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Abstract Background Historically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting. Methods Mini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 courses, and blinatumomab for 4 additional courses. Results Among 110 patients (median age, 37 years) treated, 91 (83%) responded (complete response, 69 patients, 63%). Measurable residual disease negativity was documented in 75 patients (82% of responders). Fifty-three patients (48%) received allogeneic stem cell transplantation (SCT). Hepatic sinusoidal obstruction syndrome occurred in 9/67 patients (13%) on the original inotuzumab schedule and in 1/43 (2%) on the modified schedule. With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini-Hyper-CVD plus inotuzumab and 52% with additional blinatumomab (P = 0.16). By landmark analysis at 4 months, the 3 year OS was 54%, similar between patients who did or did not receive allogeneic SCT. Conclusion Low-intensity mini-Hyper-CVD plus inotuzumab with or without blinatumomab showed efficacy in patients with relapsed-refractory ALL, with better survival after the addition of blinatumomab. Trial registration The trial was registered on clinicaltrials.gov with the identifier NCT01371630.

Abstract Migratory species have geographically separate distributions during their annual cycle, and these areas can vary between populations and individuals. This can lead to differential stress levels being experienced across a species range. Gathering information on the areas used during the annual cycle of red‐throated divers (RTDs; Gavia stellata) has become an increasingly pressing issue, as they are a species of concern when considering the effects of disturbance from offshore wind farms and the associated ship traffic. Here, we use light‐based geolocator tags, deployed during the summer breeding season, to determine the non‐breeding winter location of RTDs from breeding locations in Scotland, Finland, and Iceland. We also use δ15N and δ13C isotope signatures, from feather samples, to link population‐level differences in areas used in the molt period to population‐level differences in isotope signatures. We found from geolocator data that RTDs from the three different breeding locations did not overlap in their winter distributions. Differences in isotope signatures suggested this spatial separation was also evident in the molting period, when geolocation data were unavailable. We also found that of the three populations, RTDs breeding in Iceland moved the shortest distance from their breeding grounds to their wintering grounds. In contrast, RTDs breeding in Finland moved the furthest, with a westward migration from the Baltic into the southern North Sea. Overall, these results suggest that RTDs breeding in Finland are likely to encounter anthropogenic activity during the winter period, where they currently overlap with areas of future planned developments. Icelandic and Scottish birds are less likely to be affected, due to less ship activity and few or no offshore wind farms in their wintering distributions. We also demonstrate that separating the three populations isotopically is possible and suggest further work to allocate breeding individuals to wintering areas based solely on feather samples.

Abstract: Minimal residual disease (MRD), where leukemic cell levels are lower than the morphologic detection threshold, is the most important prognostic factor for acute lymphoblastic leukemia (ALL) relapse during first-line chemotherapy treatment and is standard of care in treatment monitoring and decision making. Limited data are available on the prognostic value of MRD response after relapse. We evaluated the relationship between MRD response and outcomes in blinatumomab-treated adults with relapsed/refractory (R/R) B-cell precursor ALL. Of 90 patients with complete remission (CR) or CR with partial hematologic recovery (CRh), 64 (71.1%) achieved a complete MRD response (no detectable individual rearrangements of immunoglobulin/T-cell receptor genes by polymerase chain reaction [PCR] at a minimum sensitivity level of 10−4). Eleven patients had MRD

Abstract Background Treatment with tyrosine kinase inhibitors (TKIs) for patients with chronic myeloid leukemia (CML) is effective but needs to continue for several years, possibly indefinitely. Although generally safe, TKI may have hitherto poorly recognized effects in the quality of life (QoL) of such patients. Methods We prospectively measured the symptom burden of patients with chronic phase CML enrolled on frontline TKI trials with dasatinib, nilotinib, or ponatinib. A total of 219 patients were enrolled and filled out the MD Anderson Symptom Inventory (MDASI)‐CML questionnaire before the start of therapy and during follow‐up at defined time points of 3, 6, 9, 12, 18, and 24 months. Results The median age was 50 years. Longitudinal analysis showed relatively stable symptom severity scores over time. Fatigue was the most common symptom in all three cohorts, both prior to the start of therapy and during therapy, including after achievement of deep molecular remission. Work was the most affected component of daily living. Overall patients tolerated therapy well with improvement of their symptoms from baseline, with few dose reductions related to toxicity or symptomatology. Although 31% of the patients who completed MDASI‐CML achieved complete molecular remission by 24 months of treatment, nearly 90% experienced persistent mild symptoms. Conclusion Side effects related to TKIs may impact the quality of life in patients with CML‐CP. Further studies should investigate factors (comorbidities, concomitant medications, dose and schedule, etc) associated with these symptoms and interventions that may improve the patients’ QoL, including treatment discontinuation when safely feasible.

Gifted education today faces a significant challenge in reaching equity as well as excellence. This is reflected in the disproportionate underrepresentation of children from Black, Hispanic, Native, and low-income families. This pattern of underrepresentation within programs for students with gifts and talents is pervasive and pernicious and impacts gifted education programming across all 50 states in the United States of America. This article describes the efforts of Milwaukee Public Schools, a large urban school district in Wisconsin, to address the need for both equity and excellence within their gifted education programming. The U~STRARS~PLUS model formed the foundation for changing the culture of the schools from “at risk” to “at potential”. Dedicated leadership and the combination of securing external support, developing internal trust, and building capacity across the district were critical to creating a strength-based focus within the schools. While the journey is not over, the authors hope that others can learn from Milwaukee’s experiences.

The BTK inhibitor ibrutinib is used to treat chronic lymphocytic leukaemia, however some patients develop resistance to the drug. Here, the authors use genomic analyses to examine the clonal evolution of 5 patients that develop resistance to ibrutinib.

Targeted therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of current research. Mixed Lineage Leukemia (MLL) mutations such as the t(4;11) translocation cause aggressive leukemias that are refractory to conventional treatment. The t(4;11) translocation produces an MLL/AF4 fusion protein that activates key target genes through both epigenetic and transcriptional elongation mechanisms. In this study, we show that t(4;11) patient cells express high levels of BCL-2 and are highly sensitive to treatment with the BCL-2-specific BH3 mimetic ABT-199. We demonstrate that MLL/AF4 specifically upregulates the BCL-2 gene but not other BCL-2 family members via DOT1L-mediated H3K79me2/3. We use this information to show that a t(4;11) cell line is sensitive to a combination of ABT-199 and DOT1L inhibitors. In addition, ABT-199 synergizes with standard induction-type therapy in a xenotransplant model, advocating for the introduction of ABT-199 into therapeutic regimens for MLL-rearranged leukemias.

The first-in-class Bruton’s tyrosine kinase inhibitor ibrutinib has proven clinical benefit in B-cell malignancies; however, atrial fibrillation (AF) has been reported in 6–16% of ibrutinib patients. We pooled data from 1505 chronic lymphocytic leukemia and mantle cell lymphoma patients enrolled in four large, randomized, controlled studies to characterize AF with ibrutinib and its management. AF incidence was 6.5% [95% Confidence Interval (CI): 4.8, 8.5] for ibrutinib at 16.6-months versus 1.6% (95%CI: 0.8, 2.8) for comparator and 10.4% (95%CI: 8.4, 12.9) at the 36-month follow up; estimated cumulative incidence: 13.8% (95%CI: 11.2, 16.8). Ibrutinib treatment, prior history of AF and age 65 years or over were independent risk factors for AF. Multiple AF events were more common with ibrutinib (44.9%; comparator, 16.7%) among patients with AF. Most (85.7%) patients with AF did not discontinue ibrutinib, and more than half received common anticoagulant/antiplatelet medications on study. Low-grade bleeds were more frequent with ibrutinib, but serious bleeds were uncommon (ibrutinib, 2.9%; comparator, 2.0%). Although the AF rate among older non-trial patients with comorbidities is likely underestimated by this dataset, these results suggest that AF among clinical trial patients is generally manageable without ibrutinib discontinuation (clinicaltrials.gov identifier: 01578707, 01722487, 01611090, 01646021).

Adults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990–2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%–41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%–50%). One- and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%–5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612

The tumor microenvironment is the cellular and molecular environment in which the tumor exists and with which it continuously interacts. In B-cell lymphomas, this microenvironment is intriguing in that it plays critical roles in the regulation of tumor cell survival and proliferation, fostering immune escape as well as the development of treatment resistance. The purpose of this review is to summarize the proceedings of the Second Annual Summit on the Immune Microenvironment in Hematologic Malignancies that took place on September 11–12, 2014 in Dublin, Ireland. We provide a timely overview of the composition and biological relevance of the cellular and molecular microenvironment interface and discuss the role of interactions between the microenvironment and neoplastic cells in a variety of B-cell lymphomas. In addition, we focus on various novel therapeutic strategies that target the tumor microenvironment, including agents that modulate B-cell receptor pathways and immune-checkpoints, chimeric antigen receptor T cells and immunomodulatory agents.

We have previously reported on the efficacy and tolerability of hyper-CVAD regimen (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) and imatinib followed by imatinib-based consolidation/maintenance therapy in 20 patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Here, we present the 13-year follow up of our study. Fifty-four patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia were enrolled: 39 (72%) with de novo disease, 6 (11%) whose disease was primary refractory after induction (without a tyrosine kinase inhibitor), and 9 (17%) in complete remission after one course of induction therapy (without tyrosine kinase inhibitor). Forty-two (93%) of the 45 patients treated for active disease achieved complete remission, one achieved complete remission with incomplete recovery of platelets, one achieved partial remission and one died during induction. Nineteen (35%) patients are alive and 18 are in complete remission. The 5-year overall survival rate for all patients was 43%. Significant negative predictors of overall survival were age over 60 years, p190 molecular transcript, and active disease at enrollment. Sixteen (30%) patients underwent allogeneic stem cell transplantation. Median overall survival was not significantly greater for patients who underwent transplant. Patients with residual molecular disease at three months had improved complete remission duration with transplant. The median time to hematologic recovery and severe toxicities with combination were not significantly different from those observed with conventional chemotherapy. Only one patient discontinued therapy due to toxicity. HyperCVAD chemotherapy and imatinib is an effective regimen for Philadelphia-positive acute lymphoblastic leukemia. Transplant may not be indicated in all patients with Philadelphia-positive acute lymphoblastic leukemia. (clinicaltrials.gov identifier: NCT00038610)

Response to tyrosine kinase inhibitors at three months is a predictor for long-term outcome in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. We analyzed 456 newly diagnosed chronic myeloid leukemia patients treated with tyrosine kinase inhibitors to determine their outcome based on their response at six months. Forty-four (10%) patients did not achieve major cytogenetic response at three months: 18 of 67 (27%) patients treated with imatinib 400; 18 of 196 (9%) with imatinib 800; and 8 of 193 (4%) with 2nd generation tyrosine kinase inhibitors. Among them, 19 (43%) achieved major cytogenetic response at six months and subsequently had an overall outcome similar to the patients who achieved a major cytogenetic response at three months. In conclusion, the response to tyrosine kinase inhibitors at three months is a static, one-time measure. Assessing the response at six months of patients with poor response at three months may provide a better predictor for long-term outcome.

CLL cell trafficking between blood and tissue compartments is an integral part of the disease process. Idelalisib, a phosphoinositide 3-kinase delta (PI3Kδ) inhibitor causes rapid lymph node shrinkage, along with an increase in lymphocytosis, prior to inducing objective responses in CLL patients. This characteristic activity presumably is due to CLL cell redistribution from tissues into the blood, but the underlying mechanisms are not fully understood. We therefore analyzed idelalisib effects on CLL cell adhesion to endothelial and bone marrow stromal cells (EC, BMSC). We found that idelalisib inhibited CLL cell adhesion to EC and BMSC under static and shear flow conditions. TNFα-induced VCAM-1 (CD106) expression in supporting layers increased CLL cell adhesion and accentuated the inhibitory effect of idelalisib. Co-culture with EC and BMSC also protected CLL from undergoing apoptosis, and this EC- and BMSC-mediated protection was antagonized by idelalisib. Furthermore, we demonstrate that CLL cell adhesion to EC and VLA-4 (CD49d) resulted in the phosphorylation of Akt, which was sensitive to inhibition by idelalisib. These findings demonstrate that idelalisib interferes with integrin-mediated CLL cell adhesion to EC and BMSC, providing a novel mechanism to explain idelalisib-induced redistribution of CLL cells from tissues into the blood.

Background Outcomes in chronic myeloid leukemia have improved with tyrosine kinase inhibitor treatment. However, little is known about outcomes of chronic myeloid leukemia in adolescent and young adult patients.Design and Methods We reviewed all 468 chronic myeloid leukemia patients treated at our institution with tyrosine kinase inhibitors as initial therapy: imatinib (n=281), nilotinib (n=98) or dasatinib (n=89).Results Median age was 47 years, median follow up 71 months and median treatment time with initial tyrosine kinase inhibitors 48 months. Adolescent and young adult was defined as aged 15–29 years. Sixty-one adolescent and young adult patients were identified. The only significant differences between adolescent and young adult and older patients were incidence of splenomegaly and distribution in Sokal risk groups. Only 3 adolescent and young adult patients have died. Rates of complete cytogenetic, major molecular and complete molecular response were significantly higher in older patients compared to adolescent and young adult patients, with a favorable trend in event-free survival for older patients. Transformation-free and overall survival were similar for the two groups.Conclusions The unfavorable trend in outcome for adolescent and young adult patients with chronic myeloid leukemia is unexpected. Additional research in this population is required to better define outcomes, understand the cause of this difference, and to help make better treatment recommendations.

We investigated the impact of carrying more than one BCR-ABL1 mutation in 207 patients with chronic myeloid leukemia (102 chronic, 61 accelerated, and 44 blast phase) post-imatinib failure. Seven (8%) of 92 patients carrying mutations had more than one mutation: 4 (4%) in chronic phase, 2 (2%) in accelerated phase, and one (1 %) in blast phase. The cytogenetic response rate to second generation TKIs for patients with no, one, or more than one mutation was 88%, 69%, 50% (P=0.03) in chronic phase, 54%, 42%, 50% in accelerated phase (P=0.67), and 35%, 25%, 0% (P=0.63) in blast phase, respectively. No differences were observed in event free survival or overall survival in accelerated or blast phase according to their mutational status. However, the 4-year event free survival rates among patients in chronic phase with no, one, or more than one BCR-ABL1 mutation were 56%, 49%, and 0%, respectively (P=0.02), with overall survival rates of 91%, 69%, and 75%, respectively (P=0.13). In conclusion, patients with more than one BCR-ABL1 mutation fare worse than those with no or one mutation.

We developed and validated a two-gene signature that predicts prognosis in previously-untreated chronic lymphocytic leukemia (CLL) patients. Using a 65 sample training set, from a cohort of 131 patients, we identified the best clinical models to predict time-to-treatment (TTT) and overall survival (OS). To identify individual genes or combinations in the training set with expression related to prognosis, we cross-validated univariate and multivariate models to predict TTT. We identified four gene sets (5, 6, 12, or 13 genes) to construct multivariate prognostic models. By optimizing each gene set on the training set, we constructed 11 models to predict the time from diagnosis to treatment. Each model also predicted OS and added value to the best clinical models. To determine which contributed the most value when added to clinical variables, we applied the Akaike Information Criterion. Two genes were consistently retained in the models with clinical variables: SKI (v-SKI avian sarcoma viral oncogene homolog) and SLAMF1 (signaling lymphocytic activation molecule family member 1; CD150). We optimized a two-gene model and validated it on an independent test set of 66 samples. This two-gene model predicted prognosis better on the test set than any of the known predictors, including ZAP70 and serum β2-microglobulin.

BACKGROUND: The JAK2 V617F mutation in exon 14 is the most common mutation in chronic myeloproliferative neoplasms (MPNs); deletion of the entire exon 14 is rarely detected. In our previous study of >10,000 samples from patients with suspected MPNs tested for JAK2 mutations by reverse transcription-PCR (RT-PCR) with direct sequencing, complete deletion of exon 14 (Deltaexon14) constituted

Background and Objectives : Quantitation of BCR-ABL mRNA is emerging as the standard of care to monitor the status of chronic myeloid leukemia (CML). Peripheral blood plasma was analyzed in this study because of previous detection of nucleic acids and proteins from tumor cells in plasma samples.Design and Methods : Reverse transcriptase polymerase chain reaction was used to establish ratios of BCR-ABL:ABL mRNA in peripheral blood cells and plasma, and absolute levels of BCR-ABL mRNA per unit volume of plasma. Samples from 160 CML patients and 180 control individuals without CML were tested. Cells and plasma samples from 93 of the CML patients were re-analyzed 3–12 months after imatinib treatment.Results : Ratios of BCR-ABL:ABL mRNA in paired cell and plasma samples of the 160 CML patients correlated significantly (r=0.83; p