Search

Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) represent a heterogeneous population and therefore there is no standard of care first salvage regimen. We conducted a multicenter, retrospective analysis to compare chemotherapy (e.g. HyperCVAD, MOAD, Larson/CALGB-9511, etc.) to novel agents (blinatumomab or inotuzumab) in first salvage. The primary endpoint, overall survival (OS), was not significantly different among treatment arms, with a median OS of 10.6 months with chemotherapy and 10.1 months with novel therapy (

The cornerstone of management in patients with acute promyelocytic leukemia (APL) is early diagnosis and prompt initiation of treatment with an all-trans retinoic acid (ATRA)-based regimen. Identification of the t(15;17)(PML-RARA) chromosomal translocation through conventional cytogenetics fluorescence in-situ hybridization (FISH) or detection of the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) fusion through RT-PCR represent the current standard of care for diagnosing APL. However, about 1–2% of patients with APL have a variant translocation involving other fusion partners with RARα besides PML. These patients present a unique diagnostic and clinical challenge in that conventional cytogenetics in addition to FISH and/or RT-PCR for PML-RARα may fail to identify these clinically relevant genetic lesions leading to an inappropriate diagnosis and treatment. We present two cases of patients who had APL with variant translocations whose bone marrow specimens were sent to the University of Michigan for enrollment in the MI-ONCOSEQ study (HUM00067928) after standard testing failed to identify PML-RARα or t(15;17) despite a phenotypic concern for this diagnosis. In these two patients, whole exome and transcriptome profiling via the MI-ONCOSEQ platform identified a PRKAR1A-RARα fusion in one patient and ZBTB16-RARα fusion in another patient. These cases illustrate the utility of whole exome and transcriptome profiling in diagnosing variant translocations in patients in whom there is a high clinical suspicion for APL based on hematopathology review.

Background Patients diagnosed with acute myeloid leukemia with a FLT3 mutation (FLT3+ AML) have historically had poor outcomes. While the addition of the FLT3 inhibitors to induction therapy has been shown to improve survival outcomes in FLT3+ AML, interactions and overlapping toxicities between FLT3 inhibitors and standard of care medications used during induction therapy (e.g. azole antifungals, anthracyclines) and logistical barriers have complicated their use. To avoid these concerns, our institution has opted to defer initiation of midostaurin until after completion of induction therapy. However, to our knowledge no study confirming the effectiveness of this strategy for real world FLT3 inhibitor use has been published. Methods We performed a single center, propensity-score matched, retrospective cohort study characterizing efficacy and safety of our strategy for use of FLT3 inhibitors in the treatment of FLT3+ AML. The primary outcome was median event-free survival (EFS), while secondary endpoints included median overall survival (OS), overall response rate (ORR), 30-day mortality, duration of neutropenia, duration of thrombocytopenia, consolidation cycle delays, documented infections, and all-cause hospital readmission. Results A total of 83 FLT3+ AML patients treated with intensive induction therapy were included in the study, of whom 48 were propensity-score matched and analyzed. Baseline characteristics were similar between the patients who received a FLT3 inhibitor after induction therapy and the historical control arm. Median EFS was not significantly different but compared favorably between the FLT3 inhibitor cohort and historical controls (not reached vs 8 months, p = 0.343) with 18-month EFS of 54% and 43% for the two cohorts, respectively. Similarly, no significant differences were noted with regard to median OS (not reached vs 28.7 months, p = 0.752), ORR (79.2% vs 79.2%), or safety outcomes between groups. Conclusion Compared to historical controls, addition of a FLT3 inhibitor to intensive chemotherapy post-induction may improve EFS or OS in a real world patient cohort with longer follow-up and a larger sample size. The omission of midostaurin in induction allowed for the use of an azole antifungal and the intensification of anthracycline dose may have contributed to high remission rates in both groups.

Novel treatment strategies have shifted the treatment landscape for patients with diffuse large B-cell lymphoma, particularly for those with relapsed/refractory disease. However, uncertainty remains regarding the therapeutic value of these novel agents compared to existing salvage chemotherapy regimens. In addition, the high cost associated with these agents puts both patients and health systems at risk of financial toxicity, further complicating their use. The development of clinical pathways incorporating oncology stewardship principles are necessary in order to maximize value-based care. This comprehensive review assesses the efficacy and safety data available for novel treatment options in relapsed/refractory diffuse large B-cell lymphoma and applies stewardship principles to evaluate their optimal place in therapy, with the aim of optimizing safe, effective, and financially responsible patient care.

Liposomal daunorubicin/cytarabine (CPX-351) gained FDA approval for secondary AML after demonstrating improved outcomes over daunorubicin and cytarabine (7 + 3). A number of study limitations prompted a comparison of safety/efficacy of CPX-351 against regimens containing a purine analogue and high-dose cytarabine (HIDAC). This retrospective study compared complete response rates with/without count recovery (CR/CRi) between HIDAC-based regimens and CPX-351 in 169 patients with newly diagnosed sAML. The CR/CRi rate was 62.7% in the HIDAC-based therapy arm vs. 47.9% in the CPX-351 arm (

PEG-asparaginase is a key component in treatment regimens for acute lymphoblastic leukemia (ALL). Major side effects include thrombosis and bleeding; however, there is currently no consensus on methods to prevent these complications. In this multi-center retrospective cohort study of 101 adults, we compared two prophylaxis strategies: cryoprecipitate and fresh frozen plasma (Cryo/FFP) versus cryoprecipitate and antithrombin (ATIII). The overall incidence of venous thromboembolism (VTE) was not significantly different between the two groups (19.7% for Cryo/FFP and 8.6% in Cryo/ATIII,ip/i = 0.17), and neither was grade ≥3 bleeding (3% for Cryo/FFP and 11.4% for Cryo/ATIII,ip/i = 0.18). Given the significant cost associated with ATIII without a clear benefit, a careful benefit and risk analysis should be considered before utilizing ATIII as a prophylaxis strategy to prevent thrombosis or bleeding following asparaginase administration.

This paper offers a case study to demonstrate how a complex scoring model tool called CNS-TAP, originally created by a neuro-oncology team at one institution, was upgraded and made accessible to a wider audience. In the Results and Discussion, many issues of web app design, development, and sustainability are covered. Overall, we chart a path to expand access to many unique software tools created and needed by today’s medical specialists.

The use of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion protein have dramatically changed the clinical management and outcomes for patients with chronic myelogenous leukemia (CML)...

BackgroundPediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. We hypothesized that co-treatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib.MethodsDose response, synergism studies, P-gp inhibition and pharmacokinetic studies were performed on in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus.ResultsDasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with reduction in mTOR signaling that persists after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended survival of PPK tumor bearing mice. Pediatric patients (n=6) with glioma tolerated this combination without significant adverse events. Recurrent patients (n=4) demonstrated median overall survival of 8.5 months.ConclusionEfficacy of dasatinib treatment of PDGFRα-driven HGG is improved with everolimus and suggests a promising route for improving targeted therapy for this patient population.Trial RegistrationClinicalTrials.gov NCT03352427FundingThe authors thank the patients and their families for participation in this study. CK is supported by NIH/NINDS K08-NS099427-01, the University of Michigan Chad Carr Pediatric Brain Tumor Center, the Chad Tough Foundation, Hyundai Hope on Wheels, Catching up With Jack, Prayers from Maria Foundation, U CAN-CER VIVE FOUNDATION, Morgan Behen Golf Classic, and the DIPG Collaborative. The PEDS-MIONCOSEQ study was supported by grant 1UM1HG006508 from the National Institutes of Health Clinical Sequencing Exploratory Research Award (PI: Arul Chinnaiyan).

Daratumumab and elotuzumab have demonstrated improvements in overall response rates (ORR) and progression-free survival (PFS) in relapsed/refractory multiple myeloma (RRMM). There is a lack of comparative clinical trials and an even larger lack of consensus on the optimal integration of these novel agents into the treatment paradigm. Clinical outcomes were compared retrospectively in 37 patients who received daratumumab before elotuzumab (dara-first

BACKGROUND De novo purine synthesis promotes glioblastoma growth and stemness, invasiveness, and resistance to chemoradiation. Mycophenolate mofetil (MMF) is an FDA-approved inhibitor of de novo purine synthesis that sensitizes glioblastoma to radiation and chemotherapy in mice. This Phase 0/I trial of MMF with Radiotherapy in Recurrent Glioblastoma (NCT04477200) aims to determine the maximum-tolerated dose of MMF that can be combined with radiation,and the extent to which the active metabolite of MMF accumulates in brain tumors and inhibits de novo purine synthesis. METHODS Key eligibility criteria are age ≥18, KPS score ≥60%, and recurrent glioblastoma or gliosarcoma with clinical indication for re-irradiation (phase I) or re-resection/biopsy (phase 0). Patients with tumors involving ≥3 lobes or leptomeningeal space or bevacizumab use within 8 weeks are excluded. MMF 500-2000mg PO BID is given one week pre-operatively in Phase 0 (N=8), and up to 2000mg PO BID (starting 1000mg) on TITE-CRM dose escalation on Phase 1 cohort (N=30). RESULTS Since 7/2020, three Phase 0 and six Phase I subjects have been enrolled. On the phase I cohort, 1500mg BID dose has been reached. Studyrelated toxicities have been limited to mainly grade 1-2 nausea and fatigue. No notable study related hematotoxicity have been noted. Additionally, mass spectrometry-based correlative measurements of the activity of de novo GTP synthesis are ongoing. CONCLUSION MMF has been well tolerated up to 1500mg BID combined with radiotherapy in recurrent glioblastoma patients in this interim analysis. An additional upfront glioblastoma cohort with MMF with standard of care will activate in 2021. These studies will determine the maximum tolerated dose of MMF in combination with radiation and chemotherapy and provide a preliminary efficacy estimate at that dose. Encouraging results would support a randomized clinical trial to determine efficacy of MMF combined with chemoradiation in glioblastoma, and to define potential biomarkers for effectiveness.

This retrospective study was conducted to determine whether the number of peripherally inserted central-catheter lumens affected the rate of central-line associated bloodstream infections (CLABSIs) in adult patients with acute leukemia. The results show that CLABSI rates were not significantly different between patients with triple-lumen or double-lumen PICCs (22.1% vs 23.4%; P = .827).

Bendamustine is a preferred first-line chemoimmunotherapy regimen for indolent non-Hodgkin's lymphoma (iNHL). Emerging evidence suggests an increased incidence of late-onset complications with bendamustine-based regimens compared with CHOP/CVP; however, this evidence is limited. We retrospectively compared late-onset complications from January 2005 to May 2020 in adults with previously untreated iNHL who received rituximab or obinutuzumab with CHOP, CVP, or bendamustine. Forty-six patients received CHOP/CVP; 119 received bendamustine. No difference in incidence of late-onset infections was observed. Bendamustine led to a higher rate of prolonged and unresolved lymphocytopenia and a greater incidence of late-onset neutropenia. Many patients receiving bendamustine did not have lymphocyte recovery even three years following administration. Ongoing infection prophylaxis with bendamustine-based regimens may offset translation of these laboratory findings to late-onset infectious risk.

PURPOSE: Panobinostat, an orally bioavailable pan-HDAC inhibitor, has demonstrated potent activity in multiple malignancies, including pediatric brain tumors such as DIPG, with increased activity against H3K27M mutant cell lines. Given limited evidence regarding the CNS penetration of panobinostat, we sought to characterize its BBB penetration in a murine model. METHODS: Panobinostat 15 mg/kg was administered IV to 12 CD-1 female mice. At specified time points, mice were euthanized, blood samples were collected, and brains were removed. LC–MS was performed to quantify panobinostat concentrations. C(max) and AUC were estimated and correlated with previously published pharmacokinetic analyses and reports of IC-50 values in DIPG cell lines. RESULTS: Mean panobinostat plasma concentrations (ng/mL) were 27.3 ± 2.5 at 1 h, 7.56 ± 1.8 at 2 h, 1.48 ± 0.56 at 4 h, and 2.33 ± 1.18 at 7 h. Mean panobinostat brain concentrations (ng/g) were 60.5 ± 6.1 at 1 h, 42.9 ± 5.4 at 2 h, 33.2 ± 6.1 at 4 h, and 28.1 ± 4.3 at 7 h. Brain-to-plasma ratio at 1 h was 2.22 and the brain to plasma AUC ratio was 2.63. Based on the published human pharmacokinetic data, the anticipated C(max) in humans is expected to be significantly higher than the IC-50 identified in DIPG models. CONCLUSION: It is expected that panobinostat would be effective in CNS tumors where the IC-50 is in the low nanomolar range. Thus, our data demonstrate panobinostat crosses the BBB and achieves concentrations above the IC-50 for DIPG and other brain tumors and should be explored further for clinical efficacy.

Background Current literature has demonstrated the utility of the MRSA nasal screen as a de-escalation tool to decrease unnecessary anti-MRSA antibiotic therapy. However, data on the applicability of this test in patients with hematologic malignancy is lacking. Methods This is a single-center, retrospective cohort study of patients with acute myeloid leukemia (AML) with or without history of hematopoietic cell transplant (HCT), with pneumonia and MRSA nasal screening with respiratory cultures obtained. The primary outcome was to determine the negative predictive value (NPV) of the MRSA nasal screen for MRSA pneumonia. Secondary outcomes included sensitivity, specificity, positive predictive value (PPV) of the MRSA nasal screen and prevalence of MRSA pneumonia. Results Of 98 patients with AML and pneumonia, the prevalence of MRSA pneumonia was 4.1% with confirmed positive MRSA respiratory cultures observed in 4 patient cases. In patients with confirmed MRSA pneumonia, 3 had positive MRSA nasal screens while 1 had a false negative result, possibly due to a long lag time (21 days) between MRSA nasal screen and pneumonia diagnosis. Overall, the MRSA nasal screen demonstrated 75% sensitivity and 100% specificity, with a PPV of 100% and a NPV of 98.9%. Conclusions Given the low prevalence, empiric use of anti-MRSA therapy in those AML and HCT patients with pneumonia may not be warranted in clinically stable patients. For patients in whom empiric anti-MRSA antibiotics are initiated, nasal screening for MRSA may be utilized to de-escalate anti-MRSA antibiotics in patients with AML with or without HCT.

Internal tandem duplications and tyrosine kinase mutations in the fms-like tyrosine kinase 3 (FLT3) receptor can occur in acute myeloid leukemia (AML) and portend a poor prognosis. Midostaurin, a multikinase inhibitor that targets FLT3, demonstrated a survival benefit in FLT3-mutated AML in combination with front-line chemotherapy. Despite this advancement, the use of FLT3 inhibitors in clinical practice is complicated by significant drug-drug interactions and uncertainty about optimal timing, duration, and sequencing of therapy. As monotherapy, the utility of FLT3 inhibitors was initially limited by incomplete and transient clinical responses and the development of acquired resistance. This led to the development of more potent and selective FLT3 inhibitors designed to overcome common resistance mechanisms. One of these second generation FLT3 inhibitors, gilteritinib, is now FDA-approved for the treatment of relapsed or refractory AML. Now that multiple FLT3 inhibitors are commercially available, it is important to further delineate the role of these agents in the AML population. This review aims to provide a comprehensive overview of the role of FLT3 inhibitors in AML and apply the current literature to clinical practice.

The availability of Erwinia Asparaginase has been limited across the world due to manufacturing shortages or for some countries due to the high acquisition cost, putting patients at risk for inferior outcomes. This manuscript provides guidance on how to manage hypersensitivity reactions and utilize therapeutic drug monitoring (TDM) to conserve and limit Erwinia use. The clinical and financial impact of a multidisciplinary committee are also discussed. Faced with a global Erwinia shortage, a multidisciplinary asparaginase allergy committee was created to review all hypersensitivity reactions to asparaginase therapy, staff education was performed on the management of asparaginase hypersensitivity reactions, an institution-wide premedication policy was mandated, and standardized guidelines were created for TDM. This multidisciplinary approach reduced the PEG-asparaginase to Erwinia switch rate from 21% (35 of 163) to 7% (10 of 134) (

As the field of neuro-oncology makes headway in uncovering the key oncogenic drivers in pediatric glioma, the role of precision diagnostics and therapies continues to rapidly evolve with important implications for the standard of care for clinical management of these patients. Four studies at major academic centers were published in the last year outlining the clinically integrated molecular profiling and targeting of pediatric brain tumors; all 4 demonstrated the feasibility and utility of incorporating sequencing into the care of children with brain tumors, in particular for children and young adults with glioma. Based on synthesis of the data from these studies and others, we provide consensus recommendations for the integration of precision diagnostics and therapeutics into the practice of pediatric neuro-oncology. Our primary consensus recommendation is that next-generation sequencing should be routinely included in the workup of most pediatric gliomas.

Secondary AML is associated with a disproportionately poor prognosis, consistently shown to exhibit inferior response rates, event-free survival, and overall survival in comparison with de novo AML. Secondary AML may arise from the evolution of an antecedent hematologic disorder, or it may arise as a complication of prior cytotoxic chemotherapy or radiation therapy in the case of therapy-related AML. Because of the high frequency of poor-risk cytogenetics and high-risk molecular features, such as alterations in TP53, leukemic clones are often inherently chemoresistant. Standard of care induction had long remained conventional 7 + 3 until its reformulation as CPX-351, recently FDA approved specifically for secondary AML. However, recent data also suggests relatively favorable outcomes with regimens based on high-dose cytarabine or hypomethylating agents. With several investigational agents being studied, the therapeutic landscape becomes even more complex, and the treatment approach involves patient-specific, disease-specific, and therapy-specific considerations.

2062 Background: The number of available targeted therapies has vastly expanded in recent years; however, only a selection of such therapies achieve adequate central nervous system (CNS) penetration. The CNS Targeted Agent Prediction (CNS TAP) Tool was developed to aid in the selection of precision medicine therapies based on preclinical data, clinical data, patient-specific genomic data, and importantly, optimal blood brain barrier penetration. Using a standardized murine pharmacokinetic (PK) model, we sought to determine the concordance of CNS penetration prediction by the CNS TAP Tool compared to the SwissADME BOILED-Egg computational model. Methods: Eleven drugs were chosen based on the most commonly altered and targeted pathways by our CNS tumor board. Mice were injected individually with the compounds of interest and sacrificed at four different time points to quantify drug concentration via LC-MS in brain tissue and blood samples for PK analyses (1,2,4,7 hours). The percent brain penetration (AUCbrain/plasma) was compared to published human phase I PK data and pathway IC-50 to determine if agents were adequately CNS penetrant. These results were compared against the CNS TAP Tool and BOILED-Egg prediction of CNS penetrance. Results: All 11 drugs chosen (Table) demonstrated adequate CNS penetration, suggesting likely CNS efficacy. The CNS TAP Tool correctly predicted 10/11 agents (91% concordance), the lone exception being panobinostat. In contrast, the BOILED-Egg model only successfully predicted 3/11 agents (27%). When restricting the analysis to drugs with >50% CNS penetration (ponatinib, panobinostat, and ONC-201), the BOILED-Egg model successfully predicted CNS penetration of all agents. Conclusions: The clinician-curated CNS TAP Tool more accurately predicted CNS penetration of precision medicine therapies than the BOILED-Egg computational model, which performed best for drugs that achieve extremely high CNS penetration. The resulting PK and CNS penetration data for all agents was utilized to update and refine the CNS TAP tool for future patient use. [Table: see text]

Purpose Brain tumors have become the leading cause of cancer-related mortality in young patients. Novel effective therapies on the basis of the unique biology of each tumor are urgently needed. The goal of this study was to evaluate the feasibility, utility, and clinical impact of integrative clinical sequencing and genetic counseling in children and young adults with high-risk brain tumors. Patients and Methods Fifty-two children and young adults with brain tumors designated by the treating neuro-oncologist to be high risk (> 25% chance for treatment failure; mean age, 10.2 years; range, 0 to 39 years) were enrolled in a prospective, observational, consecutive case series, in which participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed in a multi-institutional brain tumor precision medicine teleconference. Results Sequencing revealed a potentially actionable germline or tumor alteration in 25 (63%) of 40 tumors with adequate tissue, of which 21 (53%) resulted in an impact on treatment or change of diagnosis. Platelet-derived growth factor receptor or fibroblast growth factor receptor pathway alterations were seen in nine of 20 (45%) glial tumors. Eight (20%) sequenced tumors harbored an oncogenic fusion isolated on RNA sequencing. Seventeen of 20 patients (85%) with glial tumors were found to have a potentially actionable result, which resulted in change of therapy in 14 (70%) patients. Patients with recurrent brain tumors receiving targeted therapy had a median progression-free survival (from time on therapy) of 4 months. Conclusion Selection of personalized agents for children and young adults with high-risk brain tumors on the basis of integrative clinical sequencing is feasible and resulted in a change in therapy in more than two thirds of children and young adults with high-risk glial tumors.

Background Acute leukemia with mixed-phenotype blasts is associated with poor outcomes. There are no standard treatment regimens. Due to disease heterogeneity, controversy exists over whether an AML-based, ALL-based, or a combined (hybrid) AML/ALL-based regimen is most appropriate. Materials and Methods We conducted a single-center, retrospective case series review of patients with acute leukemia with mixed phenotype blasts as described by the European Group for Immunological Characterization of Leukemia (EGIL) or the 2008 WHO classification. Patients were treated from November 2014 and December 2019 with the combination chemotherapy regimen FLAG-idarubicin-vincristine-prednisone with or without rituximab. Outcomes included induction response, time to transplant, time to relapse, overall survival, time to neutrophil or platelet recovery, infection, and duration of hospitalization. Results The median age was 68 years (range 21−77). Six patients (87.5 %) had unfavorable/complex cytogenetics. All patients achieved a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). Estimated 1-year overall survival was 85.7 %. There were no deaths during induction, with a 22 day median duration of hospitalization for induction. Conclusion The combination of FLAG, idarubicin, vincristine, and prednisone (FLAG-VIPR) demonstrated favorable induction responses in a disease state with historically poor outcomes and should be studied in a prospective clinical trial.

Background: All-trans retinoic acid (ATRA) serves as the backbone of the management of patients with acute promyelocytic leukemia (APL), with guidelines recommending the initiation of ATRA as soon as APL is suspected. As a regional referral center for patients with acute leukemia, those who are suspected of having APL are often transferred to our facility. However, many referring centers are unable to initiate treatment using ATRA. We conducted an exploratory analysis of the clinical availability of ATRA and the factors limiting access to this critical drug. Patients and Methods: The United States was divided into 6 geographic regions: Northwest, Southwest, Central, Southeast, Northeast, and the Great Lakes. Twenty hospitals were randomly selected from states within each of these regions and were surveyed as to whether they typically treated patients with acute leukemia, the availability of ATRA at their institution, and reported reasons for not stocking ATRA (if not available). Results: Less than one-third of hospitals queried (31%) had ATRA in stock. Neither the size of the hospital nor the hospital’s status as academic versus nonacademic (53% vs 31%; P=.08) influenced ATRA availability. Of the hospitals that referred patients with APL, only 14% (7/49) had ATRA readily available. Hospitals that treated patients with APL were more likely to have ATRA available than referring centers (58% vs 14%; P=.000002). Conclusions: Nearly two-thirds of the hospitals surveyed that cared for patients with acute leukemia do not have ATRA immediately available. Moreover, the vast majority of hospitals that refer patients to other centers do not have ATRA. These findings should spur investigation into the impact of immediate ATRA availability on the morbidity and mortality of patients with APL. A call by hematologists nationwide to their formulary committees is warranted to ensure that this lifesaving medication is available to patients suspected of having APL.

Acquired thrombotic thrombocytopenic purpura is a rare blood disorder with a high early mortality rate, if untreated. Standard of care plasma exchange and glucocorticoids have dramatically improved survival. However, additional advancements are necessary to further decrease mortality. Caplacizumab-yhdp (Cablivi®) is the first Food and Drug Administration-approved treatment indicated for adult patients with acquired thrombotic thrombocytopenic purpura, in combination with plasma exchange and immunosuppressive therapy. However, there are considerable risks associated with the use of caplacizumab and they must be weighed against the benefits of the medication.

The original version of this review article unfortunately contained a mistake in the author group section.

PURPOSE OF REVIEW: H3K27M is a frequent histone mutation within diffuse midline gliomas and is associated with a dismal prognosis, so much so that the 2016 CNS WHO classification system created a specific category of “Diffuse Midline Glioma, H3K27M-mutant”. Here we outline the latest pre-clinical data and ongoing current clinical trials that target H3K27M, as well as explore diagnosis and treatment monitoring by serial liquid biopsy. RECENT FINDINGS: Multiple epigenetic compounds have demonstrated efficacy and on-target effects in pre-clinical models. The imipridone ONC201 and the IDO1 inhibitor indoximod have demonstrated early clinical activity against H3K27M-mutant gliomas. Liquid biopsy of cerebrospinal fluid has shown promise for clinical use in H3K27M-mutant tumors for diagnosis and monitoring treatment response. SUMMARY: While H3K27M has elicited a widespread platform of pre-clinical therapies with promise, much progress still needs to be made to improve outcomes for diffuse midline glioma patients. We present current treatment and monitoring techniques as well as novel approaches in identifying and targeting H3K27M-mutant gliomas.

Central nervous system (CNS) relapse in acute myeloid leukemia (AML) confers a poor prognosis. Despite the identification of risk factors for CNS relapse (e.g. hyperleukocytosis), there is no standard practice for CNS relapse risk reduction with intrathecal (IT) chemotherapy in patients. We compared outcomes of 50 patients who did not receive IT chemotherapy with 18 patients who did receive IT chemotherapy with a hyperleukocytosis at diagnosis (defined as white blood cell count ≥100,000 cells/mcL). There were three occurrences of CNS relapse, all within patients who did not receive prophylaxis. There was no difference in the incidence of CNS relapse between the patient cohorts (

Background: There is minimal data evaluating the safety of antibiotic de-escalation in patients with acute myeloid leukemia (AML) with fever and ongoing neutropenia. Therefore, this study evaluated antibiotic prescribing, infection-related outcomes, and patient outcomes of an antibiotic de-escalation initiative. Patients and Methods: This pre–post quasiexperimental study included adult patients with AML hospitalized with febrile neutropenia. An antibiotic de-escalation guideline was implemented in January 2017, which promoted de-escalation or discontinuation of intravenous antipseudomonal β-lactams. The primary outcome assessment was the incidence of bacterial infection in a historical control group before guideline implementation compared with an intervention group after guideline implementation. Results: A total of 93 patients were included. Antibiotic de-escalation occurred more frequently in the intervention group (71.7% vs 7.5%; PPClostridioides difficile colitis (5.7% vs 27.5%; P=.007). Conclusions: Implementation of an antibiotic de-escalation guideline resulted in decreased use of intravenous antipseudomonal β-lactams and fewer episodes of C difficile colitis, without adversely impacting patient outcomes. Additional studies are needed, preferably in the form of randomized controlled trials, to confirm these results.

Introduction Blast-phase (BP), or leukemic transformation is a rare and devastating complication of myeloproliferative neoplasms (MPNs) (primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET), and post-PV/ET myelofibrosis). Patients with BP-MPNs have a poor prognosis with a median overall survival of less than 6 months, and there is no standard treatment regimen for these aggressive diseases (Dunbar et al, Blood. 2020). The development of hypomethylating agent (HMA)/venetoclax (Ven) combination offers new hope for some with AML, but has been relatively disappointing in BP-MPN, though data are limited and retrospective (Masarova et al, Blood Adv. 2021; Gangat et al, Am J Hematol. 2021). Here, we add our experience with several common treatment regimens for BP-MPN. Methods We retrospectively analyzed data from 39 consecutive patients with BP-MPNs diagnosed from December 2008 to February 2021 who received treatment at the University of Michigan. We included all patients with a previous diagnosis of MPNs who had ≥ 20% blasts in the peripheral blood or bone marrow, and subsequently received systemic therapy. One patient with a myeloid sarcoma was included as well. Disease characteristics at time of BP-transformation were noted. Patients were divided into the following groups based on 1 st-line induction therapy: 7+3 (daunorubicin and cytarabine), FLAG (fludarabine, high-dose cytarabine and G-CSF), hypomethylating agent only (decitabine or azacitidine), and HMA/Ven. Patients were followed for 2 years post-diagnosis. Differences in induction response were assessed using the Chi-square test. Differences in overall survival were calculated using the Kaplan-Meier regression with the log-rank test. Two patients who received alternate induction therapy outside of the four groups were not included in these analyses. Results The composite BP-MPN population had a median advanced age of 69 years old and a median ECOG performance status (PS) of 1. Most (97.4%) had received systemic treatment prior to their transformation for their MPN, with 71.8% receiving hydroxyurea and 41.0% receiving ruxolitinib. The rate of response (CR, CRi, MLFS) was highest in the HMA/Ven group at 42.9%, followed by FLAG (29.4%), HMA only (11.1%), and 7+3 (0%), p = 0.033 (Table 3). Despite the higher response rate, differences in 2-year OS were not significantly different among the 4 groups: 7+3 (25.0%), FLAG (7.7%), HMA (0%), HMA/Ven (20.0%) (p=0.92, Figure 1). Median time to relapse after achieving remission ranged from 2-10 months, and did not vary significantly based on induction regimen. Patients in the HMA and HMA/Ven groups had higher incidences of death with induction at 77.8% and 28.6%, respectively (Table 3). Conclusions The highest rates of response, including complete remission, were achieved with the combination of HMA and venetoclax compared to intensive induction chemotherapy or HMA alone. However, this did not translate into significant differences in OS, which is consistent with other retrospective reports. No responses were seen with 7+3 induction, though several patients were able to go on salvaged with other therapies and subsequent allogeneic stem cell transplantation thereafter. Finally, the baseline poor ECOG PS of the HMA group and borderline ECOG PS of the HMA/Ven group also contribute to their low survival rates.Larger, prospective studies comparing currently available treatment regimens in BP-MPN would be helpful, but ultimately new therapies are desperately needed for this high-risk disease. Figure 1 Figure 1. Disclosures Bixby: Takeda: Consultancy. Talpaz: Constellation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Grant/research support ; Celgene: Consultancy; Imago: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction Aplastic anemia is a challenging disease to treat due to its rarity and severity. The current standard of care for severe and very severe aplastic anemia includes consideration of frontline allogeneic stem cell transplant (ASCT) in patients who are under 40 years of age and have an HLA-matched sibling. For patients who do not meet this criteria, immunosuppressive therapy (IST) consisting typically of horse antithymocyte-globulin (ATG) and cyclosporine (CsA) is considered, with recent data supporting the addition of eltrombopag. The main risks of IST are infusion reactions, serum sickness, kidney injury, and infection. While it is generally well tolerated in younger patients, older patients have historically been treated with transfusion support alone due to concerns for higher complications. Unfortunately, data to support clinical decisions regarding these concerns is limited, with small studies showing that reduced dosing or attenuated doses of ATG with or without CsA is safe and can be effective. At the University of Michigan, we have been treating older patients with attenuated doses of ATG +/- CsA since the late-2000s and have recently added eltrombopag to our standard of care. Herein, we present the results of our experience using IST to treat aplastic anemia, specifically presenting our outcomes in patients over 60 years old at the time of initiation of IST. Methods We used the Electronic Medical Record Search Engine (EMERSE) to query patients with aplastic anemia who were treated at the University of Michigan between 1995 and 2021. Patients included in our analysis were diagnosed with idiopathic aplastic anemia or hepatitis-associated aplastic anemia, were 18 years or older at the date of initiating IST, were treated with IST first-line, had adequate physician follow up at the University of Michigan, and were reported as being complaint with IST. Patients diagnosed or with high concern for hypoplastic myelodysplastic syndrome (MDS) were excluded in addition to those who received treatment for paroxysmal nocturnal hemoglobinuria (PNH). Statistical analysis was performed using SPSS Statistics v.27 (IBM, 2020). Results We identified 62 patients aged 18 - 60 and 54 patients over 60 years old who met inclusion criteria. Descriptive statistics of the two cohorts are available in Table 1. All patients in our study received horse ATG in addition to cyclosporine. 63% of patients over 60 received full dose horse ATG (20mg/kg for 5 days) and 37% received attenuated horse ATG (20mg/kg for 5 days), while 46% received eltrombopag as part of their IST. OS was superior in patients 18-60 receiving IST with median OS NR vs. 2760 days (Figure 1; p=0.009). In patients over 60, no difference in OS was observed in those who received attenuated (3646 days) vs. full dose IST (2760 days) (Figure 2, p=0.83). Lastly, no difference in median OS was seen in patients > 60 years old who received eltrombopag compared to those who did not (2821 vs 2760 days, Figure 3, p=0.795). Using a Chi-squared test, no statistically significant differences in rates of PR at 12 months, CR at 12 months, primary refractory disease, febrile neutropenia within 6 months of IST, bacterial infections within 6 months IST, and viral infections within 6 months of IST were noted between those who received dose attenuated ATG and those who received full dose ATG in patients > 60. PR in older patients was 48% (12) and 36% (9) at 3 and 12 months with eltrombopag, compared to 40% (10) and 36% (9) without. CR in older patients was 12% (3) and 16% (4) with eltrombopag at 3 and 12 months, compared to 12% (3) and 12% (3) without. In patients > age 60 who received dose attenuated IST, the addition of eltrombopag did not affect OS (Figure 4). A trend toward better OS was seen in patients 18-60 who received eltrombopag, but this was not statistically significant (Figure 5). Discussion In conclusion, we present our experience using IST to treat aplastic anemia at the University of Michigan. Dose attenuated IST has been proposed as a potential option for elderly patients, but we found no significant difference in OS, rates of response, or rates of infection between patients who received full dose and those who did not. There was also a trend toward improved survival with the addition of eltrombopag in younger patients, but additional follow up time is needed. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Genetic sequencing of diffuse intrinsic pontine gliomas (DIPG) has revealed genomic heterogeneity, sparking an interest in individualized and targeted treatment options for this particularly devastating disease. A feasibility study, PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), was completed within the Pacific Pediatric Neuro-Oncology Consortium. In this study, a multidisciplinary tumor board reviewed detailed molecular and genomic profiling of each participant’s tumor and made molecularly-targeted treatment recommendations. Separately, our team developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to derive numeric scores for targeted anticancer agents, aimed to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within CNS-TAP would overlap with the agents recommended by the tumor board in PNOC003. For each study participant, we used the genomic profiling report to identify actionable alterations and incorporated these data into CNS-TAP to identify the highest-scoring agents. We compared high-scoring agents within CNS-TAP with recommendations from the tumor board for each of the enrolled 28 participants. Overall, 93% of patients (26/28) had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% of all agents (36/95) recommended by the tumor board were also selected by CNS-TAP. We identified factors that likely contributed to the differences in therapy recommendations between these two methods: CNS-TAP requires additional clinician input to account for drug-drug interactions, includes only classically-defined anticancer agents, and cannot easily be updated in real-time as new data emerge. However, CNS-TAP provides an objective evaluation of targeted therapies, whereas tumor boards are inherently subjective. A prospective study incorporating both CNS-TAP and a molecular tumor board for targeted therapy selection in high-grade glioma is currently ongoing to further compare and objectively evaluate these methods.

The 5-year overall survival (OS) in patients ≥ 60 years old with acute myeloid leukemia (AML) remains

Asparaginase is an integral component of multiagent chemotherapy regimens for the treatment of acute lymphoblastic leukemia (ALL). Adequate asparagine depletion is believed to be an important factor in achieving optimal therapeutic outcomes. Measurement of asparaginase activity allows practitioners to evaluate the potential effectiveness of therapy in real time. Asparaginase activity levels can be used to identify patients with silent inactivation and modify therapy in these patients. Patients with silent inactivation to asparaginase who are switched to therapy with an immunologically distinct asparaginase exhibit outcomes similar to patients who never developed silent inactivation. Despite these benefits, there exists no universally agreed-upon guideline for treatment adjustments based on asparaginase activity levels. The goal of this manuscript is to review the clinical evidence linking asparaginase activity levels to outcomes in patients with ALL and to provide an overview of how asparaginase activity levels may be used to guide treatment.

Context: The current standard of care for Ph+ ALL is concurrent chemotherapy or corticosteroids with a TKI, followed by an allogeneic transplant for those who are eligible and have attained complete morphologic remission. However, recent studies have suggested that transplant may not be necessary for all patients with Ph+ ALL, especially those who achieve CMR after induction. Objective: Our objective is to analyze the outcomes and characteristics of patients with Ph+ ALL treated within our institution who did not undergo allogeneic stem cell transplant. Design: We conducted a retrospective cohort study of patients with Ph+ ALL who did not undergo allogeneic stem cell transplant treated at the University of Michigan between 2007 and 2019. Main Outcome Measures: The primary outcome measurements of our study were overall survival (OS) and event-free survival (EFS). Results: 31 patients were identified in our database and met eligibility criteria. 30/31 patients received an upfront TKI (20 received dasatinib, 9 received imatinib, and 1 received ponatinib). 11 patients had molecular testing, and 4 had an IKZF1 mutation. The median OS was 388 days, with a median EFS of 247 days. 7 patients were deemed medically eligible for transplant but did not undergo transplant for reasons including patient preference and lack of an adequately matched donor. The median OS was 372 days for these 7 patients. 10/31 patients achieved CMR, with a median time to CMR of 148.5 days. The median OS in patients who achieved CMR was 551 days. The median OS for those who survived at least 50 days after diagnosis was 494 days. Cox regression analysis found an HR of.129 [0.020–0.841] for initial induction with hyperCVAD + TKI and an HR of 10.177 [1.209–85.677] with dexamethasone, vincristine, and TKI. No significant difference in OS was observed based on the choice of TKI. All patients who achieved CR experienced relapse or death during follow-up. Conclusions: Our results reveal poor outcomes in non-transplanted patients with Ph+ ALL and support the current standard of care utilizing concomitant chemotherapy and TKI with allogeneic transplant in those who are medically eligible.

Genetic sequencing of diffuse intrinsic pontine gliomas (DIPG) has revealed genomic heterogeneity, fueling an interest in individualized targeted therapies. A feasibility study, PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), was completed within the Pacific Pediatric Neuro-Oncology Consortium in which a multidisciplinary tumor board reviewed molecular and genomic profiling of each participant’s tumor to make targeted therapy recommendations. Separately, our team developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to derive numeric scores for anticancer agents to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that agents highly-scored by CNS-TAP would overlap with agents recommended by the PNOC003 tumor board. For each study participant, we retrospectively utilized the genomic profiling report to identify actionable alterations and incorporated these data into CNS-TAP to find the highest-scoring agents. We compared these CNS-TAP-recommended agents with recommendations from the tumor board for each of the 28 PNOC003 participants. Overall, 93% of patients (26/28) had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% of all agents (36/95) chosen by the tumor board were also selected by CNS-TAP. When only molecularly targeted anticancer agents were included in a sub-analysis, 60% of agents (34/57) were recommended by both methods. At present, we are prospectively evaluating the CNS-TAP tool within PNOC008: A Pilot Trial Testing the Clinical Benefit of Using Molecular Profiling to Determine an Individualized Treatment Plan in Children and Young Adults with High-Grade Glioma (NCT03739372). The CNS-TAP tool recommendations are shared during the PNOC008 molecular tumor board meetings once a consensus treatment recommendation has been reached. Subsequent analyses will focus on any adjustments in therapy decisions within the tumor board that result from the CNS-TAP tool output.

Background Relapsed/refractory acute myeloid leukemia (AML) confers a poor prognosis, and there is no single standard of care first-line salvage regimen. FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) is a common salvage regimen with a favorable toxicity and efficacy profile in poor-risk AML. Materials and Methods We conducted a single-center, retrospective analysis of first relapse/primary refractory patients with AML that received salvage chemotherapy from January 2009 to July 2019. We propensity-score matched patients 1:1 (based on age at diagnosis, cytogenetic risk group, Charlson comorbidity index, de novo vs. secondary AML, and whether or not they received an allogeneic stem cell transplant in first complete remission) into 2 groups, FLAG (Group 1) or non-FLAG (Group 2) as first-line salvage regimen, with 66 patients in each group. The primary endpoint was overall response rate (complete response and complete response with incomplete hematologic recovery). Results The median patient age was 59 years (range, 19-80 years). Patients treated with FLAG had a higher overall response rate (complete response/complete response with incomplete hematologic recovery) (71.2% vs. 50.0%; odds ratio, 2.47; 95% confidence interval [CI], 1.21-5.08; P = .013), longer event-free survival (8.9 vs. 2.1 months; hazard ratio [HR], 0.58; 95% CI, 0.39-0.86; P = .005), and longer overall survival (14.2 vs. 5.9 months; HR, 0.62; 95% CI, 0.41-0.93; P = .019). Patients who received FLAG had a shorter median duration of neutropenia (22 vs. 34 days; HR, 0.43; 95% CI, 0.29-0.64; P Conclusion This analysis supports the FLAG regimen as an effective and well-tolerated salvage therapy for patients with relapsed/refractory AML.

Recently, sequencing of diffuse intrinsic pontine glioma (DIPG) biopsy specimens has revealed genomic heterogeneity of these tumors, fueling an interest in individualized, targeted treatment options. The Pacific Pediatric Neuro-Oncology Consortium recently completed enrollment onto a feasibility study PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), in which a multidisciplinary tumor board recommended molecularly-targeted agents based on genomic and molecular profiling of each patient’s tumor. Separately, our group developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to allow for numeric scoring of targeted anticancer agents to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within CNS-TAP would overlap with the agents recommended by the tumor board in this study. For each PNOC003 participant, we utilized the genomic report to identify actionable alterations and input patient-specific data into CNS-TAP to identify the highest scoring agents. We compared high-scoring agents within CNS-TAP with recommendations from the PNOC003 tumor board for each of the enrolled 28 subjects. Overall, 93% (26/28) of patients had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% (37/95) of all agents recommended by the tumor board were also selected by CNS-TAP. Furthermore, we identified factors that likely contributed to the discordance between these two methods. Without clinician input, CNS-TAP is unable to account for drug-drug interactions, includes only designated anticancer agents, and cannot easily be updated in real time. However, CNS-TAP provides an objective evaluation of targeted therapies, whereas tumor boards are inherently subjective. Given the discordance identified between these methods and the strengths of each, a prospective study incorporating both CNS-TAP and a molecular tumor board for targeted therapy selection in DIPG patients is warranted.

2048 Background: Genetic sequencing of diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) biopsy specimens has revealed genomic heterogeneity, fueling an interest in individualized, targeted treatment options. The Pacific Pediatric Neuro-Oncology Consortium recently completed a feasibility study PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), in which a multidisciplinary tumor board recommended targeted agents based on the molecular and genetic profiling of each patient’s tumor. Separately, our group developed a numeric scoring tool of targeted anticancer agents, the Central Nervous System Targeted Agent Prediction (CNS TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to generate a numeric score for each agent to objectively evaluate these targeted therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within the CNS-TAP tool would overlap, at least in part, with the agents recommended by the molecular tumor board in PNOC003. Methods: For each study participant (n=28), a retrospective analysis was completed, utilizing the genomic report to identify actionable genetic alterations and to input patient-specific data into CNS TAP to identify the highest scoring agents. We compared high-scoring agents within the CNS TAP tool with recommendations from the PNOC003 tumor board for each of the enrolled 28 patients. Results: Overall, 93% (26/28) of patients had at least one agent recommended by both the tumor board and CNS TAP. Additionally, 39% (37/95) of all agents recommended by the tumor board were also selected by CNS TAP, with additional analysis ongoing. Conclusions: There was significant overlap between the highest-scoring and selected agents via CNS TAP compared with those chose by the molecular tumor board. Through this work, we also identified factors that likely contributed to the discordance in choice of targeted therapies. Without clinician input, the CNS TAP tool is unable to account for drug-drug interactions, includes only designated anticancer agents, and cannot easily be updated in real time, requiring extensive manual literature review for each included agent. However, CNS TAP provides an objective evaluation of targeted therapies, in contrast to inherently subjective recommendations of a tumor board. Given the discordance identified between these methods and the strengths of each, a prospective study incorporating both CNS TAP and a molecular tumor board for targeted therapy selection in patients with high grade glioma is warranted.

Purpose Allogeneic hematopoietic cell transplant recipients undergo myelosuppressive chemotherapy to allow engraftment of stem cells and are at particularly high risk for bacterial infections and adverse outcomes. Patients undergoing hematopoietic cell transplant are at increased risk for healthcare-associated infections, including infections with multidrug-resistant pathogens. Cefepime is a commonly prescribed antibiotic for empiric therapy in hematopoietic cell transplant patients, but there is minimal data describing cefepime resistance rates, risk factors for resistance, and clinical outcomes associated with cefepime-resistant infections. Methods Adult (≥18 years old) allogeneic hematopoietic cell transplant recipients with a culture positive for a gram-negative rod between January 2010 and January 2016 were spilt into two groups: cefepime susceptible and cefepime nonsusceptible . The primary objective of this study was to identify risk factors for cefepime nonsusceptible through multivariable logistic regression. Results A total of 107 patients were included (27 cefepime nonsusceptible, 80 cefepime-susceptible), yielding a 25.2% nonsusceptibility rate. Multivariable analysis yielded age >60 years old, Klebsiella spp. infection, Acinetobacter spp. infection, healthcare exposures within 90 days, acute gastrointestinal graft-vs-host-disease, and chronic graft-vs-host-disease at multiple locations as significant risk factors for cefepime nonsusceptible. The receiver operating characteristic area under the curve of the model was 0.851. Thirty-day all-cause mortality (29.6% versus 16.3%, p = 0.13) and length of hospitalization (19 versus 12.5 days, p = 0.0650) were numerically higher in the cefepime nonsusceptible group. Conclusions Hematopoietic cell transplant patients with acute gastrointestinal graft versus host disease, extensive chronic graft-vs-host-disease, advanced age, previous healthcare exposures, or infections with Klebsiella and Acinetobacter are at increased risk for cefepime nonsusceptible. Patients infected with cefepime nonsusceptible pathogens may have higher rates of mortality and length of hospitalization.

Asparaginase remains a cornerstone of ALL therapy and is one of the key contributing factors to improved outcomes in adolescent and young adult (AYA) patients treated on pediatric protocols. Asparagine depletion has been associated with improved outcomes in ALL patients; this has led to an increased emphasis on optimizing asparagine depletion in ALL patients of all ages. To ensure adequate asparagine depletion, the use of therapeutic drug monitoring of asparaginase therapy holds much promise, yet remains underutilized in practice. Data regarding asparaginase activity level monitoring and associated outcomes are reviewed, and an evidence-based asparaginase activity level monitoring algorithm is presented. Finally, unique management strategies for key asparaginase toxicities in ALL patients are discussed, as well as a discussion of novel asparaginase formulations on the horizon.

Approximately 1–5% of pediatric intracranial tumors originate in the thalamus. While great strides have been made to identify consistent molecular markers in adult oligodendrogliomas, such as the 1p/19q co-deletion, it is widely recognized that pediatric oligodendrogliomas have a vastly different molecular make-up. While pediatric thalamic or “central oligodendrogliomas” are histologically similar to peripheral pediatric oligodendrogliomas, they are behaviorally distinct and likely represent a cohesive, but entirely different entity. We describe a case of a 10-year-old girl who was diagnosed with an anaplastic glioma with features consistent with the aggressive entity often diagnosed as central or thalamic oligodendroglioma. We performed whole-exome (paired tumor and germline DNA) and transcriptome (tumor RNA) sequencing, which demonstrated an FGFR3-PHGDH fusion. We describe this fusion and our rationale for pursuing personalized, targeted therapy for the patient’s tumor that may potentially play a role in the treatment of similar cases.

Posaconazole is the prophylactic antifungal of choice for patients with haematological malignancies at high risk of invasive fungal infections (IFIs). Studies have demonstrated that subtherapeutic concentrations of posaconazole are associated with breakthrough fungal infections and specific risk factors for subtherapeutic troughs associated with the suspension formulation have been identified. However, these risk factors have not been evaluated in a large patient population with the recently approved tablet formulation.To determine the risk factors for subtherapeutic posaconazole troughs associated with the tablet formulation in patients receiving posaconazole as IFI prophylaxis.From 1 February 2013 to 31 March 2015 all posaconazole serum trough concentrations were evaluated. A total of 157 patients receiving posaconazole tablet for prophylaxis during induction therapy for haematological malignancies and allogeneic stem cell transplant recipients with graft-versus-host disease were included for analysis.Overall, 28 patients (18%) had subtherapeutic troughs (700 ng/mL). Patients were more likely to have subtherapeutic troughs if they had diarrhoea (n = 24; 83%) (P 0.001), were receiving a proton pump inhibitor (n = 27; 93%) (P = 0.016) and weighed90 kg (n = 14; 48%) (P = 0.047).While the posaconazole tablet has provided more consistent therapeutic concentrations when compared with the suspension there may still be a role for therapeutic drug monitoring (TDM). These results may guide us to a specific population in which TDM is necessary to identify subtherapeutic troughs.

Asparaginase is commonly de-emphasized/omitted in adult acute lymphoblastic leukemia regimens due to poor tolerability, including hepatotoxicity (HTX). Adult patients (n = 100) given induction therapy containing pegylated asparaginase (PEG) from January 2008 to February 2016 were evaluated for HTX. Sixteen patients met criteria for HTX (direct bilirubin >3 g/dL). A multivariable model identified body surface area >2m2 (OR 7.40; 95% CI: 1.73–31.61, p = .007), albumin

Objectives The incidence of Clostridium difficile infection (CDI) in adults with malignancy is 7%-14% compared with 1%-2% in the general hospitalized population. Despite the increased incidence of CDI in this population, a major concern is the propensity of CDI to recur, leading to delays in therapy impacting outcomes. We conducted a retrospective case-control study to identify risk factors for recurrent CDI (rCDI) and to determine the impact of rCDI on adult patients with a haematological malignancy. Methods Adult haematology patients with CDI from June 2010 to December 2014 were divided into two groups: rCDI and non-rCDI. Multivariable models using logistic regression were constructed to identify risk factors for rCDI. Results A total of 100 patients in our study yielded a 41% recurrence rate. CDI impacted chemotherapy significantly more in the rCDI group (53.7% versus 11.9%, P