bims-hemali 2024-12-22 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2024–12–22
sixteen papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Efficacy and Safety of Ibrutinib in Central Nervous System Lymphoma: A Systematic Review and Meta-Analysis.
Philadelphia Chromosome as a Clinically Favorable Prognostic Factor of B-cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma in Transplant-Ineligible Elderly Patients in the Era of Molecular-Targeted Therapy.
Lisocabtagene Maraleucel for Relapsed/Refractory Large B-Cell Lymphoma: A Cell Therapy Consortium Real-World Analysis.
The Synchronous Diagnosis of Multiple Myeloma (MM) and Chronic Myeloid Leukemia (CML).
Serum free light chain level-based and non-fixed cycle daratumumab treatment strategy for patients with light chain amyloidosis.
Olutasidenib demonstrates significant clinical activity in mutated IDH1 acute myeloid leukaemia arising from a prior myeloproliferative neoplasm.
Asciminib add-on to imatinib demonstrates sustained high rates of ongoing therapy and deep molecular responses with prolonged follow-up in the ASC4MORE study.
Retrospective Study of CD20 Expression Loss in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma.
Outpatient subcutaneous alemtuzumab is feasible and safe for aplastic anemia and associated with high response rates.
Treatment of Vietnamese patients diagnosed with myelodysplastic neoplasms: Practical experience in a developing country.
Safety and efficacy of amulirafusp alfa (IMM0306), a fusion protein of CD20 monoclonal antibody with the CD47 binding domain of SIRPα, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: a phase 1/2 study.
Expression profile of Bcl-2 family proteins in newly diagnosed multiple myeloma patients.
Comprehensive Review of Bispecific Antibody Constructs In Multiple Myeloma: Affinities, Dosing Strategies and Future Perspectives.
Lymphomas of the Parotid Gland in Denmark: A Nationwide Cohort Study.
De-escalated Induction Therapy and Thiotepa/Busulfan-based Autologous Stem Cell Transplantation for Primary Central Nervous System Lymphoma.
A GIMEMA survey on therapeutic use and response rates of FLT3 inhibitors in acute myeloid leukemia: Insights from Italian real-world practice.

Crit Rev Oncol Hematol. 2024 Dec 15. pii: S1040-8428(24)00340-8. [Epub ahead of print] 104597

Efficacy and Safety of Ibrutinib in Central Nervous System Lymphoma: A Systematic Review and Meta-Analysis.

Jaber H Jaradat, Ibraheem M Alkhawaldeh, Yousef Al-Bojoq, Monther N Ramadan, Mohammad T Abuawwad, Yasmeen Jamal Alabdallat, Abdulqadir J Nashwan.

   BACKGROUND: Primary central nervous system lymphoma (CNSL) is a rare, aggressive non-Hodgkin lymphoma confined to the CNS. Although radiation and chemotherapy, particularly high-dose methotrexate (HD-MTX), are effective treatments, the relapse rates remain high, prompting the exploration of novel therapeutic options. Ibrutinib, an irreversible Bruton tyrosine kinase (BTK) inhibitor, has shown promise in various B-cell malignancies, including CNSL.
OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the safety and efficacy of ibrutinib in the treatment of CNSL, focusing on overall response (OR), complete response (CR), partial response (PR), progression-free survival (PFS), overall survival (OS), and adverse events.
METHODS: A comprehensive search of the PubMed, Google Scholar, and Scopus databases was conducted. The included studies were prospective and retrospective studies focusing on ibrutinib as monotherapy or in combination with CNSL. Data extraction and quality assessment were independently performed by two reviewers, and statistical analyses were conducted using R version 4.4.0.
RESULTS: Fourteen studies (eight cohort studies and six clinical trials) involving 784 patients were included. The median age was 61 years, with nearly equal sex distribution. The meta-analysis for CNSL, the partial response rate was 29.52%, complete response rate was 49.19%, and overall response rate was 72.11%. For PCNSL, the partial response rate was 20.85%, complete response rate was 48.13%, and overall response rate was 66.92%. For SCNSL, the partial response rate was 29.42%, complete response rate was 44.64%, and overall response rate was 66.82%. Significant heterogeneity was observed in some comparisons. There were no significant differences in the efficacy of ibrutinib between CNSL subtypes.
CONCLUSIONS: Ibrutinib shows promising efficacy in improving partial and complete response rates in CNSL. The substantial heterogeneity observed underscores the need for further well-designed studies to confirm these findings and explore the optimal use of ibrutinib in CNSL treatment protocols. Future trials should consider comparing ibrutinib to standard therapies and investigate its long-term efficacy and safety profile.

Keywords:  BTK; Bruton tyrosine kinase inhibitor; CNSL; Central nervous system lymphoma; Ibrutinib; lymphoma

DOI:  https://doi.org/10.1016/j.critrevonc.2024.104597
Cureus. 2024 Nov;16(11): e73988

Philadelphia Chromosome as a Clinically Favorable Prognostic Factor of B-cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma in Transplant-Ineligible Elderly Patients in the Era of Molecular-Targeted Therapy.

Masuho Saburi, Takumi Nishikawa, Kuniaki Maehara, Keiichi Uraisami, Hiroyuki Takata, Yasuhiko Miyazaki, Kumiko Narahara, Hitohiro Sasaki, Miyuki Abe, Kazuhiro Kohno, Toshiyuki Nakayama, Eiichi Ohtsuka.

  Background and objective There is scarce data on the treatment outcomes of B-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (B-ALL/LBL) in elderly patients in the era of tyrosine kinase inhibitors (TKIs), blinatumomab, and inotuzumab ozogamicin. In light of this, we aimed to address this gap in data by conducting this retrospective study. Methods Treatment outcomes were retrospectively evaluated by using data from transplant-ineligible patients aged 65 years or older with newly diagnosed B-ALL/LBL (n=29) at two hospitals in Oita, Japan between 2013 and 2023. Results The median age of the cohort was 72 (65-88) years, and 10 patients were male; 17 patients had Philadelphia chromosome (Ph)-positive ALL, and the others had Ph-negative ALL. Dasatinib combined with prednisolone was the most common induction therapy for Ph-positive ALL (88.2%). Complete response (CR) was achieved in 93.1%, and the CR rate did not differ significantly between Ph-positive ALL (100%) and Ph-negative ALL (83.3%) (p=0.16). The median observation period was 1.52 (range: 0.03-8.98) years. Overall survival (OS) and event-free survival (EFS) were significantly longer in Ph-positive ALL patients than in Ph-negative ALL patients on univariate analysis (OS: p=0.011, EFS: p=0.041). Multivariate analyses showed that the presence of Ph was signiﬁcantly and independently associated with longer OS [hazard ratio (HR): 0.29, 95% confidence interval (CI): 0.10-0.87, p=0.027] and EFS (HR: 0.34, 95% CI: 0.12-0.91, p=0.03). There was no difference in relapse-free survival (RFS); 13 patients (76.5%) with Ph-positive ALL were treated with ponatinib (salvage therapy, n=7; consolidation or maintenance therapy in CR, n=6). Six of seven patients (85.7%) with ponatinib salvage therapy achieved CR, and all six patients treated with ponatinib consolidation or maintenance therapy retained CR at the last follow-up. Six patients (Ph-positive ALL: n=4; Ph-negative ALL: n=2) were treated with blinatumomab, including salvage therapy for primary refractory or relapse (n=3), and consolidation therapy due to intolerance to conventional chemotherapies (n=3). Two of three patients with blinatumomab salvage therapy achieved CR, and all three patients with blinatumomab consolidation therapy maintained CR in follow-up. Two patients (Ph-positive ALL: n=1; Ph-negative ALL: n=1) were treated with inotuzumab ozogamicin for relapsed or refractory ALL. A patient with Ph-positive ALL for the third relapse achieved CR, which was sustained for three years. The other patient with Ph-negative ALL for primary refractory achieved CR but relapsed after the fourth course of inotuzumab ozogamicin. Conclusions Elderly patients with Ph-positive ALL showed significantly longer OS and EFS than those with Ph-negative ALL in the era of molecular-targeted therapy.

Keywords:  b-cell all (acute lymphoblastic leukemia); blinatumomab; inotuzumab ozogamicin; philadelphia chromosome negative; philadelphia chromosome positive; tyrosine kinase inhibitor (tki)

DOI:  https://doi.org/10.7759/cureus.73988
Blood Adv. 2024 Dec 10. pii: bloodadvances.2024014164. [Epub ahead of print]

Lisocabtagene Maraleucel for Relapsed/Refractory Large B-Cell Lymphoma: A Cell Therapy Consortium Real-World Analysis.

Peter A Riedell, Connor B Grady, Loretta J Nastoupil, Alejandro Luna De Abia, Nausheen Ahmed, Richard T Maziarz, Marie Hu, Jamie Brower, Wei-Ting Hwang, Stephen J Schuster, Andy I Chen, Olalekan O Oluwole, Veronika Bachanova, Joseph P McGuirk, Miguel-Angel Perales, Michael R Bishop, David L Porter.

Lisocabtagene maraleucel (liso-cel) is an autologous CD19-directed CAR T cell therapy approved for the treatment of relapsed/refractory large B-cell lymphoma (LBCL). We present a multicenter retrospective study evaluating safety, efficacy, and resource utilization of liso-cel in the standard-of-care setting. Patients received commercial liso-cel at 7 US medical centers and patient selection, toxicity management, and disease assessment followed institutional practices. Among 101 infused patients, the median age was 71 years (35% ≥75 years), 68% had a Charlson Comorbidity score ≥3, and 10% had secondary CNS involvement. Median number of prior therapies was 3, and due to comorbidities, 33% would have been ineligible for the TRANSCEND study. Bridging therapy was used in 60% (43% received polatuzumab-based treatment). Any Grade CRS occurred in 49% (3% Grade ≥3) with any Grade ICANS in 26% (10% Grade ≥3). The overall response rate (ORR) to bridging therapy was 45% with 18% achieving a complete response (CR). Following liso-cel infusion, the day 90 ORR was 66% (60% CR), and with a median follow-up of 15.5 months, 12-month progression-free survival (PFS) and overall survival were 55% and 68%, respectively. A normal lactate dehydrogenase pre-lymphodepletion was associated with improved PFS and OS. These analyses confirm similar efficacy and safety of commercial liso-cel compared to pivotal trial results. Notably, these outcomes were achieved in patients predominantly of advanced age and with significant comorbidities. Results also likely reflect advancements in patient selection, toxicity management, and the use of novel bridging strategies.

DOI: https://doi.org/10.1182/bloodadvances.2024014164
Cureus. 2024 Nov;16(11): e73583

The Synchronous Diagnosis of Multiple Myeloma (MM) and Chronic Myeloid Leukemia (CML).

Shinoj Pattali, Shimin Hu, Qaiser Bashir, Richard E Champlin, Muzaffar H Qazilbash.

  The synchronous presentation of chronic myeloid leukemia (CML) and multiple myeloma (MM) is extremely rare. CML is a myeloproliferative neoplasm originating from an abnormal pluripotent hematopoietic stem cell. It is associated with the BCR-ABL fusion gene located on the Philadelphia chromosome. In contrast, multiple myeloma is a multifocal, bone marrow-based plasma cell neoplasm associated with the production of M-protein in the serum and/or urine. We present a case with a synchronous diagnosis of chronic myeloid leukemia and multiple myeloma. Both cancers were aggressively treated. The patient received autologous stem cell transplantation (ASCT) for multiple myeloma and tyrosine kinase inhibitor for chronic myeloid leukemia concurrently to achieve the complete response.

Keywords:  autologous hematopoietic stem cell transplantation; chronic myeloid leukemia (cml); molecularly targeted therapy; synchronous multiple myeloma; treatment choices

DOI:  https://doi.org/10.7759/cureus.73583
Ann Med. 2025 Dec;57(1): 2442075

Serum free light chain level-based and non-fixed cycle daratumumab treatment strategy for patients with light chain amyloidosis.

Zhen Li, Jinzhou Guo, Wencui Chen, Liang Zhao, Guisheng Ren, Xianghua Huang.

   BACKGROUND: In recent years, daratumumab (DARA) has gained widespread use in the treatment of systemic light chain (AL) amyloidosis. In this study, we assessed the efficacy and safety of a DARA treatment strategy based on serum free light chain (sFLC) levels and non-fixed cycles.
METHODS: The study included 123 patients with Al amyloidosis who received DARA at our center between July 2020 and September 2023. All patients received the standard DARA treatment (16 mg/kg weekly for four weeks) during the first course. Subsequent treatments were adjusted based on sFLC levels and the physician's judgment.
RESULTS: The results demonstrated an impressive overall hematologic response rate (ORR) of 94.3%, with a hematologic very good partial response (VGPR) and complete response (CR) rate of 84.5%. Median time to best hematologic response was 1 months. Cardiac and renal response rates were 39.3% and 60.3%, respectively. Thirty patients experienced grade 1/2 infusion-related reactions after the first infusion. The rate of grade 3/4 adverse events was 21%. The most common adverse events of grade 3 or 4 were pulmonary infection (6.5%), neutropenia and lymphocytopenia (5.7%), elevated transaminases (1.6%), acute kidney injury (1.6%). After a median follow-up of 13 months (range 1-38), The 1-year OS and PFS estimates were 96.5% and 84.4%, respectively.
CONCLUSION: These findings indicate that the sFLC levels based and non-fixed cycle DARA strategy is an efficacious and safe treatment strategy in both newly diagnosed and relapsed/refractory AL amyloidosis.

Keywords:  AL amyloidosis; daratumumab; non-fixed cycle therapy

DOI:  https://doi.org/10.1080/07853890.2024.2442075
Br J Haematol. 2024 Dec 19.

Olutasidenib demonstrates significant clinical activity in mutated IDH1 acute myeloid leukaemia arising from a prior myeloproliferative neoplasm.

Stéphane De Botton, Christian Récher, Jorge Cortes, Antonio Curti, Pierre Fenaux, Pierre Peterlin, Arnaud Pigneux, Karen Yee, Andrew Wei, Alice Mims, Gary Schiller, Mwe Mwe Chao, Hua Tian, Justin M Watts.

  Acute myeloid leukaemia (AML) arising from a myeloproliferative neoplasm (MPN) is more aggressive and less responsive to therapies compared to de novo AML. Olutasidenib, an oral small-molecule inhibitor of mutated IDH1 (mIDH1), showed encouraging and durable responses in a phase 1/2 study of adults with post-MPN mIDH1 AML. Patients received olutasidenib 150 mg BID monotherapy or in combination with azacitidine. Primary end-points: safety and best response defined as complete remission (CR), CR with partial haematological recovery or morphological leukaemia-free state (MLFS). Analysis included 15 patients with post-MPN mIDH1 AML; 10 had relapsed or refractory AML and five had newly diagnosed AML. Six were treated with olutasidenib monotherapy and nine in combination with azacitidine. Treatment emergent adverse events occurred in 15 patients, three of whom discontinued therapy. CR: 40% (n = 6/15); median duration of response: 15.6 months (range: 1.7-44.3); CR with incomplete haematological recovery: 13% (n = 2/15); MLFS: 7% (n = 1/15); composite complete remission (CRc): 53% (n = 8/15); and overall response rate (ORR): 60% (9/18). Median duration of CRc and ORR: 13.15 (range: 2.4-48.7) and 14.3 months (range: 2.4-48.7), respectively, and median overall survival: 13.8 months (95% confidence interval: 3.70-23.7). Olutasidenib demonstrated encouraging response rates with a manageable safety profile for patients with post-MPN mIDH1 AML.

Keywords:  IDH1 mutation; acute myeloid leukaemia; blast‐phase myeloproliferative neoplasm; myeloproliferative neoplasms

DOI:  https://doi.org/10.1111/bjh.19944
J Hematol Oncol. 2024 Dec 18. 17(1): 125

Asciminib add-on to imatinib demonstrates sustained high rates of ongoing therapy and deep molecular responses with prolonged follow-up in the ASC4MORE study.

Timothy P Hughes, Giuseppe Saglio, Jan Geissler, Dong-Wook Kim, Elza Lomaia, Jiri Mayer, Anna Turkina, Shruti Kapoor, Ana Paula Cardoso, Becki Nieman, Sara Quenet, Jorge E Cortes.

   BACKGROUND: Up to 65% of patients with chronic myeloid leukemia (CML) who are treated with imatinib do not achieve sustained deep molecular response, which is required to attempt treatment-free remission. Asciminib is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket. This unique mechanism of action allows asciminib to be combined with adenosine triphosphate-competitive tyrosine kinase inhibitors to prevent resistance and enhance efficacy. The phase II ASC4MORE trial investigated the strategy of adding asciminib to imatinib in patients who have not achieved deep molecular response with imatinib.
METHODS: In ASC4MORE, 84 patients with CML in chronic phase not achieving deep molecular response after ≥ 1 year of imatinib therapy were randomized to asciminib 40 or 60 mg once daily (QD) add-on to imatinib 400 mg QD, continued imatinib 400 mg QD, or switch to nilotinib 300 mg twice daily.
RESULTS: More patients in the asciminib 40- and 60-mg QD add-on arms (19.0% and 28.6%, respectively) achieved MR4.5 (BCR::ABL1 ≤ 0.0032% on the International Scale) at week 48 (primary endpoint) than patients in the continued imatinib (0.0%) and switch to nilotinib (4.8%) arms. Fewer patients discontinued asciminib 40- and 60-mg QD add-on treatment (14.3% and 23.8%, respectively) than imatinib (76.2%, including crossover patients) and nilotinib (47.6%). Asciminib add-on was tolerable, with rates of AEs and AEs leading to discontinuation less than those with nilotinib, although higher than those with continued imatinib (as expected in these patients who had already been tolerating imatinib for ≥ 1 year). No new or worsening safety signals were observed with asciminib add-on vs the known asciminib monotherapy safety profile.
CONCLUSIONS: Overall, these results support asciminib add-on as a treatment strategy to help patients with CML in chronic phase stay on therapy to safely achieve rapid and deep response, although further investigation is needed before this strategy is incorporated into clinical practice.
TRIAL REGISTRATION: NCT03578367.

Keywords:  ASC4MORE; Add-on; Asciminib; CML; Combination; Deep molecular response; Imatinib; Tyrosine kinase inhibitors

DOI:  https://doi.org/10.1186/s13045-024-01642-6
J Hematol. 2024 Dec;13(6): 268-277

Retrospective Study of CD20 Expression Loss in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma.

Joseph P Marshalek, Xin Qing, Marcin Dragan, Sarah Tomassetti.

   Background: CD20-targeted therapies are widely used in the management of B-cell lymphomas. Re-treatment with CD20-directed agents is common; however, previous research has demonstrated loss of CD20 expression at relapse in a subset of patients.
Methods: In this single-center retrospective cohort of 243 patients, CD20 analysis was performed by immunohistochemistry (IHC) and/or flow cytometry at diagnosis and at relapse if a biopsy was performed.
Results: Of 109 patients with relapsed or refractory B-cell lymphoma, 59 patients with CD20-positive lymphoma at diagnosis underwent a biopsy at relapse for a total of 76 biopsies across all relapses. The rate of partial or complete CD20 expression loss was 11.9% (four patients with partial loss, three patients with complete loss). There were four cases of CD20 loss at first relapse (three IHC, one flow cytometry), two at second relapse (one IHC, one IHC and flow cytometry), and one at fifth relapse (IHC and flow cytometry). CD20 antigen escape was observed in marginal zone lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma (DLBCL). All patients with CD20 expression loss previously received rituximab. Among patients with CD20 antigen escape, 85.7% had stage IV disease, and median overall survival after CD20 loss was 4 months. In the group of five patients with indolent lymphoma and CD20 expression loss, three patients (60%) had concurrent transformation to high-grade lymphoma.
Conclusions: This study, which reinforces the importance of repeating a biopsy at relapse before implementing CD20-directed therapy, is particularly relevant given the widespread use of rituximab along with the emerging significance of CD20-targeted bispecific antibodies in the management of B-cell lymphomas.

Keywords:  Antigen escape; CD20; Lymphoma; Rituximab

DOI:  https://doi.org/10.14740/jh1341
Blood Adv. 2024 Dec 18. pii: bloodadvances.2024014159. [Epub ahead of print]

Outpatient subcutaneous alemtuzumab is feasible and safe for aplastic anemia and associated with high response rates.

Ana Rita Bm da Fonseca, Caio Cesar Justino, Vinicius Campos de Molla, Patricia Eiko Yamakawa, Iara Baldim Rabelo, Louise M Arnold, Richard J Kelly, Morag Griffin, Talha Munir, Anita Hill, Elvira D R P Velloso, Thales Dalessandro, Antonio Maria Risitano, Phillip Scheinberg, Austin G Kulasekararaj, Celso Arrais-Rodrigues.

Immunosuppressive therapy (IST) using horse antithymocyte globulin (h-ATG) combined with cyclosporine (CsA) and eltrombopag is the standard care for aplastic anemia (AA) in patients without a suitable matched donor. However, in many countries, h-ATG use has been discontinued, leaving rabbit ATG (r-ATG), which has a lower response rates and poorer survival, as the only alternative. In previous studies, alemtuzumab (ALZ), a humanized monoclonal antibody targeting CD52, combined with CsA resulted in an adequate ORR in AA patients. This study describes a multicenter, international retrospective analysis of ALZ for treating AA. We analyzed a series of patients who received subcutaneous ALZ for AA in four centers in Brazil and the United Kingdom from March 2009 to January 2024. We analyzed 64 ALZ treatments in 61 AA adult patients, 76% with SAA or very severe aplastic anemia (VSAA). Overall response rate (ORR) was 59.4% at 12 months (complete: 21.9%, partial: 37.5%). Cumulative incidence (CI) of response was 54.7% at 6 months, and 59.4% at 12 months. Younger patients (under 65) had higher CI of response (67% vs. 31%, P=0.03), as well as patients treated with a total dose of 103 mg (70% vs. 38%, P=0.02). Overall survival (OS) was 86% at 1 year, 78% at 2 years, and 70% at 4 years, significantly higher in responders (90% vs. 44%, P<0.0001). Adverse events were of low grade, and infectious events were infrequent. Subcutaneous ALZ is a feasible, effective, and safe alternative to r-ATG for AA patients requiring immunosuppressive treatment where h-ATG access is limited.

DOI: https://doi.org/10.1182/bloodadvances.2024014159
Leuk Res Rep. 2025 ;23 100490

Treatment of Vietnamese patients diagnosed with myelodysplastic neoplasms: Practical experience in a developing country.

Quang Hao Nguyen, Minh Phuong Vu, Ha Trang Kieu, Duc Binh Vu, Ha Thanh Nguyen, Quoc Khanh Bach.

   Background: Treatment of patients diagnosed with myelodysplastic neoplasms (MDS) is difficult and the outcome is still limited, especially in developing countries. We conducted this study in order to share some experience in treating patients diagnosed with MDS in developing countries.
Methods: This was a retrospective study that included 32 patients with newly MDS. 13 lower-risk patients, including 2 patients with MDS 5q- were treated with erythropoiesis stimulating agent (ESA). 19 patients with higher risk were treated with hypomethylating agent (HMA), which was decitabine.
Results: In the ESA treatment group, the rate of hematologic improvement-erythroid was 69.2 %, the rate of total hematologic improvement (with 3 lineages improvement) was 61.5 %. In the HMA treatment group, the overall response rate was 52.6 %. The follow-up times were 42 months. The overall survival (OS), leukemic transformation-free survival (LFS), and progression-free survival (PFS) of the ESA treatment group were 30.44, 28.91, and 28.29 months; respectively. The OS, LFS, and PFS of the HMA treatment group were 34.27, 31.45, and 26.83 months; respectively.
Conclusions: Patients with lower risk MDS, including MDS 5q-, may benefit from treatment with erythropoiesis stimulating agent (ESA). Patients with higher risk MDS may have a favorable outcome with decitabine (HMA) treatment.

Keywords:  Decitabine; Erythropoiesis stimulating agent; Hypomethylating agent; MDS; Myelodysplastic neoplasms

DOI:  https://doi.org/10.1016/j.lrr.2024.100490
J Hematol Oncol. 2024 Dec 18. 17(1): 123

Safety and efficacy of amulirafusp alfa (IMM0306), a fusion protein of CD20 monoclonal antibody with the CD47 binding domain of SIRPα, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: a phase 1/2 study.

Jianliang Yang, Yongping Song, Keshu Zhou, Zhiming Li, Mingzhi Zhang, Hongmei Jing, Zhen Wang, Li Yu, Wei Meng, Qiying Lu, Wenzhi Tian, Yuankai Shi.

BACKGROUND: Amulirafusp alfa (IMM0306) is a fusion protein of CD47 binding domain of signal-regulatory protein alpha (SIRPα) with CD20 monoclonal antibody on both heavy chains. This study aimed to evaluate the safety and preliminary efficacy of amulirafusp alfa in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL).
METHODS: We enrolled patients with CD20 + r/r B-NHL who had previously received at least two lines of therapy to receive a single-dose of amulirafusp alfa in the first 2 weeks, followed by a multiple-dose period, in which the patients received the same intravenous dose every week in 4-week cycles. The primary endpoints were to evaluate the safety, determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of amulirafusp alfa.
RESULTS: Between May 22, 2020 and February 10, 2022, 48 patients with r/r B-NHL were enrolled and received amulirafusp alfa at the doses of 40-2000 μg/kg. As of the data cut-off date of April 18, 2024, no dose-limiting toxicity was observed, and the MTD was not reached. The dose of 2000 μg/kg was identified as the RP2D. All grades and ≥ grade 3 treatment-related adverse events (TRAEs) occurred in 48 (100%) and 33 (68.8%) patients, respectively. The most common ≥ grade 3 TRAEs were lymphocyte count decreased (28/48, 58.3%), white blood cell count decreased (10/48, 20.8%), absolute neutrophil count decreased (9/48, 18.8%) and anemia (5/48, 10.4%). At the doses of 800-2000 μg/kg, objective response rate in follicular lymphoma and marginal zone lymphoma was 41.2% (7/17, 95% confidence interval [CI] 18.4-67.1) and 33.3% (2/6, 95% CI 3.7-71.0), respectively.
CONCLUSION: Amulirafusp alfa showed favorable safety profile and preliminary efficacy in patients with r/r B-NHL, meriting further investigation. Trial registration NCT05805943.

DOI: https://doi.org/10.1186/s13045-024-01646-2
Hemasphere. 2024 Dec;8(12): e70036

Expression profile of Bcl-2 family proteins in newly diagnosed multiple myeloma patients.

GEM/PETHEMA cooperative study group

Antiapoptotic Bcl-2 family proteins are involved in myeloma cell survival. To date, their expression in multiple myeloma (MM) patients has mostly been analyzed at the RNA level. In the present study, we quantified for the first time the protein expression of the Bcl2-family members using a capillary electrophoresis immunoassay in 120 newly diagnosed MM patients, aged ≤65 years, treated in the context of the PETHEMA/GEM2012 study. We found that the pattern of expression of Bcl-2 family proteins was highly heterogeneous among patients. Although cases with t(11;14) had significantly higher levels of Bcl-2/Bcl-xL and Bcl-2+Bim+Bax/Bcl-xL ratios than those without t(11;14), the presence of this translocation was not synonymous with such high levels of expression. Conversely, some patients with other genetic alterations also showed higher levels of those ratios. Survival analysis revealed that the high expression of Bad and Puma proteins was associated with significantly longer overall survival (p = 0.001 and p < 0.001, respectively). Bcl-2 protein ratios predicting sensitivity to venetoclax in vitro were also able to distinguish patients with shorter time to progression after triplet-based induction therapy and ASCT. This is the first study to assess the expression of the most important Bcl-2 family proteins by a quantitative method in a large set of MM patients according to their cytogenetic abnormalities. We shed light on the impact of these proteins on MM prognosis, which could help to consider the levels of proteins involved in apoptosis in the development of new therapeutic strategies.

DOI: https://doi.org/10.1002/hem3.70036
Clin Lymphoma Myeloma Leuk. 2024 Nov 22. pii: S2152-2650(24)02423-6. [Epub ahead of print]

Comprehensive Review of Bispecific Antibody Constructs In Multiple Myeloma: Affinities, Dosing Strategies and Future Perspectives.

Johannes M Waldschmidt, Leo Rasche, K Martin Kortüm, Hermann Einsele.

  Despite significant advancements, multiple myeloma (MM) remains incurable, and there is still a pressing need for new therapeutic strategies with highly selective mechanisms of action and balanced off-target toxicity. In recent years, the development of "off-the-shelf" bispecific antibodies (bsAbs) has significantly enhanced our ability to treat relapsed or refractory MM. Teclistamab, elranatamab (both BCMA × CD3), and talquetamab (GPRC5D × CD3) are approved for treating MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Meanwhile, the range of available bsAbs is rapidly expanding, offering patients and healthcare providers a broad selection of options that vary in target antigens, binding domains, construct designs, dosing regimens, and side effects. As linvoseltamab, alnuctamab, and ABBV-383 (all BCMA × CD3), as well as forimtamig (GPRC5D × CD3) and cevostamab (FcRH5 × CD3) progress through late-stage clinical development, emerging trispecific antibodies are now available that target either 2 different MM-associated antigens or provide additional co-stimulatory signals to prevent T-cell exhaustion. Despite this plethora of therapeutic options, resistance to bsAbs is an inevitability, and the optimal positioning of these drugs within the current MM treatment landscape remains to be determined. In this review, we examine the available data on all clinically accessible bsAbs, evaluating their potential, current limitations, and implications for efficacy and safety, with the aim of achieving deeper responses and longer overall survival for MM patients.

Keywords:  Bispecific antibodies; Construct design; Different formats; Resistance mechanisms; Side effects

DOI:  https://doi.org/10.1016/j.clml.2024.11.012
Laryngoscope. 2024 Dec 17.

Lymphomas of the Parotid Gland in Denmark: A Nationwide Cohort Study.

Fahd Al-Shahrestani, Ahmed Ehsan Al-Khafaf, Zain Asheer, Jelena Jelicic, Iman Chanchiri, Catharina E Blocher, Anne Kathrine Aalling Sørensen, Lars Møller Pedersen, Lise Mette Rahbek Gjerdrum, Steffen Heegaard, Preben Homøe.

   OBJECTIVE: We examined the epidemiology of parotid gland lymphomas (PGL), the incidence, survival rates, clinical features, and association with primary Sjögren's syndrome (pSS).
METHODS: This retrospective nationwide cohort study analyzed data from Danish patients diagnosed with PGL between 2000 and 2020. Data were collected from medical records, the National Pathology Register, and the Danish lymphoma database. Statistical analyses included Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models.
RESULTS: A total of 433 patients were included. The incidence rate was 0.39 per 100,000 person-years, with PGL constituting 1.9% of all non-Hodgkins lymphoma in Denmark. The average annual incidence was 2.7% (incidence rate ratio = 1.027, p < 0.01). Follicular lymphoma (FL) was the most common subtype with 154 cases (35.6%), followed by large B-cell lymphoma (LBCL) with 119 cases (27.5%), and extranodal marginal zone lymphoma (EMZL) with 84 cases (19.4%). The median overall survival (OS) for FL was 9.5 years (95% CI 6.9-10.2), with 5-year and 10-year OS rates of 70% and 44%, respectively. For LBCL, the median OS was 7.8 years (95% CI 5.0-8.8), with 5-year and 10-year OS rates of 59% and 33%. EMZL had a median OS of 12.8 years (95% CI 9.0-16.3), with 5-year and 10-year OS rate of 83% and 55%. EMZL was significantly associated with pSS, relative risk 21.97 (95% CI 2.81-171.53). Advanced age, B symptoms, and elevated LDH levels were significantly linked to poorer overall survival.
CONCLUSION: This study offers new epidemiological, clinical, and prognostic insights, with a focus on their association with pSS.
LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Keywords:  Sjögren syndrome; lymphoma; parotid gland; survival

DOI:  https://doi.org/10.1002/lary.31929
Clin Lymphoma Myeloma Leuk. 2024 Dec 13. pii: S2152-2650(24)02419-4. [Epub ahead of print]

De-escalated Induction Therapy and Thiotepa/Busulfan-based Autologous Stem Cell Transplantation for Primary Central Nervous System Lymphoma.

Robert Puckrin, Colin Stewart, Carolyn Owen, Lesley E Street, Sarah Perry, Peter Duggan, Mona Shafey, Neil Chua, Douglas A Stewart.

   BACKGROUND: Thiotepa-based autologous stem cell transplantation (ASCT) improves survival in primary central nervous system lymphoma (PCNSL), but > 30% of patients are unable to undergo ASCT following commonly used intensive induction regimens.
METHODS: This retrospective population-based study included consecutive patients ≥ 18 years old with PCNSL who were intended for ASCT in Alberta, Canada between 2011 and 2022. A reduced-intensity induction protocol was further abbreviated in 2018 to decrease toxicity and expediate ASCT by incorporating rituximab, procarbazine, and only 2 doses of high-dose methotrexate and 1 cycle of high-dose cytarabine before consolidation with thiotepa-busulfan conditioning. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method.
RESULTS: Among 71 patients with median age 58 years (range 26-72), ASCT was completed in 56 (79%), with the transplantation rate among patients > 60 years old increasing by 30% following the abbreviation of induction therapy. With median follow-up time 3.9 years, 4-year PFS and OS were 69% (95% CI 56%-79%) and 80% (95% CI 67%-88%) for all patients and 75% (95% CI 57%-86%) and 85% (95% CI 68%-93%) for ASCT recipients, respectively. There was 1 death due to treatment-related mortality during induction and none after ASCT, including among 17 transplanted patients > 60 years old.
CONCLUSION: An abbreviated induction regimen followed by thiotepa-busulfan-based ASCT achieves high transplantation rates with low risks of relapse and treatment-related mortality, thereby providing an effective treatment strategy for PCNSL.

Keywords:  ASCT; Busulfan; High-Dose Methotrexate; PCNSL; Thiotepa

DOI:  https://doi.org/10.1016/j.clml.2024.11.008
EJHaem. 2024 Dec;5(6): 1274-1277

A GIMEMA survey on therapeutic use and response rates of FLT3 inhibitors in acute myeloid leukemia: Insights from Italian real-world practice.

Monica Messina, Alfonso Piciocchi, Leonardo M Siena, Stefano Soddu, Francesco Buccisano, Cristina Mecucci, Giovanni Martinelli, Antonio Curti, Roberto Cairoli, Paola Fazi, Marco Vignetti, Maria Teresa Voso, Adriano Venditti, Anna Candoni.

  Given the limited data on the real-life therapeutic use of feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) inhibitors in Italy, we surveyed investigators at 59 Italian hematology centers to gain insight into the proportion of acute myeloid leukemia (AML) patients receiving FLT3 inhibitors and we collected data on the efficacy and safety of these agents. The survey results showed that in the real-life setting the response rate of the 3/7 + midostaurin regimen in newly diagnosed FLT3-mutated AML and of gilteritinib in the relapsed/refractory AML were comparable to that reported in the registrative clinical trials. The 3/7 + midostaurin treatment resulted in a 63% of complete remission (CR) rates and gilteritinib in a 44% of CR rates. The discontinuation rate of gilteritinib for intolerance or toxicity was low (accounting for 4% of treated cases).

Keywords:  FLT3 inhibitors; acute myeloid leukemia; gilteritinib; midostaurin; real‐world

DOI:  https://doi.org/10.1002/jha2.1045