المؤلفون: Natalie S. Callander, Rebecca Silbermann, Jonathan L. Kaufman, Kelly N. Godby, Jacob Laubach, Timothy M. Schmidt, Douglas W. Sborov, Eva Medvedova, Brandi Reeves, Binod Dhakal, Cesar Rodriguez, Saurabh Chhabra, Ajai Chari, Susan Bal, Larry D. Anderson, Bhagirathbhai R. Dholaria, Nitya Nathwani, Parameswaran Hari, Nina Shah, Naresh Bumma, Sarah A. Holstein, Caitlin Costello, Andrzej Jakubowiak, Tanya M. Wildes, Robert Z. Orlowski, Kenneth H. Shain, Andrew J. Cowan, Huiling Pei, Annelore Cortoos, Sharmila Patel, Thomas S. Lin, Smith Giri, Luciano J. Costa, Saad Z. Usmani, Paul G. Richardson, Peter M. Voorhees

المصدر: Blood Cancer Journal, Vol 14, Iss 1, Pp 1-8 (2024)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10–5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high–risk disease (≥2 HRCAs). Video Abstract

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2044-5385

URL الوصول: https://doaj.org/article/ebc38d6b2c3c4c4a957f6410c2bc2f56

المؤلفون: Rebecca W. Silbermann, Timothy Martin Schmidt, Susan Bal, Binod Dhakal, Bhagirathbhai Dholaria, Eden Biltibo, Saurabh Chhabra, Smith Giri, Kelly N. Godby, Sonia Gowda, Eva Medvedova, Robert F. Cornell, Natalie S. Callander, Luciano J. Costa

المصدر: eJHaem, Vol 4, Iss 3, Pp 775-778 (2023)

مصطلحات موضوعية: immunodeficiency, measurable residual disease, multiple myeloma, Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: Abstract Quadruplet induction, autologous hematopoietic cell transplant (AHCT), and measurable residual disease (MRD) response‐adapted consolidation yield an unprecedented depth of response in newly diagnosed multiple myeloma. Patients treated on MASTER (NCT03224507) ceased therapy and entered active surveillance (MRD‐SURE) after achieving MRD negativity. This study characterizes quantitative changes in the immunoglobulin (Ig) gene repertoire by next‐generation sequencing and serum gamma globulin levels. Quadruplet therapy leads to profound hypogammaglobulinemia and reduction in the Ig gene repertoire. Immune reconstitution (IR) is delayed in patients who received post‐AHCT consolidation compared to those who do not. Eighteen months after treatment cessation, there was no statistically significant difference between the groups.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2688-6146

URL الوصول: https://doaj.org/article/49799bc37a3c41b190e485728196e1a4

المؤلفون: Guru Subramanian Guru Murthy, Soyoung Kim, Noel Estrada-Merly, Muhammad Bilal Abid, Mahmoud Aljurf, Amer Assal, Talha Badar, Sherif M. Badawy, Karen Ballen, Amer Beitinjaneh, Jan Cerny, Saurabh Chhabra, Zachariah DeFilipp, Bhagirathbhai Dholaria, Miguel Angel Diaz Perez, Shatha Farhan, Cesar O. Freytes, Robert Peter Gale, Siddhartha Ganguly, Vikas Gupta, Michael R. Grunwald, Nada Hamad, Gerhard C. Hildebrandt, Yoshihiro Inamoto, Tania Jain, Omer Jamy, Mark Juckett, Matt Kalaycio, Maxwell M. Krem, Hillard M. Lazarus, Mark Litzow, Reinhold Munker, Hemant S. Murthy, Sunita Nathan, Taiga Nishihori, Guillermo Ortí, Sagar S. Patel, Marjolein van der Poel, David A. Rizzieri, Bipin N. Savani, Sachiko Seo, Melhem Solh, Leo F. Verdonck, Baldeep Wirk, Jean A. Yared, Ryotaro Nakamura, Betul Oran, Bart Scott, Wael Saber

المصدر: Haematologica, Vol 108, Iss 7 (2023)

مصطلحات موضوعية: Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P

وصف الملف: electronic resource

Relation: https://haematologica.org/article/view/10975; https://doaj.org/toc/0390-6078; https://doaj.org/toc/1592-8721

URL الوصول: https://doaj.org/article/3607fa3e9937487db3f85032af240a0d

المؤلفون: Saurabh Chhabra, Aniko Szabo, Annelie Clurman, Katelynn McShane, Nicholas Waters, Daniel Eastwood, Lisa Samanas, Teng Fei, Gabriel Armijo, Sameen Abedin, Walter Longo, Parameswaran Hari, Mehdi Hamadani, Nirav N. Shah, Lyndsey Runaas, James H. Jerkins, Marcel van den Brink, Jonathan U. Peled, William R. Drobyski

المصدر: Haematologica, Vol 108, Iss 1 (2022)

مصطلحات موضوعية: Diseases of the blood and blood-forming organs, RC633-647.5

وصف الملف: electronic resource

Relation: https://haematologica.org/article/view/10798; https://doaj.org/toc/0390-6078; https://doaj.org/toc/1592-8721

URL الوصول: https://doaj.org/article/871d38df3c8a4209b9a71cabe44d7912

المؤلفون: Sara Beltrán Ponce, MD, Saurabh Chhabra, MD, MS, Parameswaran Hari, MD, MRCP, Selim Firat, MD

المصدر: Advances in Radiation Oncology, Vol 7, Iss 5, Pp 100964- (2022)

مصطلحات موضوعية: Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Purpose: Allogeneic hematopoietic cell transplantation (HCT) serves as the only curative treatment option for patients with myelofibrosis and other myeloproliferative neoplasms. Splenomegaly commonly manifests in patients with myeloproliferative neoplasms and can lead to delayed or poor engraftment, increased transfusion burden, and worse survival. Methods to decrease the effect of splenomegaly include splenectomy and splenic irradiation. We sought to report on clinical outcomes for patients treated with splenic irradiation as part of their transplant conditioning. Methods and Materials: Patients with splenomegaly measuring greater than 22 cm were referred for splenic irradiation. They received radiation to the entire spleen to 10 Gy in 5 fractions using 3-dimensional conformal radiation with anteroposterior/posteroanterior or opposed tangent fields. Blood counts were monitored closely on treatment. Changes in splenic size were measured using first and last treatment image guided radiation therapy and pre- and posttransplant diagnostic imaging. Results: Seventeen patients completed pretransplant splenic irradiation between 2012 and 2021. Median platelet, white blood cell, and hemoglobin levels decreased on treatment. One patient required platelet transfusion and 3 required packed red blood cell transfusions. Mean decrease in spleen size during radiation was -8.5% in the craniocaudal dimension. Prolonged decreases, measured 2 to 12 months after transplant, averaged 14.64%. All patients engrafted. Fourteen (82.4%) were alive at time of analysis with median follow-up of 4.2 years from hematopoietic cell transplantation. Conclusions: Splenic irradiation offers a safe method of managing significant splenomegaly as part of transplant conditioning. Transplant outcomes in this series were excellent. Prospective data may be beneficial to determine the absolute benefit of this addition to pretransplant conditioning in this patient population.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2452109422000719; https://doaj.org/toc/2452-1094

URL الوصول: https://doaj.org/article/dfdb79dbc775430faf0476a16eebcb22

المؤلفون: Michael Pisano, Yan Cheng, Fumou Sun, Binod Dhakal, Anita D’Souza, Saurabh Chhabra, Jennifer M. Knight, Sridhar Rao, Fenghuang Zhan, Parameswaran Hari, Siegfried Janz

المصدر: Frontiers in Immunology, Vol 12 (2021)

مصطلحات موضوعية: genetically engineered mouse models of human cancer, auto- and xenografting, immune, immunodeficient mice models, immune pathogenesis, Myeloma, Immunologic diseases. Allergy, RC581-607

الوصف: Mouse models of human cancer provide an important research tool for elucidating the natural history of neoplastic growth and developing new treatment and prevention approaches. This is particularly true for multiple myeloma (MM), a common and largely incurable neoplasm of post-germinal center, immunoglobulin-producing B lymphocytes, called plasma cells, that reside in the hematopoietic bone marrow (BM) and cause osteolytic lesions and kidney failure among other forms of end-organ damage. The most widely used mouse models used to aid drug and immunotherapy development rely on in vivo propagation of human myeloma cells in immunodeficient hosts (xenografting) or myeloma-like mouse plasma cells in immunocompetent hosts (autografting). Both strategies have made and continue to make valuable contributions to preclinical myeloma, including immune research, yet are ill-suited for studies on tumor development (oncogenesis). Genetically engineered mouse models (GEMMs), such as the widely known Vκ*MYC, may overcome this shortcoming because plasma cell tumors (PCTs) develop de novo (spontaneously) in a highly predictable fashion and accurately recapitulate many hallmarks of human myeloma. Moreover, PCTs arise in an intact organism able to mount a complete innate and adaptive immune response and tumor development reproduces the natural course of human myelomagenesis, beginning with monoclonal gammopathy of undetermined significance (MGUS), progressing to smoldering myeloma (SMM), and eventually transitioning to frank neoplasia. Here we review the utility of transplantation-based and transgenic mouse models of human MM for research on immunopathology and -therapy of plasma cell malignancies, discuss strengths and weaknesses of different experimental approaches, and outline opportunities for closing knowledge gaps, improving the outcome of patients with myeloma, and working towards a cure.

وصف الملف: electronic resource

Relation: https://www.frontiersin.org/articles/10.3389/fimmu.2021.667054/full; https://doaj.org/toc/1664-3224

URL الوصول: https://doaj.org/article/cc4625eaeb1c471084a103fb04009478

المؤلفون: Anita D'Souza, Aniko Szabo, Kathryn E. Flynn, Binod Dhakal, Saurabh Chhabra, Marcelo C. Pasquini, Dorothee Weihrauch, Parameswaran N. Hari

المصدر: EClinicalMedicine, Vol 23, Iss , Pp 100361- (2020)

مصطلحات موضوعية: Doxycycline, Systemic light chain amyloidosis, Early mortality, Medicine (General), R5-920

الوصف: Background: Although, doxycycline use is associated with improved outcomes in amyloidosis in retrospective studies, evidence from clinical trials is limited. Methods: This phase 2 trial of doxycycline (clinicaltrials.gov: NCT02207556) in newly diagnosed light chain (AL) amyloidosis enrolled 25 patients with systemic AL amyloidosis on treatment with doxycycline for 1 year along with chemotherapy. Outcomes of interest included mortality, organ response, and hematologic response rates at 1 year. Findings: The median age was 62 years, 64% were male, and 68% had the AL lambda subtype. Patients had Mayo 2012 stage 3 in 24% and stage 4 in 28%. Cardiac involvement was present in 60% of patients, renal involvement in 72%, and 60% patients had 3 or more organs involved. Target organ was cardiac in 14(56%), renal in 7(28%), hepatic in 1(4%) and soft tissue in 3(12%). At 1 year, mortality was 20% (95% confidence interval, 8.9–41.6%) and organ response was 36% (18–57%). Hematologic response in 1-year survivors was 100%, including 30% complete and 55% very good partial response. Autologous hematopoietic cell transplant was performed in 60%; among transplanted patients, day-100 transplant-related mortality was 0. Doxycycline use was safe and not attributed to any grade 2 or higher toxicity. Interpretation: In addition to a low 1-year mortality, doxycycline use was safe and associated with high transplant utilization rate. We thus contend that doxycycline should be studied in a placebo-controlled study in newly diagnosed AL patients in the first year, particularly among patients with advanced disease and cardiac involvement.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S258953702030105X; https://doaj.org/toc/2589-5370

URL الوصول: https://doaj.org/article/9a3a87a806894b258fd111a96184bfdd

المؤلفون: Jennifer M. Knight, Stephanie A. Kerswill, Parameswaran Hari, Steve W. Cole, Brent R. Logan, Anita D’Souza, Nirav N. Shah, Mary M. Horowitz, Melinda R. Stolley, Erica K. Sloan, Karen E. Giles, Erin S. Costanzo, Mehdi Hamadani, Saurabh Chhabra, Binod Dhakal, J. Douglas Rizzo

المصدر: BMC Cancer, Vol 18, Iss 1, Pp 1-12 (2018)

مصطلحات موضوعية: ß-blocker, Propranolol, Feasibility, Repurposed drugs, Multiple myeloma, Hematopoietic cell transplantation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Repurposing existing medications for antineoplastic purposes can provide a safe, cost-effective, and efficacious means to further augment available cancer care. Clinical and preclinical studies suggest a role for the ß-adrenergic antagonist (ß-blocker) propranolol in reducing rates of tumor progression in both solid and hematologic malignancies. In patients undergoing hematopoietic cell transplantation (HCT), the peri-transplant period is a time of increased activity of the ß-adrenergically-mediated stress response. Methods We conducted a proof-of-concept randomized controlled pilot study assessing the feasibility of propranolol administration to patients between ages 18–75 who received an autologous HCT for multiple myeloma. Feasibility was assessed by enrollment rate, tolerability, adherence, and retention. Results One hundred fifty-four patients underwent screening; 31 (20%) enrolled in other oncology trials that precluded dual trial enrollment and 9 (6%) declined to enroll in the current trial. Eighty-nine (58%) did not meet eligibility requirements and 25 (16%) were eligible; of the remaining eligible patients, all were successfully enrolled and randomized. The most common reasons for ineligibility were current ß-blocker use, age, logistics, and medical contraindications. 92% of treatment arm patients tolerated and remained on propranolol for the study duration; 1 patient discontinued due to hypotension. Adherence rate in assessable patients (n = 10) was 94%. Study retention was 100%. Conclusions Findings show that it is feasible to recruit and treat multiple myeloma patients with propranolol during HCT, with the greatest obstacle being other competing oncology trials. These data support further studies examining propranolol and other potentially repurposed drugs in oncology populations. Trial registration This randomized controlled trial was registered at clinicaltrials.gov with the identifier NCT02420223 on April 17, 2015.

وصف الملف: electronic resource

Relation: http://link.springer.com/article/10.1186/s12885-018-4509-0; https://doaj.org/toc/1471-2407

URL الوصول: https://doaj.org/article/83c55287993342728511687fa8453133

المؤلفون: Anita D'Souza, Kathryn Flynn, Saurabh Chhabra, Binod Dhakal, Mehdi Hamadani, Kirsten Jacobsen, Marcelo Pasquini, Dorothee Weihrauch, Parameswaran Hari

المصدر: Contemporary Clinical Trials Communications, Vol 8, Iss C, Pp 33-38 (2017)

مصطلحات موضوعية: Phase 2 clinical trial, Doxycycline, Amyloidosis, Light chain, Chemotherapy, Medicine (General), R5-920

الوصف: Light chain (AL) amyloidosis is a plasma cell neoplasm associated with insoluble fibril deposition from clonal immunoglobulin chains systemically. The disease is associated with high early mortality and morbidity owing to advanced organ deposition as well as lack of proven de-fibrillogenic therapies. Pre-clinical and retrospective clinical data suggests that doxycycline has benefit in AL amyloidosis. The ongoing DUAL study is a single center, open label, phase 2 study in which patients with AL amyloidosis who are undergoing clone-directed therapy for the underlying neoplasm with oral doxycycline given for 1 year to test the hypothesis that prolonged doxycycline use will be safe, feasible, and lead to reduced early mortality in systemic AL amyloidosis and hasten organ amyloid response. Clinical follow up visits will occur at monthly intervals for systemic AL patients and at 3 monthly intervals for localized AL patients. Blood tests will be collected during these time points for hematologic response assessment. Organ testing will be conducted at 3 monthly intervals and radiologic testing will be conducted at 6 monthly intervals. Research blood samples will be collected at baseline, 6 and 12 months. Other correlative studies include matrix metalloproteinases (MMP), tissue inhibitor of metalloproteinases (TIMP) testing and patient-reported outcomes.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2451865417301138; https://doaj.org/toc/2451-8654

URL الوصول: https://doaj.org/article/f70b58f5fd314c48b0ac28b232545e84

المؤلفون: Michael M. B. Green, Nelson Chao, Saurabh Chhabra, Kelly Corbet, Cristina Gasparetto, Ari Horwitz, Zhiguo Li, Jagadish Kummetha Venkata, Gwynn Long, Alice Mims, David Rizzieri, Stefanie Sarantopoulos, Robert Stuart, Anthony D. Sung, Keith M. Sullivan, Luciano Costa, Mitchell Horwitz, Yubin Kang

المصدر: Journal of Hematology & Oncology, Vol 9, Iss 1, Pp 1-10 (2016)

مصطلحات موضوعية: CXCR4, Antagonist, Stromal-derived factor-1, Hematopoietic stem cell transplantation, Hematopoietic stem cells, Outcomes, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation. Methods We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. Results Thirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls. Conclusions Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. Trial registration ClinicalTrials.gov NCT01280955

وصف الملف: electronic resource

Relation: http://link.springer.com/article/10.1186/s13045-016-0301-2; https://doaj.org/toc/1756-8722

URL الوصول: https://doaj.org/article/8c773201044c41c09ecb20b399fbcb3c