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

Key Points Two-thirds of AYA ALL are treated in the adult cancer setting; one-quarter of AYAs in this setting receive front-line pediatric ALL therapy. Survival was superior for AYA ALL patients treated in pediatric cancer settings and in NCI-designated cancer centers.

Abstract The genetic basis underlying inferior outcome of adolescent and young adult acute lymphoblastic leukemia (AYA ALL) as compared to childhood cases is largely unknown. To comprehensively characterize the genetic landscape of AYA ALL we studied 423 adolescent (16-21 yrs; median 17.7±1.3 yrs) and 250 young adult (21-39 yrs; median 28.3±7.0 yrs) samples from the Children's Oncology Group high-risk trial AALL0232, St Jude Children's Research Hospital Total XV and XVI, Eastern Cooperative Oncology Group E2993, MD Anderson Cancer Center and the Alliance - CALGB trials. Single nucleotide polymorphism (SNP) microarray analysis and gene expression profiling were performed to identify copy number alterations and distinct genetic subgroups. Samples were also sub classified using hierarchical clustering, ROSE outlier and PAM analysis of gene expression profiling data. Sequence mutation analysis was performed on candidate genes known to be mutated in pediatric ALL (including IKZF1, PAX5, JAK1/2, NRAS, KRAS, FLT3, IL7R, SH2B3, TP53 and CREBBP), and mRNA-seq was performed on selected BCR-ABL1-like cases (n=41). The genetic subgroups were divided into ETV6-RUNX1, TCF3-PBX1, hyperdiploid (>50 chromosomes), MLL rearrangements, BCR-ABL1, BCR-ABL1-like, ERG and other (cases with no known lesions). As expected, ETV6-RUNX1 and hyperdiploid ALL were less frequent in adolescents (4% and 11%, respectively) and adults (2% for both) than in childhood ALL (<16 years; 25% for both). In contrast, the frequency of BCR-ABL1-like ALL, a recently described subgroup in 10-15% of pediatric ALL associated with kinase-activating lesions and a poor outcome, was very frequent and increased with age (21% in adolescent, 25% in young adults), similar to cases with the classic BCR-ABL1 translocation (6% in adolescent, 22% in young adults). Notably, BCR-ABL1 and BCR-ABL1-like ALL patients presented with higher white blood counts at diagnosis compared to non BCR-ABL1-like ALL patients in both adolescents (117.6 and 76.8 vs 21.9 x109/L, p<0001), and young adults (72.6 and 94.1 vs 17.6 x109/L, p<0001). BCR-ABL1-like ALL patients were also more likely to be male compared to non BCR-ABL1-like ALL patients, with 74% vs 62% in adolescents (p<0.05; Fisher's exact test), and 81% vs 63% in young adults (p=0.07; Fisher's exact test). The outcome of BCR-ABL1 and BCR-ABL1-like ALL was markedly inferior to other ALL subtypes, with 5-year event free survival (EFS) rates of 53.7+18.3 and 40.0+7.1 vs 85.0±3.3 (p<0.0001) in adolescent cases, and 23.2±9.1 and 16.1±8.5 vs 57.9±8.0 (p=0.006) for young adults (Figure 1). IKZF1 alterations, a marker of poor outcome in pediatric ALL, were enriched in BCR-ABL1 and BCR-ABL1-like ALL cases (70% and 77%, respectively) compared to non BCR-ABL1-like patients (26%). Regardless of genetic subtype, the presence of an IKZF1 alteration correlated with inferior 5 year EFS in adolescent (60.3±6.0 vs 77.4±4.1; p=0.0015) and young adults (25.7±7.0 vs 52.7±6.4; p=0.0011). We then sought to characterize the alterations activating kinase signaling in AYA BCR-ABL1-like ALL cases. As observed in pediatric ALL, approximately 55% of these cases harbored CRLF2 rearrangements. Using mRNA-seq we identified a variety of additional rearrangements involving the tyrosine kinase or cytokine receptor genes ABL1, ABL2, CSF1R, JAK2, EPOR or PDGFRB, with a marked enrichment of fusions involving JAK2 (6 different fusions in 9/20 cases sequenced), thus providing a rationale for the investigation of targeted therapies directed against these alterations. Collectively, the kinase-activating BCR-ABL1 and BCR-ABL1-like subtypes are associated with poor outcome and make up ∼25% of adolescent and ∼50% of young adult ALL patients. The identification of these patients at diagnosis will provide an opportunity to incorporate tyrosine kinase inhibitor treatment to current chemotherapeutic regimens, and significantly improve the treatment outcome for AYA ALL. Disclosures: Hunger: Bristol Myers Squibb: Consultancy.

Abstract Abstract 1527 Several pediatric-based protocols for treatment of acute lymphoblastic leukemia (ALL) in adolescents and young adults have been completed or are ongoing. Some studies have enrolled patients (pts) up to age 55 years, and, so far, results have been satisfactory. Augmented Berlin-Frankfurt-Muenster (ABFM) has been shown to be an effective and tolerable treatment for ALL in adolescents. To evaluate the efficacy and toxicity of this therapy in young adults, we designed a protocol of modified ABFM therapy for pts with ALL from age 12 to 40 years old. 83 pts have been enrolled on protocol and are evaluable for toxicity. 68 pts with de novo Philadelphia chromosome negative ALL have completed at least 29 days of therapy (induction) on protocol. They have the following characteristics: 56 (82%) pts have pre-B ALL and 12 (18%) have T-ALL. The median age is 21 (mean=23; range=13–39). The median presenting WBC=5.3 (mean=32; range= 0.4–494). 65/68 (96%) pts have achieved a remission. One patient died during induction. 50 (74%) pts have attained remission by 15 days of induction, while 15 (22%) have been slow responders. 5/68 (7%) pts have required an extension of induction by 2 weeks. At day 29 of therapy, 38 (56%) pts had negative minimal residual disease (MRD) by flow cytometry, 20 (29%) patients were positive for MRD, 10 were suspicious or not available. By day 84 of therapy, 49 (72%) pts were negative for MRD and 9 (13%) were positive. Currently, there have been 17 relapses and 10 deaths. Toxicities in the entire group include severe asparaginase allergy in 15 (18%) pts, thrombus formation in 16 (19%) pts, hyperbilirubinemia grade III-IV in 19 (23%) pts, ALT/AST grade III-IV in 23 (28%) pts, CNS stroke-like symptoms in 6 (7%) pts, hypofibrinogen grade III-IV in 26 (31%), pancreatitis in 6 (7%), and avascular necrosis in 6 (7%) pts. Hepatic toxicity has resolved completely within two weeks in almost all pts as has the CNS toxicity. In summary, induction success, by morphology and flow cytometry, has been satisfactory with this regimen. CRD and OS have not been significantly better than with HyperCVAD therapy for this age group. Expected toxicities have been prominent, but mostly transient. Hypofibrinogenemia is frequent, but bleeding is rare. Thrombosis and severe allergic reactions are more frequent than in pediatric trials. For pts 25 years of age and younger, the overall survival (OS) and disease free survival (DFS) at 2 years are 88% and 84% respectively. For pts > 25 years of age, the OS and DFS at two years are 65% and 50% respectively. This difference in OS between the groups is statistically significant. Continued enrollment is anticipated to further evaluate the survival differences between these two patient groups. Disclosures: No relevant conflicts of interest to declare.

CRA9508 Background: Historically, AYA patients (>16yrs of age) with HR-ALL have an inferior outcome compared to HR-ALL patients 1-15 yrs old, due to increased rates of both relapse and toxicity. Methods: AALL0232 was a phase III randomized trial for patients 1-30 years of age with newly diagnosed B-precursor HR-ALL that utilized a 2 x 2 factorial design with an augmented intensity Berlin-Frankfurt-Münster (BFM) backbone. Patients were randomized to receive dexamethasone versus prednisone during Induction and high dose methotrexate versus escalating Capizzi methotrexate during Interim Maintenance I. A total of 2,574 eligible, evaluable, non-Down Syndrome, non-very high risk patients were randomized between January 2004 and January 2011. AYA patients comprised 20% of this group (n=501; 16-21 yrs: 466 and 22-30 yrs: 35). Results: The 5-yr event-free survival (EFS) and overall survival (OS) rates were 68.0% and 79.8% for AYA patients compared to 80.9% and 88.4% for younger patients (p<0.0001). The 5-yr cumulative incidence of relapse was 21.3% for AYA patients and 13.4% for younger patients (p=0.0018), largely due to higher rate of marrow relapse (15.2% vs. 9.0%; p<0.0007) and not CNS relapse (5.2% vs. 3.7%; p=0.5776). In addition, fewer AYA patients achieved remission, defined as <5% marrow blasts at end induction (97.2% vs. 98.8%; p=0.0134). There was no significant difference in induction mortality between AYA and younger patients, 2.4% vs. 1.8% (p=0.36). However post-induction remission deaths were significantly higher in AYA compared with younger patients, 5.5% vs. 2.1% at 5 years (p<0.0001). Conclusions: This is the largest cohort of AYA ALL patients presented to date and confirms high cure rates for AYA patients treated on pediatric ALL trials. AYA HR-ALL patients had lower EFS and OS compared to younger patients, primarily attributable to both higher rates of marrow relapses and remission deaths. Effective strategies to improve the outcome of AYA patients with HR-ALL should be aimed at both furthering leukemia eradication and lowering toxicity of therapy for this patient population.

Abstract Retrospective and prospective studies have demonstrated that AYA patients (pts) with ALL have superior outcomes when treated with pediatric rather than adult-type regimens. Pediatric ALL regimens are therefore being applied as frontline therapy for adults up to age 30. Given the relatively favorable outcome for this group and the length of therapy employed, it will be several years before the superiority of this approach can be confirmed. MRD by multiparameter flow cytometry (MFC) might be an early measurement of treatment efficacy, since detection of MRD after initial induction has been shown to predict for decreased disease-free survival (DFS). MRD monitoring may thus provide an early indication of later success for different ALL regimens in AYA patients. MRD was measured by four color MFC using lineage specific antibodies in conjunction with antibodies directed at aberrant antigens. The limit of detection was one cell in ten-thousand. MRD data for 43 pts </= 30 years of age treated with the adult regimen of hyper CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) with or without rituximab was compared with MRD data obtained from 13 pts treated with the pediatric ABFM regimen. The median age of the two groups was 22 years (range 15–30) and 20 years (range 14–28), respectively. MRD data on day 21 of therapy was available for 33 of 43 pts (77%) treated with hyer-CVAD; 22/33 (67%) were negative, 10/33 (30%) were positive, and one pt had insufficient cells for analysis. On day 90 of therapy, 21 of the 43 pts had data available, and all were MRD negative. All pts treated with the ABFM protocol had MRD assessments performed on day 29 of induction therapy; 8 (62%) were negative, 2 (15%) had suspicious cells in an insufficient sample, and 3 (23%) were positive. Of the 9 pts with MRD measurements on day 84 of therapy, all were negative except for 1 pt who relapsed before day 84. These preliminary data indicate that AYA pts with ALL receiving either hyper-CVAD or ABFM therapy have similar MRD status at the end of induction and after approximately 3 months of consolidation. Given the likely importance of MRD in predicting DFS, this comparison suggests that hyper-CVAD and ABFM may show similar outcomes in this population. Continued accrual and longer follow-up will be required to confirm this hypothesis.

Abstract Background: Risk-adapted treatment strategies have contributed to excellent outcomes in pediatric acute lymphoblastic leukemia (ALL); however, treatment-associated acute and long-term toxicities persist. Therapy-associated toxicities of note in pediatric ALL are related to a treatment backbone that relies heavily on corticosteroids (prednisone and dexamethasone) and asparaginase (ASP). The most frequently observed toxicities include, but are not limited to, serious infection, pancreatitis, thrombosis and bony morbidities including osteonecrosis (ON) and fracture. Previous studies suggest that children of racial and ethnic minorities are at higher risk for treatment-associated toxicities. We assessed the incidence of treatment-related toxicities in Hispanic and non-Hispanic patients undergoing treatment for pediatric ALL. Patients and Methods: Retrospective cohort study investigating the incidence of treatment-related toxicities including infection, allergy to ASP, pancreatitis, thrombosis and bony morbidities in Hispanic and non-Hispanic children and adolescents with newly diagnosed ALL undergoing therapy on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001. The ethnicity of each patient was designated at the time of study enrollment by research coordinators. Descriptive statistics were calculated, mean +/- SD for continuous variables and frequency and percentages for categorical variables. Toxicity rates were based on number of patients. Comparison between groups was done by Chi-square test or FisherÕs exact test and p -value < 0.05 was considered significant. Results: Between 2005 and 2011, 794 children and adolescents (ages 1 - 18 years) were enrolled on Protocol 05-001, 730 of whom were evaluable for this investigation: 150 Hispanic (18%), 580 non-Hispanic (73%). Sixty-four patients did not have ethnicity documented. There was no significant difference in disease-risk group, age or gender between the two groups. Weight was significantly higher in Hispanic patients (31.9 ± 24.4 kg in Hispanic and 26.9 ± 18.7 kg in non-Hispanic, p = 0.021). There was no significant difference in the incidence of ASP-related toxicities (allergy, pancreatitis, thrombosis) between Hispanic and non-Hispanic patients. There was no significant difference in the overall incidence of infection between the two groups (42% in Hispanic and 50% in non-Hispanic, p = 0.081). Non-Hispanic patients had significantly higher rates of opportunistic infection (Pneumocystis pneumonia) than Hispanic patients (0.7% in Hispanic and 4% in non-Hispanic, p = 0.041). A similar difference in the incidence of bacteremia between the two groups approached, but did not reach statistical significance (p = 0.052). The overall incidence of fracture in all patients was 14.5% and was significantly higher in non-Hispanic patients (6% in Hispanic and 16.7% in non-Hispanic, p < 0.001). The overall incidence of ON was 8.9% and was significantly higher in non-Hispanic patients (3.3% in Hispanic and 10.3% in non-Hispanic, p = 0.007). (Table 1) Conclusion: The incidence of opportunistic infections and bony morbidities was significantly higher in non-Hispanic patients undergoing treatment for pediatric ALL on the DFCI ALL Consortium Protocol 05-001. The risk for, and impact of therapy-related toxicities varies by a patientÕs treatment tolerance, perhaps as a function of age and gender or as a result of disease biology or genetic polymorphisms affecting drug metabolism. Additionally, non-biologic factors such as medication adherence and nutritional status may also contribute to toxicity incidence in patients undergoing treatment for pediatric ALL. Prospective studies to further investigate our findings are warranted. Table. All Patients, (N = 730) Non-Hispanic, (N = 580) Hispanic, (N = 150) p -value Overall Infection 353/730 (48.4%) 290/580 (50%) 63/150 (42%) 0.081 Bacteremia 289/730 (39.6%) 240/580 (41.4%) 49/150 (9.3%) 0.052 Opportunistic Infection 24/730 (3.3%) 23/580 (4%) 1/150 (0.7%) 0.041 Fracture 106/730 (14.5%) 97/580 (16.7%) 9/150 (6%) <0.001 Osteonecrosis 65/730 (8.9%) 60/580 (10.3%) 5/150 (3.3%) 0.007 Thrombosis* 36/730 (4.9%) 26/580 (4.5%) 10/150 (6.7%) 0.271 Pancreatitis* 78/730 (10.7%) 60/580 (10.3%) 18/150 (12%) 0.559 ASP Allergy* 76/730 (10.4%) 57/580 (9.8%) 19/150 (12.7%) 0.310 *ASP-related toxicity Disclosures No relevant conflicts of interest to declare.

Purpose Retrospective studies have shown that adolescents and young adults with acute lymphoblastic leukemia (ALL) treated with pediatric protocols have better outcomes than similarly aged patients treated with adult protocols, but prospective studies comparing adolescents and young adults using pediatric schedules are scarce. The ALL-96 protocol was addressed to compare the toxicity and results of a pediatric-based protocol in adolescents (age 15-18 years) and young adults (age 19-30 years) with standard-risk (SR) ALL. Patients and Methods Adolescents (n = 35) and young adults (n = 46) received a standard five-drug/5-week induction course followed by two cycles of early consolidation, maintenance with monthly reinforcement cycles up to 1 year in continuous complete remission (CR) and 1 year with standard maintenance chemotherapy up to 2 years in CR. Results Adolescents and young adults were comparable in the main pretreatment ALL characteristics. The CR rate was 98% and. after a median follow-up of 4.2 years, 6-year event-free survival (EFS) and overall survival (OS) were 61% (95% CI, 51% to 72%) and 69% (95% CI, 59% to 79%), respectively, with no differences between adolescents and young adults. The hematologic toxicity in consolidation and reinforcement cycles was higher in young adults than in adolescents. Slow response to induction therapy was the only parameter associated with poor EFS (34% v 67%) and OS (40% v 76%). Conclusion The response to the pediatric ALL-96 protocol was identical in adolescents and young adults despite a slight increase in hematologic toxicity observed in adults. This justifies the age-unrestricted use of pediatric regimens to treat patients with SR ALL.

Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. These regimens, which rely heavily on corticosteroids and asparaginase (asp), are known to increase the risk of osteonecrosis (ON). In children older than 10 years (yrs), reported rates of symptomatic ON range from 5-25% (Mattano JCO 2000, Mattano Lancet Onc 2012, Toft Eur J Haematol 2016, Larsen JCO 2016). In adults, the frequency of ON and fractures (fx) are not well described including among those treated on pediatric regimens. In the recently reported C10403 trial (Stock Blood 2019), a 4% rate of ON was reported among patients aged 17-39 yrs. Here, we describe the orthopedic toxicities of AYA pts treated on sequential Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Methods: Pts aged 1-50 yrs were treated on four sequential multi-center DFCI ALL Consortium protocols between 2000 and 2018. Additional pts treated as per these protocols at DFCI, Massachusetts General Hospital (MGH), and Boston Children's Hospital (BCH) were identified by chart review. Earlier pts were enrolled on parallel Pediatric 00-001 (2000-2004) and Adult 01-175 (2002-2008) trials while later pts were enrolled on parallel Pediatric 05-001 (2005-2011) and Adult 06-254 (2007-2011) trials. Protocol 00-001 randomized pts between dexamethasone (dex) and prednisone (pred) during consolidation, while the other three trials used dex (all trials used pred during induction). Both 00-001 and 01-175 used native E.Coli asp, while later protocols (05-001, 06-254) used PEG asp for some (05-001, randomized) or all (06-254) pts. All pts were intended to receive 30 weeks of asp during consolidation. Pts aged 15-50 yrs were included in this study. Orthopedic toxicities were extracted from case report forms for trial pts and by chart review for those not on trial. Additional chart review was performed on all pts treated at DFCI, MGH, and BCH to identify surgical events. All pts were combined in the modeling based on the treatment backbone. The 5-yr cumulative incidences (CIs) of ON and fx were estimated and compared using the Gray test. Univariate and multivariable competing risk regression models were constructed with death as a competing risk. Results: A total of 367 pts with a median age of 23 yrs (68% &lt; 30 yrs) were identified. The majority (61%) of pts were male and the median BMI was 24.5 kg/m2 (46% overweight or obese). The median follow-up for pts remaining alive was 5 yrs (range, 0.01-14.1). In total, 60 pts experienced ON (5-yr CI 17%, [95% CI 13-22]) and 40 pts experienced fx (5-yr CI 12%, [8-15]). The median time to develop ON was 1.6 yrs (range, 0.5-7.7). The median time to fx was 1.4 yrs (range, 0.2-5.2). Pts &lt; 30 yrs were significantly more likely to be diagnosed with ON (21%, [16-27]) compared to those aged 30-50 yrs (8%, [4-14], univariate HR 2.77 [1.35-5.65]; p=0.005). Pts treated on PEG-asp based protocols were significantly more likely to be diagnosed with ON (5-yr CI 24% [18-30]) compared to those treated on earlier trials with native E.coli asp (5-yr CI 5% [2-10], HR 5.28 [95% CI 2.24-12.48], p&lt;0.001). These results remained statistically significant in multivariate analysis including treatment backbone, age, BMI, and sex. BMI and sex were not associated with orthopedic toxicity, although there was a trend toward fewer fx in male pts (HR 0.55, [0.29-1.02]). Of the 54 ONs for which adequate information was available, surgery was performed in 25 (46%) and total joint replacement in 18 (33%). Of the 9 fx with adequate information, 3 (33%) required surgery. Conclusions: In a large cohort of AYA ALL pts aged 15-50 yrs treated on a pediatric regimen, orthopedic toxicities were common (17% for ON, 12% for fx at 5 yrs). Younger pts (&lt; 30 yrs) experienced higher rates of ON, as well as pts treated on later-generation PEG-asp protocols which combined dex and PEG asp. Increased rates of orthopedic toxicity in later generation protocols may be driven by the pharmacokinetic drug interaction between PEG asp and dex, leading to higher dex exposure (Yan JCO 2008, Panetta Clin Pharmacol Ther 2009). Increased awareness may be useful in early identification of orthopedic toxicities. Future efforts should focus on further understanding the pathophysiology and risk factors for orthopedic toxicity in ALL AYA regimens and developing prophylactic interventions. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board. Brunner:Acceleron Pharma Inc.: Consultancy; Biogen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Forty Seven, Inc: Consultancy; Jazz Pharma: Consultancy; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Xcenda: Consultancy; GSK: Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding. DeAngelo:Blueprint Medicines Corporation: Consultancy, Research Funding; Forty-Seven: Consultancy; Jazz: Consultancy; Incyte Corporation: Consultancy; Novartis: Consultancy, Research Funding; Shire: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy; Autolos: Consultancy; Agios: Consultancy; Pfizer: Consultancy.

Background: venous thromboembolism (VTE) is a well-known complication in adults with acute lymphoblastic leukemia (ALL), especially in patients treated with asparaginase (ASNase)-including regiments. However, VTE risk in adult Philadelphia-positive ALL (Ph+ve ALL) patients treated with non-hyperCVAD chemotherapy is unclear. In this study, we examined VTE incidence in adult Ph+ve ALL patients treated with imatinib plus a pediatric-inspired asparaginase (ASNase)-free regimen modified from the Dana Farber Cancer Institute (DFCI) ALL protocol. Methods: a single centre retrospective review of Ph+ve ALL patients treated at Princess Margaret Cancer Center (PMCC) from 2008–2019 with imatinib plus modified DFCI protocol was conducted. Results: of the 123 patients included, 30 (24.3%) had at least 1 radiology confirmed VTE event from diagnosis to the end of maintenance therapy. 86.7% (26/30) of the VTE events occurred during active treatment. Of all VTE events, the majority (53.3%) were DVT and/or PE while another significant portion were catheter-related (40.0%). Major bleeding was observed in 1 patient on VTE treatment with low molecular weight heparin (LMWH). Conclusion: a high VTE incidence (24.3%) was observed in adults Ph+ve ALL patients treated with imatinib plus an ASNase-free modified DFCI pediatric ALL protocol, suggesting prophylactic anticoagulation should be considered for all adult Ph+ve ALL patients including those treated with ASNase-free regimens.

Abstract Adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) are recognized as a unique population with specific characteristics and needs. In adolescents age 15 to 20 years, the use of fully pediatric protocols is supported by many comparative studies of pediatric and adult cooperative groups. In young adults, growing evidence suggests that pediatric-inspired or even fully pediatric approaches may also dramatically improve outcomes, leading to long-term survival rates of almost 70%, despite diminishing indications of hematopoietic stem-cell transplantation. In the last decade, better knowledge of the ALL oncogenic landscape according to age distribution and minimal residual disease assessments has improved risk stratification. New targets have emerged, mostly in the heterogeneous B-other group, particularly in the Philadelphia-like ALL subgroup, which requires both in-depth molecular investigations and specific evaluations of targeted treatments. The remaining gap in the excellent results reported in children has many other contributing factors that should not be underestimated, including late or difficult access to care and/or trials, increased acute toxicities, and poor adherence to treatment. Specific programs should be designed to take into account those factors and finally ameliorate survival and quality of life for AYAs with ALL.