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Biomedical subjects

Farhad Ravandi

Publications and source records attributed to Farhad Ravandi.

At least 37 records · Page 2Linked to original sources
PubMed2006

Eradication of minimal residual disease in hairy cell leukemia.

Although the nucleoside analogs cladribine and pentostatin produce high response rates in patients with hairy cell leukemia (HCL), a significant number of patients eventually relapse. Several studies have demonstrated that patients with complete remission (CR) have a longer disease-free survival. Therefore, strategies to improve on the initial response to nucleoside analog therapy are likely to be beneficial, at least for a proportion of patients. We have treated 13 patients with newly diagnosed HCL (n = 11) or after failure of one prior chemotherapy (n = 2) with cladribine (5.6 mg/m(2) given intravenously over 2 hours daily for 5 days) followed by 8 weekly doses of rituximab (375 mg/m(2)). All patients achieved a CR and minimal residual disease (MRD) assessed by consensus primer polymerase chain reaction (PCR) or flow cytometry was eradicated in 11 (92%) of 12 and in 12 (92%) of 13 of patients, respectively. There was no decline in the absolute CD4 and CD8 lymphocyte number after rituximab. We conclude that eradication of MRD in HCL is possible. Whether this leads to a reduced risk of relapse would need to be evaluated in a larger number of patients and with longer follow-up. Disease characteristics may potentially be used to identify patients that are more likely to benefit from such additional therapy.

Adult↗
PubMed2006

Eradication of leukemia stem cells as a new goal of therapy in leukemia.

Leukemias have traditionally been classified and treated on the basis of phenotypic characteristics, such as morphology and cell-surface markers, and, more recently, cytogenetic aberrations. These classification systems are flawed because they do not take into account cellular function. The leukemia cell population is functionally heterogeneous: it consists of leukemia stem cells (LSC) and mature leukemia cells that differentiate abnormally to varying extents. Like normal hematopoietic stem cells, LSCs are quiescent and have self-renewal and clonogenic capacity. Because they are quiescent, LSCs do not respond to cell cycle-specific cytotoxic agents used to treat leukemia and so contribute to treatment failure. These cells may undergo mutations and epigenetic changes, further leading to drug resistance and relapse. Recent data suggest that mature leukemia cells may acquire LSC characteristics, thereby evading chemotherapeutic treatment and sustaining the disease. Ongoing research is likely to reveal the molecular mechanisms responsible for LSC characteristics and lead to novel strategies for eradicating leukemia.

Animals↗
PubMed2006

Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older.

Outcome of patients with acute myeloid leukemia (AML) who are older than 60 years of age remains unsatisfactory, with low remission rates and poor overall survival. We have previously established the activity of clofarabine plus cytarabine in AML relapse. We have now conducted a phase 2 study of clofarabine plus cytarabine in patients aged 50 years or older with previously untreated AML. Clofarabine was given at 40 mg/m2 as a 1-hour intravenous infusion for 5 days (days 2 to 6) followed 4 hours later by cytarabine at 1 g/m2/d as a 2-hour intravenous infusion for 5 days (days 1 to 5). Of 60 patients, 29 (48%) had secondary AML, 30 (50%) had abnormal karyotypes (monosomy 5 and/or 7 in 15 [25%]), and 11 (21%) showed FLT3 abnormalities. The overall response (OR) rate was 60% (52% CR, 8% CRp). Four patients (7%) died during induction. Adverse events were mainly grade 2 or lower and included diarrhea, nausea, vomiting, mucositis, skin reactions, liver test abnormalities, and infusion-related facial flushing and headaches. Myelosuppression was common. Clofarabine plus cytarabine has activity in adult AML, achieving a good CR rate. However, survival does not appear to be improved compared with other regimens. Modifications of this combination in AML therapy of older patients warrant further evaluation.

Acute Disease↗
PubMed2006

Monoclonal antibody therapy for hairy cell leukemia.

The use of MoAb therapy for the treatment of HCL offers great promise and potential for improving progression-free survival. Rituximab has activity in the setting of previously treated HCL and the ability to eradicate MRD after 2-CdA given as frontline therapy. Alemtuzumab, epratuzumab, Hu-Max-CD20, and other candidate MoAb's should be studied in HCL. Appropriate pharmacologic investigation, use of antigen modulation, and assessments of soluble antigen levels should be considered with future clinical trial s of MoAb's in HCL to optimize therapeutic strategies.

Antibodies, Monoclonal↗
PubMed2006

Purine analogue combinations for indolent lymphomas.

Indolent lymphomas are a group of lymphoid malignancies with differing patterns of behavior and responses to treatment. The progress in treating patients with hairy cell leukemia (HCL) using nucleoside analogues can be used as a model for other indolent B-lymphoproliferative disorders, such as follicular lymphoma. Recent advancements in therapeutic options available for these patients include combination therapy with agents that have differing mechanisms of action and non-overlapping toxicity. It has been shown that patients who are candidates for aggressive therapy might receive benefit, including disease-free survival and overall survival, from combination purine analogue therapy. Using these more aggressive therapeutic approaches earlier in the disease course and as maintenance therapy may further enhance outcomes. With the advent of these new therapies along with the molecular evaluation of these regimens, we may be nearing the time where the goal for more advanced indolent lymphoma will be to achieve a cure.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Purine analogues in advanced T-cell lymphoid malignancies.

T-cell lymphomas account for 10% to 15% of all lymphoid malignancies. In advanced stages of T-cell lymphoma, single or multiagent chemotherapy and bioimmunotherapeutic agents have been used. Purine analogues have demonstrated activity in both refractory cutaneous T-cell lymphoma and peripheral T-cell lymphoma with response rates ranging from 20% to 70%. Response rates have been higher with pentostatin (60%) than with the other compounds in this class. The potential limitation to this therapy is the prolonged immunosuppression, which increases the risk of opportunistic injections in patients who are already at heightened risk for infections. Patients should be monitored closely with CD4 counts and surveillance for opportunistic infections. Future studies of purine analogues should evaluate patients who are less heavily pretreated and combination therapy with other agents such as alemtuzumab should be investigated in order to prolong the duration of disease remission.

Humans↗
PubMed2006

Alemtuzumab in CLL and other lymphoid neoplasms.

The recent success of monoclonal antibodies in the treatment of various hematological and nonhematological cancers is the result of several decades of research in immune therapy of cancer. The identification of cancer-specific surface markers has led to the development of numerous monoclonal antibodies directed at these antigens, which have been associated with variable success in treating patients with different malignancies. Alemtuzumab, one such monoclonal antibody, is a humanized antibody directed against CD52. The target antigen is a small glycosylphosphatidylinositol (GPI)-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. A number of clinical trials have demonstrated the clinical activity of alemtuzumab in chronic lymphocytic leukemia (CLL), T-cell malignancies such as T-prolymphocytic leukemia (T-PLL) and cutaneous T-cell lymphoma (CTCL), and have examined its role as an immunosuppressive agent in transplantation and for the treatment of autoimmune disorders. Effective antibiotic prophylaxis can limit the incidence of infections, which are the major side effect associated with the profound lymphopenia occurring as a result of treatment with this agent.

Alemtuzumab↗
PubMed2006

Validation of the European Prognostic Index for younger adult patients with acute myeloid leukaemia in first relapse.

In order to validate the European Prognostic Index (EPI) for patients <or=60 years with acute myeloid leukaemia in first relapse, a cohort of 599 such patients, treated between 1980 and 2004 at the MD Anderson Cancer Center, were assessed using this prognostic index. Three risk groups were defined: favourable, 76 patients (13%) [Overall survival (OS), 64% at 1 year, 22% at 5 years]; intermediate, 137 patients (23%) (OS, 38% at 1 year, 12% at 5 years); and poor, 386 patients (64%) (OS, 17% at 1 year 6% at 5 years). The EPI is reproducible and useful.

Acute Disease↗
PubMed2006

Novel purine nucleoside analogues for T-cell-lineage acute lymphoblastic leukaemia and lymphoma.

Purine nucleoside phosphorylase (PNP) deficiency is a rare, inherited immunodeficiency disorder in which the specific molecular defect was identified. Clinically, a lack of PNP manifests as profound T-cell deficiency with minor or variable changes in the humoral system. Biochemically, the absence of PNP results in an increase in plasma deoxyguanosine (dGuo) and a T-cell-specific increase in intracellular deoxyguanosine triphosphate (dGTP). This observation has been the impetus for the search for either inhibitors of the enzyme or PNP-resistant dGuo analogues as potential anti-T-cell-lineage agents over the past 30 years. Forodesine (an inhibitor of PNP) and nelarabine (a PNP-resistant dGuo analogue) proved to be T-cell selective when tested in clinic. This review summarises the preclinical, clinical and pharmacokinetic investigations with these novel agents.

Adult↗
PubMed2005

The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

AG-013736 is an oral anti-angiogenesis agent with activity against a variety of receptor tyrosine kinases, including VEGFR-1, VEGFR-2, VEGFR-3, c-kit, and PDGFR-beta. A phase 2 study was conducted in patients with poor prognosis AML or MDS. Twelve patients (six AML; six MDS) were treated with AG-013736 at a dose of 10mg orally daily for a median of 56 days (range, 1-248 days). Median age was 80 years (range, 58-88 years). Grade 3 or 4 drug-related toxicities included hypertension (42%), mucositis (8%) and deep venous thrombosis (8%). No objective responses occurred; two patients with MDS had stable disease for 8.3 and 6.2 months, respectively. Bone marrow expression of VEGFR-1 and VEGFR-2 was observed in 11% and 0% of patients, respectively. Sustained decreases in soluble VEGFR-2 plasma levels with concomitant elevation in plasma VEGF and placental growth factor levels were obtained during the course of therapy with AG-013736. AG-01736 had minimal biologic or clinical activity in this elderly patient population.

Acute Disease↗
PubMed2005

Mature T-cell leukemias.

Mature T-cell and NK-cell leukemias are a group of relatively uncommon neoplasms derived from mature or postthymic T-cells accounting for a relatively small percentage of lymphoid malignancies. The recent availability of modern immunophenotypic and molecular tools has allowed a better distinction of these disorders from their B-cell counterparts. Similarly, identification of recurrent cytogenetic abnormalities, as well as plausible mechanisms through which these molecular events influence cellular signaling pathways, have created further insight into the pathogenesis of these disorders. Furthermore, the availability of new agents such as alemtuzumab has generated significant interest in devising specific therapeutic strategies for these malignancies. Herein, we review the clinical and pathological features of mature T-cell leukemias.

Adult↗
PubMed2005

Phase I study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, combined with cytarabine in patients with refractory leukemia.

PURPOSE: Cloretazine (VNP40101M) is a novel sulfonylhydrazine alkylating agent with significant antileukemia activity. A phase I study of cloretazine combined with cytarabine (1-beta-d-arabinofuranosylcytosine, ara-C) was conducted in patients with refractory disease. DESIGN: Ara-C was given i.v. at a fixed dose of 1.5 gm/m(2)/d by continuous infusion for 4 days (patients ages <65 years at time of diagnosis) or 3 days (patients ages > or =65 years). Cloretazine was given i.v. over 15 to 60 minutes on day 2 at a starting dose of 200 mg/m(2), with escalation in 100 mg/m(2) increments in cohorts of three to six patients until a maximum tolerated dose was established. The DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT) was measured at baseline. RESULTS: Forty patients, including 32 with acute myeloid leukemia, received 47 courses of treatment. Complete responses were seen at cloretazine dose levels of > or =400 mg/m(2) in 10 of 37 (27%) evaluable patients, and in this patient subset, AGT activity was significantly lower in patients that responded to treatment than in patients who did not (P < or = 0.027). Dose-limiting toxicities (gastrointestinal and myelosuppression) were seen with 500 and 600 mg/m(2) of cloretazine combined with the 4-day ara-C schedule but not seen with the 3-day schedule. CONCLUSION: The recommended cloretazine dose schedule for future studies is 600 mg/m(2) combined with 1.5 gm/m(2)/d continuous infusion of ara-C for 3 days. The cloretazine and ara-C regimen has significant antileukemic activity. AGT activity may be a predictor of response to cloretazine.

Adult↗
PubMed2005

Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center.

To characterize acute megakaryocytic leukemia (FAB M7 AML), we identified 37 patients with M7 AML treated at M.D. Anderson Cancer Center between 1987 and 2003 and compared them with 1800 patients with non-M7, non-M3 AML treated during the same period. The median age of the M7 AML group was 56 years (range, 21-78 years); 22 patients (59%) had an antecedent hematologic disorder or myelodysplastic syndrome or both, and 7 patients (19%) had previously received chemotherapy for other malignancies. Extensive bone marrow fibrosis was found in 23 patients (62%). Poor cytogenetic characteristics were observed in 49% of patients with M7 AML versus 33% of others (P < .001). Complete remission rates were 43% with M7 AML and 57% with non-M7 AML (P = .089). Median overall survival (OS) was 23 and 38 weeks, respectively (P = .006). Median disease-free survivals were 23 versus 52 weeks, respectively (P < .001). By multivariate analysis, M7 AML was an independent adverse prognostic factor for OS, independent of other factors including cytogenetic abnormalities (hazard ratio 1.51, P = .049). These results confirm the poor prognosis of M7 AML and indicate that other biologic characteristics beyond cytogenetic abnormalities likely play a role in this disease.

Adult↗
PubMed2005

Immune defects in patients with chronic lymphocytic leukemia.

Over the past decade, the introduction of nucleoside analogs and monoclonal antibodies into the treatment of patients with chronic lymphocytic leukemia (CLL) has resulted in higher rates and longer duration of response. This is a significant step towards achieving the ultimate goal of disease-eradication and improved survival. A continuing problem, however, is the susceptibility of these patients to infections. Profound dysregulation of the host immune system in patients with CLL and its impact on the clinical course of the disease are well established. A number of investigators have sought to identify the mechanisms underlying this innate immune dysfunction, which is further exacerbated by the actions of the potent therapeutic agents. The early recognition of infections as well as prophylactic administration of appropriate antibiotics has been the mainstay of managing infections in patients with CLL. Hopefully, increasing understanding of the molecular events underlying the neoplastic change in CLL will lead to more targeted and less immunosuppressive therapeutic modalities. Furthermore, the understanding of the mechanisms of immune dysfunction in CLL is of pivotal importance in the novel immune-based therapeutic strategies currently under development.

Anti-Bacterial Agents↗
PubMed2005

Infections associated with purine analogs and monoclonal antibodies.

Nucleoside analogs and monoclonal antibodies are commonly used to treat lymphoproliferative disorders and have become established as the treatment of choice in chronic lymphocytic leukemia, hairy cell leukemia, and follicular lymphomas, as well as a number of other malignant lymphoid neoplasms. When used in standard doses, these agents have a low incidence of extramedullary side effects resulting in their inclusion in a number of combination regimens. The most important complications associated with these drugs are myelosuppression, immunosuppression and infections. This is further accentuated when they are used in combination with other drugs such as alkylating agents. Several investigators have attempted to delineate the risk factors predicting the risk of infections associated with these agents. Furthermore, risk-based strategies to decrease the incidence of these infectious complications have been proposed.

Antibodies, Monoclonal↗