NCCN Guidelines Insights: Acute Lymphoblastic Leukemia, Version 1.2017.

The prognosis for patients with newly diagnosed acute lymphoblastic leukemia (ALL) has improved with the use of more intensive chemotherapy regimens, tyrosine kinase inhibitors, targeted agents, and allogeneic hematopoietic cell transplantation. However, the management of relapsed or refractory (R/R) ALL remains challenging and prognosis is poor. The NCCN Guidelines for ALL provide recommendations on standard treatment approaches based on current evidence. These NCCN Guidelines Insights summarize treatment recommendations for R/R ALL and highlight important updates, and provide a summary of the panel's discussion and underlying data supporting the most recent recommendations for R/R ALL management.

[1]  K. Davis,et al.  Global Registration Trial of Efficacy and Safety of CTL019 in Pediatric and Young Adult Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL): Update to the Interim Analysis , 2017 .

[2]  M. Tallman,et al.  The evolving role of chemotherapy and hematopoietic cell transplants in Ph-positive acute lymphoblastic leukemia in adults , 2017, Bone Marrow Transplantation.

[3]  I. Aldoss,et al.  Redirecting T cells to eradicate B-cell acute lymphoblastic leukemia: bispecific T-cell engagers and chimeric antigen receptors , 2017, Leukemia.

[4]  P. Chevallier,et al.  Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[6]  A. Jemal,et al.  Cancer statistics, 2017 , 2017, CA: a cancer journal for clinicians.

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

[8]  M. Bar,et al.  Evaluation of allogeneic transplantation in first or later minimal residual disease – negative remission following adult-inspired therapy for acute lymphoblastic leukemia , 2016, Leukemia & lymphoma.

[9]  H. Kantarjian,et al.  Adult Acute Lymphoblastic Leukemia. , 2016, Mayo Clinic proceedings.

[10]  A. Jemal,et al.  Cancer statistics, 2016 , 2016, CA: a cancer journal for clinicians.

[11]  T. Brümmendorf,et al.  Long‐term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors , 2015, American journal of hematology.

[12]  Z. Estrov,et al.  Phase II study of methotrexate, vincristine, pegylated‐asparaginase, and dexamethasone (MOpAD) in patients with relapsed/refractory acute lymphoblastic leukemia , 2015, American journal of hematology.

[13]  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.

[14]  Albrecht Reichle,et al.  Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  Pamela A Shaw,et al.  Chimeric antigen receptor T cells for sustained remissions in leukemia. , 2014, The New England journal of medicine.

[16]  H. Dombret,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). , 2014 .

[17]  Huanhuan Sun,et al.  Survival improvement by decade of patients aged 0–14 years with acute lymphoblastic leukemia: a SEER analysis , 2014, Scientific Reports.

[18]  Qing He,et al.  Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia , 2014, Science Translational Medicine.

[19]  T. Brümmendorf,et al.  Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. , 2011, Blood.

[20]  H. Kantarjian,et al.  Phase II trial of hyper CVAD and dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia. , 2014, American journal of hematology.

[21]  T. Clackson,et al.  A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. , 2013, The New England journal of medicine.

[22]  J. Silverman,et al.  Pharmacokinetics and pharmacodynamics of vincristine sulfate liposome injection (VSLI) in adults with acute lymphoblastic leukemia , 2013, Journal of clinical pharmacology.

[23]  R. Larson,et al.  Phase II study of nilotinib in patients with relapsed or refractory Philadelphia chromosome—positive acute lymphoblastic leukemia , 2013, Leukemia.

[24]  Bernd Hauck,et al.  Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. , 2013, The New England journal of medicine.

[25]  Qing He,et al.  CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia , 2013, Science Translational Medicine.

[26]  Scott E. Smith,et al.  High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  I. Flinn,et al.  Ponatinib in refractory Philadelphia chromosome-positive leukemias. , 2012, The New England journal of medicine.

[28]  T. Brümmendorf,et al.  Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. , 2012, Blood.

[29]  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.

[30]  K. Neville,et al.  Successful Treatment of Fanconi Anemia and T-Cell Acute Lymphoblastic Leukemia , 2012, Case reports in hematology.

[31]  H. Einsele,et al.  Anti-CD19 BiTE Blinatumomab Induces High Complete Remission Rate In Adult Patients with Relapsed B-Precursor ALL: Updated Results of An Ongoing Phase II Trial , 2011 .

[32]  H. Dombret,et al.  Clofarabine Combinations in Adults with Refractory/Relapsed Acute Lymphoblastic Leukemia (ALL): A GRAALL Report , 2011 .

[33]  T. Brümmendorf,et al.  Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. , 2011, Blood.

[34]  Simona Soverini,et al.  BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. , 2011, Blood.

[35]  H. Kantarjian,et al.  Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy. , 2011, Clinical lymphoma, myeloma & leukemia.

[36]  L. Silverman,et al.  Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. , 2010, Blood.

[37]  H. Nakasone,et al.  Dasatinib followed by second allogeneic hematopoietic stem cell transplantation for relapse of Philadelphia chromosome-positive acute lymphoblastic leukemia after the first transplantation , 2010, International journal of hematology.

[38]  J. Klein,et al.  Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  M. Schrappe,et al.  Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  M. Tormo,et al.  Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group , 2010, Haematologica.

[41]  R. Larson,et al.  Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph‐positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study , 2010, American journal of hematology.

[42]  H. Kantarjian,et al.  Phase 1 multicenter study of vincristine sulfate liposomes injection and dexamethasone in adults with relapsed or refractory acute lymphoblastic leukemia , 2009, Cancer.

[43]  A. Pession,et al.  Clofarabine, cyclophosphamide and etoposide as single‐course re‐induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia , 2009, British journal of haematology.

[44]  F. Guilhot,et al.  Successful second allogeneic stem cell transplantation in second remission induced by dasatinib in a child with Philadelphia chromosome positive acute lymphoblastic leukemia , 2009, Pediatric blood & cancer.

[45]  Rocco Piazza,et al.  Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[46]  R. Fanin,et al.  Nilotinib and donor lymphocyte infusion in the treatment of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) relapsing after allogeneic stem cell transplantation and resistant to imatinib. , 2009, Leukemia research.

[47]  H. Kantarjian,et al.  Outcome of adults with acute lymphocytic leukemia after second salvage therapy , 2008, Cancer.

[48]  H. Kantarjian,et al.  Kinase domain point mutations in Philadelphia chromosome‐positive acute lymphoblastic leukemia emerge after therapy with BCR‐ABL kinase inhibitors , 2008, Cancer.

[49]  C. Tei,et al.  Case of a patient with Philadelphia-chromosome-positive acute lymphoblastic leukemia relapsed after myeloablative allogeneic hematopoietic stem cell transplantation treated successfully with imatinib and sequential donor lymphocyte infusions , 2008, International journal of hematology.

[50]  H. Sather,et al.  Outcome after relapse among children with standard-risk acute lymphoblastic leukemia: Children's Oncology Group study CCG-1952. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  H. Dombret,et al.  Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial , 2007, Leukemia.

[52]  J. Oldenburg,et al.  Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). , 2007, Blood.

[53]  R. Larson,et al.  Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. , 2007, Blood.

[54]  M. Baccarani,et al.  Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. , 2007, Haematologica.

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

[56]  C. Bloomfield,et al.  Effective asparagine depletion with pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia: Cancer and Leukemia Group B Study 9511. , 2005, Blood.

[57]  M. Baccarani,et al.  Contribution of ABL Kinase Domain Mutations to Imatinib Resistance in Different Subsets of Philadelphia-Positive Patients: By the GIMEMA Working Party on Chronic Myeloid Leukemia , 2006, Clinical Cancer Research.

[58]  J. Whitlock.  Down syndrome and acute lymphoblastic leukaemia , 2006, British journal of haematology.

[59]  M. Baccarani,et al.  Presence or the emergence of a F317L BCR-ABL mutation may be associated with resistance to dasatinib in Philadelphia chromosome-positive leukemia. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[60]  K. Bhalla,et al.  Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. , 2006, The New England journal of medicine.

[61]  Susan O'Brien,et al.  Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. , 2006, The New England journal of medicine.

[62]  R. Arceci,et al.  Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  M. Devidas,et al.  Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research. , 2005, Blood.

[64]  R. Larson,et al.  The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review. , 2006, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[65]  Z. Estrov,et al.  AMN107, a novel aminopyrimidine inhibitor of p190 Bcr‐Abl activation and of in vitro proliferation of Philadelphia‐positive acute lymphoblastic leukemia cells , 2005, Cancer.

[66]  J. Kurtzberg,et al.  Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[67]  Ping Chen,et al.  Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor , 2004, Science.

[68]  D. Fabbro,et al.  Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia , 2004, Nature Genetics.

[69]  M. Schrappe,et al.  ACUTE LYMPHOBLASTIC LEUKEMIA AND KLINEFELTER SYNDROME IN CHILDREN: Two Cases and Review of the Literature , 2004, Pediatric hematology and oncology.

[70]  W. Hofmann,et al.  Presence of the BCR-ABL mutation Glu255Lys prior to STI571 (imatinib) treatment in patients with Ph+ acute lymphoblastic leukemia. , 2003, Blood.

[71]  Michel Sadelain,et al.  Targeting tumours with genetically enhanced T lymphocytes , 2003, Nature Reviews Cancer.

[72]  R. Herrmann,et al.  High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. , 2002, Blood.

[73]  S. de Vos,et al.  Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation. , 2002, Blood.

[74]  K. Yamada,et al.  Eradication of residual bcr-abl-positive clones by inducing graft-versus-host disease after allogeneic stem cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia , 2002, Bone Marrow Transplantation.

[75]  H. Hasle.  Pattern of malignant disorders in individuals with Down's syndrome. , 2001, The Lancet. Oncology.

[76]  R. Collins,et al.  Donor leukocyte infusions in acute lymphocytic leukemia , 2000, Bone Marrow Transplantation.

[77]  Terry L. Smith,et al.  Primary refractory and relapsed adult acute lymphoblastic leukemia , 1999, Cancer.

[78]  O. Haas,et al.  Relapse of Philadelphia chromosome positive acute lymphoblastic leukaemia after marrow transplantation: sustained molecular remission after early and dose‐escalating infusion of donor leucocytes , 1997, British journal of haematology.

[79]  T. Ito,et al.  Successful prevention of hematological relapse for a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic bone marrow transplantation by donor leukocyte infusion , 1997, Bone Marrow Transplantation.

[80]  A. Taylor,et al.  Leukemia and lymphoma in ataxia telangiectasia. , 1996, Blood.

[81]  A Ferrant,et al.  Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. , 1995, Blood.

[82]  C. Stiller,et al.  Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. , 1994, British Journal of Cancer.

[83]  M. Tuncer,et al.  Acute lymphoblastic leukemia in fanconi's anemia , 1994, American journal of hematology.

[84]  A. Gürgey,et al.  Acute lymphoblastic leukemia associated with Klinefelter syndrome. , 1994, Pediatric hematology and oncology.

[85]  J. Dutcher,et al.  Long-term follow-up of treatment and potential cure of adult acute lymphocytic leukemia with MOAD: a non-anthracycline containing regimen. , 1993, Leukemia.

[86]  O. Eden,et al.  Acute lymphoblastic leukemia and Klinefelter's syndrome. , 1992, Pediatric Hematology & Oncology.

[87]  E. Passarge.  Bloom's syndrome: the German experience. , 1991, Annales de genetique.

[88]  W. Woods,et al.  The occurrence of leukemia in patients with the Shwachman syndrome. , 1981, The Journal of pediatrics.

[89]  R. Williams,et al.  Shwachman's syndrome and acute lymphoblastic leukaemia. , 1978, British medical journal.