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Santos F.P.S.,Hematology and Oncology Center | Verstovsek S.,University of Houston
Hematology/Oncology Clinics of North America | Year: 2012

The development of JAK2 inhibitors followed the discovery of activating mutation of JAK2 (JAK2V617F) in patients with classic Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN). It is now known that mutations activating the JAK-STAT pathway are ubiquitous in Ph-negative MPN, and that the deregulated JAK-STAT pathway plays a central role in the pathogenesis of these disorders. JAK2 inhibitors thus are effective in patients both with and without the JAK2V617F mutation. This article reviews the rationale for using JAK2 inhibitors in Ph-negative MPN, and the results of more recent clinical trials with these drugs. © 2012 Elsevier Inc.

Santos F.P.S.,Hematology and Oncology Center | O'Brien S.,University of Texas M. D. Anderson Cancer Center
Cancer Journal (United States) | Year: 2012

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, characterized by peripheral blood B-cell lymphocytosis as well as lymphadenopathy, organomegaly, cytopenias, and systemic symptoms. Chronic lymphocytic leukemia cells have a distinctive immunophenotype, and the disease has a characteristic pattern of histological infiltration in the lymph node and bone marrow. The clinical course of CLL is heterogeneous, with some patients presenting with very indolent disease and other patients having a more aggressive malignancy. It is known that genetic abnormalities underlie this difference in clinical presentation. Some patients may present solely with lymphadenopathy, organomegaly, and presence of infiltrating monoclonal B cells with the same immunophenotype as CLL cells, but lacking peripheral blood lymphocytosis. This disease is called small lymphocytic lymphoma (SLL) and has been considered for almost 2 decades to be the tissue equivalent of CLL. Both CLL and SLL are currently considered different manifestations of the same entity by the fourth edition of the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. It is suspected that differential expression of chemokine receptors (e.g., reduced expression of R1 and CCR3 in SLL cells), integrins (e.g., CLL cells have lower expression of integrin αLβ2), and genetic abnormalities (a higher incidence of trisomy 12 and lower incidence of del(13q) is found in SLL) may explain some of the clinical differences between these 2 disorders. However, there is still a lack of knowledge on the precise biological basis underlying the different clinical presentations of CLL and SLL. It is expected that future studies will shed light on the pathophysiology of both disorders. © 2012 by Lippincott Williams & Wilkins.

Santos F.P.S.,Hematology and Oncology Center | Verstovsek S.,University of Texas M. D. Anderson Cancer Center
Expert Opinion on Pharmacotherapy | Year: 2014

Introduction: The discovery of the activating JAK2 V617F mutation in patients with myelofibrosis (MF) led to the development of JAK2 inhibitors. The first such inhibitor to enter clinical trials was ruxolitinib. This review summarizes preclinical and clinical data of ruxolitinib in MF.Areas covered: A literature search through Medline employing the terms 'ruxolitinib,' 'INCB018424' and 'myelofibrosis' was undertaken. The results from Phase I/II studies in patients with MF showed that ruxolitinib led to durable improvements in splenomegaly, and symptoms associated with MF. Two Phase III trials have compared ruxolitinib against placebo and best available therapy, and in both studies ruxolitinib demonstrated superior rates of spleen control and symptom improvement, and additional analysis demonstrated a survival benefit with ruxolitinib treatment. The main toxicities seen with ruxolitinib are cytopenias, which are managed with dose adjustments. Recent reports documented sporadic cases of immunosuppression-related infections. Ruxolitinib is the first drug ever approved for the therapy of patients with MF.Expert opinion: Understanding the factors that predict the rate and duration of response to ruxolitinib would improve our ability to manage patients treated with this medication. Clinical trials combining ruxolitinib with novel compounds that are also active in MF will further improve therapy for this disease. © 2014 Informa UK, Ltd.

Patel K.P.,University of Houston | Newberry K.J.,University of Houston | Luthra R.,University of Houston | Jabbour E.,University of Houston | And 10 more authors.
Blood | Year: 2015

Although most patients with myelofibrosis (MF) derive benefit from ruxolitinib, some are refractory, have a suboptimal response, or quickly lose their response. To identify genes that may predict response to ruxolitinib, we performed targeted next-generation sequencing (NGS) of a panel of 28 genes recurrently mutated in hematologic malignancies in a cohort of patients with MF who were treated with ruxolitinib in a phase 1/2 study. We also tested for CALR deletions by standard polymerase chain reaction methods. Ninety-eight percent of patients had a mutation in ≥1 gene. Seventy-nine (82.1%) patients had the JAK2V617Fmutation, 9 (9.5%) had CALR mutations (7 type 1, 2 type 2), 3 (3.1%) had MPL mutations, and 4 (4.2%) were negative for all 3. ASXL1/JAK2 and TET2/JAK2 were the most frequently comutated genes. Mutations in NRAS, KRAS, PTPN11, GATA2, TP53, and RUNX1 were found in <5% of patients. Spleen response (≥50% reduction in palpable spleen size) was inversely correlated with the number of mutations; patients with ≤2 mutations had ninefold higher odds of a spleen response than those with ≥3 mutations (odds ratio = 9.37; 95% confidence interval, 1.86-47.2). Patients with ≥3 mutations also had a shorter time to treatment discontinuation and shorter overall survival than those with fewer mutations. In multivariable analysis, only number of mutations and spleen response remained associated with time to treatment discontinuation. Patients with ≥3 mutations had the worst outcomes, suggesting that multigene profiling may be useful for therapeutic planning for MF. © 2015 by The American Society of Hematology.

Santos F.P.S.,Hematology and Oncology Center | Tam C.S.,Peter MacCallum Cancer Center | Kantarjian H.,University of Texas M. D. Anderson Cancer Center | Cortes J.,University of Texas M. D. Anderson Cancer Center | And 3 more authors.
Leukemia and Lymphoma | Year: 2014

Splenectomy may be an effective therapeutic option for treating massive splenomegaly in patients with myeloproliferative neoplasms (MPNs). There are still limited data on its short- and long-term benefits and risks. Efficacy and short-term complications were analyzed in 94 patients with different MPNs who underwent splenectomy at M. D. Anderson Cancer Center. The long-term impact of splenectomy on overall survival (OS) and transformation free survival (TFS) was evaluated in 461 patients with myelofibrosis (MF) seen at M. D. Anderson, including 50 who underwent splenectomy during disease evolution. Splenectomy improved anemia and thrombocytopenia in 47% and 66% of patients, respectively. The most common complications were leukocytosis (76%), thrombocytosis (43%) and venous thromboembolism (16%). Post-operative mortality was 5%. Among patients with MF, splenectomy during disease evolution was associated with decreased OS (hazard ratio [HR] = 2.17, p < 0.0001) and TFS (HR = 2.17, p < 0.0001). This effect was independent of the Dynamic International Prognostic Scoring System. Splenectomy is a possible therapeutic option for patients with MF and other MPNs, and its greatest benefits are related to improvement in spleen pain and discomfort, anemia and thrombocytopenia. However, in patients with MF it appears to be associated with increased mortality. © 2013 Informa UK, Ltd.

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