A 52-Year-Old Man With Fatigue, Leukocytosis, and Moderate Splenomegaly

Koyamangalath Krishnan, MD


December 11, 2017

The treatment of choice in this otherwise reasonably healthy 52-year-old man is tyrosine kinase inhibitors. Options include the first-generation tyrosine kinase inhibitor imatinib mesylate, or a second-generation inhibitor (dasatinib or nilotinib).

The National Comprehensive Cancer Network recommends imatinib, dasatinib, and nilotinib as category 1 medications for chronic-phase CML. Imatinib has the longest survival data (>8 years) on the basis of the IRIS trial.[7,8]

Second-generation tyrosine kinase inhibitors have only 36-48 months of data, and long-term survival data are lacking. Molecular remissions are achieved earlier with the second-generation inhibitors[9] and can be considered preferentially in patients with intermediate- to high-risk prognostic scores on the Sokal or Hasford system. For patients who cannot tolerate imatinib, dasatinib, or nilotinib, options include bosutinib, interferon, or stem cell transplantation.[10]

On the basis of previous studies, milestones have been identified that help in the management of patients receiving tyrosine kinase inhibitors. These milestones help with ascertaining timeliness in responses and in determining when resistance or failure to respond has occurred.

The most important determinant of prognosis is response to therapy with tyrosine kinase inhibitors. Patients with CML treated with these inhibitors achieve 3 types of responses: hematologic, cytogenetic, and molecular. The milestones explain when such responses should occur.

With imatinib therapy, best outcomes are predicted on achieving a complete hematologic response at 3 months, at least a major cytogenetic response at 12 months, and a complete cytogenetic response at 18 months. "Major molecular response" refers to a more than 3-log reduction in the BCR/ABL transcript number on RT-PCR analysis. More than 50% of patients who achieve complete cytogenic response at 18 months have a major molecular response.[11,12,13]

In addition, 2 other molecular observations have a role in predicting long-term outcomes: achievement of a less than 10% BCR-ABL transcript level at 3 months, and recognition that earlier and deeper molecular responses are better. A 4.5-log reduction in BCR-ABL transcript number using RT-PCR at 18 months predict better outcomes and longer survival.

Patients who do not meet these milestones need to be restaged and evaluated for accelerated or blastic transformation, tested for resistance (BCR-ABL kinase domain mutation testing for the T315I mutation), and presented with a possible change in therapy. For example, in patients who acquire the T315I mutation on tyrosine kinase inhibitor therapy, ponatinib may be indicated.[14]

The standard approach is to continue tyrosine kinase inhibitors indefinitely in patients with CML. Emerging data seem to suggest that with low prognostic scores on the Sokal index or Hasford score, patients on such inhibitors as imatinib for longer than 50 months who are in complete molecular response for 2 years and are male may be able to discontinue tyrosine kinase inhibitor therapy, followed by close surveillance. This is not the criterion standard, and further studies are needed to confirm these observations.[1]

Patients treated with imatinib may initially have a complete cytogenetic response. Over time, this response may be lost. Acquired T315I mutation is one of the causes of acquired imatinib resistance.


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