Question 1: In the current era of tyrosine kinase inhibitor therapy, which prognostic model is best to assess the prognosis of a person with a new diagnosis of CML?
Correct Answer: D. All of the above
Despite not being perfect, all of these scores are reasonably effective at predicting the behavior of CML and the response to therapy. The Sokal score1 was created to predict the natural history of CML in the era of hydroxyurea and busulfan therapy; the Euro (Hasford) score2 was based on the experience of patients treated with interferon; and the EUTOS score3 is based on modern experience with tyrosine kinase inhibitor therapy. However, it is not tested in patients receiving second-generation tyrosine kinase inhibitor therapy.
In reality, we do not ever know how long a person has had CML prior to presentation and diagnosis; thus, the prognostic models reflect a rough measure of initial disease development. For example, leukocytosis and splenomegaly are disease consequences driven by the acquisition of the BCR-ABL abnormality. Patients on tyrosine kinase inhibitor therapy with a low-risk score in any of the three models have better outcomes than those patients with a high-risk score. There are, however, rare cases for which all scores will not be concurrent; in such cases, it is not clear which one to select.
In our opinion, the treating physician should exercise at least one of them not only to estimate prognosis but in certain circumstances to select the most appropriate therapy (discussed later). We prefer to use the most current EUTOS model, but it is completely acceptable for a practitioner to use the model with which he or she is more comfortable. This patient’s calculated Sokal, Euro (Hasford), and EUTOS prognostic scores are 0.61, 26.77 and 23, respectively. These numbers imply “low-risk” disease. According to the EUTOS model, the probability of achieving complete cytogenetic remission with imatinib in our patient at 18 months is 88%. Ongoing studies using more sensitive measures to guide therapy will further improve the prognostic models and outcomes.
Question 2: In this patient, what is the best front-line tyrosine kinase inhibitor therapy?
Correct Answer: A. Imatinib
The choices for front-line tyrosine kinase inhibitor therapy are imatinib, and the more potent second-generation tyrosine kinase inhibitors, nilotinib (Tasigna) and dasatinib. The selection of the “best” tyrosine kinase inhibitor for newly diagnosed chronic-phase CML is literally and figuratively the “billion dollar question.” However, in any given case, treatment goals as well as disease and patient characteristics may distill the choices.
For instance, for someone older than age 70, it may be appropriate to control disease and extend short-horizon survival (ie, years not decades), sacrificing higher potency for lesser potential serious toxicities. In someone much younger, achieving a molecular remission may be attractive, as it appears a subset of these patients may be able to successfully discontinue tyrosine kinase inhibitor therapy.4,5 In such cases, drug potency is paramount.
Next, preexisting comorbidities may discourage (or preclude) the use of certain tyrosine kinase inhibitors. For example, it may not be best to prescribe dasatinib or nilotinib, respectively, to a patient with cardiopulmonary problems or vascular disease. Other important considerations at diagnosis are the phase of the disease (chronic phase vs accelerated or blastic) and in the chronic phase of the disease, the prognostic score. If the patient seems to be on the verge of transition to accelerated or blast phase, there may be a reason to start therapy with a more potent tyrosine kinase inhibitor. In patients with a high Sokal, Euro (Hasford), or EUTOS risk score, nilotinib or dasatinib is usually preferred over imatinib.
Lastly, personal experience and the comfort level of the physician managing various side effects of specific tyrosine kinase inhibitors remain crucial factors in the decision-making process. Timely attention to patients’ concerns, medical history, and prognostic scores nicely declares imatinib (with allopurinol) to be the best management strategy in our patient with CML. However, if all things are being considered equal, the second-generation tyrosine kinase inhibitors yield superior progression-free survival over imatinib.
Three separate randomized trials6-8 showed that nilotinib or dasatinib yielded more frequent complete cytogenetic responses and major molecular responses by 12%, as well as fewer progressions to accelerated or blast phase, than imatinib. To date, however, no randomized trial has shown a benefit in overall survival of nilotinib or dasatinib over imatinib. This may be because the differences in survival between imatinib and the second-generation tyrosine kinase inhibitors are so small that it requires significantly longer follow-up and/or a much larger cohort.
Question 3: If the patient is started on imatinib, what is the best daily dose?
Correct Answer: A. 400 mg
Landmark analysis of the phase III IRIS trial9 (which pitted a 400-mg daily dose of imatinib vs interferon and cytarabine—hardly a fair fight in retrospect) demonstrated superior short-term and long-term responses in the imatinib arm. Given that this trial won imatinib U.S. Food and Drug Administration approval, the 400-mg daily dose became the scientific and regulatory benchmark for the subsequent phase III trials of nilotinib and dasatinib, as well as the U.S. Intergroup trial of imatinib vs dasatinib. Across all of these phase III trials, the cytogenetic, molecular, and survival responses are remarkably similar, and largely because of this large vat of efficacy and toxicity data, both the European Leukemia Net (ELN) and the National Comprehensive Cancer Network (NCCN) offer imatinib 400 mg daily as one of the three treatment options for newly diagnosed patients with chronic phase of the disease (along with dasatinib and nilotinib).
Several trials have compared the 400-mg and 800-mg daily doses of imatinib. The results predictably suggest that the higher dose has more efficacy and compares favorably with second-generation tyrosine kinase inhibitors, but at the expense of substantial toxicity.8,10,11
Another interesting approach pioneered by the Germans is “tolerability-adapted imatinib dosing” (ie, a daily dose of 800 mg given after 6 weeks of 400 mg to avoid excessive cytopenias).12 In case of imatinib intolerability, the dose was gradually tapered to the best tolerable dose but not less than 300 mg. They showed that the higher median dose density contributed to superior molecular remissions. In lieu of current data, it seems that a 600-mg daily dose of imatinib may be the “sweet spot,” but besides its use as the starting point for the Australasia Leukemia and Lymphoma TIDEL studies (I and II)13,14 of dose escalation and tyrosine kinase inhibitor switching in upfront CML treatment, published experience is limited. Thus, currently and in our opinion, imatinib 400 mg daily is the dose of choice for patients with chronic-phase CML. ■
Disclosure: Drs. Abutalib and Radich reported no potential conflicts of interest.
1. Sokal JE, Cox EB, Baccarani M, et al: Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 63:789-799, 1984.
2. Hasford J, Pfirrmann M, Hehlmann R, et al: A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 90:850-858, 1998.
3. Hasford J, Baccarani M, Hoffmann V, et al: Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: The EUTOS score. Blood 118:686-692, 2011.
4. Ross DM, Branford S, Seymour JF, et al: Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: Results from the TWISTER study. Blood 122:515-522, 2013.
5. Mahon FX, Réa D, Guilhot J, et al: Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: The prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11:1029-1035, 2010.
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8. Deininger MW, Kopecky KJ, Radich JP, et al: Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: Results of SWOG S0325, an intergroup randomized phase II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol 164:223-232, 2014.
9. Druker BJ, Guilhot F, O’Brien SG, et al, IRIS Investigators: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408-2417, 2006.
10. Cortes JE, Kantarjian HM, Goldberg SL, et al: High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: High rates of rapid cytogenetic and molecular responses. J Clin Oncol 27:4754-4759, 2009.
11. Cortes JE, Baccarani M, Guilhot F, et al: Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: Tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol 28:424-430, 2010.
12. Hehlmann R, Lauseker M, Jung-Munkwitz S, et al: Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29:1634-1642, 2011.
13. Hughes TP, Branford S, White DL, et al: Impact of early dose intensity on cytogenetic and molecular responses in chronic-phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood 112:3965-3973, 2008.
14. Yeung DT, Osborn MP, White DL, et al: TIDEL-II: First-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 125:915-923, 2015.