Paul Baskind

Phase I clinical and pharmacokinetic evaluation of high-dose mitoxantrone in combination with cytarabine in patients with acute leukemia.

PURPOSE To determine the maximally tolerated dose of mitoxantrone in combination with cytarabine in patients with acute leukemia and advanced phases of chronic myelogenous leukemia (CML), and to assess the pharmacokinetics of high-dose mitoxantrone in this patient population. PATIENTS AND METHODS In a phase I study, 68 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and accelerated- and blastic-phase CML received induction therapy consisting of cytarabine 3 g/m2 by infusion over 3 hours daily for 5 days, with escalating doses of mitoxantrone 40 to 80 mg/m2 over 1 to 2 days by intravenous infusion over 15 minutes. Mitoxantrone pharmacokinetics were evaluated by high-performance liquid chromatography (HPLC) in 15 patients given a single dose of mitoxantrone ranging from 40 to 80 mg/m2 in combination with cytarabine. RESULTS Severe, but reversible hyperbilirubinemia (> three times normal) was considered the dose-limiting toxicity, and was observed in 25% of all patients and in 35% of those who received 70 to 80 mg/m2 of mitoxantrone. Other extramedullary toxicity, including cardiac dysfunction, was mild. Myelosuppression was universal and the median time to complete remission (CR) was 28 days (range, 19 to 77). The CR rate for previously untreated and relapsed patients with AML was 85% (17 of 20) and 38% (seven of 18), respectively. Eighty-three percent (15 of 18) of patients with ALL achieved a CR, including all patients with previously untreated disease. Eight of 12 patients with advanced-phase CML achieved a CR. No significant changes in mean mitoxantrone plasma elimination rates (ie, terminal plasma half-life and total-body clearance rate) occurred as the mitoxantrone dose doubled, indicating linear pharmacokinetics. CONCLUSIONS The recommended phase II dose of mitoxantrone is 80 mg/m2 administered over 15 minutes as a single intravenous infusion in combination with cytarabine 3 g/m2/d for 5 days. At this dose, high concentrations of mitoxantrone are achievable in vivo to levels that have been shown to be extremely cytotoxic in vitro.

Phase I Study of Temozolomide in Relapsed/Refractory Acute Leukemia

PURPOSE To determine the dose-limiting toxicity and maximum-tolerated dose of temozolomide in patients with acute leukemia. PATIENTS AND METHODS Twenty patients (16 with acute myelogenous leukemia, two with acute lymphoblastic leukemia, and two with chronic myelogenous leukemia in blastic phase) received 43 cycles of temozolomide. Patients began treatment at two different dose levels: 200 mg/m(2)/d for 7 days or 200 mg/m(2)/d for 9 days. RESULTS Prolonged aplasia was the dose-limiting toxicity, and the maximum-tolerated dose was 7 days of temozolomide. Overall treatment was well tolerated: hospitalization was required in only nine of 43 courses, and there were no treatment-related deaths. Two patients obtained a complete response, and two others met criteria for complete response except for platelet recovery. Overall, nine of 20 patients had a significant decrease in bone marrow blasts after temozolomide treatment. CONCLUSION Temozolomide was well tolerated and had significant antileukemic activity when administered as a single agent. Further studies of temozolomide in hematologic malignancies are indicated.

A new regimen of amsacrine with high-dose cytarabine is safe and effective therapy for acute leukemia.

Amsacrine and high-dose cytarabine (HiDAc), when administered as single agents, are effective treatment of acute leukemia. When used in combination, a high remission rate is also possible. We treated 47 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and blastic phase of chronic myelogenous leukemia (CML) with a combination of amsacrine and HiDAc. The patients received amsacrine 200 mg/m2 daily for three days and, concurrently, HiDAc 3 g/m2 over three hours once daily for five days. Of 20 evaluable patients with AML in relapse, there were 12 remissions; of seven additional patients with primary refractory AML, there were two remissions, and of 12 patients with ALL in relapse, there were eight remissions. The three patients with blastic phase CML and the three patients with biphenotypic leukemia did not respond. Nausea, vomiting, stomatitis, hepatic dysfunction, and diarrhea were common, but cutaneous, conjunctival, and significant cerebellar and cerebral side effects were absent. We conclude that this regimen is highly effective therapy for AML and ALL and is also safe, eliminating the major toxicities encountered with HiDAc.

Amsacrine is safe and effective therapy for patients with myocardial dysfunction and acute leukemia

The role of amsacrine in inducing remission in patients with cardiac disease and acute leukemia was evaluated. There were 17 patients with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL), and one with biphenotypic leukemia. In this series of 24 patients whose disease had relapsed and who had reduced left ventricular ejection fraction, nine had a complete remission, seven with AML and two with ALL. In addition, four of six with newly diagnosed acute leukemia and reduced left ventricular ejection fraction also responded. Among nine patients who underwent endomyocardial biopsy, none had morphologic changes of sufficient degree to account for drug‐induced heart failure. Patients with preexisting arrhythmias received amsacrine without incident if their serum potassium level was higher than 4.0 mEq/1 at the time of drug administration. Amsacrine is safe and effective therapy for patients with acute leukemia and cardiac disease.

Acute Promyelocytic Leukemia: A 5-Year Experience with New Antileukemic Agents and a New Approach to Preventing Fatal Hemorrhage

Forty-six induction courses were administered to 32 patients with acute promyelocytic leukemia. There were 28 males and 18 females with a median age of 39.5 (range 19-68). Twelve patients were previously untreated, 32 were in relapse, and 2 were refractory to primary induction chemotherapy. Heparin 7.5-10 units/kg/h by continuous infusion, 4-6 units of platelets and 1-2 units of fresh-frozen plasma (FFP) every 12 h were given to all patients. Previously untreated patients received either daunorubicin, idarubicin or mitoxantrone in combination with cytarabine (Ara-C). For relapsed and refractory patients, regimens included amsacrine with high-dose cytarabine (Amsa/HiDac), homoharringtonine (HHT) alone, or with Ara-C, mitoxantrone and bisantrene. Hemorrhagic complications occurred in only 1 out of 46 courses (2%). Complete remission rates (CR) were as follows: previously untreated 83% (10/12), relapsed 66% (21/32), primary refractory 50% (1/2). Amsa/HiDac resulted in a 71% (10/14) CR and HHT-based regimens achieved a 46% (6/13) CR. These regimens are effective and the value of their incorporation into primary therapy should be studied. The use of heparin with platelet and FFP transfusions every 12 h reduces the risk of hemorrhage during induction therapy.

Successful treatment of ibrutinib-associated central nervous system hemorrhage with platelet transfusion support

Ibrutinib is a novel targeted therapy for B-cell malignancies. Hemorrhagic events were reported in the original trials, however the mechanism of bleeding is just being elucidated. Recent studies have demonstrated platelet dysfunction as a mechanism of bleeding. Currently we report two patients who developed life-threatening central nervous system hemorrhage while receiving ibrutinib for chronic lymphoid leukemia (CLL) and mantle cell lymphoma, respectively. Both patients improved rapidly after platelet transfusions even though their platelet counts were normal or only mildly reduced at the time of hemorrhage. We suggest that platelet transfusions can ameliorate the platelet dysfunction defect of ibrutinib and can support the patient through the critical period until new platelet production occurs.

Phase II evaluation of a high-dose mitoxantrone based induction regimen in untreated adults with acute myeloid leukemia.

To evaluate a regimen including high-dose mitoxantrone in previously untreated adults with AML, 45 patients aged 21-59 (median 41) were given cytarabine, 3 g/m2 days 1-5, mitoxantrone, 80 mg/m day 2 and etoposide, 150 mg/m days 1,3,5. Post-remission therapy consisted of 5 cycles combining the same agents at reduced doses. Complete remission was seen in 36 patients. The observed 3-year survival is 28%. Cytogenetic pattern and CD34 expression correlated with response and survival. Significant toxicity included myelosuppression, mucositis, diarrhea and hyperbilirubinemia. Ventricular ejection fraction was generally reduced, with clinical cardiac dysfunction in only 2 patients. This high-dose mitoxantrone combination can be administered to young adults with AML with tolerable toxicity and results comparable to those of other dose-intensive regimens.

Long-term follow-up of high-dose mitoxantrone-based induction therapy for patients with newly-diagnosed acute myelogenous leukemia. Twelve year results from a single institution

This report provides long-term results of the treatment of patients with newly-diagnosed AML with a single high dose of mitoxantrone combined with once daily cytarabine. One-hundred and sixty-five patients treated on four studies of high-dose mitoxantrone-based induction therapy are included. Patients with a prior antecedent hematologic disorder were eligible. The median follow-up time is 65.9 months (95% CI: 55.7–86.2 months). The overall complete remission rate was 64%, with responses in 78% of patients less than 60 years of age and 51% of patients 60 years of age or older. The median duration of response is 21.2 months and 8.0 months and overall survival is 15.4 months and 7.6 months, respectively. For a sub-set of patients who would be eligible for most US trials, the complete remission rate was 84% in younger patients and 60% in older patients. The median duration of response was 39.0 and 8.2 months and the median overall survival was 19.4 and 7.6 months, respectively. The efficacy of these regimens compared favorably to results reported with standard ‘3 + 7’ regimens. Use of a once-daily cytarabine regimen resulted in almost no neurotoxicity and allowed for administration of consolidation in the outpatient setting.

Intravenous Bolus Topotecan in Patients with Myelodysplastic Syndrome

We treated 16 patients with myelodysplastic syndromes with 24 courses of bolus topotecan. Patients received topotecan as a daily 15 minute infusion for 5 days at 3 dose levels (4.0 mg/m2/d, 2.0 mg/m2/d or 2.5 mg/m2/d). There was one complete response and one partial response (overall response rate 12%). Toxicity included myelosuppression, diarrhea, ileus and mucositis. There were 3 treatment-related deaths. The results of this schedule of topotecan appeared to be inferior to that reported with infusional topotecan in patients with MDS.

Preliminary Experience with Short Course High-Dose Mitoxantrone in Combination with High-Dose Cytarabine in Patients with Acute Leukemia and Blastic Phase of Chronic Myelogenous Leukemia

Mitoxantrone is effective therapy for patients with acute leukemia and blastic phase of chronic myelogenous leukemia (CML). In vitro mitoxantrone has a steep dose response curve, which suggests that higher doses given in a shorter duration may result in enhanced leukemic cell kill in vivo. Twenty-four patients with acute leukemia and blastic CML received mitoxantrone 20 mg/m2 I.V. daily × 2 with cytarabine 3 g/m2 I.V. once daily × 5 days. Diagnoses included 8 patients with previously untreated acute non-lymphocytic leukemia (ANLL), 9 patients with relapsed ANLL, 4 patients with refractory acute lymphoblastic leukemia (ALL) and 2 patients with blastic CML. Complete remission was achieved in 8 of 17 patients with ANLL, 1 of 4 patients with ALL and 0 of 2 with blastic CML. Extramedullary toxicity was acceptable and the median time to remission was 26 days (range 20-69). Short course high-dose mitoxantrone with high-dose cytarabine is effective and well-tolerated in patients with acute leukemia.