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Long-term outcome of a pediatric-inspired regimen used for adults aged 18–50 years with newly diagnosed acute lymphoblastic leukemia

Long-term outcome of a pediatric-inspired regimen used for adults aged 18–50 years with newly... Leukemia (2015) 29, 526 –534 OPEN © 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15 www.nature.com/leu ORIGINAL ARTICLE Long-term outcome of a pediatric-inspired regimen used for adults aged 18–50 years with newly diagnosed acute lymphoblastic leukemia 1 2 2 3 4,5 6 6 6 7 8 DJ DeAngelo , KE Stevenson , SE Dahlberg , LB Silverman , S Couban , JG Supko , PC Amrein , KK Ballen , MD Seftel , AR Turner , 9 10 11 12 13 14 1 1 1 2 B Leber , K Howson-Jan , K Kelly , S Cohen , JH Matthews , L Savoie , M Wadleigh , LA Sirulnik , I Galinsky , DS Neuberg , 3 1 SE Sallan and RM Stone On the basis of the data suggesting that adolescents and young adult patients with acute lymphoblastic leukemia (ALL) have improved outcomes when treated on pediatric protocols, we assessed the feasibility of treating adult patients aged 18–50 years with ALL with the DFCI Pediatric ALL Consortium regimen utilizing a 30-week course of pharmacokinetically dose-adjusted E. coli L-asparaginase during consolidation. Between 2002 and 2008, 92 eligible patients aged 18–50 years were enrolled at 13 participating centers. Seventy-eight patients (85%) achieved a complete remission (CR) after 1 month of intensive induction therapy. With a median follow-up of 4.5 years, the 4-year disease-free survival (DFS) for the patients achieving a CR was 69% (95% confidence interval (CI) 56–78%) and the 4-year overall survival (OS) for all eligible patients was 67% (95% CI 56–76%). The 4-year DFS for the 64 patients who achieved a CR and were Philadelphia chromosome negative (Ph − ) was 71% (95% CI 58–81%), and for all 74 Ph − patients the 4-year OS was 70% (95% CI 58–79%). We conclude that a pediatric-like treatment strategy for young adults with de novo ALL is feasible, associated with tolerable toxicity, and results in improved outcomes compared with historical regimens in young adult patients with ALL. Leukemia (2015) 29, 526–534; doi:10.1038/leu.2014.229 INTRODUCTION year-old adults and would result in improved outcomes. Therefore, we initiated a multi-center clinical trial for young adults with ALL Over the past two decades, the outcomes for children with acute and found that the pediatric-inspired regimen was well tolerated lymphoblastic leukemia (ALL) have significantly improved with and produced encouraging results compared with historical adult modifications of risk-stratified multi-agent, multi-phase chemo- ALL regimens. therapy and central nervous system (CNS) prophylaxis. Today, patients 1–18 years old who are diagnosed with ALL can expect complete remission (CR) rates that exceed 95% and long-term 1–5 event-free survival (EFS) that exceeds 80%. In contrast, outcomes MATERIALS AND METHODS for adults diagnosed with ALL remain poor. Contemporaneous trials Study design and patient population using adult ALL regimens result in long-term survival rates of Patients were eligible for protocol entry if they had newly diagnosed ALL 6–8 o50%, but these differences in response rates and outcome (excluding mature B-cell ALL) and were at least 18 years old. Initially, there cannot be explained by differences in leukemia biology alone. was no upper age limit for eligibility; the protocol was amended after the Stock et al. reported that adolescents and young adults 16–21 first eight patients were enrolled to limit the age range from 418 to 50 years old, who were eligible for either a pediatric or an adult ALL years and to exclude patients with presumed secondary ALL. Eligible patients had a Zubrod performance status of 2 or less, and exclusion regimen, had markedly improved outcomes if they received the criteria included pregnancy, active psychiatric illness, uncontrolled active pediatric regimen. Similar findings were apparent when comparing infection, prior history of pancreatitis, cerebrovascular accident or outcomes from young populations in France, the Netherlands and the 10–13 hemorrhage or evidence of infection with HIV. There were no specific United Kingdom treated with childhood versus adult regimens. exclusions based on hepatic or renal function. Recognition of the likely role of the treatment regimen in A total of 100 patients were enrolled between June 2002 and February improved outcomes in adolescents and young adult patients 2008 from 13 institutions. The study was conducted according to the treated with pediatric regimens led us to initiate a clinical trial to Declaration of Helsinki and its amendments. Before study entry, all patients determine whether an intensive pediatric ALL chemotherapy signed an informed consent document approved by the Institutional protocol for children o18 years old would be tolerable for 18–50- Review Board at each institution. 1 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, 3 4 MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute/Division of Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA, USA; National 5 6 Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada; Dalhousie University, Halifax, Nova Scotia, Canada; Massachusetts General Hospital, Boston, MA, USA; 7 8 9 Cancer Care Manitoba, Winnipeg, Manitoba, Canada; Cross Cancer Institute, Edmonton, Alberta, Canada; Hamilton Health Sciences Center, Hamilton, Ontario, Canada; 10 11 12 London Health Services, London, Ontario, Canada; Columbia University Medical Center, New York, NY, USA; Hospital Maisonneuve-Rosemont, Montreal, Quebec, Canada; 13 14 Queen’s University, Kingston, Ontario, Canada and Tom Baker Cancer Center, Calgary, Alberta, Canada. Correspondence: Dr DJ DeAngelo, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, D1B30, Boston, MA 02215, USA. E-mail: daniel_deangelo@dfci.harvard.edu Received 3 March 2014; revised 24 June 2014; accepted 17 July 2014; accepted article preview online 31 July 2014; advance online publication, 28 October 2014 Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al Therapy Table 1. Therapy on DFCI Adult ALL Consortium Protocol 01–175 Details of the treatment regimen are summarized in Table 1. Steroid therapy consisted of prednisone during the induction phase and Time Frame Treatment dexamethasone thereafter (that is, during intensification and continuation phases). Patients with persistent leukemia at the end of the first month of Induction 4 Vincristine 2 mg weekly, days 1, 8, 15 and 22 treatment were removed from the protocol and given alternative therapy Weeks Prednisone 40 mg/m /day, days 1–28 at the discretion of the treating physician. During induction, high-dose Doxorubicin 30 mg/m /dose, days 1and 2 methotrexate was administered as a 1-h infusion, whereas leucovorin Methotrexate 4 g/m (8–24 h after doxorubicin) (200 mg/m intravenously) was given 36 h later and was continued at a with leucovorin rescue on day 3 dose of 24 mg/m intravenously or orally every 6 h until the serum E coli L-asparaginase 25 000 IU/m IM × 1 dose, methotrexate level was o1 μM. The cumulative doxorubicin dose was day 5 capped at 300 mg/m . IT cytarabine 50 mg, day 0 (prior to initiation of E. coli asparaginase was given intramuscular (IM) once a week for systemic therapy) 30 weeks at a starting dose of 12 500 IU/m . Subsequent doses were IT methotrexate/cytarabine/hydrocortisone, days adjusted as indicated in Table 2 to maintain the nadir serum asparaginase 15 and 29 activity (NSAA) between 0.100 and 0.140 IU/ml. This range was considered CNS therapy Vincristine 2 mg × 1 dose to be therapeutic based upon previously reported pharmacokinetic and 3 Weeks 6-mercaptopurine (6-MP) 50 mg/m /day orally, pharmacodynamic studies, and was selected with the aim of avoiding × 14 consecutive days 14–19 excessively high or low NSAA. Serum samples were obtained just Doxorubicin 30 mg/m × 1 dose before administering the second and fourth doses of asparaginase and IT methotrexate/cytarabine twice weekly × 4 doses then every 3 weeks thereafter. Asparaginase activity was determined in Cranial radiation real-time using a validated biochemical assay with a 0.025-IU/ml lower Intensification Every 3-week cycles: limit of quantitation by a central laboratory, as previously described. 30 Weeks Vincristine 2 mg, day 1 These results were then used to adjust the dose given 2 weeks after Dexamethasone 18 mg/m /day b.i.d., orally, days obtaining the sample. Samples had to be obtained 7 days after the prior 1–5 dose to be considered evaluable. The minimum and maximum aspar- Doxorubicin 30 mg/m , day 1 of each cycle to a 2 2 (cumulative dose 300 mg/m ) aginase dose that could be given was 6000 and 25 000 IU/m , respectively. 6-MP 50 mg/m /day orally × 14 consecutive days Patients with extremely low NSAA in serial samples despite dose E. coli asparaginase adjustments were switched to an alternative asparaginase preparation Individualized dosing: 12 500 IU/m /dose (starting (either polyethylene glycol (PEG)-asparaginase or Erwinia-derived aspar- dose) aginase, as described below) for suspected silent allergy. Asparaginase Methotrexate 30 mg/m i.v. or IM weekly, 1 day activity was measured in samples from patients receiving both PEG after asparaginase (no weekly methotrexate until asparaginase and Erwinia asparaginase, although no dose adjustments doxorubicin completed). were made after switching from Escherichia coli asparaginase to another IT methotrexate/cytarabine/hydrocortisone at start preparation of the enzyme. of a cycle During the intensification and continuation phases, doses of metho- IT therapy consisting of methotrexate/cytarabine trexate and 6-mercaptopurine were adjusted to maintain absolute at start of a cycle every 18 weeks phagocyte nadirs of 0.500–0.750 × 10 /l and were reduced for transaminitis Continuation Every 3-week cycles: or mucositis. The dexamethasone dose was reduced when starting the 74 weeks Same as intensification except no asparaginase continuation phase. Therapy for all patients was stopped after 2 years of and dexamethasone dose reduced to 6 mg/m /day continuous CR. Allogeneic stem cell transplantation was not mandated but encouraged Abbreviations: ALL, acute lymphoblastic leukemia; CSF, cerebrospinal fluid; for all patients with high-risk cytogenetic features, such as the Philadelphia CNS, central nervous system; IM, intramuscular; IT, intrathecal. Patients chromosome or translocations involving the MLL gene on 11q23. The with CNS leukemia at diagnosis (CNS-2 and CNS-3) received twice weekly protocol was amended in September 2006 to add imatinib at a dose of doses of IT cytarabine until CSF was clear of blast cells on three 600 mg daily to all patients who were Philadelphia chromosome positive. b consecutive examinations. IT methotrexate 12 mg; cytarabine 40 mg; Dexamethasone was permanently discontinued in the setting of c hydrocortisone 50 mg. Patients received cranial radiation 1800 cGy symptomatic, radiographically confirmed osteonecrosis. Administration of delivered as 180 cGy fractions daily for 10 days. The dose was 24 Gy for asparaginase was held until the resolution of mild/moderate pancreatitis or patients with CNS-2 or CNS-3, regardless of CNS signs or symptoms. deep venous thrombosis and was permanently discontinued after severe d Asparaginase dose adjustments based on nadir serum asparaginase pancreatitis (signs and symptoms 472 h, see definitions below). Patients activity measurements. who experienced allergic reactions to E. coli asparaginase (of any severity, including local reactions) were switched to IM PEG asparaginase (2000 IU/ m /dose) administered every 2 weeks. Patients who reacted to PEG asparaginase were switched to IM Erwinia asparaginase (25 000 IU/m /dose twice weekly). Asparaginase was permanently discontinued after allergy to all available preparations. Table 2. Individualized asparaginase dose adjustments based on nadir serum asparaginase levels on the adult DFCI ALL Consortium Immunophenotype and cytogenetics Protocol Bone marrow cells from diagnostic aspirates were examined for cell surface NSAA (IU/ml) Change in subsequent asparaginase doses antigens using standard indirect immunofluorescence assays, and were cultured for standard G-banded metaphase cytogenetic analyses. Mole- o0.025 Increase by 80% from most recent dose cular analysis with real-time PCR allowed for the detection of BCR-ABL. 0.025 to o0.05 Increase by 60% 0.05 to o0.08 Increase by 40% Statistical methods 0.08 to o0.1 Increase by 20% The primary end point of this study was the proportion of patients who 0.1 to o0.14 No change completed 30 weeks of asparaginase treatment. A priori, it was determined 0.14 to o0.20 Decrease by 20% that the treatment would be considered ‘feasible’ if the one-sided lower 40.20 Decrease by 40% bound of the 90% exact binomial confidence interval (CI) for feasibility Abbreviations: ALL, acute lymphoblastic leukemia; NSAA, nadir (that is, the proportion of patients in whom it was feasible to administer serum asparaginase activity. Percentage change from most recent dose. this regimen for ⩾ 30 weeks) was 60% or higher, taking into account 2 2 Starting dose 12 500 IU/m . Minimum dose 6000 IU/m . Maximum dose patients who were removed from the study to undergo allogeneic stem 25 000 IU/m . cell transplantation. © 2015 Macmillan Publishers Limited Leukemia (2015) 526 – 534 Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al Outcome events were death during induction therapy, failure to achieve in the study prior to the protocol amendment excluding patients CR at the end of the 4-week induction phase, death during remission and with secondary ALL and age 450 years; and two patients were relapse. EFS was defined as the time from study registration to the first ineligible due to a diagnosis of Burkitt’s lymphoma. Patient outcome event among all patients. Disease-free survival (DFS) was defined demographics are shown in Table 3. Eighty-eight percent of as the time from CR to relapse or death, and only patients who achieved a patients were white and 94% non-Hispanic. Cytogenetic results CR were included in the calculation. Overall survival (OS) was defined as were available for 88 of the 92 eligible patients. Eighteen patients the time from study registration to the time of death from any cause for all (20%) were Philadelphia chromosome positive (Ph+); 8 (9%) had patients. Patients not experiencing an outcome event were censored at 11q23 (MLL) translocations; 13 (14%) were hyperdiploid (446 the date of last follow-up. Patients who went off treatment for a stem cell chromosomes: 9 with 47–50 chromosomes and 4 with 450 transplant in CR were not censored at the date of transplant, because chromosomes); 3 (3%) had hypodiploidy (o45 chromosomes); transplantation was the recommended treatment strategy for patients with high-risk cytogenetic abnormalities. EFS, DFS and OS were estimated 4 (4%) had 45 chromosomes and 60 (65%) were diploid. Sixty-six using the Kaplan–Meier method, and the Greenwood formula was used to patients (71%) had a Zubrod performance status of 0–1at construct 95% CI. Univariate analyses of the differences in EFS, DFS and OS diagnosis. were conducted with log-rank tests. The Common Terminology Criteria for Adverse Events (CTCAE) version Overall outcomes 2.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ docs/ctcmanual_v4_10-4-99.pdf) was used for coding toxicities. Toxicity Of the 92 eligible patients, 78 (85%) (90% exact CI: 77–91%) data reflect all submitted data, regardless of patient exclusion from achieved a CR at the end of the 4 weeks of induction therapy. One other analyses. patient died during induction due to sepsis, 10 patients (11%) had refractory disease at the end of induction (induction failure) and 3 Ph+ patients withdrew from protocol therapy to initiate imatinib Response assessment and definition of CNS status prior to achieving a CR. Sixteen of 18 (89%) patients with a T-cell Hematologic response was defined by standard criteria. The status of the immunophenotype achieved a CR, as did 62 of 74 patients (84%) cerebrospinal fluid (CSF) was defined as follows: CNS-1, no blast cells in with a pre-B-cell disease. cytospin, regardless of CSF cell count; CNS-2, fewer than five white blood cells on CSF cell count, with blasts on cytospin; CNS-3, five or more white Of the 78 patients who achieved CR, 16 underwent an allogeneic blood cells on CSF cell count, with blasts on cytospin. stem cell transplant during first remission: 11 were Ph+, 2 patients had a t(4;11) translocation, 1 patient had trisomy 8 and a t(9;12) translocation, 1 patient had a 9q34 translocation and 1 patient RESULTS had no cytogenetics available. Eleven of the 16 (69%) patients Patient characteristics who underwent transplant remain in first CR (CR1). Of the remaining 62 patients who achieved a CR and did not Between August 2002 and February 2008, 100 patients (ages undergo transplantation in CR1, 5 patients withdrew or never 18–50 years; median 28) were enrolled (see Figure 1). Eight initiated intensification therapy due to transfer of care (n = 1), patients were deemed ineligible and are excluded from further bone marrow relapse (n = 2), infection (n = 1) or withdrawal of analysis: two patients were removed from study prior to receiving consent (n = 1). Fifty-seven patients continued with intensification any chemotherapy, as they were found to have bilineage leukemia therapy with L-asparaginase. Forty-three of the 57 patients remain and received alternative therapy; four patients were enrolled early in CR1. Seven patients suffered a relapse (five bone marrow alone, one CNS alone and one CNS/optical), two patients died in Enrolled Patients remission due to pancreatitis or hepatic insufficiency and five N=100 deaths occurred while receiving off-protocol therapy. Ineligible N=8 With a median follow-up of 4.5 years (95% CI 4.1–5.0 years), the 4-year DFS for the 78 patients achieving a CR and OS for all 92 Eligible Patients eligible patients was 69% (95% CI 56–78%) and 67% (95% CI N=92 56–76%), respectively (Figure 2 and Table 4). For the 18 patients Induction Death N=1 Induction Failure N=10 who had Ph+ ALL, 14 (78%) achieved CR, 2 relapsed and 8 remain Withdrew prior to initiate in CR1. For the 74 patients who had Ph − ALL, 64 (86%) achieved imatinib/Ph+ N= 3 Complete Remission CR, 12 relapsed and 47 remain in CR1. The 4-year DFS and OS for N=78 Ph − patients with B-cell ALL was 66% (CI 50–78%) and 68% (CI 53–79%), respectively. The 4-year DFS and OS for patients with Withdrew N=2 T-cell ALL was 87% (CI 56–97%) and 76% (CI 49–90%), respectively Toxicity N=1 Early Relapse N=2 (Figures 2c and d and Table 4). EFS, DFS and OS rates were similar for patients between 18–30 and 31–50 years (Table 4). Outcomes st To SCT in 1 CR N=16 by Philadelphia chromosome status, immunophenotype, age and white blood count are shown in Table 4 and Figure 2. All Ph+ Initiated Asparaginase Alive in CCR N=11 patients had B-lineage ALL. Additional analyses of DFS and OS for Consolidation Therapy N=57 Ph − patients with B-lineage disease was performed, with patients transplanted in CR1 censored at the time of transplant. Results were unchanged (data not shown). Asparaginase tolerance Alive in CCR N=43 Relapse N=7 The primary focus of this study was to determine the feasibility of Remission Death N=2 Death after protocol therapy N=5 administering weekly IM E. coli asparagnase during the 30-week intensification phase. Among the 92 eligible patients, 57 patients Figure 1. DFCI ALL Consortium Protocol flow diagram. One hundred were evaluable for the asparaginase end point. The 35 patients patients with newly diagnosed ALL were enrolled. Ninety-two not evaluable for asparaginase tolerance had induction failure patients were considered eligible, of whom 78 (85%) achieved a (n = 10) or death (n = 1), initiated imatinib (3 patients), underwent complete remission within 1 month. Fifty-seven were evaluable for the asparaginase feasibility end point. All 92 patients were evaluable allogeneic stem cell transplantation (16 patients) and 5 were for analysis of EFS and OS. unevaluable as described above. Of the 57 evaluable patients, Leukemia (2015) 526 – 534 © 2015 Macmillan Publishers Limited Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al developed pancreatitis, 2 had allergic reactions to all asparaginase Table 3. Patient demographics and disease characteristics preparations, 6 had either a deep vein thrombosis or hepatic toxicity, 2 relapsed during the intensification phase, 1 withdrew N (%) due to non-compliance and 3 had other toxicities. N eligible patients 92 Asparaginase toxicity Age years, median (range) 28 (18, 50) Asparaginase-related toxicities included allergic reactions in 5 18–29 years 48 (52) patients (5%), thrombosis in 16 patients (17%) and pancreatitis in 30–50 years 44 (48) 10 patients (11%). There was 1 death related to pancreatitis, which occurred 10 days after completion of the 30th dose of Sex, male 56 (61) asparaginase. There were 8 bone fractures reported in 7 patients − 3 WBC at Dx × 10 , median (range) 15.5 (1.0, 360.0) and 5 patients developed osteonecrosis. Hepatic toxicity during o20 56 (61) the intensive asparaginase course was seen in 33 patients (53%), ⩾ 20 35 (38) including 10 patients who developed grade 3 or 4 hyperbilir- Unknown 1 (1) ubinemia, 3 patients who had liver dysfunction or failure (1 death); the remaining patients had transient elevations in the aspartate Immunophenotype transaminase or alanine transaminase enzyme levels. Both B cell 74 (80) T cell 18 (20) asparaginase-related and toxicities based on the CTCAE v. 2.0 are summarized in Table 5 by treatment phase. No second CNS status malignancies or clinical congestive heart failure were reported. CNS-1 (− ) CSF WBC o5 without blasts 79 (86) CNS-2 (+) CSF WBC o5 with blasts 4 (4) Individualized asparaginase dosing CNS-3 (+) CSF WBC ⩾5 with blasts 1 (1) Unknown 8 (9) Asparaginase activity was measured in 365 serum samples Philadelphia chromosome positive 18 (20) obtained from 54 patients 7 days after the prior dose of IM MLL rearrangement 8 (9) E. coli asparaginase during the intensification phase. The median Other Translocation 11 (12) number of evaluable NSAA samples obtained from each patient was 7 (range: 1–11). The median asparaginase dose (including Ploidy starting dose and all adjusted doses administered to patients Hypodiploidy (o45) 3 (3) (= 45) 4 (4) during the intensification phase) was 15 000 IU/m (range: 6000 Diploidy (= 46) 60 (65) –25 000 IU/ml) (Figure 3). Enzyme activity was o0.025 IU/ml in (= 47, 48, 49, 50) 9 (10) 20% (n = 74) of the samples, 0.025–0.099 IU/ml in 45% (n = 165), Hyperdiploidy (>50) 4 (4) 0.100–0.14 IU/ml in 14% (n = 51) and40.140 IU/ml in 21% (n = 75). Unknown 12 (13) The weekly median NSAA increased progressively until a plateau was achieved following the sixth dose. The steady-state median Performance status NSAA was 0.083 IU/ml (range: o0.025–0.66 IU/ml) for the 263 0 27 (29) samples collected from 48 patients after 6 weeks of dosing during 1 39 (42) 2 20 (22) which the median dose was 18 144 IU/m . Unknown 6 (7) In the presence of suspected silent allergy indicated by very low serial NSAA samples, 12 patients switched asparaginase preparation. ECOG risk classification Three patients received Erwinia asparaginase from which a total of SR 41 (45) 17 samples were collected: 6 were o0.025 IU/ml, 6 were 0.025– HR 51 (55) 0.099 IU/ml and 5 were40.14 IU/ml with an overall median of 0.057 (range: o0.025–0.595 IU/ml). In addition, 9 patients received PEG Race White 81 (88) asparaginase owing to unavailability of Erwinia asparaginase from Black or African American 4 (4) which a total of 37 samples were collected: 3 were o0.025 IU/ml, 3 Asian 2 (2) were 0.025–0.099 IU/ml and 31 were 40.14 IU/ml, with an overall American Indian or Alaska native 1 (1) median of 0.44 IU/ml (range: o0.025–2.45 IU/ml). Other 4 (4) Ethnicity CNS status Hispanic 5 (5) Five patients had CNS-2 or CNS-3 disease at the time of initial Non-Hispanic 86 (94) diagnosis. Subsequently, three of these patients experienced a Other 1 (1) relapse (one bone marrow, one CNS and one bone), one patient Abbreviations: CSF, cerebrospinal fluid; CNS, central nervous system; ECOG, was a remission death and one died after having completed Eastern Cooperative Oncology Group; HR, high risk; SR, standard risk; WBC, protocol therapy. There were no CNS relapses among the patients white blood cell. Eight B-cell patients and 1 T-cell patient had myeloid with CNS-1 disease at diagnosis. coexpression. Detected by cytogenetics (n= 17), both reverse transcriptase-PCR and fluorescence in situ hybridization (n= 1). ECOG risk is defined as follows: HR includes any patients with an MLL rearrangement DISCUSSION or Ph+ and B-cell patients with WBC⩾ 35 K or age ⩾ 35 years and T-cell Several retrospective analyses have compared treatment outcomes patients with WBC⩾ 100 K. for young adult patients treated with either pediatric or adult regimens, all of which have demonstrated superior outcomes for 9–13 36 (63%) completed all 30 doses with a one-sided lower exact 90% patients treated with pediatric ALL protocols. These striking binomial confidence bound of 54%, and 41 patients (72%) differences in outcome cannot be explained simply on the basis of completed 26 or more doses of asparaginase with a one-sided different biology or median age, because the pediatric and young lower exact 90% binomial confidence bound of 63%. Of the 21 adult cohorts in these studies had similar rates of Ph+ and MLL gene- patients who did not complete the 30 doses of asparaginase, 7 rearranged ALL, and other high-risk and immunophenotypic features. © 2015 Macmillan Publishers Limited Leukemia (2015) 526 – 534 Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al Figure 2. (a and b) represent the OS for 92 eligible patients and DFS for 78 patients who achieved a CR, respectively. With a median follow-up of 4.5 years, the 4-year OS for all 92 patients on protocol was 67% (95% CI; 56–76%) and the 4-year DFS was 69% (95% CI; 56–78%) for the 78 patients who achieved a CR. The solid lines represent the Kaplan–Meier estimates, and the dashed lines represent the 95% confidence bands about those estimates. (c and d) Represent OS and DFS by immunophenotype and Philadelphia chromosome status, respectively. Some of the reported differences between pediatric and adult typical pediatric regimens and adult regimens. Nevertheless, the outcomes have been attributed to attention to detail of therapy, 2-year EFS was 56% in the French study with a 2-year OS of 66%, such as attaining maximal dose intensification and timely both improvements from historical controls. The French GRAALL scheduling of drug delivery. The latter has been reported to study made use of an intensified induction therapy for poor steroid result in systematic delays in administering drugs. Most children responders, allocation of higher risk (based on disease features) with ALL are referred to academic centers and treated on clinical patients to allogeneic transplant and enrollment of patients up to an trials, whereas most adults with ALL are not. In addition, pediatric age of 60 years. However, the improved outcomes noted in the regimens administer early and more intensive CNS therapy as French study were limited to patients under the age of 45 years. The compared with adult regimens. Spanish study administered the pediatric PETHEMA ALL-96 regimen In addition, it is possible that many young adults and adolescents to patients up to the age of 30 years and showed a similar outcome are currently being ‘under dosed’ when treated on standard adult as compared with adolescent patients of age 15–18 years. ALL regimens due to lower total doses of corticosteroids, vinca Furthermore, a recent meta-analysis further supports the adminis- alkaloids and asparaginase. Our experience suggests that adults 50 tration of pediatric-inspired regimens for young adult patients. years old and younger tolerate a pediatric regimen, and that such A critical biologic difference between the pediatric and young therapy resulted in improved outcomes compared with historical adult populations pertains to the relative incidence of Ph+ disease. controls. These findings were consistent with recent reports from In our concurrently conducted pediatric (1–18 year olds) and young 22–24 French, Canadian and Spanish investigators. In both the French adult (418–50 year olds) protocols, the incidence of Ph+ leukemia and the Canadian studies, patients received significantly more was 3 and 18%, respectively. As shown in Table 4 and Figure 3, the prednisone, vincristine and asparaginase than in prior adult outcome for Ph − patients treated on the current study was regimens. Those experiences differed from ours in that the same relatively favorable. This finding is of particular importance because pediatric regimen was not offered to adult patients; instead, the outcomes from a recent Eastern Cooperative Oncology Group/ investigators employed a regimen of intermediate intensity between Medical Research Council trial reported that allogeneic stem cell Leukemia (2015) 526 – 534 © 2015 Macmillan Publishers Limited Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al Table 4. Outcome by patient characteristics 4-year DFS (%) 95% CI P-value 4-year EFS (%) 95% CI P-value 4-year OS (%) 95% CI P-value N 78 92 92 All patients 69 (56–78) 58 (47–68) 67 (56–76) Age (years) 18–29 70 (52–83) 0.54 55 (39–69) 0.61 68 (52–80) 0.93 30–50 67 (50–79) 61 (44–74) 65 (49–77) Sex Male 64 (47–77) 0.47 51 (37–64) 0.15 64 (50–76) 0.28 Female 75 (56–87) 69 (51–81) 71 (52–83) % Blasts at Dx 0–30 70 (53–82) 0.77 58 (43–71) 0.92 65 (50–77) 0.79 430 67 (47–81) 58 (40–72) 69 (52–82) –3 WBC at Dx × 10 o20 74 (59–84) 0.073 70 (56–80) o0.001 80 (66–88) 0.001 ⩾ 20 55 (32–73) 37 (21–53) 45 (28–61) Immunophenotype B cell 64 (50–75) 0.11 53 (41–64) 0.11 64 (52–74) 0.20 T cell 87 (56–97) 77 (49–91) 76 (49–90) CNS status CNS-1 ( − ) 75 (62–84) o0.001 62 (50–72) 0.005 71 (59–80) o0.001 CNS-2/3 (+) 0 (NA) 0 (NA) 0 (NA) Ph+ Yes 54 (25–76) 0.13 42 (19–63) 0.091 53 (28–73) 0.12 No 71 (58–81) 62 (49–72) 70 (58–79) MLL rearrangement Yes 63 (23–86) 0.48 63 (23–86) 0.86 60 (20–85) 0.83 No 69 (56–79) 58 (46–68) 67 (56–77) Ploidy High hyperdiploid (450) 75 (13–96) 0.95 75 (13–96) 0.57 75 (13–96) 0.74 Other 66 (52–77) 54 (42–65) 64 (52–74) Performance status 0–1 69 (55–80) 0.52 59 (45–70) 0.81 70 (57–80) 0.42 2 63 (36–82) 57 (32–76) 55 (30–75) ECOG risk SR 81 (63–91) 0.016 70 (53–82) 0.051 80 (64–90) 0.038 HR 57 (41–71) 48 (33–61) 55 (40–68) Immuno/Ph+ status T cell 87 (56–97) 0.14 77 (49–91) 0.11 76 (49–90) 0.12 B-cell Ph − 66 (50–78) 57 (42–69) 68 (53–79) B-cell Ph+ 54 (25–76) 42 (19–63) 53 (28–66) Abbreviations: CI, confidence interval; CNS, central nervous system; DFS, disease-free survival; EFS, event-free survival; HR, high risk; Ph, Philadelphia chromosome; OS, overall survival; SR, standard risk; WBC, white blood cell. transplantation offered superior OS compared with either chosen because we had previously shown that, in children, tolerance to asparaginase was associated with an exceptionally chemotherapy or autologous stem cell transplantation for 26 28 adults with standard-risk ALL. However, the OS for the favorable outcome. There was uncertainty whether adults could tolerate such intensive therapy. Our a priori protocol definition of Philadelphia-negative patients in the Eastern Cooperative Oncology Group/Medical Research Council study was only 53%, compared feasibility was based on completion of the full 30 weeks of asparaginase, but our pediatric data suggest that completion of 26 with an OS of 68% for Ph − patients treated on the current protocol. The 4-year OS for T-ALL patients on the current trial (76%) or more of the planned 30 weeks of asparaginase was similarly efficacious. We found that 72% of the patients who initiated the also compares favorably to published outcomes for adults with this subtype. 30-week asparaginase course were able to receive 26 or more We sought to determine the feasibility of treating a young adult doses (87% of targeted therapy), similar to, although slightly lower population with an intensive pediatric-inspired ALL regimen. Our than the proportion of pediatric patients. The incidence of major primary end point was the proportion of patients who completed asparaginase-related toxicities, such as pancreatitis, and throm- 30 weeks of high-dose asparaginase therapy. This end point was bosis was also similar to that reported in older children. © 2015 Macmillan Publishers Limited Leukemia (2015) 526 – 534 Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al Table 5. Toxicity summary in eligible patients–overall and by treatment phase Overall N (%) Induction N (%) CNS N (%) Intensification N (%) Continuation N (%) No. patients reporting 92 92 67 62 48 CTC grade 3–5 toxicity Neutrophils 86 (93) 82 (89) 10 (15) 52 (84) 22 (46) Platelets 75 (82) 72 (78) 1 (1) 17 (27) 5 (10) Febrile neutropenia 30 (33) 20 (22) 0 (0) 10 (16) 3 (6) Infection with grade 3/4 neutropenia 49 (53) 41 (45) 1 (1) 11 (18) 6 (13) Infection—other 7 (8) 2 (2) 1 (1) 3 (5) 2 (4) Hepatic 57 (62) 24 (26) 5 (7) 33 (53) 21 (44) Hyperglycemia 41 (45) 36 (39) 1 (1) 12 (19) 5 (10) Stomatitis 10 (11) 4 (4) 1 (1) 5 (8) 0 (0) CNS hemorrhage 1 (1) 1 (1) 0 (0) 1 (2) 0 (0) Seizure 4 (4) 1 (1) 0 (0) 3 (5) 1 (2) Asparaginase-related toxicity Pancreatitis 10 (11) 1 (1) 0 (0) 8 (13) 2 (4) Allergy/rash 5 (5) 1 (1) 0 (0) 4 (6) 0 (0) Thrombosis/embolism 16 (17) 1 (1) 0 (0) 14 (23) 2 (4) Bone fracture 7 (8) 0 (0) 0 (0) 3 (5) 5 (10) Avascular necrosis 5 (5) 0 (0) 0 (0) 2 (3) 4 (8) Abbreviation: CNS, central nervous system. There were five grade 5 events—one in each category shown and one leukoencephalopathy. Routine sampling of CSF at time of diagnosis (and concomitant administration of intrathecal chemotherapy) is a pediatric standard of care, but not necessarily so in adult ALL. Our study prospectively determined the incidence and outcome of CNS status at the time of diagnosis. We found asymptomatic CSF involvement in five (5%) patients at the time of diagnosis. Such patients received more intensive CNS therapy (a higher dose of cranial radiation and additional doses of intrathecal therapy). Of these five patients, only one relapse involved the CNS and supports the routine use of both CNS-directed diagnosis and risk- stratified treatment of adults with ALL. Most, but not all, adult ALL trials report the incidence of CR after 6,30,31 2 months of therapy. In the current trial, we employed a strategy of removing patients from protocol therapy if they did not achieve a CR after 4 weeks of therapy, as several pediatric trials reported that absence of CR after 1 month, despite presence of CR after 2 months, was associated with poor long-term 32–34 outcomes. Although this strategy may have increased our rate of induction failure compared with studies, which allowed for two induction attempts, the CR rate on our protocol was still 85%. In our current second-generation pediatric-inspired therapy for adults with ALL, we allow two cycles of chemotherapy prior to deciding induction results (NCT00476190). We believe such an approach will lead to a higher CR rate and provide an opportunity for more young adults with ALL to potentially benefit from pediatric-type consolidation strategies. In conclusion, the results of this study support that the use of a pediatric-inspired chemotherapy regimen is associated with excel- lent long-term results in children, and can be safely and efficaciously applied to adults aged 18–50 years. The 69% 4-year DFS rate reported in the current study suggests that the administration of a pediatric-inspired regimen to adult patients is meritorious, resulting in a high rate of durable CRs. Further studies, such as the US intergroup trial CALGB 10403, will hopefully confirm these results with the goal that the natural history of ALL in adults under age 50 years will be favorably impacted. CONFLICT OF INTEREST Figure 3. (a and b) Median asparaginase dose and nadir serim DJDA has received honoraria for speaking engagements from Sigma Tau. LBS has asparaginase activity during the 30-week Consolidation Course. received honoraria for serving on advisory boards for Sigma Tau and EUSA. JGS has Error bars extend to the 25th and 75th percentiles. received research support from Sigma Tau Research Inc. and EUSA Pharma (US) Inc. Leukemia (2015) 526 – 534 © 2015 Macmillan Publishers Limited Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al LAS has received honoraria for speaking engagements from Sigma Tau and Celgene. 13 Ramanujachar R, Richards S, Hann I, Goldstone A, Mitchell C, Vora A et al. SES has received research support honoraria for speaking engagements from Sigma Adolescents with acute lymphoblastic leukaemia: outcome on UK national pae- Tau, and consulted for Jazz Pharmaceuticals. The remaining authors declare no diatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer 2007; 48: 254–261. conflict of interest. 14 Ahlke E, Nowak-Gottl U, Schulze-Westhoff P, Werber G, Borste H, Wurthwein G et al. Dose reduction of asparaginase under pharmacokinetic and pharmacody- namic control during induction therapy in children with acute lymphoblastic ACKNOWLEDGEMENTS leukaemia. Br J Haematol 1997; 96:675–681. We thank Susan Buchanan, PA-C, Adriana Penicaud, PA-C and Kristina Hines for 15 Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ et al. technical assistance. This study was supported in part by NIH Grant PO1 CA068484. A randomized comparison of native Escherichia coli asparaginase and Sigma Tau has partially funded the laboratory performing Asparaginase enzyme level polyethylene glycol conjugated asparaginase for treatment of children with testing. newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 2002; 99: 1986–1994. 16 Berg SL, Balis FM, McCully CL, Godwin KS, Poplack DG. Pharmacokinetics of AUTHOR CONTRIBUTIONS PEG-L-asparaginase and plasma and cerebrospinal fluid L-asparagine concentra- tions in the rhesus monkey. Cancer Chemother Pharmacol 1993; 32: 310–314. DJDA was the overall principal investigator, performed research, analyzed data 17 Boos J, Werber G, Ahlke E, Schulze-Westhoff P, Nowak-Gottl U, Wurthwein G et al. and wrote the manuscript. KES was the principal statistician, analyzed data and Monitoring of asparaginase activity and asparagine levels in children on different edited the manuscript. SED was the principal statistician, analyzed data and asparaginase preparations. Eur J Cancer 1996; 32A:1544–1550. edited the manuscript. LBS, SES and RMS assisted in the writing of the protocol, 18 Riccardi R, Holcenberg JS, Glaubiger DL, Wood JH, Poplack DG. L-asparaginase performed research and edited the manuscript. SC, JGS, PCA, KKB, MDS, ART, BL, pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys KH-J, KK, SC, JHM, LS, MW, LAS and IG performed research and edited the and humans. Cancer Res 1981; 41: 4554–4558. 19 Rizzari C, Zucchetti M, Conter V, Diomede L, Bruno A, Gavazzi L et al. L-asparagine manuscript. depletion and L-asparaginase activity in children with acute lymphoblastic leu- kemia receiving i.m. or i.v. Erwinia C. or E. coli L-asparaginase as first exposure. Ann Oncol 2000; 11:189–193. REFERENCES 20 Vrooman LM, Supko JG, Neuberg DS, Asselin BL, Athale UH, Clavell L et al. Erwinia 1 Silverman LB, Stevenson KE, O'Brien JE, Asselin BL, Barr RD, Clavell L et al. asparaginase after allergy to E. coli asparaginase in children with acute lym- Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for phoblastic leukemia. Pediatr Blood Cancer 2010; 54:199–205. children with newly diagnosed acute lymphoblastic leukemia (1985-2000). 21 Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH et al. Leukemia 2010; 24: 320–334. Revised recommendations of the International Working Group for diagnosis, 2 Gaynon PS, Angiolillo AL, Carroll WL, Nachman JB, Trigg ME, Sather HN et al. standardization of response criteria, treatment outcomes, and reporting stan- Long-term results of the children's cancer group studies for childhood acute dards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003; 21: lymphoblastic leukemia 1983-2002: a Children's Oncology Group Report. 4642–4649. Leukemia 2010; 24: 285–297. 22 Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E et al. Pediatric- 3 Moricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H et al. inspired therapy in adults with Philadelphia chromosome-negative acute Long-term results of five consecutive trials in childhood acute lymphoblastic lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 2009; 27:911–918. leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 23 Storring JM, Minden MD, Kao S, Gupta V, Schuh AC, Schimmer AD et al. Treatment 2010; 24: 265–284. of adults with BCR-ABL negative acute lymphoblastic leukaemia with a modified 4 Pui CH, Pei D, Sandlund JT, Ribeiro RC, Rubnitz JE, Raimondi SC et al. Long-term paediatric regimen. Br J Haematol 2009; 146:76–85. results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood 24 Ribera JM, Oriol A, Sanz MA, Tormo M, Fernandez-Abellan P, del Potro E et al. acute lymphoblastic leukemia. Leukemia 2010; 24: 371–382. Comparison of the results of the treatment of adolescents and young adults with 5 Vrooman LM, Stevenson KE, Supko JG, O'Brien J, Dahlberg SE, Asselin BL et al. standard-risk acute lymphoblastic leukemia with the Programa Espanol de Tra- Postinduction dexamethasone and individualized dosing of Escherichia Coli tamiento en Hematologia pediatric-based protocol ALL-96. J Clin Oncol 2008; 26: L-asparaginase each improve outcome of children and adolescents with newly 1843–1849. diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana- 25 Ram R, Wolach O, Vidal L, Gafter-Gvili A, Shpilberg O, Raanani P. Adolescents and Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 2013; 31: young adults with acute lymphoblastic leukemia have a better outcome when 1202–1210. treated with pediatric-inspired regimens: systematic review and meta-analysis. 6 Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S et al. Long-term Am J Hematol 2012; 87: 472–478. follow-up results of hyperfractionated cyclophosphamide, vincristine, 26 Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK et al. doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in In adults with standard-risk acute lymphoblastic leukemia, the greatest benefitis adult acute lymphocytic leukemia. Cancer 2004; 101: 2788–2801. achieved from a matched sibling allogeneic transplantation in first complete 7 Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM et al. Induction remission, and an autologous transplantation is less effective than conventional therapy for adults with acute lymphoblastic leukemia: results of more than 1500 consolidation/maintenance chemotherapy in all patients: final results of the patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005; International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008; 111: 1827–1833. 106: 3760–3767. 27 Hoelzer D, Gokbuget N, Digel W, Faak T, Kneba M, Reutzel R et al. Outcome of 8 Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N et al. Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for treatment in adults with acute lymphoblastic leukemia: analysis of the acute lymphoblastic leukemia. Blood 2002; 99: 4379–4385. LALA-94 trial. J Clin Oncol 2004; 22: 4075–4086. 28 Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA et al. Improved 9 Stock W, La M, Sanford B, Bloomfield CD, Vardiman JW, Gaynon P et al. What outcome for children with acute lymphoblastic leukemia: results of Dana-Farber determines the outcomes for adolescents and young adults with acute lym- Consortium Protocol 91-01. Blood 2001; 97: 1211–1218. phoblastic leukemia treated on cooperative group protocols? A comparison of 29 Barry E, DeAngelo DJ, Neuberg D, Stevenson K, Loh ML, Asselin BL et al. Favorable Children’s Cancer Group and Cancer and Leukemia Group B studies. Blood 2008; outcome for adolescents with acute lymphoblastic leukemia treated on 112: 1646–1654. Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium 10 Boissel N, Auclerc MF, Lheritier V, Perel Y, Thomas X, Leblanc T et al. Should Protocols. J Clin Oncol 2007; 25:813–819. adolescents with acute lymphoblastic leukemia be treated as old children or 30 Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P et al. A five-drug young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin remission induction regimen with intensive consolidation for adults with acute Oncol 2003; 21: 774–780. lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 1995; 85: 11 de Bont JM, Holt B, Dekker AW, van der Does-van den Berg A, Sonneveld P, Pieters R. 2025–2037. Significant difference in outcome for adolescents with acute lymphoblastic 31 Larson RA, Dodge RK, Linker CA, Stone RM, Powell BL, Lee EJ et al. A randomized leukemia treated on pediatric vs adult protocols in the Netherlands. Leukemia controlled trial of filgrastim during remission induction and consolidation 2004; 18: 2032–2035. chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. 12 Testi A, Valsecchi M, Conter V, Vignetti M, Paoloni F, Giona F et al. Difference in Blood 1998; 92: 1556–1564. outcome of adolescents with acute lymphoblastic leukemia (ALL) enrolled in 32 Oudot C, Auclerc MF, Levy V, Porcher R, Piguet C, Perel Y et al. Prognostic factors pediatric (AIEOP) and adult (GIMEMA) protocols [abstract]. Blood 2004; 104: 539a. for leukemic induction failure in children with acute lymphoblastic leukemia and © 2015 Macmillan Publishers Limited Leukemia (2015) 526 – 534 Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al outcome after salvage therapy: the FRALLE 93 study. J Clin Oncol 2008; 26: This work is licensed under a Creative Commons Attribution- 1496–1503. NonCommercial-NoDerivs 4.0 International License. The images or 33 Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A et al. Outcomes other third party material in this article are included in the article’s Creative Commons after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med license, unless indicated otherwise in the credit line; if the material is not included under 2012; 366: 1371–1381. the Creative Commons license, users will need to obtain permission from the license 34 Silverman LB, Gelber RD, Young ML, Dalton VK, Barr RD, Sallan SE. Induction holder to reproduce the material. To view a copy of this license, visit http:// failure in acute lymphoblastic leukemia of childhood. Cancer 1999; 85: 1395–1404. creativecommons.org/licenses/by-nc-nd/4.0/ Leukemia (2015) 526 – 534 © 2015 Macmillan Publishers Limited http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Leukemia Springer Journals

Long-term outcome of a pediatric-inspired regimen used for adults aged 18–50 years with newly diagnosed acute lymphoblastic leukemia

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Springer Journals
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Copyright © 2015 by The Author(s)
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Medicine & Public Health; Medicine/Public Health, general; Internal Medicine; Intensive / Critical Care Medicine; Cancer Research; Oncology; Hematology
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10.1038/leu.2014.229
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Abstract

Leukemia (2015) 29, 526 –534 OPEN © 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15 www.nature.com/leu ORIGINAL ARTICLE Long-term outcome of a pediatric-inspired regimen used for adults aged 18–50 years with newly diagnosed acute lymphoblastic leukemia 1 2 2 3 4,5 6 6 6 7 8 DJ DeAngelo , KE Stevenson , SE Dahlberg , LB Silverman , S Couban , JG Supko , PC Amrein , KK Ballen , MD Seftel , AR Turner , 9 10 11 12 13 14 1 1 1 2 B Leber , K Howson-Jan , K Kelly , S Cohen , JH Matthews , L Savoie , M Wadleigh , LA Sirulnik , I Galinsky , DS Neuberg , 3 1 SE Sallan and RM Stone On the basis of the data suggesting that adolescents and young adult patients with acute lymphoblastic leukemia (ALL) have improved outcomes when treated on pediatric protocols, we assessed the feasibility of treating adult patients aged 18–50 years with ALL with the DFCI Pediatric ALL Consortium regimen utilizing a 30-week course of pharmacokinetically dose-adjusted E. coli L-asparaginase during consolidation. Between 2002 and 2008, 92 eligible patients aged 18–50 years were enrolled at 13 participating centers. Seventy-eight patients (85%) achieved a complete remission (CR) after 1 month of intensive induction therapy. With a median follow-up of 4.5 years, the 4-year disease-free survival (DFS) for the patients achieving a CR was 69% (95% confidence interval (CI) 56–78%) and the 4-year overall survival (OS) for all eligible patients was 67% (95% CI 56–76%). The 4-year DFS for the 64 patients who achieved a CR and were Philadelphia chromosome negative (Ph − ) was 71% (95% CI 58–81%), and for all 74 Ph − patients the 4-year OS was 70% (95% CI 58–79%). We conclude that a pediatric-like treatment strategy for young adults with de novo ALL is feasible, associated with tolerable toxicity, and results in improved outcomes compared with historical regimens in young adult patients with ALL. Leukemia (2015) 29, 526–534; doi:10.1038/leu.2014.229 INTRODUCTION year-old adults and would result in improved outcomes. Therefore, we initiated a multi-center clinical trial for young adults with ALL Over the past two decades, the outcomes for children with acute and found that the pediatric-inspired regimen was well tolerated lymphoblastic leukemia (ALL) have significantly improved with and produced encouraging results compared with historical adult modifications of risk-stratified multi-agent, multi-phase chemo- ALL regimens. therapy and central nervous system (CNS) prophylaxis. Today, patients 1–18 years old who are diagnosed with ALL can expect complete remission (CR) rates that exceed 95% and long-term 1–5 event-free survival (EFS) that exceeds 80%. In contrast, outcomes MATERIALS AND METHODS for adults diagnosed with ALL remain poor. Contemporaneous trials Study design and patient population using adult ALL regimens result in long-term survival rates of Patients were eligible for protocol entry if they had newly diagnosed ALL 6–8 o50%, but these differences in response rates and outcome (excluding mature B-cell ALL) and were at least 18 years old. Initially, there cannot be explained by differences in leukemia biology alone. was no upper age limit for eligibility; the protocol was amended after the Stock et al. reported that adolescents and young adults 16–21 first eight patients were enrolled to limit the age range from 418 to 50 years old, who were eligible for either a pediatric or an adult ALL years and to exclude patients with presumed secondary ALL. Eligible patients had a Zubrod performance status of 2 or less, and exclusion regimen, had markedly improved outcomes if they received the criteria included pregnancy, active psychiatric illness, uncontrolled active pediatric regimen. Similar findings were apparent when comparing infection, prior history of pancreatitis, cerebrovascular accident or outcomes from young populations in France, the Netherlands and the 10–13 hemorrhage or evidence of infection with HIV. There were no specific United Kingdom treated with childhood versus adult regimens. exclusions based on hepatic or renal function. Recognition of the likely role of the treatment regimen in A total of 100 patients were enrolled between June 2002 and February improved outcomes in adolescents and young adult patients 2008 from 13 institutions. The study was conducted according to the treated with pediatric regimens led us to initiate a clinical trial to Declaration of Helsinki and its amendments. Before study entry, all patients determine whether an intensive pediatric ALL chemotherapy signed an informed consent document approved by the Institutional protocol for children o18 years old would be tolerable for 18–50- Review Board at each institution. 1 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, 3 4 MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute/Division of Pediatric Hematology-Oncology, Boston Children’s Hospital, Boston, MA, USA; National 5 6 Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada; Dalhousie University, Halifax, Nova Scotia, Canada; Massachusetts General Hospital, Boston, MA, USA; 7 8 9 Cancer Care Manitoba, Winnipeg, Manitoba, Canada; Cross Cancer Institute, Edmonton, Alberta, Canada; Hamilton Health Sciences Center, Hamilton, Ontario, Canada; 10 11 12 London Health Services, London, Ontario, Canada; Columbia University Medical Center, New York, NY, USA; Hospital Maisonneuve-Rosemont, Montreal, Quebec, Canada; 13 14 Queen’s University, Kingston, Ontario, Canada and Tom Baker Cancer Center, Calgary, Alberta, Canada. Correspondence: Dr DJ DeAngelo, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, D1B30, Boston, MA 02215, USA. E-mail: daniel_deangelo@dfci.harvard.edu Received 3 March 2014; revised 24 June 2014; accepted 17 July 2014; accepted article preview online 31 July 2014; advance online publication, 28 October 2014 Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al Therapy Table 1. Therapy on DFCI Adult ALL Consortium Protocol 01–175 Details of the treatment regimen are summarized in Table 1. Steroid therapy consisted of prednisone during the induction phase and Time Frame Treatment dexamethasone thereafter (that is, during intensification and continuation phases). Patients with persistent leukemia at the end of the first month of Induction 4 Vincristine 2 mg weekly, days 1, 8, 15 and 22 treatment were removed from the protocol and given alternative therapy Weeks Prednisone 40 mg/m /day, days 1–28 at the discretion of the treating physician. During induction, high-dose Doxorubicin 30 mg/m /dose, days 1and 2 methotrexate was administered as a 1-h infusion, whereas leucovorin Methotrexate 4 g/m (8–24 h after doxorubicin) (200 mg/m intravenously) was given 36 h later and was continued at a with leucovorin rescue on day 3 dose of 24 mg/m intravenously or orally every 6 h until the serum E coli L-asparaginase 25 000 IU/m IM × 1 dose, methotrexate level was o1 μM. The cumulative doxorubicin dose was day 5 capped at 300 mg/m . IT cytarabine 50 mg, day 0 (prior to initiation of E. coli asparaginase was given intramuscular (IM) once a week for systemic therapy) 30 weeks at a starting dose of 12 500 IU/m . Subsequent doses were IT methotrexate/cytarabine/hydrocortisone, days adjusted as indicated in Table 2 to maintain the nadir serum asparaginase 15 and 29 activity (NSAA) between 0.100 and 0.140 IU/ml. This range was considered CNS therapy Vincristine 2 mg × 1 dose to be therapeutic based upon previously reported pharmacokinetic and 3 Weeks 6-mercaptopurine (6-MP) 50 mg/m /day orally, pharmacodynamic studies, and was selected with the aim of avoiding × 14 consecutive days 14–19 excessively high or low NSAA. Serum samples were obtained just Doxorubicin 30 mg/m × 1 dose before administering the second and fourth doses of asparaginase and IT methotrexate/cytarabine twice weekly × 4 doses then every 3 weeks thereafter. Asparaginase activity was determined in Cranial radiation real-time using a validated biochemical assay with a 0.025-IU/ml lower Intensification Every 3-week cycles: limit of quantitation by a central laboratory, as previously described. 30 Weeks Vincristine 2 mg, day 1 These results were then used to adjust the dose given 2 weeks after Dexamethasone 18 mg/m /day b.i.d., orally, days obtaining the sample. Samples had to be obtained 7 days after the prior 1–5 dose to be considered evaluable. The minimum and maximum aspar- Doxorubicin 30 mg/m , day 1 of each cycle to a 2 2 (cumulative dose 300 mg/m ) aginase dose that could be given was 6000 and 25 000 IU/m , respectively. 6-MP 50 mg/m /day orally × 14 consecutive days Patients with extremely low NSAA in serial samples despite dose E. coli asparaginase adjustments were switched to an alternative asparaginase preparation Individualized dosing: 12 500 IU/m /dose (starting (either polyethylene glycol (PEG)-asparaginase or Erwinia-derived aspar- dose) aginase, as described below) for suspected silent allergy. Asparaginase Methotrexate 30 mg/m i.v. or IM weekly, 1 day activity was measured in samples from patients receiving both PEG after asparaginase (no weekly methotrexate until asparaginase and Erwinia asparaginase, although no dose adjustments doxorubicin completed). were made after switching from Escherichia coli asparaginase to another IT methotrexate/cytarabine/hydrocortisone at start preparation of the enzyme. of a cycle During the intensification and continuation phases, doses of metho- IT therapy consisting of methotrexate/cytarabine trexate and 6-mercaptopurine were adjusted to maintain absolute at start of a cycle every 18 weeks phagocyte nadirs of 0.500–0.750 × 10 /l and were reduced for transaminitis Continuation Every 3-week cycles: or mucositis. The dexamethasone dose was reduced when starting the 74 weeks Same as intensification except no asparaginase continuation phase. Therapy for all patients was stopped after 2 years of and dexamethasone dose reduced to 6 mg/m /day continuous CR. Allogeneic stem cell transplantation was not mandated but encouraged Abbreviations: ALL, acute lymphoblastic leukemia; CSF, cerebrospinal fluid; for all patients with high-risk cytogenetic features, such as the Philadelphia CNS, central nervous system; IM, intramuscular; IT, intrathecal. Patients chromosome or translocations involving the MLL gene on 11q23. The with CNS leukemia at diagnosis (CNS-2 and CNS-3) received twice weekly protocol was amended in September 2006 to add imatinib at a dose of doses of IT cytarabine until CSF was clear of blast cells on three 600 mg daily to all patients who were Philadelphia chromosome positive. b consecutive examinations. IT methotrexate 12 mg; cytarabine 40 mg; Dexamethasone was permanently discontinued in the setting of c hydrocortisone 50 mg. Patients received cranial radiation 1800 cGy symptomatic, radiographically confirmed osteonecrosis. Administration of delivered as 180 cGy fractions daily for 10 days. The dose was 24 Gy for asparaginase was held until the resolution of mild/moderate pancreatitis or patients with CNS-2 or CNS-3, regardless of CNS signs or symptoms. deep venous thrombosis and was permanently discontinued after severe d Asparaginase dose adjustments based on nadir serum asparaginase pancreatitis (signs and symptoms 472 h, see definitions below). Patients activity measurements. who experienced allergic reactions to E. coli asparaginase (of any severity, including local reactions) were switched to IM PEG asparaginase (2000 IU/ m /dose) administered every 2 weeks. Patients who reacted to PEG asparaginase were switched to IM Erwinia asparaginase (25 000 IU/m /dose twice weekly). Asparaginase was permanently discontinued after allergy to all available preparations. Table 2. Individualized asparaginase dose adjustments based on nadir serum asparaginase levels on the adult DFCI ALL Consortium Immunophenotype and cytogenetics Protocol Bone marrow cells from diagnostic aspirates were examined for cell surface NSAA (IU/ml) Change in subsequent asparaginase doses antigens using standard indirect immunofluorescence assays, and were cultured for standard G-banded metaphase cytogenetic analyses. Mole- o0.025 Increase by 80% from most recent dose cular analysis with real-time PCR allowed for the detection of BCR-ABL. 0.025 to o0.05 Increase by 60% 0.05 to o0.08 Increase by 40% Statistical methods 0.08 to o0.1 Increase by 20% The primary end point of this study was the proportion of patients who 0.1 to o0.14 No change completed 30 weeks of asparaginase treatment. A priori, it was determined 0.14 to o0.20 Decrease by 20% that the treatment would be considered ‘feasible’ if the one-sided lower 40.20 Decrease by 40% bound of the 90% exact binomial confidence interval (CI) for feasibility Abbreviations: ALL, acute lymphoblastic leukemia; NSAA, nadir (that is, the proportion of patients in whom it was feasible to administer serum asparaginase activity. Percentage change from most recent dose. this regimen for ⩾ 30 weeks) was 60% or higher, taking into account 2 2 Starting dose 12 500 IU/m . Minimum dose 6000 IU/m . Maximum dose patients who were removed from the study to undergo allogeneic stem 25 000 IU/m . cell transplantation. © 2015 Macmillan Publishers Limited Leukemia (2015) 526 – 534 Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al Outcome events were death during induction therapy, failure to achieve in the study prior to the protocol amendment excluding patients CR at the end of the 4-week induction phase, death during remission and with secondary ALL and age 450 years; and two patients were relapse. EFS was defined as the time from study registration to the first ineligible due to a diagnosis of Burkitt’s lymphoma. Patient outcome event among all patients. Disease-free survival (DFS) was defined demographics are shown in Table 3. Eighty-eight percent of as the time from CR to relapse or death, and only patients who achieved a patients were white and 94% non-Hispanic. Cytogenetic results CR were included in the calculation. Overall survival (OS) was defined as were available for 88 of the 92 eligible patients. Eighteen patients the time from study registration to the time of death from any cause for all (20%) were Philadelphia chromosome positive (Ph+); 8 (9%) had patients. Patients not experiencing an outcome event were censored at 11q23 (MLL) translocations; 13 (14%) were hyperdiploid (446 the date of last follow-up. Patients who went off treatment for a stem cell chromosomes: 9 with 47–50 chromosomes and 4 with 450 transplant in CR were not censored at the date of transplant, because chromosomes); 3 (3%) had hypodiploidy (o45 chromosomes); transplantation was the recommended treatment strategy for patients with high-risk cytogenetic abnormalities. EFS, DFS and OS were estimated 4 (4%) had 45 chromosomes and 60 (65%) were diploid. Sixty-six using the Kaplan–Meier method, and the Greenwood formula was used to patients (71%) had a Zubrod performance status of 0–1at construct 95% CI. Univariate analyses of the differences in EFS, DFS and OS diagnosis. were conducted with log-rank tests. The Common Terminology Criteria for Adverse Events (CTCAE) version Overall outcomes 2.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ docs/ctcmanual_v4_10-4-99.pdf) was used for coding toxicities. Toxicity Of the 92 eligible patients, 78 (85%) (90% exact CI: 77–91%) data reflect all submitted data, regardless of patient exclusion from achieved a CR at the end of the 4 weeks of induction therapy. One other analyses. patient died during induction due to sepsis, 10 patients (11%) had refractory disease at the end of induction (induction failure) and 3 Ph+ patients withdrew from protocol therapy to initiate imatinib Response assessment and definition of CNS status prior to achieving a CR. Sixteen of 18 (89%) patients with a T-cell Hematologic response was defined by standard criteria. The status of the immunophenotype achieved a CR, as did 62 of 74 patients (84%) cerebrospinal fluid (CSF) was defined as follows: CNS-1, no blast cells in with a pre-B-cell disease. cytospin, regardless of CSF cell count; CNS-2, fewer than five white blood cells on CSF cell count, with blasts on cytospin; CNS-3, five or more white Of the 78 patients who achieved CR, 16 underwent an allogeneic blood cells on CSF cell count, with blasts on cytospin. stem cell transplant during first remission: 11 were Ph+, 2 patients had a t(4;11) translocation, 1 patient had trisomy 8 and a t(9;12) translocation, 1 patient had a 9q34 translocation and 1 patient RESULTS had no cytogenetics available. Eleven of the 16 (69%) patients Patient characteristics who underwent transplant remain in first CR (CR1). Of the remaining 62 patients who achieved a CR and did not Between August 2002 and February 2008, 100 patients (ages undergo transplantation in CR1, 5 patients withdrew or never 18–50 years; median 28) were enrolled (see Figure 1). Eight initiated intensification therapy due to transfer of care (n = 1), patients were deemed ineligible and are excluded from further bone marrow relapse (n = 2), infection (n = 1) or withdrawal of analysis: two patients were removed from study prior to receiving consent (n = 1). Fifty-seven patients continued with intensification any chemotherapy, as they were found to have bilineage leukemia therapy with L-asparaginase. Forty-three of the 57 patients remain and received alternative therapy; four patients were enrolled early in CR1. Seven patients suffered a relapse (five bone marrow alone, one CNS alone and one CNS/optical), two patients died in Enrolled Patients remission due to pancreatitis or hepatic insufficiency and five N=100 deaths occurred while receiving off-protocol therapy. Ineligible N=8 With a median follow-up of 4.5 years (95% CI 4.1–5.0 years), the 4-year DFS for the 78 patients achieving a CR and OS for all 92 Eligible Patients eligible patients was 69% (95% CI 56–78%) and 67% (95% CI N=92 56–76%), respectively (Figure 2 and Table 4). For the 18 patients Induction Death N=1 Induction Failure N=10 who had Ph+ ALL, 14 (78%) achieved CR, 2 relapsed and 8 remain Withdrew prior to initiate in CR1. For the 74 patients who had Ph − ALL, 64 (86%) achieved imatinib/Ph+ N= 3 Complete Remission CR, 12 relapsed and 47 remain in CR1. The 4-year DFS and OS for N=78 Ph − patients with B-cell ALL was 66% (CI 50–78%) and 68% (CI 53–79%), respectively. The 4-year DFS and OS for patients with Withdrew N=2 T-cell ALL was 87% (CI 56–97%) and 76% (CI 49–90%), respectively Toxicity N=1 Early Relapse N=2 (Figures 2c and d and Table 4). EFS, DFS and OS rates were similar for patients between 18–30 and 31–50 years (Table 4). Outcomes st To SCT in 1 CR N=16 by Philadelphia chromosome status, immunophenotype, age and white blood count are shown in Table 4 and Figure 2. All Ph+ Initiated Asparaginase Alive in CCR N=11 patients had B-lineage ALL. Additional analyses of DFS and OS for Consolidation Therapy N=57 Ph − patients with B-lineage disease was performed, with patients transplanted in CR1 censored at the time of transplant. Results were unchanged (data not shown). Asparaginase tolerance Alive in CCR N=43 Relapse N=7 The primary focus of this study was to determine the feasibility of Remission Death N=2 Death after protocol therapy N=5 administering weekly IM E. coli asparagnase during the 30-week intensification phase. Among the 92 eligible patients, 57 patients Figure 1. DFCI ALL Consortium Protocol flow diagram. One hundred were evaluable for the asparaginase end point. The 35 patients patients with newly diagnosed ALL were enrolled. Ninety-two not evaluable for asparaginase tolerance had induction failure patients were considered eligible, of whom 78 (85%) achieved a (n = 10) or death (n = 1), initiated imatinib (3 patients), underwent complete remission within 1 month. Fifty-seven were evaluable for the asparaginase feasibility end point. All 92 patients were evaluable allogeneic stem cell transplantation (16 patients) and 5 were for analysis of EFS and OS. unevaluable as described above. Of the 57 evaluable patients, Leukemia (2015) 526 – 534 © 2015 Macmillan Publishers Limited Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al developed pancreatitis, 2 had allergic reactions to all asparaginase Table 3. Patient demographics and disease characteristics preparations, 6 had either a deep vein thrombosis or hepatic toxicity, 2 relapsed during the intensification phase, 1 withdrew N (%) due to non-compliance and 3 had other toxicities. N eligible patients 92 Asparaginase toxicity Age years, median (range) 28 (18, 50) Asparaginase-related toxicities included allergic reactions in 5 18–29 years 48 (52) patients (5%), thrombosis in 16 patients (17%) and pancreatitis in 30–50 years 44 (48) 10 patients (11%). There was 1 death related to pancreatitis, which occurred 10 days after completion of the 30th dose of Sex, male 56 (61) asparaginase. There were 8 bone fractures reported in 7 patients − 3 WBC at Dx × 10 , median (range) 15.5 (1.0, 360.0) and 5 patients developed osteonecrosis. Hepatic toxicity during o20 56 (61) the intensive asparaginase course was seen in 33 patients (53%), ⩾ 20 35 (38) including 10 patients who developed grade 3 or 4 hyperbilir- Unknown 1 (1) ubinemia, 3 patients who had liver dysfunction or failure (1 death); the remaining patients had transient elevations in the aspartate Immunophenotype transaminase or alanine transaminase enzyme levels. Both B cell 74 (80) T cell 18 (20) asparaginase-related and toxicities based on the CTCAE v. 2.0 are summarized in Table 5 by treatment phase. No second CNS status malignancies or clinical congestive heart failure were reported. CNS-1 (− ) CSF WBC o5 without blasts 79 (86) CNS-2 (+) CSF WBC o5 with blasts 4 (4) Individualized asparaginase dosing CNS-3 (+) CSF WBC ⩾5 with blasts 1 (1) Unknown 8 (9) Asparaginase activity was measured in 365 serum samples Philadelphia chromosome positive 18 (20) obtained from 54 patients 7 days after the prior dose of IM MLL rearrangement 8 (9) E. coli asparaginase during the intensification phase. The median Other Translocation 11 (12) number of evaluable NSAA samples obtained from each patient was 7 (range: 1–11). The median asparaginase dose (including Ploidy starting dose and all adjusted doses administered to patients Hypodiploidy (o45) 3 (3) (= 45) 4 (4) during the intensification phase) was 15 000 IU/m (range: 6000 Diploidy (= 46) 60 (65) –25 000 IU/ml) (Figure 3). Enzyme activity was o0.025 IU/ml in (= 47, 48, 49, 50) 9 (10) 20% (n = 74) of the samples, 0.025–0.099 IU/ml in 45% (n = 165), Hyperdiploidy (>50) 4 (4) 0.100–0.14 IU/ml in 14% (n = 51) and40.140 IU/ml in 21% (n = 75). Unknown 12 (13) The weekly median NSAA increased progressively until a plateau was achieved following the sixth dose. The steady-state median Performance status NSAA was 0.083 IU/ml (range: o0.025–0.66 IU/ml) for the 263 0 27 (29) samples collected from 48 patients after 6 weeks of dosing during 1 39 (42) 2 20 (22) which the median dose was 18 144 IU/m . Unknown 6 (7) In the presence of suspected silent allergy indicated by very low serial NSAA samples, 12 patients switched asparaginase preparation. ECOG risk classification Three patients received Erwinia asparaginase from which a total of SR 41 (45) 17 samples were collected: 6 were o0.025 IU/ml, 6 were 0.025– HR 51 (55) 0.099 IU/ml and 5 were40.14 IU/ml with an overall median of 0.057 (range: o0.025–0.595 IU/ml). In addition, 9 patients received PEG Race White 81 (88) asparaginase owing to unavailability of Erwinia asparaginase from Black or African American 4 (4) which a total of 37 samples were collected: 3 were o0.025 IU/ml, 3 Asian 2 (2) were 0.025–0.099 IU/ml and 31 were 40.14 IU/ml, with an overall American Indian or Alaska native 1 (1) median of 0.44 IU/ml (range: o0.025–2.45 IU/ml). Other 4 (4) Ethnicity CNS status Hispanic 5 (5) Five patients had CNS-2 or CNS-3 disease at the time of initial Non-Hispanic 86 (94) diagnosis. Subsequently, three of these patients experienced a Other 1 (1) relapse (one bone marrow, one CNS and one bone), one patient Abbreviations: CSF, cerebrospinal fluid; CNS, central nervous system; ECOG, was a remission death and one died after having completed Eastern Cooperative Oncology Group; HR, high risk; SR, standard risk; WBC, protocol therapy. There were no CNS relapses among the patients white blood cell. Eight B-cell patients and 1 T-cell patient had myeloid with CNS-1 disease at diagnosis. coexpression. Detected by cytogenetics (n= 17), both reverse transcriptase-PCR and fluorescence in situ hybridization (n= 1). ECOG risk is defined as follows: HR includes any patients with an MLL rearrangement DISCUSSION or Ph+ and B-cell patients with WBC⩾ 35 K or age ⩾ 35 years and T-cell Several retrospective analyses have compared treatment outcomes patients with WBC⩾ 100 K. for young adult patients treated with either pediatric or adult regimens, all of which have demonstrated superior outcomes for 9–13 36 (63%) completed all 30 doses with a one-sided lower exact 90% patients treated with pediatric ALL protocols. These striking binomial confidence bound of 54%, and 41 patients (72%) differences in outcome cannot be explained simply on the basis of completed 26 or more doses of asparaginase with a one-sided different biology or median age, because the pediatric and young lower exact 90% binomial confidence bound of 63%. Of the 21 adult cohorts in these studies had similar rates of Ph+ and MLL gene- patients who did not complete the 30 doses of asparaginase, 7 rearranged ALL, and other high-risk and immunophenotypic features. © 2015 Macmillan Publishers Limited Leukemia (2015) 526 – 534 Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al Figure 2. (a and b) represent the OS for 92 eligible patients and DFS for 78 patients who achieved a CR, respectively. With a median follow-up of 4.5 years, the 4-year OS for all 92 patients on protocol was 67% (95% CI; 56–76%) and the 4-year DFS was 69% (95% CI; 56–78%) for the 78 patients who achieved a CR. The solid lines represent the Kaplan–Meier estimates, and the dashed lines represent the 95% confidence bands about those estimates. (c and d) Represent OS and DFS by immunophenotype and Philadelphia chromosome status, respectively. Some of the reported differences between pediatric and adult typical pediatric regimens and adult regimens. Nevertheless, the outcomes have been attributed to attention to detail of therapy, 2-year EFS was 56% in the French study with a 2-year OS of 66%, such as attaining maximal dose intensification and timely both improvements from historical controls. The French GRAALL scheduling of drug delivery. The latter has been reported to study made use of an intensified induction therapy for poor steroid result in systematic delays in administering drugs. Most children responders, allocation of higher risk (based on disease features) with ALL are referred to academic centers and treated on clinical patients to allogeneic transplant and enrollment of patients up to an trials, whereas most adults with ALL are not. In addition, pediatric age of 60 years. However, the improved outcomes noted in the regimens administer early and more intensive CNS therapy as French study were limited to patients under the age of 45 years. The compared with adult regimens. Spanish study administered the pediatric PETHEMA ALL-96 regimen In addition, it is possible that many young adults and adolescents to patients up to the age of 30 years and showed a similar outcome are currently being ‘under dosed’ when treated on standard adult as compared with adolescent patients of age 15–18 years. ALL regimens due to lower total doses of corticosteroids, vinca Furthermore, a recent meta-analysis further supports the adminis- alkaloids and asparaginase. Our experience suggests that adults 50 tration of pediatric-inspired regimens for young adult patients. years old and younger tolerate a pediatric regimen, and that such A critical biologic difference between the pediatric and young therapy resulted in improved outcomes compared with historical adult populations pertains to the relative incidence of Ph+ disease. controls. These findings were consistent with recent reports from In our concurrently conducted pediatric (1–18 year olds) and young 22–24 French, Canadian and Spanish investigators. In both the French adult (418–50 year olds) protocols, the incidence of Ph+ leukemia and the Canadian studies, patients received significantly more was 3 and 18%, respectively. As shown in Table 4 and Figure 3, the prednisone, vincristine and asparaginase than in prior adult outcome for Ph − patients treated on the current study was regimens. Those experiences differed from ours in that the same relatively favorable. This finding is of particular importance because pediatric regimen was not offered to adult patients; instead, the outcomes from a recent Eastern Cooperative Oncology Group/ investigators employed a regimen of intermediate intensity between Medical Research Council trial reported that allogeneic stem cell Leukemia (2015) 526 – 534 © 2015 Macmillan Publishers Limited Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al Table 4. Outcome by patient characteristics 4-year DFS (%) 95% CI P-value 4-year EFS (%) 95% CI P-value 4-year OS (%) 95% CI P-value N 78 92 92 All patients 69 (56–78) 58 (47–68) 67 (56–76) Age (years) 18–29 70 (52–83) 0.54 55 (39–69) 0.61 68 (52–80) 0.93 30–50 67 (50–79) 61 (44–74) 65 (49–77) Sex Male 64 (47–77) 0.47 51 (37–64) 0.15 64 (50–76) 0.28 Female 75 (56–87) 69 (51–81) 71 (52–83) % Blasts at Dx 0–30 70 (53–82) 0.77 58 (43–71) 0.92 65 (50–77) 0.79 430 67 (47–81) 58 (40–72) 69 (52–82) –3 WBC at Dx × 10 o20 74 (59–84) 0.073 70 (56–80) o0.001 80 (66–88) 0.001 ⩾ 20 55 (32–73) 37 (21–53) 45 (28–61) Immunophenotype B cell 64 (50–75) 0.11 53 (41–64) 0.11 64 (52–74) 0.20 T cell 87 (56–97) 77 (49–91) 76 (49–90) CNS status CNS-1 ( − ) 75 (62–84) o0.001 62 (50–72) 0.005 71 (59–80) o0.001 CNS-2/3 (+) 0 (NA) 0 (NA) 0 (NA) Ph+ Yes 54 (25–76) 0.13 42 (19–63) 0.091 53 (28–73) 0.12 No 71 (58–81) 62 (49–72) 70 (58–79) MLL rearrangement Yes 63 (23–86) 0.48 63 (23–86) 0.86 60 (20–85) 0.83 No 69 (56–79) 58 (46–68) 67 (56–77) Ploidy High hyperdiploid (450) 75 (13–96) 0.95 75 (13–96) 0.57 75 (13–96) 0.74 Other 66 (52–77) 54 (42–65) 64 (52–74) Performance status 0–1 69 (55–80) 0.52 59 (45–70) 0.81 70 (57–80) 0.42 2 63 (36–82) 57 (32–76) 55 (30–75) ECOG risk SR 81 (63–91) 0.016 70 (53–82) 0.051 80 (64–90) 0.038 HR 57 (41–71) 48 (33–61) 55 (40–68) Immuno/Ph+ status T cell 87 (56–97) 0.14 77 (49–91) 0.11 76 (49–90) 0.12 B-cell Ph − 66 (50–78) 57 (42–69) 68 (53–79) B-cell Ph+ 54 (25–76) 42 (19–63) 53 (28–66) Abbreviations: CI, confidence interval; CNS, central nervous system; DFS, disease-free survival; EFS, event-free survival; HR, high risk; Ph, Philadelphia chromosome; OS, overall survival; SR, standard risk; WBC, white blood cell. transplantation offered superior OS compared with either chosen because we had previously shown that, in children, tolerance to asparaginase was associated with an exceptionally chemotherapy or autologous stem cell transplantation for 26 28 adults with standard-risk ALL. However, the OS for the favorable outcome. There was uncertainty whether adults could tolerate such intensive therapy. Our a priori protocol definition of Philadelphia-negative patients in the Eastern Cooperative Oncology Group/Medical Research Council study was only 53%, compared feasibility was based on completion of the full 30 weeks of asparaginase, but our pediatric data suggest that completion of 26 with an OS of 68% for Ph − patients treated on the current protocol. The 4-year OS for T-ALL patients on the current trial (76%) or more of the planned 30 weeks of asparaginase was similarly efficacious. We found that 72% of the patients who initiated the also compares favorably to published outcomes for adults with this subtype. 30-week asparaginase course were able to receive 26 or more We sought to determine the feasibility of treating a young adult doses (87% of targeted therapy), similar to, although slightly lower population with an intensive pediatric-inspired ALL regimen. Our than the proportion of pediatric patients. The incidence of major primary end point was the proportion of patients who completed asparaginase-related toxicities, such as pancreatitis, and throm- 30 weeks of high-dose asparaginase therapy. This end point was bosis was also similar to that reported in older children. © 2015 Macmillan Publishers Limited Leukemia (2015) 526 – 534 Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al Table 5. Toxicity summary in eligible patients–overall and by treatment phase Overall N (%) Induction N (%) CNS N (%) Intensification N (%) Continuation N (%) No. patients reporting 92 92 67 62 48 CTC grade 3–5 toxicity Neutrophils 86 (93) 82 (89) 10 (15) 52 (84) 22 (46) Platelets 75 (82) 72 (78) 1 (1) 17 (27) 5 (10) Febrile neutropenia 30 (33) 20 (22) 0 (0) 10 (16) 3 (6) Infection with grade 3/4 neutropenia 49 (53) 41 (45) 1 (1) 11 (18) 6 (13) Infection—other 7 (8) 2 (2) 1 (1) 3 (5) 2 (4) Hepatic 57 (62) 24 (26) 5 (7) 33 (53) 21 (44) Hyperglycemia 41 (45) 36 (39) 1 (1) 12 (19) 5 (10) Stomatitis 10 (11) 4 (4) 1 (1) 5 (8) 0 (0) CNS hemorrhage 1 (1) 1 (1) 0 (0) 1 (2) 0 (0) Seizure 4 (4) 1 (1) 0 (0) 3 (5) 1 (2) Asparaginase-related toxicity Pancreatitis 10 (11) 1 (1) 0 (0) 8 (13) 2 (4) Allergy/rash 5 (5) 1 (1) 0 (0) 4 (6) 0 (0) Thrombosis/embolism 16 (17) 1 (1) 0 (0) 14 (23) 2 (4) Bone fracture 7 (8) 0 (0) 0 (0) 3 (5) 5 (10) Avascular necrosis 5 (5) 0 (0) 0 (0) 2 (3) 4 (8) Abbreviation: CNS, central nervous system. There were five grade 5 events—one in each category shown and one leukoencephalopathy. Routine sampling of CSF at time of diagnosis (and concomitant administration of intrathecal chemotherapy) is a pediatric standard of care, but not necessarily so in adult ALL. Our study prospectively determined the incidence and outcome of CNS status at the time of diagnosis. We found asymptomatic CSF involvement in five (5%) patients at the time of diagnosis. Such patients received more intensive CNS therapy (a higher dose of cranial radiation and additional doses of intrathecal therapy). Of these five patients, only one relapse involved the CNS and supports the routine use of both CNS-directed diagnosis and risk- stratified treatment of adults with ALL. Most, but not all, adult ALL trials report the incidence of CR after 6,30,31 2 months of therapy. In the current trial, we employed a strategy of removing patients from protocol therapy if they did not achieve a CR after 4 weeks of therapy, as several pediatric trials reported that absence of CR after 1 month, despite presence of CR after 2 months, was associated with poor long-term 32–34 outcomes. Although this strategy may have increased our rate of induction failure compared with studies, which allowed for two induction attempts, the CR rate on our protocol was still 85%. In our current second-generation pediatric-inspired therapy for adults with ALL, we allow two cycles of chemotherapy prior to deciding induction results (NCT00476190). We believe such an approach will lead to a higher CR rate and provide an opportunity for more young adults with ALL to potentially benefit from pediatric-type consolidation strategies. In conclusion, the results of this study support that the use of a pediatric-inspired chemotherapy regimen is associated with excel- lent long-term results in children, and can be safely and efficaciously applied to adults aged 18–50 years. The 69% 4-year DFS rate reported in the current study suggests that the administration of a pediatric-inspired regimen to adult patients is meritorious, resulting in a high rate of durable CRs. Further studies, such as the US intergroup trial CALGB 10403, will hopefully confirm these results with the goal that the natural history of ALL in adults under age 50 years will be favorably impacted. CONFLICT OF INTEREST Figure 3. (a and b) Median asparaginase dose and nadir serim DJDA has received honoraria for speaking engagements from Sigma Tau. LBS has asparaginase activity during the 30-week Consolidation Course. received honoraria for serving on advisory boards for Sigma Tau and EUSA. JGS has Error bars extend to the 25th and 75th percentiles. received research support from Sigma Tau Research Inc. and EUSA Pharma (US) Inc. Leukemia (2015) 526 – 534 © 2015 Macmillan Publishers Limited Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al LAS has received honoraria for speaking engagements from Sigma Tau and Celgene. 13 Ramanujachar R, Richards S, Hann I, Goldstone A, Mitchell C, Vora A et al. SES has received research support honoraria for speaking engagements from Sigma Adolescents with acute lymphoblastic leukaemia: outcome on UK national pae- Tau, and consulted for Jazz Pharmaceuticals. The remaining authors declare no diatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer 2007; 48: 254–261. conflict of interest. 14 Ahlke E, Nowak-Gottl U, Schulze-Westhoff P, Werber G, Borste H, Wurthwein G et al. Dose reduction of asparaginase under pharmacokinetic and pharmacody- namic control during induction therapy in children with acute lymphoblastic ACKNOWLEDGEMENTS leukaemia. Br J Haematol 1997; 96:675–681. We thank Susan Buchanan, PA-C, Adriana Penicaud, PA-C and Kristina Hines for 15 Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ et al. technical assistance. This study was supported in part by NIH Grant PO1 CA068484. A randomized comparison of native Escherichia coli asparaginase and Sigma Tau has partially funded the laboratory performing Asparaginase enzyme level polyethylene glycol conjugated asparaginase for treatment of children with testing. newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 2002; 99: 1986–1994. 16 Berg SL, Balis FM, McCully CL, Godwin KS, Poplack DG. Pharmacokinetics of AUTHOR CONTRIBUTIONS PEG-L-asparaginase and plasma and cerebrospinal fluid L-asparagine concentra- tions in the rhesus monkey. Cancer Chemother Pharmacol 1993; 32: 310–314. DJDA was the overall principal investigator, performed research, analyzed data 17 Boos J, Werber G, Ahlke E, Schulze-Westhoff P, Nowak-Gottl U, Wurthwein G et al. and wrote the manuscript. KES was the principal statistician, analyzed data and Monitoring of asparaginase activity and asparagine levels in children on different edited the manuscript. SED was the principal statistician, analyzed data and asparaginase preparations. Eur J Cancer 1996; 32A:1544–1550. edited the manuscript. LBS, SES and RMS assisted in the writing of the protocol, 18 Riccardi R, Holcenberg JS, Glaubiger DL, Wood JH, Poplack DG. L-asparaginase performed research and edited the manuscript. SC, JGS, PCA, KKB, MDS, ART, BL, pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys KH-J, KK, SC, JHM, LS, MW, LAS and IG performed research and edited the and humans. Cancer Res 1981; 41: 4554–4558. 19 Rizzari C, Zucchetti M, Conter V, Diomede L, Bruno A, Gavazzi L et al. L-asparagine manuscript. depletion and L-asparaginase activity in children with acute lymphoblastic leu- kemia receiving i.m. or i.v. Erwinia C. or E. coli L-asparaginase as first exposure. Ann Oncol 2000; 11:189–193. REFERENCES 20 Vrooman LM, Supko JG, Neuberg DS, Asselin BL, Athale UH, Clavell L et al. Erwinia 1 Silverman LB, Stevenson KE, O'Brien JE, Asselin BL, Barr RD, Clavell L et al. asparaginase after allergy to E. coli asparaginase in children with acute lym- Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for phoblastic leukemia. Pediatr Blood Cancer 2010; 54:199–205. children with newly diagnosed acute lymphoblastic leukemia (1985-2000). 21 Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH et al. Leukemia 2010; 24: 320–334. Revised recommendations of the International Working Group for diagnosis, 2 Gaynon PS, Angiolillo AL, Carroll WL, Nachman JB, Trigg ME, Sather HN et al. standardization of response criteria, treatment outcomes, and reporting stan- Long-term results of the children's cancer group studies for childhood acute dards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003; 21: lymphoblastic leukemia 1983-2002: a Children's Oncology Group Report. 4642–4649. Leukemia 2010; 24: 285–297. 22 Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E et al. Pediatric- 3 Moricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H et al. inspired therapy in adults with Philadelphia chromosome-negative acute Long-term results of five consecutive trials in childhood acute lymphoblastic lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 2009; 27:911–918. leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 23 Storring JM, Minden MD, Kao S, Gupta V, Schuh AC, Schimmer AD et al. Treatment 2010; 24: 265–284. of adults with BCR-ABL negative acute lymphoblastic leukaemia with a modified 4 Pui CH, Pei D, Sandlund JT, Ribeiro RC, Rubnitz JE, Raimondi SC et al. Long-term paediatric regimen. Br J Haematol 2009; 146:76–85. results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood 24 Ribera JM, Oriol A, Sanz MA, Tormo M, Fernandez-Abellan P, del Potro E et al. acute lymphoblastic leukemia. Leukemia 2010; 24: 371–382. Comparison of the results of the treatment of adolescents and young adults with 5 Vrooman LM, Stevenson KE, Supko JG, O'Brien J, Dahlberg SE, Asselin BL et al. standard-risk acute lymphoblastic leukemia with the Programa Espanol de Tra- Postinduction dexamethasone and individualized dosing of Escherichia Coli tamiento en Hematologia pediatric-based protocol ALL-96. J Clin Oncol 2008; 26: L-asparaginase each improve outcome of children and adolescents with newly 1843–1849. diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana- 25 Ram R, Wolach O, Vidal L, Gafter-Gvili A, Shpilberg O, Raanani P. Adolescents and Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 2013; 31: young adults with acute lymphoblastic leukemia have a better outcome when 1202–1210. treated with pediatric-inspired regimens: systematic review and meta-analysis. 6 Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S et al. Long-term Am J Hematol 2012; 87: 472–478. follow-up results of hyperfractionated cyclophosphamide, vincristine, 26 Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK et al. doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in In adults with standard-risk acute lymphoblastic leukemia, the greatest benefitis adult acute lymphocytic leukemia. Cancer 2004; 101: 2788–2801. achieved from a matched sibling allogeneic transplantation in first complete 7 Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM et al. Induction remission, and an autologous transplantation is less effective than conventional therapy for adults with acute lymphoblastic leukemia: results of more than 1500 consolidation/maintenance chemotherapy in all patients: final results of the patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005; International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008; 111: 1827–1833. 106: 3760–3767. 27 Hoelzer D, Gokbuget N, Digel W, Faak T, Kneba M, Reutzel R et al. Outcome of 8 Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N et al. Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for treatment in adults with acute lymphoblastic leukemia: analysis of the acute lymphoblastic leukemia. Blood 2002; 99: 4379–4385. LALA-94 trial. J Clin Oncol 2004; 22: 4075–4086. 28 Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA et al. Improved 9 Stock W, La M, Sanford B, Bloomfield CD, Vardiman JW, Gaynon P et al. What outcome for children with acute lymphoblastic leukemia: results of Dana-Farber determines the outcomes for adolescents and young adults with acute lym- Consortium Protocol 91-01. Blood 2001; 97: 1211–1218. phoblastic leukemia treated on cooperative group protocols? A comparison of 29 Barry E, DeAngelo DJ, Neuberg D, Stevenson K, Loh ML, Asselin BL et al. Favorable Children’s Cancer Group and Cancer and Leukemia Group B studies. Blood 2008; outcome for adolescents with acute lymphoblastic leukemia treated on 112: 1646–1654. Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium 10 Boissel N, Auclerc MF, Lheritier V, Perel Y, Thomas X, Leblanc T et al. Should Protocols. J Clin Oncol 2007; 25:813–819. adolescents with acute lymphoblastic leukemia be treated as old children or 30 Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P et al. A five-drug young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin remission induction regimen with intensive consolidation for adults with acute Oncol 2003; 21: 774–780. lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 1995; 85: 11 de Bont JM, Holt B, Dekker AW, van der Does-van den Berg A, Sonneveld P, Pieters R. 2025–2037. Significant difference in outcome for adolescents with acute lymphoblastic 31 Larson RA, Dodge RK, Linker CA, Stone RM, Powell BL, Lee EJ et al. A randomized leukemia treated on pediatric vs adult protocols in the Netherlands. Leukemia controlled trial of filgrastim during remission induction and consolidation 2004; 18: 2032–2035. chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. 12 Testi A, Valsecchi M, Conter V, Vignetti M, Paoloni F, Giona F et al. Difference in Blood 1998; 92: 1556–1564. outcome of adolescents with acute lymphoblastic leukemia (ALL) enrolled in 32 Oudot C, Auclerc MF, Levy V, Porcher R, Piguet C, Perel Y et al. Prognostic factors pediatric (AIEOP) and adult (GIMEMA) protocols [abstract]. Blood 2004; 104: 539a. for leukemic induction failure in children with acute lymphoblastic leukemia and © 2015 Macmillan Publishers Limited Leukemia (2015) 526 – 534 Long-term outcome of a pediatric-inspired regimen DJ DeAngelo et al outcome after salvage therapy: the FRALLE 93 study. J Clin Oncol 2008; 26: This work is licensed under a Creative Commons Attribution- 1496–1503. NonCommercial-NoDerivs 4.0 International License. The images or 33 Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A et al. Outcomes other third party material in this article are included in the article’s Creative Commons after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med license, unless indicated otherwise in the credit line; if the material is not included under 2012; 366: 1371–1381. the Creative Commons license, users will need to obtain permission from the license 34 Silverman LB, Gelber RD, Young ML, Dalton VK, Barr RD, Sallan SE. Induction holder to reproduce the material. To view a copy of this license, visit http:// failure in acute lymphoblastic leukemia of childhood. Cancer 1999; 85: 1395–1404. creativecommons.org/licenses/by-nc-nd/4.0/ Leukemia (2015) 526 – 534 © 2015 Macmillan Publishers Limited

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LeukemiaSpringer Journals

Published: Jul 31, 2014

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