Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.

The oncogenetic events that transform chronic myeloproliferative neoplasms (MPN) to acute myeloid leukemias (AML) are not well characterized. We investigated the role of several genes implicated in leukemic transformation by mutational analysis of 63 patients with AML secondary to a preexisting MPN (sAML). Frequent mutations were identified in TET2 (26.

Mycotic pulmonary artery aneurysm due to Aspergillus infection in a patient with leukemia: case report and review of the literature.

We present a case of a patient with hairy cell leukemia and pulmonary aspergillosis who developed a cycotic pulmonary artery aneurysm despite prolonged antifungal therapy. A review of the literature in regards to incidence, etiology, clinical manifestations and treatment options is included.

Experience with everolimus (RAD001), an oral mammalian target of rapamycin inhibitor, in patients with systemic mastocytosis.

KIT D816V mutation has been observed in more than 90% of patients with systemic mastocytosis (SM). This mutation constitutively activates the mammalian target of rapamycin (mTOR) signaling pathway. We tested the efficacy of everolimus (RAD001), a novel oral mTOR inhibitor, at a dose of 10 mg daily in an open label, non-comparative Phase II trial for patients with SM.

Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.

Few treatment options exist for patients with myelofibrosis (MF), and their survival is significantly shortened. Activating mutation of the JAK2 tyrosine kinase (JAK2(V617F)) is found in approximately 50% of MF patients. CEP-701 is a tyrosine kinase inhibitor that inhibits JAK2 in in vitro and in vivo experiments.

Therapeutic potential of JAK2 inhibitors.

The discovery of an activating tyrosine kinase mutation JAK2V617F in myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) has resulted in the development of JAK2 inhibitors, of which several are being evaluated in phase I/II clinical studies. It is important to recognize that because the V617F mutation is localized in a region outside the adenosine triphosphate (ATP)-binding pocket of JAK2 enzyme, ATP-competitive inhibitors of JAK2 kinase (like the current JAK2 inhibitors in the clinic) are not likely to discriminate between wild-type and mutant JAK2 enzymes. Therefore, JAK2 inhibitors, by virtue of their near equipotent activity against wild-type JAK2 that is important for normal hematopoiesis, may have adverse myelosuppression as an expected side effect, if administered at doses that aim to completely inhibit the mutant JAK2 enzyme.

Allogeneic stem cell transplantation for myelofibrosis with leukemic transformation.

Leukemic transformation (LT) from myelofibrosis has a very poor prognosis with the current treatment strategies. We hypothesized that allogeneic stem cell transplantation (ASCT) can improve outcomes for patients with LT, and reviewed 55 consecutive patients that were treated for myelofibrosis with ASCT at our institution. Fourteen patients (25%) were identified to have LT.

Efficacy and safety of intravenous voriconazole and intravenous itraconazole for antifungal prophylaxis in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome.

Purpose: To compare the efficacy and safety of voriconazole with itraconazole as prophylaxis in leukemia patients.

Methods: Open-label, randomized study. Patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome undergoing induction chemotherapy or first salvage were eligible.

Acute pulmonary failure during remission induction chemotherapy in adults with acute myeloid leukemia or high-risk myelodysplastic syndrome.

Background: Acute pulmonary failure during remission induction therapy is a serious complication in patients with acute myeloid leukemia (AML). To the authors' knowledge, the course and prognosis of such patients is not well known.

Methods: A total of 1541 patients referred for remission induction chemotherapy of AML or high-risk myelodysplastic syndrome were retrospectively reviewed.

Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera.

Purpose: We conducted a phase II study of pegylated interferon alfa-2a (PEG-IFN-alpha-2a) in patients with essential thrombocythemia (ET) and polycythemia vera (PV).

Patients And Methods: Seventy-nine patients (40 with PV and 39 with ET) have been treated. Median time from diagnosis to PEG-IFN-alpha-2a was 54 months in patients with PV and 33 months in patients with ET.

Phase II study of alemtuzumab in combination with pentostatin in patients with T-cell neoplasms.

Purpose: To examine the efficacy and safety of the combination of alemtuzumab and pentostatin in patients with T-cell neoplasms.

Patients And Methods: We treated 24 patients with a variety of T-cell leukemias and lymphomas with a combination of alemtuzumab 30 mg intravenously (IV) three times weekly for up to 3 months and pentostatin 4 mg/m(2) IV weekly for 4 weeks followed by alternate weekly administration for up to 6 months. Prophylactic antibiotics including antiviral, antifungal, and antibacterial agents were administered during the treatment and for 2 months after its completion.

Superior outcome with hypomethylating therapy in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome and chromosome 5 and 7 abnormalities.

Background: Outcome of patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) with chromosome 5 and 7 abnormalities (excluding del 5[q]) has been poor, with <10% of patients alive at 2 years.

Methods: The authors investigated whether treatment with hypomethylating agents (5-azacytidine/decitabine) leads to an improved outcome. Between January 2004 and December 2007, 81 patients (37 [46%] with AML [>or=20% blasts]; 44 [54%] with high-risk MDS) with chromosome 5 and 7 abnormalities were treated with hypomethylating agents as their initial therapy.

Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.

Purpose: Current prognostic tools in myelofibrosis (MF) fail to identify patients at the highest risk of death and are limited by their applicability only to the time of diagnosis. We aimed to define an accelerated phase (AP) in MF by characterizing disease features that can identify patients with median overall survival of
Patients And Methods: Baseline characteristics of 370 consecutive patients with MF from a single center were analyzed to identify features associated with a median overall survival of View Article and Find Full Text PDF

JAK2 inhibitors: A reality? A hope?

Myelofibrosis (MF; primary or post-polycythemia vera/essential thrombocythemia) carries the worst prognosis among BCR-ABL-negative myeloproliferative neoplasms (MPNs). Stem cell transplantation is the only curative approach but is hampered by significant nonrelapse mortality. Thus, effective, targeted therapies are needed.

Primary autoimmune myelofibrosis in a 36-year-old patient presenting with isolated extreme anemia.

Primary autoimmune myelofibrosis is a very rare condition characterized by peripheral blood cytopenias, bone marrow fibrosis with lymphoid aggregates, and by the finding of autoantibodies in peripheral blood, suggesting a systemic autoimmune process. Patients can be frequently misdiagnosed as having the more common disorder primary myelofibrosis, a myeloproliferative neoplasm. We report the case of a patient with primary autoimmune myelofibrosis with emphasis on the clinical and pathological features that lead to the diagnosis.

Cytogenetic abnormalities in essential thrombocythemia at presentation and transformation.

Cytogenetic abnormalities in patients with essential thrombocythemia (ET) are infrequent. Their role in survival of patients and disease transformation is not extensively studied. We describe cytogenetic abnormalities in 172 patients with ET at a single institution.

Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis.

Purpose: To investigate the safety and efficacy of the combination of lenalidomide and prednisone in patients with myelofibrosis (MF).

Patients And Methods: Forty patients with MF were treated. Therapy consisted of lenalidomide 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) on days 1 through 21 of a 28-day cycle for six cycles, in combination with prednisone 30 mg/d orally during cycle 1, 15 mg/d during cycle 2, and 15 mg/d every other day during cycle 3.

Pomalidomide is active in the treatment of anemia associated with myelofibrosis.

Purpose: Thalidomide and lenalidomide can alleviate anemia in myelofibrosis. However, their value is undermined by their respective potential to cause peripheral neuropathy and myelosuppression. We therefore evaluated the safety and therapeutic activity of another immunomodulatory drug, pomalidomide.

A phase I clinical trial of darinaparsin in patients with refractory solid tumors.

Purpose: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limiting toxicity (DLT) and maximum tolerated dose of darinaparsin in patients with advanced cancer.

Experimental Design: Patients with solid malignancies refractory to conventional therapies were treated with i.

Chronic myeloid leukemia (CML) with P190 BCR-ABL: analysis of characteristics, outcomes, and prognostic significance.

The most common BCR-ABL transcripts in chronic myeloid leukemia (CML) are e13a2(b2a2) and e14a2(b3a2). Other transcripts such as e1a2 are rare and their outcome with tyrosine kinase inhibitors (TKI) therapy is undefined. We analyzed 1292 CML patients and identified 14 with only e1a2 transcripts, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP).

Imatinib mesylate therapy for polycythemia vera: final result of a phase II study initiated in 2001.

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by excessive production of red blood cells. Patients with PV are at a risk of thrombosis, bleeding, and transformation to myelofibrosis or acute myeloid leukemia. Therapy for PV is based on the use of phlebotomy, aspirin, and in high-risk patients, cytoreductive agents such as hydroxyurea.

Primary myelofibrosis with concurrent precursor T-cell lymphoblastic lymphoma of the spleen in a 26-year-old patient.

Primary myelofibrosis (PMF) is rare myeloproliferative disease usually diagnosed in older patients. Reports of a concurrent acute lymphoblastic leukemia or lymphoma in PMF are rare. We present a case of a 26-year old patient with PMF and precursor T-cell acute lymphoblastic lymphoma of the spleen and lymph nodes.

MER1, a novel organic arsenic derivative, has potent PML-RARalpha-independent cytotoxic activity against leukemia cells.

Arsenic trioxide (ATO) is an inorganic arsenic derivative that is highly effective against PML-RARalpha-positive leukemia but much less against other hematological malignancies. We synthesized an organic arsenic derivative (OAD), S-dimethylarsino-thiosuccinic acid (MER1), which offers a superior toxicity profile and comparable in vitro activity relative to ATO. In Swiss Webster mice, maximally-tolerated cumulative dose of MER1 when given i.

Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms.

The discovery of the Janus kinase (JAK)2 V617F mutation in patients with myeloproliferative neoplasms was a major milestone in understanding the biology of those disorders. Several groups simultaneously reported on the high incidence of this mutation in patients with myeloproliferative neoplasms: almost all patients with polycythemia vera harbor the mutation and about 50% of patients with essential thrombocythemia and primary myelofibrosis have the mutation, making the development of JAK2 tyrosine kinase inhibitors an attractive therapeutic goal. In addition, inhibition of JAK2 kinase may have a therapeutic role in other hematologic malignancies, such as chronic myeloid leukemia or lymphoma.

Failure to achieve a complete hematologic response at the time of a major cytogenetic response with second-generation tyrosine kinase inhibitors is associated with a poor prognosis among patients with chronic myeloid leukemia in accelerated or blast phase.

Second-generation tyrosine kinase inhibitors are effective in Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). Occasionally, patients with Ph(+) ALL, or accelerated phase (AP) or blast phase (BP) CML achieve a major cytogenetic response (MCyR) but not a complete hematologic response (CHR). We analyzed 126 patients with CML in AP or BP, or with Ph(+) ALL treated with dasatinib or nilotinib after imatinib failure.