Pediatric-inspired Regimens Research Articles

ALL-237 Bortezomib and Rituximab in De Novo Adolescent/Adult CD20-Positive, Ph-Negative Pre-B-Cell Acute Lymphoblastic Leukaemia: Updated 3-Year Results

CD20 expression in B-cell precursor acute lymphoblastic leukemia (B-ALL) is associated with inferior outcomes. Treatment approaches involve the incorporation of rituximab (variable doses and scheduling between trials), intensification of chemotherapy, and allogeneic stem cell transplant in patients who continue to remain MRD- positive post-induction. Treatment intensification with chemotherapy or allogeneic stem cell transplantation for EOI MRD-positive patients is limited in resource constraint areas due to cost and infection-related morbidity and mortality. Hence, there is an unmet need to identify active and safe drugs to improve EOI MRD negative rates which can reduce the need for transplant and chemotherapy intensification. To test the activity of bortezomib and rituximab in combination with a pediatric-inspired regimen during induction therapy in newly diagnosed adolescents and adults (aged >14 years) with CD20 positive, Philadelphia-negative precursor B-ALL. Here we present updated results with longer follow up. Single-center, phase 2, nonrandomized open-label trial (Simon's two-stage design) conducted between December 2017 and August 2019. The primary endpoint of the study was the rate of (end of induction) EOI BM-MRD negativity. Secondary endpoints were EFS and OS. A total of 35 patients were enrolled between December 2017 and August 2019. EOI MRD negative rates were 70.1% compared with 51.7% in a historical cohort treated with chemotherapy. On longer follow up (median follow up 38months), 3-year EFS and OS rates were 75.6% (95% CI 62.3-91.9%), and 75.6% (95% CI 62.3-91.9%) respectively. 3-year rates of EFS based on post-induction (week 4) MRD status was 55.6% (31-99.7%) in MRD positive group compared with 86.1% (72.7-100%) in MRD negative group. 3-year rates of OS based on EOI MRD status was 55.6% (31-99.7%) in MRD positive group compared with 86.1% (72.7-100%) in MRD negative group. The median OS for patients who attained CR was not reached versus 8 months in patients who fail to achieve CR. On longer follow-up, the activity of the combination of bortezomib and rituximab is maintained without any new safety concerns. EOI MRD positivity and lack of complete remission post-induction are strong predictors of poor outcomes.

ALL-471 Long-Term Results of the Treatment of Adolescents and Adults With Acute Lymphoblastic Leukemia With a Pediatric-Inspired Regimen Delivered on an Outpatient Basis: A Single Institution Experience

The results of treatment of adolescents and adults with acute lymphoblastic leukemia (ALL) remain unsatisfactory. Pediatric-inspired treatments seem produce better outcomes. 126 adolescent and adult patients with ALL were treated in a 37-year period with a pediatric inspired combined chemotherapy (PICC) schedule, delivered on an outpatient basis and based on the St. Jude's TOTAL XI pediatric protocol employing vincristine, prednisone, asparaginase, daunorubicin, etoposide, cytarabine, methotrexate, mercaptopurine and triple intrathecal therapy. 80% of patients were able to receive the initial seven-week period of induction/consolidation fully as outpatients and 77% achieved a complete remission. In adolescents and young adults (AYAs) the median probability of overall survival (OS) was 44 months, whereas the 5-year OS was 48%. In adults, the median probability of OS was 24 months, and the 5-year OS was 32%. Patients with T-cell ALL did significantly worse than those with a B-cell phenotype (OS at 5 years 17 versus 40%, respectively). These figures are better than those informed in our country employing more aggressive, in-hospital schedules such as the hyper-CVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone). We found that, in AYAs and adult patients with ALL, the use of an asparaginase-containing PICC delivered on an outpatient basis renders acceptable results, better than those obtained in similar socioeconomic circumstances employing adult-oriented schedules. Additional studies are needed to assess the usefulness of these PICC treatments in adult individuals with ALL treated in underprivileged circumstances, such as those prevailing in LMIC.

Long-term results of the treatment of adolescents and adults with acute lymphoblastic leukemia with a pediatric-inspired regimen delivered on an outpatient basis: A single institution experience

The results of treatment of adolescents and adults with acute lymphoblastic leukemia (ALL) remain unsatisfactory. Pediatric-inspired treatments seem to be related with better outcomes. 126 adolescent and adult patients with ALL were treated in a 37-year period with a pediatric inspired combined chemotherapy (PICC) schedule, delivered on an outpatient basis and based on the St. Jude´s TOTAL XI pediatric protocol employing vincristine, prednisone, asparaginase, daunorubicin, etoposide, cytarabine, methotrexate, mercaptopurine and triple intrathecal therapy. 80 % of patients were able to receive the initial seven-week period of induction / consolidation fully as outpatients and 77 % achieved a complete remission. In adolescents and young adults (AYAs) the median probability of overall survival (OS) was 44 months, whereas the 5-year OS was 48 %. In adults, the median probability of OS was 24 months, and the 5-year OS was 32 %. Patients with T-cell ALL did significantly worse than those with a B cell phenotype (OS at 5 years 17 versus 40 %, respectively). These figures are better than those informed in our country employing more aggressive, in-hospital schedules such as the hyper-CVAD. We found that, in AYAs and adult patients with ALL, the use of an asparaginase-containing PICC delivered on an outpatient basis renders acceptable results, better than those obtained in similar socioeconomic circumstances employing adult-oriented schedules. Additional studies are needed to assess the usefulness of these PICC treatments in adult individuals with ALL treated in underprivileged circumstances, such as those prevailing in LMIC.

Monoclonal antibodies for the treatment of acute lymphocytic leukemia: A literature review.

Acute lymphocytic leukemia (ALL) is a type of blood cancer that is more prevalent in children. Several treatment methods are available for ALL, including chemotherapy, upfront treatment regimens, and pediatric-inspired regimens for adults. Monoclonal antibodies (Mabs) are the novel Food and Drug Administration (FDA) approved remedies for the relapsed/refractory (R/R) adult ALL. In this article, we aimed to review studies that investigated the efficacy and safety of Mabs on ALL. We gathered studies through a complete search with all proper related keywords in ISI Web of Science, SID, Scopus, Google Scholar, Science Direct, and PubMed for English language publications up to 2020. The most commonly studied Mabs for ALL therapies are CD-19, CD-20, CD-22, and CD-52. The best results have been reported in the administration of blinatumomab, rituximab, ofatumumab, and inotuzumab with acceptable low side effects. Appling personalized approach for achieving higher efficacy is one of the most important aspects of treatment. Moreover, we recommend that the wide use of these Mabs depends on designing further cost-effectiveness trials in this field.

Efficacy and safety of asparagine-depleting regimens versus HyperCVAD in adults with Philadelphia chromosome-positive B-ALL: A retrospective analysis.

e19040 Background: The optimal treatment of adults with Philadelphia chromosome-positive (Ph+) B-ALL remains unclear. Use of pediatric-inspired regimens (PIRs) featuring asparagine depletion is associated with high responses, although at the expense of increased toxicity. Moreover, PIRs have not directly been compared with regimens that do not contain asparagine depletion (e.g., hyperCVAD). Thus, the aim of this study was to compare toxicity and efficacy of asparagine-depleting PIRs versus hyperCVAD in a matched retrospective population of adults with Ph+ B-ALL. Methods: We identified 30 patients ≥21 years with Ph+ B-ALL treated at our institution during January 2015 to January 2021. In the upfront setting, 9 were treated with PIRs. A comorbidity-matched cohort of 21 patients ≤60 years treated with hyperCVAD was selected as a comparison. Baseline patient demographics were obtained, including age, ECOG score, and comorbidities at diagnosis, cytogenetic and molecular profiling, toxicity, response, MRD analysis, survival, and receipt of hematopoietic stem cell transplant (HSCT). Results: In the PIR cohort, the median age was 37, 55.6% were male, median ECOG score was 1, and median Charlson Comorbidity Index (CCI) score was 2. CALGB 10403 was used in 88.9% of patients and 11.1% received ECOG 1910; all patients received a TKI. All patients experienced at least one grade ≥3 toxicity, and there was a total of 31 unique grade ≥3 toxicities and no deaths during induction. The composite response rate (CRR) was 77.8% and 50.0% of responders were MRD-negative. In the cohort treated with hyperCVAD and TKIs, there was no difference in age (p = .125), sex (p = .694), ECOG (p = .538), or CCI score (p = .851). There were 18 unique grade ≥3 or higher toxicities, which was significantly fewer than the PIR cohort (p = .021), though the rate of neutropenic fever was higher in hyperCVAD (p = 0.016). There were no deaths during induction and the CRR was 94.4% – not significantly different from the PIR cohort (p = .250) with 60.0% MRD-negative. HSCT was performed for 61.9% of patients in the hyperCVAD group versus 44.4% in the PIR cohort (p = .443). Despite this, the median survival was not reached in either cohort after a median follow-up time of 3.3 years. The cumulative probability of survival at 5.4 years was 100% in the PIR cohort and 76.9% in the hyperCVAD cohort. Conclusions: Our findings suggest that PIRs feature significantly increased grade ≥3 toxicity with evidence of a higher probability of survival at 5.4 years compared to hyperCVAD, although the median survival was not reached and there was no difference between the two arms at the time of follow-up. Patients must be carefully selected for receipt of PIRs given the expected increased burden of toxicity with these regimens. Although long-term survival appears to favor PIRs, larger studies and longer follow-up are needed to confirm these findings.

Effects of age, obesity, and body surface area on asparaginase-associated toxicities during acute lymphoblastic leukemia induction therapy: A report from the Children’s Oncology Group.

7000 Background: Asparaginase is integral to pediatric-inspired regimens (PIR) to treat acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA). However, asparaginase-associated toxicities (AAT) often preclude delivery of planned therapy. Older age, obesity and/or large body surface area (BSA) have been associated with higher risk of AAT in PIR, but data are conflicting, and the impact of dose modification based on these factors is unknown. Methods: We examined induction toxicity data from patients ages 1-30 years enrolled in the frontline Children’s Oncology Group (COG) trials for high-risk B-ALL (AALL0232, 2004-2011) and T-ALL (AALL0434, 2007-2014). During Induction, patients received pegaspargase (2,500 IU/m2 without prescribed dose-capping) plus daunorubicin, vincristine, and prednisone or dexamethasone. AAT were defined as CTCAE v4 hyperbilirubinemia (Grade ≥3), elevated alanine aminotransferase (ALT) (Grade ≥4), thrombosis (any), or pancreatitis (any, included consolidation phase). Obesity was classified using population norms as body mass index (BMI) ≥30 (or ≥95th percentile for age/sex). BSA was analyzed continuously and dichotomized at 1.5 m2 (equivalent to pegaspargase 3,750 IU, the threshold for permissible dose-capping in PIR). The association of AAT with end-Induction minimal residual disease (MRD) ≥0.01% was assessed. Results: Among 4,925 patients, 25% were ≥15 years, 39% had BSA >1.5m2, and 18% had obesity. Multivariable logistic analyses inclusive of BMI and BSA together found increased risk for any AAT in age groups ≥10 years (10-15y, odds ratio (OR) 2.0, 15-20y OR 2.2, ≥21 OR 3.3, p=0.002). Only patients with both obesity and high BSA (>1.5m2) were at additional risk (OR 3.3, p<0.0001). Similarly, risks for hyperbilirubinemia, ALT elevations, and thrombosis were increased in patients with both high BSA and obesity (OR 3.5, 95% confidence interval [CI] 2.2-5.7), OR 3.3, 95%CI 1.7-6.6, and OR 3.1 95%CI 1.5-6.5, respectively), but not in those with high BSA without obesity. The risk of hyperbilirubinemia was greater with increasing obesity (p<0.0001) and was also higher in all age groups ≥10 years (OR 6.3-7.9, p<0.0001). Age was not associated with thrombosis or ALT elevation; risk for pancreatitis was associated with Hispanic ethnicity, but not with age, BMI, or BSA. AAT were not associated with pooled trial MRD ≥0.01%. Conclusions: We report here the largest dataset of AAT in children and AYAs receiving ALL Induction therapy without routinely prescribed dose-capping of pegaspargase. Risk for AAT was increased in patients >10 years and in those with obesity, but not high BSA alone. Dose capping may not be necessary for children and AYAs with high BSA without obesity. Prospective studies of AAT pharmacogenomics and modifiable risk factors will support safer dosing in PIR. Clinical trial information: NCT00075725, NCT00408005.

Clinical Characteristics and Outcomes of Acute Lymphoblastic Leukemia in Adolescents and Young Adults in Malawi.

PURPOSEThere are limited data on treatment and outcomes for acute lymphoblastic leukemia (ALL) among adolescents and young adults in sub-Saharan Africa. We describe a prospective observational cohort in Malawi.METHODSPatients age 15-39 years with newly diagnosed ALL at Kamuzu Central Hospital, Malawi, were enrolled from 2013 to 2019; follow-up was censored on December 2020. ALL diagnosis was confirmed on-site using immunohistochemistry and telepathology consultation involving pathologists in Malawi and the United States. All but four patients were treated with a modified pediatric-inspired regimen (Cancer and Leukemia Group B 10403 protocol). Key modifications included omission of asparaginase and no dose escalation for methotrexate.RESULTSOf 19 participants, the median age was 22 (range 15-36) years. Of the 15 patients who initiated treatment, 11 (73%) achieved remission after induction, one (7%) died during induction, two (13%) had refractory disease, and one (7%) absconded. No patients were lost to follow-up. Eventually, 10 of 11 patients (91%) with confirmed remission relapsed. The median duration of first remission was 10 (range 3-22) months. Twelve of 15 treated patients (80%) had died at the time of censoring. Among treated patients, the 12- and 24-month overall survival was 50% (95% CI, 23 to 72) and 17% (95% CI, 3 to 42), respectively. CNS involvement was associated with worse survival.CONCLUSIONIt is possible to treat adolescents and young adults with ALL in low-resource settings using a low-cost, pediatric-inspired regimen; however, outcomes are poor. Both cost and limitations in supportive care infrastructure limit intensive cytotoxic approaches such as asparaginase. Patient-reported outcomes are needed to understand the quality of life and cost-effectiveness. Critically, innovative, leap-frog therapies, such as monoclonal or bispecific antibodies, and feasible economic models for resource-limited settings are urgently needed.

The risks of thrombotic and bleeding events in patients receiving PEGylated asparaginase for treatment of acute lymphoblastic leukemia.

e19015 Background: The prognosis of adult patients with acute lymphoblastic leukemia (ALL) has improved with the adoption of pediatric-inspired chemotherapy regimens. PEGylated asparaginase (PEG-Asp) is essential to these regimens. Although PEG-Asp is associated with an increased risk of coagulopathy, venous thromboembolism, and depletion of antithrombin III (AT3), there is limited data evaluating the risk of thrombosis and bleeding and optimal antithrombotic interventions in these patients are unknown. Methods: We performed a single-center retrospective study of patients ≥ 18 years-old who received PEG-Asp for B- or T-ALL at the University of Virginia between 2015 and 2020. The primary outcomes were the incidence of thrombosis and bleeding events. All patients received prophylactic AT3 repletion for activity level <60% & cryoprecipitate for fibrinogen <100mg/dL. None received prophylactic anticoagulation. All received prednisone during induction at a median daily dose of 1 mg/kg. Results: We identified 57 patients who received PEG-Asp for ALL. Median age was 32 years (range 18-63). Five patients (8.8%) had a thrombotic event during induction versus five (16%) during post-induction. Four patients (7%) had a bleeding event during induction versus five (10%) during post-induction. The most common type of thrombosis was deep venous thrombosis, with the majority being catheter-associated. Pulmonary embolism and CNS thrombosis were less common. During induction, the median time to thrombotic event was 18 days after last PEG-Asp administration. 60% and 80% of patients received AT3 and cryoprecipitate, respectively. During post-induction, the median time to thrombotic event was 58 days after last PEG-Asp administration. 38% and 63% of the patients received AT3 and cryoprecipitate, respectively. There was one episode of major bleeding during induction and six during post-induction. Conclusions: Though the increase in thrombotic risk in adult patients receiving PEG-Asp is well-characterized, rates of reported thromboses vary widely. Studies examining bleeding risk associated with PEG-Asp regimens are even scarcer and with variable outcomes. There was a significant occurrence of both thrombotic and bleeding events associated with administration of PEG-Asp. More investigation into the relative thrombotic and bleeding risks associated with PEG-Asp is needed to determine optimal antithrombotic interventions in adult patients with ALL.[Table: see text]

Asparaginase in the Treatment of Acute Lymphoblastic Leukemia in Adults: Current Evidence and Place in Therapy.

Acute lymphoblastic leukemia (ALL) is a rare hematologic malignancy resulting in the production of abnormal lymphoid precursor cells. Occurring in B-cell and T-cell subtypes, ALL is more common in children, comprising nearly 30% of pediatric malignancies, but also constitutes 1% of adult cancer diagnoses. Outcomes are age-dependent, with five-year overall survival of greater than 90% in children and less than 20% in older adults. L-asparaginase, an enzyme not found in humans, depletes serum levels of L-asparagine. As leukemic cells are unable to synthesize this amino acid, its deprivation results in cell death. The success of asparaginase-containing regimens in the treatment of pediatric ALL, and poor outcomes with conventional cytotoxic regimens in adults, have led to trials of pediatric or pediatric-inspired regimens incorporating asparaginase in the adolescent and young adult (AYA) and adult populations. Initially purified from Escherichia coli, newer formulations of asparaginase have been developed to address short half-life, high immunogenic potential, and manufacturing difficulties. Unfamiliarity with asparaginase use and management of its unique toxicities may result in treatment-decisions that negatively impact outcomes. In this review, we address the current use of asparaginase in the treatment of ALL, with an emphasis on its role in the treatment of adults, key clinical trials, recognition and management of toxicities, and ongoing directions of study.

Controversies in the Treatment of Adolescents and Young Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

The incidence of acute lymphoblastic leukemia (ALL) has been increasing steadily in the adolescent and young adult (AYA) population. In this review article focused on the management of AYAs with Philadelphia chromosome-negative (Ph-) B-ALL, we examine topics of clinical interest and identify areas of controversy in need of further investigation. We explore four areas of active investigation: pediatric-inspired front-line treatment regimens, the optimal time of measurable residual disease (MRD) assessment, the role of hematopoietic stem cell transplant and the optimal salvage therapy for relapsed/refractory B-ALL in AYAs. There has been rapid advancement in the management of ALL in the AYA patient population, which has resulted in improved outcomes. We must build on the successes by continuing to promote multi-center innovative clinical research with clinical trial populations reflecting the AYA ALL patient spectrum. The incorporation of novel targeted immunotherapy into front-line treatment will be transformative and redefine treatment paradigms in the coming years.

Prognostic significance of IKZF1 gene deletions in patients with B-cell acute lymphoblastic leukemia

目的分析IKZF1基因缺失在急性B淋巴细胞白血病（B-ALL）患者中的预后意义。方法回顾性分析2016年3月至2019年9月南方医科大学附属南方医院收治的142例接受儿童样化疗方案的B-ALL患者的临床资料，分析IKZF1缺失患者的临床特征。无事件生存（EFS）和总生存（OS）的多因素分析使用Cox回归模型。将患者分为IKZF1缺失/单纯化疗组（A组）、IKZF1缺失/移植组（B组）、IKZF1非缺失/单纯化疗（C组）、IKZF1非缺失/移植（D组）四组比较患者生存。结果142例患者，50例（35.2％）检出IKZF1基因缺失，其中4～7号外显子缺失占44.0％；与非缺失型比较，IKZF1缺失组B-ALL患者初诊时白细胞计数升高比例更高（52.0％对28.3％，P＝0.005）、诱导治疗第14天微小残留病转阴率更低（MRD1，40.0％对70.7％，P<0.001）以及Ph染色体阳性比例更高（52.0％对21.7％，P<0.001）。单因素分析显示，IKZF1缺失组3年EFS率、OS率明显低于IKZF1非缺失组［（37.1±7.3）％对（54.7±5.4）％，P＝0.025；（51.8±7.9）％对（73.9±4.7）％，P＝0.013］；多因素分析显示IKZF1缺失是影响B-ALL患者EFS（HR＝1.744，95％CI 1.082～2.812，P＝0.022）、OS（HR＝2.036，95％CI 1.119～3.705，P＝0.020）的独立危险因素。其中，A组的3年EFS、OS、无病生存率（DFS）均明显低于其他亚组。在IKZF1缺失患者中，接受异基因造血干细胞移植（allo-HSCT）组3年OS率为（67.9±10.4）％，3年EFS率为（46.6±10.5）％，均明显高于非移植组的（31.9±11.0）％和（26.7±9.7）％（P值分别为0.005、0.026）。结论IKZF1基因缺失的B-ALL患者整体预后差，儿童样化疗方案不能完全纠正IZKF1缺失对预后的不良影响；儿童样方案联合allo-HSCT可显著改善IKZF1缺失B-ALL的整体预后。

The treatment development for T cell acute lymphoblastic leukemia in children, adolescents, and young adults

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10%-15% of pediatric ALL, and its frequency increases during the adolescent and young adult (AYA) periods. The improvements in pediatric T-ALL outcomes have been achieved through the treatment intensification strategies addressing the cranial radiotherapy omission issue. Furthermore, pediatric-inspired regimens have been adopted for AYA patients with T-ALL, improving outcomes. In Japan, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-T11/JALSG T-ALL-211-U trial has been conducted for newly diagnosed patients with T-ALL aged <25 years and has been shown to have excellent outcomes. While early T cell precursor ALL is not an obvious poor prognostic factor in recent treatment strategies for pediatric T-ALL, the minimal residual disease (MRD) has been recognized as the most reliable prognostic indicator. Therefore, MRD is now widely used in T-ALL clinical trials for risk stratification and stem cell transplantation indications. Further progress in the novel therapeutic approaches can potentially improve the outcomes of pediatric and AYA patients with T-ALL.

924. Cytomegalovirus (CMV) Retinitis during Maintenance Chemotherapy for Acute Lymphoblastic Leukemia

Abstract Background Acute leukemia patients are at risk for cytomegalovirus (CMV) retinitis following hematopoietic stem cell transplantation, though the disease can also occur in non-transplant adult leukemia patients. Emerging data suggest a shift to pediatric-inspired chemotherapy regimens in adults with acute lymphoblastic leukemia (ALL) can lead to increasing cytopenias and impaired functional immunity, placing these patients at risk for this opportunistic infection. Here we describe a case of CMV retinitis in an ALL patient following a lower-intensity regimen during maintenance chemotherapy. Methods Chart review. Results A 55-year-old male with ALL presented to his optometrist with complaints of visual changes including “fogginess” and “floaters”. The patient had completed 8 cycles of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) and achieved complete remission. He had been on maintenance chemotherapy with 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP) for 2 months at the time of symptom onset. He was referred to his local ophthalmologist who had concerns for bilateral, zone 1 CMV retinitis based on fundoscopic exam (Figure 1). Vitreous aspiration was performed and CMV DNA PCR returned positive at 1.6 million IUs/ml. Peripheral blood CMV DNA PCR was also positive at 1133 IU/ml. He was started on combination therapy with intravitreal ganciclovir injections and oral valganciclovir 900 mg twice daily (Figure 2). The patient received 14 intravitreal injections with resultant stability of his eye exam, though he remained on induction valganciclovir for 5 months due to persistent blood CMV DNAemia. Letermovir was added to help suppress his peripheral CMV DNAemia and he attained partial vision recovery. Figure 1. Fundoscopic images Conclusion CMV retinitis is an uncommon and highly morbid infection that can occur during maintenance chemotherapy in adult non-transplant ALL patients. Early identification of the disease is imperative as delay can result in blindness or further systemic CMV disease. Treatment is challenging, involving systemic and intravitreal antiviral therapy, serial ophthalmologic exams, serum CMV monitoring, and close coordination with the treating hematologist. Disclosures Michael Boeckh, MD PhD, AlloVir (Consultant)Ansun Biopharma (Grant/Research Support)Astellas (Grant/Research Support)EvrysBio (Consultant, Other Financial or Material Support, Options to acquire equity, but have not exercised them)Gilead Sciences (Consultant, Grant/Research Support)GlaxoSmithKline (Consultant)Helocyte (Consultant, Other Financial or Material Support, Options to acquire equity, but have not exercised them)Janssen (Grant/Research Support)Kyorin (Consultant)Merck (Consultant, Grant/Research Support)Moderna (Consultant)Symbio (Consultant)Takeda (formerly known as Shire) (Consultant, Grant/Research Support)VirBio (Consultant, Grant/Research Support) Ryan Cassaday, MD, Amgen (Grant/Research Support, Advisor or Review Panel member)Kite/Gilead (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support)Pfizer (Grant/Research Support, Advisor or Review Panel member)Seagen (Other Financial or Material Support, Spouse is employee and hold stock)Vanda Pharmaceuticals (Grant/Research Support)

Hepatotoxicity in Adolescent and Young Adult Hispanic Patients Treated with Pediatric Regimens for Acute Lymphoblastic Leukemia

Introduction: Pediatric or pediatric-inspired regimens are used in the treatment of adolescent or young adult (AYA) patients with acute lymphoblastic leukemia (ALL). While overall survival is improved with these regimens, hepatotoxicity and metabolic complications are common adverse events related to the increased dosages of asparaginase and steroids used vs adult ALL regimens. Among ethnicities, prevalence of metabolic syndrome and hepatic steatosis is highest in the Hispanic population, which comprises ~20% of the US population and carries an increased risk of ALL. Surprisingly, there is limited literature describing hepatotoxicity in this at-risk population. Herein we describe our experience with this adverse effect in AYA Hispanic patients (<50 yrs) treated with pediatric ALL regimens at an urban academic medical center.Methods: Single-center retrospective chart review of patients with ALL treated from January 1, 2010 to May 30, 2021 at the University of Illinois at Chicago. Patients with an associated ALL diagnosis were identified through an internal pathology database. Demographic information, clinical characteristics, treatment history and complications [grade 3/4 transaminitis, development of non-alcoholic fatty liver (NAFLD) on imaging, non-alcoholic steato-hepatitis (NASH)/fibrosis/cirrhosis on biopsy, pancreatitis, treatment change or drug discontinuation secondary to hepatotoxicity] were abstracted from the EMR. Descriptive statistics were used to determine outcome frequencies.Results: We identified 33 Hispanic (n= 20) and Non-Hispanic White (NHW; n = 13) patients with either B-ALL or T-ALL, with each demographic stratified by pediatric or adult regimen therapy (Table 1). Pediatric regimens include Children's Oncology Group protocols and E1910; the adult regimen was HyperCVAD.Of 16 Hispanic patients who received pediatric regimens, 7 (44%) had pre-existing diabetes, 1 had fatty liver on baseline imaging and 1 biopsy-confirmed NASH. During treatment, 12/16 (75%) developed grade 3/4 hepatotoxicity, 11 (69%) developed mild-severe NAFLD on imaging, 2 additional patients developed cirrhosis, and 4 (25%) pancreatitis. Treatment-related adverse events prompted therapy change or drug discontinuation in 25%. Hispanic patients, (n = 4), on adult and NHW patients, (n = 7), on pediatric regimens had low rates of pre-existing comorbidities, but of the older NHW patients, (n = 6), on an adult regimen, 4/6 (67%) and 1/6 had underlying diabetes or NAFLD, respectively. We found similar high rates of grade 3/4 hepatotoxicity in Hispanics on an adult regimen (100%) and NHW patients on either a pediatric (71%) or adult regimen (50%). However, fewer patients developed NAFLD (4/17, 24%), only 1 (Hispanic) patient developed fibrosis, and none developed pancreatitis. There was no difference in mean BMI between Hispanic and NHW patients.Conclusions: While grade 3/4 transaminitis is described during ALL treatment, in this retrospective analysis we observed that Hispanic AYA patients treated on pediatric protocols frequently develop more serious complications including hepatic steatosis, cirrhosis or pancreatitis. Co-existing metabolic syndrome is associated with a higher incidence of simple steatosis (SS; 70% in obesity, 90% in diabetes), and Hispanic patients have a higher baseline SS incidence (45% in Hispanics vs 33% in NHW), which in the context of use of higher doses of steroids and asparaginase may explain their increased frequency of progression to NASH and fibrosis. As few underwent biopsy, the true incidence is likely underrepresented. Additionally, Hispanics treated on a pediatric regimen more frequently developed pancreatitis than NHW patients on the same regimen. SS is related to the accumulation of hepatic free fatty acids and triglycerides, thus patients with SS or at risk may have impaired free fatty acid metabolism that predisposes to pancreatitis with asparaginase use. Limitations of this study include a small sample size, partial availability of baseline imaging, and non-standardized radiographic interpretations of the degree of steatosis. However, our findings suggest further investigation is warranted and a multi-center study is in progress. Our study highlights the need for closer monitoring of Hispanic patients to mitigate the risk of serious liver disease with the use of curative pediatric regimens for ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Adults with Ph-like ALL

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Adults with Ph-like ALL

Safety and Pharmacokinetics of Calaspargase Pegol in Adults with Newly Diagnosed Philadelphia-Negative ALL: A Phase 2/3 Study

Safety and Pharmacokinetics of Calaspargase Pegol in Adults with Newly Diagnosed Philadelphia-Negative ALL: A Phase 2/3 Study

T-Cell Acute Lymphoblastic Leukemia-Current Concepts in Molecular Biology and Management.

T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon, yet aggressive leukemia that accounts for approximately one-fourth of acute lymphoblastic leukemia (ALL) cases. CDKN2A/CDKN2B and NOTCH1 are the most common mutated genes in T-ALL. Children and young adults are treated with pediatric intensive regimens and have superior outcomes compared to older adults. In children and young adults, Nelarabine added to frontline chemotherapy improves outcomes and end of consolidation measurable residual disease has emerged as the most valuable prognostic marker. While outcomes for de-novo disease are steadily improving, patients with relapsed and refractory T-ALL fare poorly. Newer targeted therapies are being studied in large clinical trials and have the potential to further improve outcomes. The role of allogeneic stem cell transplant (HSCT) is evolving due to the increased use of pediatric-inspired regimens and MRD monitoring. In this review we will discuss the biology, treatment, and outcomes in pediatric and adult T-ALL.

Blinatumomab resistant clone presenting as mixed phenotype myeloid sarcoma causing cord compression

Abstract Introduction/Objective Blinatumomab is a monoclonal antibody directed against CD19/CD3 utilized for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) and for the treatment of B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) ≥0.1%. Although Blinatumomab treatment has shown better overall survival, progression-free survival, and complete remission when compared to chemotherapy, most patients have a relapse and ultimately succumb to the disease. Interestingly, there are a number of cases reporting relapse in extramedullary places. The mechanisms for relapse in these unusual extramedullary sites are not well-understood. We herein report a case of a 20-year-old African American male with primary refractory Philadelphia-negative (Ph-) precursor B cell ALL with MLL rearrangement, who received treatment with Blinatumomab after achieving morphological remission with a pediatric-inspired regimen but found to be MRD +. Methods/Case Report A 20 year old African American male was found to have B cell precursor ALL. It was found to be Ph-. While initally receiving vincristine, prednisone, and aspariginase, the ALL proved to be refractory to treatment. Blinatumomab was used as second line therapy after the first failed remission. The patient remained with morphological response; however, remained MRD+ after three cycles of Blinatumomab. During the fourth cycle, the patient presented with back pain and lower extremity weakness. A spine MRI revealed an extradural mass in the thoracic spine causing cord compression. A thoracic laminectomy with partial removal of the mass, followed by radiation, was performed with improvement of symptoms. Pathology results of the extradural mass revealed a myeloid sarcoma with MLL rearrangement. Results (if a Case Study enter NA) NA Conclusion This case report demonstrates how patients treated with blinatumomab can have relapse in unusual extramedullary places. The possibility of leukemia manifesting in extramedullary sites should always be kept in mind by clinicians treating patients with Blinatumomab. The mechanisms of resistance against Blinatumomab are not well- understood and need further elucidation.

Orthopedic toxicities among adolescents and young adults treated in DFCI ALL Consortium Trials

AbstractAdolescent and young adult patients with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. Pediatric ALL regimens rely heavily on corticosteroids and asparaginase and are known to increase the risk of osteonecrosis (ON) and fractures in children, particularly adolescents. Orthopedic toxicity among young adults treated on pediatric-inspired regimens is not well described. Here, we report the symptomatic orthopedic toxicities of patients aged 15 to 50 years treated on sequential Dana-Farber Cancer Institute ALL Consortium protocols. Among 367 patients with a median age of 23 years (range, 15-50 years; 68% aged <30 years), 60 patients were diagnosed with ON (5-year cumulative incidence, 17%; 95% confidence interval [CI], 13-22), and 40 patients experienced fracture (5-year cumulative incidence, 12%; 95% CI, 8-15). Patients aged <30 years were significantly more likely to be diagnosed with ON (5-year cumulative incidence, 21% vs 8%; P = .004). Patients treated more recently on pegaspargase-based protocols were significantly more likely to be diagnosed with ON compared with those treated on earlier trials with native Escherichia coli asparaginase (5-year cumulative incidence, 24% vs 5%; P < .001). Of the 54 ON events for which adequate information was available, surgery was performed in 25 (46%). Patients with ON had superior overall survival (OS) compared with those without (multivariable OS hazard ratio, 0.15; 95% CI, 0.05-0.46; P = .001; ON included as a time-varying exposure). Increased rates of orthopedic toxicity in late-generation protocols may be driven by the pharmacokinetic drug interaction between pegaspargase and dexamethasone, leading to higher dexamethasone exposure.

Pediatric-inspired regimen with late intensification and increased dose of L-asparaginase for adult acute lymphoblastic leukemia: the KALLA 1406/1407 study.

Background/AimsThe objective of this study was to evaluate the efficacy and feasibility of the pediatric-inspired regimen of the adult acute lymphoblastic leukemia (ALL) Working Party, the Korean Society of Hematology.MethodsData of 99 patients with newly diagnosed ALL, who were treated with the KALLA 1406/1407 protocol, were retrospectively analyzed. All patients equally received age-adjusted daunorubicin, vincristine, and prednisolone. L-asparaginase was additionally administered to Philadelphia (Ph)-negative patients according to age, whereas Ph-positive patients received 600 mg/day of imatinib.ResultsA total of 99 patients were enrolled in this study, of whom 62 (62.6%) were diagnosed with Ph-negative ALL and 37 (37.3%) were diagnosed with Ph-positive ALL. The median age of patients in the Ph-negative ALL group was 46 years, and that of patients in the Ph-positive ALL group was 49 years. In patients with Ph-negative ALL, 57 (92%) patients achieved complete remission (CR) and CR with incomplete hematologic recovery (CRi). Disease-free survival (DFS) and overall survival (OS) rates at 2 years were estimated to be 42% and 63%, respectively. In patients with Ph-positive ALL, 32 (86%) patients achieved CR/CRi, and 2-year DFS and OS were 31.2% and 49.1%, respectively. Patients who were able to proceed to the allogeneic hematopoietic cell transplantation and younger patients showed significantly superior survival in both Ph-negative ALL and Ph-positive ALL. Neutropenic fever and bacterial infection were the most common and severe adverse events.ConclusionsThe KALLA 1406/1407 protocol showed tolerable toxicities in adult ALL patients. Especially, younger patients had more survival benefits with KALLA 1406/1407 protocol.