cladribine

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.

Our findings showed the combination regimen CLAG(M)/Ven is feasible in pts with AML. It also provided better characterization in terms of early mortality and survivals in these pts, which can help inform future clinical trial design. ORR was similar to what was previously reported with CLAG(M); however, it is encouraging that those who achieved CR/CRi and had MRD testing also achieved MRD negativity.

In FLT3 mutated pts standard induction/consolidation therapy was enriched with midostaurin. Low intensity treatment consisted of azacitidine (1 pts), low dose Ara-C (LDAra-C, 2 pts) and LDAra-C + cladribine (1 pts)...ConclusionsOur preliminary results indicate the signaling pathways disturbed in high-risk AML patients. The miR-125b-5p, miR-15a-5p as well as the TEK and SPP1 gene expression may possibly act as biomarkers in patients with de novo AML.

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.

Given innate fragility and higher chemo sensitivity in patients with DS, we elected to treat him off protocol with Cladribine and low dose Ara-C alternating with Decitabine. AML treatment in DS remains a challenge and further research is warranted to develop tailored regimens effectively balancing curative intent and reduced toxicity. This regimen could be considered in pediatric patients with Down Syndrome and other comorbidities.

Four pts (33%) were refractory to venetoclax (VEN)-based therapy and 3 pts (25%) had previous alloHCT (Table 1)... Combination of cladribine with standard dose of CPX-351 is well tolerated. Cladribine dose 5 mg/m 2 was selected as RP2D. Safety profile does not indicate any significant additional myelosuppression.

There is evidence FLAG-IDA may be superior to 7+3 (Solh et al Leuk Res 2020), and that cladribine is superior to fludarabine (Holowiecki et al JCO 2012)...Chemotherapy consisted of cladribine 5 mg/m 2 daily times 5 days, cytarabine 2 gm/m 2 over 4 hrs daily times 5 days (given 2 hours after the completion of each cladribine dose), plus G-CSF 300 ug daily during chemotherapy and then based on weight after that. Patients with adequate cardiac function also received 3 days of mitoxantrone 12 mg/m 2 (CLAG-M) or idarubicin 12 mg/m 2 (CLAG-IDA) on days 1-3 or 2-4... CLAG provides an alternative induction regimen to 7+3. Interestingly, in contrast to 7+3, CR rates did not differ significantly by age or cytogenetic risk group. The older patients treated on this trial were a select group that were considered eligible for intensive chemotherapy.

The VCR combination is a well-tolerated, low toxicity and effective regimen for MCL, especially for untreated MCL. Cladribine 5 mg/m 2 is a tolerable dose with manageable toxicity. Individual patient methylation profile may affect response to VCR therapy.

Arginine Vasopressin Deficiency (AVP-D) was diagnosed, and desmopressin was initiated...While it is effective in adults, its limited tolerance favors the use of cytarabine or cladribine. NCT02670707 is an ongoing trial comparing cytarabine monotherapy versus Vinblastine/Prednisone for frontline treatment. BRAF inhibitors are also being increasingly investigated. Prospective trials to optimize the duration of therapy (LCH-IV) and potential combination therapies are currently underway.

P2, N=100, Recruiting, Shanghai Jiao Tong University School of Medicine | N=30 --> 100

P2, N=237, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P1, N=20, Recruiting, University of Washington | Suspended --> Recruiting

P2, N=48, Recruiting, The First Affiliated Hospital of Soochow University | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Sep 2023 --> Oct 2024

P1/2, N=80, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

She received first-line therapy with a 5-day course of Cladribine (0.15 mg/kg/day) with initial resolution of leukocytosis, normalization of platelets, and a 50% reduction in spleen size...Soon after the 2nd dose of Rituximab, leukocytosis recurred, and she was initiated on second-line therapy with Bendamustine (90 mg/m2 on days 1 and 2) along with Rituximab (BR)...As she was clinically unstable, we attempted to control leukocytosis with corticosteroids, leukapheresis aggressively and started the patient on Ibrutinib, but she succumbed to her disease...Additionally, more novel therapies could be considered sooner in the treatment course to control the disease and these lesions. Finally, our patient did not harbor BRAF V600E mutation, which likely resulted in further worse outcomes and limited the usage of targeted therapies like BRAF inhibitors.

Among treated patients, 47/54 (87%) received cladribine and 7/54 (13%) pentostatin...A similar decrease in sIL-2R levels after therapy was observed in 4 relapsed patients treated with rituximab-vemurafenib (median pre-therapy sIL-2R 11.460 vs. 467 kU/L after treatment, p = 0.03; median reduction 10.848 kU/L)...While more data is required to validate its use in clinical routine, sIL-2R could be used as an effective marker for disease monitoring. Moreover, given the prognostic significance of post-therapy levels, sIL-2R may represent a prognostic factor alongside MRD to identify those patients that are more likely to develop early relapse.

Cladribine added to a backbone regimen of high dose cytarabine [≥ 1 gram per m2 intravenously (IV) for up to 5 days] and idarubicin (CLIA; further HD-clad) or low dose cytarabine [LDAC; 20 mg twice daily subcutaneously (SQ) for up to 10 days] alternating every two cycles with hypomethylating agent (HMA; regimen referred as LD-clad) have been routinely used in the treatment of AML at our institution. Cladribine added to chemotherapy is an effective approach in patients with AML from MPN, either as an induction therapy for those eligible for SCT or acceptable long-term therapy for non-eligible patients. Noticeably, almost 40% of patients without SCT were alive past 12 months since the initiation of LD-clad therapy. HMA pretreated patients had lower response rates and poor survival even in the frontline setting.

CLAD-LDAC-Ven combination offers an encouraging ORR with long term OS and EFS. In these pts, the ELN 2022 showed a better risk group discrimination regarding OS, compared to the PRSc. Pts of the intermediate-benefit of the PRSc (enriched in RAS/FLT3 mutations) could benefit the most of CLAD-LDAC-Ven, in which an HMA-Ven approach is associated with a mOS of 12 months.

The phase 2 trial of Ven added to alternating Clad+LDAC and Aza showed promising remission rates of 57% in pts with ND AML having TP53 mut/loss and high rates of MRD negativity in responders; median RFS and OS was not reached at 9 mos follow-up. Five pts (36% overall, and 50% of the responders) could be consolidated with HSCT, with none of them relapsing after HSCT. The trial continues to accrue pts.

We retrospectively reviewed patients treated in three clinical trials of frontline ven in combination with chemotherapy—cladribine (clad) + LDAC + ven, CLIA + ven, and FLAG-IDA + ven—who had documented relapsed disease at any time. Among patients with relapsed AML after treatment with 3 frontline ven-containing regimens, we observed varying profiles. Mutational profiles exhibiting previously undetected aberrancies in RUNX1, DNMT3A, TET2, and SMC3 were most frequently observed at the time of relapse. Meanwhile, the most frequent karyotypic changes observed at the time of relapse were the acquisition -7/7q among patients, with the greatest number of acquisitions occurring among the clad + LDAC + ven cohort.

Background: Venetoclax (Ven) in combination with hypomethylating agents is approved for treatment in patients (pts) with newly diagnosed (ND) acute myeloid leukemia (AML) who are ≥75 years old or unfit for intensive chemotherapy (IC), based on the longer median overall survival (OS) with Ven+azacitidine (Aza) compared with Aza in combination with placebo in the Phase III VIALE-A study (NCT02993523)...Additionally, Ven in combination with cladribine (CLAD) and low-dose cytarabine (LDAC) is currently under investigation in a Phase II single-arm study (NCT03586609) amongst older pts (aged ≥60 years) with ND AML... In this large real-world data study, we observed older pts (aged ≥60 years) with ND AML receiving IC treatment had a median OS of <14 months and <35% of pts remained alive 2 years after IC initiation. Findings from this study suggest the need for other novel treatment options, including Ven based regimens, to improve OS in older pts (aged ≥60 years) with ND AML who are eligible for IC. Future studies are warranted to conduct randomized controlled trials to comparatively evaluate IC vs other novel treatment options in older pts (aged ≥60 years) with ND AML, or conduct the appropriate statistical adjustment to minimize confounding in indirect treatment comparisons from different studies.

Patients received myeloablative conditioning with a modified Bu/Cy/Flu/Ara-c (busulfan/cyclophosphamide/fludarabine/cytarabine) or MCBC (melphalan/cladribine/busulfan/cyclophosphamide) preparative regimen. The main prognostic factors affecting transplant outcomes included pre-transplant MRD status and the application of maintenance therapy. Thus, introduction of FLT3 inhibitors as post-transplant maintenance therapy and the development of highly sensitive MRD assays will further reduce disease recurrence and improve survival.