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Philadelphia-Positive Acute Lymphoblastic Leukemia—Is Bone Marrow Transplant Still Necessary?

2010; Elsevier BV; Volume: 17; Issue: 1 Linguagem: Inglês

10.1016/j.bbmt.2010.11.023

1523-6536

Adele K. Fielding,

Eosinophilic Disorders and Syndromes

IntroductionAcute lymphoblastic leukemia (ALL) in which the chromosome translocation t(9;22)—known as the Philadelphia (Ph) chromosome—is detected has been associated with a considerably lower rate of complete remission (CR) and a lower long-term overall survival (OS) than in Philadelphia negative disease. Ph+ ALL accounts for approximately one-quarter of all adult ALL [1Mullighan C.G. Miller C.B. Radtke I. et al.BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros.Nature. 2008; 453: 110-114Crossref PubMed Scopus (799) Google Scholar] but only about 2% of ALL in children [2Jones L.K. Saha V. Philadelphia positive acute lymphoblastic leukaemia of childhood.Br J Haematol. 2005; 130: 489-500Crossref PubMed Scopus (52) Google Scholar]. Clinical trials have typically assigned patients with this form of ALL to "very high-risk" treatment arms and outside of a clinical trial, most physicians would recommend myeloablative hematopoietic stem cell transplant (HSCT) for adult patients in CR where a matched sibling or unrelated donor is available. However, with the advent of tyrosine kinase inhibitors, there is the possibility to target therapy more precisely by inhibiting the function of the oncogenic protein products of one or more of the genetic lesions involved in this disease using tyrosine kinase inhibitors. Numerous studies have now reported on the use of the selective tyrosine kinase inhibitor (TKI) imatinib in de novo Ph+ ALL. Some studies are also beginning to report outcomes of using dasatinib, a TKI that also inhibits Src kinase activity. In children, where the outcome of treatment for ALL is much better than that in adults in addition, the long-term consequences of allogeneic HSCT have a greater impact. Hence, there is already increasing reluctance to offer allogeneic HSCT to children in the "TKI era," but do the data fully substantiate this approach? In this article I will interrogate published evidence to address the question of whether in the "TKI era" allogeneic HSCT is still a necessary component of therapy for patients with Ph+ ALL.A Historic Perspective: Benefits of Myeloablative Allogeneic Stem Cell Transplant in Ph+ ALL in the "Pretyrosine Kinase Inhibitor" EraAll studies reporting outcomes of myeloablative sibling allogeneic HSCT in adults with ALL published to date conclude that, in selected individuals with the disease, disease-free survival (DFS) and OS are better than would be expected had patients been treated with chemotherapy alone [3Dombret H. Gabert J. Boiron J.M. 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: 2357-2366Crossref PubMed Scopus (287) Google Scholar, 4Forman S.J. O'Donnell M.R. Nademanee A.P. et al.Bone marrow transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.Blood. 1987; 70: 587-588PubMed Google Scholar, 5Chao N.J. Blume K.G. Forman S.J. Snyder D.S. Long-term follow-up of allogeneic bone marrow recipients for Philadelphia chromosome-positive acute lymphoblastic leukemia.Blood. 1995; 85: 3353-3354PubMed Google Scholar, 6Barrett A.J. Horowitz M.M. Ash R.C. et al.Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia.Blood. 1992; 79: 3067-3070PubMed Google Scholar, 7Snyder D.S. Nademanee A.P. O'Donnell M.R. et al.Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission.Leukemia. 1999; 13: 2053-2058Crossref PubMed Scopus (92) Google Scholar]. However, many of them were nonrandomized "transplant-only" studies reporting only outcomes on series of patients who underwent the procedure—none of them included a control group that did not receive a transplant. Stronger support for the overall benefit of sibling alloHSCT in unselected patients with Ph+ ALL comes from the two largest studies conducted in this disease. The LALA-94 trial [3Dombret H. Gabert J. Boiron J.M. 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: 2357-2366Crossref PubMed Scopus (287) Google Scholar] prospectively studied 154 patients with Ph+ ALL and showed that among 103 patients eligible for HSCT, the existence of a sibling allogeneic donor was independently predictive of remission duration. The UKALL12/E2993 study [8Fielding A. Rowe J. Richards S. 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: 4489-4496Crossref PubMed Scopus (219) Google Scholar] examined an outcome of 267 patients with Ph+ ALL in the preimatinib era. An unrelated donor was permissible if no sibling donor was available. An analysis of treatment received showed that patients who received myeloablative sibling allogeneic HSCT had a much better outcome than those receiving chemotherapy alone—the same was true for those receiving unrelated donor HSCT. However, the overall rate of stem cell transplantation was relatively low—fewer than 28% of the study population were able to reach allogeneic HSCT. The main reason for this was older age or disease resistance or relapse.In high-risk ALL, matched unrelated donors (MUD) have long been used as sources of stem cells when sibling donors are unavailable, and there is evidence that a well-MUD HSCT is commensurate with that of a sibling HSCT. In a single-center study of 84 patients with high-risk ALL (not all of which were Ph+), where a considerable proportion were beyond CR1, the outcome for patients who received a TBI-based conditioning regimen, did not differ significantly between sibling and unrelated donor stem cells. However, the median age of patients was only 23 years and the population included children [9Dahlke J. Kroger N. Zabelina T. et al.Comparable results in patients with acute lymphoblastic leukemia after related and unrelated stem cell transplantation.Bone Marrow Transplant. 2006; 37: 155-163Crossref PubMed Scopus (60) Google Scholar]. A larger study including 72 patients with Ph+ disease and an older median age [10Kiehl M.G. Kraut L. Schwerdtfeger R. et al.Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: no difference in related compared with unrelated transplant in first complete remission.J Clin Oncol. 2004; 22: 2816-2825Crossref PubMed Scopus (177) Google Scholar] also showed equivalent (equally high) treatment-related mortality (TRM) between matched sibling (43%) and unrelated donor HSCT (50%). Again, patients beyond CR1 were included—an obvious adverse influence on treatment morbidity and mortality. Another retrospective study of patients with poor risk ALL, 97 of whom were Ph+, a very high TRM of 54%was reported but balanced against a 6% relapse among patients transplanted in CR1, there was a relatively respectable 37% DFS. This compared favorably with DFS after treatment with chemotherapy alone and was equivalent to outcomes recorded following HLA-identical sibling transplantation [11Cornelissen J.J. Carston M. Kollman C. et al.Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome.Blood. 2001; 97: 1572-1577Crossref PubMed Scopus (204) Google Scholar].In childhood ALL, t(9,22) remains an indication for HSCT. However, due to the rarity of the disease studies have been hard to carry out. A German (BFM) and Italian (AIEOP) study of 61 children confirmed the superiority of sibling alloHSCT over chemotherapy alone with a good early response to steroid being crucially predictive of outcome [12Schrappe M. Aricò M. Harbott J. et al.Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome.Blood. 1998; 92: 2730-2741PubMed Google Scholar]. In a large, international cooperative study of 326 children involving 10 study groups or large single institutions, the difference in outcome between sibling HSCT—where almost three-quarters of patients were long-term disease-free survivors, and chemotherapy where only one-quarter of patients survived long term—was further evidence in favor of sibling allogeneic HSCT in children [13Arico M. Valsecchi M.G. Camitta B. et al.Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia.N Engl J Med. 2000; 342: 998-1006Crossref PubMed Scopus (477) Google Scholar]. However, in that study, the evidence supporting unrelated donor transplants in children with Ph+ ALL was less persuasive. A 43% TRM, although comparable to that seen in adult studies at the time, did not result in a survival advantage to MUD HSCT because of the better outcome with chemotherapy alone in children compared to adults. It is worth noting that among the survivors of MUD HSCT, the relapse rate was very low, at 19%. As a result of these data there is a reluctance to expose children to the morbidity and mortality of an unrelated donor HSCT.Taken together, the weight of evidence in the pre-TKI era has been interpreted in favor of myeloablative HSCT using either a sibling or unrelated donor in CR1 in adults with Ph+ ALL and in favor of sibling myeloablative HSCT in children in CR1 with Ph+ ALL.Nonmyeloablative Transplant in Ph+ ALLNo prospective studies of transplant using reduced-intensity conditioning (RIC) have been reported to date. Hence, published reports are subject to considerable bias as described below. To compound difficulty in interpretation of the data, most series include patients beyond CR1. The EBMT reported 97 patients who received a variety of different RIC regimens, many of which were delivered in conjunction with some form of T cell depletion [14Mohty M. Labopin M. Tabrizzi R. et al.Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation.Haematologica. 2008; 93: 303-306Crossref PubMed Scopus (79) Google Scholar]. A 2-year OS of 52% for those transplanted in CR1 was reported. A German multicenter study examined the outcome of a very mixed group of 22 patients with high-risk ALL receiving nonmyeloablative allogeneic HSCT [15Arnold R. Massenkeil G. Bornhauser M. et al.Nonmyeloablative stem cell transplantation in adults with high-risk ALL may be effective in early but not in advanced disease.Leukemia. 2002; 16: 2423-2428Crossref PubMed Scopus (84) Google Scholar], 11 of whom had Ph+ disease. Half were beyond CR1. Few patients survived long term and mortality was high, but for many, this was a second HSCT after relapse making a good outcome very unlikely. Another retrospective study included 27 patients from 4 different studies who had undergone nonmyeloablative allogeneic HSCT [16Martino R. Giralt S. Caballero M.D. et al.Allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning in acute lymphoblastic leukemia: a feasibility study.Haematologica. 2003; 88: 555-560PubMed Google Scholar]. More than 80% of the patients whose median age was 50 years were beyond CR1. Two year OS was 31%. TRM was relatively modest (23%) for such a high-risk population. A City of Hope series [17Stein A. O'Donnell M. Snyder D.S. et al.Reduced-Intensity Stem Cell Tansplantation for high-risk acute lymphoblastic leukaemia.Biol Blood Marrow Transplant. 2007; 13: 134Abstract Full Text Full Text PDF Google Scholar] reported on 24 adult patients with high-risk ALL treated with fludarabine and melphalan conditioning without T cell depletion. Nearly half of the patients were over 50 years of age. There was a 2-year OS and DFS of 61.5% with a TRM of 21.5%. Bachanova and colleagues [18Bachanova V. Verneris M.R. DeFor T. Brunstein C.G. Weisdorf D.J. Prolonged survival in adults with acute lymphoblastic leukemia after reduced-intensity conditioning with cord blood or sibling donor transplantation.Blood. 2009; 113: 2902-2905Crossref PubMed Scopus (84) Google Scholar] reported a 3-year OS of 50% among 22 patients with a median age of 49 years, all with high-risk ALL. Patients received a uniform reduced-intensity approach of fludarabine, cyclophosphamide, and low-dose total-body irridiation (TBI) in the University of Minnesota Transplant Program. Nonmyeloablative allogeneic HSCT approaches are promising but require careful prospective studies to define their role in Ph + ALL. The forthcoming study from the UK National Cancer Research Institute Group, UKALL14 will assign all patients with ALL aged 40 or over to a nonmyeloablative approach with fludarabine, melphalan, and alemtuzumab in an attempt to reduce the very high incidence of graft-versus-host disease (GVHD) (86%) that occurred in the City of Hope where fludarabine and melphalan was used without T cell depletion.Difficulties in Evaluation of the Role of HSCT in Ph+ ALLBefore considering the impact of TKIs on the role and outcome of HSCT in Ph+ ALL, it is worth pausing to note the problems with interpreting the evidence regarding of the role of myeloablative HSCT in this disease.Equipoise in trial design has forestalled trials including a randomization of allograft versus chemotherapy. Hence, the most straightforward method of obtaining a relatively unbiased, prospective view of the contribution of HSCT to outcome has been the so-called "biologic randomization." An intention-to-treat analysis based on the availability or otherwise of a matched sibling donor—assumed to be a random occurrence—can control for the main sources of bias in analyzing transplant outcomes as long as the analysis is confined to patients who were all tissue typed prospectively at the time point of having an apparent equal chance to have a transplant in the future, with sibling donor availability being taken as the only deciding factor. However, the increasing availability of alternative donors means that a great many of those without a sibling donor can nonetheless receive an allograft. This means that very careful analysis and scrutiny of data are required to make a firm conclusion about the benefits of myeloablative allogeneic HSCT. The 2 main problems to be aware of are selection bias and immortal time bias.In retrospective studies, a strong selection bias is often at work. This is a particular problem for retrospective "transplant-only" studies, which report on the outcome of patients who have already received HSCT. Patients considered by their physicians to be unsuitable candidates by virtue of advancing age, poor performance status, or lack of desire to undergo the procedure will simply not be referred for this therapy, and their outcome is not taken into account in such studies.In prospective studies, there is an additional problem in interpreting data resulting from "survivor treatment selection bias," also known as "immortal time bias." In essence, a patient with Ph+ ALL on a prospective study who receives a transplant is guaranteed to have achieved—and have remained in—CR between presentation and to have survived induction and subsequent therapy, resulting in a period of "immortal time." Clearly, a patient who has died either of disease or treatment-related causes within the immortal time window could not have received a transplant, resulting in an immortal time bias. This bias is very strong in studies of Ph+ ALL because of the lower rates of CR than in Ph− ALL, the tendency for short remission duration, and the toxicity of initial therapy.Data can be analyzed with a view to attempt to control for an immortal time bias which means, pragmatically, when comparing the outcome of chemotherapy alone with the outcome of transplant in Ph+ ALL it is necessary to eliminate from the analyses all chemotherapy-treated subjects who did not have an equal chance of reaching HSCT, for example, those who are beyond the upper age limit, unfit because of comorbid conditions, or who have relapsed before transplant. A good example of how the potential benefits of HSCT to a population of patients presenting with Ph+ ALL can be overestimated by a simple analysis of treatment received is provided by the UKALL12/ECOG 2993 trial [8Fielding A. Rowe J. Richards S. 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: 4489-4496Crossref PubMed Scopus (219) Google Scholar]. Analysis by treatment received showed that those who received sibling or MUD HSCT had a much better 5-year OS (44% and 36%) than those receiving chemotherapy whose survival was only 19% at 5 years. These differences—and differences in event-free survival (EFS) and relapse-free survival (RFS)—were highly statistically significant. However, when the analysis was repeated adjusting for age, gender, and presenting white blood cell count (WBC) and chemotherapy-treated patients who relapsed or died before the median time to transplant were excluded, only relapse free survival remained significantly superior in the transplanted group.Do the Benefits of Tyrosine Kinase Inhibitors in Ph+ ALL Render Allogeneic Transplant Obsolete?Having reviewed the data on bone marrow transplantation in the "pre-imatinib" era, we can conclude that, in patients who achieve remission, are sufficiently fit, young, and have a donor, transplant appears to be the optimal postremission therapy. Therefore, important questions regarding TKI, by far the most studied of which is imatinib, are1.Is there a higher rate of complete remission without additional toxicity when TKI are added to therapy?2.Do more patients receive HSCT when TKI is added to therapy?3.Is there a survival advantage to receiving TKI?4.Does this survival advantage occur in the absence of HSCT?Questions 1 and 2 have been adequately answered by numerous large studies represented in Table 1. To summarize the data from studies in Table 1, rates of complete remission are considerably higher than seen in Ph+ ALL in the past and now easily reach and often exceed those attained in Ph− ALL because TKI can result in CR with minimal induction mortality. Consequently, transplant rates appear much higher than in preimatinib studies.Table 1Studies of Imatinib in Ph+ ALLAuthor/YearStudy GroupNCR (%)Transplant Rate (%)Overall SurvivalPublished studies Thomas et al., 2004 24Thomas D.A. Faderl S. Cortes J. et al.Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate.Blood. 2004; 103: 4396-4407Crossref PubMed Scopus (456) Google ScholarMD Anderson20935075% at 20 months Yanada et al., 2006 25Yanada M. Sugiura I. Takeuchi J. et al.Prospective monitoring of BCR-ABL1transcript levels in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia undergoing imatinib-combined chemotherapy.Br J Haematol. 2008; : 8Google ScholarJapanese Adult Leukemia Study Group80966175% at I year Wassmann et al., 2006 26Wassmann 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: 1469-1477Crossref PubMed Scopus (263) Google ScholarGerman Multicenter ALL group92957736% (alternating schedule) 43% (concurrent schedule at 2 years De Labarathe et al., 2007 27de Labarthe A. Rousselot P. Huguet-Rigal F. et al.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: 1408-1413Crossref PubMed Scopus (271) Google ScholarGRAALL45964865% at 18 months Vignetti et al., 2007 22Vignetti 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: 3676-3678Crossref PubMed Scopus (279) Google ScholarGIMEMA30100N/A74% at 12 months Ottman et al., 2007 25Yanada M. Sugiura I. Takeuchi J. et al.Prospective monitoring of BCR-ABL1transcript levels in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia undergoing imatinib-combined chemotherapy.Br J Haematol. 2008; : 8Google ScholarGMALL5596 (imatinib)50 (chemo)N/A42% at 24 months Ribera et al., 2009 28Ribera JM, Oriol A, Gonzalez 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. 95:87-95.Google ScholarPETHEMA30907030% at 4 years Bassan et al., 2010 17Stein A. O'Donnell M. Snyder D.S. et al.Reduced-Intensity Stem Cell Tansplantation for high-risk acute lymphoblastic leukaemia.Biol Blood Marrow Transplant. 2007; 13: 134Abstract Full Text Full Text PDF Google ScholarNorthern Italian Leukemia Group59926338% at 5 years Schultz et al., 2009 20Schultz K. Bowman W. Aledo A. et al.Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a Children's Oncology Group Study.J Clin Oncol. 2009; : 8PubMed Google ScholarChildren's Oncology Group92Not statedN/A80% (EFS) at 3 years Fielding et al., 2010 21Fielding AK, Buck, G, Lazarus HM, et al. Imatinib significantly enhances long term outcomes in Philadelphia positive ALL, Final results of the UKALLXII.ECOG2993 Trial. Abstract.Google ScholarUK National Cancer Research Institute, Eastern Co-operative Oncology Group145954443% at 3 years Chalandon et al., 29Chalandon Y TX, Hayette S, et al. First results of the GRAAPH-2005 study in younger adult patients with de novo Philadelphia positive acute lymphoblastic leukemia. Blood. 112:Abstract 12.Google ScholarGRAALL188100 (imatinib DIV)96 (imatinib hyper-CVAD)6262% at 2 yearsEFS indicates event-free survival; CVAD, central venous access device. Open table in a new tab The third question, whether there is a survival benefit to TKI therapy, is slightly harder to answer from current published data, because many of the studies report results with short follow-up and include only historic controls. However, emerging evidence is increasingly suggestive of improved long-term outcomes. A recent Italian study [19Bassan 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. 28:3644-3652.Google Scholar] included 94 patients 35 of whom were a (nonrandomized) control group who did not receive imatinib. The patients who received imatinib had a statistically significant improvement in 5-year OS—38% versus 23% for those who did not receive the drug. However, the largest study of TKI in Ph+ ALL adults is the UKALL12/ECOG2993 study, which has recently been reported in abstract form. The existence of a very large historic control group treated on the same study prior to imatinib facilitates a reasonable estimate of long-term survival benefits. There was a large, imatinib-attributable difference in all outcome measures with OS improving from 23% in the preimatinib era to 43% when imatinib was given.The final question of whether the potential survival benefit ensuing from TKI therapy can occur in the absence of HSCT is a much more difficult question to answer, because most studies automatically assign patients to allograft wherever possible. Among the few published studies to report upon the outcome of a substantial group of patients of "transplantable age" who did not receive transplant was the ALL202 trial from the Japanese Adult Leukemia Study Group trial in which the combination of imatinib and chemotherapy was evaluated in 80 adult patients, 31 of whom did not undergo alloHSCT. When compared to historic controls in whom there were no event-free survivors at 24 months, the 2-year estimated EFS was significantly better for those receiving imatinib as part of their therapy. Another study in which patients who received imatinib but were not subjected to alloHSCT was carried out by the US Children's' Oncology Group [20Schultz K. Bowman W. Aledo A. et al.Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a Children's Oncology Group Study.J Clin Oncol. 2009; : 8PubMed Google Scholar]. Patients with an upper age limit of 21 years were treated in cohorts with imatinib added to chemotherapy, the final cohort receiving continuous imatinib. AlloHSCT was only permitted on protocol when a sibling donor was identified. This allowed a comparison by treatment—those who received chemotherapy in combination with imatinib but did not proceed to alloHSCT and those who did. Interpretation was confounded by the relatively high rate of off-protocol use of unrelated donor alloHSCT. However, at 3 years, the outcomes were not significantly different for those treated with chemotherapy plus imatinib (N = 25) compared to those treated with alloHSCT (N = 21). More than 85% of patients were alive and disease free at 3 years without alloHSCT. The study was not designed or powered to ask the question of whether imatinib/chemotherapy could replace sibling alloHSCT for children with Ph + ALL but the data are provocative and open the way for further discussion.The UKALL12/ECOG2993 study reported in abstract form also contains a large cohort of patients who were treated with imatinib and chemotherapy and who did not receive alloHSCT, in whom the 3-year OS is 28%. By comparison, the 5-year OS of historic controls in the preimatinib era was 19%. As the data mature it will become clearer whether this represents an improved outcome based solely on adding imatinib to therapy. The other group of studies in which imatinib was given without alloHSCT are those involving older patients. Certainly, there are the same impressive initial responses seen in the younger population, but these responses have not been shown to result in long-term DFS [22Vignetti 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: 3676-3678Crossref PubMed Scopus (279) Google Scholar, 23Ottmann O.G. 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: 2068-2076Crossref PubMed Scopus (173) Google Scholar].ConclusionPresently, myeloablative allogeneic stem cell transplant is still warranted for adults with Ph+ ALL. No data to date suggest that a TKI, either alone or in combination with chemotherapy, has considerably increased the proportion of patients with ALL becoming long-term disease-free survivors. However, this proposition has never been formally tested in a study designed to answer that question. It is possible that the major benefit of using TKI will be in accompaniment to transplant; first, to allow a greater proportion of patients to receive allogeneic HSCT, and second to provide a sufficient level of posttransplant disease suppression to allow time for a graft-versus-leukemia effect to eliminate residual ALL in those who enter transplant in a setting of persistent minimal residual disease that is not eradicated by the conditioning therapy. With the expanded application of RIC for ALL transplants and their use in an older patient population, this situation is increasingly likely. The first patient group in whom omission of transplant is likely to be tested will be in children, because in younger patients there is a better outcome to treatment with chemotherapy alone, and younger individuals have more to lose by risking the long-term adverse consequences of allogeneic HSCT. However, because Ph+ ALL is rare in children, the question of whether HSCT can be a dispensable part of their therapy may not be answered for some time. IntroductionAcute lymphoblastic leukemia (ALL) in which the chromosome translocation t(9;22)—known as the Philadelphia (Ph) chromosome—is detected has been associated with a considerably lower rate of complete remission (CR) and a lower long-term overall survival (OS) than in Philadelphia negative disease. Ph+ ALL accounts for approximately one-quarter of all adult ALL [1Mullighan C.G. Miller C.B. Radtke I. et al.BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros.Nature. 2008; 453: 110-114Crossref PubMed Scopus (799) Google Scholar] but only about 2% of ALL in children [2Jones L.K. Saha V. Philadelphia positive acute lymphoblastic leukaemia of childhood.Br J Haematol. 2005; 130: 489-500Crossref PubMed Scopus (52) Google Scholar]. Clinical trials have typically assigned patients with this form of ALL to "very high-risk" treatment arms and outside of a clinical trial, most physicians would recommend myeloablative hematopoietic stem cell transplant (HSCT) for adult patients in CR where a matched sibling or unrelated donor is available. However, with the advent of tyrosine kinase inhibitors, there is the possibility to target therapy more precisely by inhibiting the function of the oncogenic protein products of one or more of the genetic lesions involved in this disease using tyrosine kinase inhibitors. Numerous studies have now reported on the use of the selective tyrosine kinase inhibitor (TKI) imatinib in de novo Ph+ ALL. Some studies are also beginning to report outcomes of using dasatinib, a TKI that also inhibits Src kinase activity. In children, where the outcome of treatment for ALL is much better than that in adults in addition, the long-term consequences of allogeneic HSCT have a greater impact. Hence, there is already increasing reluctance to offer allogeneic HSCT to children in the "TKI era," but do the data fully substantiate this approach? In this article I will interrogate published evidence to address the question of whether in the "TKI era" allogeneic HSCT is still a necessary component of therapy for patients with Ph+ ALL.