Chronic myeloid leukemia (CML) is a clonal proliferative disorder of the hematopoietic cells of myeloid lineage1-3 driven by a reciprocal translocation between chromosomes 9 and 22, resulting in the so-called Philadelphia (Ph) chromosome. This translocation consists of a head-to-tail fusion of the breakpoint cluster region (BCR) on chromosome 22 and the Abelson gene (ABL) on chromosome 9 that results in the formation of the BCR-ABL hybrid oncogene,1,3 and is the hallmark of this disease. BCR-ABL is the major driver of leukemogenesis in CML, largely through a deregulated activity in ABL’s intrinsic tyrosine kinase activity.3
CML is a relatively rare disease (accounting for only 15% of adult leukemias4) that affects mainly older patients (median age at diagnosis, 65 years4). Most patients with CML are asymptomatic, receive their diagnosis after a routine complete blood cell count (CBC), and present clinically in the initial and indolent form of this triphasic disease, the chronic phase (CP). Untreated or with ineffective treatment, CP-CML progresses within 3 to 5 years to the symptomatic and aggressive phases of the disease, ie, the accelerated phase (AP) and the rapidly fatal blast phase (BP).3
Better understanding of the pathophysiology of this disease has led to the development and the first successful clinical application of targeted therapy in cancer. Five tyrosine kinase inhibitors (TKIs) are now commercially available, and these agents have dramatically improved the outcomes of patients with CML.5 This article focuses on the SRC-ABL inhibitor bosutinib (Bosulif), and reviews practical aspects for the management of patients treated with this drug.
A 23-year-old patient presented with a 4-week history of abdominal pain, bloating, early satiety, anorexia, night sweats, and dramatic weight loss. Physical evaluation revealed splenomegaly, which led to a CBC that showed hyperleukocytosis with a white blood cell count of 92,000/µL. A bone marrow aspirate and biopsy showed a hypercellular marrow (100%) with no increase in blasts, and cytogenetic analyses confirmed the presence of the Ph+ in 20 metaphases. The diagnosis of CP-CML was therefore confirmed and the patient started imatinib (Gleevec) at the dose of 800 mg daily. Treatment with imatinib was complicated by diarrhea, pleural effusions requiring thoracentesis, myalgias, arthralgias, facial rash, and pancytopenia requiring a temporary hold of imatinib. With recurrence of these adverse events despite dose reduction to 400 mg daily the patient was deemed imatinib intolerant and was offered enrollment in a trial, the Phase 1/2 Study of SKI-606 [or bosutinib] in Philadelphia Chromosome Positive Leukemias (ClinicalTrials.gov identifier: NCT00261846). The patient started bosutinib at 500 mg daily on March 12, 2008.
Treatment with bosutinib was associated with early onset of gastrointestinal adverse events (nausea, vomiting, and diarrhea) and transient facial rash, both of which resolved without dose interruptions or reduction. The patient promptly achieved a complete hematologic remission (CHR) and a major cytogenetic remission (MCyR) that became complete (CCyR) at 6 months. BCR-ABL mRNA levels were no longer detected by quantitative real-time polymerase chain reaction (qPCR), and therefore the patient also achieved a complete molecular remission (CMR). More than 4 years later, the patient is still receiving bosutinib and remains in CHR, CCyR, and CMR.
Treatment of CML
Previously, allogeneic hematopoietic stem cell transplantation was considered the only “curative” option for CML, and was offered up front to young and otherwise healthy patients who had a suitable donor.2,3 However, given the high responses with first-line TKI treatment, the sustainability of these responses, the excellent tolerability of these oral agents, and the availability of effective second-line TKIs, transplants are no longer recommended as a first-line option. Three TKIs are approved for first-line treatment for patients with CML: imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna). Both dasatinib and nilotinib were previously approved as second-line agents,6,7 and more recently ponatinib (Iclusig) was approved for the treatment of adults with CML and Ph+ acute lymphoblastic leukemia.8 However, and despite spectacular responses, a subgroup of patients are intolerant or develop resistance to these agents, often due to the development of ABL kinase domain mutations.
On September 4, 2012, the US Food and Drug Administration (FDA) approved bosutinib tablets for the treatment of CP, AP, or BP Ph+ CML in adult patients with resistance or intolerance to previous TKI therapy.9 Formally known as SKI-606, bosutinib is an effective TKI that competitively inhibits both the BCR-ABL and SRC kinases.10,11 Furthermore, bosutinib demonstrates greater inhibition as well as increased selectivity for the tyrosine kinase domains, thus resulting in minimal inhibitory activity against c-KIT or platelet-derived growth factor.
Bosutinib is bioavailable orally in 100 mg or 500 mg tablets. The recommended dose is 500 mg once daily with food for optimal absorption.12 Bosutinib is metabolized by the cytochrome P3A4 enzyme and cleared by the liver; therefore, dose reductions are required for preexisting hepatic impairment.
Response to treatment in CML is initially determined by the resolution of splenomegaly, normalization of both the CBC and marrow cellularity (CHR), and subsequently by quantitative assessments of blood or marrow samples for the presence of BCR-ABL mRNA. Cytogenetic response is determined by the number of marrow Ph+ metaphases: minor response when the Ph+ is detected in 36% to 65% of the metaphases, major when the number of Ph+ metaphases decreases to <35%, and the absence of Ph+ metaphases defines CCyR.1 Molecular methods that can also be reliably performed on blood samples include fluorescence in situ hybridization (FISH) and the very sensitive qPCR.13 Major molecular response (MMR) is defined as a ≥3-log reduction (International Scale) of the BCR-ABL mRNA and CMR by the absence of detectable BCR-ABL mRNA.1
Efficacy of Bosutinib in CML
Bosutinib has activity in all phases of CML that is resistant or intolerant to imatinib and/or dasatinib or nilotinib. Overall, 86% of imatinib-resistant and 85% of imatinib-intolerant CP patients achieved CHR14; 55% of AP and 28% of BP patients achieved an overall hematologic response defined as either CHR, a return to a second CP, or no evidence of leukemia.15 Additionally, 41% of imatinib-resistant CP, 41% of imatinib-intolerant CP, 33% of AP, and 29% of BP patients achieved CCyR.14,15 The overall survival at 2 years for imatinib-resistant and -intolerant CP patients was 88% and 98% with a progression-free survival of 72% and 89%, respectively.14 Bosutinib was also effective when administered as a third-line agent to 119 patients with CP-CML resistant or intolerant to imatinib, dasatinib, or nilotinib16; of these patients, 62% to 80% achieved CHR and 33% to 48% achieved MCyR that was complete in 19% to 43%.17 Table 1 summarizes the activity of bosutinib in previously treated patients with CP-CML. Data from this trial led to the FDA approval of bosutinib for the treatment of resistant CP-CML.
A phase 3 trial, Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia, was conducted comparing imatinib with bosutinib.18 The primary end point was to determine the proportion of patients who achieved CCyR at 12 months in both arms of the trial. Results of this trial showed comparable rates of CCyR in both arms, achieved in 68% and 70% of imatinib- and bosutinib-treated patients, respectively. However, the MMR rate at 12 months was higher with bosutinib than imatinib (41% vs 27%), and median time to achieve CCyR and MMR was significantly faster for bosutinib-treated patients compared with imatinib-treated patients (12.9 weeks vs 24.6 weeks and 37.1 weeks vs 72.3 weeks, respectively).18
Adverse Events and Management
Common adverse events associated with the use of bosutinib are summarized in Table 2. Overall, bosutinib is well tolerated, and adverse events are often transient, manageable, and rarely result in drug discontinuation. The most common nonhematologic adverse events are gastrointestinal, and include diarrhea (84%), nausea (44%), and vomiting (35%).14 The mechanisms that lead to diarrhea are unknown; however, the pattern is very predictable: early onset (median of 2 days) after initiation of bosutinib in the majority of cases is grade 1 to 2 (75%) and lasts a median of 2 days. Antidiarrheals (ie, loperamide or diphenoxylate atropine) are very effective. If bosutinib needs to be temporarily held, resumption of the drug is usually not associated with diarrhea recurrence. Diarrhea is rarely grade 3 to 4 (9%), is very infrequently chronic, and led to bosutinib discontinuation in only 1% of patients in clinical trials.
Myelosuppression is the main hematologic adverse effect associated with bosutinib, with anemia occurring in 90%, thrombocytopenia in 66%, and neutropenia in 40% of patients.14 Median onset of myelosuppression is 22 days, and median duration is 14 days. Hematologic adverse effects are generally managed with transfusions as indicated and standard supportive care measures. Hematopoietic growth factors are rarely used in CP patients; however, dose interruptions, reductions, or discontinuations are at times required in the management of severe myelosuppression. The mechanisms that lead to myelosuppression are multifactorial and include direct marrow drug toxicity and possibly effective suppression of a predominantly Ph+ driven hematopoiesis.19
Elevation of liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) occurs in 59% and 49% of patients, respectively.14 Median time to onset of liver enzymes elevation is 31 days, and median duration is 20 days. These abnormalities usually resolve with dose reduction or transient drug interruption, and rarely recur with reintroduction of the drug. No cases of liver failure were reported, and abnormal liver function tests led to drug discontinuation in 2% of patients in clinical trials. Overall, adverse events that led to discontinuation of bosutinib in clinical trials included thrombocytopenia, neutropenia, and elevated ALT.
Predictors of Resistance to Bosutinib
Baseline factors predicting resistance to bosutinib include the presence of ABL-domain mutations that include the detection of V299L and T315I.20 Responses to bosutinib are observed regardless of the presence of ABL domain mutations. Indeed, impressive response rates are observed, with 75% achieving CHR and 43% achieving MCyR among patients with CP-CML and ≥1 baseline mutation. Furthermore, resistance to previous TKI therapies is also associated with lower response rates to bosutinib. At the time of progression while receiving bosutinib therapy, new emergent mutations were reported in 24% of patients with CP-CML, with V299L and T315I mutations detected in 11% and 5%, respectively.20
Development of resistance is suspected in the setting of progressive rise in BCR-ABL as measured by qPCR, loss of cytogenetic response, or loss of hematologic response.1,21 Monitoring response by qPCR can be challenging because benign minor fluctuations often occur.22 Unless there is a steady rise in qPCR mRNA levels (which is a prelude for a loss of cytogenetic response) and progression is observed, treatment rarely needs to be altered.
Although 3 very effective and overall well-tolerated TKIs are available for the upfront treatment of CML, failure of first-line therapy remains a challenge. The selection of the second- or third-line agent is affected by several factors, predominantly the detection of specific ABL-kinase domain mutations, physician’s preference, dose schedule, timing of drug administration (food restrictions), baseline comorbidities that may increase the risk of drug-specific adverse effects, and risks for cross-intolerance. Given the significant and sustained activity in settings of second-line treatment and beyond, bosutinib is an effective addition to the armamentarium for the treatment of CML, that with the exception of V299L and T315I, has shown activity across all ABL domain mutations.
The authors thank Dr H. Jean Khoury for providing guidance, suggestions, and review of this paper.
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