Mariana Serpa

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.

Pretherapeutic Expression of the hOCT1 Gene Predicts a Complete Molecular Response to Imatinib Mesylate in Chronic-Phase Chronic Myeloid Leukemia

In this retrospective study we evaluated the pretherapeutic mRNA expression of the hOCT1 (human organic cation transporter 1) gene in patients with chronic-phase (CP) chronic myeloid leukemia (CML) who varied in terms of their response to imatinib (IM). hOCT1 mRNA was quantified by real-time PCR. Patients were classified as expressing either high (n = 44) or low hOCT1 mRNA (n = 44). The complete cytogenetic response rates observed at 6, 12 and 18 months were 47.7, 84.1 and 91%, respectively, in patients with high hOCT1 mRNA and 47.5, 81.8 and 86.3%, respectively, in patients with low hOCT1 transcripts. The major molecular response rates were not significantly different between patients with high and low hOCT1 mRNA after 6 months of therapy (22.7 vs. 9.1%; p = 0.07), but they were significantly different after 12 months (54.5 vs. 31.8%; p = 0.026) and 18 months (77.2 vs. 56.8%; p = 0.034). Complete molecular responses were observed in 5 patients with low and 17 patients with high hOCT1 mRNA (p = 0.003). The 5-year event-free and overall survival analyses revealed no significant differences between the groups. These data imply that knowledge of the pretherapeutic level of hOCT1 could be a useful marker to predict IM therapy outcome in treatment-naïve CP CML patients.

Response to Dasatinib in a Patient with Concomitant Chronic Myeloid Leukemia and Chronic Lymphocytic Leukemia

While chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are common diseases in the elderly, they rarely occur simultaneously in the same patient. Here we present the case of a 77-year-old patient diagnosed with CML in the chronic phase who showed an optimal response to 400 mg/day of imatinib. This patient progressed to Binet B-CLL with an 11q22.3 deletion and CD38 positivity in the 4th month of treatment. During the follow-up, his lymphocyte number doubled in <6 months. Based on previous reports, dasatinib was chosen instead of imatinib. After 6 months of treatment with 100 mg/day of dasatinib, the patient demonstrated a partial response, characterized by the regression of lymph node enlargement, a hemoglobin level of 10.7 g/dl, neutrophils of 1.7 × 109/l, a 82% reduction in the lymphocyte number and an increase in cytotoxic CD8+ and large granular lymphocytes. This partial response has persisted to the present time. While little data have been published regarding the in vitro effect of dasatinib monotherapy for CLL, this case report provides some evidence of the clinical activity of dasatinib in CLL.

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.

Diagnóstico da Deficiência de Hormônio de Crescimento, a Rigor de IGF-1

O diagnostico da deficiencia de IGF-1 por anormalidade do eixo GH-IGF deve utilizar os parâmetros diagnosticos mais adequados para cada faixa etaria e estagio puberal. Propomos o diagnostico da deficiencia de GH (DGH) baseado em uma hierarquia de dados clinicos e laboratoriais. A avaliacao clinica e os exames laboratoriais gerais, incluindo funcao tireoideana, permitem excluir etiologias de deficiencia de IGF que nao as intrinsecas ao eixo GH-IGF. Nestas, a dosagem do IGF-1 serico deve ser o primeiro hormonio a ser dosado nos grupos pre-puberes, puberes e idosos. No grupo de adultos jovens, a dosagem do ALS livre e a mais adequada. As concentracoes de IGF-1 podem caracterizar 4 situacoes: muito reduzido, reduzido, normal e elevado. IGF-1 menor que 35µg/L ou -2 DP da media para a idade cronologica (EDP-IC) permite o diagnostico de deficiencia de IGF-1. Nesta situacao, a realizacao de apenas um teste de secrecao de GH e necessaria para diferenciar deficiencia e resistencia ao GH. O teste de geracao de IGF-1 ajuda a confirmar o diagnostico de resistencia ao GH. IGF-1 menor que 70µg/L em pre-puberes ou adultos e menor que 170µg/L em individuos puberes, ou entre -2 e -1 EDP-IC indicam provavel deficiencia de IGF-1. A realizacao de 2 testes de secrecao de GH e recomendada; resposta sub-normal em ambos indica DGH. Exame de imagem da regiao hipotalamo-hipofisaria deve ser realizado nos casos de DGH. Resposta normal ao teste de secrecao do GH frente a forte suspeita clinica e laboratorial de deficiencia de IGF-1 indica a realizacao de perfil noturno de GH para afastar o diagnostico de disfuncao neurossecretora de GH. IGF-1 maior que -1 DP, mas menor que a media para idade cronologica sugere ausencia de deficiencia de IGF-1. Concentracoes altas de IGF-1 impoem a dosagem das IGFBPs e consideracao da resistencia ao IGF-1. Apesar das dificuldades, todo o esforco deve ser feito no sentido de diagnosticar adequadamente as alteracoes do eixo GH-IGF para instituir a terapia apropriada.

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

Ruxolitinib in steroid-refractory chronic graft-versus-host disease: experience of a single center

Graft-versus-host disease (GVHD) represents a major complication after allogeneic hematopoietic stem cell transplantation [1]. Chronic GVHD (cGVHD) is a significant cause of morbidity, increased risk of infection, and reduced quality of life (QOL) after transplant, affecting ~40% of patients. First-line systemic therapy consists of systemic corticosteroids, and response rates are variable. Secondand further-line options for treatment of steroidrefractory cGVHD are needed in 40–60% of cases, and most of the therapies available are less than ideal, with low response rates and significant toxicities [2]. The skin is the most commonly affected site (75%) [3, 4]. Cutaneous manifestations have a broad clinical spectrum, including lichen planus-like eruption, scleroderma, xerosis and ichthyosis, poikiloderma, dyspigmentation, acral erythema, keratosis pilaris-like and papulosquamous eruptions, and psoriasiform and eczematous eruptions [3, 4]. Although there are still no randomized studies demonstrating its efficacy, ruxolitinib, a JAK1/2 inhibitor, appears to be a promising therapy for GVHD, as reported in a few reports with a small number of patients [5–8]. Its mechanism of action seems to be related to suppression of the proinflammatory signaling that mediates tissue damage and by the promotion of tolerogenic regulatory T (T-reg) cells [9]. In this report, we share a real-life experience using ruxolitinib in the treatment of steroid-refractory cGVHD in 20 patients from a single center in Sao Paulo, Brazil. We treated off-label 20 patients with steroid-refractory cGVHD from March 2016 to July 2017 with ruxolitinib. The starting dose was 5 or 10 mg twice daily, depending on the hematological parameters, and if the patient had good tolerance and no toxicities, the dose was increased until a maximum of 20 mg twice daily, at the physician’s discretion. Patient and disease characteristics are shown in Table 1. Organ sites affected and GVHD grading before starting ruxolitinib were classified according to the National Institutes of Health (NIH) 2014 criteria [10]. Steroidrefractory cGVHD was defined as any disease that failed to respond to previous immunosuppressive therapy with steroids at a dose of ≥0.5 mg/kg/day for at least 4 weeks or inability to taper it with or without additional immunosuppressive drugs. Treatment responses were evaluated at 1, 3, and 6 months after starting ruxolitinib and were categorized according to the NIH 2014 criteria [11] as a complete response (CR), partial response (PR), or lack of response (unchanged, mixed response, or progression). A CR to ruxolitinib was defined as a resolution of all disease manifestations in each organ or site involved. PR was defined as an improvement in at least one organ or site, without progression in any organ or site. Lack of response was defined as disease progression in any organ or site, outcomes that did not meet criteria for CR or PR, or in cases in which additional agents were used to control GVHD after treatment with ruxolitinib. Toxicities were defined according to National Cancer Institute Common Terminology Criteria for Adverse Events grades. The 20 patients treated with ruxolitinib had moderate (11/20; 55%) or severe (9/20; 45%) NIH grade cGVHD before ruxolitinib was started. The median number of organ sites affected was 3 (range, 1–5), with 95% of patients presenting with skin involvement, 70% with mouth, 50% with eyes, 30% with gastrointestinal tract, 30% with pulmonary, 15% with liver, and 5% with joint and genital involvement. The median number of previous immunosuppressive treatments before starting ruxolitinib was 3 (range, 1–6). The overall response rate was 75% (15/20): most of the patients who responded (73%) had achieved a PR. Four * Aliana Meneses Ferreira ali_ferreira@hotmail.com

early Detection of t(8;21) chromosomal Translocations During Treatment of PML-RARA positive Acute promyelocytic Leukemia: A case study

Here we describe a female patient who developed acute promyelocytic leukemia (APL) characterized by t(l5;17) translocation at diagnosis. The patient began treatment with all-trans retinoic acid (ATRA) + chemotherapy. During follow up, the patient was found to be negative for the t(15;17) transcript after 3 months of therapy which remained undetectable, thereafter. However, the emergence of a small clone with a t(8;21) abnormality was observed in the bone marrow and peripheral blood (PB) cells between 3 and 18 months following treatment initiation. The abnormal translocation observed in PB cells obtained at 3 months was detected after the second cycle of consolidation therapy and reappeared at 15 months during maintenance treatment, a period without ATRA. Although based on a single case, we conclude that genetic screening of multiple translocations in AML patients should be requested to allow early identification of other emerging clones during therapy that may manifest clinically following treatment.