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Biomedical subjects

M Dhodapkar

Publications and source records attributed to M Dhodapkar.

13 recordsLinked to original sources
PubMed2001

Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine.

Immunization to multiple defined tumor antigens for specific immune therapy of human cancer has thus far proven difficult. Eighteen HLA A*0201(+) patients with metastatic melanoma received injections s.c. of CD34(+)progenitor-derived autologous dendritic cells (DCs), which included Langerhans cells. DCs were pulsed with peptides derived from four melanoma antigens [(MelAgs) MelanA/MART-1, tyrosinase, MAGE-3, and gp100], as well as influenza matrix peptide (Flu-MP) and keyhole limpet hemocyanin (KLH) as control antigens. Overall immunological effects were assessed by comparing response profiles using marginal likelihood scores. DC injections were well tolerated except for progressive vitiligo in two patients. DCs induced an immune response to control antigens (KLH, Flu-MP) in 16 of 18 patients. An enhanced immune response to one or more MelAgs was seen in these same 16 patients, including 10 patients who responded to >2 MelAgs. The two patients failing to respond to both control and tumor antigens experienced rapid tumor progression. Of 17 patients with evaluable disease, 6 of 7 patients with immunity to two or less MelAgs had progressive disease 10 weeks after study entry, in contrast to tumor progression in only 1 of 10 patients with immunity to >2 MelAgs. Regression of >1 tumor metastases were observed in seven of these patients. The overall immunity to MelAgs after DC vaccination is associated with clinical outcome (P = 0.015).

Adult↗
PubMed2000

Melphalan plus total body irradiation (MEL-TBI) or cyclophosphamide (MEL-CY) as a conditioning regimen with second autotransplant in responding patients with myeloma is inferior compared to historical controls receiving tandem transplants with melphalan alone.

The role of more intense conditioning for second transplant was evaluated in myeloma patients achieving at least partial remission (PR) after first transplant with melphalan at 200 mg/m2. Forty-three patients received more intensive conditioning for the second transplant. Nineteen patients received cyclophosphamide 120 mg/kg along with melphalan 200 g/m2 (MEL-CY; group 1) while 24 patients received total body irradiation (1125 cGy) in conjunction with melphalan 140 mg/m2 (MEL-TBI; group 2). Forty-three matched control patients were identified from 450 patients receiving melphalan alone for second transplant (MEL200; group 3). Engraftment and toxicities were comparable among the groups with the exception of increased treatment-related mortality of 8% in group 2 compared to none in groups 1 and 3 (P = 0.07). Despite identical CR rates of 74, 71 and 70%, respectively, in groups 1, 2 and 3 (P = 1.0), event-free survival (median: 27, 15 and 61; P < 0.0001) and overall survival (median: 39, 25 and 76 months; P = 0.003) were significantly decreased in patients receiving more intensive conditioning (groups 1 and 2). Lymphocyte recovery, evaluated as a surrogate for immune recovery, was inferior in more intensively treated patients (groups 1 and 2 compared to group 3). Our findings suggest that more intense conditioning appears to have no benefit in patients responding to their first cycle of high-dose therapy and may even be detrimental in this setting. Bone Marrow Transplantation (2000) 25, 483-487.

Antigens, CD34↗
PubMed1999

Antitumor activity of thalidomide in refractory multiple myeloma.

BACKGROUND: Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease. METHODS: Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by 200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks. RESULTS: The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone marrow did not change significantly in patients with a response. At least one third of the patients had mild or moderate constipation, weakness or fatigue, or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare. As of the most recent follow-up, 36 patients had died (30 with no response and 6 with a response). After 12 months of follow-up, Kaplan-Meier estimates of the mean (+/-SE) rates of event-free survival and overall survival for all patients were 22+/-5 percent and 58+/-5 percent, respectively. CONCLUSIONS: Thalidomide is active against advanced myeloma. It can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy.

Angiogenesis Inhibitors↗
PubMed1999

High-dose therapy with autologous haemopoietic stem cell support for Waldenström's macroglobulinaemia.

Standard doses of alkylating agents or purine analogues effect response rates of up to 50% in Waldenström's macroglobulinaemia (WM); however, complete responses are infrequent and there are no cures. We have evaluated the feasibility, safety and efficacy of high-dose chemotherapy with peripheral blood stem cell support in six patients aged 45-69 years (median 51.5) with WM; four patients relapsed after prior therapy inclusive of purine analogues and two patients proceeded with transplant after minimal therapy. Four patients mobilized adequate numbers of stem cells; however, two patients with more extensive fludarabine therapy failed to mobilize and required a second attempt at stem cell collection. Five patients were treated with melphalan 200 mg/m2, including one patient who received tandem transplants and one patient who received melphalan 140 mg/m2 with added total body irradiation (TBI). There was no treatment-related mortality and non-haematological toxicities were manageable. Engraftment was prompt except in one patient with extensive prior use of fludarabine. All the six patients achieved at least partial response (PR), including one who achieved complete response (CR). Five patients are alive and four are event-free at 52+, 15+, 12+ and 2+ months post transplant. This pilot study suggests safety and efficacy of high-dose therapy in WM and suggests that the peripheral blood stem cells should preferably be procured prior to extensive use of purine analogues.

Aged↗
PubMed1998

Nervous system dysfunction in Waldenström's macroglobulinemia: response to treatment.

A patient presented with a peripheral neuropathy and was found to have Waldenstrom's macroglobulinemia with high serum titers of antibodies to myelin-associated glycoprotein. He developed parkinsonism that was poorly responsive to levodopa. He failed conventional therapy and was treated with autologous bone marrow transplantation, which resulted in improvement of the neuropathy but not his parkinsonism. Critical cytoreduction in the B-cell clone may be necessary for improvement of the neuropathy of Waldenstrom's macroglobulinemia.

Antibodies, Monoclonal↗
PubMed1997

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer.

Temozolomide (TMZ) is a new imidazotetrazine derivative with early clinical activity in glioma and melanoma. The purpose of this Phase I study is to characterize the toxicity, pharmacokinetics, and antitumor activity of TMZ administered on an oral 5-day schedule to patients with or without prior exposure to nitrosourea (NU). Thirty-six eligible patients received a total of 77 cycles of therapy with TMZ administered p.o. at doses ranging from 50 mg/m2/day to 250 mg/m2/day for 5 days, every 4 weeks. Separate dose escalations were carried out in patients, with or without prior exposure to NU. Pharmacokinetic studies were performed during the first cycle of treatment on days 1 and 5. Dose-limiting toxicity was thrombocytopenia, and the maximally tolerated doses for patients with and without prior exposure to NU were 150 mg/m2/day for 5 days (total dose, 750 mg/m2) and 250 mg/m2/day for 5 days (total dose, 1250 mg/m2), respectively. Significant (grade 3 or higher) thrombocytopenia was observed in six patients during cycle 1. The median times to nadir and recovery were 17 and 15 days, respectively. Nonhematological toxicity was generally manageable and consisted of fatigue, nausea, and vomiting. There were two complete responses (one glioma and one melanoma) in patients without prior NU. No objective responses were seen in patients with prior NU treatment. Pharmacokinetic studies showed rapid absorption with a mean time to peak concentration of 60 min and mean t1/2 of 109 min (range, 80-121 min). The area under the curve and the peak plasma concentrations were linear over the dose range of 50-250 mg/m2/day. The mean apparent oral clearances on day 1 for patients with and without prior NU exposure were 102+/- 27 and 115+/- 22 ml/min/m2, respectively. Apparent oral clearances on days 1 and 5 were found to differ with respect to NU exposure (P = 0.047). Renal clearance of the parent drug and its metabolism to 3-methyl-2, 3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxylic acid were minor pathways of TMZ elimination. We conclude that TMZ is well tolerated in this oral 5-day schedule with dose-limiting thrombocytopenia and that it has promising activity in glioma and melanoma. The recommended doses for Phase II studies in patients with and without prior NU are 125 mg/m2/day for 5 days and 225 mg/m2/day for 5 days, respectively.

Administration, Oral↗
PubMed1995

Abnormal regional hypermethylation of the calcitonin gene in myelodysplastic syndromes.

Abnormal regional hypermethylation of the calcitonin gene can be detected in up to 95% of patients with acute nonlymphocytic leukemia (ANLL). We used a polymerase chain reaction (PCR) based assay to detect abnormal regional hypermethylation at this locus in patients with primary myelodysplastic syndromes (MDS). Hypermethylation was detected in 13 of 20 patients (65%) with MDS and was detected in nine patients with MDS and normal cytogenetics. There was no correlation between detection of this abnormality and the subtype of MDS. Four of the 13 patients (30%) with abnormal methylation have progressed to ANLL with a median time to progression of 3.5 months. The actuarial median survival of the cohort with abnormal methylation was 17 months, while that of the cohort with normal methylation is not yet reached. These preliminary findings suggest that detection of abnormal methylation at this locus may be useful as a diagnostic tool in MDS. Furthermore, hypermethylation of the calcitonin gene may be a poor prognostic feature that predicts progression to acute leukemia in patients with primary MDS.

Aged↗
PubMed1994

Reversible encephalopathy after cryopreserved peripheral blood stem cell infusion.

We report two patients who experienced severe reversible encephalopathy following infusion of peripheral blood stem cells cryopreserved in 10% dimethylsulfoxide (DMSO). In one patient, reduction of DMSO level with plasmapheresis resulted in marked improvement in encephalopathy. Infusion of large volumes of cryopreserved stem cells may result in a significant toxic reaction. Plasmapheresis may be a treatment option for patients with significant toxicity related to DMSO.

Brain Diseases↗
PubMed1994

Regular use of a verbal pain scale improves the understanding of oncology inpatient pain intensity.

PURPOSE: This study was undertaken to determine if the daily use of a verbal pain scale could improve the correlation of pain perception between hospitalized oncology patients and their caregivers. PATIENTS AND METHODS: Hospitalized oncology patients were asked to rate verbally their average pain over the past 24 hours on a scale ranging from 0 to 10. The patients' primary-care physicians and nurses were asked the same question on the same morning after they had evaluated their patients. RESULTS: During a baseline study, only 64% of caregivers' pain scores were within two points of the respective patient's score. Caregivers tended to underestimate patients' pain scores. Caregivers were alerted to these poor results and then requested to ask each patient daily for the average pain score and record this score on the patient's medical record. Nonetheless, correlation between patients' and caregivers' pain scores remained poor (68% within two points of each other) during a second study. The major reason for the poor results appeared to be because caregivers did not routinely ask patients for pain scores. Subsequently, a renewed, more intensive educational effort was undertaken and a third study was conducted. During the third study, 85% of caregivers' and patients' pain scores were within two points of each other (P = .001 when compared with baseline). CONCLUSION: The enforced use of a simple verbal pain assessment tool appears to improve caregiver's understanding of the pain status of hospitalized oncology patients.

Caregivers↗
PubMed1993

Prognostic features and survival in young adults with early/intermediate chronic lymphocytic leukemia (B-CLL): a single institution study.

Information regarding natural history and prognostic factors for early/intermediate B-cell chronic lymphocytic leukemia (B-CLL) in young adults is limited. We analysed 62 young adults (< or = 50 years old) with early/intermediate B-CLL who were seen at our institution during initial diagnosis over a 15-year period. These patients had been followed for a median duration of 7 years. Median age for the entire group was 44 years and 72% were > or = 40 years old. Actuarial median survival from initial diagnosis for the entire group was 140 months. Upon univariate analysis, significant survival advantage was observed in patients with Rai stages 0 and 1 versus stage II disease (median survival 140 versus 60 months, p = 0.01) and in those with lymphocyte doubling time (LDT) of > 1 year versus < or = 1 year (median survival 150+ versus 94 months, p = 0.06). Similarly there was a trend towards longer survival in patients with a leucocyte count of < or = 50,000/microliters when compared to those with higher counts although the difference was not statistically significant. The bone marrow infiltration pattern was not prognostically useful. Upon multivariate analysis, only Rai stage and LDT were prognostically useful. Patients who did not respond to initial therapy with alkylating agents had the worst prognosis, with a median survival of only 19 months. Assessment of presenting clinical stage, LDT, and degree of initial treatment response may prompt earlier consideration of alternative therapeutic modalities such as purine nucleoside analogs or bone marrow transplantation in younger patients with early/intermediate B-CLL.

Adolescent↗