ALBERT

Description: Acute lymphoblastic leukemia (ALL) diagnosed in the first month of life (congenital ALL) is very rare. Although congenital ALL is often assumed to be fatal, no studies have been published on outcome except for case reports. The present study reports the outcome of 30 patients with congenital ALL treated with the uniform Interfant-99 protocol, a hybrid regimen combining ALL treatment with elements designed for treatment of acute myeloid leukemia. Congenital ALL was characterized by a higher white blood cell count and a strong trend for higher incidence of MLL rearrangements and CD10-negative B-lineage ALL compared with older infants. Induction failure rate was 13% and not significantly different from that in older infants (7%, P = .14), but relapse rate was significantly higher in congenital ALL patients (2-year cumulative incidence [SE] was 60.0 [9.3] vs 34.2 [2.3], P 〈 .001). Two-year event-free survival and survival of congenital ALL patients treated with this protocol was 20% (SE 9.1%). Early death in complete remission and treatment delays resulting from toxicity were not different. The survival of 17% after last follow-up, combined with a toxicity profile comparable with that in older infants, justifies treating congenital ALL with curative intent. This trial was registered at www.clinicaltrials.gov as no. NCT 00015873, and at www.controlled-trials.com as no. ISRCTN24251487.

Description: Abstract 321 BACKGROUND: The DFCI-ALL Consortium Protocol 00-01 aimed to determine the relative efficacy and toxicity of 1) dexamethasone (DEX) vs. prednisone (PRED) and 2) asparaginase (ASP) with individualized dosing (ID) based on pharmacokinetic measurements vs. standard fixed dosing (FD) based on body surface area, in the treatment of children with newly diagnosed acute lymphoblastic leukemia (ALL). PATIENTS and METHODS: Between 2000 and 2004, 492 eligible patients (pts) ages 1-18 years (yrs) with newly diagnosed ALL enrolled on Protocol 00-01 from 10 institutions. 282 pts were standard risk (SR) and 210 high risk (HR). Post-induction treatment for all patients included 30 weeks of intramuscular E. coli ASP (beginning at week 7) and vincristine/corticosteroid pulses every 3 weeks for 24 months. Pts who achieved complete remission (CR) were eligible for two randomized comparisons: 1) Steroids: Pts were randomized to receive either DEX or PRED given as 5-day pulses every 3-weeks, and 2) ASP: Pts were randomized to receive either FD (25,000IU/m2) or ID (starting dose 12,500 IU/m2) for 30 weeks. Nadir serum ASP activity (NSAA) was assessed every 3 weeks, and ASP doses on the ID arm were adjusted to maintain NSAA between 0.10-0.14 IU/mL. NSAA was assayed centrally by a validated biochemical assay. RESULTS: 473 pts (96%) achieved CR. With a median follow-up of 4.9 years, the 5-year event-free survival (EFS) ± standard error for all 492 pts was 80 ± 2% and overall survival (OS) was 91 ± 1%. Steroid randomization: 408/473 pts (86%) participated in the steroid randomization (DEX: 201, PRED: 207). Pts randomized to DEX had 5-yr EFS of 90 ± 2% compared with 81 ± 3% for PRED (p=0.01) [Table I]. For pts 10-18 yrs of age, there was a significant increase in the rate of osteonecrosis (ON) with DEX, with 5-yr cumulative incidence (CI) of 23% compared with 4.7% for PRED (p=0.02). There was no difference in the 5-yr CI of ON based on steroid type in pts 1-10 yrs of age (DEX: 2.6% vs. PRED: 4.3%, p=0.43). Fractures were also more common in pts 10-18 yrs of age randomized to DEX (p=0.06), but not in younger pts (p=0.25). Infection (positive blood culture or radiographic evidence of invasive fungal disease) developed in 38 pts (18.8%) randomized to DEX compared with 22 pts (10.6%) randomized to PRED (p=0.03). There was no difference in remission death rate based on steroid randomization (DEX 0% vs. PRED 2%, p=0.5). ASP randomization: 384/473 pts (81%) participated in the ASP randomization (FD: 195, ID: 189). Pts randomized to ID had superior EFS with 5-yr EFS of 90 ± 2% compared with 82 ± 3% for FD (p=0.04) [Table I]. There was no difference between the two arms in the frequency of ASP-related allergy (p=0.46), pancreatitis (p=0.66) or thrombosis (p=0.77). There was also no difference by treatment arm in the proportion of pts able to complete at least 25 weeks of ASP (FD: 88% vs. ID: 87%, p=0.76). There was no difference between the two arms in the proportion of pts with non-detectable NSAA, although fewer pts on the ID arm had high NSAA (〉0.14 IU/mL). On multivariable analysis, both DEX and ID ASP were independent predictors of favorable outcome (hazard ratio 0.49 for DEX, p=0.02; hazard ratio 0.52 for ID, p=0.04), with no indication of an interaction. Only 5/92 (5%) pts randomized to both DEX and ID ASP experienced an event. CONCLUSIONS: DEX was associated with superior EFS, but also more bone and infectious toxicities, especially in older children/adolescents. Future studies should focus on minimizing DEX toxicity in older pediatric pts without compromising efficacy. ID of ASP was feasible and was associated with superior EFS. The improved EFS with ID was not due to a reduction in ASP-related toxicity or improved tolerability, but was associated with a reduction in the proportion of pts with high NSAA. Disclosures: Supko: Enzon Inc.: Research Funding. Sallan:Enzon Inc.: Research Funding; Enzon Inc.: Contributed to support of an investigator meeting.

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: Despite profound T-cell immunodeficiency, most patients treated with chemotherapy do not succumb to infection. The basis for residual protective immunity in lymphopenic patients is not known. We prospectively measured T-cell numbers, thymopoiesis, and T-cell memory in 73 children undergoing a 2-year chemotherapy regimen for acute lymphoblastic leukemia (ALL) and compared them to an age-matched cohort of 805 healthy children. Most patients had profound defects in CD4 and CD8 T-cell numbers at diagnosis that did not recover during the 2 years of therapy. Thymic output and the fraction of naive T cells were significantly lower than in healthy controls. However, the remaining T-cell compartment was enriched for antigen-experienced, memory T cells defined both by phenotype and by function. This relative sparing of T-cell memory may, in part, account for the maintenance of protective immunity in lymphopenic patients treated for ALL. Moreover, because the memory T-cell compartment is least affected by ALL and its treatment, strategies to induce immunity to pathogens or tumor antigens in cancer patients may be most successful if they seek to expand pre-existing memory T cells. (Blood. 2005; 106:1749-1754)

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: One-hundred thirty-nine patients with acute lymphoblastic leukemia (ALL) and hypodiploidy (fewer than 45 chromosomes) were collected from 10 different national ALL study groups and single institutions. Patients were stratified by modal chromosome number into 4 groups: 24 to 29 (N = 46); 33 to 39 (N = 26); 40 to 43 (N = 13); and 44 (N = 54) chromosomes. Nine patients were Philadelphia chromosome (Ph) positive (4 cases: 44 chromosomes; 5 cases: 40-43 chromosomes) and were not considered further. Event-free survival (EFS) and overall survival (OS) of the remaining 130 patients were 38.5% ± 4.4% and 49.8% ± 4.2% at 8 years, respectively. There were no significant differences in outcome between patients with 24 to 29, 33 to 39, or 40 to 43 chromosomes. Compared with patients with fewer than 44 chromosomes, patients with 44 chromosomes had a significantly better EFS (P = .01; 8-year estimate, 52.2% vs 30.1%) and OS (P = .017; 69% vs 37.5%). For patients with 44 chromosomes, monosomy 7, the presence of a dicentric chromosome, or both predicted a worse EFS but similar OS. Doubling of the hypodiploid clone occurred in 32 patients (24-29 chromosomes [n = 25] and 33-39 chromosomes [n = 7]) and had no prognostic implication. Children and adolescents with ALL and hypodiploidy with fewer than 44 chromosomes have a poor outcome despite contemporary therapy.

Description: Background. A recent phase III trial (AZA-001) showed AZA is the first treatment to significantly extend overall survival (OS) in higher-risk MDS patients (pts) (Blood2007;110:817). MDS incidence increases with age resulting in limited treatment options, particularly for those ≥75 years of age, given the poor tolerability and ineffectiveness of cytotoxic therapies. This subgroup analysis compared the effects of AZA vs CCR on OS, hematologic improvement (HI), transfusion independence (TI), and tolerability in pts ≥75 yrs of age. Methods. Higher-risk MDS (FAB: RAEB, RAEB-T, CMML and IPSS: Int-2 or High) pts were enrolled. All pts were pre-selected by site investigators – based on age, performance status, and comorbidities – to receive 1 of 3 CCR: best supportive care only (BSC); lowdose ara-C (LDAC), or intensive chemotherapy (IC). Pts were then randomized to AZA (75 mg/m2/d SC × 7d q 28d), or to CCR. Those randomized to AZA received AZA; those randomized to CCR received their pre-selected treatment. Randomization was stratified based on FAB subtype (RAEB and RAEB-T) and IPSS (Int-2 or High). Erythropoiesis stimulating agents were disallowed. OS was assessed using Kaplan-Meier (KM) methods and HI and TI were assessed per IWG 2000. To adjust for baseline imbalances, a Cox proportional hazards model was used, with ECOG status, LDH, number of RBC transfusions, Hgb, and presence or absence of -7/del(7q) at baseline as variables in the final model. Adverse events (AEs) were evaluated using NCI-CTC v. 2.0. Results. Of all enrolled pts (N=358, median age 69 yrs), 87 pts (24%) were ≥75 yrs of age (AZA n=38, CCR n=49 [BSC, n=33; LDAC, n=14; IC, n=2]). The majority of pts randomized to CCR received BSC only, suggesting clinicians are generally reticent to use active treatment in this population. Similar to the overall AZA-001 results, treatment with AZA was associated with prolonged survival in pts ≥75 yrs of age, with KM median OS in the AZA group not reached at 17.7 months of follow-up, vs KM median OS for CCR at 10.8 months (HR: 0.48 [95%CI: 0.26, 0.89]; p=0.0193). In these pts, OS rates at 2 years were significantly higher in the AZA group vs CCR: 55% vs 15% (p=0.0003). Two-fold more RBC transfusion-dependent pts at baseline in the AZA group achieved TI vs CCR: 10/23 (44%) vs 7/32 (22%), p=0.1386, respectively. Similarly, more pts in the AZA group achieved HI (major + minor) vs CCR: 58% vs 39%, (p=0.0875), respectively. As previously reported, AZA was generally well tolerated. Anemia, neutropenia, and thrombocytopenia were seen in 42%, 66%, and 71% of pts in the AZA group, respectively, vs 47%, 26%, and 40% in the CCR group, who were predominately receiving BSC only. Infections were reported by 79% and 60% of AZA and CCR pts, respectively. Discontinuations due to an AE occurred in 13% of AZA and 8% of CCR pts ≥75 yrs of age. Conclusion. Data from this subgroup analysis indicate pts ≥75 yrs of age with higher-risk MDS receiving active treatment with AZA experience significantly prolonged 2-year OS and reduced risk of death. AZA is generally well tolerated in this elderly patient population.

Description: Abstract 3073 Poster Board III-10 An increased risk of thrombotic complications during asparaginase (ASP) therapy has been described, but few studies report the management and outcome of these individuals. METHODS We retrospectively reviewed the medical records of patients (pts) ages 0-50 years (y) with ALL who developed venous thromboembolic events (VTE) while receiving ASP. Pediatric (ped) cases (age 0-17 y) were identified from 501 pts treated between 1991-2008; adult cases (age 18-50 y) were identified from 47 pts treated between 2001-2008. All pts were treated on DFCI ALL Consortium trials (including 20-30 consecutive weeks of ASP) at a single academic center (Boston, MA). VTE was diagnosed by symptoms and confirmed by diagnostic imaging in all pts. RESULTS Of 548 pts treated for ALL, 44 (8%) developed VTE, including 27/501 (5.4%) ped pts and 17/47 (36.2%) adults. The sites of VTE included upper extremity (n=18), lower extremity (n=9), and sinus venous thrombosis (n=9). 7 pts experienced a pulmonary embolism. 15 VTE were line-related. 8 VTE occurred during induction and 36 post-induction. Median time to VTE was 3.5 months (mos) (0.5-17.8 mos) with no difference in timing between adult and ped pts. Univariate predictors of VTE are shown in Table 1. There were no differences by sex, race, or ethnic group. In the multivariate model, age was the only significant predictor of VTE with the odds ratio (OR) of VTE increasing with age. Using the 0-5 y age group as a reference (VTE rate 2%), OR were as follows: ages 5-10 y, OR 4.0 (VTE 7%, p=0.02); ages 10-20 y, OR 12.2 (VTE 19%, p

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: We have previously reported encouraging overall complete remission (CR) rates and an acceptable safety profile using the combination of clofarabine, cyclophosphamide and etoposide in relapsed or refractory childhood acute leukemia. Here, we report follow-up results of the phase I portion of the study and provide an update on phase II which is currently enrolling patients. Patients between 1 and 21 years of age with refractory or relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) (Phase I portion only) were enrolled. A standard 3+3 design was followed to determine the maximally tolerated dose combination in phase I. Five dosing cohorts evaluated escalating doses of clofarabine 20–40 mg/m2/day, etoposide 75–100 mg/m2/day and cyclophosphamide 340–440 mg/m2/day. All 3 study drugs were administered via IV infusion daily for 5 consecutive days in induction and 4 consecutive days in consolidation. Patients received up to 2 induction cycles, followed by consolidation (up to a maximum of 8 cycles in total). Dose-limiting toxicities in the phase I portion have been previously reported. The recommended phase II doses were clofarabine 40 mg/m2/day, cyclophosphamide 440 mg/m2/day, and etoposide 100 mg/m2/day. The phase II portion of the study is a single-arm open-label study with a planned total enrollment of 33 patients. Twenty-five patients (ALL: 20 patients; AML: 5 patients) were enrolled in the 5 phase I dose cohorts. The median number of prior induction regimens was 2, 7 patients (5 ALL, 2 AML) were refractory to their immediately preceding regimen, and 4 patients (1 ALL, 3 AML) had a prior hematopoietic stem cell transplant (HSCT). Based on investigator’s assessment, data showed complete remission (CR) in 10 patients (9 ALL, 1 AML) and complete remission without platelet recovery (CRp) in 6 patients (2 ALL, 4 AML) for an overall response rate of 64% (ALL: 55%; AML: 100%). Of the 16 responders (CR + CRp), 9 patients proceeded to HSCT after treatment. The median duration of remission (censored at the last known date of follow-up regardless of alternative therapy) for the 16 responders was 18.2 weeks (range 6.6 to 61.4 weeks) (ALL: median 31.4 weeks, range 6.6 to 61.4 weeks; AML: median 15.6 weeks, range 7.3 to 48.9+ weeks), including 31.4 weeks for the 10 patients with CR and 15.3 weeks for the 6 patients with CRp. At the last known date of follow-up, 7 of the 16 responders were alive and 4 of these remained in CR (three of these had undergone post-therapy HSCT). One patient with ALL completed 8 cycles of therapy, with a duration of remission of 61.4 weeks. In phase II, 3 of the first 8 ALL patients enrolled achieved a response (1 CR, 2 CRp). However, 4 patients developed severe hepatotoxicity (3 veno-occlusive disease, 1 hyperbilirubinemia). The study was amended to exclude patients with prior HSCT, viral hepatitis and/or cirrhosis, or elevated conjugated bilirubin levels. Four additional patients have since been enrolled in the amended phase II portion of the study and no cases of severe hepatotoxicity have been observed to date. In summary, the combination of clofarabine, cyclophosphamide and etoposide induced durable remission in children with relapsed or refractory acute leukemia. The recommended phase II doses of clofarabine, cyclophosphamide, and etoposide were 40 mg/m2/day, 440 mg/m2/day, and 100 mg/m2/day, respectively, each given for 5 days in induction. The phase II portion of the study is now actively enrolling patients with ALL without a history of prior HSCT following development of hepatoxicity in 4 patients. An update of all patients enrolled in phase II will be presented at the meeting.