PurposeTo investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo.MethodsH2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell killing was evaluated 48 h later. Female nude mice bearing H2052 xenografts were treated with varying doses and schedules of the antifolate PDX and LV.ResultsIn vitro, H2052 cells were more sensitive to PDX as compared to MTX and pemetrexed. Administration of LV 24 h after antifolate treatment reduced efficacy of antifolates MTX and pemetrexed, but not PDX. In vivo, LV was found to reduce toxicity of PDX at the maximum tolerated dose without sacrificing efficacy. Lethal doses of PDX were rescued by LV, and mice bearing the H2052 tumor demonstrated prolonged and enhanced tumor regression.ConclusionsHigh-dose PDX with subsequent LV rescue may be a viable treatment strategy in mesothelioma and other cancers. The inclusion of LV rescue into new and existing PDX treatment protocols should be explored as a way to expand the tolerability and effectiveness of PDX in the clinic.
PurposeTo investigate the effectiveness of a combination of 6-thioguanine (6-TG) and pralatrexate (PDX) in methylthioadenosine phosphorylase (MTAP)-deficient T-cell acute lymphoblastic leukemia (T-cell ALL).MethodsCCRF-CEM (MTAP−/−) and Molt4 (MTAP+/+) T-cell ALL cell lines were treated with 6-TG or PDX and evaluated for efficacy 72 h later. NOD/SCID gamma mice bearing CEM or Molt4 xenografts were treated with 6-TG and PDX alone or in combination to evaluate antitumor effects.ResultsCEM cells were more sensitive to 6-TG and PDX in vitro than Molt4. In vivo, CEM cells were very sensitive to PDX and 6-TG, whereas Molt4 cells were highly resistant to 6-TG. A well-tolerated combination of PDX and 6-TG achieved significant tumor regression in CEM xenografts.ConclusionsThe loss of MTAP expression may be therapeutically exploited in T-cell ALL. The combination of 6-TG and PDX, with the inclusion of leucovorin rescue, allows for a safe and effective regimen in MTAP-deficient T-cell ALL.
Pralatrexate is a second generation antifolate that targets dihydrofolate reductase. It was found to have a higher affinity to reduced folate carrier type 1 (RFC-1), the primary folate transporter, and has high intracellular retention via enhanced polyglutamylation. Mucositis, rather than bone marrow toxicity, is the dose limiting toxicity (DLT) in patients. In this study, we examine whether the use of leucovorin (folinic acid) can reduce pralatrexate DLT when used in mouse xenografts, and possibly enable high dose pralatrexate treatment. Nude mice bearing H2052 mesothelioma xenografts were treated with pralatrexate at normal and toxic doses with or without leucovorin administration 24 hours later. Tumors were measured three times weekly and toxicity monitored through weight loss. Leucovorin was found to abrogate pralatrexate toxicities at high doses without sacrificing efficacy. These results demonstrate that high dose pralatrexate with subsequent leucovorin rescue may be a viable treatment strategy in mesothelioma and other cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A266. Citation Format: Philip M. Tedeschi, Iqra Farooqi, Yamini Kathari, Joseph R. Bertino. Leucovorin rescue of high dose pralatrexate in mesothelioma xenografts. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A266.
Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with features of both myeloproliferative neoplasm and myelodysplastic syndrome (MDS). CMML is characterized by persistent blood monocytosis >1 x 109/L, bone marrow dysplasia in one or more hematopoietic cell lines, and increased risk of transformation to acute myeloid leukemia (AML). Our review of SEER Medicare data (Haematologica 2013;98:584) demonstrated that, compared to MDS, CMML has shorter overall survival (OS) and more frequent progression to AML. Hypomethylating agents (HMAs) have become standard therapy for CMML, with reported response rates of 37-69%, but their impact on AML transformation and OS is unclear. Methods: We retrospectively reviewed CMML patients treated at the University of Maryland Greenebaum Comprehensive Cancer Center between January 2000 and December 2019. Clinical characteristics, treatments, AML progression, time to AML progression (TTP), and OS were recorded and analyzed. Descriptive statistics were used for baseline characteristics and Kaplan-Meier analysis was performed for time-to-event data. Statistical analyses were performed using GraphPad Prism 8®. Results: We identified 71 patients with CMML, 82% male and 73% white, with a median age of 69 (range 25 - 96) years; 51% had <10% bone marrow (BM) blasts and 45% had low-risk cytogenetic findings (normal karyotype or -Y). Most patients treated prior to 2005 received hydroxyurea and/or erythropoiesis-stimulating agents or were enrolled on clinical trials, while patients treated since 2005 received HMAs as primary therapy. Median follow-up was 41.1 months. The median OS of the entire cohort was 20 months, with 46% of patients progressing to AML with a median TTP of 11.5 months. By the MD Anderson Prognostic Scoring System at time of diagnosis, CMML was low-risk in 24 patients, intermediate-1 in 16, intermediate-2 in 14, and high-risk in 17. Forty-six patients received HMAs, with an overall response rate (ORR) of 54% (complete response or partial response), while 25 patients did not receive HMAs. Patient and disease characteristics were similar in HMA- and non-HMA-treated patients (Table 1). The estimated OS of HMA-treated patients was 20 months, compared to 14 months for non-HMA-treated patients (p =0.43) (Figure 1). AML transformation occurred in 52% of patients treated with HMAs, with TTP ranging from 3 to 65 months, and in 33% patients not treated with HMAs, with TTP ranging from 5 to 47 months. Most patients receiving HMAs (63%) received ≥ 6 cycles; 46% transformed to AML despite initial response, often in a sudden and unpredictable manner. HMAs were azacitidine in 13 patients, decitabine in 24, azacitidine followed by decitabine in 4, and decitabine followed by azacitidine in 5. Five CMML patients in our cohort underwent allogenic stem cell transplantation. Four of the five relapsed with transformation to AML post transplant, and only one patient remains in remission, 9 months post transplant. Conclusions: Despite a 54% ORR, HMA treatment did not have a significant impact on frequency of AML transformation, or OS in our cohort. Based on our data, favorable response rates previously reported with HMAs and also seen in our patients do not appear to translate into decreased frequency of AML transformation or prolonged OS. Though our study is a retrospective study with inherent selection bias, our results underscore the ongoing need for novel therapies and for clinical trials for CMML patients. Disclosures Niyongere: Kartos Therapeutics: Other: Received clinical trial research support with Kartos Therapeutics ; Forty Seven: Other: Received clinical trial research support with Forty Seven. Emadi:Amgen: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor; NewLink Genetics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding. Doung:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial research support; Incyte: Other: clinical trial research support; Astex: Other: clinical trial research support; MedPacto: Other: clinical trial research support. Baer:Takeda: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Kite: Other: Institutional research funding; Incyte: Other: Institutional research funding; Forma: Other: Institutional research funding; Astellas: Other: Institutional research funding; AbbVie: Other: Institutional research funding.
In T-cell acute lymphoblastic leukemia (ALL), the genes CDKN2A (p16 and p14) and MTAP are homozygously co-deleted, with a frequency of ∼35 %. MTAP cleaves the natural substrate, 5′-deoxy-5′-methylthioadenosine, to adenine and 5-methylthioribose-1-phosphate, which are converted to adenine nucleotides and methionine. Cells lacking MTAP are unable to salvage adenine through this pathway and rely on the de novo pathway for purine synthesis. This variation between normal MTAP+ cells and tumor MTAP-/- cells led to several studies showing that MTAP -/- cells are more sensitive to inhibitors of de novo purine synthesis. Pralatrexate (PDX) is a second generation antifolate that targets dihydrofolate reductase and via conversion to polyglutamylates, inhibits de novo purine synthesis. 6-Thioguanine (6TG), an antimetabolite analog of guanine, also target de novo purine synthesis. MTAP-deficient ALL cells should be more sensitive to these agents, remarkably so in combination. We tested single agent PDX and 6TG as well as a combination treatment in MTAP+ (Molt4) and MTAP-/- (CEM) ALL xenografts. CEM xenografts were more sensitive to PDX treatment than MOLT4 xenografts. CEM xenografts were also much more sensitive to 6TG, while Molt4 xenografts were resistant to 6TG. Early results of the combination of PDX and 6TG in vivo show promise as an effective therapy of MTAP-/- T-cell ALL. Citation Format: Philip M. Tedeschi, Yamini K. Kathari, Iqra Farooqi, Joseph R. Bertino. Methylthioadenosine phosphorylase (MTAP)-deficient T-cell ALL xenografts are sensitive to pralatrexate and 6-thioguanine alone and in combination. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 843. doi:10.1158/1538-7445.AM2014-843
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