Gislaine Oliveira-Duarte

Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma

Despite the good response of stem cell transplant (SCT) in the treatment of multiple myeloma (MM), most patients relapse or do not achieve complete remission, suggesting that additional treatment is needed. We assessed the impact of thalidomide in maintenance after SCT in untreated patients with MM. A hundred and eight patients (<70 years old) were randomized to receive maintenance with dexamethasone (arm A; n = 52) or dexamethasone with thalidomide (arm B; n = 56; 200 mg daily) for 12 months or until disease progression. After a median follow‐up of 27 months, an intention to treat analysis showed a 2‐year progression‐free survival (PFS) of 30% in arm A (95% CI 22–38) and 64% in arm B (95% CI 57–71; P = 0.002), with median PFS of 19 months and 36 months, respectively. In patients who did not achieve at least a very good partial response, the PFS at 2 years was significantly higher when in use of thalidomide (19 vs. 59%; P = 0.002). Overall survival at 2 years was not significantly improved (70 vs. 85% in arm A and arm B, respectively; P = 0.27). The addition of thalidomide to dexamethasone as maintenance improved the PFS mainly in patients who did not respond to treatment after SCT. Am. J. Hematol.

Cytomegalovirus (CMV) genotype in allogeneic hematopoietic stem cell transplantation

BackgroundBased on sequence variation in the UL55 gene that encodes glycoprotein B (gB), human cytomegalovirus (CMV) can be classified into four gB genotypes. Previous studies have suggested an association between CMV gB genotype and clinical outcome in patients who underwent an allogeneic hematopoietic stem cell transplant (HSCT). The goals of this study were identify patients with active infection caused by CMV in recipients of HSCT; determine the prevalence of CMV genotypes in the study group; correlate genotype with CMV disease, acute GVHD and overall survival.MethodsThe diagnosis of active CMV infection after allogeneic HSCT was detected by antigenemia (AGM) and/or nested-PCR (N-PCR). Positive samples from patients with active CMV infection were submitted to genotyping using N-PCR to amplify a region of UL55, followed by restriction analysis based on HinfI and RsaI digestion. Real-time PCR (qPCR) was used to determine the viral load during active CMV infection and antiviral treatment.ResultsSixty-three allogeneic HSCT recipients were prospectively evaluated; 49/63 (78%) patients were infected with CMV genotypes – gB1 19/49 (39%), gB2 17/49 (35%), gB3 3/49 (6%), gB4 7/49 (14%) – and 3 (6%) had mixed CMV genotypes (gB1 + gB3, gB1 + gB4 and gB2 + gB4). Characterized by gastrointestinal disease, CMV disease occurred in 3/49 (6.1%) patients, who had CMV gB3 genotype. These gB3 genotype patients presented an increasing AGM number, mean 125 (± 250) (P = 0.70), and qPCR copies/ml, mean 37938 (SD ± 50542) (P = 0.03), during antiviral treatment, when compared with other CMV genotypes. According to CMV genotypes, stratified overall survival was 55% for gB1, 43% for gB2; 0% for gB3 and 57% for gB4 (P = 0.03).ConclusionsOne of the restrictions of the presented study was the low number of CMV gB sub-cohorts). However, we demonstrated that the frequency of active CMV infection in this HSCT population was high, and the most prevalent genotype in these patients with active CMV infection was gB1 and gB2 genotype (74%). In Brazil, HSCT recipients seem to carry mainly gB1 and gB2 CMV genotype.

Treatment with dasatinib or nilotinib in chronic myeloid leukemia patients who failed to respond to two previously administered tyrosine kinase inhibitors - a single center experience

OBJECTIVE: To evaluate hematological, cytogenetic and molecular responses as well as the overall, progression-free and event-free survivals of chronic myeloid leukemia patients treated with a third tyrosine kinase inhibitor after failing to respond to imatinib and nilotinib/dasatinib. METHODS: Bone marrow karyotyping and real-time quantitative polymerase chain reaction were performed at baseline and at 3, 6, 12 and 18 months after the initiation of treatment with a third tyrosine kinase inhibitor. Hematologic, cytogenetic and molecular responses were defined according to the European LeukemiaNet recommendations. BCR-ABL1 mutations were analyzed by Sanger sequencing. RESULTS: We evaluated 25 chronic myeloid leukemia patients who had been previously treated with imatinib and a second tyrosine kinase inhibitor. Nine patients were switched to dasatinib, and 16 patients were switched to nilotinib as a third-line therapy. Of the chronic phase patients (n=18), 89% achieved a complete hematologic response, 13% achieved a complete cytogenetic response and 24% achieved a major molecular response. The following BCR-ABL1 mutations were detected in 6/14 (43%) chronic phase patients: E255V, Y253H, M244V, F317L (2) and F359V. M351T mutation was found in one patient in the accelerated phase of the disease. The five-year overall, progression-free and event-free survivals were 86, 54 and 22% (p<0.0001), respectively, for chronic phase patients and 66%, 66% and 0% (p<0.0001), respectively, for accelerated phase patients. All blast crisis patients died within 6 months of treatment. Fifty-six percent of the chronic phase patients lost their hematologic response within a median of 23 months. CONCLUSIONS: Although the responses achieved by the third tyrosine kinase inhibitor were not sustainable, a third tyrosine kinase inhibitor may be an option for improving patient status until a donor becomes available for transplant. Because the long-term outcome for these patients is poor, the development of new therapies for resistant chronic myeloid leukemia patients is necessary.

BCR-ABL1 Transcript Levels at 3 and 6 Months Are Better for Identifying Chronic Myeloid Leukemia Patients with Poor Outcome in Response to Second-Line Second-Generation Tyrosine Kinase Inhibitors after Imatinib Failure: A Report from a Single Institution.

Early reduction of BCR-ABL1 transcript levels has been associated with improved outcome in chronic myeloid leukemia (CML) treatment. We evaluated 54 chronic-phase CML patients treated with imatinib who switched therapy to dasatinib (n = 33) or nilotinib (n = 21). BCR-ABL1 transcript levels were measured in peripheral blood using real-time quantitative PCR (RQ-PCR) every 3 months from the start of second-line treatment. Patients with BCR-ABL transcript levels >10% at 3 months and >1% at 6 months had significantly inferior progression-free (PFS) and event-free survival (EFS) than patients with RQ-PCR <10% at 3 months and <1% at 6 months (66 vs. 100%, p = 0.01, and 33 vs. 73%, p = 0.02, respectively). Patients with RQ-PCR <10% at 3 months and >1% at 6 months also had inferior PFS and EFS than patients with RQ-PCR <10% at 3 months and <1% at 6 months (48 vs. 100%, p = 0.002, and 25 vs. 73%, p < 0.0001, respectively). Two measurements of BCR-ABL levels were better than a single one to stratify chronic-phase CML patients as failure after second-line therapy.

Brazilian Experience Using High-Dose Sequential Chemotherapy Followed by Autologous Hematopoietic Stem Cell Transplantation for Relapsed or Refractory Hodgkin Lymphoma

PURPOSE We evaluate the effectiveness and toxicity of high-dose sequential chemotherapy (HDS) as salvage therapy in patients with advanced-stage Hodgkin lymphoma. PATIENTS AND METHODS We performed a retrospective analysis on 77 patients receiving HDS between 1998 and 2006. Patients enrolled were in disease progression or relapsed disease, or did not achieve a complete remission after first-line treatment. HDS consisted of the sequential administration of cyclophosphamide and granulocyte colony-stimulating factor with stem cell harvesting, followed by methotrexate plus vincristine and etoposide. RESULTS The majority of patients had stage III/IV (64%) and B symptoms (71.4%). Disease status improvement after HDS was observed in 24 of 57 patients (42%) previously in disease progression or relapse. HDS-related deaths occurred in 8 of 77 patients (10.4%). Four patients (5.2%) developed acute myeloid leukemia/myelodysplastic syndrome. Overall, disease-free and progression-free survival was 27%, 57%, and 25%, respectively. CONCLUSION Despite the treatment-related mortality, HDS is feasible, with satisfactory response rates, even in patients with poor prognosis.

Normal variation of bone marrow B-cell precursors according to age - reference ranges for studies in myelodysplastic syndromes in Brazil: Normal Variation of Bone Marrow B-Cell Precursors

Normal B lymphoid maturation occurs in bone marrow (BM) throughout life, but immature B‐cell progenitors (BCPs) are more numerous in children than in adults. To assess the normal values according to age became important as BCPs are decreased in myelodysplastic syndromes and have been considered an important diagnostic and prognostic feature in these clonal disorders.

Imbalance between proliferation and in vitro apoptosis rates predicts progression in chronic lymphocytic leukemia

Dear Editor, We have read with great interest the paper by Witowska et al. (1) concerning the predictive value of in vitro apoptosis rate of circulating lymphocytes for disease progression in chronic lymphocytic leukemia (CLL). The apoptosis rate measured after 48 h of culture was more meaningful than after 24 h. This is in keeping with old results of our Group (2–4) which they acknowledge. However, in these publications, we also called attention to the fact that, besides the apoptotic rate, the total tumor mass (TTM), which is a clinical measure of the accumulated tumor mass and “AgNOR clusters” that are a measure of cells entering the proliferative cell cycle, were important to predict disease progression and need for treatment. AgNORs are argyrophylic nucleolar proteins, especially nucleolin and protein B23, that evidence sites of rRNA transcription associated with progression of the cells in the cell cycle and not only with stimulation of ribosomal gene transcription. Other markers, such as Ki67, have also been used to estimate the proliferative fraction in CLL. We also stated that disease progression was associated with the decrease in susceptibility to apoptosis and increase in proliferation rate (2) based on a former study (3) which showed that the treatment-free period in CLL was also predicted by the proliferation rate of the circulating lymphocytes. This has also been true for other hematological neoplasms (5). In a more recent paper, comparing the predictive value of an index based on TTM and the proliferation rate with the in vitro apoptotic rate, this index remained as the only independent predictive marker for duration of the treatment-free period (4). Witowska et al. (1) have also assessed lymphocyte doubling time (LDT), but only as a categorical variable (<12 months?—this is not clear in the text, especially in Table 1) and found no correlation with the treatment-free period. One could question that if LDT would have been analyzed as a continuous variable, a significant correlation could be obtained. On the other hand, the same could be true for the quantification of the expression of Bcl-2 and the Bax/Bcl-2 ratio. LDT has long been established as a clinical measure for proliferative activity and imbalance of proliferation and apoptosis rate in CLL and is easy to perform in the clinical setting. Concerning phenotypic variables such as ZAP-70 and expression of CD38, these techniques have been considered difficult to standardize and have a poor correlation with the immunoglobulin heavy chain variable genes (IGVH) mutation status (6). Cytogenetic studies, flourescence in situ hybridization (FISH), assessment of the IVGH mutation status, and the study of other biomarkers have disclosed the complex genetic and epigenetic mechanisms underlying the variable clinical spectrum in CLL. It was found that cell activation and proliferation of CLL cells is likely driven by B-cell receptor (BCR) signaling (6). All these techniques are expensive and time-consuming and are not always feasible in a clinical setting. On the other hand, it has been shown that the 13q14 deletion, frequently found in CLL, involves the miR15a/16 locus, associated with the regulation of Bcl-2 expression. So, this deletion is associated with upregulation of Bcl-2 (7,8). Very recent works have drawn attention to the fact that the expression of CD49d is an unfavorable prognostic marker in CLL. CD49d is a subunit of VLA-4, involved in extravasation and organ homing of the neoplastic cells in CLL (8). It is of note that new inhibitors of BCR signaling such as ibrutinib, act at least in part, by mobilizing CLL cells from lymphoid organs. So, new techniques must be taken into account to help treatment decisions in CLL, but they should always evaluate, besides spontaneous in vitro apoptosis rate of peripheral lymphocytes, the proliferation rate, phenotypic markers, and if possible cytogenetic and molecular markers.

Brazilian experience using high dose sequential chemotherapy followed by autologous hematopoietic stem cell transplantation for malignant lymphomas

Objective To evaluate the use of high-dose sequential chemotherapy in a Brazilian population. Methods High-dose cyclophosphamide followed by autologous hematopoietic stem cell transplantation is an effective and feasible therapy for refractory/relapsed lymphomas; this regimen has never before been evaluated in a Brazilian population. All patients (106 with high-grade non-Hodgkin lymphoma and 77 with Hodgkins lymphoma) submitted to this treatment between 1998 and 2006 were analyzed. Chemotherapy consisted of the sequential administration of high-dose cyclophosphamide (4 or 7 g/m2) and granulocyte-colony stimulating factor (300 µg/day), followed by peripheral blood progenitor cell harvesting, administration of etoposide (2g/m2) and methotrexate (8 g/m2 only for Hodgkins lymphoma) and autologous hematopoietic stem cell transplantation. Results At diagnosis, non-Hodgkin lymphoma patients had a median age of 45 (range: 8-65) years old, 78% had diffuse large B-cell lymphoma and 83% had stage III/IV disease. The Hodgkins lymphoma patients had a median age of 23 (range: 7-68) years old, 64.9% had the nodular sclerosis subtype and 65% had stage III/IV disease. Nine Hodgkins lymphoma patients (13%) and 10 (9%) non-Hodgkin lymphoma patients had some kind of cardiac toxicity. The overall survival, disease-free survival and progression-free survival in Hodgkins lymphoma were 29%, 59% and 26%, respectively. In non-Hodgkin lymphoma, these values were 40%, 49% and 31%, respectively. High-dose cyclophosphamide-related mortality was 10% for Hodgkins lymphoma and 5% for non-Hodgkin lymphoma patients. High-dose cyclophosphamide dosing had no impact on toxicity or survival for both groups. Conclusions Despite a greater prevalence of poor prognostic factors, our results are comparable to the literature. The incidence of secondary neoplasias is noteworthy. Our study suggests that this approach is efficient and feasible, regardless of toxicity-related mortality.