The introduction of agents targeted at specific molecular events is changing the treatment paradigms in a number of malignancies. Historically, we have relied entirely on DNA-interactive, cytotoxic drugs for treating patients with leukemia. Increased understanding of the leukemic cell biology and pathogenesis, and the ways they evade the immune surveillance mechanisms, will likely lead to the development of more effective agents, and regimens less reliant on chemotherapy, able to achieve deep levels of disease eradication. In Philadelphia chromosome–positive acute lymphoblastic leukemia, the introduction of increasingly potent tyrosine kinas inhibitors (TKIs) has revolutionized therapy. These drugs have been established as the cornerstone of any therapeutic strategy in this disease, and a number of trials have better defined the best ways to incorporate them into the established paradigms. Despite using TKIs, we have continued to remain reliant on cytotoxic chemotherapy regimens and allogeneic hematopoietic cell transplant to achieve the best long-term outcomes. However, with the introduction of more potent TKIs and other novel agents, as well as better methods for monitoring minimal/measurable residual disease, we are entering an era where we hope to diminish our reliance on transplantation and cytotoxic chemotherapy in this disease.

The pivotal description of the translocation between chromosomes 9 and 22 leading to the short chromosome 22 by Nowell and Hungerford,1  followed by determination of the translocation product BCR/ABL1 and its direct role in leukemogenesis eventually led to the development of a number of tyrosine kinase inhibitors (TKIs) that have revolutionized the management of patients with disorders harboring the BCR/ABL1 transcript.2-7  In Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), although allogeneic hematopoietic cell transplant (allo-HCT) remains the standard strategy for achieving long-term disease-free survival, increasing number of patients who are unable to undergo the procedure have been treated effectively with regimens combining TKIs with chemotherapy.8  Fielding and colleagues clearly demonstrated the benefit of the addition of imatinib to standard therapy in these patients.9  The long-term follow-up of these studies has demonstrated that a number of patients treated with such regimens and without allo-HCT in first remission continue to remain disease-free several years after initiation of therapy raising the probability of achieving cure without allo-HCT (Table 1).8  However, a significant proportion of patients with this disease continue to fail to achieve long-term cure, with or without allo-HCT (Table 1). The ability to monitor for persistence of residual disease or for molecular recurrence has further opened avenues for deciding who should be transplanted in first remission.10  Also, the introduction of more potent TKIs and the recent development of effective monoclonal antibodies have provided more options for treating patients with relapsed disease.11,12  As the number of options for treating patients with Ph+ ALL have increased, it is important to select the best potential therapy for each individual patient in order to improve the long-term outcome for all patients. This should take into account the risks and benefits of each strategy, both short term and long term, for each individual. Here, in this case-based review, we discuss how individualized treatment may provide the best outcome for the majority of patients with Ph+ ALL. Although, based on the author’s personal practice, this review focuses on the hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (hyper-CVAD) regimen, many of the points illustrated are applicable to other widely used regimens such as the Berlin, Frankfurt, Munster–type regimens.

Table 1.

Selected trials incorporating TKIs in the initial therapy of Ph+ ALL

ReferenceNAge, median [range]RegimenCMR rate, %Allo-HCT rate, %RFS rate, %OS rate, %
Imatinib        
 45 80 48 [15-63] Intensive chemotherapy 50 (day 63) 49 — 76 (1 y) 
 39 29 69 [61-83] Corticosteroids — 48 (1 y) 74 (1 y) 
 46 59 45 [20-66] Intensive chemotherapy — 72 39 (5 y) 38 (5 y) 
 9 169 42 [16-64] Intensive chemotherapy — 72 50 (4 y) 38 (4 y) 
 57 54 51 [17-84] Intensive chemotherapy 45 (overall) 30 43 (5 y) 43 (5 y) 
 15 133 45 [21-59] Intensive chemotherapy 23 (2 cycles) 65 — 46 (5 y) 
135 49 [18-59] Low-intensity chemotherapy 29 (2 cycles) 62 — 46 (5 y) 
 37 34 45 [24-57] Intensive chemotherapy — 44 46 (5 y) 51 (5 y) 
 25 92 10 [1.3-21] Intensive chemotherapy — — 70 (5 y) — 
Dasatinib        
 19 53 54 [24-77] Corticosteroids 15 (day 85) 42 22 (20 mo) 31 (20 mo) 
 47 72 55 [21-80] Intensive chemotherapy 65 (overall) 17 44 (5 y) 46 (5 y) 
 16 97 44 [20-60] Intensive chemotherapy — 42 62 (3 y) 69 (3 y) 
 40 71 69 [55-83] Low-intensity chemotherapy 24 (consolidation) 10 28 (5 y) 36 (5 y) 
 26 60 10.2* [1.5-27.6] Intensive chemotherapy — 32 60 (5 y) 86 (5 y) 
Nilotinib        
 31 90 47 [17-71] Intensive chemotherapy 77 (3 mo) 63 72 (2 y) 72 (2 y) 
Ponatinib        
 17 37 51 [27-75] Intensive chemotherapy 78 (overall) 24 — 80 (2 y) 
 41 44 68 [27-85] Corticosteroids 61 (evaluable; 6 mo) — — 87.5 (1 y) 
ReferenceNAge, median [range]RegimenCMR rate, %Allo-HCT rate, %RFS rate, %OS rate, %
Imatinib        
 45 80 48 [15-63] Intensive chemotherapy 50 (day 63) 49 — 76 (1 y) 
 39 29 69 [61-83] Corticosteroids — 48 (1 y) 74 (1 y) 
 46 59 45 [20-66] Intensive chemotherapy — 72 39 (5 y) 38 (5 y) 
 9 169 42 [16-64] Intensive chemotherapy — 72 50 (4 y) 38 (4 y) 
 57 54 51 [17-84] Intensive chemotherapy 45 (overall) 30 43 (5 y) 43 (5 y) 
 15 133 45 [21-59] Intensive chemotherapy 23 (2 cycles) 65 — 46 (5 y) 
135 49 [18-59] Low-intensity chemotherapy 29 (2 cycles) 62 — 46 (5 y) 
 37 34 45 [24-57] Intensive chemotherapy — 44 46 (5 y) 51 (5 y) 
 25 92 10 [1.3-21] Intensive chemotherapy — — 70 (5 y) — 
Dasatinib        
 19 53 54 [24-77] Corticosteroids 15 (day 85) 42 22 (20 mo) 31 (20 mo) 
 47 72 55 [21-80] Intensive chemotherapy 65 (overall) 17 44 (5 y) 46 (5 y) 
 16 97 44 [20-60] Intensive chemotherapy — 42 62 (3 y) 69 (3 y) 
 40 71 69 [55-83] Low-intensity chemotherapy 24 (consolidation) 10 28 (5 y) 36 (5 y) 
 26 60 10.2* [1.5-27.6] Intensive chemotherapy — 32 60 (5 y) 86 (5 y) 
Nilotinib        
 31 90 47 [17-71] Intensive chemotherapy 77 (3 mo) 63 72 (2 y) 72 (2 y) 
Ponatinib        
 17 37 51 [27-75] Intensive chemotherapy 78 (overall) 24 — 80 (2 y) 
 41 44 68 [27-85] Corticosteroids 61 (evaluable; 6 mo) — — 87.5 (1 y) 

CMR, complete molecular remission; OS, overall survival; RFS, relapse-free survival.

*

Mean value provided.

Event-free survival provided.

Patient 1

A 48-year-old man with no significant medical problems presented in March 2011 with fatigue and was found to have a white blood cell count (WBC) of 153 × 109/L with 60% blasts, hemoglobin (Hb) 11.7 g/dL, and platelet count 26 × 109/L. A bone marrow (BM) exam was consistent with the diagnosis of precursor B-cell ALL (CD19+, CD20, CD10+, CD22+, CD34+, TdT+), and fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction (RT-PCR) were positive for the presence of BCR/ABL1 (coding for a 210-kDa protein). Cytogenetic analysis showed t(9;22)(q34;q11.2) as well as t(1;6) in 7 metaphases. He was enrolled in the Southwest Oncology Group 0805 (SWOG0805) clinical trial (#NCT00792948) and received initial induction with hyper-CVAD. Dasatinib 100 mg daily was started on day 1 and was interrupted after 14 days to allow recovery of the blood counts. BM exam on day 21 was consistent with achieving complete remission (CR). BM repeated after 3 months showed CMR. He then underwent an allo-HCT from an HLA-identical sibling with total body irradiation and etoposide as the preparative regimen. There were no major complications, and the patient was started back on dasatinib 100 mg daily ∼100 days after the stem cell infusion. This was associated initially with thrombocytopenia leading to the reduction of the dose of dasatinib to 50 mg daily. Later, he developed recurrent pleural effusions (a well-known toxicity of dasatinib13 ) with further reduction of the dasatinib dose to 20 mg daily. He continues to remain in remission for more than 7 years while continuing maintenance low-dose dasatinib.

When an appropriate donor is available and the potential risks of allo-HCT are limited, allo-HCT in first CR remains the standard of care.14  In the Medical Research Council United Kingdom ALL XII/Eastern Cooperative Group 2993 trial there was an advantage for patients undergoing allo-HCT in first CR, which was further enhanced when imatinib was introduced after induction.9,14  This was attributed to be at least in part because of more patients being able to undergo allo-HCT after imatinib was introduced.9  A number of other studies have suggested a benefit for allo-HCT particularly in younger adult patients.9,15,16  In the SWOG0805 trial, there was a relapse-free and overall survival benefit for the patients who underwent allo-HCT when a landmark analysis at 175 days posttransplant (the longest time to transplant) was performed.16  The French group conducted a randomized trial in patients younger than 60 who received either low-intensity induction with imatinib, vincristine, and steroids or hyper-CVAD plus imatinib.15  All patients were eligible to undergo an allo-HCT in first CR, and they reported an OS advantage for the patients who received allo-HCT.

Clearly, allo-HCT is a long-established and potent strategy in patients with Ph+ ALL only limited by its availability and potential risks. The current body of evidence suggests that in younger patients who have a fully matched donor and have no significant comorbid conditions, this strategy continues to be beneficial. Better assays for detecting persistent residual disease that may better identify patients that could be spared the potential toxicity of this strategy are in development. Whether the introduction of more potent TKIs such as ponatinib, able to produce deeper molecular remissions earlier, will have an impact on the role of allo-HCT in Ph+ ALL will remain to be established.17  In a younger patient with available donor who is destined to undergo allo-HCT, it can be argued that initial therapy should be limited to TKI plus steroids and vincristine in order to minimize the risks attributable to more intensive chemotherapy.15  However, a patient unable or unwilling to undergo transplantation likely requires the combination of ALL-based chemotherapy regimens with TKIs.18,19  Potential benefits of the more intensive regimens including high doses of cytarabine and methotrexate may include deeper disease eradication and better central nervous system (CNS) penetration.

Another area of debate is whether to continue therapy with TKIs after allo-HCT to reduce the risk of relapse.20  There are limited data in this area, but a number of retrospective analyses have demonstrated the feasibility of posttransplant maintenance TKI.20  Small prospective trials, mainly with imatinib, have further suggested that this strategy may be beneficial in reducing the risk of relapse posttransplant.20  In the only randomized trial conducted to date, engrafted patients received imatinib either prophylactically or after detection of minimal/measurable residual disease (MRD) by RT-PCR.21  Although there was a trend for longer molecular remission in the prophylactic group, the leukemia-free survival (LFS) and OS were the same in the 2 groups. However, the authors concluded that despite the low rate of compliance in the study, the use of either strategy was beneficial in reducing the risk of hematological relapse and improving long-term outcome.21  A retrospective analysis by the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party also reported that prophylactic administration of TKIs post–allo-HCT was associated with significant improvement in LFS and OS.22 

In the author’s practice, younger patients with an available donor are encouraged to consider an allo-HCT in first CR especially when the more potent TKI ponatinib is not a component of therapy and when CMR has not been achieved relatively early in the course of therapy. In patients achieving early CMR, a detailed discussion of risks and benefits of allo-HCT vs continued therapy is undertaken to ensure an informed decision process. Several studies have suggested that early initiation of therapy with a TKI,9  as well as continuous administration of TKI,23  particularly during consolidation and maintenance (compared with alternating strategies24 ), may improve outcomes. Therefore, with the exception of the first cycle of induction when we administer TKI for only 14 days, we recommend continuous administration of TKI when in CR, based on the experience with TKIs in chronic myelogenous leukemia. We also encourage continuation of TKI therapy posttransplant, when feasible, although there are no extensive published data to support this. Although ponatinib may be the preferred TKI based on its activity against the T315I mutants, there are no data to support the use of any specific TKI over the others, posttransplant.

Patient 2

A 23-year-old man was treated for bronchitis with antibiotics without improvement in July 2007. Initial investigations showed a WBC of 0.2 × 109/L, Hb 8.8 g/dL, and platelet count of 54 × 109/L. BM was consistent with precursor B-ALL with the blast cells expressing CD19, CD10, HLA-DR, CD33, TDT, CD34, CD22, and CD79a. Cytogenetics showed the presence of t(9;22)(q34; q11.2), and molecular testing was positive for the BCR-ABL1 transcripts (coding for a 190-kDa protein). He was started on a clinical trial of hyper-CVAD plus dasatinib (#NCT00390793) and achieved CR after 1 cycle of therapy. He did not have any siblings, and a search to identify an unrelated matched donor was unsuccessful. The patient declined cord blood transplant and completed 7 more cycles of therapy achieving CMR. He received maintenance therapy with dasatinib 100 mg daily with monthly steroids and vincristine. He developed a right-sided pleural effusion after 2 years of dasatinib, which responded to steroids and reduction of dose to 50 mg daily. He has continued daily dasatinib 50 mg and remained in CR for 11 years.

The investigators from the Children’s Oncology Group reported the long-term follow-up of their study in children (median age 10, range 1.3 to 21 years) showing equivalent outcomes in patients who received at least 280 continuous days of imatinib to those who underwent allo-HCT.23,25  More recently, Slayton and colleagues26  reported excellent outcomes for 60 children treated with chemotherapy plus dasatinib with 5-year survival of 86%. Of note, only 19 (32%) patients underwent allo-HCT with outcomes similar for those who did and did not undergo allo-HCT. They concluded that allo-HCT should be limited only to patients with high-risk disease based on flow cytometry-based MRD clearance and presence of IKZF1 deletions at diagnosis.26  Other studies have also reported on the negative prognostic impact of a number of genomic abnormalities in addition to IKZF1 deletions, including deletions of CKND2A/2B and PAX5 genes with some maintaining this adverse impact despite allo-HCT.27-29  These genomic aberrations, as well as other reported prognostic factors such as high presentation WBC or presence of additional cytogenetic abnormalities, are not yet routinely considered when deciding on allo-HCT.15,30 

Reported pediatric studies have raised questions about the necessity of allo-HCT in first CR. However, the applicability of these data to the adult population remains unproven. Assessment of MRD using RT-PCR for BCR-ABL1 transcripts after initial induction and consolidation may better allow the identification of patients who are more likely to relapse and therefore should be definitely considered for allo-HCT. Short and colleagues have reported that using the hyper-CVAD regimen plus a TKI (imatinib, dasatinib, or ponatinib) and without allo-HCT, patients who achieve CMR at 3 months had a significantly better survival than those with lesser molecular responses.10  On multivariate analysis, only achieving CMR at 3 months was prognostic for survival.10  Others have shown that achieving deeper molecular responses 3 months after achieving morphological CR is associated with better outcomes.31  Even among the allo-HCT recipients, those who had deeper molecular responses prior to allo-HCT had better long-term outcomes.31  In a French trial, patients who had achieved CMR seemed to do as well if they did or did not undergo allo-HCT.15  Furthermore, patients who achieved major molecular response had similar outcomes whether they received allo-HCT or autologous stem cell transplant (SCT).15  These data suggest that monitoring for MRD using RT-PCR for BCR-ABL1 transcripts is a very useful tool in assisting management decisions in patients with Ph+ ALL. This is likely to be even more important if more precise assays for detecting MRD are introduced.32  North American pediatric trials have commonly used flow cytometry–based assays for detecting MRD.25,26  However, molecular-based assays such as RT-PCR for BCR-ABL1 transcripts or clone-specific PCR for immunoglobulin or T-cell receptor gene rearrangements tend to be more sensitive. More recent methods such as amplicon-based next generation sequencing of immunoglobulin/T-cell receptor may overcome some of the limitations of RT-PCR and enhance sensitivity.33,34  Other novel and highly sensitive assays such as droplet digital PCR are also in development.35,36  Achieving deep molecular responses using TKI-based regimens has also rekindled interest in autologous SCT with some studies reporting equivalent long-term outcomes for patients undergoing allo-HCT and autologous SCT.15,37,38  However, this remains a question to be further explored in clinical trials.

Patient 3

A 53-year-old man with morbid obesity, diabetes mellitus, emphysema, and coronary artery disease presented with severe back and chest pain to his local emergency center in August 2004. Investigations ruled out cardiac and other causes, but his blood counts were abnormal including a WBC of 19.9 × 109/L, Hb of 13 g/dL, and platelet count of 33 × 109/L. BM exam was consistent with Ph+ ALL, and he received induction therapy with hyper-CVAD plus imatinib 400 mg daily on a clinical trial (#NCT00038610). He achieved CR and was referred for allo-HCT. A suitable donor was not identified, and he was considered to be at high risk of developing complications for an investigational transplant. He completed 7 further courses of chemotherapy including 8 intrathecal chemotherapy administrations as devised by the protocol. He remained well and as he had achieved a major molecular response but not CMR, his imatinib dose was increased to 300 mg twice daily during maintenance. He tolerated this well but had diabetes-related renal impairment. Unfortunately, after 8 years in CR, he presented with left eye visual loss, partial ptosis, and decreased hearing in the left ear; magnetic resonance imaging was suggestive of leptomeningeal disease involving several cranial nerves, and examination of cerebrospinal fluid confirmed CNS relapse. BM examination showed molecular relapse. He received intrathecal chemotherapy until his cerebrospinal fluid became negative for leukemic cells as well as systemic therapy with dose-modified hyper-CVAD plus dasatinib for his molecular relapse. His renal function had also deteriorated, and he became debilitated and died of the complications of his concurrent medical conditions.

Treatment of older and medically unfit patients who are unable to tolerate chemotherapy has been difficult. In order to circumvent the toxicity associated with intensive chemotherapy, a number of groups have investigated the use of a TKI with minimal chemotherapy in this population.19,39,40  Although these studies have produced almost universal responses with no induction mortality, the remissions have not been durable unless consolidated with intensive chemotherapy, autologous HCT, or allo-HCT. The European Working Group for Adult ALL (EWALL) combined dasatinib with vincristine and steroids for the initial therapy of older patients with newly diagnosed Ph+ ALL, followed by consolidation with more intensive chemotherapy.40  They reported a CR rate of 96% with a 5-year survival of 36%. Therefore, although reduction or elimination of chemotherapy can reduce the initial morbidity and mortality, long-term cure cannot be achieved in the majority of patients using this strategy. In the same study, EWALL showed that among the patients who relapsed, there was a high incidence of the TKI-resistant T315I mutants.40  Using more potent TKIs such as ponatinib that are active against resistance-inducing mutations, it may be possible to have higher and more durable responses. However, only limited long-term data with such a strategy are available.17,41  The choice of TKI in this population should also take into account the presence of concomitant medical disorders and the potential toxicities of various TKIs.

Solitary CNS relapse is uncommon, but with an increasing number of individuals achieving long-term remission, more patients are at risk of developing extramedullary relapse, and appropriate prophylaxis to reduce this risk is crucial. In the recently reported pediatric study by the Children’s Oncology Group, there was a trend toward increased risk of CNS relapse among the nontransplanted patients.26  Our group has increased the number of intrathecal prophylactic chemotherapy from 8 to 12, and with this strategy, we have decreased this risk significantly in our more recent regimens.17  Even with allo-HCT, further CNS therapy may be necessary to prevent these events particularly in patients with initial presentation with CNS involvement, although this is not our routine practice.42 

Patient 4

A 67-year-old man presented to his local physician in March 2013 with progressive fatigue, fevers, and sinus congestion. A complete blood count showed pancytopenia, and he was referred to a local hematologist who performed a BM exam revealing a hypercellular marrow with 80% cellularity and increased lymphoblasts (47%) with CD34, CD10, TDT, CD19, CD38, CD22, CD52, HLA-DR, and dim CD13 and CD20 expression. PCR was reported as positive for BCR-ABL1 including both p210 and p190 transcripts. He was enrolled in a clinical trial combining the hyper-CVAD regimen with ponatinib (#NCT01424982)17  and received ponatinib 45 mg daily, achieving morphological CR as well as CMR after 1 cycle of therapy. His therapy was continued with further cycles of the regimen as well as continuous therapy with ponatinib 45 mg per day. He tolerated ponatinib well, but in November 2013, ponatinib dose was decreased to 15 mg daily after information regarding ponatinib-related cardiovascular risk became available.43  Alternative TKI therapy was discussed, but the patient chose to remain on the study. He continued to remain in CMR and remained adherent to ponatinib 15 mg daily until in October 2016 when he presented to the emergency center with chest pain. Coronary angiography revealed multivessel coronary artery disease requiring percutaneous balloon dilatation and stent placement. He tolerated the procedure well; ponatinib was discontinued, and he was initiated on maintenance imatinib 400 mg daily, which he continues to receive to date while he remains in CMR.

Despite the revolutionary success of imatinib in the treatment of Ph+ leukemias, a proportion of patients are resistant to it, and next-generation inhibitors have been developed to overcome this resistance. In Ph+ ALL, the introduction of imatinib in combination with standard ALL regimens significantly improved long-term outcomes and allowed more patients to undergo allo-HCT in first CR.9,44-46  However, a significant proportion of patients continue to relapse with 3- to 5-year survival rates of 33% to 46% in the published studies.8  The introduction of second-generation TKIs capable of overcoming resistance-inducing ABL1 kinase domain mutations (with the notable exception of T315I) led to their introduction in the management of Ph+ ALL with a few studies reporting higher progression-free and overall survival, albeit shorter follow-up.16,31,47 

A number of studies have demonstrated that T315I mutations are commonly detected in patients with Ph+ ALL who relapse after prior TKI-containing therapy.19,40,47  In the study by the EWALL, using dasatinib and lower-intensity chemotherapy in older adults, 75% of patients who relapsed and had samples for mutation analysis had the T315I mutations.40  Furthermore, using allele-specific oligonucleotide PCR, they demonstrated the presence of the mutants in a number of patients enrolled in the study at the outset and before receiving any therapy.40  Other studies have also reported the occurrence of ABL1 kinase domain mutations at relapse.18,19,47  These data suggest that development of ABL1 kinase domain mutations, and particularly T315I, is an important contributor to the development of relapse in Ph+ ALL suggesting that a more potent inhibitor with activity against the resistance-inducing mutations, such as ponatinib, is likely to be beneficial in this disease. Indeed early reports of use of this agent in the frontline setting have suggested impressive activity with high response rates including high and early CMR rates.17,41  We use ponatinib in the setting of clinical trials in the frontline setting and when possible and in the absence of contraindications in the relapse setting. Chemotherapy-free combination of ponatinib and blinatumomab is under investigation in the frontline therapy, particularly of elderly and unfit patients.

Patient 5

A 43-year-old man presented to his local doctor in December 2012 with progressive fatigue and was found to have a WBC of 52.2 × 109/L with 79% circulating blasts, Hb of 7.9 g/dL, and platelet count of 43 × 109/L. BM examination revealed 82% blasts consistent with precursor B-ALL, and cytogenetics were positive for the presence of the Philadelphia chromosome with fluorescence in situ hybridization and RT-PCR confirming the presence of the BCR-ABL1 transcripts (coding for a 190-kDa protein). He was initiated on therapy with the hyper-CVAD plus dasatinib on SWOG0805 protocol (#NCT00792948) and achieved CR after 1 cycle of therapy. He was referred for an allo-HCT, but neither a suitable sibling donor nor a matched unrelated donor could be identified, and the patient declined a haplo-identical transplant. He continued to receive 7 consolidation cycles of chemotherapy with continuous dasatinib 70 mg daily without major complications. He then received maintenance therapy with monthly vincristine and prednisone while continuing dasatinib at 100 mg daily. Maintenance therapy was complicated by cytomegalovirus reactivation requiring therapy with valgancyclovir, as well as episodes of clostridium difficile diarrhea requiring courses of metronidazole and oral vancomycin with good response. He completed 1 year of maintenance followed by dasatinib monotherapy at 100 mg daily until, 5 years later, he was found to have molecular relapse on routine peripheral blood PCR monitoring with a value of 0.21%. A BM examination showed frank morphological relapse with 68% blasts. He received salvage therapy with combination of bosutinib plus inotuzumab and achieved CR, but therapy was discontinued because of suspected veno-occlusive disease of the liver and the detection of a mutant T315I positive clone.48  He was then initiated on the combination of blinatumomab and ponatinib and after 1 cycle of therapy, achieved a second CMR.49  He then underwent a double cord blood and natural killer cell allo-HCT with conditioning regimen of lenalidomide, fludarabine, cyclophosphamide, and total body irradiation in January 2018. He has remained well and in CMR with full donor chimerism while continuing posttransplant ponatinib, which was started ∼5 months after transplant.

With the development of newer, more potent TKIs, as well as monoclonal antibodies such as blinatumomab12,50  and inotuzumab,51  a number of effective salvage options with limited toxicity have become available, thereby allowing the possibility of achieving a second CR before proceeding to allo-HCT. Other strategies such as chimeric antigen receptor T-cell therapy can also be potentially considered in this setting.52 

Management of patients with Ph+ ALL is evolving rapidly. Prior to the introduction of imatinib, few patients survived long-term without undergoing an allogeneic SCT in first CR, and these were typically younger, fit patients.53  A number of adult and pediatric studies have shown the benefit of the addition of early and continuous therapy with TKIs to the traditional ALL-based regimens.9,25,26,54,55  In younger, fitter patients and especially using the first- and second-generation TKIs, allo-HCT in first CR remains the standard of care, although long-term data from both pediatric and adult studies suggest the possibility of long-term LFS without an allo-HCT in first CR. Whether the addition of newer, more potent agents such as ponatinib, as well as monitoring for MRD with more reliable and sensitive assays, can change this standard should be evaluated in the setting of carefully designed large randomized trials. In older and unfit patients unable or unwilling to undergo a transplant, use of TKIs in addition to low-intensity chemotherapy does produce high response rates with minimal or no induction mortality.19,40,41  However, it does not appear that such a strategy can produce long-term RFS, and perhaps future regimens incorporating blinatumomab or inotuzumab may be associated with more durable responses, particularly when combined with the more potent inhibitors. Frontline trials in elderly patient evaluating such strategies are ongoing. Other methods of enhancing the activity of TKIs such as combination with the BCL-2 inhibitor venetoclax have been demonstrated in preclinical studies and may provide a promising approach to be investigated in future trials.56  The availability of more effective agents both in the frontline and relapse settings is providing a range of possibilities for treating this disease that may allow individualized therapy based on patient characteristics, donor availability (including novel donor sources such as haplo-identical donors), and MRD clearance.

Contribution: F.R. wrote the manuscript.

Conflict-of-interest disclosure: F.R. has received research funding from Bristol Myers Squibb, Abbvie, and Amgen and has received honoraria from Abbvie, Ariad, and Amgen.

Correspondence: Farhad Ravandi, Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: fravandi@mdanderson.org.

1.
Nowell
PC
,
Hungerford
DA
.
Chromosome studies on normal and leukemic human leukocytes
.
J Natl Cancer Inst
.
1960
;
25
:
85
-
109
.
2.
Rowley
JD
.
Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining
.
Nature
.
1973
;
243
(
5405
):
290
-
293
.
3.
Groffen
J
,
Stephenson
JR
,
Heisterkamp
N
,
de Klein
A
,
Bartram
CR
,
Grosveld
G
.
Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22
.
Cell
.
1984
;
36
(
1
):
93
-
99
.
4.
Daley
GQ
,
Van Etten
RA
,
Baltimore
D
.
Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome
.
Science
.
1990
;
247
(
4944
):
824
-
830
.
5.
Druker
BJ
,
Tamura
S
,
Buchdunger
E
, et al
.
Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells
.
Nat Med
.
1996
;
2
(
5
):
561
-
566
.
6.
Druker
BJ
,
Talpaz
M
,
Resta
DJ
, et al
.
Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia
.
N Engl J Med
.
2001
;
344
(
14
):
1031
-
1037
.
7.
Druker
BJ
,
Sawyers
CL
,
Kantarjian
H
, et al
.
Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome
.
N Engl J Med
.
2001
;
344
(
14
):
1038
-
1042
.
8.
Ravandi
F
.
Current management of Philadelphia chromosome positive ALL and the role of stem cell transplantation
.
Hematology Am Soc Hematol Educ Program
.
2017
;
2017
:
22
-
27
.
9.
Fielding
AK
,
Rowe
JM
,
Buck
G
, et al
.
UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia
.
Blood
.
2014
;
123
(
6
):
843
-
850
.
10.
Short
NJ
,
Jabbour
E
,
Sasaki
K
, et al
.
Impact of complete molecular response on survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia
.
Blood
.
2016
;
128
(
4
):
504
-
507
.
11.
Cortes
JE
,
Kim
DW
,
Pinilla-Ibarz
J
, et al
;
PACE Investigators
.
A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias
.
N Engl J Med
.
2013
;
369
(
19
):
1783
-
1796
.
12.
Martinelli
G
,
Boissel
N
,
Chevallier
P
, et al
.
Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-arm, multicenter study
.
J Clin Oncol
.
2017
;
35
(
16
):
1795
-
1802
.
13.
Quintás-Cardama
A
,
Kantarjian
H
,
O’brien
S
, et al
.
Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure
.
J Clin Oncol
.
2007
;
25
(
25
):
3908
-
3914
.
14.
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
(
19
):
4489
-
4496
.
15.
Chalandon
Y
,
Thomas
X
,
Hayette
S
, et al
;
Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)
.
Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia
.
Blood
.
2015
;
125
(
24
):
3711
-
3719
.
16.
Ravandi
F
,
Othus
M
,
O’Brien
SM
, et al
.
US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL
.
Blood Adv
.
2016
;
1
(
3
):
250
-
259
.
17.
Jabbour
E
,
Kantarjian
H
,
Ravandi
F
, et al
.
Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study
.
Lancet Oncol
.
2015
;
16
(
15
):
1547
-
1555
.
18.
Chiaretti
S
,
Vitale
A
,
Vignetti
M
, et al
.
A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study
.
Haematologica
.
2016
;
101
(
12
):
1544
-
1552
.
19.
Foà
R
,
Vitale
A
,
Vignetti
M
, et al
;
GIMEMA Acute Leukemia Working Party
.
Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia
.
Blood
.
2011
;
118
(
25
):
6521
-
6528
.
20.
Giebel
S
,
Czyz
A
,
Ottmann
O
, et al
.
Use of tyrosine kinase inhibitors to prevent relapse after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome–positive acute lymphoblastic leukemia: a position statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
.
Cancer
.
2016
;
122
(
19
):
2941
-
2951
.
21.
Pfeifer
H
,
Wassmann
B
,
Bethge
W
, et al
;
GMALL Study Group
.
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
(
6
):
1254
-
1262
.
22.
Brissot
E
,
Labopin
M
,
Beckers
MM
, et al
.
Tyrosine kinase inhibitors improve long-term outcome of allogeneic hematopoietic stem cell transplantation for adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia
.
Haematologica
.
2015
;
100
(
3
):
392
-
399
.
23.
Schultz
KR
,
Bowman
WP
,
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
;
27
(
31
):
5175
-
5181
.
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
(
5
):
1469
-
1477
.
25.
Schultz
KR
,
Carroll
A
,
Heerema
NA
, et al
;
Children’s Oncology Group
.
Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s Oncology Group study AALL0031
.
Leukemia
.
2014
;
28
(
7
):
1467
-
1471
.
26.
Slayton
WB
,
Schultz
KR
,
Kairalla
JA
, et al
.
Dasatinib plus intensive chemotherapy in children, adolescents, and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: results of Children’s Oncology Group Trial AALL0622
.
J Clin Oncol
.
2018
;
36
(
22
):
2306
-
2314
.
27.
Martinelli
G
,
Iacobucci
I
,
Storlazzi
CT
, et al
.
IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: a GIMEMA AL WP report
.
J Clin Oncol
.
2009
;
27
(
31
):
5202
-
5207
.
28.
Pfeifer
H
,
Raum
K
,
Markovic
S
, et al
.
Genomic CDKN2A/2B deletions in adult Ph+ ALL are adverse despite allogeneic stem cell transplantation
.
Blood
.
2018
;
131
(
13
):
1464
-
1475
.
29.
Fedullo
AL
,
Messina
M
,
Elia
L
, et al
.
Prognostic implications of additional genomic lesions in adult Ph+ acute lymphoblastic leukemia [published online ahead of print 6 September 2018]
.
Haematologica
.
doi:10.3324/haematol.2018.196055
.
30.
Short
NJ
,
Kantarjian
HM
,
Sasaki
K
, et al
.
Poor outcomes associated with +der(22)t(9;22) and -9/9p in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia receiving chemotherapy plus a tyrosine kinase inhibitor
.
Am J Hematol
.
2017
;
92
(
3
):
238
-
243
.
31.
Kim
DY
,
Joo
YD
,
Lim
SN
, et al
;
Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology
.
Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia
.
Blood
.
2015
;
126
(
6
):
746
-
756
.
32.
Brüggemann
M
,
Raff
T
,
Kneba
M
.
Has MRD monitoring superseded other prognostic factors in adult ALL?
Blood
.
2012
;
120
(
23
):
4470
-
4481
.
33.
Brüggemann
M
,
Kotrova
M
.
Minimal residual disease in adult ALL: technical aspects and implications for correct clinical interpretation
.
Hematology Am Soc Hematol Educ Program
.
2017
;
2017
:
13
-
21
.
34.
Pulsipher
MA
,
Carlson
C
,
Langholz
B
, et al
.
IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients
.
Blood
.
2015
;
125
(
22
):
3501
-
3508
.
35.
Coccaro
N
,
Anelli
L
,
Zagaria
A
, et al
.
Droplet digital PCR is a robust tool for monitoring minimal residual disease in adult Philadelphia-positive acute lymphoblastic leukemia
.
J Mol Diagn
.
2018
;
20
(
4
):
474
-
482
.
36.
Iacobucci
I
,
Lonetti
A
,
Venturi
C
, et al
.
Use of a high sensitive nanofluidic array for the detection of rare copies of BCR-ABL1 transcript in patients with Philadelphia-positive acute lymphoblastic leukemia in complete response
.
Leuk Res
.
2014
;
38
(
5
):
581
-
585
.
37.
Wetzler
M
,
Watson
D
,
Stock
W
, et al
.
Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance)
.
Haematologica
.
2014
;
99
(
1
):
111
-
115
.
38.
Tanguy-Schmidt
A
,
Rousselot
P
,
Chalandon
Y
, et al
.
Long-term follow-up of the imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: a GRAALL study
.
Biol Blood Marrow Transplant
.
2013
;
19
(
1
):
150
-
155
.
39.
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
(
9
):
3676
-
3678
.
40.
Rousselot
P
,
Coudé
MM
,
Gokbuget
N
, et al
;
European Working Group on Adult ALL (EWALL) group
.
Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL
.
Blood
.
2016
;
128
(
6
):
774
-
782
.
41.
Martinelli
G
,
Piciocchi
A
,
Papayannidis
C
, et al
.
First report of the Gimema LAL1811 Phase II Prospective Study of the combination of steroids with ponatinib as frontline therapy of elderly or unfit patients with Philadelphia chromosome-positive acute lymphoblastic leukemia [abstract]
.
Blood
.
2017
;
130
(
suppl 1
). Abstract
99
.
42.
Hamdi
A
,
Mawad
R
,
Bassett
R
, et al
.
Central nervous system relapse in adults with acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation
.
Biol Blood Marrow Transplant
.
2014
;
20
(
11
):
1767
-
1771
.
43.
Groarke
JD
,
Cheng
S
,
Moslehi
J
.
Cancer-drug discovery and cardiovascular surveillance
.
N Engl J Med
.
2013
;
369
(
19
):
1779
-
1781
.
44.
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
(
12
):
4396
-
4407
.
45.
Yanada
M
,
Takeuchi
J
,
Sugiura
I
, et al
;
Japan Adult Leukemia Study Group
.
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
(
3
):
460
-
466
.
46.
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
(
22
):
3644
-
3652
.
47.
Ravandi
F
,
O’Brien
SM
,
Cortes
JE
, et al
.
Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia
.
Cancer
.
2015
;
121
(
23
):
4158
-
4164
.
48.
Jain
N
,
Cortes
JE
,
Ravandi
F
, et al
.
Inotuzumab ozogamicin in combination with bosutinib for patients with relapsed or refractory Ph plus ALL or CML in lymphoid blast phase [abstract]
.
Blood
.
2017
;
130
(
suppl 1
). Abstract
143
.
49.
Assi
R
,
Kantarjian
HM
,
Short
NJ
, et al
.
Safety and efficacy of blinatumomab in combination with a tyrosine kinase inhibitor for the treatment of relapsed Philadelphia chromosome-positive leukemia [abstract]
.
Blood
.
2017
;
130
(
suppl 1
). Abstract
2598
.
50.
Kantarjian
H
,
Stein
A
,
Gökbuget
N
, et al
.
Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia
.
N Engl J Med
.
2017
;
376
(
9
):
836
-
847
.
51.
Kantarjian
HM
,
DeAngelo
DJ
,
Stelljes
M
, et al
.
Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia
.
N Engl J Med
.
2016
;
375
(
8
):
740
-
753
.
52.
Maude
SL
,
Laetsch
TW
,
Buechner
J
, et al
.
Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia
.
N Engl J Med
.
2018
;
378
(
5
):
439
-
448
.
53.
Ravandi
F
,
Kebriaei
P
.
Philadelphia chromosome-positive acute lymphoblastic leukemia
.
Hematol Oncol Clin North Am
.
2009
;
23
(
5
):
1043
-
1063
.
54.
Biondi
A
,
Gandemer
V
,
Campbell
M
, et al
.
A treatment protocol with imatinib and intensive chemotherapy for pediatric Philadelphia positive acute lymphoblastic leukemia patients: a single-arm, intergroup study (EsPhALL 2010-2014) [abstract]
.
Blood
.
2017
;
130
(
suppl 1
). Abstract
97
.
55.
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
(
12
):
2070
-
2077
.
56.
Leonard
JT
,
Rowley
JS
,
Eide
CA
, et al
.
Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia
.
Sci Transl Med
.
2016
;
8
(
354
):
354ra114
.
57.
Daver
N
,
Thomas
D
,
Ravandi
F
, et al
.
Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia
.
Haematologica
.
2015
;
100
(
5
):
653
-
661
.
Sign in via your Institution