Acute Lymphoblastic Leukemia In First Relapse Research Articles

P360: EFFICACY AND SAFETY OF DARATUMUMAB IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH RELAPSED/REFRACTORY T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA OR LYMPHOBLASTIC LYMPHOMA: RESULTS FROM PHASE 2 DELPHINUS STUDY

Background: Approximately 15-20% of pediatric patients with T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) will be refractory to/relapse after frontline treatment; relapsed disease is associated with poor outcomes. In a phase 2 study, 2 of 7 (28.6%) patients with T-cell ALL in first relapse achieved a complete response (CR) using the vincristine, prednisone, PEG-asparaginase, and doxorubicin (VPLD) reinduction backbone. Daratumumab (DARA), a human IgGκ monoclonal antibody targeting CD38 approved for treating multiple myeloma, has shown preclinical efficacy in ALL models. Aims: Here we report the initial results of DARA plus VPLD in pediatric and young adult patients with relapsed/refractory T-cell ALL or LL enrolled in the phase 2, open-label DELPHINUS study. Methods: Eligible patients were aged 1-30 y, had T-cell ALL or LL in first relapse or refractory to 1 prior induction/consolidation regimen, and had a performance status ≥70. DARA (16 mg/kg IV QW) was given with VPLD in Cycle 1 and with methotrexate, cyclophosphamide, cytarabine, and 6-mercaptopurine in Cycle 2. Patients received age/risk-adjusted intrathecal therapy. Response was measured at the end of each cycle by local bone marrow morphology. The primary endpoint for ALL patients was CR rate in pediatric patients at the end of Cycle 1. Patients achieving CR after Cycles 1 or 2 could proceed to allogeneic HSCT off study. Overall response rate (ORR) was defined as CR or CR with incomplete hematological recovery (CRi) at any time before start of subsequent therapy or HSCT. Minimal residual disease (MRD) negativity (<0.01%) at any time before disease progression, start of subsequent therapy, or HSCT was centrally reviewed by flow cytometry. Results: Twenty-four pediatric (age 1-17 y) and 5 young adult (age 18-30 y) ALL patients and 10 LL patients (age 1-30 y) received ≥1 DARA dose. Median (range) age was 10.0 (2-25) y (ALL) and 14.5 (5-22) y (LL); median (range) time from initial diagnosis to first study treatment was 2.0 (0.1-6.1) y (ALL) and 0.8 (0.5-6.0) y (LL). Pediatric ALL patients received a median (range) of 2 (1-3) treatment cycles; young adult ALL patients and LL patients each received 2 (1-2). Among pediatric ALL patients, 10 (41.7%) patients (90% CI, 24.6-60.3) achieved CR at the end of Cycle 1. ORR was 83.3% (CR, 13 [54.2%] patients; CRi, 7 [29.2%] patients) in pediatric and 60.0% (all CR) in young adult ALL patients and 40.0% (all CR) in LL patients. Ten (41.7%) pediatric ALL patients achieved MRD negativity. All pediatric ALL patients had a grade 3/4 TEAE. No pediatric ALL pt discontinued DARA primarily due to AEs and 1 (4.2%) died due to TEAEs (brain edema and hepatic failure) attributed to study treatment but unrelated to DARA. Summary/Conclusion: The addition of DARA to VPLD in pediatric and young adult patients with relapsed/refractory T-cell ALL or LL showed initial activity, generating improved response rates compared to those achieved with backbone therapy alone, with a manageable safety profile.

Efficacy and safety of daratumumab (DARA) in pediatric and young adult patients (pts) with relapsed/refractory T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL): Results from the phase 2 DELPHINUS study.

10001 Background: Approximately 15-20% of pediatric pts with ALL or LL will be refractory to/relapse after frontline treatment; relapsed disease is associated with poor outcomes. In a phase 2 study, 2 of 7 (28.6%) pts with T-cell ALL in first relapse achieved a complete response (CR) using the vincristine, prednisone, PEG-asparaginase, and doxorubicin (VPLD) reinduction backbone. DARA, a human IgGκ monoclonal antibody targeting CD38 approved for treating multiple myeloma, has shown preclinical efficacy in ALL models. We report the initial results of DARA plus VPLD in pediatric and young adult pts with relapsed/refractory T-cell ALL or LL enrolled in the phase 2, open-label DELPHINUS study. Methods: Eligible pts were aged 1-30 y, had T-cell ALL or LL in first relapse or refractory to 1 prior induction/consolidation regimen, and had a performance status ≥70. DARA (16 mg/kg IV QW) was given with VPLD in Cycle 1 and with methotrexate, cyclophosphamide, cytarabine, and 6-mercaptopurine in Cycle 2. Pts received age/risk-adjusted intrathecal therapy. Response was measured at the end of each cycle by local bone marrow morphology. The primary endpoint for ALL pts was CR rate in pediatric pts at the end of Cycle 1. Pts achieving CR after Cycles 1 or 2 could proceed to allogeneic HSCT off study. Overall response rate (ORR) was defined as CR or CR with incomplete hematological recovery (CRi) at any time before start of subsequent therapy or HSCT. Minimal residual disease (MRD) negativity (&lt; 0.01%) at any time before disease progression, start of subsequent therapy, or HSCT was centrally reviewed by flow cytometry. Results: Twenty-four pediatric (age 1-17 y) and 5 young adult (age 18-30 y) ALL pts and 10 LL pts (age 1-30 y) received ≥1 DARA dose. Median (range) age was 10.0 (2-25) y (ALL) and 14.5 (5-22) y (LL); median (range) time from initial diagnosis to first study treatment was 2.0 (0.1-6.1) y (ALL) and 0.8 (0.5-6.0) y (LL). Pediatric ALL pts received a median (range) of 2 (1-3) treatment cycles; young adult ALL pts and LL pts each received 2 (1-2). Among pediatric ALL pts, 10 (41.7%) pts (90% CI, 24.6-60.3) achieved CR at the end of Cycle 1. ORR was 83.3% (CR, 13 [54.2%] pts; CRi, 7 [29.2%] pts) in pediatric and 60.0% (all CR) in young adult ALL pts and 40.0% (all CR) in LL pts. Ten (41.7%) pediatric ALL pts achieved MRD negativity. All pediatric ALL pts had a grade 3/4 TEAE. No pediatric ALL pt discontinued DARA primarily due to AEs and 1 (4.2%) died due to TEAEs (brain edema and hepatic failure) attributed to study treatment but unrelated to DARA. Conclusions: The addition of DARA to VPLD in pediatric and young adult pts with relapsed/refractory T-cell ALL or LL showed initial activity, generating improved response rates compared to those achieved with backbone therapy alone, with a manageable safety profile. Clinical trial information: NCT03384654.

Tisagenlecleucel Therapy Is Safe and Effective for Children with Down Syndrome with ALL in First Relapse

Introduction: Children with Down Syndrome (DS) have a 20-fold increased incidence of acute lymphoblastic leukemia (ALL) and a 70% higher risk of relapse than children with ALL and no DS. Treatment for DS children with relapsed ALL is challenging due to the high treatment-related mortality associated with both intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) as well as high rates of second relapse. Outcomes for relapsed ALL in DS are dismal, with recent studies citing an event-free survival (EFS) as low as 17%. Alternative treatment approaches are needed for this patient population. Treatment with anti-CD19 chimeric antigen receptor T-cells (CARTs) have shown high remission rates in patients with multiple relapsed/refractory ALL with an acceptable safety profile. CARTs are generally not indicated for first relapse of ALL; DS-specific indications for CARTs do not exist. In Ontario, due to the specific susceptibility of children with DS-ALL, CARTs were made available to this population upon first relapse. We describe the population-based Canadian experience using CARTs for first relapse of DS-ALL.Methods: Efficacy and safety data on all children referred for CARTs at the Hospital for Sick Children, in Toronto, Canada were retrospectively collected in a central database and validated by treating clinicians. Here we report all patients with DS suffering a first relapse of ALL at age <18 years referred for commercially available CARTs (tisagenlecleucel) between 2019 and 2021.Results: Five patients with DS received tisagenlecleucel for first relapse of ALL during the study period. Median age at original diagnosis was 6.3 years (range 3.4-11.5). Four patients presenting with National Cancer Institute (NCI) standard risk and one with NCI high-risk disease were initially treated on Children's Oncology Group based protocols. Four patients presented with relapse >36 months from diagnosis and one patient with early relapse. Mononuclear cells were successfully collected for all patients on the first attempt. Patients were bridged from collection to infusion with low intensity chemotherapy regimens. Tisagenlecleucel was successfully manufactured for all patients and infused at a median of 69 days (range 56-101) from collection of T cells. Four patients developed CRS: two patients grade 1, one patient grade 2, and one patient grade 4 requiring ICU care and treatment with tocilizumab and steroid. All patients achieved minimal residual disease (MRD) negative remission one month after infusion, with B-cell aplasia. Two patients showed early (< 6months post infusion) B-cell recovery consistent with CAR T-cell loss; both received off-label reinfusions of tisagenlecleucel and again achieved B-cell aplasia. One patient had a seizure with the first Fludarabine dose of lymphodepleting (LD) chemotherapy for re-infusion and was found to have elevated intracranial pressure. After treatment with Topiramate and anti-seizure prophylaxis the patient tolerated LD chemotherapy without further neurological events. No patient received further ALL therapy; none went on to HSCT. One patient suffered a CD19-negative relapse 7 months post infusion and was transitioned to palliative-intent treatment. Two patients developed prolonged neutropenia with one patient showing recovery (ANC>1x10E9/l) at 5 months post infusion and the patient who had relapsed disease remained neutropenic until relapse. Infectious complications in the first 6 months post infusion were rare. One patient, who was not neutropenic, required two hospital admissions for line related sepsis. With a median follow-up time of 519 days (range 197-785), the 1-year estimated EFS and overall survival were both 80% (95 th confidence interval 52-100%; Figure 1).Conclusions: Tisagenlecleucel was safe and effective in a small cohort of children with DS and first relapse of CD19+ ALL, with achievement of long-term remissions without further therapy, and an EFS superior to that seen in historical cohorts. Rate of acute complications were not increased compared with reported outcomes in patients without DS. Further evaluation of tisagenlecleucel in this setting is warranted. [Display omitted] DisclosuresKrueger: KITE/Gilead: Consultancy; Novartis: Consultancy; SOBI: Consultancy. Whitlock: Sobi Pharmaceuticals: Consultancy; Novartis: Research Funding; Amgen; Jazz Pharmaceuticals: Honoraria. Gupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure:tisagenlecleucel for early B-cell recovery

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab (Blina) As Salvage Therapy for Patients (Pts) with Acute Lymphoblastic Leukemia (ALL) in First Relapse

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab (Blina) As Salvage Therapy for Patients (Pts) with Acute Lymphoblastic Leukemia (ALL) in First Relapse

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (Mini-hyper-CVD) with or without Blinatumomab Is Highly Effective in Patients (pts) with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in First Relapse

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (Mini-hyper-CVD) with or without Blinatumomab Is Highly Effective in Patients (pts) with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in First Relapse

Outcome of Patients with Philadelphia Negative B-Cell Acute Lymphoblastic Leukemia (ALL) and Isolated Central Nervous System (CNS) Relapse

Introduction: Since the increase in survival in patients with ALL with new induction regimens, extramedullary relapses in sanctuary sites such as central nervous system (CNS) became a common event. CNS prophylaxis has greatly reduced incidence of this. However, early or late relapses at extramedullary sites are still a clinical problem in these patients.Method: Patients with Philadelphia negative B-Cell ALL in first relapse treated at our institution between 2000 and 2014 were analyzed. Information regarding initial treatments, characteristics at the time of relapse, response to therapy and duration of remission was evaluated. Survival outcomes were analyzed in terms of presence of a CNS isolated relapse. Statistical analysis included Chi-squared for categorical variables, T-student for continuous variables and Kaplan-Meier for OS.Results: A total of 166 patients were evaluated. A total of 20 (12%) patients had isolated CNS relapse and 140 (88%) had systemic relapse. Patient characteristics are summarized in Table 1. Median time to relapse was 23 compared to 26 months (p=0.71) for patients with or without isolated CNS relapse, respectively. Patients with isolated CNS relapse tended to be younger (29 vs 41 years, p=0.08); No differences in baseline characteristics were observed between both groups. After relapse, data on therapy and response to therapy was available in 8 patients with isolated CNS disease and 71 patients with systemic relapse (Table 1). The 8 patients with isolated CNS relapse were treated with augmented HCVAD (3/8), HCVAD-R (2/8), and FLAG-Ida (2/8). All patients received intrathecal chemotherapy and 5 received radiation therapy. Response to therapy monitored as CSF clearance was observed in 6 patients with 2 patients not responding and progressing to systemic disease. 3 (38 %) received subsequent allogeneic stem cell transplantation (allo-SCT), with only one of them remaining alive in CR at the last follow-up. Median follow-up was 49 months (15-151). Median survival after relapse was significantly longer in patients with isolated CNS relapse compared to those with systemic relapse (39 vs 7 months, p=0.03) (Figure 1).Conclusions: Isolated CNS relapse occurs at a rate of 12% and is associated with significantly better outcome than systemic relapses in patients with B-cell ALL.Table 1Studied factorIsolated CNS RelapseN (%) [range]Systemic RelapseN (%) [range]p valueAge29 [16-62]41 [18-84]p=0.08SexMale14 [70%]82 [56%]Female6 [30%]64 [44%]TreatmentHCVAD-R12 (60)52 (37)HCVAD1 (5)54 (38)Augmented BFM7 (35)33 (24)Baseline CharacteristicsHemoblogin93. [7-13.4]8.9 [3.6-15.1]p=0.47White blood cell count17 [1.5-112]36 [0.6-602]p=0.39Platelet count66 [15-386]60 [0-393]p=0.16Bone marrow blasts80 [17-97]81 [0-100]p=0.86LDH2124 [649-7882]2277 [172-28261]p=0.87Cytogenetics at BaselineDiploid8 (40)53 (36)Hyperdiploid1 (5)17 (12)Hypodiploid06 (4)Complex2 (10)26 (18)Other9 (45)29 (20)Not available015 (10)Median overall survival (months)39 [range]8 [range]p=0.03 [Display omitted] DisclosuresCortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Daver:ImmunoGen: Other: clinical trial, Research Funding.

Outcome After First Relapse Or Refractory Acute Lymphoblastic Leukemia In Children From 1996 To 2011 – Comparison Of Two Different Treatment Strategies

IntroductionNewly diagnosed acute lymphoblastic leukemia (ALL) has achieved a cure rate of 80-85% in developed countries. Nevertheless, up to 20% of patients still relapse or have a refractory disease. Approximately 50% of these patients are long term survivors. In our institution, the strategy for relapsed patients had changed from hematopoietic stem cell transplantation (HSCT) after reinduction to all patients to a more tailored approach, offering HSCT to patients at high risk of relapse (e.g. those relapsing early after or during treatment) or for those with late marrow relapse with a related donor after a re-induction treatment. The aims of this study was to analyse the results of treatment for children with ALL in first relapse or refractory disease and to compare the outcome based on the strategy of treatment: re-induction followed by HSCT for all patients versus re-induction followed by HSCT or chemotherapy according the risk of relapse. Patients and MethodsThis retrospective study analysed treatment and outcome of children (up to 18 years-old) with a first relapse or refractory ALL treated in a single institution from 1996 until 2011. All patients were previously treated according to DFCI protocol 95, 00 or 05. Two treatment strategies have been used for patients refractory or with marrow relapse. Until 2007, they were all treated with a re-induction treatment (usually the same protocol used as first-line induction) followed by an allogeneic HSCT with a related or unrelated donor once complete remission was attained. Starting from 2007, patients with a late marrow relapse were treated with chemotherapy alone (or with HSCT if an HLA sibling donor was available), and patients refractory or with an early relapse received at least 3 cycles of chemotherapy before HSCT (with a related or unrelated donor), to reduce pre-transplant residual disease. Results64 patients had been diagnosed with a first relapse (n=55) or refractory (n=11) ALL whereas 453 patients were diagnosed with ALL during this fifteen years period. At first diagnosis, median WBC was 20 x109/L, 54 (84.5%) patients were B-ALL, 21 (33%) had a positive CNS and 26 (40.5%) had a favourable or a normal karyotype. According to risk stratification at first diagnosis, 26 (40.5%), 30 (47%) and 8 (12.5%) patients were classified as standard, high- and very high risk, respectively. Median ages at relapse diagnosis were 5.9 (range 1.3-17.1) for relapsed and 8.4 (range 1.4-18.4) years for refractory patients. At relapse, median WBC was 6 x109/L and 39 (61%), 14 (22%) and 11 (17%) presented with an isolated marrow, combined and extramedullary (EM) relapse, respectively. Median interval between diagnosis and relapse was 32.5 (range 0.6-135.1) months and 11 (17 %) were classified as refractory, 25 (39%) were classified as early relapse (<36 months from diagnosis to relapse) and 28 (44%) as late relapse (≥ 36 months from diagnosis to relapse). Until 2007, 29 (85 %) patients with marrow relapse received an allogeneic HSCT. After 2007, 14 (70%) received an allo-HSCT and 6 (30%) were treated with chemotherapy after induction. Estimated 3-year event-free survival (EFS) for the whole population was 53% (28% for early and 84% for late relapse [p>0.001]). Before and after 2007, estimated 3-year EFS was respectively 46% and 65% (p=0.3). ConclusionIntroduction of a more intensive re-induction therapy and the treatment of the late relapse with chemotherapy alone had permitted to improve the survival of children with relapse/refractory leukemia, probably due to a better control of minimal residual disease (MRD). MRD-guided reinduction therapy is currently the standard of care for these patients and new therapeutics approaches are still needed for patients with early relapse. Disclosures:No relevant conflicts of interest to declare.

Outcome after first relapse in children with acute lymphoblastic leukemia: A report based on the Dutch Childhood Oncology Group (DCOG) relapse all 98 protocol

We report on the treatment of children and adolescents with acute lymphoblastic leukemia (ALL) in first relapse. The protocol focused on: (1) Intensive chemotherapy preceding allogeneic stem cell transplantation (SCT) in early bone marrow relapse; (2) Rotational chemotherapy in late relapse, without donor; (3) Postponement of cerebro-spinal irradiation in late isolated CNS relapse; and (4) Treatment in very late bone marrow relapse with chemotherapy only. From January 1999 until July 2006 all 158 Dutch pediatric patients with ALL in first relapse were recorded. Ninety-nine patients were eligible; 54 patients with early and 45 with late relapse. Eighteen patients had an isolated extra-medullary relapse; 69 patients had bone marrow involvement only. Five-years EFS rates for early and late relapses were 12% and 35%, respectively. For early relapses 5 years EFSs were 25% for patients transplanted; 0% for non-transplanted patients. For late relapses 5 years EFS was 64% for patients treated with chemotherapy only, and 16% for transplanted patients. For very late relapses EFS was 58%. Our data suggest the superiority of SCT for early relapse patients. For late relapses a better outcome is achieved with chemotherapy only using the rotational chemotherapy scheme. The most important factor for survival was interval between first CR and occurrence of the first relapse.

A prognostic scoring system for adult patients less than 60 years of age with acute lymphoblastic leukemia in first relapse

The outcome of patients with acute lymphoblastic leukemia (ALL) in first relapse is poor. We retrospectively evaluated patients with ALL in first relapse, 18–60 years of age, to define a prognostic score. For all patients, a scoring system of 0–3 was developed with 1 point for each of the following: age at diagnosis ≥45 years, lactate dehydrogenase (LDH) at the time of relapse ≥1.5 times upper limits of normal (ULN), not proceeding to allogeneic bone marrow transplant (BMT). A similar scoring system was developed for patients proceeding to BMT. LDH ≥1.5 times ULN at the time of relapse predicted poor overall survival. Patients with a prognostic score of greater than 1 have a poor prognosis, even with BMT, and should be considered for treatment with innovative approaches such as Phase 1 clinical trials.

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse

Using flow cytometric techniques capable of detecting 0.01% leukemic cells, we prospectively studied minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) after first relapse. At the end of remission reinduction, 41 patients had a bone marrow sample adequate for MRD studies; 35 of these were in morphologic remission. Of the 35 patients, 19 (54%) had MRD >/=0.01%, a finding that was associated with subsequent leukemia relapse. The 2-year cumulative incidence of second leukemia relapse was 70.2+/-12.3% for the 19 MRD-positive patients and 27.9+/-12.4% for the 16 MRD-negative patients (P=0.008). Among patients with a first relapse off therapy, 2-year second relapse rates were 49.1+/-17.8% in the 12 MRD-positive and 0% in the 11 MRD-negative patients (P=0.014); among those who received only chemotherapy after first relapse, the 2-year second relapse rates were 81.5+/-14.4% (n=12) and 25.0+/-13.1% (n=13), respectively (P=0.004). Time of first relapse and MRD were the only two significant predictors of outcome in a multivariate analysis. We conclude that MRD assays should be used to guide the selection of postremission therapy in patients with ALL in first relapse.

Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: a pediatric oncology group study

AbstractThe relapse rate in childhood acute lymphoblastic leukemia (ALL) is approximately 30% but few reinduction regimens have investigated the intensive use of polyethylene glycol Escherichia coliasparaginase (PEG-Asp). Therefore, we assessed the pharmocokinetics and efficacy of PEG-Asp in this setting. Children with B-precursor ALL, in first marrow and/or extramedullary relapse were eligible. Reinduction included doxorubicin on day 1, prednisone for 28 days, vincristine weekly for 4 weeks, and PEG-Asp either weekly or biweekly by randomization. Asparaginase levels and antibody to both E coli asparaginase and PEG-asp were measured weekly just before each PEG-asp dose. Overall, 129 of 144 patients (pts) (90%) achieved a complete remission (CR). There was a highly significant difference in CR rates between weekly (69 of 71; 97%) and biweekly (60 of 73; 82%) PEG-Asp dosing (P = .003). Grade 3 or 4 infectious toxicity was common (50%), but only 4 pts died of sepsis during induction. Other toxicities were infrequent and hypersensitivity was rare (6 of 144; 4%). Low asparaginase levels were associated with high antibody titers to either native (P = .024) or PEG asp (P = .0013). The CR rate was significantly associated with higher levels of asparaginase (P = .012). Patients with ALL in first relapse receiving weekly PEG-Asp had a higher rate of second remission compared with biweekly dosing. Low levels of asparaginase were associated with high antibody titers. Increased asparaginase levels may correlate with an improved CR rate. The use of intensive PEG-Asp should be explored further in the treatment of ALL.

Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: a pediatric oncology group study

The relapse rate in childhood acute lymphoblastic leukemia (ALL) is approximately 30% but few reinduction regimens have investigated the intensive use of polyethylene glycol Escherichia coliasparaginase (PEG-Asp). Therefore, we assessed the pharmocokinetics and efficacy of PEG-Asp in this setting. Children with B-precursor ALL, in first marrow and/or extramedullary relapse were eligible. Reinduction included doxorubicin on day 1, prednisone for 28 days, vincristine weekly for 4 weeks, and PEG-Asp either weekly or biweekly by randomization. Asparaginase levels and antibody to both E coli asparaginase and PEG-asp were measured weekly just before each PEG-asp dose. Overall, 129 of 144 patients (pts) (90%) achieved a complete remission (CR). There was a highly significant difference in CR rates between weekly (69 of 71; 97%) and biweekly (60 of 73; 82%) PEG-Asp dosing (P = .003). Grade 3 or 4 infectious toxicity was common (50%), but only 4 pts died of sepsis during induction. Other toxicities were infrequent and hypersensitivity was rare (6 of 144; 4%). Low asparaginase levels were associated with high antibody titers to either native (P = .024) or PEG asp (P = .0013). The CR rate was significantly associated with higher levels of asparaginase (P = .012). Patients with ALL in first relapse receiving weekly PEG-Asp had a higher rate of second remission compared with biweekly dosing. Low levels of asparaginase were associated with high antibody titers. Increased asparaginase levels may correlate with an improved CR rate. The use of intensive PEG-Asp should be explored further in the treatment of ALL.