Goldstone, Anthony H.

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 On intergroup phase III trial, MRC UKALLXII/ECOG2993, 25% of 613 ECOG patients were positive for Ph or its molecular equivalent, BCR/ABL; all were B-lineage ALLs (B-ALL). When compared to Ph(−) B-ALL, Ph(+) ALL had more blasts expressing CD25 (α-chain of interleukin-2 [IL-2] receptor) (p=3E-31), CD34 (p=4E-10), CD13 (p=3.9E-16) and CD33 (p=3.5E-09), and blasts with higher density of CD10 (p=9.6E-12). There was no difference in antigen expression profiles between pts with e1a2 (N=107) and b2a2/b3a2 (N=48) BCR/ABL transcripts. Complete remission (CR) rate was lower (p= 7.4E-6) and overall survival (OS) was shorter in Ph(+) compared with Ph(−) B-ALL (p=6.5E-5). There was no difference in outcome between e1a2 and b2a2/b3a2 pts (p=0.65). CD25 was the most powerful prognostic indicator in Ph(+) cases, both for CR (p=0.004) and OS (p=1.3E-05). Strikingly, CD25 negatively affected OS in a continuous fashion; 1% increase in CD25 was related to a 1% increase in the hazard of death. On the other hand, CD25 expression was not associated with OS in Ph(−) pts (p=0.66). Among 152 Ph(+) pts, 30 lacked CD25 expression, 24 with e1a2 and 6 with b2a2/b3a2 transcripts. When analyzed separately, CD25(−)Ph(+) pts had outcome indistinguishable from that of Ph(−) pts (p=0.89). Compared to CD25(+)Ph(+) pts, CD25(−) Ph(+) pts had lower WBC counts at presentation (p=4.1E-05). Both CD25(+) and CD25(−) Ph(+) blasts expressed the γ-chain but not the β-chain of the IL-2 receptor, arguing against the presence of a functional IL-2 receptor. There was no association between CD25 expression or outcome and the presence of additional cytogenetic abnormalities seen in 52% of Ph(+) pts. To further examine the prognostic impact of CD25, BCR/ABL levels were quantitated by real-time PCR in 136 Ph(+) pts at presentation. There was no correlation between presenting BCR/ABL levels and blast count (p=0.98), achievement of CR (p=0.73), or OS (p=0.67). However, higher blast counts at diagnosis were associated with shorter survival (p=0.003). BCR/ABL levels were measured in 43 pts 1 month after induction therapy. Changes in BCR/ABL after therapy were classified as undetectable, >90% reduction, >50% reduction, or no change. While CR status did not correlate with BCR/ABL reduction (p=0.97), the chance of survival ranked in the order of undetectable (p=0.01), >90% reduction (p=0.05), >50% reduction (p=0.37), or no change (p=0.87). CD25 expression at presentation correlated with that order (p=0.002). CD25(−)Ph(+) pts fell into the group with undetectable BCR/ABL levels after treatment, whereas pts with highest initial CD25 expression fell into the group with no change. In conclusion, CD25(−)Ph(+) blasts are more sensitive to non-TKI therapy than CD25(+) Ph(+) blasts. Outcome in Ph(+) ALL is thus determined by CD25 expression rather than the presence of Ph per se. RESPONSE CD25(+)Ph(+) CD25(−)Ph(+) Ph(−) B-Lin ALL n 122 30 308 % CR Rate 57% 71% 81% MedianOS (months) 12.2 30.2 27.7

Abstract MRC UKALLXII/ECOG2993 accrued 739 ECOG pts over 13 years. ECOG’s reference laboratories centrally characterized 613 (91%) and 505 were B-Lin ALLs. Expression of 32 antigens (Ags), including 9 myeloid-associated Ags, was determined by multiparameter flow cytometry on gated blasts, both as percentage of Ag expressing blasts and intensity of antibody staining (equivalent of Ag density). To test for the potential therapeutic efficacy of monoclonal antibodies, such as rituximab, epratuzumab, alemtuzumab, or gemtuzumab in future trials, expression of Ags for these antibodies (CD20, CD22, CD52, or CD33, respectively) was determined. In E2993, 14% of pts typed as Pro-B (CD10 negative), 71% as Early Pre-B (CD10 positive), 13% as Pre-B (intracytoplasmic mu positive), and 2% as Mature B-ALL (surface mu chains positive). CD20 expression correlated with the stage of B-lymphoid maturation (p=5.4E-13) (see table). Median CD20 intensity of fluorescence was lowest in Pro-B and highest in Mature B-ALL. Membrane expression of CD22 was lower in Pro-B compared with the other three groups, Early Pre-B, Pre-B and Mature B (p=1.0E-5) but indistinguishable among the latter three (p=0.21). While levels of CD20 and CD22 had no effect on complete remission (CR) and overall survival (OS) univariatly, higher CD22 expression was significantly correlated with better OS (p=0.02) in a bivariate Cox model of CD20 and CD22. With respect to myeloid Ags, CD33/CD13 expression was associated with Early Pre-B (p=0.02), and CD65(s)/CD15(s) with Pro-B ALL (p<0.0001). While CD65(s) and CD15(s) did not affect outcome, the combined expression of CD33/ CD13 conferred an inferior prognosis; this effect was due to the association of CD33/ CD13 with BCR/ABL positivity (p<0.0001). BCR/ABL negative B-Lin ALL (N=350) expressed CD33 on a median of only 4% of blasts, compared with a median of 54% in BCR/ABL positive ALL (N=152) (p=3.5E-09). However, intensity of CD33 staining was significantly lower in both BCR/ABL negative and positive blasts (median 3.1) compared with leukemic myeloblasts (median 56) (p=<0.001). Median CD52 expression was higher in BCR/ABL positive versus negative B-Lin ALL (p=3.5E-06); in neither group was CD52 associated with outcome. We conclude that antibodies to CD52 are better suited for BCR/ ABL positive than negative B-Lin ALL. Since expression of CD33 in ALL is weak, CD33- independent effects of gemtuzumab must be investigated. Low CD20 combined with high CD22 expression confers superior OS. The expression of these Ags in most B-Lin ALL pts justifies the incorporation of antibodies into frontline chemotherapy regimens. B-Lin ALL Stage CD20 Percentage Median Intensity CD22 Percentage Median Intensity ≥20% ≥50% ≥75% ≥20% ≥50% ≥75% Pro-B 21 10 3 2 88 72 55 12 Early PreB 66 48 37 21 96 90 84 28 Pre-B 61 46 37 21 100 90 81 37 Mature B 87 80 64 106 92 84 80 9

Summary Late relapse [>3 years from complete remission (CR)] in acute lymphoblastic leukaemia (ALL), is unusual. Data from the MRC UKALLXII/ECOG E2993 trial are presented to evaluate the incidence and characteristics of late relapse in adult ALL. Of 1,909 patients, 1,752 (92%) achieved CR and among these 757 (43·2%) relapsed; 691 (91·3%) within three years and 66 (8·7%) beyond. Among these 66 patients, median time to relapse was 47 (37–144) months. Relapse beyond three years occurred in 3·8% of all who achieved CR. The cumulative risk of relapse was 40%, 43% and 45% at three, five and ten years respectively. Out of the 1 752 patients who achieved CR, 11·7% underwent autologous and 40·6% allogeneic transplant, while in CR1. Of the autologous patients, 43·2% relapsed early and 3·4% relapsed late. However, among the allogeneic patients, 13·2% relapsed early and only 1·3% late. The five‐year overall survival from relapse was 5·8% and 20% in the early and late relapse patients respectively. In conclusion, late relapse in adults with ALL is not uncommon, and is associated with better outcome after relapse compared to early relapse.

Abstract The UKALLXII/ECOG2993 international study for adults with acute lymphoblastic leukeamia (ALL) included a separate, single-arm study (still open) to evaluate the role of etoposide/TBI conditioned allogeneic bone marrow transplantation (BMT) in patients with Philadelphia chromosome positive (Ph pos) disease. Patients received 2 phases of induction, intensification with high dose methotrexate and BMT using unrelated donor stem cells where a matched sibling was not available. 267 patients with Ph pos ALL were treated from 1993 onwards, in the pre-imatinib era. The study was amended in 2003 to add imatinib 600mg per day following induction and after BMT for 2 years or until relapse. A subsequent amendment at the end of 2005, added imatinib 600mg per day also to phase 2 of induction. 153 patients have now been treated on the imatinib-containing protocol − 89 received imatinib following induction and 64 started imatinib with phase 2 induction. Complete remission (CR) rate at the end of 2 phases of induction was 91% with imatinib started in induction, 81% with imatinib started in consolidation only & 83% in the pre imatinib era. 128 of the 153 patients treated with any imatinib were eligible for BMT. Of the 98 patients with over 6 months follow-up, 57 (58%) actually received BMT. This transplant rate does not differ from the 62% in the pre-imatinib era although the data pertain mostly to those whose imatinib started later during therapy. Overall survival of the imatinib-treated group as a whole is 23% at 3 years, which does not differ from the 26% pre-imatinib rate as shown in the figure. Hence, imatinib started post-induction does not appear to improve survival. Imatinib given with induction may improve the CR rate, but there is insufficient follow up to assess transplant or survival rates. Earlier imatinib may be optimal but overall, our study does not provide evidence yet that imatinib alters the outcome of this disease. Figure Figure Patient characteristics Pre-imatinib (N=267) Post-imatinib (N=153) Gender: Male 150 (56%) 96 (63%) WBC (x 10 ^9/l) (2 unknown): <30 141(53%) 86 (56%) ≥ 30 124 (47%) 67 (44%) Median (range) 26.8 (1.5–438) 21.0 (0.5–491) Age: median (range) 40 (15–60) 42 (16–64) CNS disease (82 unknown) 14 (8%) 4 (3%)

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 493 The International MRC UKALL XII/ECOG E2993 trial for adults with newly diagnosed acute lymphoblastic leukemia (ALL) recruited 1,914 patients to the main part of the trial from 1995 up to its closure in 2006, of whom 100 were over the age of 55 years (median 57, range 55–65). Beginning in 2003 (MRC) or 2004 (ECOG), patients with Philadelphia chromosome positive (Ph+ve) disease were entered into an Imatinib sub-study. We report here baseline characteristics, treatment course and outcomes, and discuss implications for future management strategies. Direct comparison of the 100 patients over 55 yrs with 1,814 under 55 yrs showed that the groups are comparable for gender, immunophenotype and white cell count but there is an indication that more elderly patients had Ph+ve disease (28% aged ≥55 vs 17% aged <55 of those entered before the start of the Imatinib trial; p=0.02). All patients in this trial received a 2 stage induction regimen, consisting of Daunorubicin, Vincristine, Asparaginase and Steroid followed by Cyclophosphamide, Cytarabine, 6-Mercaptopurine and Methotrexate. CNS prophylaxis with IT Methotrexate and Cytarabine was given during both phases. There was a randomisation to autograft or chemotherapy, but only a small number of patients in this age group were randomised (13 autograft and 13 consolidation chemotherapy). Outcomes Complete remission (CR) rate, event-free survival (EFS) and overall survival (OS) were all worse in the over 55 age group, and even after achieving CR, the 5-year OS rate was reduced. There were more infections in phase I induction (67% vs 45%, p<0.0001) and more deaths during induction chemotherapy (18% vs 4% p<0.0001). Excluding those who died in induction, 47% had drug dose reductions in phase I or phase II vs 27% <55 yrs (P=0.0006). Of these, Asparaginase was the most common in those aged ≥55 years, usually due to hepatotoxicity. Age p-value <55 vs ≥55 <55 ≥55 Number 1814 100 CR No v Yes p<0.0001 No 131 (7%) 27 (27%) No (died in induction) 70 (4%) 18 (18%) No (but survived induction) 61 (3%) 9 (9%) Yes 1641 (90%) 70 (70%) Unknown 42 (2%) 3 (3%) Deaths 1112/1814 (61%) 78/100 (78%) Relapses 750/1683 (45%) 36/73 (49%) Overall survival at 5 years (95% CI) 41% (38–43%) 21% (12–29%) p<0.0001 Event free survival at 5 years (95% CI) 37% (34–39%) 19% (10–27%) p<0.0001 Relapse free survival at 5 years (95% CI) 50% (48–53%) 38% (25–52%) p=0.08 Overall survival at 5 years (95% CI) in those who achieved CR 44% (41–46%) 30% (18–41%) p=0.03 In those patients aged ≥55 years, baseline factors causing a significantly worse 5-yr EFS were Ph-positivity (0% vs 23%, p=0.005), unfavourable vs standard cytogenetic risk (7% vs 26%, p=0.02) and a presenting WCC >50 × 109/l (0% vs 25% for WCC between 10 and 49.9 × 109/l and 23% for WCC <10 × 109/l, p=0.003). Infection during induction chemotherapy predicted for worse EFS; this was especially significant in those who had infection in both phases of induction (6% vs 38%, p=0.007). In those patients who received chemotherapy and were not transplanted, the differences in outcome were smaller: 5-yr OS 25% in ≥55 years vs 38% in <55 years (p=0.06), 5-yr EFS 22% vs 32% (p>0.1). Conclusion Older adults fared significantly worse than younger adults both in terms of achieving an initial CR and long-term survival. This difference cannot be explained solely by a difference in disease characteristics, and the marked increase in infection and deaths during induction reflect the inability of many older patients to tolerate the intensive level of treatment. This is also supported by the large numbers of drug omissions or dose reductions seen. Our data show that this inability to tolerate induction chemotherapy is a major contributor to the poor outcomes seen in this age group. The less marked differences between age groups when transplant patients are excluded, indicates the significant mortality associated with these procedures in older patients. Alternative approaches to consider in this group include less intensive induction with a steroid and vinca alkaloid combination, in conjunction with targeted therapies (eg Rituximab in B-lineage CD20+ disease, Imatinib Mesylate in Ph+ disease). Even amongst those patients who do achieve CR however, the long-term outcome is worse. Reduced intensity allografts may play a role in carefully selected patients in this age group, and the emerging use of MRD monitoring may also assist in selecting patients for more or less intensive approaches. Disclosures: McMillan: EUSA: Honoraria. Goldstone: Roche: Honoraria, Speakers Bureau.

Abstract This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and the Medical Research Counsel, United Kingdom, and supported in part by Public Health Service Grants CA180820, CA180794, CA180790, CA189859, CA180853, CA180791, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Background: Late relapse in acute leukemia is considered a relatively rare event. Patients with acute myeloid leukemia (AML) are often considered cured of the disease at 3 years, but information regarding adult acute lymphoblastic leukemia (ALL) patients is scarce. Data are presented from one of the largest prospective adult ALL studies, the MRC UKALLXII/ECOG E2993, to evaluate the rate and characteristics of late relapse in ALL. For this purpose, late relapse was defined, arbitrarily, as relapse 3 years post achievement of complete remission (CR) and very late relapse was defined as relapse > 5 years from CR. Methods: The UKALLXII/ECOG E2993 was an international ALL trial conducted jointly by the MRC in the United Kingdom and ECOG in the United States. All patients received identical induction therapy, followed by central nervous system prophylaxis. Patients with a sibling donor (or a matched unrelated donor in Philadelophia-chromosome-positive ALL) were assigned to receive an allogeneic hematopoietic stem cell transplant (HSCT); all others were randomized to undergo an autologous transplant or protracted standard consolidation/ maintenance therapy. The study accrued 2109 patients from 1993 to 2008. Following relapse, patients were followed for survival. For this report only patients registered before the tyrosine kinase inhibitors era are included in the analysis. Results: 1518 study patients were eligible for this analysis, 1208 (79.6%) Philadelphia-chromosome negative (Ph-neg) and 267 (17.5%) Philadelphia-chromosome positive (Ph-pos). 1381 (91%) of the patients achieved CR; 93% of the Ph-neg and 82% of the Ph-pos. 572 patients (37.7%) underwent allogeneic HSCT. The median duration of follow-up of patients who achieved CR was 10 years. Among the 1381 patients who achieved CR, 626 (45.3%) had a documented relapse; 566 (90.4%) relapsed within 3 years of CR and 60 (9.6%) relapsed beyond 3 years ('late relapse') (Figure 1). Among these 60 patients, 18(2.9%) relapsed after 5 years ('very late relapse'). Table. Patients n CR All relapses Relapses< 3 years Relapses≥ 3 years Relapses≥ 5 years All patients 1518 1381 (91%) 626 (45.3%) 566 (90.4%) 60 (9.6%) 18 (2.9%) Ph-neg 1208 (79.6%) 1123 (93%) 485 (40.1%) 429 (88.5%) 56 (11.5%) 17 (3.5%) Ph-pos 268 (17.5%) 219 (82%) 124 (56.6%) 122 (98.4%) 2 (1.6%) 1 (0.8%) Relapse beyond 3 years occurred in 4.3% of all who achieved CR, in 5% of Ph-neg and 0.01% of Ph-pos patients. Among the 60 late relapses, the median time to relapse was 46 months. 61.7% of the late-relapse patients were males, median age was 32 years, 88.3% were B-lineage ALL and the median white cell count at diagnosis was 6000/ul. 56.7% were in cytogenetic standard risk, 8.3% at high risk and the data of 35% are unknown. The median survival for the late relapse patients was longer than for those who relapsed within 3 years. The overall survival (OS) of the 56 Ph-neg patients who relapsed beyond 3 years is shown in Fig 2. Table.Relapse > 3 yearsRelapse > 3 yearsMedian survival from relapse (months)5.411.23-year OS from relapse6.5%29%5-year OS from relapse5.6%19% Conclusions: Late relapses in adults with Ph-neg ALL are not uncommon. About 10% of relapses occur beyond 3 years and 4.3% of all ALL patients who achieved a CR can expect to have a late relapse. These data are in contrast to AML where only 1% of patients relapse beyond 3 years (Watts JM et al, 2014). Most of the late relapse patients were at standard risk and appeared to have a relatively favorable outcome post relapse. Patients with ALL, particularly those who are Ph-neg, cannot be considered as cured at 3 years and need to be closely followed. Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Disclosures Rowe: Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Douer:Gilead: Consultancy.

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.