bims-hemali 2025-03-02 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2025–03–02
thirty-two papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

[Efficacy and Safety of Venetoclax in Combination with Hypomethylating Agents for the Treatment of High-Risk Myelodysplastic Syndromes].
Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes.
Real world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: a meta-analysis of clinical studies.
Treatment-Emergent Resistance to Asciminib in Chronic Myeloid Leukemia Patients Due to Myristoyl-Binding Pocket-Mutant of BCR::ABL1/A337V Can Be Effectively Overcome with Dasatinib Treatment.
Up-front Blinatumomab Improves MRD Clearance and Outcome in Adult Ph- B-lineage ALL: the GIMEMA LAL2317 Phase 2 Study.
Long term results of venetoclax combined with FLAG-IDA induction and consolidation for newly diagnosed and relapsed or refractory acute myeloid leukemia.
Combination of Brentuximab Vedotin and Pembrolizumab as Salvage Treatment Before Autologous Stem Cell Transplantation and Maintenance in Patients with Relapsed/Refractory Hodgkin Lymphoma.
[Research Progress on Tyrosine Kinase Inhibitors Discontinuation in Patients with Chronic Myeloid Leukemia --Review].
Improved Outcomes of Myeloma Cast Nephropathy in Newly Diagnosed Multiple Myeloma With Modern Anti-Myeloma Therapies.
Ixazomib or Lenalidomide combined with cyclophosphamide and dexamethasone in the treatment of elderly transplant-ineligible newly diagnosed multiple myeloma.
Venetoclax and Decitabine vs Intensive Chemotherapy as Induction for Young Patients with Newly Diagnosed AML.
Venetoclax Plus CyBorD Induction Therapy and Venetoclax Maintenance Treatment for Immunoglobulin Light Chain Amyloidosis with t(11;14) Translocation.
A phase 2 study of chidamide in combination with CAG and venetoclax-azacitidine in acute myeloid leukemia: Clinical safety, efficacy, and correlative analysis.
Outcomes of Melflufen Treatment in Patients With Relapsed/Refractory Multiple Myeloma.
The MURANO study: final analysis and retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL.
[The Comparison of Efficacy and Safety between Venetoclax Combined with Demethylating Drugs and the "3+7" Drug Regimen for Acute Myeloid Leukemia].
MDM2 inhibitors induce apoptosis by suppressing MDM2 and enhancing p53, Bax, Puma and Noxa expression levels in imatinib‑resistant chronic myeloid leukemia cells.
Risk-stratified treatment of sonrotoclax with chemotherapy in newly diagnosed acute myeloid leukemia: a study protocol.
Pirtobrutinib in Chinese patients with relapsed or refractory B-cell malignancies: A single-arm, open-label, phase 2, multicenter trial.
Clinical and Molecular Predictors of Response and Survival Following Venetoclax Plus Hypomethylating Agents in Relapsed/Refractory Acute Myeloid Leukemia: A Single-Center Study in Chinese Patients.
Molecular Predictors of Response and Survival in Patients with Relapsed/Refractory Acute Myeloid Leukemia following Venetoclax plus Hypomethylating Agent Therapy.
[Efficacy and Safety of BeEAM, a Conditioning Regimen for Autologous Stem Cell Transplantation in Malignant Lymphoma].
Maintenance therapy with oral decitabine plus cedazuridine after allogeneic stem cell transplantation for myelodysplastic syndrome.
Use of Primary Prophylaxis with G-CSF in Acute Myeloid Leukemia Patients Undergoing Intensive Chemotherapy Does Not Affect Quality of Response.
Total psoriasis regression in a patient with chronic myeloid leukemia treated using nilotinib.
The Future of Follicular Lymphoma Management: Strategies on the Horizon.
Azacitidine in combination with HAG for newly diagnosed and relapsed/refractory AML: a prospective cohort study.
Thromboprophylaxis in multiple myeloma.
[Mutation Detection of Plasma Circulating Tumor DNA Associated with Multiple Myeloma].
XPO1/Exportin-1 in Acute Myelogenous Leukemia; Biology and Therapeutic Targeting.
Challenges determining the best target duration of deep molecular response after which to attempt achieving therapy-free remission in chronic myeloid leukaemia.
Sustained bone marrow and imaging MRD negativity for 3 years drives discontinuation of maintenance post ASCT in myeloma.

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2025 Feb;33(1): 168-174

[Efficacy and Safety of Venetoclax in Combination with Hypomethylating Agents for the Treatment of High-Risk Myelodysplastic Syndromes].

Yang Xu, Jian Zhang, Zhi-Hong Lin, Jun Chen, Li-Min Liu, Hui-Ying Qiu, De-Pei Wu.

   OBJECTIVE: To investigate the clinical efficacy and safety of venetoclax (VEN) in combination with hypomethylating agent (HMA) in the treatment of patients with high-risk myelodysplastic syndromes (MDS).
METHODS: A total of 30 patients with high-risk MDS who received the combination of VEN and HMA from March 2019 to November 2022 were included. The overall response rate (ORR), modified overall response rate (mORR), overall survival (OS), progression-free survival (PFS), and adverse events of all included patients were evaluated.
RESULTS: Among the 30 high-risk MDS patients treated with VEN combined with HMA regimen, 24 cases achieved complete response (CR)/ marrow complete response (mCR), 2 cases achieved partial response (PR), the ORR was 24/30, the median OS was 28.1 months, and the median PFS was 28.1 months. In addition, patients who achieved complete remission / marrow complete remission after treatment had a significantly longer OS than those who did not. Moreover, 12 patients were treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). There were grade 3 or higher hematologic adverse events including thrombocytopenia (14 cases), neutropenia (14 cases), febrile neutropenia (10 cases) and anemia (7 cases) as well as gastrointestinal adverse events of any grade, such as vomiting (7 cases), diarrhea (5 cases), and constipation (4 cases).
CONCLUSION: VEN in combination with HMA is an effective and safe treatment option in patients with high-risk MDS. This regimen combined with allo-HSCT can improve the prognosis of these patients. Continuous attention to the monitoring and management of adverse events is essential for the patients' safety in this combination therapy.

Keywords:   myelodysplastic syndromes; venetoclax; hypomethylating agents; adverse events

DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2025.01.024
Leukemia. 2025 Feb 27.

Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes.

Thierry Facon, Philippe Moreau, Katja Weisel, Hartmut Goldschmidt, Saad Z Usmani, Ajai Chari, Torben Plesner, Robert Z Orlowski, Nizar Bahlis, Supratik Basu, Cyrille Hulin, Hang Quach, Michael O'Dwyer, Aurore Perrot, Caroline Jacquet, Christopher P Venner, Noopur Raje, Mourad Tiab, Margaret Macro, Laurent Frenzel, Xavier Leleu, Gordon Cook, George Wang, Huiling Pei, Maria Krevvata, Robin Carson, Fredrik Borgsten, Shaji K Kumar.

In the MAIA study, daratumumab plus lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). We report updated efficacy and safety from MAIA (median follow-up, 64.5 months), including a subgroup analysis by patient age (<70, ≥70 to <75, ≥75, and ≥80 years). Overall, 737 transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint, PFS, was improved with D-Rd versus Rd (median, 61.9 vs 34.4 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45-0.67; P < 0.0001). Median OS was not reached in the D-Rd group versus 65.5 months in the Rd group (HR, 0.66; 95% CI, 0.53-0.83; P = 0.0003); estimated 60-month OS rates were 66.6% and 53.6%, respectively. D-Rd achieved higher rates of complete response or better (≥CR; 51.1% vs 30.1%), minimal residual disease (MRD) negativity (32.1% vs 11.1%), and sustained MRD negativity (≥18 months: 16.8% vs 3.3%) versus Rd (all P < 0.0001). D-Rd demonstrated clinically meaningful efficacy benefits across age groups. No new safety concerns were observed. Updated results (median follow-up, >5 years) continue to support frontline use of D-Rd in transplant-ineligible patients with NDMM.

DOI: https://doi.org/10.1038/s41375-024-02505-2
BMC Pharmacol Toxicol. 2025 Feb 25. 26(1): 43

Real world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: a meta-analysis of clinical studies.

Mohammad Amin Karimi, Hanieh Norooziseyedhosseini, Reza Khademi, Alireza Ghajary, Haniyeh Kargar, Seyyedeh Sana Abdollahi, Mohaddeseh Belbasi, Mahdyieh Naziri, Niloofar Deravi, Sajjad Hajihosseini, Saharnaz Mofidi.

   BACKGROUND: Chronic lymphocytic leukemia (CLL) is a B-cell malignancy primarily diagnosed in older adults. For younger patients, treatment options often include regimens based on fludarabine, cyclophosphamide, and rituximab; however, at least 20% of patients exhibit resistance to these therapies. Ibrutinib, a covalent Bruton's tyrosine kinase (BTK) inhibitor, has demonstrated enhanced safety compared to conventional treatments. This meta-analysis examines the efficacy and safety of ibrutinib in managing relapsed/refractory CLL.
METHOD: Relevant keywords were used to conduct a comprehensive search across online databases, including PubMed, Scopus, and Google Scholar. Data related to complete response (CR), overall response rate (ORR), and adverse events were extracted to evaluate the efficacy and safety of ibrutinib treatment. The results were presented in forest plots illustrating event rates and risk ratios with 95% confidence intervals (CI), while heterogeneity was assessed using I² statistics. Funnel plots were employed to examine potential publication bias visually.
RESULT: Twenty-one studies were included in this meta-analysis. Ibrutinib as a single-agent treatment was associated with a 9% complete response (CR) rate (95% CI: 5-14%) and a 77% overall response rate (ORR) (95% CI: 70-83%). When combined with other agents, ibrutinib achieved a CR rate of 21% (95% CI: 9-41%) and an ORR of 84% (95% CI: 80-88%). Adverse events were not significantly correlated with treatment outcomes. Funnel plots indicated no significant publication bias.
CONCLUSION: Single-agent ibrutinib has proven to be an effective therapy for patients with relapsed/refractory CLL. However, combining ibrutinib with other agents has demonstrated enhanced treatment efficacy. Further studies are needed to evaluate the safety profile of this therapeutic regimen thoroughly.

Keywords:  Chronic lymphocyte leukemia; Ibrutinib; Meta-analysis; Refractory CLL; Relapsed CLL

DOI:  https://doi.org/10.1186/s40360-024-00832-9
Curr Oncol. 2025 Feb 09. pii: 97. [Epub ahead of print]32(2):

Treatment-Emergent Resistance to Asciminib in Chronic Myeloid Leukemia Patients Due to Myristoyl-Binding Pocket-Mutant of BCR::ABL1/A337V Can Be Effectively Overcome with Dasatinib Treatment.

Peter Batar, Gabriella Mezei, Arpad Illes.

  Despite the groundbreaking success of tyrosine kinase inhibitor therapy, the management of chronic myeloid leukemia patients is often impaired by resistance due to specific point mutations in the BCR::ABL1 oncogene. Upon classical ATP-competitive inhibitor treatment, these single nucleotide variants occur in the tyrosine kinase domain of ABL1. The novel allosteric BCR::ABL1 inhibitor asciminib was developed to treat CML patients alone or in combination to overcome or potentially prevent these treatment-emergent TKD mutations. Here, we present a case of a patient undergoing first-line asciminib therapy, and subsequently develop a specific BCR::ABL1/A337V point mutation, which resulted in asciminib resistance. Switching to second-line dasatinib treatment successfully overcame asciminib resistance and helped to achieve a deep molecular response. In case of treatment failures caused by single asciminib-specific point mutations, dasatinib therapy is a feasible choice.

Keywords:  TKI resistance; allosteric inhibitor; chronic myeloid leukemia; single nucleotide variant; tyrosine kinase inhibitor

DOI:  https://doi.org/10.3390/curroncol32020097
Blood. 2025 Feb 26. pii: blood.2024027500. [Epub ahead of print]

Up-front Blinatumomab Improves MRD Clearance and Outcome in Adult Ph- B-lineage ALL: the GIMEMA LAL2317 Phase 2 Study.

Renato Bassan, Sabina Chiaretti, Irene Della Starza, Alessandra Santoro, Orietta Spinelli, Manuela Tosi, Loredana Elia, Deborah Cardinali, Maria Stefania De Propris, Matteo Piccini, Federico Lussana, Mario Annunziata, Patrizia Chiusolo, Patrizia Zappasodi, Erika Borlenghi, Matteo Leoncin, Catello Califano, Monica Bocchia, Francesco Di Raimondo, Francesco Grimaldi, Mario Tiribelli, Anna Candoni, Albana Lico, Ernesta Audisio, Monia Lunghi, Anna Maria Mianulli, Mariangela Di Trani, Valentina Arena, Monica Messina, Alfonso Piciocchi, Paola Fazi, Alessandro Rambaldi, Robin Foà.

The GIMEMA LAL2317 protocol investigated the frontline chemotherapy-blinatumomab combination in adult Philadelphia- CD19+ B-lineage acute lymphoblastic leukemia (Ph- B-ALL) to improve minimal residual disease (MRD) response and clinical outcome. Two cycles of intravenous blinatumomab were administered after chemotherapy cycles 3 and 6. The primary endpoint was the rate of molecular MRD negativity following blinatumomab 1. One hundred and forty-nine patients were enrolled (median age 41 years, range18-65); 132 entered remission, 122 received blinatumomab and 109 had a pre- and post-blinatumomab 1 MRD assessment. MRD negativity increased from 72% to 93% (P<0.001) after blinatumomab, with 23/30 MRD+ patients (73%) becoming MRD-, fulfilling the primary endpoint. At a median follow-up of 38.1 months (0.5-62.8), the median overall and disease-free survivals (OS, DFS) were not reached and the estimated 3-year OS and DFS were 71% and 65%, with an excellent outlook for the patients aged 18-40 years who achieved an early MRD negativity (DFS 92%). Pre-blinatumomab MRD predicted a worse outcome, especially in genetics high-risk patients. Notably, the 3-year survival of blinatumomab-treated patients was 82%. Survival and relapse rates were 91% and 15% in patients assigned to standard chemotherapy, 59% and 35% in patients assigned to HSCT, and 69% and 19% in transplant recipients. Blinatumomab toxicity was manageable, with only 8 permanent discontinuations. This chemotherapy-blinatumomab risk-oriented program yielded remarkable results that need further improvement in higher-risk patients displaying early MRD persistence. Blinatumomab should be considered as a standard component of induction/consolidation for adult Ph- B-ALL. ClinicalTrials.gov # NCT03367299.

DOI: https://doi.org/10.1182/blood.2024027500
Leukemia. 2025 Feb 25.

Long term results of venetoclax combined with FLAG-IDA induction and consolidation for newly diagnosed and relapsed or refractory acute myeloid leukemia.

Courtney D DiNardo, Wei-Ying Jen, Koichi Takahashi, Tapan M Kadia, Sanam Loghavi, Naval G Daver, Lianchun Xiao, Patrick K Reville, Ghayas C Issa, Nicholas J Short, Koji Sasaki, Sa A Wang, Jillian K Mullin, Sherry Pierce, Corey Bradley, Gautam Borthakur, Abhishek Maiti, Yesid Alvarado, Naveen Pemmaraju, Alessandra Ferrajoli, Mahesh Swaminathan, Maro Ohanian, Hussein A Abbas, Danielle Hammond, Jan Burger, Fadi Haddad, Guillermo Montalban-Bravo, Kelly Chien, Lucia Masarova, Musa Yilmaz, Nitin Jain, Michael Andreeff, Guillermo Garcia-Manero, Steven Kornblau, Farhad Ravandi, Elias Jabbour, Marina Y Konopleva, Hagop M Kantarjian.

Intensive chemotherapy remains the standard for newly diagnosed (ND) acute myeloid leukemia (AML); however, relapse risk remains high. Additionally, most patients with relapsed/refractory (RR) AML have poor outcomes. We report the long-term experience of 138 patients, 77 ND and 61 RR, treated with FLAG-IDA in combination with venetoclax. In the ND cohort, the overall response rate (ORR) was 97%, with a composite complete remission (CRc) rate of 95% and undetectable measurable residual disease (MRD) status by flow cytometry in 90%. The 3-year OS and EFS rates were 66 and 64%, respectively. Outcomes were similar across European LeukemiaNet (ELN) 2022 risk groups. Sixty-four percent transitioned to allogeneic hematopoietic stem cell transplantation (allo-SCT) in CR1. In the RR cohort, the ORR was 67%; CRc rate 41% and flow negative MRD rate 74%; 57% transitioned to allo-SCT. The patients with RR AML in first salvage with wild-type TP53 status had particularly favorable outcomes, with an ORR of 79%, CRc rate of 74% (76% MRD undetectable) and 3-year OS rate of 51%. Infectious and hematologic adverse events were common, with low 30- and 60-day mortality similar to other intensive chemotherapy regimens. FLAG-IDA + VEN is effective for remission induction in both ND and RR AML.ClinicalTrials.gov Identifier: NCT03214562.

DOI: https://doi.org/10.1038/s41375-025-02531-8
Biomedicines. 2025 Jan 21. pii: 252. [Epub ahead of print]13(2):

Combination of Brentuximab Vedotin and Pembrolizumab as Salvage Treatment Before Autologous Stem Cell Transplantation and Maintenance in Patients with Relapsed/Refractory Hodgkin Lymphoma.

Hanne Massa, Fulvio Massaro, Marie Maerevoet.

  Background: In relapsed or refractory classical Hodgkin lymphoma, achieving complete remission on 18FDG PET-CT before autologous stem cell transplantation improves progression-free survival. However, the optimal salvage therapy to achieve this remains undefined. Brentuximab vedotin combined with PD1 inhibitors has shown promise, though limited data exist on the combination of brentuximab vedotin and pembrolizumab. Methods: We retrospectively collected data from 24 adult patients with confirmed relapsed or refractory classical Hodgkin lymphoma, who started salvage treatment with brentuximab vedotin and pembrolizumab with the intention of consolidation with high-dose chemotherapy, followed by autologous stem cell transplantation and brentuximab vedotin maintenance. Results: After two cycles of brentuximab vedotin and pembrolizumab, 95.2% achieved an overall response and 81.0% achieved complete metabolic response. 20 patients (83.3%) were in complete response at the end of maintenance, of whom one relapsed at 28 months after the end of treatment. Grade 3 and 4 toxicities during salvage treatment consisted mainly of hematological toxicity, one thyrotoxicosis, one hemophagocytic lymphohistiocytosis, and one arthralgia. Non-hematological grade 3-4 toxicities following transplantation were an inflammatory pneumonitis and one cryptococcal meningitis. One death occurred during prolonged post-transplant aplasia. During maintenance, dose reductions for toxicity were necessary in 16 patients, mainly due to peripheral neuropathy. Conclusions: For heavily pretreated relapsed or refractory classical Hodgkin lymphoma patients, our data suggest that salvage therapy with brentuximab vedotin and pembrolizumab before autologous stem cell transplantation followed by brentuximab vedotin maintenance is a highly active strategy, with acceptable toxicities. Further studies with larger cohorts are necessary to confirm these data.

Keywords:  Hodgkin lymphoma; antibody–drug conjugate; autologous stem cell transplantation; brentuximab vedotin; immune checkpoint inhibition; pembrolizumab; relapsed/refractory; salvage therapy

DOI:  https://doi.org/10.3390/biomedicines13020252
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2025 Feb;33(1): 300-305

[Research Progress on Tyrosine Kinase Inhibitors Discontinuation in Patients with Chronic Myeloid Leukemia --Review].

Jun-Xia He, Xi-Yuan Jiang, Ya-Ming Xi.

  Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients with chronic myeloid leukemia (CML), and achieving treatment-free remission (TFR) has become a new goal for these patients. Various methods of discontinuing medication are continuously being explored, with successful cessation linked to factors such as the duration of TKI treatment, the sustainability of deep molecular response (DMR), transcript type, and immunological factors. Early switching of TKI, combining other therapies, and targeting leukemia stem cells may help increase the TFR rate. This article reviews the latest research developments on the exploration of TKI cessation, factors affecting TFR, selection of patients for discontinuation, strategies to enhance TFR, and monitoring after cessation, expecting to provide reference and guidance for achieving TFR in CML patients.

Keywords:  Chronic myeloid leukemia; treatment discontinuation; tyrosine kinase inhibitors；treatment free remission

DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2025.01.046
Eur J Haematol. 2025 Feb 24.

Improved Outcomes of Myeloma Cast Nephropathy in Newly Diagnosed Multiple Myeloma With Modern Anti-Myeloma Therapies.

Michael Sang Hughes, Metodi Balev, Jai Radhakrishnan, Divaya Bhutani, Markus Mapara, Suzanne Lentzsch, Rajshekhar Chakraborty.

  Myeloma cast nephropathy (MCN) is a driver of renal failure in newly diagnosed multiple myeloma (NDMM) and has been historically associated with increased early mortality. Since patients with moderate to severe renal insufficiency are typically excluded from trials, we performed a retrospective study to characterize modern-era outcomes in MCN. We reviewed 274 consecutive NDMM patients from 2017 to 2023 at an academic center and identified 46 patients (16.8%) with MCN. Among them, 96% had received bortezomib and 67% anti-CD38+ monoclonal antibody in frontline therapy. As per the International Myeloma Working Group criteria, the renal overall response rate was 76.1% (35/46), and the renal complete response (CR) rate was 32.6% (15/46) at 6 months. Overall survival (OS) at 6 months did not differ between MCN (100%) and controls (98.2%). At a median follow-up of ~3 years, the mean MCN OS was within 7 months of control (p = 0.039) by equivalence testing. Most involved free light chain (iFLC) and proteinuria reduction occurred within 1 month of treatment (83.1%, 3.9 g/d, respectively). In summary, we report excellent 6-month renal recovery without early mortality in MCN patients with modern anti-myeloma therapies. Prospective studies focused on MCN are urgently needed to further improve the renal CR rate.

Keywords:  cast nephropathy; daratumumab; multiple myeloma; renal impairment

DOI:  https://doi.org/10.1111/ejh.14403
Sci Rep. 2025 Feb 24. 15(1): 6538

Ixazomib or Lenalidomide combined with cyclophosphamide and dexamethasone in the treatment of elderly transplant-ineligible newly diagnosed multiple myeloma.

Yan Wang, Yuan-Fang Liu, Shi-Wei Jin, Yi Tao, Wei-Ping Zhang, Jian-Lin Chen, Song-Fu Jiang, Jian-Qing Mi.

  Oral-drug based regimens are useful in certain circumstances for transplant-ineligible newly diagnosed multiple myeloma (TI-NDMM), but few studies have compared Ixazomib based regimen with lenalidomide based regimen head-to-head. We carried out a prospective randomized, open, parallel group trial in patients with TI-NDMM in 3 China centers from March 2020 to December 2022. Sixty-three patients were available for final analysis, ICd (Ixazomib/cyclophosphamide/dexamethasone, n = 31) and RCd (lenalidomide/cyclophosphamide/dexamethasone, n = 32). The primary objective was to compare the two regimens by analyzing the overall response rate (ORR), safety profiles, progression-free survival (PFS) and overall survival (OS). We also explored clinical and the biological characteristics of the patients with primary drug resistance. Baseline characteristics were well balanced between ICd and RCd groups, with the median age 70 vs. 70 years; 12.9% vs. 12.5% of patients had stage III disease; 25.8% vs. 28.1% had high-risk cytogenetic abnormalities. The overall response rate (ORR) at the end of 4 cycles was 87.1% vs. 71.9% (odds ratio [OR], 1.212; 95% CI, 0.938-1.565; P = 0.213); the best ≥ VGPR rate was 41.9% vs. 31.2% (OR, 1.342; 95% CI 0.694-2.597; P = 0.439). Among high-risk cytogenetic patients, ORR was higher in the ICd group, 75% vs. 55.5% (P = 0.620), respectively. After 35 months follow-up, the median PFS were 22 and 23 months between ICd and RCd groups (P = 0.897). Median OS was not reached, estimated 3-year OS rate was 86.4% vs. 85.4% (P = 0.774). The most common adverse events of grade 3 or 4 were neutropenia (6.5% in the ICd group vs. 31.3% in the RCd group), anemia (19.4% vs. 18.8%), pneumonia (0 vs. 15.6%) and diarrhea (12.9% vs. 0). Treatment emergent adverse events (TEAEs) induced dose reduction and discontinuation were 22.6% vs. 37.5% and 3.2% vs. 6.3% in the ICd vs. RCd group, respectively. Exploration data showed that patients with t (4;14) were insensitive to initial RCd treatment. The ICd regimen showed a tendency towards improved ORR compared to RCd regimen. Both ICd and RCd regimens demonstrated less dose reduction and treatment discontinuation, suggesting their tolerability and feasibility for older individuals with TI-NDMM.Trial registration: This study was registered at Chinese Clinical Trial Register (ChiCTR). Trial registration number: ChiCTR2000029863. Date of registration: 15/02/2020.

Keywords:  Cyclophosphamide; Ixazomib; Lenalidomide; Multiple myeloma

DOI:  https://doi.org/10.1038/s41598-025-91126-5
Blood. 2025 Feb 26. pii: blood.2024027217. [Epub ahead of print]

Venetoclax and Decitabine vs Intensive Chemotherapy as Induction for Young Patients with Newly Diagnosed AML.

Jing Lu, Shengli Xue, Ying Wang, Xuefeng He, Xiaohui Hu, Miao Miao, Yang Zhang, Zaixiang Tang, Jundan Xie, Xiaofei Yang, Mingzhu Xu, Yaoyao Shen, Feng Du, Qian Wu, Mengxing Xue, Yun Wang, Ailing Deng, Xueqing Dou, Yang Xu, Haiping Dai, Depei Wu, Suning Chen.

Venetoclax combined with hypomethylating agents is approved for frontline therapy in older/unfit acute myeloid leukemia (AML) patients. However, prospective data on this low intensity therapy in treatment-naive younger AML patients are lacking. This study investigated the efficacy and safety of venetoclax plus decitabine (VEN-DEC) as induction in untreated young fit AML patients in a randomized trial. Patients aged 18-59 years eligible for intensive chemotherapy were randomized 1:1 to receive VEN-DEC or IA-12 (idarubicin and cytarabine). All patients achieving CR/CRi underwent high-dose cytarabine consolidation. The primary endpoint was the composite complete remission rate (CRc) rate after induction therapy. Of 255 screened, 188 were enrolled and randomly assigned, with 94 in each group. In the intention-to-treat population, CRc was 89% (84/94) in the VEN-DEC group versus 79% (74/94) in IA-12 (non-inferiority P = 0.0021). MRD negativity after induction was 80% (67/84) versus 76% (56/74), respectively. VEN-DEC showed superior CRc in patients aged ≥40 years (91% vs. 75%), those with adverse risk (91% vs. 42%) or epigenetic mutations (91% vs. 67%) , but lower CRc in RUNX1::RUNX1T1 fusion cases (44% vs. 88%) compared to IA-12. Patients in the VEN-DEC group experienced fewer grade ≥3 infections (32% vs. 67%) and shorter severe thrombocytopenia duration (median 13 vs. 19 days, P < 0.001). At a median follow-up of 12.1 months, overall and progression-free survival were similar between groups. In conclusion, VEN-DEC demonstrated non-inferior response rates with superior safety over IA-12 in young AML patients. The trial was registered at ClinicalTrials.gov as #NCT05177731.

DOI: https://doi.org/10.1182/blood.2024027217
Curr Oncol. 2025 Jan 26. pii: 63. [Epub ahead of print]32(2):

Venetoclax Plus CyBorD Induction Therapy and Venetoclax Maintenance Treatment for Immunoglobulin Light Chain Amyloidosis with t(11;14) Translocation.

Gréta Garami, Omar Obajed Al-Ali, István Virga, Anita Gulyás, Judit Bedekovics, István Tornai, Árpád Illés, Ferenc Magyari.

  Background: A total of 50% of patients with AL amyloidosis have t(11;14) translocation, allowing us to use the selective oral BCL-2 inhibitor venetoclax in their treatment. Case presentation: Our patient was admitted to the gastroenterology department due to weight loss and abdominal pain. An abdominal CT scan revealed some enlarged lymph nodes; therefore, he was referred to the hematology department. A bone marrow biopsy showed massive amorphous amyloid deposition. The sample was positive on Congo red staining and exhibited double refraction under a polarized light microscope. Serum-free light chains and the difference between involved and uninvolved free light chains (dFLCs) were elevated. Using fluorescent in situ hybridization, we detected t(11;14) translocation. Further examinations confirmed the involvement of the liver, colon and heart. Stage II AL amyloidosis was confirmed. Our patient received combined induction therapy with CyBorD and venetoclax due to the presence of the t(11;14) translocation. After six cycles, the patient achieved complete remission. Autologous stem cell transplantation (ASCT) was performed. At 100 days post-ASCT, the patient had complete hematologic remission. Venetoclax maintenance treatment was initiated. The follow-up examinations showed that the patient is in very good partial remission. Conclusions: In the case of our AL amyloidosis patient with t(11;14) translocation, the combined treatment with CyBorD and venetoclax was well tolerated and effective.

Keywords:  14) translocation; CyBorD; autologous stem cell transplantation; dFLC; immunoglobulin-related/light chain amyloidosis; maintenance treatment; plasma cell disorder; t(11; venetoclax

DOI:  https://doi.org/10.3390/curroncol32020063
Int Immunopharmacol. 2025 Feb 21. pii: S1567-5769(25)00258-9. [Epub ahead of print]151 114268

A phase 2 study of chidamide in combination with CAG and venetoclax-azacitidine in acute myeloid leukemia: Clinical safety, efficacy, and correlative analysis.

Jingjing Yang, Qingyang Liu, Xiawei Zhang, Yu Jing, Ning Le, Meng Li, Lingmin Xu, Weijia Zhao, Sai Huang, Daihong Liu, Liping Dou.

  Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by elevated mortality. Epigenetic therapy plays an essential role in the treatment of AML. However, the clinical outcomes of the combination of multiple epigenetic agents and conventional chemotherapy remain unclear. We conducted a phase 2 study to evaluate the clinical safety and efficacy of chidamide combined with CAG and venetoclax-azacitidine (referred to as CACAG-VEN) in AML patients (NCT05659992). Patients received induction treatment with aclarubicin (10 mg/m2/d on days 1, 3, and 5), azacitidine (75 mg/m2 on days 1-7), cytarabine (75 mg/m2 bid on days 1-5), chidamide (30 mg, twice/week for 2 weeks), and venetoclax (100 mg on day 1, 200 mg on day 2, 400 mg on days 3-14). Granulocyte colony-stimulating factor 5 μg/kg/day was administered. After one cycle of CACAG-VEN, the overall response rate was 96.7 %, with a composite complete response (CRc) rate of 93.3 %. The CRc rates (86.7 %) were remarkable among patients with adverse NCCN risk. Patients receiving two cycles of CACAG-VEN achieved a CRc rate of 100 %. The 12-month overall survival rate was 69.7 %. The median time to recovery was 19 days for platelets ≥50,000/μL and 17 days for an absolute neutrophil count ≥500 cells/μL after induction therapy. The single-cell RNA sequence showed most immune cells exhibited no significant change in proportion after removing tumor cells. In conclusion, this regimen resulted in a high CRc rate in newly diagnosed AML patients, particularly in adverse-risk patients. And this regimen had minimal impact on immune cells.

Keywords:  Acute myeloid leukemia; Bcl-2 inhibitor; Dual-epigenetic regimen

DOI:  https://doi.org/10.1016/j.intimp.2025.114268
Eur J Haematol. 2025 Feb 23.

Outcomes of Melflufen Treatment in Patients With Relapsed/Refractory Multiple Myeloma.

Shahrier Hossain, Clifton Mo, Sarah Patches, Houry Leblebjian, Kathryn Goodrich, Eileen Regan, Kathleen O'Neill, Kim Noonan, Paul G Richardson, Jacob Laubach.

   OBJECTIVE: Melphalan flufenamide (melflufen) plus dexamethasone is fully approved in Europe for patients with relapsed/refractory multiple myeloma (RRMM) with ≥ 3 prior lines of therapy. We analyzed the efficacy and safety of melflufen in the real-world setting.
METHODS: In this retrospective analysis, we examined baseline features, efficacy, and safety outcomes with melflufen plus dexamethasone in a cohort of 12 patients with heavily pre-treated RRMM at the Dana-Farber Cancer Institute, USA.
RESULTS: Patients had received a median of 5.5 prior lines of therapy. Three patients (25%) had extramedullary disease, three (25%) cytogenetically high-risk features, and five (42%) had received prior autologous stem cell transplantation. The overall response rate was 55% (complete response: three [27%], very good partial response: one [9%], partial response: two [18%] patients). Five patients (42%) had stable disease; one was non-evaluable. Adverse events (AEs) were mostly hematologic and proved manageable; two patients had Grade 2 infections. Reasons for melflufen discontinuation were progressive disease (42%), drug withdrawal from the United States market (33%), AEs (17%), and sudden death (8%) unrelated to treatment.
CONCLUSIONS: Consistent with clinical trial data, melflufen had an expected safety profile with manageable toxicity and clinically meaningful efficacy in patients with RRMM treated in the real-world setting.

Keywords:  melflufen; melphalan flufenamide; real world; relapsed refractory multiple myeloma

DOI:  https://doi.org/10.1111/ejh.14398
Blood. 2025 Feb 26. pii: blood.2024025525. [Epub ahead of print]

The MURANO study: final analysis and retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL.

Arnon P Kater, Rosemary Anne Harrup, Thomas J Kipps, Barbara Eichhorst, Carolyn Owen, Sarit E Assouline, Nicole Lamanna, Tadeusz Robak, Javier de la Serna, Ulrich Jaeger, Guillaume Cartron, Marco Montillo, Clemens Mellink, Anton W Langerak, Brenda Chyla, Relja Popovic, Yanwen Jiang, Rosemary Millen, Marcus Lefebure, Maria Thadani-Mulero, Michelle Boyer, John F Seymour.

Fixed-duration venetoclax-rituximab (VenR) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) in the phase 3 MURANO trial (NCT02005471) resulted in superior progression-free survival (PFS) and overall survival (OS) vs bendamustine-rituximab (BR). We report the final analyses of MURANO (median 7 years follow-up). Patients were randomized to VenR (venetoclax 400 mg daily for 2 years plus monthly rituximab for 6 months; n = 194) or BR (6 months; n = 195). In a substudy, patients with progressive disease (PD) received VenR as retreatment or crossover from BR. At the final data cut (3 August 2022), median PFS with VenR was 54.7 vs 17.0 months with BR. Seven-year PFS with VenR was 23.0%. Seven-year OS was 69.6% and 51.0%, respectively. Among VenR-treated patients with undetectable (u) minimal residual disease (MRD) and no PD at end of treatment (EOT) (n = 83), median PFS from EOT was 52.5 vs 18.0 months in patients with MRD at EOT (n = 35; P < 0.0001). Fourteen patients had enduring uMRD. Three distinct mutations in BCL2 in four patients were identified. In the substudy, 25 patients were retreated with VenR and nine patients crossed over to VenR; median PFS was 23 and 27 months, and best overall response rate was 72% and 89%, respectively. At the end of combination treatment, following retreatment or crossover, eight and six patients achieved uMRD, respectively. No new safety findings were observed. Overall, these final MURANO analyses support consideration of fixed-duration VenR therapy for patients with relapsed/refractory CLL.

DOI: https://doi.org/10.1182/blood.2024025525
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2025 Feb;33(1): 25-31

[The Comparison of Efficacy and Safety between Venetoclax Combined with Demethylating Drugs and the "3+7" Drug Regimen for Acute Myeloid Leukemia].

Na Cui, Li-Jing Wang, Chang-Yong Yuan.

   OBJECTIVE: To explore the efficacy and safety of venetoclax combined with demethylating drugs and intense chemotherapy in the treatment of acute myeloid leukemia (AML).
METHODS: The clinical data of 76 patients with AML treated in Qilu Hospital of Shandong University Dezhou Hospital from January 2019 to March 2024 were retrospectively analyzed. Patients were divided into observation group and control group. 38 patients in the observation group received venetoclax combined with demethylating drugs (decitabine or azacytidine) and 38 patients in the control group with the "3+7" intensive chemotherapy regimen. The primary endpoints of clinical observation were complete remission (CR), CR with incomplete hematologic recovery (CRi), partial remission (PR), non remission (NR), and overall response rate (ORR). Secondary endpoints were overall survival (OS) and drug safety.
RESULTS: After 2 courses of treatment, the CR+CRi rate in observation group and control group was 71.05% and 65.79%, respectively, and the ORR was 81.58% and 78.95%, respectively. After all courses of treatment, CR+CRi rate in the observation group and the control group was 73.68% and 78.95%, respectively, and the ORR was 81.58% and 84.21%, respectively, with no statistical significance between the two groups (P >0.05). After 1 course of treatment, there were statistically significant differences in the proportion and degree of myelosuppression, the duration of neutropenia and the duration of thrombocytopenia between the two groups (P < 0.05), while there were no statistically significant differences in the occurrence of neutropenia with fever between the two groups (P >0.05). The incidence of non-hematological adverse reactions was highest in infection (mainly pulmonary infection) and gastrointestinal reaction. Among the many adverse reactions, there were statistically significant differences in the infection and hypokalemia between the two groups (P < 0.05), the incidence of hypokalemia in observation group and control group was 42.11% and 15.79%, respectively, and the infection rate in observation group and control group was 73.68% and 94.74%, respectively. The median OS was 13.13(1.67-53.63) months in the observation group and 16.60(0.57-59.67) months in the control group.
CONCLUSION: The combination of venetoclax and demethylating drugs has a low degree of myelosuppression, but a long recovery time, a response rate as good as that of intensive chemotherapy, and a lower infection rate. However, the incidence of hypokalemia is low in the intensive chemotherapy regimen, and the regimen significantly improves the long-term outcome of patients.

Keywords:   acute myeloid leukemia; elderly; venetoclax; demethylation; safety; strong chemotherapy

DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2025.01.004
Biomed Rep. 2025 Apr;22(4): 65

MDM2 inhibitors induce apoptosis by suppressing MDM2 and enhancing p53, Bax, Puma and Noxa expression levels in imatinib‑resistant chronic myeloid leukemia cells.

Akihiro Kimura, Masanobu Tsubaki, Teruki Obana, Taira Matsuo, Rie Komori, Noriaki Nagai, Tetsushi Yamamoto, Shozo Nishida.

  Activation of BCR::ABL1 tyrosine kinase is the main pathogenic mechanism underlying chronic myeloid leukemia (CML) in 90% of affected patients. The prognosis for individuals with CML who receive treatment with BCR::ABL1 tyrosine kinase inhibitors (TKIs) such as imatinib, is promising, with a 5-year survival rate of >90%. However, unfortunately, 20-30% of patients who are treated with imatinib may become resistant to the BCR::ABL1 TKIs. The objective of the present study was to determine whether inhibitors of E3 ubiquitin-protein ligase Mdm2 (MDM2), a regulator of p53 that promotes apoptosis and is highly expressed in CML, could induce cell death in imatinib-resistant CML cells. Apoptosis and cell viability were evaluated using Annexin-V-positive cell count and caspase-3 activity, as well as trypan blue dye exclusion assay. Expression levels of MDM2, p53, Bax, Puma, Noxa, p21, and cleaved caspase-3 were determined via western blotting. MDM2 levels in both the cytoplasm and nucleus were found to be ~3-fold higher in K562/IR cells compared with K562 cells, while the levels of p53 in both cell structures were markedly lower. In addition, an examination of a publicly accessible database revealed that the levels of MDM2 were evidently greater in patients who did not respond to imatinib compared with those who did respond to the drug. NSC-66811 and Nutlin-3, MDM2 inhibitors, increased the percentage of Annexin-positive cells in K562/IR cells by 43 and 62% at concentrations of 10 and 25 µM, respectively. Furthermore, the MDM2 inhibitors increased the levels of Bax, Puma, Noxa, and p21 by increasing the expression of p53 and decreasing the expression of MDM2 in K562/IR cells. Additionally, pifithrin-α, a p53 inhibitor, suppressed MDM2 inhibitor-induced cell death in K562/IR cells. Overall, the findings of the present study highlight the therapeutic potential of MDM2 inhibitors for imatinib-resistant CML.

Keywords:  E3 ubiquitin-protein ligase Mdm2; chronic myeloid leukemia; imatinib resistance; p53

DOI:  https://doi.org/10.3892/br.2025.1943
Future Oncol. 2025 Feb 26. 1-6

Risk-stratified treatment of sonrotoclax with chemotherapy in newly diagnosed acute myeloid leukemia: a study protocol.

Yunxiang Zhang, Min Wu, Zhen Jin, Li Yang, Xufei Huang, Weiming Li, Hongming Zhu, Wenfang Wang, Qiusheng Chen, Ligen Liu, Zhichao Chen, Shaoyuan Wang, Junmin Li.

  Acute myeloid leukemia (AML) treatment relied on anthracyclines and cytarabine based intensive chemotherapy. However, clinical outcomes are unsatisfied for patients with intermediate/adverse cytogenetics based on European Leukemia Net (ELN) risk stratification 2022 (ELN 2022), and relapses also remain common even in patients with favorable-risk cytogenetics with measurable residual disease (MRD). There is an urgent unmet need for optimizing intensive chemotherapy regimens with novel agents, to enhance the MRD-negative rate, achieve durable remission, and improve the prognosis of AML. Preliminary results showed that adding a B-cell lymphoma-2 (BCL-2) inhibitor to intensive chemotherapy could improve treatment efficacy. Sonrotoclax is a potent, selective, next-generation BCL-2 inhibitor that effectively inhibits both the wide-type BCL-2 and several BCL-2 mutants. We hypothesize that the addition of sonrotoclax to intensive chemotherapy may enhance the treatment efficacy for AML without untoward toxicity. Here, we describe the rationale and design of a single-arm, multicenter, phase 2 study evaluating the efficacy and safety of sonrotoclax combined with chemotherapy as an induction therapy in newly diagnosed patients with AML who are fit for intensive chemotherapy, followed by stratified subsequent consolidation and maintenance treatment based on patients' ELN2022 at diagnosis and MRD results after induction.Clinical Trail Registration: NCT06497062.

Keywords:  Acute myeloid leukemia; B-cell lymphoma-2 inhibitor; European Leukemia Net; intensive chemotherapy; measurable residual disease; risk stratification; sonrotoclax

DOI:  https://doi.org/10.1080/14796694.2025.2469487
Int J Cancer. 2025 Feb 28.

Pirtobrutinib in Chinese patients with relapsed or refractory B-cell malignancies: A single-arm, open-label, phase 2, multicenter trial.

Yanyan Liu, Ningjing Lin, Shuhua Yi, Huiqiang Huang, Ye Guo, Qingyuan Zhang, Haiyan Yang, Huilai Zhang, Liling Zhang, Ru Feng, Yijiao Qian, Jiankun Zhu, Yuqin Song, Jun Zhu.

  Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi), demonstrated clinically meaningful antitumor responses in covalent BTKi pretreated mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in the global phase 1/2 BRUIN study. In this multi-center, open-label, phase 2 trial, we investigated the efficacy and safety of pirtobrutinib in Chinese patients with BTKi pretreated relapsed/refractory (R/R) MCL, CLL/SLL, or other B-cell malignancies. All patients received pirtobrutinib once daily in continuous 28-day cycles. The primary endpoint was the overall response rate (ORR). Efficacy was assessed in patients with MCL and CLL/SLL with prior BTKi treatment and safety in all enrolled patients who received at least one dose of pirtobrutinib. Among 35 patients with covalent BTKis (cBTKi) pretreated MCL, the ORR was 62.9% (95% CI: 44.9, 78.5), the median duration of response (DOR) was not reached, and the 12-month DOR rate was 59.7% (95% CI: 35.3, 77.5). Among 11 patients with cBTKi pretreated CLL/SLL, the ORR was 63.6% (95% CI: 30.8, 89.1), and the 12-month DOR rate was 83.3% (95% CI: 27.3, 97.5). The most common adverse events in the safety population (n = 87) were anemia (32.2%) and neutrophil count decreased (31.0%). Grade ≥3 hemorrhage occurred in 2.3% of patients and there were no cases of atrial fibrillation/flutter. Pirtobrutinib demonstrated clinically meaningful efficacy in Chinese patients with cBTKi pretreated R/R MCL, preliminary antitumor activity in Chinese patients with cBTKi pretreated R/R CLL/SLL and was generally well-tolerated with no new safety signals observed.

Keywords:  chronic lymphocytic leukemia/small lymphocytic lymphoma; mantle cell lymphoma; noncovalent BTK inhibitor; pirtobrutinib

DOI:  https://doi.org/10.1002/ijc.35339
Cancers (Basel). 2025 Feb 08. pii: 586. [Epub ahead of print]17(4):

Clinical and Molecular Predictors of Response and Survival Following Venetoclax Plus Hypomethylating Agents in Relapsed/Refractory Acute Myeloid Leukemia: A Single-Center Study in Chinese Patients.

Linya Wang, Haitao Gao, Qiang Fu, Qian Jiang, Hao Jiang, Yu Wang, Lanping Xu, Xiaohui Zhang, Xiaojun Huang, Feifei Tang.

   PURPOSE: This study aimed to investigate the efficacy and the clinical and molecular predictors of response and survival following venetoclax plus hypomethylating agents (VEN + HMAs) in adult relapsed/refractory acute myeloid leukemia (R/R AML) patients.
METHODS: We retrospectively analyzed 197 adult R/R AML patients who received the VEN + HMAs regimen. Molecular profiling was performed using targeted next-generation sequencing (NGS) of 139 genes to explore potential response and survival genetic predictors.
RESULTS: The median treatment cycle was 1 (1-4) cycle. The composite complete remission (CRc) rate, encompassing complete remission (CR) and CR with incomplete hematologic recovery (CRi), was 44.7%, while the overall response rate (ORR) reached 59.9%. With a median follow-up period of 14.0 months (range: 0.7-54.0 months), the 1-year and 2-year overall survival (OS) rates were 55.4% and 40.2%, respectively. Multivariate analyses revealed that mutations in NPM1 and SRSF2 were significantly associated with improved response rates. Conversely, prior exposure to HMA therapy, early relapse, and the presence of GATA2 mutations were linked to lower response rates. Regarding survival outcomes, the CBFB-MYH11 fusion gene, as well as mutations in NPM1 and IDH1/2, were found to be favorable prognostic factors for OS, whereas mutations in FLT3-ITD, TP53, DNMT3A, and GATA2 were associated with worse OS.
CONCLUSIONS: The VEN + HMAs regimen demonstrated considerable efficacy in the treatment of R/R AML patients, with both response rates and overall survival being influenced by distinct genetic features. These findings provide valuable insights into optimizing personalized treatment strategies for this challenging patient population.

Keywords:  genetic characteristics; hypomethylating agents; relapsed or refractory AML; venetoclax

DOI:  https://doi.org/10.3390/cancers17040586
Haematologica. 2025 Feb 27.

Molecular Predictors of Response and Survival in Patients with Relapsed/Refractory Acute Myeloid Leukemia following Venetoclax plus Hypomethylating Agent Therapy.

Isla M Johnson, Rimal Ilyas, Kristen McCullough, Aref Al-Kali, Hassan B Alkhateeb, Kebede H Begna, Abhishek Mangaonkar, Antoine Saliba, Mark R Litzow, William Hogan, Mithun Shah, Mrinal M Patnaik, Animesh Pardanani, Ayalew Tefferi, Naseema Gangat.

Not available.

DOI: https://doi.org/10.3324/haematol.2024.286991
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2025 Feb;33(1): 241-245

[Efficacy and Safety of BeEAM, a Conditioning Regimen for Autologous Stem Cell Transplantation in Malignant Lymphoma].

Feng-Quan Gou, Jia-Jia Li, Jun-Feng Zhu, Kai Zhu, Li-Li Han, Meng Wang, Feng Zhang.

   OBJECTIVE: To investigate the efficacy and safety of the conditioning regimen BeEAM (bendamustine+et-oposide+cytarabine+melphalan) in autologous stem cell transplantation (ASCT) for patients with malignant lymphoma.
METHODS: The clinical data of 20 patients with malignant lymphoma who underwent ASCT after conditioning with BeEAM regimen from January 2021 to December 2022 in the First Affiliated Hospital of Bengbu Medical University were collected, and the clinical characteristics before transplantation, conditioning-related toxicity, hematopoietic reconstitution after transplantation, and therapeutic effects were analyzed. 67 patients with malignant lymphoma who did not undergo ASCT during the same period were selected as the control group, and the 1-year progression-free survival (PFS) rate and overall-survival (OS) rate between the ASCT group and the non-ASCT group were compared.
RESULTS: 15 cases achieved complete remission (CR) and 5 cases achieved partial remission (PR) before transplantation in ASCT group. During the conditioning process of patients in the ASCT group, 14 cases experienced gastrointestinal adverse reactions, 13 cases experienced neutropenic fever, 10 cases experienced oral mucositis, 2 cases experienced abnormal liver function, and only 1 case experienced acute renal injury. All the adverse reactions resolved after symptomatic treatment. After transplantation, 19 cases achieved hematopoietic reconstitution, and only one case had poor platelet engraftment. The median time of peripheral white blood cell (WBC) engraftment was 9 (9-16) days, and the median time of platelet engraftment was 12 (10-23) days. By the end of follow-up, there were no transplant-related deaths. The 1-year PFS rates in the ASCT group and the non-ASCT group were 94.4% and 68.5%, respectively; The 1-year OS rates were 94.4% and 83.5%, respectively. The median PFS and OS time for both groups were not reached. The PFS in the ASCT group was significantly better than that in the non-ASCT group (P < 0.05), and there was no significant difference in OS between the two groups ( P >0.05).
CONCLUSION: BeEAM regimen is safe and effective as a conditioning treatment for ASCT in patients with malignant lymphoma, with tolerable adverse reactions, controllable non-hematological toxicity, smooth hematopoietic reconstitution, and considerable short-term efficacy. However, further follow-up is required to evaluate its long-term efficacy.

Keywords:  malignant lymphoma; autologous stem cell transplantation; BeEAM regimen; therapeutic effect

DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2025.01.036
Haematologica. 2025 Feb 27.

Maintenance therapy with oral decitabine plus cedazuridine after allogeneic stem cell transplantation for myelodysplastic syndrome.

Portia Smallbone, Terri Lynn Shigle, Oren Paslovsky, Chitra Hosing, Amin Alousi, Qaiser Bashir, Yosra Aljawai, Jeremy Ramdial, Uday Popat, Richard Champlin, Elizabeth J Shpall, Betül Oran.

Disease relapse remains the primary challenge for patients undergoing allogeneic transplantation (HSCT) for myelodysplastic syndrome (MDS). Maintenance therapies with hypomethylating agents are under investigation for use in mitigating relapse in high-risk patients. In this retrospective study, we assessed the safety and efficacy of oral decitabinecedazuridine maintenance in 18 high-risk MDS patients post-HSCT. 66.7% (n=12) received decitabine-cedazuridine (35/100mg) on days 1 and 3, while 33.3% (n=6) received therapy on days 1-3. Patients completed a median of six treatment cycles (range; 1-20), with one third of patients completing all planned cycles. No unexpected adverse events were observed, with the primary toxicity being myelosuppression. Grade 1-2 upper respiratory tract infections occurred in 4 patients, and fungal pneumonia in one patient. Overall, patients achieved a median 2-year relapse-free survival (RFS) of 66.7% (95% CI, 40.4-83.4%) and 2-year overall survival of 72.2% (95% CI, 45.6%-87.4%), with relapses occurring predominantly in TP53- mutated cases. Prospective clinical trials are essential to confirm the best tolerated dose with potential to improve transplant outcomes.

DOI: https://doi.org/10.3324/haematol.2024.287177
J Clin Med. 2025 Feb 14. pii: 1254. [Epub ahead of print]14(4):

Use of Primary Prophylaxis with G-CSF in Acute Myeloid Leukemia Patients Undergoing Intensive Chemotherapy Does Not Affect Quality of Response.

Valeria Mezzanotte, Giovangiacinto Paterno, Ilaria Cerroni, Lucrezia De Marchi, Kristian Taka, Elisa Buzzatti, Flavia Mallegni, Elisa Meddi, Federico Moretti, Francesco Buccisano, Luca Maurillo, Raffaele Palmieri, Carmelo Gurnari, Adriano Venditti, Maria Ilaria Del Principe.

  Background/Objectives: The objective of our study was to evaluate the safety and efficacy of granulocyte colony-stimulating factor (G-CSF) as primary prophylaxis in adult patients with acute myeloid leukemia (AML) undergoing intensive chemotherapy. Methods: We retrospectively analyzed 112 AML patients treated with intensive chemotherapy at Fondazione Policlinico Tor Vergata in Rome between January 2014 and March 2024. Patients were divided into G-CSF and non-G-CSF (nG-CSF) groups. We assessed the incidence of neutropenia, its severity and duration; duration of hospitalization and its costs; incidence of febrile neutropenia (FN) and septic shock; duration of antibiotic therapy (ABT) and antifungal therapy (AFT); complete remission (CR) rates; measurable residual disease (MRD) status; relapse rates; and outcomes. Results: G-CSF administration significantly reduced the duration of neutropenia (median 14 vs. 18 days, p < 0.05) and length of hospitalization (median 28 vs. 35 days, p < 0.05), in both induction and consolidation therapy. There were no significant differences in CR rates (73% vs. 67%, p = 0.64), MRD negativity achievement (52% vs. 48%, p = 0.68), leukemia relapse rates (43% vs. 62%, p = 0.14), or overall survival (OS) (median 16.7 vs. 12.3 months, p = 0.3) between G-CSF and nG-CSF groups. Thanks to a shorter hospitalization, the use of G-CSF led to €300,000 in savings over the last 4 years. Conclusions: Our findings support the safety of G-CSF in AML patients, demonstrating no adverse impact on treatment response. G-CSF abbreviated the duration of neutropenia and hospitalization, highlighting its potential clinical and cost-effective role in AML treatment.

Keywords:  acute myeloid leukemia; febrile neutropenia; granulocyte colony-stimulating factor

DOI:  https://doi.org/10.3390/jcm14041254
Ann Hematol. 2025 Feb 28.

Total psoriasis regression in a patient with chronic myeloid leukemia treated using nilotinib.

Tomáš Horňák, Daniela Žáčková, Jiří Mayer.

  Chronic myeloid leukemia (CML) treatment has been revolutionized over last 20 years because of tyrosine kinase inhibitors (TKIs) and patients with CML now have life expectancy of general population. Chronic TKI treatment may cause adverse effects (AEs) that vary in frequency and severity. Nilotinib shows common AEs with metabolic changes and skin AEs. Here, we present a case report of patient who experienced full psoriasis regression while treated with nilotinib. Dose reductions and an attempt to stop nilotinib treatment resulted in prompt psoriasis reappearance. This is the first documented case of positive effect of nilotinib on psoriasis.

Keywords:  Adverse effects; Chronic myeloid leukemia; Nilotinib; Psoriasis; Tyrosine kinase inhibitors

DOI:  https://doi.org/10.1007/s00277-025-06228-x
Blood. 2025 Feb 28. pii: blood.2024026017. [Epub ahead of print]

The Future of Follicular Lymphoma Management: Strategies on the Horizon.

Erin Mulvey, Sarah C Rutherford, John P Leonard.

Progress in the therapy of follicular lymphoma (FL), the most common indolent lymphoma subtype, has been achieved in recent years with significant improvement in median overall survival. Most patients diagnosed with FL will now die from other causes. Multiple novel immunotherapy and other targeted therapies are now approved for relapsed and refractory disease. However, early progression and transformation to aggressive lymphoma remain key issues requiring further innovation. We expect that bispecific antibodies will likely move to earlier use and in novel combinations. Future generations of these and chimeric antigen receptor T-cell therapy will be developed in an effort to minimize toxicity and improve efficacy. New technologies, such as circulating tumor DNA assays, may enable more rational selection and guidance of therapy duration or changes in treatment, as well as possibly substituting for follow up imaging while monitoring patients. We also look forward to more extensive use of quality of life tools to select treatment in patients who have a favorable long-term outlook with multiple options. Finally, patients and clinicians now envision a day when FL is no longer referred to as "incurable". Having a definition and possibility of a "cure" and being able to optimize such a mindset in the approach of FL would represent a major advance in our future management strategy.

DOI: https://doi.org/10.1182/blood.2024026017
Ann Hematol. 2025 Feb 27.

Azacitidine in combination with HAG for newly diagnosed and relapsed/refractory AML: a prospective cohort study.

Hong Pan, Zhen Gao, Yu Lian, Jingyu Zhao, Lele Zhang, Weiwang Li, Ruonan Li, Qian Liang, Jing Xu, Liyun Li, Xiao Yu, Zhexiang Kuang, Jun Shi, Liwei Fang.

  While Azacitidine combined with HAG (HHT, low-dose cytarabine, G-CSF) regimen has shown promise in treating older and unfit patients with acute myeloid leukemia (AML), its efficacy in younger patients remains understudied. This study evaluates the effectiveness and safety of Azacitidine combined with the HAG regimen in a broader patient cohort, including newly diagnosed and relapsed/refractory AML patients. This single-center, prospective cohort included patients with acute myeloid leukemia admitted to our center from June 2019 to Oct 2022 for induction chemotherapy with the HAGA regimen (Azacitidine combined with HAG). We focused on patients' remission rate, MRD (minimal residual disease) conversion and safety. 71 patients with newly diagnosed or R/R AML were enrolled in this study, with a median follow-up time of 20.5 months. After two cycles of HAGA, patients received 3 cycles intermediate-dose Cytarabine and 1 cycle HAGA regimen as consolidation therapies. The CRc (composite complete remission) rate of HAGA regimen as induction chemotherapy for the overall cohort was 85.9% (61/71), which included 71.8% (51/71) CR and 14.1% (10/71) CRi. The CRc with MRD-negative rate was 76.1%. Median OS (overall survival) and DFS (disease free survival) were not yet reached, and the estimated 24-month OS rate was 65.4% (95%CI: 48.4-78.0%), the estimated 24-month DFS rate 66.0% (95%CI: 48.1-79.0%). Only one patient died in induction. The HAGA regimen can be a new option in addition to intense chemotherapy for newly diagnosed or R/R AML, and with high safety.

Keywords:  AML; Azacitidine; HAGA; Induction therapy; Minimal residual disease

DOI:  https://doi.org/10.1007/s00277-024-06171-3
Res Pract Thromb Haemost. 2025 Jan;9(1): 102685

Thromboprophylaxis in multiple myeloma.

Laurent Frenzel.

DOI: https://doi.org/10.1016/j.rpth.2025.102685
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2025 Feb;33(1): 142-149

[Mutation Detection of Plasma Circulating Tumor DNA Associated with Multiple Myeloma].

Qing-Zhao Li, Hai-Mei Chen, Zhao-Hui Yuan, Chan-Juan Shen, Guo-Yu Hu, Juan Peng.

   OBJECTIVE: To explore the clinical significance of 26 circulating tumor DNA (ctDNA) associated with multiple myeloma (MM) in peripheral blood of new diagnosed patients.
METHODS: We conducted a study to detect 26 ctDNA mutations in the peripheral blood of 31 newly diagnosed multiple myeloma (NDMM) patients.
RESULTS: Among the 31 NDMM patients, the ctDNA detection rate was 93.55%, significantly higher than that of FISH and chromosome screening methods. The most frequently mutated genes in NDMM were ACTG1 and GNAS. Notably, ACTG1 mutations were exclusive to NDMM patients, furthermore, resulted from the missense mutation of the exon 4. ACTG1 was the gene most frequently co-mutated with others. All patients with ACTG1 mutations were surviving, and there was a positive correlation between ACTG1 mutation and the survival of patients. GNAS mutations were confined to exon 1.
CONCLUSION: The detection rate of ctDNA sequencing in peripheral blood of NDMM patients was higher than that in bone marrow. ACTG1 and GNAS genes have a guiding role in the prognosis of newly diagnosed patients.

Keywords:   multiple myeloma; circulating tumor DNA; gene mutations

DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2025.01.020
Biomolecules. 2025 Jan 24. pii: 175. [Epub ahead of print]15(2):

XPO1/Exportin-1 in Acute Myelogenous Leukemia; Biology and Therapeutic Targeting.

Øystein Bruserud, Frode Selheim, Maria Hernandez-Valladares, Håkon Reikvam.

  Exportin 1 is responsible for the export of hundreds of proteins, several RNA species and ribosomal components from the nucleus to the cytoplasm. Several transported proteins are important for regulation of cell proliferation and survival both in normal and malignant cells. We review the biological importance and the possibility of therapeutic targeting of Exportin 1 in acute myeloid leukemia (AML). Exportin 1 levels can be increased in human primary AML cells, and even exportin inhibition as monotherapy seems to have an antileukemic effect. The results from Phase I/II studies also suggest that exportin inhibition can be combined with conventional chemotherapy, including intensive induction and consolidation therapy possibly followed by allogeneic stem cell transplantation as well as AML-stabilizing therapy in elderly/unfit patients with hypomethylating agents. However, the risk of severe toxicity needs to be further evaluated; hematological toxicity is common together with constitutional side effects, electrolyte disturbances, and gastrointestinal toxicity. A recent randomized study of intensive chemotherapy with and without the Exportin inhibitor selinexor in elderly patients showed reduced survival in the selinexor arm; this was due to a high frequency of relapse and severe infections during neutropenia. Experimental studies suggest that Exportin 1 inhibition can be combined with other forms of targeted therapy. Thus, Exportin 1 inhibition should still be regarded as a promising strategy for AML treatment, but future studies should focus on the risk of toxicity when combined with conventional chemotherapy, especially in elderly/unfit patients, combinations with targeted therapies, identification of patient subsets (AML is a heterogeneous disease) with high susceptibility, and the possible use of less toxic next-generation Exportin 1 inhibitors.

Keywords:  Exportin 1; RNA; XPO1; acute myeloid leukemia; clinical studies; selinexor; therapeutic targeting

DOI:  https://doi.org/10.3390/biom15020175
Leukemia. 2025 Feb 25.

Challenges determining the best target duration of deep molecular response after which to attempt achieving therapy-free remission in chronic myeloid leukaemia.

Xiaowen Gong, Xiaolin Zhai, Qiujin Shen, Robert Peter Gale, Junren Chen.

DOI: https://doi.org/10.1038/s41375-025-02540-7
Blood. 2025 Feb 26. pii: blood.2024027686. [Epub ahead of print]

Sustained bone marrow and imaging MRD negativity for 3 years drives discontinuation of maintenance post ASCT in myeloma.

Evangelos Terpos, Panagiotis Malandrakis, Ioannis Ntanasis-Stathopoulos, Ioannis V Kostopoulos, Evangelos Eleutherakis-Papaiakovou, Nikolaos Kanellias, Vassiliki Spiliopoulou, Magdalini Migkou, Despina V Fotiou, Foteini Theodorakakou, Efstathios Kastritis, Maria Gavriatopoulou, Ourania Tsitsilonis, Meletios-Athanasios A Dimopoulos.

Discontinuation of lenalidomide maintenance post autologous transplantation (ASCT) is a burning question within the myeloma (MM) community, especially after the inclusion of MRD in the disease response criteria. In this prospective study, we evaluated the conversion to MRD positivity, the treatment-free survival (TFS) and the progression-free survival (PFS) in 52 MM patients, who discontinued lenalidomide maintenance, after achievement of sustained bone marrow and imaging MRD negativity for three years. Patients who developed MRD positivity after lenalidomide discontinuation, restarted lenalidomide maintenance at the same dose. The median follow-up from lenalidomide discontinuation was 3 years. Overall, 12 (23%) patients obtained MRD positivity and restarted lenalidomide maintenance. Only four (7.6%) patients progressed; 3 had a biochemical progression and one had a clinical progression. The overall median PFS was not reached, while the 7-year PFS from diagnosis was 90.2%. The 1-, 2- and 3-year TFS rates were 93.9%, 91.6% and 75.8%, respectively, whereas the 1-, 2- and 3-year landmark PFS rates from maintenance discontinuation (study entrance) were 96.0%, 96.0% and 92.9%, respectively. There were no statistically significant associations between age, gender, R2-ISS, type of induction therapy and use of consolidation therapy and the effect outcomes of PFS, TFS. We conclude that MRD discontinuation after 3-year sustained marrow and imaging MRD negativity is associated with low rates of MRD conversion and progressive disease. Thus, in the era of modern anti-myeloma treatments, a subgroup of patients may remain treatment free while in complete remission, without jeopardizing disease response.

DOI: https://doi.org/10.1182/blood.2024027686