nelarabine

To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent...ACHM-025 was significantly more effective than cyclophosphamide both as a single agent and when used in combination with cytarabine/6-mercaptopurine. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo. The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providing a predictive biomarker for response. Together, our work provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL.

P2, N=160, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2024 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2026

Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

P1/2, N=50, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P3, N=83, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

P3, N=1033, Active, not recruiting, University College, London | Trial completion date: Jul 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=0, Withdrawn, National Cancer Institute (NCI) | N=154 --> 0 | Not yet recruiting --> Withdrawn

P3, N=560, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Nov 2028 --> Nov 2034

P2, N=145, Not yet recruiting, St. Jude Children's Research Hospital

P2, N=154, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2024 --> Aug 2024

P3, N=1895, Active, not recruiting, National Cancer Institute (NCI)

P2, N=154, Not yet recruiting, National Cancer Institute (NCI)

Most importantly, the drug sensitivity analysis revealed a positive correlation between ARL4C expression and the heightened sensitivity of tumors to Staurosporine, Midostaurin, and Nelarabine. The findings from our study indicate that the expression level of ARL4C may exert an influence on cancer development, prognosis, and susceptibility to immunotherapy drugs. In addition, the involvement of ARL4C in the tumor immune microenvironment has expanded the concept of ARL4C-targeted immunotherapy.

Remarkably, EdC was resistant to cytidine deamination and SAMHD1 metabolism mechanisms and exhibited higher potency against ALL compared to FDA approved nelarabine. Finally, EdC was highly effective against DLBCL tumors and B-ALL in vivo. These data characterize EdC as a pre-clinical nucleoside prodrug candidate for DLBCL and ALL.

This research underscores the significance of a disulfidptosis-associated gene signature in breast cancer prognosis.

Induction chemotherapy was given as per COG AALL1231 protocol with dose modifications including 50% decrease in vincristine and cyclophosphamide...He was given 150 mg/m2 for 7 days directly followed by nelarabine...Patients with AT have increased risk of toxicity from chemotherapy agents which requires dose modifications in their chemotherapy regimen. Venetoclax augmentation may be a viable approach for patients with AT or DNA repair disorders.

P3, N=1033, Active, not recruiting, University College, London | Recruiting --> Active, not recruiting | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Dec 2022 --> Dec 2023

Salvage therapy with Venetoclax-Decitabine was administered with a transient CR before a second hematological and extramedullary relapse occurred...She experienced an isolated CNS relapse before the initiation of maintenance; thus we performed biweekly triple intrathecal therapy administrations followed by high250 dose cytosine arabinoside and mitoxantrone (HAM) regimen, obtaining CNS1...The NCE regimen was generally safe and manageable. None of the patients experienced neurotoxicity events; intrathecal prophylaxis was delayed in order to mitigate this risk.

P1/2, N=50, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2026

ACHM-025 was designed to improve drug specificity and minimize toxicity observed with currently used DNA alkylating agents, such as cyclophosphamide (CPM), a prodrug which is activated systemically via liver enzymes...For the consolidation therapy comparison, ACHM-025 (IP Days 0, 7) or CPM (IP Days 0, 7) combined with cytarabine (Ara-C; IP Days 0-4, 7-11) and 6-mercaptopurine (6MP; IP Days 0-4, 7-11) were assessed against a T-ALL PDX derived from a patient at relapse... ACHM-025 exerted profound in vivo efficacy against T-ALL PDXs and eradicated the disease in 7 aggressive T-ALL PDXs. ACHM-025 was significantly more effective than CPM both as a single agent and when used in combination with Ara-C/6MP. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo.

NELA was given at 1,500 mg/sqm/day at day 1,3 and 5 in combination with etoposide and cyclophosphamide for a maximum of 5 courses during consolidation (2 cycles) and maintenance (3 cycles). While NELA did not yield an overall improved outcome in the study population, benefits were observed in favorable MRD responders and non-ETP patients. Additional prospective studies are needed to further delineate the specific patient subgroups that might benefit from NELA.

Among 21 drugs, seven showed significant differences in overall LC50 between children and adults (P<0.05 after Bonferroni correction): children displayed higher sensitivity to asparaginase, prednisolone, mercaptopurine, daunorubicin, and inotuzumab, while adults showed higher sensitivity to dasatinib and nelarabine...In the KMT2A subtype, cases in C-a exhibited an over-representation of the KMT2A::AFF1 fusion, and resistance to mercaptopurine (P=0.029), prednisolone (P=0.0039), vincristine (P=0.046) and cytarabine (P=0.0037)...In conclusion, these studies have revealed important new insights into the pharmacogenomic basis of age-related differences in B-ALL treatment response. These results indicate that both inter- and intra-subtype heterogeneity contribute to inferior prognosis in adults with ALL, but also point to therapeutic opportunities to improve their outcomes.

In relapse/refractory (R/R) patients, standard of care treatments, including nelarabine, yield response rate of about 20-40% and responses are of short duration...For example, TTOs included Tofacitinib and Venetoclax (Tofa/Ven) in case of IL7R (CD127) expression or IL7R-pathway alterations (IL7RALT), 5-azacytidine and Venetoclax (Aza/Ven) in case of T-ALL/LL with epigenetic regulators alterations (DNMT3A, ASXL1, PHF6, TET2, PRC2, IDH1/2, SRSF2...) or Temsirolimus, Erwinase and Venetoclax (Tem/Erw/Ven) in case of PI3K signaling pathway alterations (PI3KALT)...Twenty-five patients received a TTO, including 14 Aza/Ven (56%), 8 Tofa/Ven (32%), 2 Tem/Erw/Ven (8%) and 1 Trametinib/Ven (4%)...A better knowledge of the oncogenetic landscape of T-ALL, and a close collaboration between clinicians and biologists, resulted in individualized treatment strategies. With a 3 months cumulative incidence of response of 70%, TTOs appear to be a promising approach in R/R T-ALL.

Objectives Cohort 1: To evaluate the safety of venetoclax + navitoclax + AALL0434 chemotherapy backbone (Arm 4) before initiating randomization...Cohort 3: To evaluate the safety of modified AALL0434 chemotherapy backbone (including nelarabine)...Prior treatments with hydroxyurea, all-trans retinoic acid, corticosteroids, and leukapheresis to reduce peripheral blast count and prevent complications from leukostasis are permitted. A single dose of intrathecal cytarabine and/or methotrexate is permitted...Initially, 10 eligible participants will be enrolled on each of Cohort 2 and Cohort 3. If two or fewer participants experience a TOI in a cohort and Arm 4 treatment is found to be safe in Cohort 1, then 10 additional participants will be enrolled to that cohort.

Prior nelarabine therapy is not required, but patients who do not receive nelarabine during initial induction or post-remission treatment are eligible only if the physician does not feel they would benefit from other, multi-agent chemotherapy. Patients must not have had chemotherapy within 14 days prior to registration except for steroids, oral 6-mercaptopurine, oral methotrexate, vincristine, intrathecal chemotherapy, or hydroxyurea...This dose level temporarily closed on December 22, 2022, to fully assess the safety profile of the cohort. Three additional patients will be enrolled at dose level 3 after the study is reopened with a protocol amendment to relocate the MRD testing lab.

Prior nelarabine therapy is not required, but patients who do not receive nelarabine during initial induction or post-remission treatment are eligible only if the physician does not feel they would benefit from other, multi-agent chemotherapy. Patients must not have had chemotherapy within 14 days prior to registration except for steroids, oral 6-mercaptopurine, oral methotrexate, vincristine, intrathecal chemotherapy, or hydroxyurea...This dose level temporarily closed on December 22, 2022, to fully assess the safety profile of the cohort. Three additional patients will be enrolled at dose level 3 after the study is reopened with a protocol amendment to relocate the MRD testing lab.

Salvage therapy with venetoclax-decitabine was administered with a transient CR before a hematological and extramedullary relapse occurred...She experienced an isolated CNS relapse just before maintenance; thus, we performed biweekly triple intrathecal therapy administrations followed by a high-dose cytosine arabinoside and mitoxantrone (HAM) regimen, obtaining CNS1...The NCE regimen was generally safe and manageable. None of the patients experienced neurotoxicity events.

After demonstrating efficacy in relapsed T-ALL, nelarabine is being increasingly incorporated into frontline T-ALL regimens...Immunotherapy and cellular therapy regimens are also under early investigation in T-cell malignancies. This review outlines the clinical and biological characteristics of T-ALL and provides an overview of novel treatment options for refractory and relapsed T-ALL.

We constructed a novel 8-gene (ATP7A, GLS, CDKN2A, BAK1, CHMP4B, NLRP6, NOD1 and GZMA) prognostic model and explored potential functional information and microenvironment of HCC, which might be worthy of clinical application. In addition, several potential chemotherapy drugs were screened and Fludarabine might be effective for HCC patients whose GZMA was low expressed.

P1, N=8, Completed, Emory University | Recruiting --> Completed | N=15 --> 8

We also found that HIC1 was significantly correlated with the sensitivity of several anti-cancer drugs, such as axitinib, batracylin, and nelarabine. Our investigation provided an integrative understanding of the clinicopathological significance and functional roles of HIC1 in pan-cancer. Our findings suggested that HIC1 can function as a potential biomarker for predicting the prognosis, immunotherapy efficacy, and drug sensitivity with immunological activity in cancers.

Since its approval in 2005, nelarabine has been studied in combination with other chemotherapy agents for relapsed disease and is also being studied as a component of initial treatment in pediatric and adult patients. Here, we review current data with nelarabine and present our approach to the use of nelarabine in the treatment of patients with T-ALL/LBL.

The outcome of IF in T-ALL remains poor with current therapy. The lack of a unifying genetic driver suggests alternative approaches, particularly using immunotherapy, are urgently needed.

We discuss results of recent clinical trials incorporating use of nelarabine and bortezomib, choice of induction steroid, role of cranial radiotherapy, and risk stratification markers to identify patients at highest risk of relapse and to further refine current treatment strategies. Because prognosis for relapsed or refractory T-LLy patients is poor, we discuss ongoing investigations incorporating novel therapies, including immunotherapeutics, into upfront and salvage regimens and the role of hematopoietic stem cell transplantation.

No abstract available

The ALL-T11 protocol produced encouraging outcomes with acceptable toxicities despite limited cranial radiotherapy and HSCT use.

P2/3, N=793, Active, not recruiting, St. Jude Children's Research Hospital | Recruiting --> Active, not recruiting

A new complete remission is attained in 20-40% of patients, but prolonged disease free survival is observed in around 10-15% of cases only.1-4 Nelarabine is approved for R/R T-ALL in second relapses and the registration study showed a CR rate of 36%...Responding patients will have the opportunity to continue the selected TTO for a total of 6 months. Non-responding patients in the control arm will be proposed to cross-over to the selected TTO option proposed before randomization.

No abstract available

The frequency of T-ALL in our series (32%) is higher than those described in the literature (10 to 15%). This high frequency is also found in other Tunisian series as well as in the Tunisian multicenter study of 2005 (37%). The frequency of corticoresistance in our study (38%) is comparable to the literature (38 to 40%).

Pts received mini-Hyper-CVD alternating with methotrexate and cytarabine for up to 8 cycles (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m 2 x 4 doses)...Rituximab (if CD20+ B-ALL) and prophylactic IT chemotherapy x8 doses were given for the first 4 cycles. Pts with T-ALL received additional 2 cycles of nelarabine and peg-asparaginase during consolidation without Ven, and 2 cycles of nelarabine plus peg asparaginase during maintenance. Responding pts received vincristine and prednisone maintenance with venetoclax daily on days 1-14 of each 28-day cycle for up to 2 years...Among the 18 B-ALL pts, 16 (89%) had received prior blinatumomab and 7 (39%) prior inotuzumab... In pts with R/R Ph-negative ALL, the combination of low-intensity chemotherapy mini-Hyper-CVD with Vendemonstrated clinical efficacy with a response rate of 67% and a favorable safety profile. Further studies examining the role of Ven-based therapies in ALL are needed for newly diagnosed and R/R pts. Venetoclax, Phase II, Acute lymphoblastic leukemia