bims-hemali Biomed News
on Hematologic malignancies
Issue of 2024–11–24
37 papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Selinexor combined with bortezomib, lenalidomide, and dexamethasone for the treatment of newly diagnosed multiple myeloma with extramedullary disease.
  2. Ibrutinib With Bendamustine and Rituximab for Treatment of Patients With Relapsed/Refractory Aggressive B-Cell Lymphoma.
  3. MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide and dexamethasone in newly diagnosed multiple myeloma.
  4. Glofitamab plus gemcitabine and oxaliplatin (GemOx) versus rituximab-GemOx for relapsed or refractory diffuse large B-cell lymphoma (STARGLO): a global phase 3, randomised, open-label trial.
  5. First Line Treatment of Newly Diagnosed Transplant Eligible Multiple Myeloma Recommendations From a Canadian Consensus Guideline Consortium.
  6. Selinexor in combination with pomalidomide and dexamethasone for the treatment of primary plasma cell leukemia with 1q21+ abnormality: A case report.
  7. Comparison of CAR T-cell and bispecific antibody as third-line or later-line treatments for multiple myeloma: a meta-analysis.
  8. Clinical Characteristics and Survival Outcomes of Patients With Primary and Secondary Plasma Cell Leukemia According to the 2021 Definition: A Single Center Retrospective Study.
  9. Sintilimab plus decitabine for higher-risk treatment-naïve myelodysplastic syndromes: efficacy, safety, and biomarker analysis of a phase II, single-arm trial.
  10. Safety and Efficacy of Teclistamab in Patients With Relapsed or Refractory AL Amyloidosis.
  11. The incidence and clinical significance of monoclonal and oligoclonal protein bands in multiple myeloma patients after BCMA-CAR-T cell therapy: A retrospective study based on LEGEND-2.
  12. Nelarabine-combined chemotherapy improves outcome of T-cell acute lymphoblastic leukemia but shows more severe neurotoxicity: JALSG T-ALL213-O.
  13. Comparison of regimens targeting complete remission in the first-line treatment of acute myeloid leukemia patients.
  14. Liposomal Doxorubicin, Vinblastine and Dacarbazine Plus Consolidation Radiotherapy of Residual Nodal Masses for Frontline Treatment in Older Adults With Advanced Stage Classic Hodgkin Lymphoma: Improved Outcome in a Multi-Center Real-Life Study.
  15. Development of ALL-Hematotox (ALL-HT): Predicting post CAR T-cell hematotoxicity in B-cell acute lymphoblastic leukemia.
  16. Efficacy and safety of daratumumab for the treatment of refractory/relapsed multiple myeloma. A systematic review of meta-analyses.
  17. Optimizing resources: low-dose nivolumab combinations in the management of relapsed/refractory Hodgkin lymphoma.
  18. Multiple myeloma: retrospective assessment of routine thromboprophylaxis and utility of thrombotic risk scores.
  19. Treatment Intensification With Either Fludarabine, AraC, G-CSF and Idarubicin, or Cladribine Plus Daunorubicin and AraC on the Basis of Residual Disease Status in Older Patients With AML: Results From the NCRI AML18 Trial.
  20. High-dose chemotherapy with autologous haematopoietic stem cell transplantation in patients with isolated vitreoretinal lymphoma: a LOC network study.
  21. Economic Evaluation of Adding Daratumumab to Carfilzomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma.
  22. A systematic review on the epidemiology and treatment options of multiple Myeloma in Asia.
  23. Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib: A Phase 1b Randomized Clinical Trial.
  24. Clinical characteristics and risk factors of infection in initially treated patients with multiple myeloma during the induction period.
  25. A phase 2 clinical trial of luspatercept in non-transfusion-dependent patients with myelodysplastic syndromes.
  26. Efficacy and safety of blinatumomab for the treatment of patients relapsing after allogeneic hematopoietic cell transplantation: a systemic review and meta-analysis.
  27. Impact of prior CAR-T cell therapy on mosunetuzumab efficacy in patients with relapsed or refractory B-cell lymphomas.
  28. The modified melphalan and busulfan-based regimen combined with maintenance therapy improved the survival of patients with refractory/relapsed AML after allogeneic transplantation: middle-term outcome of a multicenter trial.
  29. Efanesoctocog Alfa Versus Emicizumab in Adolescent and Adult Patients With Haemophilia A Without Inhibitors.
  30. Imetelstat, a novel, first-in-class telomerase inhibitor: Mechanism of action, clinical, and translational science.
  31. Odronextamab: First Approval.
  32. Cyclin D1-negative Mantle Cell Lymphoma.
  33. Real-world toxicity and efficacy of asciminib in heavily pretreated patients with chronic myeloid leukemia.
  34. Review of BCL2 inhibitors for the treatment of Waldenström's macroglobulinaemia and non-IgM lymphoplasmacytic lymphoma.
  35. The Hidden Danger Unveiling the Connection Between Multiple Myeloma and Pleural Effusion.
  36. RCHOP plus BTK inhibitor improves clinical outcomes in double expressor diffuse large B-cell lymphoma, unlike RCHOP plus lenalidomide.
  37. Symptom experience of patients undergoing treatment for multiple myeloma: a longitudinal real-world electronic patient-reported outcomes study.
  1. Sci Rep. 2024 11 19. 14(1): 28557
    Selinexor combined with bortezomib, lenalidomide, and dexamethasone for the treatment of newly diagnosed multiple myeloma with extramedullary disease.
    Junjing Yin, Xia Zhou, Xuemei Li, Chenglu Yuan, Xiaoxia Chu, Lumei Hao, Hongying Wu, Yuping Zhong.
       OBJECTIVE: We aimed to explore the efficacy and safety of Selinexor combined bortezomib, lenalidomide, and dexamethasone (XVRd) protocol in newly diagnosed multiple myeloma with extramedullary disease.
    METHODS: This is a single-arm, open, observational clinical study. For induction/consolidation(21-day cycles), patients received 8 cycles of XVRd protocol. In maintenance (28-day cycles), patients received XR (Selinexor + Lenalidomide) at least 2 years until disease progression, death or withdrawal. The primary endpoints were overall response rates and minimal residual disease negative rates.
    RESULTS: The median age of the 10 patients was 62 (range 55-81) years. R-ISS stage 3 was present in 2 (20%) patients. 3 patients had high risk cytogenetic and 1 patient with plasma cell leukocyte. According to IMWG criteria, the ORR of 10 patients with NDMM was 100%, including 2 stringent complete response (sCR), 2 complete remission (CR), 4 very good partial response (VGPR) and 2 partial response (PR). Median progression-free survival and overall survival were not achieved. The most common grade 3-4 treatment-emergent adverse events (occurring in 10% of patients) were thrombocytopenia. The most common non-hematological adverse events were grade 1 or 2, including nausea (30%), fatigue (40%), and anorexia (20%). Overall, the severe toxicities were manageable.
    CONCLUSION: The XVRd regimen had good efficacy and safety in newly diagnosed multiple myeloma with extramedullary disease.
    Keywords:  Extramedullary disease; Multiple myeloma; Selinexor
    DOI:  https://doi.org/10.1038/s41598-024-79537-2
  2. Hematol Oncol. 2024 Nov;42(6): e70001
    Ibrutinib With Bendamustine and Rituximab for Treatment of Patients With Relapsed/Refractory Aggressive B-Cell Lymphoma.
    Meirav Kedmi, Elena Ribakovsy, Ohad Benjamini, Ginette Schiby, Iris Barshack, Stephen Raskin, Yael Eshet, Ramit Mehr, Netanel Horowitz, Ronit Gurion, Neta Goldschmidt, Chava Perry, Itai Levi, Ariel Aviv, Katrin Herzog-Tzarfati, Arnon Nagler, Abraham Avigdor.
      Therapy for relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (aB-NHL) post autologous stem cell transplantation (ASCT) or in elderly patients can be challenging. In this single-center, single-arm, phase II clinical study, we investigated the efficacy of ibrutinib (560 mg once daily) in combination with bendamustine and rituximab (IBR) given for six 28-day cycles in their standard dose, to patients with R/R aB-NHL who were either transplant ineligible in first or second relapse or post-ASCT for second relapse. The primary endpoint was overall response rate (ORR). Fifty-six patients (54% male, median age 69.7 years) were included. ORR was 49.1% among 55 patients treated with ≥ 1 cycle of IBR and 69.4% among 36 patients treated with ≥ 3 cycles. Patients with relapsed disease had significantly higher ORR compared to those with refractory disease (72.3% vs. 37.8%, p = 0.024). Median overall survival (OS) was 11.6 months (95% CI, 7.1-22.3) and median progression-free survival was 5.3 months (95% CI, 2.5-7.4). Patients with complete and partial responses had significantly longer median OS compared to those with stable and progressive disease (28.1 vs. 5.2 months, p < 0.0001). Adverse events included thrombocytopenia (19.6%), anemia (16.1%), neutropenia (7.1%), fatigue (35.7%), diarrhea (28.6%) and nausea (28.6%). At the first efficacy evaluation 8 patients were referred to transplantation, and 3 more were referred during follow-up. These data indicate that the IBR regimen is a safe and effective treatment option that can also be used for bridging to transplantation in patients with R/R aB-NHL.Trial Registration: ClinicalTrials.gov: NCT02747732.
    Keywords:  aggressive B‐cell lymphoma; elderly; ibrutinib bendamustine and rituximab; refractory disease; relapsed disease
    DOI:  https://doi.org/10.1002/hon.70001
  3. Blood Adv. 2024 Nov 22. pii: bloodadvances.2024014417. [Epub ahead of print]
    MRD-driven phase 2 study of daratumumab, carfilzomib, lenalidomide and dexamethasone in newly diagnosed multiple myeloma.
    Manisha Bhutani, Myra Robinson, David Foureau, Shebli Atrash, Barry A Paul, Fei Guo, Jason Grayson, Anna Ivanina-Foureau, Mauricio Pineda-Roman, Cindy Varga, Reed Friend, Christopher J Ferreri, Xhevahire Begic, Sarah Norek, Tiffany Drennan, Michelle B Anderson, James T Symanowski, Peter M Voorhees, Saad Z Usmani.
      In newly diagnosed multiple myeloma (NDMM), measurable residual disease (MRD) status is prognostically important, but its role in treatment-decisions remains unclear. In a phase II trial (NCT04113018), we assessed daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction followed by a next generation sequencing (NGS) based MRD-adapted strategy. The primary endpoint was rate of complete response and stringent complete response (≥CR) after induction. Flow cytometry was used to profile T cells. Among 39 patients, 21 (54%) achieved ≥CR post-induction (P=0.375) with MRD-negative rates of 59% (10-5) and 41% (10-6). MRD-negative patients (n=24, group A) received lenalidomide maintenance, showing sustained MRD-negativity in 14/18 (77.8%) for ≥12 cycles. MRD-positive transplant-eligible patients (n=8, group B) underwent ASCT, with 5 (62.5%) converting to MRD-negative (10-5) and 3 (37.5%) at 10-6. MRD-positive transplant-ineligible patients (n=4, group C) received KRd consolidation. MRD-negative rates improved to 77% (10-5) and 72% (10-6) at any time. No additional safety concerns were identified beyond those already known for Dara-KRd. With a median follow-up of 30.1 months, three, two and one patient(s) in groups A, B, and C have experienced disease progression or death. The 2-year PFS rate was 82.5%. We observed that the Dara-KRd regimen strongly activated memory T cells, which was associated with an MRD-negative state after induction. Although the primary endpoint was not met, Dara-KRd induction in NDMM achieved high rates of ≥CR and MRD-negativity without new safety concerns. The post-induction MRD-adapted strategy deepened responses in the MRD-positive group while maintaining durable MRD control in the negative group.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014417
  4. Lancet. 2024 Nov 16. pii: S0140-6736(24)01774-4. [Epub ahead of print]404(10466): 1940-1954
    Glofitamab plus gemcitabine and oxaliplatin (GemOx) versus rituximab-GemOx for relapsed or refractory diffuse large B-cell lymphoma (STARGLO): a global phase 3, randomised, open-label trial.
    Jeremy S Abramson, Matthew Ku, Mark Hertzberg, Hui-Qiang Huang, Christopher P Fox, Huilai Zhang, Dok Hyun Yoon, Won-Seog Kim, Haifaa Abdulhaq, William Townsend, Charles Herbaux, Jan M Zaucha, Qing-Yuan Zhang, Hung Chang, Yanyan Liu, Chan Yoon Cheah, Herve Ghesquieres, Stephen Simko, Victor Orellana-Noia, Richard Ta, James Relf, Mark Dixon, Martine Kallemeijn, Estefania Mulvihill, Huang Huang, Linda Lundberg, Gareth P Gregory.
       BACKGROUND: Glofitamab monotherapy induces durable remission in patients with relapsed or refractory diffuse large B-cell lymphoma after two or more previous therapies, but has not previously been assessed as a second-line therapy. We investigated the efficacy and safety of glofitamab plus gemcitabine-oxaliplatin (Glofit-GemOx) versus rituximab (R)-GemOx in patients with relapsed or refractory diffuse large B-cell lymphoma.
    METHODS: The phase 3, randomised, open-label STARGLO trial was done at 62 centres in 13 countries in Asia and Australia, Europe, and North America. We recruited transplant-ineligible patients (aged ≥18 years) with histologically confirmed relapsed or refractory diffuse large B-cell lymphoma after one or more previous therapies. Patients were randomly assigned in permuted blocks (block size of six) via an interactive voice or web response system (2:1; stratified by 1 vs ≥2 previous lines of therapy and relapsed vs refractory status) to Glofit-GemOx (intravenous gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2 plus glofitamab step-up dosing to 30 mg; for a total of eight cycles, plus four additional cycles of glofitamab monotherapy) or R-GemOx (intravenous gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2 plus rituximab 375 mg/m2; for a total of eight cycles). The trial independent review committee, which evaluated all response-based endpoints, was masked to treatment assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat in all randomly assigned patients. We present results from both the primary analysis (cutoff: March 29, 2023) and updated analysis after all patients had completed study therapy (cutoff: Feb 16, 2024). Safety analyses included all patients who received any study treatment. This study is registered with ClinicalTrials.gov, NCT04408638, and is ongoing (closed to recruitment).
    FINDINGS: From Feb 23, 2021, to March 14, 2023, 274 patients were enrolled and randomly assigned to receive Glofit-GemOx (n=183) or R-GemOx (n=91). 158 (58%) patients were male and 116 (42%) were female; median age was 68 years (IQR 58-74). At the primary analysis after a median follow-up of 11·3 months (95% CI 9·6-12·7), overall survival was significantly improved with Glofit-GemOx versus R-GemOx (median not estimable [NE; 95% CI 13·8 months-NE] vs 9·0 months [7·3-14·4]; hazard ratio [HR] 0·59 [95% CI 0·40-0·89]; p=0·011). At the updated analysis after a median follow-up of 20·7 months (19·9-23·3), a consistent improvement in overall survival was observed with Glofit-GemOx versus R-GemOx (median 25·5 months [18·3-NE] vs 12·9 months [7·9-18·5]; HR 0·62 [0·43-0·88]). In the safety sets, 180 (100%) patients in the Glofit-GemOx group and 84 (96%) of 88 patients in the R-GemOx group had at least one adverse event during the study period. Cytokine release syndrome occurred in 76 (44%) of 172 glofitamab-exposed patients and was predominantly low grade. Deaths related to glofitamab or rituximab occurred in five (3%) patients in the Glofit-GemOx group and in one (1%) patient in the R-GemOx group.
    INTERPRETATION: Glofit-GemOx had a significant overall survival benefit compared with R-GemOx, supporting its use in transplant-ineligible patients with relapsed or refractory diffuse large B-cell lymphoma after one or more previous lines of therapy.
    FUNDING: F Hoffmann-La Roche.
    DOI:  https://doi.org/10.1016/S0140-6736(24)01774-4
  5. Clin Lymphoma Myeloma Leuk. 2024 Oct 23. pii: S2152-2650(24)02385-1. [Epub ahead of print]
    First Line Treatment of Newly Diagnosed Transplant Eligible Multiple Myeloma Recommendations From a Canadian Consensus Guideline Consortium.
    Sahar Khan, Debra J Bergstrom, Julie Côté, Rami Kotb, Richard LeBlanc, Martha L Louzada, Hira S Mian, Ibraheem Othman, Gabriele Colasurdo, Alissa Visram.
      The availability of effective therapies for multiple myeloma (MM) has sparked debate on the role of first line autologous stem cell transplantation (ASCT), particularly in standard-risk patients. However, treatment for individuals with high-risk disease continues to display suboptimal outcomes. With novel therapies used earlier, practice is changing rapidly in the field of MM. Presently, quadruplet induction therapy incorporating an anti-CD38 monoclonal antibody to a proteasome inhibitor and an immunomodulatory drug prior to ASCT followed by maintenance therapy stands as the foremost strategy for attaining deep and sustained responses in transplant eligible MM (TEMM). This Canadian Consensus Guideline Consortium (CGC) proposes consensus recommendations for the first line treatment of TEMM. To address the needs of physicians and people diagnosed with MM, this document focuses on ASCT eligibility, induction therapy, mobilization and collection, conditioning, consolidation, and maintenance therapy, as well as, high-risk populations, management of adverse events, assessment of treatment response, and monitoring for disease relapse. The CGC will periodically review the recommendations herein and update as necessary.
    Keywords:  Adverse events; Canadian guidelines; Comorbidity and frailty assessment; Response and relapse monitoring; TEMM
    DOI:  https://doi.org/10.1016/j.clml.2024.10.012
  6. Medicine (Baltimore). 2024 Nov 15. 103(46): e40447
    Selinexor in combination with pomalidomide and dexamethasone for the treatment of primary plasma cell leukemia with 1q21+ abnormality: A case report.
    Wenxia Fan, Lei Wang, Xinyou Wang, Ying Liu, Mingling Sun, Nadia Abduklimu, Rui Zhang, Ming Jiang, Xinhong Guo.
       RATIONALE: Primary plasma cell leukemia is a rare and highly aggressive malignancy of the blood system, with rapid disease progression and a high early mortality rate. Currently, there is no recognized therapeutic regimen, leading to the adoption of strategies typically utilized for multiple myeloma, which, however, exhibit limited efficacy. Selinexor is considered effective in treating relapsed/refractory multiple myeloma, but there are currently no reports on its application in primary plasma cell leukemia. Here, we reported a case of primary plasma cell leukemia with multiple high-risk genetic factors (including 1q21+, 17p-, and 13q-) who received a chemotherapy regimen including selinexor, pomalidomide, and dexamethasone.
    PATIENT CONCERNS: This case was a 58-year-old male presenting with lower back pain, abdominal pain, and various systemic symptoms.
    DIAGNOSES: The initial diagnosis of intestinal obstruction at a local hospital was followed by a referral to our emergency department due to abnormal blood test results indicative of a hematologic disorder. Further investigations confirmed a rare diagnosis of primary plasma cell leukemia of the IgA-k light chain subtype.
    INTERVENTIONS: The patient was promptly treated with a chemotherapy regimen comprising selinexor, pomalidomide, and dexamethasone in addition to supportive care.
    OUTCOMES: Subsequent assessments showed a significant response to treatment, with improvement in symptoms, normalization of blood parameters, and achievement of very good partial response. However, due to financial constraints, the patient declined hematopoietic stem cell transplantation and eventually opted to discontinue treatment, leading to disease progression.
    LESSONS: The combination of selinexor with pomalidomide and dexamethasone has shown good efficacy in primary plasma cell leukemia with high-risk genetic abnormalities. Our case may provide evidence for developing an effective selinexor-based regimen for treating primary plasma cell leukemia with high-risk genetic abnormalities.
    DOI:  https://doi.org/10.1097/MD.0000000000040447
  7. J Immunother Cancer. 2024 Nov 17. pii: e010064. [Epub ahead of print]12(11):
    Comparison of CAR T-cell and bispecific antibody as third-line or later-line treatments for multiple myeloma: a meta-analysis.
    Xiaojie Liang, Yufan Wang, Baiwei Luo, Bingyu Lin, WeiXiang Lu, Shengyu Tian, Dan Liu, Liang Wang.
       BACKGROUND: CAR-T-cell therapy and bispecific antibody have revolutionized the treatment landscape for multiple myeloma. However, there is currently a lack of studies comparing the efficacy and safety of these two approaches. This meta-analysis assesses the efficacy and safety of B-cell maturation antigen (BCMA)-directed CAR-T-cell therapies and BCMA×CD3 bispecific antibodies as third-line or later interventions for relapsed/refractory multiple myeloma (RRMM).
    METHODS: We searched PubMed, Embase, Web of Science, and Cochrane databases up to May 31, 2024, identifying 11 eligible studies encompassing 1269 participants. Random-effects models evaluated the primary (complete response (CR) rate) and secondary (overall response rate (ORR)) outcomes, while meta-regression analyses adjusted for relevant covariates.
    RESULTS: CAR-T-cell therapy achieved significantly higher pooled CR rate (0.54 (95% CI 0.42-0.69) vs bispecific antibodies 0.35 (0.30-0.41), p<0.01) and pooled ORR (0.83 (0.76-0.90) vs 0.65 (0.59-0.71), p<0.01). However, CAR-T therapy had a higher incidence of adverse events, particularly cytokine release syndrome (CRS 0.83 (0.70-0.97) vs bispecific antibodies 0.59 (0.43-0.74), p<0.05). Severe CRS (grade ≥3) occurred at a rate of 0.07 (0.03-0.14) in the CAR-T cell group, contrasting with a negligible rate of 0.01 (0.00-0.02) in the bispecific antibody group (p<0.01). Hematologic adverse events, including neutropenia (grade ≥3; 0.88 (0.81-0.95) vs 0.48 (0.30-0.67), p<0.01) and anemia (grade≥3; 0.55 (0.47-0.62) vs 0.34 (0.28 to 0.40), p<0.01), were also more frequent in the CAR-T-cell group. Furthermore, differences in efficacy were observed among various CAR-T products, with ciltacabtagene autoleucel showing greater efficacy in CR rate (0.77 (0.71-0.84) vs 0.37 (0.32-0.41), p<0.01) and ORR (0.91 (0.83-0.99) vs 0.73 (0.68-0.77), p<0.01) compared with idecabtagene vicleucel.
    CONCLUSION: CAR-T-cell therapy demonstrated superior CR rates compared with bispecific antibodies, although with an increase in severe adverse events.
    Keywords:  bispecific T cell engager - BiTE; chimeric antigen receptor - CAR; hematologic malignancies; multiple myeloma
    DOI:  https://doi.org/10.1136/jitc-2024-010064
  8. Clin Lymphoma Myeloma Leuk. 2024 Oct 28. pii: S2152-2650(24)02399-1. [Epub ahead of print]
    Clinical Characteristics and Survival Outcomes of Patients With Primary and Secondary Plasma Cell Leukemia According to the 2021 Definition: A Single Center Retrospective Study.
    Khalid Shalaby, Farhan Azad, Sarah Parker, Chong Wang, Han Yu, Kristopher Attwood, Jens Hillengass.
       INTRODUCTION: Plasma cell leukemia (PCL) is a rare malignancy with poor overall survival (OS). Recently, its diagnostic criteria were revised by lowering the threshold of circulating plasma cells from ≥ 20% to ≥ 5%.
    METHODS: Between 2010 and 2024, patients with primary PCL (pPCL) and secondary PCL (sPCL) were identified at a tertiary center. We retrospectively analyzed baseline characteristics, treatment, and survival in months (m).
    RESULTS: We identified 30 patients with pPCL and 29 patients with sPCL. The median time to sPCL in patients who received Daratumumab (Dara)-containing regimens for multiple myeloma was 46.8m compared with 12.3m in patients who did not (P=0.007). Of the whole cohort, 51.9% received an induction regimen with novel agents without chemotherapy. Of the evaluable patients with pPCL and sPCL, 82.1% (23/28) and 64.7% (11/17) achieved partial response or better respectively. Median progression free survival was significantly worse in patients with sPCL than pPCL (2.2 vs. 38.3 months; HR 0.16; 95% CI (0.07-0.35), P < .001). Median OS was also worse in patients with sPCL compared with pPCL (3.1 months vs. NR [not reached]; HR 0.09; 95%CI 0.04-0.23, P < .001). The median post-SCT survival for patients with pPCL was NR compared with 6.7m for patients with sPCL (HR 0.17; 95% CI (0.03-0.83), P = .03). Dara-refractory status was associated with worse OS (HR 5.63; 95% CI (2.75-11.51), P < .0001).
    CONCLUSION: Outcomes of pPCL are improving but remain dismal for sPCL. We explored the role of novel agents, especially Dara, in the treatment of PCL. More prospective trials are needed to improve its outcomes.
    Keywords:  Daratumumab; Multiple myeloma; Prognosis; Stem cell transplant
    DOI:  https://doi.org/10.1016/j.clml.2024.10.014
  9. J Immunother Cancer. 2024 Nov 21. pii: e010355. [Epub ahead of print]12(11):
    Sintilimab plus decitabine for higher-risk treatment-naïve myelodysplastic syndromes: efficacy, safety, and biomarker analysis of a phase II, single-arm trial.
    Jing Wang, Siqi Li, Hao Jiang, Ying-Jun Chang, Xiaosu Zhao, Jinsong Jia, Xiaolu Zhu, Lizhong Gong, Xiaohong Liu, Wenjing Yu, Xiaojun Huang.
       BACKGROUND: Immunotherapy combined with azacitidine was feasible in higher-risk myelodysplastic syndromes (MDSs) with limited sample size of treatment-naïve patients, while the optimization of treatment strategies, including the optimal immune checkpoint inhibitor and hypomethylating agent and possible benefiting population, remained undefined. This study first evaluates the efficacy and safety of sintilimab, a PD-1 blockade, plus decitabine in treatment-naïve higher-risk MDS patients and investigates biomarkers for predicting treatment response.
    METHODS: In this phase II, single-arm trial (ChiCTR2100044393), treatment-naïve higher-risk MDS patients with an International Prognostic Scoring System-Revised score >3.5 received sintilimab (200 mg, days 1 and 22) and decitabine (20 mg/m2, day 1-5) over 6-week cycles. The primary endpoint was the overall response rate (ORR), including complete remission (CR), partial remission (PR) or marrow CR.
    RESULTS: A total of 54 eligible patients were enrolled and treated, with 25 (46.3%) having very high-risk MDS. Among 53 evaluable patients, the ORR was 77.4% (n=41), including 26.4% CR (n=14). The overall clinical improvement rate (CR, PR, marrow CR or hematological improvement) reached 81.1%. With a median follow-up of 20.0 months, the median event-free survival was 23 months with 12 progressing to acute myeloid leukemia. Median overall survival was not reached. Treatment was generally well tolerated, with hematologic toxicities being the most common adverse events. Biomarker analysis highlighted a negative correlation between T cell exhaustion markers, particularly TIM-3 and PD-1, with ORR.
    CONCLUSIONS: The combination of sintilimab and decitabine shows promise efficacy for higher-risk MDS, with a favorable safety profile. The potential predictive value of T cell exhaustion biomarkers might help screen the possible benefiting population.
    TRIAL REGISTRATION NUMBER: ChiCTR210044393.
    Keywords:  Immunotherapy
    DOI:  https://doi.org/10.1136/jitc-2024-010355
  10. Eur J Haematol. 2024 Nov 17.
    Safety and Efficacy of Teclistamab in Patients With Relapsed or Refractory AL Amyloidosis.
    Margaret Stalker, Alfred Garfall, Adam Cohen, Dan T Vogl, Mia Djulbegovic, Sandra Susanibar-Adaniya, Edward Stadtmauer, Oxana Megherea, Adam J Waxman.
       INTRODUCTION: Teclistamab has demonstrated deep responses in patients with multiple myeloma in the MajesTEC-1 study. However, the safety and efficacy of teclistamab in patients with AL amyloidosis are unknown.
    METHODS: We retrospectively analyzed patients with biopsy-proven relapsed/refractory AL amyloidosis who were treated with teclistamab from December 2022 to February 2024 at the University of Pennsylvania. The data cutoff was 2/29/24. Adverse events (AE) were extracted from the electronic medical record. Patients were assessed for hematologic and organ response per consensus guidelines.
    RESULTS: Eight patients were included in this case series: median age 63 (range 59-67), 75% female, 88% White. All eight patients achieved at least very good partial response (VGPR) and had normalization of free light chains (FLC), and six (75%) patients achieved undetectable FLC levels. Of the six patients with immunofixation completed, all six (100%) achieved hematologic complete response (hCR). The median time to hematologic VGPR and hCR was 13 days (range 12-18 days) and 88 days (range 32-150 days), respectively. The median duration of follow-up was 8.5 months (range 1-14 months). Of the five patients with cardiac involvement, four (80%) achieved a cardiac response. Of the seven patients with renal involvement, two patients already achieved renal response prior to teclistamab, and of the remaining five, three (60%) achieved renal response. Six patients (75%) developed low-grade cytokine release syndrome (CRS). No patients developed ICANS. Neutropenia and AKI both occurred in 25% of patients, respectively.
    CONCLUSIONS: In this series of patients, teclistamab showed outstanding depth of response and was well-tolerated. Teclistamab shows promise in treating patients with relapsed AL amyloidosis.
    Keywords:  AL amyloidosis; bispecific antibody; safety and efficacy; teclistamab
    DOI:  https://doi.org/10.1111/ejh.14348
  11. Hemasphere. 2024 Nov;8(11): e70054
    The incidence and clinical significance of monoclonal and oligoclonal protein bands in multiple myeloma patients after BCMA-CAR-T cell therapy: A retrospective study based on LEGEND-2.
    Rui Liu, Gongzhizi Gao, Hongli Chen, Ruijun Dong, Wanggang Zhang, Wanhong Zhao, Jie Liu, Jianli Wang, Bo Lei, Baiyan Wang, Jiali Liu, Xuezhu Xu, Zujie Lin, Ruoyu Yang, Yiwen Wang, Aili He, Fangxia Wang, Ju Bai.
      The emergence of abnormal protein bands (APBs), also known as oligoclonal protein bands, has been documented in patients with multiple myeloma (MM) post hematopoietic stem cell transplantation. However, the incidence rate and clinical significance of APBs remain contentious. Few studies have explored the occurrence and prognostic implications of APBs in patients with MM treated with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR)-T therapy. In this retrospective study, we examined the frequency, isotypes, and duration of APBs, as well as their correlation with MM disease characteristics, treatment response, clinical outcomes, and immune signature in patients with relapsed/refractory MM who had received LCAR-B38M therapy at the Xi'an site of the phase 1 LEGEND-2 trial. Among 47 patients assessed, 23 (48.9%) developed APBs following CAR-T therapy, with IgG being the most common isotype. The median onset and duration of APBs post-CAR-T infusion were 3.6 and 5.8 months, respectively. Patients with APBs demonstrated significantly improved response to LCAR-B38M therapy, along with longer overall and progression-free survival. Furthermore, those with APBs exhibited enhanced recovery rates of immunoglobulins and higher absolute counts of white blood cells, neutrophils, and lymphocytes post-CAR-T treatment compared to those without APBs. However, no significant differences were observed between the two groups in the percentages of various T-cell subsets and natural killer cells. Overall, the presence of APBs in patients with MM following CAR-T treatment was associated with deeper remission and a more favorable prognosis, suggesting a robust humoral response and subsequent immune reconstitution.
    DOI:  https://doi.org/10.1002/hem3.70054
  12. Cancer Sci. 2024 Nov 21.
    Nelarabine-combined chemotherapy improves outcome of T-cell acute lymphoblastic leukemia but shows more severe neurotoxicity: JALSG T-ALL213-O.
    Japan Adult Leukemia Study Group (JALSG)
      We investigated the effectiveness and safety of nelarabine (NEL)-combined chemotherapy for newly diagnosed adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We conducted a phase II trial, T-ALL213-O, where adult T-ALL patients aged 25 to 64 were treated by a regimen based on that used in our previous study, ALL202-O. The main modifications from ALL202-O to T-ALL213-O were as follows: (1) NEL-combined chemotherapy, instead of consolidation (C)1, was used for non-complete remission (CR) patients after induction therapy (IND)1 as IND2; (2) NEL treatments were inserted into C3 and C5 on day 29. Twenty-four patients were analyzed. Ten patients did not receive NEL treatment due to therapy termination prior to C3. Three-year event-free survival (EFS) was 70%, with 52% as the lower limit of its 90% confidence interval, which exceeded the threshold of 25%; thus, the study treatment was considered effective. The CR rates by IND1, IND2, and both were 75%, 100%, and 88%, respectively. The 5-year EFS and 5-year overall survival rates were 66% and 70%, respectively, with median follow-ups of 7.7 and 7.8 years. The addition of NEL improved the CR rate but not survival, compared with T-ALL patients in ALL202-O. Severe neuropathy after NEL administration was observed at a high frequency. Seven (50%) of 14 patients treated with NEL showed grade 3 peripheral neuropathy and/or gait disturbance. The neurotoxicity was considered stronger than that previously reported. Combination therapy of NEL at this dose and intensive multidrug chemotherapy is associated with a high risk of severe neurotoxicity (JALSG T-ALL213-O, UMIN000010642).
    Keywords:  T‐ALL; acute lymphoblastic leukemia; clinical trial; nelarabine; neuropathy
    DOI:  https://doi.org/10.1111/cas.16405
  13. Eur Rev Med Pharmacol Sci. 2024 Nov;pii: 36908. [Epub ahead of print]28(21): 4493-4506
    Comparison of regimens targeting complete remission in the first-line treatment of acute myeloid leukemia patients.
    S Yavuz, U Y Malkan.
       OBJECTIVE: Standard treatment for adults with acute myeloid leukemia (AML) involves anthracycline and cytarabine, while alternative regimens are necessary for elderly and frail patients. This study aims to compare the effectiveness and safety of various induction regimens in AML patients.
    PATIENTS AND METHODS: The retrospective study included 130 adult AML patients treated at a tertiary care center from January 2014 to December 2022. Patients received one of the following induction regimens: anthracycline and cytarabine (n = 82), azacitidine and venetoclax (n = 11), etoposide and cytarabine (n = 22), or reduced-dose anthracycline and cytarabine (n = 15). Data on demographics, clinical characteristics, treatment-related toxicities, and infectious complications were collected. Outcomes included overall survival and remission rates.
    RESULTS: The anthracycline and cytarabine regimen demonstrated the highest overall survival rate, although remission rates did not significantly differ among the treatment groups. Patients receiving azacitidine and venetoclax experienced a significantly longer duration of neutropenia. The use of antiviral prophylaxis increased over the study period, reflecting improved management strategies. Infection remained the leading cause of mortality.
    CONCLUSIONS: Effective management of prolonged neutropenia and infections is crucial for improving patient outcomes. Future research should focus on optimizing prophylactic and infection treatment strategies to further enhance survival in AML.
    DOI:  https://doi.org/10.26355/eurrev_202411_36908
  14. Hematol Oncol. 2024 Nov;42(6): e70003
    Liposomal Doxorubicin, Vinblastine and Dacarbazine Plus Consolidation Radiotherapy of Residual Nodal Masses for Frontline Treatment in Older Adults With Advanced Stage Classic Hodgkin Lymphoma: Improved Outcome in a Multi-Center Real-Life Study.
    M Picardi, A Vincenzi, C Giordano, L De Fazio, N Pugliese, A Scarpa, E Vigliar, G Troncone, D Russo, M Mascolo, G Esposito, M Prastaro, C Santoro, R Esposito, C G Tocchetti, C Mainolfi, R Fonti, S Del Vecchio, M Carchia, C Quagliano, A Salemme, V Damiano, R Bianco, F Trastulli, F Ronconi, M Annunziata, F Pane.
      In elderly patients with high-risk classic Hodgkin lymphoma (c-HL), we evaluated the impact of a new modality treatment without bleomycin, that is, liposomal doxorubicin (NPLD)-based regimen plus consolidation radiotherapy of residual nodal masses (RNMs), on overall survival (OS) and progression free survival (PFS). In this retrospective study (2013-2023) conducted in tertiary hospitals in the bay of Naples (Italy), 50 older adults (median age, 69 years; range, 60-89) with advanced stage c-HL received frontline treatment with MVD ± irradiation. MVD consisted of 25 mg/m2 of NPLD along with standard Vinblastine and Dacarbazine for a total of 6 cycles (twelve iv administrations, every 2 weeks) followed by radiation of RNMs with size ≥ 2.5 cm at computed tomography. Patients underwent MVD with a median dose intensity of 92%. At 2-deoxy-2[F-18] fluoro-D-glucose positron emission tomography (FDG-PET), 90% of patients (45/50 patients; one failed to perform final FDG-PET due to early death) reached complete responses. Altogether, 17 patients (34%) received consolidation radiotherapy of RNMs with Deauville score ≥ 3. At 5-year median follow-up, the OS and PFS of the entire population were 87.5% (95% confidence interval [CI], 78.7-97.4) and 81.6% (95% CI, 71.4-93.2), respectively. Eleven patients (22%) experienced grade ≥ 3 adverse events, and 4 of them required hospitalization. Our data suggest that in older adults with high-risk c-HL NPLD-driven strategy (without bleomycin) plus consolidation radiotherapy (if needed) may be a promising up-front option, to test in phase II clinical trials for improving survival incidence.
    Keywords:  MVD; consolidation radiotherapy; c‐HL; elderly patients; non‐pegylated liposomal doxorubicin
    DOI:  https://doi.org/10.1002/hon.70003
  15. Blood. 2024 Nov 19. pii: blood.2024025910. [Epub ahead of print]
    Development of ALL-Hematotox (ALL-HT): Predicting post CAR T-cell hematotoxicity in B-cell acute lymphoblastic leukemia.
    Monica S Nair, Sara K Silbert, Kai Rejeski, Karilynn A Wilson, Adam Joseph Lamble, Yannis K Valtis, Bonnie Yates, Alexa Morales Arana, Roni Shouval, Kevin J Curran, Rebecca A Gardner, Haneen Shalabi, Colleen Annesley, Jae H Park, Marion Subklewe, Nirali N Shah.
      Immune effector cell-associated hematotoxicity (ICAHT) is a major B-cell targeted chimeric antigen receptor (CAR) T-cell related toxicity. While ICAHT incidence and severity is documented in large B-cell lymphoma (LBCL), mantle cell lymphoma (MCL), and multiple myeloma (MM), ICAHT has not been described in B-cell acute lymphoblastic leukemia (B-ALL). Similarly, the CAR-HEMATOTOX (CAR-HT) model, designed to predict severe prolonged neutropenia (>14 days of ANC <500/µl), has been validated in LBCL, MCL, and MM, but not in B-ALL. As B-ALL bone marrow (BM) infiltration can impact cytopenias, we sought to describe ICAHT and assess CAR-HT for predicting hematotoxicity in B-ALL. In a cohort of 156 children and young adults with relapsed/refractory B-ALL, the median duration of severe neutropenia (ANC <500/µl) was 13 days (95% CI 10-16), with 83 (53%) experiencing grade >3 ICAHT. Applying CAR-HT, nearly 90% were classified as high-risk, demonstrating limited discriminative power and prompting further development. Using the association identified between BM disease burden and post-infusion neutropenia (r=0.64, p<0.0001), we developed the ALL-Hematotox (ALL-HT) score which substitutes BM disease burden for ferritin in CAR-HT. The ALL-HT score associated with severe prolonged neutropenia (area under the curve=0.84, p<0.0001), and appropriately discriminated high-risk patients (47%) who had more cumulative days of neutropenia (26 vs 4 days, p<0.0001), fewer rates of complete response (88% vs 98%, p=0.03), and shorter median overall survival (9.8 vs 24 months, logrank p=0.0002). ALL-HT was also validated in two independent cohorts. The ALL-HT score refines a widely accepted predictive model of post-infusion hematotoxicity, applicable in B-ALL.
    DOI:  https://doi.org/10.1182/blood.2024025910
  16. J Oncol Pharm Pract. 2024 Nov 21. 10781552241290452
    Efficacy and safety of daratumumab for the treatment of refractory/relapsed multiple myeloma. A systematic review of meta-analyses.
    Diala Alhaj Moustafa, Laila Shafei, Ruba Sulaiman, Mohamed A Yassin, Dina Abushanab, Yousef Algarabli, Daoud Al-Badriyeh.
       INTRODUCTION: Several meta-analyses (MAs) of the efficacy and safety of daratumumab in refractory/relapsed multiple myeloma (RRMM) exist. They include different types of populations, Daratumumab regimens, and outcomes. Moreover, there is a wide variation in methodological quality and risk of bias.
    OBJECTIVE: This study aimed to conduct a systematic review of MAs to summarize the literature on the efficacy and safety profile of daratumumab use in RRMM, and also provide an assessment of the quality and risk of bias of the MAs if sufficient data is available.
    METHODS: The literature databases Pubmed, Embase, Web of Science, and Cochrane were searched since inception. The quality of methodology was assessed by the AMSTAR-2 tool, and the risk of bias was assessed by the ROBIS tool.
    RESULTS: Eight MAs were included in the SR. Most studies reported ORR and CR improvement by adding daratumumab to the chemotherapy regimen. Five MAs reported improvement in PFS in daratumumab-based regimens compared to non- daratumumab-based regimens. Only two MAs reported molecular response, favoring daratumumab. Dara was associated with adverse drug events (ADEs), including pneumonia and diarrhea. Conflicting evidence regarding hematological ADEs association with daratumumab exists. The overall quality of the studies is poor, but the MAs had a low risk of bias overall.
    CONCLUSION: Despite including low-quality MAs, this SR provides a summary that simplifies clinicians' access to efficacy and safety outcomes of daratumumab in RRMM patients. Future studies are required to reduce the uncertainty and produce higher-quality Mas, particularly regarding daratumumab's safety.
    Keywords:  Daratumumab; hematology; meta-analysis; multiple myeloma; refractory; systematic review
    DOI:  https://doi.org/10.1177/10781552241290452
  17. Ann Hematol. 2024 Nov 19.
    Optimizing resources: low-dose nivolumab combinations in the management of relapsed/refractory Hodgkin lymphoma.
    Perla R Colunga-Pedraza, Héctor A Vaquera-Alfaro, Zulia Guzmán-Martínez, Marion Carolina Alemán-Jiménez, Antonio Vega-Mateos, Andrés Gómez-De León, Luis Mario Villela, David Gómez-Almaguer.
      Up to one-third of patients with classical Hodgkin lymphoma (cHL) are not responsive to first-line therapy or eventually relapse. Immune checkpoint inhibitors (ICIs) have been successfully employed to treat relapsed/refractory cHL (r/r cHL) but place patients at risk of financial toxicity. Early-phase trials and observational data suggest that low doses of ICIs may achieve similar results to those obtained with high doses. In this study, we report a single-center experience using low-dose nivolumab (LD-Nivo) in different combinations for r/r cHL, including monotherapy, LD-Nivo plus brentuximab vedotin (BV), and LD-Nivo plus chemotherapy. The primary outcome was to assess the efficacy of LD-nivo in patients with r/r cHL. We included 23 consecutive patients (median age 27 years; 57% female). LD-Nivo was prescribed in 40, 100, and 140 mg fixed doses Q2W. Survival analysis was performed employing the Kaplan-Meier method. 73% of patients achieved an overall response, 43% complete response, and 30% partial response. One-year overall survival was 94.4% (95% CI, 0.84-1), and the 1-year progression-free survival was 89.4% (95% CI, 0.77-1). OS and PFS were similar accross combinations. The median dose of nivolumab was 0.78 mg/kg (range, 0.62-1.11), and the median number of cycles until a response was documented was 6 (range, 2-9). During follow-up, 18 patients received transplantation (11 autologous, 6 allogeneic). No statistically significant differences in survival or response were detected between nivolumab combinations or doses. Adverse events were observed in 61% of the patients, with none grade 3-4. LD-Nivo demonstrated promising results in relapsed/refractory HL, highlighting its potential as a cost-effective treatment option. Further research is needed to validate these findings and guide clinical practice.
    Keywords:  Checkpoint inhibitors; Hodgkin lymphoma; Low-dose; Nivolumab; Refractory disease; Relapse
    DOI:  https://doi.org/10.1007/s00277-024-06098-9
  18. Res Pract Thromb Haemost. 2024 Oct;8(7): 102571
    Multiple myeloma: retrospective assessment of routine thromboprophylaxis and utility of thrombotic risk scores.
    Omar Eduardo Fernandez-Vargas, Isabel Amezcua, Beatriz Cabello, Andrea Quintana Martinez, Ramiro Espinoza, Gabriela Cesarman-Maus.
       Background: The high risk of venous thromboembolism (VTE) in multiple myeloma (MM) warrants primary thromboprophylaxis for most patients. Myeloma-specific thrombotic risk scores (TRSs), such as IMPEDE-VTE, SAVED, and PRISM, were developed to improve risk assessment and guide antithrombotic strategies. Their performance is variable and has not yet been tested in Latin America.
    Objectives: We aimed to assess the use of primary thromboprophylaxis, the incidence of VTE and bleeding events, and the effectiveness of TRSs in patients with newly diagnosed MM.
    Methods: This was a retrospective, single-center study. Cumulative VTE rates and TRS performance were analyzed using survival and receiver operating characteristic curves.
    Results: The study included 250 newly diagnosed MM patients; the vast majority (98.6%) received aspirin as thromboprophylaxis. VTE occurred in 8% within the initial 6 months, increasing to 14.8% over a median follow-up of 19 months. High rates of major bleeding (4.8%) and clinically relevant nonmajor bleeding (4.4%) events were documented. A minimal proportion (0.8%, 0.5%, and 1.2%) of patients were classified as low risk by IMPEDE-VTE, PRISM, and SAVED scores, respectively. Only IMPEDE-VTE exhibited a trend for distinguishing between intermediate-risk (7.14%) and high-risk (13.2%) groups (P = .09). PRISM and SAVED scores showed limited utility. VTE did not impact survival.
    Conclusion: Aspirin as primary thromboprophylaxis carries an unacceptable risk of VTE and bleeding in patients at intermediate or high thrombotic risk. The IMPEDE-VTE score performed best, although without reaching statistical significance. We confirm that VTE does not portend poor overall survival in MM.
    Keywords:  aspirin; multiple myeloma; prophylaxis; risk factors; venous thromboembolism
    DOI:  https://doi.org/10.1016/j.rpth.2024.102571
  19. J Clin Oncol. 2024 Nov 18. JCO2400259
    Treatment Intensification With Either Fludarabine, AraC, G-CSF and Idarubicin, or Cladribine Plus Daunorubicin and AraC on the Basis of Residual Disease Status in Older Patients With AML: Results From the NCRI AML18 Trial.
    Nigel H Russell, Abin Thomas, Robert K Hills, Ian Thomas, Amanda Gilkes, Nuria Marquez Almuina, Sarah Burns, Lucy Marsh, Paresh Vyas, Marlen Metzner, Nicholas McCarthy, Georgia Andrew, Jennifer Byrne, Rob S Sellar, Richard Kelly, Paul Cahalin, Ulrik Malthe Overgaard, Priyanka Mehta, Mike Dennis, Steven Knapper, Sylvie D Freeman.
       PURPOSE: To evaluate the survival benefit of chemotherapy intensification in older patients with AML who have not achieved a measurable residual disease (MRD)-negative remission.
    METHODS: Five hundred twenty-three patients with AML (median age, 67 years; range, 51-79) without a flow cytometric MRD-negative remission response after a first course of daunorubicin and AraC (DA; including 165 not in remission) were randomly assigned between up to two further courses of DA or intensified chemotherapy-either fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (FLAG-Ida) or DA with cladribine (DAC).
    RESULTS: Overall survival (OS) was not improved in the intensification arms (DAC v DA: hazard ratio [HR], 0.74 [95% CI, 0.55 to 1.01]; P = .054; FLAG-Ida v DA: HR, 0.86 [95% CI, 0.66 to 1.12]; P = .270); OS at 3 years was 34%, 46%, and 42% for DA, DAC, and FLAG-Ida, respectively. Early deaths and other adverse events were more frequent with FLAG-Ida (9% day 60 deaths v 4% after DA or DAC; P = .032). Of patients entering random assignment, 131 had MRD unknown status. In this subgroup of patients lacking evidence of residual leukemia by flow cytometry, there was no detectable survival advantage from intensification. A planned sensitivity analysis excluding these patients demonstrated a survival benefit for both DAC (HR, 0.66 [95% CI, 0.46 to 0.93]; P = .018) and FLAG-Ida (HR, 0.72 [95% CI, 0.53 to 0.98]; P = .035); OS at 3 years was 30%, 46%, and 46% for DA, DAC, and FLAG-Ida, respectively. There was a concordant reduction in relapse (DAC v DA: HR, 0.66 [95% CI, 0.45 to 0.98]; P = .039; FLAG-Ida v DA: HR, 0.70 [95% CI, 0.49 to 0.99]; P = .042). DAC benefit was maintained when survival was censored for transplant (P = .042).
    CONCLUSION: In this study of older patients with AML considered fit and with evidence of residual disease after first induction, chemotherapy intensification improved survival. DAC intensification was better tolerated than FLAG-Ida.
    DOI:  https://doi.org/10.1200/JCO.24.00259
  20. Bone Marrow Transplant. 2024 Nov 19.
    High-dose chemotherapy with autologous haematopoietic stem cell transplantation in patients with isolated vitreoretinal lymphoma: a LOC network study.
    Adam Mainguy, Carole Soussain, Valérie Touitou, Amin Bennedjai, Laurent Kodjikian, Hervé Ghesquières, Gandhi Damaj, Rémy Gressin, Jean-Baptiste Ducloyer, Olivier Chinot, Anaïs Vautier, Cécile Moluçon-Chabrot, Guido Ahle, Luc Taillandier, Jean Pierre Marolleau, Adrien Chauchet, Fabrice Jardin, Nathalie Cassoux, Denis Malaise, Adélaïde Toutée, Sara Touhami, Magali Le Garff-Tavernier, Khê Hoang-Xuan, Sylvain Choquet, Caroline Houillier.
      Despite its indolent evolution, vitreoretinal lymphoma (VRL) has a poor prognosis due to a major risk of relapse in the central nervous system (CNS) and may necessitate aggressive therapy. However, the use of high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is poorly documented. We retrospectively analysed from the French LOC network database the adult immunocompetent patients treated with HCT-ASCT for isolated VRL. Thirty-eight patients underwent consolidation with HCT-ASCT for isolated VRL between 2008 and 2019 after induction chemotherapy. Twenty patients had primary VRL, and 18 had an isolated VRL relapse of a primary CNS lymphoma. Three patients underwent HCT-ASCT in first-line treatment, 24 in second-line treatment, and 11 in subsequent lines. At HCT-ASCT, the median age was 61 years, and the median KPS was 90. Thirty-two patients (84%) received high-dose thiotepa-based HCT. One patient (3%) died from HCT-ASCT toxicity. Nineteen (50%) patients relapsed after HCT-ASCT, including 17 cases occurring in the brain. The median progression-free survival, brain-free survival and overall survival from HCT-ASCT were 96, 113 and 92 months, respectively. HCT-ASCT represents an effective therapeutic strategy for select VRL patients, with a tolerable safety profile. However, the risk of subsequent brain relapse remains significant.
    DOI:  https://doi.org/10.1038/s41409-024-02477-y
  21. Risk Manag Healthc Policy. 2024 ;17 2829-2837
    Economic Evaluation of Adding Daratumumab to Carfilzomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma.
    Lidan Yi, Qiao Liu, Chongqing Tan, Xiaomin Wan, Xia Luo, Yinbo Li, Haiying Li, Xiaohui Zeng.
       Objective: To assess the cost-effectiveness of adding daratumumab to carfilzomib and dexamethasone (KdD) in patients with relapsed or refractory multiple myeloma (RRMM).
    Materials and Methods: A Markov model was established to estimate health and economic outcomes of carfilzomib and dexamethasone (Kd) with or without daratumumab for RRMM patients over a lifetime horizon. The patients and intervention of the two arms were modeled according to the CANDOR trial. Costs were collected from the Chinese health system perspective. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to evaluate the robustness of our conclusions.
    Results: Compared with the Kd arm, KdD achieved an additional 0.537 quality-adjusted life-years (QALYs) at an incremental cost of $138,084, resulting in an incremental cost-utility ratios (ICURs) of $257,319 per QALY. Uncertainty analyses revealed that the model is robust to all the input parameters.
    Conclusion: From the Chinese healthcare system perspective, adding daratumumab to the Kd regimen for patients with RRMM appears to lack cost-effectiveness. Exploring alternative avenues such as negotiating for a more favorable price or introducing a financial assistance program dedicated to daratumumab and/or carfilzomib could prove to be an effective strategy in enhancing accessibility of this combination.
    Keywords:  China; Markov model; cost-effectiveness; daratumumab; multiple myeloma
    DOI:  https://doi.org/10.2147/RMHP.S475048
  22. Heliyon. 2024 Nov 15. 10(21): e39698
    A systematic review on the epidemiology and treatment options of multiple Myeloma in Asia.
    Wee-Joo Chng, Chandramouli Nagarajan, Shang-Yi Huang, Pankaj Malhotra, Yu-Yan Hwang, Vivian Blunk, Manmohan Singh, Lin Wang.
      Multiple myeloma (MM) accounts for almost 15 % of all neoplastic malignancies around the globe. This systematic review intends to analyse data on the treatment and management of MM in selected regions in Asia to identify and prioritize areas that need attention. A comprehensive review of original articles, published in English from 2005 to 2022, derived from the PubMed/MEDLINE database was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. There were 98 studies from select regions of Asia (China, India, Taiwan, Hong Kong, and Singapore) on newly diagnosed MM and relapsed/refractory MM. This review evaluated the trends in disease outcomes with the gradual shift in treatment regimens from doublet to triplet. Additionally, this review also explored autologous stem cell transplant outcome and anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy in MM patients. This is the first systematic review attempting to collect data on the utility and comparison of innovative agents and modifications in treatment regimens in the context of the Asian population. This review established that the body of evidence for the management of MM was generally of poor quality and there is a need for more versatile studies in the region. Novel and innovative drug regimens may help in combating the illness but consorted efforts by researchers, industry partners, policymakers, and the government are key factors in the long-term survival of MM patients. In the current systematic review, the authors have tried to give a comprehensive account of the available treatments, trends in MM management and prognosis for MM in Asia.
    Keywords:  Autologous stem cell transplant; B-cell maturation antigen targeted chimeric antigen receptor T-cell therapy; Newly diagnosed multiple myeloma; Proteasome inhibitors; Relapsed/refractory multiple myeloma
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e39698
  23. JAMA Oncol. 2024 Nov 21.
    Olverembatinib After Failure of Tyrosine Kinase Inhibitors, Including Ponatinib or Asciminib: A Phase 1b Randomized Clinical Trial.
    Elias Jabbour, Vivian G Oehler, Paul B Koller, Omer Jamy, Elza Lomaia, Anthony M Hunter, Olga Uspenskaya, Svetlana Samarina, Sudipto Mukherjee, Jorge E Cortes, Maria R Baer, Vera Zherebtsova, Vasily Shuvaev, Anna Turkina, Igor Davydkin, Huanshan Guo, Zi Chen, Tommy Fu, Lixin Jiang, Cunlin Wang, Hengbang Wang, Dajun Yang, Yifan Zhai, Hagop Kantarjian.
       Importance: Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) resistant or intolerant to BCR-ABL1 tyrosine kinase inhibitors (TKIs) have limited treatment options. Olverembatinib, which is approved in China, has only been tested in Chinese patients.
    Objective: To assess the pharmacokinetics, safety, efficacy, and recommended dose of olverembatinib in patients with CML or Philadelphia chromosome-positive ALL resistant or intolerant to at least 2 TKIs.
    Design, Setting, and Participants: This multicenter phase 1b randomized clinical trial was conducted from January 28, 2020, to January 2, 2024, with a median (range) follow-up of 48 (0-166) weeks. Patients with CML or Philadelphia chromosome-positive ALL were enrolled. This bridging study was performed in part to confirm that there are no racial differences in the pharmacokinetic profile of olverembatinib.
    Interventions: Patients were randomly assigned to 30, 40, or 50 mg of olverembatinib orally every other day in 28-day cycles.
    Main Outcomes and Measures: Pharmacokinetic profile of olverembatinib.
    Results: Of 80 included patients, 46 (58%) were male, and the median (range) age was 54.0 (21-80) years. The pharmacokinetic profile of olverembatinib was compatible with alternate-day dosing and similar to that in Chinese patients. Based on investigators' assessments, 60 patients (75%) experienced at least 1 treatment-related adverse event; 32 (40%) experienced grade 3 or higher treatment-related adverse events; and 12 (15%) experienced treatment-related serious adverse events, none of which were fatal. Frequently reported (10% or more) treatment-emergent adverse events included elevated blood creatine phosphokinase (all grades, 31 [39%]; grade 3 or higher, 10 [13%]) and thrombocytopenia (all grades, 23 [29%]; grade 3 or higher, 14 [18%]). Among evaluable patients with chronic-phase CML, complete cytogenetic response (CCyR) occurred in 31 of 51 patients (61%; 95% CI, 46.1-74.2), and major molecular response (MMR) occurred in 25 of 59 patients (42%; 95% CI, 29.6-55.9). Cytogenetic and molecular responses were similar in patients with or without T315I variants. A total of 15 of 26 patients with prior ponatinib treatment (58%; 95% CI, 36.9-76.6) achieved CCyR, and 11 of 30 (37%; 95% CI, 19.9-56.1) achieved MMR. A total of 4 of 8 patients with asciminib resistance (50%; 95% CI, 15.7-84.3) had CCyR, and 4 of 12 (33%; 95% CI, 9.9-65.1) had MMR. The recommended phase 3 dose of olverembatinib is 30 mg every other day in patients without T315I variants.
    Conclusions and Relevance: In this trial, olverembatinib had a favorable pharmacokinetic profile, was generally well tolerated, and showed strong antileukemic activity in patients with heavily pretreated chronic-phase CML with or without T315I variants, including prior ponatinib and/or asciminib failure. Olverembatinib may provide a viable new treatment option for patients after failure of 2 or more TKIs.
    Trial Registration: ClinicalTrials.gov Identifier: NCT04260022.
    DOI:  https://doi.org/10.1001/jamaoncol.2024.5157
  24. J Infect Chemother. 2024 Nov 18. pii: S1341-321X(24)00309-X. [Epub ahead of print]
    Clinical characteristics and risk factors of infection in initially treated patients with multiple myeloma during the induction period.
    Qianying Pan, Beihui Huang, Junru Liu, Meilan Chen, Jingli Gu, Lifen Kuang, Xiaozhe Li, Juan Li.
       BACKGROUND: Multiple myeloma (MM) is a common hematologic malignancy and immune dysfunction is a hallmark of the disease. It leads to an increased infection risk, which is still a major cause of mortality. The infection spectrum and characteristics have evolved with the introduction of novel agents. An understanding of risk factors that increasing susceptibility to infection is critical in fighting them. This retrospective study aimed to identify risk factors associated with infection and develop nomogram to qualify the risk of infection.
    METHODS: We retrospectively reviewed the data of patients who were diagnosed with MM between April 1, 2018 and December 31, 2021 in our department. Independent predictors for infection were determined by the univariate and multivariate logistic regression analysis. Nomogram was established and evaluated by receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA).
    RESULTS: A total of 230 MM patients who were diagnosed or treated in our department were included. Infections were identified in 37.4% of MM patients in the first treatment course. The most common infection was the pulmonary infection. The first treatment course had the highest infection rate. With three or more comorbidities, anemia, high LDH level and high β2-MG level were independent risk factors for infection in MM patients during the induction period. The area under the curve (AUC) of nomogram was 0.746 (95% CI: 0.679-0.814). The calibration curve and DCA indicated the good performance of the nomogram.
    CONCLUSION: Multiple myeloma patients with one or more of these mentioned risk factors should be monitored with particular care in order to decrease the incidence and severity of infective complications. Nomogram was established to predict the incidence of infection in MM patients. Nomogram has satisfactory accuracy, and clinical utility may benefit for clinical decision-making.
    Keywords:  Infection; Multiple myeloma; Nomogram; Risk factors
    DOI:  https://doi.org/10.1016/j.jiac.2024.11.012
  25. Int J Hematol. 2024 Nov 21.
    A phase 2 clinical trial of luspatercept in non-transfusion-dependent patients with myelodysplastic syndromes.
    Hiroshi Kosugi, Tomoaki Fujisaki, Hiromi Iwasaki, Atsushi Shinagawa, Hiroatsu Iida, Tatsuro Jo, Shiro Kubonishi, Yasuyoshi Morita, Yasuhiro Nakashima, Koichi Onodera, Kenshi Suzuki, Takahiro Suzuki, Yotaro Tamai, Kensuke Usuki, Akira Yokota, Hideyuki Yonaga, Jin Hayakawa, Shuichi Midorikawa, Mitsufumi Nishio, Makoto Suda, Kosei Matsue.
      Luspatercept has shown durable clinical efficacy for the treatment of anemia in transfusion-dependent patients with lower-risk myelodysplastic syndromes (LR-MDS). We report the results of a prespecified primary analysis of a phase 2 trial of luspatercept in non-transfusion-dependent (NTD) Japanese patients with anemia due to LR-MDS. Luspatercept (starting dose 1.0 mg/kg) was administered subcutaneously once every 3 weeks. The primary endpoint was the proportion of patients who achieved hematological improvement-erythroid (HI-E) response (≥ 1.5 g/dL increase in hemoglobin level for 8 weeks) without transfusions within the first 24 weeks of treatment. At the primary analysis data cutoff, 21 patients had been enrolled/treated; 17 and 10 patients had completed 24 and 48 weeks of treatment, respectively. HI-E response occurred within 24 weeks in 10 patients (47.6%; 95% confidence interval, 25.7-70.2; P < 0.0001), which was significantly higher than the predefined threshold (10%). By week 48, HI-E response occurred in 12 patients (57.1%) and 17 patients (81.0%) remained NTD. Luspatercept was well tolerated. Three patients (14.3%) had grade 3-4 treatment-related treatment-emergent adverse events. Luspatercept resulted in statistically and clinically significant improvements in hemoglobin levels, and may help delay the need for transfusions in NTD patients with LR-MDS.
    Keywords:  Anemia; Low risk; Luspatercept; Myelodysplastic syndromes; Non-transfusion dependent
    DOI:  https://doi.org/10.1007/s12185-024-03872-3
  26. Hematology. 2024 Dec;29(1): 2422151
    Efficacy and safety of blinatumomab for the treatment of patients relapsing after allogeneic hematopoietic cell transplantation: a systemic review and meta-analysis.
    Huai-Peng Guo, Ying Liu, Lei Kang, Cong Liu, Wei-Wei Qin.
       OBJECTIVE: We aim to evaluate the efficacy and safety of blinatumomab for the treatment of post-transplant relapse patients with acute lymphoblastic leukemia (ALL).
    METHODS: The search was conducted using several databases including the PubMed, Cochrane Library, Embase, Chinese National Knowledge Infrastructure (CNKI) and Wanfang Data Knowledge Service Platform to collect clinical studies related to blinatumomab. The primary outcome measures were complete remission (CR), 1-year overall survival (OS), 2-year OS, median OS and adverse events (AEs). Grade ≥3 AEs were mainly analyzed for safety, including anemia, thrombocytopenia, neutropenia, encephalopathy, peripheral paresthesia, tremor and cytokine release syndrome (CRS).
    RESULTS: A total of 7 studies, involving a total of 292 patients were included in the analysis. The analysis results showed CR rate of 48%, 1-year OS rate of 40% 2-year OS rate of 21%, median OS 7.47. For safety analysis, the incidence of grade ≥3 AEs, including the incidence of grade ≥3 anemic toxicity was 13% , the incidence of grade ≥3 thrombocytopenia toxicity was 7% , the incidence of grade ≥3 neutropenia toxicity 24%, the incidence of grade ≥3 encephalopathic toxicity was 4% , the incidence of grade ≥3 peripheral paresthesia toxicity 4%, the incidence of grade ≥3 tremor toxicity 8% , the incidence of grade ≥3 CRS toxicity was 4%.
    CONCLUSION: Blinatumomab may be a safe and an effective treatment approach for post-transplant relapse patients with ALL, but its long-term efficacy is still a big challenge. In regard to Regarding AEs, serious CRS and neurological events were infrequent and manageable.
    Keywords:  Acute lymphoblastic leukemia (ALL); allogeneic hematopoietic stem-cell transplantation (alloHSCT); meta-analysis
    DOI:  https://doi.org/10.1080/16078454.2024.2422151
  27. Blood Adv. 2024 Nov 21. pii: bloodadvances.2024013640. [Epub ahead of print]
    Impact of prior CAR-T cell therapy on mosunetuzumab efficacy in patients with relapsed or refractory B-cell lymphomas.
    Elise A Chong, Elicia Penuel, Ellen B Napier, Rachel K Lundberg, Lihua Elizabeth Budde, Mazyar Shadman, Matthew J Matasar, Nancy L Bartlett, Ian W Flinn, Francesc Bosch, Keith Fay, Andre Goy, Anita Kumar, Loretta J Nastoupil, Michael C Wei, Mei Wu, Shen Yin, Joseph A Fraietta, Emeline R Chong, Stephen J Schuster.
      Mosunetuzumab and other CD20/CD3 bispecific antibodies (BsAbs) have efficacy in B-cell lymphomas relapsing after or refractory to CD19-directed chimeric antigen receptor-modified T cells (CAR-T). The optimal timing of BsAbs and biomarkers of BsAb response after CAR-T are unknown. We addressed these questions using clinical data and blood samples from patients previously treated with CAR-T treated on a phase I/II study of mosunetuzumab (clinicaltrials.gov; NCT02500407). Thirty patients had paired samples at baseline and after 1 cycle of mosunetuzumab. Median time from CAR-T to mosunetuzumab was significantly longer for responding than for nonresponding patients (p=0.006, unadjusted for multiple comparisons). Most patients (20/30) did not receive intervening therapy between CAR-T administration and mosunetuzumab. The remainder of patients received one intervening therapy after a protocol-mandated drug washout. After mosunetuzumab, responding patients had higher lymphocytes (995 vs 400 cells/µL, p = 0.02) and greater increases in CD4 and CD8 cells (median change, 73 vs -90 cells/µL, p=0.005; 243 vs -103 cells/µL, p=0.004, respectively). Additionally, responding patients had an increase in activated CD8 cells (median 1.7-fold-change, p=0.02). Non-responders had a relative decrease in CAR transgene levels (N=16; p=0.04). This is the first study to assess changes in lymphocytes, T cells, and CAR transgene levels in patients treated with BsAb after CAR-T. These findings suggest an interaction between prior CAR-T and BsAb outcomes, and have implications for optimal timing of BsAb after CAR-T.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013640
  28. Am J Cancer Res. 2024 ;14(10): 4969-4978
    The modified melphalan and busulfan-based regimen combined with maintenance therapy improved the survival of patients with refractory/relapsed AML after allogeneic transplantation: middle-term outcome of a multicenter trial.
    Shulian Chen, Xiaoyu Zhang, Ting Niu, Yajing Xu, Guangxun Gao, Shengjin Fan, Zeping Zhou, Fang Zhou, Fei Li, Li Liu, Wei Yang, Qifa Liu, Xi Zhang, Yi He, Sizhou Feng, Mingzhe Han, Weihua Zhai, Erlie Jiang.
      Allogeneic hematopoietic stem cell transplantation (allo-HSCT) maintains the only promising curative option for patients with refractory/relapsed (R/R) acute myeloid leukemia (AML). However, the long-term survival results are suboptimal. Optimization of the conditioning regimen aims to eradicate leukemia blasts and reduce early relapse. Here we reported of the preliminary result of the prospective multicenter single arm study to evaluate the efficacy and safety of a modified dual alkylator-conditioning regimen, MCBC (regimen including Melphalan, Cladribine, Busulfan and Cyclophosphamide) (ChiCTR Registration ID: ChiCTR2000029936). This trial enrolled 56 patients from July 2020 to January 2022. With a median follow-up of 854 days (range 48 to 1343), the 2-year overall survival (OS) and relapse-free survival (RFS) were 60.7 ± 6.5% (95% CI 47.5-73.9) and 57.1 ± 6.6% (95% CI 43.8-70.5), respectively, the estimated 3-year OS and RFS rates were 58.9 ± 6.6% (95% CI 45.6-72.2) and 55.4 ± 6.6% (95% CI 41.9-68.8), respectively. A total of 19 patients experienced relapse, the 2-year cumulative incidence relapse (CIR) rate was 34.2 ± 6.6% (95% CI 19.5-44.8), the estimated 3-year CIR rate was 36.3 ± 6.7% (95% CI 21.1-46.7). Six patients died of severe infection or graft-versus-host disease (GVHD). The non-relapse mortality (NRM) rate was 11.8 ± 4.5% (95% CI 2.4-19.1). Mucositis was the main reported regimen-related toxicity, and it was well controlled. Subgroup analyses illustrated that blasts count ≥ 20% before HSCT and the absence of maintenance treatment after HSCT were poor predictors. Our study confirmed the excellent anti-leukemia activity and acceptable toxicity of the MCBC conditioning regimen in R/R AML. Opportune maintenance treatment after HSCT led to significantly improved OS and RFS.
    Keywords:  allo-HSCT; cladribine; conditioning regimen; melphalan and busulfan-based regimen; refractory/relapsed acute myeloid leukemia
    DOI:  https://doi.org/10.62347/SKXB3242
  29. Adv Ther. 2024 Nov 22.
    Efanesoctocog Alfa Versus Emicizumab in Adolescent and Adult Patients With Haemophilia A Without Inhibitors.
    María Teresa Álvarez Román, Nana Kragh, Patricia Guyot, Amanda Wilson, Piotr Wojciechowski, Wojciech Margas, Marlena Wdowiak, Elena Santagostino, Alix Arnaud.
       INTRODUCTION: The phase 3 XTEND-1 trial (NCT04161495) demonstrated that efanesoctocog alfa prophylaxis provided superior bleed protection compared with pre-trial factor VIII (FVIII) prophylaxis in patients with severe haemophilia A. The aim of this study was to indirectly compare the efficacy of efanesoctocog alfa with non-factor replacement therapy emicizumab in adolescent and adult patients with severe haemophilia A without inhibitors.
    METHODS: A systematic literature review was conducted to identify phase 3 trials of emicizumab. Matching-adjusted indirect comparisons were used to compare annualised bleeding rates (ABRs) for any, treated, joint, and spontaneous bleeds, and joint health (measured using Hemophilia Joint Health Score [HJHS]), between efanesoctocog alfa and emicizumab. Estimated effects for different emicizumab regimens were pooled using random-effect meta-analysis to evaluate the overall difference in bleed outcomes between efanesoctocog alfa and emicizumab.
    RESULTS: One emicizumab trial was included (HAVEN 3), which investigated three dosing regimens. In meta-analyses, efanesoctocog alfa once-weekly (Q1W) was associated with significantly lower ABRs for any (incidence rate ratio [95% CI] 0.33 [0.20; 0.53]), any treated (0.49 [0.30; 0.80]) and treated joint (0.51 [0.28; 0.91]) bleeds compared with emicizumab Q1W in non-inhibitor patients with prior prophylaxis or on-demand treatment. Efanesoctocog alfa Q1W was also associated with a significantly better improvement from baseline in HJHS Joint Score (mean difference [95% CI] -2.06 [-3.97; -0.14]) and Total Score (-2.37 [-4.36; -0.39]) versus emicizumab Q1W or every 2 weeks.
    CONCLUSION: Efanesoctocog alfa prophylaxis was associated with significantly lower rates of any, treated, and joint bleeds and improved joint health compared with emicizumab in patients with severe haemophilia A.
    Keywords:  Annualised bleeding rate; Efanesoctocog alfa; Emicizumab; Factor VIII; Haemophilia A; Indirect treatment comparison
    DOI:  https://doi.org/10.1007/s12325-024-03031-4
  30. Clin Transl Sci. 2024 Nov;17(11): e70076
    Imetelstat, a novel, first-in-class telomerase inhibitor: Mechanism of action, clinical, and translational science.
    Ashley L Lennox, Fei Huang, Melissa Kelly Behrs, Mario González-Sales, Neha Bhise, Ying Wan, Libo Sun, Tymara Berry, Faye Feller, Peter N Morcos.
      Most cancers and neoplastic progenitor cells have elevated telomerase activity and preservation of telomeres that promote cellular immortality, making telomerase a rational target for the treatment of cancer. Imetelstat is a first-in-class, 13-mer oligonucleotide that binds with high affinity to the template region of the RNA component of human telomerase and acts as a competitive inhibitor of human telomerase enzymatic activity. Pharmacokinetics, pharmacodynamics, exposure-response analyses, efficacy, and safety of imetelstat have been evaluated in vitro, in vivo, and clinically in solid tumor and hematologic malignancies, including lower-risk myelodysplastic syndromes (LR-MDS) and myeloproliferative neoplasms. Imetelstat was approved in the United States in June 2024 for the treatment of adult patients with LR-MDS with transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents, with a recommended dosing regimen of 7.1 mg/kg administered via 2-h intravenous infusion every 4 weeks. In the pivotal trial, significantly more patients treated with imetelstat versus placebo achieved ≥8-week and ≥24-week red blood cell-transfusion independence, and imetelstat was associated with a manageable safety profile characterized primarily by short-lived and manageable neutropenia and thrombocytopenia. This mini-review summarizes the mechanism of action, pharmacokinetic and pharmacodynamic characteristics, clinical development, and clinical efficacy and safety data of imetelstat.
    DOI:  https://doi.org/10.1111/cts.70076
  31. Drugs. 2024 Nov 19.
    Odronextamab: First Approval.
    Hannah A Blair.
      Odronextamab (Ordspono™), a CD20xCD3 bispecific antibody, is being developed by Regeneron Pharmaceuticals for the treatment of B-cell non-Hodgkin's lymphoma. On 26 August 2024, odronextamab received its first approval in the EU as monotherapy for the treatment of adult patients with relapsed/refractory follicular lymphoma (FL) or relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after ≥ 2 lines of systemic therapy. Clinical trials in various other B-cell non-Hodgkin's lymphoma, including mantle cell lymphoma, marginal zone lymphoma and chronic lymphocytic leukaemia, are underway in multiple countries. This article summarizes the milestones in the development of odronextamab leading to this first approval for the treatment of adult patients with relapsed/refractory FL or relapsed/refractory DLBCL.
    DOI:  https://doi.org/10.1007/s40265-024-02112-6
  32. Hum Pathol. 2024 Nov 19. pii: S0046-8177(24)00207-7. [Epub ahead of print] 105698
    Cyclin D1-negative Mantle Cell Lymphoma.
    Chi Young Ok, L Jeffrey Medeiros.
      Cyclin D1-negative mantle cell lymphoma (MCL) is regarded as a B-cell neoplasm that has morphologic and immunophenotypic findings indistinguishable from typical MCL. These neoplasms lack cyclin D1 overexpression by immunohistochemistry and t(11;14)(q13;q32)/ IGH::CCND1. Since cyclin D1-negative MCL was first recognized by gene expression profiling in 2003, there has been diagnostic confusion regarding this entity, mostly attributable to a lack of diagnostic tools to recognize these neoplasms in most clinical laboratories. Accumulated data show that most cyclin D1-negative MCL cases harbor CCND2 or CCND3 translocation with a variety of gene partners. In this review, the concept of cyclin D1-negative MCL is discussed in chronological order to further our understanding of this entity. We then discuss currently available diagnostic approaches and we conclude with future directions. We also suggest that the more specific terms CCND2-rearranged MCL or CCND3-rearranged MCL be used for neoplasms in which the rearranged gene is known, and that we reserve the term cyclin D1-negative MCL for neoplasms in which the rearranged gene in unknown.
    DOI:  https://doi.org/10.1016/j.humpath.2024.105698
  33. Int J Hematol. 2024 Nov 19.
    Real-world toxicity and efficacy of asciminib in heavily pretreated patients with chronic myeloid leukemia.
    Yoshimi Ishii, Shin Fujisawa, Takuya Miyazaki, Yuki Nakajima, Ayako Matsumura, Katsumichi Fujimaki, Taisei Suzuki, Maki Hagihara, Marika Tanaka, Chizuko Hashimoto, Hideaki Nakajima.
      Although tyrosine kinase inhibitors (TKIs) have improved the prognosis of chronic myeloid leukemia (CML), some patients do not respond to TKIs. We evaluated 21 patients with CML treated with asciminib, which is effective in heavily pretreated patients. The median age was 63 years (range 25-82). Fourteen patients (67%) had been treated with at least three TKIs (range 2-5 prior lines). The switch to asciminib was due to intolerance in 14 patients (67%) and failure in seven patients (33%). The median duration of asciminib exposure was 237 days. With a median follow-up of 273 days, three patients (14%) discontinued asciminib due to failure and two (10%) due to intolerance. Among the 20 evaluable patients, the cumulative rates of molecular response with a two-log reduction, major molecular response, and four-log reduction were 80%, 60%, and 15%, respectively. The six-month event-free survival rate was 74.7%. The most frequent adverse events were liver dysfunction (29%), elevated amylase levels (14%), and renal dysfunction (10%). No patient experienced cardiovascular events. Six patients (29%) experienced cross-intolerance to asciminib, a rate similar to that for previous TKIs. Our study supports the efficacy and tolerability of asciminib in heavily pretreated CML patients in real-world settings.
    Keywords:  Asciminib; Chronic myeloid leukemia; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1007/s12185-024-03873-2
  34. Front Oncol. 2024 ;14 1490202
    Review of BCL2 inhibitors for the treatment of Waldenström's macroglobulinaemia and non-IgM lymphoplasmacytic lymphoma.
    Oliver Tomkins, Shirley D'Sa.
      Lymphoplasmacytic lymphoma (LPL) is a relatively rare form of indolent B-cell non-Hodgkin's lymphoma, termed Waldenström's macroglobulinaemia (WM) in the presence of an IgM paraprotein. Although traditionally treated with combination chemoimmunotherapy, the management is evolving in the era of targeted molecular therapies including Bruton's tyrosine kinase inhibitors (BTKi). However, intolerance and refractoriness to BTKi mean newer agents are required, and the prognosis of so-called quadruple-refractory patients is poor. BCL2 is an anti-apoptotic, pro-survival protein that promotes lymphoma cell survival. Inhibition of BCL2 using first-in-class agent venetoclax has already altered the treatment paradigm in other conditions, including chronic lymphocytic leukaemia (CLL). In-vivo inhibition of BCL2 has been shown to lead to apoptosis of LPL/WM cells. Five studies have published results on the use of BCL2 inhibitors in WM to date, including oblimersen sodium, venetoclax, and sonrotoclax. Fixed-duration venetoclax resulted in high response rates, but many patients relapsed following the completion of therapy. The combination of venetoclax with ibrutinib resulted in higher and relatively deep response rates, but unexpected deaths due to ventricular events mean this combination cannot be explored. Two pivotal trials are currently evaluating the use of fixed-duration venetoclax, either in combination with rituximab or pirtobrutinib, whereas another multi-arm study is studying the use of continuous sonrotoclax monotherapy for R/R WM or in fixed-duration combination with Zanubrutinib for treatment-naïve patients. The potential role of BCL2 inhibitors in WM/LPL remains under study, with many hopeful that they may provide an additional chemotherapy-free oral alternative for patients requiring treatment. In an indolent condition with existing effective treatment regimens, including CIT and cBTKi, cost-effectiveness and toxicity profile will be key, although an additional treatment modality for quadruple-refractory patients with limited treatment options is urgently required.
    Keywords:  BCL2; Waldenström’s macroglobulinaemia; lymphoplasmacytic lymphoma; sonrotoclax; venetoclax
    DOI:  https://doi.org/10.3389/fonc.2024.1490202
  35. Oncology (Williston Park). 2024 Nov 05. 38(11): 410-412
    The Hidden Danger Unveiling the Connection Between Multiple Myeloma and Pleural Effusion.
    Fnu Fatima, Faryal Arif, Muhammad Hamza Gul, Neha Siddiqui, Muhammad Zulqarnain, Abdul Baseer Wardak.
      We present a 65-year-old man with multiple myeloma who developed a rare complication of pleural effusion. Initial laboratory results showed elevated creatinine, calcium, and protein electrophoresis with an M spike. A bone marrow biopsy confirmed 80% plasma cells. Despite the rarity of pleural effusion in patients with multiple myeloma, our patient demonstrated significant improvement with targeted therapy and palliative care. This case highlights the importance of early recognition and management of pleural effusion in patients with multiple myeloma and underscores the need for further research into optimal management strategies and underlying mechanisms.
    DOI:  https://doi.org/10.46883/2024.25921028
  36. Leuk Res. 2024 Nov 09. pii: S0145-2126(24)00188-7. [Epub ahead of print]148 107622
    RCHOP plus BTK inhibitor improves clinical outcomes in double expressor diffuse large B-cell lymphoma, unlike RCHOP plus lenalidomide.
    Demei Feng, Shenrui Bai, Dong Liang, Xiaoqin Chen, Zhongjun Xia, Yang Liang, Hua Wang.
       BACKGROUND: Double-expressor diffuse large B-cell lymphoma (DE-DLBCL) has a poor prognosis, and optimal treatment strategies remain unclear. This study evaluates the efficacy and safety of RCHOP, R2-CHOP (RCHOP plus lenalidomide), and RCHOP plus Bruton's Tyrosine Kinase inhibitors (BTKi) in DE-DLBCL treatment.
    METHODS: Data from 213 DE-DLBCL patients treated from January 2019 and February 2024. Among them, 112 received R-CHOP, 65 received R2-CHOP, and 36 received R-CHOP plus BTKi. We evaluated clinical characteristics, overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) for each groups.
    RESULTS: Baseline characteristics were comparable across groups. ORRs were 95.5 % for R-CHOP, 96.9 % for R2-CHOP, and 97.2 % for R-CHOP plus BTKi, with CR rates of 76.5 %, 80 %, and 75 %, respectively. BTKi significantly improved PFS (p=0.033) but not affect OS (p=0.165). Lenalidomide showed no benefit in PFS (p=0.153) or OS (p=0.351). With median follow-up times of 20.6 months for R-CHOP, 23.5 months for R2-CHOP, and 17.6 months for R-CHOP plus BTKi, the 1-year PFS rates were 73.6 %, 82.2 %, and 93.3 %, and the 1-year OS rates were 96.2 %, 93.2 %, and 100 %, respectively. Grade 3-4 adverse events included leukopenia, neutropenia, and anemia, and thrombocytopenia, with no significant differences among groups.
    CONCLUSION: The addition of BTK inhibitor enhances progression-free survival in DE-DLBCL, especially in advanced-stage patients, without introducing new severe adverse reactions. In contract, adding lenalidomide does not offer additional efficacy or survival benefits.
    Keywords:  Bruton's Tyrosine Kinase inhibitors (BTKi); Double-expressor diffuse large B-cell lymphoma (DE-DLBCL); Lenalidomide; R-CHOP regimen
    DOI:  https://doi.org/10.1016/j.leukres.2024.107622
  37. Support Care Cancer. 2024 Nov 18. 32(12): 802
    Symptom experience of patients undergoing treatment for multiple myeloma: a longitudinal real-world electronic patient-reported outcomes study.
    Mihir N Patel, Anneli Nina, Brenda Branchaud, Kris W Herring, Suzanne Johnson, Julie Scott, Thomas W LeBlanc.
       PURPOSE: Patients with multiple myeloma (MM) experience significant symptom burden. We used a symptom monitoring app to longitudinally characterize the MM treatment experience in detail based on line of therapy (LOT).
    METHODS: Adults with MM on active treatment completed weekly symptom monitoring surveys. Patients on their 4th LOT or greater were considered heavily pretreated. We characterized moderate to very severe (MOD-VS) symptom prevalence, weekly symptom burden, symptom bother (FACT-GP5), and health-related quality of life (HR-QoL) (EORTC QLQ-C30 Item 30) per LOT.
    RESULTS: We considered 109 patients on LOT < 4 and 47 on LOT ≥ 4. The top MOD-VS symptoms were fatigue (71.6% of patients), muscle pain (59.8%), general pain (51.6%), numbness/tingling (48.4%), and insomnia (47.6%). More patients on LOT ≥ 4 experienced numbness/tingling (66.7% vs. 41.3%; OR 2.84, 95% CI 1.27-6.37; p = 0.0098) and fatigue (83.3% vs. 65.6%; OR 2.60, 95% CI 0.96-7.09; p = 0.0557). Some symptoms (fatigue, muscle pain, anxiety) persisted for months among patients on LOT ≥ 4, but patients on LOT < 4 also had unmet longitudinal needs (numbness/tingling, dyspnea). Patients on LOT ≥ 4 had more weeks with ≥ 3 MOD-VS symptoms (27.1% of weeks vs. 15.7%; OR 2.56, 95% CI 1.07-6.08; p = 0.0337) and experienced high symptom bother more often (39.1% of surveys vs. 30.0%; OR 4.23, 95% CI 1.37-13.10; p = 0.0123). HR-QoL was similar between groups.
    CONCLUSION: Heavily pretreated patients experienced greater symptom burden and bother, but patients at earlier LOTs also had unmet needs. Interventions are needed to improve symptom management in MM regardless of LOT, but most pressingly for heavily pretreated patients.
    Keywords:  Digital health; Multiple myeloma; Patient-reported outcomes; Quality of life; Symptom burden
    DOI:  https://doi.org/10.1007/s00520-024-08985-3
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