Adolescents And Young Adults Acute Lymphoblastic Leukemia Research Articles

The burden of acute lymphoid leukemia among adolescents and young adults in the Western Pacific Region: evidence from Global Burden Disease 2019.

Acute lymphoblastic leukemia (ALL) is a type of blood cancer that affects white blood cells. Here, we use data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, to estimate the burden and incidence rate changes in adolescents and young adults (AYA) ALL in the Western Pacific Region and to reveal potential risk factors of incidence- and mortality rates. The GBD 2019 study data was stratified by sex, age, country, and territory. We calculated the Estimated annual percentage changes (estimated APC) in mortality and incidence rates for each of the 25 countries and territories of the western Pacific region from 1990 to 2019. This study found global AYA ALL incidence rates had increased while the mortality rates had decreased between 1990 and 2019. Moreover, healthcare access and quality (HAQ), and government per capita health spending were identified as country-level risk factors of AYA ALL incidence rates, while HAQ, male education, and sex were identified as mortality rate predictors in 25 Western Pacific Region countries. To address and reduce the burden of incidence and mortality among AYA, various regions around the world, particularly developing countries, could revise their AYA prevention and treatment strategies.

Improved MRD Negativity Rates in Adverse Genomic Risk B-ALL Patients with Chemotherapy / Blinatumomab Induction: Experience from the Australasian Leukaemia Lymphoma Group (ALLG) ALL06/09 Studies

Introduction: Despite the benefits conferred by pediatric treatment protocols, outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) remain inferior to children. Poor outcomes in AYA ALL have been associated with reduced tolerability of intensive cytotoxics and higher incidence of adverse risk disease. Our earlier ALLG ALL06 study demonstrated intensive pediatric induction/consolidation could be delivered in a similar time frame as in children suggesting tolerability was not a major contributor to poor outcome in AYA ALL. ALL06 established post consolidation (TP2=d79) minimal residual disease (MRD) positivity (MRD+) and high BMI was predictive of inferior disease free- and overall survival (OS). In order to improve TP2 MRD negativity (MRD-) in B-cell disease, the ALLG ALL09 study substituted standard consolidation for blinatumomab (blin) in phase I and II of a BFM-style protocol . We present the impact of blin on outcomes in genomic cohorts from ALL09 and compare these to similar cohorts from ALL06 treated with standard chemotherapy. Methods: Between Sep 2020 and Apr 2022, 55 patientswere enrolled to ALL09. Of these, 45 had appropriate samples for genomic analyses and 39/45 had an MRD marker identified. These 39 patients formed the genomic cohort presented below. Genomic subtyping was performed using whole transcriptome sequencing, MLPA, karyotype and FISH analyses, and disease was classified into genomic adverse (AR) vs standard (SR) risk based on contemporary literature classifiers. Bone marrow MRD was assessed using ASO-PCR for IGH and TCR rearrangements, at d33 post induction (TP1), and TP2 post blin consolidation. Differences in TP2 MRD were assessed, with estimated 3 yr relapse free survival (RFS) and OS calculated using the Kaplan-Meier method. Results: In the ALL09 cohort, median follow up was 629 days with 3 yr RFS 84.5% and OS 87.1%. In the genomic cohort, median follow up was 602 days with 3 yr RFS 88.8% and OS 93.2%, respectively. These compared favorably to 3 yr RFS and OS (both 67.5%) in the B-cell genomic cohort from ALL06. Between ALL09 and ALL06 there were similar proportions of AR patients (73% and 62.5%, respectively). In ALL09, the most frequent subtypes were PAX5alt (18%) and PAX5 p.P80R (11%) versus KMT2Ar and DUX4r (both 17.5%) in ALL06. In ALL09, Ph-like disease represented 13% vs 12.5% in ALL06. In the ALL09 genomic cohort, the MRD+ rate reduced between TP1 and TP2 (p< 0.001), with the reduction in the rate of positivity being more pronounced in the AR cohort (AR MRD+ TP1=85% vs AR TP2=39%; p< 0.001). In contrast, in ALL06 MRD+ in the AR cohort reduced by only 28% between TP1 and TP2 (p >0.05). This suggests a positive impact of blin consolidation in AR patients in ALL09. Despite improved AR MRD+ rates overall, not all genomic subtypes in ALL09 followed this trend (Table 1). To date, there are 5 relapses in the ALL09 cohort, 4 from the genomic cohort. Of these, 1 was hypodiploid and strikingly the remaining 3 patients harbored a TCF3 rearrangement ( TCF3r). All 4 relapses were significantly associated with MRD+ at TP2 (RFS: MRD-, 100% (n=14) vs MRD+, 71% (n=25); p= 0.013), and all were observed in the AR genomic group. Of interest, the fifth case, outside of the genomic cohort, was classified as PAX5alt. In ALL09, high-risk (HR) patients proceeded to intensive HR block chemotherapy with the aim of eliminating MRD prior to allogeneic transplant (SCT). In the genomics cohort 15 patients proceeded to HR therapy, n=12 were considered AR. Sustained MRD+ through HR blocks 1 and 2 was noted in patients harboring PAX5 p.P80R (3/3), KMT2Ar (2/2) and TCF3r (2/3). Of the 9 patients who proceeded to SCT, 3 had PAX5 p.P80R 1 had PAX5alt, 2 were KMT2Ar and there was 1 each of DUX4r, hypodiploid and TCF3r. The 3 patients who remained MRD+ in the SR cohort had PAX5 p.P80R and all 3 proceeded to SCT. Conclusion: This is the first report of the impact of blin consolidation on genomic subsets of de novo AYA ALL. Our study suggests blin sensitivity as assessed by TP2 MRD response may be genomic subtype dependent, with TCF3r associated with sustained MRD+, leading to eventual relapse (3/3 patients). In addition, the PAX5 p.P80R subset was also associated with sustained high levels of TP2 MRD+ (3/4 with an MRD marker) and SCT (3/5 patients). These results may assist with identification of AYA ALL subsets that could benefit from alternative approaches as blin becomes increasingly incorporated into front-line protocols.

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.

Disparities Among Adolescent and Young Adult Patients with Acute Lymphoblastic Leukemia

Introduction: Acute lymphoblastic leukemia (ALL) in the pediatric population has a 5-year overall survival that exceeds 90%, however, the survival rate drops significantly in the adolescent and young adult (AYA) population. Notably, the AYA contribute to 80% of ALL mortality despite representing less than one-fourth of total ALL cases. The challenges related to caring for adolescents and young adults with malignancies have become increasingly well recognized and the impacts of racial, socioeconomic, and psychosocial disparities as potential contributors to AYA ALL survival rates are only recently being characterized. Methods: We conducted a retrospective cohort study using the Nationwide Inpatient Sample (NIS), the largest all-payer database of hospital admissions in the United States, from January 1, 2011 through December 31, 2020. The study sample consisted of AYA patients 15-39 years of age, as defined by the National Cancer Institute. ALL-related hospitalizations were captured using ICD-9 and 10 codes indicative of ALL. We performed temporal trends analysis to assess inpatient death among ALL hospitalizations by race/ethnicity using joinpoint regression. We used adjusted survey logistic regression analyses to assess associations between race/ethnicity and in-hospital mortality among ALL hospitalizations. Results: Our data captured 138,923 ALL-related hospital encounters of AYA patients from 2011 to 2020. In our cohort, 73.1% of ALL hospitalizations were in patients younger than 30, and 26.9% were in patients between the ages of 30 and 39. AYA NH-Black patients with ALL had twice the odds of inpatient mortality as compared to NH-White patients [odds ratio (OR), 95% confidence interval: 1.75 (1.34-2.29)] (Table 1). While the rate of inpatient mortality improved in the overall AYA population over our 10-year study period, strikingly, the rate of inpatient mortality instead increased in NH-Black patients (Figure 1). In contrast, NH-White patients saw the lowest rate of inpatient mortality, both at the start and at the end of our study period (Figure 1). Although the inpatient mortality rate in Hispanic patients improved over time, these patients remained at an increased likelihood of inpatient mortality compared to their NH-White counterparts [OR 1.32 (1.08-1.61)] (Table 1). Conclusion: Survival gains in the AYA population have improved only modestly compared to that of their pediatric and adult counterparts, and here we report that these survival gains are even further stratified and disparate depending on patient race/ethnicity with worse outcomes in NH-Black patients. It is important to better understand the disparities that impact the AYA population, which is particularly vulnerable to social factors impacting their care. Study limitations include lack of data pertaining to treatment received, including pediatric versus adult treatment protocol or bone marrow transplant status. Disparate access to centers of excellence, stem cell transplant and blinatumomab may certainly be contributors to the disparate outcomes described herein.

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.

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.

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

An MRD-stratified pediatric protocol is as deliverable in adolescents and young adults as in children with ALL

AbstractPediatric regimens have improved outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL). However, results remain inferior to children with ALL. The Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study (anzctr.org.au/ACTRN12611000814976) was designed to assess whether a pediatric ALL regimen (Australian and New Zealand Children's Haematology and Oncology Group [ANZCHOG] Study 8) could be administered to patients aged 15 to 39 years in a comparable time frame to children as assessed by the proportion of patients completing induction/consolidation and commencing the next phase of therapy (protocol M or high-risk [HR] treatment) by day 94. Minimal residual disease (MRD) response stratified patients to HR treatment and transplantation. From 2012 to 2018, a total of 86 patients were enrolled; 82 were eligible. Median age was 22 years (range, 16-38 years). Induction/consolidation was equally deliverable in ALL06 as in Study 8. In ALL06, 41.5% (95% confidence interval [CI], 30.7-52.9) commenced protocol M or HR therapy by day 94 vs 39.3% in Study 8 (P = .77). Median time to protocol M/HR treatment was 96 days (interquartile range, 87.5-103 days) in ALL06 vs 98 days in Study 8 (P = .80). Induction mortality was 3.6%. With a median follow-up of 44 months (1-96 months), estimated 3-year disease-free survival was 72.8% (95% CI, 62.8-82.7), and estimated 3-year overall survival was 74.9% (95% CI, 65.3-84.5). End induction/consolidation MRD negativity rate was 58.6%. Body mass index ≥30 kg/m2 and day 79 MRD positivity were associated with poorer disease-free survival and overall survival. Pediatric therapy was safe and as deliverable in AYA patients as in children with ALL. Intolerance of pediatric ALL induction/consolidation is not a major contributor to inferior outcomes in AYA ALL.

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.

Widening Survival Disparities between AYA with ALL Treated in Pediatric Vs. Adult Centers: A Population-Based Study Using the IMPACT Cohort

Background: Survival outcomes in adolescents and young adults (AYA) with cancer have not improved at the same rates as those in children. Studies in AYA with acute lymphoblastic leukemia (ALL) have shown that pediatric-based treatment protocols result in better survival compared to adult protocols. Consequently, many adult centers have begun to treat AYA ALL with pediatric protocols. Whether this change in practice has diminished survival disparities between pediatric and adult centers has not been established.Methods: The IMPACT Cohort comprises all Ontario, Canada AYA 15-21 years old diagnosed with one of six common cancers (including ALL) between 1992 and 2011. Detailed demographic, disease, treatment, and outcome data were collected through chart abstraction and validated by content experts. Locus of cancer care (pediatric vs. adult center) was determined based on where the majority of chemotherapy was delivered in the first three months after diagnosis. Linkage to population-based health administrative data identified cancer events (relapse, death) that were not detected through chart abstraction. Various predictors of locus of care were examined, including age (continuous variable), gender, time period (1992-1998 vs. 1999-2005 vs. 2006-2011), rural residence, and socioeconomic status using logistic regression. The impact of the above predictors and of locus of care on event-free (EFS) and overall survival (OS) was determined using Cox proportional hazard models. Events included disease progression, relapse, death, and second malignancies.Results: The cohort included 271 patients with ALL, 152 (56%) of whom received therapy at an adult center. In multivariable analysis, older patients [odds ratio (OR) 11.9 per year; 95th confidence interval (CI) 6.1-25.0] and those in the earliest time period (1992-1998 vs. 2006-2011, OR 3.5; 95CI 1.1-10.7) were more likely to be treated in an adult center. The 5-year EFS of patients treated at a pediatric center was 69.8%±4.2% vs. 50.7%±4.0% at adult centers (p=0.0006). 5-year OS was 78.0%±3.9% vs. 58.7%±5.5% (p=0.0006). For the entire cohort, there was no significant improvement in EFS over time. In multivariable analysis, only locus of care was significantly associated with EFS [adult vs. pediatric hazard ratio (HR) 4.0; 95CI 1.4-11.9]; age and time period were not predictive. The disparity in both EFS and OS between pediatric and adult cancer centers widened over time (Table 1). In the earliest time period (1992-1998) there was no significant different in OS between adult vs. pediatric centers (HR 1.8; 95CI 0.8-4.3). The HR increased and became statistically significant in the middle time period (1999-2005; HR 2.4; 95CI 0.9-5.6) and widened further in the most recent time period (2006-2011; HR 4.3; 95CI 1.4-13.8).Conclusions: Despite studies showing improved survival outcomes in AYA with ALL treated on pediatric-based protocols, and the increased use of such protocols at adult centers, outcomes in Ontario did not improve over the 20-year study period. Contrary to expectations, disparities in survival between pediatric and adult centers widened, with the largest disparities seen in the most recent time period. These results suggest that at a population-level, the use of pediatric protocols may not be sufficient to abolish locus of care-based outcome disparities. Future analyses will look at the impact of protocol adherence, delays in therapy, toxicity, and hospital volume on survival. [Display omitted] 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.

Outcomes and prognostic factors in adolescents and young adults with ALL treated with a modified BFM-90 protocol

AbstractThe use of pediatrics-inspired protocols in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) results in superior survival compared with the adult protocols. Pediatrics-inspired protocols carry an increased risk of toxicity and treatment-related mortality in low resource settings, which can offset the potential benefits. We studied the outcomes and prognostic factors in the treatment of AYA ALL with a pediatrics-inspired regimen. We retrieved data regarding demographics, investigations, treatment details, and toxicities from the electronic medical records of patients diagnosed with ALL in the 15- to 25-year-old age group who were initiated on a modified Berlin-Frankfurt-Münster 90 (BFM-90) protocol between January 2013 and December 2016 at the Tata Memorial Centre. A total of 349 patients in the 15- to 25-year-old age group were treated with a modified BFM-90 protocol. The use of this pediatrics-inspired protocol resulted in a 3-year event-free survival (EFS) and overall survival (OS) of 59.4% and 61.8%, respectively. Only 15 patients underwent an allogeneic stem cell transplant. Minimal residual disease (MRD) persistence postinduction emerged as the only factor predictive of poor outcomes. A modified BFM-90 protocol is an effective and safe regimen for AYA ALL with an OS and EFS comparable to the published literature.

Orthopedic Toxicity Among Adolescents and Young Adults Treated on DFCI ALL Consortium Trials

Orthopedic Toxicity Among Adolescents and Young Adults Treated on DFCI ALL Consortium Trials

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.

Late Effects in Survivors of Adolescent and Young Adult Acute Lymphoblastic Leukemia.

BackgroundKnowledge regarding late effects (medical conditions and subsequent neoplasms) in survivors of adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) is lacking.MethodsUsing the population-based California Cancer Registry linked with California hospitalization data, we evaluated late effects in 1069 AYAs (aged 15–39 years) diagnosed with ALL in California between 1995 and 2012 and surviving a minimum of 3 years from diagnosis.ResultsThe estimated 10-year cumulative incidence of subsequent endocrine disease (28.7%, 95% confidence interval [CI] = 25.8% to 31.6%) and cardiac disease (17.0%, 95% CI = 14.6% to 19.5%) were strikingly high; avascular necrosis (9.6%, 95% CI = 7.8% to 11.6%), liver disease (6.5%, 95% CI = 5.0% to 8.3%), respiratory disease (6.2%, 95% CI = 4.8% to 8.0%), seizure and/or stroke (4.3%, 95% CI = 3.1% to 5.8%), renal disease (3.1%, 95% CI = 2.1% to 4.4%), and second neoplasms (1.4%, 95% CI = 0.7% to 2.4%) were estimated to occur at 10 years with the reported frequencies. Multivariable analyses including the entire patient cohort demonstrated that public or no insurance (vs private and/or military insurance) and receipt of hematopoietic cell transplantation were independently associated with the occurrence of all late effects considered. In multivariable analyses limited to the 766 AYAs who were not transplanted, we continued to find a statistically significant association between public and no insurance and the occurrence of all late effects. Frontline regimen type (pediatric vs adult) was not statistically significantly associated with any of the late effect categories.ConclusionsThis large population-based analysis is among the first to describe late effects in survivors of AYA ALL. The strong association between insurance type and late effects suggests that AYAs with public or no insurance may have reduced access to survivorship care following completion of ALL therapy.

Late Effects and Subsequent Neoplasms in Survivors of Adolescent and Young Adult Acute Lymphoblastic Leukemia: A Population-Based Analysis Including Impact of Front-Line Regimen Type

Background: Numerous studies have demonstrated superior survival for adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated with pediatric-inspired as opposed to adult-type front-line ALL regimens. However, very little is known regarding the potential impact of therapeutic regimen type on late effects and subsequent neoplasms (SN) in AYA ALL survivors. Using population-based data, we describe associations between subsequent medical conditions/SN, sociodemographics, and ALL therapies, including regimen type (pediatric versus adult) in a large cohort of AYA ALL survivors. Methods: The California Cancer Registry (CCR) linked with California hospitalization data was used to evaluate socio-demographics, therapies, and subsequent medical conditions (late effects) amongst AYAs (15-39 years) diagnosed with ALL in California between 1995-2012 surviving a minimum of three years from diagnosis. The CCR was used to identify front-line therapeutic regimen, receipt of cranial irradiation (CRI), and SN; hematopoietic cell transplantation (HCT) and late effects were captured through hospitalization data. Late effects were categorized as cardiac (hypertensive disease, coronary artery disease, heart failure), neurologic (stroke, seizure), endocrine (thyroid disease, diabetes, ovarian/testicular dysfunction, other metabolic diseases), respiratory (asthma, chronic obstructive pulmonary disease, pulmonary fibrosis), renal (chronic kidney disease, hemodialysis, kidney transplant), liver (chronic liver disease, pancreatitis, cirrhosis, liver transplant), and avascular necrosis (AVN). The 10-year cumulative incidence (CMI) of developing each late effect/SN was estimated, accounting for death as a competing risk. Multivariable Cox proportional hazards regression analyses (MVA) examined the impact of sociodemographic factors and therapies (pediatric vs adult ALL regimen, HCT, CRI) on the occurrence of each late effect/SN. Front-line regimen type (pediatric vs adult) was highly correlated with receipt of HCT (P&amp;lt;0.001); thus, the impact of front-line regimen was evaluated in separate MVA for those who did and did not receive HCT. Results: Of the 1,069 survivors of AYA ALL (median follow-up, 8.2 years), 44% were 15-19 years at diagnosis, 32% were 20-29 years, 24% were 30-39 years; 62% were male and 50% were Hispanic. Thirty-nine percent resided in the lowest neighborhood socio-economic status (SES) tertile and 35% had public or no insurance. The majority (60%) received an adult-type front-line ALL regimen; 19% received CRI and 28% underwent HCT. Twenty-four SN occurred; thyroid, head and neck, and breast cancers were most common. The 10-year CMI of endocrine disease (29%) and cardiac disease (17%) were strikingly high; AVN (10%), respiratory disease (6%), liver disease (7%), seizure/stroke (4%), renal disease (3%) and SN (3%) occurred with descending incidence. Multivariable analyses including the entire patient cohort demonstrated that public or no insurance (vs private/military insurance) and receipt of HCT were independently associated with both late effects across organ systems and SN (Table 1A). Race/ethnicity, sex and neighborhood SES were not associated with late effects/SN. In MVA limited to the 766 AYAs who did not receive HCT, we continued to find a significant association between public and no insurance and all late effects, including SN. Front-line regimen type was not significantly associated with any of the late effect categories, nor was CRI (Table 1B). Among the 303 AYAs who received HCT, lower neighborhood SES was associated with higher risk of all late effects/SN considered. Conclusions: This large population-based analysis is amongst the first to describe late effects and SN in survivors of AYA ALL. Public or no health insurance and receipt of HCT were independently associated with the development of late effects across organ systems and SN, while front-line regimen type (adult vs. pediatric) among non-transplanted AYAs was not. The strong association between insurance type and late effects suggests that AYAs with public or no insurance may have reduced access to survivorship care following completion of ALL therapy. While additional follow-up is necessary to discern the full burden of late effects in survivors of AYA ALL, these findings suggest significant ongoing healthcare needs in this cancer survivor population. Disclosures Muffly: KITE: Consultancy; Pfizer: Consultancy; Adaptive: Research Funding.

Outcomes in Adolescent and Young Adult (AYA) Acute Lymphoblastic Leukemia (ALL): A Report from the Indian Acute Leukemia Research Database (INwARD) of the Hematology Cancer Consortium (HCC)

Introduction Acute lymphoblastic leukemia (ALL) diagnosed in adolescent and young adults (AYA) poses unique challenges. Despite using more intensive "pediatric-type" protocols, outcomes are generally inferior to those seen in children. The reasons are wide ranging, but when compared to pediatric ALL, AYA ALL has higher-risk biology, poorer tolerance to intensive treatments, and worse compliance with treatment regimens. India has one of the largest AYA populations in the world and AYA-ALL form a significant proportion of leukemias. The Indian acute leukemia research database [INwARD] was established in 2018 and had reported outcomes of ALLs from various centers of all age groups (Korula A, et al. Blood 2018 132:1374). Here, we present data focused on AYA-ALL from this database. Methods Retrospective data of AYA (15-29 years) patients with ALL (diagnosed between January 2012 to December 2017) from 9 centers were entered into an independent centralized online data capture system and analyzed for presenting characteristics, treatment and survival outcomes. Protocol choice was based on individual-center preference. For the purpose of this analysis, patients with WBC ≥30000 (B cell) and ≥100,000 (T-cell and other subtypes) were considered as high risk. Intensive protocols (MCP-841, BFM-95, COG), predominantly meant for children were labeled as "pediatric-type" and less intense protocols (GMALL, Hyper CVAD, UKALL) were considered as "adult-type". Results In the 6-year period, 1454 patients were registered [Males: 1114(76%), Median age: 20 years (15-29), Fig. 1.B; Subtype: B -ALL: 916(63%), T-ALL: 396 (27%); Fig. 1.C; High risk disease: 406 (28%)]. Of these,1100 (75%) underwent treatment. Poor financial support was the major reason for not taking treatment (Fig. 1.A). "Pediatric-type" protocols were used in 881 (81%) patients. After induction, 72% achieved complete remission (CR), 11% were refractory, 4% died during induction and 14% were not evaluable. Minimal residual disease was assessed in 581 and was present in 356 (61%). Attainment of CR, induction mortality, or MRD achievement was not affected by the type of regimen. Among these 1100 patients, 138 (12%) were lost to follow up and did not complete treatment. BCR ABL was tested in 636 and was positive in 112 (17%) [19% among patients with B-ALL (107/557)]and 106 of these were treated with additional tyrosine kinase inhibitors [imatinib (N=83) and dasatinib (N=23)]. Survival analysis: After a median follow up of 21 months, 270 patients relapsed [median time to relapse: 24 months (73% medullary, 17% CNS or testis, and 10% had a combined relapse) and 259 had died. The estimated 2-year event-free (EFS), relapse-free (RFS) and overall survival (OS) were 64%, 75% and 75% respectively. On univariate analysis the factors associated with inferior survival were as follows: EFS: WBC count ≥30,000/cmm, and ECOG PS 2-4; RFS: WBC count ≥30,000/cmm and ECOG PS 2-4; OS: use of "adult-type" protocols, ECOG PS 2-4, and BCR-ABL positive disease. On multivariate cox regression analysis, the only factors associated with inferior OS were: use of "adult" protocols (HR: 1.6), and BCR -ABL positive status (HR1.56) (Fig. 1.D). High WBC count at presentation predicted for inferior RFS while no factor could predict EFS on multivariate analysis. Conclusions In a multicenter analysis of AYA-ALL from different parts of India, we found that a quarter of newly diagnosed patients do not start treatment and another 12% are lost from follow up before treatment completion. Majority (80%) of the centers used "pediatric-type" protocols to treat AYA-ALL. Though superior survival was achieved with "pediatric-type" protocols, results must be interpreted with caution as these regimens were likely to be used more often in in younger patients. Variations in treatment protocols used between centers and the retrospective nature of the data are other caveats. Despite these limitations, this is one of the largest reports of AYA ALL from any part of the world and serves as a benchmark for planning prospective studies. Disclosures No relevant conflicts of interest to declare.