Page 1483 - Williams Hematology ( PDFDrive )

1458 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1459

effective treatment options for CML resistant to standard-dose imatinib. imatinib-resistant CML are sensitive to inhibitors of the BCR-ABL1
Both were FDA approved for this indication in 2012. Bosutinib is active chaperone hsp90, such as geldanamycin. Many of these agents have
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with F317L, Y253H, and F359C/I/V mutations. Ponatinib is also effec- not yet entered clinical trials, but some are in early phase trials, such as
tive against many mutations resistant to nilotinib or dasatinib and has inhibitors of the hedgehog pathway, which is activated in CML but not
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activity in cases with a T315I mutation (see Table 89–6). normal hematopoietic stem cells. Some are being used in conjunction
Bosutinib is a dual SRC-ABL1 TKI that resulted in a CCyR in 24 with imatinib in resistant cases.
percent and CHR in 73 percent of patients who had used two prior Combined Therapy Agents that have been proposed for use in
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TKIs. All mutations except T315I were responsive. It is approved for combination to improve response rates or to overcome resistance to
chronic phase, accelerated phase, or blast phase in those resistant or imatinib have included IFN-α, cytarabine, omacetaxine multiagent che-
intolerant to prior TKI therapy. The dose is 500 mg/day, orally, with motherapy, arsenic trioxide, and decitabine, with some supporting in
food. Diarrhea, nausea, decreased platelet count, other gastrointestinal vitro data. 581–586 Combining imatinib with chemotherapeutic agents is
complaints, rash, and anemia were the most common adverse events, more myelosuppressive, and final effects on response rates and survival
and most of these were of low-grade. Bosutinib is not yet approved have yet to be determined. This approach is rarely used in chronic phase
for use as an initial agent in CML, as it did not demonstrate signifi- CML, but is used in accelerated or blast phase or in Ph chromosome–
cant improvement in CCyR rates at 1 year compared to imatinib. It positive acute lymphoblastic leukemia. 587
was, however, associated with higher 1-year MMR rates, faster time to
response, and less disease progression. 491
Ponatinib blocks native and mutated BCR-ABL1 including the Disease Prognosis and Monitoring During Tyrosine Kinase
gatekeeper mutation T315I. In a phase I dose escalation study, pancre- Inhibitor Therapy
atitis, rash, and myelosuppression were major toxicities. In 12 patients Treatment failure should lead to alterations in therapeutic strategy.
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with T315I mutations, 92 percent had a MCyR. In those with acceler- For patients treated initially with imatinib, BCR-ABL1 expression in
ated or blast phase, or Ph chromosome–positive ALL, 36 percent had cytogenetic responders and nonresponders was similar. BCR-ABL1
a major hematologic response and 32 percent had a MCyRs. Arterial expression became significantly different 3 months after treatment and
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thrombotic events occurred, however. Retrospective analyses of these became increasingly different between responders and nonresponders
incidents led to temporary withdrawal of this medication, which is now with continued therapy at 6, 9, and 12 months. 589
used primarily in cases of T315I mutation or failure of several other One mode of monitoring patients undergoing TKI therapy is to
TKIs. If vascular occlusion occurs, therapy should be halted immedi- measure blood counts at least once per month and to obtain marrow
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ately. Ponatinib has a black box warning for vascular occlusion, heart samples every 6 months until a complete cytogenetic remission is
failure, and hepatotoxicity. obtained. Thereafter, marrow samples are obtained no more often
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A third-line TKI should be considered in patients who have failed than yearly to monitor for other clonal abnormalities. Quantitative
two prior generations of TKI therapy, but responses tend to be infre- RT-PCR is performed every 3 months on blood or marrow. A 1-log
quent and are usually not durable, so clinical trials, other agents, or allo- increase in the level of BCR-ABL1 reactivity, confirmed on a repeat
geneic hematopoietic stem cell transplantation should be considered. sample at least 1 month later, suggests a loss of response to treatment.
A prior CCyR on either imatinib or subsequent nilotinib or dasatinib In patients who do not have a CHR at 3 months, or a MCyR after
therapy was the only predictor of a cytogenetic remission on a third-line 6 to 12 months, other therapeutic options are considered. The molec-
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therapy. 570 ular response after 2 to 3 months of therapy is a strong predictor of
clinical and cytogenetic response. Sequencing the BCR-ABL1 kinase
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Non–Tyrosine Kinase Inhibitor Therapies domain can reveal emergence of resistant clones and is useful if there is
Omacetaxine Omacetaxine (homoharringtonine) is a Cephalotaxus an insufficient initial response to imatinib or a second-generation TKI
alkaloid that has activity against the T315I mutation. Omacetaxine was (see Table 89–5) or any sign of loss of response, such as relapse to Ph
approved on the basis of a study that recruited patients who had already chromosome–positive status, a 1-log increase in BCR/ABL1 transcript
been on two or more TKIs. In those enrolled in chronic phase, 67 ratio, or loss of a MMR. 417
percent had a CHR; a MCyR or a CCyR was achieved in 22 and 4 per- In patients receiving second-generation TKIs as second-line ther-
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cent, respectively. Median overall survival was 30 months. In those apy, those who have no cytogenetic response at 3 to 6 months should
with T315I mutations enrolled on a separate study, MMR was achieved be considered for allogeneic transplantation or switched to an alter-
in 17 percent of patients and the T315I clone was reduced in 61 percent native therapy in a clinical trial. After CCyR is attained, molecular
of patients. The most common side effects with this medication are monitoring is recommended every 3 months for 3 years and every 4 to
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cytopenias. This agent also has activity in accelerated phase CML, but 6 months thereafter. After 12 months, those with a MCyR had a signifi-
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little in blast phase. It was approved by the FDA in October 2012 for cant survival advantage over those with lesser responses. Those with
chronic and accelerated phase patients intolerant of other therapy or in BCR-ABL1 transcripts greater than 10 percent following initial imatinib
cases not responding to two or more TKIs. treatment should be switched to dasatinib, nilotinib, or bosutinib. If this
Several inhibitors of signal transduction mediators involved in is not an option because of cost or availability, high-dose imatinib can
the downstream effects of BCR-ABL have been proposed for use in be considered, but it also unlikely to have benefit for more than a few
imatinib-resistant CML. These inhibitors include the JAK2 inhibitor months. For those already on a second-generation TKI, a clinical trial or
AG490, SRC kinase inhibitors, mTOR (mammalian target of rapamy- alternative TKI could be tried or patients may continue on the same TKI
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cin) inhibitors, such as rapamycin, the proteasome inhibitor borte- with very careful followup, as the impact of this benchmark on overall
573
492
zomib, 574,575 histone deacetylators, 576,577 PI3K or MEK (mitogen-activated survival is not yet known. The 6-month evaluation should identify
kinase) inhibitors and inhibitors of the WNT/β-catenin pathway thought patients with a poor outcome. For those who have MCyR or BCR-ABL1
to be active in CML stem cells. Imatinib resistance often is associated of less than 10 percent at 6 months, overall survival was 100 percent
with restored activation of the BCR-ABL1 signal transduction pathway, as compared to 79 percent for those with no response. At 12 and
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417
suggesting that BCR-ABL1 remains a valid target to overcome resistance 18 months, CCyR is the optimal response. In those who have achieved
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in these cases. BCR-ABL1 point mutations isolated from patients with CCyR, MMR may not be of prognostic significance. 595

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