Ioannis Mantzaris

Abnormal platelet count is an independent predictor of mortality in the elderly and is influenced by ethnicity

Even though alterations in platelet counts are presumed to be detrimental, their impact on the survival of patients has not been studied in large cohorts. The prevalence of thrombocytopenia and thrombocytosis was examined in a large inner city outpatient population of 36,262 individuals aged ≥65 years old. A significant association with shorter overall survival was found for both thrombocytopenia (HR=1.45; 95% CI: 1.36–1.56) and thrombocytosis (HR=1.75; 95% CI: 1.56–1.97) when compared to the survival of patients with normal platelet counts. This effect persisted across all ethnic groups. However, African-Americans (non-Hispanic Blacks) with either thrombocytopenia or thrombocytosis were at significantly lower risk compared to non-Hispanic Caucasians (HR=0.82; 95% CI: 0.69–0.96 and HR=0.70; 95% CI: 0.53–0.94, respectively). Furthermore, Hispanics with thrombocytosis were found to have a lower mortality risk compared to non-Hispanic Caucasians with thrombocytosis (HR=0.60; 95% CI: 0.44–0.81). A value of <125,000 platelets per microliter was a better prognostic marker for non-Hispanic Blacks and these subjects with this platelet count had similar overall survival to that of Caucasians with a value of <150,000 per microliter. In conclusion, thrombocytosis and thrombocytopenia are independently associated with shorter overall survival in elderly subjects and this effect is modified by ethnicity. Using different thresholds to define the association of thrombocytopenia and thrombocytosis with overall mortality risk among non-Hispanic Blacks may, therefore, be warranted.

Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34(+) stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML. Cancer Res; 76(16); 4841-9. ©2016 AACR.

Pharmacological inhibition of the transcription factor PU.1 in leukemia

The transcription factor PU.1 is often impaired in patients with acute myeloid leukemia (AML). Here, we used AML cells that already had low PU.1 levels and further inhibited PU.1 using either RNA interference or, to our knowledge, first-in-class small-molecule inhibitors of PU.1 that we developed specifically to allosterically interfere with PU.1-chromatin binding through interaction with the DNA minor groove that flanks PU.1-binding motifs. These small molecules of the heterocyclic diamidine family disrupted the interaction of PU.1 with target gene promoters and led to downregulation of canonical PU.1 transcriptional targets. shRNA or small-molecule inhibition of PU.1 in AML cells from either PU.1lo mutant mice or human patients with AML-inhibited cell growth and clonogenicity and induced apoptosis. In murine and human AML (xeno)transplantation models, treatment with our PU.1 inhibitors decreased tumor burden and resulted in increased survival. Thus, our study provides proof of concept that PU.1 inhibition has potential as a therapeutic strategy for the treatment of AML and for the development of small-molecule inhibitors of PU.1.

High prevalence and allele burden-independent prognostic importance of p53 mutations in an inner-city MDS/AML cohort

High prevalence and allele burden-independent prognostic importance of p53 mutations in an inner-city MDS/AML cohort

Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

Dual inhibition of MDMX and MDM2 by an α-helical p53-stapled peptide (ALRN-6924) results in robust antitumor activity in acute myeloid leukemia. A new staple of leukemia treatment? As suggested by their name, tumor suppressor genes prevent tumorigenesis, and their expression or activity is often lost in cancer cells. One of the best known tumor suppressors is p53, which is inactivated in a variety of cancer types, often through up-regulation of its endogenous suppressors. Despite numerous attempts to reactivate p53 by a variety of approaches, none have successfully advanced beyond clinical trials thus far. Now, Carvajal et al. applied yet another tactic to restore p53 activity by using a stapled peptide to inactivate both of its endogenous inhibitors, for situations where the tumor suppressor is inactive but not completely lost. The authors demonstrated the effectiveness of this approach in human acute myeloid leukemia using in vitro and in vivo models, along with preliminary testing in a patient with leukemia. The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. We demonstrate that dual MDMX/MDM2 inhibition with a stapled α-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell–enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Our study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.

Adult T-cell leukemia/lymphoma in the Caribbean cohort is a distinct clinical entity with dismal response to conventional chemotherapy

Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive disease caused by human T-cell lymphotropic virus type 1 that predominantly affects Japanese and Caribbean populations. Most studies have focused on Japanese cohorts. We conducted a retrospective analysis of 53 cases of ATLL who presented to our institution between 2003-2014. ATLL in the Caribbean population presents more often as the acute and lymphomatous subtypes, is associated with complex cytogenetics, and has a high rate of CNS involvement. The overall response rate to first-line therapies with anthracycline-based regimens was poor (32%), with a median survival of only 6.9 months. A complete or partial response to first-line regimens was associated with better survival. There was no difference in survival between patients who received chemotherapy alone versus chemotherapy with antiviral agents. Allogeneic transplantation was performed in five patients, two of whom achieved complete remission despite residual or refractory disease. Recipients of allogeneic transplantation had significantly improved overall survival compared to non-transplanted patients. This is the first analysis to describe ATLL pathological features, cytogenetics, and response to standard therapy and transplantation in the Caribbean cohort.

Sites of extranodal involvement are prognostic in patients with stage 1 follicular lymphoma

Objectives Follicular lymphoma (FL) is the most common indolent B cell lymphoma in the United States and a quarter of patients present with stage I disease. The objective of this study was to examine if primary site of disease influences survival in early stage lymphoma. Results The most common extranodal primary sites were the integumentary system (8%), followed by the GI tract (6.4%) and head & neck (5.6%). We stratified patients into a pre-rituximab era (1983-1998) and the rituximab era (1999-2011). In multivariable analysis, integumentary disease was associated with better overall survival (Hazard Ratio [HR], 0.77; Confidence Interval [CI], 0.66-0.9) while primary site FL of the nervous system (HR, 2.40; CI, 1.72-3.38) and the musculoskeletal system (HR, 2.14; CI, 1.44-3.18) were associated with worse overall survival when compared to primary nodal FL. Treatment in the pre-rituximab era, male gender and older age at diagnosis were associated with worse survival. Methods We queried the SEER database from 1983 to 2011. We included all adult patients (>18 years) with histologically confirmed stage I FL, active follow-up, and a single primary tumor. A total of 9,865 patients met eligibility criteria, with 2520 (25%) having an extranodal primary site. We classified the primary sites by organ or anatomic location into 11 sites. Conclusion Primary site of disease is a prognostic factor for patients with early stage FL and may help identify subsets of patients that could benefit from early, aggressive treatment.

Analysis of chronic myelogenous leukemia in an underserved, inner-city cohort shows a significant five year overall survival that is not affected by choice of tyrosine kinase inhibitor

Tyrosine kinase inhibitors (TKIs) have become the firstline treatment of choice for chronic myelogenous leukemia (CML) after imatinib was shown to offer improved and durable responses.[1,2] Second generation TKIs such as nilotinib [3,4] and dasatinib [5,6] have shown superior efficacy in achieving faster remissions in the first-line setting. Patients who achieve a complete cytogenetic response at two years have a life span similar to that of the general population as long as they receive adequate therapy and adhere to treatment.[7] Despite efficacy, the cost of TKIs created a significant financial burden which led leaders in the field to speculate on whether such prices are justifiable.[8] Individuals with ‘adequate’ healthcare coverage are not immune and may have a 20% out of pocket co-payment. Adherence to therapy is essential to achieve adequate responses.[9] Higher socioeconomic status was linked to better imatinib adherence [10] and patients with higher copayments were more likely to have poorer adherence.[11] To examine the impact of cost of TKIs on efficacy, we conducted a retrospective analysis to determine the treatment patterns in an inner-city population comprised predominantly of ethnic minorities with low socioeconomic status. We aimed to study access to different generations of TKI, reasons for switching TKIs as well as overall survival (OS). We included CML cases that presented to Montefiore Medical Center between 1997 and 2014 in the Bronx, New York. Cases were identified by a data-mining software (Clinical Looking Glass , CLG) used to search by ICD-9 diagnosis code. Records were manually reviewed to confirm diagnosis and to collect relevant demographic and CML-specific data. The population number (n value) was adjusted to reflect the number of records with available data pertaining to each variable. As such, the number of evaluable records for phase at diagnosis, first-line therapy, line of therapy at the conclusion of the study, and line of therapy at expiration was 77, 118, 125, and 20 patients, respectively. All chart review was conducted by one of the study authors and discrepancies were reviewed by at least two authors. This research was approved by our institutional review board and ethics committee. For comparison, we obtained data from the Surveillance, Epidemiology and End Results (SEER) program database. SEER collects cancer incidence, treatment, and survival information from 18 geographic areas in the United States, representing 28% of the entire population. We used direct case listings extracted by SEER*Stat software (version 8.1.5, released March 31, 2014) and included patients with a diagnosis of CML with the International Classification of Disease for Oncology, third edition, ICD-0-3 histology code 9863, 9875, 9876, 9945, 9946 until the latest follow-up recorded in the SEER submission. For analysis of categorical variables, we reported proportions and p values calculated with Pearson chi square or Fisher exact test as appropriate. Kaplan–Meier curves were used to compare survival and significance was examined using the log rank test. Statistical analyses were performed with computer software (SPSS 18, SPSS, Inc., Chicago, IL) and a two-tailed alpha of 0.05 was used to denote significance.

IL1RAP potentiates multiple oncogenic signaling pathways in AML

The surface molecule interleukin-1 receptor accessory protein (IL1RAP) is consistently overexpressed across multiple genetic subtypes of acute myeloid leukemia (AML) and other myeloid malignancies, including at the stem cell level, and is emerging as a novel therapeutic target. However, the cell-intrinsic functions of IL1RAP in AML cells are largely unknown. Here, we show that targeting of IL1RAP via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo, without perturbing healthy hematopoietic function or viability. Furthermore, we found that the role of IL1RAP is not restricted to the IL-1 receptor pathway, but that IL1RAP physically interacts with and mediates signaling and pro-proliferative effects through FLT3 and c-KIT, two receptor tyrosine kinases with known key roles in AML pathogenesis. Our study provides a new mechanistic basis for the efficacy of IL1RAP targeting in AML and reveals a novel role for this protein in the pathogenesis of the disease.

Analysis of overall survival in a large multiethnic cohort reveals absolute neutrophil count of 1,100 as a novel prognostic cutoff in African Americans

Although absolute neutrophil counts (ANC) below 1.5x103/uL are used to define neutropenia as a marker of increased susceptibility to infections, their relationship with survival has not been examined. Since low counts trigger extensive investigations, determining prognostic cutoffs especially for different ethnicities and races is critical. A multiethnic cohort of 27,760 subjects, 65 years old and above, was utilized to evaluate the association of neutropenia with overall survival in different ethnicities and races. The mean ANC was 4.6±1.51x103/uL in non-Hispanic whites, 3.6±1.57x103/uL in non-Hispanic blacks and 4.3±1.54x103/uL in Hispanics (p<0.001). An ANC below 1.5x103/uL was associated with significantly shorter overall survival among whites (HR 1.74; 95% CI 1.18 - 2.58; p<0.001), but not in blacks (HR 0.89; 95% CI 0.86 - 1.17; p=0.40) or Hispanics (HR 1.04; 95% CI 0.76 - 1.46; p=0.82), after adjustment for age, sex, comorbidities, anemia and thrombocytopenia. Using Cox regression multivariable models, an ANC below 1.1x103/uL in blacks was found to be associated with increased mortality (HR 1.86; 95%CI 1.21 - 2.87; p<0.01). We found no association between neutropenia and mortality at any ANC cutoff in elderly Hispanics. In conclusion, neutropenia was found to be an independent prognostic variable in the elderly, when determined in race-specific manner. Most importantly, a cutoff of 1.1x103 neutrophils/uL may be a more prognostically relevant marker in elderly blacks and could serve as a novel threshold for further evaluation and intervention in this population.