Adolescents And Young Adults Acute Lymphoblastic Leukemia Patients Research Articles

Socioeconomic Disadvantage Is Associated with Decreased Long-Term Survival in Adolescent and Young Adult Patients with Acute Lymphoblastic Leukemia

Background: The treatment of acute lymphoblastic leukemia (ALL) in the adolescent and young adult (AYA) population has dramatically improved over the past decade with the use of pediatric-inspired regimens increasing long-term survival rates to over 60%. Despite these advances, AYA patients with ALL have seen persistent disparities in survival by race and ethnic background. The primary objective of this study is to examine socioeconomic disadvantage as a driver of the racial and ethnic disparities that exist among AYAs with ALL using a nationally representative cancer registry. Methods: The cohort was identified using the SEER*Stat software, which utilizes Surveillance, Epidemiology, and End Results (SEER) data from the National Cancer Institute (NCI). All SEER patients diagnosed at age 15 to 39 years with ALL from January 1, 2005 to December 31, 2019 were included in the analysis. Patients were excluded from analysis if they had an unknown cause of death, were diagnosed with ALL only postmortem, had no survival time listed, or did not have a recorded age. We utilized the area deprivation index (ADI) as a measure of socioeconomic disadvantage, and patients were excluded if they were in a county that did not have a corresponding ADI score (0.3%). ADI scores were calculated by county using the ‘Sociome’ package in R software. Both the 2009 and 2019 county ADI scores were used based on patient diagnosis year. ADI quartiles were then assigned by decade (2000-2009 and 2010-2019). The quartiles were calculated by first identifying the median ADI score for each decade, and then assessing the median of the lower and upper half to determine the lower and upper quartile value. Analyses were also completed by state Medicaid expansion status. Both cause-specific and observed survival (OS) were calculated by five-year periods from 2005 to 2019. The net survival time was assessed at 12 to 60 months in 12-month increments for 2005-2014 with only an upper limit of 48 months survival able to be calculated for patients diagnosed between 2015-2019. The Kaplan-Meier Method was used for all survival calculations. Results: A total of 4,382 patients were found to meet criteria for inclusion. Specific characteristics of the analyzed population are listed in Table 1. OS for the entire group was 60.6% at 60 months (95% CI 58.9%-62.3%), with a cause-specific survival at 60 months of 64.3% (95% CI 62.7%-65.9%). For AYA ALL patients diagnosed from 2005 to 2009, cause-specific survival for the ADI quartiles diverged over time and at 48 months was significantly higher in patients residing in a county with an ADI value of 1 (least disadvantaged) than in those residing in a county with an ADI value of 4 (most disadvantaged) [66.6%, 95% CI 62.5-70.4% versus 51.2%, 95% CI 40.2-61.2% p<0.05], although this difference was not significant at 60 months. This difference was also seen in OS at 48 months and persisted at 60 months [62.0%, 95% CI 57.9-65.8% versus 45.7%, 95% CI 35.3-55.5% (48 mo.) and 59.7%, 95% CI 55.6-63.5% versus 45.7%, 95% CI 35.3-55.5% (60 mo.) p<0.05]. There was no significant difference in cause-specific or OS by ADI quartile for patients diagnosed from 2010-2014. However, this difference in survival reoccurred in the most recent data available (Figure 1). For AYA ALL patients diagnosed from 2015 to 2019, cause-specific survival at 36 and 48 months was significantly higher in patients residing in a county with an ADI value of 1 than in those residing in a county with an ADI value of 4 [79.7%, 95% CI 75.6-83.2% versus 65.8%, 95% CI 55.8-74.0% (36 mo.) and 78.6%, 95% CI 74.2-82.3% versus 62.4%, 95% CI 51.8-71.3% (48 mo.) all p<0.05]. This difference was also seen in OS for all survival intervals from 12 to 48 months [90.2%, 95% CI 87.6-92.3% versus 81.3%, 95% CI 74.4-86.5% (12 mo.); 82.9%, 95% CI 79.4-85.8% versus 72.9%, 95% CI 64.9-79.3% (24 mo.); 77.1%, 95% CI 72.9-80.7% versus 62.1%, 95% CI 52.4-70.3% (36 mo.); and 76.0%, 95% CI 71.6-79.8% versus 58.8%, 95% CI 48.6-67.7% (48 mo.) all p<0.05]. There were no statistically significant differences noted in cause-specific and observed survival between states that expanded Medicaid versus those that did not. Conclusions: Socioeconomic disadvantage was associated with significantly worse long-term survival in AYA patients with ALL. This gap reappears over time despite both treatment innovations and public policy changes. Urgent interventional approaches are needed to target this highly vulnerable population.

Allogeneic Hematopoietic Stem Cell Transplantation in Adolescents and Young Adults with Acute Lymphoblastic Leukemia - Retrospective Dual-Center Study

Background: Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are treated with various chemotherapy regimens. Some patients undergo allogeneic hematopoietic stem cell transplantation (HCT) due to high-risk genetic characteristics, chemo-resistant disease (failure to achieve timely measurable residual disease (MRD) negative remissions, or relapse or refractory disease. There is paucity of data on outcomes of AYA ALL patients receiving HCT. Methods: We performed a dual-center analysis of data from MD Anderson Cancer Center (MDACC) and Dana-Farber Cancer Institute (DFCI) to evaluate outcomes of AYA patients who received HCT for Philadelphia-negative (Ph neg) ALL and examined variables that might have an impact on these outcomes. We included all patients who received their first HCT between the ages of 15-40 years between the years 2010-2022. MRD status was evaluated using flow cytometry with a sensitivity of 0.01%. Acute and chronic graft versus host disease (GvHD) were classified according to consensus criteria. The primary endpoint was overall survival (OS), and secondary endpoints included progression rate and non-relapse mortality (NRM). Cox proportional hazards regression analysis was used to evaluate predictors of OS, and Fine and Gray regression for predictors of relapse and NRM. Competing risks were accounted for in analyses pertaining to progression and NRM. Results: A total of 376 Ph neg ALL AYA patients were included in the analysis, 247 from MDACC and 129 from DFCI. The median age at transplant was 25 (range 15-40) years, 39 patients (10%) were aged ≤18 years at time of HCT and 251 (67%) were males.The majority had B-ALL (n=282, 75%), 42 (11%) had complex karyotype and 28 patients (7%) had translocation (4:11). Most patients received either pediatric-inspired (48%) or hyper- cyclophosphamide, vincristine sulfate, doxorubicin, dexamethasone (CVAD) based (42%) frontline induction regimens, and the median time from diagnosis to HCT was 11 (range 2-283) months. At transplant, most patients were in CR1 or CR2 (44% each); 63% of patients achieved MRD negativity prior to HCT. Most patients received an HCT from a matched unrelated donor (MUD) (33%) or a matched sibling donor (MSD) (32%), and most patients received myeloablative conditioning (MAC) (79%) ( Table 1). The cumulative incidence of grade 2-4 acute GvHD and grade 3-4 acute GvHD at 6 months was 37% (95% CI 33%-42%) and 13% (95% CI 10%-17%), respectively. The cumulative incidence of chronic GvHD at 3 years was 28% (95% CI 23%-33%), with most patients experiencing either mild (39%) or moderate (36%) chronic GvHD, and 25% had severe chronic GvHD. For patients transplanted in CR1, CR2 and CR3/PD the estimated 3-year OS was 69% (95% CI 61%-77%), 53% (95% CI 44%-61%) and 29% (95% CI 16%-43%), respectively; the 3-year NRM rate was 9% (95% CI 5%-15%), 18% (95% CI 13%-25%) and 27% (95% CI 16%-43%), respectively; and the 3-year progression rate was 27% (95% CI 20%-35%), 36% (95% CI 29%-45%) and 48% (95% CI 36%-65%), respectively. In multivariate analysis, HCT in CR3/PD was associated with inferior OS (HR 4.3, p<0.001) and higher NRM (HR 2.3, p=0.04, Table 2), however there was no difference in survival between HCT at CR1 vs. CR2 (p=0.3); >2 lines of therapy prior to HCT was associated with inferior OS (HR 1.8, p=0.004) and higher rate of progression (HR 1.9, p=0.008); HCT-CI>3 was associated with inferior OS (HR 1.6, p=0.01) and higher NRM (2.3, p=0.004); positive MRD status prior to HCT was associated with inferior OS (HR 1.9, p=0.004) and higher rate of progression (HR 3.3, p<0.001); use of bone marrow graft was associated with lower rate of progression (HR 0.6, p=0.02) and use of a matched donor (MSD/MUD) was associated with lower NRM (HR 0.5, p=0.01). Conclusions: In this analysis of a large dual-center cohort of AYA Ph -ALL patients that received HCT, we found that patients transplanted in CR1 had the most favorable outcomes with 69% 3-year OS. Patients not in CR1/CR2, patients who received HCT after >2 lines of therapy and those with positive MRD pre-HCT had inferior OS on MVA. Although patients who received HCT at CR3/PD had inferior OS, an estimated one-third of patients were still alive at 3 years after HCT.

Disparities in trial enrollment and outcomes of Hispanic adolescent and young adult acute lymphoblastic leukemia

AbstractIn this secondary analysis of Hispanic adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated on Cancer and Leukemia Group B (CALGB) 10403, we evaluated outcomes and geographic enrollment patterns relative to US population data. We used demographic, clinical, and survival data on AYAs enrolled on CALGB 10403 (N = 295, 2007-2012). Surveillance, Epidemiology, and End Results registries provided overall survival (OS) for US AYA ALL by ethnicity/race. North American Association of Cancer Registries provided AYA ALL incidence overall and proportion among Hispanics by US state. Of AYAs enrolled on CALGB 10403, 263 (89%) reported ethnicity/race: 45 (17%) Hispanic, 172 (65%) non-Hispanic White (NHW), 25 (10%) non-Hispanic Black (NHB), and 21 (8%) other. Compared with NHWs, Hispanic and NHB patients had lower household income, and Hispanic patients were more likely to harbor high-risk CRLF2 aberrations. Relative to US estimates, where Hispanic patients represented 46% of newly diagnosed AYA ALL patients and experienced inferior OS compared with NHW (P < .001), Hispanic AYAs on CALGB 10403 did as well as NHW patients (3 year OS, 75% vs 74%; P = NS). Hispanic patients also had higher rates of protocol completion (P = .05). Enrollments on CALGB 10403 differed relative to the distribution of Hispanic AYA ALL in the United States: enrollment was highest in the Midwest; t and only 15% of enrollees were from states with a high proportion of Hispanic AYA ALL patients. In summary, Hispanic patients treated on CALGB 10403 did as well as NHWs and better than population estimates. Geographical misalignment between trial sites and disease epidemiology may partially explain the lower-than-expected enrollment of Hispanic AYA ALL patients.

Enrollment Characteristics and Outcomes of Hispanic and Black AYA ALL Patients Enrolled on a U.S. Intergroup Clinical Trial: A Comparison of the CALGB 10403 (Alliance) Cohort with U.S. Population-Level Data

Enrollment Characteristics and Outcomes of Hispanic and Black AYA ALL Patients Enrolled on a U.S. Intergroup Clinical Trial: A Comparison of the CALGB 10403 (Alliance) Cohort with U.S. Population-Level Data

Are Adolescents and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL) Receiving Pediatric or Adult ALL Regimens: A Population-Based Statewide Evaluation of the Approach to AYA ALL across Pediatric and Adult Cancer Centers

▪Background:Abundant evidence suggests that AYA with ALL have improved outcomes when treated following pediatric-inspired, as opposed to adult, ALL chemotherapy regimens. Given the complexity of pediatric ALL protocols, it is unclear whether this approach has been universally accepted by medical oncologists treating AYA ALL patients across the population.Methods:The population-based California Cancer Registry (CCR) was used to evaluate socio-demographics, location of ALL induction therapy (adult- vs pediatric-setting), and therapies administered to AYAs (15-39 years) with ALL newly diagnosed and treated in the state of California between 2004-2014. Specific ALL regimens were determined through abstraction of registry treatment text fields. Facility volume was defined as AYA ALL inductions per year and categorized by quartiles (≥7/year highest and <1/year lowest). Chi-square and student t-tests characterized differences by patient demographics, treating facilities, and treatment regimens. Multivariable logistic regression was performed to examine the association of the sociodemographic and clinical factors with receipt of pediatric-inspired ALL regimen at an adult cancer center, adjusted for clustering by induction facility. Results are presented as adjusted odds ratios (OR) and associated 95% confidence intervals (CI).Results:Of 1591 AYAs with ALL, 61% were treated in an adult oncology-setting and 28% were treated in a pediatric-setting. Treatment setting could not be determined in 11% (n=175) of patients who were excluded from additional analyses. 32% of patients were 15-18 years, 39% were 19-29 years, and 29% were 30-39 years. The majority of patients were males (64%), of Hispanic race/ethnicity (64%), and had public (46%) or private (44%) insurance. AYAs who were younger (P<0.001), diagnosed in more recent years (P=0.03), and those with public insurance (P= 0.01) were more likely to receive induction treatment in a pediatric-setting. 59% and 41% of AYAs treated in a pediatric- versus adult-setting, respectively, received induction therapy at an NCI-designated cancer center (P<0.001). Only 5% of AYAs treated in the pediatric-setting received care at low volume (<1 AYA ALL case per year) facilities, whereas 27% of AYAs treated in the adult setting received care at low volume facilities (P<0.001). ALL treatment regimen was evaluable in 1131 (79%) of patients and revealed that amongst AYAs treated in the adult-setting, 22% received pediatric-inspired and 78% received adult ALL regimens over the decade. Although pediatric-inspired regimens were administered more frequently by medical oncologists over-time, 62% of AYAs treated by medical oncologists from 2013-2014 received adult ALL regimens, with Hypercvad used most commonly (70%). Multivariable regression revealed that younger patient age (19-24 vs 35-39 years: OR 2.1, 95% CI 1.4-3.2), treatment at an NCI-designated cancer center (OR 5.3, 95% CI 2.5-11.3), and treatment at higher volume AYA ALL facility (mid quartile versus lowest quartile: OR 2.3, 95% CI 1.0-5.2; highest quartile versus lowest quartile: OR 7.4, 95% CI 2.7-20.4) were significantly associated with receipt of pediatric-inspired ALL regimens by medical oncologists; whereas, year of diagnosis, sex, race/ethnicity, and insurance had no significant association.Conclusions:Our population-level findings demonstrate that AYAs with ALL across the state of California are most commonly treated in adult oncology community settings where the volume of AYA ALL patients seen on a yearly basis is frequently very low. Strikingly, as recently as 2014, AYAs with ALL continue to be treated predominantly with adult ALL regimens. Receipt of pediatric-inspired ALL regimens is significantly more likely if AYAs with ALL receive treatment at NCI-designated cancer centers and/or centers that treat a higher yearly volume of AYA ALL patients. DisclosuresNo relevant conflicts of interest to declare.

Retrospective study of Dana Farber Consortium Protocol in newly diagnosed Egyptian adolescents and young adults with acute lymphoblastic leukemia: Tanta experience

BackgroundIntensive acute lymphoblastic leukemia (ALL) regimens in children improve the 5-year event-free survival (EFS) to reach ~ 90%. Adolescents and young adults (AYA) have EFS (30% to 45%). Young AYA ALL patients treated with pediatric chemotherapy protocols such as Dana Farber Consortium Protocol (DFCP) experience a better prognosis. This study aimed to assess the efficacy [EFS and overall survival (OS)] and the toxicity of DFCP in the treatment of Egyptian AYA with newly diagnosed ALL. A retrospective study was performed on 41 patients with newly diagnosed ALL (15 and 39 years) who were treated with DFCP. EFS and OS were estimated using the Kaplan-Meier method.ResultsThirty-eight patients (92.68%) achieved complete remission (CR). Eleven patients (26.83%) relapsed. Ten (24.39%) patients died. One, two, and three years of EFS were 75.61%, 72.91%, and 67.51% respectively. One, two, and three years OS were 85.3%, 77.26%, and 74.39% respectively. Neutropenia was the most common adverse event observed in 100% of patients.ConclusionDFCP can be considered as an effective ALL protocol for the AYA group of patients with good CR, EFS, and OS rates. DFCP seemed to be feasible in AYA despite the toxicities experienced.

Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic cell transplantation in older adolescents and young adults with Ph-negative acute lymphoblastic leukemia in first complete remission: analysis from CALGB 10403 and the CIBMTR

Optimal post-remission therapy for adolescents and young adults (AYAs) with Ph-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not established. We compared overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) for patients receiving post-remission therapy on CALGB 10403 to a cohort undergoing myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT) in CR1. In univariate analysis, OS was superior with chemotherapy compared to MA allogeneic HCT (3-year OS 77% vs. 53%, P < 0.001). In multivariate analysis, allogeneic HCT showed inferior OS (HR 2.00, 95% CI 1.5–2.66, P < 0.001), inferior DFS (HR 1.62, 95% CI 1.25–2.12, P < 0.001), and increased NRM (HR 5.41, 95% CI 3.23–9.06, P < 0.001) compared to chemotherapy. A higher 5-year relapse incidence was seen with chemotherapy compared to allogeneic HCT (34% vs. 23%, P = 0.011). Obesity was independently associated with inferior OS (HR 2.17, 95% CI 1.63–2.89, P < 0.001), inferior DFS (HR 1.97, 95% CI 1.51–2.57, P < 0.001), increased relapse (1.84, 95% CI 1.31–2.59, P < 0.001), and increased NRM (HR 2.10, 95% CI 1.37–3.23, P < 0.001). For AYA ALL patients in CR1, post-remission therapy with pediatric-style chemotherapy is superior to MA allogeneic HCT for OS, DFS, and NRM.

Incidence of venous thrombosis after peg-asparaginase in adolescent and young adults with acute lymphoblastic leukemia.

Aim:There are limited data describing incidence of symptomatic venous thromboembolism (VTE) in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) patients receiving peg-asparaginase.Materials & methods:Single-institution retrospective analysis of 44 AYA ALL patients treated with peg-asparaginase. Rates of VTE and proposed risk factors were assessed.Results:18 patients (41%) had a symptomatic VTE following peg-asparaginase. The cumulative incidence rate was 25% (95% CI: 13–38%) within 30 days of the initial dose. Personal history of thrombosis was statistically significantly associated with an increased risk of VTE with HR of 2.73 (95% CI: 1.40–5.33, p = 0.003) after adjusting for gender.Conclusion:These data indicate a high rate of VTE in the AYA ALL population following treatment with peg-asparaginase.

TP4 A RETROSPECTIVE MEDICAL CLAIMS ANALYSIS OF ACUTE LYMPHOBLASTIC LEUKEMA TREATMENT TRENDS AMONG ADOLESCENTS AND YOUNG ADULTS

Clinical studies have demonstrated that adolescents and young adults (AYAs) diagnosed with acute lymphoblastic leukemia (ALL) have better survival outcomes when treated with pediatric-inspired ALL regimens. The purpose of this retrospective analysis was to examine the trends in use of pediatric-inspired ALL regimens over time among AYA ALL patients. Newly diagnosed ALL patients within the IQVIA medical claims database (representing 3.2 million oncology patients in the US) were retrospectively identified by diagnosis code C91.00. Patients aged 18 to 39 were included and assigned to time cohorts based on date of new ALL diagnosis, and were designated as having received treatment with regimens consisting of chemotherapy only (e.g. HYPER-CVAD), or with pediatric-inspired ALL regimens containing chemotherapy and asparaginase. The study period was from July 2016 to June 2019. 1,476 patients were included. Median patient age of 25 years (min=18, max=39), 64% male and 36% female, 4% Medicaid. Patient sample was geographically representative of the four US census regions. Median patient follow-up from diagnosis was 14.1 months. Over the course of the study period, the minimum and maximum percentages of patients receiving pediatric-inspired ALL regimens were 33% and 41%, respectively with 33% in the second half of 2016 (beginning of study period) and 35% in the first half of 2019 (end of study period). The likelihood ratio test from a generalized linear regression model with time as a categorical predictor indicated that the percentage of patients receiving pediatric-inspired regimens did not change significantly over time (p=0.48). In this retrospective medical claims analysis, the percentage of AYA ALL patients receiving pediatric-inspired ALL regimens did not substantially improve since 2016, despite substantial clinical evidence supporting their use. These findings suggest there is a need for continued education on pediatric-inspired ALL regimens in AYA ALL populations to help improve patient survival outcomes.

Improved Outcome of a Pediatric-Inspired Protocol for High-Risk Adolescent and Young Adult Acute Lymphoblastic Leukemia Patients Using Peg-Asparaginase and Escalating Dose of Methotrexate: Tolerability and Outcome

BackgroundTreatment of acute lymphoblastic leukemia (ALL) in adolescent and young adult (AYA) patients using traditional adult chemotherapy protocols give low overall survival (OS) rates. Data are growing regarding the use of pediatric-inspired chemotherapy protocols in AYA patients with improvement in OS. Patients and MethodsTo assess efficacy and tolerability of using a pediatric-inspired protocol in AYA patients, we initiated our local prospective trial using a modified version of the Children’s Cancer Group 1900 protocol for newly diagnosed high-risk Philadelphia chromosome-negative ALL patients. ResultsA total of 40 patients were enrolled in the study (from 2015 to 2018). The median age was 18 years (range, 14-34 years). The complete remission rate after induction was 37 patients [93%] and after a median follow-up of 5 years, OS, disease-free survival (DFS), and event-free survival were 75%, 72%, and 60%, respectively. Use of this protocol was well tolerated with manageable toxicities. Pegylated asparaginase was given to all patients during the induction phase and was well tolerated. ConclusionThe use of a pediatric-inspired protocol for high-risk AYA ALL patients was effective and well tolerated with improvement in OS and DFS compared with historical data using adult protocols in such populations.

Hematopoietic Cell Transplantation in First Remission Amongst Adolescent and Young Adult Acute Lymphoblastic Leukemia: A Population-Level Analysis across the United States

Background:The optimal role of allogeneic hematopoietic cell transplantation (HCT) for adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) is an area of clinical debate. In this population-based evaluation of AYA ALL patients across the United States (US), we sought to describe recent patterns of care and outcomes regarding HCT in first complete remission (CR1) amongst AYAs with ALL.Methods:Data were abstracted from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Patterns of Care (POC) study focused on AYA cancers. AYAs (15-39 years) with ALL newly diagnosed between January 1, 2012 through December 31, 2013 and registered in the SEER program were included. Allogeneic HCT in CR1 was defined as occurrence of HCT without relapse/progression prior to the HCT date; HCT was considered a time-dependent variable in survival models. Multivariable logistic regression was used to evaluate associations with HCT in CR1; cox proportional hazards regression was used to evaluate associations with survival.Results:Three-hundred and ninety-nine AYAs (15-39 years) with newly diagnosed ALL between 2012-2013 were included; median follow-up for survival was 19 months (range, 0-35 months). The median age was 24 years; 85% had B-cell ALL, 27% had high risk ALL cytogenetics. One-third of AYA ALL patients received care from pediatric oncologists while two-thirds were treated by adult hematologist/oncologists; a majority (86%) received care at a teaching hospital. Fifty-eight percent received an asparaginase-containing ALL front-line regimen, 32% received hyperCVAD; 5.9% and 4.5% received another/unknown regimens, respectively. One-hundred and two (29%) AYAs underwent allogeneic HCT in CR1. Excluding patients with relapse/progression or death within three months of diagnosis (n=32), older age, high-risk ALL cytogenetics, treatment by an adult hematologist/oncologist, and front-line therapy with hyperCVAD were variables significantly associated (all P< 0.05) with increased odds of HCT in CR1 in univariate analysis, while Hispanic ethnicity and public or no/other insurance were associated with significantly lower odds of HCT in CR1. In multivariate adjusted analysis, only high-risk cytogenetics (odds ratio (OR) 4.84, 95% confidence interval (CI) 2.99-7.83) and receipt of hyperCVAD (OR 1.84, 95% CI 1.07-3.16) retained significant associations with HCT in CR1. The two-year cumulative incidence of relapse, relapse-free survival (RFS), and overall survival (OS) of the entire cohort were 28.3% (95% CI 23.4%-33.4%), 69.3% (95% CI, 63.6%-74.3%), and 84.1% (95% CI 79.7%-87.5%), respectively. Two-year cumulative incidence of relapse was significantly lower in patients receiving HCT in CR1 as opposed to those not receiving HCT in CR1 (15.1%, 95% CI 8.1%-24.1% vs 32.8%, 95% CI 26.9%-38.9%). This translated into a significant improvement in 2-year RFS (83.6%, 95% CI 72.6%-90.5% vs 64.3%, 95% CI 57.5%-70.3%), but no statistically significant differences in 2-year OS (88.9%, 95% CI 80.8%-93.7% vs 82.5%, 95% CI 77.2%-86.7%). Among all patients, receipt of care at a non-teaching hospital (hazard ratio (HR) 2.14, 95% CI 1.22-3.75) and use of another/unknown regimen (HR 9.08, 95% CI, 4.83-17.06) were significantly associated with inferior OS.Conclusions:In the US, allogeneic HCT in CR1 is most commonly administered to AYA ALL with high risk cytogenetics and as consolidation therapy for those who receive front-line hyperCVAD, as opposed to asparaginase-containing ALL regimens. Consistent with prior studies, AYA ALL patients treated at non-teaching hospitals have inferior survival. Although the landscape of ALL therapy is changing, these data provide an important snapshot of the modern state of HCT in CR1 for AYA ALL. DisclosuresMuffly:Shire Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding.

Recent Developments in Adolescent and Young Adult (AYA) Acute Lymphoblastic Leukemia.

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

Acute lymphoblastic leukemia in adolescents and young adults

Treatments for acute lymphoblastic leukemia (ALL) have been developed, independently, by both pediatric and adult study groups. Adolescents and young adults (AYA) represent a minority of patients enrolled in either pediatric or adult clinical studies and have not been the focus of trials. However, it has become evident that intensified pediatric chemotherapy regimens might be associated with better outcomes for not only AYA but also adult patients. During the last decade, the survival of AYA ALL patients has been greatly improved with the use of pediatric or pediatric-inspired protocols. The 5-year overall survival rate is now expected to exceed 70% when AYA ALL is treated employing pediatric-type protocols. In this new context, the risk factors and the application of stem cell transplantation need to be reassessed.

Favorable Outcomes for Older Adolescents and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL): Early Results of U.S. Intergroup Trial C10403

▪Background: Retrospective analyses have demonstrated significantly improved survival for AYA ALL patients (pts) aged 16-21 years (yrs) when treated on pediatric versus adult U.S. NCI Cooperative group regimens where 2-yr event-free survivals (EFS) have been only 35-40%. The purpose of C10403, a large prospective US intergroup trial, was to evaluate the feasibility and effectiveness [with EFS as a primary endpoint), of treating AYA ALL pts (ages 16-39 yrs) using the standard arm of the successful Children’s Oncology Group regimen (COG AALL0232) .Methods: Newly diagnosed AYA patients with B-precursor (B-ALL) or T-precursor (T-ALL) ALL were eligible to enroll on C10403. Burkitt type and Ph+ ALL were excluded. The regimen was identical to the Capizzi methotrexate arm of COG AALL0232 (Larsen E. JCO 2011; 29 suppl:3) and consisted of four intensive courses: remission induction, remission consolidation, interim maintenance, delayed intensification, and prolonged maintenance therapy. Pts with M2 marrow response (>5% but < 25% lymphoblasts) after remission induction received an extended remission induction course of therapy. Events were defined as induction failure (M3 [³25% blasts] day 29 of induction or M2 day 43 of extended induction), death, relapse, or second malignancy. Key correlative science studies in a subset of the total accrued population included assessment of Minimal Residual Disease (MRD) using quantitative real-time PCR of clonal IgH or TCR gene rearrangements as well as Low Density Microarray (LDA) assays designed to detect a previously validated gene expression profile (Harvey, R; ASH 2013, abstract 826) which can prospectively identify ALL pts with Ph-like (BCR-ABL1-like) ALL.Results: 318 pts were enrolled on C10403 from 11/2007 to 8/2012; 22 withdrew prior to therapy. Of 296 evaluable pts, the median age at diagnosis was 24 yrs (range: 17 to 39): 25% were 17-20 yrs, 53% were 21-29 yrs, and 22% were 30-39 yrs. The majority had B-ALL (76%) and were male ( 61%). Approximately 25% were non-Caucasian and 15% were Hispanic or Latino. 32% of pts were obese (BMI³30). There were 5 (2%) treatment-related deaths during protocol therapy: liver failure (n=2, both during induction), infection (1 in induction, 1 in consolidation), and ventricular arrhythmia (1 in induction). Overall, treatment toxicities were similar to those reported in the standard arm of COG AALL0232, with an increased thrombosis and early hyperbilirubinemia for C10403 pts, as reported previously (Advani A, ASH 2013, abstract 303). To date, 70 deaths have been reported and 87 pts remain on protocol therapy. With a median follow-up of 28 months for surviving pts, 105 events have been observed. The median EFS overall is 59.4 months (95% CI: 38.4 to NR) and the 2-yr EFS rate overall is 66% (95% CI: 60 – 72%) [Fig 1a] with similar 2-yr EFS rates for B and T- ALL pts (65%, and 68%). The 2-yr OS rate is 78% (95% CI: 72 – 83%)[Fig 1b], which is similar for B (78%, 95% CI: 72 – 84%) and T-ALL, (80%, 95% CI: 70 – 91%). These results allow rejection of the null hypothesis of this Phase II trial that the true median EFS is, at most, 32 months. In multivariable analysis of presenting clinical features, age > 20 years and initial WBC count ³ 30k/microliter were significantly associated with worse EFS and OS. Presence of MRD at day 28 following initiation of induction therapy and presence of a Ph-like gene expression signature were significantly associated with both worse EFS and OS. Notably, absence of detectable MRD noted in 22/58 [38%] evaluable pts at day 28 of induction was associated with 100% EFS (p=0.0006). The Ph-like like signature was detected in 28% of pts tested on C10403 and the 2 yr EFS for these patients was only 52%, compared to 81% for those without Ph-like disease (p = 0.04).Conclusions: This large prospective US adult intergroup trial (C10403) for pts 16-39 years old employing an intensive pediatric regimen demonstrates a significant improvement (compared to historical controls) in AYA EFS and OS and validates this approach for treatment of AYA with ALL by adult hematologists. The improved clinical outcomes and the predictive value of the correlative studies in this trial lay the foundation for the design of future trials, where incorporation of novel agents to eradicate MRD, and/or use of tyrosine kinase inhibitors to target the frequently detected Ph-like ALL in AYA pts may further improve survival for young adults with ALL. [Display omitted] [Display omitted] DisclosuresStock:Sigma-Tau: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Advani:Sigma Tau: Membership on an entity’s Board of Directors or advisory committees; Jazz: Membership on an entity’s Board of Directors or advisory committees. Liedtke:Onyx: Membership on an entity’s Board of Directors or advisory committees. Larson:Novartis: Consultancy, Research Funding.

Treatment of Adolescent and Young Adult Acute Lymphoblastic Leukemia with the Pediatric Protocol: Results from a Single Institution in Taiwan

BackgroundIt remains unclear whether pediatric protocols provide a better outcome to adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) than adult protocols in Taiwan. Therefore, we conducted a case-control study to compare the outcome events, disease-free survival (DFS), and overall survival (OS) in Taiwanese AYA patients receiving either pediatric or adult ALL protocols. MethodsTwenty-three Taiwanese AYA patients with ALL were retrospectively reviewed: eight patients received the pediatric ALL protocol modified from the Taiwan Pediatric Oncology Group (mTPOG) regimen, and 15 were treated by using the Cancer and Leukemia Group B study 8811 (CALGB-8811) regimen. ResultsThe DFS rates for patients in the mTPOG and CALGB-8811 groups were 100% versus 33.3% (p = 0.016) at one year, and 100% versus 22.2% (p = 0.006) at two years, respectively. The OS rates for patients in mTPOG and CALGB-8811 groups were 100% versus 37.0% (p = 0.013) at one year, and 100% versus 22.2% (p = 0.003) at two years, respectively. ConclusionsOur results suggested that the pediatric mTPOG protocol provides AYA ALL patients a better DFS and OS than the adult CALGB-8811 protocol.

Frontline-Treatment Of Acute Lymphoblastic Leukemia (ALL) In Older Adolescents and Young Adults (AYA) Using a Pediatric Regimen Is Feasible: Toxicity Results of the Prospective US Intergroup Trial C10403 (Alliance)

BackgroundSeveral retrospective trials suggest a superior outcome for adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) when they are treated with pediatric-inspired therapeutic regimens. C10403 is the largest prospective study to evaluate the feasibility of a pediatric regimen (Children's Oncology Group (COG) AALL0232: COG0232) (Larsen et al. JCO 2011; 29(18) suppl: 3) in AYA ALL patients (pts) (16-39 yrs of age) treated by adult hematologist/ oncologists (HO). One objective was to identify age-related increases in specific treatment-related toxicities that may limit the applicability of these regimens. We describe here the adverse event (AE) profiles by age cohorts for pts enrolled on C10403 and compare them with data reported from the pediatric COG0232 trial in pts ≥ 16 yrs of age using the same regimen. In the COG study, AYA comprised 20% of enrolled pts, 66% were ages 16-21. MethodsC10403 was a single arm study. All pts received treatment with the “PC” (prednisone/ ‘Capizzi' methotrexate) Interim Maintenance (IM) arm from the AALL0232 regimen and were treated by adult HO. Descriptive statistics were used to summarize toxicities. For this report, we focused on Grade 3-5 events with at least a possible relationship to treatment. The comparison group from COG0232 included 159 pts randomized to the PC arm; however, in COG0232 slow responders received additional treatment compared to C10403 pts. ResultsBetween Nov 2007 and Dec 2012, 318 pts in the United States 16-39 yrs of age were enrolled by 3 cooperative groups (CALGB, SWOG, ECOG). 61% were male; 74% white, 10% African American, and 16% Hispanic. The median age was 25 yrs, older than the COG0232 AYA pts. 14% were < 20, 58% 20-29, and 28% 30-39 yrs of age. Induction (indn) toxicities are summarized in Table 1. The rates of Grade 3-4 hyperglycemia, hyperbilirubinemia, pancreatitis, thrombosis, and febrile neutropenia during indn in the C10403 trial were higher than in AYAs treated on COG0232. However, indn mortality rates for C10403 and COG0232 were both low, 2%. Grade 3-5 AEs at any point during treatment are listed in Table 2. During IM, 5.6% of pts on C10403 developed Grade 3-4 mucositis. Grade 3-4 hypersensitivity reactions to peg-asparaginase declined from 12.9% to 7.9% after a C10403 protocol amendment to require premedication. There were no significant differences in the incidence of Grade 3-5 AEs by age cohort among C10403 pts except for increased incidences of neuropathy, osteonecrosis, and mucositis in pts ≥ 20 yrs old. In comparison, AYAs on COG0232 had higher rates of hypersensitivity (no premedication) and motor neuropathy and lower rates of thrombosis than the C10403 pts. Hepatic toxicities, incidence of pancreatitis and osteonecrosis were similar between the two studies. Toxicities were manageable by adult HO on C10403, and the overall treatment-related mortality rate on C10403 was low (3%). Attribution of toxicities to specific components of therapy, particularly peg-asparaginase, is being evaluated. Clinical outcomes of pts enrolled on C10403 are still being evaluated.Table 1Indn-only AE Comparison (Grade 3-5)C10403 (%)COG02321 (%)Hyperglycemia29.322.0Hyperbilirubinemia15.96.7Allergic reaction0.70.8Pancreatitis1.10.5Thrombosis2.91.5Febrile neutropenia (indn)19.27.0Table 2Grade 3-5 AEs at Any Time During Treatment (events left blank were not available for AALL0232)C10403 (%)COG0232 (%)Allergic reaction9.419.0Coagulation AbnormalitiesFibrinogen41.09.5Prothrombin time1.00.6Partial thromboplastin time3.5DIC0.71.3CNS hemorrhage1.0Thrombosis7.63.8Line-related thrombosis0.7HepaticLiver failure1.01.9ALT50.048.7AST30.222.2Bilirubin22.924.7Pancreatitis4.23.8BoneFracture0.30.6Osteonecrosis2.13.2Hyperglycemia32.335.4NeurologicCNS ischemia1.0Confusion1.70.6Encephalopathy0.75.1Motor neuropathy5.915.8Sensory neuropathy14.211.4Seizure2.81.9Speech impairment2.1Somnolence0.70Febrile neutropenia (cycles other than indn)46.040.9 ConclusionsThese data indicate that treatment with a pediatric regimen (C10403) is feasible when administered by adult HOs to an AYA population up to 40 years of age. C10403 can be used as a foundation for the design of successor trials in this pt population.(1) Larsen E, Salzer W, Nachman J, et al. Blood, Nov 2011; 118: 1510. Disclosures:Stone:Amgen: Consultancy.

Impact of aberrant DNA methylation patterns including CYP1B1 methylation in adolescents and young adults with acute lymphocytic leukemia

Aberrant promoter DNA methylation is a well-described mechanism of leukemogenesis within hematologic malignancies, including acute lymphoblastic leukemia (ALL). However, the importance of methylation patterns among the adolescent and young adult (AYA) ALL population has not been well established. DNA methylation of 18 candidate genes in 33 AYA ALL patients was analyzed at diagnosis and during treatment, to evaluate the frequency and clinical relevance of aberrant methylation in an AYA population treated on a uniform therapeutic regimen. Of 16 informative genes, there was a median of 6 methylated genes per AYA ALL patient. Correlations were identified between increasing number of methylated genes with male sex (P = 0.04), increased white blood cell (WBC) count (P = 0.04) and increased bone-marrow blast percentage (P = 0.04). Increasing age was associated with EPHA5 methylation (P = 0.05). Overall, patients experienced favorable outcomes with median survival that was not reached. On univariate analysis, methylation of CYP1B1 was associated with worse overall survival (HR 10.7, 95% CI 1.3-87.6, P = 0.03), disease-free survival (HR 3.7, 95% CI 1.1-9.2, P = 0.04) and correlated with decreased CYP1B1 gene expression. A significant incidence of methylation within the AYA ALL population was identified, with increased methylation associated with distinct clinicopathologic features including male gender and elevated WBC count. Our results suggest aberrant methylation among AYA patients is frequent, and may provide a common pathogenic mechanism. The inferior outcome identified with methylation of the cytochrome p450 gene CYP1B1, an enzyme involved in drug metabolism and steroid synthesis, warrants further investigation.

Adolescents with acute lymphoblastic leukemia treated at pediatric versus adult hospitals

The objective was to compare 5-year overall survival (OS) between adolescent and young adult (AYA) patients (age 15-19) with acute lymphoblastic leukemia (ALL) treated at a pediatric versus an adult center. This was a population-based analysis using administrative data of Ontario ALL AYA patients diagnosed between 1986-2009. We calculated predicted survival proportions (PSPs) and 95% confidence intervals (CI). We also surveyed sites to determine whether pediatric or adult-based protocols were used in each period. Overall, 290 patients between 15-19 years of age were diagnosed with ALL during the study period; 144 patients (49.7%) were treated at an adult center. When adjusted for gender, age, income quintile and time period, AYA patients treated at a pediatric center did not have a significantly different PSP (0.65, 95% CI: 0.56-0.75) in comparison to those treated at an adult center (0.62, 95% CI 0.52-0.73; P = 0.87). Most AYA patients treated at adult centers received pediatric protocols in the recent periods. Using population-based data, AYA ALL patients had similar outcomes whether treated at a pediatric or an adult center. Early introduction of aggressive treatment protocols in adult centers may have negated differences in outcomes among AYA patients by site of care.

Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric‐inspired regimens: Systematic review and meta‐analysis

Survival of adults with acute lymphoblastic leukemia (ALL) is inferior to that of pediatric patients. Strategies to improve the outcome of adult population are warranted. This study aims to evaluate the efficacy and safety of pediatric-inspired regimens given to adolescents and young adults (AYA), usually defined as 16-39 years, with ALL. Systematic review and meta-analysis of comparative trials of AYA patients with ALL given induction chemotherapy with either pediatric-inspired regimens or conventional-adult chemotherapy was conducted. Relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. Our search yielded 11 trials, including 2,489 patients. AYA patients given pediatric-inspired regimens had a statistically significant lower all cause mortality rate at 3 years (RR 0.58; 95% CI 0.51-0.67). Complete remission rate after induction chemotherapy and event free survival were superior in the pediatric-inspired regimens arm (RR 1.05; 95% CI 1.01-1.10 and RR 1.66; 95% CI 1.39-1.99, respectively). Relapse rate was also lower in patients given pediatric-inspired regimens (RR 0.51; 95% CI 0.39-0.66) with comparable nonrelapse mortality between the two groups (RR 0.53, 95% CI 0.19-1.48). Pediatric-inspired regimens are superior to conventional-adult chemotherapy in AYA ALL patients. Further randomized controlled studies to investigate this approach in adult ALL patients are warranted.

Outcomes and Prognostic Factors in Adolescents and Young Adults Undergoing Intensive Therapy for Acute Lymphoblastic Leukemia

Abstract 4248 Background: According to US SEER data, 10.3% of patients diagnosed with Acute Lymphoblastic Leukemia (ALL) during 2004–2008 were 20–34 years old. The majority of patients, 60.3%, diagnosed were under 20, and the remainder were over 35 years of age. Many retrospective trials have looked at treatment of adolescents and young adults (AYA) with ALL, and overall survival (OS) rates after treatment with pediatric regimens versus adult protocols. European studies done in the early 2000’s found improvement in OS and progression free survival (PFS) in this population when treated with pediatric regimens. Differences in pediatric versus adult regimens include increased doses of non-myelosuppressive drugs such as glucocorticoids, Vincristine and Aspariginase, more frequent CNS prophylaxis, and longer maintenance therapy. These differences, unfortunately, often cause harsh toxicities, not well tolerated by adults. Here we present our experience at Moffitt Cancer Center (MCC), in treating AYA’s (age &lt;30 years) with ALL after treatment with pediatric or adult protocols. Methods: We used the MCC Total Cancer Care database to identify patients with ALL who underwent intensive therapy. Patient medical records were reviewed, and patients between 18–30 years of age were included in this analysis. Hyper-CVAD was the most common adult regimen, while CALGB 10403 and ECOG 2993 were the most common pediatric regimens. Descriptive data were reported, t-test was used to compare continuous variables while chi square test was used for categorical variables. Kaplan Meier curves were used for OS and PFS. Log rank test was used to compare survival times between groups. Cox regression was used for multivariable analysis. All analyses were conducted using SPSS version 19.0. Results: Between 1/1/2004 and 6/30/2011, 42 AYA ALL patients were treated at MCC. Males accounted for 74%, while 26% were female. Hyper-CVAD was used as frontline chemotherapy in 64% of patients, while 31% received a pediatric regimen. Of the 42 patients, 64% were white, 5% African American, 12% Hispanic and 19% were classified as other. Pre-B ALL made up 69% of patients, while 31% had T-cell origin. Cytogenetics category at diagnosis was adverse in 29% of patients, intermediate in 55% and favorable in 12% of the population, while 5% were unknown. Philadelphia chromosome was positive in 17%. At diagnosis 38% had lymphadenopathy, 33% had splenomegaly and 12% had CNS disease. Overall, 45% underwent allogeneic stem cell transplant (SCT) in CR1, while 55% did not. Overall, 85% of patients achieved CR, including 81% receiving Hyper-CVAD and 92% with pediatric regimens. Median PFS was 30.8 months (95% CI 21.9–39.7) for the entire AYA population, 31.2 months (95% CI 13.2–49.3) in the Hyper-CVAD group and 21.3 months (95% CI 0.0–49.6) in the pediatric regimen group. (P=0.124) (Figure 1) Median OS in the entire AYA population was 31 months (95% CI 15.3–46.7). OS with Hyper-CVAD was 31 months (95% CI 19.7–42.2) versus 30 months (95% CI 3.1–56.9) in the pediatric group (P=0.984). (Figure 2) Median PFS was 44.8 months in patients who had an allogeneic SCT versus 23 months in those who did not (P=0.009). Further, there was a trend toward worse outcomes in patients with adverse cytogenetics. Median OS in patients who had an allogeneic SCT was 39 months (95% CI 16.8–61.2) versus 31 months (95% CI 15.2–46.8) in those who did not. (P=0.424). In univariable analysis, no difference in outcome was found based on race, gender, T or B cell origin, lymphadenopathy or splenomegaly. Using Cox regression analysis, Philadelphia chromosome positivity (P= 0.009), elevated WBC (P=0.008) and CNS disease at diagnosis (P=0.029) were statistically significant independent variables for OS for all patients. Conclusion: Optimal treatment of AYA with ALL remains unclear. The role of pediatric versus adult regimens remains controversial, and further prospective investigation is necessary. In our experience, outcomes in AYA appear similar between Hyper-CVAD and pediatric regimens. Improvement in PFS is noted if patients are able to undergo allogeneic SCT. In addition, Philadelphia chromosome positivity, elevated WBC at diagnosis and CNS disease appear to be independent variables that negatively affect prognosis in these young patients, for whom more novel therapies are needed. Disclosures: No relevant conflicts of interest to declare.