Current paradigms in the management of Philadelphia chromosome positive acute lymphoblastic leukemia in adults
Abstract
Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) is a biologically, clinically, and genetically distinct subtype of precursor-B ALL. The Ph chromosome, results from a reciprocal translocation of the ABL1 kinase gene on chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22. Depending on the translocation breakpoint, typically a p210 BCR-ABL1 or a p190 BCR-ABL onc protein are generated; both are constitutively active tyrosine kinases that play a central role to alter signaling pathways of cell proliferation, survival, and self-renewal, leading to leukemogenesis. In Ph-positive ALL, the p190-BCR-ABL (minor [m]-bcr) subtype is more frequent than the p210-BCR-ABL (major [M]-bcr) subtype, commonly found in chronic myeloid leukemia. The Philadelphia chromosome is the most frequent recurrent cytogenetic abnormality in elderly patients with ALL. Its incidence increases with age, reaching ∼50% in patients with ALL aged 60 years and over. Patients traditionally had a very poor outcome with chemotherapy, particularly if they do not undergo allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1). With the availability of multiple tyrosine kinase inhibitors (TKI), the therapeutic armamentarium is expanding quickly. However, there is no consensus on how to best treat Ph-positive ALL. With modern therapy, improved outcomes have led to the emergence of a number of controversies, including the need for intensive chemotherapy, the ideal TKI, and whether all eligible patients should receive an allo-HSCT, and if so, what type. Here, we discuss these controversies in light of the available literature.
1 INTRODUCTION
In the era preceding the availability of tyrosine kinase inhibitors (TKIs), the presence of the Philadelphia chromosome (Ph) conferred a poor prognosis to patients with acute lymphocytic leukemia (ALL), with long-term survival rates of ∼10%–20%.1-5 Allogeneic hematopoietic stem cell transplantation (allo-HCT) was considered the only potential curative option. Although this notion is being challenged with the availability of TKIs, this strategy is still considered as standard of care. Allo-HCT from a related or unrelated donor was widely used for consolidation, with 30%–65% long-term survival for patients receiving allo-HCT in first complete remission (CR1).5-7 Improvements in outcome after incorporating TKIs into the traditional combination chemotherapy protocols has generated significant discussions regarding the optimal chemotherapy-TKI combination and the role of allo-HCT in CR1 with the emerging hypothesis that the use of TKIs in frontline and during the entire therapy might improve the outcome of these to the point where an allo-HCT may not be necessary in CR1.8, 9 It may even be argued that with improvements in outcomes using newer more effective TKIs, the presence of the Ph abnormality may no longer be considered a high risk feature.
2 TKI IN THE MANAGEMENT OF PH-POSITIVE ALL
Historically, before the availability of TKIs and using standard ALL chemotherapy regimens, the CR rate for patients with Ph-positive ALL was lower than patients with Ph-negative disease.2, 5. The incorporation of imatinib into standard ALL therapy improved remission rates, and the depth of remissions.9, 10 Several cooperative ALL study groups demonstrated CR rates consistently above 90%, irrespective of whether imatinib was used alone or combined with multiagent chemotherapy.9, 11-18 These results were superior to previously reported CR rates of 65%–90% in younger patients2, 4, 19, 20 and 40%–60% in patients older than 60–65 years of age.21-23 The outcomes were even better when the TKIs are incorporated early and given daily and continuously with chemotherapy.10, 14, 26-28 These results led to the adoption of TKIs combined with chemotherapy as a standard of care for all patients with Ph-positive ALL. Several studies have been published with different TKIs combined with different chemotherapy protocols (Table 1).
| Number of patients | CR | OS | Comments | |
|---|---|---|---|---|
| GMALL18 | 55 | 96.3% with imatinib | 42% at 2 years for the whole group and no difference between groups | DFS 18.3 vs. 7.2 months in patient with negative PCR for BCR-ABL1 |
| 50% without imatinib | ||||
| GMALL14 | 92 | 95 | 36% at 2 years | PCR negativity 52% with concurrent vs. 19% with alternating schedule |
| GRAAPH 200331 | 45 | 96% | 68% at 18 months | PCR negativity of 29% |
| MDACC: hyperCVAD plus imatinib29 | 54 | 93% | 43% at 5 yrs | 39 de novo, 6 induction failure, 9 in CR from prior therapy |
| JALSG12 | 80 | 96% vs. 51% in historic control treated with same chemotherapy without imatinib | 57.9% at 2 years | 70% BCR-ABL1 transcript negativity |
| NILG30 | 59 compared with 35 patient who were treated without imatinib | 92% vs. 80.5% in the nonimatinib | 38% at 5 years | 63% proceeded to allo-HCT in the imatinib arm vs. 39% in the nonimatinib arm |
| MRC/ECOG24 | 441 (266 from preimatinib era and 175 after imatinib) | 92% with imatinib vs. 82% in the preimatinib era | 38% with imatinib vs. 22% preimatinib at 4 years | Earlier addition of imatinib was better than late |
| MDACC: hyperCVAD plus dasatinib33 | 72 patients | 96% | 46% at 67 months follow-up | 93% of patients achieved MMolR at 4 weeks |
| MDACC: hyperCVAD plus ponatinib65,66 | 64 patients | 98% | 76% at 3 years | 77% CMR |
| US intergroup34 | 97 patients | 88% | 69% at 3 years | Superior relapse free and OS reported in transplanted patients |
2.1 Imatinib
The German Multicenter Study Group for Adult ALL (GMALL) was the first randomized study that compared chemotherapy alone induction to imatinib alone induction. Despite the small sample size (55 patients), this trial established the safety [severe adverse events significantly more frequent during chemotherapy alone induction (90% vs. 39%; P = .005)] and efficacy [CR rate significantly higher in the imatinib arm (96.3% vs. 50% P = .0001)] in comparison to chemotherapy alone induction. It also showed that deeper responses led to longer disease control [disease free survival (DFS) 18.3 months in patients with undetectable breakpoint cluster region (BCR)-ABL1 vs. 7.2 months P = .002].18 In another trial, the same group (GMALL) demonstrated that concurrent administration of imatinib plus chemotherapy resulted in deeper responses compared with an alternating schedule [52% polymerase chain reaction (PCR) negativity for BCR-ABL1 in the concurrent imatinib chemotherapy arm vs 19% in patients in the alternating treatment arm; P = .01].14 The MD Anderson Cancer Center (MDACC) group published their experience using the hyperCVAD regimen (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) combined with imatinib in patients with de novo or minimally treated Ph-positive ALL, they reported a CR rate of 93% and 5-year OS rate of 43%.9, 29 The Japan Adult Leukemia Study Group (JALSG) treated 80 patients with multiagent chemotherapy protocol combined with imatinib.12 They reported CR rates of 96% with 70% BCR-ABL1 transcript negativity, compared with 51% CR in historic controls treated on the same chemotherapy protocol without imatinib.12 The 2-year event-free and overall survival (OS) rates were 45%, and 58%, respectively, both significantly better than in historical controls treated with chemotherapy alone (P < .0001 and P = .0002).
The Northern Italian Leukemia Group (NILG) reported the outcomes of 59 patients with newly diagnosed Ph-positive ALL treated with pulses of imatinib/chemotherapy, and compared them to 35 historical controls. They reported a CR rate of 92% in the imatinib group vs. 80.5% in the control group. The group 5-year survival rate was 0.38 vs. 0.23 in the control arm (P = .009); and 5-year DFS rate was 0.39 vs. 0.25 in the control arm (P = .044).30
The GRAAPH 2003 study31 enrolled 45 patients with newly diagnosed Ph-positive ALL. Imatinib was administered with HAM consolidation (mitoxantrone with intermediate-dose cytarabine) in early responders (corticosensitive and chemosensitive ALL) or with induction in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). They reported a CR of 96% and PCR-negativity of 29%. At 18 months, the cumulative incidence of relapse was 30%, DFS was 51% and OS was 65%, all 3 points compared favorably with results obtained in the preimatinib LALA-94 trial.
The UKALL12/E2993 study,24 the largest, included 175 patients treated with imatinib added to standard therapy, and compared then with a large historic cohort of 266 patients treated on the same trial in the pre-imatinib era. The study showed a considerable survival advantage for the imatinib-containing regimen. The earlier addition of imatinib during therapy resulted in the best outcome.5 The CR rate was 92% in the imatinib cohort vs. 82% in the preimatinib cohort (P = .004). At 4 years, the OS of all patients in the imatinib cohort was 38% vs. 22% in the preimatinib cohort (P = .003).
2.2 Second generation TKIs
Like imatinib, nilotinib, and dasatinib (second generation TKIs) function through competitive inhibition at the ATP-binding site of BCR-ABL1, leading to the inhibition of tyrosine phosphorylation of proteins that are involved in the intracellular signal transduction that BCR-ABL1 mediates.
2.2.1 Dasatinib
Dasatinib, a SRC and BCR-ABL1 inhibitor, is 325 times more potent against BCR-ABL1 than imatinib.32 It is active against all imatinib-resistant kinase domain (KD) mutations, except T315I.33 The MDACC group published their experience using the hyperCVAD regimen combined with dasatinib.25, 34, 35 Patients who achieved CR received maintenance with daily dasatinib and monthly vincristine and prednisone for 2 years, followed by dasatinib indefinitely. Among 72 patients treated, 96% achieved CR, 83% achieved cytogenetic CR after the first cycle, 93% achieved major molecular response (MMR) at a median of 4 weeks and 94% were negative for minimal residual disease (MRD) by flow cytometry at a median of 3 weeks with a median follow-up of 67 months, 46% were alive and 43% in CR. The median OS and DFS were 47 and 31 months, respectively. Seven relapsed patients had BCR-ABL1 KD mutations, including four with the threonine-to-isoleucine mutation at position 315 (T315I). Dasatinib-related grade 3 and 4 adverse events included bleeding, pleural/pericardial effusions, and elevated transaminases. HyperCVAD combined with dasatinib also showed good activity in the relapse setting (CR rate 96%; 5-years OS 46%).36 In imatinib-resistant Ph-positive ALL, responses to dasatinib-chemotherapy combination were short-lived, and most patients relapsed within 4 months.37 Dasatinib combination with lower intensity chemotherapy trials have been published and are detailed later.38-40
2.2.2 Nilotinib
In a phase II multicenter Korean study incorporating nilotinib with mulitagent chemotherapy, the CR rate was 91% and the molecular CR rate was 86%. Among 90 patients, 57 received an allograft. The achievement of a deep molecular response and the performance of allo-HSCT were associated with survival benefit. Even among patients who did not receive an allograft, MR5 (molecular remission with a BCR-ABL1 ratio <10−5) rate was 56% and MR3 (molecular remission with a BCR-ABL1 ratio <10−3) rate was 72%. Of note, among patients who achieved a molecular remission, the estimated 2-year molecular relapse free survival rates were not different between non-recipients and recipients of allo-HCT (65% vs. 53%), suggesting that a transplant may not be necessary for long-term survival if a deep remission is achieved.41 Nilotinib showed limited activity in imatinib-resistant Ph-positive ALL.42
2.3 Third generation TKIs
Despite the high remission rates obtained with the combination of chemotherapy with first and second-generation TKIs, long-term survival remains at 40%–50%, with most relapses attributed to TKI-resistance by acquiring the T315I mutation,39 or clones that confer a high degree of resistance.25, 27, 33, 39, 40, 43, 44 Both acquired and intrinsic resistance to TKIs have been described.45, 46
Ponatinib is a small molecule third generation TKI active against mutated and unmutated BCR-ABL1, including T315I, which is present in up to 20%–50% of patients with TKI resistant disease and confers resistance to all other approved BCR-ABL1 TKIs.47-52 It contains a novel triple-bond linkage that avoids the steric hindrance caused by the bulky isoleucine residue at position 315 in the T315I mutant.53 It is the only registered TKI with activity against all single residue BCR-ABL1 mutant-clones.54 Ponatinib, through its multikinase inhibitor activity,55 is able to suppress mutations and control the genomic instability that can activate other oncogenic routes or promote the emergence of other mutations in advanced disease.56, 57 These characteristics support the hypothesis for a role of ponatinib not only in patient resistant to prior TKI therapy but also in untreated ALL Ph-positive patients, in order to prevent the emergence of resistance. Compound mutations involving the T315I variant potentially confer resistance to ponatinib.58 The incidence of these compound mutations is not known. One study showed that these are frequent in the advanced phase of disease,59 while another study showed the opposite.59 Compound mutations in BCR-ABL1 may develop sequentially and have been associated with resistance to other TKIs.60-63
In a phase II trial of heavily pretreated patients who had CML or Ph-positive ALL (32 patients) with resistance to or unacceptable side-effects from dasatinib or nilotinib, or who had the BCR-ABL T315I mutation64 41% of Ph-positive ALL patients treated achieved hematologic response, 47% had a major cytogenetic response, 38% obtained a complete cytogenetic response (CCyR), showing that ponatinib provides significant benefit despite previous intolerance or refractoriness to other TKIs.
In a phase II trial65, 66 ponatinib combined with hyperCVAD achieved a CCyR rate of 98%, a MMR rate 97% and a complete molecular response (CMR) rate of 77%. After a median follow up of 33 months, the 3-year OS and remission rates were 76% and 79%, respectively, a significant improvement compared with first and second-generation tyrosine-kinase inhibitors.67 The reported 2-year CR and OS for imatinib plus hyperCVAD were 58% and 67%, respectively, and for dasatinib plus hyperCVAD 70% and 64%, respectively.23, 27 Grade ≥3 pancreatitis and thrombotic events was reported in 19% and 11% of ponatinib-treated patients, respectively. No grade ≥3 vascular events occurred after the protocol amendment (ponatinib dose was reduced to 30 mg daily continuously starting with the second cycle, and then reduced to 15 mg daily continuously once a CMR was achieved).
A propensity score matching analysis comparing HyperCVAD + ponatinib versus HyperCVAD + dasatinib revealed a significantly improved rate of CMR with ponatinib (82% vs. 65%, P = .05, respectively) and improved 3-year EFS (69% vs. 46%, P = 0.4) and 3-year OS (83% vs. 56%, P = .03).68 NCT02776605 is an ongoing trial evaluating the efficacy of ponatinib with standard chemotherapy (according to PETHEMA ALL Ph08 trial) in young patients with Ph-positive ALL.
Due to concerns of thrombotic vascular events, ponatinib was transiently withdrawn from the US market in October 2013, upon the recommendation of the FDA, and later reintroduced in January 2014. The initial dose of 45 mg daily was linked to a boxed warning regarding arterial thrombosis and hepatotoxicity. In the phase 1–2 studies of ponatinib, toxicity rates were dose-dependent, and the pharmacokinetic and pharmacodynamic activities of the 30 and 45-mg doses were roughly equivalent.54, 64 Additionally, at a dose of 30 mg, the ponatinib concentration in the plasma was enough to be active against all the reported BCR-ABL1 mutations and to inhibit the emergence of resistant clones.69 Furthermore, follow-up of the PACE study showed that most patients with BCR-ABL1 T315I had maintained cytogenetic responses despite the dose reductions.70
The rate of thrombotic events with ponatinib in the early studies was 37% and 24% in the phase I and II clinical trials, respectively.71, 72 Most patients experiencing thrombotic events in previous clinical trials had pre-existing risk factors for cardiovascular events.73, 74 A post hoc analysis of previous clinical trials using ponatinib projected that dose reductions of 15 mg/day were associated with a 40% reduction in relative risk of arterial thrombosis.75
The development of thrombosis is a major safety concern of ponatinib. Thrombosis has been reported with all TKIs, although at different frequencies.76-79 Because ponatinib is a multikinase inhibitor, it is possible that inhibition of certain kinases such as VEGF, FGFR, or PDGFR can promote endothelial dysfunction, which predisposes to thromboembolic events.80, 81 Selecting patients with minimal or no cardiovascular risk factors, reducing the dose of ponatinib to 30 mg after remission induction and to 15 mg after achieving CMR are options to decrease the risk of thromboembolic complications.
The combination of cytotoxic chemotherapy with TKIs is now the standard of care for patients with Ph-positive ALL. It has been established that TKI therapy be started immediately upon recognition of Ph-positive disease, and that continuous exposure is superior to pulsed or intermittent administration.2, 10, 14, 27, 28, 30
3 DO WE STILL NEED INTENSE CHEMOTHERAPY PROTOCOLS IN THE MANAGEMENT OF PH-POSITIVE ALL?
There are two possible strategies for the management of Ph-positive ALL: intensive chemotherapy such as hyperCVAD with a TKI, or less intense chemotherapy with a TKI. Given the central role of TKIs in controlling the malignant clone in Ph-positive ALL, the need for intensive chemotherapy, especially in older adults, has been brought into question.
The GIMEMA group (Gruppo Italiano Malattie Ematologiche dell'Adulto) fırst reported the efficacy of a chemotherapy-free regimen in elderly patients with Ph-positive ALL using imatinib 800 mg/day with prednisone.17 Complete remission was obtained in all patients with low toxicity; however remission duration was short in patients not eligible for allo-HCT.17 The median survival was 20 months, with a 12-month OS rate of 74%. The GRAALL AFR07 trial enrolled older patients (>55 years) with advanced Ph-positive ALL and CML lymphoid blastic phases on a vincristine and dexamethasone combination with high-dose imatinib (800 mg/day).82 They reported a CR rate of 90%. A similar induction regimen was used in the ALLOPH07 study from the PETHEMA group (53 patients aged > 55 years), followed by maintenance without consolidation. High remission rates were observed (87%) median survival was 37.3 months.83
The GRAAPH-2005 study84 is the only randomized trial that compared reduced intensity chemotherapy with imatinib to standard therapy (hyperCVAD) combined with imatinib. Two hundred and sixty-eight adults (median age, 47 years) with Ph-positive ALL were randomized to receive induction with hyperCVAD and imatinib versus low intensity chemotherapy (vincristine and dexamethasone) with imatinib. Post induction chemotherapy was similar in the two groups (with intensive chemotherapy) and the use of imatinib was intermittent. With fewer induction deaths, the complete remission rate was higher in the reduced chemotherapy arm than in the standard therapy arm (98% vs. 91%; P = .006). The MMolR rate was similar in both arms (66% vs. 64%). The 5-year EFS and OS were 37.1% and 45.6%, respectively, with no difference between the two arms. A substantial proportion of patients underwent allogeneic or autologous stem cell transplant. A donor versus no donor analysis did not show a benefit for allo-HCT in patients achieving MMolR.
The EWALL-PH-01 international study enrolled older patient (>55 yrs) on a low-intensity chemotherapy regimen combined with dasatinib. Seventy-one patients (median age 69 years) were enrolled; 77% had a high comorbidity score. The CR rate was 96% and the MMR rate was 65%. At 5years, the OS was 36% (45% taking into account deaths unrelated to disease or treatment).39 The GIMEMALAL1205 trial demonstrated a 100% hematologic remission rate with dasatinib monotherapy.40 The GIMEMA LAL1509, evaluated dasatinib and corticosteroid induction treatment, but added chemotherapy and/or allo-HCT for patients who did not reach a sustained CMR.85 They reported an OS of 60% and DFS of 50% at 36 months. The same group is exploring ponatinib as a single agent in the frontline setting for old or unfit patients for intensive therapy or allo-HCT (NCT01641107).
While both approaches may achieve a similar remission rate, the CMR rates are superior with intensive chemotherapy, although there is no head-to head prospective study comparing CMR with these two approaches.
4 TRANSPLANT FOR PHILADELPHIA POSITIVE ALL
Currently, allo-HCT remains the standard consolidation therapy in Ph-positive ALL. Several reports have demonstrated a clear survival benefit for post-induction allo-HCT over chemotherapy-imatinib combination.27, 84, 86-88 In some studies, patients ineligible for HCT have been treated with TKI-based maintenance therapy.10, 16-18, 35 Although early results with short follow-up were promising, late relapses still occurred after a median duration of remission of 20–25 months and this approach currently cannot be considered curative. Most relapses were associated with a highly resistant phenotype and BCR-ABL1 gene mutations including T315I.89, 90 The use of MRD monitoring by quantitative PCR for BCR-ABL1 will probably help selecting patients where allo-HCT is not needed in CR1 (mirroring the utility of MRD in Ph-negative ALL). Recently, two studies showed improved outcomes with the achievement of MMolR or deeper response at 3 months of therapy. These patients probably can be spared from allo-HCT in CR1.91,92
The LALA-94 trial showed that a matched sibling donor transplant improved remission duration.2 The UKALL12/E2993 trial showed that transplanted patients with Ph-positive ALL had a better outcome than those receiving chemotherapy alone.5 However, the children's oncology group study showed better outcomes in children treated with imatinib/chemotherapy (25 patients) compared to those receiving with allo-HCT (21 patients); however the number of patients was small and the study was not powered to detect statistical significance for such difference.26 Most recently, a multicenter US intergroup trial showed superior RFS and OS for the transplanted patients, after induction with hyperCVAD and dasatinib.35
With the advent of TKIs and the deep remissions attained from the combination of TKI-chemotherapy, auto-HCT has become an attractive option. A retrospective review of 177 with Ph-positive ALL patients from the European group compared the outcomes of auto-HCT before and after the era of TKI. This review showed improvement in OS and leukemia-free survival (LFS) during the era of TKI, especially in patients with MRD negative state at the time of transplant.93 The CALGB Study 10001 enrolled 58: patients; 19 underwent autologous and 15 underwent allo-HCT. The OS and LFS were similar among patients who underwent auto-HCT or allo-HCT.94 These results are supported by other studies demonstrating success of auto-HCT in Ph-positive ALL, especially in the setting of negative MRD.30, 84, 95-97 The French and Northern-Italian study groups reported, encouraging results with LFS exceeding 60%, and the French group already recommends auto-HCT for patients with low level of MRD.10, 30
Post-transplant TKI, either as prophylaxis or triggered by MRD-positivity, is a standard of care in most parts of the world, despite the fact that no trials have shown a benefit with maintenance TKI. The GMALL reported a prospective, randomized, multicenter trial of imatinib administered either prophylactically (26 patients) or only after detection of BCR-ABL transcripts (29 patients).98 The study did not find a difference in outcome between the two arms.
4.1 Relapse
KD mutations are present in minor leukemic-cell clones at diagnosis (up to 40% of newly diagnosed, treatment-naive patients can carry these mutations in a minor clone).89 Importantly, at relapse, these minor clones become dominant. Interestingly, these pre-existing mutations (including T315I mutation) did not impact the CR rate or MMolR achievement following imatinib or chemotherapy when compared with unmutated patients at diagnosis.89 This means that imatinib initially suppressed the dominant, unmutated leukemic population and, at relapse, the mutated clone reemerged. KD mutations are also reported in around 80% of patients at the time of relapse,50, 89 even among initially unmutated patients. In the EWALL-PH-01 36 patients relapsed, 24 were T315I-positive.39 This same study reported the mutational analysis on 43 patients before receiving any therapy, 23% (10 patients) had T315I-positive clones at the sensitivity level of 0.05%. Eight of these 10 mutated patients relapsed, all with T315I mutation. Two patients did not relapse, one received allogeneic HCT, and the other died in CR at 9.6 months from lung adenocarcinoma. During the initial phase of the disease, resistance to TKI therapy seems to be mainly dependent on the selection and expansion of clones harboring BCR-ABL1 mutations. At later stages of the disease, resistance to TKI therapy rely mainly on the activation of BCR-ABL1-independent mechanisms,99 which involve oncogenic pathways other than BCR-ABL.
Patients with relapsed Ph-positive ALL have a poor prognosis. Given the emergence of T315I mutations in over 50% of patients, and the expansion of these clones in relapse, patients who did not receive ponatinib in the upfront setting may benefit from it in relapse. There are also emerging antibody therapies that may have role in therapy.
In a phase II study of blinatumomab in patients with Ph-positive ALL who had relapsed after or were refractory to at least one second-generation or later TKI (dasatinib, nilotinib, bosutinib, ponatinib), or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib, blinatumomab resulted in a CR/CRh rate of 36%, with responses seen in patients with T315I mutations. Blinatumomab induced complete MRD responses in 88% of patients who achieved a remission, making it an attractive bridge to transplant.100 The INO-VATE study of inotuzumab included Ph-positive patients who were CD22 positive, also showed the drug activity in Ph-positive ALL.101 Combinations using these new agents (blinatumomab, inotuzumab, ponatinib…) might prove to be very effective.
5 CENTRAL NERVOUS SYSTEM (CNS) INFILTRATION WITH ALL
In the MRC UKALLXII/ECOG 2993 study, CNS disease occurred in 5% of patients diagnosed with conventional criteria (unequivocal morphologic evidence of lymphoblasts in the cerebrospinal fluid, cranial nerve palsies, or significant neurologic dysfunction).102 Patient with Ph-positive ALL were not more likely than those with Ph-negative disease to have CNS leukemia. Most regimens include high-dose methotrexate/and or high dose cytarabine that cross the blood brain barrier. Intrathecal chemotherapy is a vital component of CNS-directed therapy. Many protocols still incorporate radiation therapy in the presence of CNS disease. CNS positivity currently does not affect the choice of TKI. Studies have shown that dasatinib can cross the blood-brain barrier.103-105 In a mouse model, ponatinib had the ability to cross the blood-brain barrier.55
6 FUTURE DIRECTIONS
This review highlights the recent advances and the paradigm change in the management of Ph-positive ALL. TKIs have improved the outcomes of Ph-positive ALL dramatically. The emergence of mutations and the toxicity remain significant problems. Many questions remain unanswered: how to optimize the combination of TKIs and chemotherapy; which TKI is better; which chemotherapy is better; is allogeneic transplant still the better best therapeutic approach after achieving CR1? The combination of cytotoxic chemotherapy with TKIs is now the standard of care for patients with Ph-positive ALL. Tyrosine-kinase inhibitor treatment should be started immediately upon recognition of Ph-positive disease, and continuous exposure to TKIs is superior to pulsed or intermittent exposure.2, 10, 14, 27, 28, 30 The achievement of CMR (defined as the absence of a detectable BCR-ABL1 transcripts) early on during therapy is associated with promising results [longer median OS (127 months vs. 38 months, respectively, P = .009) and RFS (126 vs. 18 months, respectively, P = .007)].85, 92 CMR at 3 months may identify patients with Ph-positive ALL who have excellent long term outcomes without allo-HCT in CR1, or at a cost of continuing TKI therapy as maintenance indefinitely with all the cost and side-effects implications. Ponatinib is probably the most powerful TKI available: CMR rates are reported to be 78% with ponatinib,66 28%–50% with imatinib29, 106, 107 and 45%–65% with dasatinib.34, 108 The thrombotic risk, universal with all TKIs, is concerning with ponatinib. The use of lower-dose ponatinib and patient selection preserve efficacy and decrease the risk of thrombotic events. There is no consensus as to the best chemotherapy regimen to combine with TKIs. Intensive chemotherapy and low-intensity chemotherapy regimens combined with different TKIs have been reported. The efficacy of low dose chemotherapy with TKIs is compelling and less toxic. Regimens without chemotherapy (steroids and TKIs) are being explored and seem to be an attractive choice. Auto-HCT in the setting of low level MRD may be equivalent to Allo-HCT. Finally, a personalized approach to consolidate these patients may be reasonable. A patient who achieves an early CMR might benefit from an auto-HCT rather than the more toxic allo-HCT, and a short course of TKI after auto-HCT, which can decrease the risk of exposure to TKI and the side-effects should be explored. A patient with persistently positive BCR.ABL1 transcripts probably still needs to be offered allo-HCT from any graft source at the time when disease control is achieved.
