NCI Standard Risk Patients Research Articles

UKALL 2011: Randomised Trial Investigating a Short Induction Dexamethasone Schedule for Children and Young Adults with Acute Lymphoblastic Leukaemia

▪Dexamethasone is associated with a higher risk of infectious and non-infectious morbidity and mortality than prednisolone in induction therapy of children and young adults with Acute Lymphoblastic Leukaemia (ALL). We tested whether a 2 week induction dexamethasone schedule is less toxic than the standard 4 week schedule. Patients aged 1 -24 years with a new diagnosis of ALL or lymphoblastic lymphoma (excluding mature B lymphoma and ALL) in the UK and Ireland were randomly allocated to receive dexamethasone 5 mg/m2twice daily for 14 days (continuous in age <10 years and discontinuous week on/week off in age > 10 years) (Short) or 3 mg/m2 twice daily for 29 days followed by a 7 day wean (Standard). The primary end-point was a reduction in steroid related toxicity defined as any induction treatment related death, all serious adverse events (SAEs) within 8 weeks of the start of induction, and adverse events (AEs) which were classified as steroid related or contributory.At diagnosis, patients were stratified by NCI (Standard Risk = age <10 and white cell count <50 x 109/l, High Risk = age > 10 years or white cell count >50x 109/l) and cytogenetic risk to receive one of 3 escalating intensity treatment regimens (A, B, C). NCI standard risk (SR) patients received a 3 drug induction (Regimen A) whilst high risk (HR) patients received 4 drugs including daunorubicin (Regimen B). Patients with poor risk cytogenetics were transferred to Regimen C. Minimal Residual Disease (MRD) was measured at the end of induction (day 29) and end of consolidation (week 14) using a Real Time Quantitative PCR technique with a sensitivity of 0.01%. Patients were classified as MRD low risk (day 29 <0.005%), intermediate risk (day 29 > 0.005% - 5%, week 14 <0.5%) or high risk (day 29 > 5% or week 14 >0.5%).Between April 2012 and April 2017, 1904 eligible patients were randomly allocated to short (951) or standard dexamethasone (953) arms which were balanced for NCI risk, sex, immunophenotype and disease type (ALL or LBL). Analysis was intention to treat. Recruitment was stopped early on the recommendation of the data monitoring committee (IDMC) due to concerns about a non-significant excess of induction treatment related deaths in NCI standard risk patients with the short schedule (Short =9/503 (1.8%), Standard =4/506 (0.8%) (p =16) which led to a futility analysis demonstrating that there was <10% power of showing a significant improvement with short dexamethasone. At a median follow-up of 22.8 months, there is no statistically significant difference in steroid related toxicity, MRD response or relapse free survival between arms (Table).A shorter induction schedule of dexamethasone 10 mg/m2/day x 2 weeks is no less toxic than 6 mg/m2/day x 4 weeks in children and young adults with ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Whole Exome Sequencing of Pediatric Acute Lymphoblastic Leukemia Patients Identify Mutations in 11 Pathways: A Report from the Children's Oncology Group

Survival for childhood acute lymphoblastic leukemia (ALL) now approaches 90% with risk adapted therapy based on National Cancer Institute risk group (NCI RG) at diagnosis, somatic lymphoblast genetics, and early response to therapy as measured by minimal residual disease (MRD). Recent studies have identified multiple somatic genetic mutations in ALL, some of which confer increased risk of relapse or identify opportunities for additional targeted therapies. However, there are few genome sequencing analyses of representative cohorts of childhood ALL treated on contemporary regimens.To define the mutational landscape of childhood B-ALL, we performed whole exome sequencing (WES) on diagnostic tumor and remission samples of 192 patients with B-ALL consecutively enrolled between 4/1/06-9/8/06 on the Children’s Oncology Group AALL03B1 classification trial that enrolled 11,145 patients up to age 30, which included patients enrolled on clinical trials for standard-risk (SR) B-ALL (N=5226, age 1-10 years and white blood cell count (WBC) < 50,000/uL) and high-risk (HR) B-ALL (N=2907; age ≥10 years or WBC ≥50,000/uL). An 8-gene expression low density array card identified Ph-like patients, and single nucleotide polymorphism arrays and multiplex ligation assays were used to determine DNA copy number alterations. Approximately 2/3 NCI SR and 1/3 NCI HR patients with sufficient banked samples were selected to reflect a population-based cohort (Table 1). Comparison of those selected vs. those not revealed significantly more NCI SR patients with a higher WBC and MRD, and fewer with double trisomy 4 and 10. Selected NCI HR patients were younger, had a higher WBC, and had more ETV6/RUNX1.There were a total of 3576 non-silent mutations with a median of 15 mutations/case (range 1-134). One case had 102 non-silent mutations and a germline mutation in MSH3. The additional mutations clustered in 11 pathways (Table 2), several of which were novel including cell-matrix interaction (e.g. SSPO, FAT1) and intracellular trafficking/cytoplasmic transport (e.g. DYNC2H1, ANK3, UNC13C). Most commonly altered were B-cell development (49.4%), transcription factors (45.8%), tumor suppressor genes (32.7%), cytoplasmic transport (27.3%), and Ras signaling (26.7%). Several pathways Ras signaling, Jak/STAT, and transcription factor mutations/deletions were associated with genetic lesions commonly used for risk stratification. Other pathways (epigenetic, B-cell development, or tumor suppressor) occurred in all subtypes. The most commonly identified genetic mutations were NRAS (n=33), KRAS (n=26), FLT3 (n=13), PAX5 (n=10), CREBBP (n=10), XBP1 (n=9), WHSC1 (n=7), and UBA2 (n=7). XBP1 and UBA2 mutations were novel. XBP1 (X-Box binding Protein 1) encodes a transcription factor that regulates the unfolded protein response. UBA2 (ubiquitin like modifier activating enzyme 2) encodes a protein involved in sumoylation to regulate protein structure and intracellular localization. Univariable analysis revealed no significant associations with any of these pathways or mutations with an increased risk of relapse with the exception of IKZF1 mutations or deletions (n=36; p=0.0087). Multivariable analysis modeling including IKZF1, age, presenting WBC, gender, NCI RG, ETV6/RUNX1, BCR/ABL1, Ph-like, white race, and MRD revealed only BCR/ABL1 and MRD positivity being significantly predictive of relapse. However, the risk of relapse was significantly increased based on the number of mutations identified in any one single patient (HR 1.02, 95% CI 1.01-1.023, p < 0.0004). Of note, only 18 patients (NCI SR, n=8, NCI HR, n=10) were Ph-like in this cohort, likely explaining the lack of significance between Ph-like status and an increased risk of relapse in this analysis.In summary, WES of a consecutively enrolled cohort of NCI SR and HR patients revealed a large number of novel genetic mutations that could be broadly assigned to 11 classes. Outcomes for patients overall were not influenced by any one of these classes, demonstrating that sentinel genetic alterations currently used in risk stratification are of paramount importance in directing therapy intensification for ALL. These data provide important information about pathways commonly mutated in childhood ALL, identifying classes of drugs that can be considered for clinical testing to further improve outcome. [Display omitted] [Display omitted] DisclosuresLoh:Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Abbvie: Research Funding. Hunger:Amgen: Equity Ownership; Pfizer: Equity Ownership; Merck: Equity Ownership; Jazz Pharmaceuticals: Honoraria; Sigma Tau Pharmaceuticals: Honoraria; Erytech: Honoraria; Patent: Patents & Royalties: Dr. Hunger is a co-inventor of a patent (#8658,964) for the identification of novel subgroups in high risk B-ALL and outcome correlations and diagnostic methods related to the same; Spectrum Pharmaceuticals: Honoraria.

Improved Outcome for Children and Young People with T-Acute Lymphoblastic Leukaemia: Results of the UKALL 2003 Trial

▪T-ALL accounts for around 15% of paediatric ALL and carries a less favourable prognosis than B-ALL due to a higher relapse rate (RR) and poor response to salvage therapy. We sought to determine if the outcome for patients with T-ALL had improved on a contemporary, response based treatment protocol, UKALL 2003, which did not include pre-emptive cranial radiotherapy or high dose methotrexate. NCI standard risk patients received a 3 drug induction with dexamethasone, vincristine and pegylated asparaginase (1000 units/m2) (regimen A). NCI high risk (HR) patients also received daunorubicin (regimen B). Early morphological marrow response was measured on day 8 for NCI HR patients and day 15 for NCI standard risk patients except patients > 16 years. Rapid early responders were stratified by minimal residual disease (MRD) at day 29 which was measured by RQ-PCR. MRD negative patients were randomised to standard or reduced intensity therapy. MRD high risk (>0.01%) patients were randomised to standard therapy (regimen A/B) or an intensified regime consisting of augmented BFM consolidation, escalating Capizzi methotrexate and 2 delayed intensifications (regimen C). Patients with high risk cytogenetics or a slow early morphological response received regimen C, regardless of MRD. Regimen A and B patients received 4 doses of pegylated asparaginase (2 in induction and 1 in each DI) and Regimen C patients received an additional 8 doses.Of 3126 patients in the trial, 388 (12.4%) had T-ALL. Of those, 73% were male with a median age of 10 yrs (range 1-24). Median WCC was 94x109/L (range 1-881) and 85% were HR by NCI criteria. 76% had a rapid early response (RER), defined as <25% bone marrow blasts. MRD was evaluable for 72% of patients. MRD at day 29 was ≥0.1% in 37%, detectable at a level of <0.1% in 22% and undetectable in 41%. Compared to the trial population as a whole, patients with T-ALL were more often stratified to receive the higher intensity regimens. T-ALL 11%, 52% and 37% treated on Regimens A, B and C compared with 51%, 26% and 23% for trial overall.With a median follow up of 5 yrs 7 mths (range 1 yr 4 mths – 9 yrs 11 mths), patients with T-ALL had an inferior outcome compared to those with B-ALL due to a higher risk of relapse (p=0.0003) and death in remission (p=0.04); 5 year event free survival (EFS) 81.2% (95% CI 77.3-85.1) vs 88.1% (86.6-89.5), overall survival (OS) 86.4% (82.9-89.9) vs 92.4% (91.4-93.4), RR 13.5% (10.0-17.0) vs 8.2% (7.0-9.4) and death in remission 4.3% (2.3-6.3) vs 2.4% (1.8-3.0). The site of excess relapses in T-ALL was both bone marrow (10.1% (7.0-13.2) vs 5.9% (4.9-6.9)) and isolated CNS (3.5% (1.5-5.5) vs 1.9% (1.3-2.5)). However, the CNS relapse rate is comparable to other protocols containing cranial radiotherapy and high dose methotrexate. The excess deaths in remission are a reflection of the higher intensity regimens that a majority of T-ALL patients received. In contrast to B-ALL (data not shown), increasing WCC was not a risk factor for relapse in T-ALL. 5 year EFS for T-ALL patients with a WCC <100 was 85% vs 81% for those with a WCC ≥100. CNS relapse rate was not different between the two groups, 5% vs 8% (p=0.3). There was no difference in outcome between those with a WCC of 100-300 and ≥300. Response to induction was the strongest predictor of relapse. Patients with a slow early response had a high relapse risk (Hazard Ratio=2.31 (1.11-4.84), p = 0.03 in multivariate analysis) despite receiving Regimen C. Patients with MRD ≥0.1% had a 5 year EFS of 71.5% compared to 89.6% for the MRD <0.1% group and 90.3% for the MRD negative group (log rank p(trend)=0.001), RR 23.2% vs 7.1% vs 8% (p=0.003). There was a trend for a worse outcome in the patients aged ≥16 although this was not statistically significant, 5 year EFS 74.1% vs 82.8% (log rank p=0.7), RR 20.8 vs 11.9%, (p=0.09). Compared with our previous trial, UKALL97/99, outcome for T-ALL patients has improved with a higher EFS, 81.7% vs 72.8% at 5 years (log rank p=0.08), due mainly to a non-significantly lower relapse rate 13.5% vs 20.6% (p=0.09).T-ALL outcomes have improved with better risk stratification and the use of dexamethasone and pegylated asparaginase. Pre-emptive cranial radiotherapy or high dose methotrexate are not essential to preventing CNS relapse. The outcome for patients with T-ALL, however, remains inferior to those with B-ALL highlighting the need for novel therapies for patients with high risk T-lineage disease. DisclosuresNo relevant conflicts of interest to declare.

Characteristics and Outcomes Of Patients With Down Syndrome Associated Acute Lymphoblastic Leukaemia Treated On UKALL 2003

Children with Down Syndrome (DS) are at significantly increased risk of developing acute leukaemia, both AML and ALL. Whilst outcomes for AML are excellent, ALL associated with DS (DS-ALL) confers an inferior survival due to a combination of increased relapse risk and high treatment related mortality (TRM). We report the outcome for children and young adults with DS-ALL treated on a modern, intensive, minimal residual disease (MRD) directed protocol, UKALL2003.Treatment was not modified for DS-ALL patients at the start of the trial. NCI standard risk patients received a 3 drug induction with dexamethasone, vincristine and pegylated asparaginase. NCI high risk patients also received daunorubicin. MRD was measured at day 29 and MRD negative patients were randomised to standard or reduced intensity therapy. MRD high risk patients were randomised to standard therapy or an intensified regime consisting of augmented BFM consolidation, escalating Capizzi methotrexate and 2 delayed intensifications. Six years after the trial opened, an unacceptably high TRM in DS patients, (10 deaths out of 46 patients), prompted modifications to their treatment. DS patients were excluded from randomisations and, regardless of NCI risk, received a three drug induction with the addition of daunorubicin at day 15 for those with a slow morphological marrow response (>25% blasts). Patients with positive MRD at day 29 or those with a slow day 15 morphological response were treated with augmented therapy described above, in the absence of established significant comorbidity. All patients received only one delayed intensification and maintenance was shortened to 2 years for boys (standard duration 3 years).Strict supportive care measures during intensive phases of treatment were mandated.Of 3126 eligible patients in the trial, 85 (2.7%) had DS with median age 4 years (range 1-23 years). DS-ALL patients were more likely than non-DS-ALL patients to be male (68% vs 56%, p=0.03) and were almost exclusively B-cell precursor ALL (99 % vs 87%, p=0.001), but there were no significant differences by age, WBC or NCI risk. Nine of 80 DS-ALL patients from whom data on cytogenetic abnormalities was available had high hyperdiploidy (11% vs 30% in non-DS-ALL, p=0.0003), and 13 had an ETV6/RUNX1 fusion (16% vs 25%, p=0.06).With a median follow-up of 4 years 10 months, patients with DS-ALL had an inferior EFS compared to non-DS-ALL patients (65.3% (95% CI 54.5-76.1%) at 5 years vs. 87.8% (86.4-89.2%); OR=8.90 (95% CI: 4.53-17.48) p<0.00005). Of the 85 DS-ALL patients, 25 have died, 7 due to relapsed disease, 2 due to induction failure and death with active disease and 16 due to TRM during first line therapy. TRM deaths occurred throughout treatment (induction = 5, CR = 11) and were not confined to the most intensive phases. In all cases, deaths were due to infection, most commonly bacterial sepsis (75%) and viral pneumonitis (25%). The excess TRM was primarily responsible for the worse EFS for DS patients, as their risk of relapse (16.4% at 5 years ) was not significantly worse (p=0.1) than for non-DS patients (8.8%).In contrast to other recently reported studies, we report excess TRM as the main cause of treatment failure in DS-ALL, possibly due to the intensity of our treatment protocol which included dexamethasone and pegylated asparaginase for all patients. There have been fewer treatment related deaths in induction after introducing the treatment modifications in 2009 (4/46 vs 1/41) without an apparent increase in relapse risk. Improvements in outcome for this vulnerable group of patients will require such risk stratified treatment modifications, better supportive care and innovative agents that can replace the more intensive elements of current treatment schedules. Disclosures:No relevant conflicts of interest to declare.

Early Response to Therapy Is Significantly Associated with Genetic Subtype of Acute Lymphoblastic Leukemia: A Report from the Children's Oncology Group.

Improved outcomes for children with acute lympboblastic leukemia (ALL) have been achieved, in part, from adaptation of risk-stratified therapy. The Children's Oncology Group (COG) has implemented a real-time risk classification system (AALL03B1) using a combination of NCI-Rome risk criteria, blast cell genetic features, and early treatment response to determine the intensity of post-induction therapy. Between December 29, 2003 and June 1, 2007, more than 4,000 children over 1 year of age with B-precursor ALL were enrolled on AALL03B1, including 2293 (62%) with NCI Standard Risk (SR) and 1406 (38%) with NCI High Risk (HR) features who were subsequently enrolled on companion clinical trials. The most favorable genetic features used in AALL03B1 were identified in legacy COG studies and included TEL/AML1(TEL) or triple trisomies of chromosomes 4, 10, and 17 (TT). Unfavorable genetic features included the presence of BCR/ABL, MLL rearrangements, or extreme hypodiploidy (DNA index <.81 or chromosomes <44). Overall, 26% of patients were TEL+ and 24.7% had TT. These genetic subsets occurred more frequently in NCI SR vs. HR patients (30.7% and 30.9% vs. 14.5% and 11.7% respectively). Children achieving an M1 day 15 bone marrow (BM) who also had minimal residual disease (MRD) < 0.1% measured by flow cytometry on day 29 of induction therapy were deemed rapid early responders (RER), while those with either an M2/M3 day 15 marrow or MRD > 0.1% at day 29 were defined as slow early responders (SER). Among the favorable cytogenetic subsets, patterns of early response differed. The presence of TEL was significantly associated with an RER to induction therapy in both NCI SR and HR groups (p< 0.0001), while the presence of TT was not (p=0.058). For NCI SR patients, the presence of TEL was significantly associated with the achievement of an M1 bone marrow by day 8 (50.9% of TEL+ pts vs. 41.2% of TEL- pts, p< 0.0001). Patients with an M1 or M2 BM on day 29 who had MRD >1% received extended induction (EI) for two weeks followed by an additional evaluation of BM morphology and MRD at day 43 of induction. One hundred and nineteen patients received EI, with 40% having NCI SR features at diagnosis. Of the patients who received EI, 63% achieved an M1 marrow with MRD < 1% by day 43 and were eligible to continue on protocol therapy. This was more likely to occur in NCI SR patients (77% vs. 55%, p<0.013). Not surprisingly, 31% of the NCI HR patients receiving EI were BCR/ABL positive, and the presence of BCR/ABL was associated with a slower early response overall. While the presence of the BCR/ABL was associated with a greater likelihood of EI, MLL rearrangements and hypodiploidy were not. These data indicate that early response to induction therapy differs among genetic subsets of pediatric patients with newly diagnosed ALL. In addition a centralized classification system allows for robust collection of data from local and centralized reference laboratories that can be used for real time treatment assignment of ∼2000 patients/year with ALL from > 220 COG institutions.

Benefit of Targeted Intensification for NCI High Risk Childhood Lymphoblastic Leukaemia: Results of the United Kingdom Medical Research Council Trial ALL97 and ALL97/99.

In November1999, the UK childhood ALL trial, ALL 97, adopted CCG risk stratification and treatment regimens in favour of the UKALL approach due to concerns over lower event-free survival (EFS) in the UK compared to the US. A key new feature in the amended trial, ALL97/99, was NCI risk group and early marrow response targeted intensification. Of 1935 patients registered in the trial between January 1997 and June 2002, 997 were treated on ALL97 and 938 on ALL97/99. EFS was better in ALL97/99 compared with ALL 97 (5 year EFS: ALL 97 = 74.1%, 95% CI 71.4%–76.8% vs ALL 97/99 = 78.9%, 76.0%–81.8%, p=0.002). To investigate whether particular sub-groups benefited more or less with the CCG approach, we compared outcomes for different risk groups within the two parts of the trial in regard to EFS, overall survival (OS) and CNS relapse risk. All p values quoted are two-sided. EFS and OS were significantly better in ALL97/99 compared with ALL97 for NCI high risk (HR) patients (5 year EFS: ALL 97 = 61.8%, 95% CI: 56.9–66.7%, ALL 97/99 = 71.8% 95% CI: 66.7–76.9%, p = 0.0006. 5 year OS: ALL97 = 71.3%, 95% CI: 66.8–75.8%, ALL97/99 = 80.3% 95% CI: 76.0–84.6%, p = 0.005), but did not differ significantly for NCI standard risk (SR) patients (5 year EFS: ALL 97 = 81.7% 95% CI: 78.6–84.8%, ALL 97/99 = 83.3% 95% CI: 79.8–86.8%, p = 0.3. 5 year OS: ALL97 = 91.2% 95% CI: 89.0–93.4%, ALL97/99 = 92.6% 95% CI: 90.4–94.8%, p = 0.5). The incidence of isolated CNS relapse was also significantly lower in ALL97/99 for NCI HR (ALL97 = 8% vs ALL97/99 = 3.5%, p = 0.01) but not NCI SR patients (ALL97 = 3.5% vs ALL97/99 = 2.7%, p = 0.6). Despite restricting the use of cranial radiotherapy to patients with overt CNS disease (CNS 3, <5% of all patients), the incidence of isolated CNS relapse in ALL97/99 was reassuringly low, even for sub-groups at high risk of CNS relapse such as those with WCC > 100 × 10 9/l (4.8%) or T cell phenotype (3.8%). Isolated CNS relapse risk in ALL97/99 patients randomised to dexamethasone (which was compared with prednisolone in the trial) was 1.8%, similar to that reported with use of cranial radiotherapy for a higher proportion of patients. A targeted intensification approach improves EFS for NCI HR patients and, especially when combined with systemic dexamethasone, results in a low incidence of isolated CNS relapse for high risk sub-groups without use of cranial radiotherapy.

Biology-Driven Classification of Childhood Acute Lymphoblastic Leukemia: A Combined Analysis of Prognostic Markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG).

Risk adapted therapy, tailoring treatment to the likelihood of relapse, has constituted a significant advance in the treatment of childhood ALL. The recent merger of the POG and CCG provided an opportunity to reassess previous approaches and to develop a new biology driven classification system based on data from both legacy groups. All children (age 12 months to 21.99 years) with newly diagnosed B-precursor (ALL), consecutively enrolled on CCG (December 1988 to August 1995, N = 3056) and POG (January 1986 to November 1999, N = 6800) protocols, were evaluated for the impact of numerous clinical and laboratory variables on event free survival at 5 and 8 years in each group separately, thereby superseding differences in treatment approaches. Infants and patients with a T- cell phenotype were excluded from the analyses. Very high risk was defined as the group for which myeloablative therapy might be indicated with an anticipated 5 year EFS <45%, while a reduction in therapy could be justified for the lowest risk patients with a >85% 5 year EFS. Patients identified as being at very high risk for relapse had hypodiploidy (<45 chromosomes) (CCG 34.8%, POG 46.5% - 5 year EFS), induction failure (CCG 11.3% 5 year EFS) or t(9;22) or BCR/ABL (POG 27.5%, CCG 29.6% 5 year EFS). Patients identified as low risk for relapse were NCI standard risk patients with either t(12;21) (TEL-AML1) (CCG 86%, POG 85% 5 year EFS) or all three trisomies of 4, 10, and 17 (CCG 91.5%, POG 89.3% 5 year EFS). Certain NCI high risk patients were identified as having a higher risk for relapse but did not fall into the VHR category: t(4;11)(POG 49.9%, CCG 50.0% 5 year EFS),CNS3 (CCG 59.3%, POG 67.8% 5 year EFS) and slow early response (SER) defined by M2/3 at day 14 (Standard risk 66% SER versus 84% and for high risk ALL 63% SER versus 75%). Other potential VHR factors that require confirmation included, slow early responder t(4;11) (CCG 11.1% 5 year EFS) and monosomy 7 (CCG 44%, POG 66.6% 5 year EFS). A balanced t(1;19) had only a minor unfavorable effect on EFS. The COG has identified a risk classification system that builds on the previous NCI risk classification system for childhood ALL, incorporating the cytogenetic and molecular genetic features of the blasts, as well as rapidity of clinical response. The division of B-precursor ALL patients into low risk (18%), standard risk (49%), high risk (30%) and very high risk (3%) groups will : 1) identify those patients for whom therapy might be reduced without sacrificing overall cure rates, 2) determine those patients who will require intensified therapy and 3) suggest underlying biological pathways that mediate cure or treatment failure.