Modern treatment approaches to adult acute T-lymphoblastic and myeloid/T-lymphoblastic leukemia: from current standards to precision medicine

Purpose of review To review the most recent advancements in the management of adult T-cell acute lymphoblastic leukemia (T-ALL), we summarize insights into molecular diagnostics, immunotherapy, targeted therapy and new techniques of drug sensitivity profiling that may support further therapeutic progress in T-ALL subsets. Recent findings With current induction/consolidation chemotherapy and/or risk-oriented allogeneic stem cell transplantation programs up to 95% adult T-ALL patients achieve a remission and >50% (up to 80% in adolescents and young adults) are cured. The group of patients who fail upfront therapy, between 25% and 40%, is enriched in high-risk characteristics (unfavorable genetics, persistent minimal residual disease) and represents the ideal setting for the study of molecular mechanisms of disease resistance, and consequently explore novel ways of restoration of drug sensitivity and assess patient/subset-specific patterns of drug vulnerability to targeting agents, immunotherapy and cell therapy. Summary The emerging evidence supports the contention that precision medicine may soon allow valuable therapeutic chances to adult patients with high-risk T-ALL. The ongoing challenge is to identify the best way to integrate all these new data into the therapeutic path of newly diagnosed patients, with a view to optimize the individual treatment plan and increase the cure rate.

[1]  D. O’Connor,et al.  Anti-CCR9 Chimeric Antigen Receptor T cells for T Cell Acute Lymphoblastic Leukemia. , 2022, Blood.

[2]  R. la Starza,et al.  Early T-Cell Precursor ALL and Beyond: Immature and Ambiguous Lineage T-ALL Subsets , 2022, Cancers.

[3]  A. Letai Functional Precision Medicine: Putting Drugs on Patient Cancer Cells and Seeing What Happens. , 2022, Cancer Discovery.

[4]  O. Kallioniemi,et al.  High-throughput ex vivo drug testing identifies potential drugs and drug combinations for NRAS-positive malignant melanoma , 2021, Translational oncology.

[5]  A. Moorman,et al.  First Analysis of the UKALL14 Randomized Trial to Determine Whether the Addition of Nelarabine to Standard Chemotherapy Improves Event Free Survival in Adults with T-Cell Acute Lymphoblastic Leukaemia (CRUK/09/006) , 2021, Blood.

[6]  J. Dipersio,et al.  A Phase 1/2 Dose-Escalation and Dose-Expansion Study of the Safety and Efficacy of Anti-CD7 Allogeneic CAR-T Cells (WU-CART-007) in Patients with Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia (T-ALL)/ Lymphoblastic Lymphoma (LBL) , 2021, Blood.

[7]  C. Mecucci,et al.  T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness , 2021, Genes.

[8]  M. Loh,et al.  Enhancer hijacking drives oncogenic BCL11B expression in lineage ambiguous stem cell leukemia. , 2021, Cancer discovery.

[9]  F. Lussana,et al.  MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL , 2021, Cancers.

[10]  S. Aerts,et al.  14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T and myeloid immature acute leukemia. , 2021, Blood.

[11]  M. Konopleva,et al.  Outcome of T‐cell acute lymphoblastic leukemia/lymphoma: Focus on near‐ETP phenotype and differential impact of nelarabine , 2021, American journal of hematology.

[12]  Chunxu Qu,et al.  Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. , 2021, Cancer discovery.

[13]  G. Roti,et al.  Targeting oncogenic Notch signaling with SERCA inhibitors , 2021, Journal of Hematology & Oncology.

[14]  M. Loh,et al.  Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. , 2020, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  R. Fanin,et al.  Nelarabine as salvage therapy and bridge to allogeneic stem cell transplant in 118 adult patients with relapsed/refractory T‐cell acute lymphoblastic leukemia/lymphoma. A CAMPUS ALL study , 2020, American journal of hematology.

[16]  E. Cencini,et al.  Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T‐cell lymphoblastic leukemia , 2020, Clinical case reports.

[17]  M. Konopleva,et al.  Outcome of adults with relapsed/refractory T‐cell acute lymphoblastic leukemia or lymphoblastic lymphoma , 2020, American journal of hematology.

[18]  N. Viiala,et al.  Relapsed/Refractory ETP-ALL Successfully Treated With Venetoclax and Nelarabine as a Bridge to Allogeneic Stem Cell Transplant , 2020, HemaSphere.

[19]  W. Stock,et al.  Biology and Treatment Paradigms in T Cell Acute Lymphoblastic Leukemia in Older Adolescents and Adults , 2020, Current Treatment Options in Oncology.

[20]  K. Stegmaier,et al.  Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia. , 2020, Cell chemical biology.

[21]  O. Heidenreich,et al.  Phase II-like murine trial identifies synergy between dexamethasone and dasatinib in T-cell acute lymphoblastic leukemia , 2020, Haematologica.

[22]  R. Foà,et al.  Design of a comprehensive fluorescence in situ hybridization assay for genetic classification of T-cell acute lymphoblastic leukemia. , 2020, The Journal of molecular diagnostics : JMD.

[23]  C. Mecucci,et al.  Targeting cytokine and therapy induced PIM1 activation in T-cell acute lymphoblastic leukemia and lymphoma. , 2020, Blood.

[24]  L. Osnes,et al.  T-cell acute lymphoblastic leukemia in patients 1–45 years treated with the pediatric NOPHO ALL2008 protocol , 2019, Leukemia.

[25]  M. Konopleva,et al.  Clinical Experience With Venetoclax Combined With Chemotherapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia. , 2019, Clinical lymphoma, myeloma & leukemia.

[26]  C. Mecucci,et al.  Venetoclax and Bortezomib in Relapsed/Refractory Early T-Cell Precursor Acute Lymphoblastic Leukemia , 2019, JCO precision oncology.

[27]  Zhiqiang Wu,et al.  Blocking CD38-driven fratricide among T cells enables effective antitumor activity by CD38-specific chimeric antigen receptor T cells. , 2019, Journal of genetics and genomics = Yi chuan xue bao.

[28]  M. Toribio,et al.  Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia. , 2019, Blood.

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

[30]  C. McMahon,et al.  Relapsed T Cell ALL: Current Approaches and New Directions , 2019, Current Hematologic Malignancy Reports.

[31]  C. Pui,et al.  Comparative features and outcomes between paediatric T-cell and B-cell acute lymphoblastic leukaemia. , 2019, The Lancet. Oncology.

[32]  P. Van Vlierberghe,et al.  A Novel t(8;14)(q24;q11) Rearranged Human Cell Line as a Model for Mechanistic and Drug Discovery Studies of NOTCH1-Independent Human T-Cell Leukemia , 2018, Cells.

[33]  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.

[34]  Julie M Gastier-Foster,et al.  Improved Survival for Children and Young Adults With T-Lineage Acute Lymphoblastic Leukemia: Results From the Children's Oncology Group AALL0434 Methotrexate Randomization. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  W. Klapper,et al.  Pre-clinical evaluation of second generation PIM inhibitors for the treatment of T-cell acute lymphoblastic leukemia and lymphoma , 2018, Haematologica.

[36]  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.

[37]  M. Loh,et al.  Genetic characterization and therapeutic targeting of MYC‐rearranged T cell acute lymphoblastic leukaemia , 2018, British journal of haematology.

[38]  Traci M. Blonquist,et al.  JDP2: An oncogenic bZIP transcription factor in T cell acute lymphoblastic leukemia , 2018, The Journal of experimental medicine.

[39]  P. Nuciforo,et al.  First-in-human phase 1-2A study of CB-103, an oral Protein-Protein Interaction Inhibitor targeting pan-NOTCH signalling in advanced solid tumors and blood malignancies. , 2018 .

[40]  Lieping Chen,et al.  B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction , 2018, Proceedings of the National Academy of Sciences.

[41]  M. Loh,et al.  Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia. , 2018, Blood.

[42]  Bing Wang,et al.  An ‘off-the-shelf’ fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies , 2018, Leukemia.

[43]  R. Foà,et al.  High PIM1 expression is a biomarker of T-cell acute lymphoblastic leukemia with JAK/STAT activation or t(6;7)(p21;q34)/TRB@-PIM1 rearrangement , 2018, Leukemia.

[44]  J. Soulier,et al.  Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia. , 2018, Blood.

[45]  S. Aerts,et al.  Defining the molecular basis of oncogenic cooperation between TAL1 expression and Pten deletion in T-ALL using a novel pro-T-cell model system , 2017, Leukemia.

[46]  M. Piris,et al.  Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies , 2017, Nature Medicine.

[47]  Li Zhang,et al.  Dasatinib and chemotherapy in a patient with early T-cell precursor acute lymphoblastic leukemia and NUP214-ABL1 fusion: A case report , 2017, Experimental and therapeutic medicine.

[48]  Ciaran M. Lee,et al.  CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. , 2017, Blood.

[49]  Cheng Cheng,et al.  THE GENOMIC LANDSCAPE OF PEDIATRIC AND YOUNG ADULT T-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA , 2017, Nature Genetics.

[50]  H. Dombret,et al.  Early Response-Based Therapy Stratification Improves Survival in Adult Early Thymic Precursor Acute Lymphoblastic Leukemia: A Group for Research on Adult Acute Lymphoblastic Leukemia Study. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  H. Dombret,et al.  Age-related clinical and biological features of PTEN abnormalities in T-cell acute lymphoblastic leukaemia , 2017, Leukemia.

[52]  J. Taunton,et al.  JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias , 2017, Leukemia.

[53]  David Tamborero,et al.  Identification of precision treatment strategies for relapsed/refractory multiple myeloma by functional drug sensitivity testing , 2017, Oncotarget.

[54]  Shana O Kelley,et al.  New Technologies for Rapid Bacterial Identification and Antibiotic Resistance Profiling , 2017, SLAS technology.

[55]  J. Aster,et al.  Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset , 2017, Oncotarget.

[56]  Sebastian Uhrig,et al.  Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia. , 2017, Blood.

[57]  J. Cools,et al.  The genetics and molecular biology of T-ALL. , 2017, Blood.

[58]  Andrew P. Stubbs,et al.  IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: A Genome Sequencing Study , 2016, PLoS medicine.

[59]  A. Ferrando,et al.  The genetics and mechanisms of T cell acute lymphoblastic leukaemia , 2016, Nature Reviews Cancer.

[60]  H. Dombret,et al.  An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study , 2016, Haematologica.

[61]  M. Loh,et al.  Mixed Lineage Leukemia Rearrangements (MLL-R) Are Determinants of High Risk Disease in Homeobox A (HOXA)-deregulated T-Lineage Acute Lymphoblastic Leukemia: A Children's Oncology Group Study , 2015 .

[62]  Hinrich W. H. Göhlmann,et al.  Understanding drugs in breast cancer through drug sensitivity screening , 2015, SpringerPlus.

[63]  J. Soulier,et al.  Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia , 2015, Haematologica.

[64]  F. Kuo,et al.  A Phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma , 2015, Blood Cancer Journal.

[65]  M. Brenner,et al.  A T-cell-directed chimeric antigen receptor for the selective treatment of T-cell malignancies. , 2015, Blood.

[66]  C. Reynolds,et al.  Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235 , 2015, Clinical Cancer Research.

[67]  N. Schork Personalized medicine: Time for one-person trials , 2015, Nature.

[68]  M. Loh,et al.  Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia. , 2015, Blood.

[69]  K. Baggerly,et al.  A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia , 2015, Clinical Cancer Research.

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

[71]  H. Dombret,et al.  The Safety and Activity of BMS-906024, a Gamma Secretase Inhibitor (GSI) with Anti-Notch Activity, in Patients with Relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL): Initial Results of a Phase 1 Trial , 2014 .

[72]  S. Chiaretti,et al.  Genetic profile of T-cell acute lymphoblastic leukemias with MYC translocations. , 2014, Blood.

[73]  A. Letai,et al.  Cell and Molecular Determinants of In Vivo Efficacy of the BH3 Mimetic ABT-263 against Pediatric Acute Lymphoblastic Leukemia Xenografts , 2014, Clinical Cancer Research.

[74]  M. Loh,et al.  Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. , 2014, Cancer discovery.

[75]  J. Cayuela,et al.  Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. , 2014, Blood.

[76]  O. Lohi,et al.  Novel activating STAT5B mutations as putative drivers of T-cell acute lymphoblastic leukemia , 2014, Leukemia.

[77]  Andrea Califano,et al.  Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. , 2013, Cancer cell.

[78]  A. Ferrando,et al.  Early T-cell precursor acute lymphoblastic leukaemia , 2013, Current opinion in hematology.

[79]  C. Mecucci,et al.  New MLLT10 gene recombinations in pediatric T-acute lymphoblastic leukemia. , 2013, Blood.

[80]  N. Perrimon,et al.  Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer. , 2013, Cancer cell.

[81]  J. McCubrey,et al.  Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia , 2012, Leukemia.

[82]  J. Soulier,et al.  Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia. , 2012, Cancer cell.

[83]  A. Ferrando,et al.  Targeting nonclassical oncogenes for therapy in T-ALL. , 2012, Cancer cell.

[84]  A. Glass,et al.  The dual kinase inhibitor NVP-BEZ235 in combination with cytotoxic drugs exerts anti-proliferative activity towards acute lymphoblastic leukemia cells. , 2012, Anticancer research.

[85]  Kiran C. Bobba,et al.  The genetic basis of early T-cell precursor acute lymphoblastic leukaemia , 2012, Nature.

[86]  A. Ferrando,et al.  Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia , 2011, Nature Genetics.

[87]  J. O'Reilly,et al.  NUP214-ABL1 positive T-cell acute lymphoblastic leukemia patient shows an initial favorable response to imatinib therapy post relapse. , 2011, Leukemia research.

[88]  Andrew P. Stubbs,et al.  Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T cell acute lymphoblastic leukemia. , 2011, Cancer cell.

[89]  D. Hoelzer,et al.  Modern therapy of acute lymphoblastic leukemia. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[90]  Andrea Califano,et al.  The TLX1 oncogene drives aneuploidy in T-cell transformation , 2010, Nature Medicine.

[91]  A. Ferrando,et al.  Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia , 2009, Nature Genetics.

[92]  M. Muckenthaler,et al.  High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-beta and PI3K-AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavorable early treatment response. , 2009, Blood.

[93]  Raphael Kopan,et al.  Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. , 2009, Cancer cell.

[94]  J. McCubrey,et al.  Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. , 2009, Cancer research.

[95]  H. Beverloo,et al.  Rapid complete cytogenetic remission after upfront dasatinib monotherapy in a patient with a NUP214-ABL1-positive T-cell acute lymphoblastic leukemia , 2009, Leukemia.

[96]  R. Pieters,et al.  Molecular‐genetic insights in paediatric T‐cell acute lymphoblastic leukaemia , 2008, British journal of haematology.

[97]  Daniela Gabriel,et al.  Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity , 2008, Molecular Cancer Therapeutics.

[98]  Andrew P. Stubbs,et al.  The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. , 2007, Blood.

[99]  Cheng Cheng,et al.  Genes contributing to minimal residual disease in childhood acute lymphoblastic leukemia: prognostic significance of CASP8AP2. , 2006, Blood.

[100]  F. Speleman,et al.  HOXA cluster deregulation in T-ALL associated with both a TCRD-HOXA and a CALM-AF10 chromosomal translocation , 2006, Leukemia.

[101]  E. Macintyre,et al.  Age-related phenotypic and oncogenic differences in T-cell acute lymphoblastic leukemias may reflect thymic atrophy. , 2004, Blood.

[102]  Francois Pognan,et al.  Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[103]  A. Ferrando,et al.  Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia , 2004, Nature Genetics.

[104]  F. Speleman,et al.  t(5;14)/HOX11L2-positive T-cell acute lymphoblastic leukemia. A collaborative study of the Groupe Français de Cytogénétique Hématologique (GFCH) , 2003, Leukemia.

[105]  J. Zucman‐Rossi,et al.  HOX11L2 expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis. , 2002, Blood.

[106]  E. Lander,et al.  Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. , 2002, Cancer cell.

[107]  J. Ritz,et al.  Disruption of the SCL locus in T-lymphoid malignancies correlates with commitment to the T-cell receptor alpha beta lineage. , 1992, Blood.

[108]  A. Hagemeijer,et al.  Heterogeneous patterns of amplification of the NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia , 2009, Leukemia.