International Journal of Hematology

, Volume 89, Issue 1, pp 3–13

Recent advances in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia

Authors

    • Department of Hematology and OncologyNagoya University Graduate School of Medicine
  • Ryuzo Ohno
    • Aichi Cancer Center
  • Tomoki Naoe
    • Department of Hematology and OncologyNagoya University Graduate School of Medicine
Review Article

DOI: 10.1007/s12185-008-0223-z

Cite this article as:
Yanada, M., Ohno, R. & Naoe, T. Int J Hematol (2009) 89: 3. doi:10.1007/s12185-008-0223-z

Abstract

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.

Keywords

Acute lymphoblastic leukemiaPhiladelphia chromosomeBCR–ABLImatinibTyrosine kinase inhibitor

1 Introduction

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) [16]. 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 [79]. 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 [10]. Both proteins constitutively enhance tyrosine kinase activity and play a central role in the pathogenesis of the leukemia [11].

The Ph chromosome is generally detected in 20–30% of adult ALL cases, but its prevalence is age-dependent [16, 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 [5]. Similar trends were observed in a large retrospective cohort [10]. 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 [16]. Additionally and most importantly, the presence of the Ph chromosome is the single most adverse prognostic factor in ALL [16, 1216]. 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

2.1 Chemotherapy

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% [16, 1216]. 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 [16]. 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

Allogeneic HSCT is a potentially curative therapy for Ph+ ALL owing to the strong anti-leukemic effect of pre-transplant myeloablative chemo/radiotherapy and post-transplant graft-versus leukemia (GVL) effect [1927]. However, high rates of relapse and non-relapse mortality (NRM) are major obstacles to the treatment success. Outcomes after allogeneic HSCT are strongly affected by disease status at the time of transplantation, and results become worse for patients undergoing allogeneic HSCT with active disease and even during the second or subsequent CR (Table 1) [23, 26, 27]. Figure 1 shows the survival curves after allogeneic HSCT according to disease status at the time of transplantation for 197 adult Ph+ ALL patients reported to the Japanese registry in the pre-imatinib era. The 5-year survival rates were 34% for patients in first CR, 21% for patients in second or subsequent CR and 9% for patients with active disease [26]. In addition to disease status, this study identified younger age, conditioning with total body irradiation, and an HLA-identical sibling donor as factors independently associated with longer survival. When the effect of graft-versus-host disease (GVHD) on survival was assessed, extensive chronic GVHD conferred a protective effect against relapse without increasing the risk of NRM, whereas severe acute GVHD predisposed patients to an increased risk of NRM without reducing the risk of relapse [26]. A French multi-center group prospectively compared allogeneic HSCT with autologous HSCT in the LALA-94 trial, in which Ph+ ALL patients aged 15–55 years were, after achieving CR, assigned to allogeneic HSCT if they had a suitable donor and to autologous HSCT if they did not [22]. An intention-to-treat analysis demonstrated that survival was significantly longer for the donor group than for the no-donor group. The estimated incidence of relapse was 50% in the donor group, whereas it reached 90% in the no-donor group. Other studies evaluating the role of autologous HSCT also found no advantage, primarily due to high rates of relapse [28, 29]. The results of these retrospective and prospective studies indicate that GVL effect may play a critical role in eradicating leukemia cells in Ph+ ALL patients and that myeloablative chemo/radiotherapy alone may not be sufficient for obtaining a cure. Currently, allogeneic HSCT with reduced-intensity conditioning (RIC) is under development, but data for Ph+ ALL patients are scarce at present. The findings described herein provide a rationale for investigating RIC-HSCT for Ph+ ALL patients who are poor candidates for conventional allogeneic transplantation. Nevertheless, because the clinical utility of RIC-HSCT for Ph+ ALL is still undetermined, allogeneic HSCT with myeloablative conditioning is the recommended form of transplantation.
Table 1

Results with allogeneic HSCT for Ph+ ALL patients during and beyond CR1

Author

Year of transplantation

No. of patients (UD-HSCT)

Relapse

Non-relapse mortality

Overall survival

Esperou et al. [23]

1992–2000

    

 CR1

 

76 (15)

37% (2 years)

Not reported

42% (4 years)

 >CR1

 

45 (16)

62% (2 years)

Not reported

5% (4 years)

Yanada et al. [26]

1991–2001

    

 CR1

 

93 (15)

35% (5 years)

32% (5 years)

34% (5 years)

 >CR1

 

104 (21)

50% (5 years)

39% (5 years)

11% (5 years)

Laport et al. [27]

1985–2005a

    

 CR1

 

49 (0)

28% (5 years)

31% (10 years)

54% (10 years)

 >CR1

 

30 (0)

41% (5 years)

54% (10 years)

29% (10 years)

HSCT hematopoietic stem cell transplantation, Ph+ ALL Philadelphia chromosome-positive acute lymphoblastic leukemia, CR1 first complete remission, UD unrelated donor

aSeventeen patients received imatinib before transplantation

https://static-content.springer.com/image/art%3A10.1007%2Fs12185-008-0223-z/MediaObjects/12185_2008_223_Fig1_HTML.gif
Fig. 1

Kaplan–Meier curves of overall survival after allogeneic hematopoietic stem cell transplantation according to disease status at the time of transplantation. Adult patients with Ph+ ALL who were reported to the Japan Society of Hematopoietic Cell Transplantation as having been allografted between 1991 and 2001 were analyzed

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

3.1 Imatinib

Imatinib is a selective ABL tyrosine kinase inhibitor designed to target the adenosine triphosphate (ATP) binding site of the protein [30]. 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 [33]. 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 [34]. 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

Remarkable efficacy was observed when imatinib was combined with chemotherapy [3540]. Results from selected studies are summarized in Table 2. Despite differences in the treatment regimens, nearly 95% of patients achieved CR, and BCR–ABL transcripts in bone marrow dropped to undetectable levels in up to 70% of cases. Such profound eradication of leukemia cells not only provides patients with a better chance for receiving allogeneic HSCT during first CR but also contributes to durable CR even without transplantation.
Table 2

Imatinib-combined chemotherapy as an initial treatment for Ph+ ALL patients

Author

No. of patients

Imatinib in induction therapy

Imatinib and chemotherapy in post-remission therapy

CR rate (%)

No. of allo-HSCT in first CR (%)

Relapse-free survival

Overall survival

Thomas et al. [35], updated

54

Yes

Concurrent

93

16 (29)

62% (3 years)

55% (3 years)

Lee et al. [36]

20

Yes

Concurrent

95

17 (85)

Not reported

Not reported

Yanada et al. [38], updated

100

Yes

Alternative

97

60 (60)

46% (3 years)

55% (3 years)

Wassmann et al. [39]

47

No

Alternative

a

36 (77)

52% (2 years)b

36% (2 years)

Wassmann et al. [39]

45

Yes

Concurrent

95

35 (77)

61% (2 years)b

43% (2 years)

de Labarthe et al. [40]

45

Yes/noc

Concurrent/Imatinib aloned

96

22 (48)

51% (1.5-years)

65% (1.5-years)

Ph+ ALL Philadelphia chromosome-positive acute lymphoblastic leukemia, CR complete remission, allo-HSCT allogeneic hematopoietic stem cell transplantation

aPatients who had achieved CR with chemotherapy were enrolled

bThe probability of continuous complete remission instead of relapse-free survival

cImatinib was given only to patients with poor early response to chemotherapy

dIn patients with poor early response to chemotherapy, imatinib monotherapy was continued until HSCT

Investigators at M. D. Anderson Cancer Center have studied the efficacy of concurrent treatment with imatinib in combination with the hyper-CVAD regimen (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) [35]. Initially, imatinib was administered at a daily dose of 400 mg on days 1–14 of each course. After the completion of eight courses, maintenance therapy including 600 mg/day of imatinib for 13 months and two interim intensification courses was administered. Several modifications have since been implemented, and the final regimen included imatinib 600 mg/day on days 1–14 of induction, 600 mg/day continuously during courses 2–8, 800 mg/day during 2 years of maintenance therapy, followed by imatinib indefinitely. Fifty-four patients with newly diagnosed or minimally treated Ph+ ALL were finally entered into this study. Of 45 patients with active disease, 42 (93%) reached CR, and 16 underwent allogeneic HSCT. The probabilities of relapse-free survival (RFS) and OS were 62 and 55%, respectively, at 3 years [41]. The Japan Adult Leukemia Study Group (JALSG) conducted a phase II study of imatinib-combined chemotherapy for patients with newly diagnosed Ph+ ALL [38, 42]. The original target sample size was 77 patients, with the CR rate defined as the primary endpoint. Eighty patients had been enrolled by January 2005, at which point enrollment was extended to 100 patients to obtain a more precise point estimate of the OS rate. For remission induction therapy, imatinib was administered from day 8 to day 63 in combination with multi-agent chemotherapy, and consolidation therapy consisted of intensive chemotherapy for odd-numbered courses and imainib alone for even-numbered courses. A total of eight courses of consolidation were followed by maintenance therapy including imatinb throughout, which was continued until 2 years from the date of CR. The daily dose of imatinib used in this study was 600 mg. Allogenic HSCT was recommended after achieving CR if the patient had a suitable donor. A total of 100 patients were accrued from September 2002 to May 2006, and 97 patients (97%) achieved CR. Frequency of severe toxicity occurrence was not different from that observed with conventional chemotherapy. For the median follow-up of 3.2 years, relapse occurred in 38 patients. A total of 60 patients received allogeneic HSCT during first CR. The probabilities of event-free and overall survival were 48 and 55% at 3 years, and the probability of RFS was 46% at 3 years. These results were significantly better than results for historical control patients treated with chemotherapy alone in the JALSG ALL 93 study, in which the 3-year OS rate was only 11% [14]. The German Multicenter ALL (GMALL) study group prospectively tested two strategies in which imatinib was incorporated either alternately to or concurrently with induction and consolidation therapy [39]. A total of 92 patients were enrolled, 47 in the alternating schedule study and 45 in the concurrent schedule study. Although severe hematological and non-hematological toxicities were observed more frequently in patients with the concurrent schedule than in those with the alternating schedule, the proportion of patients whose BCR–ABL transcripts became undetectable prior to consolidation was significantly higher in patients treated according to the concurrent schedule. In each cohort, 77% of patients underwent allogeneic HSCT in first CR, and the remission duration and OS did not differ between the cohorts (Fig. 2).
https://static-content.springer.com/image/art%3A10.1007%2Fs12185-008-0223-z/MediaObjects/12185_2008_223_Fig2_HTML.gif
Fig. 2

Overall and event-free survival for 100 Ph+ ALL patients treated with imatinib-combined chemotherapy in the JALSG Ph+ALL202 study

A number of studies have shown that imatinib-combined chemotherapy is effective for improving patients’ chances to receive allogeneic HSCT during first CR [3540]. 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 [26]. 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 [43]. 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 [44], 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 [4556], 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 [57]. 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 [58]. 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

Given that elderly patients are susceptible to treatment-related morbidity and mortality, and that most of them are not eligible for allogeneic HSCT, therapeutic approaches different from those for young patients have been investigated in these patients. In the study by the Group for Research on Adult Acute Lymphocytic Leukemia (GRAAL), imatinib and methylprednisolone were given to patients aged 55 years or older at 600 mg/day for 2 months after one course of multi-agent induction chemotherapy, irrespective of the induction result [59]. Patients in CR after the imatinib course received alternating chemotherapy and imatinib for 2 years. Of the 29 patients, CR was obtained in 21 patients after chemotherapy and in additional five patients after imatinib. The probability of OS was 66% at 1 year, which was significantly better than the 43% for historical controls treated with chemotherapy alone. The GMALL study group conducted a randomized phase II study comparing imatinib and chemotherapy for induction therapy in patients age over 55 years [60]. A total of 55 patients were assigned to receive either imatinib monotherapy at a dose of 600 mg/day for 28 days or conventional induction chemotherapy. All CR patients received the same post-remission therapy consisting of imatinib and chemotherapy for about 1 year. The CR rates were 96% for the imatinib arm and 50% for the chemotherapy arm. Severe infections during the induction course developed in 12 and 57%, respectively. Of the 11 patients who did not have CR after chemotherapy, nine subsequently achieved CR with imatinib monotherapy, and there was no difference in long-term outcome between the two arms. The high CR rate with imatinib in the GMALL study was reproduced in the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) study, in which patients older than 60 years were treated with imatinib 800 mg/day along with PSL [61]. In this study, all of the 29 patients evaluable for response achieved CR. Continuation of the same treatment until occurrence of relapse or excessive toxicity resulted in a median survival of 20 months and a median hematologic response duration of 8 months (Table 3).
Table 3

Imatinib with or without chemotherapy in elderly patients with Ph+ ALL

Author

No. of patients

Induction therapy

Post-remission therapy

CR rate (%)

Relapse-free survival

Overall survival

Delannoy et al. [59]

30

Chemo alone

Alternative

72

58% (1 year)

66% (1 year)

Ottmann et al. [60]

 Chemo arm

27

Chemo alone

Concurrent

50

35% (1.5 years)

57% (1.5 years)

 Imatinib arm

28

Imatinib alone

Concurrent

96

30% (1.5 years)

41% (1.5 years)

Vignetti et al. [61]

30

Imatinib alone

Imatinib alone

100

48% (1 year)

74% (1 year)

Ph+ ALL Philadelphia chromosome-positive acute lymphoblastic leukemia, CR complete remission

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 [6264]. 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 [65]. 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 [68]. 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 [60], the GMALL study group examined the ABL kinase domain mutation status by using a highly sensitive detecting method [69]. 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 [70]. 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

5.1 Dasatinib

Dasatinib is a dual SRC/ABL inhibitor with approximately 300-fold higher potency against BCR–ABL than imatinib [71]. 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 [72]. 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 [73]. 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 [74]. 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 [75]. 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.

5.2 Nilotinib

Nilotinib is an amynopyrimidine derivative of imatinib [76]. 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 [77]. 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 [78].

5.3 Other drugs

Bosutinib is a dual inhibitor of ABL and SRC family kinases, with an activity profile similar to that for dasatinib [79]. 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 [80]. 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 [81]. Responses in three patients with CML and Ph+ ALL harboring the T315I mutation were recently reported [82]. In addition to the drugs discussed herein, a number of novel agents are undergoing preclinical and early clinical evaluation.

6 Conclusions

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.

Copyright information

© The Japanese Society of Hematology 2008