David P Deakin

Tositumomab and Iodine I 131 Tositumomab for Recurrent Indolent and Transformed B-Cell Non-Hodgkin’s Lymphoma

PURPOSE An open-label phase II study was conducted at two centers to establish the efficacy and safety of tositumomab and iodine I 131 tositumomab at first or second recurrence of indolent or transformed indolent B-cell lymphoma. PATIENTS AND METHODS A single dosimetric dose was followed at 7 to 14 days by the patient-specific administered radioactivity required to deliver a total body dose of 0.75 Gy (reduced to 0.65 Gy for patients with platelets counts of 100 to 149 x 10(9)/L). Forty of 41 patients received both infusions. RESULTS Thirty-one of 41 patients (76%) responded, with 20 patients (49%) achieving either a complete (CR) or unconfirmed complete remission [CR(u)] and 11 patients (27%) achieving a partial remission. Response rates were similar in both indolent (76%) and transformed disease (71%). The overall median duration of remission was 1.3 years. The median duration of remission has not yet been reached for those patients who achieved a CR or CR(u). Eleven patients continue in CR or CR(u) between 2.6+ and 5.2+ years after therapy. Therapy was well tolerated; hematologic toxicity was the principal adverse event. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia were observed in 5%, 45%, and 32% of patients, respectively. Secondary myelodysplasia has occurred in one patient. Four patients developed human antimouse antibodies after therapy. Five of 38 assessable patients have developed an elevated thyroid-stimulating hormone; treatment with thyroxine has been initiated in one patient. CONCLUSION High overall and CR rates were observed after a single dose of tositumomab and iodine I 131 tositumomab in this patient group. Toxicity was modest and easily managed.

Survival benefit from high-dose therapy with autologous blood progenitor-cell transplantation in poor-prognosis non-Hodgkin's lymphoma.

PURPOSE To compare standard and intensive treatment strategies for patients with high-grade non-Hodgkins lymphoma (NHL) of poor prognosis, defined by the international prognostic index. PATIENTS AND METHODS Thirty-four patients received standard chemotherapy with 11 weeks of doxorubicin, cyclophosphamide, vincristine, bleomycin, etoposide, prednisolone, and methotrexate (VAPEC-B), and 33 received intensive treatment with 7 weeks of VAPEC-B, three cycles of ifosfamide/cytarabine, then high-dose busulfan/cyclophosphamide followed by autologous blood progenitor-cell (BPC) transplantation. RESULTS Twelve of 33 patients in the intensive group and 26 of 34 patients in the standard group have died. The median follow-up time for the surviving patients is 31 months and 68 months, respectively. At 2 years, the actuarial estimates of event-free survival (EFS) were 61% versus 35% (P = .01) and of overall survival, 64% versus 35% (P = .01). A significant reduction in the event rate (progression or death) was maintained after adjustment for age and the number of risk factors. The estimated risk of experiencing an event was 0.37 (95% confidence interval [CI], 0.16 to 0.84) in the intensive group compared with the standard group. CONCLUSION Patients with poor prognostic features who received high-dose therapy and BPC rescue had a superior EFS. The survival differences observed in this study justify a formal comparison in a randomized study.

Maintenance chlorambucil after CVP in the management of advanced stage, low-grade histologic type non-Hodgkin's lymphoma. A randomized prospective study with an assessment of prognostic factors.

One hundred sixty‐two patients with Stages III and IV non‐Hodgkins lymphoma of low‐grade histologic type were treated with combination chemotherapy using cyclophosphamide, vincristine, and prednisolone (CVP) followed by radiotherapy to sites of previous bulk disease. The patients were randomized to receive either follow‐up alone or “maintenance” chemotherapy with 2 years of intermittent chlorambucil. A complete remission was obtained in 56% of patients and the median survival was 64 months (median follow‐up, 74 months). Multivariate analysis revealed stage (P < 0.0001) and Karnofsky performance status (P = 0.021) to predict complete response (CR) and the achievement of a CR (P < 0.0001), female sex (P = 0.008), the absence of bulk disease (P = 0.038) and low serum alkaline phosphatase (P = 0.002) to predict prolonged survival. The median relapse‐free survival (RFS) of the complete responders was 41 months. A prolonged RFS was predicted by low stage (P = 0.014), low serum lactic dehydrogenase (LDH) (P = 0.045) levels, and by the administration of maintenance chlorambucil (P = 0.045). A prolonged survival of the complete responders was predicted by a low number of nodal sites of involvement with lymphoma at presentation (P = 0.022) and lack of liver involvement (P = 0.011). The administration of oral maintenance therapy with chlorambucil for a full 2 years was only possible in 38% of patients, mainly because of progression of disease and the induction of thrombocytopaenia, but despite this it prolonged the median RFS by 38 months and its use could be considered when future studies are being designed.

The value of bone marrow examination in the staging of Hodgkin's lymphoma: a review of 955 cases seen in a regional cancer centre

Summary. Bone marrow aspirates (BMA) and trephine biopsies (BMT) are commonly performed in the staging of patients with newly diagnosed Hodgkins lymphoma (HL) but the value of these procedures is controversial. The purpose of this study was to evaluate the predictive value of the blood count and erythrocyte sedimentation rate (ESR) for bone marrow involvement (BMI) and the influence of BMI on stage and prognostic score. A retrospective analysis of 955 patients with newly diagnosed HL entered into clinical trials in a regional cancer centre between 1975 and 1999 was performed. BMI was identified by BMT in 50 patients (5·2%) but in only five of these by BMA. The negative predictive values of a normal full blood count (FBC) and ESR for absence of BMI were 98·8% and 97·3%, respectively, and the positive predictive value of an abnormal FBC and ESR for presence of BMI were both 6·7%. BMT did not alter initial patient management in a single case but provided valuable prognostic information in certain subgroups of patients. BMA gave no additional staging information over BMT and abnormalities of blood count and ESR were poor predictors of infiltration. We conclude that BMA should be abandoned for staging purposes in HL and BMT restricted to patients with stage IIB or III disease, for whom valuable prognostic information may be obtained.

Prognostic factors in high and intermediate grade non-Hodgkin's lymphoma

An analysis of prognostic factors has been performed on 260 patients with high and intermediate grade non-Hodgkins lymphoma (NHL) treated over an 11-year period between 1975 and 1986. The overall 5-year survival rate was 50% with a median follow-up of 72 months. Over 20 clinical, radiological and laboratory parameters have been studied, including variables reported to be important indicators of prognosis in previous series, and these variables have been subjected to univariate and multivariate analysis. Attainment of complete remission (CR) was the most important predictor of overall survival, low serum lactate dehydrogenase (LDH), limited stage disease and a high serum albumin were also independently associated with prolonged survival in multivariate analysis. After removing remission status from the model, Ann Arbor clinical stage became the most significant pre-treatment prognostic indicator. Sixty-five per cent of patients achieved CR, and a discriminant analysis showed that failure to attain CR was associated with advanced stage disease, constitutional symptoms, increasing patient age, a low serum albumin and the presence of bulk disease. Advanced clinical stage and an elevated serum LDH predicted independently for a poor relapse-free survival, and reduced overall survival following CR. There was no significant correlation between histological subtype in the Kiel classification and prognosis. This study confirms the prognostic significance of remission status and Ann Arbor clinical stage, and illustrates additional factors including serum levels of albumin and LDH, which serve to enhance the pre-treatment prognostic evaluation of patients with unfavourable histology NHL.

A prospective study of the treatment of high-grade histology non-Hodgkin's lymphoma involving the gastrointestinal tract

Thirty-six patients presenting with stage II-IV primary gastrointestinal non-Hodgkins lymphoma of high-grade pathology were treated in a prospective study from 1975 to 1983 with combined modality therapy. A complete response rate of 56% was obtained and the overall 5-yr survival rate was 36%. The 5-yr relapse-free survival rate of the complete remitters was 79%. Multivariate analysis revealed that the remission achieved (P less than 0.001) and the completeness of primary surgery (P = 0.018) would reliably predict the duration of overall survival. The finding of diffuse histiocytic histology (Rappaport) predicted longer relapse-free survival. The majority of deaths were related to intra-abdominal complications and not to disseminated lymphoma. Gastrointestinal tract non-Hodgkins lymphoma of high-grade pathology of all stages is curable with a combination of chemotherapy and radiotherapy following surgery to remove as much macroscopic disease as is possible.

A randomized study comparing chemotherapy alone with chemotherapy followed by radiotherapy in patients with pathologically staged IIIA Hodgkin's disease.

This paper reports the five-year follow-up (range, 1-8 years) of 56 patients with pathologic stage IIIA Hodgkins disease randomized for chemotherapy alone or chemotherapy followed by radiotherapy to previous areas of disease (26 treated with mustine, vinblastine, procarbazine, and prednisolone [MVPP] alone, 30 with MVPP and radiotherapy). Of the 56 patients 53 (95%) achieved a complete remission with chemotherapy and of these only five (9%) have relapsed; three died of Hodgkins disease. There was no improvement in relapse-free survival associated with the uses of radiotherapy following chemotherapy but in view of the small numbers of relapses and the excellent results following chemotherapy alone, a significant improvement could not be expected. The use of MVPP alone can be recommended as an alternative therapy for patients with stage IIIA Hodgkins disease. This avoids both the physical and psychologic morbidity associated with the high relapse rate following extensive primary radiotherapy and the necessity of combined modality treatment for about half these patients. The question of whether radiotherapy should be given to areas of previous bulk following chemotherapy has not yet been answered in this trial which is continuing.

Results of a randomized trial comparing MVPP chemotherapy with a hybrid regimen, ChlVPP/EVA, in the initial treatment of Hodgkin's disease.

PURPOSE AND METHODS Between December 1984 and August 1992, 423 patients with newly diagnosed Hodgkins disease (HD) were entered onto a randomized clinical trial that compared the regimen of mechlorethamine, vinblastine, procarbazine, and prednisone (MVPP) with a doxorubicin-containing hybrid regimen (chlorambucil, vinblastine, procarbazine, and prednisone/etoposide, vincristine, and doxorubicin [ChlVPP/EVA]). Median age for the group was 29.5 years (range, 15.2 to 68.8), and 52% had bulk disease. RESULTS After chemotherapy, patients in the hybrid arm of the trial had a higher complete remission (CR) rate (68.1% v 55.3%) and a lower failure rate (2.4% v 12.5%) than those in the MVPP arm. There were also fewer deaths during treatment in the hybrid arm of the trial (five v 13). With a median follow-up period for survivors of 4.5 years (range, 0 to 9), actuarial 5-year progression-free survival (PFS) for all cases is 80% in the hybrid arm and 66% in the MVPP arm (P = .005). A nonsignificant trend toward a better overall survival in the hybrid arm of the trial has also been identified. CONCLUSION These results suggest that ChlVPP/EVA hybrid is superior to MVPP in the treatment of HD. It has therefore been adopted as standard first-line therapy at the two centers.

Patterns of relapse and subsequent management following high-dose chemotherapy with autologous haematopoietic support in relapsed or refractory Hodgkin's lymphoma: A two centre study

BACKGROUND High-dose chemotherapy has an established role in recurrent or refractory Hodgkins lymphoma (HL) although a significant proportion of patients subsequently relapse. This manuscript describes the clinical characteristics of such patients and documents their further management at two major UK cancer centres. PATIENTS AND METHODS Between 1987 and 1996 one hundred patients with recurrent or refractory HL received high-dose chemotherapy (HDCT) with autologous haematopoietic rescue. All had recurred within 12 months of initial therapy or had two or more recurrences. RESULTS With a median follow-up of 2 years, 56 patients are currently progression-free. There were six treatment-related deaths. One patient died of pneumonia in remission. Thirty-seven patients have relapsed, intrapulmonary disease being seen for the first time in 53% and recurrence at previous sites of disease in 81%. Following recurrence, therapy was determined by circumstances: either one agent at a time was used (single sequential approach) or multiagent chemotherapy was chosen. There was a survival advantage for those who achieved a symptomatic response (13 vs. 4 months median, P = 0.0001). A trend towards longer survival was seen for those whose disease recurred beyond six months following high-dose chemotherapy and in those who received combination chemotherapy. CONCLUSIONS These results confirm that HDCT with autologous haematopoietic support is inadequate for about half the patients who receive it for high-risk HL. Relapse in the site of prior disease is the most likely pattern with intrapulmonary disease for the first time occurring frequently. It is possible to administer further chemotherapy after failure of HDCT, and both objective as well as subjective benefit can be achieved. A few patients appear to get long-term benefit from further treatment.

The prognostic significance of mediastinal bulk in patients with stage IA-IVB Hodgkin's disease: A report from the Manchester Lymphoma Group

Three hundred and two previously untreated patients with Stage IA-IVB Hodgkins disease were reviewed to determine the prognostic significance of mediastinal involvement. Mediastinal bulk disease was defined as either a maximal mediastinal width of 7.5 cm or more, or a ratio of the maximum width of mediastinal disease to the maximum chest diameter of greater than or equal to 0.33, or a ratio of the maximum width of mediastinal disease to the chest diameter at T5-T6 greater than or equal to 0.33, or as an area of mediastinal disease greater than or equal to 100 cm2. Bulk disease outside the chest was defined as a mass of lymph nodes measuring 5 cm or more in any axis. The presence of mediastinal bulk disease was of adverse prognostic significance for remission duration and survival in patients with Stage IA-IIB Hodgkins disease, but for patients with more advanced disease the effect of mediastinal bulk on remission duration and survival was not statistically significant. The mediastinal bulk variable which most significantly related to prognosis was the ratio of the maximum mediastinal disease to the chest diameter at T5-T6.