Time to Minimal Residual Disease (MRD) Negativity Is Independently Predictive of Outcome in Adults with Acute Lymphoblastic Leukemia (ALL) Receiving Hyper-CVAD

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2498-2498
Author(s):  
Ryan D. Cassaday ◽  
Philip A. Stevenson ◽  
Brent L. Wood ◽  
Pamela S. Becker ◽  
Paul C. Hendrie ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
Philadelphia Chromosome ◽  
Time Dependent ◽  
Secondary Malignancy ◽  
Fisher Exact Test ◽  
Inadequate Response ◽  
The Impact

Abstract Background: MRD is an established prognostic/predictive factor in ALL. Achieving MRD negativity (MRDNeg) early during treatment is associated with superior outcomes with pediatric regimens. However, little is known about how to use MRD assessments with hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with methotrexate and cytarabine), one of the most commonly used regimens in adults with ALL. MRDNeg at 3 months has been shown to be predictive of outcome with hyperCVAD + tyrosine kinase inhibitor (TKI) in Philadelphia chromosome (Ph)+ ALL (Ravandi, Blood, 2013, p. 1214), but this is relatively late in the treatment course. We hypothesized that achieving MRDNeg earlyduring treatment would be associated withbetter outcomes with hyperCVAD. Methods: We performed a retrospective analysis of our center's experience since 2005 under an IRB-approved protocol. We included pts with ALL (excluding Burkitt and mixed-phenotype) age >18 years (yrs) who received hyperCVAD as initial therapy. MRD was assessed primarily by either multiparameter flow cytometry or BCR-ABL quantitative PCR on bone marrow, though other techniques (e.g., cytogenetics [CG]) were considered if obtained. Timing and nature of assessments were left to treating physicians. Pts were not defined as MRDNeg until all assays performed were unable to detect any disease. Clinical risk at diagnosis was defined by age (> 35 yrs), white blood cells (WBC; > 30 for B-ALL, > 100 for T-ALL), and CG (Ph+, MLL rearranged, -7, +8, complex, low hypodiploid, and near triploid). Events included morphologic or MRD recurrence, change in treatment due to inadequate response, death from any cause, or secondary malignancy. Frequencies of characteristics between groups were compared using a Fisher exact test. Cox proportional hazards (PH) models were used to investigate associations between variables. A test of PH was used to assess the impact of time on the association between MRD and outcome, in which MRD was modeled as a time-dependent covariate with left-truncation. Clinical follow-up was updated as of June 2015. Results: We identified 142 pts for this analysis: 18% T-ALL, 73% > 35 yrs, 24% had high WBC (6 unknown), and 48% had high-risk CG, 71% of which (34% of total) were Ph+ (11 unknown). Sixty-five pts (46%) underwent hematopoietic cell transplantation (HCT) in first remission (CR1): 32% with reduced-intensity and 68% with myeloablative conditioning. All Ph+ pts received TKI with hyperCVAD: 23 (48%) received imatinib and 25 (52%) received dasatinib. Median time of 1st MRD assessment (relative to start of treatment) was 37 days, with 27% occurring by 21 days and 85% by 90 days; 42% were MRDNeg at 1stassessment, 26% became MRDNeg later, and 32% did not become MRDNeg during treatment with hyperCVAD. Incidences of age > 35 yrs (P = 1), high-risk CG (P = 0.08), Ph+ (P = 0.72), and high WBC (P = 0.38) were not significantly different in MRDNeg pts. HCT in CR1 was more common in MRDNeg pts (P = 0.05). In Cox PH models adjusted for HCT in CR1, CG, and WBC, MRDNeg pts had significantly better overall survival (OS; hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.23-0.81; P = 0.01; 48 events) and event-free survival (EFS; HR 0.27, 95% CI 0.16-0.46; P < 0.01; 84 events). Through an exploratory landmark analysis, the benefit of MRDNeg on EFS became more pronounced after 8 weeks: pts who were MRDNeg by 8 weeks had significantly better EFS (HR 0.53, 95% CI 0.32-0.89; P = 0.02) than those who were not. Further, achieving MRDNeg earlier during treatment was associated with better EFS. In a test of PH on the time-dependent Cox PH model, time to MRDNeg had a significant impact on the association between MRD status and EFS (P = 0.02) but not OS (P = 0.19). This is depicted in Fig 1, where being MRDNeg earlier after treatment initiation is associated with a smaller beta (i.e., significantly less hazard for an event). Conclusions: MRDNeg is an independent predictor of superior OS and EFS in adults receiving hyperCVAD for ALL. Further, achieving MRDNeg earlier during treatment was associated with better EFS. When considering the time-dependent nature of MRD status relative to EFS, 8 weeks after initiation of hyperCVAD may represent an important prognostic time point. If confirmed in an independent dataset, this may prove to be a useful surrogate in both routine clinical practice and future clinical trials with this regimen. Disclosures Cassaday: Pfizer: Research Funding; Seattle Genetics: Research Funding.

scholarly journals A Phase 2 Study of Ruxolitinib with Chemotherapy in Children with Philadelphia Chromosome-like Acute Lymphoblastic Leukemia (INCB18424-269/AALL1521): Dose-Finding Results from the Part 1 Safety Phase

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 555-555 ◽  
Author(s):  
Sarah K. Tasian ◽  
Albert Assad ◽  
Deborah S Hunter ◽  
Yining Du ◽  
Mignon L. Loh
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Study ◽  
Multi Agent

Abstract Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype occurring in 15-30% of older children and adolescents/young adults (AYAs) with B-ALL. Ph-like ALL is associated with high relapse rates and poor survival despite intensive multi-agent cytotoxic chemotherapy. Development of successful treatment strategies to decrease relapse and improve cure rates in patients with Ph-like ALL remains a major therapeutic gap. Rearrangements of cytokine receptor-like factor 2 (CRLF2-R) with frequent concomitant JAK2 point mutations occur in 50% of Ph-like ALL cases and induce constitutive JAK/STAT and other kinase signaling. An additional 15-20% of Ph-like ALL harbors other JAK pathway alterations, such as JAK2 or EPOR rearrangements, that similarly activate JAK/STAT signaling. Ruxolitinib is a potent, selective JAK1/JAK2 inhibitor with demonstrated activity in preclinical Ph-like ALL models and clinical safety as monotherapy in children with relapsed/refractory cancers. We report the initial safety of ruxolitinib in combination with post-induction chemotherapy in children and AYAs with newly-diagnosed high-risk (HR) Ph-like ALL with CRLF2-R or other JAK pathway alterations treated on the non-randomized, 2-part phase 2 study INCB18424-269 (AALL1521; NCT02723994). Methods: Patients aged 1-21 years at time of diagnosis with HR B-ALL and eligible Ph-like genetic lesions who had completed 4-drug induction chemotherapy as per the Children's Oncology Group (COG) AALL1131 study (NCT02883049) were eligible to participate. Patients were stratified into 4 cohorts by genetic alterations and end-induction flow cytometric minimal residual disease (MRD) status: cohort A = CRLF2-R JAK-mutant, MRD+; B = CRLF2-R JAK-wild-type, MRD+; C = other JAK pathway alterations, MRD+, D = any CRLF2-R or JAK pathway alteration, MRD-. Patients commenced treatment on the INCB18424-269/AALL1521 study at consolidation with ruxolitinib orally twice daily in combination with augmented Berlin-Frankfurt-Münster (aBFM) post-induction chemotherapy as per AALL1131. Five discontinuous dose levels (10-50 mg/m2/dose 14-days-on/14-days-off per cycle [DL-2 to DL2]) and one continuous DL1b (40 mg/m2/dose × 28 days per cycle) of ruxolitinib with aBFM chemotherapy were explored via a standard rolling 6 design. Dose-limiting toxicities (DLTs) were assessed through Day 29 of delayed intensification (DI) and defined as hematologic and non-hematologic toxicity with higher grade or more prolonged duration than observed in children with treated with identical chemotherapy (without ruxolitinib) on other COG HR B-ALL trials. Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted using serial blood samples obtained from patients during consolidation therapy. Results: Forty patients (pts) were enrolled in Part 1 (cohort A, n=10; B, n=9; C, n=5; D, n=16). Four patients discontinued study treatment before the Day 29 DI timepoint, 3 of whom were replaced. Patients had a median age of 14 years, and 67.5% were male. Treatment-emergent adverse events occurred in all patients and included anemia (75%), platelet count decrease and/or thrombocytopenia (65%), febrile neutropenia (72.5%), and AST or ALT increase (57.5%). Thirty-three patients had Grade 3/4 events deemed possibly related to ruxolitinib without identified DLTs. Eleven patients in Part 1 (27.5%) discontinued study therapy for various reasons: CNS relapse (2 pts), end-consolidation MRD+ (4 pts), multi-system organ dysfunction (MSOD; 2 pts), elective MRD- stem cell transplantation (1 pt), psychosocial/compliance issues (2 pts). One patient died of septic shock and MSOD not attributed to ruxolitinib. Preliminary analysis of plasma drug levels at 4 hours post-dose was consistent with the known PK profile of ruxolitinib. PD studies demonstrated dose-dependent inhibition of target phosphoproteins and, importantly, sustained inhibition of phosphorylated STAT5 with continuous ruxolitinib dosing at DL1b. Discussion: These findings demonstrate safety and tolerability of ruxolitinib in combination with intensive multi-agent chemotherapy in children and AYAs with newly-diagnosed HR CRLF2-R/JAK pathway-mutant Ph-like ALL and support continued investigation of treatment efficacy in Part 2 of this trial. Disclosures Tasian: Aleta Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Incyte Corporation: Research Funding. Assad:Incyte Corporation: Employment, Equity Ownership. Hunter:Incyte Corporation: Employment. Du:Incyte Corporation: Employment.

scholarly journals Impact of a Risk-Adapted Treatment Approach in Pediatric AML: A Report of the AML-BFM Registry 2012

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 293-293
Author(s):  
Mareike Rasche ◽  
Emma Steidel ◽  
Denise Kondryn ◽  
Nils Von Neuhoff ◽  
Lucie Sramkova ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Secondary Malignancy ◽  
Hematopoietic Stem ◽  
Historical Comparison ◽  
Risk Criteria ◽  
Advisory Boards ◽  
Pediatric Aml ◽  
The Impact ◽  
Very High

BACKGROUND: A risk-adapted approach incorporating genetic data, complemented by response evaluation may help to identify patients with high-risk disease (HR) who could benefit from hematopoietic stem cell transplantation (HSCT) at initial disease. Several international study groups currently recommend HSCT in pediatric HR AML. However, the impact of a risk-adapted treatment strategy is unknown. Here, we present results of our first treatment period with a risk-adapted indication for HSCT in the AML-BFM study group. PATIENTS AND METHOD: From 2012 until 2017 a total of 324 children &lt;18 years of the AML-BFM registry 2012 (hereafter named R12; Germany, Austria and Czech Republic) with de novo AML were included. Down syndrome or secondary leukemia, FAB M3, an accompanying disease or pre-treatment &gt;14 days were excluded. Patients or guardians provided written informed consent. Treatment guidelines were recommended but were not obligatory: Chemotherapy followed the best arm of study AML-BFM 2004, but patients were stratified according to new genetic and response-adapted (≥10% leukemic blasts after induction 1 or ≥5% after induction 2) risk criteria with the indication of HSCT in HR patients. We used AML-BFM 2004 (hereafter called S04) as historical comparison. The analysis was performed following the Declaration of Helsinki. Five-year estimates of overall survival (pOS) and event-free survival (pEFS) were calculated using SPSS (version 25). EFS is defined as the time from diagnosis to the first event (relapse, death, failure to achieve remission or secondary malignancy) or until last follow-up. Data were frozen on May 1st, 2019. RESULTS: We sought to systematically decipher the impact of a risk-adapted approach in pediatric AML. The total cohort showed a pEFS of 58±5% and pOS of 78±3% (vs S04 52±2%, p=0.014 and 70±2%, p=0.059) and significantly increased rates of HSCT (S04 vs R12: p&lt;0.001). Importantly, the SR group did not change between periods. The increase in survival was rather explained by improvements in patients with genetically defined HR AML resulting in a survival similar to IR AML (pEFS IR vs HR: p=0.684; pOS: p=0.861). Next, we compared outcome of a previously well-defined subgroup with rare very high-risk criteria (VHR). The risk-adapted therapy resulted in a significantly higher pEFS (S04 vs R12: 33±5% vs 48±11; p=0.017) and higher rates of HSCT (37% vs 78%, p&lt;0.001). Nevertheless, salvage treatment was equally efficient in both periods, resulting in a pOS of 56±6% vs 72±7% (p=0.202). To evaluate the effects of inclusion of response to mere genotype-driven stratification we reanalyzed all R12 patients retrospectively according to their genetic risk only (see table 1). Response-guided re-stratification led to major shifts of patients to higher risk groups. Importantly, despite the fact that the registry made only recommendations according to the new risk stratification, compliance with guidelines including HSCT indication was very high (n=319; 98%). Discrepancies were as follows: SR have been treated with a higher intensity (i.e. more chemotherapy and/or HSCT; n=2); HR AML treated as IR (n=2), IR AML received HR treatment including HSCT (n=2). Seventy-five percent of HR AML have been transplanted. Discrepancies are explainable by early relapses or death before HSCT. To validate the response-guided re-stratification more specifically, we performed a subgroup analysis of HR AML: The survival was similar in re-stratified IR patients and genetic HR patients with poor response (p=0.656) but was higher in genetic HR patients with good response (p=0.01), indicating an effective selection of re-stratified patients with IR. CONCLUSION: This analysis indicates the benefit of risk-adapted indications for HSCT in pediatric AML: After a long period with a stable pEFS (Rasche et al. Leukemia 2018) the current cohort now demonstrates a significant improvement. The efficacy of the risk-adapted approach is reflected by remarkable survival rates for patients with HR AML. At the same time, it seems not to impair the ongoing improvement of salvage therapy. However, for patients with poorly responding IR AML the outcome is dismal despite HSCT and they require alternative treatment approaches. Further studies are also needed to detect genetically defined HR patients who may not need HSCT, but also to develop efficient re-stratification approaches to enhance the survival in SR patients. Table 1. Disclosures Reinhardt: Novartis: Other: Participation in Advisory Boards; Roche: Research Funding; CSL Behring: Research Funding; Jazz: Other: Participation in Advisory Boards, Research Funding.

scholarly journals Impact of Central Nervous System Involvement in Adult Patients with Acute Lymphoblastic Leukemia Treated in a Pediatrics-Inspired Protocol - a Graall Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 215-215
Author(s):  
Corentin Orvain ◽  
Sylvain Chantepie ◽  
Xavier Thomas ◽  
Martine Escoffre-Barbe ◽  
Francoise Huguet ◽  
...  
Keyword(s):  
Blood Cells ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
Clinical Signs ◽  
Adult Patients ◽  
High Dose ◽  
Cns Involvement ◽  
The Impact ◽  
To Receive

Abstract Background: The prognosis of central nervous system (CNS) involvement in adult patients with acute lymphoblastic leukemia (ALL) has been historically associated with a dismal outcome. Whereas the prognosis of adult patients with ALL has greatly improved since the advent of pediatrics-inspired regimens, the prognostic impact of CNS involvement has not been formerly reevaluated. We report herein the impact of CNS involvement in patients included in the pediatric-inspired prospective GRAALL-2005 study. Methods: All patients received a 5-drug induction therapy with native E. Coli-ASP intravenous injections. Patients in complete remission (CR) received two consolidation courses with alternating cycles including high dose cytarabine (2g/m2/12h on days 1 and 2), high dose methotrexate (3 g/m2 on day 1), and cyclophosphamide. All patients in persistent CR and with no indication for allogeneic stem cell transplantation (SCT) received late intensification, followed by one last consolidation course. Patients with initial CNS involvement, clinically and/or cytologically (cerebrospinal fluid), were recommended to receive an increased number of triple intrathecal therapy, CNS irradiation, and were eligible for allogeneic SCT in first CR. They received less Asp injections during induction therapy to avoid CNS adverse events. CNS irradiation included two lateral fields encompassing the skull, facial, the base of the skull, and the first two cervical vertebrae at a dose of 24 grays for those not receiving allogeneic SCT and 15 grays for those receiving allogeneic SCT. Results: Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia-negative ALL were included with 55 (7%) having initial CNS involvement. These patients were more likely to be of T-phenotype (51 versus 32%, p=.004) and had more white blood cells at diagnosis (median 23 G/l versus 11 G/l, p=.02). Most patients (36 pts, 66%) were classified as CNS-3 (&gt; 5 white blood cells/µl and a positive cytospin and/or clinical signs) whereas 5 patients (9%) were CNS-2 (&lt; 5 white blood cells/µl and a positive cytospin), and 14 (25%) have data pending. Among patients with details regarding CNS involvement, 25/41 (61%) had clinical signs including trigeminal anesthesia (9 pts, 36%), facial paralysis (4 pts, 16%), extremities paresthesia (4 pts, 16%), visual signs (2 pts, 8%), meningeal syndrome (2 pts, 8%), and motor deficit (2 pts, 8%), and 4/18 (22%) had radiological signs. Induction death, CR1 rate, and negative minimal residual disease after induction were similar whether patients had CNS involvement or not (6 vs 6%, 89 vs 89%, 73 vs 62%, 26 vs 22%, respectively). Patients with CNS involvement had a worse outcome than those without with a median event-free survival (EFS) of 391 days (versus not reached for patients without CNS involvement, HR: 1.7, 95% CI: 1.2 - 2.5, p=.002) and a median overall survival (OS) of 608 days (versus not reached for patients without CNS involvement, HR: 1.8, 95% CI: 1.3 - 2.6, p=.001) (figure). Similar results were observed when patients who received allogeneic SCT in CR1 were censored at the time of graft. As recommended, patients with CNS involvement were more likely to receive allogeneic SCT than those without (53 versus 34%, p=.01), with a median time of 169 days. A 150-day landmark analysis, excluding 12 patients with an EFS event before 150 days, was performed to study the impact of allogeneic SCT on the outcome of patients with CNS involvement. Allogeneic SCT had no impact on either EFS (HR: .5, 95% CI: .2 - 1.2, p=.15) or OS (HR: .8, 95% CI: .3 - 1.8, p=.53). Conclusion: Despite improved outcome in young adult ALL patients with pediatrics-inspired protocols, CNS involvement remains a poor-risk feature. The historical use of allogeneic SCT does not improve outcome. Specific regimens should be developed for adult ALL patients with CNS involvement. Figure 1 Figure 1. Disclosures Huguet: Amgen: Other: Advisor; BMS: Other: Advisor; Celgene: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Novartis: Other: Advisor; Pfizer: Other: Advisor. Barbieux: ASTRA-ZENECCA: Consultancy. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Boissel: Bristol-Myers Squibb: Honoraria, Research Funding; Servier: Consultancy, Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; CELGENE: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria. Mathilde: ABBVIE: Consultancy; SERVIER: Consultancy.

High-Risk Cytogenetics Multiple Myeloma: Impact of Consolidation and Maintenance

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2271-2271 ◽  
Author(s):  
Victor Jimenez-Zepeda ◽  
Peter Duggan ◽  
Paola Neri ◽  
Jason Tay ◽  
Fariborz Rashid-Kolvear ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Progression Free Survival ◽  
Categorical Variables ◽  
Rank Test ◽  
Fisher Exact Test ◽  
Free Survival ◽  
The Impact

Abstract Introduction MM is a very heterogeneous disease for which several new treatments have become available over the past decade. With the advent of novel agents, the outcomes of this disease have improved dramatically. Unfortunately, High-risk myeloma (HRM) defined by the presence of del(17p), t(4;14), t(14;16), del13q by conventional karyotype and hypodiploidy, continues to exhibit poorer outcomes. Based on the above mentioned, we aimed to assess the clinical outcomes of patients with HRM treated at our center. Methods All consecutive HRM patients who underwent single auto-SCT at Tom Baker Cancer Center (TBCC) from 01/2004 to March/2016 were evaluated. HRM was defined by FISH and conventional karyotype when available. Two-sided Fisher exact test was used to test for differences between categorical variables. A p value of <0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. All statistical analyses were performed by using the SPSS 22.0 software. Results 73 consecutive patients with HRM underwent single auto-SCT at our Institution over the defined period. Clinical characteristics are shown in Table 1. Eighty-seven percent of patient received bortezomib-containing regimens as induction regimens. Day-100 response post-ASCT is seen in Table 1. Consolidation was given to 41.7% and maintenance to 79% of cases. At the time of analysis, 43 patients are still alive and 40 have already progressed. Median OS and PFS were 50.8 and 21.9 months, respectively for the whole group. Median OS was 50.4 months for the group receiving consolidation compared to 39 months for those without (p=0.1). In addition, median PFS was longer in the group treated with consolidation (NR, Estimate 25 months vs 13.5 months, p=0.02, Fig1a). Furthermore, OS and PFS were longer in the group receiving some form of maintenance compared to those without (56.3 and 22.5months vs 19.9 and 9 months, p=0.04 and 0.01, respectively) (Fig 1b and c). In conclusion, HRM is an aggressive form of myeloma where the OS and PFS are shorter than the standard risk MM. Consolidation and maintenance strategies seemed to increase both OS and PFS in our current report, but clinical outcomes are still poor. Novel strategies such as immune modulation,check-point inhibition, among others are needed to maximize the impact of the consolidation and maintenance phases in this group of patients. Progression-Free Survival and consolidation Progression-Free Survival and consolidation Figure 1 Overall survival and maintenance Figure 1. Overall survival and maintenance Figure 2 Progression-Free survival and maintenance Figure 2. Progression-Free survival and maintenance Disclosures Jimenez-Zepeda: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene, Janssen, Amgen, Onyx: Honoraria. Neri:Celgene and Jannsen: Consultancy, Honoraria. Bahlis:Amgen: Consultancy, Honoraria; BMS: Honoraria; Onyx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau.

scholarly journals Higher Socioeconomic Status Is Associated with Improved Overall Survival in Adults with Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia: A Population Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4780-4780
Author(s):  
Anita J Kumar ◽  
Tobi Henzer ◽  
Angie Mae Rodday ◽  
Marlise R. Luskin ◽  
Wendy Stock ◽  
...  
Keyword(s):  
Marital Status ◽  
Household Income ◽  
Research Funding ◽  
Cox Regression ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Median Household Income ◽  
Genetics Research ◽  
The Impact ◽  
Hispanic White

Abstract Background: Socioeconomic status (SES) and other non-disease (social and demographic) characteristics are known to predict overall survival (OS) in children with acute lymphoblastic leukemia (ALL) (Petridou et al. Ann Oncol 2015). Less is known about the impact of these factors on survival of adults with ALL. We studied which non-biological risks impact OS in adults with Philadelphia chromosome negative (Ph negative) ALL, with emphasis on the impact of SES on survival. Methods: We assembled data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER-18) registry from 2000 to 2014. This registry covers 27.8% of the US population. We identified patients 18-69 years old diagnosed with Ph negative ALL between 2000-2012 using ICD-O-3 codes. We merged data with the Federal Information Processing Standards county codes and designated patients as metropolitan or non-metropolitan based on state and country 2013 rural-urban continuum codes. We assigned county-level median household income using the Census American Community Survey (www.census.gov). Descriptive statistics were calculated for age at diagnosis, sex, race/ethnicity, marital status, insurance status,median household income, and status with respect to the 200% of the federal poverty line (FPL). We stratified the population by age: 18-39 years (adolescent and young adult, or AYA, cohort) and 40-69 years (adult cohort). We also identified 3 eras of interest: 2000 to 2003, 2004 to 2007, and 2008 to 2012. Multivariable Cox proportional hazards (PH) regression assessed predictors of OS, with separate models for AYAs and adults. Analyses were performed using SAS. Results: In total, 5,858 patients met criteria for analysis. Median age was 41.4 years (25-75th%: 26.9-54.8), with 45.8%patients in the AYA cohort. 57.8% of patients were male, and half were non-Hispanic white (50.8%). Over 90% of all patients lived in metropolitan counties. One-third (35%) of patients lived below the 200% FPL. Median household income was $55,901 (25-75th%: $51,389-67,677). 49% of patients had missing data about insurance, so we omitted this variable from analysis. ALL lineage was B cell in 57%, T-cell in 10%, and unspecified in 33% of cases. 52% were married overall with more AYAs (61.3%) not married compared to older adults (34%). In Cox regression model for AYAs, higher median income was associated with better OS (HR=0.95 for every $10,000 above national household income, p=0.03). We also found that later era of diagnosis (2008-2012 vs. 2000-2003) was associated with better OS (HR=0.70, p<0.001), while older age (HR=1.04, p<0.0001), unspecified lineage (vs. B-cell, HR=1.20, p=0.04), and all races compared to non-Hispanic white were associated with poorer OS with the exception of Asian/Pacific Islander: American Indian (HR=2.82, p<0.001), Hispanic (HR=1.58, p<0.001), and non-Hispanic black (HR=1.50, p<0.001). Sex, marital status, and rural residence were not associated with OS in the AYA cohort. In the adult cohort, in a Cox regression model, patients with higher income had better OS (HR=0.95 for every $10,000 above median national household income, p=0.001). We also found that later era of diagnosis (2008-2012 and 2004-2007 vs. 2000-2003), and non-metropolitan geography (HR=0.81, p<0.001) predicted better OS, while older age (HR=1.03, p<0.0001), Hispanic race (HR=1.16, p=0.03), male sex (HR=1.09, p=0.03), and non-married status conferred poorer OS (HR=1.31, p<0.0001) (Table). Conclusion: We identify non-biological predictors of OS in adults with ALL in a large population-based registry. Notably, higher SES portends better OS in both AYAs and older adults with ALL, consistent with findings in the pediatric literature. Marital status affects OS only in older patients, while race/ethnicity in AYAs greatly impacts OS. All ages had improved OS in more recent years, suggesting that all age cohorts are benefitting from new ALL treatment approaches. Our findings of the impact of SES on OS call for more investigation and action to improve social support and possibly adherence in the adult population. Table. Table. Disclosures Kumar: Seattle Genetics: Research Funding. Rodday:Seattle Genetics: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Parsons:Seattle Genetics: Research Funding.

scholarly journals Fractionated Inotuzumab Ozogamicin Combined with Low-Intensity Chemotherapy Provides Very Good Outcome in Older Patients with Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: First Results from the EWALL-INO Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 511-511
Author(s):  
Patrice Chevallier ◽  
Thibault Leguay ◽  
Michael Doubek ◽  
Francoise Huguet ◽  
Cyril Salek ◽  
...  
Keyword(s):  
B Cell ◽  
Older Patients ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Newly Diagnosed ◽  
Cell Precursor ◽  
Inotuzumab Ozogamicin ◽  
Low Intensity

Abstract On behalf of the GRAALL group, the Czech Republic ALL group, the Finland ALL group and the EWALL group. Introduction. Treatment of older patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains an unmet medical need. Inotuzumab ozogamicin (INO), an anti-CD22 antibody conjugated to calicheamicin, is approved for the treatment of relapsed/refractory BCP-ALL in adults, sinusoidal obstruction syndrome (SOS) being the major adverse event associated with INO. A previous first line study conducted by the MDACC in pts 60 years or older successfully used INO in combination with a lower intensity version of the hyper-CVAD (mini-hyper-CVD). Due to the occurrence of SOS, the total doses were fixed at 1.3 mg/m² for cycle 1 followed by 3 cycles at 1 mg/m² (Kantarjian H et al. Lancet Oncol, 2018). Here, we aimed to assess the activity and safety of fractionated INO at a reduced dosage in combination with low-intensity chemotherapy as frontline therapy for older pts with CD22+ Philadelphia chromosome-negative (Ph-neg) BCP-ALL. Methods. EWALL-INO is a single arm prospective phase 2 multicentric study conducted in European centers belonging to the EWALL group. Eligibility criteria were pts aged 55y or older, performance status ≤2, and newly diagnosed CD22+ (20% or more of positive blast cells) Ph-neg BCP-ALL without central nervous system involvement. After a prephase including 5 days (D) of dexamethasone (DEX) 10mg per D and a single intrathecal injection (IT), the induction regimen was begun and split in 2 parts. Induction part I (Induc1) consisted of one triple IT, vincristine (VCR) 2 mg (1 mg over 70y) D1 D8 D15 D22 and DEX 20 mg D1D2 D8D9 D15D16 D22D23 combined with 3 injections of INO (0.8 mg/m² D1, 0.5 mg/m² D8 and D15). Induction part II (Induc2) was offered to pts in CR or CRp (CR with platelets &lt; 100 G/l) after Induc1 or as salvage therapy. Induc2 consisted of DEX 20mg D1D8, cyclophosphamide (CY) 300 mg/m² D1 to D3, one triple IT D2 and 2 injections of INO (0.5 mg/m² D1 and D8). Pts in CR/CRp were programmed to receive 6 blocks of consolidation (Ara-C 1.5g/m²/12h adapted to renal clearance D1D2 and DEX 10mg/12h D1D2, cycles 1 and 4; Methotrexate (MTX) 1.5 g/m² over 24h D1, VCR 1 or 2 mg D1, one triple IT D2 and 6-mercaptopurin (6-MP) D1 to D7, cycles 2 and 5; CY 500 mg/m² D1D2, VP16 75 mg/m² D1D2, one triple IT D2 and MTX 25 mg/m² D1, cycles 3 and 6) followed by a POMP maintenance (VCR, 6-MP, MTX, DEX) during 18 months. Allograft was allowed after at least 3 blocks of consolidation at the discretion of the investigators. The evaluable population was pts who received at least 1 dose of INO. Analyses were by modified intention to treat and performed JUN 28, 2021. All pts gave informed consent. The study is registered at ClinicalTrials.gov under the NCT number: NCT03249870. Results. Between DEC 29, 2017 and JUN 22, 2021, 115 pts (out of 130 planned pts) were enrolled including 6 pts with screen failure. The first 90 eligible pts (up to MAR 1, 2021) were considered for this analysis to obtain a minimum of 4 months follow-up. Median age was 69y (range 55-84) and median follow-up for alive pts was 1.18 years (range 0.3-3.5). At time of analysis, 90 and 88 pts had started induc1 and induc2, respectively. Treatment related mortality was 2.2% (2/90) and CR/CRp rate was 85.5% (77/90, 6 CRp) after induc1. Three cases relapsed between induc1 and induc2 and 5 pts were salvaged by induc2 allowing to a CR/CRp rate of 87.7% (79/90, 8 CRp) after induc2. One pts died from refractory disease during induc2. One, 2, 3 4 and 5 injections of INO were administered to 2 (2.2%), 2(2.2%), 11 (12.2%), 2 (2.2%) and 73 pts (81.1%) respectively. Only 6 pts were allografted. One-year OS was estimated to be 78.5% (95%CI 68-85.9) and median OS was not reached. One-year relapse free survival was 74.5% (95CI 63.5-82.6) (Figure 1). Grade 3-4 liver toxicity was observed in 8 pts (8.8%) during the study including 3 pts (3.3%) developing SOS, 2 related to INO during induc1 and one occurred after transplant. Twenty-nine pts died during the follow-up, 16 from relapses (overall incidence 18%) and 13 from adverse events (overall incidence 14.4%), including one COVID19 fatal infection during consolidation. Conclusion. Fractionated inotuzumab ozogamicin at reduced doses (0.8/0.5/0.5/0.5 mg/m²) combined with low-intensity chemotherapy is a very active and well tolerated frontline therapy for older patients with CD22+ Ph-neg BCP-ALL. Figure 1 Figure 1. Disclosures Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Raffoux: ABBVIE: Consultancy; PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy. Boissel: CELGENE: Honoraria; Servier: Consultancy, Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding; SANOFI: Honoraria. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia

scholarly journals Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3816-3816 ◽  
Author(s):  
Ryan J. Daley ◽  
Sridevi Rajeeve ◽  
Charlene C. Kabel ◽  
Jeremy J. Pappacena ◽  
Sarah E. Stump ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Hypersensitivity Reactions ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Frontline Treatment

Introduction: Asparaginase (ASP) has demonstrated a survival benefit in pediatric patients (pts) with acute lymphoblastic leukemia (ALL) and is now part of standard-of-care frontline treatment. As a result, asparaginase preparations have been incorporated into the treatment of adult ALL to improve outcomes. Pegaspargase (PEG-ASP), a modified version of asparaginase with prolonged asparagine depletion, appears to be safe in adults up to age 40 (Stock, et al., Blood, 2019), but is associated with a unique spectrum of toxicities, the risks of which appear to increase with age. Therefore, the safety of PEG-ASP remains a significant concern in older adults w/ ALL. Methods: We conducted a single center retrospective chart review of pts age ≥40 years who received PEG-ASP as part of frontline induction/consolidation or reinduction, between March 2008 and June 2018 at Memorial Sloan Kettering Cancer Center. The primary objective was to evaluate the tolerability and toxicity of PEG-ASP based on the incidence and severity of ASP-related toxicities (hypersensitivity reactions, hypertriglyceridemia, hyperbilirubinemia, transaminitis, pancreatitis, hypofibrinogenemia, etc) according to the Common Terminology Criteria for Adverse Events, version 4.03. Laboratory values recorded were either the peak or the nadir, the more appropriate for toxicity assessment, within a 4-week period following PEG-ASP administration. Secondary objectives were to determine the total number of doses of PEG-ASP administered in comparison to the number of doses intended, and to characterize the rationale for PEG-ASP discontinuation when applicable. Fisher's exact test was used to compare the incidence of PEG-ASP toxicities with respect to pt and treatment characteristics (regimen, age, BMI, gender, Philadelphia chromosome positive (Ph+) vs. Ph-, presence of extramedullary disease, PEG-ASP dose). P values were not adjusted for multiple comparisons. Results: We identified 60 pts with ALL (40 B-ALL and 20 T-ALL) who received at least one dose of PEG-ASP. Nine pts were Ph+. The median pt age at initiation of the treatment was 53, (range, 40 to 80), and 19 pts had a BMI ≥30 kg/m2. Forty-four pts received treatment for newly diagnosed ALL, and 16 pts for relapsed disease. Table 1 lists pt baseline characteristics. Among the 44 pts with newly diagnosed ALL, 27 pts received PEG-ASP as part of pediatric or pediatric-inspired regimens at doses of 2000 - 2500 units/m2, and 1 pt received a modified dose of 1000 units/m2 due to age. The remaining 16 pts received PEG-ASP at doses of 1000 - 2000 units/m2 for consolidation, per established adult regimens (ALL-2 and L-20; Lamanna, et al., Cancer, 2013). Grade 3/4 ASP-related toxicities with a >10% incidence included: hyperbilirubinemia, transaminitis, hypoalbuminemia, hyperglycemia, hypofibrinogenemia, and hypertriglyceridemia. Frontline treatment regimens in which PEG-ASP was used in consolidation cycles only (ALL-2, L-20) were associated w/ a lower incidence of hyperbilirubinemia (p=0.009) and hypertriglyceridemia (p<0.001) compared to those regimens that included PEG-ASP during induction (pediatric/pediatric-inspired regimens) (Table 2). Younger age (40-59 vs. ≥60 years) was associated with a greater risk of hypertriglyceridemia (p<0.001) and higher PEG-ASP dose (≥2000 vs. <2000 units/m2) was associated with a greater risk of hypertriglyceridemia and hypofibrinogenemia (p=0.002 and p=0.025, respectively). Thirty-eight pts (63%) received all intended doses of PEG-ASP. Six pts stopped PEG-ASP to proceed to allogeneic hematopoietic stem cell transplantation (5 in CR1, 1 in CR2), and 7 pts stopped for hypersensitivity reactions. Hepatotoxicity was the only ASP-related toxicity that led to PEG-ASP discontinuation occurring in 5 pts (hyperbilirubinemia, N=4; transaminitis, N=1). The total number of intended doses of PEG-ASP based on regimens used was 186, and 112 were administered. Conclusion: PEG-ASP was incorporated into the treatment of 60 adult ALL pts age ≥40, with manageable toxicity. Seven pts discontinued PEG-ASP due to hypersensitivity reactions and 5 discontinued due to hepatotoxicity, but other reported toxicities did not lead to PEG-ASP discontinuation and the majority of the pts completed all intended doses of PEG-ASP. This study suggests that with careful monitoring, PEG-ASP can safely be administered in adults ≥40 years of age. Disclosures Rajeeve: ASH-HONORS Grant: Research Funding. Tallman:UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. Park:Takeda: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy.

scholarly journals Ponatinib and Chemotherapy in Young Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Results of Ponalfil Clinical Trial after Completion of Recruitment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Josep-Maria Ribera ◽  
Olga García ◽  
Pau Montesinos ◽  
Pilar Martinez ◽  
Jordi Esteve ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Central Artery

Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy with first or second generation TKI (Jabbour E, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019;125:2810-2817) The results of this trial after completed recruitment are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT. TKI use as maintenance was only scheduled for pts with persistence or reappearance of MRD. By July 2020 the 30 scheduled pts were recruited. The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT) (assessed by centralized BCR-ABL/ABL ratio),event-free survival (EFS), overall survival [OS]) and toxicity are herein analyzed. Results. Median age was 50 (20-59) years and 14/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score at diagnosis was &lt;2 in 86% of pts. Median of WBC count was 6.4 (0.6-359.3) x109/L, Hb 90 (63-145) g/L, platelets 38 (11-206) x109/L. The immunologic phenotype was common in 26 cases, with molecular isoform p190 in 20 patients (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained 26/26 patients (100%) (4 are still on induction therapy), with CMR in 11/26 cases (42%), MMR in 6/26 (23%) and no molecular response in 9/26 (35%)).Two patients withdrew the trial (thrombosis of the central retina artery and severe intestinal infection, one case each). Consolidation was given to 24 patients, 2/24 are receiving consolidation and 22 patients received allogeneic HSCT (14 in CMR, 6 in MMR, 2 without molecular response). No relapses before HSCT were detected. No transplant-related mortality was observed to date, but 1 patient withdrew the trial by severe GVHD. Ponatinib was given after HSCT in 4 pts due to loss of molecular response. Three pts relapsed after HSCT, one of them after documented loss of molecular response. All pts are alive (median follow-up of 4.5 months, range 0.5-26.2.2). The EFS probability at 30 months was 91% (79%, 100%) (Figure 1). One hundred and two adverse events (AE) have been registered in 20 patients, 25 of whom were severe (SAE) and occurred in 14 patients, prompting to withdrawn of the trial in 3 (thrombosis of the central artery of the retina, severe bowel infection, grade IV aGVHD, one case each). The most frequent AE were hematologic (26%), gastrointestinal (15%), infections (10%), hepatic (8%) and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each). Conclusions. The preliminary results of the PONALFIL trial after recruitment completed show a high short-term antileukemic efficacy with acceptable toxicity profile. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Event free survival (EFS) of the whole series. Figure 1 Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.

scholarly journals Neurocognitive Functioning of Children Treated for High-Risk B-Acute Lymphoblastic Leukemia Randomly Assigned to Different Methotrexate and Corticosteroid Treatment Strategies: A Report From the Children’s Oncology Group

2017 ◽  
Vol 35 (23) ◽  
pp. 2700-2707 ◽  
Author(s):  
Kristina K. Hardy ◽  
Leanne Embry ◽  
John A. Kairalla ◽  
Shanjun Helian ◽  
Meenakshi Devidas ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
Corticosteroid Treatment ◽  
Neurocognitive Functioning ◽  
Neurocognitive Outcomes ◽  
Leucovorin Rescue ◽  
B Lineage ◽  
The Impact

Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits that are associated with treatment, individual, and environmental factors. This study examined the impact of different methotrexate (MTX) and corticosteroid treatment strategies on neurocognitive functioning in children with high-risk B-lineage ALL. Methods Participants were randomly assigned to receive high-dose MTX with leucovorin rescue or escalating dose MTX with PEG asparaginase without leucovorin rescue. Patients were also randomly assigned to corticosteroid therapy that included either dexamethasone or prednisone. A neurocognitive evaluation of intellectual functioning (IQ), working memory, and processing speed (PS) was conducted 8 to 24 months after treatment completion (n = 192). Results The method of MTX delivery and corticosteroid assignment were unrelated to differences in neurocognitive outcomes after controlling for ethnicity, race, age, gender, insurance status, and time off treatment; however, survivors who were age < 10 years at diagnosis (n = 89) had significantly lower estimated IQ ( P < .001) and PS scores ( P = .02) compared with participants age ≥ 10 years. In addition, participants who were covered by US public health insurance had estimated IQs that were significantly lower ( P < .001) than those with US private or military insurance. Conclusion Children with high-risk B-lineage ALL who were age < 10 years at diagnosis are at risk for deficits in IQ and PS in the absence of cranial radiation, regardless of MTX delivery or corticosteroid type. These data may serve as a basis for developing screening protocols to identify children who are at high risk for deficits so that early intervention can be initiated to mitigate the impact of therapy on neurocognitive outcomes.

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