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•Heptad TF occupancy is highly dynamic across HSPC subsets and associated with cell-type–specific gene expression.•Enhancers with cell-type–specific heptad occupancy share a common grammar with respect to TF binding motifs.

•Acalabrutinib has a favorable benefit-risk profile, including lower incidence of cardiovascular-related toxicities, vs ibrutinib.•AE burden score allowed further comparison of the safety of acalabrutinib vs ibrutinib accounting for AE duration, recurrence, and grade.

This review focuses on significant advances in the field of pediatric hemostasis and thrombosis, with a focus on published studies within the past decade. The evaluation and management of patients with excessive bleeding remain cornerstones of consultative hematology. We will describe the development of validated bleeding assessment tools relevant to pediatric practice, laboratory advances in the evaluation of von Willebrand disease, and a shift in clinical practice regarding the interpretation of normal coagulation studies in patients with significant bleeding phenotypes. There have also been critical advances in the management of hemostatic disorders. This review highlights new treatment paradigms in hemophilia and the rise of multidisciplinary medical homes for women living with bleeding disorders. Given the continued increase in the incidence of thrombosis, particularly in the hospital setting, a full call to arms against pediatric venous thromboembolism is now essential. We will describe recently completed clinical trials of direct oral anticoagulants in children and adolescents and ongoing work to elucidate the appropriate duration of therapy for children with provoked thrombosis. Recent work regarding the prevention of pediatric venous thromboembolism is highlighted, including studies of thromboprophylaxis and the development of risk prediction models for hospital-acquired thrombosis. Finally, we review advances in our understanding of thrombotic sequelae and the need for continued refinement of our evaluation tools. Despite the significant advances in pediatric hemostasis and thrombosis over the past decade, many unanswered questions remain for the next generation of investigators.

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib–rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (<1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4%, and 8.6% at 3, 12, 24, and 36 months for FCR, and significantly lower at 7.9%, 4.2%, and 3.7% at 12, 24, and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24, and 36 months was associated with longer progression-free survival (PFS) in the FCR arm, with hazard ratios (MRD detectable/MRD undetectable) of 4.29 (95% confidence interval [CI], 1.89-9.71), 3.91 (95% CI, 1.39-11.03), 14.12 (95% CI, 1.78-111.73), and not estimable (no events among those with undetectable MRD), respectively. In the IR arm, patients with detectable MRD did not have significantly worse PFS compared with those in whom MRD was undetectable; however, PFS was longer in those with MRD levels <10−1 than in those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate end point for PFS in patients receiving FCR. In patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, whereas those with MRD <10−1 tended to have longer PFS, although continuation of ibrutinib would very likely be necessary to maintain treatment efficacy.

Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children's Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (<0.05%) and did not receive the historically administered HD-AraC course. Interim analysis of 114 SR patients revealed a 2-year EFS of 85.6% (95% confidence interval [CI], 75.7-95.5), which was significantly lower than for MRD−patients treated with HD-AraC on AAML0431 (P= .0002). Overall survival at 2 years was 91.0% (95% CI, 83.8-95.0). Twelve SR patients relapsed, mostly within 1 year from study entry and had a 1-year OS of 16.7% (95% CI, 2.7-41.3). Complex karyotypes were more frequent in SR patients who relapsed compared with those who did not (36% vs 9%; P= .0248). MRD by error-corrected sequencing of GATA1mutations was piloted in 18 SR patients and detectable in 60% who relapsed vs 23% who did not (P= .2682). Patients with SR ML-DS had worse outcomes without HD-AraC after risk classification based on flow cytometric MRD.

Acalabrutinib has demonstrated significant efficacy and safety in relapsed chronic lymphocytic leukemia (CLL). Efficacy and safety of acalabrutinib monotherapy were evaluated in a treatment-naive CLL cohort of a single-arm phase 1/2 trial (ACE-CL-001). Adults were eligible for enrollment if chemotherapy was declined or deemed inappropriate due to comorbidities (N = 99). Patients had a median age of 64 years and 47% had Rai stage III/IV disease. Acalabrutinib was administered orally 200 mg once daily, or 100 mg twice daily until progression or intolerance. A total of 99 patients were treated; 57 (62%) had unmutated immunoglobulin heavy-chain variable gene, and 12 (18%) had TP53 aberrations. After median follow-up of 53 months, 85 patients remain on treatment; 14 discontinued treatment, mostly because of adverse events (AEs) (n = 6) or disease progression (n = 3). Overall response rate was 97% (90% partial response; 7% complete response), with similar outcomes among all prognostic subgroups. Because of improved trough BTK occupancy with twice-daily dosing, all patients were transitioned to 100 mg twice daily. Median duration of response (DOR) was not reached; 48-month DOR rate was 97% (95% confidence interval, 90-99). Serious AEs were reported in 38 patients (38%). AEs required discontinuation in 6 patients (6%) because of second primary cancers (n = 4) and infection (n = 2). Grade ≥3 events of special interest included infection (15%), hypertension (11%), bleeding events (3%), and atrial fibrillation (2%). Durable efficacy and long-term safety of acalabrutinib in this trial support its use in clinical management of symptomatic, untreated patients with CLL.

Pregnancy and postpartum are high-risk periods for different forms of thrombotic microangiopathy (TMA). However, the management of pregnancy-associated TMA remains ill defined. This report, by an international multidisciplinary working group of obstetricians, nephrologists, hematologists, intensivists, neonatologists, and complement biologists, summarizes the current knowledge of these potentially severe disorders and proposes a practical clinical approach to diagnose and manage an episode of pregnancy-associated TMA. This approach takes into account the timing of TMA in pregnancy or postpartum, coexisting symptoms, first-line laboratory workup, and probability-based assessment of possible causes of pregnancy-associated TMA. Its aims are: to rule thrombotic thrombocytopenic purpura (TTP) in or out, with urgency, using ADAMTS13 activity testing; to consider alternative disorders with features of TMA (preeclampsia/eclampsia; hemolysis elevated liver enzymes low platelets syndrome; antiphospholipid syndrome); or, ultimately, to diagnose complement-mediated atypical hemolytic uremic syndrome (aHUS; a diagnosis of exclusion). Although they are rare, diagnosing TTP and aHUS associated with pregnancy, and postpartum, is paramount as both require urgent specific treatment.

Background:Intensive chemotherapy has improved complete remission (CR) rates in T-ALL/LBL. However, long-term overall survival (OS) continues to be suboptimal at about 50%. Nelarabine (NEL) is active in relapsed/refractory T-ALL. PEG-asparaginase (PEG) containing regimens have demonstrated significant activity in the pediatric population (Dunsmore et al. COG AALL0434. J Clin Oncol. 2018 Abstr #10500). We hypothesized that incorporating NEL and PEG in the frontline setting may further improve outcomes in adult T-ALL/LBL (NCT00501826). We had previously reported on the addition of nelarabine to the hyper-CVAD regimen (Abaza Y, Am J Hematol. 2018). Here, we report outcomes with the addition of PEG and longer follow-up.

Therapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13]) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade =3 AEs (occurring in =5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Venous thromboembolism (VTE) incidence in children has sharply increased with the majority of cases secondary to central venous catheters (CVCs). Among CVCs, the number of peripherally inserted central catheters (PICCs) placed has risen significantly. In this multicenter, prospective, observational cohort study, we enrolled patients aged 6 months to 18 years with newly placed PICCs or tunneled lines (TLs). We evaluated the incidence of VTE, central line–associated bloodstream infections (CLABSIs), and catheter malfunctions in PICCs and TLs, and risk factors of CVC-related VTE. A total of 1967 CVCs were included in the analysis. The incidence of CVC-related VTE was 5.9% ± 0.63%. The majority of the cases, 80%, were in subjects with PICCs, which had a significantly higher risk of catheter-related VTE than subjects with TLs (hazard ratio [HR] = 8.5; 95% confidence interval [CI], 3.1-23; P < .001). PICCs were significantly more likely to have a CLABSI (HR = 1.6; 95% CI, 1.2-2.2; P = .002) and CVC malfunction (HR = 2.0; 95% CI, 1.6-2.4; P < .001). Increased risk of CVC-related VTE was found in patients with a prior history of VTE (HR = 23; 95% CI, 4-127; P < .001), multilumen CVC (HR = 3.9; 95% CI, 1.8-8.9; P = .003), and leukemia (HR = 3.5; 95% CI, 1.3-9.0; P = .031). Children with PICCs had a significantly higher incidence of catheter-related VTE, CLABSI, and CVC malfunction over TLs. The results suggest that pause be taken prior to placing CVCs, especially PICCs, due to the serious complications they have been shown to cause.

•Zanubrutinib sustained PFS benefit over ibrutinib; sensitivity analyses suggest this was driven by both antileukemic effect and tolerability.•Zanubrutinib maintained a favorable safety/tolerability profile with prevalence of most adverse events remaining stable or decreasing year-over-year.

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients with CLL age ≤70 years. Patients were randomly assigned (2:1 ratio) to receive ibrutinib and rituximab (IR) or six cycles of FCR. With a median follow-up of 5.8 years, median PFS is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in both IGHV mutated (HR: 0.27; P < 0.001) and IGHV unmutated patients (HR: 0.27; P < 0.001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events/complication, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. Median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in OS was observed for patients on the IR arm (HR=0.47; p=0.018). In conclusion, Ibrutinib-rituximab therapy offers superior PFS relative to FCR in both IGHV mutated and unmutated CLL patients as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. Clinical trial at NCT02048813

Patients with chronic lymphocytic leukemia (CLL) who achieve blood or bone marrow (BM) undetectable minimal residual disease (U-MRD) status after first-line fludarabine, cyclophosphamide, and rituximab (FCR) have prolonged progression-free survival (PFS), when assessed by an assay with sensitivity 10-4 (MRD4). Despite reaching U-MRD4, many patients, especially those with unmutated IGHV, subsequently relapse, suggesting residual disease <10-4 threshold and the need for more sensitive MRD evaluation. MRD evaluation by next-generation sequencing (NGS) has a sensitivity of 10-6 (MRD6). To better assess the depth of remission following first-line FCR treatment, we used NGS (Adaptive Biotechnologies Corporation) to assess MRD in 62 patients, all of whom had BM U-MRD by multicolor flow cytometry (sensitivity 10-4) at end-of-FCR treatment. Samples from these patients included 57 BM samples, 29 peripheral blood mononuclear cell (PBMC) samples, and 32 plasma samples. Only 27.4% of the 62 patients had U-MRD by NGS. Rate of U-MRD by NGS was lowest in BM (25%), compared with PBMC (55%) or plasma (75%). No patient with U-MRD by NGS in BM or PBMC was MRD+ in plasma. Patients with mutated IGHV were more likely to have U-MRD by NGS at the end of treatment (EOT; 41% vs 13%, P = .02) than those with unmutated IGHV. Median follow-up was 81.6 months. Patients with U-MRD at EOT had superior PFS vs MRD+ patients, regardless of sample type assessed (BM, P = .02, median not reached [NR] vs 67 months; PBMC, P = .02, median NR vs 74 months). More sensitive MRD6 testing increases prognostic discrimination over MRD4 testing.

Targeting both CD20 and phosphatidylinositol 3-kinase (PI3K), a protein that is critically involved in B-cell maturation, could be an efficacious strategy for treating B-cell malignancies. The safety of the next-generation compounds umbralisib, a PI3K-d inhibitor, plus ublituximab, an anti-CD20 monoclonal antibody (combination referred to as U2), was evaluated in patients with chronic lymphocytic lymphoma (CLL) or non-Hodgkin lymphoma (NHL) in this phase 1/1b study. Phase 1 dose escalation was performed with a 3 + 3 design to establish the maximum tolerated dose. In this portion, ublituximab was given intravenously (NHL, 900 mg; CLL, 600 or 900 mg) for 12 cycles. Umbralisib was given orally once daily at 800 or 1200 mg (initial formulation) or 400 to 1200 mg (micronized formulation) in the phase 1 dose escalation portion, and at 800 to 1200 mg in the phase 1b portion until progression, toxicity, or study removal. The maximum tolerated dose was not reached in either the CLL or NHL cohort, and only 1 dose-limiting toxicity was observed. U2 had low instances of grade 3 or higher diarrhea (8%), pneumonia (8%), or hepatic toxicity (4%). Treatment discontinuation due to adverse events occurred in 13% of patients, and umbralisib dose reductions occurred in 15% of patients. The overall response rate for all patients was 46% with 17% complete responses. The median duration of response was 20 months (95% confidence interval, 11.3-not reached). U2 was well tolerated, and no new safety signals were observed over single-agent umbralisib. Preliminary efficacy with this combination is promising and warrants further investigation. This study was registered at www.clinicaltrials.gov as #NCT02006485.

Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with <2 prior therapies, and the presence of TP53or SF3B1mutations showed a trend toward shorter PFS vs without these factors. Median duration of ibrutinib was 41 months, with 46% remaining on treatment at a median follow-up of 44 months. Grade ≥3 adverse events generally decreased over time, causing only a small proportion of patients to cease therapy. Ibrutinib was discontinued due to progressive disease in 27% of patients. This long-term study provides support for sustained efficacy and safety of ibrutinib in relapsed/refractory CLL and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated. This trial was registered at www.clinicaltrials.govas #NCT01578707.

Ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, is an effective therapy for patients with chronic lymphocytic leukemia (CLL). To determine whether rituximab provides added benefit to ibrutinib, we conducted a randomized single-center trial of ibrutinib vs ibrutinib plus rituximab. Patients with CLL requiring therapy were randomized to receive 28-day cycles of once-daily ibrutinib 420 mg, either as a single agent (n = 104), or together with rituximab (375 mg/m2; n = 104), given weekly during cycle 1, then once per cycle until cycle 6. The primary end point was progression-free survival (PFS) in the intention-to-treat population. We enrolled 208 patients with CLL, 181 with relapsed CLL and 27 treatment-naive patients with high-risk disease (17p deletion or TP53mutation). After a median follow-up of 36 months, the Kaplan-Meier estimates of PFS were 86% (95% confidence interval [CI], 76.6-91.9) for patients receiving ibrutinib, and 86.9% (95% CI, 77.3-92.6) for patients receiving ibrutinib plus rituximab. Similarly, response rates were the same in both arms (overall response rate, 92%). However, time to normalization of peripheral blood lymphocyte counts and time to complete remission were shorter, and residual disease levels in the bone marrow were lower, in patients receiving ibrutinib plus rituximab. We conclude that the addition of rituximab to ibrutinib in relapsed and treatment-naive high-risk patients with CLL failed to show improvement in PFS. However, patients treated with ibrutinib plus rituximab reached their remissions faster and achieved significantly lower residual disease levels. Given these results, ibrutinib as single-agent therapy remains current standard-of-care treatment in CLL. This trial was registered at www.clinicaltrials.govas #NCT02007044.

Emerging evidence indicates that cancer persister cells, including AML, stochastically and transiently upregulate stress pathways to survive acute exposure to chemotherapy. Here, we explore the biology of these persister cells and identify a T cell-based immunotherapy that targets this surviving fraction.

Background:Indolent B-cell non-Hodgkin lymphomas (NHL) remain incurable despite multiple therapeutic options, including chemoimmunotherapy, targeted therapies, bispecific antibodies, and CD19-targeted chimeric antigen receptor T (CAR-T) cells. MB-106, a fully human 3 rd-generation CD20-targeted CAR-T product with both 4-1BB and CD28 costimulatory domains, had high overall response rate (100%) and complete response (CR) rate (91%) in follicular lymphoma (FL) patients at doses ≥ 3.3×10 6cells/kg in a single institution trial (Shadman et al., 17-ICML, 2023). We seek to replicate the favorable efficacy and safety profile of MB-106 in a multicenter trial with centralized manufacturing.

Introduction:Pts who receive covalent Bruton tyrosine kinase inhibitors (cBTKis) for CLL can develop drug resistance, leading to disease progression. Often, cBTKi resistance results from the emergence of subclones with mutations at the cBTKi binding site (C481). Less frequent, non-C481 mutations, including gatekeeper residue T474 and kinase-impaired L528 mutations, have been reported in pts with progression on cBTKis. Most characterizations of cBTKi resistance mutations are derived from small or retrospective pt populations. To gain further insight into the genetic mechanisms of cBTKi resistance in a randomized population of pts with CLL, we performed next-generation sequencing (NGS) on samples from pts who had progression on zanubrutinib (zanu) or ibrutinib (ibr) in the phase 3 ALPINE study (NCT03734016; Brown et al. NEJM. 2023).

Statins (HMG-CoA-reductase inhibitors) are drugs used widely for the treatment of high cholesterol and are generally well-tolerated. There has been increasing interest in repurposing statins for oncology based on the recognition that many cancer cells are “addicted” to the mevalonate biosynthetic pathway (Iannelli et al, 2017; Juarez and Fruman 2021). We have shown that statins increase expression of the pro-apoptotic BCL2 family member PUMA (Lee at al, 2018). We have strong pre-clinical evidence that statins improve responses to the BCL2 inhibitor venetoclax (VEN) in cell line models and ex vivoprimary patient specimens from patients with both chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) (Lee et al, 2018). Additionally, retrospective review of patients enrolled into the early clinical trials of VEN in CLL revealed improved responses to VEN (complete remission [CR] and progression-free survival) in the patients who were concurrently on a statin medication (Lee et al, 2018). These retrospective analyses may underestimate the potential of statins for leukemia therapy, as the statin drugs most commonly prescribed for hypercholesterolemia are not pharmacologically optimized for oncology (Abdullah et al., 2018).

Background:Pediatric patients with ALL/LL are at increased risk for VTE and obesity further increases VTE risk. Pediatric ALL/LL patients experiencing VTE have increased risk for mortality as compared to ALL/LL patients without VTE. Therefore, effective and safe pharmacologic VTE prevention options are urgently needed. The PREVAPIX-ALL trial was a multi-center, multinational, randomized, open-label, controlled trial assessing the safety and efficacy of primary prophylaxis using apixaban for the prevention of VTE in pediatric patients with ALL/LL. PREVAPIX-ALL was a collaboration between the Bristol Myers Squibb/Pfizer Alliance and the Children's Oncology Group. Patients with ALL/LL undergoing induction chemotherapy containing asparaginase therapy were randomized to either apixaban or standard of care (SOC - no anticoagulation). The objective of the current study was to separately analyze obese patients as a subgroup of the PREVAPIX-ALL trial.

Background: Patients with sickle cell disease (SCD) suffer a significant disease burden that affects their psychosocial well-being. Digital cognitive-behavioral therapy (CBT) has been utilized in other patient populations and shown to have clinical benefits. Although evidence-based, non-pharmacological interventions for pain management are widely used in other populations, this is not well studied in SCD. There are currently no large-scale, adequately powered clinical trials that evaluate the effectiveness and dissemination potential of digital behavioral pain management interventions for adults with SCD.

Outcomes for patients with acute myeloid leukemia (AML) remain poor due to the inability of current therapies to fully eradicate disease initiating leukemia stem cells (LSCs) (Shlush et al., 2017). Many studies have demonstrated that LSCs have unique metabolic properties compared to AML blasts and normal hematopoietic stem and progenitor cells (HSPCs) (Jones et al., 2021). In this study we sought to quantify metabolite levels in LSCs compared to HSPCs using an unbiased metabolites screen. To examine metabolite levels in enriched LSCs and HSPCs we used mass spectrometry-based metabolomics analysis on enriched LSCs from 18 AML patients and HSPCs from 5 normal bone marrow (BM) specimens. Pathway analysis showed that arginine metabolism and biosynthesis were the most significantly enriched pathways in LSCs compared to HSPCs.

Background:Inotuzumab (InO), a monoclonal antibody targeting CD22 conjugated to calicheamicin, is widely used for relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) with good salvage rates (O'Brien, JCO 2022, Bhojwani, Leukemia 2019). Feasibility data on its use as a bridge to Chimeric Antigen Receptor T-cell therapy (CART) or as salvage therapy post CART is limited. Concern has been raised that InO given prior to leukapheresis might impact the quality of T-cell collection and, when used for bridging therapy prior to CART, could result in insufficient B-cell antigen load at the time of CART infusion, therefore reducing efficacy.

Introduction:The burden of the management and clinical sequelae of hemophilia B (HB) negatively impacts health-related quality of life (HRQoL), including chronic pain and mental health. Fidanacogene elaparvovec (PF-06838435, formerly SPK-9001) is an adeno-associated virus-based gene therapy vector transferring the high activity variant of human factor IX (FIX), FIX-R338L, aimed at enabling endogenous FIX expression in individuals with hemophilia B. We present descriptive data on the impact on HRQoL for participants in the fidanacogene elaparvovec phase 1/2a study.

Introduction:Patients with sickle cell disease (SCD) are highly vulnerable to pain and depression compared to their healthy peers. They also are at high risk of experiencing discrimination due to a combination of racial biases and stigma associated with SCD. Discrimination can have negative psychological effects and lead to poor health outcomes including increased pain. However, there is limited research in SCD examining the link between racial discrimination and pain, and how depression may mediate this association. A recent study found that depression significantly mediated the association between racial discrimination in the healthcare setting and pain severity and interference in adults with SCD. This study lacked a comparison group of non-SCD racial minorities to determine to what extent the link between discrimination and pain was specific to SCD. Thus, in the current study we sought to extend prior findings by comparing depression, pain, and racial discrimination between a group of adults with SCD and a demographically matched control group. We then examined whether depression in adults with SCD mediated the racial discrimination - pain association.

Background: Bruton tyrosine kinase inhibitors (BTKi) are currently widely used for the treatment of patients with chronic lymphocytic leukemia (CLL). Ibrutinib, the first BTKi approved for the treatment of CLL, was followed by the second-generation BTKi, acalabrutinib, and recently the next-generation BTKi, zanubrutinib. Both zanubrutinib and acalabrutinib were compared to ibrutinib in phase 3 randomized controlled trials in relapsed/refractory (R/R) CLL. In the ALPINE trial (NCT03734016), zanubrutinib demonstrated a superior progression-free survival (PFS) when compared with ibrutinib in the all-comer R/R CLL population with hazard ratio (HR)=0.65, whereas the ELEVATE-RR trial (NCT02477696) showed noninferior PFS of acalabrutinib vs ibrutinib in R/R CLL patients with the presence of del(17p) or del(11q) with HR=1. Recent attempts to compare the efficacy results of the ibrutinib arm across trials omitted some patient characteristics that are critical for appropriate cross-trial comparisons. This study aimed to compare the efficacy of the ibrutinib control arm across ALPINE and ELEVATE-RR trials using a comprehensive matching-adjusted indirect comparison (MAIC).

Introduction:Sickle Cell Disease (SCD) is an inherited blood disorder with profound implications on a wide variety of tissue types (Kavanagh et al., 2022). As many as 37% of patients with SCD experience silent cerebral infarction by age 14 (DeBaun et al., 2012). Neurological insults can increase risk for voice and swallow disorders which compromise physical health and diminish quality of life for many individuals (Aronson & Bless, 2009). In fact, voice disorders (dysphonia) affect 6% of adults (Roy et al., 2005), and swallowing difficulties (dysphagia) impact as many as 16% (Adkins et al., 2020). Since both phonation and deglutition require the coordination of multiple muscles and nerves (Kendall, 2008), diseases such as SCD may be associated with elevated risk for dysphonia and dysphagia. Unfortunately, the frequency of these symptoms in individuals with SCD has rarely been considered. This study examined the prevalence and nature of dysphonia and dysphagia in individuals with SCD.

INTRODUCTION

Background:

Introduction:An urgent need exists for a noninvasive telemedicine approach to alleviate the burdensome reliance on frequent invasive blood draws for monitoring blood hemoglobin (Hgb) levels in sickle cell disease (SCD) patients. SCD is the most common genetic blood disorder, impacting over 20 million people worldwide, resulting in frequent emergency healthcare use. A blood Hgb level is pivotal in managing SCD and understanding the pathophysiology of SCD including anemia. Even low blood Hgb levels may indicate painful vaso-occlusion crises (Blood 2021;137:2010). Thus, a remote noninvasive monitoring ability of blood Hgb in at-home settings can potentially enhance SCD management without iatrogenic blood loss. Advanced machine learning and spectroscopic analyses can enable digital colorimetric diagnostics for noninvasive blood Hgb quantification with high fidelity, empowering SCD patients. However, one of the key challenges in diagnostic photography is that clinical photos exhibit significant variations in colors, depending on devices, light conditions, and image file formats, hampering reliable colorimetric diagnostics.

Background

Introduction

Introduction: Adults living with sickle cell disease (SCD) most frequently seek medical care due to pain. To determine the most efficacious treatment plan for patients presenting with pain, providers must first accurately assess and diagnose the pain. Unfortunately, the current approaches for assessing pain are inadequate. Combined with medical provider biases, patients can often have their pain symptoms misinterpreted, ignored, or blatantly dismissed. To address this issue, we partnered with stakeholders, human-centered designers, and software engineers to design a novel pain assessment tool, called Painimation. Painimation allows patients to communicate their pain quality, intensity, and location using abstract animations and a paintable body image. Painimation has been validated in a general population with chronic pain, but there is limited data validating this approach in SCD. Preliminary data on the use of Painimation by adults with SCD (N = 67) found that those who described their pain using the “throbbing” animation had less severe pain symptoms than those endorsing the “shooting” animation.

Introduction:ALPINE, a randomized, multinational phase 3 study (NCT03734016) in patients with R/R CLL/SLL, established the statistical and clinically meaningful superiority of zanubrutinib over ibrutinib on progression-free survival (PFS) and overall response rate (ORR) and confirmed the favorable safety/tolerability profile of zanubrutinib (Brown et al. NEJM; 2022). Now, with 3 years of overall study follow-up, we report the results of an extended follow-up analysis.

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Background:GLUT4 inhibition via the use of a protease inhibitor, such as nelfinavir (NEL), is an attractive therapeutic option in multiple myeloma (MM), given the dependence of MM cells on glucose. Furthermore, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor, such as metformin (MET), may counter the possibility of therapeutic resistance to GLUT4 inhibition in MM cells, showing synergistic promise (Dalva-Aydemir et al., Clin Can Res 2015). In addition to GLUT4 inhibition, NEL also lowers the cytotoxicity resistance of MM cells against proteasome inhibitors such as bortezomib (BOR) (Driessen et al., Blood 2018). Thus, this study evaluated the safety and tolerability of repurposing MET and NEL, in combination with BOR for the treatment of relapsed/refractory MM (RRMM) that had progressed on all standard of care (SOC) therapies.

Tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Many older patients (pts) are not good candidates for intensive chemotherapy and are treated with TKIs plus corticosteroids or low-intensity chemotherapy. Although the remission rates with this approach have been high, the median disease-free survival (DFS) has been short. Therefore, novel treatment strategies are needed. This trial evaluated the feasibility of combining the TKI dasatinib with prednisone and blinatumomab in older pts with Ph+ ALL. Here we present updated results (median follow-up, 4.3 years).

Background: Outcomes for children with relapsed acute myeloid leukemia (AML) and subgroups with relapsed acute lymphoblastic leukemia (ALL) remain poor, and therapeutic options are limited. There is no standard of care for relapsed disease, and data collection after relapse is lacking. In recent years, extensive molecular studies of pediatric leukemias have advanced target identification and clinical trial development. Such studies have shown that pediatric leukemias are biologically distinct from adult leukemias. The current paradigm of requiring new agent studies in adults prior to conducting pediatric trials is thus not appropriate. However, the rarity of relapsed leukemia in children makes the conduct of randomized registration trials for new agents infeasible. Recognizing that impactful progress requires international collaboration, the Leukemia & Lymphoma Society is sponsoring the Pediatric Acute Leukemia (PedAL) Initiative in North America, Australia and New Zealand. In parallel, the European Pediatric Acute Leukemia (EuPAL) Foundation has established a registry for pediatric relapsed leukemia. The principal goal of this international PedAL/EuPAL collaboration is to establish a data-driven developmental therapeutics program for children with relapsed/refractory leukemias.

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