NcXHF

RECOGNIZING AND MANAGING HIGH-RISK CML
APPROACH TO THE PATIENT WITH TYROSINE
KINASE INHIBITOR RESISTANCE
The European Leukemia Net and the National Comprehensive
Cancer Network have defıned therapeutic milestones for
patients receiving TKI therapy (Table 4). 6,44 Although both
systems are generally aligned, the European Leukemia Net
uses the category of “warning” to denote a situation that does
not meet the criteria for failure, but gives rise to concern that
a poor outcome is possible. Failure to achieve therapeutic
milestones is consistent with primary resistance. Loss of response
from a given level suggests acquired TKI resistance.
Both should trigger a thorough evaluation. TKI resistance is a
clinically important diagnosis that is associated with inferior
outcomes compared with those of the average CML population.
The fırst call of order is to assess medication adherence
through a thorough history. Drug level testing may be useful
in isolated cases, but is not widely available. Additionally, patients
have been found to make up for skipped doses during
the last few days before the offıce visit. 45 Second, drug interactions
must be considered, especially in patients on multiple
comedications, including over-the-counter remedies such as
St. John’s Wort, which can drastically lower imatinib plasma
concentrations. 46 Predicting drug interactions in patients on
polypharmacotherapy is challenging, particularly in cases
with impaired renal or hepatic function and consultation of a
clinical pharmacologist is advisable. A frequent challenge is a
rise in the level of BCR-ABL1 mRNA as assessed by quantitative
polymerase chain reaction. Interpretation of changes
in BCR-ABL1 mRNA must take into account the performance
of the diagnostic laboratory. In most cases, only rises
greater than fıve-fold or greater than 10-fold are clinically relevant,
particularly in patients with a low level of residual disease.
47 In the absence of other signs of relapse, repeating the
BCR-ABL1 quantitative polymerase chain reaction in 4 to 6
weeks is recommended, before additional diagnostic studies
are initiated. If nonadherence or drug interactions are unlikely,
a complete resistance work-up is indicated that includes
a physical exam, complete blood count, bone marrow
aspirate and biopsy, bone marrow metaphase karyotyping,
and BCR-ABL1 mutation analysis. TKI resistance defınes a
high-risk situation and should be approached as a diagnosis
with important clinical implications. Key pieces of information
derived from this workup are disease phase, BCR-ABL1
mutation status, and karyotype, including CCA/Ph .
Progression of Chronic-Phase Chronic Myeloid
Leukemia
Progression with first-line imatinib. Patients whose disease
develops resistance to fırst-line imatinib, but who are still in
chronic phase, are switched to a second-generation TKI, the
selection of which is based on the fırst-line TKI, past medical
history to avoid specifıc side effects, and (if present) the type
of BCR-ABL1 mutation (Fig. 1). Patients with fırst-line imatinib
failure have a 40% to 50% chance of achieving complete
cytogenic response (CCyR) on a second-generation TKI. 48,49
Overall, however, the prognosis of these patients is guarded.
In a retrospective study, overall and progression-free survival
at 4 years were 81.9% and 35.3%, respectively, indicating that
most patients will eventually require an alternative therapy. 50
Close molecular monitoring is required. One study showed
that only 7% of patients without a minor cytogenetic response
( 65% Ph metaphases) at 3 months were in major
cytogenic response at 12 months, whereas major cytogenic
response at 12 months predicted progression-free and overall
survival (OS). 51 Another study reported that achieving less
than 10% BCR-ABL1 IS at 3 months was predictive of OS
(91.3% vs. 72.1%, p 0.02) and event-free survival (49.3% vs.
13.0%, p 0.001). Taken together, these data suggest that the
3-months evaluation is critical for determining whether the
fırst salvage is likely to work.
Progression during second-generation tyrosine kinase inhibitor
therapy and failure of multiple tyrosine kinase inhibitors.
Selecting the optimal approach in patients in whom secondgeneration
TKI fırst-line therapy fails is challenging. Current
guidelines recommend using an alternative secondgeneration
TKI, but limited data are available regarding the
effıcacy of this strategy. Retrospective studies of dasatinib, nilotinib,
and bosutinib as third-line therapies after failure of
imatinib show limited effıcacy, with CCyR rates of approximately
20%. 52,53 Moreover, responses are frequently not durable,
raising the question of ponatinib as a more effective
and durable salvage therapy. In the Ponatinib Ph ALL and
CML Evaluation (PACE) trial, 46% of CP-CML patients
achieved CCyR, 91% of which were maintained at 12 months.
In most (93%) patients, two or more TKIs had previously
failed, making ponatinib a strong consideration for patients
in whom multiple TKIs have failed. 54 Ponatinib is the drug of
choice for patients with the BCR-ABL1 T315I mutation. The
TABLE 4. Therapeutic Milestones: National Cancer Center Network versus European Leukemia Net
Month Optimal Warning Failure
3 ELN Ph 35% or BCR-ABL1 10% Ph 65–95% or BCR-ABL1 10% No CHR or Ph 95%
NCCN Ph 35% or BCR-ABL1 10% NA Ph 35% or BCR-ABL1 10%
6 ELN Ph 0% and/or BCR-ABL1 1% Ph 1–35% and/or BCR-ABL1 1–10% Ph 35% and/or BCR-ABL1 10%
NCCN Ph 35% or BCR-ABL1 10% NA Ph 35% or BCR-ABL1 10%
12 ELN BCR-ABL1 0.1% BCR-ABL1 0.1–1% Ph 0% BCR-ABL1 1%
NCCN Ph 0% NA Ph 0%
Abbreviations: ELN, European Leukemia Net; Ph, Ph bone marrow metaphases; NCCN, National Cancer Center Network; NA, not applicable; CHR, complete hematologic remission.
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