bims-hemali 2024-12-15 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2024–12–15
sixteen papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Efficacy and Safety of Venetoclax Plus Azacitidine for Patients With Treatment-Naive High-Risk Myelodysplastic Syndromes.
Efficacy and Safety of Daratumumab in Intermediate/High-risk Smoldering Multiple Myeloma: Final Analysis of CENTAURUS.
Efficacy and safety of mosunetuzumab monotherapy for Japanese patients with relapsed/refractory follicular lymphoma: FLMOON-1.
Acalabrutinib in combination with rituximab and lenalidomide in patients with relapsed or refractory follicular lymphoma: Results of the phase 1b open-label study (ACE-LY-003).
Mitoxantrone-Based Novel Conditioning Regimen Leads to Great Survival Benefit in Peripheral T-Cell Lymphoma Compared to BEAM Regimen.
Safety and Efficacy of Glofitamab for Relapsed/Refractory Large B-Cell Lymphoma in a Multinational Real-World Study.
Efficacy and Safety of Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T-Cell for the Treatment of Relapsed and Refractory AL Amyloidosis.
Has PD-1 blockade changed the standard of care for cHL?
Transplant in myeloma: who, when, and why?
Advances in epigenetic therapies for B-cell non-hodgkin lymphoma.
High-risk cytogenetic abnormalities in multiple myeloma: PETHEMA-GEM experience.
Understanding and overcoming resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML).
The evolving frontline management of CLL: are triplets better than doublets? How will we find out?
Supportive care in myeloma-when treating the clone alone is not enough.
When to use stem cell transplantation for classical Hodgkin lymphoma.
Chemotherapeutic potential of radotinib against blood and solid tumors: A beacon of hope in drug repurposing.

Blood. 2024 Dec 09. pii: blood.2024025464. [Epub ahead of print]

Efficacy and Safety of Venetoclax Plus Azacitidine for Patients With Treatment-Naive High-Risk Myelodysplastic Syndromes.

Jacqueline S Garcia, Uwe Platzbecker, Olatoyosi Odenike, Shaun A Fleming, Chun Yew Fong, Uma Borate, Meagan A Jacoby, Daniel Nowak, Maria R Baer, Pierre Peterlin, Brenda Chyla, Huipei Wang, Grace Ku, David Hoffman, Jalaja Potluri, Guillermo Garcia-Manero.

Patients with higher-risk myelodysplastic syndromes (HR MDS) have a median survival of ~1.5 years with azacitidine, and hematopoietic stem cell transplantation is their only curative option. Therefore, improved therapies are needed. This phase 1b study investigated safety and efficacy of venetoclax, a selective BCL-2 inhibitor, at the recommended phase 2 dose (RP2D: 400 mg for 14 days/28-day cycle), in combination with azacitidine (75 mg/m2 for 7 days/28-day cycle) for treatment-naive HR MDS (NCT02942290). Safety was the primary outcome, and complete remission (CR) rate was the primary efficacy outcome. Secondary outcomes included rates of modified overall response (mOR), hematologic improvement (HI), overall survival (OS), and time to next treatment (TTNT). As of May 2023, 107 patients received venetoclax and azacitidine combination at the RP2D. Best response of CR or marrow CR was observed in 29.9% and 50.5% of patients (mOR, 80.4%). Median OS was 26.0 months, with 1-year and 2-year survival estimates of 71.2% and 51.3%, respectively. Of 59 patients who were red blood cell and/or platelet transfusion-dependent at baseline, 24 (40.7%) became transfusion-independent on study, including 11 (18.6%) who also achieved CR. Fifty-one (49.0%) of 104 evaluable patients achieved HI. Median TTNT excluding transplantation was 13.4 months. Adverse events reflected known safety profiles for venetoclax and azacitidine, including constipation (53.3%), nausea (49.5%), neutropenia (48.6%), thrombocytopenia (44.9%), febrile neutropenia (42.1%), and diarrhea (41.1%). Overall, venetoclax plus azacitidine at the RP2D was well tolerated and had favorable outcomes. A phase 3 study (NCT04401748) is ongoing to confirm survival benefit of this combination.

DOI: https://doi.org/10.1182/blood.2024025464
Blood. 2024 Dec 09. pii: blood.2024025897. [Epub ahead of print]

Efficacy and Safety of Daratumumab in Intermediate/High-risk Smoldering Multiple Myeloma: Final Analysis of CENTAURUS.

Carl Ola Landgren, Ajai Chari, Yael C Cohen, Andrew Spencer, Peter M Voorhees, Irwindeep Sandhu, Matthew W Jenner, Dean Smith, Michele Cavo, Niels W C J van de Donk, Meral Beksac, Phillippe Moreau, Hartmut Goldschmidt, Diego Vieyra, Linlin Sha, Liang Li, Els Rousseau, Robyn M Dennis, Robin Carson, Craig C Hofmeister.

Early intervention of smoldering multiple myeloma (SMM) may delay progression to multiple myeloma. Here, we present the final analysis of the phase 2 CENTAURUS study (NCT02316106). In total, 123 patients with intermediate/high-risk SMM were randomized to intravenous daratumumab 16 mg/kg following a Long intense (n = 41), Intermediate (n = 41), or Short intense (n = 41) dosing schedule. At a combined median follow-up of 85.2 months, in the Long intense, Intermediate, and Short intense arms complete response or better rates were 4.9%, 9.8%, and 0%; overall response rates were 58.5%, 53.7%, and 37.5%; progressive disease/death rates were 0.096, 0.102, and 0.109 (P <0.0001 for all arms); and median progression-free survival was not reached, 84.4, and 74.1 months, respectively. Median overall survival was not reached in any arm. Thirty-six patients in the Long intense or Intermediate arms continued daratumumab in an optional extension phase after completing 20 cycles of per protocol treatment. Median (range) duration of study treatment was 44.0 (1.0-91.6), 35.2 (1.9-90.6), and 1.6 (0.1-1.9) months in the Long intense, Intermediate, and Short intense arms, respectively. No new safety signals were observed. With extended follow-up (median, ~7 years), these data highlight the tolerability of daratumumab and support ongoing trials investigating daratumumab as an early intervention for SMM. ClinicalTrials.gov Identifier: NCT02316106.

DOI: https://doi.org/10.1182/blood.2024025897
Int J Clin Oncol. 2024 Dec 09.

Efficacy and safety of mosunetuzumab monotherapy for Japanese patients with relapsed/refractory follicular lymphoma: FLMOON-1.

Hideki Goto, Takahiro Kumode, Yuko Mishima, Keisuke Kataoka, Yoshiaki Ogawa, Nobuhiro Kanemura, Kazuyuki Shimada, Toshiki Uchida, Yukano Kuroe, Atsuko Kawasaki, Jotaro Sato, Takanori Teshima.

   BACKGROUND: In a global phase I/II study (GO29781; NCT02500407), single-agent mosunetuzumab had a manageable safety profile and induced durable complete responses in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma, including in patients with R/R follicular lymphoma (FL). In this analysis, the efficacy and safety of mosunetuzumab monotherapy were evaluated in an expansion cohort, FLMOON-1, in Japanese patients with R/R FL who had received ≥ 2 prior lines of therapy in a phase I study (JO40295, jRCT2080223801).
METHODS: Mosunetuzumab was administered intravenously at the recommended phase II dose (with cycle 1 step-up dosing) for eight cycles or up to 17 cycles, or until disease progression or unacceptable toxicity. The pre-specified primary endpoint was Independent Review Facility (IRF)-assessed complete response rate (CRR; as best overall response). Secondary objectives included investigator (INV)-assessed CRR, INV- and IRF-assessed objective response rate (ORR), and safety.
RESULTS: At the data cutoff (October 13, 2023), 19 patients (median age 72 years) were evaluated. The IRF-assessed CRR and ORR were 68.4% and 78.9%, respectively; the INV-assessed CRR and ORR were 63.2% and 84.2%, respectively. Grade 3-4 adverse events (AEs) were observed in 89.5% of patients, with a low incidence of AEs leading to mosunetuzumab discontinuation (10.5%) and one fatal AE unrelated to mosunetuzumab. Cytokine release syndrome occurred in 47.4% of patients and were mostly Grade 1 in severity.
CONCLUSION: These findings indicate mosunetuzumab has a consistent efficacy and manageable safety profile in Japanese patients with R/R FL compared with previously reported data from the global phase I/II study.

Keywords:  Administration; Antibodies; Bispecific; Follicular; Intravenous; Japan; Lymphoma; Non-Hodgkin

DOI:  https://doi.org/10.1007/s10147-024-02662-5
Br J Haematol. 2024 Dec 12.

Acalabrutinib in combination with rituximab and lenalidomide in patients with relapsed or refractory follicular lymphoma: Results of the phase 1b open-label study (ACE-LY-003).

Paolo Strati, Richy Agajanian, Izidore S Lossos, Morton Coleman, Robert Kridel, Andrew Wood, Robin Lesley, Chuan-Chuan Wun, Deborah M Stephens.

  Patients with relapsed/refractory (R/R) follicular lymphoma (FL) have limited effective treatment options. Bruton tyrosine kinase inhibitors (BTKis) increase the anti-tumoural phenotype of tumour-associated macrophages, providing rationale to combine them with rituximab and lenalidomide (R2). Acalabrutinib, a second-generation BTKi, has potential to improve R2 efficacy without increasing T-cell-mediated toxicity due to its lack of interleukin-2-inducible T-cell kinase inhibition. Here, we report safety and efficacy from a phase 1b dose-finding study (NCT02180711) evaluating acalabrutinib plus R2 in patients with R/R FL. Overall, 29 patients received acalabrutinib plus R2 (lenalidomide 15 mg, n = 8; lenalidomide 20 mg, n = 21). At a median acalabrutinib exposure of 21 months, the most common grade ≥3 treatment-emergent adverse event (TEAE) was neutropenia (37.9%). The incidence of grade ≥3 serious TEAEs was 37.5% and 52.4% in the lenalidomide 15-mg and 20-mg cohorts, respectively; overall, the most common were COVID-19 pneumonia, COVID-19 infection and pneumonia. Earlier treatment withholdings/reductions were observed in the 20-mg cohort. With a median follow-up of 34.1 months, the overall response rate was 75.9%. The complete response rate was 25.0% and 42.9% in the lenalidomide 15- and 20-mg cohorts, respectively. Due to acceptable toxicity and preliminary efficacy, the lenalidomide 20-mg dose was selected for further investigation.

Keywords:  Bruton tyrosine kinase inhibitor; B‐cell lymphoma; immunotherapy; non‐Hodgkin lymphoma

DOI:  https://doi.org/10.1111/bjh.19951
Cancer Med. 2024 Dec;13(23): e70476

Mitoxantrone-Based Novel Conditioning Regimen Leads to Great Survival Benefit in Peripheral T-Cell Lymphoma Compared to BEAM Regimen.

Xinyu Zuo, Wensi Qian, Min Wu, Yanhui Xie, Jiexian Ma.

   BACKGROUND: Peripheral T-cell lymphomas (PTCL) frequently result in relapsed or refractory diseases. Upfront autologous hematopoietic stem cell transplantation (ASCT) using the BEAM (carmustine, etoposide, cytarabine, and melphalan) regimen is recommended. However, relapses are common in PTCL, highlighting a critical need for improved survival outcomes in these patients.
OBJECTIVE: Anthracycline drugs are essential in treating PTCL. We compared the efficacy and tolerability of a high-dose mitoxantrone-based conditioning regimen [mitoxantrone, cyclophosphamide, and etoposide (MCE)] to the BEAM regimen in upfront ASCT for newly diagnosed PTCL patients who achieved complete or partial remission after induction therapy.
STUDY DESIGN: A retrospective study was conducted to analyze the treatment response, progression-free survival (PFS), overall survival (OS), hematologic engraftment time, and adverse events of 64 patients between two regimens, who achieved complete or partial remission after induction chemotherapy. Twenty-eight patients received the MCE regimen, while 36 patients were treated with the BEAM regimen.
RESULTS: There were no significant differences in clinical characteristics or the incidence of adverse events between the two groups. However, the median OS significantly favored the MCE group at 102.4 (95% CI, 87.0-117.8) months compared to 62.6 (95% CI, 50.8-74.5) months in the BEAM group (p = 0.023). Similarly, the median PFS was longer in the MCE group at 87.8 (95% CI, 65.8-109.8) months versus 42.5 (95% CI, 30.0-55.0) months in the BEAM group (p = 0.031).
CONCLUSION: ASCT with the mitoxantrone-based conditioning regimen is tolerable and appears to significantly improve the prognosis of PTCL patients, offering a promising alternative to the current standard of care.

Keywords:  T‐cell lymphomas; autologous stem cell transplantation; carmustine; conditioning regimen; mitoxantrone

DOI:  https://doi.org/10.1002/cam4.70476
Blood Adv. 2024 Dec 11. pii: bloodadvances.2024014903. [Epub ahead of print]

Safety and Efficacy of Glofitamab for Relapsed/Refractory Large B-Cell Lymphoma in a Multinational Real-World Study.

Evgenii Shumilov, Rebecca Wurm-Kuczera, Andrea Kerkhoff, Meng Wang, Thomas Melchardt, Udo Holtick, Ulrike Bacher, Philipp B Staber, Paolo Mazzeo, Corinna Leng, David Böckle, Alexander Sebastian Hölscher, Joseph Kauer, Natalia Rotter, Vladan Vucinic, Jakob D Rudzki, David Nachbaur, Veit L Bücklein, Ulf Schnetzke, Isabelle Krämer, Kai Wille, Alexander Hasse, Bastian von Tresckow, Mathias Hänel, Christian Koenecke, Giuliano Filippini Velazquez, Andreas Viardot, Christoph Schmid, Lorenz Thurner, Dominik Wolf, Marion Subklewe, Martin Dreyling, Peter Dreger, Sascha Dietrich, Ulrich Keller, Ulrich Jaeger, Richard Greil, Thomas Pabst, Georg Lenz, Björn Chapuy.

Glofitamab, a bispecific antibody targeting CD20 and CD3, is approved for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) after at least two prior treatment lines, but real-world data is scarce. In this retrospective, multicenter, multinational study, we evaluated the outcomes of 70 patients with r/r DLBCL treated with glofitamab as part of the compassionate use patient program in the DACH region (Germany, Austria, Switzerland). The median number of prior treatment lines was four, with 71% of patients having received prior CAR-T therapy, and 71% being refractory to their last treatment. Cytokine release syndrome (CRS) was observed in 40% of patients (grade 3-4 in 2%), immune effector cell-associated neurotoxicity syndrome (ICANS) in 10% (grade 3 in 1%), and infections in 31% (grade 5 in 3%). The overall response rate was 47%, with 27% achieving complete responses (CR) and 20% partial responses (PR). The median progression-free survival (PFS) was 3.6 months, while the median overall survival (OS) was 5.7 months. Notably, 13 patients (19%) were in CR 6 months after initiation of glofitamab and exhibited durable responses. Elevated LDH is the most robust predictor of inferior outcome. Patients pretreated with bendamustine within 6 months prior glofitamab initiation exhibited significantly reduced PFS, suggesting that bendamustine may impair T-cell fitness and hence glofitamab efficacy. In summary, glofitamab demonstrates promising efficacy and a manageable safety profile in heavily pretreated r/r DLBCL patients in the real-world scenario and the optimal sequence of treatments should use T-cell-depleting agents before glofitamab with caution.

DOI: https://doi.org/10.1182/bloodadvances.2024014903
J Clin Oncol. 2024 Dec 09. JCO2402252

Efficacy and Safety of Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T-Cell for the Treatment of Relapsed and Refractory AL Amyloidosis.

Eyal Lebel, Nathalie Asherie, Shlomit Kfir-Erenfeld, Sigal Grisariu, Batia Avni, Shlomo Elias, Miri Assayag, Tali Dubnikov-Sharon, Marjorie Pick, Rivka Alexander-Shani, Nomi Bessig, Shlomit Herr, Alaa Shehadeh, Aseel Ishtay, Shelly Pimienta, Vladimir Vainstein, Eran Zimran, Yael Cohen, Irit Avivi, Cyrille Cohen, Polina Stepensky, Moshe E Gatt.

PURPOSE: The use of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CART) therapy for AL amyloidosis (AL) is limited owing to patient frailty. HBI0101 anti-BCMA CART was the first proof of concept for its applicability to AL. This report addresses the AL patient cohort treated to date within the phase Ia/Ib clinical trial (ClinicalTrials.gov identifier: NCT04720313).
METHODS: After lymphodepletion, most AL patients were infused with 800 × 106 CARTs.
RESULTS: Sixteen patients were treated, with a median of four previous lines of therapy (range, 3-10), 14/16 were triple class refractory, and 6/16 were refractory to belantamab. Most patients (13/16) had cardiac involvement, including five with MAYO stage IIIa/IIIb at study entry. Cytokine release syndrome was frequent (14/16) but mostly low grade (grade 3: 3/16, no grade 4/5). No neurologic toxicity or treatment-related deaths were observed. There were five grade 3 AL-related organ deteriorations resolved quickly with supportive care. The overall hematologic response rate was 15/16 (94%) and complete response (CR) was 12/16 (75%). Minimal residual disease negativity was achieved in 9/14 evaluable patients. Most patients (8/13 evaluable) achieved an objective organ response. Seven patients died during long-term follow-up, three while in CR/very good partial response, and the median overall survival was 10.1 months (95% CI, 5.8 to not reached).
CONCLUSION: This largest clinical trial of AL patients treated with anti-BCMA CART demonstrates acceptable and manageable toxicity in a highly frail and resistant population with remarkable efficacy, leading to fast organ responses. Among patients with baseline advanced cardiac disease, deaths in the first year were frequent, suggesting that this effective therapy should be considered earlier in the course of therapy. Anti-BCMA CART may become a powerful tool for improving organ function and survival in patients with AL.

DOI: https://doi.org/10.1200/JCO-24-02252
Hematology Am Soc Hematol Educ Program. 2024 12 06. 2024(1): 505-510

Has PD-1 blockade changed the standard of care for cHL?

Thomas M Kuczmarski, Ryan C Lynch.

The treatment paradigm for classic Hodgkin lymphoma (CHL) continues to evolve, particularly in light of the incorporation of programmed cell death protein 1 (PD-1) inhibitors into a variety of therapeutic settings. PD-1 inhibitors have demonstrated high efficacy and a favorable toxicity profile when added to a doxorubicin, vinblastine, dacarbazine chemotherapy backbone in patients with untreated CHL. PD-1 inhibitors are also effective treatment options in the relapsed/refractory setting. For patients who are pursuing autologous stem cell transplant (ASCT), pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin has shown marked efficacy and is an effective treatment regimen to administer prior to transplant. For patients who either are not eligible for ASCT or have relapsed after ASCT, pembrolizumab or nivolumab monotherapy have been well studied and demonstrate high efficacy even when patients have been exposed to numerous lines of prior therapy. As data from previous trials continue to mature and new clinical trials are conducted, PD-1 inhibitors will continue to become an integral component for successful management of CHL.

DOI: https://doi.org/10.1182/hematology.2024000574
Hematology Am Soc Hematol Educ Program. 2024 12 06. 2024(1): 561-568

Transplant in myeloma: who, when, and why?

Aurore Perrot.

High-dose melphalan supported by autologous transplantation has been the standard of care for eligible patients with newly diagnosed multiple myeloma for nearly 30 years. Several randomized clinical trials have reaffirmed the strong position of transplant in the era of triplets combining proteasome inhibitors, immunomodulatory drugs, and dexamethasone. Although quadruplets are becoming the standard in transplantation programs, no data are currently available on the need for a transplant with new regimens incorporating anti-CD38 monoclonal antibodies. Outcomes remain heterogeneous, with different response depths and durations depending on the cytogenetics at diagnosis. The improvement of disease prognostication using sensitive and specific tools allows for adapting the strategy to initial and dynamic risks. This review examines which patients need a transplant, when transplantation is preferable, and why.

DOI: https://doi.org/10.1182/hematology.2024000580
Ann Hematol. 2024 Dec 09.

Advances in epigenetic therapies for B-cell non-hodgkin lymphoma.

Weiwen Hu, Lanlan Zang, Xiaoxi Feng, Shuhui Zhuang, Liudi Chang, Yongjing Liu, Jinyan Huang, Yuanyuan Zhang.

  B-cell non-Hodgkin lymphomas (B-NHLs) constitute a varied group of cancers originating from B lymphocytes. B-NHLs can occur at any stage of normal B-cell development, with most arising from germinal centres (e.g. diffuse large B-cell lymphoma, DLBCL and follicular lymphoma, FL). The standard initial treatment usually involves the chemoimmunotherapy regimen. Although there is a high initial response rate, 30-40% of high-risk patients often face relapsed or refractory lymphoma due to drug resistance. Recent research has uncovered a significant link between the development of B-NHLs and various epigenetic processes, such as DNA methylation, histone modification, regulation by non-coding RNAs, and chromatin remodeling. Therapies targeting these epigenetic changes have demonstrated considerable potential in clinical studies. This article examines the influence of epigenetic regulation on the onset and progression of B-NHLs. It discusses the current therapeutic targets and agents linked to these epigenetic mechanisms, with the goal of offering new perspectives and approaches for targeted therapies and combination chemotherapy in treating B-NHLs.

Keywords:  B-NHLs; Epigenetic drugs; Epigenetics; Targeted therapy

DOI:  https://doi.org/10.1007/s00277-024-06131-x
Hemasphere. 2024 Dec;8(12): e70031

High-risk cytogenetic abnormalities in multiple myeloma: PETHEMA-GEM experience.

Veronica González-Calle, Paula Rodriguez-Otero, Maria J Calasanz, Manuela Guijarro, Joaquin Martínez-López, Laura Rosiñol, Miguel T Hernández, Ana I Teruel, Mercedes Gironella, Albert Oriol, Javier de la Rubia, Ana P González-Rodríguez, Joan Bargay, Felipe de Arriba, Luis Palomera, Marta-Sonia González-Pérez, Anna Sureda, Enrique Ocio, Juan J Lahuerta, Joan Bladé, Jesus F San Miguel, Maria V Mateos, Norma C Gutiérrez.

This study examines the impact of cytogenetic abnormalities and their co-segregation on the prognosis of newly diagnosed multiple myeloma patients. The analysis included 1304 patients from four different GEM-PETHEMA clinical trials. Genetic alterations, such as t(4;14), t(14;16), del(17p), +1q, and del(1p), were investigated using FISH on CD38 purified plasma cells. The frequency of genetic alterations detected were as follows: del(17p) in 8%, t(4;14) in 12%, t(14;16) in 3%, +1q in 43%, and del(1p) in 8%. The median follow-up was 61 months, and the median progression-free survival (PFS) and overall survival (OS) were 44 months and not reached, respectively. Consistent with previous reports, the presence of t(4;14) was associated with shorter PFS and OS. In our series, the presence of t(14;16) did not impact survival, maybe due to limitations in sample size. Del(17p) was linked to poor prognosis using a cut-off level of ≥20% positive cells, without any impact of higher cut-off in prognosis, except for patients with clonal fraction ≥80% who had a dismal outcome. Cosegregation of cytogenetic abnormalities patients worsened the prognosis in t(4;14) patients but not in patients with del(17p), which retained its adverse prognosis even as a solitary abnormality. Gain(1q) was associated with significantly shorter PFS and OS, while del(1p) affected PFS but not OS. Nevertheless, when co-segregation was eliminated, the detrimental effect of +1q or del(1p) was no longer observed. In conclusion, this study confirms the prognostic significance of high-risk cytogenetic abnormalities in MM and highlights the importance of considering co-occurrence for accurate prognosis assessment.

DOI: https://doi.org/10.1002/hem3.70031
Expert Rev Hematol. 2024 Dec 08.

Understanding and overcoming resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML).

Alessandro Laganà, Emilia Scalzulli, Maria Laura Bisegna, Claudia Ielo, Maurizio Martelli, Massimo Breccia.

   INTRODUCTION: Chronic myeloid leukemia (CML) represents one of the first neoplasms whose molecular pathogenesis was successfully unraveled, with tyrosine kinase inhibitors (TKIs) representing one of the first targeted therapies. TKIs have revolutionized long term outcomes of CML patients and their life expectancy. Nonetheless, a minority of patients will develop TKI resistance due to a complex and multifactorial process that ultimately leads to the emergence of an unresponsive cancer clone. Overcoming TKI resistance is considered one of the major challenges in CML management.
AREAS COVERED: In this review, the main findings extrapolated from published research, guidelines, and clinical trials regarding TKI resistance (published before October 2024) are discussed. Data have been obtained through broad research on Medline, Embase, Pubmed, and archives from EHA and ASH congresses.
EXPERT OPINION: Nowadays, asciminib and ponatinib have expanded the therapeutic arsenal for resistant-CML management and allogenic transplant still represents an important alternative in the context of multiple TKI failures. Off-label use of TKIs combination therapies, although theoretically appealing, lacks robust clinical evidence and regulatory approval. Looking ahead, the introduction of novel technologies such as digital PCR and next generation sequencing (NGS) holds great potential to revolutionize the management of TKI-resistant CML cases.

Keywords:  Allo-HSCT; BCR:ABL1 mutations; CML; Chronic myeloid leukemia; TKI resistance; TKIs; TKIs combination therapy; allogeneic hematopoietic stem cell transplant; asciminib; ponatinib; tyrosine kinase inhibitors

DOI:  https://doi.org/10.1080/17474086.2024.2440776
Hematology Am Soc Hematol Educ Program. 2024 12 06. 2024(1): 467-473

The evolving frontline management of CLL: are triplets better than doublets? How will we find out?

Kerry A Rogers, Jennifer A Woyach.

Frontline therapy for chronic lymphocytic leukemia (CLL) has substantially advanced in the previous decade. While monotherapy with a Bruton's tyrosine kinase (BTK) inhibitor is an excellent option for many patients, combination therapies are of high clinical interest as they can induce deep responses and durable remissions, and in many cases allow discontinuation of therapy. There are several doublet therapies that are currently in clinical use. These include combinations of BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) or BCL2 inhibitors (venetoclax) with anti-CD20 monoclonal antibodies, and combinations of BTK and BCL2 inhibitors. While BTK inhibitors with anti-CD20 monoclonal antibodies still typically require indefinite therapy, combinations involving the BCL2 inhibitor venetoclax have allowed for successful therapy discontinuation. Triplets, which combine all 3 of these paradigms, are of interest especially for patients with higher-risk disease. While triplets have been mainly studied in single-arm trials with excellent outcomes, comparative data to doublets are limited. In this article, we outline the doublet and triplet regimens that have been evaluated in CLL as well as the data from trials comparing doublets and triplets.

DOI: https://doi.org/10.1182/hematology.2024000571
Hematology Am Soc Hematol Educ Program. 2024 12 06. 2024(1): 569-581

Supportive care in myeloma-when treating the clone alone is not enough.

Sonja Zweegman, Niels W C J van de Donk.

The overall survival in patients with multiple myeloma has increased over recent decades. This trend is anticipated to further advance with the emergence of T-cell-redirecting therapies, including chimeric antigen receptor T-cell (CAR T) therapy and T-cell-engaging bispecific antibodies. Despite these therapeutic improvements, treatment-related adverse events impede quality of life. This underscores the imperative of optimizing supportive care strategies to maximize treatment outcomes. Such optimization is crucial not only for patient well-being but also for treatment adherence, which may translate into long-term disease control. We here describe a) how to prevent bone disease, b) a risk-adapted thrombosis prophylaxis approach, c) the management of on-target, off-tumor toxicity of G-protein-coupled receptor class C group 5 member D-targeting T-cell-redirecting therapies, and d) infectious prophylaxis, with a focus on infections during T-cell-redirecting therapies.

DOI: https://doi.org/10.1182/hematology.2024000579
Hematology Am Soc Hematol Educ Program. 2024 12 06. 2024(1): 517-523

When to use stem cell transplantation for classical Hodgkin lymphoma.

Miguel-Angel Perales, Sairah Ahmed.

Hodgkin lymphoma (HL) is a rare hematologic malignancy with a bimodal distribution of incidence, with most patients diagnosed between the ages of 15 and 30 years and another peak in patients older than 55 years. It is estimated that in 2023, almost 9000 people were diagnosed with HL in the United States. Most patients will be cured using conventional chemotherapy and radiotherapy. The treatment of HL has changed significantly over the past decade following the approval of highly effective novel therapies, including brentuximab vedotin and the checkpoint inhibitors (CPIs) nivolumab and pembrolizumab. The increasing use of these novel therapies has resulted in decreased utilization of both autologous and allogeneic hematopoietic cell transplantation (HCT) in patients with HL. In this review, we discuss the role of stem cell transplantation in patients with HL, with a particular focus on recent data supporting allogeneic HCT as a curative option in patients who progress on or are intolerant to CPI treatment.

DOI: https://doi.org/10.1182/hematology.2024000575
Bioorg Chem. 2024 Dec 07. pii: S0045-2068(24)00922-2. [Epub ahead of print]154 108017

Chemotherapeutic potential of radotinib against blood and solid tumors: A beacon of hope in drug repurposing.

Suryaa Manoharan, Ekambaram Perumal.

  Tyrosine kinase inhibitors (TKIs) represent a pivotal class of targeted therapies in oncology, with multiple generations developed to address diverse molecular targets. Imatinib is the first TKI developed to target the BCR-ABL1 chimeric protein, which is the key driver oncogene implicated in Philadelphia chromosome-positive chronic myeloid leukemia (CML). Several second-generation tyrosine kinase inhibitors (2GTKIs), such as nilotinib, dasatinib, bosutinib, and radotinib (RTB), followed the groundbreaking introduction of imatinib. RTB occupies the unique position of being the least explored member of this class. While nilotinib, dasatinib, and bosutinib have garnered significant attention and extensive research focus, RTB remains relatively uncharted in comparison to its counterparts. Fundamental drug characteristics, such as the pharmacokinetic and pharmacodynamic properties of RTB, remain unavailable in existing sources. Compared to other 2GTKIs, RTB has been less utilized in combinatorial drug studies, and no investigations have been reported on its effects on solid tumors to date. However, the effects of RTB have been studied in acute myeloid leukemia (AML), multiple myeloma (MM), Parkinson's disease, and idiopathic pulmonary fibrosis (IPF). Although RTB has been investigated in some conditions, these studies are still in their preliminary stages and are comparatively lesser than studies on other 2GTKIs. This review is the first attempt that extensively presents a compilation of data on RTB and describes its therapeutic potential against blood and solid tumors. Further investigations on RTB could expand its chemotherapeutic usage in various solid tumors and enhance the possibility of drug repurposing in cancer therapy.

Keywords:  BCR-ABL; CML; Cancer; Radotinib; Repurposing

DOI:  https://doi.org/10.1016/j.bioorg.2024.108017