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PTCy, Abatacept, and Short Course of Tacrolimus for GvHD Prevention Following Haploidentical Transplantation

Al-Homsi, A Samer; Cirrone, Frank; Wo, Stephanie; Cole, Kelli; Suarez-Londono, J Andres; Gardner, Sharon L; Hsu, Jingmei; Stocker, Kelsey; Bruno, Benedetto; Goldberg, Judith D; Levinson, Benjamin A; Abdul-Hay, Maher
Reducing the incidence of graft-versus host disease (GvHD) following haploidentical hematopoietic stem cell transplantation (HSCT) is warranted. Post-transplant cyclophosphamide (PTCy) is the main agent used for GvHD prevention in this setting. It remains unknown if costimulation blockade can be safely combined with PTCy and enhance its efficacy. We performed a phase Ib-II clinical trial to examine the combination of PTCy, abatacept and a short course of tacrolimus (CAST) following peripheral blood haploidentical HSCT. The primary end-point was the incidence of acute GvHD grades II-IV at day +120. The study enrolled 46 patients with a median age of 60 years (range: 18 to 74). The cumulative incidence of acute GvHD grades II-IV and III-IV was 17.4% (95% CI, 9.2% to 32.9%) and 4.4% (95% CI, 1.1% to 17.1%). With a median follow-up of 15.3 months, the cumulative incidence of one-year treatment-related mortality is 4.4% (95% CI, 1.1% to 17.1%). The estimated one-year chronic GvHD moderate to severe rate, relapse rate, progression-free survival, overall survival, and GvHD- and relapse-free survival were 15.9% (95% CI, 8% to 31.7%), 11.7% (95% CI, 5% to 27.2%), 84.1% (95% CI, 73.8% to 95.7%), 85.9% (95% CI, 75.9% to 97.2%) and 66.1% (95% CI, 53.4% to 81.8%), respectively. Toxicities were similar to those expected in patients receiving haploidentical HSCT. This clinical trial showed that CAST regimen is safe and effective in reducing the rate of grades II-IV acute GvHD following haploidentical peripheral blood HSCT (NCT04503616 at https://clinicaltrials.gov/ct2/show/NCT04503616).
PMID: 37163349
ISSN: 2473-9537
CID: 5509352

A Clinical Review of the Different Strategies to Minimize Hemorrhagic Cystitis Associated with the Use of Post-Transplantation Cyclophosphamide in Allogeneic Transplantation [Letter]

Wo, Stephanie; Cirrone, Frank; Al-Homsi, Ahmad Samer
PMID: 36436781
ISSN: 2666-6367
CID: 5383442

[S.l.] : Tandem Meetings, Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, 2023

Phase Ib-II Study of Post-Transplant Cyclophosphamide, Abatacept and Short Course of Tacrolimus (CAST) for Graft-Versus-Host Disease Prevention Following Haploidentical Peripheral Blood Stem Cell Transplantation

Al-Homsi, A Samer; Cirrone, Frank; Cole, Kelli; Londono, J Andres-Suarez; Gardner, Sharon; Hsu, Jingmei; Wo, Stephanie; Stocker, Kelsey; Goldberg, Judith; Levinson, Benjamin; Abdul-Hay, Maher
(Website)
CID: 5515802

Pulmonary Toxic Effects After Myeloablative Conditioning With Total Body Irradiation Delivered via Volumetric Modulated Arc Therapy With Fludarabine

Modrek, Aram S; Karp, Jerome M; Byun, David; Gerber, Naamit K; Abdul-Hay, Maher; Al-Homsi, Ahmad Samer; Galavis, Paulina; Teruel, Jose; Yuan, Ye
We present the case of a 56-year-old female with a diagnosis of acute T-cell lymphoblastic leukemia who received myeloablative conditioning for bone marrow transplant with total body irradiation (TBI) using volumetric modulated arc therapy (VMAT) to the upper body and anterior-posterior/posterior-anterior (AP/PA) open fields to the lower body followed by hematopoietic stem cell transplant. Her clinical course was complicated by high-grade pulmonary toxic effects 55 days after treatment that resulted in death. We discuss the case, planning considerations by radiation oncologists and radiation physicists, and the multidisciplinary medical management of this patient.
PMID: 35598860
ISSN: 1879-8519
CID: 5275182

Haploidentical vs sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia

Wieduwilt, Matthew J; Metheny, Leland; Zhang, Mei-Jie; Wang, Hai-Lin; Estrada-Merly, Noel; Marks, David I; Al-Homsi, A Samer; Muffly, Lori; Chao, Nelson; Rizzieri, David; Gale, Robert Peter; Gadalla, Shahinaz M; Cairo, Mitchell; Mussetti, Alberto; Gore, Steven; Bhatt, Vijaya Raj; Patel, Sagar S; Michelis, Fotios V; Inamoto, Yoshihiro; Badawy, Sherif M; Copelan, Edward; Palmisiano, Neil; Kharfan-Dabaja, Mohamed A; Lazarus, Hillard M; Ganguly, Siddhartha; Bredeson, Christopher; Diaz Perez, Miguel Angel; Cassaday, Ryan; Savani, Bipin N; Ballen, Karen; Martino, Rodrigo; Wirk, Baldeep; Bacher, Ulrike; Aljurf, Mahmoud; Bashey, Asad; Murthy, Hemant S; Yared, Jean A; Aldoss, Ibrahim; Farhadfar, Nosha; Liu, Hongtao; Abdel-Azim, Hisham; Waller, Edmund K; Solh, Melhem; Seftel, Matthew D; van der Poel, Marjolein; Grunwald, Michael R; Liesveld, Jane L; Kamble, Rammurti T; McGuirk, Joseph; Munker, Reinhold; Cahn, Jean-Yves; Lee, Jong Wook; Freytes, César O; Krem, Maxwell M; Winestone, Lena E; Gergis, Usama; Nathan, Sunita; Olsson, Richard F; Verdonck, Leo F; Sharma, Akshay; Ringdén, Olle; Friend, Brian D; Cerny, Jan; Choe, Hannah; Chhabra, Saurabh; Nishihori, Taiga; Seo, Sachiko; George, Biju; Baxter-Lowe, Lee Ann; Hildebrandt, Gerhard C; de Lima, Marcos; Litzow, Mark; Kebriaei, Partow; Hourigan, Christopher S; Abid, Muhammad Bilal; Weisdorf, Daniel J; Saber, Wael
The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.
PMCID:8753217
PMID: 34547770
ISSN: 2473-9537
CID: 5138232

Post-Transplant Cyclophosphamide, Abatacept and Short Course of Tacrolimus (CAST) for Graft-Versus-Host Disease Prevention Following Haploidentical Peripheral Blood Stem Cell Transplantation [Meeting Abstract]

Al-Homsi, A. Samer; Cirrone, Frank; Cole, Kelli; Suarez-Londono, Jaime Andres; Gardner, Sharon L.; Hsu, Jingmei; Wo, Stephanie; Stocker, Kelsey; Bruno, Benedetto; Goldberg, Judith; Levinson, Benjamin; Abdul-Hay, Maher
ISI:000893230300285
ISSN: 0006-4971
CID: 5515762

Post-Transplant High Dose Cyclophosphamide and Bortezomib As Graft-Versus-Host Disease Prophylaxis Following Allogeneic Hematopoietic Stem Cell Transplantation [Meeting Abstract]

Bruno, B; Cirrone, F; Cole, K; Stocker, K; Abdul-Hay, M; Suarez-Londono, J A; Hochman, T; Goldberg, J; Al-Homsi, A S S
Introduction. Prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic cell transplantation (AHCT) remains a major challenge. The combination of methotrexate (MTX) and a calcineurin inhibitor has been the standard regimen for prophylaxis in patients receiving matched sibling donor (MSD) or matched unrelated donor (MUD) transplants for the past few decades. However, over 50% of patients undergoing AHCT still develop acute or chronic GvHD or even both, causing high rates of morbidity and mortality. Moreover, calcineurin inhibitors also have untoward toxic side effects. High dose post-transplant cyclophosphamide (PTCy), initially introduced for GvHD prevention in the setting of haploidentical transplantation, has now been studied in MSD and MUD transplants. We adopted a novel approach to prevent GvHD using a short course of PTCy and bortezomib. We hypothesized that such combination is safe and effective and omits the need for calcineurin or m-TOR inhibitors. Study Design. We report the outcomes of a prospective cohort of patients who received PTCy and bortezomib for GvHD prevention following MSD or MUD transplants. Twenty-eight patients were treated in a phase I-II trial and their clinical outcomes were previously reported (al-Homsi AS et al, BBMT 2019). Most of the remaining patients were treated on an extension trial. GvHD prevention consisted of PTCy 50 mg/kg IV on day +3 and +4, and bortezomib 1.3mg/m 2 IV 6 hours after transplant and again 72 hours after. Patients receiving MUD transplants also received rabbit ATG (thymoglobulin) 5mg/kg total IV fractionated on day -4 to -2. All patients received peripheral blood grafts and standard supportive care as per Institutional policy. G-CSF was administered routinely until neutrophil engraftment. Results. Fifty-eight patients are included in this analysis. Median age was 60 (range 22-78) years. Fifty-three percent of patients were male. Underlying malignancies consisted of myeloid and lymphoid malignancies in 79.3% and 20.6%, respectively. Acute myeloid leukemia (50%) and myelodysplastic syndromes (24.1%) were the most common diseases. At transplant, disease risk index was low, intermediate, high and very high in 19.0%, 48.3%, 31.0% and 1.7% of patients, respectively. Median Pretransplant Assessment of Mortality Score (PAM) was 16.7 (5.4-29.4). Grafts were from MSD in 24.1% or MUD in 75.9% of patients. Recipient (R)/Donor (D) CMV status at transplant was as follows: R+/D+: 43%; R+/D-: 21%; R-/D+: 14% and R-/D-: 22%. Conditioning regimens consisted of reduced intensity fludarabine and busulfan in all but 2 patients who were conditioned with myeloablative fludarabine and busulfan. Overall, the regimen was remarkably well tolerated. Median times to neutrophil and platelet engraftment were 16 (13-28) and 26 (15-57) days respectively. No patient experienced primary graft failure. CMV and EBV reactivation rates were 46.6% and 24%. Cumulative incidences of grade II-IV and grade III-IV acute GVHD were 35% (95% CI: 22%-47%) and 15% (95% CI: 7%-25%) at day +120, respectively. Cumulative incidence of chronic GvHD was 14% at 1 year. Overall, 34% of patients required immunosuppression with systemic steroids after day +4 either for grade III-IV acute or chronic GvHD. Disease relapse rate was 26%. One-year cumulative incidence of transplant-related mortality was 14% (95% CI: 6%-25%). Median overall survival was 30.7 (95% CI: 15.7-not yet reached) months. One-year overall survival was 72% (95% CI: 57%-82%). One-year composite GvHD (acute and chronic) free and relapse free survival (GRFS) was 41.6% (95% CI: 28.9%-54%). Conclusion. PTCy and bortezomib combination for GvHD prophylaxis following MSD and MUD transplants is well tolerated and effective. It offers an alternative regimen to calcineurin and m-TOR inhibitor-containing regimens and may be preferred in certain settings including patients with limited resources, poor medication compliance, and with impaired renal function. A comparison of this cohort to a matched control group of patients receiving methotrexate and cyclosporine for GvHD prevention is ongoing. Disclosures: Abdul-Hay: Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Other: Advisory Board, Speakers Bureau; Jazz: Other: Advisory Board, Speakers Bureau; Abbvie: Consultancy; Takeda: Speakers Bureau. Al-Homsi: Celyad: Other: Advisory Board; Daichii Sanyko: Consultancy. OffLabel Disclosure: Cyclophosphamide and Bortezomib are used for GvHD prevention
Copyright
EMBASE:2016085618
ISSN: 1528-0020
CID: 5104412

Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults

Metheny, Leland; Callander, Natalie S; Hall, Aric C; Zhang, Mei-Jei; Bo-Subait, Khalid; Wang, Hai-Lin; Agrawal, Vaibhav; Al-Homsi, A Samer; Assal, Amer; Bacher, Ulrike; Beitinjaneh, Amer; Bejanyan, Nelli; Bhatt, Vijaya Raj; Bredeson, Chris; Byrne, Michael; Cairo, Mitchell; Cerny, Jan; DeFilipp, Zachariah; Perez, Miguel Angel Diaz; Freytes, César O; Ganguly, Siddhartha; Grunwald, Michael R; Hashmi, Shahrukh; Hildebrandt, Gerhard C; Inamoto, Yoshihiro; Kanakry, Christopher G; Kharfan-Dabaja, Mohamed A; Lazarus, Hillard M; Lee, Jong Wook; Nathan, Sunita; Nishihori, Taiga; Olsson, Richard F; Ringdén, Olov; Rizzieri, David; Savani, Bipin N; Savoie, Mary Lynn; Seo, Sachiko; van der Poel, Marjolein; Verdonck, Leo F; Wagner, John L; Yared, Jean A; Hourigan, Christopher S; Kebriaei, Partow; Litzow, Mark; Sandmaier, Brenda M; Saber, Wael; Weisdorf, Daniel; de Lima, Marcos
Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML), have a poor prognosis. An earlier Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 868 allogeneic hematopoietic cell transplantations (allo-HCTs) performed between 1990 and 2004 showed a 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%, respectively. Modern supportive care, graft-versus-host disease prophylaxis, and reduced-intensity conditioning (RIC) regimens have led to improved outcomes. Therefore, the CIBMTR analyzed 1531 allo-HCTs performed in adults with t-MDS (n = 759) or t-AML (n = 772) between and 2000 and 2014. The median age was 59 years (range, 18 to 74 years) for the patients with t-MDS and 52 years (range, 18 to 77 years) for those with t-AML. Twenty-four percent of patients with t-MDS and 11% of those with t-AML had undergone a previous autologous (auto-) HCT. A myeloablative conditioning (MAC) regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Nonrelapse mortality at 5 years was 34% (95% confidence interval [CI], 30% to 37%) for patients with t-MDS and 34% (95% CI, 30% to 37%) for those with t-AML. Relapse rates at 5 years in the 2 groups were 46% (95% CI, 43% to 50%) and 43% (95% CI, 40% to 47%). Five-year OS and DFS were 27% (95% CI, 23% to 31%) and 19% (95% CI, 16% to 23%), respectively, for patients with t-MDS and 25% (95% CI, 22% to 28%) and 23% (95% CI, 20% to 26%), respectively, for those with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low-risk t-MDS and those with t-AML undergoing HCT with MAC while in first complete remission, but worse for those with previous auto-HCT, higher-risk cytogenetics or Revised International Prognostic Scoring System score, and a partially matched unrelated donor. Relapse remains the major cause of treatment failure, with little improvement seen over the past 2 decades. These data mandate caution when recommending allo-HCT in these conditions and indicate the need for more effective antineoplastic approaches before and after allo-HCT.
PMID: 34428556
ISSN: 2666-6367
CID: 5115782

Standardizing Definitions of Hematopoietic Recovery, Graft Rejection, Graft Failure, Poor Graft Function, and Donor Chimerism in Allogeneic Hematopoietic Cell Transplantation: A Report on Behalf of the American Society for Transplantation and Cellular Therapy

Kharfan-Dabaja, Mohamed A; Kumar, Ambuj; Ayala, Ernesto; Aljurf, Mahmoud; Nishihori, Taiga; Marsh, Rebecca; Burroughs, Lauri M; Majhail, Navneet; Al-Homsi, A Samer; Al-Kadhimi, Zaid S; Bar, Merav; Bertaina, Alice; Boelens, Jaap J; Champlin, Richard; Chaudhury, Sonali; DeFilipp, Zachariah; Dholaria, Bhagirathbhai; El-Jawahri, Areej; Fanning, Suzanne; Fraint, Ellen; Gergis, Usama; Giralt, Sergio; Hamilton, Betty K; Hashmi, Shahrukh K; Horn, Biljana; Inamoto, Yoshihiro; Jacobsohn, David A; Jain, Tania; Johnston, Laura; Kanate, Abraham S; Kansagra, Ankit; Kassim, Adetola; Kean, Leslie S; Kitko, Carrie L; Knight-Perry, Jessica; Kurtzberg, Joanne; Liu, Hien; MacMillan, Margaret L; Mahmoudjafari, Zahra; Mielcarek, Marco; Mohty, Mohamad; Nagler, Arnon; Nemecek, Eneida; Olson, Timothy S; Oran, Betul; Perales, Miguel-Angel; Prockop, Susan E; Pulsipher, Michael A; Pusic, Iskra; Riches, Marcie L; Rodriguez, Cesar; Romee, Rizwan; Rondon, Gabriela; Saad, Ayman; Shah, Nina; Shaw, Peter J; Shenoy, Shalini; Sierra, Jorge; Talano, Julie; Verneris, Michael R; Veys, Paul; Wagner, John E; Savani, Bipin N; Hamadani, Mehdi; Carpenter, Paul A
Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications for transplantation, availability of alternative donor sources, less toxic preparative regimens, new cell manipulation techniques, and novel GVHD prevention methods, all of which have expanded the applicability of the procedure. These advances have led to clinical practice conundrums when applying traditional definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism, because these may vary based on donor type, cell source, cell dose, primary disease, graft-versus-host disease (GVHD) prophylaxis, and conditioning intensity, among other variables. To address these contemporary challenges, we surveyed a panel of allo-HCT experts in an attempt to standardize these definitions. We analyzed survey responses from adult and pediatric transplantation physicians separately. Consensus was achieved for definitions of neutrophil and platelet recovery, graft rejection, graft failure, poor graft function, and donor chimerism, but not for delayed engraftment. Here we highlight the complexities associated with the management of mixed donor chimerism in malignant and nonmalignant hematologic diseases, which remains an area for future research. We recognize that there are multiple other specific, and at times complex, clinical scenarios for which clinical management must be individualized.
PMID: 34304802
ISSN: 2666-6367
CID: 5003982

Objective response at low dose in the firstin- human immunicy-1 trial evaluating non-gene edited allogeneic cyad-211 anti-bcma car-t product in relapsed or refractory multiple myeloma [Meeting Abstract]

Anguille, S; Al-Homsi, A S; Deeren, D; Nishihori, T; Meuleman, N; Abdul-Hay, M; Morgan, G; Brayer, J; Braun, N; Lonez, C; Breman, E; Dheur, M -S; Alcantar-Orozco, E; Gilham, D E; Flament, A; Lehmann, F F
Background: Autologous chimeric antigen receptor (CAR) T-cells targeting B-cell maturation antigen (BCMA) have shown impressive objective response rates in patients with advanced multiple myeloma (MM). CYAD-211 is a first-in-class, non-gene edited allogeneic anti-BCMA CAR T-cell product that uses an "all-in-one" vector approach to co-express, in addition to the CAR, a single optimized short hairpin RNA (shRNA) to down-regulate the expression of the T-cell receptor (TCR) CD3zeta subunit thus reducing the risk of graft-versus-host disease (GvHD). This non-gene editing technology does not permanently alter the genome integrity, therefore decreasing the potential safety risk associated with "off-target" genome modifications. Preclinical experiments demonstrated that persistence of allogeneic T-cells produced with shRNA technology is superior to cells engineered with gene-editing technologies.
Aim(s): The objective of the open-label Phase I IMMUNICY-1 (NCT04613557) trial is to evaluate the safety and clinical activity of a single infusion of CYAD-211 in relapsed or refractory MM patients.
Method(s): A bank of clinical- grade CYAD-211 cells was generated through a single production run using a portion of a single donor apheresis. The bank generated >1010 CYAD-211 cells suitable for the entire dose escalation segment and expansion cohort of the trial. Patients with relapsed or refractory MM with measurable disease as per the International Myeloma Working Group (IMWG) response criteria are eligible for the trial.
Result(s): As of the data cutoff of February 24, 2021, enrollment in the DL1 was completed (Table). Clinical activity evaluation was performed on Day (D) 22 and D36 for the first two patients with one confirmed partial response (PR) and one stable disease (SD). No dose-limiting toxicity nor Grade >= 3 treatment-related adverse events (AE) were reported. No immune effector cell-associated neurotoxicity syndrome (ICANS) nor GvHD were observed. One cytokine release syndrome (CRS) grade 1 was observed in the patient presenting the PR. CYAD-211 cells were detected by PCR-based method in the peripheral blood of the PR patient. Summary/Conclusion: The IMMUNICY-1 clinical trial seeks to provide the proof-of-principle that single shRNA-mediated knockdown can generate safe and functional allogeneic CAR T-cells in humans. The observed clinical activity at such low DL of 30x106 cells is encouraging in the allogeneic setting. Clinical and cell kinetics data from the completed first DLs will be presented at the time of the congress.The early stages of this trial continue to support the development of allogeneic CAR T-cell therapy as a feasible approach that may overcome many of the hurdles associated with autologous CAR-T cells
EMBASE:635849280
ISSN: 2572-9241
CID: 4981962