bims-hemali 2024-12-29 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2024–12–29
nine papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Efficacy and safety of hypomethylating agents in the treatment of AML/MDS patients relapsed post allogenetic hematopoietic stem cell transplantation.
A Phase I Study of Romidepsin in Combination With Gemcitabine, Oxaliplatin, and Dexamethasone in Patients With Relapsed or Refractory Aggressive Lymphomas Enriched for T-Cell Lymphomas.
BCMA-directed CAR T-cell Therapy in patients with multiple myeloma and CNS involvement.
Novel Treatment Strategies for Chronic Myeloid Leukemia.
Significance of cycle 1 bone marrow biopsy in predicting outcomes and toxicities of venetoclax-based therapy for myeloid malignancies.
Targeting the insulin-like growth factor-1 receptor to overcome imatinib resistance in chronic myeloid leukemia.
A successful haploidentical transplantation without conditioning regimen for a relapsed/refractory multiple myeloma patient after chimeric antigen receptor T-cell therapy.
Comparison of HiDAC Versus FLAG-IDA in the Treatment of Relapsed Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome.
Combination therapy involving azacitidine for acute myeloid leukemia patients ineligible for intensive chemotherapy.

Front Oncol. 2024 ;14 1465334

Efficacy and safety of hypomethylating agents in the treatment of AML/MDS patients relapsed post allogenetic hematopoietic stem cell transplantation.

Yaxin Wang, Qingyun Wang, Hanyun Ren, Yujun Dong, Qingya Wang, Zeyin Liang, Yue Yin, Wei Liu, Weilin Xu, Na Han, Yuan Li.

   Introduction: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) constitute myeloid malignancies, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered as a potentially optimal approach for achieving a long term cure. However, post-allo-HSCT relapse remains a leading cause of mortality and therapeutic failure.
Methods: To evaluate the efficacy and safety of combining hypomethylating agents (HMAs) with Bcl-2 inhibitors in the treatment of AML/MDS relapse following allo-HSCT, we retrospectively collected data from 42 patients who experienced relapse between April 2012 and March 2022 at Peking University First Hospital. Among these patients, 21 underwent intensive chemotherapy (IC) alone, while the other 21 received treatment with HMAs after IC treatment, either alone or in combination with the Bcl-2 inhibitor venetoclax (VEN).
Results: The median overall survival (OS) was 9 ± 2.153 months, and the one-year OS rate was 41.5%. The overall response rate (ORR) in the chemotherapy group and the IC+HMAs ± VEN group was 52.38% (11/21) and 76.19% (16/21), respectively, with no significant difference found (P=0.107). Kaplan-Meier analysis revealed a significant difference in OS between the chemotherapy group and the IC+HMAs ± VEN group in our retrospective cohort study (P=0.041, χ2= 4.016). Additionally, a significant difference in overall survival (OS) rates was observed between the two groups for patients categorized as intermediate/high risk (P=0.008). The secondary relapse rate was 45.45% (5/11) in the IC cohort and 25% (4/16) in the IC+HMAs ± VEN group, respectively, with no significant difference identified between the two cohorts (P=0.268). Furthermore, upon assessing the risk of graft-versus-host disease (GvHD), infection, and agranulocytosis, no notable differences were observed with the use of HMAs, suggesting that HMAs did not increase the risk. In the IC+HMAs ± VEN group, 7 patients received VEN in addition to HMAs, and no significant statistical difference was found in OS when comparing patients who received HMAs alone and those who received HMA+VEN (P=0.183), also, a statistically significant difference in OS was noted between the two groups whenaccounting for competing risks (P=0.028).
Conclusions: This retrospective study highlights the efficacy of IC+HMAs ± VEN in treating AML/MDS patients experiencing relapse post allo-HSCT, improving survival rates, especially for those classified as intermediate/high risk, with favorable tolerability.

Keywords:  allo-HSCT; hypomethylating agents; myeloid malignancy; relapse; venetoclax

DOI:  https://doi.org/10.3389/fonc.2024.1465334
Clin Lymphoma Myeloma Leuk. 2024 Dec 04. pii: S2152-2650(24)02436-4. [Epub ahead of print]

A Phase I Study of Romidepsin in Combination With Gemcitabine, Oxaliplatin, and Dexamethasone in Patients With Relapsed or Refractory Aggressive Lymphomas Enriched for T-Cell Lymphomas.

Nicole Foley, Peter A Riedell, Nancy L Bartlett, Amanda F Cashen, Brad S Kahl, Todd A Fehniger, Anne Fischer, Chaz Moreno, Jingxia Liu, Kenneth R Carson, Neha Mehta-Shah.

   INTRODUCTION: Histone deacetylase inhibitors (HDACi) and combination chemotherapy are independently used to treat relapsed/refractory (R/R) lymphoma. In vitro studies suggest that the addition of HDACi to platinum-based chemotherapy is synergistic.
PATIENTS AND METHODS: We conducted a phase I study of romidepsin, gemcitabine, oxaliplatin and dexamethasone (Romi-GemOxD) in R/R aggressive lymphomas with an expansion cohort in T-cell lymphomas. A total of 24 patients were enrolled with median age 70; 6 patients had diffuse large B-cell lymphoma (DLBCL) and 18 patients had peripheral T-cell lymphomas (PTCL-NOS: 10; angioimmunoblastic T-cell lymphoma [AITL]: 7; ALK-negative anaplastic large cell lymphoma: 1). Patients had received a median of 2 prior lines of therapy and 10 patients were refractory to last line of therapy.
RESULTS: Using a standard 3 + 3 dose escalation design, the maximum tolerated dose of romidepsin was determined to be 10 mg/m2 in combination with GemOxD. There were no unexpected toxicities. The most common grade ≥ 3 treatment-emergent adverse events were thrombocytopenia (79%) and lymphopenia (46%). The overall response rate for Romi-GemOxD was 52% (12/23) with complete response (CR) rate of 43% (10/23). All 6 patients with AITL evaluable for efficacy achieved CR. Durable responses were seen in patients with AITL, PTCL-NOS and DLBCL. Without additional therapy, 4 patients remained in remission for more than 2 years, with 3 patients progressing at 46.5, 30.8, and 32.6 months and 1 remission ongoing at 83 months. A total of 4 patients proceeded to consolidative stem cell transplant following induction.
CONCLUSION: Romi-GemOxD represents a well-tolerated, time-limited, effective option for patients, particularly for those with AITL in which durable responses were seen. NCT02181218.

Keywords:  Angioimmunoblastic T-cell lymphoma; Gemcitabine oxaliplatin; Histone deacetylase inhibitor; Peripheral T-cell lymphoma; Romidepsin

DOI:  https://doi.org/10.1016/j.clml.2024.11.015
Blood Adv. 2024 Dec 27. pii: bloodadvances.2024014345. [Epub ahead of print]

BCMA-directed CAR T-cell Therapy in patients with multiple myeloma and CNS involvement.

Mahmoud R Gaballa, Omar Castaneda Puglianini, Adam D Cohen, Dan T Vogl, Alfred Chung, Christopher J Ferreri, Peter M Voorhees, Doris K Hansen, Krina K Patel.

We investigated BCMA-directed CART in patients with relapsed or refractory multiple myeloma (RRMM) and CNS involvement. Ten patients who received either ide-cel (n=6) or cilta-cel (n=4) were included in this analysis. Patients had brain/cranial nerve and/or spinal cord involvement/leptomeningeal disease evident on either MRI (100%) and/or CSF (40%). The time between CNS diagnosis and CART was 60 days or less in 50% of patients, >300 days in 30%, and 20% were diagnosed within 14 days after CART infusion. Seven (70%) received CNS-directed therapy during bridging in the form of different combinations of radiotherapy, intrathecal chemotherapy, and surgery. There were no excess toxicities: no CRS grade (G) 3 or more, ICANS G3 10% (n=1), and none had ICANS G4. Two patients experienced delayed but treatable neurotoxicity with no reported Parkinsonian side effects. The best overall response rate was 80%, with 70% VGPR or better, and a 100% CNS response. For patients with CNS myeloma diagnosed pre-CART (n=8), with a median follow-up of 381 days, the median OS and PFS were 13.3 and 6.3 months, respectively. Best outcomes were observed in 4 patients who had a response to bridging therapy, suggesting that optimizing pre-CART therapy may be key for improved outcomes. Our study suggests that CART in patients with CNS MM is safe and feasible and that screening for CNS involvement before CART therapy could be warranted in high-risk patients. The excellent initial response but relatively short PFS suggests consideration for post-CART maintenance. Larger studies are needed to confirm these findings.

DOI: https://doi.org/10.1182/bloodadvances.2024014345
Blood. 2024 Dec 27. pii: blood.2024026312. [Epub ahead of print]

Novel Treatment Strategies for Chronic Myeloid Leukemia.

Nataly Cruz-Rodriguez, Michael W Deininger.

Starting with imatinib, tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a lethal blood cancer into a chronic condition. As patients with access to advanced CML care have an almost normal life expectancy, there is a perception that CML is a problem of the past, and one should direct research resources elsewhere. However, a closer look at the current CML landscape reveals a more nuanced picture. Most patients still require life-long TKI therapy to avoid recurrence of active CML. Chronic TKI toxicity and the high costs of the well-tolerated agents remain challenging. Progression to blast phase still occurs, particularly in socioeconomically disadvantaged parts of the world, where high risk CML at diagnosis is common. Here we will review the prospects of further improving TKIs to achieve optimal suppression of BCR::ABL1 kinase activity, the potential of combining different classes of TKIs, and the current state of BCR::ABL1 degraders. We will cover combination therapy approaches to address TKI resistance in the setting of residual leukemia and in advanced CML. Despite the unprecedented success of TKIs in CML, more work is needed to truly finish the job, and we hope to stimulate innovative research aiming to achieve this goal.

DOI: https://doi.org/10.1182/blood.2024026312
Leuk Lymphoma. 2024 Dec 27. 1-7

Significance of cycle 1 bone marrow biopsy in predicting outcomes and toxicities of venetoclax-based therapy for myeloid malignancies.

Jeffrey Baron, Daniel Appiah, Mark G Faber, Han Yu, Tara Cronin, Jared Vega, Samantha Poblete, Pamela J Sung, Elizabeth A Griffiths, Amanda Przespolewski, James E Thompson, Steven Green, Eunice S Wang.

  For older unfit patients receiving venetoclax-based induction, data on the significance of interim bone marrow biopies (BMBx) findings on clinical outcomes is lacking. We retrospectively evaluated interim BMBx results performed on Cycle 1 days 21-28 of venetoclax-based therapy in 69 adults with myeloid malignancies to determine whether blast clearance was associated with overall survival (OS) and overall response rate (ORR). Median age was 75 years (range 69-78). Results demonstrated blast reduction (BR, <5% blasts) in 71%. Venetoclax was held to allow count recovery in 86% of these patients. Achieving interim BMBx BR was significantly associated with OS (p = 0.0033) and ORR (Cohen's kappa 0.39). Patients whose venetoclax was held experienced low rates of infection and reduced cytopenias. These findings support the importance of cycle 1 BMBx assessment during venetoclax-based therapies, specifically in predicting which patients will achieve optimal outcomes and in mitigating toxicity.

Keywords:  Myeloid malignancies; bone marrow biopsy response; low-intensity chemotherapy; therapy management; venetoclax

DOI:  https://doi.org/10.1080/10428194.2024.2444480
Discov Oncol. 2024 Dec 24. 15(1): 835

Targeting the insulin-like growth factor-1 receptor to overcome imatinib resistance in chronic myeloid leukemia.

Seiichi Okabe, Yuya Arai, Akihiko Gotoh.

  Patients with chronic myeloid leukemia (CML) frequently develop resistance to tyrosine kinase inhibitors such as imatinib. In this study, we explored the role of the insulin-like growth factor 1 (IGF-1) signaling pathway in CML and imatinib resistance. An analysis of IGF-1 gene expression using public databases revealed elevated levels of insulin-like growth factor-binding proteins in patients with chronic-phase CML. Further research revealed that IGF-1-related genes were upregulated in patients who were unresponsive to imatinib, suggesting that IGF-1 signaling plays a role in the resistance mechanism. Furthermore, we evaluated the efficacy of linsitinib, a selective insulin-like growth factor-1 receptor (IGF-1R) inhibitor, in inhibiting the growth of CML cell lines, including imatinib-resistant cell lines, and observed a notable decrease in cell viability and an increase in cytotoxicity. The combination of imatinib and linsitinib reduced cell viability and increased caspase-3/7 activity in imatinib-resistant cells. Moreover, silencing of IGF-1R by small interfering ribonucleic acid increased the sensitivity of CML cell lines to imatinib, indicating that IGF-1R could be a strategic target for overcoming resistance. These findings highlight the therapeutic potential of linsitinib and that IGF-1R inhibition may improve the treatment outcomes of patients with imatinib-resistant CML.

Keywords:  Chronic myeloid leukemia; Imatinib resistance; Insulin-like growth factor -1 receptor inhibitor

DOI:  https://doi.org/10.1007/s12672-024-01706-6
Cytotherapy. 2024 Dec 16. pii: S1465-3249(24)00901-0. [Epub ahead of print]

A successful haploidentical transplantation without conditioning regimen for a relapsed/refractory multiple myeloma patient after chimeric antigen receptor T-cell therapy.

Zigang Dai, Nanzhou Yu, Yang Cao, Jianfeng Zhou, Yicheng Zhang, Na Wang, Xiaoxi Zhou.

   BACKGROUND AIMS: With novel therapies improving prognosis, the complications of multiple myeloma after multi-line treatment, particularly myelosuppression, have become a crucial determinant of long-term outcomes. Non-myeloablative allogeneic hematopoietic stem cell transplantation is a feasible option, but the transplant-related mortality rate remains high. Our study presents a relapsed/refractory multiple myeloma patient with a 9-year disease history.
METHODS: The patient underwent multiple chemotherapy treatments and achieved partial remission. The patient then received two B-cell maturation antigen-targeting chimeric antigen receptor (CAR) T-cell treatments with lymphodepletion conditioning of fludarabine and cyclophosphamide.
RESULTS: At the fifth month after the second CAR T-cell treatment, the patient achieved complete remission but developed refractory myelosuppression (grade 4 according to Common Terminology Criteria for Adverse Events 5.0) after several severe infections. In order to facilitate hematopoietic recovery, her daughter's stem cells were infused into her, which fortunately implanted without conditioning. After thrombotic microangiopathy and acute graft-versus-host disease, the patient was discharged with consistent full donor chimerism. We assume this engraftment may be attributed to the patient's severe hematopoietic failure and further host lymphodepletion by fludarabine.
CONCLUSIONS: This study highlights the potential of allogeneic hematopoietic stem cell transplantation with reduced conditioning intensity or even the omission of conditioning, particularly for a relapsed/refractory multiple myeloma patient who struggles with severe myelosuppression after long-term treatment.

Keywords:  CAR T-cell; fortuitous implantation; multiple myeloma; severe myelosuppression; transplantation without conditioning

DOI:  https://doi.org/10.1016/j.jcyt.2024.10.005
Eur J Haematol. 2024 Dec 26.

Comparison of HiDAC Versus FLAG-IDA in the Treatment of Relapsed Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome.

Man Wai Tang, Deborah Van der Tuin, Mesire Aydin, Jarom Heijmans, Arjan A Van de Loosdrecht, Ellen Meijer, Caroline E Rutten, Mariëlle Wondergem, Jeroen J W M Janssen, Marjolein L Donker, Mette D Hazenberg, Sonja Zweegman, Bart J Biemond, David C De Leeuw, Erfan Nur.

   BACKGROUND: Relapsed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) are associated with a poor prognosis. It is unknown which re-induction therapy provides the highest chance of durable remission. Commonly used therapies are high dose cytarabine (HiDAC) and triple therapy consisting of fludarabine, cytarabine, and idarubicin combined with granulocyte colony-stimulating factor (FLAG-IDA).
METHODS: Two patient cohorts with relapsed AML or HR-MDS treated with HiDAC or FLAG-IDA between October 2015 and December 2021 in two academic hospitals in the Netherlands were retrospectively analyzed.
RESULTS: Patients were treated with either HiDAC (n=22) or FLAG-IDA (n=25). Rates of CR (71% vs. 74%, P=0.85), 1-year OS (47% vs. 51%, P=0.99) and EFS (38% vs. 35%, P=0.71) were comparable between HiDAC and FLAG-IDA. Durations of neutropenia (median 24 days (IQR 20-26) vs. 30 days (IQR 22-39), P=0.014) and thrombocytopenia (22 days (IQR 17-26) vs. 36 days (IQR 26-53)) were significantly shorter in the HiDAC group than in the FLAG-IDA group.
CONCLUSION: While remission rates and survival outcomes were similar, FLAG-IDA was associated with longer periods of myelosuppression and transfusion dependency compared to HiDAC in these two cohorts. HiDAC can be considered as a salvage chemotherapyfor relapsed AML/HR-MDS based on our study.

Keywords:  MDS; chemotherapy; cytarabine; leukemia; myelosuppression

DOI:  https://doi.org/10.1111/ejh.14370
Leuk Res. 2024 Dec 18. pii: S0145-2126(24)00204-2. [Epub ahead of print]148 107638

Combination therapy involving azacitidine for acute myeloid leukemia patients ineligible for intensive chemotherapy.

Juan Li, Shuying Fu, Chunmei Ye, Jun Li.

  Acute myeloid leukemia (AML) is a complex hematological malignancy predominantly affecting the elderly, with a median diagnosis age of 68 years. Despite advances in treatment, elderly AML patients face suboptimal survival outcomes, with an estimated 5-year survival rate below 20 %. Epigenetic dysregulation, notably DNA methylation, is a key factor in the progression of myelodysplastic syndromes (MDS) to AML. This review examines various combination regimens involving azacitidine (AZA), including those with lenalidomide, histone deacetylase inhibitors (HDACi), kinase inhibitors, metabolic enzyme inhibitors, monoclonal antibodies, immune checkpoint inhibitors, and anti-apoptotic protein inhibitors. Notable among these are the combinations with venetoclax, which has demonstrated remarkable efficacy in phase III trials, and the emerging IDH inhibitors ivosidenib and enasidenib, which have shown significant clinical benefits in patients with IDH mutations. While combination therapies with AZA hold great promise, challenges persist, including translating in vitro synergies to in vivo efficacy and identifying optimal regimens for specific patient populations. Cumulative toxicities may also offset clinical benefits, necessitating rigorous clinical trial design. Future research must focus on refining combination strategies, optimizing dosages and sequences, and thoroughly evaluating therapeutic efficacy and safety to advance the treatment of AML and improve patient outcomes.

Keywords:  Acute myeloid leukemia; Azacitidine; Combination therapy; Unfit

DOI:  https://doi.org/10.1016/j.leukres.2024.107638