Acute lymphoblastic leukemia Treatment of Philadelphia chromosome positive acute lymphoblastic leukemia

O.G. Ottmann ABSTRACT Patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) are now Department of Internal Medicine, routinely treated front-line with tyrosine kinase inhibitors (TKI), usually combined with chemotherapy, Hematology-Oncology, with unequivocal evidence of clinical benefit. The first-generation TKI imatinib induces hematologic Goethe University, Frankfurt am remissions in nearly all patients, but these are rarely maintained unless patients undergo allogeneic Main, Germany stem cell transplantation (alloSCT), the current gold standard of curative therapy. The more potent sec - ond- and third-generation TKI display greater clinical efficacy based on molecular response data and Correspondence: clinical outcome parameters. It is still uncertain whether they may obviate the need for alloSCT in Oliver G. Ottmann some adult patients who achieve a deep molecular response, whereas this appears to often be the case E-mail: [email protected] in pediatric patients. Which chemotherapy regimen is best suited in combination with the individual TKI in different subsets of patients is being explored in ongoing studies. Molecular analyses to measure MRD levels, detect BCR-ABL kinase domain mutations, or further subclassify patients according to Hematology Education: additional genomic aberrations has become increasingly important in clinical patient management. A the education program for the variety of novel targeted treatment approaches are in clinical development for patients with an unsat - annual congress of the European isfactory response to current therapy. Hematology Association Learning goals 2014;8:15-22 At the conclusion of this activity, participants should: - know about the efficacy of first- and second-generation tyrosine kinase inhibitors (TKI) in terms of inducing hematologic and molecular responses; - understand the role of chemotherapy intensity regarding efficacy and tolerability; - be able to identify the current treatment paradigm as TKI combined with chemotherapy, followed by allogeneic stem cell transplantation (alloSCT); - be able to identify BCR-ABL mutations as a principal cause of treatment failure; - understand the role of minimal residual disease assessment prior to and after SCT and the thera - peutic implications; - have some knowledge of the therapeutic options in relapsed or refractory patients.

Introduction TKI-based treatment regimens on long-term survival of patients with Ph + ALL remains The BCR-ABL translocation in Philadelphia uncertain. This is due primarily to a paucity of chromosome positive (Ph +) acute lymphoblas - large prospective phase III trials, with clinical tic leukemia (ALL) defines a subpopulation research having focused on smaller phase II trials exploring specific treatment modalities among adult ALL that encompasses approxi - + mately 25% of patients and is amenable to within subgroups of Ph ALL patients. This article will review the current state of the art treatment with tyrosine kinase inhibitors (TKI) + that target the oncogenic BCR-ABL protein. and the evolving concepts in therapy for Ph The availability of now three generations of ALL, primarily of adult patients, will highlight ABL-directed TKI has fostered numerous unresolved clinical management issues, and clinical trials exploring different strategies of will look towards future novel therapeutic approaches. TKI-based therapy, and have unequivocally improved patient outcome. Moreover, the importance of molecular diagnostics not only for up-front identification of BCR-ABL posi - Role of tyrosine kinase inhibitors during tivity but for minimal residual disease (MRD)- induction therapy guided treatment decisions during therapy and detection of mutations in case of resistance Extensive data on first-line treatment for Ph + have become universally accepted. As a conse - ALL is available for the first-generation TKI quence, results of treatment for the very high- imatinib, and experience with second-genera - + risk subset of Ph ALL have now surpassed tion (dasatinib, nilotinib) and third-generation those of BCR-ABL negative high-risk ALL in (ponatinib) TKI is growing rapidly. Current the German Multicenter Adult ALL (GMALL) efforts to optimize utilization of these TKI in cooperative group trials. Despite these treatment algorithms for newly diagnosed Ph + achievements, the precise impact of different ALL are focusing on the advantages and limi - Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 15 | 19 th Congress of the European Hematology Association

tations of the different TKIs and the intensity and type of er molecular response. chemotherapy used during induction and consolidation Several studies have investigated dasatinib in combina - cycles. It is widely accepted that TKI should be initiated tion with either low-intensity or aggressive chemotherapy as soon as the diagnosis of Ph + ALL is established, i.e. typ - regimens. The European Working Group for Adult ALL ically after pre-phase therapy. 1 Major conceptual differ - (EWALL) conducted a prospective single-arm phase II ences regarding induction strategies concern the intensity trial in elderly Ph + ALL patients in whom dasatinib was of treatment, which may rely on TKI only in combination combined with mild induction chemotherapy (vincristine, with corticosteroids, 2-4 on their combination with reduced dexamethasone and intrathecal prophylaxis), followed by 18 intensity chemotherapy, e.g. vincristine plus steroids, 5,6 or more intensive consolidation cycles. Median age of combination with intensive multi-agent induction patients was 69 years (58-83 years). Despite this low- chemotherapy. 7-10 intensity approach, the initial protocol was amended to Imatinib further reduce toxicity in patients older than 75 years of age, by decreasing the dasatinib dose from 140 mg once daily (QD) to 100 mg QD, and the dexamethasone dose The use of imatinib during induction has been most from 40 mg to 20 mg. Hospitalization rather than outpa - extensively studied over the past decade, and more than tient treatment was recommended for the early initial 90% of patients can expect to achieve complete remission, treatment phase to prevent or adequately treat tumor lysis irrespective of whether imatinib is given alone or in com - 1,3,9,11-15 and compromised renal function. In this multicenter trial, bination with chemotherapy. Concurrent adminis - the complete remission (CR) rate was 94% and early mor - tration with cytotoxic drugs commonly used for induction tality 5%. Major toxicities included sepsis, hemorrhage (anthracyclines, cytarabine, cyclophosphamide, vin - and renal function impairment. Molecular response rate cristine, 6-mercaptopurine) has proven to be feasible and after induction was approximately 25% and 50% based on reasonably well tolerated, but induction mortality may 3 log and 4.5 log reduction of BCR-ABL transcripts, reach approximately 10% even in younger patients. respectively. Primary hematologic resistance is distinctly uncommon in Dasatinib in conjunction with intensive chemotherapy previously untreated patients, in contrast to the relapse set - 16 according to the hyper-CVAD regimen was similarly ting. One of the primary goals of combining imatinib effective in terms of inducing remissions, with a CR rate only with steroids is the avoidance of induction mortality, of 94% and 6% induction mortality. 19 Septicemia and and this has been evaluated in elderly as well as young hemorrhage were the major toxicities leading to death. patients. The rate of induction deaths is indeed exceeding - SRC inhibition by dasatinib may have contributed to the ly low using such an approach, with studies reporting no 3 higher rate of clinically significant hemorrhagic events induction deaths with imatinib and steroids. The principal due to its effect on platelet function. With short (14 drawback of this approach appears to be an unsatisfactory months) median follow up, estimated 2-year survival was depth of response by MRD analysis based on quantitative 64%. To date, the results of only 2 clinical trials examining RT-PCR measurement of BCR-ABL transcripts. For nilotinib as first-line therapy for Ph + ALL have been example, only 4% molecular remissions after induction reported. 20,21 This paucity of clinical trials is possibly relat - were reported for the GIMEMA LAL0201-B protocol. ed to the poor clinical activity against p-loop mutations Concern that a poor molecular response is associated with that was observed in early phase I and II trials of nilotinib early disease recurrence and a high relapse rate is borne for relapsed or refractory Ph + ALL, and the preponderance out by clinical trials particularly, but not exclusively, in of these mutations in imatinib failure. 22 As front-line treat - elderly Ph + ALL patients who do not undergo allogeneic 2,3,7,17 ment, nilotinib proved effective and tolerable in conjunc - stem cell transplantation (alloSCT). tion with chemotherapy: the CR rate was 90%, with medi - Second-generation tyrosine kinase inhibitors an time to CR of 27 days. 20 Already at the time of CR, 55% of patients had undetectable BCR-ABL transcripts, with The greater potency of second-generation TKI and their further improvement over time, leading to a cumulative activity against a broader spectrum of BCR-ABL kinase complete molecular response rate of 84%. Death in aplasia domain mutations suggested superior efficacy compared (in 8 of 91 patients) was the principal cause of treatment with imatinib-based treatment. Dasatinib has been the failure, and organ toxicity grade 3 or greater was primarily more extensively studied second-generation TKI as front- pancreatic and hepatic, ranging from 2% to 18%, respec - line therapy for Ph + ALL. Complete remission was tively. achieved by 100% of patients receiving dasatinib and cor - In a second trial, nilotinib was alternated with imatinib using a 6-week rotation schedule during front-line treat - ticosteroids in a recently published GIMEMA study, with + no induction deaths. 4 Molecular responses were superior ment of 39 elderly Ph ALL patients over 60 years of age to imatinib monotherapy; the rates of BCR-ABL transcript or unfit for intensive therapy. Disease-free survival was levels below 0.01% after 43 and 85 days were 33% and 51% at 12 months; overall survival (OS) was 64% at two 52%, respectively. As this study encompassed only the years. Among 13 patients who relapsed, median time to first three months of treatment and left subsequent man - relapse was 7.6 months. The T315I and p-loop mutations predominated, suggesting no benefit over imatinib or agement to the discretion of the investigator, the varying 21 regimens used after the study confound the impact on dasatinib alone. long-term outcome. The lowest relapse rates were Third-generation tyrosine kinase inhibitors observed in patients who underwent alloSCT. Overall, the authors identified an MRD threshold of 0.001 as predic - The potent activity of ponatinib against native BCR- tive of relapse-free survival irrespective of subsequent ABL and essentially all clinically relevant TKD muta - treatment, confirming the importance of achieving a deep - tions, including the T315I mutation resistant to all other

| 16 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 clinically approved TKI makes this compound of particu - the longest follow up examining the combination of dasa - lar interest for Ph + ALL, which shows a high prevalence of tinib with age-adapted chemotherapy in elderly Ph + ALL this gatekeeper mutation at the time of clinical resistance patients were reported by the European Working Group to TKI. 23 Preliminary results of a phase II trial employing for Adult ALL (EWALL). 18 Median follow up was 3.3 ponatinib in combination with the Hyper-CVAD regimen years. Three-year survival was estimated as 44.7%, a for treatment of newly diagnosed Ph + ALL showed a 100% result that is in the range of reported survival in younger CR. 24 Seventy percent of patients achieved a complete adults. Relapses were associated with the T315I mutation molecular remission at a median of ten weeks from start of in most cases and a T315I signal by highly sensitive allele- therapy. Major toxicities of grade 3 or more included ele - specific PCR predicted hematologic relapse, independent - vated liver function tests, thrombotic events, myocardial ly of MRD. infarction, and pancreatitis. Dasatinib in combination with hyper-CVAD yielded an estimated 2-year survival of 64%, although median follow up was only 14 months. 19 Long-term results with TKI-based therapy No long-term outcome data for Ph + ALL are available with bosutinib or nilotinib or ponatinib. Imatinib Treatment of Philadelphia chromosome positive Several studies, none of them randomized, have demon - acute lymphoblastic leukemia in children strated improved outcome with the addition of imatinib to previous treatment regimens. Another common theme of most of these studies is the central role of alloSCT in facil - The BCR-ABL positive subtype of ALL is distinctly 7,11,15,25 uncommon in children, occurring in less than 5% of pedi - itating long-term survival, although smaller studies 28 showed no benefit for alloSCT when imatinib was com - atric ALL. While it constitutes a high-risk feature in chil - bined with intensive chemotherapy. 10,26 dren as well, CR rates exceeded 80% and survival was in the range of 40-56% after 3-5 years in the pre-imatinib era, A recently published large, prospective phase III trial 29-31 conducted by the MRC UKALLXII/ECOG2993 com - far superior to results in adults. Addition of imatinib to pared the outcome of adult patients who received imatinib intensive chemotherapy regimens significantly improved these results, particularly when imatinib was given from in addition to induction and/or consolidation chemothera - 32,33 py and those treated in the pre-imatinib era up to 2003. 11 the start of treatment immediately after diagnosis. The CR rate was significantly higher in the imatinib In a prospective, randomized trial involving several cohort than in the pre-imatinib cohort (92% vs. 82%) and national study groups, patients up to 18 years of age with OS at four years was significantly longer in the imatinib the t(9;22)(q34;q11) and good risk as determined by their cohort, 38% vs. 22%, respectively. In the pre-imatinib early treatment response were randomly assigned to cohort, 31% of those starting treatment achieved allogene - receive post-induction imatinib with chemotherapy or ic hematopoietic stem cell transplant (alloHSCT) com - chemotherapy while all poor-risk patients received post- pared with 46% in the imatinib cohort. Overall, addition of induction imatinib with chemotherapy. The “as treated” imatinib to standard therapy improved CR rate and long- analysis showed significantly superior 4-year disease-free term OS for adults with ALL, with a proportion of the OS survival for good-risk patients receiving imatinib com - benefit derived from the fact that imatinib facilitated pared to those who did not receive imatinib (75% vs . 56%; alloHSCT. An advantage of imatinib-based therapy over P=0.06). Four-year event-free survival for poor-risk patients was 53.5% (40.4-65.0%). Tolerability was similar no TKI was likewise demonstrated by the North Italian 34 Study Group (NILG), which evaluated short imatinib in both groups. pulses given in addition to chemotherapy, comparing the Taken together, available data strongly suggests a bene - results with those of a historic control group not receiving ficial effect of adding imatinib to current chemotherapy imatinib. 7 SCT rates were greater in the IM-positive group regimens in pediatric patients. Outcome improved further (alloSCT: 63% vs. 39%), and patients in the IM-group had in studies using dasatinib instead of imatinib, to an extent significantly greater probabilities of OS (38% vs. 23%) that SCT appears unnecessary in the majority of children. and DFS (39% vs. 25%) and a lower incidence of relapse The biological and genetic basis for this superior respon - siveness to TKI (plus chemotherapy) compared to adult at a median observation time of five years. With SCT, 30 post-transplantation mortality (28%) and relapse were the patients remains to be established. major obstacles to further therapeutic improvement. While it is commonly agreed that earlier initiation of imatinib Allogeneic stem cell transplantation therapy is superior to delayed onset imatinib, 1 the role of chemotherapy intensity and possibly type of regimen Allogeneic SCT is the only treatment modality that has remain an issue of ongoing investigation. Although ima - been shown to facilitate long-term disease-free survival in tinib combined with intensive chemotherapy has yielded a substantial proportion of adult patients when used as def - encouraging results in the above as well as several smaller 9,10,26 inite post-remission therapy. Imatinib has had a tremen - phase II trials, recent evidence suggests that deesca - dous impact on the frequency with which SCT can be real - lating chemotherapy, in particular during induction, while ized by inducing remissions in a larger proportion of maintaining a high imatinib dose may yield similar molec - 6,27 patients, and preventing relapse prior to the transplant pro - ular responses and at least comparable survival. cedure. 11 The increasing availability of matched unrelated Second-generation tyrosine kinase inhibitors and alternative donors has contributed to the higher trans - plant frequency, with SCT rates in first CR of 46% to 90% Results from what has so far been the largest study with in newly diagnosed Ph + ALL patients. 6,7,9,11,12,26,27,35,36

Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 17 | 19 th Congress of the European Hematology Association

Moreover, responses are deeper than in the pre-imatinib outcome after SCT, a reduction in BCR-ABL transcript era as determined by molecular MRD analysis. Only one levels of at least 3 log after the first 4-week imatinib ther - retrospective analysis failed to observe a benefit of TKI apy was the most powerful predictor of lower relapse use either prior to or after SCT. 37 Overall, it is likely that (12.1% vs. 45.1%) and better DFS (82.1% vs. 41.7%) rates second-generation TKI may further improve these results, after SCT. 49 In contrast, Rousselot showed in a largely but results of large-scale prospective clinical trials are not non-transplanted elderly population receiving dasatinib yet available. combined with chemotherapy, that the molecular response In several prospective clinical trials using imatinib as during consolidation, but not after induction, was predic - front-line TKI, survival after SCT ranged from 50% to tive of better DFS and OS. 18 MRD at the time of transplant 66% at three years or more. 7,9,11,25,36,38 When considering was a negative predictor for relapse in a study by the pre-transplant treatment regimens, type of donor and stem JALSG. 50 Taken together, these data nevertheless indicate cell source, degree of matching, conditioning regimens, that measurement of MRD in a quantitative manner may immunosuppressive strategy and post-transplant interven - often be a valid surrogate marker for outcome, and that tions, comparability of these trials is limited. BCR-ABL1 transcript levels in particular are able to dis - Myeloablative conditioning regimens based on total body criminate between subsets of Ph + ALL patients with a dif - irradiation (TBI) are currently the most widely used and ferent prognosis. Molecular relapse after alloSCT carries a considered to be the gold standard. With these regimens, high risk of relapse and should prompt intervention. 51 In non-relapse mortality (NRM) after SCT is the principal addition to classical approaches such as rapid tapering of cause of treatment failure and increases with age. In view immunosuppressive therapy and donor lymphocyte infu - of the higher median age of patients with Ph + ALL, and its sions (DLI), TKIs are an easy to use, reasonably safe and increasing frequency in older patients, reduced intensity rapidly effective modality after SCT. 9,37,41,52,53 As shown in conditioning regimens are used particularly in older a recently published randomized trial, prophylactic ima - patients to reduce NRM. In a retrospective EBMT analy - tinib reduced the incidence of molecular relapse after SCT, sis, RIC alloSCT from a human leukocyte antigen-identi - and was as effective in preventing hematologic relapse as cal donor was considered as a potential therapeutic option imatinib administration in response to detection of BCR- for ALL patients aged 45 years or over in complete remis - ABL transcripts. 54 There was no significant difference in sion and not eligible for MAC alloSCT. 39,40 In another long-term outcome between the two treatment groups, study evaluating the outcome of non-myeloablative condi - with probability of remission after five years of 91.6% tioning (fludarabine and 2 Gray total body irradiation) and with prophylactic and 75.5% with MRD-triggered ima - allogeneic transplantation in patients with high-risk ALL, tinib, and survival probability (5 years) of 80.1% and patients with Ph + ALL in first remission who also received 74.5%, respectively. The optimal duration of TKI treat - post-grafting imatinib had 3-year overall survival rate of ment after SCT remains to be resolved, particularly as tol - 62%. For the subgroup without evidence of MRD at trans - erability issues led to premature discontinuation of ima - plantation, OS was 73%. 41 While conclusive assessment of tinib in a significant number of patients. The role of other the efficacy of non-myeloablative SCT regimens is not yet TKI in this setting have not been systematically explored, possible, the latter data indicate that non-myeloablative but efficacy of second- and third-generation TKI in Ph + conditioning and alloHSCT, with post-grafting imatinib ALL relapsed after SCT suggest the potential for use in the for Ph + disease, can result in favorable long-term survival. pre-emptive or prophylactic setting. Patients not receiving prophylactic TKI after alloSCT should be closely moni - tored for evidence of molecular failure, which should then Therapeutic implications of minimal residual dis - prompt initiation of TKI therapy. ease analysis

Data from numerous studies and in various clinical set - Autologous stem cell transplantation tings, some pre-dating the TKI era, demonstrate that the presence of MRD is predictive of outcome in patients with Autologous stem cell transplant (ASCT) was largely Ph + ALL. 2,3,7,9,42-46 While this appears intuitively plausible, abandoned as a strategy for Ph + ALL in the 1990s because attention should be directed to the methodology employed of a lack of efficacy even when using autografts from for quantitation of MRD (e.g. flow cytometry vs. RT- MRD negative patients or after in vitro purging of PCR), the time points assessed, the treatment regimen and leukemic cells. 55-57 Interest in ASCT has been rekindled specific TKI used, the stage of leukemia (front-line vs. sal - following anecdotal reports and experience from small vage), and utilization and type of SCT. It is noteworthy series of patients consistently showing essentially absent that no stringent criteria for MRD analysis and appropriate transplant-associated mortality and remarkably good out - thresholds have yet been defined for Ph + ALL. Thus, come in patients who received an ASCT after achieving a measurements of BCR-ABL transcripts and Ig rearrange - very good molecular response to TKI-based therapy, with ment to assess MRD could conceivably yield different additional post-transplant TKI maintenance. 7,35,58 These results due to differences in sensitivity of the methodolo - studies reported 3- to 5-year DFS of 50-67%. In one gy, lack of BCR-ABL transcription despite presence of the series, 5-year DFS and OS was 47% and 51%, respective - fusion gene at the genomic level, or clonal evolution dur - ly, similar to alloSCT, although the number of patients was ing therapy resulting in loss of the original markers small. 59 In the largest study reported to date, 176 patients defined by Ig reaarangement. 47,48 To date, no systematic treated with ASCT in CR1 were analyzed. 58 The probabil - comparison of these methods has yet been performed. ity of OS at three years increased from 16% for transplants Thus, in a study examining the prognostic relevance of performed between 1996 and 2001 to 57% between 2007 MRD levels determined at an early treatment stage for and 2010. Relapse incidence decreased from 70% to 45%

| 18 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014

(P=0.01), non-relapse mortality was 19% and 3% whom experienced prolonged responses. 70 (P=0.08). In a subgroup of 22 patients actually treated Blinatumomab had profound clinical efficacy in non- with TKIs who were in complete molecular remission at comparative phase II trials, but is not yet approved and can the time of ASCT, the leukemia-free survival (LFS) rate at be given only in the context of clinical trials. 71 Responding three years was 65%. This improvement is most likely patients should be referred for alloSCT if possible, with attributable to the use of TKI both before and after ASCT, special consideration given to the short window of oppor - but data are limited, highlighting the need for prospective tunity. In conclusion, there is a dire need for novel exper - studies to verify the role of ASCT in this patient setting. imental compounds to be explored in clinical trials. With a greater proportion of patients achieving molecular negativity with second-generation TKI in front-line treat - Novel therapies ment regimens, ASCT may become a relevant option in a sizeable number of patients, with the greatest potential for improving therapy in elderly patients ineligible for A host of new and diverse agents have recently entered alloSCT. the pre-clinical or clinical drug development stage. These agents hold considerable promise for ALL in general and Ph + ALL in particular. Numerous oncogenic pathways Treatment of relapse have been implicated in contributing to leukemogenesis or progression of Ph + ALL, including the PI3-kinase, AKT, Relapse remains the single greatest clinical challenge mTOR pathway, B-cell signaling (e.g. SYK and BTK), and has a dismal prognosis. As single agents in patients JAK/STAT pathway, Hedgehog and WNT signaling, + Aurora kinases, apoptosis pathways (survivin, bcl-2) and with Ph ALL with resistance or intolerance to prior TKI, 72 dasatinib and nilotinib induced major hematologic others. The expectations raised by pre-clinical studies response (MHR; CR and no evidence of leukemia) in 42% have translated into sign of clinical efficacy only in few and 45%, respectively. 22,60 With dasatinib, MHR were sus - cases, e.g. with the Aurora kinase inhibitor MK-0457, which induced a CR in one of 3 relapsed Ph + ALL patients tained for at least eight months in 67% of patients, median 73 progression-free survival was 3.3 months. Responses were with a T315I mutation. Therapeutic approaches that are seen in patients with most TKD mutations at baseline, but currently attracting the most attention are antigen-directed not in those with a T315I mutation. Salvage therapy with therapies, novel BCR-ABL inhibitors, inhibitors of pro- nilotinib was associated with median overall survival of survival pathways, and inhibitors of self-renewal. Among 5.2 months and probability of survival of 27% after one the immunotherapeutic approaches, CD22 and even more year. As leukemia recurrence occurs most commonly dur - so CD19 have emerged as the preferred targets due to their ing TKI therapy, the vast majority of cases are associated selectivity for the B-cell lineage and stable expression on the majority of cells throughout B-cell development and in with TKD mutations known to confer a high-level resist - 74,75 ance to TKI. 61-64 The frequency of individual mutations B-cell malignancies. Inotuzumab ozogamicin, a CD22- varies according to the specific TKI being used; for exam - directed monoclonal antibody linked to the cytotoxic calicheamycin, has significant anti-leukemic efficacy in ple, the vast majority of patients relapsing on dasatinib + carry the T315I mutation, whereas p-loop mutations pre - patients with relapsed/refractory ALL including Ph ALL, 40% of whom achieved a CR, which was, however, lower dominate with imatinib or nilotinib treatment. The third- than for Ph-negative cohorts. Median response duration generation TKI ponatinib potently inhibits virtually all and survival were short, but this treatment provided a clinically relevant TKD mutations and showed encourag - 76,77 + bridge to transplant for some patients. Blinatumomab, ing clinical activity in relapsed and refractory Ph ALL in a T cell engaging bispecific single-chain antibody early phase I and II studies. Ponatinib has the advantage of (BiTE®) that engages T cells for redirected lysis of CD19 being the only approved TKI to inhibit the T315I gate - 65 positive target cells, has likewise shown substantial clini - keeper mutation. In the initial phase I and subsequent + + cal activity in R/R ALL including a few patients with Ph phase II trials of ponatinib in heavily pre-treated Ph ALL. Long-term outcome is particularly favorable in patients, most of whom had received at least two tyrosine patients already treated for MRD, rather than overt kinase inhibitors, major hematologic responses among the 71 + relapse. CD19 negative and extramedullary relapses patients with Ph ALL or advanced phase chronic myeloid were the principal causes of treatment failure. Autologous leukemia (CML) were 36% and 41%, and major cytoge - 66-69 T cells expressing a CD19-specific chimeric antigen netic responses 32% and 47%, respectively. Responses receptor (CD19-CAR) have shown intriguing activity were short-lived, however, confirming the notion that pre - against B-cell malignancies including B-cell precursor vention rather than treatment of overt relapse is crucial to ALL, with different constructs having entered early clini - the successful treatment of ALL. Nevertheless, when clin - cal testing. 78-80 ical trials are not available, treatment of relapse still relies primarily on TKIs, which need to be selected based on the type of mutation present. Combination with at least low- Recurrent genomic aberrations in Philadelphia dose chemotherapy, e.g. vincristine, and potent corticos - chromosome positive acute lymphoblastic teroids such as dexamethasone is commonly used, partic - leukemia ularly while awaiting the results of mutation analysis and in anticipation of an additive effect. In case of leukemic Microarray-based genome-wide profiling studies con - involvement of the central nervous system (CNS) at ducted predominantly in pediatric ALL patients have relapse, dasatinib is the only TKI demonstrated to pene - revealed novel submicroscopic genetic lesions in patients trate the blood-brain barrier and have clinical anti- with Ph + ALL. Most of these recurring genomic abnormal - leukemic efficacy in adult and pediatric patients, some of ities involve single genes which are implicated in B-cell

Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 19 | 19 th Congress of the European Hematology Association differentiation, cell survival, or cell-cycle progression, References such as CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1 and EBF1. Deletions of the CDKN2A/B tumor suppressor 1. Wassmann B, Pfeifer H, Goekbuget N, Beelen DW, Beck J, Stelljes M, et al. Alternating versus concurrent schedules of ima - locus and of the IKAROS and PAX5 genes that promote tinib and chemotherapy as front-line therapy for Philadelphia- B-lineage development have received particular attention positive acute lymphoblastic leukemia (Ph+ ALL). Blood. due to their high frequency in BCR-ABL1-positive ALL. 2006;108:1469-77. IKZF1 deletions were observed in more than 80% of pedi - 2. Ottmann OG, Wassmann B, Pfeifer H, Giagounidis A, Stelljes 81 M, Duhrsen U, et al. Imatinib compared with chemotherapy as atric BCR-ABL1 ALL cases, and 63% of adult patients front-line treatment of elderly patients with Philadelphia chro - with Ph + ALL. 82 IKZF1 deletions have been linked to an mosome-positive acute lymphoblastic leukemia (Ph+ALL). 83,84 Cancer. 2007;109:2068-76. inferior outcome in most pediatric ALL studies, as well 3. Vignetti M, Fazi P, Cimino G, Martinelli G, Di Raimondo F, as in 2 studies involving adult and adolescent Ph negative Ferrara F, et al. Imatinib plus steroids induces complete remis - BCP-ALL 85 and adult Ph + ALL, 82 respectively. These find - sions and prolonged survival in elderly Philadelphia chromo - some-positive patients with acute lymphoblastic leukemia with - ings suggest that genetic lesions resulting in the loss of out additional chemotherapy: results of the Gruppo Italiano Ikaros function are an important event, not only in the Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B development of BCR-ABL1 ALL, but may facilitate fur - protocol. Blood. 2007;109:3676-8. 4. Foa R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris M, ther subclassification of the disease with refinement of et al. Dasatinib as first-line treatment for adult patients with prognostic algorithms, provide novel targets for MRD Philadelphia chromosome-positive acute lymphoblastic assessment as well as analysis of the clonal structure of the leukemia. Blood. 2011;118:6521-8. leukemia at diagnosis and relapse, and be useful for 5. Rousselot P, Delannoy A. Optimal pharmacotherapeutic man - 86,87 agement of acute lymphoblastic leukaemia in the elderly. Drugs improving therapeutic strategies. Aging. 2011;28:749-64. 6. Ribera JM, Garcia O, Montesinos P, Brunet S, Abella E, Barrios M, et al. Treatment of young patients with Philadelphia chromo - Conclusions and outlook some-positive acute lymphoblastic leukaemia using increased dose of imatinib and deintensified chemotherapy before allo - geneic stem cell transplantation. Br J Haematol. 2012;159:78-81. The advent of TKI that potently inhibit the BCR-ABL 7. Bassan R, Rossi G, Pogliani EM, Di Bona E, Angelucci E, oncoprotein has dramatically altered the therapeutic land - Cavattoni I, et al. Chemotherapy-phased imatinib pulses + improve long-term outcome of adult patients with Philadelphia scape for Ph ALL and improved treatment results to an chromosome-positive acute lymphoblastic leukemia: Northern extent that Ph + ALL is no longer the subtype of ALL with Italy Leukemia Group protocol 09/00. J Clin Oncol. 2010;28:3644-52. the worst prognosis. Current treatment concepts utilize 8. Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, TKI in combination with chemotherapy regimens that Durrant IJ, et al. Prospective outcome data on 267 unselected vary in intensity depending on patients’ characteristics and adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic trans - on the treatment phase (i.e. induction, consolidation and plantation over chemotherapy in the pre-imatinib era: results maintenance) and alloSCT. Serial molecular analysis of from the International ALL Trial MRC UKALLXII/ECOG2993. MRD, and in case of resistance of BCR-ABL TKD muta - Blood. 2009;113:4489-96. 9. Ribera JM, Oriol A, Gonzalez M, Vidriales B, Brunet S, Esteve tions, provides information that is essential for the rational J, et al. Concurrent intensive chemotherapy and imatinib before clinical management of this disease. Maximizing molecu - and after stem cell transplantation in newly diagnosed lar response during early treatment phases while minimiz - Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica. ing toxicity is designed to minimize the risk of relapse, an 2010;95:87-95. event that still carries a disastrous prognosis. A remark - 10. Thomas DA, Faderl S, Cortes J, O’Brien S, Giles FJ, Kornblau ably large number of novel agents, representing small SM, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. molecules, antibodies and cellular therapeutics with com - Blood. 2004;103:4396-407. pletely different mechanisms of action have recently 11. Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow emerged and entered early stages of clinical testing. These MR, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in agents have the potential to further dramatically improve Philadelphia positive acute lymphoblastic leukemia. Blood. treatment results, and may eventually obviate the need for 2014;123:843-50. allo-SCT as definite curative modality. In view of these 12. Lee KH, Lee JH, Choi SJ, Lee JH, Seol M, Lee YS, et al. Clinical effect of imatinib added to intensive combination chemotherapy evolving novel treatment concepts and the small number for newly diagnosed Philadelphia chromosome-positive acute of patients with this disease, treatment outside of clinical lymphoblastic leukemia. Leukemia. 2005;19:1509-16. trials should be discouraged. Modern molecular genetics 13. Wassmann B, Gokbuget N, Scheuring UJ, Binckebanck A, Reutzel R, Gschaidmeier H, et al. A randomized multicenter methodologies already generate an abundance of data on + open label phase II study to determine the safety and efficacy of genomic aberrations and the clonal architecture of Ph induction therapy with imatinib (Glivec, formerly STI571) in ALL that should prove invaluable for further subclassifi - comparison with standard induction chemotherapy in elderly (>55 years) patients with Philadelphia chromosome-positive cation of the disease, risk stratification, target identifica - (Ph+/BCR-ABL+) acute lymphoblastic leukemia (ALL) tion and understanding of resistance mechanism. (CSTI571ADE 10). Ann Hematol. 2003;82:716-20. Ultimately, this information will translate into improved 14. Yamada M, Miyamura K, Fujiwara T, Yokoyama H, Tomiya Y, Ishizawa K, et al. Imatinib mesylate in conjunction with allo - treatment results only with well-designed, preferably ran - geneic hematopoietic stem cell transplantation in patients with domized, phase II trials conducted on an international Philadelphia chromosome positive leukemias: report of 4 cases. level that will provide robust outcome data. Tohoku J Exp Med. 2004;204:79-84. 15. Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F, et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol. 2006;24:460-6. 16. Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J,

| 20 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014

Silver RT, et al. A phase 2 study of imatinib in patients with leukemia: Children’s Oncology Group Study AALL0031. relapsed or refractory Philadelphia chromosome-positive acute Leukemia. 2014 Jan 20. [Epub ahead of print] lymphoid leukemias. Blood. 2002;100:1965-71. 34. Biondi A, Schrappe M, De Lorenzo P, Castor A, Lucchini G, 17. Delannoy A, Delabesse E, Lheritier V, Castaigne S, Rigal- Gandemer V, et al. Imatinib after induction for treatment of chil - Huguet F, Rafoux E, et al. Imatinib and methylprednisolone dren and adolescents with Philadelphia-chromosome-positive alternated with chemotherapy improve the outcome of elderly acute lymphoblastic leukaemia (EsPhALL): a randomised, open- patients with Philadelphia-positive acute lymphoblastic label, intergroup study. Lancet Oncol. 2012;13:936-45. leukemia: results of the GRAALL AFR09 study. Leukemia. 35. Tanguy-Schmidt A, Rousselot P, Chalandon Y, Cayuela JM, 2006;20:1526-32. Hayette S, Vekemans MC, et al. Long-term follow-up of the ima - 18. Rousselot P, Coude MM, Huguet F. Dasatinib (Sprycel) and low tinib GRAAPH-2003 study in newly diagnosed patients with de intensity chemotherapy for first-line treatment in patients with de novo Philadelphia chromosome-positive acute lymphoblastic novo Philadelphia positive ALL aged 55 years and over: final leukemia: a GRAALL study. Biol Blood Marrow Transplant. results of the EWALL-PH01 study ND [abstract]. Blood. 2013;19:150-5. 2012;120:(Abstract 666). 36. Pfeifer H, Goekbuget N, Volpe G. Long-term outcome of 335 19. Ravandi F, O’Brien S, Thomas D, Faderi S, Jones D, Garris R, adult patients receiving different schedules of imatinib and et al. First report of phase 2 study of dasatinib with hyper-CVAD chemotherapy as front-line treatment for Philadelphia-positive for the frontline treatment of patients with Philadelphia chromo - acute lymphoblastic leukemia (Ph+ ALL) [abstract]. Blood. some-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010;116:(Abstract 173). 2010;116:2070-7. 37. Kebriaei P, Saliba R, Rondon G, Chiattone A, Luthra R, 20. Kim D-Y, Joo YD, Kim SD, Lee JH, Lee J-H, Kim D-H, et al. Anderlini P, et al. Long-term follow-up of allogeneic hematopoi - Nilotinib Combined With Multi-Agent Chemotherapy For Adult etic stem cell transplantation for patients with Philadelphia chro - Patients With Newly Diagnosed Philadelphia Chromosome- mosome-positive acute lymphoblastic leukemia: impact of tyro - Positive Acute Lymphoblastic Leukemia: Final Results Of sine kinase inhibitors on treatment outcomes. Biol Blood Prospective Multicenter Phase 2 Study [abstract]. Blood. Marrow Transplant. 2012;18:584-92. 2013;122(21):55. 38. Lee S, Kim DW, Kim YJ, Chung NG, Ki, YL, Hwang JY, et al. 21. Papayannidis C, Fazi P, Piciocchi A, Di Raimondo F, Pizzolo G, Minimal residual disease-based role of imatinib as a first-line Carella A, et al. Treating Ph+ Acute Lymphoblastic Leukemia interim therapy prior to allogeneic stem cell transplantation in (ALL) in the Elderly: The Sequence of Two Tyrosine Kinase Philadelphia chromosome-positive acute lymphoblastic Inhibitors (TKI) (Nilotinib and Imatinib) Does Not Prevent leukemia. Blood. 2003;102:3068-70. Mutations and Relapse [abstract]. Blood. 2013;102:(Abstract 39. Mohty M, Labopin M, Tabrizzi R, Theorin N, Fauser AA, 2601). Rambaldi A, et al. Reduced intensity conditioning allogeneic 22. Ottmann OG, Larson RA, Kantarjian HM, le Coutre PD, stem cell transplantation for adult patients with acute lym - Baccarani M, Hochhaus A, et al. Phase II study of nilotinib in phoblastic leukemia: a retrospective study from the European patients with relapsed or refractory Philadelphia chromosome— Group for Blood and Marrow Transplantation. Haematologica. positive acute lymphoblastic leukemia. Leukemia. 2008;93:303-6. 2013;27:1411-3. 40. Mohty M, Labopin M, Volin L, Gratwohl A, Socié G, Esteve J, 23. Jones D, Thomas D, Yin CC, O’Brien S, Cortes JE, Jabbout E, et al. Reduced-intensity versus conventional myeloablative con - et al. Kinase domain point mutations in Philadelphia chromo - ditioning allogeneic stem cell transplantation for patients with some-positive acute lymphoblastic leukemia emerge after thera - acute lymphoblastic leukemia: a retrospective study from the py with BCR-ABL kinase inhibitors. Cancer. 2008;113:985-94. European Group for Blood and Marrow Transplantation. Blood. 24. Jabbour E, Kantarijan H, Thomas DA, Ravandi F, Cortes JE, 2010;116:4439-43. Faderl SH, et al. Phase II Study Of Combination Of Hyper- 41. Ram R, Storb R, Sandmaier BM, Maloney DG, Woolfrey A, CVAD With Ponatinib In Front Line Therapy Of Patients (pts) Flowers ME, et al. Non-myeloablative conditioning with allo - With Philadelphia Chromosome (Ph) Positive Acute geneic hematopoietic cell transplantation for the treatment of Lymphoblastic Leukemia (ALL) [abstract]. Blood. high-risk acute lymphoblastic leukemia. Haematologica. 2013;122(21):(Abstract 2663). 2011;96:1113-20. 25. Lee S, Kim YJ, Min CK, Kim HJ, Eom KS, Kim DW, et al. The 42. Dombret H, Gabert J, Boiron JM, Rigal-Huguet F, Blaise D, effect of first-line imatinib interim therapy on the outcome of Thomas X, et al. Outcome of treatment in adults with allogeneic stem cell transplantation in adults with newly diag - Philadelphia chromosome-positive acute lymphoblastic nosed Philadelphia chromosome-positive acute lymphoblastic leukemia—results of the prospective multicenter LALA-94 trial. leukemia. Blood. 2005;105:3449-57. Blood. 2002;100:2357-66. 26. Thyagu S, Minden MD, Gupta V, Yee KW, Schimmer AD, 43. Mitterbauer G, Fodinger M, Scherrer R, Knobi P, Jager U, Schuh AC, et al. Treatment of Philadelphia chromosome-posi - Laczika K, et al. PCR-monitoring of minimal residual leukaemia tive acute lymphoblastic leukaemia with imatinib combined with after conventional chemotherapy and bone marrow transplanta - a paediatric-based protocol. Br J Haematol. 2012;158:506-14. tion in BCR-ABL-positive acute lymphoblastic leukaemia. Br J 27. Chalandon Y, Thomas X, Hayette S. Is less chemotherapy detri - Haematol. 1995;89:937-41. mental in adults with Philadelphia (Ph9 chromosome-positive 44. Pane F, Cimino G, Izzo B, Camera A, Vitale A, Quintarelli C, et acute lymphoblastic leukemia treated with high-dose imatinib? al. Significant reduction of the hybrid BCR/ABL transcripts after Resuts of the prospective randomized GRAAPH-2005 study. induction and consolidation therapy is a powerful predictor of [abstract]. Blood. 2012;120:(Abstract). treatment response in adult Philadelphia-positive acute lym - 28. Pui CH, Sandlund JT, Pei D, et al. Improved outcome for chil - phoblastic leukemia. Leukemia. 2005;19:628-35. dren with acute lymphoblastic leukemia: results of Total Therapy 45. Lee S, Kim DW, Cho BS, Yoon JH, Shin SH, Yahng SA, et al. Study XIIIB at St Jude Children’s Research Hospital. Blood. Impact of minimal residual disease kinetics during imatinib- 2004;104:2690-6. based treatment on transplantation outcome in Philadelphia chro - 29. Arico M, Schrappe M, Hunger SP, Carroll WL, Conter V, mosome-positive acute lymphoblastic leukemia. Leukemia. Galimberti S, et al. Clinical outcome of children with newly 2012;26:2367-74. diagnosed Philadelphia chromosome-positive acute lymphoblas - 46. Ravandi F, Jorgensen JL, Thomas DA, O’Brien S, Garris R, tic leukemia treated between 1995 and 2005. J Clin Oncol. Faderi S, et al. Detection of MRD may predict the outcome of 2010;28:4755-61. patients with Philadelphia chromosome-positive ALL treated 30. Hunger SP. Development and Refinement of Augmented with tyrosine kinase inhibitors plus chemotherapy. Blood. Treatment Regimens for Pediatric High-Risk Acute 2013;122:1214-21. Lymphoblastic Leukemia. Am Soc Clin Oncol Educ Book. 47. Szczepanski T, Willemse MJ, Brinkhof B, van Wering ER, van 2012;32:611-5. der Burg M, van Dongen JJ, et al. Comparative analysis of Ig and 31. Hunger SP. Tyrosine kinase inhibitor use in pediatric TCR gene rearrangements at diagnosis and at relapse of child - Philadelphia chromosome-positive acute lymphoblastic anemia. hood precursor-B-ALL provides improved strategies for selec - Hematology. Am Soc Clin Oncol Educ Book. 2011;2011:361-5. tion of stable PCR targets for monitoring of minimal residual dis - 32. Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, ease. Blood. 2002;99:2315-23. Devidas M, et al. Improved early event-free survival with ima - 48. Rosenquist R, Thunberg U, Li AH, Forestier E, Lonnerholm G, tinib in Philadelphia chromosome-positive acute lymphoblastic Lindh J, et al. Clonal evolution as judged by immunoglobulin leukemia: a children’s oncology group study. J Clin Oncol. heavy chain gene rearrangements in relapsing precursor-B acute 2009;27:5175-81. lymphoblastic leukemia. Eur J Haematol. 1999;63:171-9. 33. Schultz KR, Carroll A, Heerema NA, Bowman WP, Aledo A, 49. Lee S, Kim YJ, Chung NG, Lim J, Lee DG, Kim HJ, et al. The Slayton WB, et al. Long-term follow-up of imatinib in pediatric extent of minimal residual disease reduction after the first 4- Philadelphia chromosome-positive acute lymphoblastic week imatinib therapy determines outcome of allogeneic stem

Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 21 | 19 th Congress of the European Hematology Association

cell transplantation in adults with Philadelphia chromosome- 66. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, positive acute lymphoblastic leukemia. Cancer. 2009;115:561- Chuah C, et al. A phase 2 trial of ponatinib in Philadelphia chro - 70. mosome-positive leukemias. N Engl J Med. 2013;369:1783-96. 50. Mizuta S, Matsuo K, Maeda T, Yujiri T, Hatta Y, Kimura Y, et al. 67. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, Prognostic factors influencing clinical outcome of allogeneic et al. Ponatinib in refractory Philadelphia chromosome-positive hematopoietic stem cell transplantation following imatinib- leukemias. N Engl J Med. 2012;367:2075-88. based therapy in BCR-ABL-positive ALL. Blood Cancer J. 68. Narayanan V, Pollyea DA, Gutman JA, Jimeno A. Ponatinib for 2012;2:e72. the treatment of chronic myeloid leukemia and Philadelphia 51. Spinelli O, Peruta B, Tosi M, Guerini V, Salvi A, Zanotti MC, et chromosome-positive acute lymphoblastic leukemia. Drugs al. Clearance of minimal residual disease after allogeneic stem Today (Barc). 2013;49(4):261-9. cell transplantation and the prediction of the clinical outcome of 69. Shamroe CL, Comeau JM. Ponatinib: A new tyrosine kinase adult patients with high-risk acute lymphoblastic leukemia. inhibitor for the treatment of chronic myeloid leukemia and Haematologica. 2007;92:612-8. Philadelphia chromosome-positive acute lymphoblastic 52. Carpenter PA, Snyder DS, Flowers ME, Sanders JE, Gooley TA, Martin PJ, et al. Prophylactic administration of imatinib after leukemia. Ann Pharmacother. 2013;47:1540-6. hematopoietic cell transplantation for high-risk Philadelphia 70. Porkka K, Koskenvesa P, Lundan T, Rimpilainen J, Mustjoki S, chromosome-positive leukemia. Blood. 2007;109:2791-3. Smykla R, et al. Dasatinib crosses the blood-brain barrier and is 53. Wassmann B, Pfeifer H, Stadler M, Bornhauser M, Bug G, an efficient therapy for central nervous system Philadelphia Sceuring UJ, et al. Early molecular response to posttransplanta - chromosome-positive leukemia. Blood. 2008;112:1005-12. tion imatinib determines outcome in MRD+ Philadelphia-posi - 71. Topp MS, Gokbuget N, Zugmaier G, Degenhard E, Goebeler tive acute lymphoblastic leukemia (Ph+ ALL). Blood. ME, Klinger M, et al. Long-term follow-up of hematologic 2005;106:458-63. relapse-free survival in a phase 2 study of blinatumomab in 54. Pfeifer H, Wassmann B, Bethge W, Dengler J, Bornhauser M, patients with MRD in B-lineage ALL. Blood. 2012;120:5185-7. Stadler M, et al. Randomized comparison of prophylactic and 72. Bhojwani D, Pui CH. Intrathecal liposomal cytarabine: more minimal residual disease-triggered imatinib after allogeneic stem friend than foe? Leuk. Lymphoma. 2008;49:1427-30. cell transplantation for BCR-ABL1-positive acute lymphoblastic 73. Giles FJ, Swords RT, Nagler A, Hochhaus A, Ottmann OG, leukemia. Leukemia. 2013;27:1254-62. Rizzieri DA, et al. MK-0457, an Aurora kinase and BCR-ABL 55. Carella AM, Frassoni F, Pollicardo N, Pungolino E, Ferrero R, inhibitor, is active in patients with BCR-ABL T315I leukemia. Vasallo F, et al. Philadelphia-chromosome-negative peripheral Leukemia. 2013;27:113-7. blood stem cells can be mobilized in the early phase of recovery 74. Hoelzer D. Novel antibody-based therapies for acute lym - after a myelosuppressive chemotherapy in Philadelphia-chromo - phoblastic leukemia. Hematology. Am Soc Hematol Educ some-positive acute lymphoblastic leukaemia. Br J Haematol. Program. 2011;2011:243-9. 1995;89:535-8. 75. Kantarjian H. Monoclonal antibodies in adult acute lymphoblas - 56. Atta J, Martin H, Bruecher J, Elsner S, Wassmann B, Rode C, et tic leukemia. Hematology. 2012;17(Suppl 1):S52-S54. al. Residual leukemia and immunomagnetic bead purging in 76. Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, patients with BCR-ABL-positive acute lymphoblastic leukemia. Rytting M, et al. Inotuzumab ozogamicin, an anti-CD22- Bone Marrow Transplant. 1996;18:541-8. calecheamicin conjugate, for refractory and relapsed acute lym - 57. Martin H, Atta J, Zumpe P, Eder M, Elsner S, Rode C, et al. phocytic leukaemia: a phase 2 study. Lancet Oncol. Purging of peripheral blood stem cells yields BCR-ABL-nega - 2012;13:403-11. tive autografts in patients with BCR-ABL-positive acute lym - 77. Kantarjian H, Thomas D, Jorgensen J, Kebriaei P, Jabbour E, phoblastic leukemia. Exp Hematol. 1995;23:1612-8. Rytting M, et al. Results of inotuzumab ozogamicin, a CD22 58. Giebel S, Labopin M, Gorin NC, Caillot D, Leguay T, Schaap N, et al. Improving results of autologous stem cell transplantation monoclonal antibody, in refractory and relapsed acute lympho - for Philadelphia-positive acute lymphoblastic leukaemia in the cytic leukemia. Cancer. 2013;119:2728-36. era of tyrosine kinase inhibitors: A report from the Acute 78. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Leukaemia Working Party of the European Group for Blood and et al. CD19-targeted T cells rapidly induce molecular remissions Marrow Transplantation. Eur J Cancer. 2014;50:411-7. in adults with chemotherapy-refractory acute lymphoblastic 59. Wetzler M, Watson D, Stock W, Koval G, Mulkey FA, Hoke EE, leukemia. Sci Transl Med. 2013;5(177):177ra38. et al. Autologous transplantation for Philadelphia chromosome- 79. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et positive acute lymphoblastic leukemia achieves outcomes simi - al. Efficacy and Toxicity Management of 19-28z CAR T Cell lar to allogeneic transplantation: results of CALGB Study 10001 Therapy in B Cell Acute Lymphoblastic Leukemia. Sci Transl (Alliance). Haematologica. 2014;99:111-5. Med. 2014;6:224ra25. 60. Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, 80. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold Larson RA, et al. Dasatinib induces rapid hematologic and cyto - SR, et al. Chimeric antigen receptor-modified T cells for acute genetic responses in adult patients with Philadelphia chromo - lymphoid leukemia. N Engl J Med. 2013;368:1509-18. some positive acute lymphoblastic leukemia with resistance or 81. Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma intolerance to imatinib: interim results of a phase 2 study. Blood. J, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by 2007;110:2309-15. the deletion of Ikaros. Nature. 2008;453:110-4. 61. Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg J, 82. Martinelli G, Iacobucci I, Storlazzi CT, Vignetti M, Paoloni F, Binckebanck A, et al. Kinase domain mutations of BCR-ABL Cilloni D, et al. IKZF1 (Ikaros) deletions in BCR-ABL1-positive frequently precede imatinib-based therapy and give rise to acute lymphoblastic leukemia are associated with short disease- relapse in patients with de novo Philadelphia-positive acute lym - free survival and high rate of cumulative incidence of relapse: a phoblastic leukemia (Ph+ ALL). Blood. 2007;110:727-34. GIMEMA AL WP report. J Clin Oncol. 2009;27:5202-7. 62. Pfeifer H, Lange T, Wystub S, Wassmann B, Maier J, 83. Volejnikova J, Mejstrikova E, Dorge P, Meissner B, Binckebanck A, et al. Prevalence and dynamics of bcr-abl kinase Zimmermannova O, Svohgr K, et al. Ikaros (IKZF1) alterations domain mutations during imatinib treatment differ in patients and minimal residual disease at day 15 assessed by flow cytom - with newly diagnosed and recurrent bcr-abl positive acute lym - etry predict prognosis of childhood BCR/ABL-negative acute phoblastic leukemia. Leukemia. 2012;26:1475-81. lymphoblastic leukemia. Pediatr Blood Cancer. 2013;60: 420-7. 63. Soverini S, De Benedittis C, Papayannidis C, Paolini S, Venturi C, Iacobucci I, et al. Drug resistance and BCR-ABL kinase 84. Mullighan CG, Williams RT, Downing JR, Sherr CJ. Failure of domain mutations in philadelphia chromosome-positive acute CDKN2A/B (INK4A/B-ARF)-mediated tumor suppression and lymphoblastic leukemia from the imatinib to the second-genera - resistance to targeted therapy in acute lymphoblastic leukemia tion tyrosine kinase inhibitor era: The main changes are in the induced by BCR-ABL. Genes Dev. 2008;22:1411-5. type of mutations, but not in the frequency of mutation involve - 85. Moorman AV, Schwab C, Ensor HM, Russell LJ, Morrison H, ment. Cancer. 2014;120:1002-9. Jones L, Masic D, et al. IGH@ translocations, CRLF2 deregula - 64. Soverini S, De Benedittis C, Machova PK, Polakova K, tion, and microdeletions in adolescents and adults with acute Brouckova A, Horner D, et al. Unraveling the complexity of lymphoblastic leukemia. J Clin Oncol. 2012;30:3100-8. tyrosine kinase inhibitor-resistant populations by ultra-deep 86. Hunger SP, Raetz EA, Loh ML, Mullighan CG. Improving out - sequencing of the BCR-ABL kinase domain. Blood. comes for high-risk ALL: translating new discoveries into clini - 2013;122:1634-48. cal care. Pediatr Blood Cancer. 2011;56:984-93. 65. Redaelli S, Mologni L, Rostagno R, Piazza R, Magistroni V, 87. Yang JJ, Bhojwani D, Yang W, Cai X, Stocco G, Crews K, et al. Ceccon M, et al. Three novel patient-derived BCR/ABL mutants Genome-wide copy number profiling reveals molecular evolu - show different sensitivity to second and third generation tyrosine tion from diagnosis to relapse in childhood acute lymphoblastic kinase inhibitors. Am J Hematol. 2012;87:E125-E128. leukemia. Blood. 2008;112:4178-83.

| 22 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1)