We performed a retrospective population-based study using the SEER database to assess survival trends in CBF-AML between 2000 and 2010. Median OS increased from 16 months in 2000-2002 to 25 months in 2006-2008 (p=0.002). The 3-year OS rate for patients with inv(16) was 57.3%, but in t(8;21) was only 35.5%. Patients aged 75-84 had worse survival than patients aged 15-44 (HR 5.61, P=0.0002). Black race was associated with higher mortality (HR 1.50, P=0.03). Compared to clinical trial outcomes, CBFAML survival is poorer in the general population, particularly among African Americans and the elderly, and in t(8;21) compared to inv(16) AML.
Acute Myeloid Leukemia; Core Binding Factors; Survival; Population Surveillance; Health Status Disparities
Chronic lymphocytic leukemia (CLL) is a malignancy arising from immune cells (B-lymphocytes) endowed with intrinsic antigen-presenting capabilities. Such a function however is lost during malignant transformation and CLL cells are well known for their inability to process and present antigens to the T-cell arm of the immune system. Instead, malignant CLL cells elicit a vast array of immune regulatory mechanisms conducive to T-cell dysfunction and immunosupression. Previously, we have shown that treatment of CLL cells with the demethylating agent 5-aza-2′-deoxycytidine unleashed target antigen expression. Here we show for the first time that combining two epigenetic modifiers, 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor LAQ824 effectively restores the immunogenicity of CLL cell lines as well as primary cells obtained from CLL patients. Indeed, such a combination induces the expression of novel and highly antigenic cancer testis antigens (CTAs) and co-stimulatory molecules. These changes facilitate the formation of robust supramolecular activation complexes (SMAC) between CLL cells and responder T-cells leading to intracellular signaling, lytic granule mobilization, and polarization of functional and relevant T-cell responses. This cascade of T-cell activating events triggered by CLL cells with restored APC function, points to combined epigenetic modifier treatment as a potential immunotherapeutic strategy for CLL patients.
5-aza-2′-deoxycytidine; Cancer-germline; Immunotherapy; Histone Deacetylase Inhibitor; Costimulatory
•Ganetespib is a highly potent HSP90 inhibitor in primary AML blasts.•Apoptotic induction is co-ordinate with suppression of pro-survival protein AKT.•Synergistic interaction with AraC suppressing pro-survival targets HSP70 and AKT.•Provides strong rationale for further clinical assessment of ganetespib in AML.
HSP90 is a multi-client chaperone involved in regulating a large array of cellular processes and is commonly overexpressed in many different cancer types including hematological malignancies. Inhibition of HSP90 holds promise for targeting multiple molecular abnormalities and is therefore an attractive target for heterogeneous malignancies such as Acute Myeloid Leukemia (AML).
Ganetespib is a highly potent second generation HSP90 inhibitor which we show is significantly more effective against primary AML blasts at nanomolar concentrations when compared with cytarabine (p < 0.001). Dose dependant cytotoxicity was observed with an apoptotic response coordinate with the loss of pro-survival signaling through the client protein AKT. Combination treatment of primary blasts with ganetespib and cytarabine showed good synergistic interaction (combination index (CI): 0.47) across a range of drug effects with associated reduction in HSP70 feedback and AKT signaling levels.
In summary, we show ganetespib to have high activity in primary AMLs as a monotherapy and a synergistic relationship with cytarabine when combined. The combination of cytotoxic cell death, suppression of cytoprotective/drug resistance mechanisms such as AKT and reduced clinical toxicity compared to other HSP90 inhibitors provide strong rationale for the clinical assessment of ganetespib in AML.
HSP90; AML; Ganetespib
Hypereosinophilic syndrome (HES) is a rare entity of unknown etiology that may cause a multitude of problems, from skin rash to organ failure, due to eosinophil infiltrate of tissues. Information on the interaction of hypereosinophilia and pregnancy in patients with established HES is very limited. Here we report a case of a woman with a seven year history of HES whose pregnancy resulted in the delivery of a healthy infant without complications, and no evidence of elevated eosinophils in the infants blood. During pregnancy the patient experienced significant reduction of eosinophils in her blood and resolution of signs and symptoms related to hypereosinophilia.
Pregnancy; Hypereosinophilic Syndrome
Dysregulation of hepcidin, a key iron regulating hormone, is important in the pathogenesis of iron overload in patients with myelodysplatic syndrome (MDS). However, most studies of hepcidin levels are complicated by concomitant RBC transfusions. To evaluate the relationship between iron metabolism and erythropoiesis, we measured serum levels of hepcidin, growth-differentiation factor-15 (GDF15) and other markers of erythropoiesis in 107 subjects with MDS not receiving RBC transfusions. Patients with MDS had significantly higher levels of hepcidin than normals. However, their hepcidin–ferritin ratio was markedly decreased compared to normals (P < 0.001) and varied substantially between MDS subtypes (P = 0.011). GDF15 levels positively correlated with percent of bone marrow erythroblasts (P < 0.001), soluble transferrin receptor (sTfR) (P = 0.018), and also with transferrin saturation (ISAT) (P = 0.038). The hepcidin–ferritin ratio negatively correlated with serum erythropoietin (EPO) levels (P < 0.001), and also with GDF15 levels (P = 0.014). Colony forming cells (CFC) were evaluated in 70 subjects. Those with serum ferritin (SF) levels <500 ng/ml had significantly more BFU-E than subjects with SF≥ 500 ng/L (P = 0.007), but numbers of granulocyte/macrophage-colony-forming cells (CFU-GM) were similar (P = 0.190). Our data indicate serum hepcidin levels are inappropriately low in patients MDS not receiving RBC transfusions. GDF15 levels correlated with low hepcidin levels and may contribute to iron overload in this setting. Iron overload may in turn suppress erythropoiesis by imparing the proliferative capacity of the erythroid progenitor cells.
Myelodysplastic syndromes; Iron metabolism; Hematopoiesis
Recent advances in the molecular characterization of Philadelphia chromosome-negative (Ph−) leukemias and related myeloid disorders have provided a clear rationale for investigating novel targeted therapies. Dasatinib is a tyrosine kinase inhibitor with activity against BCR-ABL, platelet-derived growth factor receptors (PDGFRs), c- KIT, fibroblast growth factor receptors (FGFRs), SRC family kinases (SFKs), and EPHA receptors, all of which have been implicated in the pathogenesis of Ph− leukemias and myeloid disorders. This review presents emerging data on the preclinical and clinical activity of dasatinib in these diseases, which suggest that larger clinical studies are warranted.
Leukemia; myeloid; Philadelphia-negative; dasatinib; myelodysplastic syndrome; myeloproliferative neoplasm
Hypereosinophilic syndrome (HES) is characterized by sustained non-clonal blood and tissue eosinophilia, leading to end-organ damage. With a molecular/cytogenetic clonality marker, the disease is classified as chronic eosinophilic leukemia (CEL). Efficacy of imatinib mesylate is well established in CEL with FIP1L1-platelet derived growth factor-α (PDGFRα) rearrangement. We treated with imatinib 18 HES patients (11 PDGFRα-negative and 7 PDGFRα-status unknown). One patient with unknown PDGFRα status achieved complete hematologic response, and two (one PDGFRα negative and one status unknown) achieved partial hematologic response. Our results confirm low response rate to imatinib in HES patients with unknown or negative PDGFRα status, and underscore the need for new therapeutic options for this disorder.
Hypereosinophilic syndrome; imatinib; gleevec; tyrosine kinase inhibitor; FIP1L1–PDGFRα
Quality of life (QoL) in patients with myelofibrosis (MF) is severely compromised by severe constitutional symptoms (i.e. fatigue, night sweats, fever, weight loss), pruritus, and symptoms from frequently massive hepatosplenomegaly. Given that no current instrument of patient reported outcomes (PRO) exists that covers the unique spectrum of symptomatology seen in MF patients, we sought to develop a new PRO instrument for MF patients for use in therapeutic clinical trials. Utilizing data from an international internet based survey of 458 patients with MF we created a 20 item instrument (MFSAF: Myelofibrosis Symptom Assessment Form) which measures the symptoms reported by >10% of MF patients, and includes a measure of QoL. We subsequently validated the MFSAF in a prospective trial of MF patients involving patient and provider feedback, as well as comparison to other validated instruments used in cancer patients. The MFSAF results were highly correlated with other instruments, judged comprehensive and understandable by patients, and should be considered for evaluation of MF symptoms in therapeutic trials.
Myelofibrosis; myeloproliferative disorder; primary myelofibrosis; fatigue; splenomegaly
Older adults with acute myeloid leukemia (AML) are commonly considered
for investigational therapies, which often only benefit subsets of patients. In
this exploratory, we assessed whether BH3 profiling of apoptotic functionality
could predict outcomes following treatment with vorinostat (histone deacetylase
inhibitor) and gemtuzumab ozogamicin (GO; CD33-targeted immunoconjugate.) Flow
cytometry of BH3 peptide priming with Noxa (anti-apoptotic protein Mcl-1
modulator) correlated with remission induction (p=.026; AUC=0.83 [CI:
0.65–1.00; p=.00042]: AUC=0.88 [CI:0.75–1.00] with age
adjustment) and overall survival (p=.027 logistic regression; AUC = 0.87
[0.64–1.00; p=.0017]). This Mcl-1-dependence suggests a pivotal role of
Bcl-2 family protein-mediated apoptosis to vorinostat/GO in AML patients.
AML; biomarker; personalized medicine; HDAC inhibitors; gemtuzumab ozogamicin
This phase I study evaluated selective JAK2 inhibitor XL019 in 30 patients with myelofibrosis. The initial dose cohorts were 100, 200, and 300 mg orally on days 1–21 of a 28-day cycle. Central and/or peripheral neurotoxicity developed in all patients. Subsequently, patients were treated on lower doses; neurotoxicity was again observed, leading to study termination. Peripheral neuropathy resolved in 50%, and central neurotoxicity in all patients within months after therapy cessation. Myelosuppression was minimal. The terminal half-life of XL019 was approximately 21 h, with steady state reached by Day 8. International Working Group defined responses were seen in three (10%) patients.
Myelofibrosis; JAK2; XL019; Mutation; Inhibitor
Chromosome 5q deletion can be found in rare cases of myelofibrosis (MF)
but the incidence, clinical significance and response to therapies are not well
studied. We retrospectively reviewed charts of 939 patients with MF and
identified 8 patients [0.8%] who carried 5q deletion. Of
the 8, seven had complex cytogenetic abnormalities and one had additional clone
with different cytogenetic abnormality. All 8 had significant three-lineage
pancytopenia. Three patients took lenalidomide and one (patient with 5q-clone)
achieved long-lasting hematologic response. Two patients responded to JAK2
inhibitor therapy. MF patients with 5q deletion often have complex karyotype and
myelofibrosis; 5q deletion; lenalidomide
Primary myelofibrosis (PMF) is myeloproliferative neoplasm whose diagnosis is based on a combination of clinical and pathology criteria. We evaluated 560 consecutive patients who were diagnosed with PMF upon a referral to our center and evaluated the frequency of and reasons for diagnostic discordance. Discordance in the diagnosis was found in 70 (12.5%) patients. Discordant cases had a significantly lower grade of bone marrow fibrosis (grade 0–1), more likely to be JAK2V617F-mutation negative, and have no peripheral blood blasts, possibly explaining the difficulty in making a proper diagnosis and underscoring the need for a complete evaluation at a tertiary center.
primary myelofibrosis; diagnostic discrepancy; JAKV617F mutation
Primary myelofibrosis (PMF) is rare myeloproliferative disease usually diagnosed in older patients. Reports of a concurrent acute lymphoblastic leukemia or lymphoma in PMF are rare. We present a case of a 26-year old patient with PMF and precursor T-cell acute lymphoblastic lymphoma of the spleen and lymph nodes. The patient was treated with splenectomy and allogeneic stem cell transplantation (allo-SCT) and remains in remission from both PMF and lymphoblastic lymphoma 6 months after the full strength allo-SCT. To our knowledge this is second report of concurrent PMF and precursor T-cell acute lymphoblastic lymphoma, and first report of a successful treatment for both underlying conditions.
primary myelofibrosis; precursor T-cell lymphoblastic lymphoma; allogeneic stem cell transplantation
Primary autoimmune myelofibrosis is a very rare condition characterized by peripheral blood cytopenias, bone marrow fibrosis with lymphoid aggregates, and by the finding of autoantibodies in peripheral blood, suggesting a systemic autoimmune process. Patients can be frequently misdiagnosed as having the more common disorder primary myelofibrosis, a myeloproliferative neoplasm. We report the case of a patient with primary autoimmune myelofibrosis with emphasis on the clinical and pathological features that lead to the diagnosis.
autoimmune myelofibrosis; anemia; diagnosis; pathology
Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is an aberrant fusion gene product with tyrosine kinase activity and is expressed in substantial subset of anaplastic large cell lymphomas (ALCL). It has been shown that NPM-ALK binds to and activates signal transducer and activator of transcription 3 (STAT3). Although NPM-ALK+ ALCL overall shows a better prognosis, there is a sub-group of patients who relapses and is resistant to conventional chemotherapeutic regimens. NPM-ALK is a potential target for small molecule kinase inhibitors. Crizotinib (PF-2341066) is a small, orally bioavailable molecule that inhibits growth of tumors with ALK activity as shown in a subgroup of non-small lung cancer patients with EML4-ALK expression. In this study, we have investigated the in vitro effects of Crizotinib in ALCL cell line with NPM-ALK fusion. Crizotinib induced marked downregulation of STAT3 phosphorylation, which was associated with significant apoptotic cell death. Apoptosis induction was attributed to caspase-3 cleavage and marked downregulation of the Bcl-2 family of proteins including MCL-1. These findings implicate that Crizotinib has excellent potential to treat patients with NPM-ALK+ ALCL through induction of apoptotic cell death and downregulation of major oncogenic proteins in this aggressive lymphoma.
Crizotinib; STAT3; ALCL; NPM-ALK; MCL-1
G0S2; Tumor suppressor; Leukemia; CML; K562
Using a mouse model with the tumor suppressor TRAF3 deleted from B cells, we identified Sox5 as a gene strikingly up-regulated in B lymphomas. Sox5 proteins were not detected in normal or premalignant TRAF3-/-B cells even after treatment with B cell stimuli. The Sox5 expressed in TRAF3-/-B lymphomas represents a novel isoform of Sox5, and was localized in the nucleus of malignant B cells. Overexpression of Sox5 inhibited cell cycle progression, and up-regulated the protein levels of p27 and β-catenin in human multiple myeloma cells. Together, our findings indicate that Sox5 regulates the proliferation of malignant B cells.
Sox5; B lymphoma; multiple myeloma; TRAF3; p27; β-catenin
Flow cytometric (FC) enumeration of abnormal plasma cells (APCs) for diagnosis and prognostication of plasma cell dyscrasias (PCD) is challenging. We studied antigen expression in normal plasma cells (NPC) (N=34) and APC in a series of unselected PCD (N=59). NPC subpopulations often demonstrated CD19(−), CD20(+), CD45(−) or dim and CD56(+), an immunophenotype observed in PCD. However abnormal CD81 was only observed in APCs (APC detection sensitivity 95%; specificity 100%). We evaluated differences in antigen expression patterns among MGUS (N=14), SMM (N=35) and MM (N=10), finding the combination of CD45 and CD56 helpful in differentiating MGUS from SMM and MM (p=0.0002).
monoclonal gammopathy of uncertain significance; smoldering multiple myeloma; multiple myeloma; normal plasma cell immunophenotype; CD81
microRNA profiling of Acute Myeloid Leukemia patient samples identified miR-125a as being decreased. Current literature has investigated miR-125a’s role in normal hematopoiesis but not within Acute Myeloid Leukemia. Analysis of the upstream region of miR-125a identified several CpG islands. Both precursor and mature miR-125a increased in response to a de-methylating agent, Decitabine. Profiling revealed the ErbB pathway as significantly decreased with ectopic miR-125a. Either ectopic expression of miR-125a or inhibition of ErbB via Mubritinib resulted in inhibition of cell cycle proliferation and progression with enhanced apoptosis revealing ErbB inhibitors as potential novel therapeutic agents for treating miR-125a-low AML.
microRNA-125a; methylation; cell cycle; apoptosis; Mubritinib
DNA repair aberrations and associated chromosomal instability is a feature of chronic lymphocytic leukemia (CLL). To evaluate if DNA repair insufficiencies are related to methylation changes, we examined the methylation of nine promoter regions of DNA repair proteins by bisulfide sequencing in 26 CLL primary samples and performed quantitative PCR on a subset of samples to examine BRCA1 expression. We also investigated if changes in cytogenetic or expression level of DNA repair proteins led to changes in sensitivity to a novel PARP inhibitor, CEP-8983, alone and in combination with bendamustine. No changes in promoter methylation were identified in BRCA1, BRCA2, FANC-C, FANC-F, FANC-L, ATM, MGMT, hMLH1 and H2AX except for two cases of minor BRCA1 hypermethylation. CLL samples appeared to have reduced BRCA1 mRNA expression uniformly in comparison to non-malignant lymphocytes irrespective of promoter hypermethylation. CEP-8983 displayed single agent cytotoxicity and the combination with bendamustine demonstrated synergistic cytotoxicity in the majority of CLL samples. These results were consistent across cytogenetic subgroups, including 17p deleted and previously treated patients. Our results provide rationale for further exploration of the combination of a PARP inhibitor and DNA damaging agents as a novel therapeutic strategy in CLL.
Chronic lymphocytic leukemia (CLL); poly (ADP-ribose) polymerase (PARP); CEP-8983; bendamustine
We report on 348 patients ≥ 70 years (median age 78 years) with acute myeloid leukemia (> 50% with secondary AML) randomized to receive either 600 mg or 300 mg of tipifarnib orally twice daily on days 1–21 or days 1–7 and 15–21, repeated every 28 days (4 treatment regimens). Responses were seen in all regimens, with overall response rate (CR + CRi + PR) highest (20%) among patients receiving tipifarnib 300 mg twice daily on days 1–21. Toxicities were acceptable. Unless predictors of response to tipifarnib are identified, further study as a single agent in this population is unwarranted.
tipifarnib; farnesyltransferase inhibitor; acute myeloid leukemia; older; untreated
We examined 1229 younger patients with acute myeloid leukemia who achieved CR1 on Eastern Cooperative Oncology Group trials. We defined late relapse as occurring after ≥3 years of CR1. With median follow-up of 11.3 years, there were 14 late relapses (1.1% of CR1 patients; 3.3% of 3-year CR1 patients). Eight achieved second CR and median overall survival after late relapse was 3.2 years. Most patients tested (9/11) had a normal karyotype at diagnosis; none had new cytogenetic abnormalities at relapse. Late relapse is rare and nearly all 3-year CR1 patients are cured. If late relapse occurs, outcomes are relatively favorable.
acute myeloid leukemia; late relapse; outcomes; clinical trials; normal cytogenetics
Adequate dosing of lenalidomide in Chronic Lymphocytic Leukemia (CLL) remains unclear. This study determined maximum tolerated dose (MTD) in relapsed CLL patients (Cohort A) and patients achieving a partial response (PR) or better to recent therapy (Cohort B). Thirty-seven patients were enrolled. MTD was 2.5 mg followed by 5.0 mg continuous. In Cohort A, tumor flare grade 1–2 occurred in 15 patients (50%) and grade 3 in 1 patient (3%). Cohort A had 19 of 23 evaluable (83%) patients, 4 PR (17%) and 15 (65%) stable disease (SD), Cohort B had 6 of 7 patients (86%) with SD. Despite overall response rate not being high, many patients remained on therapy several months with SD.
Chronic Lymphocytic Leukemia; Relapse; Lenalidomide; Tumor flare; Maintenance