William L. White

Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin's lymphoma: A phase II trial in the North Central Cancer Treatment Group

PURPOSE Patients with newly diagnosed, advanced-stage, follicular grade 1 non-Hodgkins lymphoma (NHL) are often asymptomatic and can be observed without immediate chemotherapy. The goals of this study were to assess the overall response rate (ORR) to rituximab in this patient population and to determine the time-to-progression (TTP) and time-to-subsequent-chemotherapy (TTSC). PATIENTS AND METHODS Eligible patients had untreated follicular grade 1 NHL, and measurable stage III/IV disease. Patients received rituximab 375 mg/m(2) intravenous weekly x 4 doses and were then followed for response and progression; no maintenance therapy was provided. RESULTS Thirty-seven patients were accrued; one patient was ineligible. The median age was 59 years (range, 29 to 83 years). Six patients (18%) had elevated lactate dehydrogenase levels. The ORR was 72%, with 36% complete remissions. Fourteen (39%) of 36 patients remain in unmaintained remission, two died without disease progression, and three died with disease progression. Twenty (56%) of 36 patients have disease progression. The median TTP was 2.2 years (95% CI, 1.3 to not yet reached). Eighteen patients have subsequently been treated with chemotherapy, with a median TTSC of 2.3 years (95% CI, 1.6 to not yet reached). Patients with a high lactate dehydrogenase level had a lower ORR of 33% and a short TTP of only 6 months. CONCLUSION Rituximab can be safely administered to patients with advanced-stage follicular grade 1 NHL with efficacy and minimal toxicity. This therapy is highly active and offers an acceptable alternative to observation in this patient population. Patients with high LDH should not be considered for rituximab monotherapy.

Testicular lymphoma is associated with a high incidence of extranodal recurrence

Testicular lymphoma is a rare extranodal presentation of non‐Hodgkin lymphoma. The authors report long term follow‐up information regarding a group of patients with testicular lymphoma evaluated at the Mayo Clinic and describe the outcome with special attention to patterns of recurrence.

Absolute lymphocyte count predicts overall survival in follicular lymphomas

The peripheral blood absolute lymphocyte count (ALC) recovery after autologous stem cell transplantation has been shown to be an independent prognostic factor for survival for different haematologic malignancies. The role of ALC at diagnosis for follicular (grades 1 and 2) lymphomas (FL) on survival is not well described. The primary objective of this study was to assess the role of ALC on overall survival (OS) in FL patients. Of 1104 FL patients, 228 patients were originally diagnosed, followed, and had all treatment at the Mayo Clinic from 1984 and 1999, were evaluated. The median follow‐up was 89 months (range: 8·35–248). ALC as a continuous variable was identified as a predictor for OS [Hazard ratio (HR) = 0·74, P < 0·04]. ALC ≥ 1·0 × 109/l (n = 164) predicted a longer OS versus ALC < 1·0 × 109/l (n = 64; 175 vs. 73 months respectively, P < 0·0001). When compared with the Follicular Lymphoma International Prognostic Index (FLIPI), ALC was an independent prognostic factor for OS by multivariate analysis (HR = 0·677, P < 0·0001). These data suggest a critical role of FL patients’ immune status at diagnosis on survival.

Anemia After Orchiectomy

The decrease in testosterone production associated with bilateral orchiectomy may result in normocytic anemia in men. We sought to determine the effect of orchiectomy on hemoglobin concentration. Patients were evaluated at the Mayo Clinic in 1993 and 1994 and underwent bilateral orchiectomy for prostate carcinoma. All patients were seen by one of the staff urologists. Patients were included if they had a normal preoperative complete blood cell count and serum levels of creatinine, if they remained without disease progression (suppressed prostate‐specific antigen level and no evidence of clinical progression on review), and if they had normal serum levels of creatinine and mean corpuscular volume during the follow‐up period. The patients could have no other cause of anemia. The complete blood cell count, prostate‐specific antigen level, and serum level of creatinine were determined preoperatively and at least once (>90 days) after orchiectomy. Sixty‐four patients were included in the analysis (median age, 68 years). The median decrease in hemoglobin concentration was 1.2 g/dL after orchiectomy. There was a statistically significant difference in the hemoglobin concentration before orchiectomy compared with postoperative values at all the intervals studied, both by the paired group t‐test and the Kruskal‐Wallis test. There is a clinically and statistically significant decrease in hemoglobin concentration after orchiectomy. Knowledge of this phenomenon may prevent unnecessary diagnostic work‐up in men with normocytic anemia after bilateral orchiectomy. Am. J. Hematol. 59:230–233, 1998.

Prognostic significance of mediastinal mass in adult Hodgkin's disease

The authors analyzed the prognostic significance of mediastinal involvement with Hodgkins disease in 169 pathologically stage adults (≥ 17 years) treated at the Mayo Clinic between 1974 and 1978. Sixty percent of the patients presented with mediastinal disease, evenly divided between those with a mediastinal to thoracic ratio (MTR) < 0.33 and ≥ 0.33. They were of younger average age and were more likely to have nodular sclerosis histologic subtype than those patients without a mediastinal mass. The median follow‐up from diagnosis was 4.1 years with 90% of the patients being followed for 2 or more years. The 5‐year disease‐free survival (DFS) for the radiation only group was 70% in patients without mediastinal disease, 53% in the <0.33 MTR group and 44% in the ≥0.33 MTR group (P = 0.25). The 5‐year survival was 92% in the patients without mediastinal disease, 88% in the <0.33 MTR group and 90% in the ≥0.33 MTR group (P = 0.70). This lack of significant difference both in the 5‐year DFS and survival between the three groups was also seen in the patients taken in toto (169) and in those receiving combined modality treatment (36). However, in early stage (I and II) patients, treated with radiation only, those with a large mediastinal mass had a 5‐year DFS (33%) that was significantly worse than both the small mass patients (71%) and those with no mediastinal mass (87%) P < 0.005). The pattern of relapse in the 40 patients who failed following treatment by radiation only was not affected by an increasing size of mediastinal involvement. At the time of this analysis 27 of the 40 patients who had relapsed following treatment by radiation only (all stages) had remained free from second relapse. The authors do not believe that the current data either support or negate the use of a combined modality approach in the initial treatment of Hodgkins disease patients presenting with a large mediastinal mass. Only further follow‐up will establish whether the treatment of patients, who have relapsed following radiation only, is durable and results in an overall survival comparable to that obtained by using combined modality initially.

Absolute lymphocyte count predicts therapeutic efficacy of rituximab therapy in follicular lymphomas.

The immunologic mechanisms of action of rituximab include complement mediated lysis and antibody‐dependent cellular cytotoxicity. We hypothesised that a stronger host immune system prior to rituximab therapy for follicular (grades 1and 2) lymphomas (FL) would result in better response rates and longer time to progression (TTP). Thus, we studied the role of absolute lymphocyte count (ALC) prior to rituximab therapy on treatment efficacy and TTP in FL patients. Between 1996 and 2002, 79 FL patients were treated with single agent rituximab during their lymphoma treatment at the Mayo Clinic. The median age of the cohort was 56·6 years (range: 25–98 years). The median TTP was 12·5 months (range: 1–76 months). Superior TTP was observed with an ALC ≥0·89 × 109/l (n = 40) compared with an ALC <0·89 × 109/l (n = 39) at the time of rituximab therapy (median: 36·5 vs. 8·1 months, respectively, P < 0·0009). Higher complete response rates were observed in the ALC ≥0·89 × 109/l (23/40, 58%) compared with the ALC <0·89 × 109/l (5/39, 13%) (P < 0·0001). Multivariate analysis showed ALC to be an independent predictor for TTP. This study supports our hypothesis that a higher ALC predicts longer TTP following rituximab therapy.

A pilot study of epratuzumab and rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated, diffuse large B-cell lymphoma

In this pilot study, the authors assessed the feasibility of combination epratuzumab and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (ER‐CHOP) in patients with newly diagnosed diffuse large B‐cell lymphoma (DLBCL).

Therapeutic Options in Patients With Lymphoma and Severe Liver Dysfunction

OBJECTIVES To determine the long-term outcome of patients presenting with synchronous lymphoma and severe liver dysfunction and to describe the outcome of patients treated with initial mechlorethamine-based therapy used as a bridge to more conventional chemotherapy. PATIENTS AND METHODS We reviewed the clinical course of all patients diagnosed as having lymphoma who presented with severe liver dysfunction and received intravenous mechlorethamine between September 1988 and February 2003 at the Mayo Clinic in Rochester, Minn. RESULTS Forty-one patients were identified, 33 (80%) of whom had newly diagnosed, previously untreated lymphoma. Thirty-seven (90%) had non-Hodgkin lymphoma, and 4 (10%) had Hodgkin disease. Thirty-four patients (83%) had stage IV disease, and 31 (84%) of 37 had an intermediate-high International Prognostic Index. The median total bilirubin level before therapy was 10.7 mg/dL (range, 2.5-30.2 mg/dL), and the median alkaline phosphatase level was 982 U/L (range, 233-3415 U/L). In addition to mechlorethamine, 34 patients (83%) received concomitant corticosteroids, and 12 (29%) received concomitant rituximab. Twenty-two patients (54%) had sufficient improvement in liver function to receive subsequent standard chemotherapy. Nine patients (22%) are alive and disease-free at a median of 31 months (range, 4 to > or = 87 months) after mechlorethamine treatment. Factors associated with improved overall survival included improvement in bilirubin levels (P < .001) and receiving subsequent standard chemotherapy (P = .001). CONCLUSION Mechlorethamine, high-dose corticosteroids, and rituximab are useful therapeutic interventions for this unique group of patients with lymphoma and severe liver dysfunction. Substantial clinical improvement and long-term survival are possible.

Second Malignant Lesions After Therapy for Hodgkin's Disease

Among 169 adult pathologically staged patients with Hodgkins disease who were treated at the Mayo Clinic between 1974 and 1978, we identified four cases of second malignant lesions that developed. The median duration of follow-up after diagnosis for the entire population was 4.1 years. Of the 169 patients, 73 received irradiation only, 19 received chemotherapy only, and 77 received both chemotherapy and radiation therapy. In all four patients with second malignant lesions, Hodgkins disease was in apparent remission at the time of diagnosis of the second tumor. These four patients had received either total nodal irradiation or six or more cycles of chemotherapy as initial treatment (and one of them had received both treatment modalities). Thus, intensive therapy might be hypothesized to have played a role in the development of the second malignant tumor. To our knowledge, the development of non-Hodgkins lymphoma within a previously irradiated field after treatment of Hodgkins disease with radiation therapy only has not been reported previously. Although further studies with longer follow-up should be conducted, our analysis supports a definite risk for development of a second malignant lesion not only after combined-modality treatment or chemotherapy for Hodgkins disease but also after irradiation only.

Peripheral T-Cell Lymphoma Simulating Hodgkin's Disease With Initial Bone Marrow Involvement

In a patient who had fever and cytopenias but no peripheral lymphadenopathy, bone marrow biopsy revealed findings consistent with Hodgkins disease. Subsequently lymph node biopsy specimens showed lymphoma with features more consistent with peripheral T-cell lymphoma. The clinical features of this patient were those that have been ascribed to an atypical clinical form of Hodgkins disease. This case illustrates the inadequacy of bone marrow examination as the sole criterion for establishing an initial diagnosis of Hodgkins disease, particularly in relationship to the newly recognized pleomorphic variants of T-cell malignant lymphoma.