Management of adult patients with Philadelphia positive acute lymphoblastic leukemia

Transcription

1 臨床血液 The 75th Annual Meeting of the Japanese Society of Hematology Lymphoid malignancies:all/cll EL-33 Topics Management of adult patients with Philadelphia positive acute lymphoblastic leukemia Robin FOÀ, Antonella VITALE, Sara GRAMMATICO and Sabina CHIARETTI Key words :Ph + acute lymphoblastic leukemia, BCR-ABL1, Tyrosine kinase inhibitors, Minimal residual disease Introduction For decades Philadelphia positive acute lymphoblastic leukemia (Ph + ALL) has been considered as the ALL subgroup with the worse prognosis 1 4). It occurs in 20 to 40% of adult ALL and in about 3% of pediatric patients; the frequency of the Ph chromosome increases with age and is present in over 50% of patients aged 50 years or older 5 7). The main reason for the poor clinical outcome of BCR-ABL1 + ALL is genetic instability 8). The outcome for adult Ph + ALL patients has improved considerably with the current treatment approaches that include tyrosine kinase inhibitors (TKI) and which allow to achieve complete hematological remissions (CHR) in % of patients. Indeed, treatment with a TKI, with or without chemotherapy, represents today the gold standard first line approach for patients with Ph + ALL, both in terms of CHR and of disease-free survival (DFS), and can also act as a bridge to stem cell transplantation (SCT) for eligible patients. Low levels of minimal residual disease (MRD) at the time of transplantation are likely be of great importance in this setting; therefore, a correct MRD screening by means of real-time reverse transcriptase polymerase chain reaction (RT-PCR) and BCR-ABL1 quantification is recommended, although a worldwide consensus on MRD data interpretation has not been yet reached. All patients with a diagnosis of ALL, regardless of age, should be rapidly tested for the presence of the BCR- Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy. ABL1 rearrangement; this is particularly true in the elderly, since the majority of patients are not eligible for intensive chemotherapy, while virtually all can achieve a CHR with a TKI, including patients in their eighties. Molecular diagnosis is strongly advisable, since the marker can be used to monitor MRD during the course of the disease. It should be recalled that the BCR-ABL1 protein can be detected at diagnosis also by flow cytometry with a 100% accuracy 9, 10). This may allow a rapid diagnostic work-up of Ph + ALL in geographic regions where PCR-based technologies are not available. Clinical features Ph + ALL is usually characterized by a slightly higher initial white blood cell (WBC) count compared to Ph, ALL, while other symptoms or clinical signs do not differ from those of Ph, ALL patients. A central nervous system (CNS) involvement is infrequent (5%) at initial presentation, but there is a significant risk of developing meningeal leukemia during the course of treatment. For this reason, CNS-directed prophylactic therapy should be considered mandatory in patients with Ph + ALL. Diagnostic work-up While in the past the diagnosis of Ph + ALL was made by conventional cytogenetics, nowadays these cases are better identified by RT-PCR. The molecular screening identifies the fusion product of the t(9;22) chromosome translocation, i.e. the BCR-ABL1 fusion gene. RT-PCR is much more rapid and has a higher sensitivity than cytogenetics. Quantitative RT-PCR (Q-RT-PCR) assay also allows to quantify the levels of the BCR-ABL1 rearrange- (1628)282

2 臨床血液 54:10 ment and permits an adequate MRD screening. This framework is nowadays essential for an optimal diagnostic work-up and management of ALL patients of all ages and is also crucial for a uniform monitoring of MRD during the course of the disease 11, 12). Cytogenetic analyses have improved over time and fluorescence in situ hybridization (FISH) can provide results in a very short time. However, the sensitivity of FISH is inferior to that of RT-PCR. From a research standpoint, conventional cytogenetics remains valuable in order to identify the presence of additional chromosomal abnormalities. The prognostic importance of the latter within Ph + ALL is starting to emerge. Biologic acquisitions The Ph chromosome results from a reciprocal translocation fusing the abelson (ABL1) proto-oncogene on chromosome 9 with the breakpoint cluster region (BCR) sequences on chromosome 22, creating the BCR-ABL1 fusion protein, a constitutively activated form of the ABL TK. Depending on the breakpoint of the BCR region, two types of fusion transcripts can be distinguished:the major BCR-ABL, which accounts for approximately one-third of Ph + ALL and encodes the larger p210 protein, and the minor BCR-ABL (found in two-thirds of Ph + ALL) that encodes the smaller p190 protein 13, 14). Both proteins constitutively enhance TK activity, recruit and activate multiple pathways that transduce oncogenic signals, thus leading to increased cell survival and proliferation, impaired migration and adhesion, an arrested differentiation of hematopoietic progenitors and impaired apoptosis 8, 15). The reason for the aggressive nature of BCR-ABL1-induced ALL is not fully understood and it is likely that factors other than BCR-ABL1 are involved in its development and progression. Recent works 16, 17) have described a deletion on 7p12 of IKZF1, which encodes the transcription factor Ikaros, in most Ph + ALL cases, suggesting that loss of Ikaros may contribute to the leukemia initiation by blocking B- lymphoid maturation. SRC-family kinases (SFK) may also contribute to the pathogenesis of Ph + leukemias, since they have been implicated in BCR-ABL1 signaling and, consequently, in disease progression 18). Gene expression profiling has shown that Ph + ALL displays a very heterogenous profile and is not characterized by a distinctive molecular signature; however, it is worth noting that a small set of additional protein kinases and several genes that regulate cell cycle progression have been found highly expressed in this subset of patients 19 21). Treatment The management of Ph + ALL patients can be divided into a pre- and post-tki era. The advent of TKI has completely changed the treatment and prognosis of Ph + ALL. Prior to the advent of the TKI, after an initial response to conventional chemotherapy, with rates of CHR ranging from 60 to 70% and long-term survivals in the order of 35 40% in children and less than 20% in adults 22 24), thus lower than in Ph, ALL, resistance to therapy and chemorefractory relapse occurred 25). Virtually no adult patients (?5%) could be cured with standard chemotherapy; the median survival was 8 10 months in the absence of an allogeneic SCT, which was the only potentially curative therapy 26 29). Since the disease occurs more frequently in patients over the age of 60, the curative potential of allogeneic SCT has not been fully analyzed because relatively few elderly patients have undergone the procedure in a clinical-trial setting. The whole scenario has changed in the last decade following the development of targeted therapies aimed at interfering with the molecular abnormality of the leukemic clone. The most prominent example of targeted therapy in oncology is indeed represented by the specific inhibitor of the BCR-ABL1 TK imatinib mesylate (Gleevec) 30), which has radically modified our treatment strategy for Ph + ALL 31 34). The potential of imatinib in Ph + ALL was first investigated in monotherapy studies for patients with relapsed or refractory disease. In a pilot study, 20 patients with Ph + ALL or lymphoid blast phase of CML were treated with imatinib and, of these, 20% achieved a CHR 31). In a subsequent phase II study that recruited patients with Ph + ALL experiencing a lack of response or relapse to standard chemotherapy or SCT, 19% of patients achieved a CHR 33). Thereafter, in several studies it could be documented that the addition of imatinib to frontline induction therapy resulted in much higher rates of CHR than with conventional chemotherapy 35 41). Moreover, DFS proved to be significantly longer with imatinib-based therapy than with standard chemotherapy. In older adults with Ph + ALL, imatinib has been administered alone or in combination with only low-dose 283(1629)

3 臨床血液 steroids, and it has resulted in very high CHR rates 42 44). It should be underlined that prior to the advent of the TKI, the management of elderly patients with Ph + ALL was very often palliative in view of the dismal prognosis and of the frail conditions that prevented the use of chemotherapy regimens. The results of the GIMEMA study in patients over the age of 60, who were tested for the presence of the BCR-ABL1 aberration within one week during which they underwent a steroid pre-phase, and were then treated only with imatinib 43) has represented a major advancement in the management of Ph + ALL. The possibility of achieving a CHR with a well-tolerated oral non-chemotherapy treatment in virtually all elderly Ph + ALL patients has been an important step forward. Overall, these studies indicate that first-line treatment of Ph + ALL with imatinib administered alone or in combination with chemotherapy is associated with improved responses and outcomes, and that the greatest benefits are reported when imatinib treatment is initiated during the induction phase and is used continuously alone or in combination with chemotherapy. It should, however, be noted that the combined use of imatinib and chemotherapy in adult Ph + ALL is always associated with important toxicities and deaths in induction 36, 38, 45 48). The use of imatinib may improve the chance of eligibility for an allogeneic SCT by increasing the proportion of patients achieving a CHR compared with historical controls 35 37, 39 41). In addition, the longer remission duration allows extra time for donor search and for allogeneic SCT. One prospective phase II study has reported that first-line imatinib, in combination with chemotherapy, improves the curative potential of a subsequent allogeneic SCT 49). Recently, another phase II study compared the clinical outcome of patients who received imatinib plus chemotherapy followed by allogeneic SCT in their first CHR (imatinib cohort) with the historical control patients in the pre-imatinib era, showing a significant increase of OS, DFS and relapse-free survival (RFS) for the imatinib cohort 50). Moreover, data suggest that Ph + ALL patients who are MRD + post-transplant may benefit from receiving imatinib post-sct 51, 52). Furthermore, elevated values of MRD are predictive of a subsequent relapse and allogeneic SCT can override its adverse effect 53 55). Despite the clear benefits offered by imatinib, many patients with Ph + ALL do not experience durable remissions and resistance frequently occurs. Resistance can be classified as primary (failure to achieve CHR) or acquired/secondary (relapse despite continued treatment). Second generation TKI have shown good results for these patients. Dasatinib (Sprycell) is a potent, oral inhibitor of the BCR-ABL1, c-kit and SRC kinase family, which has proven to be a more active inhibitor of BCR-ABL1 and c-kit than imatinib. Clinically, it has been shown to be effective in Ph + ALL patients resistant or intolerant to imatinib 56 59) and is currently approved by the Food and Drug Administration (FDA) for these patients. Following encouraging phase I results 56), an international phase II study (START-L) confirmed that dasatinib is associated with marked hematological and cytogenetic response rates in relapsed/resistant Ph + ALL 61, 68). The clinical responses observed with second-line dasatinib in Ph + ALL post-imatinib failure provided a rationale for the evaluation of dasatinib as a first-line therapy. Recent phase II studies report the experience of dasatinib administered either as monotherapy with prednisolone only 62) or in combination with hyper-cvad chemotherapy 60). In the GIMEMA first line study 62) virtually all adult Ph + ALL patients - irrespective of age - achieved a CHR with dasatinib alone (plus steroids); treatment was associated with a very favorable tolerability and safety profile, partly administrable at home, and with no deaths in induction. The results obtained first in the elderly with imatinib alone and then in all adult patients with dasatinib alone question the role of chemotherapy in combination with a TKI as induction treatment in Ph + ALL. In the French- German EWALL protocol, patients with Ph + ALL aged 55 years or more were treated with dasatinib combined with chemotherapy. This strategy resulted in notable toxicities, deaths during induction and treatment discontinuation in 35% of patients 63 65). Similarly, in the phase II studies combining hyper-cvad with dasatinib as frontline therapy, three deaths due to infections were recorded during induction and grade 3 4 side effects, including several bleeding episodes as well as pleural effusions occurred 60, 66). In addition, a pilot first line GIMEMA study of imatinib plus chemotherapy was emended because of toxicity (personal data) into a sequential scheme. Nilotinib (Tasigna) is a selective BCR-ABL1 inhibitor. It binds to the BCR-ABL1 kinase domain and it can overcome resistance in the BCR-ABL1 kinase domain related to mutations 67). Only few studies have been performed with nilotinib in patients with Ph + ALL postimatinib failure 68, 69) ; the results do not appear very (1630)284

4 臨床血液 54:10 promising (2/13 patients and 24% of 41 obtained a CHR, respectively) and a longer follow-up is required to assess response durability. A recent pilot study 70) reported the results of nilotinib in combination with hyper-cvad as first-line treatment; all 5 patients treated achieved a CHR. The results are encouraging, but must be extended to a larger number of patients. A phase II study tested nilotinib plus chemotherapy in 50 newly diagnosed patients obtaining a 90% CHR rate (with 4 patients who died during induction), with RFS, event-free survival (EFS) and OS at 2 years of 71.1%, 49.4% and 66.2%, respectively 71). Finally, in 2 Ph + ALL patients refractory to treatment with chemotherapy and TKI the efficacy of clofarabine could be documented:in fact, both patients obtained a CHR and a molecular response with no significant side effects 72). Minimal residual disease Monitoring of MRD is routinely utilized in clinical trials to evaluate the response to treatment in ALL patients, including Ph + ALL. The level of BCR-ABL1 reduction achieved early during therapy is a good parameter of subsequent response, while high levels of BCR-ABL1 transcripts at different treatment stages indicate poor responsiveness to chemotherapy and to TKI, and intuitively could be considered a risk factor for disease recurrence. A retrospective study based on the stratification of MRD levels after induction and consolidation chemotherapy showed that the reduction of the BCR- ABL1 transcript was the main prognostic parameter to predict outcome 73). In contrast, prospective MRD monitoring in 100 adult patients with Ph + ALL uniformly treated with imatinib and chemotherapy failed to establish an association between PCR negativity at the end of induction therapy, relapse rate or RFS, although increased levels of BCR-ABL1 transcripts during hematologic CHR were predictive of relapse in non-transplanted patients 74). Lee et al 75) were able to demonstrate that a 3-log reduction in BCR-ABL1 transcripts after 1 month of imatinib treatment strongly predicted a reduced relapse risk:this finding was confirmed in a subsequent study 76). In contrast, Yanada et al 74) observed no association between rapid achievement of BCR-ABL1 negativity and long-term outcome after an initial imatinib/chemotherapy induction regimen and also the GRAAL group 77) showed that early MRD evaluation did not significantly influence patients outcome, both in 78, 79) terms of OS and DFS. Two studies analyzing the outcome of patients with Ph + ALL who underwent a transplant showed that the persistent expression of BCR- ABL1 during the first 100 days post-transplant was associated with a higher incidence of relapse and a lower DFS. Both studies argue in favor of a maintenance therapy with imatinib after transplantation in patients with a positive MRD evaluation, and the same is suggested in recent studies 80, 81). Moreover, Pfeifer et al 82) support the prophylactic administration of imatinib after allogeneic SCT regardless of the MRD status. Finally, in the GIMEMA study 62) based on dasatinib administration BCR- ABL1 levels?10,3 at the end of the TKI induction correlated with DFS. These studies demonstrate that prospective monitoring of MRD has the potential to identify patients at risk of relapse. Open issues remain the definition of precise cut-off levels for the quantification of the disease and its increment. These issues highlight the need for standardization and harmonization of the methodologies used for BCR-ABL1 quantification in Ph + ALL 83) and the indications suggested by White et al 84) lead to a uniform international assessment of BCR-ABL1 levels. Relapse and mutations Relapse still remains a problem for patients with Ph + ALL and the emergence of resistant clones is quite common in ALL as the cause of relapse 24, 25).InPh + ALL patients treated with TKI, the relapse is an expected event and it is most often accompanied by selection of point mutations in the BCR-ABL1 kinase domain 85, 86). The occurrence of BCR-ABL1 mutations is a key element in managing leukemic patients during TKI therapy, because of the greater genetic instability occurring in patients with Ph + ALL. Other causes have pharmacokinetic or pharmacodynamic 87) bases, like disruptions in drug uptake and efflux, or are due to the development of other 16, 17) secondary genetic abnormalities and activation of alternative signaling pathways. Cytogenetic abnormalities, in addition to the Ph chromosome, are present in about one third of adult cases and have been associated with an inferior outcome 4). Members of the SRC family of kinases have been implicated in leukemogenesis and development of imatinib-resistance in BCR-ABL1 + ALL, suggesting that the simultaneous inhibition of SRC and BCR-ABL1 kinases may benefit individuals with Ph + leukemia 18). About 80 90% of patients with Ph + ALL who relapse while on imatinib are found to have BCR-ABL1 mutations, with a 285(1631)

5 臨床血液 predominance of P-loop and T315I mutations; with dasatinib, relapse is most often associated with the T315I mutation, whereas P-loop mutations are less common 87, 88). It has become of central interest whether mutations are already present in TKI-naïve patients, and this frequently appears to be the case 85, 89). Our group 89) and a previous study 85) have found that BCR-ABL1 mutations, including T315I, can be detected in a proportion of patients at diagnosis. In our series, low levels of T315I mutations could also be found at diagnosis, but this does not seem to correlate with a subsequent relapse or persistence of remission 89). Further prospective studies will conclusively clarify the implications of finding a mutation prior to treatment, which may involve only a minor subclone depending on the sensitivity of the test utilized. CNS relapses are also common with imatinib, which does not penetrate the CNS 90, 91) ; in fact, imatinib levels in the cerebrospinal fluid have been shown to reach only1to2% of serum levels 92). Thus, aggressive CNS prophylaxis is needed. Dasatinib shows a better infiltration of the CSF and achieves clinically active concentrations, as shown in small series of patients in whom stabilization and regression of CNS disease were achieved 93). It has been hypothesized that these effects, which are different from imatinib, are due to the dual specific SRC/BCR-ABL1 TK-inhibitory property of dasatinib. It remains to be determined whether the current approach to CNS-directed prophylaxis can be modified in the context of dasatinib-based treatment for Ph + ALL patients. Future perspectives While our approach to the management of Ph + ALL has greatly changed and the overall prognosis has improved, some very important questions are still open. The first is if the induction treatment should be based on a TKI alone (plus steroid and intrathecal treatment) or whether chemotherapy should be associated to the TKI. Based on the evidence that this association is invariably associated with marked toxicity and deaths in induction, the GIMEMA group prefers to induce all adult patients into CHR without systemic chemotherapy. With this approach almost 150 adult patients with Ph + ALL - with no upper age limit - have so far been treated with imatinib or dasatinib and no chemotherapy. The CHR rate is 98.4% with no single death in induction. The OS and PFS results are not inferior to those reported with the TKIchemotherapy association. While we feel that the strategy for obtaining a CHR in virtually all patients, including the elderly, may be solved, the key question today is how to manage patients after the induction phase. Since the majority of patients are MRD +, further treatment is required. In the current GIMEMA protocol, patients between 18 and 60 years are induced into CHR with dasatinib (and steroids) and then patients with a donor will undergo as soon as possible an allo-sct. Alternatively, they are consolidated with clofarabine-based chemotherapy. If a relapse occurs, the outcome is very poor. Even if a second remission can be achieved, there is no consensus on the most appropriate regimen in the setting of TKIresistant Ph + ALL. In these patients, there are emerging data with third generation TKI. Ponatinib is a potent BCR- ABL1 inhibitor active against TKI-resistant cells, including those harboring the T315I mutation. In a recent phase I study, this drug was tested in 34 CML patients and 3 Ph + ALL refractory patients, obtaining 36% of major hematological responses 94). A phase II study is currently ongoing 95, 96). Blinatumomab, a bispecific, T-cell-engaging antibody binding CD19 and CD3 is a novel agent currently being tested in a phase II study for relapsed/refractory B- precursor ALL adults patients and for patients with detectable MRD. This compound has been associated with very encouraging responses, also in Ph + ALL patients carrying a T315I mutation 97 99). Bosutinib is a dual SRC&ABL tyrosine kinase inhibitor which has shown significant activity in patients with resistant Ph + leukemias, except for those harboring the T315I mutation 100). Other agents, like the SRC/ABL inhibitors, aurora kinase inhibitors, RAF kinase inhibitors, etc are being evaluated in clinical trials. Overcoming resistance remains the therapeutic challenge; identification of a molecular signature, possibly comprehensive of specific cytogenetic abnormalities, might provide targets for new interventions in the future. It is clear that the management of patients with Ph + ALL has been revolutionized. The evidence that virtually all patients including the very elderly can obtain a CHR with a TKI alone (plus steroids) and without systemic chemotherapy would have been unthinkable only a few years ago. Now the primary challenge that the hematologic community is facing is how to eliminate or control MRD. (1632)286

6 臨床血液 54:10 Robin Foà has received honoraria for advisory boards from Roche Co.,Ltd., BMS Co.,Ltd., GSK, Celgene Co.,Ltd., and Takeda Pharmaceutical Co.,Ltd., and has received consulting fees from Roche Co., Ltd., and payment for lectures including service on speakers bureaus from Roche Co.,Ltd., BMS Co.,Ltd., GSK, Celgene Co.,Ltd., Janssen Co.,Ltd., and Mundipharma Co.,Ltd. References 1)Gleissner B, Gökbuget N, Bartram CR, et al. Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia:a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood. 2002; 99: )Mancini M, Scappaticci D, Cimino G, et al. A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL):analysis of the GIMEMA 0496 protocol. Blood. 2005; 105: )Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL):analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/ Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007; 109: )Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia:results of Southwest Oncology Group 9400 study. Blood. 2008; 111: )Burmeister T, Schwartz S, Bartram CR, Gökbuget N, Hoelzer D, Thiel E; GMALL study group. Patients age and BCR-ABL frequency in adult B-precursor ALL:a retrospective analysis from the GMALL study group. Blood. 2008; 112: )Larson RA. Management of acute lymphoblastic leukemia in older patients. Semin Hematol. 2006; 43: )Chiaretti S, Vitale A, Cazzaniga G, et al. Clinico-Biologic Features of 5202 Acute Lymphoblastic Leukemia Patients Enrolled in the Italian AIEOP and GIMEMA Protocols and Stratified in Age-Cohorts. Haematologica, Prepublished on May 28, 2013, as doi: /haematol )Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990; 247: )Weerkamp F, Dekking E, Ng YY, et al. Flow cytometric immunobead assay for the detection of BCR-ABL fusion proteins in leukemia patients. Leukemia. 2009; 23: )Raponi S, De Propris MS, Wai H, et al. An accurate and rapid flow cytometric diagnosis of BCR-ABL positive acute lymphoblastic leukemia. Haematologica. 2009; 94: )Beillard E, Pallisgaard N, van der Velden VH, et al. Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using real-time quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR)-a Europe against cancer program. Leukemia. 2003; 17: )Gabert J, Beillard E, van der Velden VH, et al. Standardization and quality control studies of real-time quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - a Europe Against Cancer program. Leukemia. 2003; 17: )Secker-Walker LM, Craig JM, Hawkins JM, Hoffbrand AV. Philadelphia positive acute lymphoblastic leukemia in adults: age distribution, BCR breakpoint and prognostic significance. Leukemia. 1991; 5: )Kantarjian HM, Talpaz M, Dhingra K, et al. Significance of the P210 versus P190 molecular abnormalities in adults with Philadelphia chromosome-positive acute leukemia. Blood. 1991; 78: )Melo JV, Gordon DE, Tuszynski A, Dhut S, Young BD, Goldman JM. Expression of the ABL-BCR fusion gene in Philadelphia-positive acute lymphoblastic leukemia. Blood. 1993; 81: )Mullighan CG, Miller CB, Radtke I, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008; 453: )Iacobucci I, Storlazzi CT, Cilloni D, et al. Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1- positive acute lymphoblastic leukemia patients:on behalf of Gruppo Italiano Malattie Ematologiche dell Adulto Acute Leukemia Working Party (GIMEMA AL WP). Blood. 2009; 114: )Li S. Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. Leuk Lymphoma. 2008; 49: )Golub TR, Slonim DK, Tamayo P, et al. Molecular classification of cancer:class discovery and class prediction by gene expression monitoring. Science. 1999; 286: )Haferlach T, Kohlmann A, Schnittger S, et al. Global approach to the diagnosis of leukemia using gene expression profiling. Blood. 2005; 106: )Chiaretti S, Li X, Gentleman R, et al. Gene Expression Profiles of B-lineage Adult Acute Lymphocytic Leukemia Reveal Genetic Patterns that Identify Lineage Derivation and Distinct Mechanisms of Transformation. Clin Cancer Res. 2005; 11: )Thomas X, Thiebaut A, Olteanu N, et al. Philadelphia chromosome positive adult acute lymphoblastic leukemia: characteristics, prognostic factors and treatment outcome. Hematol Cell Ther. 1998; 40: )Aricò M, Valsecchi MG, Camitta B, et al. Outcome of 287(1633)

7 臨床血液 treatment in children with Philadelphia chromosomepositive acute lymphoblastic leukemia. N Engl J Med. 2000; 342: )Yanada M, Ohno R, Naoe T. Recent advances in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol. 2009; 89: )Thomas X, Dombret H. Treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Leuk Lymphoma. 2008; 49: )Dombret H, Gabert J, Boiron JM, et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia results of the prospective multicenter LALA-94 trial. Blood. 2002; 100: )Laport GG, Alvarnas JC, Palmer JM, et al. Long-term remission of Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors:a 20-year experience with the fractionated total body irradiationetoposide regimen. Blood. 2008; 112: )Fielding AK, Goldstone AH. Allogeneic haematopoietic stem cell transplant in Philadelphia-positive acute lymphoblastic leukemia. Bone Marrow Transplant. 2008; 41: )Fielding AK, Rowe JM, Richards SM, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era:results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009; 113: )Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science. 2000; 289: )Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCRABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001; 344: )Gruber F, Mustjoki S, Porkka K. Impact of tyrosine kinase inhibitors on patient outcomes in Philadelphia chromosomepositive acute lymphoblastic leukaemia. Br J Haematol. 2009; 145: )Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood. 2002; 100: )Ottmann OG, Pfeifer H. First-line treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia in adults. Cur Opin Oncol. 2009; 21:S43-S46. 35)Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-cvad and imatinib mesylate. Blood. 2004; 103: )Yanada, M, Takeuchi, J, Sugiura I, et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABLpositive acute lymphoblastic leukemia:a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol. 2006; 24: )Wassmann B, Pfeifer H, Goekbuget N, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL). Blood. 2006; 108: )de Labarthe A, Rousselot P, Huguet-Rigal F, et al. Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia:results of the GRAAPH-2003 study. Blood. 2007; 109: )Pfeifer H, Goekbuget N, Volp C, et al. Long-term outcome of 335 adult patients receiving different schedules of imatinib and chemotherapy as front-line treatment for Philadelphiapositive acute lymphoblastic leukemia (Ph + ALL)[abstract]. Blood. 2010; 116:79. Abstract )Fielding AK, Buck G, Lazarus HM, et al. Imatinib significantly enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukaemia:final results of the UKALL- XII/ECOG2993 trial [abstract]. Blood. 2010; 116:77. Abstract )Thomas DA, O Brien SM, Faderl S, et al. Long-term outcome after hyper-cvad and imatinib (IM) for de novo or minimally treated Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph, ALL)[abstract]. J Clin Oncol. 2010; 28: 15S. Abstract )Delannoy A, Delabesse E, Lhéritier V, et al. Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia:results of the GRAALL AFR09 study. Leukemia. 2006; 20: )Vignetti M, Fazi P, Cimino G, et al. 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. Blood. 2007; 109: )Delannoy A, Delabesse E, Lheritier V, et al. The long-term outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) in the imatinib era [abstract]. Haematologica. 2009; Suppl 2: Abstract77. 45)Towatari M, Yanada M, Usui N, et al. Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia. Blood. 2004; 104: (1634)288

8 臨床血液 54:10 46)Ottmann OG, Wassmann B, Pfeifer H, et al. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). Cancer. 2007; 109: )Ribera JM, Oriol A, González M, et al. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica. 2010; 9: )Bassan R, Rossi G, Pogliani EM, et al. Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia:northern Italy Leukemia Group protocol 09/00. J Clin Oncol. 2010; 28: )Lee S, Kim YJ, Min CK, et al. 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. Blood. 2005; 105: )Mizuta S, Matsuo K, Yagasaki F, et al. Pre-transplant imatinib-based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR-ABLpositive acute lymphoblastic leukemia. Leukemia. 2011; 25: )Wassmann B, Pfeifer H, Stadler M, et al. Early molecular response to posttransplantation imatinib determines outcome in MRD + Philadelphia positive acute lymphoblastic leukemia (Ph + ALL). Blood. 2005; 106: )Carpenter PA, Snyder DS, Flowers ME, et al. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood. 2007; 109: )Ravandi F, Thomas DA, O Brien S, et al. Detection of minimal residual leukemia predicts the outcome of patients with Philadelphia-chromosome positive acute lymphoblastic leukemia treated with tyrosine kinase inhibitors plus chemotherapy [abstract]. Blood. 2011; 118:Abstract )Zhou Y, Jorgensen JL, Saliba RM, et al. Pre-transplant minimal residual disease detected by multiparameter flow cytometric analysis predicts for disease relapse in adult patients with acute lymphoblastic leukemia post allogeneic hematopoietic stem cell transplantation [abstract]. Blood. 2011; 118:Abstract )Lee S, Kim DW, Cho BS, et al. Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia. 2012; 26: )Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinibresistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006; 354: )Brave M, Goodman V, Kaminskas E, et al. Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res. 2008; 14: )Lilly MB, Ottmann OG, Shah NP, et al. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Phpositive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study. Am J Hematol. 2010; 85: )Liu-Dumlao T, O Brien S, Cortes JE, et al. Combination of the hypercvad regimen with dasatinib in patients with relapsed Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL) or lymphoid blast phase of chronic myeloid leukemia (CML-LB) [abstract]. Blood. 2011; 118:Abstract )Porkka K, Martinelli G, Ottman OG, et al. Dasatinib efficacy in patients with imatinib-resistant/intolerant Philadelphiachromosome-positive acute lymphoblastic leukemia:24- month data from START-L [abstract]. Haematologica 2008; 93(s1):1. Abstract )Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007; 110: )Foà R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosomepositive acute lymphoblastic leukemia. Blood. 2011; 118: )Ravandi F, O Brien S, Thomas D, et al. First report of phase 2 study of dasatinib with hyper-cvad for the frontline treatment of patients with Philadelphia chromosome positive (Ph + ) acute lymphoblastic leukemia. Blood. 2010; 116: )Rousselot P, Cayuela JM, Recher C, et al. Dasatinib (Sprycel ) and chemotherapy for first-line treatment in elderly patients with de novo Philadelphia positive ALL: results of the first 22 patients included in the EWALL-Ph-01 trial (on behalf of the European Working Group on Adult ALL (EWALL))[abstract]. Blood. 2008; 112: Abstract )Rousselot P, Cayuela JM, Hayette S, et al. Dasatinib (Sprycel ) and Low Intensity Chemotherapy for First-Line Treatment In Elderly Patients with De Novo Philadelphia Positive ALL (EWALL-PH-01):Kinetic of Response, Resistance and Prognostic Significance [abstract]. Blood. 2010; 116: Abstract )Rousselot P, Coudé MM, Huguet F, et al. Dasatinib (Sprycel ) and Low Intensity Chemotherapy for First-Line Treatment in Patients with De Novo Philadelphia Positive ALL Aged 55 and Over:Final Results of the EWALL-Ph (1635)

9 臨床血液 Study [abstract]. Blood. 2012; 120:Abstract )Lee HJ, Kantarjian HM, Thomas DA, et al. Long-term followup of combined hypercvad (hcvad) regimen with dasatinib (Db) in the front line therapy of patients (pts) with Philadelphia chromosome positive (Ph + ) acute lymphoblastic leukemia (ALL) [abstract]. Blood. 2011; 118:Abstract )Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinibresistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006; 354: )Ottmann OG, Larson RA, Kantarjian HM, et al. Phase II study of nilotinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia. 2013; 27: )Castillo E, Al-Rajabi R, Pandya DM, et al. A Pilot Study of the Combination of Nilotinib and Hyper-CVAD for Philadelphia Chromosome Positive Acute Lymphocytic Leukemia and Lymphoid Blast Crisis Chronic Myelogenous Leukemia [abstract]. Blood. 2010; 116: Abstract )Kim DY, Joo YD, Lee JH, et al. Nilotinib combined with multiagent chemotherapy for adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia:interim results of Korean Adult ALL Working Party Phase 2 Study [abstract]. Blood. 2011; 118:Abstract )Vitale A, Grammatico S, Capria S, Fiocchi C, Foà R, Meloni G. Advanced Philadelphia chromosome positive acute lymphoblastic leukemia patients relapsed after treatment with tyrosine-kinase inhibitors:successful response to clofarabine and cyclophosphamide. Haematologica. 2009; 94: )Pane F, Cimino G, Izzo B, et al. Significant reduction of the hybrid BCR/ABL transcripts after induction and consolidation therapy is a powerful predictor of treatment response in adult Philadelphia-positive acute lymphoblastic leukemia. Leukemia. 2005; 19: )Yanada M, Sugiura I, Takeuchi J, et al. Japan Adult Leukemia Study Group. Prospective monitoring of BCR-ABL1 transcript levels in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia undergoing imatinibcombined chemotherapy. Br J Haematol. 2008; 143: )Lee S, Kim DW, Kim YJ, et al. Minimal residual disease-based role of imatinib as a first-line interim therapy prior to allogeneic stem cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2003; 102: )Lee S, Kim DW, Cho BS, et al. Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia. 2012; 26: )Tanguy-Schmidt A, Rousselot P, Chalandon Y, et al. Longterm follow-up of the imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosomepositive acute lymphoblastic leukemia:a GRAALL study. Biol Blood Marrow Transplant. 2013; 19: )Radich J, Gehly G, Lee A, et al. Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation. Blood. 1997; 89: )Stirewalt DL, Guthrie KA, Beppu L, et al. Predictors of relapse and overall survival in Philadelphia chromosomepositive acute lymphoblastic leukemia after transplantation. Biol Blood Marrow Transplant. 2003; 9: )Mizuta S, Matsuo K, Maeda T, et al. Prognostic factors influencing clinical outcome of allogeneic hematopoietic stem cell transplantation following imatinib-based therapy in BCR-ABL-positive ALL. Blood Cancer J. 2012; 2:e72. 81)Chen H, Liu KY, Xu LP, et al. Administration of imatinib after allogeneic hematopoietic stem cell transplantation may improve disease-free survival for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. J Hematol Oncol. 2012; 5:29. 82)Pfeifer H, Wassmann B, Bethge W, et al. Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1 positive acute lymphoblastic leukemia. Leukemia. 2013; 27: )Pfeifer H, Cazzaniga G, Spinelli O, et al. International Standardization of Minimal Residual Disease Assessment for in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph + ALL) Expressing m-bcr-abl Transcripts: Updated Results of Quality Control Procedures by the EWALL and ESG-MRD-ALL Consortia [abstract]. Blood. 2011; 118:Abstract )White HE, Matejtschuk P, Rigsby P, et al. Establishment of the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL mrna. Blood. 2010; 116:e111-e )Pfeifer H, Wassmann B, Pavlova A, et al. 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). Blood. 2007; 110: )Jones D, Thomas D, Yin CC, et al. Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors. Cancer. 2008; 113: )van der Kuip H, Wohlbold L, Oetzel C, Schwab M, Aulitzky WE. Mechanisms of clinical resistance to small molecule tyrosine kinase inhibitors targeting oncogenic tyrosine kinases. Am J Pharmacogenomics. 2005; 5: )Soverini S, Colarossi S, Gnani A, et al. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica. 2007; 92: )Soverini S, Vitale A, Poerio A, et al. Philadelphia-positive (1636)290

10 臨床血液 54:10 acute lymphoblastic leukemia patients already harbor BCR- ABL kinase domain mutations at low levels at the time of diagnosis. Haematologica. 2011; 96: )Leis JF, Stepan DE, Curtin PT, et al. Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI- 571). Leuk Lymphoma. 2004; 45: )Pfeifer H, Wassmann B, Hofmann WK, et al. Risk and prognosis of central nervous system leukemia in patients with Philadelphia chromosome-positive acute leukemias treated with imatinib mesylate. Clin Cancer Res. 2003; 9: )Petzer AL, Gunsilius E, Hayes M, et al. Low concentrations of STI571 in the cerebrospinal fluid:a case report. Br J Haematol. 2002; 117: )Porkka K, Koskenvesa P, Lundán T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008; 112: )Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012; 367: )Kantarjian MH, Kim DW, Pinilla-Ibarz J, et al. Efficacy and Safety of Ponatinib in Patients with Accelerated Phase or Blast Phase Chronic Myeloid Leukemia (AP-CML or BP- CML) or Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph + ALL):12-Month Follow-up of the PACE Trial [abstract]. Blood. 2012; 120:Abstract )Mauro MJ, Cortes JE, Kim DW, et al. Multivariate Analyses of the Clinical and Molecular Parameters Associated with Efficacy and Safety in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph + ALL) Treated with Ponatinib in the PACE Trial [abstract]. Blood. 2012; 120: Abstract )Topp MS, Kufer P, Gökbuget N, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B- lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011; 29: )Topp MS, Gökbuget N, Zugmaier G, et al. Long-term followup of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012; 120: )Topp MS, Gökbuget N, Zugmaier G, et al. Anti-CD19 BiTE Blinatumomab Induces High Complete Remission Rate and Prolongs Overall Survival in Adult Patients with Relapsed/ Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)[abstract]. Blood. 2012; 120:Abstract )Gambacorti-Passerini C, Khoury HJ, Pinczowski H, et al. Clinical activity of bosutinib by mutational status in patients with previously treated Philadelphia chromosome-positive leukemias [abstract]. Blood. 2010; 116: Abstract (1637)