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Blood First Edition Paper, prepublished online March 24, 2015; DOI 10.1182/blood-2014-11-551481
Title: How I Treat: Acute Lymphoblastic Leukemia in Older Adolescents and Young Adults (AYAs) Running Title: Treatment of ALL in Adolescents and Young Adults (AYAs) Authors: Emily Curran, MD (first author); Wendy Stock, MD (corresponding author) Affiliate Institutions: University of Chicago and University of Chicago Comprehensive Cancer Center Corresponding author’s name/contact: Wendy Stock, MD 5841 S. Maryland Ave, M/C2115 Chicago IL 60637 Phone: 773-834-8982 Fax: 773-702-3163 Email: [email protected]
Copyright © 2015 American Society of Hematology
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Abstract At the intersection between children and older adults, the care of adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) poses unique challenges and issues beyond those faced by other age groups. While the survival of AYA patients is inferior to younger children, growing evidence suggests that AYA patients have improved outcomes, with disease free survival rates of 60-70%, when treated with pediatric-based approaches. A holistic approach, incorporating a multidisciplinary team, is a key component of successful treatment of these AYA patients. With the appropriate support and management of toxicities during and following treatment, these regimens are well-tolerated in the AYA population. Even with the significant progress that has been made during the last decade, patients with persistence of minimal residual disease (MRD) during intensive therapy still have a poor prognosis. With new insights into disease pathogenesis in AYA ALL and availability of disease-specific kinase inhibitors and novel targeted antibodies, future studies will focus on individualized therapy to eradicate MRD and result in further improvements in survival. This case-based review will discuss the biology, pharmacology, and psychosocial aspects of AYA patients with ALL, highlighting our current approach to the management of these unique patients. Introduction Acute lymphoblastic leukemia (ALL), a relatively rare malignancy, is one of the few cancers that impacts the entire lifespan, from neonates to the very elderly.1 While survival now approaches 90% for most children with ALL,2,3 older adolescents and young adults (AYA) historically have a much poorer prognosis, with an event-free survival (EFS) of only 30-45%.4-6 Factors accounting for differences in outcome include heterogeneity in disease biology, host factors (both physiologic and psychosocial) and, importantly, the therapeutic approach and experience of the health care teams.7-11 Some authors also suggest that AYAs may have had poorer outcomes, in part, because of low rates of clinical trial enrollment.12 Between 1997 and 2003, fewer than 2% of older adolescents were enrolled in clinical trials, compared to 60% of pediatric patients,13 potentially due to fewer referrals to institutions where clinical trials are offered, limited numbers of clinical trials available for the AYA population and psychosocial barriers.14 During the last decade, recognition of the unique characteristics of AYAs with ALL as well as a new focus on clinical research designed specifically for this population has led to exciting improvements in treatment outcomes, with EFS now approaching 70% for AYA ALL. The National Cancer Institute has defined the AYA cancer population broadly – ages 15-39 years old.15 While tremendous heterogeneity in this population clearly exists,16 and the age cut-off of 40 years is somewhat arbitrarily defined, emerging clinical, psychosocial, and biologic features of the disease suggest this may be a distinct population.17,18 This case-based review will focus on the AYA population most commonly treated by adult hematologists-oncologists – patients ages 18 to 39 years old. Patient 1 A 28 year-old man presents with night sweats, fatigue, palpitations and abdominal pain. He is found to have a white blood cell count of 23 x 109/L and bulky organomegaly. Bone marrow biopsy is consistent with precursor B cell ALL (CD19+, CD20-, CD10+,CD22+, CD79a+, CD34+ and TdT+). Fluorescence in situ hybridization (FISH) is negative for MLL rearrangement, BCR/ABL1, ETV5/RUNX1 and trisomies 4, 10, and 17. Cytogenetics shows a normal male karyotype.
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What is our approach? If available, we would encourage enrollment onto a clinical trial focused on AYAs with ALL that builds upon an intensive pediatric approach to treatment. Rationale: Treatment approaches for AYAs with ALL vary considerably, with the choice of regimen predicated on the familiarity and expertise of the treating physician, the availability of a clinical trial and, most importantly, the “door” that the patient enters – into a pediatric or an adult treatment center. In the United Kingdom, AYA inpatient treatment units already exist and this may facilitate a more uniform treatment approach. However, in the United States, patients younger than 18 years old are traditionally treated in pediatric departments whereas AYAs older than 18 are treated by adult hematologists/oncologists and therefore receive “adult” ALL regimens. These “adult” regimens typically consist of intensive use of myelosuppressive agents including daunorubicin, cytarabine, and cyclophosphamide, as well as allogeneic stem cell transplant in first remission.5,19,20 In contrast, pediatric regimens focus on the BerlinFrankfurt-Munster (BFM) backbone of ALL therapy:21 glucocorticoids, vincristine, asparaginase, early and frequent central nervous system (CNS) prophylaxis and prolonged maintenance therapy.22-25 Retrospective studies from large North American and European groups suggest that AYAs have superior outcomes when treated with “pediatric” regimens,21-25 and may approach those of younger children, with 5-year EFS of over 70%.26,27 Based on these data, as well as the prospective studies described below, we recommend that AYA patients be treated on a pediatric-based regimen. Encouraging survival outcomes for AYAs with ALL treated with “pediatric-inspired” regimens have recently been reported from a number of prospective cooperative group clinical trials performed in Europe and the United States.23,28-33 These trials showed an improvement in both EFS and overall survival (OS) compared to historical controls, with greater than 60% EFS and OS in the majority of studies.23,28-33 Both retrospective and prospective studies have included both B- and T-cell ALL, with quite similar EFS and OS.29,33,34 Importantly, while some groups have noted slightly poorer tolerability,29 and certain toxicities (such as hepatotoxicity) may be more common in an older population, overall these regimens have demonstrated feasibility in the AYA population. Several of these trials and regimens are outlined in Table 1 and also reviewed in a recent metaanalysis.35 The largest prospective study to evaluate the feasibility of a pediatric regimen in AYA ALL patients is the US intergroup study, C10403.36 Between November 2007 and December 2012, 318 AYAs between 16-39 years of age were treated based on the standard arm of the Children’s Oncology Group regimen (COG AALL0232).37 This study demonstrated that toxicities were manageable, with low treatment-related mortality (3%), and that treatment with this pediatric regimen is feasible when administered by adult hematologist/oncologists to an AYA population up to 40 years of age.36 On this regimen, the 2-year EFS and OS were 66% and 78%, respectively.34 Based on these very encouraging early results, the US cooperative groups are now designing a successor study using the C10403 platform that will attempt to incorporate novel targeted agents to further improve treatment outcomes. While the majority of recent studies demonstrate a survival benefit using intensive pediatric regimens for AYA, another recently published comparison study of an “adult” regimen (hyper-CVAD) versus a pediatric regimen (BFM-like) found equivalent EFS (approximately 70%).20 Because this trial was conducted at an institution with a large,
3
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experienced leukemia program, the results may not be widely generalizable but suggest that high-volume referral centers may offer benefits beyond chemotherapeutics. In fact, recent data show that outcomes for AYAs with ALL are significantly improved if treatment is administered at a university or NCI-sponsored cancer center with expertise in the complex regimens used to treat ALL.38 Treating AYA patients with pediatric-based regimens has resulted in impressive increases in EFS from 39% to 60-70%. However, further progress is still needed. Several novel agents that have shown impressive activity for relapsed/refractory disease are being evaluated in the frontline setting and will be included in the next generation of prospective clinical trials for AYAs with ALL. For instance, inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, appears to be safe and active in relapsed/refractory ALL, with response rates of 58-82% in recent clinical trials.39,40 Blinatumomab, a bispecific T-cell engaging (BiTE) antibody that directs cytotoxic T-cells to CD19-expressing target cells, had a 43% response rate in Ph-negative relapsed/refractory precursor B ALL,41 and recently received FDA approval in relapsed disease. Incorporating these agents into front-line chemotherapy will hopefully help to eradicate MRD and result in further improved survival for AYA patients. Blinatumomab is being added to frontline therapy in an ongoing trial for adults with ALL 30-70 years old (NCT02003222)42 and an NCI-approved study in the AYA population (ages 18-39 years) will test the addition of inotuzumab ozogamicin to the C10403 backbone.
Patient 1 (continued) This patient is started on induction chemotherapy according to the C10403 protocol. What prevention and monitoring should be performed in this patient during induction therapy? We recommend administering induction therapy as an inpatient until neutrophil recovery. Early treatment toxicities, including febrile neutropenia, hyperglycemia and hepatic toxicity occur commonly during induction (typically days 10-20) and can be more safely managed with close inpatient observation. We also treat with allopurinol for the first ten days of induction therapy to prevent hyperuricemia. Following induction therapy, the remainder of treatment can be safely administered as an outpatient. For antimicrobial prophylaxis, we recommend antiviral (acyclovir) and PCP prophylaxis (typically trimethoprim-sulfamethoxazole) throughout treatment (including maintenance therapy), keeping in mind that no sulfa drug or non-steroidal anti-inflammatory medications should be given on the days that the patient receives methotrexate. Fungal prophylaxis should include mold coverage during induction therapy. However, broader spectrum azole antifungals cannot be used with vincristine because of the risk of exacerbating vincristine-induced peripheral neuropathy. Therefore, we typically use an echinocandin such as micafungin for prophylaxis during induction and switch to fluconazole for outpatient management during consolidation therapy. Asparaginase related toxicities are a challenge when intensive pediatric-inspired regimens are used in the AYA population. The only asparaginase preparation available in North America for frontline ALL therapy is a long-acting pegylated form of asparaginase, PEG-asp. Little is known about the pharmacokinetics of PEG-asp in AYAs or older adults with ALL.10,11 A dose of 2500 IU/m2 PEG-asp, which was used in
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both the COG ALL 0232 and the C10403 trials, appears to result in greater hepatic toxicity in the AYA population, particularly during induction chemotherapy;36 thus, we and others have routinely begun to cap the dose at one vial, or 3750 IU. New methods for safer and more accurate dosing of PEG-asp are available, including a recently FDAapproved assay for measurement of asparaginase activity levels. Pediatric studies have demonstrated that achievement of asparaginase levels of greater than 100U/L for fourteen days following a dose of PEG-asp is associated with improved treatment outcomes.43 Our group and others have begun to prospectively test the use of lower initial doses of PEG-asp with subsequent dose adjustment, if necessary, to achieve adequate (but not excessive) asparaginase levels.32 While we are hopeful that levelbased dose adjustment may facilitate the safe use of PEG-asp in AYAs, prospective clinical trials are required to validate this hypothesis. Importantly, asparaginase activity levels allow for detection of “silent” inactivation, which may occur without clinical symptoms in up to one-tenth of patients, as a result of antibody neutralization of asparaginase.43,44 Switching asparaginase preparations when silent inactivation occurred resulted in improved EFS in a pediatric population.43 Asparaginase-related hypersensitivity reactions occur in as many as 20% of children and adults. Therefore, we routinely pre-medicate our patients with diphenhydramine, hydrocortisone and acetaminophen prior to each dose of PEG-asp. In C10403, we found that premedication resulted in a decline in significant hypersensitivity reactions to PEGasp from 15% to 6%.36 If an anaphylactic reaction occurs, no further PEG-asp is administered and we switch to Erwinia asparaginase at a dose of 25,000 IU/m2. While some may be concerned about failing to detect antibodies to asparaginase when patients are pre-medicated (resulting in silent inactivation), previous reports have demonstrated that this is a relatively uncommon event with PEG-asp.45 Furthermore, the FDA-approved assay to measure serum asparaginase levels will obviate this concern. An alternative approach in these patients would be to avoid premedication but, if hypersensitivity occurs, manage the acute toxicities and be prepared to switch to Erwinia asparaginase for subsequent treatment. Other serious toxicities of asparaginase include asthenia, pancreatitis, thrombosis, and bleeding. For a more detailed discussion regarding prevention and treatment of asparaginase toxicities in adults, a comprehensive set of recommendations was recently published by an expert panel.46 Patient 1 (continued) This patient completes induction therapy per C10403 protocol without significant complications. Bone marrow biopsy shows complete remission with no detectable minimal residual disease (MRD) by flow cytometry. When should allogeneic transplant in first complete remission (CR1) be considered? What role does MRD monitoring play in decisions for treatment? A large prospective randomized international collaborative study (MRC UKALL XII/E2993) demonstrated a significant increase in OS for allogeneic transplant in CR1 when compared to a standard adult ALL regimen (63% versus 52%).19 In contrast, a very recent International Bone Marrow Transplant Registry (IBMTR) study of adults 1850 years old found a significant benefit (HR 3.1; p5% lymphoblasts or M1 marrow with ≥1% lymphoblasts
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Number of patients Median age at diagnosis (range) Gender
DFCI Adult ALL 01-17532 Patient population
Consolidation1/Intensification
Dexamethasone 10mg/m2 PO/IV (day 1-14) 5mg/m2 PO/IV (day 15-21) Vincristine 1.5 mg/m2 - maximum 2mg IV (day 1, 8, 15) Daunorubicin 30mg/m2 IV (day 1, 2, 8, 9) Cyclophosphamide 600mg/m2 (day 1, 15) Asparaginase 10,000 U/m2 IV (day 1-3, 15-17)
Cycles every 3 weeks x 30 weeks Vincristine 2 mg (day 1) Methotrexate 30m/m2 IV/IM weekly Dexamethasone 18mg/m2 PO (day 1-5) Mercaptopurine 50mg/m2 PO (day 1-14) E. coli asparaginase 12,500 IU/m2 starting dose Doxorubicin 30mg/m2 IV (day 1)
Vincristine 1.5 mg/m2 - maximum 2mg IV (day 15, 22, 43, 50) Cyclophosphamide 1,000mg/m2 (day 1, 29) Cytarabine 500mg/m2 IV/SC (day 1-4, 811, 29-32, 36-39) Mercaptopurine 60mg/m2 PO (day 1-14, 2942) PEG-Asparaginase 2500 IU/m2 IM/IV (day 15, 43)
N/A
Duration: 8 weeks Vincristine 1.5 mg/m2 - maximum 2mg IV (day 1, 11, 21, 31, 41) Methotrexate 100m/m2 IV starting, with dose escalation (day 1, 11, 21, 31, 41) PEG-Asparaginase 2500 IU/m2 IM/IV (day 2, 22)
13
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Consolidation-2/ Interim Maintenance
Mercaptopurine 50mg/m2 PO (day 1-7) Methotrexate 3g/m2 IV (day 1, 28, 56) VM-26 150mg/m2 IV (day 14, 42) Cytarabine 500mg/m2 IV (day 14-15, 4243)
Delayed Intensification
Maintenance-1 (until week 52) Methotrexate IM 20mg/m2/wk Mercaptopurine PO 50mg/m2/d Reinduction (every 4 weeks) Vincristine 1.5 mg/m2 maximum 2mg IV (day 1) Prednisone 60mg/m2/day Asparaginase 20,000 U/m2 IV (day 1) Maintenance-2 (weeks 53-104) Methotrexate IM 20mg/m2/wk Mercaptopurine PO 50mg/m2/d
Duration: 8 weeks
N/A
Cycles every 3 weeks x 74 weeks Vincristine 2 mg (day 1) Methotrexate 30 mg/m2 IV/IM weekly Dexamethasone 6 mg/m2 PO (day 1-5) Mercaptopurine 50mg/m2 PO (day 1-14) Doxorubicin 30mg/m2 IV (day 1)
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Vincristine 1.5 mg/m2 - maximum 2mg IV (day 1, 8, 15, 43, 50) Dexamethasone 10mg/m2 PO/IV (day 1-7, 15-21) Doxorubicin 25mg/m2 IV (days 1, 8, 15) PEG-Asparaginase 2500 IU/m2 IM/IV (day 4, day 43) Cyclophosphamide 1000mg/m2 (day 29) Cytarabine 75mg/m2 IV/SC (day 29-32, 3639) Thioguanine (6-TG) 60mg/m2/day PO (days 29-42) Duration: Females 2 years, males 3 years (12 week courses) Vincristine 1.5 mg/m2 - maximum 2mg IV (day 1, 29, 57) Dexamethasone 6mg/m2 PO/IV (day 1-5, 29-33, 5761) Mercaptopurine 75mg/m2 PO (day 1-84) Methotrexate 20mg/m2 PO weekly (day 8-78) – held on day 29 during 1st 4 courses (when IT methotrexate given)
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Maintenance/ Continuation
N/A
Induction, consolidation (day 1, 29) Methotrexate 15mg IT Cytarabine 30mg IT Hydrocortisone 20mg IT Maintenance/Reinduction (day 1) Methotrexate 15mg IT Cytarabine 30mg IT Hydrocortisone 20mg IT
15
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Induction Induction Cytarabine 50mg IT (day 0) Methotrexate 15mg IT (day 8, 29) Cytarabine 40mg /methotrexate Cytarabine 70mg IT (day 1) Consolidation 12mg/ hydrocortisone 50mg IT (day 15 and 29) Methotrexate 15mg IT (day 1, 8, CNS therapy (3 weeks) 15, 22) Interim maintenance Vincristine 2mg IV (day 1) Mercaptopurine 50mg/m2 PO x 14 Methotrexate 15mg IT (day 1, 31) Delayed intensification days Methotrexate 15mg IT (day 1, 29, Doxorubicin 30mg/m2 IV x 1 dose 36) IT methotrexate/cytarabine twice Maintenance weekly x 4 doses Methotrexate 15mg IT (day 1) Cranial radiation (18-24 Gy) Intensification (30 weeks) and Also given day 29 for first 4 continuation (74 weeks) courses IT methotrexate/cytarabine/ hydrocortisone at start of cycle Outcomes EFS 61% (6-year) 58% (4-year) 66% (2-year) OS 69% (6-year) 67% (4-year) 78% (2-year) Abbreviations: HR – high risk; IV - intravenous; PO - oral; IM – intramuscular; IT - intrathecal; CCR – continuous complete remission; EFS - Event-free survival; OS - overall survival CNS prophylaxis
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Leukemia (ALL) With a Pediatric Derived Adult ALL Protocol; Results Of 1529 AYAs In 2 Consecutive Trials Of The German Multicenter Study Group for Adult ALL (GMALL). [abstract]. Blood. 2013;122(21):839. 34. Stock W, Luger S, Advani A, et al. Favorable outcomes for adolescents and young adults (AYA) with Acute Lymphoblastic Leukemia (ALL): Early results of US INTERGROUP TRIAL C10403. [abstract]. Blood. 2014;124(21):796. 35. Ram R, Wolach O, Vidal L, Gafter-Gvili A, Shpilberg O, Raanani P. Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis. Am J Hematol. 2012;87(5):472-478. 36. Advani AS, Sanford B, Luger S, et al. Frontline-Treatment Of Acute Lymphoblastic Leukemia (ALL) In Older Adolescents and Young Adults (AYA) Using a Pediatric Regimen Is Feasible: Toxicity Results of the Prospective US Intergroup Trial C10403 (Alliance). [abstract]. Blood. 2013;122(21):3903. 37. Larsen EC, Salzer WL, Devidas M, et al. Comparison of high-dose methotrexate (HD-MTX) with Capizzi methotrexate plus asparaginase (C-MTX/ASNase) in children and young adults with high-risk acute lymphoblastic leukemia (HR-ALL): A report from the Children's Oncology Group Study AALL0232. [abstract]. J Clin Oncol. 2011;29(18_suppl):3. 38. Wolfson JA, Sun C-L, Kang T, Wyatt L, Hurria A, Bhatia S. Impact of care at NCI comprehensive cancer centers (NCICCC) on cancer outcome: Results from a populationbased study. [abstract]. J Clin Oncol. 2014;32(15_suppl):6541. 39. Kantarjian H, Thomas D, Jorgensen J, et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer. 2013;119(15):2728-2736. 40. DeAngelo DJ, Stock W, Shustov AR, et al. Weekly Inotuzumab Ozogamicin (InO) In Adult Patients With Relapsed Or Refractory CD22-Positive Acute Lymphoblastic Leukemia (ALL). [abstract]. Blood. 2013;122(21):3906. 41. Topp M, Goekbuget N, Stein A, et al. Confirmatory open-label, single-arm, multicenter phase 2 study of the BiTE antibody blinatumomab in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL). [abstract]. J Clin Oncol. 2014;32(5s):7005. 42. http://www.clinicaltrials.gov. 43. Vrooman LM, Stevenson KE, Supko JG, et al. Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol. 2013;31(9):1202-1210. 44. Tong WH, Pieters R, Kaspers GJ, et al. A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia. Blood. 2014;123(13):2026-2033. 45. Douer D, Yampolsky H, Cohen LJ, et al. Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia. Blood. 2007;109(7):2744-2750. 46. Stock W, Douer D, DeAngelo DJ, et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma. 2011;52(12):2237-2253. 47. Seftel MD, Neuberg D, Zhang M-J, et al. Superiority of Pediatric Chemotherapy over Allogeneic Hematopoietic Cell Transplantation for Philadelphia Chromosome Negative Adult ALL in First Complete Remission: A Combined Analysis of Dana-Farber ALL Consortium and CIBMTR Cohorts. [abstract]. Blood. 2014;124(21):319.
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48. Vey N, Thomas X, Picard C, et al. Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006;20(12):2155-2161. 49. Nachman JB, Heerema NA, Sather H, et al. Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood. 2007;110(4):1112-1115. 50. Charrin C, Thomas X, Ffrench M, et al. A report from the LALA-94 and LALA-SA groups on hypodiploidy with 30 to 39 chromosomes and near-triploidy: 2 possible expressions of a sole entity conferring poor prognosis in adult acute lymphoblastic leukemia (ALL). Blood. 2004;104(8):2444-2451. 51. Zhang J, Ding L, Holmfeldt L, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481(7380):157-163. 52. Wood BL, Winter SS, Dunsmore KP, et al. T-Lymphoblastic Leukemia (T-ALL) Shows Excellent Outcome, Lack of Significance of the Early Thymic Precursor (ETP) Immunophenotype, and Validation of the Prognostic Value of End-Induction Minimal Residual Disease (MRD) in Children’s Oncology Group (COG) Study AALL0434. [abstract]. Blood. 2014;124(21):1. 53. Bassan R, Spinelli O, Oldani E, et al. Different molecular levels of post-induction minimal residual disease may predict hematopoietic stem cell transplantation outcome in adult Philadelphia-negative acute lymphoblastic leukemia. Blood Cancer J. 2014;4:e225. 54. Bassan R, Spinelli O, Oldani E, et al. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood. 2009;113(18):4153-4162. 55. Gokbuget N, Kneba M, Raff T, et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012;120(9):1868-1876. 56. Bruggemann M, Raff T, Kneba M. Has MRD monitoring superseded other prognostic factors in adult ALL? Blood. 2012;120(23):4470-4481. 57. Dhedin N, Huynh A, Maury S, et al. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) In Adults With Philadelphia Chromosome (Ph)-Negative Acute Lymphoblastic Leukemia (ALL): Results From The Group For Research On Adult ALL (GRAALL). [abstract]. Blood. 2013;122(21):552-552. 58. Pulsipher MA, Carlson CS, Mark K, et al. Striking Predictive Power For Relapse and Decreased Survival Associated With Detectable Minimal Residual Disease by IGH VDJ Deep Sequencing Of Bone Marrow Pre- and Post-Allogeneic Transplant In Children With B-Lineage ALL: A Subanalysis Of The COG ASCT0431/PBMTC ONC051 Study. [abstract]. Blood. 2013;122(21):919. 59. Zhang M, Luo Y, Lai X, et al. Minimal Residual Disease Levels At Time Of CR1 and Transplant Predict Outcome In Philadelphia Chromosome-Negative Adult ALL. [abstract]. Blood. 2013;122(21):713. 60. Patel B, Rai L, Buck G, et al. Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993. Br J Haematol. 2010;148(1):80-89. 61. Holowiecki J, Krawczyk-Kulis M, Giebel S, et al. Status of minimal residual disease after induction predicts outcome in both standard and high-risk Ph-negative adult acute lymphoblastic leukaemia. The Polish Adult Leukemia Group ALL 4-2002 MRD Study. Br J Haematol. 2008;142(2):227-237. 62. Bruggemann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107(3):1116-1123.
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63. Faham M, Zheng J, Moorhead M, et al. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood. 2012;120(26):51735180. 64. Malnassy G, Carlton V, Moorhead M, Faham M, Stock W. Comparison of nextgeneration sequencing and ASO-PCR methods for MRD detection in acute lymphoblastic leukemia. [abstract]. Haematologica. 2013;98(suppl 1):S537. 65. Schmiegelow K, Heyman M, Gustafsson G, et al. The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse. Leukemia. 2010;24(4):715-720. 66. Bhatia S, Landier W, Hageman L, et al. High Intra-Individual Variability In Systemic Exposure To 6 Mercaptopurine (6MP) In Children With Acute Lymphoblastic Leukemia (ALL) Contributes To ALL Relapse: Results From a Children’s Oncology Group (COG) Study (AALL03N1). [abstract]. Blood. 2013;122(21):59. 67. McLeod HL, Krynetski EY, Relling MV, Evans WE. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia. 2000;14(4):567-572. 68. Yang JJ, Landier W, Yang W, et al. Inherited NUDT15 Variant Is a Genetic Determinant of Mercaptopurine Intolerance in Children With Acute Lymphoblastic Leukemia. [published online ahead of print January 28, 2015]. J Clin Oncol. 2015:10.1200/JCO.2014.1259.4671. 69. te Winkel ML, Pieters R, Hop WC, et al. Prospective study on incidence, risk factors, and long-term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2011;29(31):4143-4150. 70. Nathan PC, Wasilewski-Masker K, Janzen LA. Long-term outcomes in survivors of childhood acute lymphoblastic leukemia. Hematol Oncol Clin North Am. 2009;23(5):10651082, vi-vii. 71. Diouf B, Crews K, Lew G, et al. Genome-Wide Association Analyses Identify Susceptibility Loci For Vincristine-Induced Peripheral Neuropathy In Children With Acute Lymphoblastic Leukemia. [abstract]. Blood. 2013;122(21):618. 72. Kawedia JD, Kaste SC, Pei D, et al. Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood. 2011;117(8):2340-2347. 73. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470-480. 74. Payne-Turner D, Pei D, Becksfort J, et al. Integrated Genomic and Mutational Profiling Of Adolescent and Young Adult ALL Identifies a High Frequency Of BCR-ABL1Like ALL with Very Poor Outcome. [abstract]. Blood. 2013;122(21):825. 75. Roberts KG, Pei D, Campana D, et al. Outcomes of Children With BCR-ABL1-Like Acute Lymphoblastic Leukemia Treated With Risk-Directed Therapy Based on the Levels of Minimal Residual Disease. [published online ahead of print July 21, 2014]. J Clin Oncol. 2014:doi:10.1200/JCO.2014.1255.4105. 76. Harvey RC, Kang H, Roberts KG, et al. Development and Validation Of a Highly Sensitive and Specific Gene Expression Classifier To Prospectively Screen and Identify B-Precursor Acute Lymphoblastic Leukemia (ALL) Patients With a Philadelphia Chromosome-Like (“Ph-like” or “BCR-ABL1-Like”) Signature for Therapeutic Targeting and Clinical Intervention. [abstract]. Blood. 2013;122(21):826. 77. Raca G, Gurbuxani S, Zhang Z, et al. RCSD1-ABL2 fusion resulting from a complex chromosomal rearrangement in high-risk B-cell acute lymphoblastic leukemia. Leuk Lymphoma. 2014:1-3.
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78. Chen IM, Harvey RC, Mullighan CG, et al. Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children's Oncology Group study. Blood. 2012;119(15):3512-3522. 79. Weston BW, Hayden MA, Roberts KG, et al. Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia. J Clin Oncol. 2013;31(25):e413-416. 80. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosomepositive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004;103(12):4396-4407. 81. Ravandi F, O'Brien S, Thomas D, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosomepositive (Ph+) acute lymphoblastic leukemia. Blood. 2010;116(12):2070-2077. 82. Porkka K, Koskenvesa P, Lundan T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosomepositive leukemia. Blood. 2008;112(4):1005-1012. 83. Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol. 2009;27(31):5175-5181. 84. Chiaretti S, Vitale A, Elia L, et al. First Results of the Multicenter Total Therapy Gimema LAL 1509 Protocol for De Novo Adult Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Patients. [abstract]. Blood. 2014;124(21):797-797. 85. Foa R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011;118(25):6521-6528. 86. Soverini S, De Benedittis C, Papayannidis C, et al. Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: The main changes are in the type of mutations, but not in the frequency of mutation involvement. Cancer. 2014;120(7):1002-1009. 87. Fielding AK, Rowe JM, Buck G, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014;123(6):843-850. 88. Dombret H, Gabert J, Boiron JM, et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia--results of the prospective multicenter LALA-94 trial. Blood. 2002;100(7):2357-2366. 89. Ravandi F, Jorgensen JL, Thomas DA, et al. Detection of MRD may predict the outcome of patients with Philadelphia chromosome-positive ALL treated with tyrosine kinase inhibitors plus chemotherapy. Blood. 2013;122(7):1214-1221. 90. Ottmann OG, Pfeifer H, Cayuela J-M, et al. Nilotinib (Tasigna®) and Chemotherapy for First-Line Treatment in Elderly Patients with De Novo Philadelphia Chromosome/BCR-ABL1 Positive Acute Lymphoblastic Leukemia (ALL): A Trial of the European Working Group for Adult ALL (EWALL-PH-02). [abstract]. Blood. 2014;124(21):798. 91. Kim D-Y, Joo YD, Kim S-D, et al. Nilotinib Combined With Multi-Agent Chemotherapy For Adult Patients With Newly Diagnosed Philadelphia ChromosomePositive Acute Lymphoblastic Leukemia: Final Results Of Prospective Multicenter Phase 2 Study. [abstract]. Blood. 2013;122(21):55. 92. Yanada M, Matsuo K, Suzuki T, Naoe T. Allogeneic hematopoietic stem cell transplantation as part of postremission therapy improves survival for adult patients with high-risk acute lymphoblastic leukemia: a metaanalysis. Cancer. 2006;106(12):26572663.
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93. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783-1796. 94. Butow P, Palmer S, Pai A, Goodenough B, Luckett T, King M. Review of adherence-related issues in adolescents and young adults with cancer. J Clin Oncol. 2010;28(32):4800-4809. 95. Kondryn HJ, Edmondson CL, Hill J, Eden TO. Treatment non-adherence in teenage and young adult patients with cancer. Lancet Oncol. 2011;12(1):100-108. 96. Kantarjian HM, O'Brien S. Insurance policies in the United States may explain part of the outcome differences of adolescents and young adults with acute lymphoblastic leukemia treated on adult versus pediatric regimens. Blood. 2009;113(8):1861. 97. Aizer AA, Falit B, Mendu ML, et al. Cancer-specific outcomes among young adults without health insurance. J Clin Oncol. 2014;32(19):2025-2030. 98. Corey AL, Haase JE, Azzouz F, Monahan PO. Social support and symptom distress in adolescents/young adults with cancer. J Pediatr Oncol Nurs. 2008;25(5):275284. 99. Sansom-Daly UM, Peate M, Wakefield CE, Bryant RA, Cohn RJ. A systematic review of psychological interventions for adolescents and young adults living with chronic illness. Health Psychol. 2012;31(3):380-393. 100. Jorngarden A, Mattsson E, von Essen L. Health-related quality of life, anxiety and depression among adolescents and young adults with cancer: a prospective longitudinal study. Eur J Cancer. 2007;43(13):1952-1958. 101. Haward RA. The Calman-Hine report: a personal retrospective on the UK's first comprehensive policy on cancer services. Lancet Oncol. 2006;7(4):336-346. 102. Fleissig A, Jenkins V, Catt S, Fallowfield L. Multidisciplinary teams in cancer care: are they effective in the UK? Lancet Oncol. 2006;7(11):935-943.
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Prepublished online March 24, 2015; doi:10.1182/blood-2014-11-551481
How I Treat: Acute Lymphoblastic Leukemia in Older Adolescents and Young Adults (AYAs) Emily Curran and Wendy Stock
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Blood First Edition Paper, prepublished online March 24, 2015; DOI 10.1182/blood-2014-11-551481
Title: How I Treat: Acute Lymphoblastic Leukemia in Older Adolescents and Young Adults (AYAs) Running Title: Treatment of ALL in Adolescents and Young Adults (AYAs) Authors: Emily Curran, MD (first author); Wendy Stock, MD (corresponding author) Affiliate Institutions: University of Chicago and University of Chicago Comprehensive Cancer Center Corresponding author’s name/contact: Wendy Stock, MD 5841 S. Maryland Ave, M/C2115 Chicago IL 60637 Phone: 773-834-8982 Fax: 773-702-3163 Email: [email protected]
Copyright © 2015 American Society of Hematology
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Abstract At the intersection between children and older adults, the care of adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) poses unique challenges and issues beyond those faced by other age groups. While the survival of AYA patients is inferior to younger children, growing evidence suggests that AYA patients have improved outcomes, with disease free survival rates of 60-70%, when treated with pediatric-based approaches. A holistic approach, incorporating a multidisciplinary team, is a key component of successful treatment of these AYA patients. With the appropriate support and management of toxicities during and following treatment, these regimens are well-tolerated in the AYA population. Even with the significant progress that has been made during the last decade, patients with persistence of minimal residual disease (MRD) during intensive therapy still have a poor prognosis. With new insights into disease pathogenesis in AYA ALL and availability of disease-specific kinase inhibitors and novel targeted antibodies, future studies will focus on individualized therapy to eradicate MRD and result in further improvements in survival. This case-based review will discuss the biology, pharmacology, and psychosocial aspects of AYA patients with ALL, highlighting our current approach to the management of these unique patients. Introduction Acute lymphoblastic leukemia (ALL), a relatively rare malignancy, is one of the few cancers that impacts the entire lifespan, from neonates to the very elderly.1 While survival now approaches 90% for most children with ALL,2,3 older adolescents and young adults (AYA) historically have a much poorer prognosis, with an event-free survival (EFS) of only 30-45%.4-6 Factors accounting for differences in outcome include heterogeneity in disease biology, host factors (both physiologic and psychosocial) and, importantly, the therapeutic approach and experience of the health care teams.7-11 Some authors also suggest that AYAs may have had poorer outcomes, in part, because of low rates of clinical trial enrollment.12 Between 1997 and 2003, fewer than 2% of older adolescents were enrolled in clinical trials, compared to 60% of pediatric patients,13 potentially due to fewer referrals to institutions where clinical trials are offered, limited numbers of clinical trials available for the AYA population and psychosocial barriers.14 During the last decade, recognition of the unique characteristics of AYAs with ALL as well as a new focus on clinical research designed specifically for this population has led to exciting improvements in treatment outcomes, with EFS now approaching 70% for AYA ALL. The National Cancer Institute has defined the AYA cancer population broadly – ages 15-39 years old.15 While tremendous heterogeneity in this population clearly exists,16 and the age cut-off of 40 years is somewhat arbitrarily defined, emerging clinical, psychosocial, and biologic features of the disease suggest this may be a distinct population.17,18 This case-based review will focus on the AYA population most commonly treated by adult hematologists-oncologists – patients ages 18 to 39 years old. Patient 1 A 28 year-old man presents with night sweats, fatigue, palpitations and abdominal pain. He is found to have a white blood cell count of 23 x 109/L and bulky organomegaly. Bone marrow biopsy is consistent with precursor B cell ALL (CD19+, CD20-, CD10+,CD22+, CD79a+, CD34+ and TdT+). Fluorescence in situ hybridization (FISH) is negative for MLL rearrangement, BCR/ABL1, ETV5/RUNX1 and trisomies 4, 10, and 17. Cytogenetics shows a normal male karyotype.
2
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What is our approach? If available, we would encourage enrollment onto a clinical trial focused on AYAs with ALL that builds upon an intensive pediatric approach to treatment. Rationale: Treatment approaches for AYAs with ALL vary considerably, with the choice of regimen predicated on the familiarity and expertise of the treating physician, the availability of a clinical trial and, most importantly, the “door” that the patient enters – into a pediatric or an adult treatment center. In the United Kingdom, AYA inpatient treatment units already exist and this may facilitate a more uniform treatment approach. However, in the United States, patients younger than 18 years old are traditionally treated in pediatric departments whereas AYAs older than 18 are treated by adult hematologists/oncologists and therefore receive “adult” ALL regimens. These “adult” regimens typically consist of intensive use of myelosuppressive agents including daunorubicin, cytarabine, and cyclophosphamide, as well as allogeneic stem cell transplant in first remission.5,19,20 In contrast, pediatric regimens focus on the BerlinFrankfurt-Munster (BFM) backbone of ALL therapy:21 glucocorticoids, vincristine, asparaginase, early and frequent central nervous system (CNS) prophylaxis and prolonged maintenance therapy.22-25 Retrospective studies from large North American and European groups suggest that AYAs have superior outcomes when treated with “pediatric” regimens,21-25 and may approach those of younger children, with 5-year EFS of over 70%.26,27 Based on these data, as well as the prospective studies described below, we recommend that AYA patients be treated on a pediatric-based regimen. Encouraging survival outcomes for AYAs with ALL treated with “pediatric-inspired” regimens have recently been reported from a number of prospective cooperative group clinical trials performed in Europe and the United States.23,28-33 These trials showed an improvement in both EFS and overall survival (OS) compared to historical controls, with greater than 60% EFS and OS in the majority of studies.23,28-33 Both retrospective and prospective studies have included both B- and T-cell ALL, with quite similar EFS and OS.29,33,34 Importantly, while some groups have noted slightly poorer tolerability,29 and certain toxicities (such as hepatotoxicity) may be more common in an older population, overall these regimens have demonstrated feasibility in the AYA population. Several of these trials and regimens are outlined in Table 1 and also reviewed in a recent metaanalysis.35 The largest prospective study to evaluate the feasibility of a pediatric regimen in AYA ALL patients is the US intergroup study, C10403.36 Between November 2007 and December 2012, 318 AYAs between 16-39 years of age were treated based on the standard arm of the Children’s Oncology Group regimen (COG AALL0232).37 This study demonstrated that toxicities were manageable, with low treatment-related mortality (3%), and that treatment with this pediatric regimen is feasible when administered by adult hematologist/oncologists to an AYA population up to 40 years of age.36 On this regimen, the 2-year EFS and OS were 66% and 78%, respectively.34 Based on these very encouraging early results, the US cooperative groups are now designing a successor study using the C10403 platform that will attempt to incorporate novel targeted agents to further improve treatment outcomes. While the majority of recent studies demonstrate a survival benefit using intensive pediatric regimens for AYA, another recently published comparison study of an “adult” regimen (hyper-CVAD) versus a pediatric regimen (BFM-like) found equivalent EFS (approximately 70%).20 Because this trial was conducted at an institution with a large,
3
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experienced leukemia program, the results may not be widely generalizable but suggest that high-volume referral centers may offer benefits beyond chemotherapeutics. In fact, recent data show that outcomes for AYAs with ALL are significantly improved if treatment is administered at a university or NCI-sponsored cancer center with expertise in the complex regimens used to treat ALL.38 Treating AYA patients with pediatric-based regimens has resulted in impressive increases in EFS from 39% to 60-70%. However, further progress is still needed. Several novel agents that have shown impressive activity for relapsed/refractory disease are being evaluated in the frontline setting and will be included in the next generation of prospective clinical trials for AYAs with ALL. For instance, inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, appears to be safe and active in relapsed/refractory ALL, with response rates of 58-82% in recent clinical trials.39,40 Blinatumomab, a bispecific T-cell engaging (BiTE) antibody that directs cytotoxic T-cells to CD19-expressing target cells, had a 43% response rate in Ph-negative relapsed/refractory precursor B ALL,41 and recently received FDA approval in relapsed disease. Incorporating these agents into front-line chemotherapy will hopefully help to eradicate MRD and result in further improved survival for AYA patients. Blinatumomab is being added to frontline therapy in an ongoing trial for adults with ALL 30-70 years old (NCT02003222)42 and an NCI-approved study in the AYA population (ages 18-39 years) will test the addition of inotuzumab ozogamicin to the C10403 backbone.
Patient 1 (continued) This patient is started on induction chemotherapy according to the C10403 protocol. What prevention and monitoring should be performed in this patient during induction therapy? We recommend administering induction therapy as an inpatient until neutrophil recovery. Early treatment toxicities, including febrile neutropenia, hyperglycemia and hepatic toxicity occur commonly during induction (typically days 10-20) and can be more safely managed with close inpatient observation. We also treat with allopurinol for the first ten days of induction therapy to prevent hyperuricemia. Following induction therapy, the remainder of treatment can be safely administered as an outpatient. For antimicrobial prophylaxis, we recommend antiviral (acyclovir) and PCP prophylaxis (typically trimethoprim-sulfamethoxazole) throughout treatment (including maintenance therapy), keeping in mind that no sulfa drug or non-steroidal anti-inflammatory medications should be given on the days that the patient receives methotrexate. Fungal prophylaxis should include mold coverage during induction therapy. However, broader spectrum azole antifungals cannot be used with vincristine because of the risk of exacerbating vincristine-induced peripheral neuropathy. Therefore, we typically use an echinocandin such as micafungin for prophylaxis during induction and switch to fluconazole for outpatient management during consolidation therapy. Asparaginase related toxicities are a challenge when intensive pediatric-inspired regimens are used in the AYA population. The only asparaginase preparation available in North America for frontline ALL therapy is a long-acting pegylated form of asparaginase, PEG-asp. Little is known about the pharmacokinetics of PEG-asp in AYAs or older adults with ALL.10,11 A dose of 2500 IU/m2 PEG-asp, which was used in
4
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both the COG ALL 0232 and the C10403 trials, appears to result in greater hepatic toxicity in the AYA population, particularly during induction chemotherapy;36 thus, we and others have routinely begun to cap the dose at one vial, or 3750 IU. New methods for safer and more accurate dosing of PEG-asp are available, including a recently FDAapproved assay for measurement of asparaginase activity levels. Pediatric studies have demonstrated that achievement of asparaginase levels of greater than 100U/L for fourteen days following a dose of PEG-asp is associated with improved treatment outcomes.43 Our group and others have begun to prospectively test the use of lower initial doses of PEG-asp with subsequent dose adjustment, if necessary, to achieve adequate (but not excessive) asparaginase levels.32 While we are hopeful that levelbased dose adjustment may facilitate the safe use of PEG-asp in AYAs, prospective clinical trials are required to validate this hypothesis. Importantly, asparaginase activity levels allow for detection of “silent” inactivation, which may occur without clinical symptoms in up to one-tenth of patients, as a result of antibody neutralization of asparaginase.43,44 Switching asparaginase preparations when silent inactivation occurred resulted in improved EFS in a pediatric population.43 Asparaginase-related hypersensitivity reactions occur in as many as 20% of children and adults. Therefore, we routinely pre-medicate our patients with diphenhydramine, hydrocortisone and acetaminophen prior to each dose of PEG-asp. In C10403, we found that premedication resulted in a decline in significant hypersensitivity reactions to PEGasp from 15% to 6%.36 If an anaphylactic reaction occurs, no further PEG-asp is administered and we switch to Erwinia asparaginase at a dose of 25,000 IU/m2. While some may be concerned about failing to detect antibodies to asparaginase when patients are pre-medicated (resulting in silent inactivation), previous reports have demonstrated that this is a relatively uncommon event with PEG-asp.45 Furthermore, the FDA-approved assay to measure serum asparaginase levels will obviate this concern. An alternative approach in these patients would be to avoid premedication but, if hypersensitivity occurs, manage the acute toxicities and be prepared to switch to Erwinia asparaginase for subsequent treatment. Other serious toxicities of asparaginase include asthenia, pancreatitis, thrombosis, and bleeding. For a more detailed discussion regarding prevention and treatment of asparaginase toxicities in adults, a comprehensive set of recommendations was recently published by an expert panel.46 Patient 1 (continued) This patient completes induction therapy per C10403 protocol without significant complications. Bone marrow biopsy shows complete remission with no detectable minimal residual disease (MRD) by flow cytometry. When should allogeneic transplant in first complete remission (CR1) be considered? What role does MRD monitoring play in decisions for treatment? A large prospective randomized international collaborative study (MRC UKALL XII/E2993) demonstrated a significant increase in OS for allogeneic transplant in CR1 when compared to a standard adult ALL regimen (63% versus 52%).19 In contrast, a very recent International Bone Marrow Transplant Registry (IBMTR) study of adults 1850 years old found a significant benefit (HR 3.1; p5% lymphoblasts or M1 marrow with ≥1% lymphoblasts
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Number of patients Median age at diagnosis (range) Gender
DFCI Adult ALL 01-17532 Patient population
Consolidation1/Intensification
Dexamethasone 10mg/m2 PO/IV (day 1-14) 5mg/m2 PO/IV (day 15-21) Vincristine 1.5 mg/m2 - maximum 2mg IV (day 1, 8, 15) Daunorubicin 30mg/m2 IV (day 1, 2, 8, 9) Cyclophosphamide 600mg/m2 (day 1, 15) Asparaginase 10,000 U/m2 IV (day 1-3, 15-17)
Cycles every 3 weeks x 30 weeks Vincristine 2 mg (day 1) Methotrexate 30m/m2 IV/IM weekly Dexamethasone 18mg/m2 PO (day 1-5) Mercaptopurine 50mg/m2 PO (day 1-14) E. coli asparaginase 12,500 IU/m2 starting dose Doxorubicin 30mg/m2 IV (day 1)
Vincristine 1.5 mg/m2 - maximum 2mg IV (day 15, 22, 43, 50) Cyclophosphamide 1,000mg/m2 (day 1, 29) Cytarabine 500mg/m2 IV/SC (day 1-4, 811, 29-32, 36-39) Mercaptopurine 60mg/m2 PO (day 1-14, 2942) PEG-Asparaginase 2500 IU/m2 IM/IV (day 15, 43)
N/A
Duration: 8 weeks Vincristine 1.5 mg/m2 - maximum 2mg IV (day 1, 11, 21, 31, 41) Methotrexate 100m/m2 IV starting, with dose escalation (day 1, 11, 21, 31, 41) PEG-Asparaginase 2500 IU/m2 IM/IV (day 2, 22)
13
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Consolidation-2/ Interim Maintenance
Mercaptopurine 50mg/m2 PO (day 1-7) Methotrexate 3g/m2 IV (day 1, 28, 56) VM-26 150mg/m2 IV (day 14, 42) Cytarabine 500mg/m2 IV (day 14-15, 4243)
Delayed Intensification
Maintenance-1 (until week 52) Methotrexate IM 20mg/m2/wk Mercaptopurine PO 50mg/m2/d Reinduction (every 4 weeks) Vincristine 1.5 mg/m2 maximum 2mg IV (day 1) Prednisone 60mg/m2/day Asparaginase 20,000 U/m2 IV (day 1) Maintenance-2 (weeks 53-104) Methotrexate IM 20mg/m2/wk Mercaptopurine PO 50mg/m2/d
Duration: 8 weeks
N/A
Cycles every 3 weeks x 74 weeks Vincristine 2 mg (day 1) Methotrexate 30 mg/m2 IV/IM weekly Dexamethasone 6 mg/m2 PO (day 1-5) Mercaptopurine 50mg/m2 PO (day 1-14) Doxorubicin 30mg/m2 IV (day 1)
14
Vincristine 1.5 mg/m2 - maximum 2mg IV (day 1, 8, 15, 43, 50) Dexamethasone 10mg/m2 PO/IV (day 1-7, 15-21) Doxorubicin 25mg/m2 IV (days 1, 8, 15) PEG-Asparaginase 2500 IU/m2 IM/IV (day 4, day 43) Cyclophosphamide 1000mg/m2 (day 29) Cytarabine 75mg/m2 IV/SC (day 29-32, 3639) Thioguanine (6-TG) 60mg/m2/day PO (days 29-42) Duration: Females 2 years, males 3 years (12 week courses) Vincristine 1.5 mg/m2 - maximum 2mg IV (day 1, 29, 57) Dexamethasone 6mg/m2 PO/IV (day 1-5, 29-33, 5761) Mercaptopurine 75mg/m2 PO (day 1-84) Methotrexate 20mg/m2 PO weekly (day 8-78) – held on day 29 during 1st 4 courses (when IT methotrexate given)
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Maintenance/ Continuation
N/A
Induction, consolidation (day 1, 29) Methotrexate 15mg IT Cytarabine 30mg IT Hydrocortisone 20mg IT Maintenance/Reinduction (day 1) Methotrexate 15mg IT Cytarabine 30mg IT Hydrocortisone 20mg IT
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Induction Induction Cytarabine 50mg IT (day 0) Methotrexate 15mg IT (day 8, 29) Cytarabine 40mg /methotrexate Cytarabine 70mg IT (day 1) Consolidation 12mg/ hydrocortisone 50mg IT (day 15 and 29) Methotrexate 15mg IT (day 1, 8, CNS therapy (3 weeks) 15, 22) Interim maintenance Vincristine 2mg IV (day 1) Mercaptopurine 50mg/m2 PO x 14 Methotrexate 15mg IT (day 1, 31) Delayed intensification days Methotrexate 15mg IT (day 1, 29, Doxorubicin 30mg/m2 IV x 1 dose 36) IT methotrexate/cytarabine twice Maintenance weekly x 4 doses Methotrexate 15mg IT (day 1) Cranial radiation (18-24 Gy) Intensification (30 weeks) and Also given day 29 for first 4 continuation (74 weeks) courses IT methotrexate/cytarabine/ hydrocortisone at start of cycle Outcomes EFS 61% (6-year) 58% (4-year) 66% (2-year) OS 69% (6-year) 67% (4-year) 78% (2-year) Abbreviations: HR – high risk; IV - intravenous; PO - oral; IM – intramuscular; IT - intrathecal; CCR – continuous complete remission; EFS - Event-free survival; OS - overall survival CNS prophylaxis
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Prepublished online March 24, 2015; doi:10.1182/blood-2014-11-551481
How I Treat: Acute Lymphoblastic Leukemia in Older Adolescents and Young Adults (AYAs) Emily Curran and Wendy Stock
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