Long-term Survivors Of Acute Lymphoblastic Leukemia Research Articles

Cumulative Dosage of Intrathecal Chemotherapy Agents Predicts White Matter Integrity in Long-Term Survivors of Acute Lymphoblastic Leukemia: A PETALE Study.

Acute lymphoblastic leukemia (ALL) stands as the most prevalent form of pediatric cancer in North America, with a current five-year survival rate of 85%. While more children achieved ALL remission and transition into adulthood, the prevalence of long-term treatment-related effects, especially neurocognitive sequelae, remains significant. This study pursues two objectives. Firstly, it investigates if Magnetization Transfer Ratio (MTR), a method assessing myelin integrity, is sensitive to white matter (WM) microstructural changes in long-term ALL survivors and whether these relate to cognitive impairments. Secondly, it examines the dose-related effects of chemotherapy agents on the MTR and its relationship to other risk factors such as female sex, early age diagnosis, and cranial radiotherapy. Magnetization transfer imaging was utilized to assess WM integrity in 35 survivors at a mean of 18.9 years after the onset of ALL (range since diagnosis: 6.9-26.8). Additionally, 21 controls matched for age, sex, and education level, with no history of cancer, were included. MTR was extracted from both the entire brain's WM and the corpus callosum through semi-automated procedures. The results indicated lower MTR means in survivors, which is linked to cognitive function. Negative associations between MTR means and intrathecal agents' (MTX, cytarabine, and hydrocortisone) cumulative doses received were highlighted. This study offers valuable insights into the connections between myelin deterioration, cognitive impairment, and the implications of IT chemotherapy, enhancing our understanding of ALL survivorship dynamics. It underscores MTR's relevance in monitoring neurotoxicity during oncological drug follow-up examinations.

Genetic Variants, Neurocognitive Outcomes, and Functional Neuroimaging in Survivors of Childhood Acute Lymphoblastic Leukemia.

Genetic predispositions may modulate risk for developing neurocognitive late effects in childhood acute lymphoblastic leukemia (ALL) survivors. Long-term ALL survivors (n = 212; 14.3[4.77] years, mean[SD]; 49% female) treated with chemotherapy completed neurocognitive testing and task-based functional neuroimaging (fMRI). Based on previous work from our team, genetic variants related to the folate pathway, glucocorticoid regulation, drug metabolism, oxidative stress, and attention were included as predictors of neurocognitive performance, using multivariable models adjusted for age, race, and sex. Subsequent analyses evaluated the impact of these variants on task-based fMRI. Statistical tests were two-sided. Survivors exhibited higher rates of impaired attention(20.8%), motor skills(42.2%), visuo-spatial memory(49.3-58.3%), processing speed(20.1%), and executive function(24.3-26.1%) relative to population norms (10%; p's < 0.001). Genetic variants implicated in attention deficit phenotypes predicted impaired attention span (synaptosome associated protein 25 [SNAP25rs3746544], F(2,172)=4.07, p = 0.019) and motor skills (monoamine oxidase A, [MAOArs1137070], F(2,125)=5.25, p = 0.007). Visuo-spatial memory and processing speed varied as a function of genetic variants in the folate pathway (methylenetetrahydrofolate reductase [MTHFRrs1801133], F(2,165)=3.48, p = 0.033; methylenetetrahydrofolate dehydrogenase 1 [MTHFD1rs2236225], F(2,135)=3.8, p = 0.025; respectively). Executive function performance was modulated by genetic variants in the folate pathway (MTHFD1rs2236225, F(2,158)=3.95, p = 0.021; MTHFD1rs1950902, F(2,154)=5.55, p = 0.005) and glucocorticoid regulation (vitamin D receptor [VDRrs154410], F(2,158)=3.29, p = 0.039; FKBP prolyl isomerase 5 [FKBP5rs1360780], F(2,154)=5.6, p = 0.005). Additionally, MTHFD1rs2236225 and FKBP5rs1360780 were associated with altered brain function during attention and working memory (p < 0.05; FWE corrected). Results extend previous findings of genetic risk of neurocognitive impairment following ALL therapy and highlight the importance of examining genetic modulators in relation to neurocognitive deficits.

Detecting Sarcopenic Obesity in Survivors of Pediatric Acute Lymphoblastic Leukemia: An Exploration of Body Mass Index and Triponderal Mass Index as Potential Surrogate Markers.

Survivors of pediatric acute lymphoblastic leukemia (ALL) often have altered body composition secondary to treatment effects, including sarcopenic obesity (SO), which increases the risk of both metabolic complications and frailty. SO is difficult to detect without using advanced imaging techniques to which access is often limited. To explore whether common clinical indices can reliably identify the presence of SO in a cohort of long-term survivors of ALL, the discriminatory capacity of body mass index (BMI) or triponderal mass index (TMI, kg/m 3 ) for detecting SO was assessed. Thresholds of BMI and TMI associated with overweight or obesity status had poor sensitivity (<50%) and specificity for detecting SO. Total misclassification rates at these thresholds exceeded 50% and positive likelihood ratios were nonsignificant. Notably, TMI is more strongly correlated with elevated adiposity than is BMI in this survivor population ( R2 =0.73 vs. 0.57), suggesting further exploration is warranted. Our study is limited by the sample size, precluding detailed regression analysis. This study highlights the challenges of identifying SO in survivors of pediatric ALL using common clinical indices. Prospective evaluation of additional potential surrogate markers in survivors, in conjunction with the component features of SO, should be a key focus of future research.

Global longitudinal strain assessment in long-term survivors of childhood acute lymphoblastic leukemia

Abstract Background The role of global longitudinal strain (GLS) in the long-term cardiac evaluation of childhood acute lymphoblastic leukemia (ALL) survivors is not clearly defined. Purpose To assess the prevalence of subclinical left ventricular systolic dysfunction (SLVD) in long-term survivors of ALL. We also aimed to compare echocardiographic measurements with a control group. Methods Patients &amp;lt;18 years of age diagnosed with ALL between 1985–2015 at our center were enrolled. Healthy siblings willing to participate were conformed the control group. GLS was measured with an automated software (AutoStrain, Tomtec). SLVD was defined as GLS&amp;lt;18.5% (absolute value) based on the lower limit of the 95% confidence interval in the control group. Group differences were accounted with nverse probability of treatment weighting. Results Of the 90 survivors included (37.8% female, time from diagnosis 18 [11–26] years), 24 (26.6%) had SLVD. Left ventricular systolic but not diastolic measurements were reduced compared to the control group (Table 1). Predictors of GLS in the survivors were smoking (p=0.004) and history of hematopoietic stem-cell transplantation (p=0.042) (Table 2). Conclusions Over ¼ of childhood ALL survivors had abnormal GLS values after a median follow-up of 18 years. Left-ventricular systolic parameters were reduced compared to a control group. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Sociedad Española de Cardiología. Sociedad Andaluza de Cardiología.

Inflammatory biomarkers after an exercise intervention in childhood acute lymphoblastic leukemia survivors.

Cancer survivors show increased risk for non-communicable diseases and chronic low-grade inflammation characterizes the development of such diseases. We investigated inflammatory plasma protein profiles of survivors of childhood acute lymphoblastic leukemia (ALL) in comparison to healthy controls and after an intervention with a home-based exercise program. Survivors of childhood ALL aged 16-30 years (n = 21) with a median age at diagnosis 4.9 (1.6-12.9) years and a median time of 15.9 years from diagnosis, and sex- and age-matched healthy controls (n = 21) were studied. Stored plasma samples were analyzed with Olink's 92-protein-wide Inflammation panel in 21 ALL long-term survivors at baseline, after a previous 16-week home-based exercise intervention (n = 17) and in 21 age- and sex-matched controls at baseline. Protein expression levels were compared between the groups. Inflammatory protein levels did not differ between the survivors and controls at baseline. Significantly reduced levels after the intervention were found in 11 proteins related to either vascular inflammation, insulin resistance, or both: tumor necrosis factor superfamily member 14 (TNFSF14), oncostatin M (OSM), monocyte chemoattractant protein 1 (MCP-1), MCP-2, fibroblast growth factor 21 (FGF-21), chemokine (C-C motif) ligand 4 (CCL4), transforming growth factor alpha (TGF-α), tumor necrosis factor-related apoptosis-inducing ligand 10 (TRAIL), adenosine deaminase (ADA), chemokine (C-X-C motif) ligand 6 (CXCL6), and latency-associated peptide transforming growth factor beta 1 (LAP TGF-β1). The ALL survivors were not significantly more affected by inflammation than controls at baseline. The survivors' 16-week exercise intervention led to significant reduction in inflammatory protein levels. Physical exercise should be promoted for survivors of childhood cancer.

The Influence of Body Composition on Bone Health in Long-term Survivors of Acute Lymphoblastic Leukemia in Childhood and Adolescence: Analyses by Dual-energy Radiograph Absorptiometry and Peripheral Quantitative Computed Tomography.

The normal interrelationship of body composition with bone health is less clear in the context of disease. Survivors of acute lymphoblastic leukemia (ALL) exhibit sarcopenic obesity and osteopenia. The impact of body composition on bone health in such survivors was examined. Survivors of ALL (N=74), >10 years from diagnosis, underwent dual-energy radiograph absorptiometry and peripheral quantitative computed tomography. Whole-body bone mineral content (WB BMC) Z scores were greater in males than females, but WB BMC indices (WB BMC/height 2 ) were comparable (0.74±0.125 and 0.72±0.069, respectively). WB BMC index (I) and fat-free mass index correlated significantly with trabecular bone mineral density, only in males. Fat mass index and appendicular lean mass index showed no such correlations. WB BMCI and fat-free mass index also correlated, again predominantly in males, with measures of strength in both trabecular and cortical bone. WB BMCI also correlated strongly with trabecular number, thickness, and hole size, also only in males. The results point to the need for enhancing muscle mass, measured by appendicular lean mass index, while reducing fat mass and maintaining good bone mineralization in long-term survivors of ALL to ensure the integrity of healthy bones.

Default-Mode Network Connectivity Changes Correlate with Attention Deficits in ALL Long-Term Survivors Treated with Radio- and/or Chemotherapy.

Simple SummaryBoth chemotherapy and radiotherapy play a role in the neurocognitive impairment of long-term survivors from acute lymphoblastic leukemia, but it is unknown if similar mechanisms are involved. We assessed neurocognitive alterations, brain tissue volumes, and functional connectivity of the main hubs of the default-mode network, in 13 patients treated with chemotherapy and radiotherapy (Group A) and in 13 treated with chemotherapy only (Group B). Correlations with neuropsychological scores, independent of group, were assessed for regions that showed significant differences between the two groups at neuroimaging. Compared to Group B, Group A performed significantly worse at the digit span and digit symbol tests and showed increased functional connectivity between the medial prefrontal cortex and the rolandic operculi, along with the absence of differences in regional brain tissue volumes. Functional connectivity in these regions correlated inversely with speed of processing in both groups, suggesting that similar mechanisms may be involved in the neurocognitive deficits in both groups.Whether chemotherapy (ChT) and radiotherapy (RT) determine neurocognitive impairment in acute lymphoblastic leukemia long-term survivors (ALL LTSs) through similar mechanisms affecting the same brain regions is still unknown. We compared neurocognitive alterations, regional brain tissue volumes (by voxel-based morphometry), and functional connectivity of the main default-mode network hubs (by seed-based analysis of resting state functional MRI data), in 13 ALL LTSs treated with RT and ChT (Group A) and 13 treated with ChT only (Group B). Group A performed significantly worse than Group B at the digit span and digit symbol tests (p = 0.023 and 0.013, respectively). Increased connectivity between the medial prefrontal cortex (the main anterior hub of the default-mode network) and the rolandic operculi was present in Group A compared to Group B, along with the absence of significant differences in regional brain tissue volumes. In these regions, the functional connectivity correlated inversely with the speed of processing scores, independent of treatment group. These results suggest that similar mechanisms may be involved in the neurocognitive deficits in ALL LTS patients, regardless of the treatment group. Further studies are needed to clarify whether these changes represent a direct expression of the mechanisms underlying the cognitive deficits or ineffective compensatory phenomena.

Bone health in long-term survivors of pediatric acute lymphoblastic leukemia. An assessment by peripheral quantitative computed tomography.

Loss of bone mineral is a common concomitant of the treatment of acute lymphoblastic leukemia (ALL) due mainly to chemotherapy, especially with corticosteroids. Osteopenia/osteoporosis may be encountered long into survivorship. Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry is limited to two-dimensionality and cannot distinguish trabecular from cortical bone. A sample of 74 subjects, ages 13.5-38.3years more than 10years from diagnosis, underwent peripheral quantitative computed tomography (pQCT) at metaphyseal (trabecular bone) and diaphyseal (cortical bone) sites in the radius and tibia. pQCT provides three-dimensional assessment of bone geometry, density, and architecture. Average values in multiple metrics were similar to those in healthy individuals, but deficits in both trabecular and cortical bones were revealed by lower Z scores using an ethnically comparable sample of healthy individuals. Connectivity, a measure of bone architecture and a surrogate measure of bone strength, was lower in females than males. Survivors of standard-risk ALL had greater connectivity in and more compact trabecular bone than high-risk survivors who had received more intensive osteotoxic chemotherapy. There were no statistically significant differences in any of the metrics at any of the sites between subjects who had or had not a history of fracture, cranial irradiation, or use of a bisphosphonate. These long-term survivors of ALL have somewhat compromised bone health, but data in comparable healthy populations are limited. Longitudinal studies in larger and more ethnically diverse cohorts will provide greater insight into bone health in this vulnerable population.

Second Primary Malignancies in Long Term Acute Lymphoblastic Leukemia Survivors of Three Age Groups

Background:Survivors of Acute Lymphoblastic Leukemia (ALL) are at an increased risk of subsequent malignancies secondary to genetic makeup, and exposure to environmental and treatment factors. Younger patients are exposed to different risk factors than older patients, which may result in differences in the risk of second malignancies. Additionally, there is not much information regarding the long term risk of subsequent malignancies. Therefore, we conducted this study to analyze and compare the risks of all second malignancies in patients aged under 15 (pediatric), 15-39 (Adolescent and Young Adult) and over 40 (Adults), five years after their initial diagnosis.Methods:Using data from the Surveillance, Epidemiology and End Results 9 database, Nov 2016 Sub {1973-2012}, we determined the risk of secondary malignancies in long term (five years out from diagnosis) survivors of ALL belonging to three age groups at diagnosis: less than 15, 15 to 39, and 40 and above. For the first cohort, patients younger than 15, there were 5200 patients with 69651 patient years of follow up. For the second age cohort, 15-39, there was a total of 949 patients with 10703 patient years of follow up, and for the third cohort, patients aged 40 and over, there were 365 patients with 2497 patient years of follow up. The risk of second primary malignancies is given as the standardized incidence ratio, which is calculated as such: observed incidence[O]/expected incidence[E]Results:Five years after an ALL diagnosis, patients under the age of 15 are at the highest relative risk of developing any type of second cancer (O/E: 3.58; CI: 2.95-4.30; N=114). Patients between the ages of 15-39 had a significantly fewer number of total cases, but still presented a high relative risk of developing any second malignancy (O/E: 1.59; CI: 1.10-2.22; N=34). Although patients over 40 had more total cases of second cancers than patients between 15-39, the data did not present any statistical significant increased relative risk for developing a second cancer when compared to matched population (O/E: 1.06; CI: 0.76-1.44 ; N=41). Patients under the age of 15 are at the highest risk of developing a second cancer of the salivary gland (O/E: 39.75; CI: 17.16-78.33; N=8). For patients under the age of 15, cancers of the oral cavity and pharynx (O/E: 15.38; CI: 7.37-28.28; N=10), brain, (O/E: 10.98; CI: 6.79-16.78; N=21) and thyroid (O/E: 7.07; CI: 4.70-10.21; N=28) represent the highest number of second cancers. Similarly, patients aged 15 to 39 are also at a high risk of developing a cancer of the salivary gland (O/E: 25.70; CI: 3.11-92.85; N=2). For patients aged 40 and above, cancer of the gum and other mouth has the highest increased risk (O/E: 14.73; CI: 1.78-53.22; N=2), but again there are relatively few patients so we cannot make any accurate estimates for second cancers. This decrease in the total number of patients may be due to an increase in the number of deaths resulting from ALL. In the database analyzed patients over 40 surviving one year, we had a total of 1,287 patients, but the same age cohort 4 more years from initial diagnosis only had 365 patients. Only 28% of patients over 40 survived after 5 years.Conclusion:There are several second malignancies that long term survivors of ALL are at increased risk of developing, even after 5 years from their initial diagnosis. These risks vary by age group, with young patients at substantially higher relative risk compared to their peers. However, unfortunately most adult patients died within the first five years of diagnosis. This information may help physicians effectively monitor survivors of ALL of all ages for any second cancers. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical utility of complex assessment with evoked potentials in acute lymphoblastic leukemia survivors: comparison of various treatment protocols

BackgroundOne of the greatest success of pediatric hematology is a prominent improvement of survival in acute lymphoblastic leukemia (ALL). Therefore, special attention needs to be paid to long-term side effects of the treatment such as neurotoxicity. One of the few diagnostic methods that allow an objective assessment of sensory systems are evoked potentials (EP).MethodsThe analyzed group consisted of 167 ALL long-term survivors, aged 4.9–28.4 years, without auditory, visual and sensory deviations. Patients were treated with New York (NY, n = 35), previous modified Berlin-Frankfurt-Münster (pBFM, n = 47) and BFM95 (n = 85) protocols. In order to assess the impact of radiotherapy on recorded EP, a joint analysis of NY and pBFM groups was performed. The control group consisted of 35 patients, aged 6–17 years. The analyzed patients underwent a complex assessment with visual EP (VEP), somatosensory EP (SEP) and brainstem auditory EP (BAEP) in accordance with current standards.ResultsALL treatment contributed to the shortening of wave I latency (1.59 vs 1.90, P = 0.003) and prolongation of I-III (2.23 vs 2.04, P = 0.004) and I-V (4.57 vs 4.24, P = 0.002) interwave latencies of BAEP. A significant effect was also noticed in P100 (106.32 vs 101.57, P < 0.001) and N135 (151.42 vs 138.22, P < 0.001) latencies of VEP and N18 amplitude (3.24 vs 4.70, P = 0.007) and P25 latency (21.32 vs 23.39, P < 0.001) of SEP. The distribution of abnormalities between protocols was similar in BAEP (NY - 68.6%, pBFM - 61.7%, BFM95–69.4%, P = 0.650), VEP (NY - 68.6%, pBFM - 42.5%, BFM95–58.3%, P = 0.053) and significantly different for SEP (NY - 62.9%, pBFM - 36.2%, BFM95–53.0%, P = 0.045). The harmful effect of radiotherapy was most clearly marked in numerous disturbances of SEP parameters.ConclusionsThe presented analysis indicates a high frequency of subclinical abnormalities in EP regardless of the analyzed protocol. To our knowledge current study is the largest and one of the most complex research examining the role of EP in ALL patients. The obtained results indicate the possibility of using a single, objective and non-invasive measurement of EP in ALL survivors in order to stratify the risk of developing sensory abnormalities in adulthood.

Polyneuropathy in Acute Lymphoblastic Leukemia Long-Term Survivors: Clinical and Electrophysiological Characteristics With the Impact of Radiotherapy.

Introduction: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer with one of the highest survival rates. Long-term complications that occur after intensive oncological treatment often impair normal daily functioning. However, existing data on peripheral nervous system condition in ALL survivors remain conflicting.Materials and Methods: The study group consisted of 215 ALL survivors. Patients were treated with New York (NY, n = 45), previous modified Berlin–Frankfurt–Münster (pBFM, n = 64), and BFM95 (n = 106) protocols. Time elapsed between the end of the treatment and the control examination varied from 0.3 to 20.9 years. The analyzed patients underwent a neurophysiological analysis with electroneurography (ENG) of motor (median and peroneal) and sensory (median and sural) nerves as well as electromyography (EMG) of tibialis anterior, vastus lateralis, and interosseous I muscles. To estimate the influence of radiotherapy on recorded neurophysiological responses, a joint analysis of NY, and pBFM groups was performed.Results: Clinical symptoms of polyneuropathy were noted among 102 (47.4%) children during the ALL therapy and in 111 (51.6%) during follow-up. At the time of treatment, polyneuropathy was diagnosed in 57.8% participants from NY group, 35.9%—pBFM and 50.0%—BFM95 (p = 0.145). A significantly higher incidence of polyneuropathy was observed during a follow-up in the NY group (68.9%; p < 0.001 vs. pBFM, p = 0.002 vs. BFM95). The most frequent abnormality within all the protocols was demyelination (NY: 44.4%, pBFM: 59.4%, BFM95: 41.5%), in contrast to the least frequently registered isolated axonal changes. The negative influence of oncological treatment on neurophysiological parameters in ALL survivors was observed. Complex disorders of motor nerves, sensory nerves, and motor unit potentials were registered. Motor-sensory neuropathy was the most frequently found pathology in all analyzed protocols. The harmful effect of radiotherapy was also observed in EMG results.Conclusions: Detailed neurophysiological analysis in long-term childhood ALL survivors has shown generalized abnormalities in registered parameters. To our knowledge, the current study is the largest and one of the most comprehensive ones among those examining disturbances in ENG and EMG in this group of patients. Moreover, we are the first ones to demonstrate the negative influence of radiotherapy on peripheral nerve conduction parameters.

Neuropsychological functioning in long-term survivors of pediatric acute lymphoblastic leukemia: A prospective cross-sectional study

Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Given the improvement in the survival of patients with ALL over the last few decades, the adverse effects of treatment and disease on survivors have become a major concern. Neuropsychological functioning has been reported to be affected in long-term survivors of ALL and can impact their quality of life. Objective: The objective of the study was to assess the neuropsychological functioning of long-term survivors of pediatric ALL. Materials and Methods: This prospective cross-sectional study was conducted at the Cancer Institute, Chennai, India, between March and August 2014. Pediatric patients with ALL who had survived at least 2 years after treatment and were in remission were included in the study. Various neuropsychological domains such as sustained attention, focused attention, verbal working memory, immediate memory, verbal learning, immediate recall, delayed recall, visuoconstructive ability, and visuomotor speed were assessed using age-appropriate tests. Data were analyzed using descriptive statistics and nonparametric tests such as the Mann–Whitney U and Kruskal–Wallis H-tests. P Results: Of the 51 participants, there were 30 male and 21 female survivors. Their median ages at diagnosis and assessment were 8.6 years and 18.3 years, respectively. Adult survivors (n = 31) were found to have deficits in immediate memory, verbal learning, immediate recall, visuoconstructive ability, and visuomotor speed. Adolescent survivors (n = 20) were found to have deficits in immediate memory and verbal working memory. Survivors aged 8 years or more at diagnosis had better focused attention and verbal working memory, while those diagnosed at age Conclusions: Long-term survivors of pediatric ALL experience deficits in various neuropsychological functions. Adult survivors have deficits in immediate memory, visuoconstructive ability, verbal learning, immediate recall, and visuomotor speed, whereas adolescent survivors have deficits in immediate memory and verbal working memory.

Cost-Effectiveness Analysis of Tisagenlecleucel for the Treatment of Pediatric and Young Adult Patients with Relapsed or Refractory B Cell Acute Lymphoblastic Leukemia in Japan

Until recently, treatment options were relatively limited for children and young adults with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL). Tisagenlecleucel is a chimeric antigen receptor T cell (CAR-T) immunotherapy with promising efficacy and manageable safety that was approved in Japan in 2019 for the treatment of CD19-positive r/r B cell ALL (B-ALL). However, there is no publication assessing the cost-effectiveness of CAR-T in Japan. The objective of this study was to assess the cost-effectiveness of a tisagenlecleucel treatment strategy compared to a blinatumomab treatment strategy and a clofarabine combination treatment strategy (i.e., clofarabine+cyclophosphamide+etoposide) in Japan for pediatric and young adult patients up to 25 years of age with r/r B-ALL. A partitioned survival model with a lifetime horizon and monthly cycle was constructed from a Japanese public healthcare payer's perspective. Patients were distributed across the following partitioned health states: event-free survival (EFS), progressive disease, and death, which were informed by the EFS and overall survival (OS) data of respective clinical trials before year 5. For the tisagenlecleucel arm, a decision-tree structure was used to partition patients based on the infusion status; those who discontinued prior to receiving infusion were assigned efficacy and cost inputs of blinatumomab and those who received infusion were assigned efficacy and costs inputs based on tisagenlecleucel-infused patients. As trial data for blinatumomab and clofarabine ended before year 5, matching-adjusted indirect comparisons were used to extrapolate OS between the end of trial observation and up to year 5. All surviving patients followed the mortality risk of long-term ALL survivors without additional risk of disease relapse after year 5, regardless of initial treatment strategies. The model accounted for pretreatment costs, treatment costs, adverse event costs, follow-up costs, subsequent allogeneic hematopoietic stem cell transplantation costs, and terminal care costs. Incremental cost-effectiveness ratios (ICERs) per life-years (LYs) gained and ICERs per quality-adjusted life-years (QALYs) gained were evaluated using a 2% discount rate, and a threshold of ¥7.5 million was used to assess cost-effectiveness. Deterministic and probabilistic sensitivity analyses were performed. The total LYs (discounted) for tisagenlecleucel, blinatumomab, and clofarabine combination treatment strategies were 13.3, 4.0, and 2.7 years, respectively; the corresponding QALYs were 11.6, 3.1, and 2.1 years, respectively. The ICERs per QALY gained for tisagenlecleucel were ¥2,035,071 versus blinatumomab and ¥2,644,702 versus clofarabine combination therapy. Extensive sensitivity analyses supported the findings. Tisagenlecleucel is a cost-effective treatment strategy for pediatric and young adult patients with r/r B-ALL from a Japanese public healthcare payer's perspective.

Chronic health conditions (CHC) and late mortality in survivors of acute lymphoblastic leukemia (ALL) in the Childhood Cancer Survivor Study.

10016 Background: The impact of evolving risk-stratified therapy on long-term morbidity and mortality in survivors of childhood ALL remains largely unknown. Methods: All-cause and health-related late mortality (HRM; captures death from late-effects occurring &gt; 5 yrs from diagnosis), subsequent (malignant) neoplasm [S(M)N], CTCAE graded CHC and neurocognitive outcomes were assessed in 5-yr survivors of ALL diagnosed &lt; 21 yrs of age from 1970-99. Therapy combinations defined 6 groups: 1970s-like ( 70s), standard and high risk 1980s- and 1990s-like ( 80sSR, 80sHR, 90sSR, 90sHR), relapse/transplant ( R/BMT). Cumulative incidence and standardized mortality ratios (SMR) were calculated. Piecewise exponential and log-binomial models estimated rate ratios (RR) with 95% confidence intervals (CI). Results: Among 6148 survivors (median age 31.5 yrs), 15-yr cumulative incidence of all-cause mortality was 5.8% (CI 5.3-6.2) and HRM was 1.5% (1.2-1.7). Compared to 70s, HRM was lower for 90sSR and 90sHR (RR 0.1, CI 0.0-0.3; 0.2, 0.1-0.7), similar to that in the US population (SMR; CI: 90sSR 1.1; 0.6-1.9, 90sHR 1.9; 0.8-3.7). 20-yr cumulative incidence of SN was 3.5% (CI 3.1-3.9). Compared to 70s, 90sSR had lower risk of benign meningioma (RR 0.1, CI 0.0-0.3) and SMN (0.3, 0.1-0.6) with no absolute excess risk compared to the US population. 90sSR was associated with a lower risk of CHCs (Table). Conclusions: More recent risk-stratified therapy has succeeded in reducing risk of late mortality and CHCs among long-term survivors of ALL. [Table: see text]

Doxorubicin treatments induce significant changes on the cardiac autonomic nervous system in childhood acute lymphoblastic leukemia long-term survivors.

Acute lymphoblastic leukemia (ALL) is one of the leading malignancies in children worldwide. The cardiotoxicity of anti-cancer treatments leads to a dysfunction of the cardiac autonomic nervous system. Protection strategies, with dexrazoxane treatments, were used to counter these adverse effects. The aim of this study was to investigate the effects of the treatments on the cardiac autonomic nervous system. A total of 203 cALL survivors were included in our analyses and were classified into 3 categories based on the prognostic risk group: standard risk, high risk with and without dexrazoxane. A 24-h Holter monitoring was performed to study the cardiac autonomic nervous system. The frequency domain heart rate variability (HRV) was used to validate the cardiac autonomic nervous system modifications. Other analyses were performed using linear HRV indexes in the time domain and non-linear indexes. A frequency domain HRV parameters analysis revealed significant differences on an overall time-period of 24h. A repeated measures ANOVA indicated a group-effect for the low frequency (p = 0.029), high frequency (p = 0.03) and LF/HF ratio (p = 0.029). Significant differences in the time domain and in the non-linear power spectral density HRV parameters were also observed. Anti-cancer treatments induced significant changes in the cardiac autonomic nervous system. The HRV was sensitive enough to detect cardiac autonomic nervous system alterations depending on the cALL risk category. Protection strategies (i.e., dexrazoxane treatments), which were used to counter the adverse effects of doxorubicin, could prevent changes observed in the cardiac autonomic nervous system.

Impact of short stature on health-related quality of life in long-term survivors of acute lymphoblastic leukemia in childhood and adolescence

PurposeSome survivors of acute lymphoblastic leukemia (ALL) in childhood and adolescence exhibit short stature, especially if their treatment included cranial irradiation. The impact of this outcome on health-related quality of life (HRQL) is uncertain and so formed the basis for the investigation reported here.MethodsThis study examined the association between self-reported HRQL and measured height in a cohort (n = 75) of survivors of ALL more than 10 years from diagnosis. HRQL was expressed as utility scores generated from a multi-attribute preference-based measure, the Health Utilities Index (HUI) which includes the complementary systems HUI2 and HUI3. For single attributes the range is from 1.00 (no limitations) to 0.00 (lowest level of function). For overall HRQL the range is 1.00 (perfect health) to 0.00 (equivalent to being dead). A negative score is associated with states of health worse than being dead.ResultsThere were no statistically significant differences in overall HRQL between subjects <25th (n = 16, 21%), 15th (n = 11, 15%) and 10th (n = 10, 13%) centiles. A greater amount of emotional morbidity, focused on anger and depression, was manifest in those <25th and 15th centiles, with clinically important differences of 0.07 (p = 0.03) and 0.077 (p = 0.016) respectively, but not in the shortest group who were < 10th centile.ConclusionsStudies in large cohorts of young adults in the general population has reported an inconsistent relationship between height and HRQL. Results from the current study suggest that no such relationship exists in long-term survivors of ALL in childhood and adolescence.

Peripheral Neuropathy, Sensory Processing, and Balance in Survivors of Acute Lymphoblastic Leukemia.

Purpose To compare peripheral nervous system function and balance between adult survivors of childhood acute lymphoblastic leukemia (ALL) and matched controls and to determine associations between peripheral neuropathy (PN) and limitations in static balance, mobility, walking endurance, and quality of life (QoL) among survivors. Patients and Methods Three hundred sixty-five adult survivors of childhood ALL and 365 controls with no cancer history completed assessments of PN (modified Total Neuropathy Score [mTNS]), static balance (Sensory Organization Test [SOT]), mobility (Timed Up and Go), walking endurance (6-minute walk test), QoL (Medical Outcomes Study 36-Item Short Form Survey), and visual-motor processing speed (Wechsler Adult Intelligence Scale). Results PN, but not impairments, in performance on SOT was more common in survivors than controls (41.4% v 9.5%, respectively; P < .001). In multivariable models, higher mTNS scores were associated with longer time to complete the Timed Up and Go (β = 0.15; 95% CI, 0.06 to 0.23; P < .001), shorter distance walked in 6 minutes (β = -4.39; 95% CI, -8.63 to -0.14; P = .04), and reduced QoL (β = -1.33; 95% CI, -1.79 to -0.87; P < .001 for physical functioning; β = -1.16; 95% CI, -1.64 to -0.67; P < .001 for role physical; and β = -0.88; 95% CI, -1.34 to -0.42; P < .001 for general health). Processing speed (β = 1.69; 95% CI, 0.98 to 2.40; P < .001), but not mTNS score, was associated with anterior-posterior sway on the SOT. Conclusion PN in long-term ALL survivors is associated with movement, including mobility and walking endurance, but not with static standing balance. The association between processing speed and sway suggests that static balance impairment in ALL survivors may be influenced by problems with CNS function, including the processing of sensory information.

DIVERGT screening procedure predicts general cognitive functioning in adult long-term survivors of pediatric acute lymphoblastic leukemia: A PETALE study.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Because of major improvements in treatment protocols, the survival rate now exceeds 80%. However, ALL treatments can cause long-term neurocognitive sequelae, which negatively impact academic achievement and quality of life. Therefore, cognitive sequelae need to be carefully evaluated. The DIVERGT is a battery of tests proposed as a screening tool, sensitive to executive function impairments in children and adolescent cancer survivors. Our study aimed at verifying the predictive value of the DIVERGT on general cognitive functioning in adult long-term survivors of ALL. ALL survivors completed the DIVERGT 13.4 years, on average, after remission (N=247). In addition, 49 of these survivors (equally selected amongst those with low, average, and high DIVERGT scores) as well as 29 controls completed a more comprehensive neuropsychological evaluation within a 3-year period from DIVERGT administration. Multivariate regression analysis was used to assess the predictive value of the DIVERGT on general intelligence, mathematics, verbal memory, and working memory. As a follow-up analysis, three performance groups were created based on the DIVERGT results. Multivariate analysis of variance (MANOVA) assessed neuropsychological differences between groups. The DIVERGT accurately predicted General Ability Index (GAI) (P<0.0001), mathematics (P<0.0001) and verbal memory (P=0.045). Moreover, the low-performance group consistently had poorer performance than the high-performance and control groups on the neuropsychological tests. The DIVERGT is a useful, time-effective screening battery for broader neurocognitive impairments identification in long-term adult ALL survivors. It could be implemented as routine examination in cancer follow-up clinics.

Body composition in long-term survivors of acute lymphoblastic leukemia diagnosed in childhood and adolescence: A focus on sarcopenic obesity.

The late effects of treatment for acute lymphoblastic leukemia (ALL) include disordered body composition, especially obesity. Less attention has been focused on the loss of skeletal muscle mass (SMM) and the combined morbidity of sarcopenic obesity. A cross-sectional study of body composition was undertaken via dual-energy x-ray absorptiometry in 75 long-term survivors of ALL (more than 10 years after the diagnosis). Measures were obtained of the fat mass (FM), fat-free mass (equivalent to the lean body mass [LBM]), and whole-body bone mineral content. Health-related quality of life (HRQL) was measured with the Health Utilities Index. The sum of the FM, LBM, and whole-body bone mineral content matched the total body weight measured directly (r = 0.998). The appendicular lean mass (ALM) was derived from the LBM in all 4 limbs and accounted for approximately 75% of the SMM. According to the fat mass index (FMI; ie, FM/height2 ), 12% of females and 18% of males were frankly obese by World Health Organization criteria. The median FMI z score was + 0.40, whereas the median z score for the appendicular lean mass index (ALMI; ie, ALM/height2 ) was -0.40. Sarcopenic obesity, defined as a positive FMI z score with a negative ALMI z score, was present in 32 subjects (43%). There were statistically significant and clinically important differences in overall HRQL between subjects with and without sarcopenic obesity. Sarcopenic obesity is prevalent in long-term survivors of ALL, and this places them in double jeopardy from excess body fat and inadequate SMM (eg, a combination of metabolic and frailty syndromes). It is associated with an adverse impact on overall HRQL. Cancer 2018;124:1225-31. © 2017 American Cancer Society.

Abstract B23: Detection of susceptibility to childhood Acute Lymphoblastic Leukemia (ALL)

Abstract Currently, there are no known methods to predict of susceptibility to, and means for prevent Acute Lymphoblastic Leukemia (ALL). We have evaluated and patented a group of proteins dubbed Protein X from a certain strain of Aspergillus Flavus (AF) and developed methods for screening and identifying totally asymptomatic patients in remission of ALL, including long term survivors of this disease, distinguishing them from normal controls. Subject to institutional approved consents/assents, 15-20 ml of blood was obtained from 40 cases of ALL in children and young adults, including long term survivors of ALL. Controls were normal individuals, sickle cell patients undergoing partial exchange transfusion and patients with solid tumors. Mononuclear leukocytes (MNL) of ALL patients in remission and controls were separated using Ficoll Paque Plus (GE Healthcare). Epstein Barr virus (EBV) was obtained commercially. Positive and negative controls for Protein X were aflatoxin and Mycocladus Corymbifera (MC). Avian leukosis virus (ALV) was used as control for EBV. MNL were co-incubated with Protein X ± EBV ± irradiation, for periods of 1-72 hours. Controls were treated identically with appropriate substitutions. Test and control MNLs were examined for genetic markers, NF-κB and cell surface markers (CSM) including CD10/CD19, CD34/CD19, and CD34/CD117. Changes were expressed as percentage of control. Using ELISA, plasmas were tested for antibodies against Protein X ± EBV time experiments reveled 72 hours was optimum for achieving results. Upon 72 hours exposure of MNL from ALL to Protein X ± EBV, cells from ALL patents in remission developed cell surface phenotypes typical of ALL. This was not seen in controls. Addition of EBV ± radiation to Protein X, enhanced these effects in MNL of ALL and not controls. Changes were statistically significant and clearly separated ALL from controls. Evaluation of NF-κB revealed enhancement in ALL and not controls. Aflatoxin indiscriminately induced cell surface marker changes in both, normal and ALL, while ALV and supernatant of MC had no effect. ELISA, using Protein X ± EBV, distinguished ALL from controls. Gene array and biomarkers confirmed transformation to leukemic cell markers upon exposure to Protein X in cells from ALL patients but not controls. These studies reveal, in vitro, upon exposure to Protein X, unlike normal controls, MNL from ALL patients in remission develop cell surface phenotypes and genetic markers typical of ALL. These techniques have potential for screening for ALL and may have implications for etiology of ALL and its prevention. Citation Format: Cameron K. Tebbi. Detection of susceptibility to childhood Acute Lymphoblastic Leukemia (ALL). [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B23.