Eccrine squamous syringometaplasia in an allogenic stem cell transplant patient undergoing chemotherapy
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Abstract:
Eccrine squamous syringometaplasia (ESS) is a rare finding defined as metaplastic change of the cuboidal epithelial cells of eccrine glands into two or more layers of squamous epithelial cells. We present a patient who developed ESS after induction of CLAG chemotherapy [2-Chlorodeoxyadenosine (2-CdA) with cytarabine (Ara-C) and (granulocyte-colony stimulating factor) G-CSF] for management of the blast crisis of his chronic myelogenous leukemia (CML). Our patient's ESS eruption presented with a variety of morphologies, thus multiple skin biopsies were taken to determine the possible diagnosis(es). All skin biopsies showed ESS and the eruption resolved with topical corticosteroids after CLAG therapy was finished.Keywords:
Induction chemotherapy
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Mitoxantrone
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Summary. The optimal dose of cytarabine for induction chemotherapy is unknown. Most studies have utilized doses of 100–200 mg/m 2 /d, although higher doses have been proposed to increase the concentration of the active metabolite ara‐CTP within leukaemia cells. To address this question 101 adults with newly diagnosed acute myeloid leukaemia were randomized to receive treatment with daunorubicin and either conventional‐dose cytarabine (200 mg/m 2 /d by continuous infusion) or an intermediate‐dose of cytarabine (500 mg/m 2 every 12 h). 36/51 (71%) patients assigned to conventional‐dose cytarabine achieved complete remission compared to 37/50 (74%) who achieved remission with intermediate‐dose cytarabine (P = 0.9). Patient age significantly affected remission rate. 8/17 patients age >60 assigned to conventional‐dose cytarabine and 10/17 assigned to intermediate‐dose cytarabine achieved complete remission compared to 27/33 patients under age 60 assigned to the conventional dose and 28/34 patients assigned to the intermediate dose arm (P=0.004). Actuarial 4‐year disease‐free survival for patients assigned to conventional‐dose cytarabine was 20.16% versus 28.17% for patients assigned to intermediate‐dose cytarabine (P=0–9). We conclude that intermediate dose cytarabine did not substantially improve results of induction chemotherapy for acute myeloid leukaemia.
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Induction therapy of acute myeloid leukaemia (AML) with standard-dose chemotherapy will result in approximately 64% of patients achieving a complete remission (CR). New drugs which are active in induction therapy in randomised clinical trials are etoposide, idarubicin and high dose cytarabine. Intensification of induction treatment with etoposide or high-dose cytarabine does not appear to alter the CR rate but prolongs remission and has some impact on survival. High-dose cytarabine in induction combinations increase relapse-free survival compared to standard approaches. These induction results appear to parallel results obtained with post-remission therapies intensified with high-dose cytarabine. These studies provide clinical evidence that intensified induction with cytarabine in AML influences subsequent outcome but is more toxic, gives more profound myelosuppression post-remission and has benefit confined to younger patients.
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Cytarabine (cytosine arabinoside) is one of the most effective drugs for the treatment of acute myeloid leukemia. The standard dose of cytarabine used to treat this leukemia is 100 mg per square meter. In an attempt to improve the effectiveness of cytarabine against acute myeloid leukemia, a high-dose treatment (3,000 mg per square meter) was introduced into therapy. The side effects of high-dose cytarabine was a major concern, especially its neurological toxicity. A review of recent clinical trials indicates that this high-dose cytarabine can be replaced by the intermediate-dose of 1,000 mg per square meter without loss of efficacy and with less toxicity. This is an important step to improve the efficacy of cytarabine for the treatment of acute myeloid leukemia. Despite the improvements in the therapy for this leukemia, the current overall survival rate for adult patients is less than 30%. To optimize the cytarabine therapy, it is important to determine how some leukemic stem cells survive treatment. Preclinical data suggest that survival of the leukemic stem cells could be due to the long 12 hour interval between infusions of cytarabine, which permits some leukemic cells to escape its S phase specific action. Among the other factors that can lead to leukemic cell survival are the high levels in the liver and spleen of cytidine deaminase, the enzyme that inactivates cytarabine and drug resistance due to deficiency in deoxycytidine kinase, the enzyme that activates the prodrug, cytarabine. Several approaches are proposed in this commentary to overcome these impediments with the goal of increasing the effectiveness of cytarabine for the treatment of acute myeloid leukemia.
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Induction chemotherapy
Mitoxantrone
Daunorubicin
Gemtuzumab ozogamicin
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The standard of care consolidation therapy for acute myeloid leukemia is high-dose cytarabine or intermediate-dose cytarabine, which are traditionally given inpatient. At Moffitt Cancer Center, we have moved the administration of high-dose cytarabine and intermediate-dose cytarabine to the outpatient setting through the inpatient/outpatient program. To facilitate outpatient administration, high-dose cytarabine and intermediate-dose cytarabine are given in a shorter interval of every 10 h instead of 12 h. The safety of a shorter duration interval of high-dose cytarabine and intermediate-dose cytarabine is unknown. This study aims to assess the safety and feasibility of administering high-dose cytarabine and intermediate-dose cytarabine consolidation therapy in the inpatient/outpatient setting.This is a retrospective chart review to analyze acute myeloid leukemia patients treated with inpatient/outpatient high-dose cytarabine or intermediate-dose cytarabine consolidation therapy at Moffitt Cancer Center from January 1, 2015, through November 1, 2018. The primary objective was to determine the incidence of hospitalization during the inpatient/outpatient administration of high-dose cytarabine or intermediate-dose cytarabine.Two hundred fifty-three of 255 cycles of high-dose cytarabine/intermediate-dose cytarabine were delivered outpatient over the reviewed time period to 118 patients. No patients receiving outpatient high-dose cytarabine/intermediate-dose cytarabine consolidation required hospitalization during chemotherapy. Our incidence of hospitalization (24%) after chemotherapy is consistent with the reported literature. Through the inpatient/outpatient administration of high-dose cytarabine and intermediate-dose cytarabine, 1265 inpatient days were saved with an approximate revenue of $3,135,176 generated in our study period.Inpatient/outpatient administration of high-dose cytarabine and intermediate-dose cytarabine is both safe and feasible. Moving high-dose cytarabine/intermediate-dose cytarabine administration to the outpatient setting resulted in significant additional revenue vs. inpatient administration.
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Resistance to cytarabine is an important cause of therapy failure in persons with acute myeloid leukemia (AML). Deoxycytidine kinase, encoded by DCK, catalyzes phosphorylation of cytarabine to cytarabine monophosphate, a necessary step for eventual incorporation of cytarabine triphosphate into DNA and for clinical efficacy. Whether DCK mutations make AML cells resistant to cytarabine is controversial. We studied DCK mutations and messenger RNA (mRNA) concentrations in leukemia cells from 10 subjects with AML who received cytarabine-based therapy and relapsed and in 2 artificially induced cytarabine-resistant AML cell lines. DCK mutations were detected in 4 subjects with AML relapsing after achieving a complete remission and receiving high-dose cytarabine postremission therapy. Most mutations were in exons 4-6 and were not present before therapy. DCK was also mutated in cytarabine-resistant but not parental AML cell lines. DCK mRNA concentrations were significantly decreased in cytarabine-resistant K562 and SHI-1 cells compared with cytarabine-sensitive parental cells. Mutation frequency of DCK and mRNA concentration did not correlate with the extent of cytarabine resistance indicating other factors operate. Overexpression of wild-type DCK restored cytarabine sensitivity to previously resistant leukemia cell lines. Our data contribute to the understanding of cytarabine resistance in persons with AML.
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Abstract Japanese Pediatric Leukemia/Lymphoma Study Group AML-12 is a seamless phase II/III cooperative study to evaluate a role of high-dose cytarabine (HDAC) in initial induction therapy and significance of measurable residual disease (MRD) at end of induction therapies for children with acute myeloid leukemia (AML). From 2014 to 2018, a total of 359 patients were enrolled; 324 patients were randomly assigned to receive standard-dose cytarabine induction or HDAC induction. Following the common second induction, patients achieving remission were stratified into either of the three risk groups and received consolidation chemotherapy with or without allogeneic hematopoietic stem cell transplantation. MRD was centrally monitored at end of Induction-1 (TP-1) and end of Induction-2. There were no significant statistical differences in the primary endpoints between the two arms; MRD-positive (≥ 0.1%) rate at TP-1 (21.5% vs. 25.2%, P = 0.517) and 3-year event-free survival rate (64.3% [95%CI, 56.5% – 71.0%] vs. 61.2% [53.1% – 68.4%], P = 0.589). MRD could be measured for 262 (94.9%) of the 276 patients for whom MRD monitoring was attempted and was demonstrated to be the strongest factor to predict the outcomes. Although, HDAC in initial induction did not improve the outcomes of children with AML, flow cytometric MRD monitoring was feasible and highly prognostic.
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