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ABSTRACT: CD4 count ≤200×10(6) cells/L has been identified as a predictor of short survival in HIV-associated acute myeloid leukemia (HIV-AML), but karyotype, which is the best predictor of survival in AML, has not been evaluated in HIV-AML patients. A retrospective cohort of 31 patients was created from 9 local cases and 22 published cases. HIV-AML karyotypes were heterogeneous and were similar in distribution to those in HIV-negative AML. Among intensively treated patients, most achieved complete remission, but succumbed to infectious complications, mostly non-opportunistic, during consolidation therapy. Median survival for intensively-treated patients with CD4 counts ≤200×10(6) cells/L was 8.5 months, compared to 48 months for those with >200×10(6) CD4 cells/L (p=0.03). In contrast, AML karyotype did not predict survival (p=0.43), albeit with small numbers in each karyotype group. Thus, CD4 count is a strong predictor of short survival in HIV-AML patients regardless of karyotype. Studies evaluating innovative strategies for infection prophylaxis and for improving immune reconstitution are needed.
Leukemia & lymphoma 09/2011; 53(4):660-4. · 2.40 Impact Factor
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Scott H Kaufmann, Judith E Karp,
Mark R Litzow,
Ruben A Mesa,
William Hogan,
David P Steensma,
Karen S Flatten,
David A Loegering,
Paula A Schneider,
Kevin L Peterson,
Matthew J Maurer,
B Douglas Smith,
Jacqueline Greer,
Yuhong Chen,
Joel M Reid,
S Percy Ivy,
Matthew M Ames,
Alex A Adjei,
Charles Erlichman,
Larry M Karnitz
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ABSTRACT: In preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced down-regulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia.
Patients received cytarabine 400 mg/m(2)/day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients.
Twenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m(2)/day for 5 days along with tanespimycin 300 mg/m(2) on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest.
Because exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine. (Clinicaltrials.gov identifier: NCT00098423).
Haematologica 07/2011; 96(11):1619-26. · 6.42 Impact Factor
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Brian Parkin,
Harry Erba,
Peter Ouillette,
Diane Roulston,
Anjali Purkayastha, Judith Karp,
Moshe Talpaz,
Lisa Kujawski,
Sajid Shakhan,
Cheng Li,
Kerby Shedden,
Sami N Malek
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ABSTRACT: Genomic aberrations are of predominant importance to the biology and clinical outcome of patients with acute myelogenous leukemia (AML), and conventional karyotype-based risk classifications are routinely used in clinical decision making in AML. One of the known limitations of cytogenetic analysis is the inability to detect genomic abnormalities less than 5 Mb in size, and it is currently unclear whether overcoming this limitation with high-resolution genomic single-nucleotide polymorphism (SNP) array analysis would be clinically relevant. Furthermore, given the heterogeneity of molecular mechanisms/aberrations that underlie the conventional karyotype-based risk classifications, it is likely that further refinements in genomic risk prognostication can be achieved. In this study, we analyzed flow cytometer-sorted, AML blast-derived, and paired, buccal DNA from 114 previously untreated prospectively enrolled AML patients for acquired genomic copy number changes and loss of heterozygosity using Affymetrix SNP 6.0 arrays, and we correlated genomic lesion load and specific chromosomal abnormalities with patient survival. Using multivariate analyses, we found that having ≥ 2 genomic lesions detected through SNP 6.0 array profiling approximately doubles the risk of death when controlling for age- and karyotype-based risk. Finally, we identified an independent negative prognostic impact of p53 mutations, or p53 mutations and 17p-loss of heterozygosity combined on survival in AML.
Blood 12/2010; 116(23):4958-67. · 9.90 Impact Factor
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Brian Parkin,
Peter Ouillette,
Yin Wang,
Yan Liu,
Whitney Wright,
Diane Roulston,
Anjali Purkayastha,
Amanda Dressel, Judith Karp,
Paula Bockenstedt,
Ammar Al-Zoubi,
Moshe Talpaz,
Lisa Kujawski,
Yang Liu,
Kerby Shedden,
Sajid Shakhan,
Cheng Li,
Harry Erba,
Sami N Malek
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ABSTRACT: This study was conducted to identify novel genes with importance to the biology of adult acute myelogenous leukemia (AML).
We analyzed DNA from highly purified AML blasts and paired buccal cells from 95 patients for recurrent genomic microdeletions using ultra-high density Affymetrix single nucleotide polymorphism 6.0 array-based genomic profiling.
Through fine mapping of microdeletions on 17q, we derived a minimal deleted region of approximately 0.9-Mb length that harbors 11 known genes; this region includes Neurofibromin 1 (NF1). Sequence analysis of all NF1 coding exons in the 11 AML cases with NF1 copy number changes identified acquired truncating frameshift mutations in two patients. These NF1 mutations were already present in the hematopoetic stem cell compartment. Subsequent expression analysis of NF1 mRNA in the entire AML cohort using fluorescence-activated cell sorting sorted blasts as a source of RNA identified six patients (one with a NF1 mutation) with absent NF1 expression. The NF1 null states were associated with increased Ras-bound GTP, and short hairpin RNA-mediated NF1 suppression in primary AML blasts with wild-type NF1 facilitated colony formation in methylcellulose. Primary AML blasts without functional NF1, unlike blasts with functional NF1, displayed sensitivity to rapamycin-induced apoptosis, thus identifying a dependence on mammalian target of rapamycin (mTOR) signaling for survival. Finally, colony formation in methylcellulose ex vivo of NF1 null CD34+/CD38- cells sorted from AML bone marrow samples was inhibited by low-dose rapamycin.
NF1 null states are present in 7 of 95 (7%) of adult AML and delineate a disease subset that could be preferentially targeted by Ras or mammalian target of rapamycin-directed therapeutics.
Clinical Cancer Research 08/2010; 16(16):4135-47. · 7.74 Impact Factor
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Francis Giles,
David Rizzieri, Judith Karp,
Norbert Vey,
Farhad Ravandi,
Stefan Faderl,
Khuda Dad Khan,
Gregor Verhoef,
Pierre Wijermans,
Anjali Advani,
Gail Roboz,
Hagop Kantarjian,
Syed Fazl Ali Bilgrami,
Augustin Ferrant,
Simon M G J Daenen,
Verena Karsten,
Ann Cahill,
Maher Albitar,
Ghulam Mufti,
Susan O'Brien
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ABSTRACT: Cloretazine (VNP40101M) is a sulfonylhydrazine alkylating agent with significant antileukemia activity. A multicenter phase II study of cloretazine was conducted in patients 60 years of age or older with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).
Cloretazine 600 mg/m2 was administered as a single intravenous infusion. Patients were stratified by age, performance score, cytogenetic risk category, type of AML, and comorbidity.
One hundred four patients, median age 72 years (range, 60 to 84 years), were treated on study. Performance status was 2 in 31 patients (30%) and no patient had a favorable karyotype. Forty-seven patients (45%) had cardiac disease, 25 patients (24%) had hepatic disease, and 19 patients (18%) had pulmonary disease, defined as per the Hematopoietic Cell Transplantation-Specific Comorbidity Index, at study entry. The overall response rate was 32%, with 29 patients (28%) achieving complete response (CR) and four patients (4%) achieving CR with incomplete platelet recovery. Response rates in 44 de novo AML patients, 45 secondary AML patients, and 15 high-risk MDS patients were 50%, 11%, and 40%, respectively. Response by cytogenetic risk category was 39% in 56 patients with intermediate cytogenetic risk and 24% in 46 patients with unfavorable cytogenetic risk. Nineteen (18%) patients died within 30 days of receiving cloretazine therapy. Median overall survival was 94 days, with a 1-year survival of 14%; the median duration of survival was 147 days, with a 1-year survival of 28% for those who achieved CR.
Cloretazine has significant activity and modest extramedullary toxicity in elderly patients with AML or high-risk MDS. Response rates remain consistent despite increasing age and comorbidity.
Journal of Clinical Oncology 02/2007; 25(1):25-31. · 18.37 Impact Factor
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Joya Chandra,
Jeannette Tracy,
David Loegering,
Karen Flatten,
Srdan Verstovsek,
Miloslav Beran,
Mercedes Gorre,
Zeev Estrov,
Nicholas Donato,
Moshe Talpaz,
Charles Sawyers,
Kapil Bhalla, Judith Karp,
Edward Sausville,
Scott H Kaufmann
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ABSTRACT: The BCR/ABL kinase has been targeted for the treatment of chronic myelogenous leukemia (CML) by imatinib mesylate. While imatinib has been extremely effective for chronic phase CML, blast crisis CML and Ph+ acute lymphoblastic leukemia (ALL) are often resistant. In particular, mutation of the T315 residue in the bcr/abl activation loop renders cells highly resistant to imatinib and to second-generation kinase inhibitors such as BMS-354825 or AMN107. Adaphostin is a tyrphostin that was originally intended to inhibit the BCR/ABL kinase by competing with its peptide substrates. Recent findings have in addition implicated reactive oxygen species (ROS) in the cytotoxic mechanism of adaphostin. In view of this unique mode of action, we examined the effects of adaphostin on numerous imatinib-resistant leukemia models, including imatinib-resistant CML and Ph+ ALL cell lines, cells harboring point mutations in BCR/ABL, and specimens from imatinib-resistant CML patients, using assays for intracellular ROS, apoptosis, and clonogenicity. Every model of imatinib resistance examined remained fully sensitive to adaphostin-induced cell death. Collectively, these data suggest that ROS generation by adaphostin overcomes even the most potent imatinib resistance in CML and Ph+ ALL.
Blood 04/2006; 107(6):2501-6. · 9.90 Impact Factor
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British Journal of Haematology 08/2003; 122(1):164-5. · 4.94 Impact Factor
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ABSTRACT: Butyrate is a small polar compound able to produce terminal differentiation and apoptosis in a variety of in vitro models at levels above 50-100 microM. Previously our group demonstrated that daily oral administration of the prodrug, tributyrin, is able to briefly achieve levels >100 microM. Given in vitro data that differentiating activity requires continuous butyrate exposure, the short t1/2 of the drug and a desire to mimic the effects of an intravenous infusion, we evaluated a three times daily schedule.
Enrolled in this study were 20 patients with advanced solid tumors for whom no other therapy was available, had life expectancy greater than 12 weeks, and normal organ function. They were treated with tributyrin at doses from 150 to 200 mg/kg three times daily. Blood was sampled for pharmacokinetic analysis prior to dosing and at 15 and 30 min and 1, 1.5, 2, 2.5, 3, 3.5 and 4 h thereafter.
The patients entered comprised 15 men and 5 women with a median age of 61 years (range 30-74 years). Prior therapy regimens included: chemotherapy (median two prior regimens, range none to five), radiation therapy (one), no prior therapy (one). There was no dose-limiting toxicity. Escalation was halted at the 200 mg/kg three times daily level due to the number of capsules required. A median butyrate concentration of 52 microM was obtained but there was considerable interpatient variability. No objective responses were seen. There were four patients with prolonged disease stabilization ranging from 3 to 23 months; median progression-free survival was 55 days. Two patients with chemotherapy-refractory non-small-cell lung cancer had survived for >1 year at the time of this report without evidence of progression.
Tributyrin is well tolerated and levels associated with in vitro activity are achieved with three times daily dosing.
Cancer Chemotherapy and Pharmacology 05/2003; 51(5):439-44. · 2.83 Impact Factor
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ABSTRACT: Mutations in transcription factors often contribute to human leukemias by providing a block to normal differentiation. To determine whether mutations in the hematopoietic transcription factor GATA1 are associated with leukemia, we assayed for alterations in the GATA1 gene in bone marrow samples from patients with various subtypes of acute leukemia. Here we summarize our findings that GATA1 is mutated in the leukemic blasts of patients with Down syndrome acute megakaryoblastic leukemia (DS-AMKL). We did not find mutations in GATA1 in leukemic cells of DS patients with other types of acute leukemia, or in other patients with AMKL who did not have DS. Furthermore, we did not detect GATA1 mutations in DNAs from over 75 other patients with acute leukemia or from 21 healthy individuals. Since the GATA1 mutations were restricted to DS-AMKL, we also investigated whether GATA1 was altered in the "preleukemia" of DS, transient myeloproliferative disorder (TMD). TMD is a common myeloid disorder that affects 10% of DS newborns and evolves to AMKL in nearly 30% patients. We detected GATA1 mutations in TMD blasts from every infant examined. Together, these results demonstrate that GATA1 is likely to play a critical role in the etiology of TMD and DS-AMKL, and that mutagenesis of GATA1 represents a very early event in DS myeloid leukemogenesis. We hypothesize that disruption of normal GATA-1 function is an essential step in the initiation of megakaryoblastic leukemia in DS.
Blood Cells Molecules and Diseases 31(3):351-6. · 2.35 Impact Factor
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ABSTRACT: PBK/TOPK is a recently identified 322 amino acid serine/threonine kinase that is phosphorylated during mitosis and may include p38 MAPK among its targets. Previous work has shown up-regulated expression of PBK/TOPK mRNA in a variety of tumor cell lines and fetal tissues, suggesting a role for this kinase in malignant cell proliferation. In this paper, PBK/TOPK protein expression was examined in a variety of primary hematologic neoplasms: PBK/TOPK was readily detected in 9 of 12 AML samples (75%), in 3 of 3 ALL samples, and in 1 sample each of a plasmacytoma and blastic type mantle cell lymphoma where it was strongly expressed. In contrast, PBK/TOPK was only weakly expressed in 2 samples of G-CSF-mobilized peripheral blood stem cells that were enriched in CD34+ progenitors by immunoselection. Furthermore, when HL-60 myeloid leukemic cells were differentiated with phorbol ester (TPA), PBK/TOPK protein expression was strongly down-regulated by 24 h. Under these same conditions, phosphorylated c-Myc was rapidly down-regulated (by 4 h), while the levels of cyclin D1 and phosphorylated p38 were constant. Notably, of 5 clinical samples that strongly expressed PBK/TOPK, 4 also strongly expressed phosphorylated c-Myc, while only 1 of 3 PBK/TOPK negative samples expressed phosphorylated c-Myc. These data show that PBK/TOPK protein is up-regulated in a variety of hematologic malignancies and may be involved in leukemic cell growth. Additional studies are warranted to determine if PBK/TOPK would be a valuable target for novel therapeutics. To this end, we also describe the derivation of clones of 293 (human embryonic kidney) cells, which carry an inducible kinase-defective mutant of PBK/TOPK. This model may be useful for studying the effects of down-regulated PBK/TOPK function.
Blood Cells Molecules and Diseases 32(1):240-5. · 2.35 Impact Factor
