bims-hemali Biomed News
on Hematologic malignancies
Issue of 2024–12–08
twelve papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Venetoclax in the Treatment of Multiple Myeloma: A Retrospective Analysis of 79 Patients.
  2. The characteristics of patients with multiple myeloma surviving over 10 years.
  3. Targeted interferon therapy with modakafusp alfa for relapsed or refractory multiple myeloma.
  4. "Real-life" Data of Zanubrutinib in Patients with Waldenström Macroglobulinemia - A Multi-Center Retrospective Study.
  5. Efficacy and safety of hetrombopag in the treatment of recombinant human thrombopoietin-resistant thrombocytopenia after allogeneic hematopoietic stem cell transplantation.
  6. Bispecific antibodies for the treatment of hematologic malignancies: The magic is T-cell redirection.
  7. Advanced-Stage Chronic Myeloid Leukemia: Options for Difficult Treatment Situations.
  8. Ponatinib vs. asciminib in post-second-generation tyrosine kinase inhibitor therapy for chronic-phase chronic myeloid leukemia: a matching-adjusted indirect comparison.
  9. Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine for Advanced-Stage Classical Hodgkin Lymphoma.
  10. Survival of HIV associated diffuse large B-cell lymphoma and Burkitt lymphoma in China.
  11. Chromosome 1 Alterations in Multiple Myeloma: Considerations for Precision Therapy.
  12. Treatment of high risk myelodysplastic syndrome.
  1. Eur J Haematol. 2024 Dec 05.
    Venetoclax in the Treatment of Multiple Myeloma: A Retrospective Analysis of 79 Patients.
    Eli Zolotov, Vanisha Patel, Yedidyah Weiss, Noa Biran, Pooja Phull, David H Vesole, David S Siegel, Harsh Parmar.
      Venetoclax, the first-in-class BCL-2 inhibitor, has shown efficacy in multiple myeloma (MM), particularly in patients with the t(11;14) translocation. This single-center retrospective analysis included MM patients treated with venetoclax from November 2017 to March 2023. Data encompassed demographics, disease characteristics, treatment regimens, and outcomes using median progression-free-survival (mPFS). Eligibility required patients to be aged 21 and older and to have received at least one venetoclax cycle. Seventy-nine patients (median age 61, 58.2% female) were included, with 31.6% having t(11;14). Patients had received a median of 5 lines of therapy (LOT) before venetoclax. The mPFS was 3.4 months, with a significant difference between t(11;14) positive (7.8 months) and negative patients (2.4 months, p < 0.01). Patients achieving a very good partial response or better had a mPFS of 7.1 months. Common adverse events included fatigue (31.6%), diarrhea (26.5%), and respiratory infections (30.3%). Univariable and multivariable analyses identified sex, disease response, and t(11;14) presence as significant survival predictors. Our real-world study suggests that venetoclax demonstrates moderate efficacy in heavily pretreated patients with relapsed/refractory MM (RRMM), compared to previous studies where patients received 1-3 prior LOT, such as the BELLINI study (mPFS of 22.4 months). Notably, the efficacy was higher in patients with t(11;14). Despite the heavily pretreated nature of our cohort, venetoclax was well tolerated, with a manageable safety profile and low incidence of severe infections, largely due to effective prophylactic measures. Venetoclax should be carefully considered in heavily pretreated populations, and further multicenter research is essential to better define its role in RRMM.
    Keywords:  BCL‐2; multiple myeloma; t(11;14); venetoclax
    DOI:  https://doi.org/10.1111/ejh.14343
  2. Front Oncol. 2024 ;14 1490630
    The characteristics of patients with multiple myeloma surviving over 10 years.
    Beihui Huang, Hongning Zhang, Junru Liu, Jingli Gu, Meilan Chen, Lifen Kuang, Xiaozhe Li, Juan Li.
       Objective: To explore the characteristics of patients with multiple myeloma (MM) who have achieved long-term survival of over 10 years in the context where novel agents and autologous stem cell transplantation (ASCT) serve as the primary therapeutic modalities.
    Methods: A retrospective analysis was conducted on 168 MM patients diagnosed and treated in our institution from January 2004 to January 2014. 44 patients with a survival period exceeding 10 years were categorized into the long-term survival group, while 124 patients with a survival period of less than 10 years were categorized into the non-long-term survival group.
    Results: Being younger than 57 years old (OR 3.634, 95%CI 1.302-10.143), having a neutrophil count of at least 3.66 * 109/L (OR 3.122, 95% CI 1.093-8.918), absence of high-risk genetic abnormalities (OR 7.146, 95%CI 1.066-47.904), and receiving frontline ASCT (OR 4.225, 95%CI 1.000-17.841) were positively associated with a survival period exceeding 10 years in patients with MM. Achieving sustained minimal residual disease (MRD) negativity for at least 24 months is associated with long-term survival regardless of the presence of high-risk cytogenetic abnormalities.
    Conclusion: Being younger, having a neutrophil count above 3.66 * 109/L, the absence of high-risk cytogenetic abnormalities, and receiving frontline ASCT are independent protective factors for transplant-eligible MM patients to survive more than 10 years. Achieving maintained MRD negativity status for over 24 months might be associated with long-term survival.
    Keywords:  long-term survival; minimal residual disease; multiple myeloma; prognostic factors; survival analysis
    DOI:  https://doi.org/10.3389/fonc.2024.1490630
  3. Blood. 2024 Dec 04. pii: blood.2024026124. [Epub ahead of print]
    Targeted interferon therapy with modakafusp alfa for relapsed or refractory multiple myeloma.
    Dan T Vogl, Shebli Atrash, Sarah A Holstein, Omar Nadeem, Don M Benson, Maria Chaudhry, Noa Biran, Kaveri Suryanarayan, Cheryl Li, Yuyin Liu, Sabrina Christine Collins, Xavier Parot, Jonathan L Kaufman.
      Interferon-alpha has activity against multiple myeloma. Modakafusp alfa is an immunocytokine comprising two attenuated interferon-alpha2b molecules and an anti-CD38 IgG4 antibody, targeting delivery of interferon-alpha to CD38+ immune and myeloma cells. This phase I/II trial (NCT03215030) enrolled patients with relapsed/refractory multiple myeloma with ≥3 prior lines of treatment and refractory to or intolerant of ≥1 proteasome inhibitor and ≥1 immunomodulatory drug. During dose escalation, modakafusp alfa was administered at ten doses in four schedules across 13 cohorts. The primary endpoint was safety for dose escalation, and overall response rate for dose expansion. We enrolled 106 patients who had received a median of 6.5 lines of prior therapy; 84% of patients had myeloma previously refractory to an anti-CD38 antibody. The most feasible dosing schedule was every 4 weeks (Q4W), at which the maximum tolerated dose was 3 mg/kg. Among 30 patients treated at 1.5 mg/kg Q4W, the overall response rate was 43.3%, with a median duration of response of 15.1 months (95% CI, 7.1-26.1); median progression-free survival was 5.7 months (95% CI, 1.2-14.0). Grade ≥3 adverse events occurred in 28 (93.3%) patients, the most common were neutropenia (66.7%) and thrombocytopenia (46.7%); infections were reported in 8 (26.7%) patients (including grade 3 in 4 [16.7%]). Modakafusp alfa therapy induced upregulation of the type I interferon gene signature score, increased CD38 receptor density in CD38+ cells, and innate and adaptive immune cell activation. Modakafusp alfa resulted in anti-tumor activity and immune activation in patients with multiple myeloma. Adverse events were primarily hematologic.
    DOI:  https://doi.org/10.1182/blood.2024026124
  4. Acta Haematol. 2024 Dec 04. 1-11
    "Real-life" Data of Zanubrutinib in Patients with Waldenström Macroglobulinemia - A Multi-Center Retrospective Study.
    Gilad Itchaki, Ohad Benjamini, Mor Levi, Anatoly Nemets, Shai Ygna, Mahdi Assaly, Anna Gourevitch, Moshe Gatt, Revital Saban, Pia Raanani, Iuliana Vaxman.
       INTRODUCTION: Waldenström macroglobulinemia (WM) is a rare indolent lymphoma. Zanubrutinib (ZAN), a second-generation BTK inhibitor, has been approved for the treatment of WM in any line of therapy in 2021. Between November 2020 and January 2022, an expanded access program of ZAN opened in Israel for the treatment of patients with relapsed refractory (RR)-WM or those ineligible for chemotherapy or ibrutinib in first line.
    METHODS: This is a multi-center retrospective study aiming to provide real-world data on ZAN in patients with WM in Israel. Demographic and clinical data were collected and coded from electronic files. Response was evaluated by the investigator's assessment. As the program closed, patients transitioned to commercial ZAN.
    RESULTS: 13 patients (12 RR; 1 treatment-naive) were enrolled across 8 centers in Israel. The median age at ZAN initiation was 71 years (range, 50-85); 6 were males; 10 had high IPSS-WM. RR pts had a median of 1 (1-4) prior lines of therapy. Other than progressive disease after chemoimmunotherapy (CIT), the most common considerations for choosing ZAN were patients' age and/or comorbidities (n=5), as well as ibrutinib toxicity. The initial ZAN dose was reduced in 4 pts. The median time on ZAN was 19.5 months (2.9-29.5). Of 12 evaluable patients, the ORR was 83% with 3 minor responses, 6 PR, and 1 VGPR. With a median follow-up of 19.6 months, 7 patients were still on ZAN, 5 progressed, 4 while on ZAN, and 1 after ZAN was stopped due to AE. 18 months PFS and OS were 60.5% and 77%, respectively. Eight (61%) patients had AEs of any grade, and 3 (23%) of grade 3-4; 2 stopped ZAN due to congestive heart failure and extreme fatigue.
    CONCLUSION: The results of this real-world high-risk population are consistent with prospective studies highlighting the efficacy and safety of ZAN.
    DOI:  https://doi.org/10.1159/000542936
  5. Res Pract Thromb Haemost. 2024 Oct;8(7): 102578
    Efficacy and safety of hetrombopag in the treatment of recombinant human thrombopoietin-resistant thrombocytopenia after allogeneic hematopoietic stem cell transplantation.
    Jing Ni, Jian Hong, Xinglin Liang, Jifei Dai, Zhangbiao Long, ChengXin Luan, Mingzhen Yang, Qingsheng Li.
       Background: Thrombocytopenia after allogeneic hematopoietic cell transplantation is a challenging clinical problem. Recombinant human thrombopoietin (rhTPO) and thrombopoietin receptor agonists are increasingly used in posttransplant thrombocytopenia. However, the use of hetrombopag in patients with posttransplant thrombocytopenia, especially in patients with resistance to rhTPO, has not yet been reported.
    Objectives: The present study aimed to investigate the efficacy and safety of hetrombopag in patients with rhTPO-resistant posttransplant thrombocytopenia.
    Methods: This retrospective study included 21 patients with rhTPO-resistant posttransplant thrombocytopenia who received hetrombopag from August 2021 to July 2022. The primary endpoint was the overall response rate, including partial response and complete response (CR). We also evaluated the predictors of hetrombopag efficacy and adverse events.
    Results: The overall response rate to hetrombopag was 81%, and the CR rate was 62%. The median time from hetrombopag initiation to response and CR were 16 and 31 days, respectively. Decreased megakaryocytes in bone marrow negatively correlated with CR to hetrombopag (P = .03). All the patients tolerated hetrombopag well without any significant increase in adverse events. At the last follow-up, 71% of responders had discontinued hetrombopag and sustained their best response.
    Conclusion: Our results suggested that hetrombopag is an effective treatment option to promote platelet recovery in patients with posttransplant thrombocytopenia, even in patients resistant to rhTPO.
    Keywords:  allogeneic hematopoietic stem cell transplantation (allo-HSCT); efficacy; hetrombopag; recombinant human thrombopoietin (rhTPO); thrombocytopenia
    DOI:  https://doi.org/10.1016/j.rpth.2024.102578
  6. Blood Rev. 2024 Nov 26. pii: S0268-960X(24)00084-5. [Epub ahead of print] 101251
    Bispecific antibodies for the treatment of hematologic malignancies: The magic is T-cell redirection.
    Geoffrey Shouse.
      Bispecific antibody therapy has revolutionized the treatment of hematologic malignancies. There are currently 7 FDA approved products with 4 different targets covering 5 indications in 4 diseases. Products include blinatumomab targeting B-cell ALL in MRD detectable first remission and in relapsed and/or refractory disease, elranatamab and teclistamab targeting BCMA in relapsed/refractory multiple myeloma, talquetamab targeting GPCR5D in multiple myeloma, and mosunetuzumab, epcoritamab and glofitamab which all target CD20 in follicular lymphoma, both follicular and large B cell lymphoma, or large B cell lymphoma alone, respectively. Each product utilizes the strategy of T-cell redirection by binding CD3 on the effector cell to target immune cells toward a tumor associated antigen. There are overlapping toxicities related to activation of the immune system and inflammation. The role of these agents in earlier lines of therapy and in novel combinations are under heavy investigation and their full utility and benefit in the treatment of hematologic malignancies is yet to be fully realized.
    Keywords:  BCMA; Bispecific antibody; CD19; GPCR5D; Leukemia; Lymphoma; Multiple myeloma; T-cell engager
    DOI:  https://doi.org/10.1016/j.blre.2024.101251
  7. Drugs. 2024 Dec 06.
    Advanced-Stage Chronic Myeloid Leukemia: Options for Difficult Treatment Situations.
    Ehab Atallah, Michael Deininger.
      A small number of patients with chronic myeloid leukemia (CML) either present with or progress to the accelerated phase (AP) or blast phase (BP). This occurs in approximately 4-7% of patients with CML. Most patients who progress to BP-CML are of myeloid lineage, while approximately 30% are of lymphoid lineage. Due to the rarity of this condition, there are no large or randomized trials that can inform clinical decisions. Most data are from retrospective chart reviews or data from old studies when tyrosine kinase inhibitors (TKIs) were initially approved. In addition, the definition of these categories has been in continuous flux over the last 20 years, making applicability of data even more confusing. In some classifications, the cutoff is 30% blasts for the definition of BP-CML, while in others a cutoff of 20% is used. In addition, more recently the World Health Organization (WHO) classification omitted the accelerated phase and recognized only a two-phase disease, while the International Consensus Classification retained a three-phase definition and retained the accelerated phase. Therapy for patients with AP/BP-CML depends on several factors, including prior therapy, BCR::ABL1 mutation, co-morbidities, cell lineage, and eligibility for allogeneic stem cell transplantation (alloHCT). Patients with AP-CML at presentation have a relatively favorable prognosis and may not need alloHCT if they respond appropriately to therapy. For patients with AP-CML who progressed while on TKI therapy or those with BP-CML, alloHCT is considered the only curative therapy. Our goal is to review the available data on the therapy of patients with AP-CML and BP-CML.
    DOI:  https://doi.org/10.1007/s40265-024-02108-2
  8. Front Oncol. 2024 ;14 1455378
    Ponatinib vs. asciminib in post-second-generation tyrosine kinase inhibitor therapy for chronic-phase chronic myeloid leukemia: a matching-adjusted indirect comparison.
    Valentin Garcia-Gutierrez, Fei Huang, Ajibade Ashaye, Mehul Dalal, Victor Laliman-Khara, Massimo Breccia, Megan Rutherford, Hoora Moradian, Petros Patos, Elias Joseph Jabbour.
       Background: Ponatinib and asciminib are approved for third-line therapy in chronic-phase chronic myeloid leukemia (CP-CML) and are the only drugs approved for patients with the T315I mutation in the United States. In Europe, only ponatinib is approved for patients with the T315I mutation.
    Methods: Clinical trials evaluating ponatinib or asciminib in patients with relapsed and refractory (R/R) CP-CML who failed one or more second-generation TKIs or had the T315I mutation were identified in a systematic review of medical literature databases. A matching-adjusted indirect comparison (MAIC) analysis with individual patient-level data with ponatinib was used to balance baseline characteristics between ponatinib and asciminib groups. After matching, the response rate was calculated using the MAIC weight for each patient and the difference in response rate was calculated using a two-independent proportion Z-test. Cumulative rates of BCR::ABL1 IS ≤1% and major molecular response (MMR) in patients without baseline response were compared. Patients were further stratified by T315I mutation status.
    Results: The MAIC included four trials (ponatinib: NCT02467270, NCT01207440; asciminib: NCT02081378, NCT03106779). In patients without baseline response of BCR::ABL1 IS ≤1%, the adjusted BCR::ABL1 IS ≤1% rate difference with ponatinib vs. asciminib was 9.33% (95% confidence interval [CI]: 0.79%-17.86%; adjusted MMR rate difference: 6.84% [95% CI: -0.95%-14.62%]) by 12 months in favor of ponatinib. In patients with the T315I mutation, adjusted BCR::ABL1 IS ≤1% rate difference with ponatinib vs. asciminib was 43.54% (95% CI: 22.20%-64.87%; adjusted MMR rate difference: 47.37% [95% CI: 28.72%-66.02%]) by 12 months.
    Conclusion: After key baseline characteristics adjustment, cumulative BCR::ABL1 IS ≤1% and MMR rates were statistically higher with ponatinib than asciminib in patients without a baseline response in most of the comparisons by 12 months. Favorable efficacy outcomes observed in ponatinib vs. asciminib were consistently stronger in the T315I mutation subgroup.
    Keywords:  BCR::ABL1 (BCR-ABL1); T315I mutation; asciminib; chronic myeloid leukemia; major molecular response; ponatinib
    DOI:  https://doi.org/10.3389/fonc.2024.1455378
  9. Blood. 2024 Dec 02. pii: blood.2024024681. [Epub ahead of print]
    Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine for Advanced-Stage Classical Hodgkin Lymphoma.
    Hun Ju Lee, Rod Ramchandren, Judah Friedman, Jason M Melear, Ian W Flinn, John M Burke, Yuliya Linhares, Paul Alan Gonzales, Matthew Peterson, Mihir Raval, Rangaswamy Chintapatla, Tatyana A Feldman, Habte A Yimer, Miguel Islas-Ohlmayer, Ameet Patel, Leland Metheny, Asad Dean, Vishal Rana, Mitul D Gandhi, John S Renshaw, Linda Ho, Michelle A Fanale, Wenchuan Guo, Christopher A Yasenchak.
      Treatment options for stage I/II bulky and advanced stage disease have recently extensively changed. For decades in North America, ABVD has been a frontline standard of care option for patients with advanced classical Hodgkin lymphoma (cHL). Recent data on combining brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine demonstrated improved overall survival compared to ABVD but increased adverse events (AEs). We hypothesized that replacing vinblastine with nivolumab (AN+AD) may improve efficacy and safety. This phase 2, open-label multi-part, multicenter study enrolled patients with treatment-naive stage II bulky or III/IV cHL. Patients received ≤6 cycles of AN+AD; granulocyte-colony stimulating factor (G-CSF) prophylaxis was optional, per institutional guidelines. At the time of planned analysis (N=57), complete response (CR) and objective response rates were 88% (95% CI, 76.3 to 94.9) and 93% (95% CI, 83.0 to 98.1), respectively. With a median follow-up of 24.2 months (95% CI, 23.4 to 26.9), the 2-year PFS rate was 88% (95% CI, 75.7 to 94.6); 88% (95% CI, 75.7 to 94.6) had a response lasting >2 years. Most common grade ≥3 treatment-related AEs were alanine aminotransferase increased (11%) and neutropenia (9%); 44% had treatment-related peripheral sensory neuropathy (grade 1/2, 40%; grade 3, 4%). No febrile neutropenia occurred; 49% received G-CSF prophylaxis. AN+AD led to a high CR rate and favorable safety profile. Further evaluation of programmed death receptor 1 inhibitor and CD30 antibody-drug conjugate combination regimens in frontline advanced stage cHL is warranted. Trial registration: NCT03646123.
    DOI:  https://doi.org/10.1182/blood.2024024681
  10. Sci Rep. 2024 Dec 05. 14(1): 30397
    Survival of HIV associated diffuse large B-cell lymphoma and Burkitt lymphoma in China.
    Yu Xiong, Weicheng Liu, Xiaoping Chen, Pingzheng Mo, Yong Xiong, Liping Deng, Yongxi Zhang.
      Combination antiretroviral therapy (ART) has improved outcomes for human immunodeficiency virus (HIV) associated non-Hodgkin lymphoma. This is an analysis of 127 patients with HIV with Burkitt lymphoma (HIV-BL) and diffuse large B-cell lymphoma (HIV-DLBCL) treated at the Zhongnan Hospital of Wuhan University over a 17-year period during the ART and rituximab era. The median CD4 count for the cohorts was 0.141 × 109/L (range, 0.001-0.861 × 109/L). DA-EPOCH ± R (54%) were most commonly used in HIV-BL. CHOP± R (42%) was most commonly used to treat HIV-DLBCL. The complete response rate after first-line curative therapy was 10/28 (36%) in HIV-BL and 25/57 (44%) in HIV-DLBCL. The 2-year progression-free survival (PFS) and overall survival (OS) for the HIV-BL cohort was 50% and 41% respectively. The 2-year PFS and OS for the HIV-DLBCL cohort was 55% and 47% respectively. Current China practice favours the treatment of HIV-BL and HIV-DLBCL similarly to the HIV-negative population with the use of concurrent ART. However, due to the extremely low percentage of patients receiving ART prior to the lymphoma diagnosis, the high percentage of patients with poor performance status, and the advanced stage at diagnosis, the treatment of HIV-related lymphoma remains the major challenge in China.
    DOI:  https://doi.org/10.1038/s41598-024-80749-9
  11. Eur J Haematol. 2024 Dec 04.
    Chromosome 1 Alterations in Multiple Myeloma: Considerations for Precision Therapy.
    Niamh McAuley, Izabela Cymer, Roisin McAvera, Ann M Hopkins, Siobhan V Glavey.
      Multiple myeloma (MM) is an incurable blood malignancy characterized by the clonal expansion of plasma cells and the secretion of monoclonal immunoglobulins. High-risk MM, defined by specific cytogenetic abnormalities, poses significant therapeutic challenges and is associated with inferior survival outcomes compared to standard-risk disease. Although molecularly targeted therapies have shown efficacy in other hematologic malignancies, currently venetoclax is the only targeted therapy approved for MM (t(11;14)). However, chromosome 1q gains, amplifications, and 1p deletions are frequently observed in MM, and have been linked to drug resistance and poor patient prognosis. Accordingly, this review focuses on emerging MM precision therapies capable of targeting dysregulated genes within these regions. It addresses gene therapies, small molecule inhibitors and monoclonal antibodies currently under investigation to antagonize oncogenic drivers including MCL-1, BCL9, F11R, and CKS1B, all of which are implicated in cell survival, proliferation or drug resistance. In conclusion, the link between chromosome 1 abnormalities and high-risk disease in MM patients offers a compelling rationale to identify and explore therapeutic targeting of chromosome 1 gene products as a novel precision medicine approach for a poorly served patient population.
    Keywords:  chromosome 1; emerging therapies; high‐risk myeloma; precision medicine
    DOI:  https://doi.org/10.1111/ejh.14352
  12. Haematologica. 2024 Dec 05.
    Treatment of high risk myelodysplastic syndrome.
    Nicolaus Kröger.
      The myelodysplastic syndrome (MDS) is considered to be a heterogeneous myeloid malignancy with a common origin in the hematopoietic stem cell compartment, generally divided into lower and higher risk. While treatment goal for lower risk MDS (LR-MDS) is to decrease transfusion burden and transformation into acute leukemia major aim for high risk MDS is to prolong survival and ultimately cure. While novel agents such as luspatercept or imetelstat have recently been approved as new treatment options for LR-MDS, hypomethylating agents (HMA) remain currently the only approved non-transplant option for HR-MDS and is the standard of care for non-transplant-eligible patients. Combinations with other drugs as first-line treatment has to date not proven more efficacious than monotherapy in HR-MDS, and outcome after HMA failure is poor. The only potential cure and standard of care for eligible patients is allogeneic stem cell transplantation (HSCT) and even if the number of transplanted - especially older - MDS patients increased over time due to a better management and donor availability the majority of MDS patients will not be eligible for this curative approach. Current challenges encompass to decrease the relapse risk, the main cause of HSCT failure. This review will summarize current knowledge of options of transplant- and non-transplant treatment approaches for these patients and demonstrate the unmet clinical need for more effective therapies.
    DOI:  https://doi.org/10.3324/haematol.2023.284946
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