Page 1482 - Williams Hematology ( PDFDrive )

1456 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1457

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have a proliferative advantage. Some of these mutations may lie out- proliferation. These include heat shock protein (hsp) 70, survivin,
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side the kinase domain, and more than 40 such mutations have been LYN kinase, SRC, and GRB2, among others. 558
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described. Screening early phase CML patients for mutations before Dose escalation, combination therapy, and treatment interruption
the start of imatinib therapy is not cost-effective because of their low have been proposed as means to overcome drug resistance. Combina-
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incidence, but in patients with evidence of an increase in CML cells tion therapy from the outset also has been proposed to prevent devel-
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while on imatinib, mutation searches are indicated. BCR-ABL1 kinase opment of resistance. Treatment interruption to stop clonal selection
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domain point mutations are rare in those who have had good cytoge- of resistant cells has been proposed. Gene-expression profiles may be
netic responses to imatinib, and when detected in that setting, their useful to predict the clinical effectiveness of imatinib for CML treatment,
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presence does not always predict relapse. Mutations in the ABL1 por- thereby allowing individualized therapy from the outset. In patients
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tion of the BCR-ABL1 oncogene are present in approximately 40 per- with relapse or resistance, alternative approaches include increasing the
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cent of patients who do not achieve a CHR or CCyR to imatinib. ABL1 dose of imatinib or switching to dasatinib or nilotinib. Allogeneic
mutations were found in those patients with both primary and acquired hematopoietic stem cell transplantation is not recommended unless
resistance. Amino acid substitutions in seven residues accounted for patients have inadequate response or intolerance to multiple TKIs or
85 percent of all mutations associated with resistance. The mutations have the T315I mutation. Mutational analysis is not recommended at
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most associated with resistance are Thr315ILe, Gly250Glu, Glu255Lys, diagnosis but is of help in selecting TKI therapy for patients with an
and Thr253His substitutions. Few of the described mutations directly inadequate initial response or loss of response to TKI therapy. Mutation
affect imatinib binding. Mutations in the ABL1–ATP phosphate-bind- type may dictate choice of the next TKI. 562
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ing loop (P-loop) are most closely associated with a poor prognosis, Management of Resistance
and these P-loop mutations predict for disease progression. Overall sur- Dose Escalation If the patient is on imatinib, 400 mg/day, dose escala-
vival is worse for P-loop and for T315I mutations, but not significantly tion to 800 mg/day can be tried. This may be most efficacious in patients
different when other mutations are present. 544 with cytogenetic relapse who had achieved a cytogenetic response with
Ultra-deep sequencing approaches have shown that routine Sanger the initial dose of imatinib, but is not likely to benefit those who have
sequencing underestimates BCR-ABL1 mutation in 55 percent of sam- not had a cytogenetic response with imatinib at 400 mg/day.
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ples where the missed mutations had low abundance. Mass spectrom- Second-Generation Tyrosine Kinase Inhibitor Therapy Several
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etry can detect a 0.05 to 0.5 percent level of mutations, as well. For TKIs are approved for use in the case of imatinib resistance or intol-
many mutations, the concentration that inhibits 50 percent (IC ) of erance. In general, outcome with each is comparable, so the choice of
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various TKIs and response have not been documented. 547 agent often depends on its side-effect profile or in some cases on muta-
Second-generation BCR-ABL1 inhibitors (see “Dasatinib and tion type (see Tables 89–2 and 89–6). 562
Nilotinib” below) are able to overcome imatinib-resistant mutants, with The 3-month molecular response after initiation of a second TKI
the exception of the T315I mutations (Table 89–6). Mutations F317L is also a predictor of overall and event-free survival for those patients in
and V299L are resistant to dasatinib and mutations Y253H, E255K, and chronic phase when switched from imatinib to another TKI. A BCR-
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F359I are resistant to nilotinib. Ponatinib was active against T315I and ABL1 level of 10 percent or less at 3 months is desirable. In patients
against other BCR-ABL1 mutations resistant to dasatinib or nilotinib. treated with nilotinib after imatinib resistance or intolerance, the 4-year
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Ponatinib may be effective against individual ABL1 point mutations but progression-free and overall survival was 85 and 95 percent, respec-
may not overcome some compound mutations, which are two or more tively, if BCR-ABL1 transcripts were 10 percent or less as compared to
mutations in the same BCR/ABL1 molecule. Some mutations may be 42 and 71 percent for those with BCR-ABL1 transcripts greater than
polyclonal as well. The T315I mutation results in steric hindrance, 10 percent at 3 months. 563
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which precludes access of some TKIs to the ATP-binding pocket of the Either dasatinib or nilotinib can be used in cases of imatinib resis-
ABL1 kinase domain. In a series of 27 patients with T315I mutation, tance or intolerance. Dasatinib is 325-fold more potent than imatinib;
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survival was dependent on stage of disease, with many of the chronic and, as a dual inhibitor of SRC and ABL1 kinases, dasatinib is able to
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phase patients described as having an indolent course. In addition to bind to BCR-ABL1 with less-stringent conformational requirements.
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ponatinib, agents such as IFN-α and homoharringtonine have also been In patients resistant to imatinib, dasatinib, 140 mg/day (70 mg q12h),
proposed as therapy for those with the T315I mutation. 552 resulted in a higher proportion of MCyR, CCyR, and MMR than did
In some cases of resistance associated with imatinib, other signal 800 mg/day (400 mg q12h) of imatinib. Treatment failure was decreased
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pathways independent of BCR-ABL1 may become important in cell and progression-free survival was improved with dasatinib. Unlike
imatinib, dasatinib penetrates the blood–brain barrier. In long-term
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followup of 670 patients with imatinib-resistant or intolerant CML,
treated with various doses of dasatinib, 28 percent of patients remained
TABLE 89–6. Prevalent ABL1 Mutations Conferring on study treatment at 6 years. Survival was in the range of 76 to 83 per-
Resistance to a Tyrosine Kinase Inhibitor cent and a MMR was achieved in 45 percent on a dose of 100 mg daily.
Mutation Treatment Recommendation Molecular and cytogenetic responses at 3 and 6 months were predic-
tive of survival. For those with BCR-ABL1 transcripts less than 10 per-
T315I Ponatinib or stem cell transplant
cent at 3 months, progression-free survival was 68 percent, whereas it
V299L, T315A, Consider nilotinib over dasatinib; bosutinib was only 26 percent for those with BCR-ABL1 transcripts greater than
F317L/V/I/C and ponatinib may be effective 10 percent. Nilotinib in a dose of 400 mg every 12 hours induced
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F359V/C/I Consider dasatinib rather than imatinib; bosu- approximately 40 percent of patients who were resistant to or intolerant
tinib and ponatinib may be effective of imatinib into a MCyR, and approximately 30 percent into a CCyR.
Nilotinib, 400 mg BID, is the recommended dose for those intolerant or
Others Any tyrosine kinase inhibitor not previously
used or high-dose imatinib resistant to imatinib.
Bosutinib and Ponatinib In addition to dasatinib and nilotinib,
The reader is referred to the text, which includes references describ- bosutinib and ponatinib, third-generation TKIs, are active against many
ing listings of known sensitivities of reported mutations. of the imatinib-resistant BCR-ABL1 kinase domain mutations and are
Kaushansky_chapter 89_p1437-1490.indd 1457 9/18/15 3:42 PM