Adolescents And Young Adults Acute Lymphoblastic Leukemia Research Articles

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.

Optimal therapy for adolescents and young adults with acute lymphoblastic leukemia-current perspectives.

Adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) have worse prognosis than children. Differing biology of ALL may account for some of this disparity in outcome, with AYA patients having far lower incidence of good risk cytogenetic abnormalities, and higher proportion of patients with genetic lesions associated with inferior survival such as Ph-like ALL. Actual chemotherapy may also contribute to differences in outcome. Retrospective studies have shown that AYA patients treated on pediatric-based regimens had higher survival than those treated with adult regimens; the superiority of pediatric protocols has also been proven in several prospective comparative trials. Increase in rate of enrollment of AYA patients in clinical trials may further improve outcome. Cure based on chemotherapy may further limit the role of allogeneic hematopoietic cell transplantation (HCT) in AYA patients. The unique biology of AYA ALL may allow for novel methods of targeted therapy, while immunotherapy, the efficacy of which has been proven for both children and adults, may also play a major role in the treatment of relapsed/refractory ALL.

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 Young Adult Acute Lymphoblastic Leukemia: A United States Population-Level Analysis.

In this population-based evaluation of adolescents and young adults (AYA) acute lymphoblastic leukemia (ALL), we describe patterns of care (POC) and outcomes regarding hematopoietic cell transplantation (HCT) in first complete remission (CR1). Data were abstracted from the 2013 United States Surveillance, Epidemiology, and End Results POC study; newly diagnosed AYA ALL were included. Multivariable logistic regression evaluated associations with HCT in CR1; Cox proportional hazards regression evaluated survival associations. Of 399 AYAs with ALL included, 102 (28.5%) underwent HCT in CR1. High-risk cytogenetics (odds ratio [OR] = 4.86, 95% confidence interval [CI] = 3.02-7.83) and hyper-cyclophosphamide, vincristine, adriamycin, and dexamethasone (CVAD) induction (OR = 1.84, 95% CI = 1.07-3.16) were associated with HCT in CR1. 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 RFS was significantly higher in patients receiving CR1 HCT relative to chemotherapy (83.6%, 95% CI = 72.6-90.5% vs. 64.3%, 95% CI = 57.5-70.3), but no difference was seen in 2-year OS (88.9%, 95% CI = 80.8-93.7 vs. 82.5%, 95% CI = 77.2-86.7). Treatment at a nonteaching hospital was independently associated with inferior OS (hazard ratio = 2.15, 95% CI = 1.23-3.76). Although the ALL landscape is changing, these data provide a snapshot of the use and outcomes of HCT for AYA ALL across the United States.

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.

Medical Conditions Among Survivors of Adolescent and Young Adult Non-Hodgkin Lymphoma (NHL), Acute Lymphoblastic Leukemia (ALL) and Acute Myeloid Leukemia (AML)

Introduction: Adolescent and young adult (AYA) cancer survivors are at an increased risk of developing subsequent medical problems, including asthma/chronic obstructive pulmonary disorder, cardiovascular disease, diabetes and second cancers. However, few population-based studies have focused on these risks in AYAs with NHL, ALL or AML or considered whether the occurrence of these and other medical conditions differ by sociodemographic factors.Methods: Data for patients aged 15-39 when diagnosed with NHL (n=4,459), ALL (n=1,100) and AML (n=1,107) during 1996-2012 and surviving a minimum of 2 years were obtained from the California Cancer Registry and followed in California hospital discharge databases. Discharge diagnoses were used to classify medical conditions as cardiac (hypertensive disease, ischemic heart disease, other heart disease), neurologic (stroke, seizure), endocrine (hypothyroidism, diabetes, ovarian/testicular dysfunction, other metabolic diseases), respiratory (asthma, chronic obstructive pulmonary disease), renal (chronic kidney disease, hemodialysis, kidney transplant), liver (chronic liver disease, pancreatitis, cirrhosis, liver transplant), and avascular necrosis. Second cancers were obtained from the cancer registry. We estimated the cumulative incidence (CMI) of developing each condition 10-years after diagnosis, accounting for death as a competing risk. We determined the impact of race/ethnicity, neighborhood socioeconomic status (SES), health insurance status and stem cell transplant (SCT) on the occurrence of each medical condition after adjusting for other demographic and clinical factors using multivariable Cox proportional hazards regression.Results: The most common medical conditions among AYA survivors at 10-years were cardiac (CMI NHL: 11.6%; ALL= 20.5%; AML= 18.2%), endocrine (CMI NHL: 18.6%; ALL= 33.0%; AML= 25.9%) and respiratory (CMI NHL: 5.1%; ALL= 7.7%; AML= 6.8%) diseases. Avascular necrosis had the highest CMI in ALL patients (CMI NHL: 1.2%; ALL= 8.7%; AML= 2.5%). Neurologic (CMI NHL: 2.1%; ALL= 4.5%; AML= 4.9%) and liver (CMI NHL: 2.0%; ALL= 5.6%; AML= 4.4%) were more common in survivors of ALL and AML than NHL. Second cancers (2.3-2.5%) and renal diseases (2.2-3.5%) were less common at 10-years. NHL survivors with advanced stage disease had a higher incidence of all medical conditions, except second cancers. Chemotherapy was associated with a higher CMI of cardiac and endocrine conditions among NHL survivors; these associations could not be assessed in ALL and AML patients as nearly all patients received chemotherapy. Initial radiation therapy was not associated with a higher CMI of medical conditions in NHL or ALL survivors, but was associated with a higher CMI of respiratory, renal and endocrine diseases in AML survivors. In multivariable models, public or no insurance (vs private) was associated with a higher risk of most medical conditions in NHL and ALL survivors, but not AML survivors (Table). The risk of developing medical conditions varied by race/ethnicity, with Hispanics ALL survivors (vs non-Hispanic whites) at a higher risk of cardiac, renal, liver, endocrine, second cancers and neurologic diseases and black AML survivors at a higher risk of all medical conditions, except endocrine diseases. AYAs with NHL who resided in lower SES neighborhoods were at a higher risk for developing cardiac, respiratory and endocrine diseases; AML survivors in lower SES neighborhoods had a higher risk of respiratory diseases. Across all cancers, AYAs undergoing a SCT were at a higher risk of most medical conditions.Conclusion: This study found that sociodemographic factors were associated with the risk of developing medical conditions in AYA NHL, ALL and AML survivors. As expected, the risk of medical conditions varied by cancer type and treatment, with those undergoing SCT having a higher risk of medical conditions regardless of cancer type. NHL and ALL survivors who were uninsured or publicly insured were at a consistently higher risk of developing medical conditions, as were Hispanic ALL survivors and Black AML survivors. Our findings highlight the higher burden of medical conditions in subgroups of cancer survivors that may relate to reduced access to preventive care, early detection/intervention and long-term surveillance. DisclosuresMuffly:Shire Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding.

Highlights of This Issue

Epidemiologic studies have examined association between human papillomaviruses (HPVs) and esophageal cancer, but results have been inconsistent. Agalliu and colleagues carried out a nested case–control study (125 cases; 372 controls) among 96,650 cancer-free participants in two large cohort studies to investigate associations of alpha, beta, and gamma HPV detection in the oral cavity and risk of esophageal cancer. Oral HPV16 detection was not associated with esophageal cancer (OR = 0.54, 95% confidence interval: 0.1–4.84). Although some oral HPV types were more common in cases than controls, none of the associations were statistically significant. Oral HPVs may not contribute to risk of esophageal cancer.Melanoma incidence has been rising over decades despite public efforts to promote sun protection behaviors. Dietary factors may also affect the development of melanoma; some have emerged as promising candidates for chemoprevention. Yang and colleagues conducted a narrative review of the relationship between dietary factors, including coffee and caffeine, citrus fruits, alcohol, polyunsaturated fatty acid, niacin/nicotinamide, folate, and vitamin D, with melanoma risk from the perspective of epidemiology. Biological mechanisms and some future directions were also discussed and outlined. The associations discussed may have important public health implications in terms of reducing melanoma incidence through dietary modification.In patients with acute lymphoblastic leukemia (ALL), adolescents and young adults (AYA) experience increased risk of relapse as compared with children, while predictors of relapse among AYA vary by time of relapse. Wolfson and colleagues found that among AYA with ALL, aspects of healthcare delivery (clinical trial enrollment, nonwhite race/ethnicity) are associated with relapse during therapy, and aspects of treatment (shorter duration of maintenance and consolidation) are associated with relapse after completing therapy. These findings highlight the importance of clinical trial enrollment and therapy duration (maintenance, consolidation) in ensuring durable remissions in AYA ALL. Future studies encompassing healthcare delivery, treatment, and biology are needed.Prenatal diethylstilbestrol (DES) exposure is associated with adverse reproductive and neoplastic outcomes. In this study by Troisi and colleagues, age-adjusted ratios of serum estrogens metabolized in the 2-pathway compared to the 16-pathway were about 30% lower in postmenopausal women who were prenatally DES exposed [2-pathway:16-pathway = 0.37, 95% confidence interval (CI) = 0.31–0.44; n = 40] than unexposed (2-pathway:16-pathway = 0.51, CI = 0.40–0.66; n = 20), and remained lower with adjustment for total estrogen, years since menopause, body mass index, parity, and alcohol intake. Lower 2-pathway metabolism is associated with increased postmenopausal breast cancer risk and could partially explain the modest increased risk observed in DES exposed women.

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.

Novel Targets Identified By in Vitro Screening of Patient Samples with Adult Acute Lymphoblastic Leukemia

Introduction: Acute lymphoblastic leukemia (ALL) is considered a success story in pediatrics, with cure rates greater than 85%. In contrast, the estimated cure rate for adolescent and young adult (AYA) patients is estimated at 60% and is just 20-40% for adults. This is thought to be secondary to chemotherapy associated toxicities for older patients as well as different disease biology. In the AYA population, more patients carry the chemo-resistant Ph-like phenotype, with an estimated incidence of up to 27%. However, the genetic profile of adult ALL has not been well described. In addition, although the ABL specific kinase inhibitors and JAK inhibitors are predicted to be active in Ph-like ALL, there are no reports on functional drug sensitivity data in AYA or adult ALL. Our group has been collecting functional data on both newly diagnosed and relapsed AYA and adult patients since 2010; in this study we summarize the functional data obtained during this time. Materials and Methods: All clinical samples were obtained with informed consent and approval of the institutional review board at OHSU. Data obtained on both newly diagnosed and relapsed patients obtained from Jan 2010 to present was reviewed. At the time of diagnosis or at relapse, mononuclear cells were isolated from bone marrow aspirates of patients and exposed to a library of 130 small molecule inhibitors at varying concentrations. After 72 hours, cell viability was assessed via an MTS based assay and drug efficacy was assessed based on the IC50 of of each panel drug against each patient sample. The calculated IC50 for each drug was compared to the median IC50 of over 1000 patient samples and was deemed hypersensitive if the IC50 value was below the 20th percentile. A pathway was considered to be actively targeted if patients had more than one inhibitor targeting that pathway identified as hypersensitive, or a single drug was considered valid if it was hypersensitive in replicate testing.Results: We identified a total of 42 adults with either B-cell or T-cell ALL who had analyzable data; those with Ph+ ALL were excluded. Of these, 28 had B cell ALL including the MLL rearrangement and 14 had T cell ALL. For the B cell ALL group, 17 had data obtained at diagnosis and 11 at relapse. 75% of patients had at least one active inhibitor identified, with the range being from 2-25 inhibitors per patient targeting from 1-5 different pathways per patient. We found that 35% of patient samples were sensitive to a JAK inhibitor, an ABL inhibitor or both. In addition, we found overlapping sensitivities with 43% of patient samples sensitive to PI3K/AKT/mTOR inhibitors, 43% of samples were sensitive to IGF1R inhibitors, 49% were sensitive to PDGFR/VEGFR inhibitors, 18% were sensitive to p38MAPK inhibitors and 11% each were sensitive to CSF1R or FLT3 inhibitors. Of note, all of the FLT3 inhibitor sensitivities were within the MLL-rearranged subgroup. Among the T-ALL group, 10 had data obtained at diagnosis and 4 at relapse. 52% of the samples had at least one inhibitor identified, with the range being from 1-20 inhibitors targeting from 1-4 pathways per patient. Drugs targeting the following pathways were identified: JAK family (57.1%), ERBBB family (57.1%), SYK (28.5%), and HDAC, MDM2 and aurora kinase (14.3% each).Discussion: This study provides the evidence that there are multiple novel potentially targetable pathways present in AYA and adult patients with ALL. Given the poor outcomes in this group of patients, further exploration of these potentially targetable pathways is warranted. DisclosuresTyner:Agios Pharmaceuticals: Research Funding; Array Biopharma: Research Funding; Aptose Biosciences: Research Funding; AstraZeneca: Research Funding; Constellation Pharmaceuticals: Research Funding; Genentech: Research Funding; Inctye: Research Funding; Janssen Research & Development: Research Funding; Seattle Genetics: Research Funding; Takeda Pharmaceuticals: Research Funding; Leap Oncology: Consultancy. Druker:Curis: Patents & Royalties; Pfizer: Patents & Royalties; Array: Patents & Royalties; Dana-Farber Cancer Institute: Patents & Royalties: Millipore royalties via Dana-Farber Cancer Institute; Oncotide Pharmaceuticals: Research Funding; Novartis: Research Funding; BMS: Research Funding; ARIAD: Patents & Royalties: inventor royalties paid by Oregon Health & Science University for licenses, Research Funding; Roche: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses; D3 Oncology Solutions: Consultancy; AstraZeneca: Consultancy; Ambit BioSciences: Consultancy; Agios: Honoraria; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Lorus: Consultancy, Equity Ownership; Cylene: Consultancy, Equity Ownership; CTI: Consultancy, Equity Ownership; Pfizer: Patents & Royalties; Curis: Patents & Royalties; Array: Patents & Royalties; Dana-Farber Cancer Institute: Patents & Royalties: Millipore royalties via Dana-Farber Cancer Institute.

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.

How I treat acute lymphoblastic leukemia in older adolescents and young adults

AbstractAt the intersection between children and older adults, the care of adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) poses unique challenges and issues beyond those faced by other age groups. Although the survival of AYA patients is inferior to younger children, growing evidence suggests that AYA patients have improved outcomes, with disease-free survival rates of 60% to 70%, when treated with pediatric-based approaches. A holistic approach, incorporating a multidisciplinary team, is a key component of successful treatment of these AYA patients. With the appropriate support and management of toxicities during and following treatment, these regimens are well tolerated in the AYA population. Even with the significant progress that has been made during the last decade, patients with persistence of minimal residual disease (MRD) during intensive therapy still have a poor prognosis. With new insights into disease pathogenesis in AYA ALL and the availability of disease-specific kinase inhibitors and novel targeted antibodies, future studies will focus on individualized therapy to eradicate MRD and result in further improvements in survival. This case-based review will discuss the biology, pharmacology, and psychosocial aspects of AYA patients with ALL, highlighting our current approach to the management of these unique patients.

A Genome-Wide Association Study of Susceptibility to Acute Lymphoblastic Leukemia in Adolescents and Young Adults

Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared to pediatric ALL. Age, as a continuous variable, is negatively correlated with prognosis, in spite of risk-adapted combination chemotherapy. To better understand the etiology of ALL in this age group, we performed the first genome-wide association study (GWAS) to comprehensively examine germline single nucleotide polymorphisms (SNPs) for their association with susceptibility to B-ALL in AYAs.In the discovery GWAS, we compared genotype frequency at 635,297 SNPs between 308 AYA ALL cases (age 16-39 years, treated on the Children’s Oncology Group [COG], the Alliance-Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, MD Anderson Cancer Center, and St. Jude Children’s Research Hospital trials) vs. 6,661 non-ALL controls. The association between genotypes at each SNP and ALL susceptibility was tested by using a logistic regression model after adjusting for genetic ancestries to control for population stratification. SNPs that reached P≤ 5×10-8 in the discovery GWAS were tested in an independent cohort of 82 AYA ALL cases from the COG protocols and 5,755 non-ALL controls.We identified a single genome-wide significant susceptibility locus on 10p14 signified by two SNPs within the GATA3 gene: rs3824662, P=2.8x10-10, odds ratio (OR)=1.77; rs3781093, P=3.2x10-9, OR=1.73, both of which were validated in the replication cohort (P=1.9x10-8 and P=4.3x10-5, respectively). We also examined the association signals in AYAs for susceptibility loci previously identified in pediatric ALL: ARID5B, IKZF1 and PIP4K2A variants were nominally significant in AYAs in the discovery GWAS and/or in the replication analysis, whereas CEBPE or CDKN2A/CDKN2B were not significant. These results imply both similarities and differences in genetic predisposition to ALL between children and AYAs.At the GATA3 locus, rs3824662 risk variant was over-represented in Philadelphia chromosome (Ph)-like ALL in AYAs (P=0.02), confirming our previous report of Ph-like ALL susceptibility variants in GATA3 (Nat Genet 45:1494). Importantly, even after excluding Ph-like cases, rs3824662 remained associated with the risk of developing ALL in AYAs, suggesting that the influence of the GATA3risk variant on ALL susceptibility in AYAs extends beyond the predisposition to Ph-like subtype.We next examined the relationship between GATA3 risk allele frequency and age at diagnosis in a cohort of unselected childhood and adolescent ALL cases enrolled in the COG P9900 protocols (N=1,827). Dividing patients into four consecutives age groups (<5, 5-10, 10-15 and >15 years), we observed a clear progressive increase in the risk allele frequency at rs3824662 (P=6.29×10-11) with increasing allelic odds ratio (i.e. relative risk of ALL conferred by each copy of the risk allele). This correlation between genotype and age was evident regardless of genetic ancestry, although the risk variant was more common among individuals with higher Native American ancestry. In contrast, the frequency of ALL susceptibility variant in ARID5B decreased progressively with increasing age at diagnosis (P=0.006), whereas PIP4K2A, CDKN2A/CDKN2B, IKZF1 and CEBPE variants were not related to age. Finally, we compared rs3824662 risk variant frequency by age in the COG P9900 protocols after stratifying the ALL cases into TCF3-PBX1, ETV6-RUNX1, hyperdiploid, MLL-rearranged and B-other. There was a trend that the risk allele was more frequent in cases older than 16 years compared to those below 16 in the five subtypes examined.In conclusion, we have identified inherited GATA3 genetic variants that strongly influence ALL susceptibility in adolescent and young adults, indicating potential age-related differences in ALL biology. DisclosuresNo relevant conflicts of interest to declare.

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.

Acute Lymphoblastic Leukemia in Adolescents and Young Adults

The cure rate of acute lymphoblastic leukemia (ALL) in children is 80%, compared to less than half in adults. A major proportion of this cure rate drop occurs in adolescents and young adults (AYAs). The age range defining this population varies between studies, biological characteristics are different from both younger children and older adults, and AYAs are treated either by pediatric or adult oncologists, who often apply different treatment approaches to the same ALL patient population. The outcome of AYAs aged 15-21 years treated by more contemporary pediatric protocols is similar to that of younger children but is inferior when using adult regimens. This motivated studying AYA patients, including those above the age of 21 years, with pediatric or ‘pediatrics-inspired' regimens that intensified nonmyelosuppressive drugs such as vincristine, steroids and asparaginase, with very promising preliminary results. Discovering new mutations in AYA ALL will help stratify patients into risk subgroups and identify targets for novel agents. This, together with fine-tuning pediatric chemotherapy principles will hopefully finally decrease the cure rate gap between children and AYAs - and even older adults.

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.

Significant Improvement Of Outcome In Adolescents and Young adults (AYAs) Aged 15-35 Years With Acute Lymphoblastic Leukemia (ALL) With a Pediatric Derived Adult ALL Protocol; Results Of 1529 AYAs In 2 Consecutive Trials Of The German Multicenter Study Group For Adult ALL (GMALL)

▪Several groups have reported results from smaller series of AYAs with ALL. Outcomes with so-called protocols for adults were generally inferior compared to so-called pediatric protocols. The GMALL protocols were originally based on pediatric BFM protocols and have been consecutively optimized for adults since 1981. We report the results of two recent protocols 05/93 (Goekbuget et al, Blood 98(11):802a, 2001) and 07/03 (Goekbuget et al, Blood 110(11):12a, 2007). In study 07 high risk (HR) pts were identified by one of the factors: B-lin with WBC>30.000, late CR (>3 wks), pro-B, early T, mature T, MLL1/AF4/t(4;11). Pts without risk factors were standard risk (SR) and those with BCR-ABL/t(9;22) very high risk (VHR). HR/VHR pts were candidates for SCT in CR1. The major innovations in study 07 were: intensified, shortened induction with dexamethasone instead of prednisone, PEG-asparaginase (ASP) instead of native ASP, intensified first consolidation, 6x HDMTX/ASP during consolidation, matched unrelated SCT for HR/VHR pts without sibling donor and SCT indication in pts with persistent MRD. After amendments in trial 07 pts partly also received intensified PEG-ASP, rituximab in CD20+ ALL and imatinib in Ph+ ALL.Overall, 1529 of 3060 (50%) pts recruited into both trials were aged between 15-35 yrs. 642 pts from 94 centres were recruited to study 05 and 887 pts from 130 centres to study 07. Patient characteristics were similar for both trials. 70% had B-Lin and 30% T-ALL (61% c/preB, 9% proB, 7% early T, 6% mature T, 17% thy T) with no significant differences across age subgroups (15-17,18-25 and 26-35 yrs). Allocation to SR, HR and VHR was 51%, 35% and 14%. VHR incidence increased from 3%, 11% to 19% in age groups (p<.0001).The CR rate increased in studies 05 to 07 from 88% to 91% (p=.001), most prominently within the age range of 26-35 yrs (86% to 90%;p=.001) (table). The OS increased from 46% to 65% (p<.0001) (significant in all age groups). Remission duration (RD) at 5 yrs increased from 49% to 61% (p=.0001), most prominently within the age range of 26-35 yrs (46% vs 59%; p=.005). OS improved from study 05 to study 07 in B-Lin (45% vs 66%; p<.0001) and T-ALL (47% vs 63%; p=.0007) overall and in subgroups as c/pre B (50% vs 68%;p<.0001), pro B (45% vs 67%;p=.05), mature T (19% vs 61%; p=.005) and thymic T (59% vs 70%;p=.09) but to a lesser extent in early T (35% vs 48%;p>.05). OS increased in SR (58% to 74%; p<.0001), HR (24% to 58%; p<.0001) and VHR (36% vs 55%;p=.0003).Table 1Results of Induction and Overall Outcome in GMALL-Studies 05/93 and 07/0305/9307/03Total15-1718-2526-35Total15-1718-2526-35Evaluable64210625238488753458376CR88%91%88%86%91%94%91%90%ED3%1%3%3%4%0%3%6%Failure9%8%8%11%5%6%5%4%RD at 5y49%52%50%46%61%60%62%59%OS at 5y46%57%45%42%65%73%69%60%15% vs 43% of all CR pts underwent SCT in CR1 in studies 05 and 07. The proportion of SCT increased from 22% to 68% (p<.0001) in HR and from 62% to 73% (p<.0001) in VHR in studies 05 vs 07. The OS after SCT improved from 36% to 68% (p<.0001), mainly due to a decrease of TRM from 34% to 12% (p<.0001).In trial 07 MRD in week 16 (after consolidation I) was tested in 353 pts. The proportion of molecular failure (MRD>0.01%) was 26% with no differences across age groups. OS was 90% in pts with mol. CR vs 53% in mol. failure (p<.0001). Amendments in study 07 led to further improvement with an OS of 71% in 274 pts aged between 15-35 yrs treated according to the final protocol version.We present here results of the so far largest cohort of AYA ALL pts treated according to pediatric-derived adult ALL protocols. Outcomes have significantly improved and reached a 73% OS in pts aged 15-17 yrs. Intensified treatment with ASP, MTX and targeted therapies as rituximab and imatinib and MRD based stratification have contributed to the improvement in study 07. SCT led to improved OS in HR and VHR ALL. Obviously, there is no indication for SCT in CR1 in young SR pts with an OS of 74%. Future GMALL studies will attempt to optimize further the combination of pediatric approaches and targeted therapies in adults.Supported by Deutsche Krebshilfe 70-2657-Ho2 and partly BMBF 01GI 9971. Disclosures:Off Label Use: RItuximab in ALL.

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.

Acute lymphoblastic leukemia in young adults

Acute lymphoblastic leukemia (ALL) is the most common and one of the most curable malignancies in children; however, it presents unique challenges in adolescents and young adults (AYAs). The purpose of this review is to discuss factors that contribute to the outcome disparities in AYAs with ALL as well as approaches that can be taken to optimize the care of this patient population. AYAs with ALL are unique and have outcomes that have lagged behind those observed in children with ALL. Contributing factors to the challenges faced by this group include distinctive disease biology, different drug pharmacology and toxicity profiles, and complex psychosocial and socioeconomic factors. Several clinical trials conducted worldwide have demonstrated that treatment with pediatric protocols significantly improves outcomes in the AYA population. Initiatives to improve outcomes for AYAs with ALL include treatment with pediatric regimens tailored to be delivered without excessive toxicity and in centers with the necessary supportive care and medical services to address the specific needs of this population. As more is understood about the unique disease biology of AYA ALL, targeted therapeutic approaches may offer promise for the future.