Recent advances in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia
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- Yanada, M., Ohno, R. & Naoe, T. Int J Hematol (2009) 89: 3. doi:10.1007/s12185-008-0223-z
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The advent of imatinib, a selective inhibitor of the ABL tyrosine kinase, has revolutionized the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Combined with chemotherapy, imatinib exerts remarkable efficacy in patients with newly diagnosed disease with a complete remission (CR) rate of 95% and a survival rate of 55% at 3 years. Profound eradication of leukemia cells not only provides patients with a better chance for receiving allogeneic hematopoietic stem cell transplantation during first CR but also contributes to durable CR even without transplantation. Despite such improvement, however, relapse does occur, mainly owing to acquisition of resistance. Growing comprehension of the molecular mechanisms of resistance to imatinib has led to the development of novel BCR–ABL inhibitors that yield higher affinity for BCR–ABL and/or potent inhibitory activity against other target molecules such as SRC family kinases. The second-generation ABL kinase inhibitors, namely dasatinib and nilotinib, are already showing clinical activity in patients with imatinib-resistant Ph+ ALL, and other novel agents are undergoing preclinical and early clinical evaluation. Further improvement in treatment results will be achieved by identifying each patient’s disease profile based on information obtained before and during treatment and by optimizing subsequent treatment accordingly.
KeywordsAcute lymphoblastic leukemiaPhiladelphia chromosomeBCR–ABLImatinibTyrosine kinase inhibitor
The translocation t(9;22)(q34;q11), known as the Philadelphia (Ph) chromosome, is the most common cytogenetic abnormality in adult acute lymphoblastic leukemia (ALL) [1–6]. The reciprocal translocation of the ABL gene on chromosome 9 onto the BCR gene on chromosome 22 results in the formation of the BCR–ABL fusion gene [7–9]. Depending on the breakpoint of the BCR region, two kinds of fusion transcripts can be distinguished. Major BCR–ABL, which is usually present in chronic myeloid leukemia (CML), accounts for approximately one-third of Ph-positive (Ph+) ALL and encodes the larger p210 protein, whereas minor BCR–ABL (found in two-thirds of Ph+ ALL) encodes the smaller p190 protein . Both proteins constitutively enhance tyrosine kinase activity and play a central role in the pathogenesis of the leukemia .
The Ph chromosome is generally detected in 20–30% of adult ALL cases, but its prevalence is age-dependent [1–6, 10]. In a prospective study involving 1,522 adults with ALL, investigators from the Medical Research Council (MRC) and the Eastern Cooperative Oncology Group (ECOG) reported that Ph+ ALL represented 4% of ALL patients age 15–19 years, 14% of those age 20–29 years, 24% of those age 30–39 years, 33% of those age 40–49 years, and 26% of those age 50 years or older . Similar trends were observed in a large retrospective cohort . Ph+ ALL is also characterized by a precursor B cell phenotype and by a higher initial white blood cell (WBC) count than is Ph-negative ALL [1–6]. Additionally and most importantly, the presence of the Ph chromosome is the single most adverse prognostic factor in ALL [1–6, 12–16]. Although multi-agent chemotherapy induces complete remission (CR) in a considerable proportion of patients, the disease is rarely curable with conventional chemotherapy alone because of the extremely high relapse rate. However, this situation has changed dramatically since imatinib, a selective inhibitor of the ABL tyrosine kinase, was introduced. This review discusses the recent therapeutic advances in Ph+ ALL with a special focus on imatinib and newer tyrosine kinase inhibitors.
2 Treatment of Ph+ ALL in the pre-imatinib era
With conventional induction chemotherapy, the CR rates for patients with Ph+ ALL range from 50 to 90%, which is moderately inferior to rates for those without the Ph chromosome. However, long-term outcome is dismal, with an overall survival (OS) rate of approximately 10% [1–6, 12–16]. The primary cause of treatment failure is relapse, and relapse occurs within the first year after achieving CR in most patients. Intensification of chemotherapy has had no significant effect on the unfavorable course . Although it has been suggested that in children, age, WBC count at diagnosis and the initial response to prednisone (PSL) pre-treatment may be useful in identifying patients with a relatively favorable prognosis [17, 18], this is not the case with adults. Therefore, the consensus is that allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for adult patients if they have a suitable donor and are fit for the procedure.
2.2 Hematopoietic stem cell transplantation
Results with allogeneic HSCT for Ph+ ALL patients during and beyond CR1
Year of transplantation
No. of patients (UD-HSCT)
Esperou et al. 
37% (2 years)
42% (4 years)
62% (2 years)
5% (4 years)
Yanada et al. 
35% (5 years)
32% (5 years)
34% (5 years)
50% (5 years)
39% (5 years)
11% (5 years)
Laport et al. 
28% (5 years)
31% (10 years)
54% (10 years)
41% (5 years)
54% (10 years)
29% (10 years)
To attain better transplantation results, therapy providing a better transition to allogeneic HSCT is needed. On the other hand, a substantial proportion of patients are ineligible for allogeneic HSCT due to lack of a suitable donor, advanced age, or underlying complications. Such patients are in even greater need of a novel therapy.
3 Therapy including imatinib for Ph+ ALL patients
Imatinib is a selective ABL tyrosine kinase inhibitor designed to target the adenosine triphosphate (ATP) binding site of the protein . It binds to the inactive conformation of the ABL kinase domain, blocks the kinase activity of the BCR–ABL protein, and inhibits the proliferation of leukemia cells harboring BCR–ABL. In CML, imatinib has been clinically shown to have an outstanding anti-leukemic activity together with a reasonable toxicity profile [31, 32], and it has become the current standard treatment for newly diagnosed CML. Because of its unique mechanism of action and significant clinical efficacy, imatinib has been the subject of eager anticipation as a therapeutic agent for another BCR–ABL-positive leukemia, i.e., Ph+ ALL.
3.2 Imatinib monotherapy for patients with relapsed or refractory disease
Early phase I and phase II studies showed that single-agent imatinib exerts tolerable toxicity and modest anti-leukemic activity in patients with Ph+ ALL who had previous unsuccessful chemotherapy [33, 34]. In a phase I study conducted for the blast crisis of CML and Ph+ ALL, imatinib was given at daily doses ranging from 300 to 1,000 mg . Of the 20 patients with Ph+ ALL and CML in lymphoid blast crisis (CML–LBC), four attained CR and ten showed a marrow response. All but one responder had relapse after a median treatment duration of 58 days. In a phase II study for relapsed and refractory Ph+ ALL and CML–LBC, 48 Ph+ ALL patients were treated with imatinib at starting doses of 400–600 mg/day . The CR rate and overall response rate were 19 and 60%, respectively, but the median time to progression was only 2.2 months. These two studies showed that response induced by imatinib was not durable, which led investigators to consider whether imatinib might be more beneficial when combined with cytotoxic chemotherapy rather than given as a single agent.
3.3 Imatinib with chemotherapy for patients with newly diagnosed disease
Imatinib-combined chemotherapy as an initial treatment for Ph+ ALL patients
No. of patients
Imatinib in induction therapy
Imatinib and chemotherapy in post-remission therapy
CR rate (%)
No. of allo-HSCT in first CR (%)
Thomas et al. , updated
62% (3 years)
55% (3 years)
Lee et al. 
Yanada et al. , updated
46% (3 years)
55% (3 years)
Wassmann et al. 
52% (2 years)b
36% (2 years)
Wassmann et al. 
61% (2 years)b
43% (2 years)
de Labarthe et al. 
A number of studies have shown that imatinib-combined chemotherapy is effective for improving patients’ chances to receive allogeneic HSCT during first CR [35–40]. Generally, young patients with a suitable donor proceed to allogeneic HSCT, based on the concept that it is the established treatment with curative potential. Currently, it is reasonable to consider that this scheme remains valid, because there has been no clear evidence so far to show that a non-transplantation strategy is better than or at least comparable with allogeneic HSCT. When we compare the non-transplantation treatment with allogeneic HSCT, it should be noted that results of allogeneic HSCT might also be improved by imatinib-combined chemotherapy because of high-quality CR status at the time of transplantation. In fact, the 3-year OS rate after allogeneic HSCT in first CR was 63% in the JALSG study, which compares very favorably with the data in the pre-imatinib era described above . Therefore, prospective comparison, for example, by using natural randomization based on donor availability along with intention-to-treat analysis, is necessary to draw a conclusion on the clinical utility of allogeneic HSCT. Post-transplantation imatinib may also improve the transplantation results. This strategy was explored by the GMALL study group . They evaluated effectiveness of imatinib monotherapy after transplantation in Ph+ ALL patients who were positive for minimal residual disease (MRD) and showed that about half of the patients experienced prolonged remission.
Prognostication is another key issue. A considerable number of patients who undergo allogeneic HSCT die of complications related to transplantation, whereas some remain alive in CR for years without undergoing transplantation. Recent development of novel tyrosine kinase inhibitors will further expand the treatment options for this disease, thus emphasizing the importance of therapeutic optimization on the basis of accurate prognostic estimation. A previous analysis of the JALSG study showed that the presence of secondary chromosome aberrations in addition to t(9;22) was predictive of inferior RFS , but longer follow-up data failed to show a statistically significant difference due to late relapses observed in several patients without additional aberrations, and only an initial WBC count was significantly associated with RFS. Therefore, the prognostic relevance of pre-treatment factors seems inconclusive. Because the level of MRD at various time points in CR (especially at the end of induction therapy) is an important prognostic factor in ALL [45–56], it may serve as a useful prognostic indicator in Ph+ ALL patients treated with imatinib-combined chemotherapy. In the JALSG study, BCR–ABL transcript levels in bone marrow were prospectively monitored using quantitative reverse transcriptase polymerase chain reaction, and the prognostic significance of MRD was analyzed . The data unexpectedly showed that negative MRD at the end of induction was not associated with a higher RFS rate or a lower relapse rate. There was an interesting finding in 29 patients who developed MRD elevation during hematologic CR: among these 29, 10 of the 16 who had proceeded to allogeneic HSCT in first CR were alive without relapse at a median of 2.9 years after transplantation, whereas 12 of the 13 who had not undergone allogeneic HSCT experienced a relapse. This result indicates that a single observation of elevated MRD is predictive of subsequent relapse, but allogeneic HSCT can override its adverse effect. Hence, frequent MRD monitoring may be beneficial in clinical decision making for Ph+ ALL patients undergoing imatinib-combined chemotherapy. Furthermore, by the genome-wide cDNA microarray analysis of 26 patients entered in the JALSG study, expression profiles of specific genes (TNK2, GLTSCR2, AP2B1, RBM15B, C10orf119, and ALS2CR4) were associated with continuous molecular response, and a scoring system based on the expression data for this set of six genes successfully predicted risk of recurrence . Although its clinical utility needs to be validated in larger studies, this approach would be encouraging.
It is indisputable that incorporating imatinib into chemotherapy has improved the overall outcome of patients with newly diagnosed Ph+ ALL. Further improvement will be achieved by identifying the risk of relapse based on information obtained before and during treatment and by optimizing subsequent treatment accordingly.
3.4 Imatinib with or without chemotherapy for elderly patients
Imatinib with or without chemotherapy in elderly patients with Ph+ ALL
No. of patients
CR rate (%)
Delannoy et al. 
58% (1 year)
66% (1 year)
Ottmann et al. 
35% (1.5 years)
57% (1.5 years)
30% (1.5 years)
41% (1.5 years)
Vignetti et al. 
48% (1 year)
74% (1 year)
These reports show that the response to imatinib clearly differs between patients with newly diagnosed disease and previously treated patients. Given these results, it is appropriate to treat previously untreated elderly Ph+ ALL patients with imatinib alone or in combination with chemotherapy. Future studies need to focus on how imatinib can most effectively be incorporated into chemotherapy in the context of the balance between efficacy and toxicity.
4 Resistance to imatinib
Nearly all patients with newly diagnosed Ph+ ALL initially respond to imatinib with or without chemotherapy, but a substantial proportion of patients experience a relapse during or after treatment. The observation in the JALSG study that two-thirds of the early relapses occurred during the consolidation courses consisting of imatinib alone implies a possible engagement of imatinib resistance. The etiology of resistance to imatinib is multi-factorial, and several mechanisms have been suggested [62–64]. These include reduced intracellular imatinib concentration, mutations of the BCR–ABL gene, amplification of the BCR–ABL gene, overexpression of the BCR–ABL oncoprotein, and overexpression of molecules downstream of BCR–ABL signaling. Among these, the mutations involving the ABL kinase domain form the most common mechanism of resistance . The mutated gene encodes specific amino acid substitutions, resulting in impaired binding affinity of imatinib to the ATP-binding site. Approximately 50 separate mutations have been identified at various regions of the ABL kinase domain, which are classified into four specific regions: the ATP-binding site (P-loop), contact site, SH2 binding site, and A-loop. The most frequently occurring are those of the P-loop, which usually confer high levels of resistance to imatinib [66, 67]. T315I, resulted from the substitution of isoleucine for threonine at ABL amino acid position 315, is the second most frequent mutation occurring at the contact site. The T315I mutation is of particular clinical importance because it exerts complete resistance not only to imatinib but also to the second-generation BCR–ABL inhibitors . Other imatinib-resistant mutations generally exhibit lower levels of resistance. Relationships between the mutation status and clinical outcome have been studied intensively in patients with CML, although data for those with Ph+ ALL are limited. In patients with newly diagnosed Ph+ ALL entered into the above-mentioned study , the GMALL study group examined the ABL kinase domain mutation status by using a highly sensitive detecting method . Their analyses demonstrated that even before exposure to imatinib, mutations were detected in 38% of the patients. Importantly, the frequency of the mutant allele was quite low at diagnosis, with median and maximum values of 0.5 and 2%, respectively. However, at the time of relapse, the dominant clone harbored the same mutation in most patients. The authors mentioned that it would be necessary to eliminate clones harboring mutations during early phase of treatment, before they have acquired additional mechanism.
Accumulated evidence suggests that imatinib resistance can occur through BCR–ABL-independent mechanisms. For example, the SRC family kinases, a family of nine structurally homologous non-receptor intracellular tyrosine kinases, are considered to be involved in disease pathogenesis as well as in resistance to imatinib in Ph+ ALL . The structural similarity between ABL and SRC has led to the development of dual inhibitors, and simultaneous inhibition of these kinases is expected to yield a synergistic activity.
5 Novel tyrosine kinase inhibitors for Ph+ ALL patients
Dasatinib is a dual SRC/ABL inhibitor with approximately 300-fold higher potency against BCR–ABL than imatinib . It also inhibits c-Kit, PDGFR, and ephrin A receptor kinase. Unlike imatinib, this compound can bind to the ABL kinase domain in both the active and inactive conformations. Dasatinib inhibits most of the imatinib-resistant mutations except for the T315I. In a phase I study, patients with CML or Ph+ ALL who could not tolerate or were resistant to imatinib were treated with doses of 15–240 mg/day . The main toxicity was myelosuppression, with pleural effusion, diarrhea, peripheral edema, and headache documented relatively frequently. A maximum tolerated dose (MTD) was not determined in this study. Complete hematologic response was achieved in seven of ten patients with Ph+ ALL and CML–LBC. A phase II study (START-L) was subsequently conducted for patients with imatinib-resistant or -intolerant Ph+ ALL. An interim analysis of 36 patients reported that treatment with dasatinib at a dose of 70 mg twice daily (BID) yielded complete hematologic and complete cytogenetic responses in 33 and 58% of the patients, respectively . Non-hematologic toxicities (grade 3 or higher) included febrile neutropenia (11%), diarrhea (8%), and asthenia (8%). Pleural effusion (any grade) was observed in 19%. In the GIMEMA LAL 1205 study, an Italian group evaluated the efficacy and safety of dasatinib in patients with previously untreated Ph+ ALL. In this study, patients were treated with dasatinib 70 mg BID and PSL up to 60 mg/m2 per day. The results of an interim analysis were presented, and all 23 patients went into CR by day 22 without significant toxicity . A phase II study of chemotherapy in combination with dasatinib was conducted in patients with newly diagnosed Ph+ ALL at M. D. Anderson. According to their early report, 20 patients were treated with the hyper-CVAD regimen in combination with dasatinib 50 mg BID . Of 19 evaluable patients, 17 achieved CR, and the remaining two died from infection during the induction course. With a median follow-up of 7 months, 2 of these 17 patients had relapse and another two died in CR.
Nilotinib is an amynopyrimidine derivative of imatinib . Like imatinib, it binds to the inactive conformation of the ABL kinase domain and inhibits BCR–ABL, c-Kit, and PDGFR. Owing to the increased binding affinity to the ABL kinase domain, nilotinib has an inhibitory activity against BCR–ABL that is approximately 20- to 50-fold greater than that of imatinib. This drug is active against most imatinib-resistant BCR-ABL point mutants, but not the T315I mutation. In a phase I study in imatinib-resistant CML and Ph+ ALL patients, nilotinib was given at doses of 50–1,200 mg/day . Myelosuppression was frequent, and common grades 3 to 4 non-hematologic toxicities included indirect hyperbilirubinemia, skin rashes, and elevated serum lipase. The MTD was determined to be 600 mg BID, and the recommended dose for phase II studies was set at 400 mg BID. In Ph+ ALL patients, one of ten patients with hematologic disease achieved a partial hematologic response, and one of three patients with molecular disease had a complete molecular remission. The efficacy and safety of nilotinib in patients with relapsed/refractory Ph+ ALL was evaluated in a phase II study. Nilotinib was administered at an initial dose of 400 mg BID, and dose escalation to 600 mg BID was allowed. According to an early report of this study, 10 (24%) of 38 patients achieved CR .
5.3 Other drugs
Bosutinib is a dual inhibitor of ABL and SRC family kinases, with an activity profile similar to that for dasatinib . Preclinical studies showed that it is up to 200-fold more potent than imatinib against BCR–ABL-positive cells. Absence of significant inhibition of c-Kit and PDGFR is expected to contribute to a more favorable safety profile than that of dasatinib. INNO-406 is another amynopyrimidine variant of imatinib . Because of increased binding to the ATP pocket and potent activity against Lyn, this compound has up to 55-fold higher inhibitory activity than imatinib in BCR–ABL-expressing cell lines. The fact that the T315I mutation confers a greater level of resistance not only to imatinib but also to novel tyrosine kinase inhibitors including dasatinib and nilotinib highlights the need for development of a T315I inhibitor. MK-0457 is a small-molecule aurora kinase inhibitor, which shows activity against cells expressing wild-type and mutated BCR–ABL, including the T315I mutation . Responses in three patients with CML and Ph+ ALL harboring the T315I mutation were recently reported . In addition to the drugs discussed herein, a number of novel agents are undergoing preclinical and early clinical evaluation.
Imatinib has now become an essential element in the treatment of Ph+ ALL. However, because of a short period of time since its introduction, several major issues remain to be addressed, in particular, the optimal combination schedule with chemotherapy and the role of allogeneic HSCT. Despite the impressive efficacy of therapy including imatinib, relapse occurs in a significant proportion of patients. Overcoming resistance remains the therapeutic challenge. Development of novel tyrosine kinase inhibitors offers hope to these patients. The second-generation ABL kinase inhibitors, i.e., dasatinib and nilotinib, are already showing significant clinical activity in patients with imatinib-resistant Ph+ ALL, and other novel agents are under investigation. In the near future, a wide range of treatment options will be available. Unlike traditional anticancer drugs, specificity to the molecular target is quite important for tyrosine kinase inhibitors. Because the characteristics of the target vary considerably from patient to patient and may change with time even within an individual patient, treatments ideally should be individualized according to the disease profile based on information obtained before and during treatment. Such an individualized treatment approach will further improve the outcome of patients with Ph+ ALL.