In a clinical phase I/II study, high-dose cytosine arabinoside and mitoxantrone (HAM) were given in combination to 40 patients with refractory acute myeloid leukemia. All patients had received a 9-day combination of thioguanine, Ara-C, and daunorubicin (TAD-9) as standardized first-line treatment. Refractoriness was defined as (a) nonresponse against two TAD-9 induction cycles, (b) early relapse within the first 6 months on monthly maintenance or after TAD-9 consolidation, (c) relapse after 6 months with nonresponse against one additional TAD-9 cycle, and (d) second and subsequent relapses after successful TAD-9 therapy at the preceding relapse. Therapy consisted of HD-Ara-C 3 g/m2 every 12 hours on days 1 through 4; mitoxantrone was started at 12 mg/m2/day on days 3, 4, and 5 and was escalated to 4 and 5 doses of 10 mg/m2/day on days 2 through 5 and 2 through 6. Of the 40 patients, 21 achieved a complete remission (53%), 1 patient had a partial remission, and 5 patients were nonresponders. Thirteen patients died in aplasia due to infections (n = 11), pericardiac effusion, or acute cardiomyopathy. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. Central nervous system (CNS) symptoms were observed during six treatment courses. Recovery of blood counts occurred at a median of 27 days from the onset of treatment; the median time to complete remission was 36 days. Two of the 21 responders underwent successful bone marrow transplantations. The median remission duration for the remaining 19 patients is 4.5 months, and the median survival time is 9 months. These data emphasize that HAM has high antileukemic activity in refractory AML and strongly suggest starting the combination at earlier stages in AML therapy.
193 patients with relapsed or refractory acute myeloid leukemia (AML) were entered into a prospective randomized comparison of high-dose versus intermediate dose cytosine arabinoside (AraC) both combined with mitoxantrone (mitox) according to the previously established sequential HD-AraC/mitox regimen (S-HAM). AraC was administered by 3 hr inf. q 12 hrs on days 1, 2, and 8, 9 at randomly assigned doses of either 3.0 versus 1.0 g/m2 in pts. < 60 years of age or 1.0 versus 0.5 g/m2 in older pts. Mitox was given to all cases at a dose of 10 mg/m2/d on days 3, 4, and 10, 11. Randomization was stratified for primary refractoriness against induction therapy and the length of first remission in relapsed cases (< 6 mths., 6-18 mths., > 18 mths.). From 151 presently evaluable cases 72 pts (48%) achieved a complete remission (CR), 38 cases (25%) were non-responders (NR) and 41 pts. (27%) died within the first 6 weeks after the start of treatment (early death = ED). No significant differences were found in CR rates being 52% and 44% for the 3.0 versus 1.0 g/m2 AraC regimens in pts. < 60 years and 48% and 45% after 1.0 versus 0.5 g/m2 AraC in older pts. No differences between the respective regimens emerged either for the time to CR (median 46 days) nor remission duration (median 4.5 mths). Analysis of treatment failures, however, demonstrated a significantly higher rate of NR after the lower dose regimens in both age groups of 41% and 32% versus 11% and 14% in pts. receiving AraC at higher doses (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Three brothers from one family died of Hodgkin disease and a fourth brother from a diffuse malignant non-Hodgkin lymphoma. This patient exhibited a constant deficiency of serum immunoglobulins and elevated antibody titers to Epstein-Barr viral antigens. Epstein-Barr virus DNA sequences were detected in DNA isolated from lymph node biopsies from two of the patients. Initially, no abnormalities in the numbers of B and T cells could be detected. Peripheral blood lymphocytes of the patients did not react in the mixed lymphocyte culture assay. We suggest that an immune deficiency to Epstein-Barr virus may favor the proliferation of malignant lymphocytes after Epstein-Barr viral infection. Monoclonal lymphoid B cell lines established spontaneously in vitro from a lymph node biopsy specimen and from peripheral blood specimens from two of the patients. The cells harbor Epstein-Barr viral DNA sequences in multiple genome equivalents and express Epstein-Barr nuclear antigen. The cells contain a tenfold increased level of c-fgr-related RNA transcripts compared with peripheral blood lymphocytes of healthy adults. No obvious amplifications or translocations of the c-myc, c-abl, or c-fgr gene could be detected.
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