Page 1218 - Hematology_ Basic Principles and Practice ( PDFDrive )

1064 Part VII Hematologic Malignancies

Toxicity Intensive efforts have been made to characterize the biologic and
clinical significance of BCR-ABL kinase mutations and to develop
Myelosuppression is particularly common in CML patients treated kinase inhibitors with efficacy against the maximum number of
with imatinib and is more common in patients with advanced disease. mutants. The structure of the ABL kinase domain in complex with
In the phase III randomized trial of newly diagnosed patients in the imatinib has been solved. This information sheds light on the mecha-
CP, grade 3 neutropenia (absolute neutrophil count [ANC] <1000/ nisms by which kinase domain mutations confer drug resistance.
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mm ) was experienced by 11% of patients, grade 4 neutropenia Mutations may affect residues that directly contact imatinib, such as
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(ANC <500/mm ) occurred in 2% of patients, grade 3 thrombocy- a mutation resulting in substitution of isoleucine for threonine in the
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topenia (platelets <50,000/mm ) occurred in 6.9% of patients, and T315 position (T315I). Mutations in the P-loop of the ABL kinase
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grade 4 thrombocytopenia (platelets <10,000/mm ) occurred in less prevent conformational changes required for imatinib binding.
than 1% of patients. Myelosuppression can occur at any time during Imatinib captures and stabilizes the ABL kinase in its inactive con-
imatinib therapy, but it usually begins within the first 2 to 4 weeks formation, but is sterically excluded from the active conformation.
of starting therapy for BC, with a slightly later onset in patients in The M351T mutation and mutations in the activation loop result in
AP or CP. Although grade 3 and 4 neutropenia is frequent, particu- the kinase remaining in the active conformation rather than the
larly in advanced phases, infectious complications are relatively rare, inactive conformation required for imatinib binding. Clinical experi-
possibly related to the lack of mucous membrane damage in patients ence with the second-generation TKIs dasatinib and nilotinib dem-
on imatinib. CNS and gastrointestinal hemorrhages may occur, most onstrates that a much narrower spectrum of mutations retain
frequently in patients in BC with platelet counts less than 20,000 insensitivity to these agents. These mutations are nonoverlapping,
and with uncontrolled leukemia. The primary goal in treating other- with the exception of the T315I mutation.
wise healthy patients in CP is to avoid the risk for potentially danger- Knowledge of BCR-ABL mutation status is being integrated into
ous neutropenia and platelet transfusion dependence. For patients therapeutic decision-making algorithms for patients. The European
with BC or high-risk AP disease (>15% blasts), a suggested approach Leukemia Net guidelines for the use of mutation testing in manage-
is to balance risks and benefits, and support patients with a platelet ment of CML patients recommends mutation testing in CP CML
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count under 10,000/mm or under 50,000/mm with clinically patients receiving first-line imatinib treatment only in case of failure
evident bleeding with platelet transfusions. In the event of clinically or suboptimal response. Mutation analysis is recommended in
significant bleeding, imatinib should be held immediately until the imatinib-resistant patients receiving an alternative TKI in case of
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bleeding is controlled. In patients whose ANC is less than 500/mm , hematologic or cytogenetic failure. 18
imatinib should be continued if the marrow is hypercellular or if there
are >30% blasts. In cases where the marrow is hypocellular and the
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ANC is <500/mm for 2 to 4 weeks, imatinib may be held, the dose Second-Generation Tyrosine Kinase Inhibitors
may be reduced, or myeloid growth factors can be used. Concurrent
administration of growth factors and imatinib is well tolerated, and Because the active conformations of ABL and SRC bear a high degree
patients have not experienced a greater rate of relapse. 17 of structural similarity, compounds with SRC kinase inhibitory activ-
The most common nonhematologic adverse events related to ity have been evaluated against native and mutant BCR-ABL. BMS-
imatinib were nausea, muscle cramps, fluid retention, diarrhea, 354825 (dasatinib, Sprycel) is a dual SRC-ABL kinase inhibitor that
musculoskeletal pain, fatigue, and skin rashes. Only a minority of exhibits approximately 300-fold higher potency against native BCR-
patients experienced grade 3 or 4 toxicity, and there was a low rate ABL. Dasatinib can effectively inhibit most clinically detected
of discontinuance of therapy because of toxicity of 5%, 3%, and 2% BCR-ABL kinase domain mutants at low nanomolar concentrations,
in the phase II studies for BC, AP, and CP, respectively. The higher with the notable exception of T315I. Another compound, AMN107
rate of severe toxicity in patients with advanced-phase disease may (nilotinib) was generated by rational modification of imatinib to
relate to the higher doses administered or to the poorer underlying enhance BCR-ABL kinase binding activity. Nilotinib binds ABL but
health of patients. Most adverse effects can be managed successfully with significantly increased avidity and can overcome resistance of
with supportive measures. Some toxicities (e.g., mild skin rashes, mild most kinase domain mutants, with the exception of T315I. It is
elevations of transaminases, bone pain, and arthralgias) may improve evident, however, that both agents have significant activity in
spontaneously despite continued therapy at the same dosage. imatinib-resistant CML. Of note, responses occurred in patients with
and without BCR-ABL kinase domain mutations at trial entry, with
the exception of patients with the T315I mutation. Responses in CP
Imatinib Resistance and, to a lesser extent, in AP have been stable. In contrast, many
patients with myeloid and all patients with lymphoid BC or
Both de novo and acquired resistance have been observed in imatinib- Ph-positive ALL have relapsed. These data are similar to the results
treated CML patients. The most commonly described mechanisms of the initial studies with imatinib and indicate that once the disease
associated with resistance are point mutations in the BCR-ABL gene has progressed beyond the CP, TKI-based monotherapy is not suffi-
that prevent imatinib from inhibiting kinase activity and BCR-ABL cient to induce lasting responses. Both dasatinib and nilotinib are
gene amplification. BCR-ABL-independent mechanisms may also approved for the treatment of patients with CML that is resistant to
play a role in imatinib resistance in some patients. Activation of the imatinib and those who are intolerant to the drug. Both agents are
SRC family kinase, LYN, has been demonstrated in cells from patients quite effective in resistant disease, yielding CCR in approximately
with acquired imatinib resistance. The Sawyers group, in an original 50% of CP cases (for cases who discontinue imatinib because of drug
study of nine patients who relapsed on imatinib treatment, detected intolerance, the CCR rates are >70%).
BCR-ABL gene amplification in three patients and kinase domain Because of this strong clinical activity, both drugs have been tried
mutations in six. Relapse was associated with reactivation of BCR-ABL as first-line therapy in newly diagnosed CP CML. Two single-center
kinase activity. Subsequent studies have shown that there are >90 trials of dasatinib and nilotinib have been performed at the MD
different amino acid substitutions detected in imatinib-resistant Anderson Cancer Center. At 18 to 24 months, both agents showed
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patients (see Fig. 67.1), occurring with varying frequency. The a similarly small but consistent benefit in CCR over historical controls
different mutations conferred varying degrees of imatinib resistance. treated on imatinib trials. An Italian phase II study of nilotinib in
In patients with stable CP disease, detection of mutations correlated newly diagnosed CP cases showed a similarly high rate of CCR of
with subsequent disease progression. Mutations have been found in >90% after 12 months of therapy. Dasatinib and nilotinib were
some patients before the start of treatment, supporting a model in compared with imatinib for front-line treatment of CP CML. The
which preexisting BCR-ABL mutations that confer imatinib resistance Dasatinib Versus Imatinib Study in Treatment-Naïve CML (DASI-
acquire a selective clonal growth advantage during imatinib SION) study tested 100 mg dasatinib daily versus 400 mg imatinib
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treatment. daily. The Evaluating Nilotinib Efficacy and Safety in Clinical Trials