Navigating the nexus of MRD and novel agents in ALL.

The landscape of acute lymphoblastic leukemia (ALL) has evolved significantly over the last few years. Identification of specific recurrent genetic alterations and of minimal residual disease (MRD) guides prognostic classification and management. Novel agents (eg, blinatumomab) have demonstrated encouraging results in relapsed/refractory (R/R) and MRD+ patients and are currently incorporated into upfront treatment in specific settings. Other new strategies include the incorporation of tyrosine kinase inhibitor-based therapy for patients with Philadelphia chromosome-like ALL and the use of DOT inhibitors and bcl-2/bcl-xl inhibitors in R/R disease. These innovations promise to improve management and outcome in this disease.

[1]  C. Buske,et al.  Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[2]  I. Aldoss,et al.  Adults with Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia: Considerations for Allogeneic Hematopoietic Cell Transplantation in First Complete Remission. , 2019, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[3]  W. Klapper,et al.  Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia , 2017, The New England journal of medicine.

[4]  A. Cherry,et al.  Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. , 2005, Blood.

[5]  Marilyn M. Li,et al.  High Incidence of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia (Ph-like ALL) in Older Adults with B-ALL , 2016, Leukemia.

[6]  B. Wood,et al.  Results of SWOG 1318: A Phase 2 Trial of Blinatumomab Followed By Pomp (Prednisone, Vincristine, Methotrexate, 6-Mercaptopurine) Maintenance in Elderly Patients with Newly Diagnosed Philadelphia Chromosome Negative B-Cell Acute Lymphoblastic Leukemia , 2018, Blood.

[7]  P. Kufer,et al.  Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia , 2017, Haematologica.

[8]  M. Tormo,et al.  Prognostic significance of complex karyotype and monosomal karyotype in adult patients with acute lymphoblastic leukemia treated with risk‐adapted protocols , 2014, Cancer.

[9]  H. Dombret,et al.  Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. , 2018, Blood.

[10]  M. Andreeff,et al.  Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  M. Davids,et al.  The rise of apoptosis: targeting apoptosis in hematologic malignancies. , 2018, Blood.

[12]  P. Houghton,et al.  Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia. , 2016, Blood.

[13]  G. Garcia-Manero,et al.  Impact of complete molecular response on survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. , 2016, Blood.

[14]  Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. , 2000 .

[15]  S. Chiaretti,et al.  New Approaches to the Management of Adult Acute Lymphoblastic Leukemia. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  F. Speleman,et al.  ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. , 2014, Blood.

[17]  M. Loh,et al.  Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. , 2017, Blood.

[18]  M. Loh,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 , 2014 .

[19]  Rajesh Chopra,et al.  Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. , 2007, Blood.

[20]  K. Roberts Why and how to treat Ph-like ALL? , 2018, Best practice & research. Clinical haematology.

[21]  Hermann Einsele,et al.  Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  M. Loh,et al.  Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232. , 2015, Blood.

[23]  H. Gadner,et al.  Rapid molecular response during early induction chemotherapy predicts a good outcome in childhood acute lymphoblastic leukemia. , 2000, Blood.

[24]  W. Evans,et al.  A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. , 2009, The Lancet. Oncology.

[25]  H. Kantarjian,et al.  Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. , 2012, The Lancet Oncology.

[26]  C. Bloomfield,et al.  A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. , 2019, Blood.

[27]  C. Bloomfield,et al.  High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  E. Thiel,et al.  Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. , 2006, Blood.

[29]  M. Liedtke,et al.  Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long‐term survival follow‐up from the randomized, phase 3 INO‐VATE study , 2019, Cancer.

[30]  M. Liedtke,et al.  Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. , 2017, Blood advances.

[31]  T. Barbui,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). , 2009, Blood.

[32]  R. Foà,et al.  BCR/ABL1–like acute lymphoblastic leukemia: How to diagnose and treat? , 2019, Cancer.

[33]  D. Maloney,et al.  Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. , 2019, Blood.

[34]  M. Liedtke,et al.  Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. , 2016, The New England journal of medicine.

[35]  M. Konopleva,et al.  Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. , 2018, The Lancet. Oncology.

[36]  Michael C. Rusch,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 In , 2013 .

[37]  M. Loh,et al.  Philadelphia chromosome-like acute lymphoblastic leukemia. , 2017, Blood.

[38]  Heather L. Mulder,et al.  Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. , 2014, The New England journal of medicine.

[39]  E. Olhava,et al.  DOT1L Inhibitor EPZ-5676 Displays Synergistic Antiproliferative Activity in Combination with Standard of Care Drugs and Hypomethylating Agents in MLL-Rearranged Leukemia Cells , 2014, The Journal of Pharmacology and Experimental Therapeutics.

[40]  C. Mullighan,et al.  Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults. , 2017, Blood.

[41]  M. Loh,et al.  Oncogenic role and therapeutic targeting of ABL-class and JAK-STAT activating kinase alterations in Ph-like ALL. , 2017, Blood advances.

[42]  P. Kufer,et al.  Immunotherapy of lymphoma and leukemia with T-cell engaging BiTE antibody blinatumomab , 2009, Leukemia & lymphoma.

[43]  R. Larson,et al.  Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. , 2015, The Lancet. Oncology.

[44]  S. Hunger,et al.  Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. , 2008, Blood.

[45]  H. Dombret,et al.  Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia. , 2016, The New England journal of medicine.

[46]  T. Chambers,et al.  BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells. , 2015, Cancer research.

[47]  G. Basso,et al.  CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy. , 2008, Blood.

[48]  A. Look,et al.  The MCL1-specific inhibitor S63845 acts synergistically with venetoclax/ABT-199 to induce apoptosis in T-cell acute lymphoblastic leukemia cells , 2018, Leukemia.

[49]  D. Berry,et al.  Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis , 2017, JAMA oncology.