First line Fludarabine treatment of symptomatic chronic lymphoproliferative diseases: clinical results and molecular analysis of minimal residual disease.

Fludarabine (25 mg/m2 for 5 d, every 4 wk, for 6 courses) was administered as first line therapy in 32 symptomatic chronic lymphoproliferative diseases. All CLL patients achieved at least partial response (5 CR, 2 nPR, 9 PR) but 44% of patients relapsed. In LG-NHLs response and relapse rate were similar. Haematological toxicity was low. VDJ rearrangement PCR analysis was performed on marrow samples at diagnosis and at the time of response evaluation. In the 3 patients who underwent high dose therapy with peripheral blood progenitor cell rescue analysis was also performed on apheresis samples and on marrow samples at the end of the procedure. Clonal VDJ rearrangement was always evident after Fludarabine therapy even in those patients who achieved histological and immunophenotypic complete remission, whereas it disappeared in 2 of 3 patients who underwent HDT. Our data confirm that Fludarabine monotherapy can reduce the neoplastic mass to a subclinical level and suggest the possibility that high dose therapy might produce true complete remission.

Long-lasting effect of cyclosporin-A on anemia associated with idiopathic myelofibrosis.

Some reports suggest that immunologic mechanisms may play a role in the pathogenesis of anemia in idiopathic myelofibrosis (IMF). Herein we report the case of a transfusion dependent IMF patient with psoriasis in whom cyclosporin-A (CyA) treatment for skin lesions (200 mg/day) was associated with long-lasting correction of anemia. After 2 months of CyA therapy the patient's Hb level increased and he became transfusion free in 4 months. After 12 months immunosuppressive therapy was discontinued due to renal toxicity, yet the Hb level remained stable for an additional 12 months. The patient is currently being administered CyA at a reduced dosage because of mild renal impairment along with transfusional support consisting of a median of 2 red cell units/month. Altogether the patient received no transfusional support for 36 months. This case, as well as other reports, suggests that the issue of immunosuppressive treatment in IMF anemia deserves further investigation.

The association of cyclophosphamide and dexamethasone in advanced refractory multiple myeloma patients.

VAD is the most active regimen in refractory myeloma patients; however, the role of vincristine and doxorubicin remains unclear. Relatively high doses of cyclophosphamide (3.6 g/sqm) increased the response rate and survival in resistant MM. Cyclophosphamide and dexamethasone were administered to 28 patients with advanced refractory myeloma. Thirteen patients received cyclophosphamide 1.2 g/sqm on days 1 and 3 and dexamethasone 40 mg/day from day 1 to day 4, every 4 weeks for 6 cycles (schedule A); 15 patients were treated with cyclophosphamide 0.5 g/sqm on days 1 and 3 and dexamethasone 40 mg/day from day 1 to day 4, every two weeks for 12 cycles (schedule B). Overall, 21 patients (75%) responded and 10 achieved an objective response (36%), while 11 reached a partial response. Twenty patients died (68%), most of them of disease progression, and 8 are still alive (32%). Median length of response and survival is 6 and 8 months, respectively. Therapy was easily applied and well tolerated. The overall response rate (75%) compares favorably with the best published results in this setting. The two schedules proved to be equally effective but patients treated with schedule B had more infections, which may have been related to the higher dosage of steroids.

High efficacy of fludarabine-containing therapy (FLAG-FLANG) in poor risk acute myeloid leukemia.

BACKGROUND: Elderly patients with acute myeloid leukemia (AML) those refractory to induction chemotherapy and those with so-called secondary leukemia have unfavorable prognoses and require innovative therapeutic approaches. Fludarabine allows an increased accumulation of Ara-CTP in leukemic cells and inhibits DNA repair mechanisms; therefore its association with Ara-C and mitoxantrone results in a synergistic effect. MATERIALS AND METHODS: From May 1993 to February 1996, fludarabine-containing regimens (FLAG and FLANG) were employed as induction therapy in 51 high-risk AML patients. Diagnosis of AML in 22 patients was preceded by a myelodysplastic syndrome lasting more than six months; 8 of the 29 de novo AML cases (28%) were refractory to previous chemotherapy, 9 (31%) were treated for early relapse, 12 (41%) presented poor prognostic factors at diagnosis. The median age was 64 (range 33-76) years and the FAB subtypes were the following: M0 3, M1 5, M2 28, M4 7, M5 8. Forty-eight per cent of patients showed poor prognosis chromosomal abnormalities. FLAG (24 patients) consisted of both fludarabine 30 mg/sqm over 30 minutes followed 4 hours later by Ara-C 2 g/sqm over 4 hours (for 5 days) and G-CSF 300 micrograms/day administered 12 hours before fludarabine, for a total of 5 doses. FLANG (27 patients) had a shorter duration (3 days), reduced Ara-C dosage (1 g/sqm) and administration of mitoxantrone (10 mg/sqm) at the end of Ara-C infusion. RESULTS: Recovery of both neutrophils (PMN > 0.5 x 10(9)/L) and platelets (Plt > 20 x 10(9)/L) required a median of 16 days from the end of therapy. Overall, 30 patients (59%) achieved CR, 6 (11%) PR and 10 (20%) were refractory; 5 (10%) experienced early death (cerebral hemorrhage or infection). The length of complete response ranged from 2 to 26 months with a median follow-up of 8 months. De novo and secondary AML registered 62 and 54% CR rates, respectively. Eight out of 10 patients refractory to conventional schemes achieved CR (80%) but only 3 out of 10 treated for relapse obtained CR (30%). CONCLUSIONS: FLAG and FLANG showed similar activity and toxicity while proving to be highly effective and relatively well-tolerated treatments for high-risk de novo AML. Secondary leukemias seemed to be responsive as well, but the presence of an unfavorable karyotype alteration lowered the response rate.

Multiple myeloma in the elderly: clinical features and response to treatment in 113 patients.

BACKGROUND: Considering the conflicting results of the few reports on geriatric MM patients and the increasing relevance of the problem, we analyzed a series of 113 patients over 64 years of age treated with conventional chemotherapy. PATIENTS AND METHODS: The median age was 71 (range 65-92). Stage IA, IIA, IIIA and IIIB patients numbered 28, 33, 45 and 7, respectively. The M component was IgG in 73 patients (65%), IgA in 30 (26%), IgD in 3 (3%), light chain in 5 (4%); no monoclonal component was detected in 2 (2%) cases. Sixty-three patients showed symptomatic skeletal disease. Melphalan/prednisone (MP) was the first-line treatment in 84 patients (74%). Patients were grouped according to age (> 64 < or = 74; > or = 75) in order to carry out analysis. RESULTS: Seventy-eight cases (69%) showed a sizable reduction in the tumor mass; objective and partial response was achieved in 57 (50%) and 21 (19%) patients, respectively. Patients with stage I-II disease fared significantly better than stage III patients (median survival: 70 vs 38 months; p = 0.017). Response to first-line treatment correlated with overall survival; patients with responsive or refractory disease had median survival rates of 64 and 20 months, respectively (p = 0.0001). CONCLUSIONS: Neither patients above nor below 75 years of age showed any difference in presentation features or in response to treatment. These results suggest that advanced age should not be considered a major obstacle to active treatment.