Pediatric Acute Lymphoblastic Leukemia Regimens Research Articles

Comprehensive view on genetic features, therapeutic modalities and prognostic models in adult T-cell lymphoblastic lymphoma.

Adult T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive subtype of non-Hodgkin's lymphoma that differs from pediatric T-LBL and has a worse prognosis. Due to its rarity, little is known about the genetic and molecular characteristics, optimal treatment modalities, and prognostic factors of adult T-LBL. Therefore, we summarized the existing studies to comprehensively discuss the above issues in this review. Genetic mutations of NOTCH1/FBXW7, PTEN, RAS, and KMT2D, together with abnormal activation of signaling pathways, such as the JAK-STAT signaling pathway were described. We also discussed the therapeutic modalities. Once diagnosed, adult T-LBL patients should receive intensive or pediatric acute lymphoblastic leukemia regimen and central nervous system prophylaxis as soon as possible, and cranial radiation-free protocols are appropriate. Mediastinal radiotherapy improves clinical outcomes, but adverse events are of concern. Hematopoietic stem cell transplantation may be considered for adult T-LBL patients with high-risk factors or those with relapsed/refractory disease. Besides, several novel prognostic models have been constructed, such as the 5-miRNAs-based classifier, 11-gene-based classifier, and 4-CpG-based classifier, which have presented significant prognostic value in adult T-LBL.

Hepatotoxicity in Adolescent and Young Adult Hispanic Patients Treated with Pediatric Regimens for Acute Lymphoblastic Leukemia

Introduction: Pediatric or pediatric-inspired regimens are used in the treatment of adolescent or young adult (AYA) patients with acute lymphoblastic leukemia (ALL). While overall survival is improved with these regimens, hepatotoxicity and metabolic complications are common adverse events related to the increased dosages of asparaginase and steroids used vs adult ALL regimens. Among ethnicities, prevalence of metabolic syndrome and hepatic steatosis is highest in the Hispanic population, which comprises ~20% of the US population and carries an increased risk of ALL. Surprisingly, there is limited literature describing hepatotoxicity in this at-risk population. Herein we describe our experience with this adverse effect in AYA Hispanic patients (<50 yrs) treated with pediatric ALL regimens at an urban academic medical center.Methods: Single-center retrospective chart review of patients with ALL treated from January 1, 2010 to May 30, 2021 at the University of Illinois at Chicago. Patients with an associated ALL diagnosis were identified through an internal pathology database. Demographic information, clinical characteristics, treatment history and complications [grade 3/4 transaminitis, development of non-alcoholic fatty liver (NAFLD) on imaging, non-alcoholic steato-hepatitis (NASH)/fibrosis/cirrhosis on biopsy, pancreatitis, treatment change or drug discontinuation secondary to hepatotoxicity] were abstracted from the EMR. Descriptive statistics were used to determine outcome frequencies.Results: We identified 33 Hispanic (n= 20) and Non-Hispanic White (NHW; n = 13) patients with either B-ALL or T-ALL, with each demographic stratified by pediatric or adult regimen therapy (Table 1). Pediatric regimens include Children's Oncology Group protocols and E1910; the adult regimen was HyperCVAD.Of 16 Hispanic patients who received pediatric regimens, 7 (44%) had pre-existing diabetes, 1 had fatty liver on baseline imaging and 1 biopsy-confirmed NASH. During treatment, 12/16 (75%) developed grade 3/4 hepatotoxicity, 11 (69%) developed mild-severe NAFLD on imaging, 2 additional patients developed cirrhosis, and 4 (25%) pancreatitis. Treatment-related adverse events prompted therapy change or drug discontinuation in 25%. Hispanic patients, (n = 4), on adult and NHW patients, (n = 7), on pediatric regimens had low rates of pre-existing comorbidities, but of the older NHW patients, (n = 6), on an adult regimen, 4/6 (67%) and 1/6 had underlying diabetes or NAFLD, respectively. We found similar high rates of grade 3/4 hepatotoxicity in Hispanics on an adult regimen (100%) and NHW patients on either a pediatric (71%) or adult regimen (50%). However, fewer patients developed NAFLD (4/17, 24%), only 1 (Hispanic) patient developed fibrosis, and none developed pancreatitis. There was no difference in mean BMI between Hispanic and NHW patients.Conclusions: While grade 3/4 transaminitis is described during ALL treatment, in this retrospective analysis we observed that Hispanic AYA patients treated on pediatric protocols frequently develop more serious complications including hepatic steatosis, cirrhosis or pancreatitis. Co-existing metabolic syndrome is associated with a higher incidence of simple steatosis (SS; 70% in obesity, 90% in diabetes), and Hispanic patients have a higher baseline SS incidence (45% in Hispanics vs 33% in NHW), which in the context of use of higher doses of steroids and asparaginase may explain their increased frequency of progression to NASH and fibrosis. As few underwent biopsy, the true incidence is likely underrepresented. Additionally, Hispanics treated on a pediatric regimen more frequently developed pancreatitis than NHW patients on the same regimen. SS is related to the accumulation of hepatic free fatty acids and triglycerides, thus patients with SS or at risk may have impaired free fatty acid metabolism that predisposes to pancreatitis with asparaginase use. Limitations of this study include a small sample size, partial availability of baseline imaging, and non-standardized radiographic interpretations of the degree of steatosis. However, our findings suggest further investigation is warranted and a multi-center study is in progress. Our study highlights the need for closer monitoring of Hispanic patients to mitigate the risk of serious liver disease with the use of curative pediatric regimens for ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

An MRD-stratified pediatric protocol is as deliverable in adolescents and young adults as in children with ALL

AbstractPediatric regimens have improved outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL). However, results remain inferior to children with ALL. The Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study (anzctr.org.au/ACTRN12611000814976) was designed to assess whether a pediatric ALL regimen (Australian and New Zealand Children's Haematology and Oncology Group [ANZCHOG] Study 8) could be administered to patients aged 15 to 39 years in a comparable time frame to children as assessed by the proportion of patients completing induction/consolidation and commencing the next phase of therapy (protocol M or high-risk [HR] treatment) by day 94. Minimal residual disease (MRD) response stratified patients to HR treatment and transplantation. From 2012 to 2018, a total of 86 patients were enrolled; 82 were eligible. Median age was 22 years (range, 16-38 years). Induction/consolidation was equally deliverable in ALL06 as in Study 8. In ALL06, 41.5% (95% confidence interval [CI], 30.7-52.9) commenced protocol M or HR therapy by day 94 vs 39.3% in Study 8 (P = .77). Median time to protocol M/HR treatment was 96 days (interquartile range, 87.5-103 days) in ALL06 vs 98 days in Study 8 (P = .80). Induction mortality was 3.6%. With a median follow-up of 44 months (1-96 months), estimated 3-year disease-free survival was 72.8% (95% CI, 62.8-82.7), and estimated 3-year overall survival was 74.9% (95% CI, 65.3-84.5). End induction/consolidation MRD negativity rate was 58.6%. Body mass index ≥30 kg/m2 and day 79 MRD positivity were associated with poorer disease-free survival and overall survival. Pediatric therapy was safe and as deliverable in AYA patients as in children with ALL. Intolerance of pediatric ALL induction/consolidation is not a major contributor to inferior outcomes in AYA ALL.

Orthopedic toxicities among adolescents and young adults treated in DFCI ALL Consortium Trials

AbstractAdolescent and young adult patients with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. Pediatric ALL regimens rely heavily on corticosteroids and asparaginase and are known to increase the risk of osteonecrosis (ON) and fractures in children, particularly adolescents. Orthopedic toxicity among young adults treated on pediatric-inspired regimens is not well described. Here, we report the symptomatic orthopedic toxicities of patients aged 15 to 50 years treated on sequential Dana-Farber Cancer Institute ALL Consortium protocols. Among 367 patients with a median age of 23 years (range, 15-50 years; 68% aged <30 years), 60 patients were diagnosed with ON (5-year cumulative incidence, 17%; 95% confidence interval [CI], 13-22), and 40 patients experienced fracture (5-year cumulative incidence, 12%; 95% CI, 8-15). Patients aged <30 years were significantly more likely to be diagnosed with ON (5-year cumulative incidence, 21% vs 8%; P = .004). Patients treated more recently on pegaspargase-based protocols were significantly more likely to be diagnosed with ON compared with those treated on earlier trials with native Escherichia coli asparaginase (5-year cumulative incidence, 24% vs 5%; P < .001). Of the 54 ON events for which adequate information was available, surgery was performed in 25 (46%). Patients with ON had superior overall survival (OS) compared with those without (multivariable OS hazard ratio, 0.15; 95% CI, 0.05-0.46; P = .001; ON included as a time-varying exposure). Increased rates of orthopedic toxicity in late-generation protocols may be driven by the pharmacokinetic drug interaction between pegaspargase and dexamethasone, leading to higher dexamethasone exposure.

Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia

Are Adolescents and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL) Receiving Pediatric or Adult ALL Regimens: A Population-Based Statewide Evaluation of the Approach to AYA ALL across Pediatric and Adult Cancer Centers

▪Background:Abundant evidence suggests that AYA with ALL have improved outcomes when treated following pediatric-inspired, as opposed to adult, ALL chemotherapy regimens. Given the complexity of pediatric ALL protocols, it is unclear whether this approach has been universally accepted by medical oncologists treating AYA ALL patients across the population.Methods:The population-based California Cancer Registry (CCR) was used to evaluate socio-demographics, location of ALL induction therapy (adult- vs pediatric-setting), and therapies administered to AYAs (15-39 years) with ALL newly diagnosed and treated in the state of California between 2004-2014. Specific ALL regimens were determined through abstraction of registry treatment text fields. Facility volume was defined as AYA ALL inductions per year and categorized by quartiles (≥7/year highest and <1/year lowest). Chi-square and student t-tests characterized differences by patient demographics, treating facilities, and treatment regimens. Multivariable logistic regression was performed to examine the association of the sociodemographic and clinical factors with receipt of pediatric-inspired ALL regimen at an adult cancer center, adjusted for clustering by induction facility. Results are presented as adjusted odds ratios (OR) and associated 95% confidence intervals (CI).Results:Of 1591 AYAs with ALL, 61% were treated in an adult oncology-setting and 28% were treated in a pediatric-setting. Treatment setting could not be determined in 11% (n=175) of patients who were excluded from additional analyses. 32% of patients were 15-18 years, 39% were 19-29 years, and 29% were 30-39 years. The majority of patients were males (64%), of Hispanic race/ethnicity (64%), and had public (46%) or private (44%) insurance. AYAs who were younger (P<0.001), diagnosed in more recent years (P=0.03), and those with public insurance (P= 0.01) were more likely to receive induction treatment in a pediatric-setting. 59% and 41% of AYAs treated in a pediatric- versus adult-setting, respectively, received induction therapy at an NCI-designated cancer center (P<0.001). Only 5% of AYAs treated in the pediatric-setting received care at low volume (<1 AYA ALL case per year) facilities, whereas 27% of AYAs treated in the adult setting received care at low volume facilities (P<0.001). ALL treatment regimen was evaluable in 1131 (79%) of patients and revealed that amongst AYAs treated in the adult-setting, 22% received pediatric-inspired and 78% received adult ALL regimens over the decade. Although pediatric-inspired regimens were administered more frequently by medical oncologists over-time, 62% of AYAs treated by medical oncologists from 2013-2014 received adult ALL regimens, with Hypercvad used most commonly (70%). Multivariable regression revealed that younger patient age (19-24 vs 35-39 years: OR 2.1, 95% CI 1.4-3.2), treatment at an NCI-designated cancer center (OR 5.3, 95% CI 2.5-11.3), and treatment at higher volume AYA ALL facility (mid quartile versus lowest quartile: OR 2.3, 95% CI 1.0-5.2; highest quartile versus lowest quartile: OR 7.4, 95% CI 2.7-20.4) were significantly associated with receipt of pediatric-inspired ALL regimens by medical oncologists; whereas, year of diagnosis, sex, race/ethnicity, and insurance had no significant association.Conclusions:Our population-level findings demonstrate that AYAs with ALL across the state of California are most commonly treated in adult oncology community settings where the volume of AYA ALL patients seen on a yearly basis is frequently very low. Strikingly, as recently as 2014, AYAs with ALL continue to be treated predominantly with adult ALL regimens. Receipt of pediatric-inspired ALL regimens is significantly more likely if AYAs with ALL receive treatment at NCI-designated cancer centers and/or centers that treat a higher yearly volume of AYA ALL patients. DisclosuresNo relevant conflicts of interest to declare.

Impact of Ethnicity on Toxicities Associated with Dose Escalating Methotrexate in Pediatric Patients with Acute Lymphoblastic Leukemia

Background: Epidemiologic studies in pediatric oncology have demonstrated disparities in Acute Lymphoblastic Leukemia (ALL) outcomes and survival for various ethnic minorities including Hispanic patients. While differences between outcomes and survival of different racial/ethnic groups in pediatric ALL is well documented, the impact of race/ethnicity on the incidence of methotrexate related toxicities in this population has not been fully described. Methotrexate, a mainstay of pediatric ALL regimens, has the potential to cause a variety of toxicities including myelosuppression, hepatic injury, acute kidney injury (AKI), mucositis, and central nervous system (CNS) injury. Recent literature suggests that Hispanic ethnicity may be associated with an increased risk of methotrexate toxicity, specifically neurotoxicity (Giordano (2017)). This project evaluated ethnicity associated with the incidence of methotrexate toxicities that could lead to dose reduction or delays in therapy such as grade 3 or 4 myelosuppression, hepatic injury, nephrotoxicity, and mucositis in patients receiving dose escalating methotrexate. Methods: A single-center, retrospective chart review was conducted at a 224 bed pediatric hospital. Patients were eligible for inclusion if they had a diagnosis of ALL and received intravenous (IV) dose escalating methotrexate between August 1, 2011 and March 31, 2019. Electronic medical records were used to identify eligible patients using medication identification numbers cross referenced with diagnosis codes. Toxicity data was collected to evaluate interruption in dose escalation of IV methotrexate due to grade 3 or 4 liver dysfunction, nephrotoxicity, mucositis, neutropenia, or thrombocytopenia. The primary outcome was percentage of doses which resulted in a dose-limiting toxicity. A two-sample t-test was performed for the primary outcome between Hispanic white and non-Hispanic white patients. Results: Of the 64 patients initially identified, 60 patients were included for final analysis. Two patients were excluded due to a diagnosis of Acute Biphenotypic Leukemia, one patient did not receive IV methotrexate per protocol due to delay in therapy and was subsequently ineligible, and one patient did not receive dose escalating methotrexate per protocol for unspecified reasons. A total of 460 doses were given to 60 patients. The sample size consisted of 22 non-Hispanic white, 21 Hispanic white, 9 Black, 3 Hispanic black, 1 Asian, 1 multi-racial, and 3 patients with unspecified ethnicity. The percentage of patients who experienced at least one toxicity was 58.3% (35 patients). The most common grade 3 or 4 toxicity experienced per dose was thrombocytopenia (6.5%), followed by neutropenia (6.3%), mucositis (1.3%), liver dysfunction (0.22%), and no patient experienced nephrotoxicity. When comparing the rate of toxicity between Hispanic and non-Hispanic patients, Hispanic patients experienced toxicity at a rate of 17.4% per dose compared to non-Hispanic patients at 12.2% per dose, although this was not a statistical significant difference (p = 0.61). Hispanic white and non-Hispanic white patients received the same amount of doses at 165 doses of IV methotrexate. Hispanic white patients experienced a toxicity rate of 19.4% per dose compared to 12.1% per dose in the non-Hispanic white patients. Hispanic white patients experience more thrombocytopenia, where as non-Hispanic white patients experienced more neutropenia. Although not statistically significant possibly due to small sample size, Hispanic ethnicity was associated with higher rates of methotrexate toxicities. Understanding the impact of methotrexate toxicity in respect to ethnicity is important to improving treatment outcomes for pediatric patients with ALL. More robust studies with a larger sample size are warranted to explore the potential impact of ethnicity on tolerability of this regimen. Disclosures No relevant conflicts of interest to declare.

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

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

A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403

AbstractRetrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.

Patterns of care and outcomes in adolescent and young adult acute lymphoblastic leukemia: a population-based study

AbstractAdolescents and young adults (AYAs, 15-39 years) with acute lymphoblastic leukemia (ALL) represent a heterogeneous population who receive care in pediatric or adult cancer settings. Using the California Cancer Registry, we describe AYA ALL patterns of care and outcomes over the past decade. Sociodemographics, treatment location, and front-line therapies administered to AYAs diagnosed with ALL between 2004 and 2014 were obtained. Cox regression models evaluated associations between ALL setting and regimen and overall survival (OS) and leukemia-specific survival (LSS) for the entire cohort, younger AYA (<25 years), and AYAs treated in the adult cancer setting only. Of 1473 cases, 67.7% were treated in an adult setting; of these, 24.8% received a pediatric ALL regimen and 40.7% were treated at a National Cancer Institute (NCI)–designated center. In multivariable analyses, front-line treatment in a pediatric (vs adult) setting (OS HR = 0.53, 95% confidence interval [CI], 0.37-0.76; LSS HR = 0.51, 95% CI, 0.35-0.74) and at an NCI/Children's Oncology Group (COG) center (OS HR = 0.80, 95% CI, 0.66-0.96; LSS HR = 0.80, 95% CI, 0.65-0.97) were associated with significantly superior survival. Results were similar when analyses were limited to younger AYAs. Outcomes for AYAs treated in an adult setting did not differ following front-line pediatric or adult ALL regimens. Our population-level findings demonstrate that two-thirds of AYAs with newly diagnosed ALL are treated in an adult cancer setting, with the majority receiving care in community settings. Given the potential survival benefits, front-line treatment of AYA ALL at pediatric and/or NCI/COG-designated cancer centers should be considered.

Adoption of pediatric-inspired acute lymphoblastic leukemia regimens by adult oncologists treating adolescents and young adults: A population-based study.

Studies have demonstrated superior outcomes for adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) who are treated using pediatric versus adult therapeutic regimens. To the best of our knowledge, whether adult oncologists in the United States have adopted this approach to ALL in AYA patients is currently unknown. The objective of the current study was to provide a population-based description of ALL treatment patterns in AYA individuals over the past decade. Data regarding AYA patients aged 15 to 39 years and diagnosed with ALL between 2004 and 2014 while living in the Greater Bay Area were obtained from the Greater Bay Area Cancer Registry (GBACR). Treating facilities were designated as pediatric or adult centers; induction treatment regimens were abstracted from registry text data fields. Of 304 patients diagnosed in the GBACR catchment region, complete treatment data were available for 229 (75%). The location of care was identified for 296 patients (97%) treated at 31 unique centers. Approximately 70% of AYA patients received induction therapy at an adult treatment center. All AYA patients who were treated at pediatric centers received pediatric ALL regimens. Among AYA patients treated by adult oncologists with complete treatment data, none received a pediatric regimen before 2008. Between 2008 and 2012, while the US Adult Intergroup C10403 pediatric-inspired ALL protocol was open to accrual, 31% of AYA patients treated by adult oncologists received pediatric regimens. This rate fell to 21% from 2013 through 2014. Adult facilities treating ≥ 2 AYA patients with ALL per year captured in the GBACR were more likely to administer pediatric regimens than lower volume centers (P = .03). As of 2014, only a minority of AYA patients with ALL received pediatric ALL regimens at adult cancer centers. Cancer 2017;122-130. © 2016 American Cancer Society.

The Toxicity Profile of Repeated Dosing of Peg-Asparaginase in 152 Adults with Acute Lymphoblastic Leukemia

PEG-Asparaginase (PEG-Asp) is an active drug in acute lymphoblastic leukemia (ALL) and due to its recognized therapeutic importance, it is universally used in all pediatric ALL regimens. In contrast, PEG-Asp is included less frequently in adult ALL regimens and there is a reluctance of using the drug by adults oncologists. The reasons are concerns that its unique toxicities are more common and of greater severity with increasing age as wells as the widespread use of other non-Asp based adult-only ALL regimens, mostly in the US. Consequently, adult oncologists are less experienced in managing PEG-Asp toxicities. More recent studies have shown improved outcomes in adult ALL using multiple PEG-asp doses. We therefore analyzed PEG-asp toxicities in a large cohort of adults with ALL treated uniformly at the University of Southern California (USC). Patients were treated with a pediatric like regimen which included 6 scheduled doses of PEG-Asp during induction and consolidation cycles (Douer D et al. J Clin Oncol. 2014;32:905-11). Patients' eligible for this retrospective analysis had ALL, aged 18 to 60 years, and were treated with PEG-Asp between the years 2003 and 2013. We identified 152 patients with a median age of 32 (18-60) years, who met the eligibility criteria of whom the majority were Hispanics (74%). The total number of recorded administered doses of PEG-Asp was 522; median number of doses per patient was 3. Among all patients, 44 (29%) completed all scheduled 6 doses of PEG-Asp. Ten patients were still undergoing treatment at time of this analysis. Among the remaining 98 patients who did not receive all scheduled PEG-Asp doses, only 29% (n=28) had to discontinue the drug because of toxicity. Other reasons for discontinuing PEG-Asp therapy were proceeding to allogeneic hematopoietic stem cell transplantation (21%), relapsed/refractory disease (17%), and death during treatment [in CR secondary to other causes not related to PEG-Asp] (9%). Grade III/IV PEG-Asp toxicities are detailed in Table 1. As expected, hepatotoxicity was the most common toxicity, with very frequent grade III/IV elevation of AST/ALT. Among patients who developed grade III/IV hyperbilirubenemia and received additional scheduled doses of PEG-Asp, only 37.5% developed recurrent grade III/IV hyperbilirubenmia. The median time for developing grade III hyperbilirubenmia was 15 days, and the median time for resolution of grade III/IV hyperbilirubinrmia (to Grade I) was 9 days. Thrombosis occurred in 11% of patients despite not using antithrombin III replacement in this cohort. Patients were not given cryoprecipitate unless fibrinogen levels were 60mg/ml or less. The only recoded PEG-Asp related death was from cavernous sinus thrombosis. All cases of thrombosis were venous in origin and 35% of them occurred after cryoprecipitate replacement for hypofibrinogenemia. Thrombosis was most common during the first 2 doses of PEG-Asp (94%). There was no recurrent thrombosis in the 10 patients who developed PEG-Asp induced thrombosis and received more PEG-Asp while they were on anticoagulation. Although hypofibrinogenemia was very common, bleeding was extremely rare. Grade III/IV hypertriglyceridemia was common and always reversible. We found no association between Grade III/IV hypertriglyceridemia and clinical pancreatitis. None of the cases of pancreatitis were fatal. PEG-Asp induced allergic reaction was an uncommon event. Table 1. Grade III/IV toxicity rate Toxicity Per total number of doses (n=522) Anytime per individual patient (n =152) Allergy 1.2% 4% Pancreatitis 3.6% 12.6% Bilirubin 9.4% 23.8% AST/ALT 28.8% 55% Thrombosis (Gr II-V) 3% 11% Bleeding 0.2% 0.7% Hypertriglyridemia 38.6% 51.4% Fibrinogen &lt; 100 17% 47.2% In summary (1) In adults (up to age 60 years) PEG-asp has a similar toxicity spectrum as pediatric patients. (2) Repeated doses can be safely administered despite hepatotoxicity. (3) PEG-Asp toxicity was not the main reason of discontinuing the drug in this study (less than third of cases). (4) The majority of patients can be safely managed without antithrombin III or cryoprecipitate therapy. Together with using recently published guidelines (Stock et al. Leuk Lymphoma. 2011;52:2237-53) our study shows that PEG-Asp toxicities are mostly tolerable and manageable, and the risk of therapy related mortality is extremely low. Disclosures Douer: Sigma Tau: Membership on an entity's Board of Directors or advisory committees.

Frequency and Characteristics of Pegaspargase Antibodies in Adults Treated with a Pediatric Acute Lymphoblastic Leukemia Regimen

Introduction:Pediatric ALL regimens emphasize higher cumulative doses of non-cytotoxic chemotherapy, particularly asparaginase (ASN). Several recent studies of pediatric regimens in adults have shown promising preliminary results. These studies commonly now employ multiple doses of the long-acting pegaspargase (PEG-ASN), rather than the native enzyme, due to fewer required doses, long duration of action and decreased immunogenicity. One concern of ASN dosing is hypersensitivity reactions, which can be overt (symptomatic) or silent. Both overt and silent hypersensitivity can provoke ASN antibody (Ab) formation. Besides the risks of severe, overt hypersensitivity, Ab formation, in general, may have deleterious therapeutic effects, due to pharmacodynamic (PD)–by blocking enzyme activity–and pharmacokinetic (PK)—via altered drug clearance–effects on PEG-ASN. While PEG-ASN Abs have been detailed in children, it has not been as well defined in adults. We report the frequency and characteristics of PEG-ASN Abs in adults treated by a pediatric ALL regimen.Methods:Regimen details, which included six planned intravenous PEG-ASN doses in individual cycles, were previously reported (Douer. J Clin Oncol. 2014;32:905). Each PEG-ASN dose was accompanied by hydrocortisone premedication plus additional protocol corticosteroid therapy for at least 7 days prior to and post-PEG-ASN dosing. Sample collections were planned during three cycles: Induction Phase 1 (IND1) and Delayed Re-Inductions (DRI) 1 and 2. Samples were collected prior to PEG-ASN dosing, the day of PEG-ASN delivery, and weekly following PEG-ASN dosing. Serum was analyzed at American International Biotechnology, LLC, in Richmond, VA, qualitatively and quantitatively for Ab presence, Ab specificity, PEG-ASN neutralization (PD), and PEG-ASN activity (PK).Results:Of 51 patients, 43 had analyzable Ab data. Abs were detected in 27 patients (63%). Baseline clinical characteristics were similar between Ab formers and the 16 non-formers (37%) regarding age, sex, presenting WBC count, immunophenotype, Philadelphia chromosome, and disease risk. 61 PEG-ASN doses were analyzed; 34 doses (56%) were associated with an Ab. The cycle breakdown for Ab positivity was: IND1 (n=25/41;61%), DRI1 (n=3/11;27%), DRI2 (n=4/7;57%) and unspecified cycle (n=2/2;100%). 27/34 doses with Abs (79%) showed positivity within seven days, although some Abs were not detected until three or four weeks post-dose. Duration of detected Abs varied from a few days to greater than one month in some instances. Abs were directed against ASN (n=33), PEG (n=3), and concurrent ASN and PEG Abs (n=2). No Abs were neutralizing (PD). 26/34 doses with Abs had sufficient PK data to assess PEG-ASN activity 14 days post-dose. Among patients with Abs, 2/26 (8%) showed evidence of increased drug clearance, with PEG-ASN activities less than 200 mIU/mL 14 days post-dose. 0/16 non-Ab formers (0%) displayed evidence of increased drug clearance at the 14-day mark. Ab formers received lower mean total PEG-ASN doses (3.4 vs 4.5) compared to non-Ab formers.For the entire trial, there were 10 patients (rash=4; allergy=6) and 13 doses (rash=5; allergy=8) with overt hypersensitivity to PEG-ASN. Only 2/34 (6%) Abs were directly associated with an overt hypersensitivity reaction in the same cycle; 32/34 Abs (94%) were silent. The other PEG-ASN doses with overt PEG-ASN hypersensitivity (n=11) occurred in cycles not assessed for Abs, but 10/11 either had previous documented Ab (n=8/10) or Ab documented subsequently (n=2/10). Four patients developed grade 3/4 allergy/anaphylaxis, with three patients having either Ab or hypersensitivity prior to high-grade hypersensitivity. Three patients stopped PEG-ASN due to allergy/anaphylaxis.Summary:In adult ALL treated with multiple PEG-ASN doses, PEG-ASN Abs: (1) are common; (2) often occur after the first dose; (3) the majority present within seven days of PEG-ASN dosing, but some may present several weeks post-dose; (4) are not associated with PD effect and uncommonly increase PEG-ASN clearance (8%); (5) often are associated with hypersensitivity.In conclusion, although PEG-ASN Abs in adult ALL potentially may impact therapy by altering enzymatic activity and duration of optimal asparagine depletion, and contributing to overt hypersensitivity, it appears that silent blocking Abs are uncommon with corticosteroid premedication. DisclosuresDouer:Sigma Tau Pharmaceuticals: Consultancy, Research Funding.

High-Grade Pegylated Asparaginase-Related Hepatotoxicity Occurrence In a Pediatric-Inspired Adult Acute Lymphoblastic Leukemia Regimen Does Not Necessarily Predict Recurrent Hepatotoxicity In Subsequent Cycles

IntroductionCure rates of pediatric acute lymphoblastic leukemia (ALL) have markedly improved to approximately 80%, while in adult ALL the rates remain 40-50%. Pediatric ALL regimens contain higher doses of non-myelosuppressive chemotherapy, e.g., vincristine, corticosteroids, and, particularly, higher cumulative doses of asparaginase. Asparaginase use in adults was previously limited due to toxicity concerns. However, several recent studies, using pediatric regimens in adults, contain higher cumulative doses of asparaginase and are showing promising preliminary results. In these studies it was also noted that the long-acting pegaspargase (PEG-ASN) was much more commonly associated with hepatotoxicity in adults than in children. Although hepatotoxicity appears to be the commonest adverse effect of PEG-ASN in adults, it has not been well defined. We report the frequency and characteristics of PEG-ASN-related high-grade hepatotoxicity after multiple doses in adults treated by a pediatric regimen. MethodsBetween July 2004 and July 2009, 51 adults aged 18 to 57 years were enrolled on a phase II trial with a pediatric ALL regimen that included six planned PEG-ASN doses. PEG-ASN-related toxicities were carefully monitored on a weekly basis after each dose and reported using NCI CTCAE v3.0 for 185 doses delivered. The PEG-ASN dosing schedule was: two doses in induction phases I and II, and four during post-induction cycles (ASH Abstract 1495, 2012). Each PEG-ASN dose was 2000 IU/m2/dose IV, given at intervals of four weeks or greater. Pegaspargase was not discontinued and subsequent doses were not reduced after hepatotoxicity. ResultsA total of 192 pegaspargase doses were delivered (3.8 doses/patient), with 23 patients receiving all six doses. Of the 28 patients who received fewer than six doses, only 10 (20%) discontinued due non-hepatic toxicity (pancreatitis, allergy, and DVT). Eight (16%) patients discontinued due to allogeneic HSCT while in CR1, while nine (18%) discontinued for other reasons (death post-induction, induction failure, and relapse). Grade 3/4 hyperbilirubinemia occurred in 16 patients (31%) and in 23 doses (12%); grade 3/4 transaminitis occurred in 33 patients (65%) and in 62 doses (34%). Patients with grade 3/4 hyperbilirubinemia tended to be older than those without hepatotoxicity (median age 39 vs 31 years), but all other baseline characteristics were similar.Results of different parameters related to high-grade liver toxicity are detailed in Table 1. Patients with grade 3/4 hyperbilirubinemia and transaminitis received a mean of 4.0 and 4.3 PEG-ASN doses, while the mean number of PEG-ASN doses causing hyperbilirubinemia and transaminitis was only 1.4 and 1.9 doses per patient, respectively. Those without hepatotoxicity received 2.8 PEG-ASN doses per patient. Induction I had the highest incidence (20% of doses delivered) of grade 3/4 hyperbilirubinemia. High-grade transaminitis was spread more evenly among cycles. Grade 3/4 hepatotoxicity was long, with a median duration of 34 days to return to grade 1 for bilirubin and 38 days to return to grade 2 for transaminitis. Of the 16 patients with grade 3/4 hyperbilirubinemia, five did not receive a subsequent PEG-ASN dose for other reasons; of the 11 other patients who received subsequent doses, five (45%) did not re-experience the same toxicity. Of the 33 patients with grade 3/4 transaminitis, eight did not receive a subsequent PEG-ASN dose due to other reasons; of the 25 other patients who received subsequent doses, 10 (40%) did not have this toxicity recur. [Display omitted] SummaryOur study shows in adults with ALL treated with multiple doses of PEG-ASN that: (1) high-grade hepatoxicity (grade 3/4 hyperbilirubinemia and transaminitis) is a common adverse effect of PEG-ASN; (2) recovery from hepatotoxicity is often long and can delay subsequent chemotherapy; (3) high-grade hepatotoxicity did not necessarily recur after subsequent doses and did not lead to PEG-ASN discontinuation; (4) the dose and schedule of other hepatically cleared or hepatotoxic drugs should be adjusted during periods of PEG-ASN-related hepatotoxicity.In conclusion, although PEG-ASN at this dose and interval is associated in adults with a high rate of hepatotoxicity, it is tolerable and can be given again despite earlier PEG-ASN-related hepatotoxicity. Disclosures:Douer:Sigma Tau Pharmaceuticals : Research Funding.

Pharmacokinetics-Based Modification of Intravenous Pegylated Asparaginase Dosing in the Context of a “Pediatric-inspired” Protocol in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)

AbstractAbstract 1495Prolonged Asparaginase (ASP) use is standard in all pediatric ALL regimens. In adults ASP is either not used or given for much shorter duration. Recently, several adult ALL protocols adopted pediatric regimens, with long duration of ASP, mostly E. coli, with better outcomes than historically reported. However, optimal implementation of pediatric regimens to adults, especially ASP dosing, has not been studied, considering its potential higher toxicity. We report the results of an ALL protocol adopted from pediatrics, modified by using the long acting pegaspargase (PEG-ASP) with a pharmacokinetics-based dosing strategy, intended for adults with newly diagnosed ALL. Methods:We adopted the augmented BFM pediatric protocol (Nachman NEJM 1998) replacing the native E. coli ASP with 6 doses of PEG-ASP. Pediatric and most pediatric-inspired adult protocols use 2,500 u/m2 PEG-ASP at 2 week intervals. Based on our PEG-ASP adult PK and PD data (Douer Blood 2007), the dose was reduced to 2,000 u/m2IV, at intervals no shorter than 4 weeks. Other modifications include 1) Each PEG-ASP dose, having a very long activity (2–4 weeks), was synchronized with the time of myelosuppressive drugs so that there anticipated different serious toxicities are less likely to coincide. 2) Replaced escalated MTX dosing plus E.coli ASP with 4 fixed high doses of MTX, timing PEG-ASP to avoid its overlapping long enzymatic activity with MTX activity. 3) hydrocortisone pre-medication and steroids for 7–14 days after each PEG-ASP dose to prevent allergic reactions. The protocol included 8 cycles of multi-agent chemotherapy, 2-year maintenance and IT MTX CNS prophylaxis. PEG-ASP was given intravenously (IV) once on day 15–17 of induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (# 3 & 6), and two cycles of delayed re-induction (# 5 & 8). Results:Between July 2004 and July 2009, 51 (17 women) adults with newly diagnosed previously untreated ALL were enrolled in 2 USC affiliated hospitals. Patient characteristics include: median age - 33 (range18–57) yrs, precursor B cell - 46, T cell-5, Ph+ 11, and median WBC-14,500 (range 800-512, 000)/dL. Total number of PEG-ASP doses was: all 6 doses - 23 pts, 4 doses- 1 pt., 3– 7 pts. 2–9 pts, 1–11pts. Twenty eight (55%) pts. did not complete 6 PEG-ASP doses due to: allogeneic HSCT −8 pts, refusal −1pt., induction failure – 2pts, death in CR −3 pts., relapse- 4 pts; and PEG-ASP related toxicities: 11 (21%) pts: including pancreatitis −7pts, allergy −3 pts, DVT-1 pt (one pt. had pancreatitis and later transplanted). Among 51 pts PEG-ASP related grade 3/4 toxicities were: anaphylaxis-2 pts.(4%); pancreatitis-7 (14%) pts.; thrombosis-8(16%) (5 catheter-related); transaminitis −33(65%); high bilirubin −22 (43%); hyperglycemia-17(33%); high triglycerides −8(16%); fatigue-4(8%). Table I shows the rates of ASP related toxicities in 173 doses. All toxicities were reversible without any PEG-ASP-related deaths. Outcome data is shown in Table 2.Table 1:Rate of ASP Related Grade 3 /4 Toxicities in 173 DosesToxicityPancreatitis5%Allergy3%DVT5%Bleeding<1%Transaminitis36%High bilirubin14%Hyperglycemia20%High triglycerides27%Fatigue3%Neuropathy1%Vomiting1%Nausea2%Table 2OutcomesAll PatientsPh -Number5140CR, No (%)49 (96%)39 (98%)CR at 4 wks, No (%)48 (98%)39 (100%)OS*51%58%DFS*58%58%OS Standard risk73% (n=17)OS High risk**40% (n=34)OS No HSCT55% (n=42)DFS No HSCT58% (n=40)*At 7 years,**High Risk: Ph+, t(4;11), WBC B cell >35,000/dL, T cell > 100,000/dL, age > 30 yrs, CR in < 4 weeks (Goldstone Blood 2009).Median follow up – 44 monthsNeutralizing antibodies measured in 247 serum samples from 34 pts. (33, 11 & 10 pts. after PEG-ASP doses # 1, 4, and 6 respectively) were detected in 1 patient Conclusion:Our rational modification of a pediatric protocol, in adult ALL (age <57 years), is feasible, has very high CR rate (98% by 4 weeks), 58% 7-years DFS, even without HSCT, and in line with reported results of other pediatric-inspired regimens. PEG-ASP toxicities were common but mostly manageable and reversible. Our study suggests the that standard PEG-ASP adult dose can be reduced to 2,000 u/m2 IV at intervals no less than 4 weeks without impairing overall outcome. Steroids may reduce clinical allergies, without masking silent neutralizing antibody formation. The concepts of this study, especially PEG-ASP dosing, could be applied in future ALL protocols. Disclosures:Douer:Sigma Tau: Research Funding, Speakers Bureau. Avramis:Sigma Tau: Consultancy.

Multiple Doses of Intravenous Pegylated Asparaginase with a “Pediatric-like” Protocol in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL): Toxicity, Clinical Outcome and Low Rate of Anti Asparaginase Antibody Formation.

Abstract 3082Poster Board III-19Several, large randomized multi-agent trials, in pediatric ALL have shown that prolonged use of asparaginase (ASP) during remission resulted in better outcomes. Adequate serum asparagine depletion from ASP administration has been suggested to have a therapeutic impact. Historically, adult ALL regimens use less, shorter or no ASP compared to pediatrics, as the drug is considered more toxic. However, a recent Adult ALL study (Huguet et al, JCO 27:911, 2009), suggested an improved outcome (EFS 55%, OS 60%) using a “pediatric-inspired” protocol, which included longer duration and higher cumulative doses of E-coli ASP. PEG-asparaginase (PEG-ASP) is a modified E.coli ASP with a longer half life, resulting in sustained asparagine depletion. PEG-ASP is also considered to be less allergogenic, and in children causes fewer clinical hypersensitivity reactions and lower rate of anti-ASP neutralizing antibodies (“silent” hypersensitivity i.e. antibodies without clinical hypersensitivity) than the native E. coli ASP. We report, the use of multiple doses (up to 6) of PEG-ASP, given throughout the induction and the post-remission phases in a “pediatric-like” protocol, to newly diagnosed adult ALL. We also determined the rate of anti-ASP neutralizing antibody formation throughout our study; currently these rates are unknown in adults. MethodsThe backbone of our protocol is an augmented BFM pediatric ALL regimen consisting of 8 cycles of multi-agent chemotherapy, followed by two year maintenance. PEG-ASP (2000 U/m2/dose) is given intravenously (IV) once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Steroids are always given before and for at least 7 (dexamethasone) or 14 (prednisone) days after the PEG-ASP dose depending on the treatment cycle. Since December 2006 Ph+ patients receive imatinib 600mg/daily. Results46 patients, aged 18-57 (median 33) years, precursor B cell - 41, T cell-5, Ph+ 11, were studied. Median WBC at diagnosis - 14,500/cumm (range 1,900-512,000). CR rate: 44(96%) pts (43 after induction phase I). So far the total number of PEG-ASP doses given was 160: 6-16 pts, 5- 3pts 3- 6 pts., 2-10 pts., 1-11 pts. Eighteen patients could not complete all doses of PEG-ASP: allogeneic SCT -8, refusal -1, pancreatitis -5 (one pt. had pancreatitis and SCT), anaphylaxis -2, DVT-1. Two additional patients died in CR from neutropenic sepsis. Patients with elevated liver enzymes, high bilirubin, DVT (except for one pt.) or hyperglycemia continued on the study. Number of pts. with PEG-ASP related grade 3/4 toxicities (at least once of each): anaphylaxis -2 (4%) (one additional patient a had grade 2 rash); pancreatitis 6 (13%) (one pt. after last dose); thrombosis- 5 (11%) with 4 of the 5 catheter-related in upper extremity; elevated liver enzymes -30 (64%); hyperbilrubinema - 11 (24%); hyperglycemia - 12 (26 %); hypertriglyceridemia -3 (7%); fatigue-5 (11%). All toxicities were reversible. Neutralizing antibodies were measured in 247 serum samples from 34 patients (33, 11 and 10 pts. after PEG-ASP doses # 1, 4, and 6 respectively). An antibody was detected in only ONE patient (after dose #1); he had PEG-ASP related rash. We confirmed the very long half life of PEG-ASP: 7 ±4.7 days after the fist dose increasing to 11.9±5.9 days after dose 4 and 6. Peak serum levels did not change significantly between the cycles. Four year EFS, OS and CIR were 59%, 64% and 32%, respectively. The 16 patients who received all 6 doses of PEG-ASP (no BMT) had a 4 year EFS of 85% (only 3 relapsed at 19, 28, 55 months). ConclusionThis study suggests that multiple IV dosing with the long acting PEG-ASP is feasible in replacing the native E.coli asparaginase in the context of “pediatric-inspired” ALL protocols in adults (age <57 years), maintaining their reported favorable outcomes, adding convenience with less frequent dosing, and acceptable toxicity. Multiple doses of PEG-ASP given IV (in conjunction with steroids) to adults, is associated with a low rate of clinical hypersensitivity reactions and neutralizing antibody formation. The very low rate, so far, of “silent” hypersensitivity in adults, suggests that PEG-ASP can be continued IV, with less concern for drug inactivation. Such approach may benefit adults with ALL. DisclosuresDouer:Enzon Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau.

Outcome for Adolescents and Young Adults (AYA) with the Hyper-CVAD (with or without Rituximab) Regimens for De Novo Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma.

Abstract 3084Poster Board III-21AYAs aged 16–20 yrs with de novo ALL or LL have superior outcomes when treated with intensive pediatric regimens; event-free survival rates range from 60–70% compared to 30–40% after conventional adult chemotherapy [Stock W, Blood 112:1646, 2008]. This is in part attributed to higher dose intensity (and cumulative dose) of the anthracycline, vincristine [VCR], corticosteroid and asparaginase components. The intensive hyper-CVAD regimen (fractionated cyclophosphamide, VCR, doxorubicin, dexamethasone alternating with methotrexate and cytarabine) was originally modeled after childhood therapy for Burkitt lymphoma, and had been applied as frontline adult ALL therapy without age restriction since 1992. In contrast to conventional adult or pediatric ALL regimens, asparaginase is not administered during induction or consolidation phases. Modifications to the regimen have included the addition of rituximab for CD20 positive precursor B-cell ALL owing to adverse influence of CD20 expression, particularly in the younger subgroup [Thomas D, Blood 113:6330, 2009]. An adapted augmented Berlin-Frankfurt-Munster (BFM) regimen modeled after the CCG experience was developed specifically as frontline therapy for adolescents and adults up to age 30 in lieu of the hyper-CVAD regimen at our institution; accrual is ongoing. We updated the previous comparative hyper-CVAD experience in this young adult subset. One hundred seventy-six pts aged 13 to 30 yrs (median 22 yrs) with de novo ALL (n=149) or LL (n=27) were treated with hyper-CVAD (n=96) or modified hyper-CVAD (25 with anthracycline intensification, 55 without; 32 overall with rituximab). Eighty-three (47%) were less than 21 years of age (median 19 yrs). Forty-nine (29%) were CD20 positive. Overall complete remission (CR) rate was 97%; overall 3-yr CR duration (CRD) and survival (OS) rates were 65% and 70%, respectively. Rates for 3-yr CRD and OS were 68% and 75% if age 21 yrs or less, compared with 60% and 66%, respectively, if age 22 to 30 yrs (p=NS). The addition of rituximab improved the 3-yr CRD rates from 26% to 65% (p=.001) and 3-yr OS rates from 47% to 75% (p=.05) for the CD20 positive precursor B-cell ALL subsets, partly accounting for the improvement in outcomes. There were no significant differences in outcome by regimen for the CD20 negative subsets (all 3-yr rates > 70%). Outcomes with the hyper-CVAD regimens in AYAs appear to more closely resemble those of the pediatric approaches than the conventional regimens; incorporation of pegylated asparaginase and intensification of vincristine/corticosteroids (e.g., augmented hyper-CVAD) may further improve the efficacy of this regimen in the frontline setting. Incorporation of rituximab or the novel CD20 antibodies such as ofatumumab into the pediatric regimens warrants consideration. DisclosuresNo relevant conflicts of interest to declare.

Young Adults with Acute Lymphoblastic Leukemia (ALL) Treated with Adapted Augmented Berlin-Frankfurt-Munster (ABFM) Therapy

The survival of teen-aged patients (pts) with acute lymphoblastic leukemia (ALL) has been analyzed by various groups, with most groups showing improved survival for these pts using pediatric ALL regimens compared to adult treatment regimens. ABFM therapy is an effective therapy for ALL pts up to age 21 and the therapy has acceptable toxicities. We designed a trial of modified ABFM therapy for adolescent/young adults (AYA) up to age 40 with acute lymphoblastic leukemia. Enrollment on the trial began in October 2006. Pts receive four drug induction with prednisone 60 mg/m2 daily for 28 days, daunorubicin 25 mg/m2 weekly for 4 doses, vincristine 2 mg weekly for 4 doses and a single dose of intravenous PEG-asparaginase in week one as well as intrathecal (IT) cytarabine on day one and IT methotrexate on day 8 and 29 depending on the presence of spinal fluid blasts. Induction is extended by two weeks for pts who do not achieve morphologic remission by day 29. Pts who have a morphologic remission by day 15 are classified as rapid early responders, and they receive one phase of delayed intensification. Patients who do not achieve morphologic remission by day 15 but who attain morphologic remission by day 29 or day 42 are slow early responders. Compared to preceding high risk ALL therapy in children, the first year of ABFM treatment uses more vincristine, asparaginase and intravenous methotrexate. As per prior pediatric protocols, central nervous system (CNS) radiation is recommended for pts with CNS involvement at diagnosis and for pts with T-cell ALL and a high presenting white blood cell count. 34 pts have been enrolled. 29 are evaluable (2 with prior relapse, 2 with lymphoblastic lymphoma, and 1 withdrew on day 1 of therapy). The median age is 20 years (range 14–34). 27 (90%) pts are in remission at day 28. Two pts are in remission with extended induction. One pt is refractory to induction. 26 (87%) have rapid early responses by marrow morphology. Minimal residual disease (MRD) testing shows 15/29 positive at day 15, 10/29 positive at day 29, and 3/24 positive at day 84. The most frequent grade 3–4 toxicities are infectious in 19 (65%), elevated transaminases in 17 (58%) patients, hyperglycemia in 13 (44%), and hyperbilirubinemia in 9 (31%). 7 (25%) have Grade 3–4 thrombosis or fatigue. Less frequent but significant toxicities include leukoencephalopathy, osteonecrosis and severe allergic reactions each seen in 3 (10%) pts. One pt had a prolonged delay in chemotherapy due to liver toxicity and relapsed. One pt has CNS relapse, and two have died of leukemia. ABFM therapy in young adults is an effective induction regimen but entails significant hepatic and infectious toxicities. The majority of these toxicities have resolved. Long-term follow-up is needed to determine if this treatment regimen offers an advantage to AYA patients with ALL.

Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LL) after Frontline Therapy with Hyper-CVAD Regimens.

AYAs aged 16–20 with de novo ALL or LL have superior outcomes when treated with intensive pediatric regimens; event-free survival (EFS) rates range from 60–70% compared to 30–40% after conventional adult chemotherapy [Stock W, Blood 2008, e-pub]. This is in part attributed to higher dose intensity (and cumulative dose) of the anthracycline, vincristine [VCR], corticosteroid and asparaginase components. Of note, the intensive hyper-CVAD regimen (cyclophosphamide, VCR, doxorubicin, dexamethasone alternating with methotrexate/cytarabine) was originally modeled after childhood therapy for Burkitt lymphoma. It has been applied as frontline adult ALL therapy without age restriction since 1992. In contrast to conventional adult or pediatric ALL regimens, asparaginase is not administered during the induction or consolidation phases. Modifications to the regimen have included the addition of rituximab for CD20 positive precursor B-cell ALL and LL owing to adverse influence of CD20 expression, particularly in the younger subgroup [Thomas D, Blood 2008, e-pub]. An adapted augmented Berlin-Frankfurt- Munster (BFM) regimen modeled after the CCG experience was developed specifically as frontline therapy for adolescents and adults up to age 30 in lieu of the hyper-CVAD regimen at our institution; accrual is ongoing. We reviewed the previous hyper-CVAD experience in the AYA subset. One hundred two pts aged 13 to 21 yrs (median 19 yrs) with de novo ALL (n=92) or LL (n=10) were treated with hyper-CVAD (15 with rituximab). Complete remission (CR) rate was 97%; 3-yr EFS and OS rates were 65% and 70%, respectively. Preliminary reports from other investigators suggest that an intensified pediatric approach may be feasible even up to age 60. The GRAALL-2003 study reported 42-mos EFS and OS rates of 55% and 58%, respectively, in 225 de novo ALL pts aged 15– 60 (median 31 yrs) [Huget F, ASCO 2008, abstr 7005]. Median follow-up was 37 mos. A similar cohort of pts treated with the hyper-CVAD regimens included 385 pts with a slightly older median age of 35 yrs. Median follow-up was 62 mos (range, 1–180 mos). EFS and OS rates for the entire cohort were 50% and 55%, respectively. For pts below the age of 35, these rates improved to 55% and 67%. Clearly age remains a prognostic factor even with intensive chemotherapy approaches. Outcomes with the hyper-CVAD regimens appear to more closely resemble those of the pediatric approaches than the conventional regimens. Continued monitoring of ongoing prospective clinical trials using pediatric regimens in adults is paramount to delineating the optimal approach.

Acute lymphoblastic leukemia in adolescents and young adults

Age at diagnosis remains one of the strongest prognostic factors in acute lymphoblastic leukemia (ALL), with older patients having inferior outcomes compared with younger patients. Adolescents and young adults (AYAs) with ALL (age 15-30 years) represent a patient subgroup with distinctive biology whose optimal therapy has yet to be determined. Compared with younger children with ALL, AYAs are more likely to present with unfavorable presenting characteristics (such as high presenting leukocyte counts, T-cell phenotype, and the Philadelphia chromosome). Additionally, AYAs with ALL experience more regimen-related toxicity than younger patients. Recent retrospective studies suggest that patients age 15 to 21 years treated on pediatric ALL regimens have better outcomes than similarly aged patients treated on adult ALL regimens. Pilot prospective studies are under way to test the feasibility of administering pediatric ALL regimens to AYAs with ALL, with promising preliminary results.