Treatment of Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Opinion Statement

With the introduction of tyrosine kinase inhibitors (TKIs) in the management of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), the prognosis of patients has improved dramatically. Currently, the standard of care in the frontline setting is TKI in combination with chemotherapy. Age-adjusted chemotherapy or corticosteroids alone have been used with TKIs in elderly patients with comorbidities with modest long-term benefit. The primary goal of treatment is the achievement of early deep molecular remission as achievement of complete molecular remission at 3 months has been demonstrated to be predictive of higher long-term survival. The probability of attaining this goal by a more potent TKIs like dasatinib or ponatinib is higher, thus we recommend the use of second or third generation TKI over imatinib. Clinicians should be aware of possible fatal cardiovascular events mainly related to ponatinib. Allogeneic hematopoietic stem cell transplantation (alloHSCT) should still be considered in first remission, especially for younger patients treated with imatinib combination therapy. A subset of patients achieving complete molecular remission at 3 months may be able to continue consolidation and maintenance with chemotherapy and TKI without the need for alloHSCT. Intrathecal chemoprophylaxis is mandatory for all patients and some studies have suggested the need for 12 intrathecal therapies. New strategies incorporating novel agents, such as antibody-drug conjugates, bispecific monoclonal antibodies, potent TKIs, and CAR T cells are under investigation.

Introduction

The Philadelphia chromosome (Ph) is the most common chromosomal abnormality in adult acute lymphoblastic leukemia (ALL), and represents an independent risk factor with inferior outcomes compared to Ph chromosome negative (Ph-) ALL patients. [1] The incidence of Ph chromosome positive (Ph+) ALL increases with age, reaching 50% in patients older than 60 years. [2] Historically, adult patients with Ph+ ALL treated with standard chemotherapy regimens alone, had very poor outcomes. Despite high rates of complete remission (CR) with induction chemotherapy reaching up to 90%, the duration of remission was short and the 5-year overall survival (OS) did not exceed 20%. [3, 4] The understanding of the pathophysiology of Ph+ leukemias and the role of BCR-ABL1 oncoprotein in leukemogenesis paved the way for the discovery of imatinib mesylate, the first generation tyrosine kinase inhibitor capable of blocking the adenosine triphosphate (ATP) binding site of BCR-ABL1 oncoprotein and preventing the activation of downstream proliferative and survival pathways. [5, 6] Since and the discovery of imatinib , ongoing research has significantly changed the landscape of therapy of Ph+ ALL. In this review, we will discuss different treatment options for adult Ph+ ALL and discover the future directions and perspectives in optimizing long-term outcomes.

Treatment Options

First-generation tyrosine kinase inhibitor: Imatinib.

Introduction of Imatinib transformed the treatment of adult patients with Ph+ ALL. Although single agent activity was modest and not durable, [7] the combination of imatinib with standard chemotherapy regimens in the frontline setting marked the beginning of a new era. The combination was generally safe, and yielded CR rates between 91 and 98% with an unprecedented 5-year OS of up to 50%. [8–15] In an updated single-institution phase II trial combining imatinib with hyperfractionated cyclophosphamide, vincristine, Adriamycin and dexamethasone (HyperCVAD) chemotherapy, 54 older patients with a median age of 51 years [range, 17–84] were treated. The CR rate was 93% with a complete molecular remission (CMR) at 3 months of 45%. Despite a low proportion of patients (30%) undergoing subsequent allogeneic hematopoietic stem cell transplantation (alloHSCT) in first remission (CR1), the 5-year OS was 43%, remarkably better than historical controls. [13] Early and concomitant administration of imatinib with chemotherapy has since been incorporated into various standard regimens used to treat newly diagnosed adult patients with Ph+ ALL. The UKALLXII/ECOG2993 study evaluated 441 adult patients newly diagnosed with Ph+ ALL with a median age of 42 years [range, 16–64]. Patients were enrolled into 3 consecutive cohorts, 266 patients in the pre-imatinib cohort, 86 in the late imatinib cohort in which imatinib was introduced as single agent after 2 induction courses, and 89 in the early imatinib cohort in which imatinib was added to the second phase of induction. Authors reported a higher CR rate in the imatinib cohort compared to pre-imatinib cohort (92% versus 82% respectively, p=0.004), and an improved 4-year OS (38% versus 22% respectively, p=0.003). The early introduction of imatinib further improved outcomes with a 4-year OS of 43%. The authors suggested that improvement in survival was in part related to the higher rate of alloHSCT with imatinib (46% in the imatinib cohort versus 31% in the pre-imatinib cohort). [11] Combining imatinib with reduced intensity chemotherapy is also feasible, and capable of achieving higher CR rate allowing the transition to alloHSCT in CR1. In the GRAAPH-2005 trial, 268 adult Ph+ ALL patients with a median age of 47 years [range,18–59] were randomized to either imatinib (400 mg twice daily from day 1–28) combined with reduced intensity chemotherapy (vincristine and dexamethasone) or imatinib (400 mg twice daily from days 1–14) with hyperCVAD chemotherapy during induction course. [12] The CR rate was higher in lower intensity chemotherapy compared to hyperCVAD (98% versus 91% respectively, p=0.006), mainly attributed to differences in induction deaths (1% versus 6% respectively). Among responders, 63% underwent alloHSCT and 14% had autologous HSCT (autoHSCT). With a median follow-up of 4.8 years, the 5-year event free survival (EFS) and OS were 37% and 46% respectively, with no differences between the two groups. [12]

Development of secondary resistance to imatinib has led to the development of a number of second and third generation TKIs designed to overcome the resistance mechanisms.

Second-generation tyrosine kinase inhibitor: Dasatinib and Nilotinib.

Dasatinib is a second-generation multikinase inhibitor of BCR-ABL1 in both active and inactive forms. Its activity is less dependent on P-loop interactions for drug binding, overcoming most of the imatinib resistant kinase domain mutations, except for T315I mutation. [16, 17] Dasatinib showed initial activity as single agent in patients with Ph+ ALL resistant or intolerant to imatinib. [18–20] In a phase 2 trial, 58% of patients with Ph+ ALL resistant or intolerant to imatinib achieved complete cytogenetic remission (CCyR) with single agent dasatinib 140 mg orally daily. [18] Another international phase 2 trial showed both major hematologic and cytogenetic responses in 35% and 52% respectively in patients with imatinib resistant or intolerant CML in lymphoid blast phase. [19] Observed responses however were short lived with a median progression free survival (PFS) of only 3 months. Ravandi et al combined dasatinib with standard chemotherapy in the frontline setting. In a single-institution phase 2 trial, 72 new diagnosed Ph+ ALL patients with a median age of 55 years [range,21–80] were treated with hyperCVAD chemotherapy in combination with dasatinib (100 mg daily for the first 14 days, then 70 mg daily continuously with consolidation and maintenance cycles). The CR rate was 96%, with CCyR and CMR achieved in 83% and 65%, respectively. The 5-year relapse-free survival (RFS) and OS were 44% and 46%, respectively with a median follow-up of 67 months for surviving patients. [21] The SWOG S0805 study included 97 newly diagnosed Ph+ ALL patients with a median age of 44 years [range, 20–60]. Patients received hyperCVAD chemotherapy with dasatinib followed by alloHSCT in CR1. The overall response rate (ORR) including CR and CR with incomplete count recovery (CRi) was 88%.41 (49%) patients underwent an alloHSCT in CR1. The 3-year RFS and OS were 62% and 69%, respectively. [22]

Not all patients can tolerate intensive chemotherapy, mainly because of higher mortality rates related to risks of severe cytopenias and infections in older patients with comorbid conditions. Several studies demonstrated the possibility of long-term survival with acceptable toxicity in elderly patients without the need for intensive chemotherapy or alloHSCT. [23–25] The GIMEMA group tested dasatinib 70 mg twice daily combined with only prednisone 10–60 mg/m2 per day and intrathecal chemotherapy for 84 days in patients with newly diagnosed Ph+ ALL. All 53 patients (median age, 54 years, [range, 24–76]) achieved CR. The rate of MMR was continuously increasing with time, starting with 22% at day 22, 33% at day 43, 40% at day 57, and reaching 52% of patients at the end of induction course (day 85). Although only 60% of patients received consolidation chemotherapy after CR, the RFS was 51% at 20 months. [23] Chiaretti et al reported similar results with 60 patients with newly diagnosed Ph+ ALL with a median age of 42 years [range, 19–59] who were treated with dasatinib 140 mg daily and steroids. At end of induction course (85 days), the CHR rate was 97%, with a sustained CMR achieved in 11 patients (19%). All patients then received chemotherapy or alloHSCT. The OS at 3 years was 58%, with a median follow-up of 28 months. [24] The European EWALL-PH-01 international study investigated dasatinib (100 −140 mg daily) in combination with low-intensity chemotherapy, consisting of vincristine and dexamethasone during induction, and L-asparaginase, high dose methotrexate and intermediate dose cytarabine in consolidation cycles, in older patients aged 55 years and above. 71 patients with a median age of 69 years [range, 59–83] were enrolled. Despite achieving CR rate in 96% of patients with a MMR rate of 65%, the 5-year RFS and OS were only 28% and 36%, respectively. In this older population, only 10% of patients underwent alloHSCT. These results confirmed the possibility of achieving remission with modest long-term survival in elderly patients without the need of intensive chemotherapy or alloHSCT.

Nilotinib is another second-generation TKI with higher affinity for BCR-ABL1 compared to imatinib. [26] In a multicentric phase 2 trial from Korea, 90 patients with newly diagnosed Ph+ ALL with a median age of 47 years [range, 17–71] were treated with nilotinib 400 mg twice daily in combination with chemotherapy (vincristine, daunorubicin and prednisolone). The CHR was 91% following induction treatment. The cumulative CMR was unprecedentedly high, reaching 94% of responders with 57 patients (70%) proceeding to alloHSCT in CR1. The 2-year RFS and OS were 72% and 72% respectively. [27] Nilotinib in combination with lower intensity chemotherapy has also been investigated. The EWALL group showed high efficacy in combining low-intensity chemotherapy with nilotinib in patients older than 55 years. Among 56 older patients treated with a median age of 65 years [range, 55–85], 87% achieved CR. With a median follow-up of 8.5 months, the OS was 73% at 2 years without the need of alloHSCT. [28] Recently, Chalandon et al presented the interim analysis of the GRAAPH-2014 trial. [29] 60 patients with newly diagnosed Ph+ ALL with a median age of 47 years were treated with low-intensity chemotherapy in combination with nilotinib. The CR rate was 98%, with a cumulative MMR rate after 4 cycles of 93%. 73% of patients were able to proceed to alloHSCT in CR1. With a median follow-up of 14 months, the 1-year PFS and OS were estimated at 85% and 96%. This trial will continue to accrue for a total of 265 patients to determine if lower intensity chemotherapy with nilotinib will lead to better outcomes in elderly patients. [29]

Third-generation tyrosine kinase inhibitor: Ponatinib.

It has become evident that patients who relapse after therapy with imatinib, often acquire kinase domain mutations that confer resistance to imatinib. T315I mutation, noted in some reports in up to 65% of cases of acquired kinase mutations at time of relapse, is known to be less sensitive to all first and second generation TKIs. [30, 31] Ponatinib is a third generation pan-BCR-ABL1 inhibitor with very high potency specifically designed to overcome most of the kinase domain mutations, including T315I. [32] Most interestingly, kinase mutations were found in 37% of patients at time of diagnosis before even the initiation of treatment. Rousselot et al identified 23% of patients with T315I mutation at diagnosis, which was associated with early relapses. Of 24 patients at time of relapse, 18 (75%) patients were harboring a T315I mutation. [25]

Ponatinib as single agent resulted in CCyR in 38% of patients (N=32) with Ph+ ALL resistant to second-generation TKI or harboring T315I mutation. The median duration of response was short at 3 months with an estimated sustained response after 12 months of 8%. The 1-year OS was reported at 40%. [33] Ponatinib in combination with intensive chemotherapy has shown the highest anti-leukemia activity to date in a single institution phase 2 trial including 37 patients with a median age of 51 years [range, 27–75]. Patients were treated with hyperCVAD chemotherapy in combination with ponatinib at a dose of 45 mg daily for 14 days for the first cycle and then continuously after the second cycle. Due to safety concern related to increased risk of cardiovascular events, the protocol was amended, and ponatinib dose was reduced to 30 mg daily starting with the second cycle, then 15 mg daily indefinitely after CMR is achieved. Adverse events possibly related to ponatinib were seen in 3 patients (8%) with venous thrombotic events, and in another 3 patients (8%) with myocardial infarction; 2 patients died. Other serious adverse events like grade 3–4 liver dysfunction and grade 3 pancreatitis were seen in 37% and 16% respectively . All patients however achieved CR and 97% achieved MRD negativity by flow cytometry. The overall CMR rate was 78%. With a median follow-up of 26 months, the estimated 2-year OS was 80%. [34]. Updated results of this trial including 67 patients with a median follow-up of 33 months [range, 2–62] were reported recently. The rate of CR and CMR remains at 97% and 77% respectively. [35] There were no grade ≥ 3 vascular events reported after amendment and dose reduction. Given that ponatinib related adverse events, mainly arterial occlusive events are related to the dosing of ponatinib, a lower dose of ponatinib would be safer, while still maintaining efficacy. [36] has Available data confirms the central role of TKIs in the management of patients with Ph+ ALL. Currently, the standard of careis combination of a TKI with chemotherapy or corticosteroids. The main remaining question is which TKI is t is preferable. Due to lack of randomized trials evaluating the superiority of one TKI over the others, statistical efforts have been made to determine the optimal frontline TKI. A matched propensity score analysis identified patients with balanced characteristics treated in two different phase 2 trials with either dasatinib or ponatinib. The combination of hyperCVAD with ponatinib appeared superior to dasatinib with a 3-year RFS and OS of 69% versus 46%, and 83% versus 56%, respectively. [37] A meta-analysis combining 25 trials using earlier generation TKI versus hyperCVAD and ponatinib also showed higher long-term efficacy of ponatinib. The rate of CMR in pooled analysis using first or second generation TKI was 34% compared to 79% with ponatinib. The 3-year OS was significantly higher using ponatinib with 79% compared to 50% with others. [38] In general, the regimen resulting in higher rate of CMR should be selected. Ponatinib is preferred over the others in patients with low risk of cardiovascular complications; otherwise, dasatinib or nilotinib in combination with chemotherapy could be used.

CNS prophylaxis remains a part of the standard of care treatment in patients with ALL. Patients can relapse within the CNS even with dasatinib, known to have a better CNS penetration. In the phase 2 trial of hyperCVAD and dasatinib, 36% of relapsing patients had CNS-only disease. [21] We always recommend a total of 12 intrathecal chemoprophylaxis in newly diagnosed patients with Ph+ ALL.

Role of allogeneic hematopoietic stem cell transplantation.

In the pre-imatinib era, the prognosis of patients with Ph+ ALL treated with multiagent chemotherapy regimens was dismal. AlloHSCT in first remission was considered standard of care for all patients with an available donor. Patients undergoing alloHSCT lived longer with a 3-year OS of 36% compared to 17% for patients receiving autoHSCT. [3] In the UKALL/ECOG 2993 trial including 267 adult patients with Ph+ ALL, only 28% proceeded to alloHSCT in first remission. The estimated 5-year OS was 44% after matched related transplant, 36% after matched unrelated transplant and only 19% after consolidation chemotherapy, confirming the superiority of alloHSCT over chemotherapy. [39] After the breakthrough introduction of TKIs to the backbone chemotherapy with promising long-term outcomes, the usefulness of alloHSCT became questionable. In the GRAAPH-2005 trial, patients with Ph+ ALL were treated with imatinib in combination with steroids or intensive chemotherapy, and those with an available donor proceeded to alloHSCT in first remission. 63% of responding patients received alloHSCT, and 14% received autoHSCT. A donor versus no donor analysis did not show a statistically significant difference in outcomes. Furthermore, patients who achieved a major molecular remission (MMR) after the second cycle had similar RFS and OS if they received alloHSCT or autoHSCT. [12] In the nilotinib study by Kim et al, the MRD status after remission was predictive of survival regardless of alloHSCT. Among the patients who achieved CMR, the 2-year molecular RFS was similar between alloHSCT non-recipients and recipients (65% vs 53% respectively, p=0.783). The OS was also similar between the two groups. [27] Clinical outcomes of patients who had alloHSCT in first molecular remission were comparable to those who received autoHSCT with an estimated OS of 70%. [40] With the emergence of hyperCVAD and ponatinib as an attractive approach in the frontline treatment of Ph+ ALL, more patients are achieving deep molecular remissions at an early stage. Patients achieving CMR at 3 months may have favorable prognosis with prolonged survival, which can obviate the need of alloHSCT in first remission. [41]

Blinatumomab.

Blinatumomab is a bispecific T-cell engager anti-CD3 and CD19 antibody construct, leading to a serial lysis of B cells by redirecting CD3+ T cells toward CD19+ B-ALL cells. [42] Blinatumomab was evaluated in relapsed and/or refractory (R/R) Ph- B-ALL, and has demonstrated superior clinical efficacy as single agent compared to standard chemotherapy. In the TOWER trial, ORR including CR and CRi was achieved in 44% of patients with an estimated median OS of 7.7 months. [43–45] Martinelli et al recently reported on significant activity of blinatumomab in patients with R/R Ph+ ALL. [46] In a phase 2 multicentric trial (ALCANTARA), 45 adult patients were treated with blinatumomab after failure of at least one second or third generation TKI. The ORR was 36% after 2 cycles of therapy, which was similar to what was reportd in the TOWER trial. Among 10 patients with T315I mutation, four achieved CR/CRi; nine had previously received therapy with ponatinib. Among responders, 88% achieved a negative MRD, and 44% had a subsequent alloHSCT. The median RFS and OS were 6.7 and 7.1 months, respectively.

A potential mechanism of resistance to blinatumomab in Ph+ ALL can be the selection of CD19-negative, BCR-ABL1-positive clones. [47] Therefore, the addition of TKI to blinatumomab can potentially overcome this mechanism and can target both CD19- positive and negative clones to prevent relapses. The safety and efficacy of this approach in patients with R/R Ph+ ALL who failed prior TKI were reported by two retrospective studies in a small number of patients. [48, 49] In one study, 12 patients with R/R Ph+ ALL were treated with blinatumomab and TKI (ponatinib, dasatinib and bosutinib), the ORR (CR/PR) after the first cycle and overall CMR rate were 67% (4/6 patients) and 75% (9/12 patients) respectively. The combination was generally safe with only two reported cases of grade 2 cytokine release syndrome. [48] Another retrospective study on five patients reported same results with CMR achieved in 3 out of 5 patients, MMR in one patient and CCyR in one patient, with no reported related side effects. [49] The combination of blinatumomab with TKI is being further investigated in frontline and R/R setting in ongoing clinical trials. NCT02744768 is a phase 2 trial exploring frontline sequential dasatinib with steroids as induction treatment, followed by blinatumomab infusion in CR. NCT02143414 and NCT03263572 are two ongoing phase 2 trials investigating the combination of blinatumomab with dasatinib and ponatinib, respectively.

Inotuzumab.

Inotuzumab ozogamicin is a CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin. [50] It was approved by the FDA based on a randomized trial comparing inotuzumab ozogamicin single agent to standard chemotherapy in patients with R/R B-ALL. The CR rate was 81% with an estimated median OS of 7.7 months with inotuzumab treatment. [51] In the phase 1/2 and phase 3 trials evaluating the efficacy of inotuzumab ozogamicin, 38 patients with Ph+ ALL failing prior TKIs were treated. [52, 51] CR/CRi were seen in 9/16 (56%) patients and 16/22 (73%) patients in the phase 1/2 and the phase 3 trials, respectively. The estimated median PFS and OS were 4.4 and 7.4 months in phase 1/2 trial, 3.9 and 8.7 in phase 3 trial, respectively. [53] Although inotuzumab ozogamicin as single agent is effective in patients with R/R Ph+ ALL, the overall outcomes were still inferior compared to outcomes of patients with Ph- ALL. Thus, combining inotuzumab ozogamicin with TKI can improve responses and ultimately survival rates. In a phase 1/2 trial, 14 R/R Ph+ ALL patients with a median age of 62 years [range, 19–74] were treated with inotuzumab ozogamicin in combination with bosutinib. Patients with T315I mutation were excluded. CR/CRi were achieved in 11 (79%) patients. Among responders, 73% achieved MRD negativity by flow cytometry and 55% achieved CMR. The median EFS and OS were 8.1 and 8.2 months respectively. [54] This trial NCT02311998 is still ongoing and recruiting patients.

Conclusion and future directions.

The advent of TKIs in the management of Ph+ ALL has dramatically improved the prognosis of patients. With the use of more potent TKIs like ponatinib in combination with chemotherapy in the frontline setting, the long-term OS is now reaching 80%, compared to as low as 10% in the pre-TKI era. Patients with increased risk of cardiovascular complications may benefit from an alternate TKI such as dasatinib and nilotinib. The achievement of CMR at 3 months regardless of the TKI used is predictive of survival and should be the ultimate goal. Patientsachieving early deep molecular remission, can potentially continue consolidation and maintenance chemotherapy with TKI without the need for alloHSCT although this has to be done with detailed discussion of the risks and benefits of either strategy. Patients not achieving this milestone may potentailly be treated with blinatumomab to eradicate measurable residual disease and facilitate the transition to alloHSCT. Higher remission rates were also observed with lower intensity age-adjusted chemotherapy with a reduced risk of early mortality and acceptable long-term outcomes. This approach is best applicable for older and unfit patients. Combinations of TKIs and antibody-drug conjugates or bispecific monoclonal antibodies, as well as CAR T cells are In development.

Table 1.

Clinical outcomes of patients newly diagnosed with Ph+ ALL treated with TKI based therapies.

Study (year)	N	Median age, [range]	Regimen	CR, %	CMR, %	AlloSCT in CR1, %	OS, %
Imatinib
Wassmann (2006) [8]	45	41 [19–63]	GMALL	96	52 (after induction)	80	43 at 24 mo
Bassan (2010) [9]	59	45 [20–66]	NILG 09/00	92	40 (3 mo)	63	38 at 60 mo
Tanguy-Schmidt (2013) [10]	45	45 [16–59]	GRAAPH 2003	96	NA	53	52 at 48 mo
Fielding (2014) [11]	175	42 [16–64]	UKALLXII/ECOG2993	92	NA	46	38 at 48 mo
Chaladon (2015) [12]	135	49 [18–59]	GRAAPH 2005 Vincristine and dexamethasone	98	29 (2 cycles)	60	48 at 60 mo
	133	45 [21–59]	GRAAPH 2005 hyperCVAD	91	23 (2 cycles)	60	43 at 60 mo
Daver (2015) [13]	54	51 [17–84]	hyperCVAD	93	45 (3 mo)	30	43 at 60 mo
Lim (2015) [14]	87	41 [16–71]	Multiagent chemotherapy	94	66 (at CR)	64	33 at 60 mo
Hatta (2018) [15]	99	45 [15–64]	JALSG ALL202	97	72	60	50 at 60 mo
Dasatinib
Foa (2011) [23]	53	54 [24–76]	LAL1205 Corticosteroids	93	15 (day 85)	34	69 at 20 mo
Ravandi (2015) [21]	72	55 [21–80]	hyperCVAD	96	65 (3 mo)	17	46 at 60 mo
Chiaretti (2015) [24]	60	42 [19–59]	Corticosteroids ± chemotherapy	97	19 (day 85)	NA	58 at 36 mo
Ravandi (2016) [22]	94	44 [20–60]	hyperCVAD	88	NA	44	69 at 36 mo
Rousselot (2016) [25]	71	69 [55–83]	EWALL Vincristine and dexamethasone	96	24	10	36 at 60 mo
Nilotinib
Kim (2015) [27]	90	47 [17–71]	Multiagent chemotherapy	91	77 (3 mo)	63	72 at 24 mo
Ponatinib
Jabbour (2015) [35]	64	48 [21–80]	hyperCVAD	100	77 (3 mo)	16	76 at 36 mo

Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; TKI, tyrosine kinase inhibitor; CR, complete remission; CMR, complete molecular remission; AlloHSCT in CR1, allogeneic hematopoietic stem cell transplantation in first remission; OS, overall survival; GMALL, German Multicentric Study Group for Adult ALL; NILG, Northern Italy Leukemia Group; GRAAPH, Group for Research on Adult Acute Lymphoblastic Leukemia; JALSG, Japan Adult Leukemia Study Group; hyperCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone; EWALL, European Working Group on adult ALL.