Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 19-20

Abstract: Introduction: Standard of care for patients (pts) with relapsed or refractory (RR) Hodgkin lymphoma (HL) is salvage therapy (tx) followed by autologous hematopoietic cell transplantation (HCT). However, most pts with high-risk RR HL will relapse after HCT. The AETHERA study demonstrated that post-HCT consolidation with brentuximab vedotin (BV) in high-risk HL pts improved progression-free survival (PFS) compared to placebo, particularly in pts with 2+ risk factors (Moskowitz, 2018). Pts with prior BV exposure were excluded from AETHERA, and BV is increasingly used prior to HCT in HL. PD1 blockade is effective in pts with RR HL and PD1 monotherapy as post-HCT consolidation in HL resulted in promising 18 mo PFS (Armand, 2019). Combined BV and nivolumab (Nivo) is a safe and effective salvage tx in HL, therefore we conducted a multicenter phase 2 study to evaluate the safety and efficacy of BV-Nivo post-HCT consolidation in high risk RR HL. Methods: After HCT, adult pts with high-risk HL defined as having ≥ 1 of the following modified AETHERA risk factors were eligible: primary refractory HL, relapse & lt; 1 year of completing initial tx, extranodal disease (dz) at relapse, B symptoms (sx) at relapse, requiring & gt; 1 salvage tx, not in CR at HCT. Prior BV or PD1 blockade were allowed if pts were not refractory. Pts underwent HCT according to institutional standards at the 5 centers. Starting between day 30-75 after HCT, pts received 1.8 mg/kg of BV and 3mg/kg nivo q21 days for a planned 8 cycles. If 1 drug was discontinued due to toxicity, the other could be continued. Investigators assessed response and progressive disease (PD) according to the 2014 Lugano classification. The primary endpoint was 18 mo PFS from study tx initiation. Secondary endpoints were overall survival (OS), safety, and the response rate in pts not in complete response (CR) at baseline. Results: 59 pts were enrolled and treated with at least one dose of study tx. Baseline characteristics are listed in Table 1. 18 (31%) pts were primary refractory, 35 (59%) had early relapse, 23 (39%) had extranodal dz and 14 (24%) had B sx at relapse, 15 (25%) received & gt; 1 salvage tx before HCT, and 48 (81%) were in CR at HCT. 21 (36%) had 1 modified AETHERA risk factor, 23 (40%) had 2 and 14 (24%) had 3+ risk factors. The median follow-up time from study tx initiation was 15.7 months (range, 2.8-35.5). Patients initiated BV-nivo a median 54 days from HCT (range, 34-75) and received a median of 8 cycles (range, 1-8). 29 (49%) pts completed all 8 cycles of BV and nivo and 45 (76%) patients completed 8 cycles of one drug. 14 (24%) pts discontinued both BV and nivo early, including 6 for adverse events (AE), 6 pt withdrawals, 1 pt lost to follow-up, and 1 pt death from PJP pneumonia unrelated to study tx. BV was discontinued in 8 (14%) pts - due to grade (gr) 3 peripheral neuropathy (PN) in 2 pts, gr 2 PN in 2 pts, carpal tunnel syndrome in 1 pt, gastrointestinal AEs in 2 pts, and infusion related reaction in 1 pt. Nivo was discontinued in 7 (12%) pts - due to pneumonitis in 2 pts, and colitis, elevated bilirubin, abnormal transaminases, pneumonia with elevated creatinine, and hypotension with fever in 1 pt each. BV was dose reduced to 1.2mg/kg in 11 (19%) pts, 9 pts for PN, and 1 each for neutropenia and arthralgia. The most common AEs related to BV-Nivo consolidation were PN (51%, 3% gr 3), neutropenia (42%, 31% gr 3-4), fatigue (37%), diarrhea (29%, 3% gr 3), nausea (25%, 2% gr 3), arthralgia (24%), AST elevation (24%, 2% gr 3). The most frequent gr 3-4 AEs were neutropenia (31%), pneumonitis (7%), and ALT elevation (5%). Immune-related (ir) AEs requiring systemic corticosteroids occurred in 18 (31%) patients. Most common Gr 2 or higher irAEs included: pneumonitis (12%), AST or ALT elevation (8%), hypothyroidism (5%), and rash (3%). 6 pts were not in CR at baseline after HCT (all PR). 5 pts converted to CR with study tx and 1 pt remained in PR without PD. There were only 2 PFS events, 1 pt with relapse at 15 months and PJP-related death after prophylaxis was self-discontinued. The estimated 18 mo PFS and OS in all patients were 95% and 98%, respectively. The estimated 18 mo PFS in pts with 2+ and 3+ risk factors were 92% and 89%, respectively. Conclusions: Post-HCT consolidation with BV-Nivo in pts with high-risk RR HL is a promising approach, with only 1 relapse observed in our cohort with short follow-up thus far. Post-HCT BV-Nivo was tolerable, though IrAEs were observed more frequently than in the pre-HCT setting and PN and neutropenia were common. Disclosures Herrera: Pharmacyclics: Research Funding; Karyopharm: Consultancy; AstraZeneca: Research Funding; Gilead Sciences: Consultancy, Research Funding; Immune Design: Research Funding; Seattle Genetics: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding. Nieto:Affimed: Consultancy, Other: Grant Support; Secura Bio: Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support. Holmberg:Sanofi: Research Funding; Seattle Genetics: Research Funding; Millenium-Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; UpToDate: Patents & Royalties: Royalties; Janssen: Research Funding; Merck: Research Funding. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Chen:Autolus Therapeutics: Current Employment. Rosen:Abbvie: Speakers Bureau; Seattle Genetics: Consultancy; NeoGenomics: Consultancy; Aileron Therapeutics: Consultancy; Novartis: Consultancy; Pebromene: Consultancy; Celgene: Speakers Bureau; paradigm Medical Communications: Speakers Bureau. Kwak:CJ Healthcare: Consultancy; Xeme Biopharma/Theratest: Other: equity; Sellas Life Sciences Grp: Consultancy; Enzychem Life Sciences: Membership on an entity's Board of Directors or advisory committees; Antigenics: Other: equity; InnoLifes, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pepromene Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Consultancy. Feldman:Portola: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Trillium: Research Funding; Janssen: Speakers Bureau; Viracta: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; AstraZeneca: Consultancy. OffLabel Disclosure: Nivolumab is not FDA-approved for use as consolidation after autologous stem cell transplantation

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-136384

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1407-1407

Abstract: Introduction: Diffuse large B-cell lymphomas (DLBCL) transformed from indolent B-cell non-Hodgkin lymphomas (B-NHL) or Richter transformation (RT) from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) are associated with a poor prognosis, particularly in patients (pts) with relapsed/refractory (RR) disease. PD-1/PD-L1 blockade has produced anti-tumor responses in pts with lymphoma; however, the response rate in pts with DLBCL is low. Preclinical data suggest that some "immunogenic" chemotherapies alter the tumor microenvironment and act synergistically with checkpoint blockade to improve anti-tumor responses. We evaluated the addition of the PD-L1 inhibitor, atezolizumab, to immunogenic chemoimmunotherapy, rituximab with gemcitabine and oxaliplatin (R-GEMOX) in pts with RR transformed DLBCL. Methods: Pts with DLBCL transformed from indolent B-NHL or RT from CLL that had received ≥ 1 prior regimen with ECOG performance status ≤ 2, and adequate organ and hematologic function were eligible for this phase 1 study. Two cohorts were enrolled, one for pts with DLBCL transformed from follicular lymphoma (FL) and another for pts with non-FL transformed DLBCL, including RT. R-GEMOX was administered without atezolizumab on C1D1, R-GEMOX+Atezo was given subsequently (Days 1+15 of 28 day cycles) for a maximum of 6 doses. Pts in CR could proceed to R+atezo q3w maintenance for up to 2 years. Pts could proceed to hematopoietic cell transplantation (HCT) without subsequent maintenance at the discretion of the treating MD. A safety lead-in (6 pts, any cohort) with dose-limiting toxicity (DLT) evaluation (28-day period, after 1 st dose of atezo) at dose level (DL) 1 (rituximab 375mg/m2, gemcitabine 1000mg/m2, oxaliplatin 100mg/m2, atezolizumab 840mg, with de-escalation dose level available) was enrolled to confirm the recommended phase 2 dose (RP2D). After confirmation of the RP2D, expansion will continue until enrollment of n=14 transformed FL and n=10 non-FL transformed DLBCL. Responses were assessed by investigators by PET-CT (after C2, C4, and then q12weeks) according to the 2014 Lugano Classification. The primary endpoint was safety and determination of the RP2D. Results: 23 pts were enrolled, 22 were evaluable for response and adverse events (AEs), 1 is too early. Baseline characteristics are summarized in Table 1. 1/6 pts had a DLT related to atezolizumab during safety lead-in: grade (G) 4 Stevens-Johnson syndrome leading to death. DL1 was the RP2D. 2 pts were replaced during safety lead-in due to progressive disease (PD) prior to completing DLT evaluation. The most common AEs with R-GEMOX+Atezo (n=22) were fatigue (50%), elevated transaminases (45%), thrombocytopenia (45%), nausea/vomiting (41%), diarrhea (32%), fever (32%), hypertension (HTN) (27%), and neutropenia (27%). Common G3-4 AEs included lymphopenia (n=4), neutropenia (n=4), HTN (n=3), leukopenia (n=3), thrombocytopenia (n=3). Among 7 pts who proceeded to maintenance R-atezo, the most common AEs were fatigue (n=4) and HTN (n=3). There were 2 deaths related to study therapy, the pt with SJS and 1 pt with infusion reaction leading to respiratory failure who also had PD with both factors likely contributing to death. In addition, 1 pt had both sepsis and PD and died during maintenance, considered possibly related to treatment. 7 deaths were unrelated to treatment, including 1 from complications after autologous HCT, and 6 after PD. 5 pts remain on treatment; 17 pts are off treatment. Reasons for study discontinuation include: insufficient response/PD (n=12), HCT (n=2), death due to toxicity (n=2), and G3 neuropathy during maintenance (n=1). Among the 22 pts, the ORR was 50% and CR rate was 29%. The 9 pts with transformed FL had an ORR of 67% and CR rate of 33%. The 13 pts with non-FL transformed DLBCL/RT had an ORR of 38% and CR rate of 23%. Of 9 pts with RT there was 1 CR and 1 PR while all 3 pts with transformed marginal zone lymphoma responded (2 CR, 1 PR). Among responders (n=11), the median duration of response was not reached (Figure 1). Of the 6 pts with CR, 2 proceeded to HCT, and 4 had ongoing CR lasting 30.7+ months (mo), 13.9+ mo, 6.8+ mo, 5.0+ mo. Of the 5 patients with PR, 1 pt died of SJS without PD, PR lasted 3 and 4 mo in 2 patients (PD), and 2 pts have ongoing response (0.5+ and 2.0+ mo). Conclusions: R-GemOx+Atezo was tolerable and produced objective responses in patients with transformed DLBCL/RT, with all pts in CR having ongoing response. Figure 1 Figure 1. Disclosures Herrera: Gilead Sciences: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Tubulis: Consultancy; Takeda: Consultancy; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm: Consultancy; Seagen: Consultancy, Research Funding. Allen: Epizyme: Consultancy; Kyowa Kirin: Consultancy; Secure Bio: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy. Popplewell: Hoffman La Roche: Other: Food; Novartis: Other: Travel; Pfizer: Other: Travel. Shouse: Beigene: Honoraria; Kite Pharma: Speakers Bureau. Siddiqi: AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncternal: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; TG Therapeutics: Research Funding. Danilov: Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Bayer Oncology: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Rigel Pharm: Honoraria. Tuscano: Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Takeda: Research Funding; Acrotech: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding. OffLabel Disclosure: Atezolizumab is not approved for the treatment of aggressive B-cell non-Hodgkin lymphoma

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-151188

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Haematologica, Ferrata Storti Foundation (Haematologica), ( 2023-07-20)

Abstract: Outcomes after programmed death-1 (PD-1) blockade in B-cell lymphomas are disappointing with few durable responses. Histone deacetylase inhibitors (HDACi) exhibit favorable immunomodulatory effects and demonstrate synergistic anti-tumor immune responses with anti-PD-1 therapy in pre-clinical models. We therefore developed a phase I study to evaluate the safety and preliminary efficacy of Pembrolizumab with Vorinostat in relapsed/refractory B-cell lymphomas. Patients were treated in a dose-escalation cohort using a Rolling 6 design followed by an expansion cohort at the recommended phase 2 dose (R2PD). Fifty-two patients were enrolled (32 Hodgkin and 20 non-Hodgkin lymphoma (NHL)). Here, we report safety data from the dose escalation cohort, and the toxicity and efficacy within NHL patients. Vorinostat was administered on twice daily on days 1-5 and 8-12 (dose-level (DL)1: 100mg; DL2: 200mg) and Pembrolizumab (200mg) was administered on day 1 of each 3-week cycle. Of 6 patients treated at DL1, 1 had a dose-limiting toxicity (DLT) (Stevens-Johnson syndrome (SJS)), and 1 of 6 had a DLT at DL2 (thromboembolism); therefore, DL2 was the RP2D. The patient developing SJS was treated with corticosteroids, infliximab, and cyclosporine but ultimately died of invasive fungal infection from the extensive immunosuppression used to treat the SJS. The most common adverse events were hypertension, diarrhea, and cytopenias. Of 20 NHL patients, 9 had follicular lymphoma (FL) and 11 had diffuse large B-cell lymphoma (DLBCL). Five DLBCL patients had primary mediastinal B-cell lymphoma (PMBL). The complete and overall response rates (CR and ORR) were 11%/22% for FL and 45%/55% for all DLBCL. Amongst DLBCLs, the CR and ORR was 80%/80% for PMBL and 17%/33% for non-PMBL. In conclusion, Pembrolizumab with Vorinostat was tolerable and produced responses in relapsed/refractory B-cell NHL, with particularly notable efficacy in PMBL.

Type of Medium: Online Resource

ISSN: 1592-8721 , 0390-6078

URL: Article

DOI: 10.3324/haematol.2023.283002

Language: Unknown

Publisher: Ferrata Storti Foundation (Haematologica)

Publication Date: 2023

detail.hit.zdb_id: 2186022-1

detail.hit.zdb_id: 2030158-3

detail.hit.zdb_id: 2805244-4

In: The Lancet Haematology, Elsevier BV, Vol. 10, No. 1 ( 2023-01), p. e14-e23

Type of Medium: Online Resource

ISSN: 2352-3026

URL: Article

DOI: 10.1016/S2352-3026(22)00318-0

Language: English

Publisher: Elsevier BV

Publication Date: 2023

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4023-4023

Abstract: Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of diseases associated with a poor outcome with anthracycline-based chemotherapy, even when intensified induction regimens and consolidative autologous stem cell transplantation (ASCT) are employed. CD30 expression is universal in anaplastic large cell lymphoma (ALCL) and variable CD30 expression has also been demonstrated in other PTCL subtypes. Brentuximab vedotin (BV) is a CD30-directed antibody drug conjugate that prolongs progression-free survival (PFS) and overall survival (OS) when combined with cyclophosphamide, doxorubicin, and prednisone (CHP) as compared to CHOP chemotherapy (Horowitz, 2019). Despite this major advance, there remains room for improvement as the 3y PFS was 57% in patients (pts) who received BV-CHP. Based on retrospective studies, CHOP plus etoposide (CHOEP) is commonly used as initial therapy for PTCL, and appears to benefit younger pts as compared to CHOP. In a phase 1 study, BV-CHP followed by BV monotherapy without consolidative ASCT led to excellent outcomes (Fanale, 2018). We performed a multicenter phase 2 trial to evaluate the safety and efficacy of adding etoposide to BV-CHP (CHEP-BV) followed by BV consolidation in pts with newly diagnosed CD30-expressing PTCL. Methods: Adult pts with newly diagnosed CD30-expressing (≥ 1% of tumor cells) PTCL were eligible, including pts with ALK+ ALCL with IPI score ≥ 2, ALK-negative ALCL, PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia or lymphoma, enteropathy-associated T-cell lymphoma, or hepatosplenic T-cell lymphoma. Pts could receive prephase steroids and/or 1 cycle of standard CHOP-equivalent chemotherapy (SOC) prior to study entry. 6 patients were treated at the expected phase 2 dose of CHEP-BV as part of a safety lead-in: 6 x 21-day cycles of BV 1.8mg/kg on d1, cyclophosphamide 750mg/m2 on d1, doxorubicin 50mg/m2 on d1, prednisone 100mg daily on d1-5, and etoposide 100mg/m2 on d1-3. G-CSF primary prophylaxis was mandatory. After the safety-lead in, a 2-stage design was employed and if 7/16 pts had a complete response (CR) after CHEP-BV, 28 pts total would be enrolled. Responding pts could receive consolidation with 1.8mg/kg BV every 21 days for up to 10 additional cycles either after ASCT or directly after CHEP-BV if no ASCT was performed at investigator discretion. The primary endpoints were safety and the CR rate by PET-CT after CHEP-BV assessed by investigators according to the 2014 Lugano classification. Secondary endpoints were PFS and OS. In this preliminary analysis, we report the overall response rate (ORR) and CR rate after 3 cycles and at completion of CHEP-BV. Results: 28 pts were enrolled and were evaluable for toxicity, 25 were evaluated for efficacy. We observed only 1/6 DLTs in cycle 1 (platelet 〈 10k) during the safety-lead-in and open enrollment proceeded. 12 pts had AITL, 11 had ALCL (1 ALK+, 10 ALK-), 4 had PTCL NOS, and 1 had T-follicular helper PTCL. Baseline characteristics are in shown in Table 1. 20 pts completed all cycles of CHEP-BV, 1 pt discontinued CHEP-BV early (MD discretion), and 7 remain on CHEP-BV. Of 20 pts who completed CHEP-BV, 1 pt had progressive disease (PD) at end of induction, 10 proceeded to ASCT and 9 did not. Of 19 consolidation-eligible pts, 1 pt discontinued prior to consolidation at MD discretion (DUSP22 rearrangement) and 18 pts are planned for or started BV consolidation. 1 pt reached EOT and 1 pt discontinued BV consolidation after 9 cycles due to pneumonia and grade (gr) 2 neuropathy. The most frequent CHEP-BV related adverse events (AE) include fatigue (75%), nausea (71%), anemia (46%), peripheral neuropathy (39%, all gr 1), thrombocytopenia (36%), neutropenia (32%), vomiting (29%), lymphopenia (25%), constipation (25%), and oral mucositis (25%). The most common gr 3-4 AEs were neutropenia (29%, 21% gr 4), anemia (21%, 7% gr 4), febrile neutropenia (21%, all gr 3), thrombocytopenia (14%, all gr 4). After 3 cycles of CHEP-BV the ORR was 100% with 58% CR (14 CR, 10 PR), and at completion of CHEP-BV the ORR was 95% with 90% CR (19 CR, 1 PR, 1 PD). Follow-up data are not yet mature, but only 2 patients have had PD to date. Conclusions: In pts with CD30-expressing PTCL, induction therapy with CHEP-BV is tolerable and associated with a high CR rate. Longer follow-up time is needed to assess the safety and efficacy of BV consolidation after CHEP-BV (+/- ASCT). Disclosures Herrera: Kite Pharma: Consultancy, Research Funding; Immune Design: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding. Zain:Seattle Genetics: Consultancy; Spectrum: Consultancy. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding; BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria. Feldman:AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Cell Medica: Research Funding; Trillium: Research Funding; Amgen: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Hakko Kirin: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Janssen: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Viracta: Research Funding; Roche: Research Funding; Corvus: Research Funding. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Popplewell:City of Hope: Employment. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Kwak:Pepromene Bio: Consultancy, Equity Ownership, Research Funding; InnoLifes: Consultancy, Equity Ownership; Xeme BioPharma, Inc: Consultancy, Equity Ownership; Enzychem LifeSciences: Consultancy; Celltrion Healthcare: Consultancy; Celltrion, Inc.: Consultancy. Iyer:Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Genentech/Roche: Research Funding; Bristol-Myers Squibb: Research Funding; Arog: Research Funding; Incyte: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123166

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 234-234

Abstract: Introduction: Despite a high response rate to PD1 blockade in patients (pts) with relapsed/refractory (RR) Hodgkin lymphoma (HL), the complete response (CR) rate is low and most patients will progress. Pts who are refractory to PD1 blockade have limited treatment options and poor outcomes. Histone deacetylase inhibitors (HDACi) have immunomodulatory effects, including enhancing antigen presentation, recruiting T-cells into tumors, and promoting T-cell function. Preclinical models in melanoma and lung cancer demonstrated enhanced anti-tumor activity when HDACi were combined with PD1 blockade. We conducted a phase I study evaluating the safety and efficacy of pembrolizumab plus vorinostat, an HDACi, in pts with RR HL, diffuse large B-cell lymphoma, and follicular lymphoma. Here, we report the results of pts with RR HL. Methods: Adult pts with RR HL who had failed at least 1 prior line of therapy and were transplant-ineligible were enrolled to receive IV pembrolizumab and oral vorinostat in 21-day cycles. Prior anti-PD1 exposure was allowed. Anti-PD1 refractory was defined as stable disease (SD) or progressive disease (PD) as best response or PD during anti-PD1 therapy after objective response. Pts were treated in a dose-escalation cohort with 2 dose levels (DL) using a Rolling 6 design and then onto an expansion cohort with treatment at the recommended phase 2 dose (RP2D). In DL1, vorinostat was administered orally at 100mg BID on days 1-5 and 8-12 and in DL2, vorinostat was administered at 200mg BID on days 1-5 and 8-12. Pembrolizumab dose was 200mg IV every 3 weeks in all DLs. Treatment could continue for a maximum of 2 years. The primary endpoint was safety and determination of the RP2D. Responses were assessed by investigators using PET-CT according to the 2014 Lugano Classification. Results: 32 HL pts were enrolled, including 2 at DL1 and 30 at DL2 (RP2D). At baseline, 69% were male, 72% were Caucasian, the median age was 35 years (range 18-79), and 75% had stage III-IV disease. The median number of prior therapies was 4 (range 2-12), 94% had prior brentuximab vedotin (BV), 66% were BV refractory, 78% had prior PD1 blockade and 56% were PD1 refractory. Baseline characteristics are shown in Table 1. The median number of cycles was 8.5 (range 1-36). The most common adverse events (AEs, any grade, Gr) were hypertension (72%), fatigue (63%), hyponatremia (63%), nausea (63%), diarrhea (47%), thrombocytopenia (44%), anemia (41%). The most common Gr 3+ AEs included hypertension (9%), neutropenia (6%), thrombocytopenia (6%), hypophosphatemia (6%), and lymphopenia (6%). Immune-related AEs included 4 pts with Gr 1-2 thyroiditis, 1 pt with Gr 1 rash, and 1 pt with Gr 3 esophagitis/duodenitis. 1 pt had vorinostat dose reduction for neutropenia. 20/32 pts discontinued treatment; treatment was discontinued for disease progression in 11 pts, stem cell transplant in 6 pts, patient preference in 2 pts, and completion of 2 years of therapy in 1 pt. Among 30 evaluable pts (2 too early), the best overall response rate (ORR) was 73% and the CR rate was 33% (Table 2). Among anti-PD1 naïve/sensitive pts (n=14), the ORR and CR rate were 93% and 64%. Among pts who were refractory to prior PD1 blockade (n=18), the ORR and CR rate were 56% and 6%. 10 evaluable anti-PD1 refractory pts had PD1 blockade as their most recent therapy (median 35 days between PD and study treatment start), and 6 (60%) had an objective response to pembro/vorinostat (all partial responses). The median follow-up time in 28 surviving pts was 18 months (mo, range 1-41). The median duration of response, progression-free survival (PFS), and overall survival (OS) in all RR HL patients were 14 mo, 14.9 mo, and not reached. The 1-year PFS and OS were 52% and 93%. Conclusions: Pembrolizumab and vorinostat was tolerable and produced a high ORR and CR rate in pts with anti-PD1 naïve/sensitive RR HL. A majority of pts with anti-PD1 refractory RR HL had objective responses, including pts who had progressed while receiving PD1 blockade as their most recent therapy. Figure 1 Figure 1. Disclosures Herrera: ADC Therapeutics: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Tubulis: Consultancy; Takeda: Consultancy; Genentech: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; Gilead Sciences: Research Funding; Karyopharm: Consultancy; Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding. Budde: Kite Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding. Nikolaenko: Rafael Pharmaceuticals: Research Funding; Pfizer: Research Funding. Chen: AstraZeneca: Current Employment; Autolus: Ended employment in the past 24 months. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Popplewell: Pfizer: Other: Travel; Hoffman La Roche: Other: Food; Novartis: Other: Travel. Kwak: Pepromene Bio, Inc.: Consultancy, Current equity holder in publicly-traded company. Mei: TG Therapeutics: Research Funding; Epizyme: Research Funding; EUSA: Honoraria; Janssen: Honoraria; Morphosys: Research Funding; BMS: Research Funding; Beigene: Research Funding. OffLabel Disclosure: Vorinostat is not FDA-approved for use in patients with Hodgkin lymphoma

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-150031

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 133-133

Abstract: Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphomas associated with poor outcomes following anthracycline-based chemotherapy, even when consolidative autologous stem cell transplantation (ASCT) is used. CD30 expression is universal in anaplastic large cell lymphoma (ALCL) and is frequently expressed in other PTCL subtypes. Brentuximab vedotin (BV) is a CD30-directed antibody drug conjugate that prolongs progression-free survival (PFS) and overall survival (OS) when combined with cyclophosphamide, doxorubicin, and prednisone (CHP) as compared to CHOP chemotherapy (Horwitz, 2020). Although a majority of pts treated with BV-CHP remained in durable remission (5y PFS 51%), there is room for improvement. Based on retrospective studies that demonstrated improved outcomes in younger pts, the addition of etoposide to CHOP (CHOEP) is commonly used as initial therapy for PTCL. We performed a multicenter phase 2 trial to evaluate the safety and efficacy of adding etoposide to BV-CHP (CHEP-BV) followed by BV consolidation in pts with newly diagnosed CD30-expressing PTCL. Methods: Adults with newly diagnosed CD30+ (≥ 1% of tumor cells by local pathology) PTCL were eligible, including pts with ALK+ ALCL and IPI score ≥ 2, ALK-negative ALCL, PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia/lymphoma (ATLL), among others. After accrual of 28 pts, the protocol was amended to allow enrollment of 20 additional pts with CD30+ non-ALCL PTCL (with ALCL allowed in Canada). Pts could receive prephase steroids and/or 1 cycle of CHOP-equivalent chemotherapy prior to study entry. 6 pts were treated in a safety lead-in cohort and all pts received CHEP-BV at the recommended phase 2 dose: 6 x 21-day cycles of CHP+BV (1.8mg/kg) on d1 and etoposide 100mg/m2 on d1-3. G-CSF prophylaxis was mandatory. Pts in response after CHEP-BV could receive BV consolidation (1.8mg/kg q3w) for up to 10 additional cycles (16 total BV cycles) either after ASCT or CHEP-BV if no ASCT was performed. The co-primary endpoints were safety and the CR rate (Deauville score 1-3) by PET-CT after CHEP-BV assessed by investigators according to the 2014 Lugano classification. Secondary endpoints were PFS and OS. Results: Accrual has completed and 48 pts were enrolled; all were evaluable for toxicity, 46 were evaluable for efficacy. 16 pts had ALCL (13 ALK+, 3 ALK-) and 32 had non-ALCL PTCL subtypes, including 18 with AITL, 11 with PTCL NOS, 2 with T-follicular helper PTCL, and 1 with ATLL. Baseline characteristics are shown in Table. 43 pts completed CHEP-BV, 2 had progressive disease (PD) prior to completion, 1 pt discontinued CHEP-BV early (MD discretion), 1 pt died due to COVID-19, and 1 remains on CHEP-BV. Of 43 pts who completed CHEP-BV, 24 proceeded to ASCT and 19 did not. 33 (74%) pts received BV consolidation (20 after ASCT, 13 directly after CHEP-BV) and completed a median 8 of the planned 10 cycles (range, 1-10). 13 pts completed all cycles of consolidation; 19 pts discontinued early - 12 due to adverse events (AE), 5 due to PD, and 2 due to patient/physician choice. The most frequent CHEP-BV related AEs (all grades, G) include fatigue (73%), peripheral sensory neuropathy (67%), anemia (62.5%), nausea (56%), neutropenia (50%), lymphopenia (44%), leukopenia (42%), thrombocytopenia (40%), elevated transaminases (33%). The most common G3+ AEs were neutropenia (37.5%), febrile neutropenia (23%), lymphopenia (21%), anemia (19%), thrombocytopenia (19%). There were 5 deaths, 4 due to PD and 1 due to COVID-19 infection during C3 of CHEP-BV. The interim (n=46) ORR and CR rates (after 3 CHEP-BV cycles, except 1 pt after 2) were 96% and 59% (27 CR, 17 PR), respectively. At completion of CHEP-BV (n=46), the ORR was 91% with 80% CR (37 CR, 5 PR, 4 PD). The ORR/CR rates in ALCL (n=16) vs non-ALCL (n=30) pts were 94%/94% vs 90%/73%, respectively. The ORR/CR rates in pts with CD30 expression 1-9% (n=15) vs 10+% (n=31) were 93%/67% and 90%/87%, respectively. The median follow-up in surviving pts is 16.1 months (range, 0.9-32.5). The overall 18mo PFS and OS were 61% and 89%; 18mo PFS by subgroup: ALCL 81%, non-ALCL 49%, CD30 1-9% 48%, CD30 10+% 67%. Landmark 1y PFS from end of CHEP-BV in responding pts (n=41) was 82% in pts who underwent ASCT vs 48% in pts who did not. Conclusions: In a cohort of pts with mostly non-ALCL CD30-expressing PTCL, CHEP-BV (+/- ASCT) followed by BV consolidation was tolerable and effective. Figure 1 Figure 1. Disclosures Herrera: Genentech: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; Gilead Sciences: Research Funding; Tubulis: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy, Research Funding. Zain: Secura Bio, DaichiSankyo, Abbvie: Research Funding; Kiyoaw Kirin, Secura Bio, Seattle Genetics: Honoraria; Secura Bio, Ono , Legend, Kiyowa Kirin, Myeloid Therapeutics Verastem Daichi Sankyo: Consultancy. Savage: Astra-Zeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Other: Institutional clinical trial funding; Roche: Research Funding; Servier: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brammer: Celgene: Research Funding; Kymera Therapeutics: Consultancy; Seattle Genetics: Speakers Bureau. Popplewell: Hoffman La Roche: Other: Food; Novartis: Other: Travel; Pfizer: Other: Travel. Budde: Kite Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding. Mei: Morphosys: Research Funding; Janssen: Honoraria; TG Therapeutics: Research Funding; EUSA: Honoraria; BMS: Research Funding; Epizyme: Research Funding; Beigene: Research Funding. Leslie: Merck: Consultancy; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Kwak: Pepromene Bio, Inc.: Consultancy, Current equity holder in publicly-traded company.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-151105

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 759-759

Abstract: Introduction: Up to 20-40% of patients (pts) with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL) and most treated pts with follicular lymphoma (FL) will have relapsed or refractory (RR) disease. Despite recent therapeutic advances, a minority of pts with transplant-ineligible RR HL or DLBCL, or RR FL will achieve durable remission with currently available treatments (tx). Effective novel therapies for pts with RR HL, DLBCL, or FL remain an unmet need. Although responses to PD1 blockade have been observed in pts with RR HL, DLBCL, and FL, there is room for improvement. Despite a high overall response rate (ORR) to anti-PD1 monotherapy in RR HL, the complete response (CR) is low and most patients with RR DLBCL or FL will not respond. Histone deacetylase inhibitors (HDACi) have immunomodulatory effects, including enhancing antigen presentation, recruiting T-cells into tumors, and promoting T-cell function. Preclinical models in melanoma and lung cancer demonstrated enhanced anti-tumor activity when HDACi were combined with PD1 blockade. We conducted a phase I study to determine the safety and efficacy of pembrolizumab plus vorinostat in RR DLBCL, FL, and HL. Methods: Adult pts with RR HL, DLBCL, or FL who had failed ≥ 1 prior line of tx and were transplant-ineligible were enrolled to receive IV pembrolizumab and oral vorinostat in 21-day cycles. Pts were treated in a dose-escalation cohort with 2 dose levels (DL) using a Rolling 6 design and then onto an expansion cohort with tx at the recommended phase 2 dose (RP2D). In DL1, vorinostat was administered at 100mg BID on days 1-5 and 8-12 and in DL2, vorinostat was administered at 200mg BID on days 1-5 and 8-12. Pembrolizumab dose was 200mg every 3 weeks in all DLs. Tx could continue for a maximum of 2 years. The primary endpoint was safety and determination of the RP2D. Responses were assessed using PET-CT (DLBCL, HL, FL) or CT (FL) by investigators according to the 2014 Lugano Classification. Results: 30 pts were enrolled, including 12 in the dose escalation and 18 in the expansion cohort. At baseline, 67% were male, 73% were Caucasian, the median age was 44 years (range 19-79), the median number of prior tx was 4 (range 1-7), 9 pts had DLBCL, 9 had FL, and 12 had HL. Among DLBCL pts, 4 had primary mediastinal large B-cell lymphoma (PMBL), 4 were non-GCB by Hans criteria, 3 had double-expressor lymphoma, and 3 had prior CAR T-cells. Among HL pts, 11 had prior BV, 7 had prior PD1 blockade, and 3 were refractory to prior PD1 blockade. Additional baseline characteristics are shown in Table 1. In 28 pts with tx data, the median number of cycles was 5 (range 1-16). Of 6 pts treated at DL1, 1 had a DLT (Grade 4 Stevens-Johnson syndrome, SJS) and 1 out of 6 pts had a DLT in DL2 (Grade 3 pulmonary embolism, PE); therefore, DL2 was chosen as the RP2D. In all pts, including the expansion cohort, the most common adverse events (AEs) were nausea (61%), fatigue (57%), hypertension (54%), anemia (50%), leukopenia (50%), hyponatremia (43%), diarrhea (43%), neutropenia (39%), and thrombocytopenia (39%). Grade (gr) 3-4 AEs included 2 pts with gr 3 neutropenia, 1 pt had Gr 4 SJS, and 1 pt each with gr 3 hypertension, anemia, thrombocytopenia, hyperkalemia, lymphopenia, or PE. Immune-related AEs included the Gr 3 SJS and 5 (18%) pts with thyroiditis. 2 patients had vorinostat dose reduction - 1 for neutropenia, 1 for GI toxicity. 12 pts remain on tx; tx was discontinued for toxicity in 3 pts (SJS, PE, elevated creatinine), stem cell transplant in 3 pts, patient preference in 2 pts, and insufficient response in 10 pts. Among 27 evaluable pts, the ORR was 59% and the CR rate was 30% (Table 2). The 9 pts with DLBCL had an ORR of 56% with a CR of 33%, including 2 CR, 1 PR, 1 PD in the 4 PMBL pts (1 had been refractory to CAR T-cells). The 9 pts with FL had an ORR of 22% and CR rate of 11%, and the 9 pts with HL had an ORR of 100% with a CR rate of 44% - both evaluable HL pts who were previously refractory to PD1 blockade responded (2 PR). The median follow-up time in all pts was 4 months (mo, range 1-11). The median duration of response, progression-free survival (PFS), and overall survival (OS) in all patients were 6 mo, 8 mo, and not reached. The overall 6 mo PFS and OS were 59% and 76%, including 67%/71% in DLBCL, 33%/40% in FL, and 80%/100% in HL. Conclusions: Pembrolizumab and vorinostat was tolerable and produced objective responses in pts with RR DLBCL, FL, and HL. A majority of DLBCL pts and all HL pts responded, including pts who had progressed on prior anti-PD1 tx. Disclosures Herrera: AstraZeneca: Research Funding; Kite Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding. Popplewell:City of Hope: Employment. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Mei:Seattle Genetics, Inc.: Research Funding. Chen:Autolus Therapeutics: Employment. Kwak:Pepromene Bio: Consultancy, Equity Ownership, Research Funding; InnoLifes: Consultancy, Equity Ownership; Xeme BioPharma, Inc: Consultancy, Equity Ownership; Enzychem LifeSciences: Consultancy; Celltrion Healthcare: Consultancy; Celltrion, Inc.: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123163

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Journal, American Society of Hematology, ( 2023-06-20)

Abstract: Introduction: This was a phase 1 dose escalation study (clinicaltrials.gov: NCT03150329) evaluating the addition of vorinostat to pembrolizumab in patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma, and follicular lymphoma. Here, we report the results in cHL. Methods: Adult patients with RR cHL who had received 1+ prior lines of therapy and were transplant ineligible received pembrolizumab and vorinostat in 21-day cycles. Prior anti-PD1 exposure was allowed. Patients were treated in a dose-escalation cohort with 2 dose levels (DL) using a Rolling 6 design and then on an expansion cohort at the recommended phase 2 dose (RP2D). Vorinostat 100mg BID (DL1) and 200 mg BID (DL2) were administered orally on days 1-5 and 8-12; all patients received pembrolizumab 200mg IV every 3 weeks. The primary endpoint was safety and determination of the RP2D. Responses were assessed by investigators using according to the 2014 Lugano Classification. Results: 32 cHL patients were enrolled, including 2 at DL1 and 30 at DL2 (RP2D). 78% had prior PD1 blockade and 56% were PD1-refractory. Gr 3+ AEs included hypertension (9%), neutropenia (9%), hypophosphatemia (9%), thrombocytopenia (6%), and lymphopenia (6%). Immune-related AEs included Gr 1-2 thyroiditis (13%), Gr 1 rash (6%) and Gr 3 esophagitis/duodenitis (3%). ORR was 72% and CR rate was 34%. Patients refractory to prior PD1 blockade (n=18) had ORR and CR rates of 56% and 11%, respectively. Conclusion: Pembrolizumab and vorinostat was well-tolerated with a high ORR rate in RR cHL including in anti-PD1-refractory disease.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2023020485

Language: English

Publisher: American Society of Hematology

Publication Date: 2023

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 774-776

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-167626

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7