Adolescents And Young Adults Group Research Articles

An Age Stratified Analysis of the Access to Care Continuum Across Three Tumor Groups: Are There Delays for AYA?

Purpose: Delays in diagnosis and treatment are regularly discussed as potential poor prognostic factors for adolescent and young adult (AYA) cancer patients. We aimed to determine whether AYA cancer patients (15-24 years of age) in the South Island of New Zealand had longer times to diagnosis and treatment than pediatric (<15 years) and adult patients (>24 years) with the same diagnosis. Methods: A retrospective review of medical records was undertaken for 201 recently diagnosed sarcoma, Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL) patients in the South Island. An age stratified analysis was undertaken with a number of intervals related to the time to diagnosis (TTD) and total interval (TI) being determined. Results: Overall, the AYA group's TTD and TI was longer than the pediatric group, but shorter than the adult group. No age-based differences in patient interval (PI) were identified. AYA and adult sarcoma patients had longer TTD and TI than pediatric sarcoma. AYA and pediatric NHL patients had a shorter TTD and TI than adult NHL. No significant age-related interval differences were found in the HL group. Conclusions: AYA patients had a longer TTD and TI when compared with the pediatric group, but not when compared with the adult group. The impact of established AYA barriers to presentation are questioned, given no age-based differences in PI were found. The influence of tumor biology and cancer service delivery is an important consideration. Improved applicability of this type of research will be enabled by international collaboration.

Chronic Myeloid Leukemia in Adolescents and Young Adults Treated with Generic Form of Imatinib in Resource Limited Setting: A Single Center Experience from Myanmar

Chronic myeloid leukemia (CML) is an acquired myelo-proliferative disorder characterized by the presence of BCR-ABL1 fusion transcript with deregulated tyrosine kinase activity. Leukemias are one of the leading causes of cancer related deaths in adolescents and young adults (AYA) particularly in resource limited countries. Recent democratic government in Myanmar holds supportive policies for treatment of cancers in younger population and subsidizes some therapies including imatinib mesylate, a selective BCR-ABL 1 tyrosine kinase inhibitor, although there is still limitation for cytogenetic and molecular monitoring of therapy. This study on response to imatinib in newly diagnosed chronic phase CML was carried out during January 2016 to February 2018 at the North Okkalapa General and Teaching Hospital of Yangon, Myanmar where molecularly confirmed new CML in chronic phase were treated with generic form of imatinib bought by hospital tender system, Unitinib (United Biotech (P) ltd. India) followed by cytogenetic analysis of bone marrow and molecular detection of BCR-ABL1 transcript from peripheral blood by in house real time PCR machine at one year. They are divided into AYA (aged 15-39 years) and adult age groups (40 years and older) and clinical parameters and response to treatment with imatinib 400mg per day were compared. Among 56 cases (median age of 39.5 years, male to female ratio of 1.5:1), half were AYA (28 of 56) with median age of 28.5 years compared to 50 years in adult group with higher male to female ratio of 3.6:1 in AYA group. Patients in AYA had larger spleen size (11 vs 5.5 cm) and higher median white cell count compared to adults (366 x 109/l vs 224 x 109/l) although initial platelet count, peripheral blood eosinophil, basophil and blast percent and Sokal score were comparable. Additional chromosomal abnormalities were detected in 2 AYA and 3 adults with CML. There was no difference in complete haematologic response at 3 and 12 months between AYA and adults (96.4% vs 96.4% and 92.9% vs 89.3% respectively). At 12 months, complete cytogenetic response of AYA at 67.9% was less than 75.0% of adults, it was statistically not significant. Using in house molecular method although not standardized, 14.3% of AYA and 32.1% of adults were molecularly undetectable at one year. The response of AYA to imatinib in this study was comparable to adults despite having adverse prognostic features and receiving only generic forms of treatment in resource limited setting and it would further help support from authorities for leukemia in younger population. DisclosuresNo relevant conflicts of interest to declare.

Outcomes of Adolescents and Young Adults With Acute Myeloid Leukemia Treated in a Single Latin American Center

IntroductionThe outcomes for adolescents and young adults (AYAs) with acute myeloid leukemia (AML) have been poorly characterized in Hispanics in low- to middle-income countries. The results are influenced by biologic and socioeconomic factors. The clinical paths for AYA patients with AML are reported. Patients and MethodsA retrospective analysis of AYA and pediatric AML patients aged 1 to 39 years during 2003 to 2016 from a single reference center in Northeast Mexico treated with a 7+3 standard protocol was performed. The 5-year overall survival (OS) and event-free survival (EFS) were estimated using Kaplan-Meier analysis. The hazard ratios for relapse and death were estimated using a Cox regression model. The patients with promyelocytic leukemia were analyzed separately. ResultsThe study included 110 non-PML AML patients, 39 children and 71 AYAs. No difference in complete remission was found (P = .446), although the overall response rate was greater in the children (87.2% vs. 69% in AYAs; P = .034). The 5-year EFS rate was 33% for the children versus 9.3% in the AYAs at a median follow-up of 22 and 9 months, respectively (P = .008). The 5-year OS rate was 51% in the children and 22% in the AYAs (P = .001). Of the 44 AYAs with complete remission, 29 (65%) developed a relapse. Of the 39 children and 71 AYAs, 20 children (51.3%) and 21 AYAs (29.6%) underwent transplantation (P = .024). Patients with refractory disease had a 1-year OS rate of 14.4%. Older age (hazard ratio [HR], 2.55; P = .002) and white blood cell count > 50 × 109/L (HR, 1.79; P = .023) were significant for death, and transplantation was protective (HR, 0.57; P = .023). ConclusionLow EFS and OS rates were found for AML patients in the AYA group. To improve survival rates, intensified chemotherapy regimens and early hematopoietic stem cell transplantation are needed.

Patterns of Involved-Field Radiation Therapy Protocol Deviations in Pediatric Versus Adolescent and Young Adults With Hodgkin Lymphoma: A Report From the Children's Oncology Group AHOD0031

The presented protocol for pediatric intermediate-risk Hodgkin lymphoma evaluated the use of a dose-intensive chemotherapy regimen (ABVE-PC [doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, prednisone]) with response-based therapy augmentation (addition of DECA [dexamethasone, etoposide, cisplatin, cytarabine]) or therapy reduction (elimination of radiation). A central review of the radiation therapy data for quality assurance was performed, and the association between radiation protocol deviation (RPD) and relapse was assessed in the pediatric group (age <15years) and adolescent and young adult (AYA) group (age ≥15-21years). Involved-field radiation therapy (IFRT) planning was reviewed before the start of treatment and at treatment completion. The records were reviewed through the Quality Assurance Review Center's central review to identify RPD, classified according to dose deviation (DD), volume deviation (VD), undertreatment (UT), and overtreatment (OT). DDs and VDs were further classified as major or minor. Of the 1712 patients enrolled, 1155 received IFRT, of whom, 216 (18.7%) had RPDs. The DD and VD patterns were similar between the pediatric and AYA groups. Minor VDs were most common. UT RPDs accounted for 69% in the pediatric group and 75% in the AYA group. Of the 35 patients with relapse and a RPD, 29 had an undertreatment RPD. Among the patients who received IFRT, a significant difference was found in the cumulative incidence rates of relapse between the pediatric and AYA groups (P=.03); however, no significant difference was found between patients with and without RPD (P=.2). Most RPDs were minor and consisted of UT in the AYA and pediatric populations both. No difference was observed in RPDs between the pediatric and AYA patients. Thus, in a well-defined and standardized protocol, the RPD distributions for AYA patients will be similar to those for pediatric population. However, the increased cumulative incidence of relapse in the AYA patients who had received IFRT compared with the pediatric population requires further exploration, given the potential differences in clinical outcomes in the AYA population.

Abstract A086: Early clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in adolescents and young adults (AYA) with cancers

Abstract Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed phase I and II trials in adult subjects with cancer that had +/- CNS involvement (AACR #1185, 2013; AACR #CT 129, 2017). The aims were to assess clinical responses, monitor toxicities/safety, and confirm MTDs for IV administered DM-CHOC-PEN (IND 68,876). We report here responses and toxicities seen in a phase I DM-CHOC-PEN trial with AYA subjects who have cancer (some of whom had CNS involvement). Subjects and Methods: DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer in escalating doses from 39 - 98.7 mg/m2. The dosing schedule accounted for the liver toxicities seen in the adult phase I trial and was 2-tiered: for subjects with liver involvement, the cutoff was 85.8 mg/m2 and for subjects with normal liver function was 98.7 mg/m2. Results: Twelve (12) AYA subjects have been treated to date (with or without CNS involvement). The common tumor types treated were oligoastrocytoma, astrocytoma, GBM; leukemia (ALL), lymphoma (NHL), melanoma, breast, and lung cancers (NSCL). Most subjects (9) had CNS involvement. The drug was well tolerated; the most common adverse effects were fatigue (17%). No neuro/cognitive, liver dysfunction, hematologic, cardiac, renal, or GI toxicities were observed. PK modeling revealed that AUCs were parallel for all dose levels (39-98.7 mg/m2). The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) were 3 and 24 hours, respectively for the AYA subjects, similar to what was seen for older adults. However, the drug and metabolite were still detectable in plasma and rbcs for 21 to 50 days in the AYA (15 - 39 yo) group vs. 3 to &amp;lt; 21 days (as observed in previously treated adult (&amp;gt;60 yo) subjects (AACR #1185, 2013). Differences in PK profiles between AYA and older adult subjects will be reviewed in depth. Three (3) of the AYA subjects (1 each with NSCLC, ALL, and astrocytoma involving the CNS) have responded with CR/PR (RECIST 1.1), improved QOL/PFS (Kaplan-Meier), and OS from 8 to 26+ mos. All subjects will be reviewed. Conclusion: DM-CHOC-PEN is safe in doses of 39 - 98.7 mg/m2 and has produced objective responses with manageable toxicities in AYA subjects with cancer involving the CNS. Complete data on subject responses and observed toxicities will be presented. We propose a 3-stage mechanism for drug entry into the CNS and into cancer cells via reversible binding with RBCs and then association with L-glutamine transport into cells. Supported by NCI/SBIR grants - R43/44CA132257 and R43CA203351A and NIH NIGMS 1 U54 GM104940. Citation Format: Lee Roy Morgan, Andrew H. Rodgers, Roy S. Weiner, Tallat Mahmood, Marcus L. Ware, Manish Bhandari, Philip Friedlander. Early clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in adolescents and young adults (AYA) with cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A086.

Acute lymphoblastic leukemia in adolescents and young adults.

Acute lymphoblastic leukemia (ALL) in the adolescent and young adult (AYA) population is a difficult clinical problem. The AYA population, generally regarded as patients aged 15 to 39 years, currently draws a good deal of attention, particularly in the area of therapy selection. The current trend is to treat this group of patients with leukemia regimens based on pediatric protocols, and results comparing pediatric approaches versus adult approaches to treatment are maturing. Results are pending from a large US trial in which pediatric-based treatment is given to AYA patients with ALL. In tandem with these new clinical trials, researchers have reported disease features in the AYA group that may explain some of the differences in response to treatment observed in the AYA population compared with the pediatric population. In addition, unique social factors in this age group add to the complexity of ALL therapy in the AYA population. AYA patients are developing independence and separating from their parents. They tend to be noncompliant. Young adults suffer from a lack of health care insurance and poor access to clinical trials, and have specific concerns regarding toxicities, in particular fertility. Cancer 2017;123:2398-403. © 2017 American Cancer Society.

Myelodysplastic Syndromes in Adolescent Young Adults: One Institution's Experience.

There has been little improvement in cancer survival of adolescent and young adult (AYA) patients, aged 18 to 39 years, possibly reflecting different disease biology. Myelodysplastic syndrome (MDS) is mainly a disease of the elderly. The characteristics, outcomes, and response to treatment are not well described in the AYA population. This was a retrospective review of patients from the Moffitt Cancer Center MDS database. We compared baseline characteristics and outcomes of the AYA population to older patients. We identified 51 AYA and 1897 older MDS patients. More female subjects and Hispanics were noted in AYA group. The AYA patients had higher risk disease, more circulating myeloblasts, and more hypoplastic MDS. Autoimmune disorders were more prevalent in older patients. The median overall survival (OS) was 47 months in the AYA group versus 40 months in the older group (P= .26). The median OS was 47 versus 56 months in lower risk AYA group and older group, respectively (P= .46). In the higher risk group, median OS was 82 months in the AYA group compared to 17 months in the older group (P= .001). Thirty individuals (59%) underwent allogeneic stem-cell transplantation in the AYA group versus 241 (13%) in the older group. The median OS for transplanted patients was 55 months in the AYA group and 46 months in the older group (P= .4). In the nontransplanted patients, median survival was 31 months for the AYA group and 39 months for the older group (P=.9). The rate of acute myeloid leukemia transformation was 37% versus 28% in the AYA and older groups, respectively (P=.17). No differences in use or response to hypomethylating agents were observed. Lenalidomide therapy was seldom used in AYA, as none presented with del5q. In AYA, poor karyotype was the only variable strongly associated with worse outcome. Fifteen patients had poor risk karyotypes (29%). The median OS was 47 months, not reached, and 29 months among patients with good, intermediate, and poor risk cytogenetics, respectively (P= .035). MDS is rare and tends to be more aggressive in the AYA population. Karyotype was the most important prognostic factor. Allogeneic stem-cell transplantation offered younger patients the best outcomes.

Adolescent and young adult (AYA) survivors of childhood cancers: A challenge in after completion of therapy (ACT) clinic in resource-constrained country.

19 Background: To assess the evaluation of late effects in childhood cancer survivors who have transitioned to AYA age group on longitudinal follow up in After Completion of Therapy (ACT) clinic at Tata Memorial Hospital, Mumbai. Methods: ACT clinic database was analyzed for childhood cancer survivors who have attained age 15-30 yrs at last follow up in the clinic for demographics, grade of late effects &amp;pattern of follow up. Results: Of 1720 childhood cancer Survivors ( &gt; , 2 yrs off therapy &amp; disease free) registered in ACT clinic from Feb 91-Feb15, 976(56.7%) are in AYA group, M.F = 707/269 (2.6:1), Hematolymphoid : Solid tumours = 543/433 (1.3:1), Mumbai based: Non Mumbai = 306/670 (1:2.2).Median age at diagnosis 8 yrs, current median age 20 yrs, median duration of ACT clinic follow up is 6 yrs. At registration 448 (47%) had no late effects. 230(24%) had grade I, 81(8.4%) grade II 195 (20%) had grade III. Only 9(1%) had grade IV late effects which increased to 53 (6%) at last follow up due to recurrence &amp; second neoplasia. Only 29(3%) were at low risk of developing potential late effects. 466(48.5%) were in intermediate risk &amp; 48.5% (466) fell in high risk category requiring at least annual follow up. 72% of survivors registered in ACT clinic from 1991-2001 had stopped follow up as compared to 36% registered in subsequent decade (p &lt; 0.01). Conclusions: AYA survivors of childhood cancers form major (56.7%) group in Long Term Follow up clinic. The increasing incidence of life threatening late effects on longitudinal follow up combined with statistically significant increasing trend of stopping follow up over period of time since ACT registration is alarming &amp; calls for innovative approaches for maintaining good follow up through survivor centric approaches such as use of IT based communication technologies &amp; formation of childhood cancer survivors support groups like Ugam.

Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) With Acute Myeloid Leukemia (AML).

Little is known about outcomes of acute myeloid leukemia (AML) in adolescents and young adults (AYA). The purpose of this study is to determine the characteristics and outcomes of AYA AML patients in comparison to older adult patients with AML. We retrospectively analyzed all AML patients treated at our institution from 1965 to 2009 who were aged 16 to 29 years. Among 3922 adult AML patients treated during this period, 432 (11%) were identified as AYA. Median age was 23 years (range, 16-29 years); 73 (17%) patients had core binding factor (CBF)-AML [inversion (16), translocation (8:21)], and 51 (12%) had acute promyelocytic leukemia. Complete remission (CR) rates were 93% for CBF AML, 78% for APL, 77% with diploid karyotype, and 68% for other AML. Univariate analysis demonstrated higher rates of CR, CR duration, and overall survival (OS) in the AYA group compared with older patients. On multivariate analysis, AYA age group was independently associated with improved CR rate and CR duration, with a trend for longer OS (P= .085). Outcome of AYA AML patients is overall better than for older adults with AML. Despite improvements in treatments and outcomes over time, there is still need for improvement in AYA with AML particularly for those with AML other than CBF and APL.

Germ Cell Tumors in Adolescents and Young Adults.

Germ cell tumors (GCTs) represent a group of biologically complex malignancies that affect patients at different sites within the body and at different ages. The varying nature of these tumors reflects their cell of origin which is the primordial germ cell, which normally gives rise to ovarian and testicular egg and sperm producing cells. These cells retain an ability to give rise to all types of human tissues, and this is illustrated by the different kinds of GCTs that occur. In adolescent and young adult (AYA) patients, GCTs predominantly present as testicular, ovarian or mediastinal primary GCTs, and represent some of the most complex therapeutic challenges within any AYA practice. The varying types of GCTs, defined by primary site and/or age at presentation, can look very similar microscopically. However, there is growing evidence that they may have different molecular characteristics, different biology and different requirements for curative treatments. Whilst in adult testicular GCTs there is evidence for an environmental cause during fetal development and a genetic component, these causative factors are much less well understood in other GCTs. GCTs are some of the most curable cancers in adults, but some patients exhibit resistance to standard treatments. Because of this, today's clinical research is directed at understanding how to best utilize toxic therapies and promote healthy survivorship. This chapter explores the biology, behavior and treatment of GCTs and discusses how the AYA group of GCTs may hold some of the keys to understanding fundamental unanswered questions of biological variance and curability in GCTs.

Leukemia.

Leukemias are a group of life threatening malignant disorders of the blood and bone marrow. In the adolescent and young adult (AYA) population, the acute leukemias are most prevalent, with chronic myeloid leukemia being infrequently seen. Factors associated with more aggressive disease biology tend to increase in frequency with increasing age, whilst tolerability of treatment strategies decreases. There are also challenges regarding the effective delivery of therapy specific to the AYA group, consequences on the unique psychosocial needs of this age group, including compliance. This chapter reviews the current status of epidemiology, pathophysiology, treatment strategies and outcomes of AYA leukemia, with a focus on acute lymphoblastic leukemia and acute myeloid leukemia.

American Brain Tumor Association Adolescent and Young Adult Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012.

Brain and central nervous system (CNS) tumors found in adolescents and young adults (AYA) are a distinct group of tumors that pose challenges not only to treatment but also to reporting. Overall, cancer that occurs in this age group is biologically distinct from those that occur in both younger and older age groups1,2 posing significant challenges for clinicians. The most commonly diagnosed histologies in AYA vary from those in both children age (0-14 years), and older adults (40+ years).3,4 Prognosis and expected survival also varies between younger and older adults, with those who are diagnosed with brain and CNS tumors at younger ages having significantly longer survival. Despite this survival advantage, recent analyses have reported that while cancer survival has been improving overall, AYA have not experienced these same increases in survival and in some cases may have worse survival than those cancers diagnosed in persons over age 40 years.5 This report provides an in depth analyses of the epidemiology of brain and CNS tumors in adolescents and young adults in the United States (US), and is the first report to provide histology-specific statistics in this population for both malignant and non-malignant brain and other CNS tumors. In 2006, the National Institutes of Health, the National Cancer Institute (NCI) and the LiveStrong Young Adult Alliance conducted a Progress Review Group to investigate AYA Oncology entitled Research and care imperatives for adolescents and young adults with cancer: A Report of the Adolescent and Young Adult Oncology Progress Review Group. This group established the standard age range for the AYA group as 15-39 years. This is the age range used by the Surveillance Epidemiology and End Results (SEER) program of the NCI, as well as in the 2015 CBTRUS Statistical Report.3,6 Brain tumors and other CNS tumors are less common in AYA than in older adults, but they have a higher incidence than brain tumors in children (age 0-14 years).3 Non-malignant tumors are significantly more common in AYA than children (Average annual age adjusted incidence in age 15-39 years: 6.17 per 100,000; age 0-14 years: 0.79 per 100,000), while malignant tumors are slightly more common in those age 0-14 years (Average annual age adjusted incidence in 15-39 years old: 3.26 per 100,000; 0-14 years old: 3.73 per 100,000). While a rare cancer overall, brain and CNS tumors are among the most common cancers occurring in this age group (4.4% of all cancers in those age 15-39 years as compared to 32.4% in children age 0-14 years, and 2.2% of cancers in adults age 40+ years).3,4,7 Malignant brain and CNS tumors are the 11th most common cancer and the 3rd most common cause of cancer death7,8 in the AYA population. Incidence rates of brain tumors overall as well as specific histologies vary significantly by age. It is, therefore, important to provide an accurate statistical assessment of brain and other CNS tumors in the adolescent and young adult population to better understand their impact on the US population and to serve as a reference for afflicted individuals, for researchers investigating new therapies and for clinicians treating patients.

Ruxolitinib Significantly Prolongs Survival in Both a Primary Mediastinal B-Cell Lymphoma (PMBL) and Hodgkin Lymphoma (HL) Xenograft NSG Mouse Model: Ruxolitinib May be a Potential Adjuvant Agent in the Treatment of PMBL and of HL

BACKGROUND: Primary Mediastinal large B-cell lymphoma (PMBL) and Hodgkin lymphoma (HL) are two of the most common malignancies among adolescents and young adults (AYA). PMBL and HL share similar molecular features by gene expression profiling and pathogenesis (Rosenwald et al., J Exp Med., 2003). HL represents only approximately 4-5% of all cancers in children younger than 15 years of age, but is the most common cancer in the 15-35 yrs AYA group. While the prognosis is excellent with AYA HL, there are significant late effects secondary to chemoradiotherapy and therefore new targeted agents are needed to avoid these morbid late effects in HL (Hochberg/Cairo et al., Br. J. Haem., 2009). Frequent gains of chromosome 9p exhibit higher Janus Kinase 2 (JAK2) transcript levels with increased JAK2 activity (Bentz et al., Genes Chromosomes Cancer, 2001), suggesting aberrant activity of JAK2 and Signal Transducer and Activator of Transcription (STAT) pathways, which may in part play an important role in the pathogenesis of HL and PMBL. Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor against myeloproliferative neoplasms (MPNs) that consistently exhibits dysregulation of the JAK1/JAK2 pathway, including those MPNs with a JAK2V617F mutation. Ruxolitinb also inhibits JAK2/STAT5 signaling in vitro and in a murine model of MPN (Quintas-Cardama et al., Blood, 2010).OBJECTIVES: We hypothesize that ruxolitinib may potentially function as targeted therapeutic agent for both PMBL and HL and therefore, investigated the efficacy of ruxolitinib in PMBL and HL cells xenografted into NSG mice.METHODS: Cell proliferation and apoptosis analysis were assessed using MTS and Caspase-3/7 assay (Promega), respectively. The expression of protein was examined by immunoblotting and statistical significance was determined by Student t-test. Karpas-1106P PMBL cell line and L-428 HL cell line were stably transfected with a firefly luciferase expression plasmid (ffluc-zeo), kindly provided by Laurence Cooper MD, PhD. The six to eight weeks old Female NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ) mice were from Jackson laboratory. The ffluc-zeo NSG mice were irradiated (2.5 Gy) and then were subcutaneously injected with 1x106 ffluc-zeo Karpas-1106P or L-428 tumor cells. Tumor burden and tumor progression were monitored by bioluminescence imaging (BLI) using the Xenogen IVIS-200 (Caliper Life Sciences) for up to 60 days. Mice were orally gavaged with either vehicle or ruxolitinib (45.0mg/kg or 90.0mg/kg) (generously provided by Incyte Corporation, Wilmington, DE, USA) for 21 days. Survival rates were analyzed by the Kaplan-Meier method and differences evaluated by log-rank test using the Prism Version 6.0 software.RESULTS: We observed that ruxolitinib significantly decreased the phosphorylation of STAT3, -5 and -6 in Karpas-1106P PMBL and L-428 HL cells. The reduction in cell proliferation by 10uM ruxolitinib are 41% in Karpas-1106P (p<0.04) and 19% in L-428 (p<0.03), respectively. In addition, ruxolitinib significantly induced Caspase-3/7 activity (p<0.05) and increased cleavage of PARP and caspase-3 fragments (p<0.001). In PMBL and HL xenografted mice models, we observed a significant decrease in tumor luminescence intensity following ruxolitinib treated PMBL (45.0mg/kg and 90.0mg/kg, p<0.05) and HL xenografted NSG mice at day 21 and 28 (45.0mg/kg, p<0.05) compared to control mice (Figure 1A). Ruxolitinib (45.0mg/kg) treated xenograft NSG mice had a significantly prolonged survival in PMBL (p<0.0001) and HL (p=0.0001) compared to control mice (Figure 1B).CONCLUSIONS: Ruxolitinib significantly inhibited JAK2 enzymatic activity by the abrogation of the phosphorylation of STAT3, STAT5 and STAT6, and ruxolitinib showed significant anti-proliferative effects. Ruxolitinib (45mg/kg) significantly inhibited tumor progression and significantly prolonged survival in PMBL and HL xenografted NSG mice compared to control mice. Ruxolitinib may be a potential adjuvant agent in the treatment of PMBL and HL. Future studies will focus on whether the addition of ruxolitinib to chemoimmunotherapy improves the survival in a NSG PMBL and HL xenograft mouse models. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Increased risk of second malignant neoplasms in adolescents and young adults with cancer.

The authors describe the incidence and characteristics of secondary malignant neoplasms (SMNs) in adolescent and young adult (AYA) cancer survivors compared with those in younger and older cancer survivors. Children aged ≤ 14 years, AYAs aged 15 to 39, and older adults aged ≥ 40 years at the time of primary diagnosis who were reported as cancer survivors in the Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 2011 were compared in this population-based analysis. The primary analysis was the risk that an SMN would occur ≥ 5 years after the original diagnosis for patients who had the more common AYA cancers (leukemia, lymphoma, testicular malignancy, ovarian malignancy, melanoma, and cancers of the thyroid, breast, soft tissue, or bone). The standardized incidence ratio (SIR), absolute excess risk (AER), and cumulative incidence of SMN for the selected cancers were assessed. The risk of SMN for the entire cohort also was analyzed. Of the 148,558 AYA survivors who were diagnosed with a selected cancer, 7384 developed an SMN 5 years after their original diagnosis. The SIRs (95% confidence intervals [CIs]) were 1.58 (95% CI, 1.55-1.62) for AYAs, 4.26 (95% CI, 3.77-4.80) for children, and 1.10 (95% CI, 1.09-1.11) for older adults, and the AERs were 22.9, 16.6, and 14.7, respectively. The cumulative incidence of SMN at 30 years was 13.9% for the AYA group. The most common SMNs in AYAs were breast cancer, gastrointestinal cancer, genital cancers, and melanoma. AYAs who had received radiation therapy had a higher cumulative incidence of SMN. AYAs who survive cancer for more than 5 years have a higher relative risk of SMN compared with the general population and have a higher absolute risk of SMN compared with younger or older cancer survivors.

Outcome and Toxicities of Modified Augmented Berlin-Frankfurt-Muenster (ABFM) Therapy Used in the Treatment of Acute Lymphoblastic Leukemia in Adolescent and Young Adult Patients, Single Center Experience From Saudi Arabia

AbstractAbstract ▪3569▪This icon denotes a clinically relevant abstract Introduction:Acute lymphoblastic leukemia (ALL) is a neoplasm of precursor lymphoid cells known as lymphoblasts. ALL is the most common cancer in children. The prognosis among Adolescents and young adults (AYA) is intermediate between children, who have a very good prognosis with a 5-year survival rate of 80%, and adults, who have a worse prognosis with an overall survival of about 30–50%. We found no studies in Saudi Arabia which assessed the use of a Berlin-Frankfurt-Muenster (BFM) to treat patients in the AYA group. The purpose of this study is to measure the outcome and toxicities of the BFM protocol used in treatment of ALL patients in the AYA population seeking treatment at Princess Noorah Oncology Center (PNOC), at the National Guard Hospital, Jeddah, Saudi Arabia. PNOC is a tertiary referral center for the Western region of the Kingdom of Saudi Arabia. Patients referred between the ages of 14 to 25 were treated according to an augmented modified version of the Berlin-Frankfurt-Muenster (BFM) protocol. Patients’ treatments were based on risk factor stratification. High risk category was identified based on the presence of one of following factors: phenotype of the leukemia (i.e. T-cell ALL is considered high risk), lack of response to therapy on day 29 of induction, cytogenetics, presence of extramedullary disease e.g. testicular or CNS disease and whether they have received steroid treatment prior to the first diagnostic marrow. High risk group was treated with doubled blocks of interim maintenance, delayed intensification the first of delayed intensification blocks included a high dose methotrexate at the dose of 5g/m2 which was first started at our center in 2008. Methodology:This study is a retrospective chart review. Patients who met the inclusion criteria within the last five years were included. The inclusion criteria were those with confirmed ALL (excluding mature B cell phenotype) aged between 14 to 25 years, and were treated with the Modified Augmented Berlin-Frankfurt-Muenster (ABFM) therapy protocol. 45 patients were indentified who fulfilled the above criteria 4 were excluded due to the lack of data and loss to follow up. Data were analyzed using SPSS version 19. Results:The mean age of 41 patients treated was 16.4 years (range; 14 – 25 years). Of 41 patients treated, 23 (56%) were males. Only one patient (2%) had CNS involvement at presentation. B cell ALL compromised 61% of the patients while 39% were T cell ALL. All 41 (100%) patients achieved complete remission after induction therapy however two patients (5%) required extended induction to achieve a complete remission status. Five (12.2%) patients relapsed at a median follow up of 30 months. Two (4.9%) patients died while in complete remission from treatment related causes. The probability of Overall Survival (OS) is 95.1% and 87.8% at 2 and 3 years, respectively. The probability of Event-free Survival (EFS) of our 41 patients is 90.2% and 82.9% at 2 and 3 years respectively. Thirty three (81%) patients developed febrile neutropenia with a total of 50 documented episodes. Thirty two (64%) of the febrile neutropenia episodes occurred during induction and re-intensification phases those two blocks were associated with a statistically significant increased risk of neutropenia (P < 0.001)compared to other blocks. Five (12%) of patients developed fungal infections there is one patient who developed two separate episodes of fungal infection. Four fungal infection episodes occurred during induction and re-intensification phases which constituted the highest risk phases for the development of fungal infections. In 38% of febrile neutropenic episodes an infectious agent was identified in 8% of episodes the isolate was a fungus. Eight patients (20%) developed Venous Thromboembolism (VTE) with a total of 9 episodes. Discussion & Conclusion:In our study population the OS & EFS were comparable to other reported groups despite the relatively increased numbers of T cell ALL (39%) patients compared to the reported average of 15–25%. The reported incidence of VTE is similar to the incidence reported by other groups while the incidence of fungal infections is relatively more than we would have expected. Complete remissions, survival, relapse and death rates are comparable to international studies. However new measures are required to lower the increased rates of fungal infections & VTE for future patients. Disclosures:No relevant conflicts of interest to declare.

Outcomes in Adolescents and Young Adults with Hodgkin Lymphoma Treated with and without Radiation Therapy On CCG 5942: A Report From the Children's Oncology Group

AbstractAbstract 3659 BackgroundCombined modality therapy with chemotherapy and radiation (RT) has resulted in excellent cure rates for Hodgkin Lymphoma (HL) but is associated with significant late effects. Modern therapeutic protocols attempt to limit cumulative doses of chemotherapy and minimize radiation therapy where possible. There is also growing attention to the optimal management of specific patient populations, including the adolescent and young adult (AYA) population. The CCG trial 5942 provides an opportunity to assess the role of RT in disease control for the AYA population (15–21 years of age) compared with a younger cohort (<15 years of age). MethodologyThe CCG 5942 study included 826 eligible patients (339 AYA) accrued during the years 1995–1998. Patients were assigned to risk-adapted chemotherapy based on stage and presence or absence of unfavourable risk factors (B symptoms, bulk disease, hilar lymphadenopathy, number of involved nodal sites). Disease response was assessed at the completion of chemotherapy and patients in CR were eligible for randomization to receive 21 Gy IFRT or no further therapy. We conducted a retrospective analysis of the CCG 5942 data to compare demographics, treatment response and survival outcomes of children and AYA. ResultsPatient demographics are shown in Table 1. The AYA patients were more likely to present with nodular sclerosing histology (NS), B symptoms, mediastinal bulk disease, and higher stage. The CR rates for children and AYA were 393/487 (80.7%) and 243/339 (71.7%) (p=.003). Of the 636 patients in CR, 498 (181 AYA) participated in the randomization. The AYA patients were less likely to be compliant with randomization to no further therapy (2/165 children vs 5/84 AYA, p=.045). The 8y EFS and OS for all children compared to AYA were 85.7% vs 80.2% (p=.052) and 94.3% vs 90.7% (p=.060) respectively. The 8y EFS and OS for all randomized children compared to AYA were 89.8 vs 81.3 (p=.011) and 97.2% vs 95.1% (p=0.30). A Cox model adjusting for both age group and histology (NS vs. lymphocyte predominant (LP) and mixed cellularity (MC)) demonstrated age to be an insignificant predictor (p=0.30) and NS histology to be a significant predictor (p=.001, HR 2.6) of worse EFS. EFS for all randomized patients with NS histology by age group and treatment received are shown in Figure 1. There is a significant difference among the groups in the overall comparison (p=0.018). There was no difference in OS with all pairwise comparisons p>0.5. ConclusionsThe AYA were more likely to present with higher risk disease and less likely to enter CR compared to younger children on the CCG 5942 trial. Among randomized patients with NS histology, both young and AYA populations show an EFS advantage with RT, though this advantage does not reach statistical significance for the AYA group. There was no difference in OS for randomized patients with NS histology in either age group. This analysis is limited by the retrospective methodology but supports further study of therapy assignment of the AYA population. Elimination of RT from AYA with NS histology may prove more challenging than for younger children. Analysis of current protocols using a uniform chemotherapy backbone and early disease response assessment with PET/CT will be particularly informative.Table 1:Patient characteristicsAll patients (n=826)Randomized patients (n=498)<15 yrs15–21 yrsp-value<15 yrs15–21yrsp-valueN%n%n%n%Gender<0.0010.005male29460%16047%19261%8648%female19340%17953%12539%9552%Histology<0.001<0.001LP6514%185%4514%106%NS32268%29088%20666%15084%MC8518%206%5819%169%LD30.6%20.6%20.6%21%Unknown12963Stage<0.0010.001I10421%319%7925%2011%II23147%20059%15047%11161%III7115%4914%4615%2614%IV8117%5917%4213%2413%B-sym0.0160.002present10922%10130%5417%5229%absent37878%23870%26383%12971%Mediastinal Mass<0.0010.002>=1/310421%10130%5818%4022%<1/318137%15245%11737%8949%no20241%8625%14245%5229%Clinical Group0.0030.017119139%9528%14646%6134%221444%18354%12941%9653%38217%6118%4213%2413% [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Survival Differences between Adolescents/Young Adults and Children with B Precursor Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Cell Transplantation

Risk-adapted therapy has been the cornerstone of treatment for pediatric B precursor acute lymphoblastic leukemia (B-ALL). Recently, age ≥13 years at diagnosis has been identified as a very high-risk feature for chemotherapy treated pediatric patients with B-ALL. Whether age at time of transplantation is associated with poor outcomes in adolescents and young adults (AYA) is unknown. We hypothesized that AYA receiving allogeneic hematopoietic cell transplantation (allo-HCT) would have greater relapse and inferior survival compared with children age <13 years. We reviewed the outcomes in 136 consecutive patients (age 0-30 years) with B-ALL who underwent myeloablative allo-HCT at our institution, including 79 children age <13 years (58%) and 57 AYA age 13-30 years (42%). Overall survival at 5 years was significantly lower in the AYA group (hazard ratio, 1.74; 95% confidence interval [CI], 1.04-2.95; P = .03). In addition, the AYA patients had a greater risk of transplantation-related mortality at 1 year (hazard ratio, 2.23; 95% CI, 1.01-4.90; P = .05), but no difference in relapse (relative risk, 0.85; 95% CI, 0.41-1.76; P = .66). Based on this analysis, AYA patients undergoing allo-HCT for B-ALL have significantly inferior survival and greater transplantation-related mortality compared with children age <13 years, but no difference in relapse, suggesting that allo-HCT may overcome relapse in AYA. Further improvements in peritransplantation care are needed to limit complications in AYA patients.

Diagnostic and treatment challenges of adolescent and young adult oncology patients.

9557 Background: Adolescent and young adult (AYA) cancer patients are faced with obstacles and challenges related to their diagnosis and treatment compared to children and older adults. The aim of this study was to explore the patient and health care system-related delays in the interval from cancer symptom onset to diagnosis and treatment as well as to identify the possible contributing factors to these delays in the AYA group. Methods: This study was based on a questionnaire conducted in 2010-2011 completed by patients diagnosed with a malignancy between the ages of 16 and 39 in addition to older patients diagnosed with a pediatric type malignancy. Four categories of delays: patient delay (time from patient symptom onset until first health care contact date), health care system delay (time from first health care contact until diagnosis date), treatment delay (time from diagnosis date until first treatment) and oncologist delay (time from first health care contact until first medical oncologist meeting) were calculated. Median delay (in days) with interquartile interval (IQI) was the main outcome measure. Median time for each category of delay was further analysed to explore how they vary with different patient characteristics. Results: We identified a median patient delay of 30 days (IQI 1-131), a median health care system delay of 53 days (IQI 1-213), a median treatment delay of 36 days (IQI 5-92) and a median oncologist delay of 77 days (IQI 30-281). Patient delay was affected by patient gender, age at diagnosis and type of first health care contact. Health care system delay was associated with patient marital status, financial situation and attitude of first health care professional. Treatment delay was related to type of cancer. Conclusions: The health care system delay (including oncologist delay) accounts for much of the delay from symptom onset to first treatment. Professional characteristics of frontline medical personnel as well as socioeconomic and biological characteristics of the patients may contribute to delay. Healthcare professionals and the general community as a whole need to be aware of the factors contributing to delay in diagnosis and treatment in the underserved patient population.

Survival in Adolescents and Young Adults with Hodgkin Lymphoma Treated with Response-Based Chemotherapy on P9425 and P9426 Protocols: A Report From the Children's Oncology Group

Abstract 91▪▪This icon denotes a clinically relevant abstract Background:Hodgkin Lymphoma (HL) is a highly curable malignancy affecting all age groups with a bimodal distribution with peaks between the 2nd and 3rd decade of life and at over 60 years of age. Children and adolescents with HL treated according to recent Pediatric Oncology Group (POG) regimens received dose dense, response-based chemotherapy with low dose radiation, decreasing both cumulative doses of chemotherapy and radiation. Treatment of adolescents and young adults (AYA) has not been consistent, with choice of adult vs. pediatric regimens depending on the referral pattern and institutional polices.The German Cooperative group reported equivalent results in the AYA group vs. adults using an adult focused protocol that included high dose alkylator therapy and high dose radiation, and used that data to recommend adult therapy for AYA. We evaluated the outcome of Pediatric vs. AYA patients in two POG trials to assess the utility of pediatric regimens for AYA HL. Purpose and Methodology:We retrospectively analyzed POG studies P9425 and P9426 to compare the survival rate of children (<15 year of age) and AYA (15 – 20 years of age) with HL.P9425 included 216 patients (104 AYA) with intermediate (IB, IIA/IIIA1 with large mediastinal adenopathy or IIIA2) or high-risk (IIB, IIIB, IV) biopsy-proven classical HL. A response-based treatment approach administered doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC) every 21 days. Rapid early responders (RER) to 3 ABVE-PC cycles received 21 Gy radiation to involved regions. Slow early responders (SER) received 2 additional ABVE-PC cycles before 21 Gy radiation. As previously published, this dose dense regimen resulted in excellent event-free and overall survival (EFS, OS) regardless of the risk assignment and early response. Five-year EFS 84%; 86% for RER, 83% for SER (P = 0.85). Five-year OS was 95%.P9426 study included 255 patients, (99 AYA) with low risk (Stage IA, IIA and IIIA) biopsy-proven HL. Chemotherapy was a response-based approach that utilized doxorubicin, bleomycin, vincristine and etoposide (ABVE) every 28 days. RER to 2 DBVE cycles received 25.5 Gy involved field irradiation. SER received 2 additional cycles of ABVE followed by irradiation. The 5-year EFS for early stage HL under this protocol was 87.8%. 5-year OS was 97.6%. Results:Of 471 eligible patients treated on POG 9425 and 9426, 203 were AYA. Table 1 shows patient characteristics. Male to female ratio was similar in both groups. The most common histology in both groups was nodular sclerosing. Mixed cellularity and lymphocyte predominant subtypes were more common in children less than 15 years of age. There was no difference in EFS for the younger vs. older patients.Table 1Patient Characteristics<15 years N %≥15 years N %Total N %Pr*STUDY0.042P9425112 51.8%104 48.2%216 100%P9426156 61.2%99 38.8%255 100%GENDER0.004Male180 67.2%110 54.2%290 61.6%Female88 32.8%93 45.8%181 38.4%HISTOLOGY<0.001**Nodular Sclerosis170 67.7%171 87.7%341 76.4%Mixed Cellularity57 22.7%16 8.2%73 16.4%Lymphocyte Predominant22 8.8%4 2.5%26 5.8%Lymphocyte Depleted2 0.8%4 2.1%6 1.4%RESPONSE0.57**RER141 54.4%103 51.8%244 53.3%SER118 45.6%96 48.2%214 46.7%*Based on Chi-square test**Chi Square test includes only available central review and early response dataFigure 1. [Display omitted] Conclusions:The outcome of adolescents treated on P9425 and P2496 with dose dense, response-based treatment and reduced dose irradiation was not different from the outcome of children less than 15 years of age. The cumulative doses of alkylators, anthracyclines, and epipodophyllotoxins used in these pediatric protocols are below thresholds usually associated with significant long-term toxicity.These data validate our preference for the treatment AYA and adolescents with HL using pediatric-focused therapy. This approach may reduce the risk for late adverse effects (cardiotoxicity, infertility, secondary malignancy) by limiting cumulative doses of alkylator agents, anthracyclines and radiation therapy. A focus on dose-limited regimens is critically important for younger patients (pediatric and AYA) who are expected to have long-term survival. Disclosures:No relevant conflicts of interest to declare.

Trailblazers in Adolescent and Young Adult Oncology.

The development of adolescent and young adult (AYA) oncology as a burgeoning discipline that is now into its own adolescence may be best illustrated by the surge in AYA oncology publications in peer-reviewed journals during the past three years. Prior to 2007, the number of articles identified by the search term ‘‘adolescents young adults cancer’’ in the PubMed database ranged from 129 to 381 per year. Since then, the number increased to 598 in 2007, 1971 in 2008, and 4045 in 2009. The dramatic increase is still well short of the 7000–7500 articles per year that the ‘‘children cancer’’ search term identifies, especially when one considers that the number of cancer patients in the AYA age group is four to six times greater, depending on what age range is used for the AYA group. Nonetheless, the change in publication rate of AYA cancer reports and reviews is striking testimony of need and partial success. To understand the history that led to this revolution, several of its pioneers in England, the United States, and Canada were convened for a roundtable discussion to offer their recall. As described below, the original seed appears to have been sowed in England, thanks to Ian Lewis and London’s Teenage Cancer Trust. A root took hold a decade later when national statistics in the United States showed a survival progress gap that was analogized to the famous London Tube gap between the platform and the Underground train. The stems that then broke ground were conferences, organizations, hospital and outpatient programs, scientific reviews, and international collaborations. The participants in this Roundtable undoubtedly neglected many other events along the way, but they are all appreciative of the emerging buds and blossoms of AYA oncology. Most of all, they sense that AYAs around the world will ultimately truly benefit in improved prevention, early detection, and treatment of cancer during the prime of their lives.