• Imatinib improves outcomes for adults with Ph1 ALL at least in part by facilitating allogeneic stem cell transplant.• Allogeneic hematopoietic stem cell transplant is not dispensible in Ph1 ALL in the imatinib era.The Philadelphia chromosome positive arm of the UKALLXII/ECOG2993 study for adult acute lymphoblastic leukemia (ALL) enrolled 266 patients between 1993 and 2003 (preimatinib cohort). In 2003 imatinib was introduced as a single-agent course following induction (N 5 86, late imatinib). In 2005 imatinib was added to the second phase of induction (N 5 89, early imatinib). The complete remission (CR) rate was 92% in the imatinib cohort vs 82% in the preimatinib cohort (P 5 .004). At 4 years, the overall survival (OS) of all patients in the imatinib cohort was 38% vs 22% in the preimatinib cohort (P 5 .003). The magnitude of the difference between the preimatinib and imatinib cohorts in event-free survival (EFS), OS, and relapse-free survival (RFS) seen in univariate analysis was even greater in the multivariate analysis. In the preimatinib cohort, 31% of those starting treatment achieved hematopoietic stem cell transplant (alloHSCT) compared with 46% in the imatinib cohort. A Cox multivariate analysis taking alloHSCT into account showed a modest additional benefit to imatinib (hazard ratio for EFS 5 0.64, 95% confidence interval 0.44-0.93, P 5 .02), but no significant benefit for OS and RFS. Adding imatinib to standard therapy improves CR rate and long-term OS for adults with ALL. A proportion of the OS benefit derives from the fact that imatinib facilitates alloHSCT. This trial was registered at clinicaltrials.gov as NCT00002514. (Blood. 2014;123(6):843-850)

CRLF2-d and IGH@-t represent distinct subtypes of adolescent and adult ALL. Deletions of key B-cell differentiation and cell cycle control genes are highly prevalent but vary in frequency by cytogenetic subgroup. CRLF2-d, IGH@-t, and IKZF1 deletions are associated with poor outcome in adolescent and adult ALL.

Summary The predictive value of molecular minimal residual disease (MRD) monitoring using polymerase chain reaction amplification of clone‐specific immunoglobulin or T‐cell Receptor rearrangements was analysed in 161 patients with non T‐lineage Philadelphia‐negative acute lymphoblastic leukaemia (ALL) participating in the UK arm of the international ALL trial UKALL XII/Eastern Cooperative Oncology Group (ECOG) 2993. MRD positivity (≥10−4) in patients treated with chemotherapy alone was associated with significantly shorter relapse‐free survival (RFS) at several time‐points during the first year of therapy. MRD status best discriminated outcome after phase 2 induction, when the relative risk of relapse was 8·95 (2·85–28·09)‐fold higher in MRD‐positive (≥10−4) patients and the 5‐year RFS 15% [95% confidence interval (CI) 0–40%] compared to 71% (56–85%) in MRD‐negative (<10−4) patients (P = 0·0002) When MRD was detected prior to autologous stem cell transplantation (SCT), a significantly higher rate of treatment failure was observed [5‐year RFS 25% (CI 0–55%) vs. 77% (95% CI 54–100%) in MRD‐negative/<10−4, P = 0·01] whereas in recipients of allogeneic‐SCT in first complete remission, MRD positivity pre‐transplant did not adversely affect outcome. These data provide a rationale for introducing MRD‐based risk stratification in future studies for the delineation of those at significant risk of treatment failure in whom intensification of therapy should be evaluated.

Safety and efficacy data on pegylated asparaginase (PEG-ASP) in adult acute lymphoblastic leukaemia (ALL) induction regimens are limited. The UK National Cancer Research Institute UKALL14 trial NCT01085617 prospectively evaluated the tolerability of 1000 IU/m2 PEG-ASP administered on days 4 and 18 as part of a five-drug induction regimen in adults aged 25–65 years with de novo ALL. Median age was 46.5 years. Sixteen of the 90 patients (median age 56 years) suffered treatment-related mortality during initial induction therapy. Eight of the 16 died of sepsis in combination with hepatotoxicity. Age and Philadelphia (Ph) status were independent variables predicting induction death >40 versus ⩽40 years, odds ratio (OR) 18.5 (2.02–169.0), P=0.01; Ph− versus Ph+ disease, OR 13.60 (3.52–52.36), P<0.001. Of the 74 patients who did not die, 37 (50.0%) experienced at least one grade 3/4 PEG-ASP-related adverse event, most commonly hepatotoxicity (36.5%, n=27). A single dose of PEG-ASP achieved trough therapeutic enzyme levels in 42/49 (86%) of the patients tested. Although PEG-ASP delivered prolonged asparaginase activity in adults, it was difficult to administer safely as part of the UKALL14 intensive multiagent regimen to those aged >40 years. It proved extremely toxic in patients with Ph+ ALL, possibly owing to interaction with imatinib.

Avascular necrosis (AVN) is a serious complication of acute lymphoblastic leukaemia (ALL) therapy. Little is known of the scope and magnitude of this problem among adults with ALL. We analysed the incidence and risk factors for AVN in 1053 patients on the UKALLXII/ECOG2993 study. AVN affected 99 joints in 42 patients at a median of 2.2 years post-diagnosis, giving a crude incidence rate of 4.0%. Statistically significant risk factors for the development of AVN were age and treatment with chemotherapy. Patients receiving prolonged chemotherapy without stem cell transplant were at significantly greater risk of developing AVN than stem cell transplant recipients (Po0.00005). The actuarial incidence of AVN was 29% at 10 years in patients o20 years old compared to 8% at 10 years in those 420 years old; P ¼ 0.0004; odds ratio 0.28 (95% CI ¼ 0.14-0.56).

Stereoscopic vision improved accuracy in laparoscopic skills for novices, which was manifested in reduced numbers of repetitions and errors. However, it does not affect the global performance time across all tasks.

Purpose: Activating Notch-1 mutations are frequent in T-cell acute lymphoblastic leukemia (T-ALL), occurring in >50% of patients. In murine models of T-ALL, Notch-1 activation can both directly initiate leukemia and cooperate secondarily to other primary events.Whether acquisition of Notch-1mutations is an early initiating event or a secondary event in the pathogenesis of human T-ALL is unclear. Experimental Design: We used denaturing high-performance liquid chromatography, sequencing, and fragment analysis to analyze Notch-1mutational status and mutant level in 62 patients at presentation as well as 16 matched presentation-relapse samples. Results: We detected Notch-1 mutations in 47 patients (76%). Seven of these were low-level mutations (quantified at V10%), despite high blast counts, suggesting that they were acquired as a secondary event in a subclone. Of 16 matched presentation-relapse samples studied, 7 were wild-type at both presentation and relapse. Five of nine mutant-positive patients at presentation relapsed with the same mutation(s) at the same high level. Four patients had evidence of a change in mutant at relapse. One lost a PEST mutation and became wild-type. Two others lost mutations at relapse but acquired different mutations, despite unchanged T-cell receptor rearrangements, suggesting that the latter event predated the acquisition of the Notch-1 mutation. One relapsed with a secondaryT-cell leukemia and different Notch mutation. Conclusions: These results suggest that Notch-1 mutations can sometimes be acquired as secondary events in leukemogenesis and must be used cautiously as solitary minimal residual disease markers.

Key Points• Human BM-MSCs can be used to successfully deliver systemic oncolytic measles virotherapy to ALL tumor targets.• This approach permits circumvention of preexisting anti-measles humoral immunity and enhanced therapeutic outcomes.Clinical trials of oncolytic attenuated measles virus (MV) are ongoing, but successful systemic delivery in immune individuals remains a major challenge. We demonstrated high-titer anti-MV antibody in 16 adults with acute lymphoblastic leukemia (ALL) following treatments including numerous immunosuppressive drugs. To resolve this challenge, human bone marrow-derived mesenchymal stromal cells (BM-MSCs) were used to efficiently deliver MV in a systemic xenograft model of precursor B-lineage-ALL. BM-MSCs were successfully loaded with MV ex vivo, and MV was amplified intracellularly, without toxicity. Live cell confocal imaging demonstrated a viral hand-off between BM-MSCs and ALL targets in the presence of antibody. In a murine model of disseminated ALL, successful MV treatment (judged by bioluminescence quantification and survival) was completely abrogated by passive immunization with high-titer human anti-MV antibody. Importantly, no such abrogation was seen in immunized mice receiving MV delivered by BM-MSCs. These data support the use of BM-MSCs as cellular carriers for MV in patients with ALL. (Blood. 2014;123(9):1327-1335) IntroductionAdult acute lymphoblastic leukemia (ALL) is an aggressive hematological malignancy with complete remission rates following initial induction therapy of 85% to 95%. [1][2][3][4][5][6][7][8] Despite cycles of combined immunosuppressive and myelosuppressive chemotherapeutics, longterm survival is achieved in fewer than half of adults, 9 and few patients with relapsed disease survive. 10 The ability to quantify and monitor minimal residual disease in the majority of patients with ALL, provides a basis-already recognized by the regulatory authorities-for early intervention with novel therapeutics prior to overt disease relapse, 11 which would be the optimal setting for novel biological therapies.Oncolytic viruses (OVs) preferentially infect and lyse transformed cells, leaving normal cells relatively unharmed. They lack crossresistance with existing therapies, and the acceptable safety profile of OVs has been demonstrated in numerous trials. [12][13][14][15][16] Vaccine-strain live, attenuated MV (MV-Edm) has shown tumor-specific replication and antitumor activity in a range of malignancies, [17][18][19][20][21][22][23][24][25][26][27][28][29][30] with published phase 1 clinical trials showing safety and some therapeutic promise in cutaneous T-cell lymphoma 31 and ovarian cancer. 32 Sophisticated manipulations of the vaccine MV genome can aid tumor targeting [33][34][35][36][37] and assist with in vivo tracking. 21,38,39 Despite this, the necessity to shield MV from neutralizing antibody during systemic delivery has not been appropriately addressed 40,41 but is likely to preclude repeat dosing regimes and impact adversely on therapy.There has been in...