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Abstract: Objective: Older adults with acute myeloid leukemia (AML) tend to have worse complete remission (CR) rates and overall survival compared to their younger counterparts. At least one reason for this is increased expression of the multidrug resistance gene (MDR1). Dose dense, high intensity chemotherapy may overcome the MDR1 effect, possibly when combined with anti-CD33 monoclonal antibody gemtuzumab ozogamicin (GO,Mylotarg™), which has been studied in older adults with relapsed AML. This phase I study was aimed at establishing safety by defining a maximum tolerated dose (MTD) by treating older AML patients with two cycles of dose-dense therapy with high dose cytarabine (HiDAC) combined with targeted therapy using GO. Materials and methods: Nine patients ≥60years with newly diagnosed, untreated CD33+ AML with adequate renal and hepatic function, and ECOG PS 0-2 were eligible. HiDAC was administered at two dose levels: 3000mg/m2 every 12h for 6 doses (cohort 1), or 9 doses (cohort 2). GO was administered at 6mg/m2 on days 1 and 8. Results: The MTD was HiDAC 3000mg/m2 for six doses along with GO 6mg/m2. All patients had grades 3–4 pancytopenia, and two patients developed reversible grade 2 neurotoxicity. There were no cases of veno-occlusive disease. Seven of nine patients had a complete response (CR or CRp). Conclusions: There was no difference in relapse-free survival in our patients when compared to historical data. However, despite high toxicity, two of nine patients treated in this dose-dense fashion remained in CR for >60months. [Copyright &y& Elsevier]

The purpose of this study was to evaluate the efficacy and safety of short-course bortezomib, melphalan, prednisone (VMP) in previously untreated multiple myeloma as frontline therapy for transplant-ineligible patients and induction prior to autologous stem cell transplantation (ASCT). Patients received up to 6 28-day cycles of bortezomib 1.3 mg/m2, days 1, 4, 8, and 11, plus melphalan 6 mg/m2 and prednisone 60 mg/m2, days 1-7. After 2-6 cycles, eligible and consenting patients could proceed to ASCT. Responses were assessed by International Uniform Response Criteria. The primary endpoint was complete response (CR) rate with VMP. Forty-five patients were enrolled. Among 44 evaluable patients, response rate was 95%, including 18% ≥CR (9% stringent CR), 27% very good partial responses (VGPR), and 50% partial responses (PR). Twenty patients proceeded to ASCT. Stem cell collection was successful in all; median yield was 5.6×106 CD34+ cells/kg. Posttransplant response rates were 30% ≥CR (10% stringent CR), 65% VGPR, and 5% PR. After median follow-up of 14.0/14.6 months, median time to progression and progression-free survival were both 19.8/27.9 months in non-ASCT/ASCT patients. Seven patients have died; 1-year survival rates were 82%/95% in non-ASCT/ASCT patients. The most common grade 3/4 toxicities were thrombocytopenia (20%), neutropenia (28%), and infection (9%). Peripheral neuropathy grade 2-4 was the most common nonhematopoietic side effect occurring 17 patients (38%), although it was typically reversible, and only 5 patients (11%) discontinued therapy as a result of it. Short-course VMP is highly effective and generally well tolerated, both as initial treatment in non-ASCT patients and induction prior to ASCT. VMP did not negatively affect stem cell collection. Longer follow-up and prospective phase III trials are required to validate these initial observations. [Copyright &y& Elsevier]

Abstract: Purpose: The decision to re-induce patients with acute myeloid leukemia (AML) based on results of the day 14 bone marrow (BM) biopsy is variable and lacks evidence based data. The aim of our review was to evaluate the accuracy of a day 14 BM biopsy in determining the need for re-induction chemotherapy. Methods: Seventy-four patients with newly diagnosed de novo AML treated with induction chemotherapy were retrospectively reviewed for the purpose of evaluating treatment decisions and outcomes based on their day 14 BM biopsy. Response to therapy in this analysis was based on morphology alone. Results: Of the 74 patients undergoing standard induction, 45 patients (61%) had no evidence of leukemia on their day 14 BM biopsy. Eighteen patients (24%) had definitive residual disease (RD), and 11 patient''s (15%) were classified as indeterminate response (IR). Fifteen patients with RD and one with IR underwent re-induction chemotherapy. However, thirteen patients (3 RD and 10 IR) were observed until count recovery without any re-induction therapy. Eleven of these 13 patients who were observed eventually attained a morphologic complete remission (CR), including two patients with RD. Conclusions: A day 14 BM biopsy may have suboptimal sensitivity for the detection of residual leukemia. Some patients with an IR on day 14 may not require re-induction chemotherapy, but instead, may benefit from careful observation until count recovery to avoid the mortality and morbidity associated with re-induction chemotherapy. [Copyright &y& Elsevier]

Abstract: Nitric oxide synthase (NOS) inhibitors induce chronic lymphocytic leukemia (CLL) cell apoptosis and have potential as CLL therapeutics. We determined the half-maximal concentration (ED50) of 22 NOS inhibitors that induced CLL cell death in vitro. There was a direct correlation of the NOS1 (but not NOS2) dissociation constant (K d) and the hydrophobicity partitioning coefficient of each NOS inhibitor and its ED50. NOS inhibitors that bound tightly to CLL cell NOS1 and were hydrophobic potently induced CLL cell death. CLL cell RNA and protein analyses confirmed CLL cell NOS1 expression. Our studies permit the rational selection of NOS inhibitors for testing as CLL therapeutics. [Copyright &y& Elsevier]

Abstract: B cell chronic lymphocytic leukemia (CLL) CD38 expression is variable and may predict outcome. Inducible nitric oxide synthase (NOS2) expression regulates CLL cell apoptosis. IL-4 and IFN-γ regulate B cell CD38 expression and NOS2 expression. We compared IL-4 and IFN-γ serum levels between CLL patients and normal individuals, and determined whether serum IL-4 and IFN-γ levels correlated with CLL cell CD38 expression and NOS enzyme activity. IL-4 levels, but not IFN-γ levels, differed between normal individuals and CLL patients. Furthermore, there was an association of IL-4 levels, but not IFN-γ levels, with CD38 and NOS2 expression in CLL patients. [Copyright &y& Elsevier]