Publications by authors named "Leo Luznik"

133 Publications

Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning.

Blood 2021 Oct 17. Epub 2021 Oct 17.

Johns Hopkins University, Baltimore, Maryland, United States.

The key immunologic signatures associated with clinical outcomes after post-transplant cyclophosphamide (PTCy)-based HLA-haploidentical (haplo) and HLA-matched bone marrow transplantation (BMT) are largely unknown. To address this gap in knowledge, we used machine learning to decipher clinically relevant signatures from immunophenotypic, proteomic, and clinical data and then examined transcriptome changes in the lymphocyte subsets that predicted major post-transplant outcomes. Kinetics of immune subset reconstitution after day 28 were similar for 70 patients undergoing haplo and 75 patients undergoing HLA-matched BMT. Machine learning based on 35 candidate factors (10 clinical, 18 cellular, and 7 proteomic) revealed that combined elevations in effector CD4+ conventional T cells (Tconv) and CXCL9 at day 28 predicted acute graft-versus-host disease (aGVHD). Furthermore, higher NK cell counts predicted improved overall survival due to a reduction in both nonrelapse mortality and relapse. Transcriptional and flow-cytometric analyses of recovering lymphocytes in patients with aGVHD identified preserved hallmarks of functional CD4+ regulatory T cells (Tregs) while highlighting a Tconv-driven inflammatory and metabolic axis distinct from that seen with conventional GVHD prophylaxis. Patients developing early relapse displayed a loss of inflammatory gene signatures in NK cells and a transcriptional exhaustion phenotype in CD8+ T cells. Using a multimodality approach, we highlight the utility of systems biology in BMT biomarker discovery and offer a novel understanding of how PTCy influences alloimmune responses. Our work charts future directions for novel therapeutic interventions after these increasingly utilized GVHD prophylaxis platforms.
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http://dx.doi.org/10.1182/blood.2021013054DOI Listing
October 2021

Safety and Efficacy of Pembrolizumab Prior to Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia.

Transplant Cell Ther 2021 Aug 30. Epub 2021 Aug 30.

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. Electronic address:

Programmed death 1 (PD-1) is an integral component of acute myelogenous leukemia (AML) immune evasion, chemotherapy resistance, and disease progression. PD-1 inhibitors are being investigated as treatment for AML in combination with hypomethylating agents and cytotoxic chemotherapy with encouraging findings. Although allogeneic stem cell transplantation (alloSCT) remains the most established curative treatment for patients with relapsed and refractory AML in complete remission, there are limited data on the clinical outcomes and safety of immune checkpoint inhibitors (ICIs) prior to alloSCT in AML. In the present study, we compared clinical outcomes of 9 patients with AML receiving high-dose cytarabine followed by pembrolizumab in a phase II clinical trial (NCT02768792) prior to alloSCT versus a historical control group of 18 AML patients who underwent alloSCT without prior ICI exposure. The nonparametric Jonckheere-Terpstra test was used to test for a difference in the ordered severity categories of acute graft-versus-host disease (GVHD) within 100 days of transplantation. Time-to-event estimates for overall survival and relapse-free survival were calculated using the Kaplan-Meier method and compared using a log-rank test. One-year survival was not significantly different between the treatment groups (67% versus 78%; P = .34). 100-day mortality was 0% in the ICI group versus 17% in the control group, and there was no increase in grade III-IV acute GVHD in patients treated with pembrolizumab prior to alloSCT. No chronic GVHD was seen in patients treated with pembrolizumab prior to alloSCT and who received post-transplantation cyclophosphamide (PTCy) as part of their conditioning regimen. These findings reinforce the safety and feasibility of ICI therapy prior to alloSCT in patients with AML, and suggest that PTCy may abrogate GVHD risk and severity in patients who receive ICI prior to undergoing alloSCT for AML.
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http://dx.doi.org/10.1016/j.jtct.2021.08.022DOI Listing
August 2021

Nonmyeloablative, HLA-Mismatched Unrelated Peripheral Blood Transplantation with High-Dose Post-Transplantation Cyclophosphamide.

Transplant Cell Ther 2021 Aug 20. Epub 2021 Aug 20.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital University School of Medicine, Baltimore, Maryland. Electronic address:

High-dose post-transplantation cyclophosphamide (PTCy) is an effective platform for prevention of severe graft-versus-host disease (GVHD) after allogeneic bone marrow (BM) transplantation with mismatched unrelated donors (mMUDs). Previous studies evaluating PTCy with mMUDs favored BM allografts over peripheral blood stem cell transplantation (PBSCT) due to concerns that PBSCT may be associated with an increased risk of acute and chronic GVHD. In addition, haploidentical PBSCT is associated with high rates of cytokine release syndrome (CRS), which is another concern with mMUD PBSCT. This study was conducted to determine the feasibility and safety of using mMUD PBSCT with PTCy as GVHD prophylaxis. Patients who received mMUD PBSCT using a PTCy-based GVHD prophylaxis at Johns Hopkins Hospital as part of a prospective clinical trial of mMUD and non-first-degree relative haploidentical transplantation with PTCy (ClinicalTrials.gov identifier NCT01203722) were included. All patients underwent T cell-replete PBSCT between November 2012 and August 2020. Statistical analyses were performed using the Kaplan-Meier method and proportional subdistribution hazard regression model for competing risks. The 29 patients in the study had a median age of 54 years, with 10 patients (34%) age ≥60 years. Nineteen grafts (66%) were matched for 9/10 HLA loci, 6 (21%) were match for 8/10, and 4 (14%) were matched for 7/10. No primary or secondary graft failure occurred. The median time to neutrophil recovery (≥500/µL) was 17 days, and that to platelet recovery (≥20,000/µL) was 28 days. Full donor chimerism was achieved in all patients by day +60. The cumulative incidence (CuI) of grade II-IV acute GVHD at 180 days was 15% (90% confidence interval [CI], 3% to 26%). There were no cases of severe chronic GVHD, 3 cases of mild chronic GVHD, and 1 case of moderate chronic GVHD. The CuI of nonrelapse mortality (NRM) was 7% (90% CI, NA to 18%) at 1 year. Eighteen patients (62%) experienced mild CRS (grade 1-2), and 1 patient (3%) experienced severe CRS (grade 3-5). At 1 year, the CuI of relapse was 29% (90% CI, 8% to 50%), overall survival was 93% (90% CI, 85% to 100%), progression-free survival was 64% (90% CI, 46% to 88%), GVHD-free relapse-free survival was 41% (90% CI, 23% to 73%), and chronic GVHD-free relapse-free survival was 64% (90% CI, 46% to 88%). Our data indicate that mMUD PBSCT using PTCy-based GVHD prophylaxis is safe and feasible. All patients engrafted, and rates of NRM (7%) and acute GVHD (15%) at 1 year were low. There was only 1 case (3%) of severe CRS. Compared with previously published outcomes, mMUD PBSCT using PTCy-based GVHD prophylaxis has a safety and efficacy profile that may not be different from that of PBSCT from matched donors. These results further solidify that all patients who require blood or BM transplantation should be able to find an acceptable donor.
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http://dx.doi.org/10.1016/j.jtct.2021.08.013DOI Listing
August 2021

Allogeneic Blood or Marrow Transplantation with Nonmyeloablative Conditioning and High-Dose Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis for Secondary Central Nervous System Lymphoma.

Transplant Cell Ther 2021 10 20;27(10):863.e1-863.e5. Epub 2021 Jul 20.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Secondary central nervous system (CNS) lymphoma is a rare and often fatal complication of non-Hodgkin lymphoma (NHL). Treatment options include radiation therapy, high-dose systemic chemotherapy, intrathecal chemotherapy, and high-dose chemotherapy with autologous stem cell rescue, but outcomes remain poor. Allogeneic blood or marrow transplantation (alloBMT) is widely used in patients with relapsed/refractory systemic NHL. We sought to understand whether a graft-versus-lymphoma effect could maintain remission in CNS disease. We reviewed outcomes in 20 consecutive patients with secondary CNS lymphoma who underwent alloBMT with nonmyeloablative conditioning using fludarabine, cyclophosphamide, and 200 cGy total body irradiation. For graft-versus-host disease prophylaxis, all patients received post-transplantation cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor. With a median follow up of 4.1 years, the median overall survival for the entire cohort was not reached. Median progression-free survival was 3.8 years (95% confidence interval [CI], 5.3 months to not reached). The cumulative incidence of relapse was 25% (95% CI, 5% to 45%), and nonrelapse mortality was 30% (95% CI, 5% to 54%) at 4 years. Of the 5 patients who relapsed, 2 were CNS only, 1 was systemic only, and 2 were combined CNS/systemic. The use of alloBMT in CNS lymphoma merits further investigation.
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http://dx.doi.org/10.1016/j.jtct.2021.07.015DOI Listing
October 2021

National Marrow Donor Program-Sponsored Multicenter, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation Using Post-Transplant Cyclophosphamide.

J Clin Oncol 2021 Jun 27;39(18):1971-1982. Epub 2021 Apr 27.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

Purpose: Hematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > 38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT.

Patients And Methods: We performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning-based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy.

Results: Notably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS.

Conclusion: Our prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.
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http://dx.doi.org/10.1200/JCO.20.03502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260905PMC
June 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2020 Etiology and Prevention Working Group Report.

Transplant Cell Ther 2021 06 2;27(6):452-466. Epub 2021 Mar 2.

Division of Hematological Malignancies and Cellular Therapy, Department of Medicine, Duke Cancer Institute, Durham, North Carolina. Electronic address:

Preventing chronic graft-versus-host disease (GVHD) remains challenging because the unique cellular and molecular pathways that incite chronic GVHD are poorly understood. One major point of intervention for potential prevention of chronic GVHD occurs at the time of transplantation when acute donor anti-recipient immune responses first set the events in motion that result in chronic GVHD. After transplantation, additional insults causing tissue injury can incite aberrant immune responses and loss of tolerance, further contributing to chronic GVHD. Points of intervention are actively being identified so that chronic GVHD initiation pathways can be targeted without affecting immune function. The major objective in the field is to continue basic studies and to translate what is learned about etiopathology to develop targeted prevention strategies that decrease the risk of morbid chronic GVHD without increasing the risks of cancer relapse or infection. Development of strategies to predict the risk of developing debilitating or deadly chronic GVHD is a high research priority. This working group recommends further interrogation into the mechanisms underpinning chronic GVHD development, and we highlight considerations for future trial design in prevention trials.
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http://dx.doi.org/10.1016/j.jtct.2021.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217141PMC
June 2021

PTCy and "The Story of the Three Bears".

Bone Marrow Transplant 2021 04 20;56(4):765-766. Epub 2020 Nov 20.

Division of Hematologic Malignancies, Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.

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http://dx.doi.org/10.1038/s41409-020-01123-7DOI Listing
April 2021

Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide.

Blood Adv 2020 10;4(20):5078-5088

Division of Hematologic Malignancy and.

Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2020002945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594402PMC
October 2020

Thrombotic Microangiopathy after Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis.

Biol Blood Marrow Transplant 2020 12 19;26(12):2306-2310. Epub 2020 Sep 19.

Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.

Transplant-associated thrombotic microangiopathy (taTMA) is a systemic vascular illness associated with significant morbidity and mortality, resulting from a convergence of risk factors after allogeneic blood or marrow transplantation (alloBMT). The diagnosis of taTMA has been a challenge, but most criteria include an elevated lactate dehydrogenase (LDH), low haptoglobin, and schistocytes on peripheral blood smear. We performed a retrospective review of the 678 consecutive adults who received high-dose post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis between January 1, 2015, and August 31, 2018. In April 2016, we initiated a monitoring program of weekly LDH and haptoglobin measurements and blood smears when those 2 parameters were both abnormal on all of our adult patients undergoing alloBMT for hematologic malignancies. During the entire period, the 1-year cumulative incidence of taTMA was 1.4% (95% confidence interval, 0.5% to 2.3%). Eight patients were taking tacrolimus at the time of diagnosis, and 1 was not on any immunosuppression. Eight of 9 patients (89%) were hypertensive. Four patients had invasive infections at the time of diagnosis, 4 patients required renal replacement therapy, and 5 of 9 patients were neurologically impaired. Eculizumab was given to 6 patients (0.9%), of whom 2 died and 4 recovered with resolution of end-organ dysfunction. The paucity of events made the determination of risk factors difficult; however, the low incidence of taTMA in this cohort may be related to the limited use of myeloablative conditioning regimens, low incidence of severe GVHD, and use of PTCy. PTCy-based GVHD prophylaxis appears to be associated with a low incidence of severe taTMA.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686062PMC
December 2020

Shortened-Duration Immunosuppressive Therapy after Nonmyeloablative, Related HLA-Haploidentical or Unrelated Peripheral Blood Grafts and Post-Transplantation Cyclophosphamide.

Biol Blood Marrow Transplant 2020 11 18;26(11):2075-2081. Epub 2020 Aug 18.

Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland; Division of Hematology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland; Division of Pediatric Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.

With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative (NMA) HLA-haploidentical (haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Previous reports have shown that discontinuation of immunosuppression (IS) as early as day 60 after infusion of a bone marrow (BM) haplo allograft with PTCy is feasible. There are certain diseases in which peripheral blood (PB) may be favored over BM, but given the higher rates of GVHD with PB, excessive GVHD is of increased concern. We report a completed, prospective single-center trial of stopping IS at days 90 and 60 after NMA PB stem cell transplantation (PBSCT). Between 12/2015-7/2018, 117 consecutive patients with hematologic malignancies associated with higher rates of graft failure after NMA conditioned BMT and PTCy, received NMA PB allografts on trial. The primary objective of this study was to evaluate the safety and feasibility of reduced-duration IS (from day 5 through day 90 in the D90 cohort and through day 60 in the D60 cohort). Of the 117 patients (median age, 64 years; range, 22 to 78 years), the most common diagnoses were myelodysplastic syndrome (33%), acute myelogenous leukemia (with minimal residual disease or arising from an antecedent disorder) (32%), myeloproliferative neoplasms (19%), myeloma (9%), and chronic lymphoblastic leukemia (7%). Shortened IS was feasible in 75 patients (64%) overall. Ineligibility for shortened IS resulted most commonly from GVHD (17 patients), followed by early relapse (11 patients), nonrelapse mortality (NRM) (7 patients), patient/ physician preference (4 patients) or graft failure (3 patients). Of the 57 patients in the D90 cohort, 33 (58%) stopped IS early as planned, and among the 60 patients in the D60 cohort, 42 (70%) stopped IS early as planned. The graft failure rate was 2.6%. After IS cessation, the median time to diagnosis of grade II-IV acute GVHD was 21 days in the D90 cohort and 32 days in the D60 cohort, with almost all cases developing within 40 days. Approximately one-third of these patients resumed IS. All outcome measures were similar in the 2 cohorts and our historical outcomes with 180 days of IS. The cumulative incidence of grade III-IV acute GVHD was low, 2% in the D90 cohort and 7% in the D60 cohort. The incidence of severe chronic GVHD at 2 years was 9% in the D90 cohort and 5% in the D60 cohort. The 2-year overall survival was 67% for both the D90 and D60 cohorts. The 2-year progression-free survival was 47% for the D90 cohort and 52% for the D60 cohort, and the GVHD-free, relapse-free survival was <35% for both cohorts. These data suggest that reduced-duration IS in patients undergoing NMA PBSCT with PTCy is feasible and has an acceptable safety profile. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.037DOI Listing
November 2020

Myeloablative haploidentical BMT with posttransplant cyclophosphamide for hematologic malignancies in children and adults.

Blood Adv 2020 08;4(16):3913-3925

Hematologic Malignancies and Bone Marrow Transplantation Program, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and.

Promising results have been reported for patients with high-risk hematologic malignancies undergoing HLA-haploidentical bone marrow transplantation (haploBMT) with posttransplantation cyclophosphamide (PTCy), but there are few data on outcomes with myeloablative conditioning in this context. We report the results of a single-institution, prospective phase 2 trial of myeloablative haploBMT using busulfan-based or total body irradiation-based conditioning in 96 children or adults (median age, 42 years; range, 1-65 years) with high-risk hematologic malignancies. Recovery of neutrophils and platelets occurred at a median of 24 and 29 days. Engraftment of donor cells with chimerism >95% was achieved in 91%. The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and grades III to IV at day 100 was 11% and 4%, and of chronic GVHD at 6 and 12 months was 4% and 15%, with 6% moderate to severe. The cumulative incidence of nonrelapse mortality was 6% at 100 days and 11% at 1 year (19% in those aged >55 years). The cumulative incidence of relapse at 1 year was 35%; at 3 years, it was 43%. In multivariable analysis, relapse was associated with increased age (P = .02 for age 20-55 years and P = .02 for age >55 years) and with minimal residual disease before transplantation (P = .05). The overall survival at 1 and 3 years is 73% and 54%, and event-free survival at 1 and 3 years is 57% and 49%. We show that haploBMT with PTCy after myeloablative conditioning is safe and efficacious for adult and pediatric patients with hematologic malignancies. Careful consideration must be given to using myeloablative conditioning in patients age >55 years. This trial was registered at www.clinicaltrials.gov as #NCT00796562.
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http://dx.doi.org/10.1182/bloodadvances.2020001648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448587PMC
August 2020

Allogeneic bone marrow transplantation with post-transplant cyclophosphamide for patients with HIV and haematological malignancies: a feasibility study.

Lancet HIV 2020 09 7;7(9):e602-e610. Epub 2020 Jul 7.

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Allogeneic blood or marrow transplantation (alloBMT) is a potentially life-saving treatment for individuals with HIV and haematological malignancies; challenges include identifying donors and maintaining antiretroviral therapy (ART). The objectives of our study were to investigate interventions to expand donor options and to prevent ART interruptions for patients with HIV in need of alloBMT.

Methods: This single-arm, interventional trial took place at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (Baltimore, MD, USA). Individuals with HIV who were at least 18 years of age and referred for alloBMT for a standard clinical indication were eligible. The only exclusion criterion was a history of documented resistance to enfuvirtide. We used post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis to expand donor options and an optimised ART strategy of avoiding pharmacoenhancers and adding subcutaneous enfuvirtide during post-transplant cyclophosphamide and during oral medication intolerance. Our primary outcome was the proportion of participants who maintained ART through day 60 after alloBMT. We measured the HIV latent reservoir using a quantitative viral outgrowth assay. This study is registered on ClinicalTrials.gov, NCT01836068.

Findings: Between June 1, 2013, and August 27, 2015, nine patients who were referred for transplant provided consent. Two patients had relapsed malignancy before donor searches were initiated. Seven patients had suitable donors identified (two matched sibling, two matched unrelated, two haploidentical, and one single-antigen mismatched unrelated) and proceeded to alloBMT. All patients maintained ART through day 60 and required ART changes (median 1, range 1-3) in the first 90 days. One patient stopped ART and developed HIV rebound with grade 4 meningoencephalitis at day 146. Among six patients who underwent alloBMT and had longitudinal measurements available, the HIV latent reservoir was not detected post-alloBMT in four patients with more than 95% donor chimerism, consistent with a 2·06-2·54 log reduction in the HIV latent reservoir. In the two patients with less than 95% donor chimerism, the HIV latent reservoir remained stable.

Interpretation: By using post-transplant cyclophosphamide as GVHD prophylaxis, we successfully expanded alloBMT donor options for patients with HIV. Continuing ART with a regimen that includes enfuvirtide post-alloBMT was safe, but life-threatening viral rebound can occur with ART interruption.

Funding: amfAR (the Foundation for AIDS Research), Johns Hopkins University Center for AIDS Research, and National Cancer Institute.
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http://dx.doi.org/10.1016/S2352-3018(20)30073-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484204PMC
September 2020

Non-Myeloablative Allogeneic Transplantation with Post-Transplant Cyclophosphamide after Immune Checkpoint Inhibition for Classic Hodgkin Lymphoma: A Retrospective Cohort Study.

Biol Blood Marrow Transplant 2020 09 24;26(9):1679-1688. Epub 2020 Jun 24.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland.. Electronic address:

: Immune checkpoint inhibitors (ICIs) are approved in relapsed classic Hodgkin lymphoma (cHL). The safety and effectiveness of allogeneic blood or marrow transplantation (alloBMT) in ICI-pretreated patients with cHL remain unclear. The aim of this study is to assess outcomes of patients with cHL receiving ICIs before alloBMT using post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis.  : We performed a retrospective study of relapsed/refractory patients with cHL undergoing alloBMT with PTCy at Johns Hopkins between November 2004 and September 2019. Engraftment, GVHD incidence, nonrelapse mortality, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving pre-alloBMT ICI or standard salvage chemotherapy.  : We identified 105 consecutive relapsed/refractory patients with cHL, of whom 37 (35.2%) received ICIs and 68 (64.7%) received chemotherapy without ICIs (no-ICI) before alloBMT. ICI and no-ICI patients experienced a 3-year estimated OS of 94% versus 78% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.08 to 1.56; P = .17) and a 3-year estimated PFS of 90% and 65% (HR, 0.3; 95% CI, 0.09 to 1; P = .05), respectively. We observed no statically significant difference in the 12-month cumulative incidence of acute grade II to IV GVHD or in the 24-month incidence of chronic GVHD.  : ICIs do not increase acute or chronic GVHD incidence compared with salvage chemotherapy. Patients with cHL receiving ICIs prior to alloBMT experienced outstanding PFS and OS. Thus, ICI therapy is safe in patients with cHL when undergoing alloBMT with PTCy and may improve post-alloBMT disease progression and survival.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486273PMC
September 2020

Post-transplantation Cyclophosphamide: From HLA-Haploidentical to Matched-Related and Matched-Unrelated Donor Blood and Marrow Transplantation.

Front Immunol 2020 9;11:636. Epub 2020 Apr 9.

Blood and Marrow Transplantation Program, NYU Langone Health, New York, NY, United States.

Following allogeneic blood and marrow transplantation (BMT), graft-versus-host disease (GvHD) continues to represent a significant cause of treatment failure, despite the routine use of conventional, mainly calcineurin inhibitor-based prophylaxis. Recently, post-transplant cyclophosphamide (PTCy) has emerged as a safe and efficacious alternative. First, omitting the need for T-cell depletion in the setting of haploidentical transplantation, growing evidence supports PTCy role in GvHD prevention in matched-related and matched-unrelated transplants. Through improved understanding of GvHD pathophysiology and advancements in drug development, PTCy emerges as a unique opportunity to design calcineurin inhibitor-free strategies by integrating agents that target different stages of GvHD development.
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http://dx.doi.org/10.3389/fimmu.2020.00636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177152PMC
March 2021

Haploidentical BMT for severe aplastic anemia with intensive GVHD prophylaxis including posttransplant cyclophosphamide.

Blood Adv 2020 04;4(8):1770-1779

Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, MD.

Severe aplastic anemia (SAA) is a stem cell disorder often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis. Outcomes of related HLA-haploidentical (haplo) donors after reduced-intensity conditioning with intensive graft-versus-host disease (GVHD) prophylaxis including posttransplantation cyclophosphamide are presented here from 37 SAA, 20 relapsed/refractory (R/R), and 17 treatment-naïve (TN) SAA patients. Median follow-up is 32 months (90% confidence interval [CI], 29-44). The median age was 25 (range, 4-69) years. The median time to neutrophil recovery was 17 days (range, 15-88). Four of 37 patients (11%) experienced graft failure (GF). There was 1 primary GF of 20 patients in the R/R group and 3 of 17 in the TN group at 200 cGy (1 primary, 2 secondary), but none in the 10 patients who received 400 cGy total body irradiation. Two patients with GF succumbed to infection and 2 were rescued with second haplo BMT. The overall survival for all patients is 94% (90% CI, 88-100) at 1 and 2 years. The cumulative incidence of grade II-IV acute GVHD at day 100 is 11%. The cumulative index of chronic GVHD at 2 years is 8%. Similar results were seen in 10 SAA patients who received the identical nonmyeloablative regimen with posttransplant cyclophosphamide but matched donor transplants. Haplo BMT with posttransplant cyclophosphamide represents a potential cure in SAA, with all 20 R/R currently alive, disease-free, and with no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates, but an increase in total body irradiation dose to 400 cGy was associated with durable engraftment without greater early toxicity. Nonmyeloablative haplo BMT in TN SAA could lead to a paradigm shift, such that essentially all patients can proceed quickly to safe, curative BMT. These trials were registered at www.cincialtrials.gov as #NCT02224872) and #NCT02833805.
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http://dx.doi.org/10.1182/bloodadvances.2020001729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189283PMC
April 2020

Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS.

Leukemia 2020 06 3;34(6):1563-1576. Epub 2020 Jan 3.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

An immunosuppressive microenvironment promoting leukemia cell immune escape plays an important role in the pathogenesis of AML. Through its interaction with cereblon, a substrate receptor for the E3 ubiquitin ligase complex, pomalidomide leads to selective ubiquitination of transcription factors Aiolos and Ikaros thereby promoting immune modulation. In this phase I trial, 51 newly diagnosed non-favorable risk AML and high-risk MDS patients were enrolled and treated with AcDVP16 (cytarabine 667 mg/m/day IV continuous infusion days 1-3, daunorubicin 45 mg/m IV days 1-3, etoposide 400 mg/m IV days 8-10) induction therapy followed by dose- and duration-escalation pomalidomide beginning at early lymphocyte recovery. Forty-three patients (AML: n = 39, MDS: n = 4) received pomalidomide. The maximum tolerated dose of pomalidomide was 4 mg for 21 consecutive days. The overall complete remission (CR + CRi) rate, median overall survival, and disease-free survival were 75%, 27.1 and 20.6 months, respectively. Subset analyses revealed 86% CR/CRi rate in AML patients with unfavorable-risk karyotype treated with pomalidomide. Pomalidomide significantly decreased Aiolos expression in both CD4 and CD8 peripheral blood and bone marrow T cells, promoted T cell differentiation, proliferation, and heightened their cytokine production. Finally, pomalidomide induced distinct gene expression changes in immune function-related ontologies in CD4 and CD8 T cells.
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http://dx.doi.org/10.1038/s41375-019-0693-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272276PMC
June 2020

How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide.

Hematology Am Soc Hematol Educ Program 2019 12;2019(1):513-521

Department of Oncology and.

HLA-haploidentical hematopoietic stem cell transplantation is now one of the most commonly employed alternative donor techniques, with most centers applying T-cell-replete strategies such as that developed by the Baltimore group using high-dose posttransplant cyclophosphamide. HLA-haploidentical hematopoietic stem cell transplantation using posttransplant cyclophosphamide is associated with low rates of severe graft-versus-host disease and nonrelapse mortality and does not require graft manipulation or storage, which results in a low graft acquisition cost. Its remarkable safety when used with reduced-intensity conditioning has been demonstrated in patients up to 75 years old with outcomes similar to those of patients in their 50s. Several large, registry-based retrospective studies have confirmed the efficacy of HLA-haploidentical hematopoietic stem cell transplantation with posttransplant cyclophosphamide, achieving results comparable to those of HLA-matched hematopoietic stem cell transplantation. In this article, we describe our approach to this rapidly available and clinically simple platform and address some of the key clinical questions associated with its use.
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http://dx.doi.org/10.1182/hematology.2019001323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913422PMC
December 2019

How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide.

Blood 2019 11;134(21):1802-1810

Department of Oncology and.

HLA-haploidentical hematopoietic stem cell transplantation is now one of the most commonly employed alternative donor techniques, with most centers applying T-cell-replete strategies such as that developed by the Baltimore group using high-dose posttransplant cyclophosphamide. HLA-haploidentical hematopoietic stem cell transplantation using posttransplant cyclophosphamide is associated with low rates of severe graft-versus-host disease and nonrelapse mortality and does not require graft manipulation or storage, which results in a low graft acquisition cost. Its remarkable safety when used with reduced-intensity conditioning has been demonstrated in patients up to 75 years old with outcomes similar to those of patients in their 50s. Several large, registry-based retrospective studies have confirmed the efficacy of HLA-haploidentical hematopoietic stem cell transplantation with posttransplant cyclophosphamide, achieving results comparable to those of HLA-matched hematopoietic stem cell transplantation. In this article, we describe our approach to this rapidly available and clinically simple platform and address some of the key clinical questions associated with its use.
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http://dx.doi.org/10.1182/blood.2019001323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872960PMC
November 2019

Allogeneic Haploidentical Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide in Chronic Lymphocytic Leukemia.

Biol Blood Marrow Transplant 2020 03 12;26(3):502-508. Epub 2019 Nov 12.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Allogeneic blood or marrow transplantation (allo-BMT) remains the only treatment for chronic lymphocytic leukemia (CLL) with curative potential. Although post-transplantation cyclophosphamide (PTCy) reduces allo-BMT toxicity by decreasing the risk of graft-versus-host disease (GVHD), its effect on CLL allo-BMT outcomes is unknown. We studied 64 consecutive patients with CLL who underwent nonmyeloablative (NMA) haploidentical allo-BMT at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. In this cohort, the 4-year overall survival was 52% (95% confidence interval [CI], 40% to 68%), and progression-free survival was 37% (95% CI, 26% to 54%). Six patients experienced engraftment failure. PTCy prophylaxis was associated with a modest cumulative incidence of 1-year grade II-IV acute GVHD (27%; %95% CI, 15% to 38%) and %%%2-year chronic GVHD (17%; 95% CI, 7% to 26%). We demonstrate that NMA haploidentical allo-BMT with PTCy is a safe and effective treatment option.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.008DOI Listing
March 2020

Inhibition of inositol kinase B controls acute and chronic graft-versus-host disease.

Blood 2020 01;135(1):28-40

Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.

T-cell activation releases inositol 1,4,5-trisphosphate (IP3), inducing cytoplasmic calcium (Ca2+) influx. In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP3 to negatively regulate and thereby tightly control Ca2+ fluxes that are essential for mature T-cell activation and differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca2+, induces apoptosis of activated T cells, and can control T-cell-mediated autoimmunity. In this study, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD). Murine-induced, Itpkb-deleted (Itpkb-/-) T cells attenuated acute GVHD in 2 models without eliminating A20-luciferase B-cell lymphoma graft-versus-leukemia (GVL). A highly potent, selective inhibitor, GNF362, ameliorated acute GVHD without impairing GVL against 2 acute myeloid leukemia lines (MLL-AF9-eGFP and C1498-luciferase). Compared with FK506, GNF362 more selectively deleted donor alloreactive vs nominal antigen-responsive T cells. Consistent with these data and as compared with FK506, GNF362 had favorable acute GVHD and GVL properties against MLL-AF9-eGFP cells. In chronic GVHD preclinical models that have a pathophysiology distinct from acute GVHD, Itpkb-/- donor T cells reduced active chronic GVHD in a multiorgan system model of bronchiolitis obliterans (BO), driven by germinal center reactions and resulting in target organ fibrosis. GNF362 treatment reduced active chronic GVHD in both BO and scleroderma models. Thus, intact Itpkb signaling is essential to drive acute GVHD pathogenesis and sustain active chronic GVHD, pointing toward a novel clinical application to prevent acute or treat chronic GVHD.
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http://dx.doi.org/10.1182/blood.2019000032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940197PMC
January 2020

Clinical applications of donor lymphocyte infusion from an HLA-haploidentical donor: consensus recommendations from the Acute Leukemia Working Party of the EBMT.

Haematologica 2020 01 19;105(1):47-58. Epub 2019 Sep 19.

Dept. of Bone Marrow Transplantation and Onco-Hematology, Maria Sklodowska-Curie Institute - Oncology Center, Gliwice Branch, Gliwice, Poland.

Donor lymphocyte infusion has been used in the management of relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. It can eradicate minimal residual disease or be used to rescue a hematologic relapse, being able to induce durable remissions in a subset of patients. With the increased use of haploidentical hematopoietic cell transplantation, there is renewed interest in the use of donor lymphocytes to either treat or prevent disease relapse post transplant. Published retrospective and small prospective studies have shown encouraging results with therapeutic donor lymphocyte infusion in different haploidentical transplantation platforms. In this consensus paper, finalized on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use of donor lymphocyte infusion from haploidentical donor, and provide recommendations on its therapeutic, pre-emptive and prophylactic use in clinical practice.
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http://dx.doi.org/10.3324/haematol.2019.219790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939532PMC
January 2020

PTCY keeps on giving!

Blood 2019 09;134(11):848-849

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

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http://dx.doi.org/10.1182/blood.2019002284DOI Listing
September 2019

Haploidentical transplantation using posttransplant cyclophosphamide as GVHD prophylaxis in patients over age 70.

Blood Adv 2019 09;3(17):2608-2616

Department of Hematologic Malignancy and.

Hematologic malignancies in older people are unlikely to be cured with chemotherapy alone. Advances in allogeneic blood or marrow transplantation (alloBMT), especially nonmyeloablative (NMA) conditioning and the use of haploidentical donors, now make this therapy available to older people; however, long-term outcomes and predictors of success are unclear. We reviewed the outcomes of 93 consecutive patients aged 70 and older (median, 72; range, 70-78), who underwent haploidentical BMT at Johns Hopkins Hospital between 1 September 2009 and 1 April 2018. All patients received NMA conditioning and posttransplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis. The 2-year overall survival was 53%, and 2-year event-free survival was 43%. The 180-day cumulative incidence (CuI) of nonrelapse mortality (NRM) was 14%, and the 2-year CuI was 27%. The 2-year CuI of relapse was 30%. Of 78 patients who were alive and had their weight recorded on day 180, weight loss predicted subsequent NRM (subdistribution hazard ratio, 1.0; 95% CI, 1-1.13; = .048). In conclusion, haploidentical BMT with PTCy is feasible and relatively safe in septuagenarians. Although early, 6-month NRM was relatively low at 14%, but overall NRM continued to climb to 27% at 2 years, at least in part because of late deaths that appeared to be somewhat age related. Further studies to elucidate predictors of NRM are warranted.
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http://dx.doi.org/10.1182/bloodadvances.2019000155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737415PMC
September 2019

HLA-haploidentical vs matched-sibling hematopoietic cell transplantation: a systematic review and meta-analysis.

Blood Adv 2019 09;3(17):2581-2585

Division of Hematology, Oncology, and Transplantation, Department of Medicine, and.

HLA haploidentical hematopoietic cell transplantation (haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) is an alternative strategy when a matched sibling donor (MSD) is not available. We performed a systematic review and meta-analysis to compare the outcomes of MSD vs haplo-HCT. Eleven studies (1410 haplo-HCT and 6396 MSD recipients) were meta-analyzed. All studies were retrospective and high quality, and 9 were multicenter. Haplo-HCT was associated with ~50% lower risk of chronic graft-versus-host disease (GVHD) (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.41-0.74), but higher risk of nonrelapse mortality (HR, 1.36; 95% CI, 1.12-1.66). Relapse, survival, acute GVHD, and GVHD-free relapse-free survival were not significantly different between the groups. Deciphering the relative contribution of PT-Cy and HLA disparity to the observed outcome differences between the groups requires further research.
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http://dx.doi.org/10.1182/bloodadvances.2019000614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737418PMC
September 2019

Post-transplantation cyclophosphamide for chimerism-based tolerance.

Bone Marrow Transplant 2019 08;54(Suppl 2):769-774

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

High-dose cyclophosphamide given post-transplant (PTCy) successfully enables tolerance induction in HLA-mismatched related blood or marrow transplantation (haploBMT) manifested by low rates of graft failure, severe acute graft-versus-host disease (GVHD), and chronic GVHD. When proceeded by nonmyeloablative conditioning, PTCy has also been associated with a low incidence of nonrelapse mortality. The safety of this platform has garnered interest in expanding its use to non-malignant indications for allogeneic blood or marrow transplantation (alloBMT). After success in a preliminary Phase I/II trial, use of a PTCy-based haploBMT platform is now being explored in a large Blood and Marrow Transplant Clinical Trials Network (BMT CTN) study for sickle cell disease. These emerging data in patients with hemoglobinopathies provided the rationale for exploring the use of PTCy in combined solid organ and BM transplantation as a means of tolerance induction through donor hematopoietic chimerism with a goal to obviate the need for a lifetime of immunosuppression. Several case reports, series, and small clinical trials have now been published of combined solid organ and alloBMT in patients with hematologic malignancies who had organ failure that would have been preclusive of alloBMT in the absence of solid organ transplantation. Here we will review the pre-clinical and clinical studies supporting the use of PTCy for chimerism-based tolerance induction.
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http://dx.doi.org/10.1038/s41409-019-0615-0DOI Listing
August 2019

Severe Cytokine Release Syndrome after Haploidentical Peripheral Blood Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 12 5;25(12):2431-2437. Epub 2019 Aug 5.

Department of Hematologic Malignancy, Johns Hopkins/Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.

Inflammatory cytokines released by activated lymphocytes and innate cells in the context of cellular therapy can cause fever, vasodilatation, and end-organ damage, collectively known as cytokine release syndrome (CRS). CRS can occur after allogeneic blood or marrow transplantation, but is especially prevalent after HLA-haploidentical (haplo) peripheral blood transplantation (PBT). We reviewed charts of all patients who underwent haplo-PBT between October 1, 2013, and September 1, 2017 and graded CRS in these patients. A total of 146 consecutive patients who underwent related haplo-PBT were analyzed. CRS occurred in 130 patients (89%), with most cases of mild severity (grade 0 to 2). Severe CRS (grade 3 to 5) occurred in 25 patients (17%). In this group with severe CRS, 13 patients had encephalopathy, 12 required hemodialysis, and 11 were intubated. Death from the immediate complications of CRS occurred in 6 patients (24% of the severe CRS group and 4% of the entire haplo-PBT cohort). The cumulative probability of nonrelapse mortality (NRM) was 38% at 6 months for the patients with severe CRS and 8% (121 of 146) in patients without severe CRS. In conclusion, CRS occurs in nearly 90% of haplo-PBTs. Older haplo-PBT recipients (odds ratio [OR], 2.4; 95% confidence interval [CI], .83 to 6.75; P = .11) and those with a history of radiation therapy (OR, 3.85; 95% CI, 1.32 to 11.24; P = .01) are at increased risk of developing severe CRS. Although most recipients of haplo-PBT develop CRS, <20% experience severe complications. The development of severe CRS is associated with a significantly increased risk of NRM.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402409PMC
December 2019

Immune reconstitution after T-cell replete HLA-haploidentical transplantation.

Semin Hematol 2019 07 26;56(3):221-226. Epub 2019 Mar 26.

Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.

Impaired immune reconstitution has been one of the perceived limitations of alternative donor transplantation. However, modern transplantation platforms such as HLA-haploidentical transplantation with either post-transplantation cyclophosphamide or with anti-thymocyte globulin combined with intense immunosuppression may be associated with robust immune recovery as inferred by low rate of infectious mortality and post-transplantation lymphoproliferative disease. Here, we review the data on immune reconstitution including individual cell subsets, the effect of reconstitution on outcomes, and comparative studies using these commonly utilized T-cell replete HLA-haploidentical platforms. We find robust recovery of neutrophils, natural killer cells, CD8 T-cells, and B-cells, with delayed CD4 T-cell recovery comparable to that after HLA-matched transplantation. In addition, while viral reactivations and infections appear more common after HLA-haploidentical when compared with HLA-matched transplantation, infectious mortality remains low likely due to modern cytomegalovirus monitoring, preemptive treatment, as well as relative frequency of nonlethal viral infections like polyomavirus hominis 1 (BK virus). Higher graft cell doses also appear to be associated with faster recovery without concomitant increases in lethal graft-vs-host disease. Finally, despite rapid numerical return of natural killer cells post-transplant, phenotypically they retain immaturity markers till day 180 or more after transplantation, which suggests an avenue for future research to improve outcomes further.
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http://dx.doi.org/10.1053/j.seminhematol.2019.03.005DOI Listing
July 2019

Post-transplant cyclophosphamide use in matched HLA donors: a review of literature and future application.

Bone Marrow Transplant 2020 01 14;55(1):40-47. Epub 2019 May 14.

Department of Adult Hematology & Stem Cell Transplant, King Faisal Hospital & Research Center, Riyadh, KSA, Saudi Arabia.

The last decade had witnessed a remarkable reduction in the incidence of acute and chronic GvHD (graft versus host disease) in both related and unrelated transplants mostly due to the improved resolution of HLA (human leukocyte antigen) typing and the new methods for GvHD prevention. The use of post-transplant cyclophosphamide (PTCY) to mitigate the bidirectional alloreactivity in the setting of haploidentical transplant have revolutionized and revived the field. Based on the promising results of PTCY in the haploidentical transplant field many groups used the same strategy in the setting of HLA-matched donors. This review will carefully examine the available data about the use of PTCY in HLA-matched setting.
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http://dx.doi.org/10.1038/s41409-019-0547-8DOI Listing
January 2020

Mechanism of action of posttransplantation cyclophosphamide: more than meets the eye.

J Clin Invest 2019 05 6;129(6):2189-2191. Epub 2019 May 6.

Division of Hematologic Malignancies, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.

For high-risk and refractory hematological malignancies, allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only available curative therapy, with benefits derived from the antigenic disparity between recipient cancer and the incoming immune system. This immunologic mismatch can also lead to lethal graft-versus-host disease (GVHD), and immunosuppression strategies, including high-dose posttransplantation cyclophosphamide (PTCy), have been developed to allow for safe alloHSCT delivery. In this issue of JCI, Wachsmuth et al. present the results of preclinical studies designed to evaluate the mechanisms that underlie efficacy of PTCy after alloHSCT. The results of this study challenge previous reports indicating that alloreactive T cell elimination and thymic clonal deletion are primary mediators of PTCy efficacy and provide strong evidence to support FoxP3+CD4+ Tregs as important effectors of PTCy benefits.
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http://dx.doi.org/10.1172/JCI128710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546449PMC
May 2019

Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation.

Nat Med 2019 04 25;25(4):603-611. Epub 2019 Mar 25.

Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.

Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-γ or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.
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http://dx.doi.org/10.1038/s41591-019-0400-zDOI Listing
April 2019
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