F. Swan

ESHAP--an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study.

PURPOSE This study attempted to determine the efficacy of the combination of etoposide (VP-16), methyl-prednisolone, and cytarabine (Ara-C) with or without cisplatin in relapsing and refractory adult lymphoma patients. PATIENTS AND METHODS The first 63 patients were randomized to receive VP-16 40 mg/m2/d for 4 days, methylprednisolone 500 mg intravenously daily for 5 days, and Ara-C 2 g/m2 intravenously over 2 to 3 hours on day 5 with or without cisplatin 25 mg/m2 IV administered by 24-hour infusion for 4 days (ESHA +/- P). Markedly different responses between ESHA (33%) and ESHAP (75%) led to deletion of the ESHA arm. A total of 122 patients on the ESHAP regimen were studied. RESULTS Forty-five patients (37%) attained a complete remission (CR) and 33 (27%) attained a partial remission (PR), for a total response rate of 64%. The median duration of CR was 20 months, with 28% of remitters still in CR at 3 years. The overall median survival duration was 14 months; the survival rate at 3 years was 31%. Overall time to treatment failure (TTF) showed 10% of all patients to be alive and disease-free at 40 months. Response and survival rates were similar in patients with low-grade (n = 34), intermediate-grade (n = 67), transformed (n = 18), and high-grade (n = 3) lymphoma. The most significant factors for response and survival by multivariate analysis were the serum lactic dehydrogenase (LDH) level, tumor burden, and age (when analyzed as a continuous variable), while prior CR was highly significant by univariate analysis. A significant difference in survival was noted for patients with normal LDH levels and low- or intermediate-tumor burden or patients with low tumor burden and elevated LDH levels (55% 3-year survival rate) versus patients with elevated LDH levels and intermediate or high tumor burden (< 20%). Major toxicities included myelosuppression, with a median granulocyte count of 500/microL and platelet count of 70,000/microL. CONCLUSION ESHAP was found to be an active, tolerable chemotherapy regimen for relapsing and refractory lymphoma. Applying a prognostic model based on tumor burden and serum LDH level shows significant differences in survival in this patient population.

Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma.

PURPOSE Although most patients with indolent lymphomas respond to initial therapy, virtually all experience relapse. Secondary therapy is often beneficial, but responses are rarely, if ever, durable. We conducted this phase II trail to evaluate the therapeutic efficacy and toxicity of fludarabine, mitoxantrone, and dexamethasone (FND) in patients with relapsed indolent lymphoma. PATIENTS AND METHODS Fifty-one patients with recurrent or refractory indolent lymphoma were treated with a regimen of fludarabine 25 mg/m2/d intravenously (IV) on days 1 to 3, mitoxantrone 10 mg/m2 IV on day 1, and dexamethasone 20 mg/d IV or orally on days 1 to 5. Treatment was repeated at 4-week intervals for a maximum of eight courses. Late in the course of this trial, trimethoprim-sulfamethoxazole (TMP-SMX) was incorporated for Pneumocystis carinii (PCP) prophylaxis. RESULTS Responses were complete (CR) in 24 patients (47%) and partial (PR) in 24 (47%). The median failure-free survival time was 21 months for CR patients and 9 months for PR patients. Notable activity of FND was seen even in the elderly, in those with high serum lactate dehydrogenase (LDH) or beta2-microglobulin levels, and in those with multiple prior treatment regimens. The predominant toxic effects were myelosuppression and infections; other toxic effects were modest. Infections occurred in 12% of courses. Almost half of the infections were proven or suspected opportunistic infections, including six cases of dermatomal herpes zoster and two cases of proven PCP pneumonia. CONCLUSION The FND combination is highly active in patients with recurrent or relapsed indolent lymphoma and results in a high percentage of CRs. Because of the risk of opportunistic infections, we currently recommend prophylaxis with TMP-SMX and advise deletion of corticosteroids for patients who develop opportunistic infections.

Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low-grade lymphoma.

PURPOSE In a phase II trial we investigated fludarabine phosphate (FAMP) as therapy for patients with relapsed lymphoma to determine its effectiveness and toxicity in this disease. PATIENTS AND METHODS The 67 assessable patients had a median age of 56 years and had received a median of three chemotherapy regimens before treatment with FAMP. The starting dose was 25 mg/m2 administered intravenously over 30 minutes daily for 5 days every 3 to 4 weeks. RESULTS High response rates were observed for follicular small cleaved-cell lymphoma (FSCCL) (62%), follicular mixed small- and large-cell lymphoma (80%), and follicular large-cell lymphoma (FLCL) (100%). Responses also occurred in small lymphocytic lymphoma (SLL) (33%), transformed lymphoma (33%), mycosis fungoides (40%), and Hodgkins disease (25%). No responses were observed in other intermediate- or high-grade lymphomas (N = 20). Overall, there were five patients with a complete response, 23 patients with a partial response, and an overall response rate of 37%. Toxicity was primarily hematologic and infectious. No significant gastrointestinal, hepatic, renal, or neurologic toxicity occurred. CONCLUSIONS We conclude that FAMP has major activity in follicular lymphoma. Fundamental research is needed to understand this differential efficacy in low-grade lymphoma yet lack of efficacy in intermediate- and high-grade lymphoma. Clinical investigations should be done using FAMP in varying dose schedules and in combination regimens.

A new serologic staging system for large-cell lymphomas based on initial beta 2-microglobulin and lactate dehydrogenase levels.

We report results of our investigation of prognostic factors for patients with large-cell lymphoma who were entered on the same treatment protocol and who had known pretreatment serum beta 2-microglobulin (beta 2M) and lactate dehydrogenase (LDH) levels. beta 2M and LDH levels were the most significant and independent variables for predicting time to treatment failure (TTF) and survival. The serum level of beta 2M correlated with tumor burden. These two serum markers defined three significantly different prognostic groups. All 27 patients in the low-risk group remain alive and in remission; in contrast, 22 of the 27 patients (81%) in the high-risk group have failed treatment, and only seven (26%) remain alive. In comparison with the Ann Arbor staging system, serum levels of beta 2M and LDH may provide a more precise system for defining risk groups and thereby allow a more rational approach to the development and analysis of treatment strategies.

Radiotherapy during pregnancy for clinical stages IA-IIA Hodgkin's disease

Between 1956 and 1990, 775 women were treated for Hodgkins disease at The University of Texas M.D. Anderson Cancer Center. Of these, 25 (3.2%) were pregnant at diagnosis. Seven of these women were in the first trimester, 10 in the second, and eight in the third. Prior to treatment, three women in the third trimester had normal deliveries, and six patients in the first trimester had abortions. Sixteen patients received radiotherapy for supradiaphragmatic presentations during their pregnancies. All these patients had nodular sclerosing Hodgkins disease: Two had clinical stage IA presentations and 14 had clinical stage IIA. In two patients radiotherapy (35 Gy) was limited to the neck, three patients were treated definitively to the neck and mediastinum (40 Gy), and 11 patients received mantle irradiation (40 Gy). Four to five half-value layers of lead were used to shield the uterus during radiotherapy. The dose to the fetus was estimated individually in nine patients, using a combination of an Alderson-Rando and a water phantom. The estimated total dose to the mid-fetus ranged from 1.4 to 5.5 cGy for treatment with 6 MV photons, and from 10 to 13.6 cGy for Cobalt 60. All 16 patients subsequently delivered full-term, normal infants. Following delivery, all of the patients had further staging procedures; eight received additional treatment. Subsequently, the disease relapsed in four patients; two eventually died of Hodgkins disease. The 10-year determinant and overall survival rates were 83% and 71%, respectively. Currently, all offspring are physically and mentally normal, and none has developed a malignancy. Radiotherapy is an appropriate initial treatment for supradiaphragmatic presentations of Hodgkins disease during the second and third trimesters of pregnancy, provided special attention is paid to treatment and shielding techniques. The outcome for women treated with irradiation for clinical stage I and II Hodgkins disease during pregnancy has not been shown to be adversely affected by pregnancy, and after the first 8 weeks of gestation, the risk to the fetus appears to be minimal.

Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP.

PURPOSE We report the results of a prospective trial in which patients with relapsing non-Hodgkins lymphomas were sequentially treated with two regimens (mesna, ifosfamide, mitoxantrone, and etoposide [MINE], and etoposide, methylprednisolone, cytarabine, and cisplatin [ESHAP]) if they had no history of disease resistance to these drugs. PATIENTS AND METHODS Ninety-two patients received MINE (mesna 4 g/m2, ifosfamide 4 g/m2, mitoxantrone 8 mg/m2, and etoposide 195 mg/m2) for a maximum of six courses followed by ESHAP (etoposide 240 mg/m2, methylprednisone 500 mg/d, high-dose cytarabine 2 g/m2, and cisplatin 100 mg/m2) for three courses to consolidate complete response (CR) or for a maximum of six cycles after a partial response (PR) or no response to MINE. Pretreatment serum levels of lactate dehydrogenase (LDH) and beta 2-microglobulin (beta 2M) were documented in 80 of 92 patients. RESULTS The response rate to MINE-ESHAP was 69% (48% CRs and 21% PRs), with a median survival time of 24 months and median time to treatment failure of 12 months. The median time to treatment failure according to histology was as follows: low-grade histologies, 16 months; low-grade transformed to intermediate-grade, 8 months; and intermediate-grade, 5 months. The most serious complication was myelosuppression, which resulted in two deaths due to neutropenic sepsis. A risk factor model based on beta 2M and LDH levels before salvage treatment showed three categories of risk, with 36-month survival rates as follows: low (beta 2M < 3 mg/dL and LDH normal), 61%; intermediate (beta 2M > or = 3 mg/dL or LDH above normal), 23%; and high (beta 2M > or = 3 mg/dL and LDH above normal), 0%. CONCLUSION MINE-ESHAP is an effective salvage strategy for patients with recurrent lymphoma. Toxicity was acceptable. Factors that determine prognostic categories at relapse merit further study.

Prognostic Value of Serum β-2 Microglobulin in Low-Grade Lymphoma

Objective: To evaluate serum beta-2 microglobulin (β-2M) and other prognostic indicators in previously untreated low-grade lymphoma. Design: Cohort study of 80 patients with uniformly treated low-g...

Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma.

PURPOSE Fludarabine is an active agent for patients with low-grade lymphoma (LGL) but has mainly been used as a single agent. This trial was designed to define the maximum-tolerated dose (MTD) of a combination of fludarabine, mitoxantrone, and dexamethasone (FND), to identify the toxicities of these agents in combination, and to make preliminary observations about the efficacy of this combination. PATIENTS AND METHODS Twenty-one patients with recurrent LGL or follicular large-cell lymphoma were treated, in cohorts of three, at stepwise escalating doses. Patients were required to have adequate marrow function and normal renal, hepatic, and cardiac function. RESULTS The MTD of the combination was found to be as follows: fludarabine, 25 mg/m2/d (days 1 to 3); mitoxantrone, 10 mg/m2 (day 1); and dexamethasone, 20 mg/d (days 1 to 5). Each course was administered monthly, and up to eight courses were given. Dose-limiting toxicities were neutropenia and infections. Thrombocytopenia was modest. Nonhematologic toxicity was very modest. Responses were seen at every dose level. The overall response rate was 71%, with a 43% complete remission (CR) rate. The median duration of CR was 18 months (with follow-up duration from 13 to 28+ months). CONCLUSION FND was well tolerated in this population. While our primary aim was to define the MTD, our preliminary observations on the efficacy of the regimen were favorable. The overall response rate was high, there was a high fraction of CRs, and our early impression is that these responses are durable.

Refractoriness to chemotherapy and poor survival related to abnormalities of chromosomes 17 and 7 in lymphoma

PURPOSE Lymphoma cells usually show cytogenetic abnormalities, but their relationship to prognosis has not been as extensively studied as in leukemia. A group of previously untreated cases of lymphoma with evaluable metaphases was examined for the association between cytogenetic abnormalities and clinical outcome. PATIENTS AND METHODS The study consisted of 104 patients, from whom fresh tumor samples were obtained for cytogenetic tests. Because of the complexity of lymphoma karyotypes, the cases were divided into four patterns according to the type of abnormality of chromosome 17 or 7 present. Treatment of patients was given based on histologic grade and stage of disease. Response to treatment was evaluated according to previously described methods. RESULTS Patients with true abnormalities of chromosome 17 or 7 (defined as those with either structural abnormalities of the short arm of these chromosomes or monosomy of these chromosomes with no associated unidentified markers) were observed to have an adverse prognosis. The overall response rate and tumor-related mortality were less favorable for patients with these cytogenetic abnormalities. By applying multivariate analysis, we found that this observation was independent of the effect of serum lactic dehydrogenase level, histologic grade, or tumor burden. CONCLUSION True abnormalities of chromosome 17 or 7 in patients with lymphoma are associated with a poor response to chemotherapy, short time to treatment failure, and high tumor-related mortality rate. These findings raise the question of the potential involvement of some gene or oncogene, perhaps the p53 oncogene, which might impart a survival advantage to the malignant cells.

Discordant bone marrow involvement in diffuse large-cell lymphoma: a distinct clinical-pathologic entity associated with a continuous risk of relapse.

From 1975 to 1988, 50 patients with lymph node biopsy-documented diffuse large-cell lymphoma (DLCL) presented with bone marrow involvement. Twenty-four patients (48%) had large-cell lymphoma (LCL) in the bone marrow and were compared with 19 (38%) patients who had small cleaved-cell lymphoma (SCCL) in the marrow. Additionally, seven patients (14%) had mixed small- and large-cell lymphoma (ML) in the marrow. Patients who had LCL marrow involvement were younger (P less than .02) and more frequently had elevated lactic dehydrogenase (LDH) levels (P less than .001), high tumor burden (P less than .01), and more sites of extranodal disease (P less than .05) than those with SCCL in the marrow. The complete response (CR) rate to multiagent chemotherapy was 16.7% in the LCL group and 89.4% in the SCCL group (P less than .001). One third of the patients with LCL in the marrow developed CNS involvement, compared with only one patient in the SCCL group (P = .06). Overall 5-year survival was 79% in patients with SCCL marrow involvement, compared with only 12% in patients with LCL in the marrow (P = .002). Despite a high CR rate, patients with marrow involved by SCCL were at a high continuous risk of relapse with only a 30% failure-free survival at 5 years. We conclude that bone marrow involvement with LCL predicts for extremely poor prognosis with low response rate and short survival. Patients with SCCL in the bone marrow have a high rate of CR and a high rate of 5-year survival; however, there is a high risk of late relapse, and only 15% are in a continuous remission at 8 years.