ALBERT

Description: The primary immunodeficiencies (PID) are rare inherited diseases characterised by severe dysfunction of adaptive and/or innate immunity. Over 200 distinct PIDs have been described, with 20 of them accounting for 〉 90% cases. The 3 most common PIDs are severe combined immunodeficiency (SCID), Wiskott Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). Many have been successfully treated by allogeneic hematopoietic stem cell transplantation (Allo-HSCT), however, almost all published series to date have focussed on paediatric patients. In the largest published series, the median age at transplant is 〈 1 year for SCID, 12.7 years for CGD, and 3 years for WAS. Early Allo-HSCT is preferred for PID patients, but not always possible. Delayed diagnosis and 'milder' clinical phenotypes may delay treatment with curative intent. With improved supportive care PID patients are more likely to survive to early adulthood without Allo-HSCT, despite serious co-morbidities. Furthermore, for several PIDs, controversy surrounding optimal timing of Allo-HSCT remains due to rarity of disease and lack of experience. Furthermore, Allo-HSCT for older adolescents and adults with PID has previously been avoided due to severe TRM and poor outcomes. Here we report the largest group of consecutive adult PID patients described to date (n=27) who underwent Allo-HSCT in the adult HSCT programme of University College London. The mean age was 24 years (range 17-50) at transplant. Of these, 11 patients had X-linked or autosomal recessive CGD and 16 had other inherited PID, including CVID (1 with T-NHL, 1 with HLH, 1 with GLILD) (n=3), autoimmune LPD (1 Fas mutation) (n=2), X-linked LPD (n=1), DCML +/- Gata2 mutation (n=2), Gata2 Defic (n=1), Cg-SCID (n=1), CID with CD27 Defic (1 with HL and DLBCL, 1 with HL) (n=2), NK Defic (n=1), AR IL12 Recb Defic (n=1), XIAP with Crohn's and HLH (n=1) and Rag2 compound heterozygote with red cell aplasia (n=1). Stem cell donors were matched unrelated (MUD) (n=14), mismatched unrelated (MMUD) (n=5, all 1 Ag mismatch) or matched related donors (MRD) (n=8). Stem cell source was PBSC (n=20) and BM (n=7). Reduced intensity conditioning was used in 26 patients including Flu/Mel/Alemtuzumab (n=17), Flu/Bu/Alemtuzumab (n=8) and Flu/Bu/ATG (n=1). One patient underwent myeloablative conditioning with Flu/Cy/TBI. Additional GVHD prophylaxis with cyclosporine was used in all patients. Reverse isolation, antimicrobial and antifungal prophylaxis were used to reduce the risk of infectious complications. Acute and chronic GVHD incidence and severity and time to engraftment, lineage specific chimerism, immune reconstitution and discontinuation of immunoglobulin replacement therapy were recorded. Overall survival (OS) at 2 years for all patients was 85.6%, and by donor was 75% for MRDs (n=8) and 89.5% for MMUD/MUD (n=19) with a mean follow up of 35 months (range: 7 to 11 years 1 month). Analysis of outcome by diagnosis demonstrated OS at 2 years of 81.8% for CGD patients (n=11) and 87.5% for other PIDs (n=16). TRM was low with only four deaths observed at a median follow-up of 22 months (n=27). 2 patients died of multi organ failure and sepsis prior to engraftment, one at 7 months post-HSCT of granulomatous meningitis and grade III aGVHD and one at 28 months post-HSCT of sepsis in the context of chronic extensive GVHD. 8 patients developed grades I-II aGVHD (6 skin only, 1 involving the gut and 1 progressing to chronic lung GVHD). GVHD had resolved in all but one patient at last follow up. For all patients, neutrophil and platelet engraftment occurred after a median of 12 and 14 days respectively. Peripheral blood chimerism was available for 22 of the 23 surviving patients at last follow up. Multilineage full donor chimerism was observed in 8 (36%) with mixed chimerism observed in at least one cell lineage tested for the remainder. At 1-year post transplant, 80% of those tested had achieved a normal lymphocyte count (1.0-2.8 x 109/L), 47% had normalization of absolute CD3+ count (0.7-2.1 x 109/L), 40% had a normal CD4+ count (0.3-1.4 x109/L) and 87% had normalisation of their CD8+ cell count (0.2-0.9 x109/L). Allo-HSCT is well tolerated in this patient group and should be considered as an alternative therapeutic option in PID patients not transplanted in childhood where an appropriate donor is available. Triggers for referral should include life threatening infections, malignancy, severe autoimmunity and refractory disease. Disclosures Fielding: Baxalta: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Description: MRC UKALL XII / ECOG E2993 was initiated in 1993, to prospectively define the role of allogeneic transplant (allo), autologous transplant (auto) or chemotherapy in adult ALL in first CR up to age 60 (65 since 2004). All patients received two phases of induction and, if in CR, patients 35 or a high WBC (〉30,000 for B-lineage or 〉100,000 for T-ALL). In a donor versus no donor analysis, patients with a sibling donor had improved OS and EFS and the relapse rate post allo was very significantly lower than for any other therapy. However, this advantage was confined to standard-risk patients. The lack of demonstrable survival benefit in high-risk patients was due to high mortality associated with age 〉35 years; the 2-year non-relapse mortality for patients with a donor was 39% (high-risk) and 20% (standard-risk) compared with 12% (high-risk) and 7% (standard-risk) among those without a donor. In an intention-to-treat analysis of chemo versus auto, patients receiving chemo had significantly better EFS. The difference between these 2 groups was not due to a higher mortality of auto but due to a higher relapse rate. Molecular monitoring of minimal residual disease (MRD) after induction phase II and intensification was highly predictive of outcome among the non-allo patients (OS 70% vs 22%; p=.0012). In summary, the data demonstrate that sibling allogeneic transplants for ALL in CR1 provide the most potent anti-leukemic therapy and considerable OS and EFS benefit for standard-risk patients. In contrast, the transplant-related mortality for high-risk older patients was unacceptably high and abrogated the reduction in relapse risk. Furthermore, the data show that there is no evidence that a single auto can replace consolidation/maintenance therapy in any risk group. Large collaborative trials are necessary, and feasible, to define the optimal therapy in uncommon disorders. 5-year data No. of Patients OS (%) EFS (%) Relapse (%) * P = 〈 .05 ** Autograft patients excluded Donor vs no donor 388 vs 527 *53 vs 45 *50 vs 41 *29 vs 54     High risk 170 vs 230 39 vs 36 38 vs 32 *36 vs 63     Standard-risk 218 vs 286 *63 vs 51 *59 vs 48 *25 vs 48 Randomized auto vs chemo 220 vs 215 37 vs 46 *33 vs 42 *61 vs 54 Donor vs no donor (chemotherapy)** 384 vs 418 *54 vs 44 *50 vs 40 *29 vs 55     High-risk 168 vs 190 41 vs 35 38 vs 31 *36 vs 63     Standard risk 216 vs 223 *64 vs 51 *59 vs 47 *24 vs 48

Description: 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):

Description: 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

Description: Background Overall survival (OS) for teenagers and young adults (TYA) aged 15-24 years (yrs) with acute lymphoblastic leukaemia (ALL) is inferior to OS for children. In the UK, five-year OS for children up to 14 years with ALL is 89%, falling to 69% for 15-19 yr olds and 52% for 20-24 yr olds (O'Hara et al, National Cancer Intelligence Network, 2013). Both disease biology and choice of protocol are likely to be important in explaining these differences. However, lower rates of inclusion into clinical trials with increasing age may also be a significant factor. In the UK 3 national paediatric and adult ALL trials were open to recruitment between 1997-2006 (table 1). In 2006 the upper age eligibility criteria for UKALL2003 was increased from 18 to 24 yrs and the lower age limit of UKALL XII was correspondingly increased to reflect emerging evidence that TYA have improved outcomes when treated on paediatric protocols. Aims 1. To examine trial accrual rates (AR) by age over a ten year period (1997-2006) to three UK national ALL trials. 2. To determine the influence of amending the age eligibility criteria for UKALL2003 on TYA accrual Methods ALL incidence figures for patients aged 1-39 yrs during the study period of 1997-2006 were obtained from a national cancer registry. Incidence data was classified according to the morphology-based coding specifically for TYA (Birch et al, BJC, 2002). Accrual rates (AR) were expressed as the ratio of patients entered onto trials during the same time period compared to incidence cases. Descriptive statistics were applied for an observational dataset where sample size or incidence cases cannot be controlled (Fern et al. BJC, 2008). We obtained a further incidence data set for cases diagnosed in 2007 and 2008 to examine the impact of age eligibility amendments in 2006 and 2008 to UKALL2003. Results ALL was diagnosed in 4,579 patients aged 1-39 yrs between 1997-2006, 2,767 were under 10 yrs. The figure shows the proportion of newly diagnosed ALL patients entering trials 1997-2006. Red arrows show age eligibility criteria of the trials. 65% of all patients were enrolled onto one of the 3 trials. AR were highest for under 10's (71.5%), declining to 55.2% for 15-16 yr olds, 43.4% for 17-18 yr olds and 40% for those aged 21-24 yrs. The amendments to age inclusion criteria for UKALL2003 and UKALL XII improved AR for 17-18 yr olds to a level equivalent to AR for 15-16 yr olds. AR for 19-20 yr olds also improved to 62.5%. However, recruitment of 21-24 year olds did not change. During 1997-2006 three quarters of 17-18 yr olds recruited to trials were enrolled onto UKALLXII. After protocol amendments, three quarters of 17-18 yrs were recruited to the paediatric trial. Conclusions We have shown a decline in trial accrual with increasing age for teenagers and young adults with ALL despite the availability of national trials spanning the age range being available during the time period studied. Due to close cooperation between adult and paediatric trial management groups, major changes were made to age eligibility criteria for both paediatric and adult trials, following increasing evidence that TYA have better outcomes when treated on paediatric protocols. We have shown an increased accrual of older teenagers to ALL trials in the UK following these changes. No improvements were observed for 21-24 year olds. However, this age group were only eligible for UKALL 2003 during the last year of our analysis. This approach to trial eligibility design may serve as a model for future trials, both in ALL and other cancers. Disclosures: No relevant conflicts of interest to declare.

Description: Minimal residual disease (MRD) testing is vital to risk assignment in acute lymphoblastic leukaemia (ALL). Quantification of patient-specific rearrangements of immunoglobulin and T-cell receptor (Ig/TCR) genes is the most standardised method in current use. Recent studies demonstrated that deletion in the IKZF1 gene is common and is prognostic of poor outcome. IKZF1 targets could offer potential for MRD monitoring in BCR-ABLnegative (neg) ALL. The 5' and 3' break points of this deletion are highly conserved, making it possible to design a universal PCR assay to amplify the fusion genomic sequence created by the deletion. With the initial aim of developing an MRD assay we studied the incidence of IKZF1 Δ 4-7 in 161 consecutive patients enrolled on the on-going adult ALL trial UKALL14, aged 25-59 years. We carried out PCR using breakpoint-specific primers designed as close as possible to the breakpoint. In order to ensure that the screening PCR enabled sensitive detection of the deletions, serial dilution of a positive control SUP-B15 cell line diluted into non-tumoral DNA was analysed. IKZF1 Δ 4-7 could be detected with a sensitivity of at least 10-4 (0.01%). PCR bands could be readily allocated to “strong” or “weak” on visual inspection; all PCR positive signals were confirmed as IKZF1 Δ 4-7 by Sanger sequencing of the PCR products and the breakpoints mapped. The frequency of the deletion in the total population studied was 80/161 (50%); 23/35 (66%) in the BCR-ABL positive (pos) subgroup and strikingly 57/126 (45%) in the BCR-ABLneg subgroup. The high rate of IKZF1 Δ 4-7 in the BCR-ABLneg patients was unexpected, being approximately double the reported incidence BCR-ABLneg adults. Real time quantitative (RQ)-PCR analyses to investigate the suitability of IKZF1 quantitation as the basis for an MRD assay was performed on 26 BCR-ABLneg cases, selected only on the basis of availability of follow-up material. Assays were assessed using the same criteria applied by EuroMRD for Ig/TCR quantification. On that basis, “limited testing” of PCR amplifications at the 10-2 (1%) and 10-4(0.01%) dilution points was performed on all 26 samples. To our surprise, only 5 samples gave acceptable data to qualify for a quantitative MRD assay. Notably, all the 21 cases that failed “limited testing” had yielded a weak PCR signal on initial screening, suggesting the PCR assay have detected intragenic deletions restricted to minor subclones. Although subclonal IKZF1 gene alterations are well described, the apparent high frequency of these events in our cohort (21/26 tested for RQ-PCR assay) was surprising. To further analyse this, we performed MRD-based genomic quantification of all 26 diagnostic specimens using SUP-B15 dilution series. The percentage of ALL cells bearing IKZF1 Δ 4-7 in the putative 21 subclonal cases was 90% in the putative 5 major clonal cases. In total, 82% of BCR-ABLneg cases gave a weak PCR band at initial screening, suggesting that most of the Δ 4-7 in BCR-ABLneg adult ALL are subclonal. In the 5 cases where a quantifiable IKZF1 Δ 4-7-based MRD assay could be developed, MRD analysis was performed on 12 follow-up samples and sensitivity and quantitative range of at least 10-4 (0.01%) and 5×10-4 (0.05%) were obtained, respectively. These parameters compare favourably with the performance of standard Ig/TCR assays. Notably in one sample MRD could only be quantified by the IKZF1 deletion approach (level= 7.79E-05, ∼ 0.008%). IKZF1 lesions are not leukaemia-initiating events, hence the stability of this alteration during the history of ALL is not clear. To address this, 14 diagnosis and relapse paired samples were analysed. Three different patterns emerged: in 5 cases the IKZF1 Δ 4-7 at diagnosis was preserved at relapse; in 3 cases the lesion was newly acquired at relapse; and in 3 cases the deletion was lost at relapse, notably all these 3 cases had showed a weak PCR signal, suggesting the deletion which was lost at relapse was subclonal at diagnosis. Theoretically this observation suggests that IKZF1deletion-based MRD monitoring carries a risk of missing a resurgent clone. In conclusion, IKZF1 Δ 4-7 can provide highly sensitive MRD assays and could be a potential candidate to add to the repertoire of currently available MRD markers. However, we have shown limited applicability due to many IKZF1 deletions occurring in putative subclones. The stability of these deletions in major clones remains to be determined. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2016 Positron emission tomography (PET) scanning is increasingly recognised to provide important prognostic information in patients with Hodgkin Lymphoma (HL) receiving chemotherapy or undergoing autologous stem cell transplantation. Its role in defining outcomes following allogeneic transplantation is less clear. We previously examined the outcomes of patients with chemosensitive lymphoma undergoing alemtuzumab-based allogeneic transplantation, and found pre-transplantation PET-CT status to have no influence on post-transplant outcomes (non-relapse mortality (NRM), relapse incidence (RI), overall survival (OS), or progression-free survival (PFS)). The numbers of patients with specific histological diagnoses were relatively small, limiting the power of subgroup analyses, and within the HL group (n=20) only 8 had metabolic complete response (mCR) prior to transplant. We now have experience of 80 patients aged 12–59 with HL undergoing alemtuzumab-based allogeneic transplantation in whom we have pre-transplantation PET data. A visual analysis using a 5-point scale was employed with a threshold of 3 or above considered positive. The development of new FDG-avid lesions scoring 3–5 in the absence of other potential causative pathologies, or significant increase in SUV of over 25% in previously positive lesions was considered compatible with relapse/progression and an indication for donor-lymphocytes following transplantation. Biopsies were performed in the former where feasible, and repeat PET-CT studies at 6–8 weeks in equivocal cases where biopsy was not possible prior to administration of donor-lymphocytes. 23 patients had negative PET studies prior to transplantation, and 57 patients had positive PET studies. 10 of the latter had progressive disease at the time of transplant. Donors were HLA-matched related in 40, HLA-matched unrelated in 28 and HLA-mismatched unrelated in 12. Within the non-progressive group (n=70) there were no significant differences according to PET status (PET- vs PET+) in either 3yr NRM (23% vs 15%) or relapse incidence (21% vs 30%, p=0.3223). The corresponding values for the progressive group were 40% and 50% respectively, reaching statistical significance only in relapse incidence for PET- vs progressive (p=0.0324), with a trend in the same direction for PET+ vs progressive (p=0.1199). Similarly, there were no significant differences within the non-progressive group according to PET status in terms of 3yr OS (77% vs 64%, p=0.5486), PFS (56% vs 52%, p=0.5631) or ‘current’ PFS (incorporating post donor-lymphocyte salvage responses in those treated for relapse (n=15); 73% vs 66%, p=0.7235), whilst all 3 were significantly worse in the progressive group (33%, 10% and 10% respectively, p=0.0001-0.0055). Within the non-progressive group there was no impact of donor source on survival outcomes (3yr OS 67% vs 70%, p=0.9496; PFS 58% vs 50%, p=0.3236, cPFS 68% vs 69%, p=0.8587 for related vs unrelated donors respectively). NRM was equivalent (18% vs 17%), as was relapse incidence (20% vs 33%). Within the non-progressive group the median number of prior lines of therapy was 4 (range 2–9), but interestingly outcomes were not influenced by number of prior lines when evaluated by less than 4, 5 or 6 compared to the remainder e.g. NRM 17% vs 18%, relapse incidence 26% vs 29% for 4 or fewer vs more than 4. Our data suggest that patients with progressive disease pre-transplant have particularly poor outcomes, but that within the non-progressive group the presence of residual FDG-avid disease pre-transplant has no significant influence on post-transplant outcomes using alemtuzumab-based T-cell depleted regimens. The results now deliverable with this strategy incorporating post-transplant PET-CT surveillance and aggressive intervention with donor-lymphocytes remain very encouraging in all non-progressive patients (63% 5yr cPFS) regardless of donor source. Outcomes appear no worse according to number of prior lines as long as the disease is non-progressive at the time of transplantation, suggesting that multiple lines of salvage are warranted to establish chemosensitivity if the patient remains fit enough, but that there may be little advantage in pursuing mCR with additional lines prior to transplantation in those that show a response. Disclosures: No relevant conflicts of interest to declare.

Description: 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.

Description: Introduction. Prognosis of patients (pts) with R/R Philadelphia chromosome-positive (Ph+) ALL is dismal despite the introduction of tyrosine kinase inhibitors (TKI) which may be used as single agents or in combination regimens. Blinatumomab is a bispecific T-cell engaging (BiTE®) antibody construct that has shown antileukemic activity. Among adults with R/R Ph-negative ALL receiving blinatumomab, 43% achieved complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles (Topp MS et al. Lancet Oncol 2015;16:57). We evaluated the efficacy and tolerability of blinatumomab in pts with R/R Ph+ ALL who progressed after or were intolerant to a 2nd or later (2+) generation TKI. Methods. Eligible adult pts (≥18 years) had Ph+ B-precursor ALL and had relapsed after or were refractory to at least one 2+ generation TKI; or were intolerant to 2+ generation TKI and intolerant or refractory to imatinib. All pts had to have 〉5% blasts in the bone marrow and Eastern Cooperative Oncology Group performance status ≤ 2. Blinatumomab was dosed by continuous IV infusion (4 weeks on/2 weeks off) for up to 5 cycles (9 μg/d on days 1-7 in cycle 1, and 28 μg/d thereafter). The primary endpoint was CR or CRh during the first two cycles; minimal residual disease (MRD) response based on RT-PCR amplification of BCR-ABL per central laboratory, relapse-free survival (RFS), overall survival (OS), and allogeneic hematopoietic stem cell transplant (alloHSCT) rate were key secondary endpoints. Complete MRD response was defined as no RT-PCR amplification of BCR-ABL at a sensitivity of 10-5. Results. Of 45 treated pts, 44 were resistant to 2+ generation TKI; one patient was resistant to imatinib and never exposed to 2+ generation TKI (protocol deviation). 53% of pts were men. Median (range) age was 55 (23-78) years (≥65 years, 27%). Ten pts (22%) had a BCR-ABL gene with T315I mutation. All pts had received prior TKI (dasatinib, 87%; ponatinib, 51%; imatinib, 56%; nilotinib, 36%; bosutinib, 2%), with 60% having received ≥ 2 prior 2+ generation TKI; most pts (96%) had received prior chemotherapy. 38% of pts had ≥ 2 prior relapses and 44% had prior alloHSCT. Efficacy outcomes for key endpoints are shown in the table. 16 pts achieved CR/CRh during the first two cycles for a response rate of 36% (95% CI: 22%, 51%); of those, 14 pts achieved CR, most of them (10/14, 71%) in cycle 1. The patient who never received 2+ generation TKI did not respond to treatment. 12 of the 14 pts (86%) with CR and two of the two pts with CRh achieved a complete MRD response. Among the 10 pts with T315I mutation, four achieved CR/CRh; all four also achieved a complete MRD response. Eight CR/CRh responders (50%) relapsed, three during treatment (including two with CR who did not achieve complete MRD response). One patient died in CR post alloHSCT. Median (95% CI) RFS was 6.7 (4.4, not estimable) months (median follow-up, 9.0 months); median OS was 7.1 (5.6, not estimable) months (median follow-up, 8.8 months). Patient incidence of grade ≥ 3 treatment-emergent adverse events (AEs) was 82%, most commonly febrile neutropenia (27%), thrombocytopenia (22%), anemia (16%), and pyrexia (11%). Five pts had fatal AEs; one (septic shock) was considered treatment-related by the investigator. Three pts discontinued because of AEs. Cytokine release syndrome (CRS) occurred in three pts (all grade 1 or 2). 21 pts (47%) had neurologic events (paraesthesia, 13%; confusional state, 11%; dizziness, 9%; tremor, 9%); three pts had grade 3 neurologic events (aphasia, hemiplegia; and depressed level of consciousness and nervous system disorder), one of which (aphasia) required treatment interruption. Conclusion. In this population of pts with R/R Ph+ ALL who have very poor prognosis after failure of 2+ generation TKI therapy, treatment with CD19-targeted immunotherapy blinatumomab as single agent showed antileukemic activity. AEs were consistent with those previously reported for pts with R/R Ph-negative ALL treated with blinatumomab. Table 1. Table 1. Disclosures Martinelli: Novartis: Speakers Bureau; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ottmann:Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Goekbuget:Bayer: Equity Ownership; Eusapharma/Jazz: Consultancy, Honoraria, Research Funding; Erytech: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; SigmaTau: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Gilead Sciences: Consultancy; Sanofi: Equity Ownership; Amgen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Fielding:Amgen: Consultancy, Honoraria. Sterling:Amgen: Employment, Equity Ownership. Benjamin:Amgen: Employment, Equity Ownership. Stein:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding.

Description: Introduction: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. The prevalence of Ph-like ALL increases with age and accounts for over 25% of patients with B-progenitor ALL between the ages of 21-39 years. However, the frequency, outcome and genetic basis of Ph-like ALL in adults over the age of 39 is unknown. The goals of this study were to define the prevalence of Ph-like ALL across the adult age spectrum, assess response to conventional chemotherapy, and define the genetic landscape of Ph-like ALL in adults. Methods: We studied 692 adults with B-ALL obtained from multiple groups including the Alliance (Cancer and Leukemia Group B), ECOG-ACRIN, MD Anderson Cancer Center, Northern Italy Leukemia Group, Princess Margaret Cancer Centre, SWOG and UK NCRI. The cohort was divided into three age groups: 21-39 years (median age 28±6 years, n=333), 40-59 years (median age 47±6 years, n=246) and 60-79 years (median age 67±7 years, n=101). RNA samples were screened using a Taqman low density array (LDA) card that identifies patients with the Ph-like ALL gene signature, in addition to BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, MLL-rearranged and ERG altered ALL. Cytogenetic data was also available for the majority of cases. High expression of CRLF2 was determined by the LDA card, and CRLF2 rearrangement (IGH-CRLF2 or P2RY8-CFRLF2) was confirmed using fluorescence in situ hybridization. Total stranded transcriptome sequencing (RNA-seq) using the Illumina platform was performed on 99 cases and sequencing data was analyzed using FusionCatcher and CICERO. Results: The overall prevalence of ETV6-RUNX1, TCF3-PBX1 and ERG ALL in adults was low (1.3%, 3.6% and 3.1%, respectively), whilst the prevalence of patients with BCR-ABL1, Ph-like and MLL-rearranged ALL was 20%, 24% and 14%, respectively. Ph-like ALL comprised 26% of patients between 21-39 years of age and 20% of patients aged 40-79. Patients with BCR-ABL1 and Ph-like ALL presented with higher white blood counts at diagnosis compared to non Ph-like ALL patients (57.7 and 65.0 vs 28.5 x 109/L). Patients with Ph-like ALL were also more likely to be male compared to patients with BCR-ABL1 and non Ph-like ALL, with 66% vs 50% and 50%, respectively(p