Introduction: Synovial sarcoma is a rare, malignant neoplasm accounting for approximately 5-10% of all soft tissue sarcomas. Synovial sarcomas generally occur in the extremities of adolescent or young adult (AYA)-aged patients; however, they have been reported to affect virtually every organ system. The mediastinum is an exceptionally rare location for synovial sarcoma and malignant pericardial effusions occurring secondary to synovial sarcoma can occur. Case Presentation: This case describes a 29-year-old male who presented with 3 weeks of dyspnea and leg swelling. An echocardiogram demonstrated a large pericardial effusion with early tamponade physiology. A subsequent pericardiocentesis returned a lymphocytic predominance with negative flow cytometry and cytology. Cross-sectional imaging with computed tomography (CT) scans of the chest, abdomen, and pelvis was negative for lymphadenopathy or detectable mass. He was discharged where repeat echocardiogram demonstrated recurrence of the effusion, but his symptoms had improved. Ultimately, he was readmitted with refractory dyspnea and edema where cardiac magnetic resonance imaging demonstrated a large mediastinal mass invading the pericardium. The biopsy demonstrated a high-grade spindle cell malignancy positive for a rearrangement of the SS18 gene, a finding diagnostic of synovial sarcoma. He passed away after one round of doxorubicin due to septic and obstructive shock (tamponade). Conclusion: Mediastinal synovial sarcomas are rare, aggressive, and highly morbid neoplasms. In some cases, they may present insidiously due to their sole presenting clinical manifestation being pericardial effusion. Particular care should be taken to rule out malignancy with MRI or PET-guided imaging in the AYA-aged population when idiopathic, recurrent pericardial effusion is found.

e19018 Background: CLL and MCL can present with rapid disease progression that requires quick control. VEN is an oral, small-molecule inhibitor of BCL-2 that requires careful dose titration to avoid TLS. However, standard outpatient titration of VEN takes 29 days to reach max dose, with the low doses achieving little disease control. A common practice at our site is to rapidly titrate VEN to 100mg within 1 week with hospitalization for careful TLS monitoring and management. We present the safety and outcomes of 39 identified patients treated as such. Methods: The rapid VEN titration plan was: VEN 20mg x 2 days, 50mg x 2 days, then 100mg daily with q6-q8 hour monitoring of TLS labs plus ongoing IV hydration and allopurinol with or without rasburicase per clinical judgment. Most patients were treated in such manner if TLS did not occur. Clinically stable patients were typically discharged after 2 days of VEN 100mg, then continued weekly outpatient dose escalation to the 200mg and then the 400mg dose levels. If a patient was progressing on a Bruton's Tyrosine Kinase inhibitor, the inhibitor was often given concurrently with the early doses of VEN. Results: Patient characteristics are listed in the table. 23% (5 of 22) of patients with CLL and 35% (6 of 17) of patients with MCL had laboratory TLS (Howard SC, NEJM2011). In the patients with CLL, 2/5 were low risk for TLS, and in the patients with MCL, 3/6 were low risk for TLS. Only 4.5% (1 of 22) of CLL patients and no MCL patients had clinical TLS (Grade 2 creatinine elevation). In that specific patient, considered low risk for TLS, the elevated creatinine did not recover but was subsequently deemed secondary to Richter’s transformation involving the kidneys. No unexpected toxicity was observed outside of those typically associated with VEN and anti-CD20 antibody, when used. The mean number of days to reach 100mg was 6.5 days (quartile [Q] 1:5d; Q3: 10d), and the mean number of days to reach the planned VEN target dose was 18.8 with range (Q1:14d; Q3: 25d). Sixty-four percent of patients achieved the 400mg dose level. Conclusions: This single-institution retrospective analysis highlights the low rate of clinical TLS when using VEN with rapid titration in a controlled environment for high-risk patients needing rapid disease control. However, lab TLS occurred in low-risk patients treated in this manner, necessitating hospitalization despite low risk. No unexpected or additional toxicity was observed. [Table: see text]

Methodology and results for exploratory aims, FISH, IHC and quality of life. SUPPLEMENTAL FIGURE 1: Change point analysis including a second inflection point in calculation of average slope of 34 evaluable patients. Supplemental Figure 2: First, last, and difference between first and last measurements for Fact-G and its components. Supplemental Figure 3: QOL trajectory for each patient by FACT-G analysis. Supplemental table 1: Mutation analysis as provided by Foundation Medicine for a subset of patients with residual tissue available for targeted mutation profiling. Table 2: Basic statistics for first, last, and difference between first and last measurements of Fact-G and its components Supplemental Figure 3: QOL trajectory for each patient by FACT-G analysis. Supplemental Table 3: Summary of adverse event counts for all consented patients. Supplemental Table 4: PET response at day 12 PET scan compared with baseline PET scans.

Atypical chronic myeloid leukemia (aCML) is a rare myeloproliferative disorder that shares clinical features with chronic myeloid leukemia but lacks the classic t(9;22) BCR-ABL1 translocation and features prominent dysgranulopoiesis and granulocytic dysplasia. Challenges of this diagnosis include clinical and biologic heterogeneity, the high risk of transformation to acute myeloid leukemia, and the lack of standard treatment options. Allogeneic hematopoietic stem cell transplant is likely the preferred treatment, but this can be limited by patient psychosocial support, age, concomitant medical conditions, and availability of an appropriate donor. We report the case of a 61-year-old male with no significant past medical history diagnosed with aCML with a rare t(2;13)(q33;q12). He presented with weight loss, night sweats, splenomegaly, hyperleukocytosis, a leukoerythroblastic differential with a predominant neutrophilia, anemia, and thrombocytopenia. Subsequent peripheral blood and bone marrow studies lead to the diagnosis of aCML. He was recommended to undergo an allogeneic stem cell transplant evaluation and declined. He was initially treated with hydroxyurea and imatinib to which he responded for approximately three years. After clinical progression, he was treated with sorafenib, a multiprotein kinase inhibitor more commonly used in the treatment of hepatocellular and renal cell carcinoma due to its off target FLT3 inhibition. The patient achieved complete hematologic response which has been sustained for 7 years with tolerable side effects.

Purpose of Review To discuss the long-term view of treating and following pediatric, adolescent, and young adult patients with acute lymphoblastic leukemia (ALL) - with review of what can be done to prevent, monitor for, and treat complications of therapy. Recent Findings Pediatric, adolescent, and young adult oncology patients, including those with ALL, are living longer with higher overall survival rates as treatments and supportive care for these patients continue to improve. These patients are burdened by the risk of significant health and quality of life consequences as a result of their treatment.. For these patients, the late effects of treatment can be life-threatening, such as secondary cancers or cardiotoxicity, or life-altering with respect to quality of life. The goal of this paper is to review the current literature, research, and surveillance guidelines regarding the late effects of ALL therapy, to outline what can be done to mitigate the toxic effects of oncology treatment, and to extend life expectancy and improve quality of life for our patients. We review risk factors and interventions available to prevent and treat cardiovascular disease, secondary malignancies, endocrine complications (obesity, osteoporosis, infertility, and premature menopause), cognitive effects, and effects on functioning and mortality.

Immunotherapeutic strategies targeting B-cell acute lymphoblastic leukemia (B-ALL) effectively induce remission; however, disease recurrence remains a challenge. Due to the potential for antigen loss, antigen diminution, lineage switch or development of a secondary or treatment-related malignancy, the phenotype and manifestation of subsequent leukemia may be elusive. We report on two patients with multiply relapsed/refractory B-ALL who, following chimeric antigen receptor T-cell therapy, developed myeloid malignancies. In the first case, a myeloid sarcoma developed in a patient with a history of myelodysplastic syndrome. In the second case, two distinct events occurred. The first event represented a donor-derived myelodysplastic syndrome with monosomy 7 in a patient with a prior hematopoietic stem cell transplantation. This patient went on to present with lineage switch of her original B-ALL to ambiguous lineage T/myeloid acute leukemia. With the rapidly evolving field of novel immunotherapeutic strategies, evaluation of relapse and/or subsequent neoplasms is becoming increasingly more complex. By virtue of these uniquely complex cases, we provide a framework for the evaluation of relapse or evolution of a subsequent malignancy following antigen-targeted immunotherapy.

Anaplastic large cell lymphoma (ALCL) is a rare type of peripheral T cell lymphoma that can be characterized by the presence or absence of the anaplastic lymphoid kinase (ALK) expression. Although relapses are uncommon and treated with standard of care brentuximab, toxicities associated with primary treatment can limit the patient's options at time of relapse. Here, we present the case of a 27-year-old male diagnosed with ALCL with central nervous system involvement and treated with first-line systemic and intrathecal chemotherapy complicated by significant peripheral neuropathy. At the time of relapse, he was treated with alectinib, a second-generation ALK inhibitor and achieved a complete response, and he underwent an allogeneic stem cell transplant. The patient relapsed early in his transplant course and responded at re-initiation of alectinib. In this case report, we present the rationale of using alectinib in ALK-expressing ALCL as well as a review of the literature supporting its use. (C) 2019 Elsevier Inc. All rights reserved.

Abstract Introduction Asparaginase is incorporated into many multi-agent chemotherapy regimens used in the treatment of acute lymphoblastic leukemia (ALL). Asparaginase depletes proteins including stores of factors in the coagulation cascade and proteins regulating it, including antithrombin III (AT) and fibrinogen. This results in an increased risk of both bleeding and thrombosis. The rate of thrombosis following administration of asparaginase ranges from 5% to 35%, depending on treatment protocol and study design. While recommendations exist for the repletion of coagulation factors with cryoprecipitate and fresh frozen plasma (FFP), there are no current consensus recommendations for the replacement of AT in patients receiving asparaginase. This study aims to assess if administration of AT replacement products decreased the risk of thrombosis in ALL, lymphoblastic lymphoma, and NK/T-cell lymphoma patients with asparaginase-induced deficiency. Secondarily, this study investigated the risk of hemorrhage, budgetary impact of AT replacement products, and survival in this patient population. Methods This retrospective study evaluated patients 18 years of age or older who received L-asparaginase, pegaspargase, or asparaginase Erwinia chrysanthemi between January 2011 and June 2018 for ALL, lymphoblastic lymphoma, or NK/T-cell lymphoma. At our institution, a change in practice occurred in 2014 which led to the monitoring and supplementation of AT in this patient population. AT levels were monitored in patients post asparaginase therapy and supplementation was provided when levels were below 60%. Patients receiving anticoagulation treatment prior to the start of asparaginase therapy were excluded from the study. Data were analyzed using Chi-squared and T-tests were used to assess for significance between the groups. Results Forty-six patients were analyzed in total; the mean age was 36 years of age and the most common diagnoses were B-cell ALL and T-cell ALL; 26 patients did not receive AT monitoring while 20 patients were monitored and received AT repletion (Table 1). There was a statistically significant difference in the development of thrombi between the groups with only 2 patients (10%) in the treatment group developing a thrombus compared to 10 patients (38%) in the non-treatment group (p=0.029) (Table 2). Two patients in the non-treatment group developed a sinus venous thrombus. It should be noted, a patient in each group developed multiple thrombi (Table 3). Overall, no patients experienced a clinically significant bleeding event that required clinical intervention. Overall survival was similar between groups with death from any cause occurring in 5 patients (25%) in the treatment group and 8 patients (31%) in the non-treatment group (p=0.67) (Table 2). The average cost of AT replacement for patients receiving supplementation was $78,370. Conclusion The monitoring and supplementation of AT in ALL, lymphoblastic lymphoma, and NK/T-cell lymphoma patients was associated with a significant decrease in the occurrence of clinically significant thrombi. Patients in both groups did not experience bleeding events and the overall survival rate was similar between groups. While the average cost of AT repletion was considerable, the cost associated with a thrombus is arguably more substantial when taking into account intensive care admissions, diagnostic exams, and anticoagulation medications. Therefore, the result of this study suggests utilization of monitoring AT activity and its supplementation in patients receiving asparaginase therapy. Disclosures No relevant conflicts of interest to declare.

Purpose of review Adolescent and Young Adult (AYA) Oncology is a relatively new field encompassing research in the unique pathophysiology, clinical care, and psychosocial issues facing patients between the ages of 15 and 40 with cancer. About 100,000 of the approximately 1.5 million people diagnosed annually with cancer in the USA are in this age range. This chapter will review notable new developments in the care of adolescents and young adults with acute lymphoblastic leukemia (ALL) within the last 3 years. Recent findings The preponderance of data favors the treatment of AYA ALL patients with pediatric-inspired treatment regimens due to better relapse-free and overall survival. Minimal residual disease (MRD) measurement is emerging as an important prognostic factor and can serve as a new measure of efficacy of the addition of novel therapies to the treatment of patients with new diagnoses. There have been several treatment advances ranging from new cytotoxic agents for ALL to new antibody-based therapy to novel immune therapies such as CAR-T cells. Summary The care of AYA ALL patients is improving as the unique issues for this patient population are addressed.

A dose-limiting effect of vincristine, which is used effectively in the treatment of acute lymphoblastic leukemia (ALL), is peripheral neuropathy. To identify potential genetic variants associated with vincristine-induced peripheral neuropathy, investigators performed a genome-wide association study involving 222 children with newly diagnosed ALL and 99 children with relapsed ALL. All patients received vincristine-based treatment …

e17721 Background: In 2008, over 130,000 people in the US under age 45 were diagnosed with cancer. Due to increased survival rates, treatment-related infertility is a growing concern among patients. ASCO issued guidelines in 2013 that recommend health care providers address fertility with patients. Methods: We conducted a single center, cross-sectional study at UVa designed to evaluate physicians’ and patients’ perceptions of chemotherapy's effects on fertility. The physician survey focused on perception of fertility risk of many chemotherapy regimens as well as barriers to referring patients to a fertility specialist. The patient survey focused on their experience with counseling, fertility preservation, and perception of treatment effect on future pregnancies and children. Patient eligibility criteria included men and women between ages 18-40 with cancer diagnoses who underwent chemotherapy with curative intent within 1 year. 42 patients and 20 physicians participated. Results: 1/3 of patients reported they were not counseled regarding effects of chemotherapy on fertility. ¾ of patients reported not being offered reproductive counseling. 27% of patients felt their risk of having a child with birth defects was either “much higher” or “almost definite” after treatment completion. 50% of physicians felt conception would be “much less likely” and thought the risk of health problems such as birth defects was much higher after treatment with the low risk regimen R-CHOP. The majority of physicians stated the reasons they do not refer patients to a fertility specialist are patients declining services and insufficient time between diagnosis and treatment. Conclusions: The study results reveal notable deficiencies in physician knowledge about effects of treatment on fertility. Physicians express wide variation in knowledge of effects of chemotherapy regimens on future fertility and birth defects. Not surprisingly, patients have similar misperceptions and many are not counseled adequately and some not at all. Fertility counseling and referral to a fertility preservation specialist should become a routine part of practice. Training for providers and education materials need to be further developed and used in fertility risk counseling.

Infertility frequently occurs in long-term survivors of hematopoietic stem cell transplant (HSCT). By the time patients are referred for HSCT, they have often undergone cancer treatments that cause infertility. The burden of early education falls on the hematology oncology team that cares for the patient upon initial cancer diagnosis. Comprehensive oncofertility education should include two areas: the risk of cancer treatment on future fertility and fertility preservation (FP) options. This study sought to characterize the education practice and attitudes of hematology oncology physicians and nurses towards oncofertility education in patients who may be HSCT eligible and to determine patients' interest in education. A multidisciplinary team developed 3 surveys to evaluate patients, nurses, and physicians using published literature and unique questions targeting our population. The University of Virginia's Institutional Review Board (IRB) authorized the surveys as IRB exempt. Practicing hematology oncology nurses and physicians were eligible. Potential HSCT eligible patients diagnosed with lymphoma, leukemia, or myeloma in the last 2 years and were either women ages 18-45 or men ages 18-60 at time of diagnosis were eligible. A total of 23 hematologic cancer patients ages 23-49 completed the survey as well as 43 providers (Figure 1). Education on the risk of cancer treatment on future fertility was received by 52% of patients, and only 26% of patients received FP options. 81% of women and 31% of men were interested in discussing their fertility, learning about FP options, or a fertility referral and counseling service. Of those interested, 67% received education on the risk of cancer treatment to fertility and 42% received FP education. Of interested patients who received education, 63% were satisfied with risk of cancer treatment education, and 80% were satisfied with FP education. Of the surveyed providers, 75% of nurses and 33% of physicians did not feel comfortable discussing FP options with patients and 89% of nurses and 86% of physicians felt they needed more information on FP options. Physicians indicated patients' illness and nurses indicated their own knowledge of FP as the greatest barriers to education (Figure 2). The majority of hematology oncology patient participants did not receive comprehensive oncofertility education. Unfortunately, many patients interested in education did not receive it. Providers need oncofertility education to improve their ability to address topics. HSCT programs should collaborate with local fertility specialists to educate primary oncologists and potential HSCT patients, thereby increasing access to FP treatment and ensuring all patients of child-bearing potential receive education at time of cancer diagnosis.Figure 2Barriers to oncofertility education practice experienced by hematology oncology physicians and nurses.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Abstract Purpose: Genetic and preclinical studies have implicated FGFR signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor of FGFR activity, may be active in ACC. Experimental Design: In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500 mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate and change in tumor growth rate. Progression-free survival, overall survival, metabolic response, biomarker, and quality of life were secondary endpoints. Results: Of 34 evaluable patients, 2 (6%) had a partial response and 22 (65%) had stable disease >4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on treatment (P < 0.001). Toxicity was moderate; 63% of patients developed grade 3–4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on 18FDG-PET scans was seen in 3 of 15 patients but did not correlate with RECIST response. MYB gene translocation was observed and significantly correlated with overexpression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib. Conclusions: Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably with those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine whether FGFR signaling is a valid therapeutic target in ACC. Clin Cancer Res; 23(15); 4138–45. ©2017 AACR.

Ph-like acute lymphoblastic leukemia (ALL) — defined as ALL with a gene-expression profile similar to Ph+ ALL — is a recently described entity in

Because treatment for childhood acute lymphoblastic leukemia (ALL) has attained 5-year event-free survival (EFS) rates of approximately 80%, research

The attainment of high cure rates for children with B-cell–progenitor acute lymphoblastic leukemia (ALL) is among the most important accomplishments of

AbstractWe describe a patient in remission from acute lymphoblastic leukemia who developed a painless common peroneal neuropathy. Magnetic resonance imaging (MRI) revealed nerve thickening and enhancement, while a positron emission tomography (PET) scan demonstrated increased fluorodeoxyglucose uptake in a large segment of the neurovascular bundle, suggesting peripheral nerve infiltration. Both findings resolved following treatment with chemotherapy that crossed the blood–nerve barrier. In selected patients presenting with peripheral neuropathy, MRI and PET scan can be helpful in the diagnosis of peripheral nerve infiltration. Muscle Nerve, 2008

Core binding factor (CBF) is a heterodimeric transcription factor composed of RUNX1 (CBFα) and CBFβ subunits which are essential for normal blood cell development. CBFβ functions to increase the DNA-binding of the RUNX1 subunit 20–40 fold and to protect the RUNX1 subunit against ubiqitination and proteasome degradation, making this protein-protein interaction critical for CBF function. Two of the most common translocations involving the subunits of CBF are the inv(16) and the t(8;21) which produce the chimeric proteins CBFβ-SMMHC and AML1-ETO, respectively, which are associated with the development of Acute Myeloid Leukemia (AML). The AML1-ETO fusion protein is a dominant inhibitor of wildtype RUNX1-CBFβ activity in vivo and causes a blockage in normal hematopoiesis, predisposing for the development of leukemia. The interaction between CBFβ and AML1-ETO is critical for its function, therefore treatments targeting AML1-ETO and blocking its interaction with CBFβ are highly likely to be therapeutically beneficial. The CBFβ-SMMHC fusion protein causes dysregulation of CBF function by means of anomalously tight binding to RUNX1. Since binding to RUNX1 is required for the dysfunction associated with CBFβ-SMMHC, this interaction represents an excellent target for inhibition as a potential therapeutic strategy. We have initiated efforts to develop small molecule inhibitors of the RUNX1-CBFβ interaction as possible therapeutics for the treatment of the associated leukemias. Both virtual screening searches, focused on the X-ray structures of RUNX1 Runt domain and CBFβ, and high-throughput screening of NCI (National Cancer Institute) and Maybridge fragment libraries were used to identify initial lead compounds interacting with these proteins and blocking heterodimerization of CBF. Compounds were tested experimentally by FRET (Fluorescence Resonance Energy Transfer) and ELISA for their inhibition of RUNX1-CBFβ interaction. This resulted in a number of initial lead compounds targeting either the Runt domain or CBFβ and inhibiting this protein-protein interaction. Based on the docking mode selected lead compounds were further optimized using medicinal chemistry approaches to increase their affinity and determine the structure-activity relationships (SAR). This resulted in several compounds with low micromolar affinity (IC50 < 10 μM) which effectively block the heterodimerization of CBF in vitro and in a cell-based assay. Interestingly, compounds targeting CBFβ bind to a site displaced from the binding interface for RUNX1 as shown by the NMR-based docking, i.e. these compounds function as allosteric inhibitors of this protein-protein interaction. The most potent compounds were tested either in the Kasumi-1 leukemia cell line harboring t(8;21) translocation or in the ME-1 cell line with inv(16), resulting in a blockage of proliferation, induction of apoptosis and differentiation of these cells. These compounds represent the first small molecule inhibitors targeting CBF and inhibiting this interaction. They represent good starting points for the development of therapeutically useful inhibitors. Several approaches are being explored to modify these compounds to achieve selectivity towards AML1-ETO or CBFβ-SMMHC oncoproteins versus wild type proteins.

The two subunits of core binding factor (Runx1 and CBFbeta) play critical roles in hematopoiesis and are frequent targets of chromosomal translocations found in leukemia. The binding of the CBFbeta-smooth muscle myosin heavy chain (SMMHC) fusion protein to Runx1 is essential for leukemogenesis, making this a viable target for treatment. We have developed inhibitors with low micromolar affinity which effectively block binding of Runx1 to CBFbeta. NMR-based docking shows that these compounds bind to CBFbeta at a site displaced from the binding interface for Runx1, that is, these compounds function as allosteric inhibitors of this protein-protein interaction, a potentially generalizable approach. Treatment of the human leukemia cell line ME-1 with these compounds shows decreased proliferation, indicating these are good candidates for further development.