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

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

Perspectives on outpatient administration of CAR-T cell therapy in aggressive B-cell lymphoma and acute lymphoblastic leukemia.

Chimeric antigen receptor (CAR) T-cell therapies that specifically target the CD19 antigen have emerged as a highly effective treatment option in patients with refractory B-cell hematological malignancies. Safety and efficacy outcomes from the pivotal prospective clinical trials of axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel and the retrospective, postmarketing, real-world analyses have confirmed high response rates and durable remissions in patients who had failed multiple lines of therapy and had no meaningful treatment options. Although initially administered in the inpatient setting, there has been a growing interest in delivering CAR-T cell therapy in the outpatient setting; however, this has not been adopted as standard clinical practice for multiple reasons, including logistic and reimbursement issues. CAR-T cell therapy requires a multidisciplinary approach and coordination, particularly if given in an outpatient setting. The ability to monitor patients closely is necessary and proper protocols must be established to respond to clinical changes to ensure efficient, effective and rapid evaluation either in the clinic or emergency department for management decisions regarding fever, sepsis, cytokine release syndrome and neurological events, specifically immune effector cell-associated neurotoxicity syndrome. This review presents the authors' institutional experience with the preparation and delivery of outpatient CD19-directed CAR-T cell therapy.

Ethnic and border differences on blood cancer presentation and outcomes: A Texas population-based study.

BACKGROUND: The Texas/Chihuahua (US/Mexico) border is a medically underserved region with many reported barriers for health care access. Although Hispanic ethnicity is associated with health disparities for many different diseases, the population-based estimates of incidence and survival for patients with blood cancer along the border are unknown. The authors hypothesized that Hispanic ethnicity and border proximity is associated with poor blood cancer outcomes. METHODS: Data from the Texas Cancer Registry (1995-2016) were used to investigate the primary exposures of patient ethnicity (Hispanic vs non-Hispanic) and geographic location (border vs non-border). Other confounders and covariates included sex, age, year of diagnosis, rurality, insurance status, poverty indicators, and comorbidities. The Mantel-Haenszel method and Cox regression analyses were used to determine adjusted effects of ethnicity and border proximity on the relative risk (RR) and survival of patients with different blood cancer types. RESULTS: Hispanic patients were diagnosed at a younger age than non-Hispanic patients and presented with increased comorbidities. Whereas non-Hispanics had a higher incidence of developing blood cancer compared with Hispanics overall, Hispanics demonstrated a higher incidence of acute lymphoblastic leukemia (RR, 1.92; 95% CI, 1.79-2.08; P < .001) with worse outcomes. Hispanics from the Texas/Chihuahua border demonstrated a higher incidence of chronic myeloid leukemia (RR, 1.28; 95% CI, 1.07-1.51; P = .02) and acute myeloid leukemia (RR, 1.17; 95% CI, 1.04-1.33; P = .0009) compared with Hispanics living elsewhere in Texas. CONCLUSIONS: Hispanic ethnicity and border proximity were associated with a poor presentation and an adverse prognosis despite the younger age of diagnosis. Future studies should explore differences in disease biology and treatment strategies that could drive these regional disparities.

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

BACKGROUND: In 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 METHODS: We 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. RESULTS: The 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. CONCLUSIONS: The 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.

Measurable Residual Disease Assessment and Allogeneic Transplantation as Consolidation Therapy in Adult Acute Lymphoblastic Leukemia in Colombia.

INTRODUCTION: Detectable minimal residual disease (MRD) after therapy for acute lymphoblastic leukemia (ALL) is the strongest predictor of hematologic relapse. The objective of the study was to assess disease-free survival (DFS) and overall survival (OS) of patients with ALL according with MRD status at the end of induction therapy in a Colombian population. PATIENTS AND METHODS: We assessed a retrospective cohort to compare DFS and OS in adults with de novo ALL according to MRD status at the end of induction chemotherapy, and the type of postinduction consolidation strategy used. RESULTS: A total of 165 adults with ALL were included in the MRD part of the study, 73 patients in the MRD-negative group and 92 in the MRD-positive group. Median DFS for the MRD-positive group was 11 months (95% confidence interval, 11.7-22.2) and was not reached for the MRD-negative group (P < .001). At 3 years, DFS was 18% and 55%, respectively (P < .001). The median OS for MRD-positive patients was 16 months (95% confidence interval, 8.8-23.15) and was not reached in the MRD-negative group. At 3 years, OS was 26% and 51% for the former and latter group, respectively. Among subjects who did not receive a transplant, median DFS was 21 months for MRD-negative patients and 9 months for MRD-positive patients (P < .001). The median DFS was not reached in either group, whereas 3-year DFS was 64% for MRD-negative and 70% for MRD-positive patients who underwent transplantation in first remission (P = .861). CONCLUSION: MRD status at the end of induction is an independent prognostic factor for DFS and OS in adult ALL. Allogeneic transplantation in first remission could overcome the adverse prognostic impact of MRD.

Distance to treatment center is associated with survival in children and young adults with acute lymphoblastic leukemia.

BACKGROUND: Socioeconomic and demographic categories such as income, race, insurance status, and treatment center type are associated with outcomes in acute leukemia. This study was aimed at determining whether the distance to treatment center affects overall survival for children and young adults with acute leukemia. METHODS: The National Cancer Database was queried for patients 39 years old or younger who were diagnosed with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). A backward elimination procedure was used to select final multivariate Cox models. RESULTS: In total, 12,301 patients with AML and 22,683 patients with ALL were analyzed. The ALL model included distance to treatment center, Charlson-Deyo score, age, race, insurance status, and community income level. US census definitions of urban and rural were not statistically significant, and no interaction was significant for included variables. Compared with distances > 50 miles, all other distances were associated with improved survival (hazard ratio [HR] for ≤10 miles, 0.91; P = .04; HR for >10 to ≤20 miles, 0.86; P = .004; HR for >20 to ≤50 miles, 0.87; P = .005). The final model for AML included the same variables as the ALL model except for distance to treatment center, which was not statistically significant. CONCLUSIONS: For children and young adults with ALL, distances > 50 miles are associated with inferior overall survival; however, no difference is seen for AML. Although it is unknown whether differences in survival for patients with ALL based on distance are driven by relapse or treatment-related mortality, increased attention to adherence, supportive care, and logistics for patients traveling long distances is warranted. LAY SUMMARY: For children and young adults with acute lymphoblastic leukemia, living more than 50 miles from the treatment center is associated with worse outcomes.

Impact of Insurance Status on Survival Outcomes in Adults With Acute Lymphoblastic Leukemia (ALL): A Single-center Experience.

BACKGROUND: Socioeconomic factors including race, ethnicity, and poverty level have been associated with disparities in survival among adult patients with acute leukemia. Insurance status is also likely to affect survival outcomes in these patients but has not been well studied. We investigated the impact of insurance status at time of diagnosis on survival in adult patients with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Adult patients diagnosed with B-lineage ALL between January 1, 2007 and October 31, 2017 were included, with follow-up through January 19, 2018. Kaplan-Meier survival curves were used to estimate overall survival (OS) and progression-free survival (PFS) for the 2 groups. Cox proportional hazard regression methods were used for univariate and multivariate analyses. RESULTS: A total of 136 patients were included in the study, 29 without insurance and 107 with insurance at time of diagnosis. Patients without insurance were younger and more likely to be Hispanic or Latino compared with insured patients. When controlling for confounding variables, patients without insurance had worse PFS. There was no statistically significant difference in OS between the 2 groups. Hispanic or Latino ethnicity was associated with improved PFS and OS in multivariate analyses. CONCLUSIONS: Adult patients with ALL without health insurance at time of diagnosis had worse PFS when controlling for other relevant clinical factors. Lack of insurance may be an obstacle to timely, effective maintenance therapy in the outpatient setting. Further research is needed to understand how insurance status impacts survival and ways to mitigate any disparities.

Cost-utility analysis of inotuzumab ozogamicin for relapsed or refractory B cell acute lymphoblastic leukemia from the perspective of Taiwan's health care system.

OBJECTIVES: We conduct a cost-utility analysis of inotuzumab ozogamicin (INO) versus chemotherapy as the standard of care (SOC) for adults with relapsed or refractory B cell acute lymphoblastic leukemia. METHODS: A Markov model incorporating transition probabilities between health states was applied to simulate disease progression. The model inputs, including overall survival, progression-free survival, and utility parameters, were obtained from the INO-VATE ALL trial and literatures. The Taiwan Cancer Registry Database and the Health and Welfare Database were utilized to identify the patient cohort and medical costs from the perspective of National Health Insurance Administration. The lifetime medical costs (in 2017 US dollars), quality-adjusted life years (QALYs) gained, and associated incremental cost-effectiveness ratio (ICER) were the main study outcomes. RESULTS: The lifetime medical costs for INO and SOC were $176,795 and $69,496, and the QALYs gained were 2.25 and 0.84, respectively. The ICER for INO versus SOC was $76,044 per QALY gained, which is slightly more than three times Taiwan's gross domestic product per capita (i.e., $73,224). Favorable economic results for INO versus SOC were found with an increased time horizon for model simulation, less discounting for the future benefit, and higher stem cell transplantation (SCT) rate after INO treatment; and among patients aged less than 55 years, with no SCT history, or in the first salvage treatment. CONCLUSIONS: INO versus SOC has higher costs but is more effective. The use of INO is favorable for patients in the early treatment course and when more future benefit associated with INO is considered.

Area deprivation is associated with poorer overall survival in children with acute lymphoblastic leukemia.

BACKGROUND: Few studies have evaluated social determinants of outcomes disparities for children with acute lymphoblastic leukemia (ALL). We investigated the association of area deprivation index (ADI), a measure of neighborhood socioeconomic disadvantage, with overall survival (OS) among children and adolescents with ALL. PROCEDURE: We obtained demographic and clinical data, geocoded addresses at diagnosis, and vital status on all Texas children diagnosed with ALL from 1995 to 2011 (N = 4104). Using the US Census Bureau 2010 geography, we computed ADI scores for all census tracts in Texas and grouped the tracts into quartiles: least, third-most, second-most, and most disadvantaged. We mapped children to ADI quartiles based on residence at diagnosis, and estimated OS using Cox regression adjusting for sex, race/ethnicity, age, and metropolitan/nonmetropolitan residence. RESULTS: Five-year OS ranged from 89% (95% confidence interval [CI] 87-91%) for children in the least disadvantaged tracts to 79% (95% CI 76-81%) for children in the most disadvantaged tracts (P = 4E-7). An elevated hazard ratio (HR) for death was observed for children in the most disadvantaged tracts (HR 1.57, 95% CI 1.23-2.00), and trends toward increased mortality were observed in the third-most and second-most disadvantaged tracts (HR 1.23, 95% CI 0.97-1.57 and HR 1.27, 95% CI 0.99-1.62, respectively). In stratified analyses, area disadvantage was more strongly associated with OS in males than females. CONCLUSIONS: Neighborhood socioeconomic disadvantage is associated with inferior OS in this analysis of over 4100 children with ALL, highlighting the substantial contributions of social-environmental factors to childhood cancer survival. This association was stronger in males than females.

A Literature Review of Racial Disparities in Overall Survival of Black Children With Acute Lymphoblastic Leukemia Compared With White Children With Acute Lymphoblastic Leukemia.

Despite major advances in acute lymphoblastic leukemia [ALL] treatment, poorer overall survival (OS) persists for Black children with ALL compared with White children with ALL. The purpose of this literature review was to examine the racial disparities on OS in Black versus White children with ALL. The Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medline, PubMed, and Academic Search Complete databases were searched using the Medical Subject Heading (MeSH) terms: survival or mortality or outcome AND black or African-American or AA or minority AND racial disparities or race or racial/ethnic disparities AND cancer in children or pediatric cancer or children with leukemia or children with ALL for articles published in English between January 2009 and July 2019. Exclusion criteria were non-research articles, systematic reviews, conference abstracts, editorials, commentaries, correspondence, and case reports. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, data were extracted, appraised, and synthesized. Sixteen articles met the inclusion criteria. Sample sizes across studies ranged from 184 to 31,866 participants. The factors most associated with disparities in OS included: age at diagnosis (e.g., <1 year and/or >10 years old), differences in clinical prognosticators (e.g., white blood cell count at diagnosis, T-cell vs. precursor B-cell immunophenotype, central nervous system disease status, cytogenetic profile) and lower socioeconomic status. Future prospective studies are needed to elucidate the role of these factors in OS of Black children with ALL.

Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia.

OPINION STATEMENT: Chimeric receptor antigen (CAR) T cells are an innovative cellular immunotherapeutic approach that involves genetic modification of T cells to express CAR targeting tumor antigen. Prior to the development of CAR-T, the only potential cure for patients with relapsed or refractory (RR) acute lymphoblastic leukemia (ALL) was allogeneic hematopoietic stem cell transplantation (HSCT). Several CAR-T cell products have been studied in prospective clinical trials which ultimately have resulted in the approval of one anti-CD19 CAR-T cell product in pediatric RR ALL: tisagenlecleucel (CD3ζ and 41BB). While some patients achieve durable responses with CAR-T, lack of response and relapse remains clinical challenges. Reasons for sub-optimal response include lack of CAR-T cell persistence and target antigen down-regulation. Future CARs are under development to improve long-term persistence and to be able to overcome resistance mechanisms associated with the disease and the hostile tumor microenvironment. With evolving understanding about CARs and new constructs under investigation, there is optimism that future products will improve the safety and efficacy from the current standard of care.

Randomized assessment of delayed intensification and two methods for parenteral methotrexate delivery in childhood B-ALL: Children's Oncology Group Studies P9904 and P9905.

The delayed intensification (DI) enhanced outcome for patients with acute lymphoblastic leukemia (ALL) treated on BFM 76/79 and CCG 105 after a prednisone-based induction. Childrens Oncology Group protocols P9904/9905 evaluated DI via a post-induction randomization for eligible National Cancer Institute (NCI) standard (SR) and high-risk (HR) patients. A second randomization compared intravenous methotrexate (IV MTX) as a 24- (1 g/m2) vs. 4-h (2 g/m2) infusion. NCI SR patients received a dexamethasone-based three-drug and NCI HR/CNS 3 SR patients a prednisone-based four-drug induction. End induction MRD (minimal residual disease) was obtained but did not impact treatment. DI improved the 10-year continuous complete remission (CCR) rate; 75.5 ± 2.5% vs. 81.8 ± 2.2% p = 0.002, whereas MTX administration did not; 4-h 80.8 ± 1.9%; 24-h 81.4 ± 1.9% (p = 0.7780). Overall survival (OS) at 10 years did not differ with DI: 91.4 ± 1.6% vs. 90.9 ± 1.7% (p = 0.25) without but was higher with the 24-h MTX infusion; 4-h 91.1 ± 1.4%; 24-h 93.9 ± 1.2% (p = 0.0209). MRD predicted outcome; 10-year CCR 87.7 ± 2.2 and 82.1 ± 2.5% when MRD was <0.01% with/without DI (p = 0.007) and 54.3 ± 8% and 44 ± 8% for patients with MRD ≥ 0.01% with/without DI (p = 0.11). DI improved CCR for patients with B-ALL with and without end induction MRD.

Results of CoALL 07-03 study childhood ALL based on combined risk assessment by in vivo and in vitro pharmacosensitivity.

We conducted a clinical trial and report the long-term outcome of 773 children with acute lymphoblastic leukemia upon risk-adapted therapy accrued in trial CoALL 07-03 (from the Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia). In a 2-step stratification, patients were allocated to receive either low- or high-risk treatment, based on initial white blood cell count, age, and immunophenotype. A second stratification was performed according to the results of in vitro pharmacosensitivity toward prednisolone, vincristine, and asparaginase (PVA score) and in vivo response after induction therapy (minimal residual disease [MRD]). Therapy was reduced for both risk groups in patients with a low PVA score or negative MRD result, and intensified in patients with a high PVA score. Overall outcome improved significantly compared with the predecessor CoALL 06-97 trial, with identical therapy backbone despite treatment reduction in 15.8% of patients (10-year probability of event-free survival, 83.5% vs 73.9%; overall survival, 90.7% vs 83.8%). Outcome for patients in the reduced treatment arms was superior to that of patients in the standard arms, associated with a profound reduction in frequency and severity of infectious complications. Importantly, we observed a lack of correlation between in vitro and in vivo drug response, as well as a lower predictive value of in vitro drug testing, reflecting an intrinsic limitation of this methodology that prevents its use for treatment stratification in future trials. In conclusion, it might be possible to reduce chemotherapy in children with acute lymphoblastic leukemia selected by stringent in vivo measurement of MRD without jeopardizing overall outcome.

Socioeconomic inequalities in survival of children with acute lymphoblastic leukemia insured by social security in Mexico: a study of the 2007-2009 cohorts.

BACKGROUND: Although acute lymphoblastic leukemia (ALL) 5 years survival in minors has reached 90%, socioeconomic differences have been reported among and within countries. Within countries, the difference has been related to the socioeconomic status of the parents, even in the context of public health services with universal coverage. In Mexico, differences in the mortality of children with cancer have been reported among sociodemographic zones. The Instituto Mexicano del Seguro Social (IMSS), the country's main social security institution, has reported socioeconomic differences in life expectancy within its affiliated population. Here, the socioeconomic inequalities in the survival of children (< 15 years old) enrolled in the IMSS were analyzed. METHODS: Five-year survival data were analyzed in cohorts of patients diagnosed with ALL during the period 2007-2009 in the two IMSS networks of medical services that serve 7 states of the central region of Mexico. A Cox proportional risk model was developed and adjusted for the socioeconomic characteristics of family, community of residence and for the clinical characteristics of the children. The slope of socioeconomic inequality of the probability of dying within five years after the diagnosis of ALL was estimated. RESULTS: For the 294 patients studied, the 5 years survival rate was 53.7%; the median survival was 4.06 years (4.9 years for standard-risk diagnosis; 2.5 years for high-risk diagnosis). The attrition rate was 12%. The Cox model showed that children who had been IMSS-insured for less than half their lives had more than double the risk of dying than those who had been insured for their entire lives. CONCLUSIONS: We did not find evidence of socioeconomic inequalities in the survival of children with ALL associated with family income, educational and occupational level of parents. However, we found a relevant gradient related social security protection: the longer children's life insured by social security, the higher their probability of surviving ALL was. These results add evidence of the effectiveness of social security, as a mechanism of wealth redistribution and a promoter of social mobility. Extending these social security benefits to the entire Mexican population could promote better health outcomes.

Treatment patterns, survival, and hospitalization in adult patients with acute lymphoblastic leukemia: an observational cohort study using SEER Medicare data.

There is little evidence about whether additional risk stratification for adult patients with acute lymphoblastic leukemia age 65 and older is warranted. Using the Surveillance, Epidemiology, and End Results data linked to Medicare claims, we examined the effects of age, comorbid conditions, and mobility limitations on treatment and survival in a cohort of 795 patients diagnosed with ALL between 1 January 2000 and 31 December 2009. In the cohort, 54% received chemotherapy within the first 90 days, of whom 74% were hospitalized during the first chemotherapy administration. Unadjusted median survival was 172 days (95% CI = 244-379) for the overall cohort, 325 days (95% CI = 244-379) for those age 65-69, but only 59 days (95% CI = 45-76) for those age ≥80. In multivariate analyses, older age groups (70-74, 75-79, and ≥80) and comorbidity score ≥2 were independently associated with poorer survival. Treatment and outcomes vary considerably among subgroups of older patients suggesting that further risk stratification may be useful.

Experience with generic pegylated L-asparaginase in children with acute lymphoblastic leukemia and monitoring of serum asparaginase activity.

BACKGROUND: Pegylated asparaginase (P-Asp) though integral to acute lymphoblastic leukemia (ALL) therapy is often not accessible to patients in developing countries. We share our clinical experience with generic P-Asp along with monitoring of asparaginase activity. METHODS: In this prospective observational study, patients ≤18 years of age with ALL were assigned to receive either generic P-Asp or native asparaginase (N-Asp) in a non-randomized manner. Treatment protocol was based on ALL BFM-95 backbone. The dose of P-Asp was 1500 IU/m2 by intravenous route during induction (Ia) and re-induction (IIa) phase of therapy. RESULTS: N-Asp or P-Asp was administered to 52 and 54 of the 106 eligible patients respectively. Demographic and disease characteristics were comparable in both arms. The mean trough levels for N-Asp and P-Asp were 156.87 ± 22.35 IU/L and 216.03 ± 73.40 IU/L, respectively (p value <0.001) and all patients achieved therapeutic levels during Ia. Incidence of asparaginase-attributable toxicity was similar in the two arms in both phases of treatment, although hospitalization due to noninfectious causes was more common in P-Asp arm during Ia (13% versus 0%, p value, 0.01). Clinical hypersensitivity and silent inactivation were not observed during Ia while these occurred in 13% and 5% of patients in the N-Asp arm and P-Asp arms of IIa, respectively. The 2-year event free survival for P-Asp and N-Asp groups was 84% and 80.7%, respectively (p value 0.85). CONCLUSION: Generic P-Asp was observed to be efficacious and well tolerated in our patients and adequate therapeutic levels were sustained for 2 weeks.

Long-term Survival and Value of Chimeric Antigen Receptor T-Cell Therapy for Pediatric Patients With Relapsed or Refractory Leukemia.

Importance: Among children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia, the rate of 5-year disease-free survival is 10% to 20%. Approval of tisagenlecleucel, a chimeric antigen receptor T-cell therapy, represents a new and potentially curative treatment option. However, tisagenlecleucel is expensive, with a current list price of $475 000 per one-time administration. Objective: To estimate the long-term survival and value of tisagenlecleucel for children and young adults with B-cell acute lymphoblastic leukemia. Design, Setting, and Participants: In this cost-effectiveness analysis, a decision analytic model was designed to extrapolate trial evidence to a patient lifetime horizon. The survival evidence for the model was extracted from 3 studies: B2202 (enrolled patients from April 8, 2015, to November 23, 2016), B2205J (enrolled patients from August 14, 2014, to February 1, 2016), and B2101J (enrolled patients from March 15, 2012, to November 30, 2015). Long-term survival and outcomes of patients younger than 25 years with B-cell acute lymphoblastic leukemia that is refractory or in second or later relapse were derived using flexible parametric modeling from the direct extrapolation of event-free survival and overall survival curves. The published Kaplan-Meier curves were digitized from November 1, 2017, to November 30, 2017, using an algorithm to impute patient-level time-to-event data. Sensitivity and scenario analyses assessed uncertainty in the evidence and model assumptions to further bound the range of cost-effectiveness. Data were analyzed from December 1, 2017, to March 31, 2018. Interventions: The primary intervention of interest was tisagenlecleucel. The comparator of interest was the chemoimmunotherapeutic agent clofarabine. Main Outcomes and Measures: Model outcomes included life-years gained, quality-adjusted life-years (QALYs) gained, and incremental costs per life-year and QALY gained. Results: Forty percent of patients initiating treatment with tisagenlecleucel are expected to be long-term survivors, or alive and responding to treatment after 5 years. Tisagenlecleucel had a total discounted cost of $667 000, with discounted life-years gained of 10.34 years and 9.28 QALYs gained. The clofarabine comparator had a total discounted cost of approximately $337 000, with discounted life-years gained of 2.43 years and 2.10 QALYs gained. This difference resulted in an incremental cost-effectiveness ratio of approximately $42 000 per life-year gained and approximately $46 000 per QALY gained for tisagenlecleucel vs clofarabine. These results were robust to probabilistic sensitivity analyses. Across scenario analyses that included more conservative assumptions regarding long-term relapse and survival, the incremental cost-effectiveness ratio ranged from $37 000 to $78 000 per QALY gained. Conclusions and Relevance: Tisagenlecleucel likely provides gains in survival and seems to be priced in alignment with these benefits. This study suggests that payers and innovators should develop novel payment models that reduce the risk and uncertainty around long-term value and provide safeguards to ensure high-value care.

Late mortality and morbidity among long-term leukemia survivors with Down syndrome: A nationwide population-based cohort study.

BACKGROUND: Late health consequences of treatment for childhood leukemia are well documented. Although individuals with Down syndrome (DS) have a substantially increased risk of leukemia, information on late effects in this group is almost nonexistent. The aim of this study was to evaluate the mortality and morbidity among 5-year leukemia survivors with DS. PROCEDURE: We compared 5-year leukemia survivors with leukemia-free individuals with DS. All individuals born with DS in Denmark between 1960 and 2007 and in Sweden between 1973 and 2009 were included. Long-term morbidity was estimated by comparing hospitalization rates between survivors and leukemia-free individuals. RESULTS: In total, we found 6,705 individuals with DS, 84 of whom were 5-year survivors of leukemia. Survivors had a higher risk of death (hazard ratio [HR] 5.9; 95% confidence interval [CI]: 2.7-13) compared with leukemia-free individuals. All deaths (n = 7) among 5-year leukemia survivors were due to relapse. Survivors had a higher hospitalization rate (HR 4.4; 95% CI: 3.1-6.2). However, most of these hospitalizations were due to relapse. Censoring individuals who either had a relapse or were being treated for a relapse more than 5 years from the initial diagnosis (n = 9) attenuated the association (HR 1.4; 95% CI: 1.0-2.1). CONCLUSION: In this study, we found that relapse was the main reason for death and hospitalization among leukemia survivors with DS, and not late effects. These results are reassuring for individuals treated for DS associated with leukemia and their parents.

Can we incorporate geriatric assessment in the management of acute lymphoblastic leukemia in older adults?

Acute lymphoblastic leukemia (ALL) is an uncommon disease. Approximately 14% of new ALL cases occur in adults aged 60 and over, and the three-year overall survival in this population is poor at 12.8%. Older adults with ALL are heterogeneous in terms of their underlying health status, which can make treatment selection challenging given the disease rarity and limited inclusion of older patients in clinical trials. A comprehensive geriatric assessment (CGA) is a compilation of tools to assess multiple domains such as physical function and cognition, and may assist in guiding treatment selection and supportive care interventions. However, studies on the use of CGA are limited in older adults with ALL. In this review, we discuss the utility of CGA in patients with various hematologic malignancies. Using two patient cases of ALL, we also describe how CGA may be use to guide treatment and supportive care interventions.