Roy, Vivek

AbstractThe objective of this case-control study was to compare the efficacy and toxicity of lenalidomide plus dexamethasone (len/dex) versus thalidomide plus dexamethasone (thal/dex) as initial therapy for newly diagnosed myeloma. We retrospectively studied 411 newly diagnosed patients treated with len/dex (228) or thal/dex (183) at the Mayo Clinic. The differences were similar in a matched-pair analysis that adjusted for age, sex, transplantation status, and dexamethasone dose. The proportions of patients achieving at least a partial response to len/dex and thal/dex were 80.3% versus 61.2%, respectively (P < .001); very good partial response rates were 34.2% and 12.0%, respectively (P < .001). Patients receiving len/dex had longer time to progression (median, 27.4 vs 17.2 months; P = .019), progression-free survival (median, 26.7 vs 17.1 months; P = .036), and overall survival (median not reached vs 57.2 months; P = .018). A similar proportion of patients in the 2 groups experienced at least one grade 3 or 4 adverse event (57.5% vs 54.6%, P = .568). Main grade 3 or 4 toxicities of len/dex were hematologic, mainly neutropenia (14.6% vs 0.6%, P < .001); the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, P = .058) and peripheral neuropathy (10.4% vs 0.9%, P < .001). Len/dex appears well-tolerated and more effective than thal/dex. Randomized trials are needed to confirm these results.

Purpose. Oral mucositis is a serious problem that affects a significant number of hematopoietic cell transplant (HCT) patients. There are many gaps in management, and evidence-based guidelines do not provide consistent recommendations. The purpose of this pilot study was to develop a mucositis oral care protocol for the prevention and management of mucositis in the HCT patient and to evaluate the clinical impact of its implementation. Methods. After receipt of Institutional Review Board approval, all patients admitted to the Hematology—Oncology service for high-dose chemotherapy followed by an autologous or allogeneic HCT were eligible for the study. As part of a change in practice, a new mucositis protocol consisting of a specific oral care regimen was instituted for prevention and treatment of mucositis. Assessment of mucositis began upon admission to the hospital and the patient was evaluated using a mucositis grading scale on a daily basis by the physician and nursing staff. The new mucositis protocol was a part of the HCT service admission orders for each patient. The group of patients treated according to the new mucositis protocol were compared with a retrospective control group consisting of patients who had undergone management of oral mucositis under the previous standard of care. The primary endpoints were to evaluate incidence, severity, and duration of oral mucositis. Secondary endpoints included days requiring narcotics; days of parenteral nutrition, febrile neutropenia, antimicrobial therapy, and length of hospital stay. Results. There were 13 patients enrolled in the control group and 12 patients in the new protocol group. The new protocol resulted in a decreased incidence (100% vs. 75%) and duration (19.2 vs. 8.3 days) of mucositis. Days of maximum grade one and three mucositis were decreased by 56%, and 70%, respectively. Days of maximum grade two mucositis, however increased by 22%. The days of narcotic use were reduced by 19% in the new protocol group (15.8 vs. 12.8 days). All patients in the new protocol group required parenteral nutrition, but days of use were reduced by 41% (17 vs. 10.2 days). The incidence of infection measured by days of febrile neutropenia and antimicrobial therapy were reduced by 35% (10.2 vs. 6.5 days) and 33% (17 vs. 11.4 days). Finally, the overall length of hospital stay was reduced by 7 days (30 vs. 23 days). Conclusion. Implementation of a standardized oral care protocol for mucositis management resulted in a decreased incidence, duration and severity of mucositis, and also reduced the global negative impact of mucositis. Future studies may further evaluate the global impact by adjusting for confounding factors. J Oncol Pharm Practice (2010) 16: 195—204.

AbstractLearning ObjectivesAfter completing this course, the reader will be able to: Describe the potential therapeutic advantages of tyrosine kinase inhibitors (TKIs) over antibody mediated inhibition with trastuzumab, such as oral bioavailability and ability to cross the blood–brain barrier.Explain the ability of TKIs to overcome resistance to and synergize with trastuzumab.Discuss the multiple tyrosine kinase inhibitors currently in development and their spectrum of targets and toxicities.This article is available for continuing medical education credit at CME.TheOncologist.com.HER-2 is a transmembrane, tyrosine kinase (TK) receptor whose overexpression is associated with adverse prognosis in breast cancer. The biological effects of HER-2 are mediated by kinase activity causing phosphorylation of tyrosine residues in the cytoplasmic domain of the receptor molecule, leading to activation of downstream growth-promoting pathways. Antibody-mediated inhibition by trastuzumab as well as TK inhibition are clinically effective anti–HER-2 strategies. Kinase inhibitors offer some potential therapeutic advantages over antibody-based therapies. Being small molecules, TK inhibitors (TKIs) have oral bioavailability and ability to cross the blood–brain barrier. Because of their different mode of action, TKIs may be able to overcome some of the mechanisms of trastuzumab resistance. Preclinical, and limited clinical data also suggest that TKIs and trastuzumab have synergistic activity. Lapatinib is the only TKI available for clinical use at present, but several molecules with anti–HER-2 activity have been identified and are undergoing evaluation. These differ in the spectrum of kinases that they inhibit, potency of HER-2 inhibition, pharmacokinetic properties, and toxicity profiles, and are at various stages of clinical development. In this article we summarize selected HER-2 TKIs approved for clinical use or in development for which clinical data are available.

Purpose Thalidomide and lenalidomide are immunomodulatory drugs (IMiDs) that produce high remission rates in the treatment of multiple myeloma. Pomalidomide is a new IMiD with high in vitro potency. We report, to our knowledge, the first phase II trial of pomalidomide administered in combination with low-dose dexamethasone for the treatment of relapsed or refractory multiple myeloma. Patients and Methods Pomalidomide was administered orally at a dose of 2 mg daily on days 1 through 28 of a 28-day cycle. Dexamethasone 40 mg daily was administered orally on days 1, 8, 15, and 22 of each cycle. Responses were recorded using the criteria of the International Myeloma Working Group. Results Sixty patients were enrolled. Thirty-eight patients (63%) achieved confirmed response including complete response in three patients (5%), very good partial response in 17 patients (28%), and partial response in 18 patients (30%). Responses were seen in 40% of lenalidomide-refractory patients, 37% of thalidomide-refractory patients, and 60% of bortezomib-refractory patients. Responses were seen in 74% of patients with high-risk cytogenetic or molecular markers. Toxicity consisted primarily of myelosuppression. Grade 3 or 4 hematologic toxicity consisted of anemia (5%), thrombocytopenia (3%), and neutropenia (32%). One patient (1.6%) had a thromboembolic event. The median progression-free survival time was 11.6 months and was not significantly different in patients with high-risk disease compared with patients with standard-risk disease. Conclusion The combination of pomalidomide and low-dose dexamethasone is extremely active in the treatment of relapsed multiple myeloma, including high response rates in patients refractory to other novel agents.

Abstract The outcome of patients with multiple myeloma is dictated primarily by cytogenetic abnormalities and proliferative capacity of plasma cells. We studied the outcome after initial therapy with lenalidomide-dexamethasone among 100 newly diagnosed patients, risk-stratified by genetic abnormalities and plasma cell labeling index. A total of 16% had high-risk multiple myeloma, defined by the presence of hypodiploidy, del(13q) by metaphase cytogenetics, del(17p), IgH translocations [t(4;14), or t(14;16)] or plasma cell labeling index more than or equal to 3%. Response rates were 81% vs 89% in the high-risk and standard-risk groups, respectively. The median progression-free survival was shorter in the high-risk group (18.5 vs 36.5 months, P < .001), but overall survival was comparable. Because of unavailability of all tests for every patient, we separately analyzed 55 stringently classified patients, and the results were similar. In conclusion, high-risk patients achieve less durable responses with lenalidomide-dexamethasone compared with standard-risk patients; no significant differences in overall survival are apparent so far. These results need confirmation in larger, prospectively designed studies.

Purpose To determine the role of myeloablative conditioning and unrelated donor (URD) bone marrow transplantation in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (CLL). Patients and Methods A total of 38 CLL patients received a matched URD transplant using bone marrow procured by the National Marrow Donor Program. The median age was 45 years (range, 26 to 57 years), the median time from diagnosis was 51 months, and the median number of prior chemotherapy regimens was three. Fifty-five percent of patients were chemotherapy refractory and 89% had received fludarabine. Conditioning included total-body irradiation in 92% of patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate with cyclosporine or tacrolimus for 82% of patients. Results Twenty-one patients (58%) achieved complete response and six (17%) achieved partial response. Incidences of grades 2 to 4 acute GVHD were 45% at 100 days and incidences of chronic GVHD were 85% at 5 years. Eleven patients are alive and disease free at a median of 6 years (range, 3.0 to 9.0 years). Five-year overall survival, failure-free survival, disease progression rates, and treatment-related mortality (TRM) were 33%, 30%, 32%, and 38% respectively. Conclusion These data demonstrate that lasting remissions can be achieved after URD transplantation in patients with advanced CLL. High TRM suggest that myeloablative conditioning and HLA-mismatched donors should be avoided in future protocols, and it is mandatory to investigate transplant strategies with a lower morbidity and mortality, including the use of nonmyeloablative regimens.

Abstract POEMS syndrome is characterized by peripheral neuropathy (PN), a clonal plasma cell disorder (PCD), organomegaly, endocrinopathy, skin changes, edema, sclerotic bone lesions, and thrombocytosis. Based on the improved response rates observed with peripheral blood stem cell transplantation (PBSCT) in patients with other PCDs, autologous PBSCT may be an attractive treatment option for this syndrome. Sixteen patients with POEMS syndrome have undergone PBSCT at Mayo. Of these patients, 15 had a severe rapidly progressive sensorimotor PN (9 were wheelchair dependent) and 14 were male. Median age was 51 years (range, 19-62 years). The median number of prior therapies was 3 (range, 0-7). From first symptoms and from diagnosis of POEMS the times to transplantation were 42 months and 5 months (ranges, 8-185 months and 2-149 months), respectively. There were 15 patients who had significantly abnormal pretransplant pulmonary function tests. There was one transplant-related death. During the peritransplant period, 5 patients required intubation for respiratory compromise, including one who required intubation during his stem cell mobilization period. Another patient required noninvasive biphasic positive airway pressure throughout his course. Of the 14 evaluable patients, all have had neurologic improvement or stabilization. Other features have improved substantially. PBSCT for POEMS syndrome is effective therapy but may also be associated with significant morbidity. (Blood. 2004;104:3400-3407)