CML TREATMENT GUIDELINES

CML TREATMENT GUIDELINES

INITIAL INVESTIGATION Propose enrolment in the CML Registry of the CML-MPN Quebec Research Group. Medical history : Question for cardio-respiratory disorders, diabetes, pancreatitis, peripheral vascular disease, and tobacco use ; Information on siblings if patient is eligible for a stem cell transplant ; Identification of drugs metabolized by CYP3A4 and drugs that prolong QTc. Blood analysis:* : CBC (with differential and smear), E+, creatinine, LDH, uric acid, bilirubin, AST, ALT, Alk P., GGT, glucose, amylase, lipase, cholesterol (total, LDL, HDL), HbA1c; Molecular biology: breakpoint identification and determination of the number of BCR-ABL transcripts by RQ-PCR (not on bone marrow) and reported according to International Scale (IS). INITIAL INVESTIGATION (NEXT) Physical examination including spleen size (in cm below the costal margin) A bone marrow aspiration, a biopsy and a marrow karyotype are mandatory at diagnosis to establish the phase of the disease and detect additional cytogenetic aberrations with impact on prognosis (2 nd Philadelphia chromosome, trisomy 8 or 19, isochromosome 17q). MD Anderson Cancer Center (MDACC) criteria for accelerated and blast phase : Accelerated phase if at least one of the following criteria is present : Blasts in blood > 15% Blasts and promyelocytes in blood > 30% Basophils in blood > 20% Persistent thrombocytopenia (< 100 X 10 9 /L) unrelated to treatment Clonal evolution Blast phase if at least one of the following criteria is present: Blasts in blood or marrow > 30% Chloroma * CBC : complete blood count ; E+: electrolytes ; LDH : lactate dehydrogenase ; AST : aspartate aminotransferase ; ALT : alanine aminotransferase ; Alk P. : alkaline phosphatase ; GGT : gamma glutamyltransferase; LDL : low density lipoprotein ; HDL : high density lipoprotein ; HbA1c : glycated hemoglobin ; RQ-PCR : real time quantitative polymerase chain reaction

INITIAL INVESTIGATION (NEXT) Sokal score should be calculated at diagnosis, prior to treatment, based on the following parameters : Age Spleen size (cm below costal margin) Platelets in blood (x 10 9 /L) Blasts in blood (%) Website to calculate : www.geoq.info/_membres/documents/ guides/varia_nb/lmc_sokal.htm#sokal www.leukemia-net.org/content/leukemias/ cml/cml_score/index_eng.html Risk category : Low : < 0,8 Intermediate : 0,8-1,2 High : >1,2 CHRONIC PHASE (CP) CML TREATMENT The following treatments are recommended : Imatinib 400 mg daily Dasatinib 100 mg daily Nilotinib 300 mg BID Approved clinical trial The CML-MPN Quebec Research Group recognizes that 2 nd generation tyrosine kinase inhibitors (TKI) lead to faster and deeper responses, are associated with less transformation and are globally better tolerated. Their superiority versus imatinib has to be balanced with the lack of long term data. For high risk patients (Sokal or Hasford score), 2 nd generation TKI are preferred. The choice of TKI is modulated by the availability of drugs, patient comorbidities, patient and doctor preferences. Generic imatinib : Bioequivalence is not a measure of therapeutic equivalence. Ideally, patients should be subject to a narrow observation and enrolment in the CML Registry is highly recommended.

TREATMENT OF MDACC DEFINED ACCELERATED PHASE (AP) CML Patient eligible for a stem cell transplant : Refer to a center with expertise in evaluation of this therapeutic option HLA typing of patient, siblings and search for an alternate donor. Following treatments are recommended : Imatinib 600 mg daily Dasatinib 140 mg daily Nilotinib 400 mg BID Approved clinical trial Stem cell transplant remains the standard of care. Patients that are ineligible or waiting for a donor are treated with a TKI until disease progression. The CML-MPN Quebec Research Group favors 2 nd generation TKI (if available). TREATMENT OF MDACC DEFINED BLAST PHASE (BP) CML Patient eligible for a stem cell transplant : Refer to a center with expertise in allograft preparation HLA typing of patient, siblings and search for an alternate donor. The following treatments are recommended : Approved clinical trial; Imatinib 800 mg daily with or without chemotherapy (reduce to 400-600 mg daily during chemotherapy); Nilotinib 400 mg BID with or without chemotherapy; Dasatinib 140 mg daily with or without chemotherapy. Stem cell transplant remains the standard of care. Patients that are ineligible or waiting for a donor are treated with a TKI until disease progression. The CML-MPN Quebec Research Group favors 2 nd generation TKI for their superiority in resistant or refractory disease as monotherapy. In combination with chemotherapy, imatinib is preferred as toxicity data with 2 nd generation TKI are lacking. The central nervous system has to be evaluated and treated if positive. In lymphoblastic phase, prophylaxis is to be given even if negative.

MONITORING CBC every 2 weeks until complete hematological response (CHR) every 3 months afterwards ; E+, renal function, hepatic enzymes, Mg, PO 4, Ca, glucose*, lipase*, amylase* (*particularly if on nilotinib) every 2 weeks until CHR every 3 months afterwards; Follow-up and treatment of peripheral vascular disease risk factors (cholesterol, diabetes, tobacco use, hypertension); Electrocardiography (ECG) before and after 1-2 weeks initiation of a 2 nd generation TKI (QTc < 500 ms) ; Chest X-Ray if symptomatic ; RQ-PCR BCR-ABL every 3 months : Once major molecular response (MMR) (0.1% IS) is achieved and stable for 2 years, it is possible to extend monitoring interval at 6 months. Verify adherence at each visit ; Search for ABL mutations if : Failure to achieve therapeutic milestones ; Expression of BCR-ABL by RQ-PCR increases more than 0.5 log in 2 consecutive blood samples, more than 0.1% IS ; Lack of response after the introduction of an alternative TKI or new loss of response. Bone marrow karyotype performed annually except if patient has a prior documented complete cytogenetic response (CCR) with an adequate karyotype or is in MMR (< 0.1% IS or 3 log reduction) with normal blood counts. THERAPEUTIC MILESTONES FOR PATIENT IN CHRONIC PHASE CML Milestones established with data from first line imatinib treated patients. Therapeutic failure if : Lack of CHR at 3 months, Lack of early molecular response : RQ-PCR BCR-ABL > 10% IS or lack of 1 log reduction at 3 months, Lack of CCR at 12 months : A bone marrow karyotype is not needed if MMR or better at 12 months, MMR not achieved at 18 months : RQ-PCR BCR-ABL > 0.1% IS or lack of 3 log reduction at 18 months.

SECONDARY RESISTANCE Transformation to AP or BP Management as AP or BP Loss of CHR, loss of CCR, loss of MMR or a confirmed increase of 0.5 log and remains in CP : Verify drug adherence ; Search for ABL mutations ; Bone marrow karyotype for clonal evolution. If first line is imatinib : Change for a 2 nd generation TKI, Consider option of a stem cell transplant according to patient s specific situation. If first line is a 2 nd generation TKI : Refer to a center with expertise in allograft preparation : HLA typing of patient, siblings and search for an alternate donor. Increase nilotinib dosage to 400 mg BID, Increase dasatinib dosage to 140 mg daily, Approved clinical trial, Change for an alternative TKI (according to ABL mutation analysis results). MANAGEMENT ACCORDING TO ABL MUTATIONS The majority of mutations that appear while on imatinib are sensitive to 2 nd generation TKI. Mutations with distinctive sensitivities : T315I : Consider stem cell allograft Role for ponatinib Approved clinical trial F317L/V/I/C, Q252H, or V299H/L : Nilotinib is preferred (take into account comorbidities) Bosutinib or ponatinib, when available, may be an option E255K/V, Y253H, or F359C/V/I : Dasatinib is preferred (take into account comorbidities) Bosutinib or ponatinib, when available, may be an option Any other mutation : Nilotinib or dasatinib is preferred Bosutinib or ponatinib, when available, may be an option

The current guidelines are intended as a reference framework to present management strategies for many aspects of CML a treatment. These guidelines are a consensus of the CML-MPN Quebec Reasearch Group based on published data as well as expert opinion and developed during consensus meetings. They do not replace in any way clinical judgment and are not intended to establish a treatment protocol that would be applicable to all cases of CML. The distribution of these guidelines has been made possible thanks to the support of Novartis Pharmaceuticals Canada Inc. and Bristol-Myers Squibb Canada.