ALBERT

Description: Detection of membrane markers and ultrastructural peroxidase activity was carried out on the blasts of 16 apparently nonmyeloid adult acute leukemias. These patients were selected from 73 adult leukemic patients by the negativity of their routine cytochemical myeloid markers: i.e., myeloperoxidase, chloresterase activity, and Sudan Black B staining. B and T acute lymphoid leukemias (ALL) were excluded from the study. After concurrent testing from human T lymphocyte antigen (HuTLA), common ALL antigen (cALL), la-like antigens, and peroxidase activity at the electron microscopic level (POEM), only two patients remained undifferentiated (cALL-, POEM-). The other cases were classified as following : 6 common ALL (cALL+, POEM-), 1 pre-T-ALL (cALL+, HuTLA+, POEM-), 5 very poorly differentiated acute myelogenous leukemia (AML) (cALL-, POEM+), and 2 mixed leukemias (cALL+, POEM+). Terminal deoxynucleotidyl transferase activity (TdT) was measured in 7 cases and was found to be present at high levels in 4 cases of cALL and in the 2 cases of acute undifferentiated leukemias (AUL): it was absent in two cases of AML. Cytogenetic analysis had showed that 2 of the cALLs, 3 of the AMLs, and the 2 mixed leukemias were PH1+. We conclude that POEM detection is useful in apparently nonmyeloid leukemias with negative immunologic lymphoid markers, and that the existence of a Ph1 chromosome should be investigated, particularly in the unusual case of mixed (lymphoid-myeloid) acute leukemia.

Description: Twenty-four patients with acute nonlymphocytic leukemia (ANLL) were treated with high-dose chemotherapy or chemoradiotherapy followed by infusion of autologous marrow purged with 100 micrograms/mL of 4- hydroperoxycyclophosphamide (4HC). The marrow harvests were performed when there were less than 5% blasts in the marrow. Seven patients were transplanted in second complete remission (CR), eight in third CR, one in fourth CR, and eight in early relapse. The median time to achieve 500 neutrophils/microL or 1,000 leukocytes/microL was 30 days. A platelet count of 20,000/microL and 50,000/microL was achieved at a median of 67 and 91 days, respectively. One patient failed to engraft by day 58. There were five other transplant-related deaths: sepsis (one), intracerebral hemorrhage (one), veno-occlusive disease (one), and interstitial pneumonia (two). Four of seven evaluable patients transplanted in early relapse obtained a CR lasting 112, 143, 189, and greater than 615 days. Eight of 11 evaluable patients transplanted in CR have relapsed at a median of 153 days (range, 104 to 311). The actuarial survival for all patients was 19%. There was a trend toward improved relapse-free survival for patients transplanted in remission as opposed to those transplanted in relapse (P = .11).

Description: To evaluate the hematologic effects of recombinant human interleukin-6 (rhIL-6, Escherichia coli, SDZ ILS 969, IL-6), and determine its toxicity profile, we performed a phase I trial of IL-6 in 22 patients with various myelodysplastic syndromes (MDS), platelet counts 〈 100,000/microL, and 〈 5% bone marrow (BM) blasts. Patients received one of four doses of IL-6 (1.0, 2.5, 3.75, and 5.0 micrograms/kg/d) as a subcutaneous injection on day 1, followed by a 7-day wash-out period, and then 28 days of IL-6 therapy. Dose-limiting toxicities of fatigue, fever, and elevated alkaline phosphatase were seen at 5.0 micrograms/kg/d; the maximum tolerated dose was 3.75 micrograms/kg/d. All patients experienced at least grade II fever and all had an increase in acute phase proteins. Eight patients (36%) experienced at least a transient improvement in platelet counts; three fulfilled the criteria for response, whereas five others had clinically significant increases that failed to meet response criteria. Various IL-6-related toxicities prevented more than three patients from receiving maintenance therapy. Two of the three patients who received maintenance IL-6 therapy had a persistent increase in platelet counts, during 3 and 12 months of IL-6 therapy, respectively. Laboratory studies indicated that IL-6 increased the frequency of higher ploidy megakaryocytes but did not significantly increase the number of assayable megakaryocytic progenitor cells, suggesting that IL-6 acts as a maturational agent rather than a megakaryocyte colony-stimulating factor. Although IL-6 therapy can promote thrombopoiesis in some MDS patients, its limited activity and significant therapy-related toxicity preclude its use as a single agent in this patient population. Further studies, combining low doses of IL-6 with other hematopoietic growth factors, are underway.

Description: A phase I trial was conducted with recombinant human interleukin-1 beta (rhIL-1 beta) in patients undergoing autologous bone marrow (BM) transplantation for acute myelogenous leukemia. rhIL-1 beta was administered at 3 dose levels (0.01, 0.02, 0.05 microgram/kg) by 30 minute intravenous infusion once a day beginning on the day of BM infusion and continuing for a total of 5 doses. A total of 17 patients were entered on the trial, and their results were compared with those of 74 consecutive historical control patients that did not receive colony stimulating factors. Moderate toxicity was observed in all patients. All 17 patients developed fever and chills within 30 minutes after initiation of rhIL-1 beta, and hypotension was observed in 14 of 17 patients 5 to 8 hours after the infusion. A total of 30% of patients required therapy (normal saline or dopamine) for treatment of hypotension. Therefore, dose escalation was discontinued at the 0.05 microgram/kg dose level. The number of days required to achieve an absolute neutrophil count greater than 500 mL in patients who received rhIL-1 beta was less than in historical patients (25 v 34; P = .02). This appeared to correlate with a reduced incidence of infection between days 0 and 28 after BM infusion (12% v 23%; P = .049). Median bilirubin, median creatinine, platelet recovery, and days in the hospital were not different between study patients and historical controls. Survival of patients who received rhIL-1 beta compared with that of historical patients was improved (30% v 20%; P = .04). These possible benefits were achieved at the cost of moderate toxicity during rhIL-1 beta administration.

Description: Detection of membrane markers and ultrastructural peroxidase activity was carried out on the blasts of 16 apparently nonmyeloid adult acute leukemias. These patients were selected from 73 adult leukemic patients by the negativity of their routine cytochemical myeloid markers: i.e., myeloperoxidase, chloresterase activity, and Sudan Black B staining. B and T acute lymphoid leukemias (ALL) were excluded from the study. After concurrent testing from human T lymphocyte antigen (HuTLA), common ALL antigen (cALL), la-like antigens, and peroxidase activity at the electron microscopic level (POEM), only two patients remained undifferentiated (cALL-, POEM-). The other cases were classified as following : 6 common ALL (cALL+, POEM-), 1 pre-T-ALL (cALL+, HuTLA+, POEM-), 5 very poorly differentiated acute myelogenous leukemia (AML) (cALL-, POEM+), and 2 mixed leukemias (cALL+, POEM+). Terminal deoxynucleotidyl transferase activity (TdT) was measured in 7 cases and was found to be present at high levels in 4 cases of cALL and in the 2 cases of acute undifferentiated leukemias (AUL): it was absent in two cases of AML. Cytogenetic analysis had showed that 2 of the cALLs, 3 of the AMLs, and the 2 mixed leukemias were PH1+. We conclude that POEM detection is useful in apparently nonmyeloid leukemias with negative immunologic lymphoid markers, and that the existence of a Ph1 chromosome should be investigated, particularly in the unusual case of mixed (lymphoid-myeloid) acute leukemia.

Description: Twenty-four patients with acute nonlymphocytic leukemia (ANLL) were treated with high-dose chemotherapy or chemoradiotherapy followed by infusion of autologous marrow purged with 100 micrograms/mL of 4- hydroperoxycyclophosphamide (4HC). The marrow harvests were performed when there were less than 5% blasts in the marrow. Seven patients were transplanted in second complete remission (CR), eight in third CR, one in fourth CR, and eight in early relapse. The median time to achieve 500 neutrophils/microL or 1,000 leukocytes/microL was 30 days. A platelet count of 20,000/microL and 50,000/microL was achieved at a median of 67 and 91 days, respectively. One patient failed to engraft by day 58. There were five other transplant-related deaths: sepsis (one), intracerebral hemorrhage (one), veno-occlusive disease (one), and interstitial pneumonia (two). Four of seven evaluable patients transplanted in early relapse obtained a CR lasting 112, 143, 189, and greater than 615 days. Eight of 11 evaluable patients transplanted in CR have relapsed at a median of 153 days (range, 104 to 311). The actuarial survival for all patients was 19%. There was a trend toward improved relapse-free survival for patients transplanted in remission as opposed to those transplanted in relapse (P = .11).

Description: A phase I trial was conducted with recombinant human interleukin-1 beta (rhIL-1 beta) in patients undergoing autologous bone marrow (BM) transplantation for acute myelogenous leukemia. rhIL-1 beta was administered at 3 dose levels (0.01, 0.02, 0.05 microgram/kg) by 30 minute intravenous infusion once a day beginning on the day of BM infusion and continuing for a total of 5 doses. A total of 17 patients were entered on the trial, and their results were compared with those of 74 consecutive historical control patients that did not receive colony stimulating factors. Moderate toxicity was observed in all patients. All 17 patients developed fever and chills within 30 minutes after initiation of rhIL-1 beta, and hypotension was observed in 14 of 17 patients 5 to 8 hours after the infusion. A total of 30% of patients required therapy (normal saline or dopamine) for treatment of hypotension. Therefore, dose escalation was discontinued at the 0.05 microgram/kg dose level. The number of days required to achieve an absolute neutrophil count greater than 500 mL in patients who received rhIL-1 beta was less than in historical patients (25 v 34; P = .02). This appeared to correlate with a reduced incidence of infection between days 0 and 28 after BM infusion (12% v 23%; P = .049). Median bilirubin, median creatinine, platelet recovery, and days in the hospital were not different between study patients and historical controls. Survival of patients who received rhIL-1 beta compared with that of historical patients was improved (30% v 20%; P = .04). These possible benefits were achieved at the cost of moderate toxicity during rhIL-1 beta administration.