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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The usefulness of cladribine is also limited by severe myelosuppression with neutropenia, anemia, and thrombocytopenia; hemolytic anemia has also been reported. High doses of cladribine have been associated with renal failure, hepatotoxicity, and severe neurotoxicity. Therefore, regular hepatic and renal monitoring is recommended. Other side effects include GI (e.g., constipation, diarrhea, abdominal pain, and flatulence) and skin (e.g., rash, pruritis, and purpura) disturbances, edema, tachycardia, dyspnea, asthenia, myalgia, and arthralgia. It is also teratogenic, and so contraception for both men and women is recommended during, and for six months after, treatment. Cladribine and fludarabine have the potential for a prolonged immunosuppressive effect, and so patients treated with either drug are more prone to serious bacterial, opportunistic fungal, and viral infections. Therefore, prophylactic anti-infective therapy is recommended for those patients at risk. To prevent potentially fatal transfusion-related graft versus host reactions, only irradiated blood products should be administered.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
The clinical features of mastocytosis result from the accumulation of neoplastic mast cells in the various organs, which results in features such as cytopenias, osteolytic bone lesions, abnormal liver function tests, and elevated serum tryptase levels.120 The prognosis of CM is good, and most children achieve spontaneous remission. Advanced SM is associated with a poor prognosis, with a median OS of 3.5 years in ASM and 2 years for SM-AHNMD; patients with MCL fare the worst, with a median survival of <6 months. Treatment decisions are based on the presence of clinical features and symptom burden. Cladribine and IFN-α have some efficacy, which is often not sustained. Responses to imatinib tend to be transient and durable in <10% of patients, largely due to the acquired resistance conferred by several resistant mutations, including D816V and T670I. Masitinib, a TKI that selectively inhibits KIT, PDGFRA, PDGFRB, and LYN kinases, has demonstrated some efficacy in indolent, but not aggressive, disease; the drug is associated with significant diarrhea and urticaria. Another orally active multi-kinase inhibitor, midostaurin, is licensed for patients with ASM, SM-AHN, and MCL. Midostaurin may also be effective in some patients with aggressive MCL, who are often treated with intensive chemotherapy followed by allo-SCT.
Myeloproliferative and Related Neoplasms
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The clinical features of mastocytosis result from the accumulation of neoplastic mast cells in the various organs, which results in features such as cytopenias, osteolytic bone lesions, abnormal liver function tests and elevated serum tryptase levels. Prognosis of CM is generally good and most children achieve spontaneous remission. Advanced SM is associated with a poor prognosis, with a median overall survival of 3.5 years in ASM and 2 years for SM-AHNMD; patients with MCL fare the worst, with a median survival of <6 months. Treatment decision are based on the presence of clinical features and symptom-burden. Cladribine and interferon 2-α have some efficacy that is often not sustained. Responses to the TKI, imatinib, tend to be transient and durable in <10% of patients, largely due to the acquired resistance conferred by several resistant mutations including D816V and T670I gatekeeper. Masitinib, a TKI which selectively inhibits KIT, PDGFRA, PDGFRB and LYN kinases, has demonstrated some efficacy in indolent disease but not aggressive; the drug is also associated with diarrhoea and urticaria. Another orally active multi-kinase inhibitor, midostaurin, was licensed in April 2017, by the FDA, for patients with ASM, SM-AHN and MCL following the demonstration of acceptable safety and efficacy in a phase II study. Midostaurin may also be effective in the aggressive MCL, for which intensive chemotherapy followed by allo-SCT is probably the only reasonable treatment option at present.
Treatment of hairy cell leukemia
Published in Expert Review of Hematology, 2020
Dai Chihara, Robert J. Kreitman
Although the anti-CD20 monoclonal antibody (Mab) rituximab has been commonly used for relapsed disease, single-agent activity of rituximab is rather disappointing, even in second line where it is recommended if patients are unable to receive purine analogs [31,43]. Nieva et al. conducted a phase II study giving weekly rituximab 375 mg/m2 for four weeks in patients with relapsed HCL who had received one or more courses of cladribine [43]. The median age of 24 patients enrolled was 53.5 years (range: 38–81), the median time from diagnosis was 91 months (range: 24–157) and the median time from last cladribine infusion was 73 months (range: 20–140). The number of prior courses of cladribine was 1 in 15 (63%) patients, 2 in 8 (33%), and 3 in 1 (4%) patient. Although the treatment was well tolerated, only three patients achieved CR (13%), and one of them had MRD by bone marrow immunohistochemistry. Interestingly, patients who responded to rituximab had a trend for lower bone marrow involvement compared to those who did not respond (17% vs 39%, P = 0.054), suggesting that rituximab monotherapy is inadequate in treating high tumor burden.
An update on the safety of treating relapsing-remitting multiple sclerosis
Published in Expert Opinion on Drug Safety, 2019
Clara G. Chisari, Simona Toscano, Emanuele D’Amico, Salvatore Lo Fermo, Aurora Zanghì, Sebastiano Arena, Mario Zappia, Francesco Patti
Due to its mechanism of action, cladribine must not be administered during pregnancy and, if an unplanned pregnancy occurs, treatment should be stopped [117]. While teratogenic effects have been shown in mice [207], data on pregnancy are mostly limited to case reports [210] in humans. However, an integrated analysis of safety was carried out on patients under treatment with cladribine in clinical trials reporting 44 pregnancies in 38 exposed women. Pregnancy outcomes were 41% of live births, 20% of miscarriages, 7% of medically indicated abortions, 32% of induced abortions, with no detected congenital malformations [211]. EMA concluded that cladribine interferes with spermatogonial cells, implying a minimal risk of inheritable genetic damage after discontinuation of treatment for a period long enough for a new spermatogenetic cycle to achieve completion [207]. Both women treated with cladribine and partners of men treated with this drug should take precautions to avoid a pregnancy during the treatment and for at least 6 months after the last dose in each treatment year. Moreover, a barrier method of contraception should be added to hormonal contraception during therapy and for at least 4 weeks after the last dose [117]. Breastfeeding is contraindicated during treatment with cladribine and for at least 1 week after [117,209].
Assessing the risk of multiple sclerosis disease-modifying therapies
Published in Expert Review of Neurotherapeutics, 2019
Xavier Ayrignac, Philippe-Antoine Bilodeau, Alexandre Prat, Marc Girard, Pierre Labauge, Jacques Le Lorier, Catherine Larochelle, Pierre Duquette
Cladribine is a purine analog. Most safety data come from CLARITY, ORACLE and ONWARD trials. The most common AEs were headache, lymphopenia, nasopharyngitis, URTI and nausea. Infections were seen in almost half of patients (47.7%) including 20 herpes zoster infections (2.3%, three reported as serious) whose occurrence was inversely correlated with absolute lymphocyte counts [57]. Three primary VSV infections were also reported. Some cases of tuberculosis reactivation have been reported when cladribine was used to treat hairy cell leukemia. There were seven malignant neoplasms in CLARITY and ORACLE and none on the extension trial [57–59]. A meta-analysis found no increased risk of cancer compared to the general population [60]. There were six cases of benign leiomyomas [57–59]. The most common hematological anomaly was lymphopenia, with 25.6% grade 3 and 4 lymphopenia in CLARITY and 12% in ORACLE [57,61]. The ONWARD trial for add-on to IFN-beta reported even higher rates at 63.7% [61].