group (49% versus 41%; P = .04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3+ T cell dose and the risk of either aGVHD grade II-IV (P = .10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4+ T cells, CD8+ T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3+ T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4+ and CD8+ T cell doses were not possible given our small sample size.
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    Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide
    (Elsevier, 2020-08) Im, Annie; Rashidi, Armin; Wang, Tao; Hemmer, Michael; MacMillan, Margaret L.; Pidala, Joseph; Jagasia, Madan; Pavletic, Steven; Majhail, Navneet S.; Weisdorf, Daniel; Abdel-Azim, Hisham; Agrawal, Vaibhav; Al-Homsi, A. Samer; Aljurf, Mahmoud; Askar, Medhat; Auletta, Jeffery J.; Bashey, Asad; Beitinjaneh, Amer; Bhatt, Vijaya Raj; Byrne, Michael; Cahn, Jean-Yves; Cairo, Mitchell; Castillo, Paul; Cerny, Jan; Chhabra, Saurabh; Choe, Hannah; Ciurea, Stefan; Daly, Andrew; Perez, Miguel Angel Diaz; Farhadfar, Nosha; Gadalla, Shahinaz M.; Gale, Robert; Ganguly, Siddhartha; Gergis, Usama; Hanna, Rabi; Hematti, Peiman; Herzig, Roger; Hildebrandt, Gerhard C.; Lad, Deepesh P.; Lee, Catherine; Lehmann, Leslie; Lekakis, Lazaros; Kamble, Rammurti T.; Kharfan-Dabaja, Mohamed A.; Khandelwal, Pooja; Martino, Rodrigo; Murthy, Hemant S.; Nishihori, Taiga; O'Brien, Tracey A.; Olsson, Richard F.; Patel, Sagar S.; Perales, Miguel-Angel; Prestidge, Tim; Qayed, Muna; Romee, Rizwan; Schoemans, Hélène; Seo, Sachiko; Sharma, Akshay; Solh, Melhem; Strair, Roger; Teshima, Takanori; Urbano-Ispizua, Alvaro; Van der Poel, Marjolein; Vij, Ravi; Wagner, John L.; William, Basem; Wirk, Baldeep; Yared, Jean A.; Spellman, Steve R.; Arora, Mukta; Hamilton, Betty K.; Medicine, School of Medicine
    Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .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 to 2.62; P = .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 haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.