Amer Assal

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.

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.

In-stent thrombosis following DDAVP administration: case report and review of the literature.

A 67-year-old man with a drug-eluting stent in his proximal left anterior descending artery was admitted to the hospital after sustaining a traumatic injury to the skull. Due to persistent bleeding from a subgaleal hematoma, intravenous 1-desamino-8-D-arginine vasopressin (DDAVP) was administered. Five hours later, the patient complained of crushing chest pain. A 12-lead electrocardiogram demonstrated 2 mm ST-segment elevations in the precordial leads with reciprocal depressions in the inferior leads. Emergency cardiac catheterization demonstrated total occlusion of the proximal left anterior descending stent with TIMI 0 flow. Another drug-eluting stent was placed inside the original stent with restoration of TIMI 3 flow. During the catheterization, the patient became progressively hypoxic and hypotensive requiring intubation, dopamine drip, and placement of an intra-aortic balloon pump. The patients hospitalization was complicated by prolonged shock requiring inotropes and vasopressors. This is the first reported case of an ST-elevation myocardial infarction due to in-stent thrombosis occurring after DDAVP administration. Though DDAVP is well tolerated and efficacious in treating several types of coagulopathies, this case illustrates its potential pro-thrombotic effects. Therefore, DDAVP should be used with caution in patients with known coronary artery disease and coronary stents.

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.

Lenalidomide in the treatment of Rosai Dorfman disease—a first in use report

To the Editor: A 43-year-old Hispanic male was evaluated waxing and waning bilateral submandibular masses, associated with fevers, night sweats, bilateral flank pain, and a 20pound weight loss. The complete blood count revealed mild leukocytosis (13.6 3 10/l), and normocytic anemia with a left shift in the granulocyte series (11.7 3 10/l). ESR and CRP were 90 and 210, respectively. Electrophoresis was notable for a polyclonal hypergammaglobulinemia with free lambda chains. Excisional biopsy of the supraclavicular nodes showed sinus histiocytosis with emperipolesis which was S-100 positive and CD1a negative consistent with Rosai Dorfman disease (RDD) (Fig. 1). There have been various reports of different agents used for the treatment of RDD; including corticosteroids, rituximab, chemotherapy, and radiotherapy [1]. Typical initial treatment consists of high dose steroids at 1 mg/kg and our patient achieved a quick remission with a reduction in the size of cervical lymph nodes, a reduction of inflammatory markers, weight gain, and an improvement in his lytic lesions. Unfortunately, steroid tapering was associated with a relapse of RDD. During every relapse, the patient presented with increasing lymph nodes, fevers, weight loss, and an increase in inflammatory markers namely erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Due to the concern for long-term toxicity with steroids, the patient was started on Rituximab and underwent six cycles of chemotherapy with Cyclophosphamide, Vincristine, and Prednisone (CVP). The patient achieved remission but relapsed again after 2 months. The relatively short remission and relapse achieved by administering CVP suggested that RDD could have responded to the immunosuppressive component of the CVP regimen. The patient was treated with Cladribine which is known to markedly immunosuppress the lymphocytes but 3 months after such treatment, the patient relapsed once again. Since the patient responded to immunosuppression, he was switched to Azathioprine, which resulted in a partial response. But since he developed azathioprine induced visual loss, he was switched to thalidomide, an immunomodulating (Imid) agent. With thalidomide, he developed a Grade 3 skin rash and was switched to Lenalidomide and is currently in complete remission with Lenalidomide. Recent studies indicate that among the histiocytosis, RDD is not associated with BRAF mutations or other clonal abnormalities that are seen in other histiocytic disorders [2]. This suggests that RDD could be an aberrant immune mediated disease rather than a clonal disorder. On the basis of the above response, we hypothesize two mechanisms of control (1) immunosuppression and (2) immunomodulation. In keeping with this hypothesis, the patient responded to immunosuppression with steroids (consistent with the literature), cyclophosphamide and azathioprine but did not achieve a remission. Why should immunomodulation work? Two mechanisms of action of Imids in RDD can be postulated. (1) RDD is associated with high levels of TNF-a and IL-6 [3] and Lenalidomide is known to decrease TNF-a expression and decrease IL-6 levels [4]. (2) RDD cells have strong expression of macrophage colony-stimulating factor (M-CSF) [5], which is the suspected mechanism for emperipolesis and human monocytes treated with M-CSF produced high levels of IL-10. IL-10 expression positively regulates the proliferation and differentiation of monocytes in conjunction with M-CSF. We hypothesize that M-CSF activated macrophages in RDD, induce IL-10 release and alter T-cell-mediated immune response which is abrogated by Lenalidomide [4]. Our patient with RDD did not achieve remission with the previously studied treatments and only achieved remission with the use of Lenalidomide. The lack of clonal mutations and the response to immune suppression/immune modulation suggest that this could be an immune-mediated disease rather than a clonal disorder. Lenalidomide may be an appropriate therapy in refractory disease and the first reported case of Lenalidomide inducing remission in RDD.

Risk factors and prognosis of ovarian vein thrombosis.

&NA; Ovarian vein thrombosis (OVT) remains poorly understood with no consensus regarding its importance or treatment. In this retrospective study, we investigated the clinical features, risk factors, treatment patterns, and prognosis of patients with OVT, including venous thromboembolism (VTE) recurrences. Adult patients who presented to our medical center with an identifiable diagnosis of OVT over a 10-year period were included in this retrospective observational study. Individual patient charts were reviewed to collect baseline and outcomes data. We identified 223 women with OVT. Median follow-up was 857 days. Only 36.6% presented with abdominal pain and 61.4% reported a history of gynecologic surgery. Overall, right or left OVT incidence was similar (44.6 and 41.4%, respectively) but peripartum patients were more likely to have right OVT (60.0%, P = 0.03). VTE recurred in 22 (9.9%) women, all of which were remote from the OVT and there were no recurrences in peripartum patients. Mean (± SD) time to recurrence was 409 (± 421) days. Only 7.6% of OVT patients were anticoagulated for OVT; these women had a 38% reduction in VTE recurrence but because of low numbers, this was not statistically significant. VTE recurrence after OVT was associated with greater mortality in all patients, including patients with cancer. OVT is associated with an increased rate of non-OVT recurrence. Peripartum OVT patients appear to constitute a different patient population as they were younger, exhibited different risk factors, and had no increased incidence of recurrence. Although only a minority of patients with OVT was anticoagulated, this group had a reduction in VTE recurrence. A prospective study is needed to determine the utility of anticoagulation for women with OVT.