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Physicians’ Education Resource®, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgement of Commercial Support

This activity is supported by educational grants from Adaptive Biotechnologies and Amgen.

Community Practice Connections: How the Experts Treat Acute Lymphoblastic Leukemia—From Adolescent to Adult


Release Date: February 28, 2019
Expiration Date: February 28, 2020
Media: Internet - based

Activity Overview

Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic malignancy that can present at different stages of life. Progress is being made with the understanding of new cytogenetic and molecular abnormalities associated with ALL and its pathophysiology, as well as the development of novel agents for the treatment of with this disease. Studies have supported the role of minimal residual disease as a prognostic patients factor for patients with ALL, and recent data may inform optimal MRD assessment approaches and timing. These new developments have led to a more individualized treatment approach based on immunophenotypic, cytogenetic, and molecular features. Optimal treatment strategies for ALL incorporate a multitude of factors that may be particularly challenging to implement for any busy clinician.

This CME activity has been developed to help you meet this challenge by addressing a wide range of topics, including factors that may influence risk stratification for patients with ALL, recent safety and efficacy data from clinical trials evaluating different classes of therapy for ALL, and treatment decisions in multiple lines of therapy. This activity features video commentary of leading clinical experts in the management of ALL who will provide their thoughts on these topics.

Acknowledgement of Commercial Support

This activity is supported by educational grants from Adaptive Biotechnologies and Amgen.

Instructions for This Activity and Receiving Credit

  • You will need to log in to participate in the activity.
  • Each presentation may contain an interactive question(s). You may move forward through the presentation; however, you may not go back to change answers or review audio files/content until you finish the presentation.
  • At the end of the activity, educational content/audio files will be available for your reference.
  • In order to receive a CME certificate, you must complete the activity.
  • Complete the Posttest and pass with a score of 70% or higher, complete the Evaluation, and then click on “Request for Credit.” You may immediately download a CME certificate upon completion of these steps.


Target Audience

This educational activity is intended for hematologists, medical oncologists, and other healthcare professionals interested in the latest advances in the treatment of patients with acute lymphoblastic leukemia. Fellows, researchers, nurses, nurse practitioners, physician assistants, and other healthcare professionals interested in the treatment of patients with hematologic malignancies are also invited to participate.

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

  1. Identify prognostic factors that are essential for acute lymphoblastic leukemia (ALL) risk stratification and develop appropriate treatment plans for individual patients based on cytogenetic and immunophenotypic study results
  2. Evaluate the clinical utility of minimal residual disease assessment and how this may inform treatment decision making for adolescents and adults
  3. Discuss novel strategies for the management of ALL in multiple settings, including monoclonal antibodies, antibody drug conjugates, and CAR T-cell therapies
  4. Identify patients in multiple lines of care who may be eligible for emerging ALL treatment approaches

Faculty, Staff, and Planners' Disclosures

Faculty

Elias Jabbour
Elias Jabbour, MD
Professor, Department of Leukemia
The University of Texas MD Anderson Cancer Center
Houston, TX

Disclosures: Grant/Research Support: Bristol-Myers Squibb, Novartis, Amgen, Takeda, Pfizer, AbbVie.

Daniel J. DeAngelo
Daniel J. DeAngelo, MD, PhD
Associate Professor of Medicine
Harvard Medical School
Institute Physician, Adult Leukemia Program
Dana-Farber Cancer Institute
Boston, MA

Disclosures: Grant/Research Support: GlycoMimetics; Consultant: Novartis, Amgen, Pfizer, Shire, Takeda, Incyte, Blueprint Medicines. .

Stephan A. Grupp
Stephan A. Grupp, MD, PhD
Chief, Cellular Therapy and Transplant Section
Director, Cancer Immunotherapy Program
Director, Translational Research, Center for Childhood Cancer Research
Children’s Hospital of Philadelphia
Novotny Professor of Pediatrics, Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA

Disclosures: Consultant: Novartis (SSC), TCR2 Therapeutics (SAB), Eureka Therapeutics (SAB), Adaptimmune (SAB), Cellectis/Servier (ad hoc SAB)

Hervé Dombret
Hervé Dombret, MD
Chief, Blood Disease Department (Leukemia Unit)
University Hospital Saint-Louis, AP-HP
Director, University Institute of Hematology
University Paris Diderot
Paris Alliance of Cancer Research Institutes
Paris, France

Disclosures: No relevant financial relationships with commercial interests.

Ching-Hon Pui
Ching-Hon Pui, MD
Member, Saint Jude Children’s Research Hospital Faculty
Chair, Oncology Department
Co-leader, Hematological Malignancies Program
Director, China Region, Saint Jude Global
American Cancer Society Professor
Fahad Nassar Al-Rashid Chair of Leukemia Research
Memphis, TN

Disclosures: Scientific Advisor: Adaptive Biotechnologies

The staff of PER® have no relevant financial relationships with commercial interests to disclose.

Disclosure Policy and Resolution of Conflicts of Interest (COI)

As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.

Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.

Off-Label Disclosure and Disclaimer

This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or the companies that provided commercial support for this activity.

PER Pulse™ Recaps


1 of 3
PER Pulse™ Recap
Understanding Key Features of Acute Lymphoblastic Leukemia and the Clinical Relevance of MRD Assessment

Acute lymphoblastic leukemia (ALL) can occur at any age, with a peak incidence between ages 2 and 4 years and a second, smaller peak in the elderly population.1,2 Approximately 6000 ALL cases are diagnosed each year; about 55% of these occur in patients younger than 20 years (median age, 15 years).2 Although ALL has historically been considered a nonhereditary disease, many pediatric patients inherit gene polymorphisms associated with the development of ALL.3 Thirteen distinct genes are associated with the development of childhood ALL,3 and germline mutations are associated with ALL risk. Whole-genome analysis has demonstrated that approximately 5% of pediatric patients with ALL have germline mutations in these cancer predisposition genes: ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72, TERC, TERT, and TP53.4 Germline TP53 mutations occur commonly in pediatric cases of low-hypodiploid ALL5 while germline PAX5 G183S mutations occur in familial ALL6 and germline ETV6 mutations have been associated with familial thrombocytopenia and hematopoietic malignancy.7

Although pediatric and adult patients have the same spectrum of genetic abnormalities, there are variations in the frequency of different subtypes according to age. Pediatric patients have a higher incidence of favorable genetic subtypes, such as hyperdiploidy (25%-30%) and ETV6-RUNX1 (20%-25%), while adults have a greater incidence of unfavorable subtypes such as Philadelphia chromosome (Ph)-positive ALL (25%) and Ph-like ALL (25%).8,9

Minimal residual disease (MRD) is an independent prognostic indicator for patients with adult and pediatric ALL. Event-free survival and overall survival outcomes have been shown to be better with MRD negativity for both pediatric and adult patients.10 Multiple assays are available to assess MRD status for patients with ALL. Flow cytometry is commonly used, with a target of assessment of leukemic immunophenotypes and a sensitivity of 0.01%. Allele-specific oligonucleotide polymerase chain reaction amplification of immunoglobulin and T-cell receptor genes has a sensitivity of 0.001%.11 Deep sequencing may also be considered, with a sensitivity of 0.0001%.11 This technology recently received FDA approval for MRD assessment in ALL. Negative MRD assessment via high-throughput sequencing has identified highly curable children with standard-risk ALL. For pediatric patients who achieve MRD negativity by next-generation sequencing (NGS) prior to transplant, the risk for relapse is lower than for patients who achieve MRD negativity by multiparameter flow cytometry.11 Posttransplant NGS MRD status has been shown to be more predictive of relapse than flow cytometry MRD status.12

Key Points:

  • ALL can occur in any age group, with a peak incidence between ages 2 and 4 years and a second, smaller peak in the elderly population.
  • Children have more favorable and fewer unfavorable ALL genetic subtypes; within different specific genetic subtypes, pediatric patients fare better than adult patients.
  • Adult ALL has more cooperative mutations and epigenetic mutations than childhood ALL. Risk-directed therapy should be based on genotype as well as on MRD status.
  • Despite the risk for toxicities associated with targeted therapies, these advancements have improved survival rates for adult patients with ALL.

References

  1. Key statistics for acute lymphocytic leukemia (ALL). American Cancer Society website. cancer.org/cancer/acute-lymphocytic-leukemia/about/key-statistics.html. Updated January 8, 2019. Accessed February 5, 2019.
  2. Cancer facts & figures 2019. American Cancer Society website. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf Published 2019. Accessed February 1, 2019.
  3. Pui CH, Nichols KE, Yang JJ. Somatic and germline genomics in paediatric acute lymphoblastic leukemia [published online December 13, 2018]. Nat Rev Clin Oncol. doi: 10.1038/s41571-018-0136-6.
  4. Zhang J, Walsh MF, Wu G, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373(24):2336-2346. doi: 10.1056/NEJMoa1508054.
  5. Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45(3):242-252. doi: 10.1038/ng.2532.
  6. Shah S, Schrader KA, Waanders E, et al. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat Genet. 2013;45(10):1226-1231. doi: 10.1038/ng.2754.
  7. Zhang MY, Churpek JE, Keel SB, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet. 2015;47(2):180-185. doi: 10.1038/ng.3177.
  8. Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005-1015. doi: 10.1056/NEJMoa1403088.
  9. Roberts KG, Mullighan CG. Genomics in acute lymphoblastic leukaemia: insights and treatment implications. Nat Rev Clin Oncol. 2015;12(6):344-357. doi: 10.1038/nrclinonc.2015.38.
  10. Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol. 2017;3(7):e170580. doi: 10.1001/jamaoncol.2017.0580.
  11. Faham M, Zheng J, Moorhead M, et al. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood. 2012;120(26):5173-5180. doi: 10.1182/blood-2012-07-444042.
  12. Pulsipher MA, Carlson C, Langolz B, et al. IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients. Blood. 2015;125(22):3501-3508. doi: 10.1182/blood-2014-12-615757.

2 of 3
PER Pulse™ Recap
How Can We Optimize the Frontline Treatment of Newly Diagnosed ALL?

There have been recent advancements in the frontline treatment of adult patients with acute lymphoblastic leukemia (ALL). Treatment intensification approaches based on pediatric-inspired protocols have been studied, including assessment of the upper age limit of such protocols. Tyrosine kinase inhibitors (TKIs) have been used in patients with Philadelphia chromosome (Ph)-positive and Ph-like ALL. Other targeted agents have been evaluated in the context of frontline therapy, including inotuzumab ozogamicin and blinatumomab.

For younger adult patients (aged 18-59 years), benefits in overall survival (OS) have been seen in patients with Ph-negative and Ph-positive ALL, with a near doubling of survival probability over the past 15 years.1-5 For patients with Ph-negative disease, improvements have been seen with increasing cumulative doses of some treatments in the management of pediatric ALL, such as steroids, vincristine, and L-asparaginase.3 Advancements in Ph-positive disease have come largely through the incorporation of TKI therapy, beginning with imatinib.2,4

More recent studies have assessed later-generation TKIs, such as nilotinib and ponatinib, and have yielded promising results. A GIMEMA study of ponatinib in older patients (median age, 68 years) showed a complete response (CR) rate of 95%, with a complete molecular response (CMR) rate of 46% at 24 weeks.6 A GRAAPH study of nilotinib in patients 18-59 years of age showed a CR rate of 96%, with a major molecular response (MMR) rate of 93% at 16 weeks.7 These studies support the concept of combining a TKI with lower-intensity chemotherapy. In a study of full hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and ponatinib as first-line therapy for adult patients with Ph-positive ALL, patients had a CR rate of 100%, with a MMR rate of 97% and a CMR rate of 83%.8,9

Several studies are evaluating the role of inotuzumab ozogamicin in frontline management of patients with ALL. One such study has assessed the combination of inotuzumab ozogamicin with mini–hyper-CVD  (hyperfractionated cyclophosphamide, vincristine, and dexamethasone) for older patients (median age, 68 years), with a CR rate of 95%, a 2-year progression-free survival rate of 59%, and a 2-year OS of 66%.10 Blinatumomab has been evaluated in the frontline setting in the BLAST study, which included patients ≥18 years in first or later CR and persistent or recurrent minimal residual disease (MRD) ≥10-3 after at least 3 blocks of intensive chemotherapy.11 The complete MRD response rate was noted to be 78% among evaluable patients for those receiving blinatumomab.11 Several other studies are evaluating blinatumomab in the frontline setting, with many utilizing MRD as a primary endpoint. One study from The University of Texas MD Anderson Cancer Center is evaluating the combination of inotuzumab ozogamicin and blinatumomab for older patients with ALL.12

Key Points:

  • Major advances have been seen with pediatric-like treatment intensification in adolescents and young adults with ALL.
  • In patients ≥55 years, worse tolerance and compliance are associated with intensive chemotherapy. Frontline incorporation of new options may improve outcomes for older patients with ALL.
  • • The incorporation of treatments such as inotuzumab ozogamicin and blinatumomab into frontline strategies is a subject of active clinical investigation.

References

  1. Huguet F, Chevret S, Leguay T, et al; Group of Research on Adult ALL (GRAALL). Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial. J Clin Oncol. 2018;36(24):2514-2523. doi: 10.1200/JCO.2017.76.8192.
  2. Chalandon Y, Thomas X, Hayette S, et al; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015;125(24):3711-3719. doi: 10.1182/blood-2015-02-627935.
  3. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study [erratum in J Clin Oncol. 2009;27(15):2574]. J Clin Oncol. 2009;27(6):911-918. doi: 10.1200/JCO.2008.18.6916.
  4. de Labarthe A, Rousselot P, Huguet-Rigal F, et al; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood. 2007;109(4):1408-1413.
  5. Thomas X, Boiron JM, Huguet F, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004;22(20):4075-4086.
  6. Martinelli G, Piciocchi A, Papayannidis C, et al. First report of the GIMEMA LAL1811 phase II prospective study of the combination of steroids with ponatinib as frontline therapy of elderly or unfit patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2017;130(suppl 1; abstr 99). bloodjournal.org/content/130/Suppl_1/99?sso-checked=true.
  7. Chalandon Y, Rousselot P, Cayuela J-M, et al. Nilotinib combined with lower-intensity chemotherapy for front-line treatment of younger adults with Ph-positive acute lymphoblastic leukemia: interim analysis of the GRAAPH-2014 trial. Presented at: 23rd Congress of European Hematology Association; June 14-17, 2018, Stockholm, Sweden. Abstract PS922. learningcenter.ehaweb.org/eha/2018/stockholm/215254/yves.chalandon.nilotinib.combined.with.lower-intensity.chemotherapy.for.html.
  8. Jabbour E, Kantarjian H, Ravandi F, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome–positive acute lymphoblastic leukaemia: a single-centre, phase II study. Lancet Oncol. 2015;16(15):1547-1555. doi: 10.1016/S1470-2045(15)00207-7.
  9. Jabbour E, Short NJ, Ravandi F, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome–positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase II study. Lancet Haematol. 2018;5(12):e618-e627. doi: 10.1016/S2352-3026(18)30176-5.
  10. Kantarjian H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase II study. Lancet Oncol. 2018;19(2):240-248. doi: 10.1016/S1470-2045(18)30011-1.
  11. Gӧkbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531. doi: 10.1182/blood-2017-08-798322.
  12. Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Older Patients With Previously Untreated Acute Lymphoblastic Leukemia. clinicaltrials.gov/ct2/show/NCT01371630. Updated December 25, 2018. Accessed February 5, 2019.

3 of 3
PER Pulse™ Recap
Evolving Options for Patients With Relapsed/Refractory ALL

Despite the achievement of high rates of remission in acute lymphoblastic leukemia (ALL), relapses do occur, and survival rates after first relapse have historically been low. The results of one key study show a 5-year overall survival (OS) rate of 7% for patients with ALL following first relapse,1 while the results of another study show 2-year and 5-year OS rates of 11% and 8%, respectively.2 Salvage chemotherapy and transplant approaches have been used, but the quest to improve outcomes further for patients with relapsed/refractory (R/R) ALL has prompted great interest in immuno-oncology. Antibody–drug conjugates, immunotoxins, bispecific T-cell engagers, and chimeric antigen receptor T-cell therapies have all been studied.3

For salvage therapy for ALL, blinatumomab, inotuzumab ozogamicin, and tisagenlecleucel are all FDA approved for the treatment of patients with pre-B-cell ALL. Nelarabine is available for T-cell ALL, and multiple chemotherapy regimens have been employed for ALL salvage. Blinatumomab was approved in 2014, largely based on the results of the phase III TOWER trial, which evaluated patients with R/R Philadelphia chromosome (Ph)-negative ALL.4 In this study, the 2-year OS rate for patients receiving blinatumomab was 24%. Adverse events (AEs) associated with the use of blinatumomab included cytokine release syndrome and neurologic events.

Inotuzumab ozogamicin was approved largely based on the results of the phase III INOVATE trial, in which patients with R/R ALL were randomized to receive either inotuzumab ozogamicin or standard-of-care chemotherapy. At the 2-year follow-up mark, the OS rate for patients receiving inotuzumab ozogamicin was 22.8% compared with 10.0% for patients receiving chemotherapy.5 Patients who received inotuzumab ozogamicin in salvage 1 and achieved minimal residual disease (MRD) negativity had a median survival of 15.6 months, with a 2-year survival of approximately 30%.6

The role of chimeric antigen receptor T-cell (CAR T) therapies for patients with ALL continues to evolve. For adult ALL, several studies with CAR T therapy are ongoing. A recent phase I study evaluated CAR T therapy for adult patients with relapsed B-cell ALL.7 The median OS was 12.9 months (95% CI, 8.7-23.4) in the overall cohort and 20.1 months among those with low disease burden (<5% bone marrow blasts).7 Patients with high disease burden (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of AEs, such as cytokine release syndrome and neurotoxic events, as well as shorter long-term survival.

Key Points:

  • Effective salvage therapies for patients with R/R ALL are available. It is possible to achieve high rates of MRD negativity with combination regimens, and better efficacy outcomes are frequently seen when these approaches have been used in salvage 1.
  • Investigations evaluating combinations involving inotuzumab ozogamicin, chemotherapy, and blinatumomab for patients with ALL are ongoing.
  • CAR T therapy has joined the treatment armamentarium for patients with ALL, and ongoing investigation may help to further shape the treatment paradigm for these patients.

References

  1. Fielding AK, Richards SM, Chopra R, et al; Medical Research Council of the United Kingdom Adult ALL Working Party; Eastern Cooperative Oncology Group. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109(3):944-950.
  2. Tavernier E, Boiron JM, Huguet F, et al; GET-LALA Group; Swiss Group for Clinical Cancer Research SAKK; Australasian Leukaemia and Lymphoma Group. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia. 2007;21(9):1907-1914.
  3. Jabbour E, O’Brien S, Ravandi F, Kantarjian H. Monoclonal antibodies in acute lymphoblastic leukemia. Blood. 2015;125(26):4010-4016. doi: 10.1182/blood-2014-08-596403.
  4. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847. doi: 10.1056/NEJMoa1609783.
  5. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin (InO) versus standard of care (SC) in patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL): long-term results of the phase III INO-VATE study. Blood. 2017;130(suppl 1):2574.
  6. Jabbour E, Gökbuget N, Advani AS, et al. Impact of minimal residual disease (MRD) status in clinical outcomes of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) treated with inotuzumab ozogamicin in the phase III INO-VATE trial. J Clin Oncol. 2018;36(suppl 15, abstr 7013). doi: 10.1200/JCO.2018.36.15_suppl.7013.
  7. Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449-459. doi: 10.1056/NEJMoa1709919.

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