Allogeneic transplantation for patients with Philadelphia chromosome positive acute lymphoblastic leukemia: Is it imperative in the tyrosine kinase inhibitor era?

Before the advent of tyrosine kinase inhibitors (TKIs), Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) was associated with dismal survival without allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent evidence has demonstrated that the combination of TKI and chemotherapy can result in a high rate of complete remission, thereby enabling more patients to proceed to allo-HSCT. However, with more studies reporting non-inferior outcomes with TKI and chemotherapy combination without allo-HSCT, the need for allo-HSCT in Ph+ ALL has become less certain. This review summarizes evidence that will address the relevance of allo-HSCT in Ph+ ALL.     

Imatinib in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia: current status and evolving concepts

Until recently, progress in the treatment of patients with Ph(+) acute lymphoblastic leukaemia (ALL) has been limited, and long-term survival, even with high-dose intensified chemotherapy, is rare. Allogeneic stem cell transplantation is potentially curative, but treatment-related mortality and rate of disease recurrence are substantial. With the advent of the ABL-selective tyrosine kinase inhibitor STI571 (imatinib mesylate, Glivec), it has become apparent that the understanding of crucial leukaemogenic pathways at the molecular level can lead to the development of specific and selective agents. In recent clinical trials, imatinib has demonstrated significant anti-leukaemic efficacy in patients with advanced Ph(+) ALL, in conjunction with a remarkably favourable safety profile. Clinical resistance to imatinib develops rapidly, highlighting the limitations of using imatinib as a single agent; however, the value of imatinib as an element of treatment has become apparent. Resistance mechanisms have already been identified that will enable the development of rational strategies to prevent or overcome resistance. On the basis of available clinical results, combinations of imatinib with established anti-leukaemic agents, as well as with novel, molecularly targeted treatment modalities, will need to be evaluated in advanced Ph(+) ALL. Incorporation of imatinib in the first-line treatment of de novo Ph(+) ALL and in the setting of minimal residual disease is a promising therapeutic approach which is currently being studied in clinical trials. Better understanding of targeted therapies, including strategies based on recruitment of host immune functions, as well as the prudent use of active chemotherapy agents, may eventually improve the outlook for patients with Ph(+) ALL.     

CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells

Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) have poor prognosis despite intensive therapeutic intervention. Recently, imatinib, a BCR-ABL tyrosine kinase inhibitor, has been proven to be an effective treatment for Ph(+) ALL, but nearly all patients rapidly acquire resistance. High-dose imatinib administration might overcome this resistance; however, systemic toxicities would likely limit this approach. Therefore, a new delivery system allowing for the specific targeting of imatinib is urgently needed. Because almost all Ph(+) ALL cells express CD19 on their surface, we have developed an immunoliposome carrying anti-CD19 antibody (CD19-liposomes). The internalization efficiency of the CD19-liposomes approached 100% in all Ph(+) ALL cells but was very low in CD19(-) cells. The cytocidal effect of imatinib-encapsulated CD19-liposomes (imatinib-CD19-liposomes) on Ph(+) ALL cell lines and primary leukemia cells from patients with Ph(+) ALL was much greater than that of imatinib with or without control liposomes. Importantly, the imatinib-CD19-liposomes did not affect the colony formation of CD34(+) hematopoietic cells, even at inhibitory concentration of free imatinib. Taken together, these data clearly demonstrate that the imatinib-CD19-liposomes induced specific and efficient death of Ph(+) ALL cells. This new therapeutic approach might be a useful treatment for Ph(+) ALL with fewer side effects than free imatinib.     

Poor outcomes associated with +der(22)t(9;22) and −9/9p in patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia receiving chemotherapy plus a tyrosine kinase inhibitor

In patients with Philadelphia chromosome‐positive (Ph+) acute lymphoblastic leukemia (ALL) treated with chemotherapy plus a tyrosine kinase inhibitor (TKI), the prognostic impact of additional chromosomal abnormalities (ACAs) is not well‐established. We evaluated the prognostic impact of individual ACAs in 152 patients with Ph+ ALL receiving first‐line intensive chemotherapy plus either imatinib (n = 36), dasatinib (n = 74), or ponatinib (n = 42). ACAs were identified in 118 patients (78%). Compared to outcomes of patients without ACAs, ACAs were not associated with differences in either relapse‐free survival (RFS; P = 0.42) or overall survival (OS; P = 0.51). When individual ACAs were evaluated, +der(22)t(9;22) and/or ?9/9p in the absence of high hyperdiploidy (HeH) was present in 16% of patients and constituted a poor‐risk ACA group. Patients with one or more poor‐risk ACAs in the absence of HeH had significantly shorter RFS (5‐year RFS rate 33% versus 59%, P = 0.01) and OS (5‐year OS rate 24% versus 63%, P = 0.003). Poor‐risk ACAs were prognostic in patients who received imatinib and dasatinib but not in those who received ponatinib. By multivariate analysis, this poor‐risk ACA group was independently associated with worse RFS (HR 2.03 [95% CI 1.08‐3.30], P = 0.03) and OS (HR 2.02 [95% CI 1.10‐3.71], P = 0.02). Patients with Ph+ ALL who have +der(22)t(9;22) and/or ?9/9p in the absence of HeH have relatively poor outcomes when treated with chemotherapy plus a TKI.     

Intermediate dose of imatinib in combination with chemotherapy followed by allogeneic stem cell transplantation improves early outcome in paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL): results of the Spanish Cooperative Group SHOP studies ALL-94, ALL-99 and ALL-2005

Philadelphia‐chromosome acute lymphoblastic leukaemia (Ph+ ALL) is a subgroup of ALL with very high risk of treatment failure. We report here the results of the Sociedad Española de Hematología y Oncología Pediátricas (SEHOP/SHOP) in paediatric Ph+ ALL treated with intermediate‐dose imatinib concurrent with intensive chemotherapy. The toxicities and outcome of these patients were compared with historical controls not receiving imatinib. Patients with Ph+ ALL aged 1–18 years were enrolled in three consecutive ALL/SHOP trials (SHOP‐94/SHOP‐99/SHOP‐2005). In the SHOP‐2005 trial, imatinib (260 mg/m² per day) was given on day‐15 of induction. Allogeneic haematopoietic stem‐cell transplantation (HSCT) from a matched related or unrelated donor was scheduled in first complete remission (CR1). Forty‐three patients were evaluable (22 boys, median age 6·8 years, range, 1·2–15). Sixteen received imatinib whereas 27 received similar chemotherapy without imatinib. Seventeen of 27 and 15 of 16 patients in the non‐imatinib and imatinib cohort, respectively, underwent HSCT in CR1. With a median follow‐up of 109 and 39 months for the non‐imatinib and imatinib cohorts, the 3‐year event‐free survival (EFS) was 29·6% and 78·7%, respectively (P = 0·01). These results show that, compared to historical controls, intermediate dose of imatinib given concomitantly with chemotherapy and followed by allogeneic HSCT markedly improved early EFS in paediatric Ph+ ALL.     

The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia

Previously, we suggested that imatinib incorporation into conventional chemotherapy as an alternative (imatinib interim therapy) might be a useful strategy for bridging the time to allogeneic stem cell transplantation (SCT) for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). Here, we provide an updated report on this strategy in 29 patients. At the time of enrollment, 23 patients (79.3%) achieved complete remission (CR). After the first imatinib cycle, the median breakpoint cluster region-Abelson oncogene locus (BCR-ABL)/ABL ratios decreased by 0.77 log in 25 (86.2%) responders, and their BCR-ABL/ABL ratios decreased further by 0.34 log after the second imatinib cycle, which included 7 molecular CR. One patient (4.3%) relapsed during the imatinib therapy. The remaining 3 patients were primarily refractory to both imatinib and chemotherapy. Twenty-five (86.2%) of the 29 patients received transplants in first CR. With a median follow-up duration of 25 months after SCT, the 3-year estimated probabilities of relapse, nonrelapse mortality, disease-free survival, and overall survival were 3.8%, 18.7%, 78.1%, and 78.1%, respectively. In comparison to our historical control data, first-line imatinib interim therapy appears to provide a good quality of CR and a survival advantage for patients with Ph(+) ALL. Further long-term follow-up is needed to validate the results of this study.     

Imatinib mesylate in combination with chemotherapy in four children with de novo and advanced stage Philadelphia chromosome-positive acute lymphoblastic leukemia

The role of imatinib in childhood Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) has not been established. We treated four children with imatinib in combination with conventional chemotherapy (CT) before stem cell transplantation (SCT). Response evaluation consisted of fluorocytometric analysis of minimal residual disease (MRD) and standard qualitative RT-PCR follow-up.     

异基因造血干细胞移植治疗成人费城染色体阳性急性淋巴细胞性白血病的疗效分析

目的:探讨异基因造血干细胞移植(allo-HSCT)治疗成人费城染色体阳性(Ph+)的急性淋巴细胞白血病(ALL)的疗效。方法:回顾性分析经VDP(长春新碱、蒽环类、糖皮质激素)±C(环磷酰胺或异环磷酰胺)±L(左旋门冬酰胺酶或培门冬酶)方案诱导化学治疗(化疗)的12例Ph+ALL患者。初始诱导缓解患者在等待移植期间进行巩固化疗,并加用伊马替尼(400～800 mg/d),与化疗同步或交替应用。初始诱导失败患者及巩固治疗期间复发患者应用Hyper-CVAD/LALA(大剂量环磷酰胺、长春新碱、多柔比星、地塞米松或米托蒽醌、阿糖胞苷)方案联合伊马替尼或达沙替尼进行再次诱导。所有患者缓解后经白消安联合环磷酰胺(Bu-Cy)或改良Bu-Cy方案预处理后进行allo-HSCT。部分患者干细胞回输后2～3个月始继续服用酪氨酸激酶抑制剂。结果:12例患者移植前均获得血液学缓解、7例获得分子学缓解。其中完全缓解(CR)1期9例、CR 2期2例、初发难治性1例。移植前11例患者应用伊马替尼;移植后5例患者应用酪氨酸激酶抑制剂,其中4例应用伊马替尼、1例应用达沙替尼。中位随访时间12.7(3～54)个月,7例患者生存,3例患者死于疾病复发,2例患者死于治疗相关并发症。所有患者均植入,移植后2年总生存率66.7%±13.6%;2年累计复发率40.6%±16.0%;2年累计非复发病死率16.7%±10.8%。首次缓解(CR1)后移植治疗的2年总生存率70.0%±14.5%;2年累计复发率40.0%±18.2%;2年累计非复发病死率20.0%±12.6%。结论:酪氨酸激酶抑制剂可能会使更多患者获得缓解,从而有机会进行allo-HSCT。CR1的生存获益更大。allo-HSCT联合酪氨酸激酶抑制剂为Ph+ALL患者有前景的治疗方案。     

Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study

The combination of imatinib with chemotherapy has been recently reported as very promising in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). During 2004 and 2005, 45 patients with newly diagnosed Ph+ ALL were treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAAPH) 2003 study, in which imatinib was started with HAM (mitoxantrone with intermediate-dose cytarabine) consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). Imatinib was then continuously administered until stem cell transplantation (SCT). Overall, complete remission (CR) and BCR-ABL real-time quantitative polymerase chain reaction (RQ-PCR) negativity rates were 96% and 29%, respectively. All of the 22 CR patients (100%) with a donor actually received allogeneic SCT in first CR. At 18 months, the estimated cumulative incidence of relapse, disease-free survival, and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context.     

How I treat childhood CML

Chronic myeloid leukemia (CML) is composed of 3% of pediatric leukemias, making evidence-based recommendations difficult. Imatinib has revolutionized the treatment for adult CML by eliminating allogeneic stem cell transplantation for almost all patients in chronic phase. Shown effective in pediatric CML, imatinib and successive tyrosine kinase inhibitors (TKI) have provided more therapeutic options. Because stem cell transplantation has been better tolerated in children and adolescents, the decision to treat by either TKI or transplantation is controversial. We present a recent case of a 12-month-old boy diagnosed with BCR-ABL(+) CML to highlight the controversies in treatment recommendations. We review the pediatric stem cell transplantation outcomes as well as the pediatric experience with imatinib and other TKIs. Finally, we compare the side effects as well as costs associated with allogeneic stem cell transplantation versus TKI therapy. We recommend that frontline therapy for pediatric CML in chronic phase is TKI therapy without transplantation. Patients in accelerated or blast crisis or who fail to reach landmarks on TKIs either because of intolerance or resistance should pursue stem cell transplantation. Although we recommend adopting adult clinical experience to guide therapeutic decision making, the issues of infant CML, drug formulation, pharmacokinetics, and adolescent compliance merit clinical investigation.     

Philadelphia chromosome‐positive mixed phenotype acute leukemia in the imatinib era

Although the introduction of imatinib dramatically improved the outcomes for patients with Philadelphia chromosome‐positive B‐cell precursor acute lymphoblastic leukemia (Ph+BCP‐ALL), the survival benefit of imatinib has not been assessed in the context of Ph+ mixed phenotype acute leukemia (Ph+MPAL). To clarify this important issue, we studied 42 Ph+ acute leukemia (Ph+AL) patients who received intensive chemotherapy and concurrent administration of imatinib. Of the 42 Ph+AL patients, 13 (31%) patients were categorized as Ph+MPAL (positive for both myeloid and B‐cell lineage), 27 (64%) were categorized as Ph+BCP‐ALL, and two (5%) were categorized as Ph+ acute myeloid leukemia. The complete remission rates after the initial induction therapy were not significantly different when comparing Ph+MPAL and Ph+BCP‐ALL patients (100% vs. 85%, respectively, P = 0.14). Likewise, there were no significant differences in the 5‐yr overall survival (OS) or disease‐free survival (DFS) rates when comparing the MPAL and BCP‐ALL groups (OS: 55% vs. 53%, respectively, P = 0.87, DFS: 46% vs. 42%, respectively, P = 0.94). These findings suggest that concurrent imatinib administration with chemotherapy improved the outcomes of Ph+MPAL patients to the level seen in Ph+BCP‐ALL patients and should, therefore, be considered as the standard therapy for these patients.     

Early prediction of response in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) treated with imatinib

Imatinib has pronounced but brief antileukemic activity in advanced Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL). We assessed the prognostic impact of pretreatment disease features and the early bone marrow (BM) response in 68 consecutive patients with Ph(+)ALL receiving imatinib salvage therapy. A complete hematologic or marrow response was achieved by 92% of patients with BM blasts below 5% on day 14, whereas 62.5% of patients with more than 5% BM blasts on day 14 were nonresponders. Similarly, time to progression (TTP) was superior in patients with a good day 14 response (5.2 versus 0.9 months; P <.0001). Prior complete remission of less than 6 months, white blood cell count of more than 10 x 10(9)/L, circulating peripheral blood blasts at diagnosis, additional Philadelphia chromosomes, or at least 2 Bcr-Abl fusion signals were associated with significantly inferior remission rate and response duration. In patients without poor prognostic features, single-agent imatinib may be appropriate before transplant salvage therapy. Conversely, patients with clinically or cytogenetically defined poor-risk features are candidates for trials of upfront imatinib in combination with other agents.     

Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL)

Acquired imatinib resistance in advanced Philadelphia-positive acute lymphoblastic leukemia (Ph(+) ALL) has been associated with mutations in the kinase domain (KD) of BCR-ABL. We examined the prevalence of KD mutations in newly diagnosed and imatinib-naive Ph(+) ALL patients and assessed their clinical relevance in the setting of uniform frontline therapy with imatinib in combination with chemotherapy. Patients enrolled in the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia (GMALL) trial ADE10 for newly diagnosed elderly Ph(+) ALL were retrospectively examined for the presence of BCR-ABL KD mutations by denaturing high-performance liquid chromatography (D-HPLC), cDNA sequencing, and allele-specific polymerase chain reaction (PCR). A KD mutation was detected in a minor subpopulation of leukemic cells in 40% of newly diagnosed and imatinib-naive patients. At relapse, the dominant cell clone harbored an identical mutation in 90% of cases, the overall prevalence of mutations at relapse was 80%. P-loop mutations predominated and were not associated with an inferior hematologic or molecular remission rate or shorter remission duration compared with unmutated BCR-ABL. BCR-ABL mutations conferring high-level imatinib resistance are present in a substantial proportion of patients with de novo Ph(+) ALL and eventually give rise to relapse. This provides a rationale for the frontline use of kinase inhibitors active against these BCR-ABL mutants.     

Current paradigms in the management of Philadelphia chromosome positive acute lymphoblastic leukemia in adults

Philadelphia chromosome‐positive (Ph‐positive) acute lymphoblastic leukemia (ALL) is a biologically, clinically, and genetically distinct subtype of precursor‐B ALL. The Ph chromosome, results from a reciprocal translocation of the ABL1 kinase gene on chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22. Depending on the translocation breakpoint, typically a p210 BCR‐ABL1 or a p190 BCR‐ABL onc protein are generated; both are constitutively active tyrosine kinases that play a central role to alter signaling pathways of cell proliferation, survival, and self‐renewal, leading to leukemogenesis. In Ph‐positive ALL, the p190‐BCR‐ABL (minor [m]‐bcr) subtype is more frequent than the p210‐BCR‐ABL (major [M]‐bcr) subtype, commonly found in chronic myeloid leukemia. The Philadelphia chromosome is the most frequent recurrent cytogenetic abnormality in elderly patients with ALL. Its incidence increases with age, reaching ～50% in patients with ALL aged 60 years and over. Patients traditionally had a very poor outcome with chemotherapy, particularly if they do not undergo allogeneic hematopoietic cell transplantation (allo‐HCT) in first complete remission (CR1). With the availability of multiple tyrosine kinase inhibitors (TKI), the therapeutic armamentarium is expanding quickly. However, there is no consensus on how to best treat Ph‐positive ALL. With modern therapy, improved outcomes have led to the emergence of a number of controversies, including the need for intensive chemotherapy, the ideal TKI, and whether all eligible patients should receive an allo‐HSCT, and if so, what type. Here, we discuss these controversies in light of the available literature.     

High-hyperdiploidy in Philadelphia positive adult acute lymphoblastic leukaemia: case-series and review of literature

Patients with Philadelphia positive (Ph(+)) adult acute lymphoblastic leukaemia (ALL) have a poor prognosis. Stem cell transplantation (SCT) is increasingly being recognised as the treatment of choice in eligible patients with Ph(+)ALL, but disease-relapse remains a problem in a proportion of patients prior to and after SCT. Genetic abnormalities in addition to the Ph chromosome may influence the biology and clinical course of ALL, but there are not many studies on the potential genetic heterogeneity of adult Ph(+)ALL and clinical outcomes. Here, we report on five patients with ALL who were double Ph(+) and also had a high-hyperdiploid karyotype (Ph(+)/hyperdiploid) at diagnosis. In contrast to the presence of the Ph(+) chromosome, high-hyperdiploidy (>50 chromosomes) as the sole karyotypic abnormality in ALL is associated with a favourable clinical outcome. In our series, four patients with a Ph(+)/hyperdiploid karyotype achieved a cytogenetic remission after induction chemotherapy and proceeded to stem cell transplantation (SCT). The fifth had five subclones including Ph(+)/hyperdiploid, as well as those that were only Ph(+); the latter emerged as the dominant clone after induction therapy and the patient died of disease-relapse. Of the patients who underwent SCT, only one relapsed, but achieved a durable remission with donor lymphocyte infusions. Thus, it is conceivable that the presence of high-hyperdiploidy as an additional karyotypic abnormality may confer a better prognosis to Ph(+)ALL, presumably by altering the kinetics of Ph(+) neoplastic cells. We have discussed these results in the context of recent studies on the significance of high-hyperdiploidy in Ph(+) adult ALL.     

Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol

Thirty elderly (> 60 years) Philadelphia chromosome-positive (Ph(+)) patients with acute lymphoblastic leukemia (ALL) received imatinib, 800 mg daily, associated to steroids without further chemotherapy as frontline treatment. Median age was 69 years (range, 61-83 years). Twenty-nine patients were evaluable for response and all of them obtained a hematologic complete remission, with a median BCR-ABL reduction of 2.9 and 2.0 logs in p190(+) and p210(+) cases, respectively. Most of the induction treatment did not require admission of the patients. No major toxicities occurred and the treatment was well tolerated. Median survival from diagnosis was 20 months. This study shows that elderly Ph(+) patients with ALL-often considered eligible only for palliative treatment strategies-may benefit from an imatinib-steroids protocol, which does not require chemotherapy nor a long hospitalization, is feasible, highly active, and associated with a good quality of life.     

Clonal evolution with +11q 13, t(1;7) and t(1;4) at relapse in a patient with Ph positive acute lymphocytic leukemia (ALL) treated with single agent front line imatinib followed by dasatinib

Imatinib, a selective ABL kinase inhibitor has improved therapeutic outcome in patients with Philadelphia positive chronic or acute leukemia. In the present study, we describe a 56-year-old male with Philadelphia chromosome positive acute lymphocytic leukemia (ALL) who was treated with up-front single agent imatinib and achieved complete hematologic, cytogenetic and molecular remission. At relapse 11 months later, new chromosomal translocations involving chromosomes 1, 7 and 4 and cryptic addition to chromosome 11 were identified in Ph+ cells and the patient had rapid deterioration with progressive disease. The significance of additional chromosomal abnormalities in imatinib treated patients and secondary chromosomal abnormalities in Philadelphia positive chronic myeloid leukemia and ALL are discussed briefly in this report.     

Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice

It is generally believed that shutting down the kinase activity of BCR-ABL by imatinib will completely inhibit its functions, leading to inactivation of its downstream signaling pathways and cure of the disease. Imatinib is highly effective at treating human Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but not Ph(+) B cell acute lymphoblastic leukemia (B-ALL) and CML blast crisis. We find that SRC kinases activated by BCR-ABL remain fully active in imatinib-treated mouse leukemic cells, suggesting that imatinib does not inactivate all BCR-ABL-activated signaling pathways. This SRC pathway is essential for leukemic cells to survive imatinib treatment and for CML transition to lymphoid blast crisis. Inhibition of both SRC and BCR-ABL kinase activities by dasatinib affords complete B-ALL remission. However, curing B-ALL and CML mice requires killing leukemic stem cells insensitive to both imatinib and dasatinib. Besides BCR-ABL and SRC kinases, stem cell pathways must be targeted for curative therapy of Ph(+) leukemia.