Tugrul Elverdi

Chronic myeloid leukemia patients who develop grade I/II pleural effusion under second-line dasatinib have better responses and outcomes than patients without pleural effusion

Dasatinib is a potent second generation TKI, and it is widely used in patients with CML, both in the up-front setting and failure after imatinib. Lymphocytosis in cases receiving dasatinib therapy has been shown to be associated with pleural effusion (PE) and better outcome. Although patients who gather lymphocytosis during dasatinib have superior responses, there is only little data about the correlation between PE, response rates, and survival. In order to answer this question, the aim of our study was to determine the frequency of PE and lymphocytosis among our CML patients receiving second-line dasatinib, and to compare the responses and outcomes between patients with or without PE. There were 18 patients (44%) who developed PE, in a total of 41 patients, with a median time of 15 months. Lymphocytosis was observed in nine patients (9/41, 22%) with a median duration of 6.5 months of dasatinib treatment. There were fourteen patients with at least one comorbidity that may play a role in the generation of PE. The cumulative MMR and CCyR rates were greater in PE+ patients (p<0.05). The PFS was significantly higher in PE+ group than PE- patients (p=0.013), also the OS was higher among PE+ patients than PE- group (p=0.042). In patients with a grade I/II PE, and durable responses under dasatinib, performing the management strategies for the recovery of effusion, together with continuing dasatinib can be a reasonable choice mainly in countries where third generation TKIs are not available. But alternative treatment strategies such as nilotinib or third generation TKIs can be chosen in patients with grade III/IV PE especially if the quality of life is severely affected.

The efficacy of generic formulations of imatinib mesylate in the treatment of chronic myeloid leukemia.

Th e treatment of chronic myeloid leukemia (CML) has changed greatly, and the outlook of patients with CML has improved dramatically, with the introduction of tyrosine kinase inhibitors (TKIs) [1]. Th e fi rst TKI developed for CML was imatinib mesylate (IM) (Glivec; Novartis, Basel, Switzerland) [2], and thereafter many other TKIs became available on the market [3]. Th e high cost of new cancer drugs including those developed for CML is a major concern for healthcare payers, especially in countries with restricted resources. Reimbursement policies worldwide, therefore, encourage generic drug use to lower the prices. It is true that generics lead to considerable cost savings, but they also give rise to questions associated with their effi cacy, safety and quality. In Turkey, there are three commercially available generics of IM (Imatis; Deva, Imatenil; Logus and Imavec; Ko c ak Farma), which have been licensed for the treatment of CML for more than a year. Th ere is a price diff erence between Glivec and the generics, and due to the reimbursement policy, patients who prefer to receive the original molecule must pay the price diff erence; the price diff erence was the only reason for switching from Glivec to any generic among our cohort. Th e fi rst issue that physicians caring for patients with CML encounter is whether the effi cacy of these generics is comparable to that of the original molecule; the second issue is what the potential adverse events (AEs) are, other than those with use of Glivec, if any. To answer these questions, we retrospectively reviewed our data.

First line treatment of chronic phase chronic myeloid leukaemia patients with the generic formulations of imatinib mesylate

in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America. British Journal of Haematology, 146, 546–556. Vogiatzi, M.G., Macklin, E.A., Fung, E.B., Cheung, A.M., Vichinsky, E., Olivieri, N., Kirby, M., Kwiatkowski, J.L., Cunningham, M., Holm, I.A., Lane, J., Schneider, R., Fleisher, M., Grady, R.W., Peterson, C.C., Giardina, P.J. & Thalassemia Clinical Research Network (2009b) Bone disease in thalassemia: a frequent and still unresolved problem. Journal of Bone and Mineral Research, 24, 543–557.

Comparison of International Prognostic Index and NCCN-IPI in 324 patients with de novo diffuse large B-cell lymphoma: a multi-center retrospective analysis.

Erman Öztürk, Murat Özbalak, Selin Berk, Işıl Erdoğan, Emin Avşar, Anıl Dolgun, Mustafa Çetiner, Nil Molinas Mandel, Fevzi Fırat Yalnız, Tuğrul Elverdi, Ayşe Salihoğlu, Ahmet Emre Eşkazan Muhlis Cem Ar, Şeniz Öngören, Zafer Başlar, Yıldız Aydın, Teoman Soysal & Burhan Ferhanoğlu Division of Hematology, Department of Internal Medicine, Koç University, School of Medicine, Istanbul, Division of Hematology, Department of Internal Medicine, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Division of Oncology, V.K.V. American Hospital, Istanbul, Department of Biostatstics, Hacettepe University, Ankara, and Division of Oncology, Department of Internal Medicine, Koç University, School of Medicine, Istanbul, Turkey

Outcomes of Chronic Myeloid Leukemia Patients With Early Molecular Response at 3 and 6 Months: A Comparative Analysis of Generic Imatinib and Glivec

Micro‐Abstract We retrospectively evaluated 90 patients with chronic myeloid leukemia receiving either upfront original imatinib (OI) or generic imatinib (GI) for the effect of the early molecular response on the long‐term outcome. We demonstrated that achieving an optimal response at 3 and 6 months in patients receiving either first‐line GI or OI was clearly associated with greater response and event‐free survival rates. Background: The molecular response at 3 months of the original imatinib (OI) in patients with chronic myeloid leukemia has prognostic significance; however, this has never been tested for generic imatinib (GI). Patients and Methods: We evaluated the BCR‐ABL1 [international reporting scale (IS)] transcript levels at 3 and 6 months to determine whether an early molecular response (EMR) had a prognostic effect on the outcome among chronic myeloid leukemia patients receiving GI. Ninety patients were divided into 2 groups, according to the imatinib they received, as OI (group A) and GI (group B). Results: Two groups were equally balanced for age, gender, Sokal risk score, and optimal response. The 2 groups did not differ in achieving an EMR at 3 months, and patients with EMR at 3 months had significantly superior complete cytogenetic response and major molecular response rates compared with patients who did not achieve an EMR in both groups. The percentage of an optimal response [BCR‐ABL1 (IS), < 1%] and a warning response [BCR‐ABL1 (IS), 1%‐10%] at 6 months was 93% and 95% for groups A and B, respectively (P = .553). Patients with an optimal response (OR) at both 3 and 6 months had significantly superior event‐free survival rates compared with patients without an OR in groups A and B. Conclusion: The results of the present study have demonstrated most probably for the first time that an OR at 3 and 6 months in patients receiving either first‐line GI and OI is clearly associated with greater response and event‐free survival rates. Prospective randomized trials with larger numbers of patients and longer follow‐up periods are needed to address the effect of EMR in patients receiving GI.

Imatinib reduces bone marrow fibrosis and overwhelms the adverse prognostic impact of reticulin formation in patients with chronic myeloid leukaemia

Aims Before the era of tyrosine kinase inhibitors (TKIs), the presence of bone marrow fibrosis (MF) in patients with chronic myeloid leukaemia (CML) has been established as a poor prognostic factor. The aim of the present study was to evaluate the effects of imatinib treatment on MF and the prognostic significance of MF at this new era of CML therapy. Methods The study cohort consisted of 135 patients with CML who were exposed to imatinib. The grades of MF pre and post imatinib together with cytogenetic and molecular responses were evaluated. Results Severe MF (grade II–III) was observed in 44 (33%) patients prior to imatinib therapy, and in 8 (8%) after 12 months of imatinib treatment (p=0.001). The complete cytogenetic response (CCyR) rates at 12 months did not differ according to the pre-imatinib MF grades, and CCyR rates in patients with grades 0, I, II and III MF were 36/47 (76.5%), 26/33 (78.7%), 12/23 (52.1%) and 7/10 (70%), respectively (p=0.127). There was no significant difference between patients with or without CCyR at 12 months of imatinib regarding grades of MF (p=0.785). The distribution of the major molecular response rates at 18 months according to pre-treatment grades of MF were determined as grade 0 in 38/45 (84.4%), grade I in 21/28 (75%), grade II in 14/21 (66.6%) and grade III in 7/10 (70%) (p=0.112). There was no significant difference in overall survival rates between initial MF mild (grade 0–I) and severe (grade II–III) groups (p=0.278). Conclusions According to our findings, MF regresses with imatinib therapy over time, and the MF grades at diagnosis do not have a negative impact on the responses to imatinib treatment. Therefore, the adverse prognostic impact of the MF among patients with CML seems to disappear in the era of the TKIs.

Third-line treatment with second-generation tyrosine kinase inhibitors (dasatinib or nilotinib) in patients with chronic myeloid leukemia after two prior TKIs: real-life data on a single center experience along with the review of the literature

ABSTRACT Objectives: Newer tyrosine kinase inhibitors (TKIs) (bosutinib, ponatinib) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be utilized as a salvage therapy in patients with chronic myeloid leukemia (CML) who failed two lines (imatinib → nilotinib or imatinib → dasatinib) of TKI therapy. However, these TKIs are not available in many countries and not all patients can undergo allo-HSCT. Methods: In this study, CML patients who received dasatinib or nilotinib as a third-line treatment were retrospectively evaluated. Results: Out of 209 patients, third-line dasatinib/nilotinib was administered in 21. During the follow-up, 16 out of 21 patients gained and/or maintained an optimal response, and 4 patients died due to progression. Seventeen patients were alive at the time of the analysis, of which 13 were still on TKI, whereas 4 patients quit treatment. Discussion: In patients failing two lines of TKI, dasatinib or nilotinib can be beneficial and safely administered as a third-line treatment especially in nations with restricted resources.

Relapse after allogeneic hematopoietic stem cell transplant in patients with chronic myeloid leukemia: tyrosine kinase inhibitors, donor lymphocyte infusions or both?

Before the introduction of the tyrosine kinase inhibitors (TKIs), the median survival of patients with chronic myeloid leukemia (CML) was 5–7 years [1], and the only possible treatment option that ...

Deep sequencing of BCR-ABL1 kinase domain mutations in chronic myeloid leukemia patients with resistance to tyrosine kinase inhibitors

Abstract Tyrosine kinase inhibitor (TKI) therapy is the current treatment of choice for patients with chronic phase chronic myeloid leukemia (CML) leading to rapid and durable hematological as well as molecular responses. However, emergence of resistance to TKIs has been the major obstacle to treatment success on long term. In this regard kinase domain mutations are the most common mechanism of therapy failure. In this study, we analyzed peripheral blood samples from 17 CML patients who had developed resistance to various TKIs by using next-generation sequencing parallel to Sanger sequencing. BCR-ABL1 kinase domain mutations have been found in 59% of the cohort. Our results demonstrate that next-generation sequencing results in a higher mutational detection rate than reported with conventional sequencing methodology. Furthermore, it showed the clonal diversity more accurately.

Vincristine as an Adjunct to Therapeutic Plasma Exchange for Thrombotic Thrombocytopenic Purpura: A Single Institution Experience

Background: Thrombotic thrombocytopenic purpura is a potentially life-threatening condition. Although the introduction of therapeutic plasma exchange has reduced mortality rates from over 90% to 10%-20%, approximately 40% of patients relapse, and outcomes may be fatal in refractory patients. There is clearly a need for additional therapeutic approaches. Aims: To describe the outcomes of relapsed/refractory thrombotic thrombocytopenic purpura patients treated with vincristine as an adjunct to therapeutic plasma exchange. Study Design: Cross-sectional study. Methods: The medical records of all relapsed/refractory patients with thrombotic thrombocytopenic purpura treated with vincristine adjunct to therapeutic plasma exchange between October 2000 and December 2016 were retrospectively reviewed. Diagnosis of thrombotic thrombocytopenic purpura was based on clinical history, physical examination, and laboratory examinations. Patient demographics, laboratory findings, initial date and duration of therapeutic plasma exchange, dosage and time of administration of vincristine, and outcomes were recorded. Results: The study included 15 patients [median age: 37 years (range: 26-65); 7 women and 8 men] with either relapsed or refractory thrombotic thrombocytopenic purpura who were treated with vincristine as an adjunct to therapeutic plasma exchange for a total of 22 episodes. Eighty-seven percent of patients achieved remissions in 20 of 22 episodes, with a median duration of remission of 29.5 months (range: 3-105). After a median follow-up of 55 months, 11 patients were alive. Vincristine was well tolerated with no safety concerns. Conclusion: Vincristine offers a reasonable option for the treatment of patients with relapsed/refractory thrombotic thrombocytopenic purpura. Further studies evaluating vincristine in the front-line setting and in the relapsed/refractory setting are needed to validate the role of vincristine in thrombotic thrombocytopenic purpura patients.