cladribine

The association of Cladribine (CDA) with rituximab (R) is the standard first-line treatment in fit HCL and HCL variant patients. BRAF and BTK inhibitors are options in relapsed/refractory HCL patients. The optimal treatment sequences remain to be determined.

RFS of these 8 patients after purine analog monotherapy was also inferior compared to a control group of 34 patients who received cladribine monotherapy and began prospective follow-up before any relapses (19.9 vs 271.8 months, p<0.0001). Non-V600E BRAF mutations were observed in patients with classic HCL immunophenotype, some of which were co-mutations in BRAF with V600E. In view of the inferior RFS in these patients when purine analog was not combined with rituximab, these mutations may constitute a higher risk for relapse or chemoresistance. While those with BRAF V600 mutations might be candidates for BRAF inhibition, those with other BRAF mutations represent an opportunity for development of other specific inhibitors, not only for HCL/HCLv, but also for other malignancies.

P1/2, N=37, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Dec 2026 --> Oct 2024 | Trial primary completion date: Dec 2026 --> Oct 2024

P2, N=52, Not yet recruiting, H. Lee Moffitt Cancer Center and Research Institute

Herein, we describe recent case examples of model-informed Asia-inclusive global clinical development in the EMD Serono portfolio, as applied to the ataxia telangiectasia and Rad3-related inhibitors, tuvusertib and berzosertib (oncology), the toll-like receptor 7/8 antagonist, enpatoran (autoimmune diseases), the mesenchymal-epithelial transition factor inhibitor tepotinib (oncology), and the antimetabolite cladribine (neuroimmunological disease). Through these case studies, we illustrate pragmatic approaches to ethnic sensitivity assessments and the application of a model-informed drug development toolkit including population pharmacokinetic/pharmacodynamic modeling and pharmacometric disease progression modeling and simulation to enable early conduct of Asia-inclusive MRCTs. These examples demonstrate the value of a Totality of Evidence approach where every patient's data matter for de-risking ethnic sensitivity to inter-population variations in drug- and disease-related intrinsic and extrinsic factors, enabling inclusive global development strategies and timely evidence generation for characterizing benefit/risk of the proposed dosage in Asian populations.

Finally, analysis of the CellMiner database predicted that VDAC3 expression was positively correlated with chelerythrine and cladribine, but negatively correlated with Ergenyl. Our study suggests that VDAC3 may be a potential biomarker for early diagnosis, prognosis, and treatment of COAD.

Two patients were treated with venetoclax and azacitidine for induction (one patient achieved partial remission by combination with afatinib, while there was no remission after combination with dasatinib in the other patient). Two patients did not achieve complete remission despite treatment with cladribine and imatinib, respectively...Overall, MCL is a rare subtype of systemic mastocytosis with heterogeneous clinical course, and these patients have poor outcome. A better understanding of the clinical characteristics, treatment, and prognosis of MCL is urgently needed.

P2, N=60, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Feb 2025 --> Dec 2025

P2, N=86, Recruiting, Memorial Sloan Kettering Cancer Center | Not yet recruiting --> Recruiting

P2, N=86, Not yet recruiting, Memorial Sloan Kettering Cancer Center

P1/2, N=20, Not yet recruiting, Stanford University

P2, N=172, Recruiting, The First Affiliated Hospital of Soochow University

During the induction phase of the CCLG-AML-2019 treatment protocol, the DAH (Daunorubicin, Cytarabine, and Homoharringtonine) and IAH (Idarubicin, Cytarabine, and Homoharringtonine) regimens, in conjunction with targeted drug therapy, did not achieve remission. Subsequently, the patients were shifted to the relapsed/refractory chemotherapy regimen C + HAG (Cladribine, Homoharringtonine, Cytarabine, and G-CSF) for two cycles, which also failed to induce remission...The therapeutic conclusion is that pediatric AML patients with the aforementioned co-expression do not respond to chemotherapy. Non-remission transplantation, supplemented with tailor-made pre- and post-transplant strategies, may enhance treatment outcomes.

P2, N=40, Not yet recruiting, OHSU Knight Cancer Institute

Current treatments, i.e. the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation...Overall, the most efficient/selective single-agents and combinations (in vitro and in mice) in-cluded Cladribine, Romidepsin ((H)DAC), Venetoclax (BCL2), and/or Idasanutlin (MDM2)...Our data emphasize the therapeutic potential of pharmacologic strategies to reinstate P53-mediated apoptotic responses. The identified efficacies and their synergies provide an informative background on compound and patient selection for trial designs in T-PLL.

P1, N=22, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=324, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2027

While our results call for PPP2R1A mutant and context-dependent effects upon clofarabine/nucleoside analogue monotherapy, combining clofarabine with a pharmacologic PP2A inhibitor proved synergistically in all tested conditions, highlighting a new generally applicable strategy to improve treatment outcome in USC.

P2, N=324, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting | N=103 --> 324

His HCL was put into remission with a single course of cladribine and rituximab chemotherapy; however, his M kansasii infection persisted for 6 months despite aggressive antimicrobial and surgical therapy. It was finally controlled using high-dose rifampin in combination with azithromycin and ethambutol...Notable possibilities include HCL cells acting as sanctuary sites for M kansasii to evade the immune system, and subclinical M kansasii infections causing NLRP3 inflammasome overactivation to trigger the oncogenic transformation to HCL. More research into the pathophysiologic link between HCL and M kansasii infections would allow for more effective prevention, diagnosis, and treatment of these severe atypical infections which are the major cause of morbidity in the cladribine era of HCL treatment.

P3, N=618, Completed, The First Affiliated Hospital of Soochow University | Recruiting --> Completed

P2, N=150, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

These data confirm an excellent prognosis for HCL patients treated with cladribine-based therapy. On the contrary, HCLv with its aggressive behavior represents a group of patients in whom novel treatment approaches are needed.

P2, N=39, Recruiting, University of Maryland, Baltimore | Trial completion date: Feb 2025 --> Feb 2027 | Trial primary completion date: Jan 2024 --> Jun 2026

Cladribine plus BuCy intensive conditioning regimen before allo-HSCT exhibits favorable treatment efficacy with acceptable toxicity in R/R AML patients.

Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance. The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.

The use of chemo-immunotherapy combining cladribine (CDA) and rituximab (R) represents an increasingly used therapeutic approach. Management of relapsed/refractory disease is based on the use of BRAF inhibitors (BRAFi) plus R, MEK inhibitors (MEKi), recombinant immunoconjugates targeting CD22, Bruton tyrosine kinase inhibitors (BTKi), and Bcl-2 inhibitors (Bcl-2i). However, the optimal sequence of the different treatments remains to be determined.

P2, N=30, Recruiting, First Affiliated Hospital of Zhejiang University | Trial completion date: Aug 2024 --> Jun 2025 | Initiation date: Oct 2022 --> Jun 2023 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=103, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P1/2, N=37, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P2, N=203, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P2, N=160, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Feb 2025 --> Feb 2026 | Trial primary completion date: Feb 2025 --> Feb 2026

P2, N=60, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

P2, N=160, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

P1, N=120, Recruiting, Fred Hutchinson Cancer Center | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2023 --> Dec 2025

P2, N=98, Not yet recruiting, University of Florida

TPI1 is dramatically overexpressed in LSCC than in normal tissue, and the high expression of TPI1 may promote LSCC deterioration through its metabolic and non-metabolic functions. This study contributes to advancing our knowledge of LSCC pathogenesis and may have implications for the development of targeted therapies in the future.

Venetoclax combined with azacitidine followed by cladribine provides a new treatment option for patients with relapsed/refractory AML who have poor efficacy in early induction remission theragy, showing good efficacy and safety.

In this study, we made refinements in the conditioning regimen with two alkylating agents, namely MCBA (the combination of melphalan, cladribine, busulfan, and cytarabine)...Azacytidine, venetoclax or geritinib were the main maintenance therapies... The preliminary data demonstrated the efficiency of MCBA conditioning regimen for auto-HSCT in low-risk and intermediate-risk AML patients who achieved CR after one course of induction chemotherapy. The regimen-related toxicity was well tolerated.

Introduction: Fludarabine and cyclophosphamide (Flu/Cy) lymphodepletion (LD) prior to chimeric antigen T-cell (CAR T) infusion favorably impacts CAR T expansion and efficacy...Three deaths (2 Cla/Cy) occurred before day 100, all due to refractory fungemia post anakinra... Cla/Cy LD prior to brexu-cel is feasible in ALL and MCL patients with comparable efficacy. Toxicity rates including CRS, ICANS and early infections were similar to those seen with Flu/Cy, but there was a trend towards earlier recovery of neutrophils, B-, and T-cells with Cla/Cy. The trend was demonstrable even in patients at high risk of prolonged post-CAR T neutropenia as identified by the HS.

Treatment was ruxolitinib and hydroxyurea...He started dasatinib and decitabine, which resulted in a drop from 28...However, hyperuricemia and renal failure led to a change in regimen and the patient was started on asciminib and ropeginterferon alfa-2b-njft in January 2022...He received cladribine and cytarabine, but was found to have leukemic infiltration of the spinal cord five months later...However, he always maintained a high CALR burden. This patient's mutational profile and disease course argue for the importance of early testing for CALR and BCR-ABL in addition to JAK2 and MPL in the setting of an MPN and for further research into the underlying causes of these overlap conditions.

Recent study showed venetoclax (Ven) added to CLAG+Ida as frontline treatment of AML acquired a good response and well toleration...CLAG±Ida/Mito+Ven: cladribine 5mg/m 2 day 1-5, cytarabine 1-1. 5g/m 2 day 1-5, PEG-G-CSF 6mg day 0, idarubicin 6mg/m 2 day 1-3 or mitoxantrone 6mg/m 2 day 1-3 (lipo-Mito 20mg/m 2 day 1), Ven 400mg day 2-8... CLAG±Ida/Mito+Ven might be a chioce for salvage therapy of RR-AML, with the CR/CRi rate of 66. 7%, MRD-negative rate of 68. 2% and well toleration.