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Anemia is a key survival prognostic factor in lower-risk myelodysplastic syndromes (MDS). Lenalidomide (LEN) can correct anemia in 25% of MDS patients without deletion 5q (del5q). As this therapy will inevitably fail, understanding the outcome of these patients will facilitate development of subsequent treatment strategies. To answer this question, an international retrospective study focused on LEN-treated lower-risk, non-del5q, MDS patients was performed. We analyzed the overall survival after LEN failure, its prognostic factors and the impact of post LEN treatment options. We included a total of 384 patients. The median overall survival after failure of LEN was 43 months. In multivariate analysis, adverse cytogenetics, excess of blasts at the initiation of LEN, and the type of failure (classified as stable disease, relapse, intolerance, or progression) were the main determinants of outcome. Subsequent therapy with hypomethylating agents was associated with a prolonged survival compared to BSC (median OS= 51m vs. 36m, p=0.01). In conclusion, the survival for non-del5q MDS patients after failure of LEN remains relatively prolonged, though with a wide range. Clinical trial participation remains the recommendation for these patients even if options such as hypomethylating agents may be considered.

Purpose Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 61.5%, and median response duration was 17 months. Of 1,147 patients experiencing ESA failure, 653 experienced primary failure and 494 experienced relapse after a response. Primary failure of ESAs was associated with a higher risk of acute myeloid leukemia (AML) progression, which did not translate into an OS difference. Of 450 patients (39%) who received second-line treatment, 194 received HMAs, 148 received LEN, and 108 received other treatments (MISC), whereas 697 received RBC transfusions only. Five-year AML cumulative incidence was 20.3%, 20.3%, and 11.3% for those receiving HMAs, LEN, and MISC, respectively ( P = .05). Five-year OS for patients receiving HMA, LEN, and MISC was 36.5%, 41.7%, and 51%, respectively ( P = .21). In a multivariable analysis adjusted for age, sex, revised International Prognostic Scoring System score, and progression at ESA failure, there was no significant OS difference among the three groups. Conclusion In this large, multicenter, retrospective cohort of patients with non-del(5q) lower-risk MDS treated with ESAs, none of the most commonly used second-line treatments (HMA and LEN) significantly improved OS. Early failure of ESAs was associated with a higher risk of AML progression.

Risk of subsequent primary malignancies (SPMs) associated with lenalidomide therapy in multiple myeloma (MM) patients, outside the context of melphalan-based therapy is not established. We assessed the risk of SPMs in lenalidomide treated MM patients (n = 1653) at Moffitt Cancer Center (2004-2012) outside the context of melphalan-based induction therapy and post-melphalan maintenance therapy, via (1) cohort analysis and (2) nested case-control study. Incident SPMs (n = 51) were matched to controls (n = 102) on age at MM diagnosis, gender, follow-up time, and date of diagnosis. Incidence of SPM differed significantly (p = 0.0038) between MM patients treated with and without lenalidomide (5-year incidence estimates of 3.2 and 6.2%, respectively), although not significant after adjustment for age and year of diagnosis (HR = 0.82, 95%CI = 0.43-1.57). Lenalidomide treatment was inversely associated with SPM in the nested case-control analysis (OR = 0.03, 95%CI = 0.002-0.34). In this large cohort of MM patients, lenalidomide treatment was not associated with an increased risk of SPM.

Background: Transfusion of blood products is a key component of the supportive management in patients with acute leukemia (AL). However high-quality trial evidence and clinical outcome data to support specific transfusion goals for blood products for patients with AL remain limited leading to diverse transfusion practices. The primary objective of this study was to determine the spectrum of transfusion patterns in a variety of care settings among providers who treat AL patients., Study Design and Methods: A 31-question survey queried providers caring for AL patients about the existence of institutional guidelines for transfusion of blood products, transfusion triggers for hemoglobin (Hb), platelets (PLTs), and fibrinogen in various settings including inpatient and outpatient and before procedures., Results: We analyzed 130 responses and identified divergent transfusion Hb goals in hospitalized and ambulatory patients, fibrinogen goals for cryoprecipitate transfusions, and variation in practice for use of certain PLTs and red blood cell products. The least variable transfusion patterns were reported for PLT goals in thrombocytopenia and in the setting of invasive procedures such as bone marrow biopsy and lumbar punctures., Conclusions: This survey confirmed wide variations in blood product transfusion practices across several clinical scenarios in patients with AL. The findings emphasized the need for large prospective randomized trials to develop standardized evidence-based guidelines for blood product transfusions in patients with AL with the goal of limiting unnecessary transfusions without compromising outcomes., (© 2016 AABB.)

The myelodysplastic syndromes (MDS) comprise a heterogenous group of myeloid disorders with a highly variable disease course. Diagnostic criteria to better stratify patients with MDS continue to evolve, based on morphology, cytogenetics, and the presence of cytopenias. More accurate classification of patients will allow for better treatment guidance. Treatment encompasses supportive care, treatment of anemia, low-intensity therapy, and high-intensity therapy. This portion of the guidelines focuses on diagnostic classification, molecular abnormalities, therapeutic options, and recommended treatment approaches., (Copyright © 2017 by the National Comprehensive Cancer Network.)

Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1β (IL-1β) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and β-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear β-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention., (© 2016 by The American Society of Hematology.)

Introduction: No drug has resulted in a survival advantage in patients with lower-risk myelodysplastic syndromes (MDS). While hypomethylating agents (HMA) have revolutionized treatment options for patients with higher-risk MDS, the prognosis remains dismal after HMA treatment failure. Novel effective therapies are urgently needed especially after HMA failure., Areas Covered: This review covers the current approach to disease prognostication and risk-adaptive therapy, as well as novel therapeutic approaches. We discuss the recent advancements in the understanding of MDS disease biology as a basis of targeted drug development. Several classes of novel agents are reviewed including drugs targeting dysregulated epigenetic control mechanisms, signaling pathways, abnormal splicing, as well as agents that target the immune system and the MDS bone marrow niche., Expert Opinion: Significant advancements in the understanding of the underlying biology of MDS are only starting to be translated into novel treatment options for MDS. Epigenetic therapy has shown significant clinical activity with HMA but the results of clinical trials combining HMAs with histone deacetylase inhibitors (HDACi) have been disappointing to date. Similarly, targeting several aberrant pathways in MDS has not resulted in significant improvements in therapy. Future therapies will focus both on synergic combination of existing drugs as well as novel agents targeting dysregulated immune responses and abnormal RNA splicing in MDS.

Background: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are myeloid neoplasms in which outgrowth of neoplastic clones disrupts normal hematopoiesis. Some patients with unexplained persistent cytopenias may not meet minimal diagnostic criteria for MDS but an alternate diagnosis is not apparent; the term idiopathic cytopenia of undetermined significance (ICUS) has been used to describe this state. MDS and AML occur primarily in older patients who are often treated outside the clinical trial setting. Consequently, our understanding of the patterns of diagnostic evaluation, management, and outcomes of these patients is limited. Furthermore, there are few natural history studies of ICUS. To better understand how patients who have MDS, ICUS, or AML are managed in the routine clinical setting, the Connect MDS/AML Disease Registry, a multicenter, prospective, observational cohort study of patients newly diagnosed with these conditions has been initiated., Methods/design: The Connect MDS/AML Disease Registry will capture diagnosis, risk assessment, treatment, and outcomes data for approximately 1500 newly diagnosed patients from approximately 150 community and academic sites in the United States in 4 cohorts: (1) lower-risk MDS (International Prognostic Scoring System [IPSS] low and intermediate-1 risk), with and without del(5q); (2) higher-risk MDS (IPSS intermediate-2 and high risk); (3) ICUS; and (4) AML in patients aged ≥ 55 years (excluding acute promyelocytic leukemia). Diagnosis will be confirmed by central review. Baseline patient characteristics, diagnostic patterns, treatment patterns, clinical outcomes, health economics outcomes, and patient-reported health-related quality of life will be entered into an electronic data capture system at enrollment and quarterly for 8 years. A tissue substudy to explore the relationship between karyotypes, molecular markers, and clinical outcomes will be conducted, and is optional for patients., Discussion: The Connect MDS/AML Disease Registry will be the first prospective, observational, non-interventional study in the United States to collect clinical information, patient-reported outcomes, and tissue samples from patients with MDS, ICUS, or AML receiving multiple therapies. Results from this registry may provide new insights into the relationship between diagnostic practices, treatment regimens, and outcomes in patients with these diseases and identify areas for future investigation., Trial Registration: Connect MDS/AML Disease Registry ( NCT01688011 ). Registered 14 September 2012.

Chronic lymphocytic leukemia (CLL) is an incurable disease in need of new therapeutic strategies. The immunomodulatory agent, lenalidomide, has shown activity as salvage therapy for CLL. In this phase II trial, we combined lenalidomide with rituximab in 25 patients (range, 41-79) with refractory/relapsed CLL. Lenalidomide was administered orally on escalating doses, with cycle 1 doses of 2.5mg daily on days 1-7, 5mg on days 8-14, and 10mg on days 15-21 followed by 7days off. On cycle 2 and beyond, lenalidomide was administered at 20mg daily on days 1-21. Rituximab was administered at 375mg/m(2) intravenously on a weekly basis for the first cycle starting on day 15 for 4 doses, with each cycle being 28days. Treatment was continued until disease progression or toxicity. Overall response rate was 45.8% on intent-to-treat and 61.1% in evaluable patients (all partial responses). Median time to treatment failure was 14.3 months for evaluable patients, and median overall survival was not reached. The most common grade 3/4 toxicity was neutropenia (72% of patients). The most common nonhematologic toxicity was infection (29% of patients). Lenalidomide combined with rituximab showed activity in heavily treated refractory CLL with an acceptable toxicity profile., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Adult T-cell leukemia/lymphoma (ATLL) is aggressive mature T-cell lymphoproliferative disorder with a poor outcome., Methods: We present 10 patients with acute and lymphomatous subtypes of ATLL treated with distinct induction regimens, including CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], prednisone or prednisolone), interferon/zidovudine, and VCAP-AMP-VECP (vincristine, cyclophosphamide, doxorubicin, prednisone; doxorubicin, ranimustine, prednisone; vindesine, etoposide, carboplatin, prednisone)., Results: The overall response rate was 50%, with 10% complete remission (CR). Two patients achieved CR with the second-line regimen. Three patients underwent consolidation with allogeneic stem cell transplantation (ASCT) in the first CR. The median overall survival was 51 months for the entire group and 84 months for the patients who had undergone ASCT versus 34 months for the non-ASCT patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: There has been little improvement in cancer survival of adolescent and young adult (AYA) patients, aged 18 to 39 years, possibly reflecting different disease biology. Myelodysplastic syndrome (MDS) is mainly a disease of the elderly. The characteristics, outcomes, and response to treatment are not well described in the AYA population., Patients and Methods: This was a retrospective review of patients from the Moffitt Cancer Center MDS database. We compared baseline characteristics and outcomes of the AYA population to older patients. We identified 51 AYA and 1897 older MDS patients. More female subjects and Hispanics were noted in AYA group., Results: The AYA patients had higher risk disease, more circulating myeloblasts, and more hypoplastic MDS. Autoimmune disorders were more prevalent in older patients. The median overall survival (OS) was 47 months in the AYA group versus 40 months in the older group (P = .26). The median OS was 47 versus 56 months in lower risk AYA group and older group, respectively (P = .46). In the higher risk group, median OS was 82 months in the AYA group compared to 17 months in the older group (P = .001). Thirty individuals (59%) underwent allogeneic stem-cell transplantation in the AYA group versus 241 (13%) in the older group. The median OS for transplanted patients was 55 months in the AYA group and 46 months in the older group (P = .4). In the nontransplanted patients, median survival was 31 months for the AYA group and 39 months for the older group (P = .9). The rate of acute myeloid leukemia transformation was 37% versus 28% in the AYA and older groups, respectively (P = .17). No differences in use or response to hypomethylating agents were observed. Lenalidomide therapy was seldom used in AYA, as none presented with del5q. In AYA, poor karyotype was the only variable strongly associated with worse outcome. Fifteen patients had poor risk karyotypes (29%). The median OS was 47 months, not reached, and 29 months among patients with good, intermediate, and poor risk cytogenetics, respectively (P = .035)., Conclusion: MDS is rare and tends to be more aggressive in the AYA population. Karyotype was the most important prognostic factor. Allogeneic stem-cell transplantation offered younger patients the best outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Immunosuppressive therapy (IST) in low risk myelodysplastic syndrome (MDS) is known to achieve hematologic improvement but remains an underutilized treatment option. We report our experience using antithymocyte globulin (ATG) and cyclosporine A (CSA) to explore clinical predictive response factors., Patients and Methods: Patients treated with IST identified in the Moffitt Cancer Center MDS database were analyzed using baseline data, IST details, and response rates., Results: Sixty-six patients treated with IST were identified. The median age was 61 years; the majority were at low risk and had a good karyotype. The median time to start IST was 1 year. All patients received ATG, 60% rabbit (r-ATG), 32% equine ATG (e-ATG), and 60% received CSA. Overall hematologic improvement was 42% with a trend favoring e-ATG over r-ATG (52% vs. 39%; P = .09). Erythroid improvement was evaluated in 30 patients, and 60% responded; neutrophil improvement was evaluated in 15, and 39% responded; platelet improvement was evaluated in 18, and 57% responded. Six of 18 pancytopenic patients experienced trilineage response. Mean time from ATG to next therapy was 12 months. None of the patients with very high risk or high risk revised International Prognostic Scoring System (IPSS-R) responded. Poor karyotype had a lower response rate, 25%, compared to 41% for intermediate and 44% for good karyotype. No difference in predicting response was found based on the National Institutes of Health Response Model; 38% with low and 45% with high probability responded. A trend favored treatment within 2 years from diagnosis, with 46% responding compared to 33% treated after 2 years. First-line ATG or after lenalidomide responded better than after azacitidine or third-line therapy. CSA provided an advantage: the disease of 51% responded compared to 27% with ATG alone (P = .05). Ten patients experienced transformation to acute myeloid leukemia, 7% with disease that responded to therapy and 24% with disease that did not respond to therapy (P = .08). Overall survival was 67.2 months without difference between those with and without response. Adverse events were reported in 55 patients. Infusion reactions occurred in 85% but was similar between ATG types. Infection rate was 25% and higher with e-ATG. Serum sickness was reported in 18% and significantly higher with r-ATG., Conclusion: IST has a hematologic improvement response rate in the range of other therapies approved for lower risk MDS. High risk IPSS-R, poor karyotype, and treatment after 2 years from diagnosis have unfavorable response trend. ATG with CSA has higher response than ATG alone. First-line ATG or after lenalidomide had better response trend compared to third-line therapy or azacitidine therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Peptide vaccines are capable of eliciting immune responses targeting tumor-associated antigens such as the Wilms' Tumor 1 (WT1) antigen, often overexpressed in myeloid malignancies. Here, we assessed the safety, tolerability, and immunogenicity of a polyvalent WT1 peptide vaccine. Individuals with WT1-positive acute myeloid leukemia (AML) in first (CR1) or second (CR2) remission or with higher-risk myelodysplastic syndrome (MDS) following at least 1 prior line of therapy were vaccinated with a mixture of peptides derived from the WT1 protein, with sargramostim injections before vaccination to amplify immunogenicity. Six vaccinations were delivered biweekly, continuing then monthly until patients received 12 vaccinations or showed disease relapse or progression. Therapeutic efficacy was evaluated by progression-free and overall survival. Immune responses were evaluated by delayed-type hypersensitivity testing and T-cell IFNγ ELISPOT at specified intervals. In 16 patients who received at least one vaccination, 10 completed the planned course of six vaccinations and six continued for up to six additional monthly vaccinations. Vaccinations were well tolerated, with no patients discontinuing due to toxicity. One of two patients with high-risk MDS experienced a prolonged decrease in transfusion dependence. Two of 14 AML patients demonstrated relapse-free survival >1 year. Both patients were in CR2 at time of vaccination, with duration of their remission exceeding duration of their first remission, suggesting a potential benefit. Our WT1 vaccine was well-tolerated. The clinical benefit that we observed in several patients suggests engagement of a protective immune response, indicating a need for further trials., (© 2015 Wiley Periodicals, Inc.)

Patients with chronic lymphocytic leukemia (CLL) have a 2- to 5-fold risk of developing a second malignancy compared with the general population. The incidence of myeloid malignancies, such as acute myeloid leukemia and myelodysplastic syndrome, is increased in CLL and has been linked to previous therapy. In this study, we aim at describing characteristics and determining risk factors for developing second myeloid disorders (SMDs) in patients with CLL. From a total of 1269 patients diagnosed with CLL during the study time period, 30 (2.4%) were found to have an SMD. The majority of SMDs were myelodysplastic syndrome or acute myeloid leukemia (76.7%). The median time from diagnosis of CLL to diagnosis of SMD was 4.47 years. Most patients who developed an SMD had received treatment for their CLL (86%). The median time from treatment of CLL to diagnosis of SMD was 4.19 years. The overall survival of patients with CLL with no second malignancy was significantly longer than those with an SMD (11.9 vs. 7.1 years, P = .001). There was no association between developing SMD and age, gender, expression of CD38, expression of ZAP-70, and unmutated immunoglobulin heavy chain gene status. The risk of developing SMD in our cohort was higher in patients who received fludarabine- or alkylator-based therapy. Our analysis is one of the largest series showing that patients receiving fludarabine or alkylator-based therapies for CLL have a higher risk of developing SMD. Our study also confirms previous reports that prognostic factors in CLL do not increase the risk for development of SMD. Clinicians should understand the leukemogenicity of fludarabine or alkylator-based treatments when considering treatments for patients with CLL., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The International Prognostic Scoring System (IPSS) is the most widely used tool for risk assessment and treatment decisions for myelodysplastic syndrome (MDS). Several new models have been proposed to identify a subset of lower-risk patients with MDS who are experiencing inferior than expected outcomes. We validated the Lower-Risk MD Anderson Risk Model (LR-MDAS) in 1288 lower-risk patients with MDS by the IPSS. On the basis of the LR-MDAS, 228 patients (17%) were in category 1, 730 patients (57%) were in category 2, 315 patients (25%) were in category 3, and 15 patients (1%) were in an unknown category. The median overall survival for the corresponding LR-MDAS categories was (1) 109 months (95% confidence interval [CI], 82-137), (2) 56 months (95% CI, 58-73), and (3) 29 months (95% CI, 24-35) (P < .005). Overall, 25% of patients were upstaged to category 3. LR-MDAS refined prognostic value among very low-, low-, and intermediate-risk Revised IPSS. The rate of acute myeloid leukemia transformation according to LR-MDAS was 15%, 18%, and 29% for categories 1, 2, and 3, respectively (P < .005). Our data validate the prognostic value of the LR-MDAS model, but the utility of it as a treatment decision tool should be studied prospectively., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening syndrome of excessive immune activation and an inflammatory cytokine storm leading to multiple organ failure. We report our experience in a large tertiary referral center on HLH in the setting of hematologic malignancies and describe responses to therapy and outcomes. Seventeen cases of HLH were included in which the most common underlying diagnosis was aggressive lymphoma (n = 7). The median time from diagnosis of primary hematologic condition to HLH was 3.1 months. The most common presenting features were fever (n = 15), splenomegaly (n = 13), and transaminitis (n = 14). The mean serum ferritin level was 21,000 ng/mL. Fourteen patients demonstrated evidence of hemophagocytosis in bone marrow or other organs. Among all patients, 12 received etoposide, 14 received dexamethasone, and 3 received cyclosporine. Intrathecal chemotherapy was administered to 3 patients. Overall, 7 patients (41%) responded to treatment with clinical and laboratory improvement. The median overall survival (OS) from the time of HLH diagnosis and the primary hematologic diagnosis was 8.4 months and 29.5 months, respectively. The OS was better among patients with HLH with aggressive lymphomas (12 months). Response to treatment was associated with better OS. Recognition of manifestations and prompt diagnosis of HLH are crucial to initiate prompt therapy and improve outcome., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which include essential thrombocythemia, polycythemia vera, and myelofibrosis (MF), are in a new era of molecular diagnosis, ushered in by the identification of the JAK2(V617F) and cMPL mutations in 2005 and 2006, respectively, and the CALR mutations in 2013. Coupled with increased knowledge of disease pathogenesis and refined diagnostic criteria and prognostic scoring systems, a more nuanced appreciation has emerged of the burden of MPN in the United States, including the prevalence, symptom burden, and impact on quality of life. Biological advances in MPN have translated into the rapid development of novel therapeutics, culminating in the approval of the first treatment for MF, the JAK1/JAK2 inhibitor ruxolitinib. However, certain practical aspects of care, such as those regarding diagnosis, prevention of vascular events, choice of cytoreductive agent, and planning for therapies, present challenges for hematologists/oncologists, and are discussed in this article., (Copyright © 2015 by the National Comprehensive Cancer Network.)

Purpose: Data suggest that activity of p38 MAPK and Tie2 kinases is dysregulated in myelodysplastic syndromes (MDS) and may be targets for novel therapies. A phase I study of ARRY-614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by International Working Group 2006 criteria., Experimental Design: Forty-five patients received ARRY-614 either once daily or twice daily in dose escalation (400, 600, 900, or 1,200 mg once daily; 200 or 300 mg twice daily) or expansion cohorts., Results: The 300 mg twice daily schedule was not tolerated, and an MTD was not reached for once daily dosing. Treatment-related adverse events were primarily grade 1-2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Interpatient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 red blood cell transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI., Conclusions: ARRY-614 was well tolerated and has sufficient activity to warrant further evaluation in this patient population. We recommend 1,200 mg once daily as the optimal dose for further study., (©2014 American Association for Cancer Research.)

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) comprise a heterogeneous group of myeloid disorders with a highly variable disease course that depends largely on risk factors. Risk evaluation is therefore a critical component of decision-making in the treatment of MDS. The development of newer treatments and the refinement of current treatment modalities are designed to improve patient outcomes and reduce side effects. These NCCN Guidelines Insights focus on the recent updates to the guidelines, which include the incorporation of a revised prognostic scoring system, addition of molecular abnormalities associated with MDS, and refinement of treatment options involving a discussion of cost of care., (Copyright © 2015 by the National Comprehensive Cancer Network.)

We prospectively evaluated the allogeneic hematopoietic cell transplantation (HCT) outcomes in high-risk myelodysplastic syndrome (MDS) patients who received pretransplantation 5-azacitidine. Twenty-five patients evaluated for allogeneic HCT consult and considered medically eligible for a donor search were enrolled. Azacitidine was administered at 75 mg/m(2) for 5 to 7 days every 4 weeks until a suitable donor was found. A median of 3 (range, 0 to 6) cycles of 5-azacitidine were administered. Preallogeneic HCT responses to 5-azacitidine, based on the International Working Group criteria, were 48% partial response, 33% stable disease, and 19% progressive disease. Four patients did not proceed to allogeneic HCT. Twenty-one patients, a median age of 55 (range, 25 to 67) years, received allogeneic HCT after myeloablative pharmacokinetically targeted i.v. busulfan and fludarabine conditioning regimen. Donors were either HLA-matched related or unrelated, except for 1 mismatch unrelated donor. With a median follow-up of 30 months, 1-year relapse-free and overall survivals were 52% (95% confidence interval [CI], 30% to 71%) and 62% (95% CI, 38% to 79%), respectively. Preallogeneic HCT 5-azacitidine administration was well tolerated and provided reasonable disease control before allogeneic HCT. (Registered at ClinicalTrials.gov as NCT00660400)., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

CPX-351 is a liposomal formulation of cytarabine:daunorubicin designed to deliver synergistic drug ratios to leukemia cells. In this phase 2 study, newly diagnosed older acute myeloid leukemia (AML) patients were randomized 2:1 to first-line CPX-351 or 7+3 treatment. The goal was to determine efficacy and identify patient subgroups that may benefit from CPX-351 treatment. Response rate (complete remission + incomplete remission) was the primary end point, with event-free survival (EFS) and overall survival (OS) as secondary end points. The 126 patients entered were balanced for disease and patient-specific risk factors. Overall, CPX-351 produced higher response rates (66.7% vs 51.2%, P = .07), meeting predefined criteria for success (P < .1). Differences in EFS and OS were not statistically significant. A planned analysis of the secondary AML subgroup demonstrated an improved response rate (57.6% vs 31.6%, P = .06), and prolongation of EFS (hazard ratio [HR] = 0.59, P = .08) and OS (HR = 0.46, P = .01). Recovery from cytopenias was slower after CPX-351 (median days to absolute neutrophil count ≥1000: 36 vs 32; platelets >100 000: 37 vs 28) with more grade 3-4 infections but without increase in infection-related deaths (3.5% vs 7.3%) or 60-day mortality (4.7% vs 14.6%), indicating acceptable safety. These results suggest a clinical benefit with CPX-351, particularly among patients with secondary AML, and provide the rationale for a phase 3 trial currently underway in newly diagnosed secondary AML patients. This study is registered at Clinicaltrials.gov as #NCT00788892., (© 2014 by The American Society of Hematology.)

Chronic myelomonocytic leukemia (CMML) is an aggressive malignancy characterized by peripheral monocytosis and ineffective hematopoiesis. It has been historically classified as a subtype of the myelodysplastic syndromes (MDSs) but was recently demonstrated to be a distinct entity with a distinct natural history. Nonetheless, clinical practice guidelines for CMML have been inferred from studies designed for MDSs. It is imperative that clinicians understand which elements of MDS clinical practice are translatable to CMML, including which evidence has been generated from CMML-specific studies and which has not. This allows for an evidence-based approach to the treatment of CMML and identifies knowledge gaps in need of further study in a disease-specific manner. This review discusses the diagnosis, prognosis, and treatment of CMML, with the task of divorcing aspects of MDS practice that have not been demonstrated to be applicable to CMML and merging those that have been shown to be clinically similar.

The myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias, dysplasia in one or more myeloid lineages, and the potential for development of acute myeloid leukemia. These disorders primarily affect older adults. The NCCN Clinical Practice Guidelines in Oncology for MDS provide recommendations on the diagnostic evaluation and classification of MDS, risk evaluation according to established prognostic assessment tools (including the new revised International Prognostic Scoring System), treatment options according to risk categories, and management of related anemia.

This phase II study to determine the safety and efficacy of denileukin diftitox (DD) and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) enrolled patients with newly diagnosed peripheral T-cell lymphoma (PTCL). Forty-nine received DD 18 μg/kg/day (days 1, 2) with CHOP (day 3) every 21 days for ≤ 6-8 cycles. Intent-to-treat (ITT) and safety populations comprised all patients. In the ITT population, the overall response rate was 65%, median duration of response was 30 months and median progression-free survival was 12 months. Median overall survival was not attained at the end of the study, and the overall survival rate was 63.3%. The two most frequent treatment-related adverse events (AEs) were fatigue and nausea. Most frequent AEs ≥ grade 3 within the hematologic system were lymphopenia (24.5%), neutropenia (20.4%) and leukopenia (18.4%). Three treatment-related deaths occurred. DD plus CHOP was well tolerated, and progression-free and overall survival improved versus historical comparison with CHOP alone. Confirmation in larger trials is warranted.

Purpose: Tyrosine kinase inhibitors (TKIs) are now standard treatment for chronic myeloid leukemia (CML). While TKIs have less toxicity than previous treatments, they have side effects that can impact quality of life (QOL)., Methods: This study compared CML patients taking a TKI for an average of 4.01 years (range 0.50-9.79 years) to age- and gender-matched controls with no history of cancer on measures of symptom burden, depression, fatigue, sleep, and health-related QOL., Results: Compared to controls (n = 62), CML patients (n = 62) taking a TKI (imatinib 55 %, nilotinib 31 %, and dasatinib 14 %) reported significantly worse fatigue severity (p < .001), fatigue interference (p < .001), depression (p = .007), symptom burden (p < .001), and physical QOL (p < .001). TKI patients were also more likely meet established cutoffs for clinically meaningful fatigue (p values < .001) and depression (p = .004). There were no differences in mental QOL or sleep (p values > .010). Regarding specific symptoms, TKI patients were more likely to report nausea, diarrhea, itching, skin changes, swelling of arms or legs, and not looking like themselves (p values < .001)., Conclusions: These data suggest the need for interventions to address QOL in CML patients taking TKIs.

Lenalidomide and azacitidine each have activity in myelodysplastic syndromes (MDS) patients, where both microenvironment and cell-regulatory mechanisms contribute to disease pathogenesis. The objective of this multicenter, phase 2 expansion trial was to determine the efficacy and safety of combination therapy with azacitidine (75 mg/m(2)/d for 5 days) and lenalidomide (10 mg/d for 21 days; 28-day cycle) in patients with higher-risk MDS. Among 36 patients enrolled (18 phase 1, 18 phase 2), median age was 68 years (range, 47-78 years) and follow-up was 12 months (range, 3-55 years). IPSS categories included intermediate-1 (n = 5 patients with excess blasts), intermediate-2 (20), and high (11). Common grade 3/4 nonhematologic adverse events included febrile neutropenia (22% of patients), other infection (11%), pulmonary (11%), cardiac (11%), constitutional (11%), and dermatologic (11%). The overall response rate (per modified MDS International Working Group criteria) was 72%: 16 patients (44%) achieved a complete response (CR), and 10 (28%) had hematologic improvement. Median CR duration was 17+ months (range, 3-39+); median overall survival was 37+ months (range, 7-55+) for CR patients, and 13.6 months for the entire cohort (range, 3-55). TET2/DNMT3A/IDH1/2 mutational status was associated with response in a limited number of patients. The lenalidomide/azacitidine combination is well-tolerated and highly active in treating greater-risk MDS.

Myelofibrosis (MF) is characterized by splenomegaly, anemia and a debilitating symptom burden (e.g., fatigue, night sweats, pruritus, bone and muscle pain, undesired weight loss). Moreover, these symptoms impair activities of daily living and quality of life. Until recently, there have been no approved therapies for MF, and management of MF has been predominantly palliative. Dysregulated JAK-STAT signaling is associated with the pathologic MF disease state. A novel class of therapies, the JAK inhibitors, offers the potential to abrogate this pathologic signaling pathway. In clinical trials of patients with intermediate- and high-risk MF, JAK inhibitors have demonstrated efficacy in reducing splenomegaly and MF-associated symptoms. Evidence from ruxolitinib trials also suggests that JAK inhibitors may improve survival outcomes.

Background: The last decade witnessed the emergence of several therapeutic options for patients with chronic lymphocytic leukemia (CLL) for first-line and relapsed settings. The vast majority of patients with relapsed or refractory CLL carry poor prognostic features, which are strong predictors of shorter overall survival and resistance to first-line treatment, particularly fludarabine-based regimens., Methods: This article highlights the current role of immunomodulatory drugs (IMiDs) and active immunotherapy as treatment options for this select group. The rationale of using IMiDs is discussed from the perspective of lenalidomide as a novel active agent. Relevant clinical trials using IMiDs alone or in combinations are discussed. New immunotherapeutic experimental approaches are also described., Results: As a single agent, lenalidomide offers an overall response rate of 32% to 47% in patients with relapsed/refractory disease. Recent studies have shown promising activity as a single agent in treatment-naive patients. The combination of lenalidomide with immunotherapy (rituximab and ofatumumab) has also shown clinical responses. Encouraging preclinical and early clinical data have been observed with different immunotherapeutic approaches., Conclusions: The use of IMiDs alone or in combination with immunotherapy represents a treatment option for relapsed/refractory or treatment-naive patients. Mature data and further studies are needed to validate overall and progression-free survival. The toxicity profile of lenalidomide might limit its use and delay further studies. Immunotherapy offers another potential alternative, but further understanding of the immunogenicity of CLL cells and the mechanisms of tumor fl are reaction is needed to improve the outcomes in this field.

Opinion Statement: The 5q- syndrome is a myelodsyplastic syndrome (MDS) characterized by symptomatic anemia and an indolent natural history with low transformation potential. Our understanding of the molecular pathogenesis of this disease has advanced considerably, paralleled by the delineation of the relevant targets underlying selective lenalidomide sensitivity. The context in which one treats the 5q- syndrome, and all lower risk MDS, is critical. The focus of treatment should remain the amelioration of refractory cytopenias. In the 5q- syndrome, lenalidomide is the treatment of choice for patients with symptomatic anemia as it relieves the burden of transfusion dependence and iron overload in the majority of cases. We discuss herein the current understanding of the biology of the 5q- syndrome, actions of efficacy of lenalidomide and strategies for clinical management.

The relationship between telomere length (TL) and predisposition to myelodysplastic syndromes (MDS) remains unclear. We compared peripheral blood leukocyte (PBL) TL among cases of histologically confirmed MDS (n = 65) who were treatment-naive with no prior cancer history to age-matched controls (n = 63). Relative TL was measured in PBLs and saliva by quantitative polymerase chain reaction (PCR) and in CD15+ and CD19+ cells by flow cytometry-fluorescence in situ hybridization (flow-FISH). Human telomerase reverse transcriptase gene (hTERT) mutations were assessed by PCR. After adjustment for age and sex, relative TLs were reduced in PBLs (p = 0.02), CD15+ (p = 0.01), CD19+ (p = 0.25), and saliva (p = 0.13) in MDS cases versus controls, although only the PBL and CD15+ results were statistically significant. Among MDS cases, CD15+ and CD19+ cell TLs were positively correlated (p = 0.03). PBL TL was reduced among those occupationally exposed to paints and pesticides, but was not associated with hTERT genotype. Future studies are needed to further investigate constitutional telomere attrition as a possible predisposing factor for MDS.

The 5q- syndrome is a unique subtype of myelodysplastic syndromes typified by a relatively indolent course and responsiveness to lenalidomide. Here, we review the salient biologic features of this disease. Hemizygous deletion of a segment of chromosome 5q is believed to be the disease-initiating event. Recent molecular techniques have isolated the common deleted region and characterized key candidate genes contributing to the disease phenotype. Gene-specific RNA interference strategies revealed that haplo-insufficiency for the RPS14 gene, which encodes a ribosomal protein, is a critical effector of the p53-dependent erythroid hypoplasia and apoptotic loss of erythroid precursors. Disease-specific sensitivity to lenalidomide results from the drug's inhibitory effect on two haplodeficient phosphatases, PP2Acα and CDC25c, which are coregulators of the G(2)/M checkpoint. Hyperphosphorylation of MDM2, as a result of inhibition of PP2A phosphatase activity, stabilizes MDM2, permitting p53 degradation and transition to G(2) arrest and clonal suppression. With the emerging data elucidating the pathogenesis of the 5q- syndrome and the success of clinical trials, a cohesive story connecting the biology and pharmacology associated with this subtype of myelodysplastic syndromes has emerged.

These suggested practice guidelines are based on extensive evaluation of the reviewed risk-based data and indicate useful current approaches for managing patients with MDS. Four drugs have recently been approved by the FDA for treating specific subtypes of MDS: lenalidomide for MDS patients with del(5q) cytogenetic abnormalities; azacytidine and decitabine for treating patients with higher-risk or nonresponsive MDS; and deferasirox for iron chelation of iron overloaded patients with MDS. However, because a substantial proportion of patient subsets with MDS lack effective treatment for their cytopenias or for altering disease natural history, clinical trials with these and other novel therapeutic agents along with supportive care remain the hallmark of management for this disease. The role of thrombopoietic cytokines for management of thrombocytopenia in MDS needs further evaluation. In addition, further determination of the effects of these therapeutic interventions on the patient's quality of life is important.(116,119,120,128,129) Progress toward improving management of MDS has occurred over the past few years, and more advances are anticipated using these guidelines as a framework for coordination of comparative clinical trials.

Objective: Reports indicate that esophageal carcinoma is changing with a shift from squamous cell carcinoma (SCC) to adenocarcinoma (AC) along with worse survival in black patients. However, data on esophageal carcinoma in the Veteran Affairs (VA) population is lacking. We set to describe site-specific and histology-specific characteristics of esophageal cancer in the VA population over the past decades., Methods: We queried the VA Central Cancer Registry database for esophageal cancer cases between 1995 and 2005. Patient characteristics and treatment methods were obtained and overall survival was estimated using the Kaplan-Meier method., Results: There were 7929 patients included in the study. The median survival in the period 1995 to 1999 was 7.53 months and 2000 to 2005 was 8.33 months. The median survival in AC was 8.93 months; SCC was 7.30 months. Cox-regression multivariate model revealed that location, age, histology, stage, and treatment were independent predictors of survival. Blacks were less likely to undergo surgery and more likely to undergo radiation., Conclusions: In nonmetastatic esophageal cancer at the VA, SCC has worse outcome as compared with AC. Blacks with AC have worse outcome than whites. Despite equal access to health care blacks are less likely to undergo surgery, which may contribute to their worse outcome. We recommend further studies to determine factors leading to selection of treatment modalities in minority patients.

Objectives: Locally advanced breast cancer (LABC) poses a difficult clinical challenge with an overall poor long-term prognosis. The strength of the association between tumour characteristics, treatment response, and outcome is not well defined. In the present study, we attempted to gain further insight into LABC by reviewing tumour characteristics of patients treated with neoadjuvant chemotherapy and by studying the association of those characteristics with outcome. We calculated the residual cancer burden (RCB) score obtained at surgery and attempted to study its correlation with event-free survival (EFS) and overall survival (OS)., Methods: We studied patients diagnosed primarily with LABC (n = 45). Pathologic and clinical responses were determined. Pathology slides were reviewed., Results: Of the 45 study patients, 9% had stage IIB disease; 29%, stage IIIA; 51%, stage IIIB; and 11%, stage IIIC. Inflammatory breast cancer (IBC) was found in 16%. Pathologic complete response (pCR) was achieved in 22% of all patients. None of the patients with ibc achieved pcr. Patients with estrogen receptor-negative (ER-)/progesterone receptor-negative (PR-) tumours were more likely to achieve pcr than were those with ER+/PR+ tumours. Among patients with tumours that overexpressed human epidermal growth factor receptor 2 (HER2/neu), 17% achieved pCR as compared with 25% of patients with non-overexpressing tumours; only 1 patient had received trastuzumab. The RCB scores were calculated in 32 patients and ranged between 0 and 4.6., Conclusions: The present study examined practical issues related to the classification and management of LABC and IBC. The RCB, defined from routine pathology materials, was easily quantifiable. It appears to be a better predictor than pCR of outcome following neoadjuvant chemotherapy in LABC. Higher RCB scores were associated with lower efs and a lower rate of os. A continual quest for reliable predictive and correlative prognostic markers, and for better surrogate endpoints for outcome, is essential to advance our understanding of LABC and to improve treatment outcomes.

Background: The incidence of male breast cancer (MBC) continues to rise. The Veterans Affairs (VA) Central Cancer Registry (VACCR) provides a unique source for the study of MBC. The objective of this retrospective analysis was to compare the characteristics and outcome of patients with MBC and patients with female breast cancer (FBC) in the VA population., Methods: VACCR data were used to analyze the database of VA patients who had breast cancer diagnosed between 1995 and 2005. It includes 120 VA medical centers. Primary site codes were identified for breast cancer (500-508). Data were entered and analyzed using biostatistical software., Results: In total, 3025 patients' records were reviewed, and 612 patients who had MBC were compared with 2413 patients who had FBC. The mean age at diagnosis was 67 years for patients with MBC and 57 years for patients with FBC (P < .005). More patients with MBC were black, and patients with MBC presented with higher disease stage and more lymph node-positive disease. The dominant histology in MBC was ductal carcinoma. No difference in grade or laterality was observed. Estrogen and progesterone receptor-positive tumors were more common in MBC compared with FBC. Overall, patients with MBC received less chemotherapy, whereas no statistical difference was observed in the use of hormone treatment. The median overall survival for patients who had MBC was 7 years compared with 9.8 years for patients who had FBC (log-rank test; P < .005). There was no statistically significant difference in median survival for patients with stage III disease and stage IV disease. However, the median survival differed significantly for patients with stage I disease and stage II disease. In lymph node-negative patients, the median survival was 6.1 years for patients with MBC and 14.6 years for patients with FBC (P < .005), whereas the median survival did not differ significantly in lymph node-positive patients. Using Cox regression analysis age, sex, clinical stage, and lymph node status were independent prognostic factors for survival, whereas race, histology, and grade were not., Conclusions: To the authors' knowledge, this is the largest series of MBC and FBC to date in the veterans population. The results suggested the presence of differences in the biology, pathology, presentation, ethnicity, and survival between patients with MBC and patients with FBC in the VA population. It is noteworthy that the survival of patients with MBC was inferior for those with early-stage disease and lymph node-negative tumors, suggesting that there are differences between the sexes in the pathogenesis and biology of breast cancer. In patients with hormone receptor-positive MBC, survival was inferior despite similar hormone treatment practices between MBC and FBC. This observational study calls for a better understanding of this disease that would allow new opportunities for specific therapeutic intervention.

Background: Recognizing the growing need for an infusion of new investigators into the cancer researchers, and realizing that well-trained cancer researchers are a dying breed, the Southwest Oncology Group (SWOG) initiated the Young Investigator Training Program (YITP) in 1999, supported by the Hope Foundation. The first author was one of four applicants accepted in 2004 and is reporting on this experience., Methods: After a rigorous and competitive application process, four physicians beginning their career in Hematology-Oncology are chosen each year. Each investigator would have submitted an original research concept. Each class receives intensive training in statistical principles, data collection and analysis, critical decision making, and protocol development guidelines. Each investigator spends 4 days at the SWOG operations office in San Antonio, Texas, and 4 days at the statistical center in Seattle, Washington., Results: As part of the training course, each investigator will design a clinical protocol that will be reviewed by the appropriate disease committees within SWOG. Once approved, it will be submitted to the National Cancer Institute for further review. The four investigators will receive a certificate at the successful completion of the training course and will be recognized at the group meeting. With the class of 2004, 31 investigators will have joined the ranks of seasoned researchers. Fifteen protocols have been introduced and activated at institutions across the United States. Four other protocols are in various stages of the development and approval process., Conclusion: The Hope Foundation sponsored SWOG YITP is a unique opportunity. It allows participants to acquire a thorough understanding of the conduct of cancer clinical trials through SWOG. Large institutions are urged to continue sponsoring similar programs. This will build an infrastructure of well-trained cancer researchers to foster and continue the progress achieved in cancer research.

Allogeneic hematopoietic stem cell transplantation (SCT) is a potentially curative treatment for patients with myelodysplastic syndrome (MDS). Relapses after transplantation however, are not uncommon and are usually due to re-emergence of a recipient derived, neoplastic, stem cell clone. We report a unique case of MDS recurring 5 months after non-myeloablative, sibling, allogeneic SCT. Interestingly, chimerism analysis at relapse showed hematopoiesis to be entirely of donor origin confirming donor cell MDS. Donor lymphocyte infusion (DLI) produced a hematological response lasting several months. Our review of the literature shows donor-derived MDS to be very rare, with only four such cases described previously. In this report, we describe the details of our case and discuss putative mechanisms underlying the genesis of donor cell MDS and the observed response to DLI., (Copyright 2004 Wiley-Liss, Inc.)

A 45-year-old male presented with fever, night sweats, splenomegaly, high LDH, high uric acid, and high blast count with atypical L3 morphology. Flow cytometry showed neoplastic clone consistent with pre B-cell immunophenotype, on the basis of lack of cytoplasmic immunoglobulins, surface immunoglobulins, and light chain immunoglobulins. Cytogenetic analysis revealed t(8;14)(q24; q32), the characteristic translocation of Burkitt's leukemia. A few similar case reports of Burkitt's leukemia with precursor B-cell immunophenotype have been described primarily in pediatric literature and usually with typical L3 morphology. This case recognizes this subset in adult ALL and emphasizes the need for comprehensive diagnostic analysis.

Myelodysplastic syndrome is a neoplastic clonal stem cell disorder characterized clinically by bone marrow failure and a tendency to progress to acute myelogenous leukemia. Dysplasia is the pathologic hallmark. The French-American-British classification served as the gold standard for more than two decades. Under the auspice of the World Health Organization, more than 100 hematopathologists in a 3-year cumulative effort issued the new World Health Organization classification, which recognizes multilineage dysplasia. Refractory anemia with excess blasts is divided into two groups. Chronic myelomonocytic leukemia is reclassified under a separate category. Refractory anemia with excess blasts in the transformation group was omitted. Finally, 5q-syndrome is a new subgroup. In addition to the pathologic classification, various prognostic predictors were formatted into scoring systems. Bone marrow blast percentage, cytopenias, and cytogenetics are the backbone for those prognostic models. The International Prognostic Scoring System is a product of pooled data from previous scoring systems and a useful tool to predict survival and acute myelogenous leukemia evolution. This paper discusses the classification and prognosis of myelodysplastic syndromes and their evolution.