Adult Acute Lymphoblastic Leukemia Protocols Research Articles

Pediatric-Inspired Protocol Improved Overall Survival in Young Adult Aged 18-30 Years Old with Philadelphia-Negative Acute Lymphoblastic Leukemia Compared to the Standard Adult Hypercvad Protocol

Background:Pediatric acute lymphoblastic leukemia (ALL) have excellent overall survival (OS) compared to adult ALL even in the young adult group. The difference in OS was thought to be due to the difference in treatment protocol with the pediatric-inspired protocol being more intensive and with minimal residual disease (MRD) driven. Strong data has emerged over the past decade from different ALL study groups from Europe and North America to support the use of pediatric-inspired protocol for young adult up to age 30-40 years.HyperCVAD protocol, designed by MD Anderson group in early 90s, has been our standard treatment for adult ALL including young adult since year 2000. Over the past decade, a locally designed pediatric-inspired and MRD driven protocol - known as MASPORE Protocol was used with increasing frequency for those age 30 years and below. MASPORE protocol has higher cumulative dose of vincristine and methotrexate, and use of L-Asparaginase compared to HyperCVAD.In this retrospective study, we aimed to evaluate the safety, tolerability and efficacy of MASPORE protocol in relation to the standard adult ALL protocol - HyperCVAD in young adult aged 18-30 years who were diagnosed with Philadelphia-negative (Ph-) ALL.Method:Patients aged 18 to 30 years old with Ph- ALL who had received HyperCVAD or MASPORE regimen were retrospectively identified via our institution database. Clinical data, toxicity profile, and treatment outcome were collected, compared and analyzed.High risk disease was defined as high white blood cell (WBC) (>30x109/L for B-ALL, and >100x109/L for T-ALL), failure to achieve complete remission (CR) after induction, failure to achieve MRD target at 4 weeks and 8 weeks (in MASPORE group), hypodiploidy, t(9;22), t(4;11) and other MLL-gene rearrangement. An intensified chemotherapy regimen would be given to those high-risk disease in MASPORE regimen, while HyperCVAD regimen has a fixed intensity irrespective of risk.Results:A total of 30 consecutive Ph- ALL patients aged between 18 to 30 years old who were treated with HyperCVAD or MASPORE protocol were included in the analysis. 16 were treated with MASPORE protocol while 14 were treated with HyperCVAD protocol. The median age was 22 years old (Range: 18 - 29 years old). Median follow-up for MASPORE was 37.0 months and HyperCVAD was 85.0 months. HyperCVAD-treated patients were mainly from year 2004 to 2011, while more than 80% of MASPORE patients were treated after year 2013.18 patients had B-ALL, 11 with T-ALL and 1 with mixed phenotypes. 2 patients (1 in each group) had high cytogenetic risk. Median WBC was 14.1 (range: 1.9-287) and 10.1 (range: 1.2-242) for HyperCVAD and MASPORE respectively.All patients achieved CR at the end of induction with no early death (within 60 days of induction). Overall relapse rate was 33.3% with lower relapse rate observed in in MASPORE (18.8%) compared to 50.0% in HyperCVAD. (p-value: 0.07). 4 in HyperCVAD and 3 in MASPORE received allo-SCT subsequently.Median OS in MASPORE was not reached. Median OS for HyperCVAD was 26.3 months (95% CI: 3.6-49.1 months). Overall survival at 3 years were 84.0% and 46.2% in the MASPORE and HyperCVAD, respectively, p=0.038 (Figure 1).Median Leukemia Free Survival (LFS) in MASPORE was not reached. Median LFS in HyperCVAD was 12.5 months (95% CI: 4.2-20.8 months). LFS at 3 years were 75.8% and 38.5% in the MASPORE and HyperCVAD respectively, p=0.089 (Figure 2).6 patients in MASPORE had thrombotic events (3 with cerebral venous thrombosis and 3 with deep vein thrombosis (DVT)) while only 1 patient had DVT in HyperCVAD group. 11 patients in MASPORE group had at least 1 episode of grade 3 or more transaminitis, compared to 3 patients in HyperCVAD. 7 patients in HyperCVAD group had at least one episode of bacteremia during the course of treatment compared to 4 patients in the MASPORE group. Two treatment-related death were observed, both from HyperCVAD group.ConclusionsMASPORE protocol was well tolerated albeit higher rate of thrombotic events and transaminitis which most likely related to L-asparaginase, but with lower incidence of bacteremia and treatment related death. It showed a superior overall survival compared to HyperCVAD protocol and a trend towards improved leukemia free survival. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PEG‐asparaginase‐induced hepatic steatosis is associated with PKA activation and white adipose tissue lipolysis

BackgroundPEGylated L‐asparaginase (PEG‐ASNase) is an essential chemotherapeutic agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL) that depletes L‐asparagine and leads to leukemic cell apoptosis. However, this agent is avoided in adult ALL protocols due to its high risk of liver toxicity. Clinical studies have implied that the mechanism of PEG‐ASNase‐induced liver toxicity is due to defect in hepatic β oxidation; however, no study has investigated the mechanism or the role of β oxidation in PEG‐ASNase‐induced hepatic toxicity. Our study aims to demonstrate that PEG‐ASNase‐induced liver toxicity is not due to hepatic defects in fatty acid oxidation, VLDL secretion, or fatty acid synthesis. Rather, our data suggest that the toxicity may be due to a novel mechanism of fatty liver involving drug‐induced adipose lipolysis.Methods8‐week‐old male Balb/c mice received 1,500 IU/kg of PEG‐ASNase and were sacrifice at 1, 3, 5, or 7 days after drug administration. Blood, liver, and white adipose tissue (WAT) were harvested after sacrifice. Liver lipids were directly quantified and further assessed via Oil red O and H&E staining. Total and direct bilirubin, ALT, AST, and non‐esterified fatty acids (NEFA) were measure in plasma. The mRNA and protein levels of genes involved in hepatic fatty acid oxidation, lipid synthesis, and VLDL secretion were determined. To assess the effect of PEG‐ASNase on WAT lipolysis, the protein levels of Atgl, phosphorylated Hsl, and protein kinase A (PKA) were measured.ResultsPEG‐ASNase treatment in mice led to total body, liver, and WAT weight loss. Mice developed hepatic microvesicular steatosis after 3–7 days of drug administration. Plasma direct and total bilirubin levels were elevated 8‐fold relative to controls, whereas ALT, AST, and NEFA concentrations were elevated 2‐fold 3–7 days after PEG‐ASNase. Furthermore, we found, that the hepatic mRNA and protein levels of Srebp‐1c and Fas, which are involved in fatty acid synthesis, were downregulated suggesting a decrease in lipid synthesis after PEG‐ASNase. Furthermore, the hepatic gene and protein expression of Pparα, Lcad, and Mcad, which are involved in fatty acid oxidation, were upregulated after PEG‐ASNase. In vivo VLDL secretion was also increased 3 days after PEG‐ASNase administration. Taken together, our data indicate that other lipid sources are mediating the drug‐induced fatty liver. Among WAT, we found that PEG‐ASNase elevated ATGL, phosphorylated HSL, and PKA protein levels, consistent with the WAT weight loss and the increased plasma NEFA levels.ConclusionOur data suggest that PEG‐ASNase‐induced WAT lipolysis leads to the development of microvesicular hepatic steatosis and toxicity. Our future studies will determine whether PEG‐ASNase hepatic steatosis can be inhibited via the pharmacological or genetic inhibition of adipose lipolysis and identify the molecular mechanism leading to PKA activation and lipolysis.Support or Funding InformationNIH Grants RO1 CA216815. University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261.

Adolescent and Young Adult Oncology Patients with Acute Lymphoblastic Leukemia: Shifting Location of Care over Time

BackgroundOver the past decade, research has demonstrated superior outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) when they are treated on pediatric versus adult ALL protocols, which occurs more frequently at academic centers. We hypothesized that this knowledge resulted in a greater proportion of younger adults with ALL receiving treatment at National Cancer Institute (NCI)/Children's Oncology Group (COG) designated centers over the past decade, and that an increased proportion of younger AYAs (ages 18-21) received care at pediatric (COG) versus adult centers.MethodsWe used the Office of Statewide Health Planning and Development patient discharge database to conduct a retrospective analysis of AYA patients with ALL, ages 18 to 25 and diagnosed and treated in California from 2004 to 2013. The primary outcome was receiving care at a NCI/COG designated center up to 5 years after diagnosis. Multivariable logistic regression was used to determine socio-demographic factors associated with AYAs ever receiving care from an NCI/COG designated center. Descriptive analyses were used to evaluate changes in the percentage of admissions from NCI and COG designated centers over time using a chi-square test to make comparison of proportions over time.ResultsThere were 703 patients, ages 18-25 years (52.5%, 18-21; 47.5%, 22-25 years) who were newly diagnosed with ALL and hospitalized in California between 2004 and 2013. Sixty-five percent were male and 51% had private insurance. Of these patients, 37% always received care at an NCI/COG center, while 28% sometimes and 35% never received care at these centers. Younger AYAs (18-21 years) had a higher odds of ever being discharged from a NCI/COG center (OR 1.52, CI 1.10-2.10), while AYAs living farther from a NCI/COG center were less likely to receive care at these centers (OR 0.45, CI 0.27-0.76 for 10-20 vs 0-5 miles). Over the past decade, there was an increase in the percentage of admissions to NCI/COG centers among 18-21 year-olds (53% in 2004 to 72% in 2013; p<0.001), whereas there was no significant increase for 22-25 year-olds (44% in 2004 to 49% in 2013; p=0.435) (Figure). When admissions to an NCI and COG center were considered separately, differences were observed by age group. There was a lower percentage of admissions to NCI centers over time in 18-21 year-olds (34% in 2004 to 27% in 2013; p=0.183), but a significant increase in admissions to NCI centers in 22-25 year-olds (27% in 2004 to 40% in 2013; p=0.035). Alternatively, there was a significant increase in the percentage of admissions to COG centers in the 18-21 year-olds (48% to 67%; p<0.001), with a somewhat smaller increase in admissions to COG centers in 22-25 year-olds (25% to 32%; p=0.278) from 2004 to 2013.ConclusionsOver the past decade, approximately 37% of younger (18-25 years) AYAs with ALL always received care at NCI/COG designated centers, with younger age and shorter geographical distance to a NCI/COG designated center being the main predictors for receiving care at these centers. Over the study period, the percentage of admissions increased at NCI centers for 22-25 year-olds and COG centers for 18-21 year-olds. These findings support our hypothesis that there has been a shift in treatment of younger AYAs (18-21 years) to COG designated centers over the past decade. Further research is warranted to determine the roles that referral patterns, insurance networks, patient preference and other barriers play in receiving care at NCI and/or COG institutions and the effect of care at these centers on survival in population-based data. [Display omitted] DisclosuresWun:Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi: Research Funding.

Relapse in Teenage and Young Adult (TYA) Patients Treated on a Pediatric Minimal Residual Disease (MRD) Stratified Protocol Is Associated with a Poor Outcome: Results from UKALL2003

The superior outcomes of teenage and young adult (TYA) patients with acute lymphoblastic leukemia (ALL) treated on contemporary pediatric minimal residual disease (MRD) directed chemotherapy regimens compared to adult ALL protocols are well established. However, there are limited data on the outcome of relapse following such regimens and consequently no consensus on optimal salvage strategies.UKALL 2003 was a prospective, randomised controlled trial investigating treatment modification according to MRD status at the end of induction in consecutively diagnosed children and young people with ALL recruited from the UK and Republic of Ireland between October 2003 and June 2011. The trial was initially open to children up to the age of 18 years but the upper age limit was increased to 20th birthday in 2006 and 25th birthday in 2007. Here we report the relapse outcomes of 16 - 24 year old TYA patients recruited to the trial.All TYA patients recruited to UKALL 2003 who subsequently relapsed were identified using the trial database, which also provided data regarding prognostic factors at presentation, MRD risk group, treatment allocation, site of and time to relapse and overall outcome. Individual centers were then contacted for follow up information including salvage chemotherapy, disease response, use of transplantation, subsequent outcome and cause of death.Of a total of 229 TYA patients recruited, 42 (18.3%) relapsed. The immunophenotype in those who subsequently relapsed was precursor B cell (B-ALL) in 30 patients and T cell (T-ALL) in 12. The median white cell count at diagnosis was 22x109/l and 1 patient had central nervous system (CNS) involvement. In B-ALL, 4 had good risk cytogenetics (all high hyperdiploid), 13 had intermediate risk, 6 had high risk (3 with MLL rearrangements), and 7 had unknown cytogenetics. End of induction MRD risk group was low risk in 2, intermediate risk in 11 and high risk in 29.The median time from diagnosis to relapse was 17 months (17.5 months for B-ALL and 14 months for T-ALL, p=0.1). The site of relapse was isolated bone marrow (BM) in 30 patients, combined BM and CNS in 4, combined BM and testicular in 1, and isolated CNS in 6 (T-ALL; 8 BM, 3 BM+CNS, 1 isolated CNS) (B-ALL; 23 BM, 1 BM+CNS, 1 BM + testicular, 5 isolated CNS).36 of the 42 relapsed patients were given salvage chemotherapy, using a variety of regimens including R3 (n=9), Fludarabine/Cytarabine/Idarubicin based (n=16), and Clofarabine based (n=4). One patient received Blinatumamab and one entered the MARALL study (a Phase I/II study of the combination of Veltuzumab (anti-CD20) and Epratuzumab (anti-CD22) with intensive chemotherapy in patients with relapsed B-cell ALL). A second complete remission rate was achieved in 22 patients (61%) and a further 2 had an empty marrow without count recovery. 23 patients proceeded to an allogeneic hemopoietic stem cell transplant.The median overall survival (OS) from relapse was 213 days (actuarial 5 year OS of 18%). 9 patients remain alive; 8 in remission (1 unconfirmed) and 1 undergoing active treatment. The cause of death in the 33 patients who died was relapsed/refractory disease in 20, complications of re-induction treatment in 4, transplant related complications in 6 and unknown in 2. 1 further patient died of sepsis post transplant in the context of pancytopenia and suspected (though unproven) relapse.Those relapsing earlier than the median of 17 months had a shorter median survival and 5 year OS from relapse compared to those relapsing at >17 months (median 113.5 v 400 days, and OS 10% v 37%, p=0.0075). When this analysis was restricted to only the B-ALL cohort the effect was even more marked (median 151 v 595 days, OS 0% v 45%). No patient with B-ALL relapsing ≤24 months was salvageable. There were no differences in salvage approach between the early and late relapsing cohorts, nor differences in MRD risk. The late relapsing cohort did have more patients with good risk cytogenetics, and fewer with high risk cytogenetics.TYA patients with ALL who relapse despite intensive, contemporary MRD directed chemotherapy have an extremely poor outcome. Patients with B-ALL relapsing at 24 months from diagnosis or earlier are unsalvageable. Improving the outcomes of TYA ALL patients will depend on a) more accurate early identification of those destined to relapse and b) use of innovative therapies in those at high risk of relapse or with overt relapse. DisclosuresNo relevant conflicts of interest to declare.

Treatment of Adolescent and Young Adult Acute Lymphoblastic Leukemia with the Pediatric Protocol: Results from a Single Institution in Taiwan

BackgroundIt remains unclear whether pediatric protocols provide a better outcome to adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) than adult protocols in Taiwan. Therefore, we conducted a case-control study to compare the outcome events, disease-free survival (DFS), and overall survival (OS) in Taiwanese AYA patients receiving either pediatric or adult ALL protocols. MethodsTwenty-three Taiwanese AYA patients with ALL were retrospectively reviewed: eight patients received the pediatric ALL protocol modified from the Taiwan Pediatric Oncology Group (mTPOG) regimen, and 15 were treated by using the Cancer and Leukemia Group B study 8811 (CALGB-8811) regimen. ResultsThe DFS rates for patients in the mTPOG and CALGB-8811 groups were 100% versus 33.3% (p = 0.016) at one year, and 100% versus 22.2% (p = 0.006) at two years, respectively. The OS rates for patients in mTPOG and CALGB-8811 groups were 100% versus 37.0% (p = 0.013) at one year, and 100% versus 22.2% (p = 0.003) at two years, respectively. ConclusionsOur results suggested that the pediatric mTPOG protocol provides AYA ALL patients a better DFS and OS than the adult CALGB-8811 protocol.

Pharmacokinetics-Based Integration of Multiple Doses of Intravenous Pegaspargase in a Pediatric Regimen for Adults With Newly Diagnosed Acute Lymphoblastic Leukemia

Asparaginase treatment is standard in all pediatric acute lymphoblastic leukemia (ALL) regimens, whereas in adults, it is either excluded or administered for a shorter duration. Several adult ALL protocols are adapting pediatric regimens, but the optimal implementation of asparaginase is not well studied, considering its potential higher toxicity. We studied a pegaspargase dosing strategy based on its pharmacokinetic characteristics in adults. Between 2004 and 2009, 51 adults age 18 to 57 years with newly diagnosed ALL were treated with a regimen adapted from a pediatric trial that included six doses of intravenous pegaspargase at 2,000 IU/m(2) per dose. Intervals between doses were longer than 4 weeks and rationally synchronized with other chemotherapy drugs to prevent overlapping toxicities. Pegaspargase was administered with steroids to reduce hypersensitivity. Asparaginase-related toxicities were monitored after 173 pegaspargase doses. The most common grade 3/4 asparaginase-related toxicities were lengthy hyperbilirubinemia and transaminitis, occasionally resulting in subsequent treatment delays. All toxicities resolved spontaneously. Forty-five percent of patients were able to receive all six doses of pegaspargase, and 61% received ≥ three doses. In only 20% of patients, the drug was discontinued after pegaspargase-related serious toxicity. Ninety-six percent achieved complete remission, almost all within 4 weeks, and a low induction death rate was seen. Seven-year disease-free and overall survival were 58% and 51%, respectively. Our dose and schedule of pegaspargase, based on its pharmacokinetics, and our detailed toxicity profile could be applied for safer adaptation of pediatric ALL protocols in adults.

Significant Improvement Of Outcome In Adolescents and Young adults (AYAs) Aged 15-35 Years With Acute Lymphoblastic Leukemia (ALL) With a Pediatric Derived Adult ALL Protocol; Results Of 1529 AYAs In 2 Consecutive Trials Of The German Multicenter Study Group For Adult ALL (GMALL)

▪Several groups have reported results from smaller series of AYAs with ALL. Outcomes with so-called protocols for adults were generally inferior compared to so-called pediatric protocols. The GMALL protocols were originally based on pediatric BFM protocols and have been consecutively optimized for adults since 1981. We report the results of two recent protocols 05/93 (Goekbuget et al, Blood 98(11):802a, 2001) and 07/03 (Goekbuget et al, Blood 110(11):12a, 2007). In study 07 high risk (HR) pts were identified by one of the factors: B-lin with WBC>30.000, late CR (>3 wks), pro-B, early T, mature T, MLL1/AF4/t(4;11). Pts without risk factors were standard risk (SR) and those with BCR-ABL/t(9;22) very high risk (VHR). HR/VHR pts were candidates for SCT in CR1. The major innovations in study 07 were: intensified, shortened induction with dexamethasone instead of prednisone, PEG-asparaginase (ASP) instead of native ASP, intensified first consolidation, 6x HDMTX/ASP during consolidation, matched unrelated SCT for HR/VHR pts without sibling donor and SCT indication in pts with persistent MRD. After amendments in trial 07 pts partly also received intensified PEG-ASP, rituximab in CD20+ ALL and imatinib in Ph+ ALL.Overall, 1529 of 3060 (50%) pts recruited into both trials were aged between 15-35 yrs. 642 pts from 94 centres were recruited to study 05 and 887 pts from 130 centres to study 07. Patient characteristics were similar for both trials. 70% had B-Lin and 30% T-ALL (61% c/preB, 9% proB, 7% early T, 6% mature T, 17% thy T) with no significant differences across age subgroups (15-17,18-25 and 26-35 yrs). Allocation to SR, HR and VHR was 51%, 35% and 14%. VHR incidence increased from 3%, 11% to 19% in age groups (p<.0001).The CR rate increased in studies 05 to 07 from 88% to 91% (p=.001), most prominently within the age range of 26-35 yrs (86% to 90%;p=.001) (table). The OS increased from 46% to 65% (p<.0001) (significant in all age groups). Remission duration (RD) at 5 yrs increased from 49% to 61% (p=.0001), most prominently within the age range of 26-35 yrs (46% vs 59%; p=.005). OS improved from study 05 to study 07 in B-Lin (45% vs 66%; p<.0001) and T-ALL (47% vs 63%; p=.0007) overall and in subgroups as c/pre B (50% vs 68%;p<.0001), pro B (45% vs 67%;p=.05), mature T (19% vs 61%; p=.005) and thymic T (59% vs 70%;p=.09) but to a lesser extent in early T (35% vs 48%;p>.05). OS increased in SR (58% to 74%; p<.0001), HR (24% to 58%; p<.0001) and VHR (36% vs 55%;p=.0003).Table 1Results of Induction and Overall Outcome in GMALL-Studies 05/93 and 07/0305/9307/03Total15-1718-2526-35Total15-1718-2526-35Evaluable64210625238488753458376CR88%91%88%86%91%94%91%90%ED3%1%3%3%4%0%3%6%Failure9%8%8%11%5%6%5%4%RD at 5y49%52%50%46%61%60%62%59%OS at 5y46%57%45%42%65%73%69%60%15% vs 43% of all CR pts underwent SCT in CR1 in studies 05 and 07. The proportion of SCT increased from 22% to 68% (p<.0001) in HR and from 62% to 73% (p<.0001) in VHR in studies 05 vs 07. The OS after SCT improved from 36% to 68% (p<.0001), mainly due to a decrease of TRM from 34% to 12% (p<.0001).In trial 07 MRD in week 16 (after consolidation I) was tested in 353 pts. The proportion of molecular failure (MRD>0.01%) was 26% with no differences across age groups. OS was 90% in pts with mol. CR vs 53% in mol. failure (p<.0001). Amendments in study 07 led to further improvement with an OS of 71% in 274 pts aged between 15-35 yrs treated according to the final protocol version.We present here results of the so far largest cohort of AYA ALL pts treated according to pediatric-derived adult ALL protocols. Outcomes have significantly improved and reached a 73% OS in pts aged 15-17 yrs. Intensified treatment with ASP, MTX and targeted therapies as rituximab and imatinib and MRD based stratification have contributed to the improvement in study 07. SCT led to improved OS in HR and VHR ALL. Obviously, there is no indication for SCT in CR1 in young SR pts with an OS of 74%. Future GMALL studies will attempt to optimize further the combination of pediatric approaches and targeted therapies in adults.Supported by Deutsche Krebshilfe 70-2657-Ho2 and partly BMBF 01GI 9971. Disclosures:Off Label Use: RItuximab in ALL.

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.

A Pediatric Treatment of Ph-Negative Acute Lymphoblastic Leukemia (ALL) Is Effective and Safe In Adolescents and Young Adults (AYAs) until 29 Years of Age

AbstractAbstract 2125 Background:Over the last three decades, progress in the treatment of childhood acute lymphoblastic leukemia (ALL) has considerably improved the outcome of children, leading to 5-year OS of more than 80%. Numerous comparisons, including the French LALA/FRALLE (Boissel et al. JCO 2001), have reported a better outcome in teenagers treated with pediatric as compared to standard historical adult ALL protocols. Even if modern pediatric-inspired adult ALL protocols have recently reported impressive improvements, especially in younger patients (Huguet et al. JCO 2009), the issue of whether younger adults (YAs) should be treated according to pediatric or adult protocols remains an open one. The aim of this study was first to evaluate the feasibility and the results of a non-modified pediatric protocol (the French FRALLE 2000) in adolescents and younger adults (AYAs, aged 15–29 years) treated in adult departments. Methods:From February 2001 to June 2010, 72 AYAs with Ph-negative ALL were treated according to the pediatric FRALLE 2000-BT protocol in 12 adult hematology units in France and Belgium. After a prednisone prephase and a four-drug induction (prednisone, daunorubicin, vincristine and L-asparaginase), patients in CR received a consolidation, a 1st delayed intensification, an interphase, a 2nd delayed intensification, and a maintenance chemotherapy during two years. Results:The median age was 19 years (range, 15–29 years). The cohort was separated in 2 subgroups: 44 adolescents aged 15–19 years and 28 young adults (YAs) aged 20–29 years. There were no significant differences between the adolescent and the YA populations in term of sex ratio, white blood cell count (WBC), central nervous system involvement, and phenotype (BCP- vs T-ALL). As expected, few recurrent cytogenetical abnormalities were identified in this population and did not differed between both subgroups. In the adolescent group, we identified 2 patients with t(4;11), 1 patient with t(1;19), and 3 patients with hypodiploïdy and/or neartriploïdy, whereas this repartition was 2/2/1 in YAs. Rates of good early response to prednisone were in 68% in adolescents and 61% in YAs (p=.52), while rates of good early response to chemotherapy were 80% and 86%, respectively (p=.51). No patient died during induction. Complete remission (CR) rate did not differ between subgroups (98% vs 100%, p=.42). With a median follow up of 4.8 years, 5-year EFS was 57% (41% in adolescents vs 79% in YAs, p=.03) and 5-year OS was 67% (56% and 82% respectively, p=.09). In patients with BCP-ALL, 5-year EFS was 60% (43% in adolescents vs 91% in YAs, p=.02) and 55% in T-ALL (57% vs 50% respectively, p=.81). Twelve patients (17%) received an allogeneic stem cell transplantation (SCT) in first CR (5 adolescents and 7 YAs). Four patients died in first CR, all after SCT, (2 adolescents and 2 YAs). In univariate analysis, a high WBC (continuous variable, p=.02) and a poor early response to chemotherapy (33% vs 63%, p=.02), but not phenotype or poor early response to prednisone, were significantly associated with a shorter EFS. In multivariate analysis, age (adolescents vs YA, p=.04), WBC (continuous variable, p=.0005), and poor early response to chemotherapy (p=.006) had still an impact on EFS. The poor outcome of adolescents compared to YAs, also observed in the French adult GRAALL protocol (not published), was not explained by differences in ALL characteristics, early response to therapy, or treatment-related toxicity. Conclusion:The pediatric protocol FRALLE 2000 is effective and safe for the treatment of selected AYAs with Ph-negative ALL referred to adult departments. The results observed in the YA population are promising, warranting prospective comparisons with the more recent pediatric-inspired adult protocols. The unexpected poorer outcome of adolescents deserves further investigations to explore a potential impact of the quality of care delivered in an adult environment. Disclosures:No relevant conflicts of interest to declare.

Matched Unrelated Donor Allogeneic Stem Cell Transplantation in High Risk Acute Lymphoblastic Leukemia (ALL) After a Preparative Regimen of Hyperfractionated Total Body Irradiation and High-Dose Etoposide – A Feasibility Study within the German Multicenter Study Group for Adult ALL.

Abstract 3389Poster Board III-277 Introduction:The optimal preparative regimen for allogeneic hematopoietic stem cell transplantation (alloHCT) using matched unrelated donors (MUD) for adult patients (pts) with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is currently undefined. There is some evidence from one comprehensive retrospective comparative analysis that a higher dose of hyperfractionated total body irradiation (fTBI) or the use of high-dose etoposide instead of cyclophosphamide is able to reduce the leukemic relapse risk of adult pts transplanted in second CR from HLA-identical sibling donors (ISD) (Marks, DI et al. J Biol Blood Marrow Transplant 12: 438-453, 2006). Purpose:Within the framework of the German multicenter study group for adult ALL (GMALL) protocols 06/1999 and 07/2003, the combination of 12 Gy fTBI + 120 mg/kg cyclophosphamide is the standard preparative regimen for MUD alloHCT in CR1. In these protocols, a preparative regimen of 12 Gy fTBI + 60 mg/kg etoposide before ISD alloHCT in CR1 has shown particular promising results compared to 12 Gy fTBI + cyclophosphamide. Therefore, this pilot study tested the feasibility of the12 Gy fTBI + etoposide regimen for MUD alloHCT in CR1 adult ALL pts. Patients and methods:In the GMALL protocol 07/2003, alloHCT is generally performed after the first consolidation therapy according to predefined prognostic disease features indicating a high relapse risk for pts up to the age of 55 years (yrs). This study prospectively included 20 consecutive (very) high-risk pts (median age: 39 [range 17 to 55] yrs) from two major GMALL transplant centers, who underwent alloHCT using MUD between 01/07 and 03/09. TBI was applied in 2 daily fractions of 2 Gy on 3 consecutive days (days -6 to -4) followed by etoposide on day -3 (alloHCT on day 0). For prophylaxis of acute graft-versus-host disease (GvHD), 3 × 20 mg/kg antithymocyte globuline was given on days -3 to -1 and ciclosporin combined with prednisone thereafter. Results:Neutrophil reconstitution > 0.5/nL was reached after a median of 18 (range 12 to 32) days and self-sustaining platelet counts > 20/nL were attained after a median of 25 (range 13 to 36) days. The cumulative incidence of grades I – IV acute GvHD reached 64 %. Three pts. (15 %) developed acute GvHD > grade II. The cause-specific non-relapse mortality (NRM) incidences at 3, 12 and 24 months are 5 %, 18 %, and 22 % (4/20 pts), respectively. Causes of NRM were infections (2 pts), graft failure and toxic epidermiolysis (1 patient each). The cause-specific leukemic relapse incidence reaches 18 % (3/20 pts) after 12 and 24 months. Two pts were successfully rescued by a 2nd alloHCT after leukemic relapse. After a median follow-up period of 22 months for the 15 surviving pts, the 2-year overall survival estimate is 73 % (95 % confidence limits: 47 % - 89 %). Conclusions:This pilot study demonstrates that the preparative regimen of fTBI + etoposide before MUD alloHCT is feasible in CR1 adult high-risk ALL pts after intensive induction and consolidation courses as applied in the GMALL protocol 07/2003. The comparatively low relapse rate in high-risk ALL pts further supports that the substitution of cyclophosphamide by etoposide leads to better disease control and may thereby improve transplant outcome in this setting. Based on these results, a prospective study comparing fTBI in combination with either etoposide or cyclophosphamide appears justified. Disclosures:No relevant conflicts of interest to declare.

Adaptation of Augmented Berlin-Frankfurt-Munster (ABFM) Therapy in Adolescents and Young Adults with Acute Lymphoblastic Leukemia (ALL).

Comparisons of survival of adolescents up to age 21 years of age treated on either pediatric or adult ALL protocols so far show improved survival for patients (pts) treated with pediatric therapies. ABFM therapy has been shown to be effective therapy for teen-aged pts up to age 21, and is the standard therapy arm of the current Children's Oncology Group high-risk ALL trial. We have initiated a trial of ABFM based therapy for pts up to the age of 30 with lymphoblastic leukemia. Pts receive four drug induction with prednisone 60 mg/m2 daily for 28 days, daunorubicin 25 mg/m2 weekly for four doses, vincristine 2 mg weekly for four doses, and a single dose of intravenous pegylated asparaginase (PEG-asp) in week one of therapy. Intrathecal (IT) cytarabine is given on day one, and IT methotrexate is given on days 8 and 29. IT therapy is intensified depending on the presence of spinal fluid blasts. Induction is extended by two weeks for patients who do not acheive a bone marrow morphologic remission (MR) by day 29. Pts that are in MR by day 15 are rapid early responders; they receive one phase of delayed intensification. Pts who are not in MR by day 15 but enter MR by day 29 or 42 are slow early responders; they receive two delayed intensifications. Upon completion of induction, pts continue with intensive phases of chemotherapy for approximately 6 months. They then start 24 months of maintenance therapy. 13 patients with newly diagnosed ALL have been enrolled with a planned enrollment of 80. The median age is 20 (range 14–28). 10(77%) have pre-B ALL and 3(23%) have T-ALL. 12(92%) are rapid early responders. All pts are in MR by day 29. Minimal residual disease (MRD) status is evaluated at day 29 and day 84 by four-color flow cytometry. 8(62%)pts are MRD negative by day 29. All pts so far are MRD negative by day 84. One pt has relapsed. There are no treatment related deaths. Treatment delays for bone marrow suppression are common. There has been 1 allergic reaction to PEG-asp and 2 cases of clinical pancreatitis. 2 pts have had stroke-like symptoms with MRI findings compatible with treatment toxicity; complete clinical resolution has occurred in both. 4 pts have had grade (Gr) 3–4 hyperglycemia. 2 pts have had Gr 3–4 hyperbilirubinemia. 2 patients have been non-compliant. One pt has had Gr 4 sepsis. Other infectious complications are not common. Early evaluation indicates that ABFM therapy is effective in inducing rapid MR in young adults with ALL. The regimen appears tolerable, but morbidity is frequent. Gr 3–4 toxicity occurs more often than recently reported for similar therapy in adults with ALL (Douer D, et al. Blood , 1 Apr 2007, 2744050).

Towards a Pediatric Approach in Adults with Acute Lymphoblastic Leukemia (ALL): The GRAALL-2003 Study.

Introduction: In a recent French FRALLE versus LALA comparison, we have demonstrated a large benefit in outcome when adolescents and young adults were treated in a pediatric rather than an adult ALL protocol (Boissel JCO 2003). Similar provocative results have been observed in three other pediatric versus adult ALL studies (Stock ASH 2000, de Bont Leukemia 2004, Testi ASH 2004). One explanation may be the larger amounts of steroids, vincristine (VCR), and L-asparaginase (L-aspa) administered in pediatric patients. The GRAALL-2003 study was thus designed to offer a pediatric approach in adults with Ph-negative ALL until 60 years of age.Methods: Treatment included a 5-drug induction, high dose-intensity consolidation blocks, delayed intensification, and 2-year maintenance. The comparison with the former LALA-94 protocol showed a 8.6-fold, 3.7-fold, and 16-fold increase in cumulative doses of prednisone, VCR, and L-aspa, respectively. One difference with childhood ALL therapy remained indication of allogeneic SCT in first CR which was offered to all patients with high-risk factor and a donor. In addition, induction was reinforced with a hyper-cyclophosphamide sequence (HyperC) in case of poor early response (cortico- and/or chemoresistant ALL). In the present report, 212 GRAALL-2003 patients with Philadelphia-negative ALL aged 15–55 years with a median follow-up of 18 months were compared to 712 patients previously treated in the LALA-94 trial.Results: Cohorts were comparable in terms of prognostic factors. CR rate was significantly higher in GRAALL patients (93 vs 88%, P=0.02) due to a reduction in resistant disease (0.5 vs 8%, P<0.001) with comparable induction death (6 vs 5%, P=0.37) rate. When compared to the LALA-94 study, 2-year EFS and overall survival were markedly improved (56 vs 41% and 66 vs 54%; P=0.0002 and 0.02, respectively). Similar differences were observed after censoring SCT patients at transplant time, underlining the role played by chemotherapy modification. Because of a worse tolerance to induction and post-remission therapy, the benefit associated with the GRAALL approach decreased with advanced age, becoming not statistically significant over 40 years of age. Finally, outcome improvement was higher in T- than in B-lineage ALL (2-year overall survival, 75 vs 51% and 61 vs 56%; P=0.016 and 0.25, respectively). Among patients with T-ALL, poor early responders (allocated to HyperC induction) tended to have a better EFS than good early responders, suggesting a major role of HyperC in this ALL subset.Conclusion: In conclusion, a pediatric approach benefits to younger adults with ALL.

Outcome for Adolescent and Young Adults 16–21 years of age (AYA) with Acute Lymphoblastic Leukemia (ALL) Treated on the Children' s Cancer Group (CCG) 1961 Study.

AYA Patients 16–21 years of age with ALL are treated on both pediatric and adult ALL protocols. Recent publications have suggested that AYA patients treated on pediatric protocols have a significantly better outcome than those treated on adult protocols. From November 1996 to May 2002, 262 AYA ALL patients were entered on the CCG 1961 protocol. Treatment was based on the following observations from the previous CCG 1882 Protocol (1989–1995). 1) For patients with rapid early response (< = 25% blasts in a day seven bone marrow aspirate-RER), in the context of CCG modified BFM therapy (S-BFM), pre-symptomatic central nervous system therapy with intensive intrathecal (IT) methotrexate (MTX) alone provided equivalent results to standard IT MTX and cranial radiation (CRT). 2) For patients with slow early response (> than 25 blasts on day 7-SER), the augmented BFM (A-BFM) regimen produced a significant improvement in outcome compared to S-BFM. A-BFM featured a significant increase in dose intensity for vincristine (VCR), L-asparaginase (L-ASP), and steroid, the use of intravenous MTX without rescue in conjunction with VCR and L-ASP in interim maintenance (IM), and a second IM and delayed intensification (DI) phase. RER patients on 1961 were randomized to one of four arms; S-BFM, S-BFM with a second standard IM and DI phase, A-BFM with only 1 IM/DI phase, and full A-BFM. SER patients were randomized to A-BFM or A-BFM with Idarubicin/Cytoxan pulses added to the 2 DI phases. One hundred ninety patients had < 50K WBC (73.4%) and 21% had T cell immunophenotype. Seven patients had a t (9/22) and three patients had a t (4/11). Five year EFS for AYA patients treated on CCG 1961 was 68% ± 3.7% and the five-year survival was 77% ± 3.2%. The majority of events were isolated bone marrow relapses. For RER AYA patients, five year EFS for patients treated on the augmented intensity arms (N=87) was 83.2% compared to 60.8% for patients treated on the standard intensity arms (N=76) (P = .10). Within the augmented intensity arms, there was no difference in EFS for patients randomized to one or two DI phases. There was no difference in EFS for the 2 SER treatment arms. 5 year EFS was 78% for the Idarubicin/Cytoxan arm and 74% for the ABFM arm. Five year EFS for AYA patients with < 50K WBC was 73.2% (N=190) versus 54% for AYA patients with > 50K WBC. Unlike younger patients, there was no difference in outcome for males and females. Conclusions: 1) AYA patients with ALL have a 68% 5 year EFS when treated with BFM based chemotherapy. 2) WBC < 50K predicts for a favorable outcome. 3) Early augmented intensity therapy appears to improve outcome for AYA ALL patients showing a rapid response to induction therapy.