At the center of advances in hematology and molecular medicine Philadelphia chromosome-positive chronic myeloid leukemia Robert E. Richard MD PhD rrichard@uw.edu robert.richard@va.gov Philadelphia chromosome Cytogenetics Clonality of cancer Success of allogeneic transplant Molecularly defined therapy Routine use of PCR to follow therapeutic response The BCR-ABL1 fusion The kinase activity of BCR-ABL1 is elevated and constitutive. The molecular pathways that are deregulated are numerous. Epidemiology 15 to 20% of all adult leukemias 1 to 2 cases per 100,000 Median age is 60 (age of patients enrolled on clinical trials is 50) Ionizing radiation is the only known risk factor No familial predisposition Incidence is increasing due to success of therapy 1
Three Phases of CML Defining Chronic Phase - WHO 85% of patients present in Chronic phase Defined as not meeting the criteria of accelerated or blast phases. Three Phases of CML Defining Accelerated Phase - WHO Blasts in blood or marrow 10-19% Basophils in blood >= 20% Persistent thrombocytopenia (<100 x10 9 /L) unrelated to therapy Clonal chromosome abnormalities in Ph+ cells on treatment Thrombocytosis (>1000x x10 9 /L) unresponsive to therapy Increasing spleen size and increasing WBC count unresponsive to therapy. Three Phases of CML Defining Blast Phase - WHO Blasts in blood or marrow >= 20% Extramedullary blast proliferation, apart from spleen Large foci of blasts in the bone marrow biopsy Allogeneic transplant The most important prognostic factor for survival following allogeneic HCT for CML is disease phase Leukemia free survival in patients with acute and chronic leukemia after BM and PBSC transplantation Schmitz N et al. Blood 2006;108:4288-4290 2
The development of Imatinib Proof of principle in cell culture and animal models IRIS study (Druker et al, NEJM 355:2408-2417, 2006) Definition of a response Complete hematologic response Platelets < 450 x 109/L WBC < 10 x 109/L Normal differential, < 5% basophils Non-palpable spleen Complete cytogenetic response Molecular response Definition of a response Complete hematologic response Cytogenetic response Conventional Complete No Ph + Partial 1-35%, Minor 36-65%, Minimal 66-95%, None >95% Molecular response Definition of a response Complete hematologic response Cytogenetic response Molecular response Complete BCR-ABL Transcripts not detected Major BCR-ABL to control gene ratio >= 0.1 3
Levels of molecular response and corresponding log-reduction and BCR-ABL1 transcript levels on the International Scale. Assessing response Monitor with QPCR every 3 months, should be less than 10% after 3 months Than every 3 months for 3 years than every 3 to 6 months if stable Bone marrow at 12 months if CCyR or MMR are not achieved Mutational analysis if poor response, loss of response or disease progression Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Hughes T, et al. Blood. 2006 Jul 1;108(1):28-37. Baccarani M, and Soverini S Blood 2014;124:469-471 2014 by American Society of Hematology Treatment questions with Imatinib Is high-dose imatinib (800 mg daily) superior to standard dose? Patients achieved CCyR and MMR earlier with highdose (6-month CCyR 57% vs 45% with standard dose; P =.0145), but the rates eventually reached the same level. Cortes JE, et al. High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J Clin Oncol 2009;27(28):4754-475 Should imatinib still be front line therapy? When should mutation analysis be performed The development of additional TKIs for CML Nilotinib 300 mg twice daily Faster, deeper responses compared to imatinib may be associated with QT prolongation peripheral artery occlusive disease? T315I resistant mutants may appear at a higher rate Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Rosti G, et al. Blood. 2009;114(24):4933 Dasatinib 4
The development of additional TKIs for CML Nilotinib Dasatinib Dasatinib has not been directly compared with nilotinib Faster, deeper responses compared to imatinib Pleural effusions, headache, and diarrhea 35% of patients required dose reduction Dasatinib vs. Imatinib Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Kantarjian HM, Shah NP, Cortes JE, Blood. 2012;119(5):1123. Kantarjian H et al. N Engl J Med 2010;362:2260-2270 Expense Two second generation TKIs The patent on imatinib was to expire but 5,521,184 GLEEVEC 28-May-13 586 days 04-Jan-15 35 USC 156(e)(2) or 156(d)(5) Imatinib $89/400 mg Nilotinib $93/300 or 400 mg Dasatinib - $90/50 or 70 mg The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Experts in Chronic Myeloid Leukemia. Blood. 2013 May 30;121(22):4439-42. Bosutinib - $118 000 per year The CCyR rate at 12 months was not different for bosutinib (70%; versus imatinib (68). GI and liver-related events were more frequent with bosutinib High rate of drug discontinuation (19%) Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. Cortes JE, et al., J Clin Oncol. 2012;30(28):3486 Ponatinib - $138 000 per year The only drug that treats the T315I mutation 5
Non-TKI therapies Interferon May have a role to induce remission Re-emergence of interferon-α in the treatment of chronic myeloid leukemia. Talpaz M, et al., Leukemia. 2013 Apr;27(4):803-12. Omacetaxine (homoharringtonine) Approved for adult patients with chronic or accelerated phase CML with resistance and/or intolerance to two or more TKIs. Protein translation inhibitor $28 000 for induction and $14 000 per maintenance course thrombocytopenia, anemia, neutropenia, febrile neutropenia, asthenia/fatigue, pyrexia and diarrhea probably holds a record for the longest time of development of an anticancer agent until FDA approval almost 40 years. Who should be referred for transplant? Disease progression to accelerated or blast phase Failure of 2 or 3 or 4 TKIs? Evidence of resistance to TKI? May change with the availability of ponatinib Can TKI ever be stopped? Future Stop Imatinib (STIM) trial 100 CP-CML patients on imatinib therapy with undetectable peripheral blood BCR-ABL transcripts x 2 years 50 stopped imatinib and were followed closely Overall probability of maintaining CMR at 36 months was 39% Similar results were obtained in the CML8 study conducted by the Australasian Leukaemia & Lymphoma Group Severeni et al Unraveling the complexity of tyrosine kinase inhibitor resistant populations by ultra deep sequencing of the BCR-Abl kinase domain Blood 2013; 122(9):1634 Combining treatments TKI +? Immunotherapy? 6