ALBERT

Description: Background: In children with ALL, current chemotherapy regimens produce an event-free survival (EFS) of greater than 80%. Adults with ALL have a much poorer prognosis, with EFS rates of 30–40%. Recent retrospective studies suggest that young adult patients may have superior outcomes when treated on more intensive pediatric regimens, but prospective studies are lacking. A phase II trial was performed in an effort to determine if an intensive pediatric regimen can be administered to adults with ALL. Methods: The therapeutic backbone of this protocol is based upon the high-risk arm of the DFCI Childhood ALL Consortium Protocol 00–01. Patients with newly diagnosed ALL were enrolled and received intensive multiagent remission induction chemotherapy, which included doxorubicin, prednisone, vincristine, high-dose methotrexate, high-dose asparaginase, and triple intrathecal therapy. CNS prophylaxis included triple intrathecal therapy and cranial radiation. Intensification therapy consisted of 3 week courses of doxorubicin, vincristine, dexamethasone, 6-mercaptopurine and 30 weeks of high-dose asparaginase that was individually dosed in order to maintain asparagine depletion. Continuation therapy consisted of 3 week courses of vincristine, dexamethasone, methotrexate and 6-mercaptopurine for a total of 2 years from an established complete remission (CR). Results: 71 patients have been enrolled to date. Although there was no initial upper age restriction, the protocol was amended to include only patients between the ages of 18–50 with de novo ALL; this amendment excluded 4 patients from the analysis. Two patients were enrolled but never received therapy. Demographic data are available for 61 evaluable patients. The median age was 28 years, (range, 18–50), 65% were male, 75% had B-lineage phenotype, and 13% were Philadelphia chromosome positive. In the 54 patients for whom response data was available, the 4 week CR rate was 82%. Among the patients who had the opportunity to complete Intensification therapy, asparaginase data was available for 23 patients, 18 (78%) of whom completed all 30 weeks. One death occurred during induction therapy from sepsis. Four patients developed grade 3 pancreatitis and one patient died of grade 5 pancreatitis. The latter case represented the only remission death on study. There were two cases of osteonecrosis, 10 cases of thrombosis/embolism and 12 cases of neutropenic infection that occurred during the post-remission period. At the median follow-up time of 18.4 months, the estimated EFS is 75% (95%CI: 61–89%) and the overall survival is 79% (95%CI: 65–93%). Conclusions: These results suggest that administration of a dose intensified pediatric-like strategy is feasible. Although the high EFS rate requires longer follow up and larger confirmatory studies, such intensive treatment of young adults with ALL could represent a major therapeutic advance.

Description: In a retrospective analysis, we previously reported that children whose leukemia cells harbored the TEL/AML1 gene rearrangement have excellent outcomes. From 1996 to 2000, we conducted a prospective study to determine the incidence and outcomes of children with TEL/AML1-positive acute lymphoblastic leukemia (ALL). Children with newly diagnosed ALL were treated on DFCI ALL Consortium Protocol 95-01. Patients were risk stratified primarily by current National Cancer Institute (NCI)–Rome risk criteria. With a median follow-up of 5.2 years, the 5-year event-free survival for TEL/AML1-positive patients was 89% compared with 80% for TEL/AML1-negative B-precursor patients (P = .05). The 5-year overall survival rate was 97% among TEL/AML-positive patients compared with 89% among TEL/AML1-negative patients (P = .03). However, in a multivariable analysis, risk group (age and leukocyte count at diagnosis) and asparaginase treatment group, but not TEL/AML1 status, were found to be independent predictors of outcome. We conclude that TEL/AML1-positive patients have excellent outcomes, confirming our previous findings. However, factors such as age at diagnosis and presenting leukocyte count should be taken into consideration when treating this group of patients.

Description: BACKGROUND: E.coli L-asparaginase (ASP) is an important component of multiagent chemotherapy for childhood ALL; however, allergic symptoms develop in 25–30% of patients (pts). Erwinia ASP is an alternative preparation which has been used after E.coli ASP allergy; however, it has not been previously shown how well E.coli ASP-allergic pts tolerate Erwinia ASP or whether they achieve therapeutic ASP levels. METHODS: On DFCI ALL Consortium Protocol 00–01 (2000–2005), newly diagnosed children with ALL (aged 1–18 years) received 30 weeks (wks) of IM ASP during consolidation beginning 7 weeks after diagnosis. All pts initially received weekly E.coli ASP. Nadir serum ASP concentrations were measured every 3 wks by a validated biochemical assay and antibodies to E.coli and Erwinia ASP were measured by ELISA every 6 wks. If E.coli ASP allergy developed, children received Erwinia ASP (25000 IU/m2/dose twice weekly) until 2003, when Erwinia ASP became unavailable. RESULTS: We analyzed the data of all 44 patients treated between 2000–2002 who received Erwinia ASP after E.coli ASP-allergy. Median age at diagnosis was 5.5 years. Median duration of E.coli ASP prior to development of allergy was 5 wks (range 1–23). 26 (59%) pts were positive for E.coli ASP antibodies. Erwinia ASP toxicities included: allergy in 15 (34%) pts (which occurred a median 8 wks after starting Erwinia, range 2–15.5), pancreatitis in 1 (2%) and insulin-requiring hyperglycemia in 1 (2%) pt. 18 (41%) pts became positive for Erwinia ASP antibodies, 4 of whom developed Erwinia ASP allergy. Highest nadir ASP concentrations observed after Erwinia ASP in the 44 E.coli-allergic pts are displayed in the Table (below). Prior data has suggested that a nadir serum ASP level of 〉=0.1 IU/mL is associated with asparagine depletion (therapeutic level). Nadir Serum ASP Levels after Erwinia ASP in E.coli ASP-allergic pts N Median (range) ASP Level (IU/mL) % with ASP Level 〉= 0.1 IU/mL All E.coli ASP allergic pts 44 0.231(0.00–3.33) 84% Subsequent allergy to Erwinia Yes 15 0.418 (0.00–3.33) 80% No 29 0.215 (0.00–0.93) 86% E.coli ASP antibody positive 26 0.171 (0.00–3.33) 73% negative 18 0.318 (0.10–0.93) 100% Erwinia ASP antibody Positive 18 0.171 (0.00–3.33) 72% negative 26 0.322 (0.00–0.93) 92% Highest ASP concentration with E.coli ASP prior to allergy Subtherapeutic(=0.1 IU/mL) 24 0.323 (0.00–3.33) 83% Excluding pts who switched to PEG when Erwinia became unavailable in 2003 (N=11), pts remained on Erwinia ASP for a median of 16 wks (range 2–28). 31 pts (70%) ultimately completed all planned 30 wks of ASP consolidation. CONCLUSIONS: We conclude that twice-weekly Erwinia ASP is well-tolerated and achieves detectable and potentially therapeutic serum ASP levels in the majority of E.coli ASP-allergic pts, including those with ASP antibodies (E.coli and/or Erwinia), pts who developed subsequent allergy to Erwinia ASP and pts who never achieved therapeutic nadir levels with prior E.coli ASP. Erwinia ASP should be considered as alternative therapy for pts with ALL who develop E.coli ASP allergy.

Description: Optimal re-expression of genes silenced through promoter methylation requires treatment with a DNA methyltransferase inhibitor (DNMTi) followed by the addition of a histone deacetylase inhibitor (HDACi). MS-275 is an orally bioavailable HDACi with a 50 hour half-life. A phase I study combining 5-azacitidine (5AC; 30, 40, or 50 mg/m2/dose) and MS-275 (2, 4, 6, 8 mg/m2/dose) was conducted in patients with MDS, CMMoL, and AML. Subcutaneous 5AC was self-administered daily for 10 days as per the most successful dose schedule of a prior study with 5AC plus sodium phenylbutyrate. MS-275 was administered on days 3 and 10 of each 28 day treatment cycle, following the in vitro paradigm requiring initial exposure to the DNMTi alone for optimal reversal of epigenetic transcriptional silencing. 31 patients were treated: 13 MDS, 4 CMMoL (8 IPSS Int-1, 7 Int-2, 2 proliferative CMMoL), 14 AML (7 AML with trilineage dysplasia [AML-TLD], 4 relapsed, 3 primary-refractory). Median age was 63 years (35 – 84). 5 patients received 〈 4 cycles and are not considered evaluable for response (declining performance status- 3, sepsis and death - 1, recurrent dose limiting toxicity [DLT]-1). DLT occurred in four patients treated with MS-275 8 mg/m2/dose (5AC 40 and 50 mg/m2/dose): laryngeal edema (2), delayed neutrophil recovery 〉 21 days (1), asthenia (1). No DLT occurred at any combination with lower doses of MS-275; however, grade 2 fatigue was common at MS-275 6 mg/m2/dose and was considered excessive for chronic administration. 12/27 evaluable patients responded, including 2 CR, 4 PR, 6 bilineage hematologic improvement (2000 IWG criteria). Responses occurred at all dose combinations, in patients with MDS (7), CMMoL (1), AML-TLD (3), and relapsed AML (1). Combining MDS and AML-TLD, responses developed in 10/20. The median number of cycles administered to date to responding patients is 11 (6 – 22). Median time to first objective hematologic response was 2 cycles (1 – 5); median time to best hematologic response was 4 cycles (2 – 9). 20 patients had clonal cytogenetic abnormalities including 6 clinical responders: all 6 had a minimum decrease in abnormal metaphases of 50%, with 4 cytogenetic CR. Median time to best cytogenetic response was four cycles (4 – 6). Following 3 days of 5AC alone, H3 or H4 acetylation (PBMC) was increased in 10/30 patients. Overall, H3 acetylation increased in 25/29 patients (median 2.5 fold, range 1.5 - 〉1000-fold); H4 acetylation increased in 28/29 patients (median 4-fold, range 1.5 −154-fold). The DNA damage-associated H2AXγ was induced in 7/29 patients after 3 days of 5AC (PBMC) and 20/29 patients after the administration of MS-275. Median fold-increase in H2AXγ-expression was 5.3 (range 1.5 - 〉1000). The 5AC/MS-275 combination is clinically tolerable and leads to substantive cytogenetic remissions. The relative contribution of the HDACi is under examination in a current Intergroup study randomizing patients to the 5AC/MS-275 combination versus the comparable dose schedule of 5AC alone.

Description: BACKGROUND: E.coli L-asparaginase (E.coli-ASP) is an important component of multiagent chemotherapy for childhood ALL, but is associated with multiple toxicities, including allergy in 25–30% of patients. Pegaspargase (PEG), the polyethylene glycol conjugate of E.coli ASP, has a longer circulating half-life and potentially decreased immunogenicity. All ASP preparations, including PEG, have generally been given intramuscularly (IM) in North America, although limited data suggests that PEG ASP may be safely given intravenously (IV). METHODS: On DFCI ALL Consortium Protocol 05-01 (open since May 2005), all patients (pts) with newly diagnosed ALL (ages 1–18 years) receive a single dose of IV PEG (2500 units/m2) on Day 7 of a 32-day multiagent induction regimen. Serum ASP enzyme levels (measured by validated biochemical assay) are assayed 4, 11, 18 and 25 days after the PEG dose. Lower limit of quantitation of the assay is 0.025 IU/mL. ASP levels 〉=0.1 IU/mL have previously been correlated with asparagine depletion. RESULTS: Between May 2005–April 2006, 66 eligible pts were enrolled and received a single dose of IV PEG during remission induction. Median age was 5 years (range 1–16 years), median WBC was 11.3K/microliter, 60% were male and 16% had T-cell phenotype. 58% were considered standard risk and 42% high risk. ASP-related toxicities occurred in 3 (4.5%) pts. Toxicities included hypersensitivity during PEG infusion (N=1), deep venous thrombosis (N=1, 24 days after PEG), and mild pancreatitis (N=1, 20 days after PEG). 1 patient died of Bacillus sepsis (14 days after PEG). Serum ASP enzyme levels were obtained in 62 patients (Table 1). There was no significant difference in serum ASP levels at any timepoint (using Wilcoxon Rank Sum Test) when comparing pts 〈 10 years old with those 〉=10 years old (Table 2), or when comparing male and female pts. CONCLUSIONS: We conclude that IV administration of PEG is feasible and tolerable in children with ALL. Most pts have potentially therapeutic serum ASP levels (〉=0.10 IU/mL) for up to 18 days after a single dose. Serum ASP levels after IV PEG are similar to those seen after IM administration. In order to determine toxicity, efficacy and pharmacodynamics of repeated doses of IV PEG, we are currently randomizing children with ALL to receive 30 weeks of either IV PEG (given every 2 weeks) or IM E.coli (given weekly) during post-induction consolidation. Table 1: Serum ASP levels after single dose IV PEG Days After IV PEG N Minimum Level Maximum Level Median Level %pts with level ≥ 0.10 Serum ASP levels in IU/mL 4 45

Description: The Dana-Farber Cancer Institute (DFCI) Childhood ALL Consortium Protocol 95-01 was designed to minimize therapy-related morbidity for children with newly diagnosed ALL without compromising efficacy. Patients participated in randomized comparisons of (1) doxorubicin given with or without dexrazoxane, a cardioprotectant (high-risk patients), (2) intensive intrathecal chemotherapy and cranial radiation (standard-risk patients), and (3) Erwinia and Escherichia coli asparaginase (all patients). Between 1996 and 2000, 491 patients (aged 0-18 years) were enrolled (272 standard risk and 219 high risk). With a median of 5.7 years of follow-up, the estimated 5-year event-free survival (EFS) for all patients was 82% ± 2%. Dexrazoxane did not have a significant impact on the 5-year EFS of high-risk patients (P = .99), and there was no significant difference in outcome of standard-risk patients based on type of central nervous system (CNS) treatment (P = .26). Compared with E coli asparaginase, Erwinia asparaginase was associated with a lower incidence of toxicity (10% versus 24%), but also an inferior 5-year EFS (78% ± 4% versus 89% ± 3%, P = .01). We conclude that (1) dexrazoxane does not interfere with the antileukemic effect of doxorubicin, (2) intensive intrathecal chemotherapy is as effective as cranial radiation in preventing CNS relapse in standard-risk patients, and (3) once-weekly Erwinia is less toxic than E coli asparaginase, but also less efficacious.