Gregory Bociek

Phase I Trial of Iodine-131 Tositumomab With High-Dose Chemotherapy and Autologous Stem-Cell Transplantation for Relapsed Non-Hodgkin's Lymphoma

PURPOSE To determine the maximum outpatient dose of iodine-131 tositumomab (up to 0.75 Gy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem-cell transplantation (ASCT) for the treatment of chemotherapy-resistant relapsed or refractory B-cell non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS Twenty-three patients with chemotherapy-refractory or multiply-relapsed B-cell NHL were treated in a phase I trial combining iodine-131 tositumomab (ranging from 0.30 to 0.75 Gy total-body dose [TBD]) with high-dose BEAM followed by ASCT. RESULTS The complete response rate after transplantation was 57%, and the overall response rate was 65%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 38 months (range, 27 to 60 months), the overall survival (OS) rate was 55%, and the event-free survival (EFS) rate was 39%. CONCLUSION There were no significant added toxicities apparent with the addition of iodine-131 tositumomab up to a dose of 0.75 Gy TBD to high-dose BEAM chemotherapy followed by ASCT. The EFS and OS were encouraging in this group of chemotherapy-resistant or refractory B-cell NHL patients. A follow-up phase II trial with iodine-131 tositumomab at the dose of 0.75 Gy TBD with BEAM is currently ongoing.

Autologous hematopoietic stem cell transplantation for mantle cell lymphoma

This study evaluated the outcomes of patients who underwent high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (autoHSCT) for mantle cell non-Hodgkins lymphoma and the effect of clinical and treatment characteristics. The clinical outcome and prognostic factors in 40 patients who underwent HDC and autoHSCT for mantle cell lymphoma between June 1991 and August 1998 were analyzed. With a median follow-up of 24 months for the surviving patients (range, 4-68 months), the 2-year overall survival was 65% and the 2-year event-free survival (EFS) was 36%. In univariate analysis, characteristics predictive of a poor EFS were blastic morphology (P = .019) and the patient having received 3 or more prior chemotherapy regimens (P = .004). In a multivariate analysis, the only factor associated with a poor EFS was the number of prior chemotherapy regimens. Those patients who received 3 or more prior therapies had a 2-year EFS of 0%, and those who received <3 therapies had a 2-year EFS of 45% (P = .004). Patients with mantle cell lymphoma can obtain prolonged EFS with HDC and autoHSCT; however, this strategy for prolonged EFS appears to work optimally in patients who are less heavily pretreated. Whether this therapy will increase the overall survival or EFS in patients receiving transplants in first complete remission will need to be tested in prospective randomized clinical trials.

Hodgkin’s Disease in the Elderly: Improved Treatment Outcome With a Doxorubicin-Containing Regimen

PURPOSE Hodgkins disease (HD) is a malignancy that displays a bimodal age distribution. Previous reports of treatment in patients greater-than-or-equal 60 years have found a poor outcome, particularly in patients with advanced disease. Because of an improved side-effect profile, the regimen of chlorambucil, vinblastine, procarbazine, and prednisone (ChlVPP) has been proposed for use in elderly patients. PATIENTS AND METHODS From September 1982 to May 1998, 262 patients with previously untreated HD received either ChlVPP (n = 176) or ChlVPP plus doxorubicin/bleomycin/vincristine (ChlVPP/ABV hybrid; n = 86). Fifty-six patients were greater-than-or-equal 60 years old, and 206 were younger than 60 years. RESULTS The 5-year overall survival (OS; 87% v 39%) and the 5-year event-free survival (EFS; 75% v 31%) favored patients younger than 60 years of age. Prognostic factors analyzed in patients greater-than-or-equal 60 years of age, other than type of therapy, included sex, stage, Karnofsky performance score, lactic dehydrogenase, number of extranodal sites, B symptoms, size of largest mass, and histologic subtype. In patients older than 60 years, none of the clinical features was a statistically significant predictor of EFS; however, ChlVPP/ABV hybrid was associated with a decreased risk of an event (relative risk, 0.40; 95% confidence interval, 0.19 to 0.83; P =.014) compared with ChlVPP. The 5-year OS for patients greater-than-or-equal 60 years who received ChlVPP was 30%, compared with 67% for those patients receiving the ChlVPP/ABV regimen (P =.0086) CONCLUSION Patients greater-than-or-equal 60 years with HD who require chemotherapy are better treated with ChlVPP/ABV hybrid than with ChlVPP alone.

Circulating CD20 and CD52 in patients with non-Hodgkin's lymphoma or Hodgkin's disease

Summary.  The cell surface proteins CD20 and CD52 differ significantly in their structures and are expressed on the majority of B cells. Both circulating CD20 (cCD20) and circulating CD52 (cCD52) have been recently documented in patients with chronic lymphocytic leukaemia. A retrospective study to establish whether cCD20 and/or cCD52 were detectable in patients with lymphoma, and the clinical associations of these soluble antigens if detected, was conducted. cCD20 and cCD52 levels were analysed in a cohort of 65 patients with non‐Hodgkins lymphoma (NHL) and 37 with Hodgkins disease (HD). Patients with NHL had elevated pretherapy levels of cCD20 and cCD52 compared with normal individuals. Patients with HD had significantly lower than normal pretherapy levels of both cCD20 and cCD52. cCD20 levels were marginally elevated post‐therapy in NHL patients while in patients with HD, cCD20 levels remained significantly lower than normal after therapy. Serum cCD52 levels became significantly lower than normal post‐therapy in NHL patients, and remained significantly lower than normal in HD patients. No predictive effects were found for pretherapy or post‐therapy levels of cCD52 on survival for either cohort of patients. Post‐therapy cCD20 levels independently highly correlated with survival in patients with NHL. Prospective evaluation will be required to establish if cCD20 and cCD52 may be used as biomarkers in the diagnosis, prognostic categorization, and monitoring of the clinical course in patients with lymphoma. The clinical significance of circulating antigen in patients receiving monoclonal antibody therapy directed against CD20 and/or CD52 warrants study.

Acute Coronary Syndromes Complicating the First Infusion of Rituximab

The aim of this study was to describe the occurrence of acute coronary syndromes in 3 cases of rituximab infusions. We reviewed the records of 3 patients with lymphoproliferative disorders who experienced acute coronary syndromes associated with their initial infusion of rituximab. All 3 patients received rituximab according to a standardized institutional rate schedule, and all received pre-medication with acetaminophen and diphenhydramine. The median age of patients was 61 years. One patient had known atherosclerotic heart disease, and 2 patients had risk factors for coronary artery disease. All patients had varying degrees of evidenced high tumor burden, including lymphocytosis, elevated lactate dehydrogenase values, bulky tumor masses, and bone marrow involvement by lymphoma. All 3 patients experienced fairly typical chest pain syndromes and experienced elevations of cardiac enzymes consistent with myocardial ischemia. One patient died of an arrhythmia that deteriorated into asystole, and 2 patients recovered and underwent coronary angiography. Acute coronary syndromes can be associated with the infusion of rituximab. Patients with a history of previous coronary artery disease or risk factors for coronary artery disease should be observed closely for signs of myocardial ischemia, particularly during the initial infusion. The occurrence of symptoms that could be ascribed to an acute coronary syndrome should always be taken seriously during the first rituximab infusion and investigated aggressively. Patients should be aware that this is a rare, albeit serious, complication of treatment with rituximab.

CNOP for diffuse aggressive non-Hodgkin's lymphoma: The Nebraska Lymphoma Study Group experience

The purpose of this study was to evaluate the CNOP regimen (cyclophosphamide, mitoxantrone, vincristine, and prednisone) throughout a community based oncology network with a large number of elderly non-Hodgkins lymphoma (NHL) patients. Three hundred and seventy-three previously untreated patients with diffuse aggressive NHL received the CNOP regimen administered through a community oncology network, the Nebraska Lymphoma Study Group (NLSG). The complete response rate was 60% with an overall response rate of 73%. The estimated 4-year event-free survival for patients <60 years was 44%, compared to 38% for those >age 60 (p =0.18). However, the 4-year estimated overall survival for patients <60 years was 62% compared to 44% for those >60 years (p <0.001). Prognostic factors predictive for a poor event-free survival were male gender, stage III/IV disease, Karnofsky score <80, and elevated lactic dehydrogenase (LDH). The lymphoma specific cumulative death rate was 29% for patients <60 years compared with 33% for patients >60 years (p =0.07). After failing CNOP the 4-year overall survival (OS) was 19%. The estimated 4-year OS for patients who failed CNOP and went on to receive high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplant (ASCT) was 64% for patients < age 60 and 48% for those >60 years (p =0.23). In conclusion, CNOP chemotherapy administered to patients with diffuse aggressive NHL in a community oncology network produces similar result to that reported for other anthracycline based regimens reported in the literature. Patients >age 60 had a higher rate of failure due to causes other than lymphoma which accounted for a worse survival long-term. However, patients of all ages who failed CNOP and who were able to receive HDC and ASCT demonstrated long-term disease survival after the transplant.

Diffuse large B cell lymphoma with mediastinal mass at presentation.

6585 Background: Primary mediastinal B cell lymphoma (PMBL) has been recognized as a subtype of diffuse large B cell lymphoma (DLBCL) with distinct characteristics (e.g.: seen most often in young females) and is thought to be of thymic origin. Other subtypes of DLBCL may involve the mediastinum and may be confused with PMBL. The value of radiotherapy in DLBCL with a mediastinal mass is debated. We conducted this retrospective analysis to study clinical characteristics and treatment outcomes in patients with DLBCL and a mediastinal mass at presentation. METHODS This is an analysis of 61 patients diagnosed with diffuse large B-cell lymphoma presenting with a mediastinal mass> 5 cms who received their initial treatment between June 1984 and October 2000. RESULTS The median age was 41 years and 50% were females. 66% presented with elevated LDH and 63% had limited stage disease (stage I and II). 46 % of the patients presented with mediastinal mass >10cms and 69% had B symptoms. 27% received adjuvant radiation therapy. All patients received anthracycline-containing chemotherapy. A complete remission was achieved in 62% and partial remission in 22% of the patients. The median follow-up of surviving patients is 7.6 years and the 5-year overall (OS) and event-free survival (EFS) is 55% and 38%, respectively. Older patients had significantly poorer OS (p = 0.016), but age was not associated with EFS. Stage III and IV patients had poorer outcome compared to stage I and II (EFS 58% vs. 24%, p = 0.025 and OS 84% vs. 30%, p < 0.001). Tumor size, B symptoms, LDH and number of extra nodal sites were not significantly associated with outcome. Patients who received adjuvant radiation therapy compared to those who did not had better EFS (65% vs. 32%, p< 0.01), and OS (72% vs. 45%, p = 0.081). The use of radiation therapy improved outcome in patients with stages I and II and not in III and IV. The advantage was most pronounced for stage II patients (EFS p = 0.014 and OS p= 0.013). CONCLUSIONS Patients with DLBCL with mediastinal mass who present with limited stage disease benefit from adjuvant radiation therapy. No significant financial relationships to disclose.

Multicenter Phase II Study of Sequential Brentuximab Vedotin and Doxorubicin, Vinblastine, and Dacarbazine Chemotherapy for Older Patients With Untreated Classical Hodgkin Lymphoma

PURPOSE To improve the curability of older patients with newly diagnosed Hodgkin lymphoma. PATIENTS AND METHODS We conducted a multicenter phase II study that administered brentuximab vedotin (Bv) sequentially before and after standard doxorubicin, vinblastine, and dacarbazine (AVD) for untreated patients with Hodgkin lymphoma age 60 years or older. After two lead-in doses of single-agent Bv (1.8 mg/kg once every 3 weeks), patients received six cycles of AVD chemotherapy followed by four consolidative doses of Bv in responding patients. RESULTS Patient characteristics included median age of 69 years (range, 60 to 88 years), 63% male, median Eastern Cooperative Oncology Group performance status 1, 81% stage III to IV disease, 60% International Prognostic Score 3 to 7, median Cumulative Illness Rating Scale-Geriatric comorbidity score of 7 (52% grade 3 to 4); and 12% had loss of instrumental activities of daily living at diagnosis. Thirty-seven (77%) of 48 patients completed six cycles of AVD, and 35 patients (73%) received at least one Bv consolidation. Overall response and complete remission rates after initial Bv lead-in dose were 18 (82%) of 22 and 8 (36%) of 22, respectively, and 40 (95%) of 42 and 34 (90%) of 42, respectively, after six cycles of AVD among 42 response-evaluable patients. Twenty (42%) of 48 patients experienced a grade 3 to 4 adverse event, most commonly neutropenia (44%), febrile neutropenia and pneumonia (8%), or diarrhea (6%); 33% had grade 2 peripheral neuropathy, which was reversible in a majority of patients. By intent-to-treat, the 2-year event-free survival, progression-free survival, and overall survival rates were 80%, 84%, and 93%, respectively. Furthermore, 2-year progression-free survival rates for patients with a Cumulative Illness Rating Scale-Geriatric comorbidity score of ≥ 10 versus < 10 were 45% versus 100%, respectively (P < .001), and with baseline loss versus no loss of instrumental activities of daily living were 25% versus 94% (P < .001), respectively, the latter persisting on multivariable analyses. CONCLUSION Altogether, sequential Bv-AVD was well tolerated and was associated with robust outcomes. Furthermore, geriatric-based measures were strongly associated with patient survival.

Influence of rituximab (R) on survival of patients (pts) with grade 1 and 2 follicular lymphoma (FL 1-2) over the past three decades.

e18509 Background: Advanced stage FL 1-2 is considered incurable with conventional therapies. Randomized trials over the past decade have demonstrated a survival advantage associated with the use of R in combination with chemotherapy compared to chemotherapy alone. We performed an analysis of pts in the Nebraska Lymphoma Study Group database to evaluate the impact of the use of R on survival over the past three decades. METHODS All pts diagnosed with FL 1-2 between June 1981 and January 2008 were included. Patient and treatment related variables were collected for analyses. Treatment related variables included the use of radiation therapy, use of autologous stem cell transplantation (ASCT), and use of R. Pts were classified as having never received R (R-N), those who received R with salvage (R-S), and those who received R with initial therapy (R-I). Overall survival was calculated from the date of diagnosis to date of death from any cause. Univariate comparison of survival probability was conducted using Kaplan-Meier estimates with log rank testing. Multivariate analysis used the Cox proportional hazards regression to control for other prognostic factors. RESULTS The median duration of follow-up for survivors was 10 yr, 11 yr and 6 yr (R-N, R-S, R-I). The median age at diagnosis was 60, 53, and 52 yrs for these groups, respectively. The 5-year probability of survival for R-N, R-S, and R-I groups was 72%, 90%, ad 89% respectively (p<0.001 by log rank). In multivariate analysis, compared to R-N, R-S and R-I had a significantly lower risk of death (Hazard ratio [HR]; 95% confidence interval [CI] = 0.60; 0.41-0.89 for R-S and 0.33; 0.17-0.64 for R-I. The follicular lymphoma international prognostic index (FLIPI) score was also independently predictive of survival (HR; 95% CI =1.69; 1.11-2.58 for the intermediate risk group vs low, and 3.39; 2.31-4.96 for the high risk group vs low). CONCLUSIONS In this analysis, pts in the Nebraska Lymphoma Study Group database with FL 1-2 treated with R had prolonged survival compared to those who never received R. This effect was independent of FLIPI score and the effect size was greatest for pts who received R starting with their initial therapy.

Preliminary quality-of-life findings of patients undergoing hematopoietic stem cell transplant utilizing the city of hope national medical center and functional assessment of cancer therapy instruments

INTRODUCTION: Advances in clinical and supportive care have significantly improved survival in hematopoietic stem cell transplant (HSCT) recipients, resulting in greater interest in the long-term morbidity and quality of life (QOL) of patients undergoing this procedure. SIGNIFICANCE: As the number of HSCT survivors increases, longitudinal studies designed to collect preand post-HSCT QOL data will provide clinicians and researchers with important information regarding changes and adaptations in physical, psychosocial, and other QOL domains. METHODS: The University of Nebraska Medical Center (UNMC) is conducting a pilot, longitudinal study of HSCT recipients’ QOL to measure physical functioning and psychosocial, emotional, and spiritual well-being at baseline (pre-HSCT) and at day 100, 6 months, and annually post HSCT utilizing the Medical Outcomes Study Short Form-36 Health Survey, City of Hope (COH) Quality of Life in Bone Marrow Transplant (BMT) Survivors, and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) instruments. RESULTS: Since August 2001, 43 patients have received an autologous HSCT and completed their pre-HSCT, day-loo, and 6-month post-HSCT QOL questionnaires. Forty-nine percent of participants are female, 93% are nonHispanic white, and the median age at transplant was 54 years (range, 27-70). Patients received transplants for lymphoma (79%) or multiple myeloma (21%). All have survived 1 year post HSCT, 8 of whom have relapsed. Data were analyzed using repeated measures analysis of variance, and preliminary results regarding QOL as measured by the FACT-BMT and COH-BMT are reported below as means and standard deviations (SD). No statistically significant differences in the FACT-BMT total score or subscale scores were found across the 3 assessments,