Moorman, Anthony V.

Abstract Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1− B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non–risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.

Abstract Background: Pre-treatment cytogenetics is a known predictor of outcome in haematological malignancies. However, its value in adult ALL is generally limited to the presence of the Philadelphia (Ph) translocation; mostly due to the low incidence of other recurrent chromosomal abnormalities. Methods: Since 1993, cytogenetic data from patients enrolled on a joint MRC/ECOG trial have been collated and reviewed centrally in the UK and US. Karyotype data from patients registered before the Imatinib amendment were pooled using standard cytogenetic definitions and classification criteria. Results: A successful cytogenetic result was achieved in 938/1235 (76%) cases; while 297 (24%) failed with <20 normal metaphases analyzed. Patients were classified into the following mutually exclusive groups: t(9;22)(q34;q11) n=193(21%); t(4;11)(q21;q23) n=50(5%); other MLL translocations n=11(1%), t(8;14)(q24;q32) and variants n=14(1%); t(1;19)(q23;p13) n=23(2%); T cell receptor translocations n=35(4%); low hypodiploidy (30–39 chromosomes) /near triploidy n=23(2%); high hyperdiploidy n=83(9%); tetraploidy n=12(1%); complex karyotype (>=5 aberrations) n=48(5%); other abnormal n=255(27%); normal n=191(20%). MRC and ECOG patients showed similar cytogenetic distributions, except for t(9;22), which was significantly more prevalent in the ECOG cohort (27% v 18%, p<0.001). However, the incidence of t(9;22) increased with age and ECOG patients were significantly older. Overall, the 5 year event free survival (EFS) was 32% (95% CI 30%–35%) with a median follow-up time of 5.1 years and did not differ between the two cohorts. The EFS of t(9;22) patients [15% (11%–21%)] was significantly inferior compared with all other cases [36% (32%–39%)] (p<0.001) and was independent of age and white cell count (WCC). Univariate logrank analyses identified t(4;11) and high hyperdiploidy as indicators of poor and good prognosis, respectively, compared with other Ph negative cases, but neither was independent of age and WCC. Three subgroups were shown to have a significantly worse EFS compared to other Ph negative cases by logrank analyses after adjusting for age and WCC: t(8;14) 14% (2%–37%) v 36% (32%–40%) (p=0.01); low hypodiploidy 22% (8%–40%) v 36% (32%–40%) (p=0.02); complex karyotype 21% (10%–33%) v 32% (29%–35%) (p=0.005). Neither of the latter two subgroups were associated with other poor risk features such as age, WCC or failure to achieve a remission within 4 weeks. Conclusions: This is the largest cytogenetic dataset of adult ALL reported to date and demonstrates the importance of combining cohorts to increase the number of cases available for analysis. The observation that low hypodiploidy and, for the first time, karyotype complexity confer a poor risk, demonstrates that cytogenetic subgroups other than the Ph translocation can and should be used to risk stratify adults with ALL to alternative treatments.

Abstract The International ALL trial, conducted jointly by the MRC in the UK and ECOG in the US (UKALL XII/E2993), recruited 1929 patients between 1993 and 2006. All patients aged 16 to 64 years with newly diagnosed ALL, received the identical two phases of induction therapy. Patients with an HLA-identical sibling were assigned to a sibling allogeneic transplant and those who were Ph-positive could also get an unrelated-donor transplant. Patients who did not have a donor were to be randomized between a single autologous transplant, after conditioning with etoposide/total body irradiation, versus consolidation/maintenance therapy for 2.5 years. Following randomization, but prior to receiving the assigned or randomized therapy, all patients received intensification with 3 cycles of high-dose methotrexate. After excluding patients assigned to an allogeneic transplant, 1028 patients were eligible for randomization but, as in other major transplant studies, only 457 were randomized. The rationale underlying the randomization was based on the fact that protracted consolidation/maintenance therapy in adults, extrapolated from the pediatric experience, had never been prospectively evaluated in the era of intensive chemotherapy. Given that the mortality from autotransplant is not higher than chemotherapy (Goldstone et al. Blood. 2008), it was postulated that if a single autologous transplant is at least as good as standard protracted chemotherapy that may make it the preferable option, except possibly in females in whom fertility may be an issue. The overall survival and the event-free survival were significantly superior among the chemotherapy patients (p = .05) as previously reported (Goldstone et al. Blood. 2008). Because the literature contains reports suggesting a trend in favor of autologous transplantation in some patients with ALL (Dhédiu et al. Leukemia, 2006), an analysis was performed to see if any subgroup of patients could be identified in whom: 1. chemotherapy may not be superior to autologous transplant and 2. autologous transplant may be superior. The table lists a detailed analysis of overall survival looking at various age groups, B- versus T-lineage, the rapidity with which a complete remission was achieved –after phase I or only after phase II of induction. Detailed analysis was also performed by cytogenetics looking at those with standard risk versus those with high risk abnormalities [ t(9;22), t(4;11), t(8;14)] and low hypodiploidy/near triploidy or a complex karyotype (Moorman et al. Blood. 2007)]. In all groups, the chemotherapy group was at least as efficacious as the autograft group, and in some was even significantly superior to autologous transplantation. There is no evidence that other risk factors, such as relapse rate or treatment-related mortality, influenced these overall survival data. In addition, the tests for heterogeneity were not significant across any group. In conclusion, the overall survival was longer in patients randomized to chemotherapy, although the superiority was not statistically significant in most of the groups. There is no clinical indication for autologous transplantation at any age and particularly this should not be considered for patients over age 50, those with high-risk cytogenetics or T-lineage, and late remitters, for whom it might appear most attractive. Overall Survival (OS) at 5 years in 457 Randomized Patients Chemo Auto Subgroups n OS n OS P (log rank) Age (years) < 20 50 58% 43 46% > 0.1 20–29 61 52% 70 43% > 0.1 30–39 46 39% 46 32% > 0.1 40–49 38 31% 35 31% > 0.1 50 + 33 38% 35 31% > 0.1 B-lineage 169 46% 158 35% 0.03 T-lineage 45 54% 54 49% > 0.1 Time to CR phase I 193 48% 190 41% 0.1 phase II 26 36% 29 19% 0.08 Cytogenetics standard-risk 109 51% 122 44% > 0.1 high-risk 29 23% 27 7% 0.02

Abstract Abstract 524 The International UKALLXII/E2993 trial enrolled 2091 pts with newly diagnosed adult ALL between 1993 and 2006. Patients received 2 months of combination induction chemotherapy followed by an intensification course of high dose methotrexate and L-asparaginase after which pts were randomized to autologous hematopoietic stem cell transplant (HSCT) or consolidation and maintenance chemotherapy. Patients <55 years of age with a matched sibling donor were assigned myeloablative allogeneic HSCT (Goldstone, et al, Blood 2008; 111:1827). Here we report a detailed analysis of 1,229 pts from this trial with B-ALL, excluding Philadelphia-chromosome-positive patients. The median age was 30 years (range 14–65) and 59% were male. The median WBC was 9.2×109/L (range 0.1–930) and 73% of pts had a WBC <30 × 109/L. CNS involvement was present in 4% of pts at diagnosis. Comprehensive centralized immunophenotyping was performed in 372 of the 409 (91%) ECOG pts enrolled and initial analysis demonstrated pro-B/pre-pre-B in 17%, early pre-B in 52%, pre-B in 14%, either early pre-B or pre-B in 6%, mature B in 2% and B-lineage, not otherwise specified, in 9%. Outcomes were similar between patients with immunophenotyping data and those without. The complete remission (CR) rate was 93% and there were 4% induction deaths. The overall survival (OS), event-free survival (EFS), relapse risk (RR) and non-relapse mortality (NRM) at 5 years for the overall group is shown in the table. There were no significant differences in CR rate, OS, EFS, RR or NRM for the immunophenotypic subgroups. There was better OS and EFS with less relapse and similar risk of NRM for pts randomized to chemotherapy as compared with autologous HSCT (Figure 1). In the matched sibling donor-no donor comparison, OS and EFS were improved, RR was less and NRM was higher in the donor group (Figure 2). Cytogenetic analysis confirmed that patients with t(4;11) (n=77, 8% total), t(8;14) (n=19, 2% total), a complex karyotype (≥5 abnormalities in the absence of an established chromosomal abnormality) (n=38, 5% total), or low hypoploidy/near triploidy (n=41, 5% total) had an inferior OS and patients with high hyperdiploidy had a superior OS when compared to other patients. In conclusion, this is the largest series of B-ALL in uniformly treated adults ever reported and confirms the superior outcome of patients randomized to chemotherapy as compared with autologous HSCT and shows that patients with a matched sibling donor have an improved survival over patients without a donor. No difference in CR rates or outcome was noted for patients with different immunophenotypic subtypes of B-ALL. Future improvements in outcome of pts with B-ALL will rely on the addition of new agents such as B cell monoclonal antibodies and improvements in allogeneic HCT.Table.Outcomes at 5 years of follow-upnCR rate (%)OSEFSRRNRMOverall12299342375021Pro-B/pre-pre-B639236345421Early pre-B/pre-B2689340345421Age ≤ 35 years746 (61%)9653454516Chi square p<0.0001<0.0001<0.0001<0.0001<0.0001Age >35 years483 (39%)8932265930Randomized to autologous HSCT15735316610Log rank p0.030.010.01NSRandomized to chemotherapy1694742558Matched sib donor34452483032Chi square p0.050.03<0.001<0.001No Donor47445415510Values are % except n and p values. CR=complete remission, OS=overall survival, EFS=event-free survival, RR=relapse risk, NRM=non-relapse mortality NS=not significant. The p values represent the difference between age groups for the first comparison, randomized to autologous HSCT versus chemotherapy for the second comparison and between matched sibling donor and no donor for the third comparison. Overall survival by randomized allocation at 10 years Overall survival by donor availability at 10 years Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 663 Introduction: The biology and outcome of adult t(4;11) ALL are poorly understood. We report here 85 patients treated uniformly on the prospective trial (UKALL XII/ECOG 2993) with the aim of describing outcome and identifying prognostic factors and optimal therapy. Patients and methods: 1914 adult patients (≥15 years) with ALL were registered on the UKALL XII/ECOG 2993 study in the UK or United States from 1993–2006. Cell lineage was classified by local institutions (UK) or central immunophenotyping (ECOG). Cytogenetic, FISH and RT-PCR analyses of pre-treatment samples were either performed locally and reviewed centrally or performed centrally. Results: The 85 patients with t(4;11) were predominantly female (68%). Median age was 38 years (vs 32 years in the non-t(4;11) group) and 42% were >40 years. They had high white cell counts with 87% >30 and 66% >100 × 109/l (vs 7% in the non-t(4;11) group). Among the 27 ECOG patients, 22 (81%) had the typical pro-B (CD10NEG) immunophenotype, compared to 12% in t(4;11)NEG patients. Aside from expression of myeloid antigens, CD65 and CD15, which is part of the pro-B immunophenotype, t(4;11)POS lymphoblasts showed a unique combination of stem cell antigens: lower expression of CD34 and CD105, but higher expression of CD133 and CD135 compared to t(4;11)NEG blasts (p<0.0001). Additional cytogenetic abnormalities (ACAs) were present in 31/75 (41%) evaluable cases. Most common ACAs were gain of chromosome X (n=13), i(7)(q10) (n=7) and abnormalities of 1p (n=4). Deletion of IKZF1 or CDKN2A/B was present in 18% of patients tested; neither affected outcome. Seventy seven evaluable patients attained complete remission (CR1, 93%). Treatment received in CR1 was either chemotherapy (n=46, 59%) or a myeloablative allograft (N=31, 16 matched sibling, 1 mismatched related and 15 unrelated donors UD). CR1 treatment received strongly correlated with age with the number of allografts decreasing with age: <25 years 12/17 patients; 24–39 years 13/29 and 40+ years 6/31 (p=0.001). At median follow up of 5.4 years, five year EFS was 34% (24–44%, 95% CI) and OS 35% (25–45%). Five year relapse rate was 45% (33–58%); only 1 relapsed patient survived, nearly all events had occurred by 2 years. The 46 patients who received chemotherapy had 24% survival and 69% relapsed but 5 year OS of patients who had sibling or UD allografts was 56% and 67% respectively (p=0.013) and only 3/31 relapsed. An allograft improved OS, EFS and relapse in the <40 year group. Age was also strongly associated with outcome (figure). Conclusions: This is the largest series of adult t(4;11) ALL patients treated uniformly. Allograft in CR1 from sibling or unrelated donors is an effective strategy. Current prospective trials of intensive pediatric-type regimens in younger patients will determine if CR1 allografts are necessary. Older patients have a poor outcome and different strategies such as reduced intensity allografting should be explored. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 169 The Philadelphia positive (Ph+) arm of the international adult acute lymphoblastic leukaemia (ALL) trial UKALL12/ECOG2993 opened in 1993 and is the largest single study of patients with Ph+ ALL, with a total of 441 participants. The first cohort of study patients was treated prior to Imatinib (N=266 “Pre Imatinib“) with 2 phases of induction therapy given over 2 months followed by matched sibling or unrelated donor myeloablative allogeneic haematopoietic stem cell transplant (alloHSCT) whenever possible. The treatment protocol and outcome for these patients has been published (Fielding et al, Blood 2009). Beginning March 2003, a second cohort of study patients had Imatinib 600mg daily added, as a consolidation block after the second induction chemotherapy, (N=86, “Late Imatinib”). From late 2005, a final cohort within the trial were given Imatinib earlier, in conjunction with the second phase of induction (N=89, “Early Imatinib”). Patients in both Imatinib cohorts resumed the drug for a further 2 years following alloHSCT, if tolerated. If alloHSCT was not possible, Imatinib was permitted for 2 years, with maintenance. The trial closed to recruitment in December 2006 (USA) and October 2008 (UK). All except 8 patients have now completed therapy. An earlier analysis of these data did not indicate a clear long-term advantage to receiving Imatinib. We now report 3-year follow-up, which shows large outcome differences between the 3 groups. There were no pre-existing differences between the 3 cohorts in terms of gender, presenting white blood cell counts and presence of central nervous system disease at diagnosis. However, the Pre-Imatinib cohort was younger than the two Imatinib cohorts, due to an increase in the upper age limit for study entry. Percentage complete remission (CR) rates and survival of induction therapy are shown in table 1. The total CR rate for the imatinib cohorts was significantly higher than for the pre-imatinib cohort (p=0.004). Table 1 Pre-Imatinib With Imatinib N=266 Total With Imatinib N=175 Part 1 Late Imatinib N=86 Part 2 Early Imatinib N=89 Died in induction<d56 5 5 3 7 Survived induction but never achieved remission 13 3 5 1 Total not achieving CR 18 8 8 8 CR on protocol induction 67 77 73 80 Total CR rate (includes those achieving remission later than post induction) 82 92 92 92 Pre- Imatinib, only 28% of patients went on to receive alloHSCT as per protocol. With any Imatinib, 44% of patients received alloHSCT as per protocol. Survival outcomes of patients in the 3 cohorts are shown in the table 2. Overall survival (OS), event free survival (EFS) and relapse free survival (RFS) are all at 3 years with 95% confidence intervals (CI) shown in brackets. The P values are for two comparisons - ** denotes the comparison between patients receiving any Imatinib and patients receiving none and ^ denotes the comparison between the Early and Late Imatinib cohorts. Table 2 Pre-Imatinib With Imatinib Total With Imatinib Part 1 Late Imatinib Part 2 Early Imatinib % OS (95% CI) (see also Figure 1) 25 (20–30) 42 (34–49) 34 (24–44) 48 (36–60) p=0.0001** p=0.05^ % EFS (95% CI) 19 (14–24) 36 (29–44) 29 (19–38) 45 (34–56) p=0.0001** p=0.04^ % RFS (95% CI) 36 (28–43) 54 (45–63) 45 (33–57) 62 (50–75) p=0.0001** p=0.02^ Figure 1 Three-year OS for patients who received per protocol alloHSCT was 59% vs. 28% (with no plateau on the curve) for those who did not receive alloHSCT as per protocol. By comparison, pre-imatinib, 5 year OS was 40% for transplanted- and 19% for non-transplanted patients. Hence, the extent to which Imatinib without subsequent alloHSCT can improve the outcome for adult Ph+ ALL is not yet clear. Figure 1. Three-year OS for patients who received per protocol alloHSCT was 59% vs. 28% (with no plateau on the curve) for those who did not receive alloHSCT as per protocol. By comparison, pre-imatinib, 5 year OS was 40% for transplanted- and 19% for non-transplanted patients. Hence, the extent to which Imatinib without subsequent alloHSCT can improve the outcome for adult Ph+ ALL is not yet clear. In conclusion, receiving any Imatinib during induction for Ph+ ALL significantly enhances CR rate and increase alloHSCT rate. This translates into a highly significant EFS, OS and RFS advantage to receiving Imatinib during therapy. An earlier start to Imatinib is significantly better than a later start. Though comparisons between study cohorts are not randomised, the large differences seen are unlikely to be explained by factors other than treatment. There can be no basis for omitting Imatinib from the initial therapy of adult patients with Ph+ ALL. However, our data show that the best outcome is seen when patients receive Imatinib followed by myeloablative alloHSCT, where nearly 60% of such patients survive 3 years from diagnosis. Disclosures: Goldstone: Roche: Honoraria, Speakers Bureau.

Key Points Imatinib improves outcomes for adults with Ph+ ALL at least in part by facilitating allogeneic stem cell transplant. Allogeneic hematopoietic stem cell transplant is not dispensible in Ph+ ALL in the imatinib era.

SummaryAlthough the incidence rate of acute lymphoblastic leukaemia (ALL) is slightly higher in older than in younger adults, response rates to induction chemotherapy and survival rates are poorer. The contribution of disease‐related versus treatment‐related factors remains unclear. We analysed 100 older patients (aged 55–65 years) treated on the UKALLXII/ECOG2993 trial compared with 1814 younger patients (aged 14–54 years). Baseline characteristics, induction chemotherapy course, infections, drug reductions and survival outcomes were compared. There were more Philadelphia‐positive (Ph+) patients in the older group (28% vs. 17%, P = 0·02), and a trend towards higher combined cytogenetic risk score (46% vs. 35%, P = 0·07). The complete remission rate in older patients was worse (73% vs. 93%, P < 0·0001) as was 5‐year overall survival (21% vs. 41%, P < 0·0001) and event‐free survival (EFS) (19% vs. 37%, P < 0·0001). Older patients had more infections during induction (81% vs. 70%, P = 0·05), and drug reductions (46% vs. 28%, P = 0·0009). Among older patients, Ph+ and cytogenetic risk category as well as infection during induction predicted for worse EFS. Poorer outcomes in these patients are partly due to cytogenetic risk, but there is significant morbidity and mortality during induction chemotherapy with frequent delays and drug reductions. New approaches, including better risk stratification and use of targeted therapies, could improve treatment for these patients.

AbstractThe biology and outcome of adult T-cell acute lymphoblastic leukemia are poorly understood. We present here the clinical and biologic features of 356 patients treated uniformly on the prospective trial (UKALL XII/ECOG 2993) with the aim of describing the outcome and identifying prognostic factors. Complete remission was obtained in 94% of patients, and 48% survived 5 years. Positivity of blasts for CD1a and lack of expression of CD13 were associated with better survival (P = .01 and < .001, respectively). NOTCH1 and CDKN2A mutations were seen in 61% and 42% of those tested. Complex cytogenetic abnormalities were associated with poorer survival (19% vs 51% at 5 years, P = .006). Central nervous system involvement at diagnosis did not affect survival (47% vs 48%, P = not significant). For 99 patients randomized between autograft and chemotherapy, 5-year survival was 51% in each arm. Patients with a matched sibling donor had superior 5-year survival to those without donors (61% vs 46%, χ2, P = .02); this was the result of less relapse (25% vs 51% at 5 years, P < .001). Only 8 of 123 relapsed patients survive. This study provides a baseline for trials of new drugs, such as nelarabine, and may allow risk-adapted therapy in patients with poor-prognosis T-cell ALL.

Abstract Prospective data on the value of allogeneic hematopoietic stem cell transplantation (alloHSCT) in Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) are limited. The UKALLXII/ECOG 2993 study evaluated the outcome of assigning alloHSCT with a sibling (sib) or matched unrelated donor (MUD) to patients younger than 55 years of age achieving complete remission (CR). The CR rate of 267 patients, median age 40, was 82%. Twenty-eight percent of patients proceeded to alloHSCT in first CR. Age older than 55 years or a pre-HSCT event were the most common reasons for failure to progress to alloHSCT. At 5 years, overall survival (OS) was 44% after sib alloHSCT, 36% after MUD alloHSCT, and 19% after chemotherapy. After adjustment for sex, age, and white blood count and excluding chemotherapy-treated patients who relapsed or died before the median time to alloHSCT, only relapse-free survival remained significantly superior in the alloHSCT group (odds ratio 0.31, 95% confidence interval 0.16-0.61). An intention-to-treat analysis, using the availability or not of a matched sibling donor, showed 5-year OS to be nonsignificantly better at 34% with a donor versus 25% with no donor. This prospective trial in adult Ph+ ALL indicates a modest but significant benefit to alloHSCT. This trial has been registered with clinicaltrials.gov under identifier NCT00002514 and as ISRCTN77346223.