Faculty Bibliography

PURPOSE: To determine the toxicity and recommended phase II doses of the combination of fludarabine plus cyclophosphamide in chemotherapy-naive patients with low-grade lymphoma. PATIENTS AND METHODS: Previously untreated patients with low-grade lymphoma were entered onto dosing cohorts of four patients each. The cyclophosphamide dose, given on day 1, was increased from 600 to 1, 000 mg/m(2). Fludarabine 20 mg/m(2) was administered on days 1 through 5. The first eight patients were treated every 21 days; later patients were treated every 28 days. Prophylactic antibiotics were required. RESULTS: Prolonged cytopenia and pulmonary toxicity each occurred in three of eight patients treated every 3 weeks. The 19 patients treated every 28 days, who were given granulocyte colony-stimulating factor as indicated, did not have undue nonhematologic toxicity. Dose-limiting toxicity was hematologic. At the recommended phase II/III dose (cyclophosphamide 1,000 mg/m(2)), grade 4 neutropenia was observed in 17% of all cycles and 31% of first cycles. Grade 3 or 4 thrombocytopenia was seen in only 1% of all cycles. The median number of cycles per patient was six (range, two to 11) for all patients enrolled. The response rate was 100% of 27 patients entered; 89% achieved a complete and 11% a partial response. Nineteen of 22 patients with bone marrow involvement had clearing of the marrow. Median duration of follow-up was more than 5 years; median overall and disease-free survival times have not been reached. Kaplan-Meier estimated 5-year overall survival and disease-free survival rates were 66% and 53%, respectively. CONCLUSION: The recommended dosing for this combination in patients with previously untreated low-grade lymphoma is cyclophosphamide 1, 000 mg/m(2) day 1 and fludarabine 20 mg/m(2) days 1 through 5. The regimen has a high level of activity, with prolonged complete remissions providing 5-year overall and disease-free survival rates as high as those reported for other therapeutic approaches in untreated patients

Large-cell variants are uncommon in mantle cell lymphoma (MCL). Here we describe the pathologic and clinical findings in five patients with large-cell lymphoma related to MCL (L-MCL), and compare them to a group of classic small-cell MCL (s-MCL) cases. Histologically, the MC origin of the large cells was evinced by their association with a small mantle cell component in the same tissue, or their distribution in a classic mantle zone pattern, or their development in a patient with previous s-MCL. The large cells were either pleomorphic mantle cells (case 1) or transformed blast-like cells (case 2-5). The median nuclear diameter, median nuclear area and proliferation index of L-MCLs and s-MCLs, were statistically different. Immunophenotypic characterization of four specimens of L-MCL and 10 of s-MCLs with a large panel of antibodies showed the classic findings of MCL, i.e. the IgM+ D+/-, CD5+, CD10-, CD23- phenotype in all cases except two (one CD5- and one CD23+), and the association with a loose follicular dendritic cell network. Two of four L-MCLs and 5/10 s-MCLs demonstrated rearrangements of the bcl-1 gene by Southern blot or by polymerase chain reaction (PCR); 2/4 L-MCLs and 1/9 s-MCLs had p53 mutations on single-strand conformation polymorphism analysis; none of the 14 specimens showed rearrangement of bcl-2 by PCR or bcl-6 and c-myc by Southern blot. All patients with 'transformed' histology (versus 37% of all others) died of lymphoma; their survival (15-18 months; median 17) was much shorter than that of all the others (28-117+ months; median 43) (P=0.0035). All three patients with p53 anomalies, two of whom had tumours with transformed histology, died of their disease in a short time (15, 18 and 28 months). In contrast, the presence of bcl-1 rearrangements did not have prognostic implications. This study documents the existence of large-cell variants of MCL and the poor prognosis associated with the 'transformed' cytologic type and/or p53 abnormalities

Since trisomy 12 is the most common chromosome abnormality found in CLL and MDM2 has been mapped to this chromosome, we examined the possible association of MDM2 in the pathogenesis of CLL. A rearrangement of the MDM2 gene was observed in 4 of 11 peripheral blood mononuclear cells (PBMC) from patients with CLL by Southern blot hybridization. Expression of MDM2 was detected in all of the CLL samples examined by Northern blot. However, neither gross amplification nor overexpression of the MDM2 gene was found in CLL. The data suggest that MDM2 may play a role in the pathogenesis of CLL and may help to explain how abnormalities of chromosome 12 are related to CLL

PURPOSE: The objective of this trial was to define the maximum-tolerated dose (MTD) of topotecan for a 21-day infusion schedule, repeated every 28 days, in patients with cancer. PATIENTS AND METHODS: Cohorts of four patients received continuous ambulatory infusions of topotecan in escalated duration with doses beginning at 0.20 mg/m2/d for 7 days. Forty-four patients with a histologic diagnosis of cancer refractory to standard therapy were treated with infusions of topotecan for a total of 115 cycles and 1,780 patient-days of infusion. The median number of treatment cycles per patient was two (range, one to eight). All patients were heavily pretreated with chemotherapy and/or radiation. RESULTS: The dose-limiting toxicity (DLT) was myelo-suppression, with thrombocytopenia greater than neutropenia seen at the dose level of 0.70 mg/m2/d for 21 days. At the MTD of 0.53 mg/m2, ten patients were treated for a total of 20 courses, resulting in one episode of grade 4 thrombocytopenia and leukopenia, one grade 3 thrombocytopenia, and two grade 3 leukopenias. This dose regimen was well tolerated, with minimal nonhematologic toxicity. Local infusion port complications developed in two patients and two had bacteremia, including one patient with repeated local skin infections. Objective responses were observed in this heavily pretreated population for patients with ovarian cancer (two partial responses and one mixed response in six patients), breast cancer (one partial response and one mixed response in two patients), and for one patient each with renal and non-small-cell lung cancer (two partial remissions). CONCLUSION: Twenty-one-day topotecan infusion is well tolerated at 0.53 mg/m2, with dose-intensity exceeding other schedules for administration of topotecan. The DLT is hematologic, with thrombocytopenia somewhat exceeding leukopenia. Objective responses were observed in seven patients with breast, ovarian, renal, and non-small-cell lung cancer

Topotecan (TPT), a semi-synthetic, water soluble analog of camptothecin (CPT), acts by topoisomerase-1 inhibition. Previous studies with CPT analogs in human xenograft-bearing mice show that prolonged depot administration at nontoxic doses were curative (Giovanella et al, Science, 246:1046, 1989). We treated 33 patients (pts) (16 F, 17 M) with prolonged continuous infusion using ambulatory CADD pumps delivering 7 cc/day (d) with cassette changes every 3 d. Cohorts of 4-6 pts began at a dose of 0.2 mg/m2/day x 7 days with escalation to 10, 14, 17, and 21 days q 28 d. Further escalations were 0.3, 0.4, and 0.53 mg/m2/d x 21 d q 28 d. Disease sites included colon ca (13), NSCLC (4), sarcoma (3), gastric (3), ovarian (3), pancreatic (2); H and N, breast, renal, melanoma, anal (each 1). Median age was 63 (range 29 -79) yr; PS 1 (0-2); prior chemo = 33 (med 2 regimens); prior RT=10. A total of 72 cycles (med 2, range 1-6) were given for a total of 1090 pt-days of infusion. One infectious complication was seen (Mediport-pocket), 4 pts required transfusion; one pt with 3 prior chemo regimens and pelvic RT developed gr 4 leukopenia and thrombocytopenia at the 0.4 mg/m2 x 21 d level. No other hematologic toxicity has been observed. Nonhematologic toxicity included fatigue only. Steady state plasma conc for the active lactone form of TPT at 0.4 mg/m2/d was 1.4 +/- 0.29 ng/ml (N=3) and 4.4 +/- 0.99 (N=3) at the 0.53 level. Best responses were 1 PR (NSCLC), 1 mixed response (breast), 11 stable, 15 progression and 5 too early. TPT administration by this schedule is feasible and safe; we continue to accrue. Dose-limiting heme toxicity has not yet been reached, yet dose intensity (2.8 mg/m2/wk) exceeds that achieved using the recommended Phase II 1.5 mg/m2/d x5 schedule (1.9 mg/m2/wk). Once an MTD is reached, Phase III trials comparing this schedule to the daily x5 bolus schedule will be warranted. (C) American Society of Clinical Oncology 1997

The Eastern Cooperative Oncology Group (ECOG) conducted a study in which patients with advanced chronic lymphocytic leukemia (CLL) were randomized between a regimen consisting of chlorambucil (30 mg/m2 orally day 1) and prednisone (80 mg orally days 1 to 5) (C + P) administered every 2 weeks and a more intensive regimen of cyclosphosphamide (300 mg/m2 orally days 1 to 5), vincristine (1.4 mg/m2 intravenously [IV] day 1), and prednisone (100 mg/m2 orally days 1 to 5) (CVP) given every 3 weeks. Treatment was continued for up to 18 months to maximal response. Of the 122 eligible patients, 60 received C + P, while 62 received CVP. With a median follow-up of 7 years, there were no significant differences in survival (4.8 v 3.9 years, P = .12), complete remission (CR) rate (25% v 23%; P = .83), or duration of response (2.0 v 1.9 years; P = .78) between C + P and CVP. Toxicity was modest despite the prolonged treatment. The long median survival of 4.1 years for stage III and IV patients is superior to that usually reported. This could stem from continuing treatment to maximal response rather than an increase in intensity of therapy. These results are comparable to those reported with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy by other investigators. The data suggest that intermittent C + P administered to maximal response continues to be the standard treatment approach for advanced CLL