Michael L. Tidwell

Targeting Vascular Endothelial Growth Factor for Relapsed and Refractory Adult Acute Myelogenous Leukemias: Therapy with Sequential 1-β-d-Arabinofuranosylcytosine, Mitoxantrone, and Bevacizumab

Purpose: Vascular endothelial growth factor (VEGF) promotes acute myelogenous leukemia (AML) cell growth and survival and may contribute to drug resistance. bevacizumab, an anti-VEGF monoclonal antibody, exhibits clinical activity against diverse malignancies when administered with cytotoxic chemotherapy. We conducted a Phase II clinical trial of bevacizumab administered after chemotherapy to adults with refractory or relapsed AML, using a timed sequential therapy (TST) approach. Experimental Design: bevacizumab 10 mg/kg was administered on day 8 after 1-β-d-arabinofuranosylcytosine 2 g/m2/72 h beginning day 1 and mitoxantrone 40 mg/m2 beginning day 4. In vivo laboratory correlates included AML cell VEGF receptor-1 (FLT-1) expression, marrow microvessel density, and free serum VEGF before and during TST with bevacizumab. Results: Forty-eight adults received induction therapy. Myelosuppression occurred in all of the patients similar to other TST regimens. Toxicities were decreased ejection fraction (6%), cerebrovascular bleed (4%), and mortality of 15%. Overall response was 23 of 48 (48%), with complete response (CR) in 16 (33%). Eighteen (14 CR and 4 partial response) underwent one consolidation cycle and 5 (3 CR and 2 partial response) underwent allogeneic transplant. Median overall and disease-free survivals for CR patients were 16.2 months (64%, 1 year) and 7 months (35%, 1 year). Marrow blasts demonstrated FLT-1 staining before bevacizumab and marked decrease in microvessel density after bevacizumab. VEGF was detected in pretreatment serum in 67% of patients tested, increased by day 8 in 52%, and decreased in 93% (67% undetectable) 2 h after bevacizumab. Conclusions: In this single arm study, cytotoxic chemotherapy followed by bevacizumab yields a favorable CR rate and duration in adults with AML that is resistant to traditional treatment approaches. The clearance of marrow blasts in some patients after bevacizumab suggests that VEGF neutralization might result directly in leukemic cell death. The potential biological and clinical activity of bevacizumab in AML warrants additional clinical and laboratory study.

Timed sequential therapy of acute myelogenous leukemia in adults: a phase II study of retinoids in combination with the sequential administration of cytosine arabinoside, idarubicin and etoposide

Clinical outcome in acute myeloid leukemia (AML) is unsatisfactory. One strategy to augment cytotoxicity is TST. All-trans retinoic acid (ATRA) down-regulates bcl-2 expression and heightens AML sensitivity to cytosine arabinoside (ara-C)-induced apoptosis in vitro. We designed a trial of ATRA plus ara-C-based TST in an attempt to enhance drug-induced apoptosis and clinical outcome. Between January 1998 and February 2000, 63 patients received induction TST (oral ATRA days 1-6, ara-C and idarubicin days 2-4, VP-16 days 9-11) followed by consolidation TST (ATRA, ara-C and idarubicin followed by a second ara-C infusion days 11-13). Complete remission (CR) was 60%, with higher rates for patients of <60 years (79%), de novo AML (70%), and non-adverse cytogenetics (81%). Median disease-free survival (DFS) for CR patients was 11.2 months (32% at 3+ years). For patients <60 years with de novo AML and non-adverse cytogenetics who underwent two-cycle TST, DFS was 67% at 3+ years. However, patients of age equal to 60 years and those with poor-risk disease features still have poor CR and DFS, despite the addition of ATRA.

Subdural hematomas in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy

Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that inhibit BCR–ABL have had a favorable impact on the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). TKIs are generally well tolerated, but they can induce platelet dysfunction, which is of particular concern in the setting of thrombocytopenia in patients with acute leukemia. We present three patients with Ph+ ALL receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy who developed subdural hematomas (SDHs). All three were thrombocytopenic and had undergone repeated lumbar punctures for prophylactic intrathecal chemotherapy, but they were not coagulopathic and did not have meningeal leukemia. SDHs occurred in three of a total of 10 adult patients with Ph+ ALL receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy at our institution from 2007 to 2010, but in none of 22 adult patients with Ph− ALL receiving the same therapy without imatinib mesylate (p < 0.05). Patients with Ph+ ALL receiving imatinib mesylate, and likely also dasatinib, in conjunction with systemic and intrathecal chemotherapy may be at increased risk of SDH, and should be closely monitored for subtle manifestations of this complication.

Ten-day decitabine as initial therapy for newly diagnosed patients with acute myeloid leukemia unfit for intensive chemotherapy

Abstract We retrospectively reviewed outcomes in 45 previously untreated patients with acute myeloid leukemia (AML) considered unfit for chemotherapy who were treated with 10-day courses of decitabine 20 mg/m2 daily outside of a clinical trial, with no cut-offs for organ function or performance status (PS). Nineteen had Eastern Cooperative Group performance status (ECOG PS) ≥ 2, and 39 had ≥ 2 comorbidities. Fourteen patients (31%) achieved complete remission (CR) and five (11%) CR with incomplete count recovery, for an overall response rate of 42%, after a median of 2 (range, 1–4) courses. The only pretreatment characteristic that differed significantly between responders and non-responders was percent marrow blasts (median 42% vs. 65%; p = 0.01). Median overall survival was 9.0 months; it was 19.4 and 2.3 months for responders and non-responders, respectively (p < 0.001). Thus 10-day decitabine therapy has efficacy in patients with AML considered unfit for chemotherapy, and may serve as a backbone for the addition of other novel agents.

Racial differences in presentation, referral and treatment patterns and survival in adult patients with acute myeloid leukemia: A single-institution experience

BACKGROUND Disease presentation and outcomes differ by race in a number of malignancies, but data in adult acute myeloid leukemia (AML) are limited. MATERIALS AND METHODS We conducted a retrospective analysis of pretreatment characteristics, referral and treatment patterns, and outcomes in 548 AML patients evaluated at the University of Maryland Greenebaum Cancer Center, a tertiary care referral center in Baltimore, MD, from 2000 through 2009. Cases were analyzed for time from diagnosis to referral, age, race, gender, socioeconomic status, antecedent hematologic disorder, cytotoxic or radiation therapy for prior malignancy, karyotype, fms-like tyrosine kinase receptor-3 (FLT3) mutations, intensive chemotherapy, clinical trial participation, hematopoietic stem cell transplantation (HSCT) and overall survival (OS). RESULTS Black patients (n=105) were younger than white patients (n=396) (54 vs. 61 years, p<0.001), were more commonly female (55% vs. 45%, p<0.001), and had a lower estimated median household income (

Lack of objective response of myelodysplastic syndromes and acute myeloid leukemia to decitabine after failure of azacitidine

42,677 vs.

Treatment of catheter-related deep vein thrombosis in patients with acute leukemia with anticoagulation

53,534 per year, p<0.001). Black patients more frequently had complex karyotypes (26% vs. 12%, p=0.002) and less frequently normal karyotypes (27% vs. 42%, p=0.02). FLT3 mutation frequency was similar. Time to referral and proportion of patients receiving intensive chemotherapy did not differ, but both clinical trial participation (43% vs. 54%, p=0.04) and HSCT (17% vs. 35% for patients ≤70 years old, p=0.001) were less frequent in blacks than whites. Nevertheless, OS was similar in all black and white patients (median 15 vs. 14 months, p=0.23), and when stratified by age, gender and karyotype risk classification. CONCLUSION AML presentation and treatment differed in black and white patients, but OS was similar. Black patients appear to have barriers to clinical trial participation and HSCT, and there may be barriers to tertiary care referral for black males.

Tertiary center referral patterns for patients with myelodysplastic syndrome are indicative of age and race disparities: a single-institution experience.

Abstract The hypomethylating agents azacitidine and decitabine are standard therapy for myelodysplastic syndromes (MDS), and are often used to treat patients with acute myeloid leukemia (AML) unlikely to benefit from cytotoxic chemotherapy. Switching hypomethylating agents after treatment failure is common, but this approach is not well studied. We retrospectively reviewed data on 25 patients with MDS, MDS/myeloproliferative neoplasm (MDS/MPN) or AML who were treated with decitabine after primary or secondary azacitidine failure at the University of Maryland Greenebaum Cancer Center. Five patients with MDS or MDS/MPN achieved stable disease with decitabine, but no patient achieved complete or partial remission or hematologic improvement. Most patients discontinued therapy due to disease progression or death after a median of 2 cycles and median survival was 5.9 months after decitabine initiation. Based on our data, decitabine therapy after azacitidine failure is of little benefit beyond disease stabilization in some patients.

Risk assessment in human immunodeficiency virus-associated acute myeloid leukemia

Abstract Patients with acute leukemia develop venous thrombosis (VT) related to central venous catheters (CVCs). Anticoagulation (AC) in these patients who are thrombocytopenic and often coagulopathic is challenging. To evaluate the safety and efficacy of AC in treating CVC-related VT, we retrospectively compared outcomes of patients with acute leukemia who were treated or not with AC during induction chemotherapy and post-discharge. Twenty-one patients with CVC-related VT received AC, 14 did not. VT resolved in 80% of patients in the AC group (similarly with low-dose and high-dose enoxaparin) and 45% in the non-AC group (p = 0.11). Fourteen (67%) patients in the AC group are alive (median survival not reached), compared to four patients (29%) in the non-AC group (median survival 9 months) (p = 0.015) with a hazard ratio (HR) of 0.32 (95% confidence interval: 0.12–0.85) in favor of AC. HR remained < 1 after adjustments for leukemia type and cytogenetics. Bleeding (< grade 4) occurred in five and one patients in the AC vs. non-AC groups, respectively (p = 0.37).

Race and overall survival in acute myeloid leukemia.

Abstract Little is known about disparities in myelodysplastic syndromes (MDS). We performed a retrospective chart review of patients with MDS (n = 252) evaluated at the University of Maryland Greenebaum Cancer Center between 2000 and 2010. The median age at diagnosis was 65 years, which was lower than the median age of 76 years for patients with MDS in the Surveillance, Epidemiology and End Results database. Black males were younger than white males (62 vs. 68 years; p = 0.03) and had longer time to referral (9 vs. 1.5 months; p = 0.03), but black and white females did not differ in age or in time to referral. A difference in World Health Organization subtype classification was noted in black and white patients at diagnosis, but not at referral. There was no difference between all other pretreatment characteristics, treatment and survival by race. Our data suggest barriers to tertiary care referral for older patients and for black males.