Acute Lymphoblastic Leukemia In Adolescents Research Articles

Safety and Feasibility of Hippocampal Sparing Cranial Radiation in Pediatric and Adolescent Acute Lymphoblastic Leukemia Patients: A Prospective Study.

Introduction Acute lymphoblastic leukemia (ALL) constitutes a significant portion of pediatric malignancies, with central nervous system (CNS) relapse posing a considerable threat to patient outcomes. While cranial radiation therapy (CRT)has been utilized to mitigate CNS relapse, it is associated with neurocognitive (NC) side effects. This study explores the feasibility and safety of using volumetric arc therapy (VMAT) with hippocampal sparing (HS) during cranial radiation therapy for ALL patients, aiming to reduce these side effects. Methodology This prospective observational study included pediatric and young adult patients with ALL who werein remission. HS was achieved using VMAT, and NC assessments were performed at baseline, six months, one year, and, to a limited extent, four years posttreatment. Results VMAT enabled precise hippocampal-sparing CRT with minimal dose to the hippocampus. Dosimetric analysis revealed that patients receiving 18 Gy had mean doses to planning target volume (PTV) and bilateral hippocampus of 18.9 and 9 Gy, respectively. Those receiving 12 Gy had corresponding doses of 13.3 and 7 Gy, respectively. Conformity and homogeneity indices were 0.9 and 0.1, and no brain relapses were observed among the patients in this study. NC assessments demonstrated no decline in intelligence quotient (IQ) scores over time, while only a subset of patients could be assessed at the four-year mark; telephone interviews suggested no significant cognitive decline. Conclusions This study highlights the potential of VMAT with HS as a promising approach to CRT for ALL patients in reducing the risk of NC side effects. The absence of brain relapses and preservation of NC function are encouraging findings, though larger studies are necessary to establish conclusive evidence.

Comparable Outcomes of Relapsed Acute Lymphoblastic Leukemia in Adolescents and Young Adults (AYA) Patients Treated with Pediatric-Inspired Chemotherapy (R3 protocol) Versus Adult-Based Salvage (FA) Protocol

Background Although the survival rate of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) has improved by using pediatric-based treatment protocols, those who experience a relapse still have poor outcomes when treated with adult chemotherapy salvage-regimens, which have traditionally included high doses of Ara-C. The long-term survival rate for patients treated with these salvage-regimens is less than 10%. Salvage treatment with blinatumomab for adults with relapsed B-cell ALL results in a complete remission (CR) rate of 34%, a median survival of 7.7 months, and an overall survival (OS) of less than 30% at 18 months. In contrast, the ALLR3 protocol for relapsed ALL in patients up to the age of 18 years achieved a CR rate of 97% and an overall survival rate of 72%. Therefore, this study aims to compare the outcomes of AYA patients treated with pediatric-inspired regimen (R3 regimen) to those treated with adult-based regimen (FA (Fludarabine/Cytarabine) protocol). Methods The R3 protocol treated 17 AYA patients with relapsed Philadelphia-negative ALL, aged between 14 to 40 years old, who had received first-line therapy. Patients who achieved CR underwent allogenic transplant. The protocol included vincristine, mitoxantrone, asparaginase, dexamethasone, and intrathecal methotrexate. In comparison, 60 patients were treated with FA protocol, with patients achieved CR proceeded to allogeneic stem cell transplantation. Relapses were classified as very early (< 18 months from diagnosis), early (>18 months from diagnosis and <6 months from the end of therapy), and late (>6 months from the end of therapy). Patients' characteristics, response rate (RR) and overall survival (OS) were analyzed. Results The two arms had comparable characteristics. The median age in the R3 arm was 16 years (range: 14-40 years) compared to 22 years (range: 18-32 years) in the FA protocol arm. In the R3 arm, 88.2% of patients had B-cell ALL, while in the FA protocol arm, 92.2% had B-cell ALL. CNS involvement was seen in 28.8% and 17.6% of cases in the R3 and FA protocol arms, respectively. Relapses were classified as very early, early, or late in 2 (12%), 5 (29%), and 7 (41%) of cases in the R3 arm and were mostly late (25.2%) in the FA protocol arm. Relapses in the R3 arm were isolated bone marrow (BM), isolated extramedullary (EMD), or combined BM and EMD in 14 (82%), 1 (6%), and 2 (12%) cases, respectively, while EMD was around three times higher (16.9%) in the FA arm. The overall CR rate was 60% at the end of R3 induction, with negative MRD (<10 −4 cells) in 47.1% of patients. The overall CR rate was higher in the FA arm (76.3%), but the difference with the R3 arm was not statistically significant (p-value 0.1). The disease was refractory to subsequent salvage therapy in 42% of cases in both arms. About half of the patients who responded to R3 proceeded to allogeneic stem cell transplant (52.3%), while 78% of the patients post-FA underwent transplantation. Eight patients died (47%) in R3 arm, but only one patient died due to treatment-related sepsis, while the other seven patients died due to disease-related causes. At a median follow-up of 4 years, OS was 53% in the R3 arm compared to 30.8% in the FA arm, but the difference was not significant (p-value=0.8). The post-FA mortality was mainly due to infections (15.3% in FA vs. 5.9% in R3). Conclusion Pediatric-inspired protocols that have shown significant benefits in the front-line setting for ALL in the AYA population did not demonstrate a significant difference when compared to traditional adult-based salvage chemotherapy regimens in relapsed disease.

Pediatric-Inspired Regimens in the Treatment of Acute Lymphoblastic Leukemia in Adolescents and Young Adults: A Systematic Review.

Adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) have significantly worse outcomes than their younger counterparts. Current treatment guidelines rely mostly on non-randomized retrospective studies. We performed a systematic review of studies published within the last 15 years comparing pediatric-inspired regimens (PIR) versus adult-type regimens or performing an age-stratified analysis of outcomes in the AYA population. Due to the heterogeneity of data, a meta-analysis was not possible. However, the gathered data show a trend toward improvement in outcomes and an acceptable toxicity profile in patients treated with PIRs compared to conventional adult-type regimens. There is still room for further improvement, as older patients within the AYA population tend to perform poorly with PIR or conventional adult-type chemotherapy. Further randomized studies are needed to develop an optimal treatment strategy for AYA with ALL.

PH negative acute lymphoblastic leukemia in adolescents and young adults treated according a MRD adapted BFM ALL IC 2009 protocol: Argentine real-world data on 171 patients.

Intensified pediatric chemotherapy regimens to treat adolescents and young adults (AYA) patients with Philadelphia negative acute lymphoblastic leukemia (ALL) have been associated with better outcomes. The local BFM 2009-based scheme complements the risk stratification assessing the measurable residual disease (MRD) along the induction phase with increasing levels of sensitivity. The present retrospective multicenter analysis included 171 AYA (15-40 years) patients treated accordingly between 2013 and 2019. Ninety-one percent obtained morphological complete remission, 67% a negative (<0.1%) MRD at day 33 (TP1), and 78% a negative (<0.01%) MRD at day 78 (TP2). The overall survival (OS) and the event-free survival (EFS) at 2 years were 62%±4.1 and 55%±4.1, respectively. The OS and EFS were significant better for prednisone responders, who achieved <10% BM blast at day 15, a negative MRD at TP1 or at TP2, and for low-risk patients. Age ≤30 years and WBC <30×109/L, particularly among B-phenotype, were also associated with longer OS. In the multivariable analyses, TP1 MRD positive (OS HR 2.8, 95% CI 1.4-5.7, p=0.004; EFS HR 3.0, 95% CI 1.6-5.7, p=0.001) and at TP2 (OS HR 2.6, 95% CI 1.3-5.3, p=0.012; EFS HR 2.6, 95% CI 1.3-5.1, p=0.006) were independently associated with earlier events. Age >30 years was also associated with a shorter survival (HR 3.1, 95% CI 1.3-7.5, p=0.014). Therefore, those 68 patients ≤30 years with TP1/TP2 negative MRD depicted a longer OS (2 years 85%±4.8). Based on our real-world data, the pediatric-based scheme is feasible in Argentina associated with better outcomes for younger AYA patients who achieved negative MRD at day 33 and 78.

Treatment of Ph-Negative Acute Lymphoblastic Leukemia in Adolescents and Young Adults with an Affordable Outpatient Pediatric Regimen.

B-cell acute lymphoblastic leukemia is frequent in Hispanic adolescents and young adults. Outcomes of implementation of pediatric-inspired regimens in low-and middle-income countries are not well known. In this study we treated 94 adolescents and young adults with a local BFM regimen designed to be affordable with the use of native L-asparaginase and mitoxantrone administered in an outpatient fashion, and the of BCR/ABL and measurable residual disease (MRD) determined by high sensitivity flow cytometry for risk stratification. Induction mortality was 11%; 25% of patients had to abandon treatment or be transferred to another health system. Two-year overall (OS) and event free survival (EFS) were 61.5% and 49.8%, MRD-negative patients had a 24-month OS of 85.6% vs. 69.6% (p = .024) and EFS of 76% vs. 45.5% (p = .004). Patients older than 40 years and those who abandoned treatment had worse EFS. Overall drug costs in our regimen were 52% lower than those of CALGB10403. The treatment of AYAs with ALL with an outpatient focus was implemented successfully at a reduced cost. Genetic risk assessment, treatment abandonment and lack of access to novel therapies remain major barriers for improving outcomes.

Risk Stratified Therapy with Nelarabine and Intensified Administration of L-Asparaginase for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia in Adolescents and Young Adults (JPLSG T-11/JALSG T-ALL-211-U): An Intergroup Phase 2 Study

Risk Stratified Therapy with Nelarabine and Intensified Administration of L-Asparaginase for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia in Adolescents and Young Adults (JPLSG T-11/JALSG T-ALL-211-U): An Intergroup Phase 2 Study

Clinical Characteristics and Outcomes of Acute Lymphoblastic Leukemia in Adolescents and Young Adults in Malawi.

PURPOSEThere are limited data on treatment and outcomes for acute lymphoblastic leukemia (ALL) among adolescents and young adults in sub-Saharan Africa. We describe a prospective observational cohort in Malawi.METHODSPatients age 15-39 years with newly diagnosed ALL at Kamuzu Central Hospital, Malawi, were enrolled from 2013 to 2019; follow-up was censored on December 2020. ALL diagnosis was confirmed on-site using immunohistochemistry and telepathology consultation involving pathologists in Malawi and the United States. All but four patients were treated with a modified pediatric-inspired regimen (Cancer and Leukemia Group B 10403 protocol). Key modifications included omission of asparaginase and no dose escalation for methotrexate.RESULTSOf 19 participants, the median age was 22 (range 15-36) years. Of the 15 patients who initiated treatment, 11 (73%) achieved remission after induction, one (7%) died during induction, two (13%) had refractory disease, and one (7%) absconded. No patients were lost to follow-up. Eventually, 10 of 11 patients (91%) with confirmed remission relapsed. The median duration of first remission was 10 (range 3-22) months. Twelve of 15 treated patients (80%) had died at the time of censoring. Among treated patients, the 12- and 24-month overall survival was 50% (95% CI, 23 to 72) and 17% (95% CI, 3 to 42), respectively. CNS involvement was associated with worse survival.CONCLUSIONIt is possible to treat adolescents and young adults with ALL in low-resource settings using a low-cost, pediatric-inspired regimen; however, outcomes are poor. Both cost and limitations in supportive care infrastructure limit intensive cytotoxic approaches such as asparaginase. Patient-reported outcomes are needed to understand the quality of life and cost-effectiveness. Critically, innovative, leap-frog therapies, such as monoclonal or bispecific antibodies, and feasible economic models for resource-limited settings are urgently needed.

Treatment strategy for acute lymphoblastic leukemia in adolescent and young adults

Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is a relatively new concept that refers to patients aged 15-39 years with unique pathophysiology and requiring specific clinical care. Many clinical studies have revealed that treatment with the pediatric protocol has better disease-free and overall survival than the adult protocol for AYA-ALL. AYA-ALL survival was significantly improved from 30% with the adult regimen to 60-70% with the pediatric regimen. Two types of strategies are available to adapt pediatric regimens to AYA-ALL, a pediatric-inspired and a fully pediatric regimen. Determining the recommended strategy from these two strategies is difficult at this time. New knowledge of AYA-ALL-specific genetic characteristics provides new strategies for targetable ALL, especially Ph-like ALL. New immunotherapy has been approved for refractory and recurrent ALL; however, treatment results of AYA-ALL were improved by introducing the first line of immunotherapy in BCP-ALL, which may have a poor prognosis such as residual MRD. Pediatric and adult hematologists must work together to improve the prognosis of AYA-ALL.

Acute Lymphoblastic Leukemia in Adolescents and Young Adults: A Polish Perspective.

Acute lymphoblastic leukemia (ALL) is a disease that affects immature lymphocytes in the blood and presents a high prevalence rate in children and adolescent young adult (AYA) populations (15-39 years). AYAs are a unique group who face a significant therapeutic disadvantage when treated with the adult regimen, as evident with lower remission rates, whereas the opposite is true in children. A recent study by EUROCARE-5 showed a marked decrease with age in 5 years relative to survival outcomes based on cancer registries of 27 European countries: 85.8% for patients 0-14 years of age and a decreased 62.2% and 52.8% for patients 15-19 and 20-39 years, respectively. There is growing evidence demonstrating that the pediatric ALL treatment regimen is effective and beneficial when treating AYAs. Treatment of ALL in AYAs around the world is showing improved remission rates with therapeutic advancements and increasing amount of data available with updated clinical trials and regimens. The addition of l-asparaginase into adult treatment regimens has significantly increased the remission rates. This administration to AYAs is more difficult but shows a positive benefit in comparison with the toxicity ratio. This review article will discuss the controversy of AYA patients diagnosed with ALL treated with pediatric or adult protocols and their perspectives in Poland and will focus on ALL etiology, epidemiology, and prognostic factors with comparison of compliance of medications between both populations of patients.

Systematic Review of the Burden and Treatment Patterns of Adult and Adolescent Acute Lymphoblastic Leukemia in India: Comprehending the Challenges in an Emerging Economy

BackgroundIn the present systematic literature review, we sought to describe the burden and treatment practices of adult acute lymphoblastic leukemia (ALL) in India, which reflect the realities and outcomes in a middle-income country. Materials and MethodsWe conducted a search for reported studies using terms such as “adult ALL,” “epidemiology,” and “treatment” in the Medline, Embase, Cochrane, and other database sources. We obtained 249 articles and 18 conference abstracts reported until December 2019. A total of 40 studies were selected to qualitatively summarize the data. ResultsThe proportion of ALL among adult patients diagnosed with acute leukemia at reporting institutions from 16 Indian studies ranged from 7.3% to 57.8%. Most studies were performed in Northern India (n = 12), had a male preponderance (range, 57%-80%), and had a predominance of B-ALL (range, 65.2%-75.9%). The treatment protocols used for ALL included MCP-841, BFM (Berlin-Frankfurt-Münster)-90, chemotherapy plus a tyrosine kinase inhibitor, GMALL (German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia), and hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone). The complete remission rates and median overall survival for these protocols ranged from 46.7% to 91.4% and 7 to 46 months, respectively. The overall relapse rates were 24.3% to 57.1% within median time of 9 to 24 months, with bone marrow the most frequent relapse site. After relapse, most patients had chosen palliative therapy (range, 78.7%-96.0%). The major treatment-related toxicities included neutropenia, myelosuppression, and infection. ConclusionsThe results from Indian studies on adult ALL are heterogeneous, reporting a diverse incidence and poor overall outcomes using varied non-contemporaneous treatment protocols adapted from the developed world. A comprehensive countrywide approach to diagnosis, treatment, and follow-up and the potential incorporation of novel therapies could improve the prognosis and outcomes of adult ALL in India.

Progress against childhood and adolescent acute lymphoblastic leukaemia in the Netherlands, 1990\u20132015

We assessed the epidemiologic progress against childhood and adolescent acute lymphoblastic leukaemia (ALL) in the Netherlands over a 26 year period. ALL patients <18 years were selected from the Netherlands Cancer Registry and the Dutch Childhood Oncology Group. Trend analyses were performed over time and by age group and ALL subtype. Between 1990 and 2015, 2997 ALL patients were diagnosed, i.e. 115 patients (range 87–147) per year. Overall incidence remained stable at 37 per million children, despite increases for B-cell precursor ALL (BCP-ALL) at age 10–14 years (AAPC + 1.4%, p = 0.04) and T-cell ALL at 15–17 years (AAPC + 3.7%, p = 0.01). Five-year survival increased from 80% in 1990–94 to 91% in 2010–15 (p < 0.01). Mortality decreased by 4% annually (p < 0.01). Patients 15–17 years were increasingly treated in a paediatric oncology centre, from 35% in 1990–94 to 87% in 2010–15 and experienced a 70% reduction of risk of death compared to those treated outside such a centre (p < 0.01). Significant progress against childhood ALL has been made in the Netherlands, visible by improved survival rates coinciding with declining mortality rates. These outcomes were accompanied by stable incidence rates, despite increases for BCP-ALL at age 10–14 years and T-cell ALL at age 15–17 years.

Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia in Adolescents and Young Adults.

Adolescents and young adults (AYAs) with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) represent a unique patient population with a disproportionate survival disadvantage compared with younger children. Substantial progress has been made as we began to understand and address the multifaceted drivers behind this outcome disparity. New insights into the biology of B-cell ALL have uncovered distinct genetic characteristics more commonly found in AYAs that affect prognosis. Dramatic improvements in survival have been achieved with the use of pediatric-inspired protocols in the front-line setting, as well as antibody-based and chimeric antigen receptor T-cell therapies in the relapsed and refractory setting. Guided by the incorporation of minimal residual disease testing to inform clinical decision making, these represent major paradigm shifts in management. Efforts to design clinical trials geared toward AYAs and to enroll AYAs in available clinical trials will ensure ongoing progress. Holistic care of AYAs with ALL further involves recognition of psychosocial issues arising as a consequence of their diagnosis and the delivery of age-appropriate supportive care.

Persistent Gut Microbial Dysbiosis in Children with Acute Lymphoblastic Leukemia (ALL) During Chemotherapy.

Prophylactic or therapeutic antibiotic use along with chemotherapy treatment potentially has a long-standing adverse effect on the resident gut microbiota. We have established a case-control cohort of 32 pediatric and adolescent acute lymphoblastic leukemia (ALL) patients and 25 healthy siblings (sibling controls) to assess the effect of chemotherapy as well as antibiotic prophylaxis on the gut microbiota. We observe that the microbiota diversity and richness of the ALL group is significantly lower than that of the control group at diagnosis and during chemotherapy. The microbiota diversity is even lower in antibiotics-exposed ALL patients. Although the gut microbial diversity tends to stabilize after 1-year post-chemotherapy, their abundances were altered because of chemotherapy and prophylactic antibiotic treatments. Specifically, the abundances of mucolytic gram-positive anaerobic bacteria, including Ruminococcus gnavus and Ruminococcus torques, tended to increase during the chemotherapy regimen and continued to be elevated 1 year beyond the initiation of chemotherapy. This dysbiosis may contribute to the development of gastrointestinal complications in ALL children following chemotherapy. These findings set the stage to further understand the role of the gut microbiome dynamics in ALL patients and their potential role in alleviating some of the adverse side effects of chemotherapy and antibiotics use in immunocompromised children.

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

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

SLC1A3 contributes to L-asparaginase resistance in solid tumors.

L‐asparaginase (ASNase) serves as an effective drug for adolescent acute lymphoblastic leukemia. However, many clinical trials indicated severe ASNase toxicity in patients with solid tumors, with resistant mechanisms not well understood. Here, we took a functional genetic approach and identified SLC1A3 as a novel contributor to ASNase resistance in cancer cells. In combination with ASNase, SLC1A3 inhibition caused cell cycle arrest or apoptosis, and myriads of metabolic vulnerabilities in tricarboxylic acid (TCA) cycle, urea cycle, nucleotides biosynthesis, energy production, redox homeostasis, and lipid biosynthesis. SLC1A3 is an aspartate and glutamate transporter, mainly expressed in brain tissues, but high expression levels were also observed in some tumor types. Here, we demonstrate that ASNase stimulates aspartate and glutamate consumptions, and their refilling through SLC1A3 promotes cancer cell proliferation. Lastly, in vivo experiments indicated that SLC1A3 expression promoted tumor development and metastasis while negating the suppressive effects of ASNase by fueling aspartate, glutamate, and glutamine metabolisms despite of asparagine shortage. Altogether, our findings identify a novel role for SLC1A3 in ASNase resistance and suggest that restrictive aspartate and glutamate uptake might improve ASNase efficacy with solid tumors.

A Step Forward in the Treatment of Adolescent and Young Adult B-cell Acute Lymphoblastic Leukemia

A Step Forward in the Treatment of Adolescent and Young Adult B-cell Acute Lymphoblastic Leukemia

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.

Risk of hospitalization among survivors of childhood and adolescent acute lymphoblastic leukemia compared to siblings and a general population sample

BackgroundAcute Lymphoblastic Leukemia (ALL) has a high survival rate, but cancer-related late effects in the early post-treatment years need documentation. Hospitalizations are an indicator of the burden of late effects. We identify rates and risk factors for hospitalization from five to ten years after diagnosis for childhood and adolescent ALL survivors compared to siblings and a matched population sample. Methods176 ALL survivors were diagnosed at ≤22 years between 1998 and 2008 and treated at an Intermountain Healthcare facility. The Utah Population Database identified siblings, an age- and sex-matched sample of the Utah population, and statewide inpatient hospital discharges. Sex- and birth year-adjusted Poisson models with Generalized Estimating Equations and robust standard errors calculated rates and rate ratios. Cox proportional hazards models identified demographic and clinical risk factors for hospitalizations among survivors. ResultsHospitalization rates for survivors (Rate:3.76, 95% CI=2.22–6.36) were higher than siblings (Rate:2.69, 95% CI=1.01–7.18) and the population sample (Rate:1.87, 95% CI=1.13–3.09). Compared to siblings and population comparisons, rate ratios (RR) were significantly higher for survivors diagnosed between age 6 and 22 years (RR:2.87, 95% CI=1.03–7.97 vs siblings; RR:2.66, 95% CI=1.17–6.04 vs population comparisons). Rate ratios for diagnosis between 2004 and 2008 were significantly higher compared to the population sample (RR:4.29, 95% CI=1.49, 12.32), but not siblings (RR:2.73, 95% CI=0.54, 13.68). Survivors originally diagnosed with high-risk ALL did not have a significantly higher risk than siblings or population comparators. However, high-risk ALL survivors (Hazard ratio [HR]:3.36, 95% CI=1.33–8.45) and survivors diagnosed from 2004 to 2008 (HR:9.48, 95% CI=1.93–46.59) had the highest risk compared to their survivor counterparts. ConclusionsFive to ten years after diagnosis is a sensitive time period for hospitalizations in the ALL population. Survivors of childhood ALL require better long-term surveillance.

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.

Risk-Benefit Analysis of Pediatric-Inspired Versus Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone Protocols for Acute Lymphoblastic Leukemia in Adolescents and Young Adults.

Purpose: To estimate the risk–benefit trade-off of a pediatric-inspired regimen versus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) for first-line treatment of adolescents/young adult (AYA; ages 16–39 years) patients with Philadelphia-negative acute lymphoblastic leukemia.Methods: Patient outcomes were simulated using a 6-state Markov model, including complete response (CR), no CR, first relapse, second CR, second relapse, and death. A Weibull distribution was fit to the progression-free survival curve of hyper-CVAD–treated AYA patients from a single-center study, and comparable patient data from a retrospective study of pediatric regimen–treated AYA patients were utilized to estimate a relative progression difference (hazard ratio = 0.51) and model survival differences. Health-state utilities were estimated based on treatment stage, with an assumption that the pediatric protocol had 0.10 disutility compared with hyper-CVAD before the maintenance phase of treatment. Total life-years and quality-adjusted life-years (QALYs) were compared between treatment protocols at 1, 5, and 10 years, with additional probabilistic sensitivity analyses.Results: Treatment with the pediatric-inspired protocol was associated with a 0.04 increase in life-years, but a 0.01 decrease in QALYs at 1 year. By years 5 and 10, the pediatric-inspired protocol resulted in 0.18 and 0.24 increase in life-years and 0.25 and 0.32 increase in QALYs, respectively, relative to hyper-CVAD. The lower quality of life associated with the induction and intensification phases of pediatric treatment was offset by more favorable progression-free survival and overall survival relative to hyper-CVAD.Conclusions: Our exploratory analysis suggests that, compared with hyper-CVAD, pediatric-inspired protocols may increase life-years throughout treatment stages and QALYs in the long term.