Publications by authors named "Lode J Swinnen"

75 Publications

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

Prospective SPECT-CT Organ Dosimetry-Driven Radiation-Absorbed Dose Escalation Using the In-111 (In)/Yttrium 90 (Y) Ibritumomab Tiuxetan (Zevalin) Theranostic Pair in Patients with Lymphoma at Myeloablative Dose Levels.

Cancers (Basel) 2021 Jun 6;13(11). Epub 2021 Jun 6.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.

Purpose: We prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin's lymphoma using the theranostic pair of In and Y anti-CD20 ibritumomab tiuxetan (Zevalin) at myeloablative radiation-absorbed doses with autologous stem cell support. We also assessed acute non-hematopoietic toxicity and early tumor response in this two-center outpatient study.

Methods: 24 patients with CD20-positive relapsed or refractory rituximab-sensitive, low-grade, mantle cell, or diffuse large-cell NHL, with normal organ function, platelet counts > 75,000/mm, and <35% tumor involvement in the marrow were treated with Rituximab (375 mg/m) weekly for 4 consecutive weeks, then one dose of cyclophosphamide 2.5 g/m with filgrastim 10 mcg/kg/day until stem cell collection. Of these, 18 patients with successful stem cell collection (at least 2 × 10 CD34 cells/kg) proceeded to RIT. A dosimetric administration of In ibritumomab tiuxetan (185 MBq) followed by five sequential quantitative planar and one SPECT/CT scan was used to determine predicted organ radiation-absorbed dose. Two weeks later, Y ibritumomab tiuxetan was administered in an outpatient setting at a cohort- and patient-specific predicted organ radiation-absorbed dose guided by a Continuous Response Assessment (CRM) methodology with the following cohorts for dose escalation: 14.8 MBq/kg, and targeted 18, 24, 28, and 30.5 Gy to the liver. Autologous stem cell infusion occurred when the estimated marrow radiation-absorbed dose rate was predicted to be <1 cGy/h. Feasibility, short-term toxicities, and tumor response were assessed.

Results: Patient-specific hybrid SPECT/CT + planar organ dosimetry was feasible in all 18 cases and used to determine the patient-specific therapeutic dose and guide dose escalation (26.8 ± 7.3 MBq/kg (mean), 26.3 MBq/kg (median) of Y (range: 12.1-41.4 MBq/kg)) of ibritumomab tiuxetan that was required to deliver 10 Gy to the liver. Infused stem cells engrafted rapidly. The most common treatment-related toxicities were hematological and were reversible following stem cell infusion. No significant hepatotoxicity was seen. One patient died from probable treatment-related causes-pneumonia at day 27 post-transplant. One patient at dose level 18 Gy developed myelodysplastic syndrome (MDS), 4 patients required admission post-Y RIT for febrile neutropenia, 16/18 patients receiving Y ibritumomab tiuxetan (89%) responded to the therapy, with 13 CR (72%) and 3/18 PR (17%), at 60 days post-treatment. Two patients had progressive disease at sixty days. One patient was lost to follow-up. Median time to progression was estimated to be at least 13 months. MTD to the liver is greater than 28 Gy, but the MTD was not reached as the study was terminated due to unexpected discontinuation of availability of the therapeutic agent.

Conclusions: Patient-specific outpatient Y ibritumomab tiuxetan RIT with myeloablative doses of RIT up to a targeted 30.5 Gy to the liver is feasible, guided by prospective SPECT/CT + planar imaging with the theranostic pair of In and Y anti-CD20, with outpatient autologous stem cell transplant support. Administered activity over 5 times the standard FDA-approved activity was well-tolerated. The non-hematopoietic MTD in this study exceeds 28 Gy to the liver. Initial tumor responses were common at all dose levels. This study supports the feasibility of organ dosimetry-driven patient-specific dose escalation in the treatment of NHL with stem cell transplant and provides additional information on the radiation tolerance of the normal liver to radiopharmaceutical therapy.
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http://dx.doi.org/10.3390/cancers13112828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201215PMC
June 2021

Challenges in the Treatment of Newly Diagnosed and Recurrent Primary Central Nervous System Lymphoma.

J Natl Compr Canc Netw 2020 11 2;18(11):1571-1578. Epub 2020 Nov 2.

Center for CNS Lymphoma, Dana-Farber Cancer Institute, Boston, Massachusetts.

Primary central nervous system lymphomas (PCNSLs) are rare cancers of the central nervous system (CNS) and are predominantly diffuse large B-cell lymphomas of the activated B-cell (ABC) subtype. They typically present in the sixth and seventh decade of life, with the highest incidence among patients aged >75 years. Although many different regimens have demonstrated efficacy in newly diagnosed and relapsed or refractory PCNSL, there have been few randomized prospective trials, and most recommendations and treatment decisions are based on single-arm phase II trials or even retrospective studies. High-dose methotrexate (HD-MTX; 3-8 g/m2) is the backbone of preferred standard induction regimens. Various effective regimens with different toxicity profiles can be considered that combine other chemotherapies and/or rituximab with HD-MTX, but there is currently no consensus for a single preferred regimen. There is controversy about the role of various consolidation therapies for patients who respond to HD-MTX-based induction therapy. For patients with relapsed or refractory PCNSL who previously experienced response to HD-MTX, repeat treatment with HD-MTX-based therapy can be considered depending on the timing of recurrence. Other more novel and less toxic regimens have been developed that show efficacy in recurrent disease, including ibrutinib, or lenalidomide ± rituximab. There is uniform agreement to delay or avoid whole-brain radiation therapy due to concerns for significant neurotoxicity if a reasonable systemic treatment option exists. This article aims to provide a clinically practical approach to PCNSL, including special considerations for older patients and those with impaired renal function. The benefits and risks of HD-MTX or high-dose chemotherapy with autologous stem cell transplantation versus other, better tolerated strategies are also discussed. In all settings, the preferred treatment is always enrollment in a clinical trial if one is available.
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http://dx.doi.org/10.6004/jnccn.2020.7667DOI Listing
November 2020

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 11 2;18(11):1537-1570. Epub 2020 Nov 2.

5The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.
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http://dx.doi.org/10.6004/jnccn.2020.0052DOI Listing
November 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

Positron Emission Tomography-Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001.

J Clin Oncol 2020 09 13;38(26):3003-3011. Epub 2020 Jul 13.

Division of Hematology/Oncology, Wilmot Cancer Institute, University of Rochester, Rochester, NY.

Purpose: Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity.

Methods: Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy.

Results: Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes.

Conclusion: To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.
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http://dx.doi.org/10.1200/JCO.20.00999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479758PMC
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

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

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

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

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

NCCN Guidelines Insights: B-Cell Lymphomas, Version 3.2019.

J Natl Compr Canc Netw 2019 06;17(6):650-661

National Comprehensive Cancer Network.

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin's lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.
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http://dx.doi.org/10.6004/jnccn.2019.0029DOI Listing
June 2019

Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial.

Lancet Haematol 2019 Apr 14;6(4):e183-e193. Epub 2019 Mar 14.

Hematologic Malignancies and Bone Marrow Transplantation Program, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Although severe haemoglobinopathies can be cured with allogeneic blood or bone marrow transplantation, availability of matched donors and toxic effects can be problematic. We previously found that non-myeloablative haploidentical related bone marrow transplantation with post-transplantation cyclophosphamide expanded the donor pool while limiting graft-versus-host disease (GVHD). However, graft failure-albeit with full host haemopoietic recovery-occurred in 50% of patients. In this study, we investigated whether increasing total body irradiation from 200 cGy to 400 cGy would improve engraftment while maintaining the safety profile.

Methods: This study was done at Johns Hopkins Hospital (Baltimore, MD, USA). Patients aged 2-70 years receiving their first bone marrow transplant were eligible for inclusion in the study. Patients received rabbit-derived intravenous anti-thymocyte globulin 0·5 mg/kg on day -9 and 2 mg/kg on days -8 and -7, intravenous fludarabine 30 mg/m on days -6 to -2, intravenous cyclophosphamide 14·5 mg/kg on days -6 and -5, and total body irradiation 400 cGy administered as a single fraction on day -1. We collected unmanipulated bone marrow and infused on day 0. GVHD prophylaxis comprised intravenous cyclophosphamide 50 mg/kg per day on days 3 and 4 after transplantation, oral mycophenolate mofetil 15 mg/kg per dose (maximum 1 g) every 8 h on days 5 to 35, and oral sirolimus to maintain a level of 5-15 ng/dL for at least 1 year starting on day 5. The original planned primary objectives of this phase 2 clinical trial were transplant-related mortality and progression-free survival. However, the coverage decision by the Centers for Medicare and Medicaid Services to only provide payment for allogeneic bone marrow transplantation for patients with sickle cell disease on a clinical trial that had a comparison arm with patients not receiving bone marrow transplantation prompted the closure of this trial to accrual in 2017. Therefore, as we were unable to perform our planned statistical analysis, the primary objective was modified to evaluate engraftment, assessed by chimerism. This trial is registered with ClinicalTrials.gov, number NCT00489281. The study is closed to new participants and this is the primary analysis.

Findings: Between Sept 24, 2014, and Aug 1, 2017, we enrolled 17 consecutive patients: 12 (71%) with sickle cell disease and 5 (29%) with β-thalassaemia major. The median patient age was 16 years (range 6-31, IQR 7·7-27·5). One (6%) of 17 patients had primary graft failure with recovery of host haemopoiesis. 13 (76%) of 17 patients achieved full donor chimerism and three (18%) had mixed donor-host chimerism. Five (29%) of 17 patients developed grade 2-4 acute GVHD, including four (24%) with maximal grade 2 GVHD and one (6%) with grade 3 GVHD. Chronic GVHD developed in three (18%) patients. As of their last follow-up visit, GVHD had resolved in all patients and no patients were receiving systemic GVHD therapy. All patients remained alive as of Aug 4, 2019, and the median follow-up duration was 705 days (range 355-1294; IQR 398-943). Only one (6%) of the 16 engrafted patients remained transfusion dependent, and 14 (88%) discontinued immunosuppression.

Interpretation: Increasing total body irradiation to 400 cGy substantially reduced graft failure while maintaining the safety of haploidentical bone marrow transplantation with post-transplantation cyclophosphamide. These results suggest that engraftment after haploidentical bone marrow transplantation for haemoglobinopathies is possible, and primary graft failure-the main problem previously reported-might be addressed by this strategy. Therefore, this curative approach should no longer be restricted to patients with HLA-matched donors.

Funding: Maryland Stem Cell Research Fund and US National Institutes of Health.
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http://dx.doi.org/10.1016/S2352-3026(19)30031-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506220PMC
April 2019

R-CHOP without radiation in frontline management of primary mediastinal B-cell lymphoma.

Leuk Lymphoma 2019 05 18;60(5):1261-1265. Epub 2019 Jan 18.

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

Prior to the introduction of rituximab, primary mediastinal B-cell lymphoma (PMBCL) had high rates of treatment failure with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), prompting the use of consolidative mediastinal radiation or more intensive chemotherapy regimens. Cure rates improved dramatically with rituximab, but mediastinal radiation was still commonly employed with R-CHOP. We performed a retrospective review of patients treated with R-CHOP alone without radiation for PMBCL. Of 43 patients with PMBCL, 16 received R-CHOP alone. High-risk factors included 56% with bulky disease, 75% with elevated LDH, 25% with SVC syndrome, and 13% with stage IV disease. Three-year progression-free survival (PFS) and overall survival (OS) were 93% and 100% respectively. These results suggest that R-CHOP alone has a high cure rate in PMBCL while avoiding the side effects of mediastinal radiation.
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http://dx.doi.org/10.1080/10428194.2018.1519812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472975PMC
May 2019

Development of Grade II Acute Graft-versus-Host Disease Is Associated with Improved Survival after Myeloablative HLA-Matched Bone Marrow Transplantation using Single-Agent Post-Transplant Cyclophosphamide.

Biol Blood Marrow Transplant 2019 06 30;25(6):1128-1135. Epub 2018 Dec 30.

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

Post-transplant cyclophosphamide (PTCy) can be used as the sole immunosuppression after myeloablative conditioning (MAC) for HLA-matched bone marrow transplantation (BMT). However, the effects of graft-versus-host disease (GVHD) with this platform are undefined. We retrospectively analyzed 298 consecutive adult patients with hematologic malignancies who engrafted after MAC HLA-matched sibling donor (MSD; n = 187) or HLA-matched unrelated donor (MUD; n = 111) T-cell-replete BMT with PTCy 50 mg/kg on days +3 and +4. After MSD and MUD BMT, 35% and 57% of patients, respectively, developed grade II acute GVHD (aGVHD) by 100 days, 11% and 14% grade III to IV aGVHD by 100 days, and 9% and 16% chronic GVHD (cGVHD) by 1 year. In landmark analyses at 100 days after HLA-matched BMT, 4-year overall survival (OS) and progression-free survival (PFS) were 57% (95% confidence interval [CI], .49 to .67) and 40% (95% CI, .31 to .51) in patients without grades II to IV aGVHD, and 68% (95% CI, .59 to .78) and 54% (95% CI, .44 to .65) in patients with grade II aGVHD. In adjusted time-dependent multivariable analyses, grade II aGVHD was associated with improved OS (hazard ratio, .58; 95% CI, .37 to .89; P = .01) and PFS (hazard ratio, .50; 95% CI, .34 to .74; P < .001) after HLA-matched BMT with PTCy. The ability of PTCy to limit grades III to IV aGVHD and cGVHD while maintaining grade II aGVHD may contribute to its effectiveness, and further attempts to reduce aGVHD may be detrimental.
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http://dx.doi.org/10.1016/j.bbmt.2018.12.767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559825PMC
June 2019

Immune checkpoint inhibitors as a bridge to allogeneic transplantation with posttransplant cyclophosphamide.

Blood Adv 2018 09;2(17):2226-2229

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

Published reports suggest that immune checkpoint inhibitors (ICIs) before allogeneic blood or marrow transplantation (alloBMT) may increase the incidence of graft-versus-host disease (GvHD), immune-related adverse events, and nonrelapse mortality (NRM); this led to the US Food and Drug Administration issuing a "Warning and Precaution" regarding the potential for life-threatening immune-mediated complications associated with alloBMT after nivolumab and pembrolizumab. We retrospectively reviewed the outcomes of 14 consecutive patients who received ICIs as their final salvage therapy before T-cell-replete alloBMT using reduced-intensity conditioning. All patients received posttransplant cyclophosphamide (PTCy), which significantly limits severe GvHD, even in the mismatched-donor setting. There was no grade 3-4 acute GvHD (aGvHD), and all 6 cases of grade 2 aGvHD readily resolved with immunosuppression. No patient experienced veno-occlusive disease of the liver, other immune-related adverse events, chronic GvHD, or NRM. There have been 2 relapses (15-month median follow-up), with 12 of 14 patients remaining alive, well, and progression-free. The only death was a result of disease relapse. Although more experience is needed, our data suggest that concerns over immunologic complications associated with ICIs should not preclude allogeneic bone marrow transplantation with PTCy as GvHD prophylaxis.
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http://dx.doi.org/10.1182/bloodadvances.2018019208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134225PMC
September 2018

Early Fever after Haploidentical Bone Marrow Transplantation Correlates with Class II HLA-Mismatching and Myeloablation but Not Outcomes.

Biol Blood Marrow Transplant 2018 10 15;24(10):2056-2064. Epub 2018 Jun 15.

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

Noninfectious fevers are common early after T cell-replete HLA haploidentical (haplo) peripheral blood transplants and have been associated with cytokine release syndrome and overall mortality. However, less is known regarding the incidence and associations of early fever after bone marrow transplantation (BMT) with post-transplant cyclophosphamide (PTCy). We hypothesized that early fever would be associated with myeloablative conditioning (MAC), because of its relative increase in tissue damage augmenting antigen presentation and class II HLA-mismatching because of recognition of antigen-presenting cells by CD4 T cells. In 672 recipients of MAC HLA-matched related donor (MRD) (n = 183), MAC HLA-matched unrelated donor (MUD) (n = 115), MAC haplo (n = 79), or nonmyeloablative (NMA) haplo (n = 295) T cell-replete BMT with PTCy, we retrospectively analyzed early noninfectious fever defined as temperature of ≥38.3°C once or ≥38.0°C twice or more on days 1 to 6. Fever occurred in 13% after MAC MRD, 23% after MAC MUD, 44% after NMA haplo, and 84% after MAC haplo BMT (P < .0001). Survival outcomes did not differ between patients with and without early fever. In NMA haplo BMT, mismatch in the graft-versus-host direction at HLA-DRB1 or -DPB1 (but not HLA-A, -B, -Cw, or -DQB1) was associated with early fever compared with no mismatches at these loci (P < .0001 and P = .02, respectively). In multivariable modeling, -DRB1 or -DPB1 mismatch and higher CD3 graft cell dose were significantly associated with early fever. Early fever is more common after haplo compared with HLA-matched BMT. Fever is associated with myeloablation, -DRB1 or -DPB1 mismatching, and higher CD3 graft cell dose but not survival.
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http://dx.doi.org/10.1016/j.bbmt.2018.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385878PMC
October 2018

Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide Using Non-First-Degree Related Donors.

Biol Blood Marrow Transplant 2018 05 13;24(5):1099-1102. Epub 2018 Feb 13.

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

Outcomes of nonmyeloablative (NMA) haploidentical (haplo) blood or marrow transplant (BMT) with post-transplantation cyclophosphamide (PTCy) using non-first-degree relatives are unknown. We evaluated 33 consecutive adult patients (median age, 56 years) with hematologic malignancies who underwent NMA haplo T cell-replete BMT with PTCy at Johns Hopkins using second- or third-degree related donors. Donors consisted of 10 nieces (30%), 9 nephews (27%), 7 first cousins (21%), 5 grandchildren (15%), and 2 uncles (6%). Thirty-one patients (94%) reached full donor chimerism by day 60. The estimated cumulative incidence (CuI) of grades II to IV acute graft-versus-host disease (aGVHD) at day 180 was 24% (90% confidence interval [CI], 9% to 38%). Only 1 patient experienced grades III to IV aGVHD. At 1 year the CuI of chronic GVHD was 10% (90% CI, 0% to 21%). The CuI of nonrelapse mortality at 1 year was 5% (90% CI, 0% to 14%). At 1 year the probability of relapse was 31% (90% CI, 12% to 49%), progression-free survival 64% (90% CI, 48% to 86%), and overall survival 95% (90% CI, 87% to 100%). The 1-year probability of GVHD-free, relapse-free survival was 57% (90% CI, 41% to 79%). NMA haplo BMT with PTCy from non-first-degree relatives is an acceptably safe and effective alternative donor platform, with results similar to those seen with first-degree relatives.
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http://dx.doi.org/10.1016/j.bbmt.2018.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439277PMC
May 2018

Phase II study of rituximab given in conjunction with standard chemotherapy in primary central nervous system lymphoma (PCNSL): a trial of the ECOG-ACRIN cancer research group (E1F05).

Oncotarget 2018 Jan 6;9(1):766-773. Epub 2017 Nov 6.

Johns Hopkins University, Baltimore, Maryland, USA.

Background: Therapy of primary CNS lymphoma (PCNSL) has focused on multi-agent chemotherapy designed to cross the blood brain barrier. Rituximab has demonstrated activity in PCNSL. E1F05 is an ECOG-ACRIN multicenter phase 2 prospective trial of rituximab with high-dose methotrexate (HD-MTX)-based chemotherapy similar to the RTOG 93-10 regimen, omitting radiotherapy.

Methods: Immunocompetent patients with newly diagnosed PCNSL received HD-MTX 3.5g/m2 with vincristine every two weeks for 5 doses; procarbazine for 7 days in weeks 1, 5, and 9; cytarabine 3g/m2/day IV for 2 days in weeks 11 and 14; a dexamethasone taper over 6 weeks; and rituximab 375mg/m2 IV infusion 3 times per week for weeks 1-4. Subjects with CSF involvement received intrathecal methotrexate 12mg every two weeks.

Results: Twenty-six patients were enrolled; median age was 57. Sixteen subjects (65%) completed treatment per protocol; the most common reason for discontinuation was adverse events, and 2 subjects discontinued due to progressive disease (PD). Complete response (CR) + unconfirmed CR (CRu) was 16/25 (64%), overall response rate was 20/25 (80%), and 4/25(16%) had PD as best response. Median progression free survival (PFS) was 34 months, and median overall survival has not been reached at 40 months' median follow up. Two year PFS was 63%. The most common grade 3-4 toxicities were hematologic.

Conclusion: The addition of rituximab to multi-agent chemotherapy is well tolerated. Outcomes are comparable to or better than those seen in RTOG 93-10, which included RT. These and other results suggest rituximab has activity in the CNS. [ECOG-ACRIN E1F05].

Clinical Trial Registration: NCT00335140, clinicaltrials.gov.
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http://dx.doi.org/10.18632/oncotarget.22332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787508PMC
January 2018

Shortened-Duration Tacrolimus after Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation.

Biol Blood Marrow Transplant 2018 05 17;24(5):1022-1028. Epub 2018 Jan 17.

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

With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative HLA-haploidentical (NMA haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Early discontinuation of immunosuppression may reduce the risk of relapse and improve immune reconstitution, but may increase the risk of GVHD. We conducted a prospective trial of NMA haplo BMT for patients with hematologic malignancies (median age, 61 years), evaluating the safety of early discontinuation of tacrolimus. All patients received T cell-replete bone marrow followed by high-dose PTCy, mycophenolate mofetil, and tacrolimus. Tacrolimus was prespecified to stop without taper at day +90, +60, or +120, contingent on having ≥5% donor T cells, no relapse, and no grade II-IV acute or significant chronic GVHD. Safety stopping rules were based on ≥5% graft failure, ≥10% nonrelapse mortality (NRM), or a ≥20% combined incidence of severe acute and chronic GVHD from the tacrolimus stop date through day +180. Of the 47 patients in the day +90 arm, 23 (49%) stopped tacrolimus as planned. Of the 55 patients in the day +60 arm, 38 (69%) stopped as planned. Safety stopping criteria were not met. In both arms, at day +180, the probability of grade II-IV acute GVHD was <40%, that of grade III-IV acute GVHD was <8%, and that of NRM was <5%. The 1-year probabilities of chronic GVHD and NRM were <15% and <10%, respectively, in both arms. The 1-year GVHD-free relapse-free survival was higher in the day 60 arm. Thus, stopping tacrolimus as early as day +60 is feasible and carries acceptable risks after NMA haplo BMT with PTCy. This approach may facilitate post-transplantation strategies for relapse reduction.
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http://dx.doi.org/10.1016/j.bbmt.2018.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977987PMC
May 2018

Solid Organ Transplantation in Selected Patients With a History of Lymphoma: Has the Time Come?

Authors:
Lode J Swinnen

J Oncol Pract 2018 01;14(1):21-22

Johns Hopkins University, Baltimore, MD.

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http://dx.doi.org/10.1200/JOP.2017.029223DOI Listing
January 2018

Prospective study of nonmyeloablative, HLA-mismatched unrelated BMT with high-dose posttransplantation cyclophosphamide.

Blood Adv 2017 6;1(4):288-292. Epub 2017 Jan 6.

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

Allogeneic blood or marrow transplantation (BMT) candidates may lack HLA-matched, related haploidentical, and unrelated umbilical cord options. Barriers to partially HLA-mismatched, unrelated donor (mMUD) BMT include excess graft-versus-host disease (GVHD), graft failure, and death. We prospectively studied nonmyeloablative (NMA) mMUD BMT with high-dose posttransplantation cyclophosphamide (PTCy) for patients with hematologic malignancies. Three transplants were performed with busulfan/fludarabine conditioning, with subsequent change to fludarabine/Cy/total body irradiation (flu/Cy/TBI). Twenty mMUD transplants are reported using flu/Cy/TBI, T-cell replete bone marrow grafts, and PTCy, mycophenolate mofetil, and sirolimus or tacrolimus (1 patient) for GVHD prophylaxis. The median patient age was 56. Ofthese unrelated grafts, 45% had ≥2 mismatched HLA loci, 25% had ≥3 mismatched loci, and 50% had HLA-C mismatches. No graft failure or grades 3-4 acute GVHD occurred. The median times to neutrophil recovery (≥500/μL) and platelet recovery (≥20 000/μL) were 19 days and 31 days, respectively. Full-donor chimerism was achieved in 95% of evaluable patients by day 60. The 180-day probability of grades 2-4 acute GVHD (all grade 2) was 25%, and the 1-year probability of any chronic GVHD was 16% (none severe). The 2-year nonrelapse mortality probability was 6%. With 4-year median follow-up, the 1-year progression-free and overall survival probabilities were 65% and 75%, respectively. NMA, T-cell replete mMUD BMT is thus a potentially viable option for patients without other suitable donors. This trial was registered at www.clinicaltrials.gov as #NCT01203722.
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http://dx.doi.org/10.1182/bloodadvances.2016002766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726600PMC
January 2017

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017.

J Natl Compr Canc Netw 2017 11;15(11):1331-1345

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.
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http://dx.doi.org/10.6004/jnccn.2017.0166DOI Listing
November 2017

Major Histocompatibility Mismatch and Donor Choice for Second Allogeneic Bone Marrow Transplantation.

Biol Blood Marrow Transplant 2017 Nov 25;23(11):1887-1894. Epub 2017 Jul 25.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Division of Hematologic Malignancies, Bunting Blaustein Cancer Research Bldg., 1650 Orleans Street, Baltimore, Maryland. Electronic address:

Large alternative donor pools provide the potential for selecting a different donor for a second allogeneic (allo) bone or marrow transplant (BMT). As HLA disparity may contribute to the graft-versus-tumor effect, utilizing new mismatched haplotype donors may potentially improve the antitumor activity for relapsed hematologic malignancies despite a previous alloBMT. Data from patients who received a second alloBMT for relapsed hematologic malignancies at Johns Hopkins were analyzed. Outcomes were compared between patients who received a second allograft with the same MHC composition and those who received an allograft with a new mismatched haplotype. Loss of heterozygosity analysis was performed for patients with acute myeloid leukemia (AML) whose first allograft was haploidentical. Between 2005 and 2015, 40 patients received a second BMT for a relapsed hematologic malignancy. The median follow-up is 750 (range, 26 to 2950) days. The median overall survival (OS) in the cohort is 928 days (95% confidence interval [CI], 602 to not reached [NR]); median event-free survival (EFS) for the cohort is 500 days (95% CI, 355 to NR). The 4-year OS is 40% (95% CI, 25% to 64%), and the 4-year EFS is 36% (95% CI, 24% to 55%). The cumulative incidence of nonrelapsed mortality by 2 years was 27% (95% CI, 13% to 42%). The cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) at 100 days was 15% (95% CI, 4% to 26%); the cumulative incidence of extensive chronic GVHD at 2 years was 22% (95% CI, 9% to 36%). The median survival was 552 days (95% CI, 376 to 2950+) in the group who underwent transplantation with a second allograft that did not harbor a new mismatched haplotype, while it was not reached in the group whose allograft contained a new mismatched haplotype (hazard ratio [HR], .36; 95% CI, .14 to .9; P = .02). EFS was also longer in the group who received an allograft containing a new mismatched haplotype, (NR versus 401 days; HR, .50; 95% CI, .22 to 1.14; P = .09). Although the allograft for this patient's second BMT contained a new mismatched haplotype, AML nevertheless relapsed a second time. Second BMTs are feasible and provide a reasonable chance of long-term survival. An allograft with a new mismatched haplotype may improve outcomes after second BMTs for relapsed hematologic malignancies.
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http://dx.doi.org/10.1016/j.bbmt.2017.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881910PMC
November 2017

Allogeneic Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Multiple Myeloma.

Biol Blood Marrow Transplant 2017 Nov 12;23(11):1903-1909. Epub 2017 Jul 12.

School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Allogeneic blood or marrow transplantation (alloBMT) may lead to long-term disease control in patients with multiple myeloma (MM). However, historically, the use of alloBMT in MM has been limited by its high nonrelapse mortality (NRM) rates, primarily from graft-versus-host disease (GVHD). We previously demonstrated that post-transplantation cyclophosphamide (PTCy) decreases the toxicities of both acute and chronic GVHD after alloBMT. Here, we examine the impact of PTCy in patients with MM undergoing alloBMT at Johns Hopkins Hospital. From 2003 to 2011, 39 patients with MM underwent bone marrow or peripheral blood alloBMT from HLA-matched related/unrelated or haploidentical related donors after either myeloablative or nonmyeloablative conditioning. Post-transplantation GVHD prophylaxis consisted of cyclophosphamide (50 mg/kg) on days +3 and +4 with or without mycophenolate mofetil and tacrolimus. Engraftment was detected in 95% of patients, with neutrophil and platelet recovery at a median of 15 and 16 days, respectively. The cumulative incidences of acute grades 2 to 4 and grades 3 and 4 GVHD were .41 and .08, respectively, and no cases of grade 4 acute GVHD were observed. The cumulative incidence of chronic GVHD was .13. One patient succumbed to NRM. All cases of chronic GVHD involved extensive disease and 60% of these patients received systemic therapy with complete resolution. After alloBMT, the overall response rate was 62% with complete, very good partial, and partial response rates of 26%, 21%, and 15%, respectively. The median progression-free survival was 12 months and was associated with the depth of response but not cytogenetic risk. The estimated cumulative incidence of relapse was .46 (95% confidence interval [CI], .3 to .62) at 1 year and .56 (95% CI, .41 to .72) at 2 years. At last follow-up, 23% of patients remain without evidence of disease at a median follow-up of 10.3 years after alloBMT. The median overall survival was 4.4 years and the 5-year and 10-year overall survival probabilities were 49% (95% CI, 35% to 67%) and 43% (95% CI, 29% to 62%), respectively. The use of PTCy after alloBMT for MM is feasible and results in low NRM and GVHD rates. The safety of this approach may allow the development of novel post-transplantation maintenance strategies to improve long-term disease control.
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http://dx.doi.org/10.1016/j.bbmt.2017.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682203PMC
November 2017

NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2017.

J Natl Compr Canc Netw 2017 03;15(3):293-311

Yale Cancer Center/Smilow Cancer Hospital

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL.
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http://dx.doi.org/10.6004/jnccn.2017.0030DOI Listing
March 2017

Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide.

Blood 2017 03 3;129(10):1389-1393. Epub 2017 Jan 3.

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

The intensive and prolonged immunosuppressive therapy required to prevent or treat graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT) puts patients at substantial risk for life-threatening infections, organ toxicity, and disease relapse. Posttransplantation cyclophosphamide (PTCy) can function as single-agent GVHD prophylaxis after myeloablative, HLA-matched related (MRD), or HLA-matched unrelated (MUD) donor T-cell-replete bone marrow allografting, obviating the need for additional prophylactic immunosuppression. However, patients who develop GVHD require supplemental treatment. We assessed the longitudinal requirement for immunosuppressive therapy in 339 patients treated with this transplantation platform: 247 receiving busulfan/cyclophosphamide (BuCy) conditioning (data collected retrospectively) and 92 receiving busulfan/fludarabine (BuFlu) conditioning (data collected prospectively). Approximately 50% of MRD patients and 30% of MUD patients never required immunosuppression beyond PTCy. In patients requiring further immunosuppression, typically only 1 to 2 agents were required, and the median durations of systemic pharmacologic immunosuppression for the BuCy MRD, BuFlu MRD, BuCy MUD, and BuFlu MUD groups all were 4.5 to 5 months. For these 4 groups, 1-year probabilities of being alive and off all systemic immunosuppression were 61%, 53%, 53%, and 51% and 3-year probabilities were 53%, 48%, 49%, and 56%, respectively. These data suggest that PTCy minimizes the global immunosuppressive burden experienced by patients undergoing HLA-matched alloBMT.
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http://dx.doi.org/10.1182/blood-2016-09-737825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345732PMC
March 2017

Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide.

Haematologica 2017 02 20;102(2):391-400. Epub 2016 Oct 20.

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

Composite endpoints that not only encompass mortality and relapse, but other critical post-transplant events such as graft-versus-host disease, are being increasingly utilized to quantify survival without significant morbidity after allogeneic blood or marrow transplantation. High-dose, post-transplantation cyclophosphamide reduces severe graft-versus-host disease with allogeneic marrow transplantation, making composite endpoints after this management particularly interesting. We retrospectively analyzed 684 adults with hematologic malignancies who received T-cell-replete bone marrow grafts and cyclophosphamide after myeloablative HLA-matched related (n=192) or unrelated (n=120), or non-myeloablative HLA-haploidentical (n=372) donor transplantation. The median follow up was 4 (range, 0.02-11.4) years. Graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without grade III-IV acute graft-versus-host disease, chronic graft-versus-host disease requiring systemic treatment, relapse, or death. Chronic graft-versus-host disease-free, relapse-free survival was defined as the time after transplantation without moderate or severe chronic graft-versus-host disease, relapse, or death. One-year graft-versus-host disease-free, relapse-free survival and chronic graft-versus-host disease-free, relapse-free survival estimates were, respectively, 47% (95% CI: 41-55%) and 53% (95% CI: 46-61%) after myeloablative HLA-matched related, 42% (95% CI: 34-52%) and 52% (95% CI: 44-62%) after myeloablative HLA-matched unrelated, and 45% (95% CI: 40-50%) and 50% (95% CI: 45-55%) after non-myeloablative HLA-haploidentical donor transplantation. In multivariable models, there were no differences in graft-versus-host disease-free, or chronic graft-versus-host disease-free, relapse-free survival after either myeloablative HLA-matched unrelated or non-myeloablative HLA-haploidentical, compared with myeloablative HLA-matched related donor transplantation. Although limited by inclusion of dissimilar cohorts, we found that post-transplantation cyclophosphamide-based platforms yield comparable composite endpoints across conditioning intensity, donor type, and HLA match.
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http://dx.doi.org/10.3324/haematol.2016.144139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286947PMC
February 2017
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