Monika Conchon

Successful Pregnancy and Delivery in a Patient with Chronic Myeloid Leukemia while on Dasatinib Therapy.

Here we report the case of an 18-year-old woman with chronic myeloid leukemia (CML) who became pregnant while undergoing treatment with dasatinib. Before pregnancy, she received imatinib mesylate therapy but could not tolerate the treatment. The regimen was then changed to dasatinib at a dose of 70 mg b.i.d. While she was in hematological remission and on dasatinib therapy, she became pregnant. The unplanned pregnancy was identified after the patient had experienced four weeks of amenorrhea. Because the patient elected to continue the pregnancy to term, dasatinib was stopped immediately. Meanwhile, CML hematological relapse occurred and then she was treated with interferon-α (IFN-α) (9 million IU/day) throughout the pregnancy without a complete hematological response. She successfully gave birth to a male baby at 33 weeks by cesarean section delivery with no sequelae or malformations. Although this experience is limited to a single patient, it provides a useful contribution for counselling patients inadvertently exposed to dasatinib during pregnancy.

Granulocytic sarcoma of the small intestine with CBFβ/MYH11 fusion gene: report of an aleukaemic case and review of the literature

Granulocytic sarcomas (GS) are rare extramedullary tumours composed of immature myeloid cells. Inversion of chromosome 16 [inv(16)] is a cytogenetic marker for M4Eo subtype of acute myeloid leukaemia (AML). The possibility of an association between the development of granulocytic sarcoma of the small intestine (GSSI) and the M4Eo subtype of AML was suggested in nine previous case reports. Here we report an aleukaemic case of GSSI with inv(16) and its molecular equivalent, the CBFbeta/MYH11 fusion gene, detected by reverse transcriptase-polymerase chain reaction (RT-PCR), that after treatment with conventional AML chemotherapy followed by autologous bone marrow transplantation, achieved complete haematological and molecular remission on bone marrow examination. After chemotherapy, a thickened ileum wall positive for CBFbeta/MYH11 on tumour mass samples was still observed on computed tomography (CT) studies, raising the question of residual GS representing a reservoir of malignant cells. This case demonstrates the critical need of multidisciplinary diagnosis and follow-up of this entity combining immunopathologic, cytogenetic and molecular studies, reinforcing the potentiality of risk-adapted therapy strategies, as it is increasingly claimed for patients with overt AML.

First case of immune-mediated haemolytic anaemia associated to imatinib mesylate.

Abstract: Imatinib mesylate is a specific inhibitor of protein tyrosine kinase activity secondary to bcr‐abl, mostly indicated for the treatment of patients with Philadelphia chromosome positive chronic myeloid leukaemia (CML). Generally, the undesirable effects of imatinib administration observed in clinical trials were of mild‐to‐moderate degree, and no haemolysis has been associated with this drug. We report here a case of immune‐mediated haemolytic anaemia associated to imatinib mesylate successfully treated with prednisone in a patient with CML. Laboratory investigation showed anaemia [haemoglobin (Hb) of 59 g/L], reticulocyte of 61 × 109/L and a positive direct antiglobulin test. Anti‐drug in vitro studies revealed a positive result with gel microcolumn assay by an adsorption mechanism. Seventy‐four days after prednisone therapy, the patients Hb level was of 110 g/L with negative direct antiglobulin test and drug in vitro studies. This case demonstrated that patients treated with imatinib mesylate can present immune‐mediated haemolysis and adequate management of this event can be done maintaining the drug and associating corticosteroids.

BCR-ABL Mutations in Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors and Impact on Survival

This is the largest Latin American study of BCR-ABL mutations in chronic myeloid leukemia (CML) patients, resistant to imatinib (IM). In 195/467 (41%) patients, mutations were detected. The most frequent mutation was T315I (n = 31, 16%). Progression-free (PFS) and overall survival (OS) at 5 years were lower in patients with BCR-ABL mutations (43% vs. 65%, p = 0.07 and 47% vs. 72%, p = 0.03, respectively) and in those with the T315I mutation (p = 0.003 and p = 0.03). OS and PFS were superior in subgroup who switched to second generation inhibitors (SGIs) after IM failure (OS: 50% vs. 39% p = 0.01; PFS: 48% vs. 30% p = 0.02). BCR-ABL mutations conferred a significant poor prognosis in CML patients.

Molecular measurement of BCR-ABL transcript variations in chronic myeloid leukemia patients in cytogenetic remission

BackgroundThe monitoring of BCR-ABL transcript levels by real-time quantitative polymerase chain reaction (RT-qPCR) has become important to assess minimal residual disease (MRD) and standard of care in the treatment of chronic myeloid leukemia (CML). In this study, we performed a prospective, sequential analysis using RT-qPCR monitoring of BCR-ABL gene rearrangements in blood samples from 91 CML patients in chronic phase (CP) who achieved complete cytogenetic remission (CCyR) and major molecular remission (MMR) throughout imatinib treatment.MethodsThe absolute level of BCR-ABL transcript from peripheral blood was serially measured every 4 to 12 weeks by RT-qPCR. Only level variations > 0.5%, according to the international scale, was considered positive. Sequential cytogenetic analysis was also performed in bone marrow samples from all patients using standard protocols.ResultsBased on sequential analysis of BCR-ABL transcripts, the 91 patients were divided into three categories: (A) 57 (62.6%) had no variation on sequential analysis; (B) 30 (32.9%) had a single positive variation result obtained in a single sample; and (C) 4 (4.39%) had variations of BCR-ABL transcripts in at least two consecutive samples. Of the 34 patients who had elevated levels of transcripts (group B and C), 19 (55.8%) had a < 1% of BCR-ABL/BCR ratio, 13 (38.2%) patients had a 1% to 10% increase and 2 patients had a >10% increase of RT-qPCR. The last two patients had lost a CCyR, and none of them showed mutations in the ABL gene. Transient cytogenetic alterations in Ph-negative cells were observed in five (5.5%) patients, and none of whom lost CCyR.ConclusionsDespite an increase levels of BCR-ABL/BCR ratio variations by RT-qPCR, the majority of CML patients with MMR remained in CCyR. Thus, such single variations should neither be considered predictive of subsequent failure and nor an indication for altering imatinib dose or switching to second generation therapy. Changing of imatinib on the basis of BCR-ABL/BCR% sustained increase and mutational studies is a prudent approach for preserving other therapeutic options in imatinib-resistant patients.

Evaluation of Long-Term Outcomes, Cytogenetic and Molecular Responses with Imatinib Mesylate in Early and Late Chronic-Phase Chronic Myeloid Leukemia: A Report from a Single Institute

Here we compare the management and survival outcomes of chronic myeloid leukemia (CML) patients who had early or late imatinib mesylate (IM) therapy. The cytogenetic and molecular responses of 189 CML patients were analyzed. Of this group, 121 patients were classified as the early chronic phase (ECP) group and started IM within 12 months of diagnosis. The other 68 patients were classified as the late chronic phase (LCP) group who had been treated with interferon (IFN)-alpha-2 and crossed over to IM more than 12 months after diagnosis. The overall rates of complete cytogenetic response (CCyR) and major molecular response (MMR) at last follow-up were 83.6 and 78.1% in the ECP and LCP groups, respectively. The CCyR rates were 89.3 (for ECP patients) versus 73.5% (for LCP patients; p < 0.0001). At last follow-up, 82.4% ECP and 64.2% LCP patients had achieved an MMR (p < 0.0001). No significant differences were noted between the two groups with regard to survival outcomes. Our experience reveals that IM is an effective rescue therapy in most CML LCP patients who are intolerant or in whom IFN-alpha therapy fails. Such therapeutic options should be considered in LCP patients, particularly in countries where IM may not be available.

Chronic myeloid leukemia treatment guidelines: Brazilian Association of Hematology, Hemotherapy and Cell Therapy. Brazilian Medical Association Guidelines Project - 2012.

The guidelines project is a joint initiative of the Associacao Medica Brasileira and the Conselho Federal de Medicina. It aims to bring together information in medicine to standardize conduct in order to help decision-making during treatment. The data contained in this manuscript were prepared by and are recommended by the Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular. Even so, all possible conducts should be evaluated by the physician responsible for treatment depending on the patients setting and clinical status.

Efficacy and Tolerability after Unusually Low Doses of Dasatinib in Chronic Myeloid Leukemia Patients Intolerant to Standard-Dose Dasatinib Therapy

We report our experience in 4 patients with chronic myeloid leukemia (CML) who had discontinued imatinib as a result of adverse events and had switched to dasatinib. The chronic phase (n 2) and accelerated phase (n 2) CML patients received dasatinib at starting dose of 100 and 140 mg once daily, respectively. Reappearance of hematological toxicity was observed in 3 patients and pancreatitis in one patient. Treatment was given at a lower dose and patients were followed. The median follow-up was 13 months and the median dose of dasatinib until achievement of complete cytogenetic remission (CCyR) was 60 mg daily (range = 20 to 120 mg). All four patients had achieved CCyR at a median of 4 months (range = 3 to 5 months) and among them, three had also achieved major molecular remission. We conclude that low-dose dasatinib therapy in intolerant patients appears safe and efficacious and may be tried before drug discontinuation.

Achievement of complete donor-type chimerism and remission with dasatinib in Philadelphia chromosome-positive ALL relapsing after allogeneic transplantation

Achievement of complete donor-type chimerism and remission with dasatinib in Philadelphia chromosome-positive ALL relapsing after allogeneic transplantation

The Use of Imatinib Mesylate as a Lifesaving Treatment of Chronic Myeloid Leukemia Relapse after Bone Marrow Transplantation

We describe the response of imatinib as lifesaving treatment of chronic myeloid leukemia (CML) relapse in seven patients who underwent allogeneic bone marrow transplantation (alloBMT) at our institution over a period of 4 years. Retrospective analysis of their medical records revealed that a mean age at transplant was 45.2 years. The median time to diagnosis was 7.4 years after transplant. At relapse, four, two, and one patients were classified as having hematologic, major molecular, and cytogenetic relapse, respectively. At imatinib initiation, five had CML in a chronic phase, while one patient was diagnosed as having accelerated phase and blast crisis. All these patients could be evaluated for the therapeutic efficacy. At a mean of follow-up of 1.9 years of therapy, all evaluable patients achieved major molecular response without compromising safety. Consistent with available data, our results indicate that imatinib is safe and effective treatment option for patients with relapse after BMT.