Acute myeloid leukemia in a father and son with a germline mutation of ASXL1.

BACKGROUND: Myelodysplastic syndromes and acute myeloid leukemia usually occur sporadically in older adults. More recently cases of familial acute myeloid leukemia and/or myelodysplastic syndrome have been reported. CASE PRESENTATION: Currently we report a father and son who both developed myelodysplastic syndrome that progressed to acute myeloid leukemia. Both patients were found to have the identical mutation of ASXL1 on nextgen sequencing of both hematologic and nonhematologic tissues. CONCLUSIONS: These cases support the diagnosis of a germline mutation of ASXL1.

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.

CLAG-based induction therapy in previously untreated high risk acute myeloid leukemia patients.

The CLAG regimen is highly active in patients with relapsed and/or refractory acute myeloid leukemia (AML). We administered CLAG-based chemotherapy to 20 previously untreated AML patients who were poor candidates for standard induction therapy. Responding patients received further CLAG as post-remission therapy followed by additional therapy that was tailored to their AML subtype. Patients were considered poor candidates for standard therapy due to either cardiac disease, prior chemotherapy for another malignancy, prior myeloproliferative disease, or myelodysplastic syndrome that had progressed after hypomethylator therapy. Overall, thirteen patients had a complete response (CR) to the first cycle of therapy (65%), one patient had a CR without platelet recovery, and 3 patients had a partial response (PR). Two of the patients with PR converted to CR after further therapy. The median duration of response has not been reached; the mean duration of response is 36.8 months (95% CI 28.8-44.8 months). Median overall survival (including deaths from all causes) is 29.0 months (95% CI 18.0-46.0 months). Patients with de novo AML had a CR rate of 90.9% and a median overall survival of 38.5 months. CLAG-based therapy is a well-tolerated, efficacious induction strategy in previously-untreated patients with high risk AML. CLAG-based regimens should be studied in a broader group of newly diagnosed AML patients.

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.

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.