Caroline Berube

Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9

Objective Warfarin dosing remains challenging because of its narrow therapeutic window and large variability in dose response. We sought to analyze new factors involved in its dosing and to evaluate eight dosing algorithms, including two developed by the International Warfarin Pharmacogenetics Consortium (IWPC). Methods we enrolled 108 patients on chronic warfarin therapy and obtained complete clinical and pharmacy records; we genotyped single nucleotide polymorphisms relevant to the VKORC1, CYP2C9, and CYP4F2 genes using integrated fluidic circuits made by Fluidigm. Results When applying the IWPC pharmacogenetic algorithm to our cohort of patients, the percentage of patients within 1 mg/d of the therapeutic warfarin dose increases from 54% to 63% using clinical factors only, or from 38% using a fixed-dose approach. CYP4F2 adds 4% to the fraction of the variability in dose (R2) explained by the IWPC pharmacogenetic algorithm (P<0.05). Importantly, we show that pooling rare variants substantially increases the R2 for CYP2C9 (rare variants: P=0.0065, R2=6%; common variants: P=0.0034, R2=7%; rare and common variants: P=0.00018; R2=12%), indicating that relatively rare variants not genotyped in genome-wide association studies may be important. In addition, the IWPC pharmacogenetic algorithm and the Gage (2008) algorithm perform best (IWPC: R2=50%; Gage: R2=49%), and all pharmacogenetic algorithms outperform the IWPC clinical equation (R2=22%). VKORC1 and CYP2C9 genotypes did not affect long-term variability in dose. Finally, the Fluidigm platform, a novel warfarin genotyping method, showed 99.65% concordance between different operators and instruments. Conclusion CYP4F2 and pooled rare variants of CYP2C9 significantly improve the ability to estimate warfarin dose.

Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia

There are limited treatment options for older patients with acute myeloid leukemia and prognosis of these patients remains poor, thereby warranting development of novel therapies. We evaluated the efficacy and safety of azacitidine in combination with lenalidomide as front-line therapy for older patients with acute myeloid leukemia. Patients ≥60 years of age with untreated acute myeloid leukemia received azacitidine 75 mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 days starting on day 8 of each cycle every 6 weeks. Patients received continued therapy until disease progression, unacceptable toxicity, or completion of 12 cycles. Forty-two patients (median age, 74 years) were enrolled with equal distribution according to European LeukemiaNet risk. The overall response rate was 40% (rate of complete remission with or without complete recovery of blood counts = 28%). The median time to complete remission with or without complete recovery of blood counts was 12 weeks, and duration of this status was 28 weeks (range, 4 - >104 weeks). Therapy-related acute myeloid leukemia and a high score on the Hematopoietic Cell Transplantation Comorbidity Index were negative predictors of response. Early death was noted in 17% of patients. Grades ≥ 3 toxicities were uncommon and most adverse events were gastrointestinal, fatigue and myelosuppression. In conclusion, a sequential combination of azacitidine plus lenalidomide has clinical activity in older patients with acute myeloid leukemia, and further studies of this combination are underway. This study is registered at www.clinicaltrials.gov as # NCT00890929.

Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: a single-center experience.

The majority of patients with acute myeloid leukemia (AML) will require second‐line chemotherapy for either relapsed or refractory disease. Currently, only allogeneic hematopoietic cell transplantation (HCT) offers a curative option in this setting and no preferred regimen has been established. The reported efficacy of second‐line regimens is widely disparate, thus limiting informed clinical decision making. A retrospective review of 77 patients receiving therapy between 2001 and 2008 with relapsed, 42, and refractory, 35, AML was performed to determine overall response rate and survival following mitoxantrone (8 mg/m2/day), etoposide (100 mg/m2/day), and cytarabine (1,000 mg/m2/day) chemotherapy administered over 5 days. Among 77 patients (median age of 54 years and 64% intermediate risk karyotype) with median follow‐up of 153 days, 18% achieved a complete response and 8% a morphologic leukemia‐free state. Fifty‐seven (74%) experienced treatment failure, 10 of whom achieved a remission after additional therapy. Median overall survival (OS) was 6.8 months. Among patients achieving a response, 50% received consolidation with allogeneic HCT, autologous HCT (5%), or consolidation chemotherapy alone (45%). A nonsignificant trend in overall response (50%, 27%, and 23.8%) and median OS (8.3, 6.8, and 4.7 months) was observed by cytogenetic stratification into favorable, intermediate, and unfavorable risk. Patients with refractory versus relapsed disease had similar overall responses (20% and 31%, P = 0.41) and median OS (5.3 and 7.6 months, P = 0.36). Despite risk stratification by the European Prognostic Index, our series demonstrates inferior rates of response and survival, illustrating the limited activity of this regimen in our cohort. Am. J. Hematol., 2010.

Eculizumab Induces Sustained Remission in a Patient With Refractory Primary Catastrophic Antiphospholipid Syndrome.

Catastrophic antiphospholipid syndrome (CAPS) is fatal in approximately 44% of patients in whom the diagnosis is made, thus demonstrating the inadequacy of current medical therapy. In this report, we discuss a 47-year-old man with a known history of primary antiphospholipid syndrome, who presented with CAPS after undergoing cholecystectomy and a treatment-refractory early relapse after development of colitis. Given the potential therapeutic efficacy of complement inhibition in antiphospholipid syndrome, the patient was administered eculizumab, a terminal complement inhibitor. Progressive clinical improvement and laboratory improvement were observed upon initiation of eculizumab. He has remained in remission for over 16 months of follow-up while on eculizumab. In conclusion, this case represents successful use of eculizumab for the treatment of primary CAPS.

Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia.

Background This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy. Design and Methods Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts. Results Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6–65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients. Conclusions Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.

Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome

Abstract The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). This study describes a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1–7, followed by lenalidomide 50 mg orally daily on days 8–28. The median number of treatment cycles on study was two (range = 1–11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders vs non-responders was 9.8 vs 4.0 months, respectively (HR = 0.36, p = 0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.

Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial

Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.

Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia.

The survival of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is poor. We performed a retrospective analysis of 40 patients treated with five days of mitoxantrone 8mg/m(2)/day, etoposide 100mg/m(2)/day, and cytarabine 1000mg/m(2)/day (MEC). The complete remission rate was 30% and median remission duration was 11.2 months. Median overall survival was 6.5 months. In univariate analysis, patients in first relapse had improved overall survival compared to ≥second relapse (p=0.02). Thirty-day mortality rate was 7.5%. In relapsed or refractory ALL, MEC demonstrated moderate activity, but did not improve survival compared to published salvage chemotherapy regimens.

Prochemerin cleavage by Factor XIa links coagulation and inflammation

Chemerin is a chemoattractant and adipokine that circulates in blood as inactive prochemerin (chem163S). Chem163S is activated by a series of C-terminal proteolytic cleavages resulting in diverse chemerin forms with different levels of activity. We screened a panel of proteases in the coagulation, fibrinolytic, and inflammatory cascades to identify those that process prochemerin in plasma. Factor XIa (FXIa) cleaved chem163S, generating a novel chemerin form, chem162R, as an intermediate product, and chem158K, as the final product. Processing at Arg162 was not required for cleavage at Lys158 or regulation of chemerin bioactivity. Contact phase activation of human platelet-poor plasma by kaolin led to cleavage of chem163S, which was undetectable in FXI-depleted plasma and markedly enhanced in platelet-rich plasma (PRP). Contact phase activation by polyphosphate in PRP resulted in 75% cleavage of chem163S. This cleavage was partially inhibited by hirudin, which blocks thrombin activation of FXI. After activation of plasma, levels of the most potent form of chemerin, chem157S, as well as inactive chem155A, increased. Plasma levels of chem163S in FXI-deficient patients were significantly higher compared with a matched control group (91 ± 10 ng/mL vs 58 ± 3 ng/mL, n = 8; P < .01) and inversely correlated with the plasma FXI levels. Thus FXIa, generated on contact phase activation, cleaves chem163S to generate chem158K, which can be further processed to the most active chemerin form, providing a molecular link between coagulation and inflammation.