Tyrosine kinase inhibitors for the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a heterogeneous disorder, with the greatest prevalence in children, but it also affects adults, and has an increasing incidence with age. Chromosomal abnormalities in ALL have been frequently described, the most common is the Philadelphia chromosome (Ph). The resulting fusion gene, BCR-ABL1, encodes for a chimerical oncoprotein (BCR-ABL) with constitutive tyrosine kinase activity, which leads to uncontrolled cell proliferation, reduced apoptosis, and impaired cell adhesion. Treating Philadelphia chromosome-positive (Ph+) ALL patients with conventional chemotherapy has not substantially improved their long-term outcomes. Recently, however, BCR-ABL-targeted strategies have been successfully adopted. Imatinib is an oral competitive inhibitor of ABL with demonstrated phase 2 efficacy in patients with treatment-naive and pretreated ALL. Despite its efficacy, imatinib may induce specific resistance in a large proportion of patients, mainly because of the occurrence of ABL1 mutations. Therefore, novel inhibitors have been developed. Dasatinib is a multitargeted kinase inhibitor of BCR-ABL, SRC, C-KIT, PDGFRs, and ephrin A receptor kinases. Unlike imatinib, it binds both the active and inactive BCR-ABL as well as the majority of ABL mutants. Dasatinib is approved for treatment of imatinib-pretreated Ph+ ALL, and chronic myeloid leukemia (CML) on the basis of phase 2 trials that demonstrated impressive efficacy and favorable tolerability profiles. Nilotinib is another BCR-ABL targeted agent that is similar in structure to imatinib but has significantly greater binding affinity. It also has demonstrated promising efficacy in Ph+ ALL but is still being evaluated in phase 2 trials. In this article, the authors reviewed current knowledge on novel tyrosine-kinase inhibitors in adult Ph+ ALL patients.     

酪氨酸激酶抑制剂在费城染色体阳性急性淋巴细胞白血病诱导治疗中的作用

目的 探讨低剂量化疗联合酪氨酸激酶抑制剂(TKI)作为初诊费城染色体阳性急性淋巴细胞白血病(Ph+ ALL)一线诱导治疗方案的可行性.方法 回顾性分析61例初诊Ph+ ALL患者接受不同诱导治疗方案的疗效与不良反应.结果 全部患者初次诱导治疗的完全缓解(CR)率为73.8％(45/61),再次诱导CR率为86.7％(13/15),两程诱导治疗总的CR率为95.1％(58/61),治疗相关死亡1例(1.6％).无论是否联用TKI,常规剂量组与低剂量组有效率差异无统计学意义[未联用组:65.5 ％(19/29)比60.0％(3/5),P=0.812;联用组:90.5％(19/21)比100.0％(6/6),P=0.432];低剂量化疗联合TKI的有效率与单用常规剂量化疗比较,差异亦无统计学意义(P=0.089).无论化疗强度如何,联合TKI均能提高初次诱导治疗有效率(常规剂量组:P=0.041;低剂量组:P=0.087);联用TKI方案总有效率显著高于未联用TKI方案[92.6％(25/27)比64.7％(22/34),P=0.010].对于未获CR患者,初次诱导时未联用TKI者再次诱导治疗联用TKI的有效率明显高于初次诱导曾联用TKI者[100.0％(8/8)比33.3％(1/3),P=0.011].不同遗传学亚组间初次诱导治疗的有效率差异无统计学意义(均P＞0.05),联用TKI可在一定程度上提高有效率,但差异均无统计学意义(均P＞0.05).全部患者初次诱导治疗的感染率为50.8％(31/61),出血发生率为4.9％(3/61).常规剂量组总感染率[56.0％(28/50)]高于低剂量组[27.3％(3/11)],但差异无统计学意义(P=0.084),两组总出血发生率差异亦无统计学意义[6.0％(3/50)比0(0/11),P=0.405].低剂量化疗联合TKI组的感染率低于常规剂量化疗联合TKI组[0(0/6)比71.4％(15/21),P=0.002],也低于单用常规剂量化疗组[0(0/6)比44.8％(13/29),P=0.039],组间出血发生率差异均无统计学意义(均P＞ 0.05).结论 低剂量化疗联合TKI作为Ph+ ALL一线诱导治疗方案值得进一步探索.     

Philadelphia chromosome-positive acute lymphoblastic leukemia: current treatment and future perspectives

The Philadelphia chromosome (Ph) is the most common cytogenetic abnormality associated with adult acute lymphoblastic leukemia (ALL). Before the advent of tyrosine kinase inhibitors (TKIs), Ph-positive ALL carried a dismal prognosis and was characterized by a poor response to most chemotherapy combinations, short remission durations, and poor survival rates. Outcomes for patients with Ph-positive ALL improved substantially with the introduction of TKIs, and the TKI imatinib induced complete remissions in >95% of patients with newly diagnosed Ph-positive ALL when it was combined with chemotherapy. However, imatinib resistance remains a problem in a substantial proportion of patients with Ph-positive ALL, and multiple molecular mechanisms that contribute to imatinib resistance have been identified. Second-generation TKIs (eg, dasatinib and nilotinib) have demonstrated promising efficacy in the treatment of imatinib-resistant, Ph-positive ALL. Future strategies for Ph-positive ALL include novel, molecularly targeted treatment modalities and further evaluations of TKIs in combination with established antileukemic agents. For this article, the authors reviewed past, current, and future treatment approaches for adult and elderly patients with Ph-positive ALL with a focus on TKIs and combined chemotherapeutic regimens.     

Efficacy of the polo-like kinase inhibitor rigosertib,alone or in combination with Abelson tyrosine kinase inhibitors,against break point cluster region-c-Abelson-positive leukemia cells

The potency of Abelson (ABL) tyrosine kinase inhibitors (TKIs) against chronic myeloid leukemia (CML) has been demonstrated. However, ABL TKI resistance can develop. In this study, we investigated the efficacy of a combination therapy including rigosertib (ON 01910.Na), a polo-like kinase (PLK) and phosphoinositide 3-kinase (PI3K) inhibitor, and ABL TKIs. A 72-h rigosertib treatment was found to inhibit cell growth, induce apoptosis, reduce phosphorylation of the breakpoint cluster region-c (BCR)-ABL and its substrate Crk-L, and increase the activities of caspase 3 and poly (ADP-ribose) polymerase (PARP). This combination therapy also exerted a synergistic inhibitory effect on Philadelphia chromosome (Ph)-positive cell proliferation and reduced the phosphorylation of BCR-ABL and Crk-L while increasing that of cleaved PARP and the H2A.X histone. Rigosertib also potently inhibited the growth of ABL TKI-resistant cells, and cotreatment with ABL TKIs and rigosertib induced higher cytotoxicity. These results indicate that rigosertib treatment may be a powerful strategy against ABL TKI-resistant cells and could enhance the cytotoxic effects of ABL TKIs.     

BCR-ABL1 kinase domain mutations may persist at very low levels for many years and lead to subsequent TKI resistance

Background:

BCR-ABL1 mutation analysis is recommended for chronic myeloid leukaemia patients. However, mutations may become undetectable after changing therapy, and it is unknown whether they have been eradicated.

Methods:

We examined longitudinal data of patients with imatinib-resistant mutations, which became undetectable by Sanger sequencing to determine whether mutations could reappear, and the related circumstances.

Results:

Identical imatinib- and nilotinib-resistant mutations reappeared following further therapy changes in five patients, and was associated with subsequent nilotinib resistance in four.

Conclusion:

The data suggest that some BCR-ABL1 mutations may persist at undetectable levels for many years after changing therapy, and can be reselected and confer resistance to subsequent inhibitors.     

Tyrosine kinase inhibitor prophylaxis after transplant for Philadelphia chromosome‐positive acute lymphoblastic leukemia

Tyrosine kinase inhibitor (TKI) administration after allogeneic hematopoietic stem cell transplantation (HSCT) may carry a survival benefit in Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL). Therefore, we investigated whether TKI prophylaxis for negative‐minimal residual disease (MRD) after HSCT would improve patient outcomes in this nationwide retrospective cohort study. We included patients with Ph+ ALL who underwent their first allogeneic HSCT between 2001 and 2016, received TKI before HSCT, and achieved negative‐MRD status within 180 days after HSCT. Of 850 patients for inclusion, 50 patients received TKI prophylaxis, mostly imatinib or dasatinib (median dose: 400 mg with imatinib and 40 mg with dasatinib). In a multivariate analysis, disease status at HSCT was the sole risk factor for relapse (hazard ratio, 3.58; P < .001 for positive‐MRD with complete remission [CR] and hazard ratio, 6.13; P < .001 for active disease). TKI prophylaxis was not associated with a decreased risk of relapse or superior overall survival in either the whole cohort or in the analysis limited to negative‐MRD or positive‐MRD with CR1 at HSCT. Meanwhile, TKI prophylaxis limited to dasatinib might be associated with a decreased risk of relapse (hazard ratio, 0.34; P = .140), unlike imatinib. Alternative strategies using new‐generation TKI for high‐risk patients are warranted to improve the outcomes after allogeneic HSCT.     

FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development

FMS‐like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that plays an important role in hematopoietic cell survival, proliferation and differentiation. The most clinically important point is that mutation of the FLT3 gene is the most frequent genetic alteration and a poor prognostic factor in acute myeloid leukemia (AML) patients. There are two major types of FLT3 mutations: internal tandem duplication mutations in the juxtamembrane domain (FLT3‐ITD) and point mutations or deletion in the tyrosine kinase domain (FLT3‐TKD). Both mutant FLT3 molecules are activated through ligand‐independent dimerization and trans‐phosphorylation. Mutant FLT3 induces the activation of multiple intracellular signaling pathways, mainly STAT5, MAPK and AKT signals, leading to cell proliferation and anti–apoptosis. Because high‐dose chemotherapy and allogeneic hematopoietic stem cell transplantation cannot sufficiently improve the prognosis, clinical development of FLT3 kinase inhibitors expected. Although several FLT3 inhibitors have been developed, it takes more than 20 years from the first identification of FLT3 mutations until FLT3 inhibitors become clinically available for AML patients with FLT3 mutations. To date, three FLT3 inhibitors have been clinically approved as monotherapy or combination therapy with conventional chemotherapeutic agents in Japan and/or Europe and United states. However, several mechanisms of resistance to FLT3 inhibitors have already become apparent during their clinical trials. The resistance mechanisms are complex and emerging resistant clones are heterogenous. Further basic and clinical studies are required to establish the best therapeutic strategy for AML patients with FLT3 mutations.     

The effect of interleukin 11 on thrombocytopenia associated with tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia

BACKGROUND.: During therapy with tyrosine kinase inhibitors (TKIs), approximately 20% to 50% of patients with chronic myeloid leukemia (CML) develop grade >/=3 thrombocytopenia leading to treatment interruptions and dose reductions. Interleukin 11 (IL-11) reduces the incidence and the severity of thrombocytopenia in solid tumors. METHODS.: The authors investigated the efficacy and safety of low-dose IL-11 for improving thrombocytopenia associated with TKI therapy in 14 patients with CML. The starting dose of IL-11 was 10 mug/kg 3 times weekly, and the dose was escalated by 1 dose level every 2 weeks if the patients had no sustained platelet increase. RESULTS.: The median patient age was 52 years. The median platelet count at the time IL-11 was started was 37 x 10(9)/L. All patients had prior TKI dose reductions. After the initiation of IL-11, 8 of 14 patients (57%) had an increase in platelet count with a median peak platelet count of 110 x 10(9)/L. One additional patient had no platelet increase but was able to tolerate an imatinib dose increase. Eleven patients had a decrease in the number of days of TKI therapy interruption secondary to thrombocytopenia after the initiation of IL-11 (6% of total treatment time vs 34% of total treatment time before IL-11). Therapy was well tolerated. CONCLUSIONS.: The current results indicated that IL-11 may correct thrombocytopenia associated with TKI therapy for patients with CML and that it has a favorable toxicity profile. Cancer 2008. (c) 2008 American Cancer Society.     

Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia

The BCR-ABL kinase inhibitor imatinib has shown significant efficacy in chronic myeloid leukemia (CML) and is the standard front-line therapy for patients in chronic phase. However, a substantial number of patients are either primarily refractory or acquire resistance to imatinib. While a number of mechanisms are known to confer resistance to imatinib, increasing evidence has demonstrated a role for BCR-ABL - independent pathways. The Src-family kinases (SFKs) are one such pathway and have been implicated in imatinib resistance. Additionally, these kinases are key to the progression of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The dual SFK/BCR-ABL inhibitor dasatinib is now clinically available and has markedly greater potency compared with imatinib against native BCR-ABL and the majority of imatinib-resistant BCR-ABL mutants. Therefore, this agent, as well as other dual SFK/BCR-ABL inhibitors under development, could provide added therapeutic advantages by overcoming both BCR-ABL - dependent (i.e. BCR-ABL mutations) and - independent forms of imatinib resistance and delaying transition to advanced phase disease. In this review, we discuss the preclinical and clinical evidence demonstrating the involvement of SFKs in imatinib resistance and the progression of CML and Ph+ ALL, as well as the potential role of dual SFK/BCR-ABL inhibition in the management of these diseases.     

Practical advice for determining the role of BCR-ABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia

Data demonstrating the superiority of nilotinib over imatinib in the frontline treatment of chronic myeloid leukemia (CML) and ongoing studies with dasatinib and bosutinib are rapidly changing the treatment landscape for CML. In this review, the authors discuss currently available therapies for CML, focusing on mechanisms of resistance to imatinib and treatment strategies to overcome resistance. Relevant articles were identified through searches of PubMed and abstracts from international hematology/oncology congresses. Additional information sources were identified from the bibliographies of these references and from the authors' own libraries and expertise. In vitro 50% inhibitory concentration (IC(50) ) data alone are not sufficient to guide the choice of a tyrosine kinase inhibitor (TKI) in the presence of a mutant breakpoint cluster region-v-abl Abelson murine leukemia viral oncogene homolog (BCR-ABL) clone, because there is a lack of data regarding how well such IC(50) values correlate with clinical response. A small subset of BCR-ABL mutant clones have been associated with impaired responses to second-generation TKIs (tyrosine to histidine mutation at codon 253 [Y253H], glutamic acid to lysine or valine mutation at codon 255 [E255K/V], and phenylalanine to cysteine or valine mutation at codon 359 [F359C/V] for nilotinib; valine to leucine mutation at codon 299 [V299L] and F317L for dasatinib); neither nilotinib nor dasatinib is active against the threonine to isoleucine mutation at codon 315 (T315I). For each second-generation TKI, the detection of 1 of a small subset of mutations at the time of resistance may be helpful in the selection of second-line therapy. For the majority of patients, comorbidities and drug safety profiles should be the basis for choosing a second-line agent. Clinical trial data from an evaluation of the response of specific mutant BCR-ABL clones to TKIs is needed to establish the role of mutation testing in the management of CML.     

Novel Abl kinase inhibitors in chronic myeloid leukemia in blastic phase and Philadelphia chromosome-positive acute lymphoblastic leukemia

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome, which is associated with a balanced translocation involving chromosomes 9 and 22 to produce a fusion gene (bcr-abl) that gives rise to a constitutively activated Abl tyrosine kinase. This kinase led to the discovery of several small-molecule inhibitors, imatinib being the first and most successful of these. Resistance to imatinib results in some patients from Abl kinase point mutations. Overcoming imatinib resistance represents one of the biggest challenges facing clinicians in the modern management of CML. In this review, we discuss the current understanding of CML pathophysiology and mechanisms of imatinib resistance and how advancing this knowledge has led to the design of novel therapies in the area of blastic phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia with previous imatinib failure.     

Measuring response to BCR-ABL inhibitors in chronic myeloid leukemia

In patients with chronic myeloid leukemia (CML), the hallmark Philadelphia chromosome is the marker of disease that can be detected by conventional metaphase cytogenetics, fluorescence in situ hybridization, or polymerase chain reaction. The current "gold standard" of treatment response is cytogenetic response. Cytogenetic response to imatinib is strongly associated with disease progression and survival. Various strategies aimed at improving cytogenetic response have been explored, such as escalation of imatinib and switching to the newer breakpoint cluster region/v-abl Abelson murine leukemia viral oncogene (BCR-ABL) inhibitors dasatinib and nilotinib. Data from recent randomized trials of dasatinib and nilotinib as first-line therapy of newly diagnosed chronic-phase CML suggest that these agents are more effective than imatinib in achieving 6-month and 12-month complete cytogenetic responses. However, it is still too early to know whether or not this early response will translate into a long-term survival advantage. In addition, more sensitive assays to detect residual disease also may be associated with improved long-term outcomes. The deepest measure of response-a complete molecular response-may help identify patients who can stop taking imatinib for the short term, although the long-term consequences of this strategy remain unknown.     

Bosutinib: a third generation tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia

Bosutinib is an oral tyrosine kinase inhibitor (TKI) with very potent dual inhibitory activity against SRC and abelson gene. Bosutinib was approved in 2012 for the treatment of resistant Philadelphia chromosome positive chronic myeloid leukemia (CML). Bosutinib is a very effective TKI against all phases of intolerant or resistant CML regardless of the presence or absence of an abelson gene domain mutation, except for cases with detectable T315I or V299L. Bosutinib is overall well tolerated and associated with a unique, but manageable toxicity profile. Factors that influence the prescribing pattern of this drug are complex and include physicians’, and increasingly patients and families’ preference, patients’ comorbid conditions, schedule of administration, as well as financial factors. This paper provides an overview of CML, the TKI market, pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of bosutinib.     

Comparison of microtransplantation,chemotherapy and allogeneic transplantation in post-remission therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia

Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) have poor prognosis, and the efficacy of chemotherapy plus tyrosine kinase inhibitors (TKIs) followed by mismatched donor stem cell infusion (microtransplantation, MST) has not been determined. We retrospectively summarized 45 patients including 11 undergoing MST with TKIs, 17 receiving allogeneic transplant and 17 undergoing chemotherapy with TKIs. Improved 4-year overall survival rate was observed in the MST group (91%) compared with either transplant group (31%, P = .005) or chemotherapy group (36%, P = .013). The MST group also had higher 2-year and 4-year leukemia-free survival rates (91% and 72%, respectively) compared with either transplant group (33%, P = .005 and 33%, P = .021, respectively) or chemotherapy group (41%, P = .017 and 31%, P = .023, respectively). 2-year and 4-year cumulative incidences of hematologic relapse were lower in the MST group (9% and 28%, respectively) compared with those in the chemotherapy group (56%, P = .025 and 67%, P = .034, respectively). In patients undergoing MST, donor microchimerism was detected (1.07 × 10^-5 to 6.6 × 10^-4 copies from 9 to 1499 days) in 7 patients, and donor/patient-derived HLA*0201/2402⁺WT1⁺CD8⁺ T cells were found from 0.05% to 0.67% in 6 patients. MST may provide a favorable treatment for patients with Ph⁺ ALL.