Extramedullary T-lymphoblastic Crisis in a Myelodysplastic/Myeloproliferative Neoplasm with a t(12;22)/MN1::ETV6 Translocation.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are not a single disease, but rather a heterogenous group of entities which are increasingly subclassified according to recurrent genetic abnormalities. Chromosomal translocations involving meningioma 1 (MN1) and ETS variant 6 (ETV6) genes are extremely rare, but recurrent in myeloid neoplasms. We describe the case of a patient with a myelodysplastic/myeloproliferative neoplasm with neutrophilia, who developed an extramedullary T-lymphoblastic crisis with the t(12;22)(p13;q12) translocation as the only cytogenetic abnormality. This case shares several clinical and molecular features with myeloid/lymphoid neoplasms with eosinophilia. The treatment of this patient was challenging, as the disease proved to be highly refractory to chemotherapy, with allogenic stem cell transplantation as the only curative option. This clinical presentation has not been reported in association with these genetic alterations and supports the concept of a hematopoietic neoplasm originating in an early uncommitted precursor cell. Additionally, it stresses the importance of molecular characterization in the classification and prognostic stratification of these entities.

Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial.

BACKGROUND: Most older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. In the pivotal QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly prolonged overall survival by 9.9 months (P < 0.001) and relapse-free survival by 5.3 months (P < 0.001) compared with placebo in patients with AML in first remission after IC who were not candidates for transplant. Currently, the QUAZAR AML-001 trial provides the most comprehensive safety information associated with oral azacitidine maintenance therapy. Reviewed here are common adverse events (AEs) during oral azacitidine treatment in QUAZAR AML-001, and practical recommendations for AE management based on guidance from international cancer consortiums, regulatory authorities, and the authors' clinical experience treating patients in the trial. METHODS: QUAZAR AML-001 is an international, placebo-controlled randomized phase 3 study. Patients aged ≥ 55 years with AML and intermediate- or poor-risk cytogenetics at diagnosis, who had attained first complete remission (CR) or CR with incomplete blood count recovery (CRi) within 4 months before study entry, were randomized 1:1 to receive oral azacitidine 300 mg or placebo once-daily for 14 days in repeated 28-day cycles. Safety was assessed in all patients who received ≥ 1 dose of study drug. RESULTS: A total of 469 patients received oral azacitidine (n = 236) or placebo (n = 233). Median age was 68 years. Patients received a median of 12 (range 1-80) oral azacitidine treatment cycles or 6 (1-73) placebo cycles. Gastrointestinal AEs were common and typically low-grade. The most frequent grade 3-4 AEs during oral azacitidine therapy were hematologic events. AEs infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications. CONCLUSION: Oral azacitidine maintenance had a generally favorable safety profile. Prophylaxis with antiemetic agents, and blood count monitoring every other week, are recommended for at least the first 2 oral azacitidine treatment cycles, and as needed thereafter. Awareness of the type, onset, and duration of common AEs, and implementation of effective AE management, may maximize treatment adherence and optimize the survival benefits of oral azacitidine AML remission maintenance therapy. Trial registration This trial is registered on clinicaltrials.gov: NCT01757535 as of December 2012.

Recommendations from a Portuguese Expert Group for Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia Patients in Clinical Practice.

Until recently, the main goal of chronic myeloid leukemia therapy was disease control with the best overall survival, which required lifelong treatment. However, currently, the treatment-free remission concept is becoming an important goal in clinical practice, and several tyrosine kinase inhibitors discontinuation studies have shown that round 50% of patients with a durable deep molecular response beyond major molecular response successfully interrupt tyrosine kinase inhibitors for at least three years without loss of molecular response. However, and regardless of the existing evidence, the exact conditions for attempting treatment-free remission remain poorly defined. Different authors tried to guide the clinical decision regarding this topic but there are some points that differ, namely with respect to the recommended duration of tyrosine kinase inhibitors therapy and the appropriate molecular response prior to treatment-free remission. The goal of this article is to propose an algorithm to guide clinical practice in Portugal concerning chronic phase-chronic myeloid leukemia patients who wish to attempt treatment-free remission, since there are no national guidelines.

Até recentemente, o objectivo principal do tratamento da leucemia mielóide crónica era o controlo da doença com o maior tempo possível de sobrevivência, o que requeria tratamento durante toda a vida. No entanto, e actualmente, o conceito de remissão livre de tratamento está a tornar-se um objectivo importante na prática clínica, e vários estudos de descontinuação de inibidores de tirosina cinase mostraram que cerca de 50% dos doentes com uma resposta molecular profunda duradoura, para além da resposta molecular major, interrompem tratamento com inibidores de tirosina cinase com sucesso durante pelo menos três anos sem perda da resposta molecular. No entanto, e apesar da evidência existente, as condições concretas e exactas para tentar remissão livre de tratamento são ainda pouco conhecidas. Diferentes autores tentaram guiar a decisão clínica sobre este tópico mas alguns pontos permanecem não consensuais, nomeadamente no que respeita à duração recomendada de tratamento com inibidores de tirosina cinase e à resposta molecular apropriada antes de tentar remissão livre de tratamento. O objectivo desta publicação é propor um algoritmo que permita guiar a prática clínica em Portugal relativa a doentes com leucemia mielóide crónica ou em fase crónica que pretendam tentar remissão livre de tratamento, dada a ausência de recomendações nacionais.

Clinical outcomes of AML patients treated with Azacitidine in Portugal: A retrospective multicenter study.

Retrospective data was collected from 77 elderly acute myeloid leukemia (AML) patients treated with Azacitidine (AZA) and 50 elderly AML patients treated with intensive chemotherapy (IC) from 4 Portuguese Hospitals. Median OS was 10.6 months in those receiving AZA as 1st line. Response (overall response rate 44%) had a significant impact on overall survival (p=<0.0001). Median OS of the comparator IC cohort was significantly inferior to that observed in the cohort treated with AZA in first line (p=0.0104). These results support the efficacy of AZA in AML in the elderly in any line of treatment.

Treatment of acute erythroleukemia with Azacitidine: A case series.

Acute erythroleukemia (AEL) is a rare form of acute myeloid leukemia (AML) often associated with a poor prognosis. It is more frequent in elderly patients, limiting the use aggressive therapies. Azacitidine is a hypomethylating agent with recognized efficacy in high risk myelodysplasia and AML in the elderly. Here we report 5 cases of AEL treated with Azacitidine. The cohort included 4 men and 1 woman, median age 70. One patient had been refractory to intensive chemotherapy, the others received Azacitidine as first line. Treatment was well tolerated. Four patients achieved transfusion independence. Two patients achieved complete remission and 1 achieved partial remission. After a median follow up time of 20 months, the median survival of the cohort was 20 months. Three patients died of disease progression. These results confirm the therapeutic value of Azacitidine in AEL.

Burkitt's Lymphoma in a Pregnant Woman: Case Report and Review of the Literature.

Burkitt's lymphoma (BL) is an aggressive B-cell malignancy with very high proliferation rate, more common in males than females. Here, we describe a case of Burkitt's lymphoma in a 24-week pregnant woman with cervical and abdominal involvement. The common genetic event of virtually all BL is a reciprocal chromosomal translocation involving the proto-oncogene MYC and one of the Ig gene heavy or light chain loci. Supportive treatment was administered until early delivery, after which the patient was treated according to protocol LMB96. Pregnancy and tumorogenesis share some important events such as immunologic tolerance, angiogenesis, and editing the host immune response. Little is known about the relationship between these events in pregnancy and in tumorogenesis.

Efficacy and tolerability of 5-day azacytidine dose-intensified regimen in higher-risk MDS.

Higher-risk myelodysplastic syndromes (MDS) are aggressive disorders with rapid progression to AML and short survival. Azacitidine has shown unprecedented survival advantage in these patients but its treatment schedule involves daily hospital administrations for 7 days every 4 weeks. Due to patient and staffing constraints, we have treated 50 patients with a 5-day dose-intensified (500 mg/m(2) total monthly dose divided in 5 days) azacitidine schedule in our center. The regimen was well tolerated, with Grade 3/4 adverse events seen in 24 % patients and only two discontinuations due to toxicity. The response rate was similar to that reported with the 7-day schedule: 16 % complete remissions, 32 % partial remissions, and 62 % transfusion independence. The median survival was 19.2 months from diagnosis. In addition, this regimen reduced hospital visits by 28 % and drug use by 30 %. Our results demonstrate the safety and efficacy of a dose-intensified 5-day regimen.

Treatment of chronic myelomonocytic leukemia with 5-Azacitidine: a case series and literature review.

Chronic myelomonocytic leukemia (CMML) is a clinically heterogeneous disease, with no standard treatment. We present the outcome of ten patients diagnosed with CMML and treated with AZA in our institutions between 2005 and 2010. All patients were transfusion dependent at the time of initiation of therapy. The overall response rate was 60%. Responses were obtained in 2/3 of the patients with proliferative CMML. The median survival from start of therapy was 20 months. AZA treatment was well-tolerated and associated with a significant response rate in all forms of the disease.