Bortezomib may be safely combined with Y-90-ibritumomab tiuxetan in patients with relapsed/refractory follicular non-Hodgkin lymphoma: a phase I trial of combined induction therapy and bortezomib consolidation.

Preclinical studies suggest that bortezomib, through inhibition of nuclear factor-κB (NF-κB) activation, may enhance the effects of radioimmunotherapy. This phase I trial was designed to determine the maximum tolerated dose (MTD) of weekly bortezomib induction combined with Y-90-ibritumomab tiuxetan followed at the time of count recovery by weekly bortezomib consolidation in patients with relapsed/refractory follicular or transformed non-Hodgkin lymphoma. Grade 3 or 4 toxicities were observed in eight of nine treated patients, and all but one of these toxicities were hematologic. One patient had grade 3 cardiotoxicity. A dose limiting toxicity (DLT) of grade 4 thrombocytopenia was observed in two of three patients treated with bortezomib at 1.6 mg/m(2), resulting in a MTD of 1.3 mg/m(2). The overall response rate was 89% (two complete response [CR], six partial response [PR], one stable disease [SD]), with a median progression-free survival of 6.5 months (range: 3-22.5+ months). A phase II trial at the MTD is under way to better define the toxicity and effectiveness of this regimen.

Multiple myeloma presenting with high-output heart failure and improving with anti-angiogenesis therapy: two case reports and a review of the literature.

INTRODUCTION: Common manifestations of multiple myeloma include osteolytic lesions, cytopenias, hypercalcemia, and renal insufficiency. Patients may also exhibit heart failure which is often associated with either past therapy or cardiac amyloidosis. A less recognized mechanism is high-output heart failure. Diuretic therapy in this setting has little efficacy in treating the congested state. Furthermore, effective pharmacotherapy has not been established. We report two patients with multiple myeloma and high-output heart failure who failed diuretic therapy. The patients were given dexamethasone in conjunction with lenalidomide and thalidomide, respectively. Shortly thereafter, each patient demonstrated a significant improvement in symptoms. This is the first report of successful treatment of multiple myeloma-induced high-output failure via the utilization of these agents. CASE PRESENTATION: Two patients with multiple myeloma were evaluated for volume overload. The first was a 50-year-old man with refractory disease. Magnetic resonance imaging demonstrated diffuse marrow replacement throughout the pelvis. Cardiac catheterization conveyed elevated filling pressures and a cardiac output of 15 liters/minute. He quickly decompensated and required mechanical ventilation. The second patient was a 61-year-old man recently diagnosed with multiple myeloma and volume overload. Skeletal survey demonstrated numerous lytic lesions throughout the pelvis. His cardiac catheterization also conveyed elevated filling pressures and a cardiac output of 10 liters/minute. Neither patient responded to diuretic therapy and they were subsequently started on dexamethasone plus lenalidomide and thalidomide, respectively. The first patient's brisk diuresis allowed for extubation within 48 hours after the first dose. He had a net negative fluid balance of 15 liters over 10 days. The second patient also quickly diuresed and on repeat cardiac catheterization, his cardiac output had normalized to 4.7 liters/minute. CONCLUSION: Multiple myeloma can cause high-output failure. The mechanism is likely extensive bony involvement causing innumerable intramedullary arteriovenous fistulas. Diuretic therapy is not effective in treating this condition. Lenalidomide and thalidomide, both of which inhibit angiogenesis, seem to be viable treatment options. Based on the rapid and effective results seen in these two patients, a potential novel mechanism of 'pharmacologic fistula ligation' with these agents may be the most effective way to treat this presentation.

Bevacizumab in the treatment of colorectal cancer.

Colorectal cancer is a common disease with therapy that has a proven effectiveness in the adjuvant and metastatic setting. Bevacizumab, a vascular endothelial growth factor inhibitor, is an antiangiogenesis monoclonal antibody that has benefit in response rate and overall survival when used in combination with existing metastatic colorectal cancer regimens. It is well tolerated with a few important side effects to be cognizant of, including hypertension, arterial thrombosis and bowel perforation. Existing treatment and research strategies are examining its use in the adjuvant setting or in combination with other angiogenesis inhibitors.

G-CSF is not necessary to maintain over 99% dose-intensity with ABVD in the treatment of Hodgkin lymphoma: low toxicity and excellent outcomes in a 10-year analysis.

Dose-intensity of chemotherapy is important in the treatment of Hodgkin lymphoma (HL) and granulocyte-colony stimulating factor (G-CSF) is commonly used to maintain it. We reviewed all newly diagnosed HL patients who were treated at our institution between 1996 and 2005. Fifty-nine patients received adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy with no dose reductions, treatment delays, and without G-CSF, regardless of absolute neutrophil count (ANC). The median ANC on all ABVD treatment days (n = 658) was 0.925 x 10(9)/l, and was <0.5 x 10(9)/l on 26% of treatment days. Median normalised ABVD dose-intensity was 99.1% (range, 93-100%) and median cycle duration was 28.2 d. Incidence of bleomycin lung toxicity was 1.6%, 0.44% treatments were complicated by febrile neutropenia, and no secondary malignancies have occurred (median follow-up 48 months; range, 11-130 months). Five-year event-free (EFS) and overall survival (OS) were 92.9% and 97.4% respectively. Furthermore, the 5-year EFS and OS (87.4% and 94.1% respectively) for advanced stage patients compared favourably with a similar ABVD patient group who received routine prophylactic G-CSF (n = 23) with EFS 80.0% and OS 91.3% (P = 0.46 and 0.67 respectively). Our experience suggests that ABVD may be safely and effectively administered at >99% dose-intensity without G-CSF support, regardless of the ANC.

Radioimmunotherapeutic strategies in autologous hematopoietic stem-cell transplantation for malignant lymphoma.

High-dose therapy followed by autologous hematopoietic stem-cell transplantation is the preferred therapy for relapsed chemotherapy-sensitive aggressive non-Hodgkin lymphoma, and may play a role in the treatment of high-risk first-remission aggressive lymphomas, mantle-cell lymphomas and relapsed follicular lymphomas. The primary cause of failure of this approach is disease recurrence despite initial responses. Traditional high-dose regimens have relied upon myeloablative combinations of chemotherapy with or without total body irradiation. In the Western world, over 90% of lymphomas are of B-cell origin, and the vast majority of those that come to transplant remain CD20-positive. The development of radioimmunotherapeutic approaches targeting this antigen allows for either dose escalation with stem-cell support, or the addition of targeted therapy to conditioning regimens either as a replacement for total body irradiation or in addition to myeloablative chemotherapy regimens. Results to date with yttrium-90 ibritumomab tiuxetan (Zevalin) and I-131 tositumomab (Bexxar) suggest that the addition of radioimmunoconjugate therapy to conventional conditioning regimens results in a toxicity profile similar to that seen with chemotherapy conditioning alone. Demonstration of improved disease control will ultimately require phase-III studies, though preliminary results are promising.

Adjuvant therapy for colon cancer.

Colon cancer is a leading cause of cancer and cancer deaths in Western countries. Although 5-fluorouracil is still the basis of adjuvant therapy, advances in drug development have led to increased efficacy with the addition of oxaliplatin and options for oral therapy with capecitabine. The benefit of adjuvant therapy for stage II disease is consistently small and not statistically significant. Future studies will evaluate the role of the biologic agents that have proved to be effective in metastatic disease and better delineate the population at risk by identifying prognostic and predictive markers.

Radioimmunotherapy and autologous stem cell transplantation for the treatment of B-cell lymphomas.

Relapse continues to be the primary cause of treatment failure in patients with non-Hodgkin's lymphomas (NHL) undergoing high-dose therapy and autologous stem cell transplantation. The anti-CD20 radioimmunoconjugates, Y-90 ibritumomab tiuxetan (Zevalin; Biogen Idec, Inc., Cambridge, MA, USA) and I-131 tositumomab (Bexxar; Corixa, Seattle, WA; and Glaxo Smith Kline; Philadelphia, PA, USA) have been associated with high response rates, durable remissions and limited toxicity apart from myelosuppression, making them ideal candidates for use in autotransplantation. Tested first as single agents in relapsed patients with indolent and transformed NHL, and then at much higher doses with stem cell support, these agents have now been combined with high-dose chemotherapy prior to autologous stem cell transplant. Radioimmunoconjugates have been used to replace total body irradiation (TBI) in some studies and to augment standard chemotherapy regimens in others. Thus far the results are promising, with combinations of radioimmunoconjugates and chemotherapy producing long-lasting responses in high-risk patients with no more toxicity than that caused by standard conditioning regimens. These results are notable in light of the fact that the dose of radiation delivered to the tumor is 10-fold higher than the dose achievable with TBI. Whether this increase in radiation dose to the targeted lymphoma translates into more durable remissions and an improvement in overall survival requires further investigation.

Definition of myeloid engraftment after allogeneic hematopoietic stem cell transplantation.

Neutrophil counts continued to rise after reaching 0.5x10(9)/L in 78 allograft recipients receiving granulocyte colony-stimulating factor (G-CSF) post-transplant. This was confirmed in 44 subsequent patients not receiving G-CSF. This suggests that the first day of neutrophils >or=0.5x10(9)/L can be considered a valid definition of myeloid recovery after allogeneic transplantation.