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Farhad Ravandi

Publications and source records attributed to Farhad Ravandi.

51 records · Page 3Linked to original sources
PubMed2005

Alemtuzumab.

Alemtuzumab is a humanized monoclonal antibody against CD52, a small glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on normal T- and B-lymphocytes, and on a large proportion of malignant lymphoid cells, but not on hematopoietic progenitor cells. Over the past several years, a number of clinical trials have demonstrated the clinical activity of alemtuzumab in treating patients with chronic lymphocytic leukemia, T-cell malignancies such as T-prolymphocytic leukemia and cutaneous T-cell lymphoma, as well as in the prevention and therapy of graft-versus-host disease in the setting of allogeneic stem cell transplantation. Its application in a number of autoimmune disorders is currently under investigation. The most significant side effect of alemtuzumab is predisposition to infections related to the associated profound lymphopenia. Despite this, and with appropriate and more effective antibiotic prophylaxis, it is likely that we will witness an expansion of the role of alemtuzumab in the future.

Alemtuzumab↗
PubMed2005

T-cell prolymphocytic leukemia: a single-institution experience.

BACKGROUND: T-cell prolymphocytic leukemia is an uncommon, aggressive, mature T-cell leukemia characterized by proliferation of T-cell lymphocytes. The recent availability of modern immunophenotypic and molecular tools has allowed a better distinction of this disorder from its B-cell counterpart and other mature T-cell leukemias. PATIENTS AND METHODS: The clinical, pathologic, and cytogenetic features of 57 patients with T-PLL who were evaluated at the Department of Leukemia, M. D. Anderson Cancer Center (MDACC) from 1986 to 2004 were examined. RESULTS: The most common cytogenetic abnormality was inv(14)(q11;q32), which was present in 7 patients. In all 7 patients, this abnormality was associated with other chromosomal aberrations. Patients treated with alemtuzumab at MDACC had a significantly better response rate (P = 0.02) and survival rate (P = 0.002). There were no significant differences in survival based on Tcl-1 expression or different patterns of CD4 and CD8 expression. CONCLUSION: Treatment with alemtuzumab results in higher response rates and a better survival rate in patients with T-cell prolymphocytic leukemia.

Adult↗
PubMed2005

Chronic lymphoid leukemias other than chronic lymphocytic leukemia: diagnosis and treatment.

The World Health Organization classification divides lymphoid malignancies into precursor B-cell and T-cell neoplasms as well as mature B-cell and T-cell neoplasms. Mature B-cell neoplasms comprise more than 85% of non-Hodgkin lymphomas worldwide and can be further subclassified according to the postulated cell of origin by using specific morphologic, immunophenotypic, and molecular characteristics. Similarly, the more uncommon mature T-cell neoplasms have been better characterized to include numerous distinct entities with widely varying natural histories. The distinction between lymphoma and leukemia is somewhat arbitrary and is based on variable involvement of the bone marrow, peripheral blood, and lymphatic system. In this article, we review the diagnostic and clinical features of mature B-cell and T-cell lymphoproliferative disorders that commonly have a leukemic presentation.

Diagnosis, Differential↗
PubMed2004

Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells.

Imatinib mesylate (STI571), a specific inhibitor of the BCR-ABL tyrosine kinase, exhibits potent antileukemic effects in vitro and in vivo. Despite the well established role of STI571 in the treatment of chronic myelogenous leukemia, the precise mechanisms by which inhibition of BCR-ABL tyrosine kinase activity results in generation of antileukemic responses remain unknown. In the present study we provide evidence that treatment of CML-derived BCR-ABL-expressing leukemia cells with STI571 results in activation of the p38 mitogen-activated protein (MAP) kinase signaling pathway. Our data indicate that STI571 induces phosphorylation of the p38 and activation of its kinase domain, in KT-1 cells and other BCR-ABL-expressing cell lines. We also identify the kinases MAP kinase-activated protein kinase-2 and Msk1 as two downstream effectors of p38, activated during inhibition of BCR-ABL activity by STI571. Importantly, pharmacological inhibition of p38 reverses the growth inhibitory effects of STI571 on primary leukemic colony-forming unit granulocyte/macrophage progenitors from patients with CML. Altogether, our data establish that activation of the p38 MAP kinase signaling cascade plays an important role in the generation of the effects of STI571 on BCR-ABL-expressing cells. They also suggest that, in addition to activation of mitogenic pathways, BCR-ABL promotes leukemogenesis by suppressing the function of growth inhibitory signaling cascades.

Antineoplastic Agents↗
PubMed2004

New agents in acute myeloid leukemia and other myeloid disorders.

Over the past several decades, improvements in chemotherapeutic agents and supportive care have resulted in significant progress in treating patients with acute myeloid leukemia (AML). More recently, advances in understanding the biology of AML have resulted in the identification of new therapeutic targets. The success of all-trans-retinoic acid in acute promyelocytic leukemia and of imatinib mesylate in chronic myeloid leukemia have demonstrated that targeted therapy may be more effective and less toxic when well defined targets are available. At the same time, understanding mechanisms of drug resistance and means to overcome them has led to modification of some of the existing cytotoxic agents. Rational design and conduct of clinical trials is necessary to ensure that the full potential of these new agents is realized.

Antineoplastic Agents↗
PubMed2004

Comprehensive analysis of CBFbeta-MYH11 fusion transcripts in acute myeloid leukemia by RT-PCR analysis.

CBFbeta-MYH11 fusion transcripts are expressed in acute myeloid leukemias of the M4Eo subtype. Patients who express CBFbeta-MYH11 fusion transcripts respond favorably to high-dose chemotherapy and are generally spared allogeneic bone marrow transplantation. Hence it is important to identify this fusion in all patients with acute myeloid leukemia M4Eo leukemia. The fusion can be detected by cytogenetics, fluorescence in-situ hybridization (FISH), or by molecular analysis with RT-PCR. Multiple fusion transcripts arising as a result of various breakpoints in the CBFbeta and MYH11 have been identified. In this report we describe a comprehensive RT-PCR assay to identify all known fusion transcripts and provide an algorithm for molecular analysis of CBFbeta-MYH11 fusions from patient specimens. Further, identification of the fusion transcript by such an assay would help in the diagnosis and follow up of patients with cryptic inversion 16 translocations (such as patient 2 in this report) not detected by standard cytogenetics or FISH and for rational design of probes for quantitative analysis by real-time PCR.

Algorithms↗
PubMed2004

Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma.

Despite aggressive and innovative therapy, patients with multiple myeloma (MM) invariably relapse and die of their disease. New options for non-cytotoxic salvage therapy and additional therapeutic strategies are needed. Arsenic trioxide, an antitumour agent with a multifaceted mechanism of action, induces apoptosis in vitro in MM cell lines and freshly isolated cells from MM patients and, in preliminary studies, displayed clinical activity in patients with late-stage MM. A phase 2, multicentre, open-label study of arsenic trioxide was conducted in 24 MM patients; eight had relapsed and 16 were refractory to prior therapy. Patients received arsenic trioxide 0.25 mg/kg/d for 5 d/week during the first 2 weeks of each 4-week cycle. Sixteen patients had grade 3 or 4 neutropenia and one required antibiotics. Reductions (25% or more) in serum M-protein levels occurred in eight of 24 (33%) patients. An additional six (25%) patients had stable disease. The median time to response was 67.5 d, with a median duration of response of 130 d. Arsenic trioxide therapy lowered serum creatinine levels in two patients with high baseline values. These data indicate that arsenic trioxide is active and reasonably well tolerated as a single-agent salvage therapy, even in patients with late-stage, relapsed and refractory MM.

Adult↗
PubMed2003

Long-term follow-up of a phase I study of high-dose decitabine, busulfan, and cyclophosphamide plus allogeneic transplantation for the treatment of patients with leukemias.

BACKGROUND: Decitabine is a hypomethylating agent that has activity in patients with leukemia. The authors combined decitabine with busulfan and cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. METHODS: Patients with high-risk acute myeloid leukemia (AML) (n = 12 patients); chronic myelomonocytic leukemia (CMML) (n = 1 patient); acute lymphocytic leukemia (ALL) (n = 1 patient); or late chronic phase, accelerated, or blastic phase chronic myelogenous leukemia (n = 9 patients) were eligible for the study. The treatment plan was comprised of busulfan, 12 mg/kg orally; cyclophosphamide, 100 mg/kg (n = 4 patients) or 120 mg/kg (n = 19 patients); and decitabine, intravenously at 3 dose levels: 400 mg/m(2) (n = 10 patients), 600 mg/m(2) (n = 8 patients), and 800 mg/m(2) (n = 5 patients). Donors were human leukocyte antigen-identical siblings in all cases, and all but one patient received peripheral blood stem cells. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus based in all but one patient. RESULTS: The median time to neutrophil and platelet engraftment was 12.5 days and 17.5 days, respectively. Twenty-one patients were engrafted and achieved disease remission. At a median of 3.3 years posttransplantation, 26% of patients (40% of patients with AML) were alive and disease free. The median survival for the group was 17.2 months, and the disease free survival for the group was 8.9 months. Causes of death were disease recurrence (nine patients), chronic GVHD (four patients), infections (three patients), and acute GVHD (one patient). The 100-day mortality rate was 9%. No decitabine dose-limiting toxicity was documented. The treatment-related mortality rate at 3 years was 35%. Responders were treated at all three decitabine dose levels, and no dose-response correlation was observed. CONCLUSIONS: There was a high response rate with low treatment-related mortality, with 26% of patients alive in remission 3.3 years after transplantation.

Adolescent↗
PubMed2003

Chronic lymphocytic leukemia (B-CLL) occurring with human immunodeficiency virus (HIV) infection: implications.

Although chronic lymphocytic leukemia (CLL) is the most common leukemia in the west and over the past two decades the incidence of infection with the human immunodeficiency virus (HIV) has significantly increased, few reports of the coincidence of these diseases exist in the literature. Other lymphoid malignancies such as non-Hodgkin's lymphomas (NHL) and Hodgkin's disease (HD) occur frequently with HIV and indeed the former is an acquired immune deficiency syndrome (AIDS)-defining illness. It is not clear why HIV infected patients have a predisposition for some B-cell disorders and not others. This may be related to the different age ranges for patients with CLL and HIV infection although an overlap clearly does exist. Here, we describe our experience with a patient with co-existing HIV infection and CLL and explore possible implications.

AIDS-Related Opportunistic Infections↗
PubMed2003

Modulation of cellular signaling pathways: prospects for targeted therapy in hematological malignancies.

The high remission rates observed in patients with chronic myelogenous leukemia who receive Imatinib mesylate (Gleevec) indicate that targeted therapy for hematological malignancies is achievable. At the same time, progress in cellular biology over the past decade has resulted in a better understanding of the process of malignant transformation, a better classification of subtypes of each disease on the basis of molecular markers, and a better characterization of the molecular targets for drug development. These advances have already spawned the development of such effective agents as monoclonal antibodies and specific enzyme inhibitors. This review attempts to provide a practical introduction to the complex and growing field of targeted therapy in hematological malignancies.

Antineoplastic Agents↗
PubMed2002

Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide.

Arsenic trioxide induces differentiation and apoptosis of malignant cells in vitro and in vivo, but the mechanisms by which such effects occur have not been elucidated. In the present study we provide evidence that arsenic trioxide induces activation of the small G-protein Rac1 and the alpha and beta isoforms of the p38 mitogen-activated protein (MAP) kinase in several leukemia cell lines. Such activation of Rac1 and p38-isoforms results in downstream engagement of the MAP kinase-activated protein kinase-2 and is enhanced by pre-treatment of cells with ascorbic acid. Interestingly, pharmacological inhibition of p38 potentiates arsenic-dependent apoptosis and suppression of growth of leukemia cell lines, suggesting that this signaling cascade negatively regulates induction of antileukemic responses by arsenic trioxide. Consistent with this, overexpression of a dominant-negative p38 mutant (p38betaAGF) enhances the antiproliferative effects of arsenic trioxide on target cells. To further define the relevance of activation of the Rac1/p38 MAP kinase pathway in the induction of arsenic-dependent antileukemic effects, studies were performed using bone marrows from patients with chronic myelogenous leukemia. Arsenic trioxide suppressed the growth of leukemic myeloid (CFU-GM) progenitors from such patients, whereas concomitant pharmacological inhibition of the p38 pathway enhanced its growth-suppressive effects. Altogether, these data provide evidence for a novel function of the p38 MAP kinase pathway, acting as a negative regulator of arsenic trioxide-induced apoptosis and inhibition of malignant cell growth.

Antioxidants↗
PubMed2002

CD56 expression predicts occurrence of CNS disease in acute lymphoblastic leukemia.

We examined the pre-treatment bone marrow samples from 200 consecutive adult patients with acute lymphoblastic leukemia (ALL) treated on various protocols at the University of Texas, M.D. Anderson Cancer Center between 1986 and 1998. Standard MFC techniques were used to determine CD56 expression on the leukemia blasts cells. The expression of CD56 was correlated with clinical characteristics at diagnosis, response to therapy, survival and disease-free survival. Blast expression of CD56 (> or = 20% of leukemic blasts) was seen in 16 (8%) of patients, with a median expression of 67% (range 20-99%). CD56 expression was associated with a higher incidence of central nervous system (CNS) disease at diagnosis (19% versus 4%; P=0.016). Incidence of CNS disease at any time was higher in patients with CD56+ disease (31% versus 14%; P=0.057). Among the 109 patients uniformly treated with the hyperCVAD regimen, CD56 expression was associated with a statistically significant higher incidence of CNS disease (33% versus 9%; P=0.026). CD56 expression in ALL is uncommon but may predict a higher risk for CNS disease. If these results are confirmed, CD56 expression could be used in combination with other high-risk features (e.g. lactate dehydrogenase (LDH), S-phase fraction, mature B-cell phenotype) to design a risk-oriented approach to CNS prophylaxis.

Adolescent↗
PubMedDate not supplied

Novel agents in acute myeloid leukemia.

In the past 40 years, advances in supportive care and development of chemotherapeutic agents have led to improved outcomes in patients with acute myeloid leukemia. High relapse rates following remission have led to extensive efforts to develop techniques and regimens for detecting and eliminating minimal residual disease. However, the best postremission therapy has not been identified. Better understanding of the biology and the molecular pathogenesis of AML has led to the development of new, more specific agents and strategies for AML treatment. Targeted therapy has improved outcomes in some patients. Most of the new agents are less toxic then their predecessors, and they can be used in combination with the more intensive traditional regimens.

Acute Disease↗