bims-hemali 2025-01-26 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2025–01–26
ten papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone Induction in Newly Diagnosed Myeloma: Analysis of the MIDAS Trial.
Total marrow irradiation as part of autologous stem cell transplantation for patients with multiple myeloma.
Consolidation With Second High Dose Therapy and Autologous Stem Cell Transplantation Is Associated With Improved Overall Survival in Patients With Multiple Myeloma in First Relapse.
Nivolumab and rituximab in treatment naive follicular lymphoma: the phase II '1st FLOR' study.
Final Analysis of the Phase 1b Chemotherapy And Venetoclax in Elderly Acute Myeloid Leukaemia Trial (CAVEAT).
A complete response with daratumumab, venetoclax, azacitidine and dexamethasone in a heavily pre-treated, chemo-refractory early T-precursor acute lymphoblastic leukemia/lymphoma patient.
Pediatric relapsed/refractory ALK+ anaplastic large cell lymphoma treatment and outcomes in the targeted drug era.
CM313 Monotherapy in Patients With Relapsed/Refractory Multiple Myeloma or Marginal Zone Lymphoma: A Multicenter, Phase 1 Dose-Escalation and Dose-Expansion Trial.
Venetoclax and azacitidine in combination with homoharringtonine, cytarabine, and aclarubicin for salvage therapy of relapsed/refractory T cell acute lymphoblastic leukemia.
Exploring the significance of MDM2 gene promoter variants in chronic myeloid leukemia.

Blood. 2025 Jan 22. pii: blood.2024026230. [Epub ahead of print]

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone Induction in Newly Diagnosed Myeloma: Analysis of the MIDAS Trial.

Aurore Perrot, Cyrille Touzeau, Jerome Lambert, Cyrille Hulin, Denis Caillot, Lionel Karlin, Bertrand Arnulf, Philippe Rey, Laurent Garderet, Margaret Macro, Martine Escoffre-Barbe, Julie Gay, Thomas Chalopin, Romain Gounot, Jean Marc Schiano de Colella, Mourad Tiab, Mohamad Mohty, Frédérique Kuhnowski, Jean Fontan, Salomon Manier, Frederique Orsini Piocelle, Laure Vincent, Sophie Rigaudeau, Xavier Leleu, Benjamin Hébraud, Laurent Flet, Jean-Valère Malfuson, Caroline Jacquet, Driss Chaoui, Nathalie Meuleman, Wajed Abarah, Lydia Montes, Riad Benramdane, Cécile Sonntag, Hacene Zerazhi, Alina Danu, Olivier Allangba, Mamoun Dib, Murielle Roussel, Sophie Cereja, Julien Depaus, Nicolas Branche, Hélène Demarquette, Valentine Richez, Cherel Bruiec, Laurent Frenzel, Marie-Christiane Mb Vekemans, Noemie Bigot, Hervé Avet-Loiseau, Jill Corre, Philippe Moreau.

In patients with transplant-eligible newly diagnosed multiple myeloma, induction therapy with a quadruplet regimen prior to autologous transplant is the standard of care. The phase III IFM2020-02-MIDAS study (NCT04934475) assessed a minimal residual disease (MRD)-driven consolidation and maintenance strategy following induction with isatuximab, carfilzomib, lenalidomide, and dexamethasone (IsaKRD). Here, we report safety and efficacy outcomes of six 28-day cycles of IsaKRD. Between December 2021 and July 2023, 791 patients were enrolled across 72 centers. The median age was 59 years; 13% had ISS-stage III, 5% had R-ISS-stage III, and 8% had high-risk cytogenetics (IFM Linear Predictor cytogenetic score >1). Overall, 96% (N=757) of patients completed induction. The median CD34+ cell yield was 7 × 106/Kg, with 94% of patients able to proceed with a potential tandem transplant. The best overall response rate was 95%. In the intent-to-treat population, 91% achieved a very good partial response or better after induction, with MRD-negativity rates of 63% at 10-5 and 47% at 10-6. MRD-negativity rates differed across ISS stages and cytogenetic subgroups. During induction, 7 patients experienced disease progression, and 5 died due to disease progression (N=1), cardiac events (N=2), or other causes (N=2). The most common grade 3/4 adverse events were neutropenia (25%), thrombocytopenia (5%), and infections (7%); only 13% of patients reported any grade peripheral neuropathy. IsaKRD induction yielded deep responses and high MRD-negativity rates while ensuring successful stem cell collection, with no new safety signals. Continued follow-up of this ongoing study is required to confirm these findings.

DOI: https://doi.org/10.1182/blood.2024026230
Ann Hematol. 2025 Jan 24.

Total marrow irradiation as part of autologous stem cell transplantation for patients with multiple myeloma.

Qing-Xiu Zhong, Fan-Yi Meng, Hong-Yu Chen, Xin Li, Xiao-Guo Wang, Shun-Hua Huang, Ming-Yan Wu, Jian-Hua Yu, Ying Xue, Yi-Hong Wu, Da-Na Yao, Jia-Xin Long, Xiao-Hong He.

  The efficacy and safety of total marrow irradiation (TMI) plus a reduced dose of melphalan as autologous stem cell transplantation (ASCT) preconditioning for multiple myeloma (MM) patients were evaluated. The 11 patients with MM had a median age of 57 (range: 46-75) years; six of them were at standard risk and five of them were at high risk based on the Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART) standard risk factors. Before ASCT, three patients achieved stringent complete response (sCR), two patients achieved complete remission (CR), and the rest of the patients had either partial response (PR) or progressive disease. Most of the 11 patients were pretreated with melphalan 120-140 mg/m2 and TMI 12 Gy. The intravenous infusion median mononuclear cell count (MNC) was 8.13 (4.16-11.84) × 108/kg, and the median CD34+ count was 4.74 (2.51-21.98) × 106/kg. The minimal residual disease (MRD) in the grafts as determined by flow cytometry (FCM) and fluorescence in situ hybridization (FISH) were negative in 10 patients but positive in the progressive patient. All patients stopped maintenance therapy after transplantation, and further observation focused on the efficacy and tolerability of the transplantation. The neutropenic and thrombocytopenia durations were 11 (7-28) and 14 (8-70) days, respectively. The primary acute non-hematological toxicities were mild oral and gastrointestinal mucositis; there were no transplant-related deaths or serious complications. Of the eight patients who did not achieve sCR before transplantation, seven converted to sCR and one converted to VGPR after transplantation. The median follow-up period was 24 (10-57.5) months. Only one patient relapsed, and the progression-free survival (PFS) was 90.9%, while the overall survival (OS) was 100%. Our preliminary results suggest that melphalan 120-140 mg/m2 plus TMI 12 Gy/6f as a conditioning regimen is safe and efficient for patients with MM.

Keywords:  Autologous stem cell transplantation; Melphalan; Multiple myeloma; Total marrow irradiation

DOI:  https://doi.org/10.1007/s00277-025-06219-y
Clin Lymphoma Myeloma Leuk. 2024 Dec 24. pii: S2152-2650(24)02449-2. [Epub ahead of print]

Consolidation With Second High Dose Therapy and Autologous Stem Cell Transplantation Is Associated With Improved Overall Survival in Patients With Multiple Myeloma in First Relapse.

Koen M Klomberg, Miriam Gelderloos, Hilde A M Kooistra, Marcel Nijland, Gerwin A Huls, Wilfried W H Roeloffzen, Wouter J Plattel.

   BACKGROUND: High dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) remains the preferred first line consolidation strategy for newly diagnosed multiple myeloma (MM). However, The role of HDT/ASCT in first relapse is uncertain in the context of novel therapies. This study evaluates real-world outcomes of MM patients in first relapse, focusing on the role of consolidative HDT/ASCT.
PATIENTS AND METHODS: This retrospective cohort study was conducted at a large tertiary referral center in Northern Netherlands. MM patients who received first-line HDT/ASCT and obtained a good response were included. The time to next treatment or death (TTNT-D 2) and overall survival (OS) were evaluated, while identifying prognostic factors. A landmark analysis was performed at 6 months, including only patients with a partial response (PR) or better after re-induction.
RESULTS: This study identified 237 patients potentially eligible for repeated HDT/ASCT of whom 111 (47%) underwent a second consolidative HDT/ASCT. The median follow-up is 40 months. Baseline characteristics were largely similar, though second HDT/ASCT was applied only after achieving PR or better. In the landmark analysis, absence of high-risk cytogenetics and good performance status were associated with longer TTNT-D 2. Consolidative second HDT/ASCT, absence of high-risk cytogenetics and longer first response duration were associated with longer OS. Transplantation-related mortality rate was < 1%.
CONCLUSION: This study highlights the viability of second HDT/ASCT as treatment option for relapsed MM, particularly for patients with good responses to first-line HDT/ASCT. In the era of novel agents, second HDT/ASCT should be considered a feasible and effective consolidative strategy.

Keywords:  Relapsed multiple myeloma; Second high dose therapy and autologous stem cell transplantation

DOI:  https://doi.org/10.1016/j.clml.2024.12.010
Blood Adv. 2025 Jan 24. pii: bloodadvances.2024015487. [Epub ahead of print]

Nivolumab and rituximab in treatment naive follicular lymphoma: the phase II '1st FLOR' study.

Allison Barraclough, Sze Ting Lee, Melinda Burgess, Leonid Churilov, Geoffrey Chong, Denise Lee, Michael Gilbertson, Tineke Fancourt, Kate Manos, David Ritchie, Rachel M Koldej, Andrew Scott, Colm Keane, Eliza A Hawkes.

Follicular lymphoma (FL) outcomes are heavily influenced by host immune activity with immune anti-tumor activity mitigated by PD-1/PD-L1 pathway engagement. Combination CD20-directed therapy plus PD-1 inhibition (PD-1i) increases T-cell tumor killing and NK-cell antibody-dependent cell cytotoxicity (ADCC). Mounting evidence supports immune-priming using PD-1i before cancer-directed agents. Our multicentre, open-label, phase II 1st FLOR study (NCT03245021) enrolled 39 previously-untreated advanced-stage FL patients to receive 4 cycles of nivolumab (240mg) then 4 cycles of 2-weekly nivolumab plus rituximab 375mg/m2 (induction) then 1 year of monthly nivolumab (480mg) plus 2 years of 2-monthly rituximab maintenance. Participants with complete response (CR) after nivolumab priming continued nivolumab monotherapy. The primary endpoint was toxicity during induction. Adverse events (AEs) ≥ grade 3 during induction occurred in 33% (n=13); most commonly elevated amylase/lipase (15%), liver enzyme derangement (11%) and infection (10%). Three patients discontinued nivolumab secondary to toxicity; two pancreatitis, one acute kidney injury. Overall response rate (ORR) was 92% (CR 59%). Median follow-up was 51 months. Median and 4-year progression-free survival (PFS) were 61 months (95%CI 2-72) and 58% (95%CI 34-97); 70% of responders remained in CR. 4-year overall survival was 95%. High baseline total metabolic tumor volume and total lesion glycolysis conferred inferior PFS (p=0.04 and p=0.02). Additionally, high baseline tumor CD8A gene expression was associated with improved PFS (p=0.03). Nivolumab priming followed by nivolumab-rituximab in treatment-naive FL is associated with favorable toxicity and high response rates potentially providing an alternative to chemotherapy. TMTV and high tumor CD8A expression are promising immunotherapy biomarkers for FL.

DOI: https://doi.org/10.1182/bloodadvances.2024015487
Blood Adv. 2025 Jan 18. pii: bloodadvances.2024014900. [Epub ahead of print]

Final Analysis of the Phase 1b Chemotherapy And Venetoclax in Elderly Acute Myeloid Leukaemia Trial (CAVEAT).

Chong Chyn Chua, Sun Loo, Chun Yew Fong, Stephen B Ting, Ing S Tiong, Shaun A Fleming, Natasha S Anstee, Adam Ivey, Michael Ashby, Tse-Chieh Teh, John Reynolds, Andrew W Roberts, Andrew H Wei.

Venetoclax plus azacitidine represents a key advance for older, unfit patients with acute myeloid leukemia (AML). The chemotherapy and venetoclax in elderly AML trial (CAVEAT) was first to combine venetoclax with intensive chemotherapy in newly diagnosed patients ≥65 years. In this final analysis, 85 patients (median age 71 years) were followed for a median of 41.8 months. The CAVEAT induction combined cytarabine and idarubicin with 5 dose levels of venetoclax (50-600 mg) for up to 14 days. Two additional cohorts explored adjusted-dose venetoclax (50 mg, 100 mg) with posaconazole. CAVEAT induction was well tolerated, with low mortality (4%) and limited high-grade gastrointestinal toxicity (4%). Delayed hematological recovery after consolidation was ameliorated by omitting idarubicin from post-remission therapy. The overall response rate (ORR: CR + CRh + CRi) was 75% with a median overall survival (OS) of 19.3 months (95% CI 11.1-31.3). Among de novo AML, ORR was 88% and median OS 33.1 months (95% CI 19.3-54.3). Almost one-third have not relapsed, many benefiting from prolonged treatment-free remission (median 17.9 months). CAVEAT induction was well tolerated and associated with high ORR that was durable, particularly for de novo AML. CAVEAT represents an effective time-limited treatment option for fit older patients with AML. (https://www.anzctr.org.au; ACTRN12616000445471).

DOI: https://doi.org/10.1182/bloodadvances.2024014900
Ann Hematol. 2025 Jan 23.

A complete response with daratumumab, venetoclax, azacitidine and dexamethasone in a heavily pre-treated, chemo-refractory early T-precursor acute lymphoblastic leukemia/lymphoma patient.

Süreyya Yiğit Kaya, Mehrad Vatani, Rima Akil, Tansel Cakir, Senem Maral, Leylagül Kaynar, Ömür Gökmen Sevindik.

  Early T-precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) is a rare and aggressive subtype of T-cell leukemia with poor prognosis and resistance to standard treatments. We report a 21-year-old male with ETP-ALL/LBL who, after an initial complete remission with the HOELZER protocol, experienced early relapse and was refractory to subsequent FLEND and BFM protocols. Following disease progression and complications, he was treated with a combination of daratumumab, venetoclax, azacitidine, and dexamethasone. This regimen achieved complete remission after one cycle. This case highlights the potential of this combination therapy as an effective treatment for refractory ETP-ALL/LBL, suggesting further research is warranted to validate its efficacy and safety.

Keywords:  Allogeneic hemopoietic stem cell transplantation; Azacitidine; Daratumumab, Venetoclax; Dexamethasone; Early T-precursor acute lymphoblastic leukemia/Lymphoma

DOI:  https://doi.org/10.1007/s00277-024-06118-8
Blood Adv. 2025 Jan 22. pii: bloodadvances.2024014745. [Epub ahead of print]

Pediatric relapsed/refractory ALK+ anaplastic large cell lymphoma treatment and outcomes in the targeted drug era.

Lianna J Marks, Victor Ritter, Jennifer Agrusa, Kala Y Kamdar, Julie Rivers, Rebecca A Gardner, Matthew J Ehrhardt, Kaitlin J Devine, Charles A Phillips, Anne F Reilly, Keith August, Joanna L Weinstein, Prakash Satwani, Christopher Jon Forlenza, Christine Moore Smith, Chelsee Greer, Zeinab Afify, Carol H Lin, Jennifer A Belsky, Hilda Ding, David Hoogstra, Keri Toner, Michael P Link, Liora M Schultz, Eric J Lowe, Catherine Aftandilian.

Treatment options for patients with relapsed or refractory (R/R) anaplastic large cell lymphoma (ALCL) have increased in the era of targeted therapies such as brentuximab vedotin (BV) and Anaplastic Lymphoma Kinase (ALK) inhibitors. However, there is no standard treatment and limited published data evaluating their use. The goal of this retrospective study is to describe current real-world treatment and outcomes of pediatric, adolescent, and young adult patients with R/R ALK-positive ALCL. We conducted a retrospective, multi-institutional study identifying 81 patients with R/R ALK-positive ALCL ≤ 21 years old at initial diagnosis treated between 2011-2022 across 18 institutions. Median time from diagnosis to relapse was 8.9 months (range 2.6-131.9). Initial reinduction regimens included ALK inhibitor monotherapy (n=37, 46%), BV monotherapy (n=19, 23%), chemotherapy without targeted therapy (n=12, 15%), chemotherapy with targeted therapy (n=9, 11%), or vinblastine monotherapy (n=4, 5%) with 83% of patients achieving a complete response to initial reinduction regimen. Fifty-eight patients received a hematopoietic stem cell transplant (HSCT), 11 autologous and 48 allogeneic, with one receiving both. Duration of treatment for patients receiving BV or the ALK-inhibitor crizotinib (CZ) varied widely (BV 1-11 years; CZ 2-10 years). Five-year event-free survival 63% (95% CI 53-75%) and five-year overall survival 91% (95% CI 84-98%). This is the largest collection of patients with R/R ALK+ ALCL treated in the era of targeted therapy. Patients achieved excellent responses to ALK-inhibitor or BV monotherapy, but questions remain about duration of therapy and role of HSCT.

DOI: https://doi.org/10.1182/bloodadvances.2024014745
Am J Hematol. 2025 Jan 22.

CM313 Monotherapy in Patients With Relapsed/Refractory Multiple Myeloma or Marginal Zone Lymphoma: A Multicenter, Phase 1 Dose-Escalation and Dose-Expansion Trial.

Huixing Zhou, Zhongxia Huang, Baijun Fang, Hongmei Jing, Zhongjun Xia, Yuqin Song, Zhen Cai, Gang An, Ling Qin, Li Bao, Xin Li, Yuzhang Liu, Yanrong Wang, Ling Li, Wenming Chen.

DOI: https://doi.org/10.1002/ajh.27573
Int J Hematol. 2025 Jan 23.

Venetoclax and azacitidine in combination with homoharringtonine, cytarabine, and aclarubicin for salvage therapy of relapsed/refractory T cell acute lymphoblastic leukemia.

Lin-Sen Feng, Hui-Yuan Li, Ai Tang, Meng-Li Xu, San-Bin Wang.

   BACKGROUND: The treatment of relapsed/refractory T cell acute lymphoblastic leukemia (R/R T-ALL) is a significant challenge in hematologic oncology, and no standard salvage treatment plan exists. Both Chinese and international clinical guidelines recommend combination chemotherapy including venetoclax.
METHODS: Efficacy and safety of venetoclax, azacitidine, homoharringtonine, cytarabine, and aclarubicin (VA-HAA) combination therapy were retrospectively analyzed in 3 patients with R/R T-ALL at the Department of Hematology, 920th Hospital of the Joint Logistics Support Force, Chinese People's Liberation Army.
RESULTS: The chemotherapy resulted in CR/CRi with negative flow MRD in all 3 patients. Quantitative negative conversion was achieved in 2 patients with fusion genes, and the frequency of monoclonal TCR gene rearrangements was significantly reduced in 1 patient. All patients received stem cell rescue after the chemotherapy. Hematologic toxicity may be manageable, with a median of 24 days for complete recovery of neutrophils (ANC) and 36 days for partial recovery of platelets. There were no major bleeding events or chemotherapy-related deaths.
CONCLUSION: VA-HAA may be an effective and safe salvage treatment for R/R T-ALL, and prospective clinical trials are needed to verify its specific clinical efficacy.

Keywords:  Efficacy; Safety; Salvage therapy; T cell acute lymphoblastic leukemia

DOI:  https://doi.org/10.1007/s12185-025-03915-3
Leuk Res. 2025 Jan 07. pii: S0145-2126(25)00004-9. [Epub ahead of print]149 107644

Exploring the significance of MDM2 gene promoter variants in chronic myeloid leukemia.

María Belén Fontecha, María Del Rosario Anadón, Inés María Martínez Lahitou, Natalia Weich, Raquel Bengió, Beatriz Moiraghi, Irene Larripa, Ariela Freya Fundia.

  Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 are highly successful in chronic myeloid leukemia (CML). However, extensive interpatient variability in therapeutic responses and resistance supports the need to find new prognostic biomarkers. We have previously reported that TP53 SNP215 variant affects CML risk and clinical outcome. We aimed to evaluate the role of MDM2 genetic variants in CML susceptibility and treatment response to TKIs. We genotyped five MDM2 promoter variants (del1518, SNP309, SNP285, SNP288 and SNP344) in 135 CML patients and 136 healthy individuals. Our study showed that MDM2 variants alone or in combination had no effect on CML susceptibility. The analysis of MDM2 genotypes in relation to patients' clinical parameters revealed that individuals with SNP309 G/G genotypes were at a significantly increased risk of undergoing molecular response failure (p = 0.044). Improved overall survival was also observed for non-responders with the alternative MDM2 del1518 del allele (p = 0.017) as well as for MDM2 del1518-SNP309 combinations with alternative genotypes (p = 0.014). In addition, combinatorial analysis demonstrated that alternative MDM2 SNP309 and TP53 SNP215 genotypes together are associated with faster achievement of MR2 (p = 0.029) and MMR (p = 0.042) in non-responders, suggesting a relationship with a favorable outcome. Overall, our study highlights the influence of MDM2 variants on clinical outcome, supporting that specific genotypes, alone or in combination, underlie the treatment-responsive phenotype.

Keywords:  Chronic myeloid leukemia; Genetic variants; MDM2 Gene; Polymorphisms; Susceptibility; Tyrosine kinase inhibitors

DOI:  https://doi.org/10.1016/j.leukres.2025.107644