MTX Arm Research Articles

SAT0104 MAINTENANCE OF SDAI REMISSION AND PATIENT-REPORTED OUTCOMES (PROS) FOLLOWING DOSE DE-ESCALATION OF ABATACEPT IN MTX-NAÏVE, ANTI-CITRULLINATED PROTEIN ANTIBODY (ACPA)+ PATIENTS WITH EARLY RA: RESULTS FROM AVERT-2, A RANDOMISED PHASE IIIB STUDY

Background:The Phase IIIbAssessingVeryEarlyRATreatment (AVERT)-2 trial (NCT02504268) evaluated SC abatacept (ABA) + MTX vs ABA placebo (PBO) + MTX in ACPA+ patients (pts) with early, active RA.1Results from the 56-wk induction period (IP) showed a significantly greater proportion of pts treated with ABA + MTX (vs MTX alone) reported clinically meaningful improvements in HAQ-DI, global disease activity and pain, which were sustained at 52 wks.2Objectives:To report maintenance of SDAI remission and PROs from the AVERT-2 de-escalation (D-E) period.Methods:Pts received blinded SC ABA (125 mg once wkly [QW]) + MTX or ABA PBO + MTX induction treatment for 56 wks. In this analysis, pts who completed induction with ABA + MTX and had sustained SDAI remission (≤3.3 at Wks 40 and 52) were re-randomised 1:1:1 to ABA QW + MTX, stepwise D-E (ABA every other wk + MTX for 24 wks then ABA PBO + MTX for 24 wks), or ABA QW + MTX PBO for 48 wks in the D-E period. PROs included physical function (HAQ-DI [0–3; decrease=improvement] and Short-Form 36 [SF-36] v2.0 Physical Functioning Scale [PFS]; 0–100; increase=improvement), and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F] score; 0–52; decrease=improvement). Endpoints included: proportion of pts in SDAI remission and pts with HAQ-DI response (decrease from IP Day [D]1 in HAQ-DI ≥0.30); adjusted mean change (adMC) from D-E D1 in HAQ-DI, SF-36 PFS or FACIT-F to D-E Wk 48. adMCs were estimated using a mixed effect model with repeated measures.Results:147 ABA + MTX-treated pts were re-randomised in the D-E period. Across re-randomised arms, the range of mean scores was 1.87–2.52 for SDAI and 0.18–0.30 for HAQ-DI at entry into D-E period (D-E D1). 74% of pts receiving ABA QW + MTX maintained SDAI remission at D-E Wk 48 (Fig 1); this proportion was higher than in the ABA withdrawal and ABA QW + MTX PBO arms. Pts continuing ABA QW + MTX maintained HAQ-DI response during D-E (Fig 1), but by D-E Wk 48 the proportion of pts with HAQ-DI response in the ABA withdrawal arm declined by 30%. At D-E Wk 48, a small numerical decrease (adMC –0.04) in HAQ-DI was observed in the ABA QW + MTX arm; increases were seen in the withdrawal (adMC 0.26) and ABA QW + MTX PBO arms (adMC 0.16). By D-E Wk 48, SF-36 PFS increased (adMC 1.68) in the ABA QW + MTX arm but decreased in the withdrawal (adMC –3.34) and ABA QW + MTX PBO (adMC –1.45) arms. FACIT-F score increased during D-E in all arms, but the increase at D-E Wk 48 was lower in the ABA QW + MTX arm (adMC 0.79) vs the withdrawal (adMC 4.12) and ABA QW + MTX PBO (adMC 2.41) arms. Similar trends were seen for other PROs including Work Productivity and Activity Impairment-RA; while activity impairment remained stable in the ABA QW + MTX arm, there was a trend for worsening in the withdrawal arm.Conclusion:In the AVERT-2 D-E period, continued combination therapy (abatacept + MTX) resulted in maintenance of benefits on PROs, particularly physical functioning, in seropositive pts with early RA. D-E of abatacept followed by complete withdrawal was associated with the greatest loss of remission as well as worsening of PROs. The PRO results corresponded well to the maintenance of clinical (SDAI) remission.

THU0215 WHOLE BLOOD TRANSCRIPTIONAL CHANGES FOLLOWING SELECTIVE INHIBITION OF JANUS KINASE 1 (JAK1) BY FILGOTINIB IN ADULTS WITH MODERATELY-TO-SEVERELY ACTIVE RHEUMATOID ARTHRITIS WITH PRIOR INADEQUATE RESPONSE TO METHOTREXATE (FINCH1)

Background:Filgotinib (FIL), an oral selective JAK1 inhibitor, has shown efficacy and safety in multiple phase 3 studies in adults with moderately-to-severely active rheumatoid arthritis (RA). We have previously described the molecular response to FIL in large-scale RNA sequencing studies of gene expression in other RA populations1-3and herein conducted a similar study in RA patients (pts) with prior inadequate response to methotrexate (MTX; FINCH1).Objectives:Identify RA-associated gene transcripts and biological pathways that are altered in response to FIL treatment.Methods:RA pts who had an inadequate response to MTX were enrolled in FINCH1 (ClinicalTrials.govNCT02889796) and randomized to receive either a stable dose of MTX with placebo (PBO+MTX), adalimumab (ADA+MTX), or one of two doses of FIL (FIL 100mg+MTX, FIL 200mg+MTX) once daily (QD). Whole blood samples were collected from pts using PAXgene tubes at baseline, week 4, and week 12. RNA from these samples was extracted and sequenced on the Illumina HiSeq 2500 platform following globin RNA depletion. Correlations between baseline gene expression and disease measurements were performed using Spearman’s rank partial correlation with covariates. Differentially expressed genes (DEGs) were identified using voom-limma. Pathway analysis was performed on v6.1 of the Molecular Signature Database using single sample gene set enrichment analysis (GSEA) with the focus on immune signaling pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG). A false-discovery rate of 5% was applied for all analyses.Results:Differential gene expression analyses comparing baseline samples with after-treatment samples revealed more rapid transcriptional kinetics for FIL-treated pts compared to ADA+MTX-treated pts. No significant DEGs were observed in PBO-treated pts. More significant DEGs were observed in the FIL 200mg+MTX arm compared to the FIL 100mg+MTX arm, consistent with the superior clinical efficacy of the FIL 200mg dosage. As with other FIL clinical trial RNA-seq studies and consistent with the selective MoA of FIL, JAK-STAT pathway-induced genes SOCS2 and CISH were significantly downregulated across both FIL treatment arms and timepoints, but not in the ADA+MTX arm. RA disease activity associated genes2-3FAM20A and METTL7B were significantly reduced at both 4 and 12 weeks only in the FIL 200mg+MTX arm. While no significant changes in KEGG immune signaling pathways were observed in the PBO+MTX arm, a dose-dependent effect on pathway modulation was observed in the FIL arms. The most prominently down-regulated KEGG pathways included JAK-STAT signaling and leukocyte transendothelial migration.Conclusion:More rapid and sustained changes of transcriptional activity were observed in the whole blood transcriptional profile of RA pts following FIL 200mg+MTX compared to ADA+MTX treatment. Dose-dependent changes were observed in FIL-treated pts, most notably in the KEGG JAK-STAT signaling pathway. These observations confirm an inhibition of JAK-STAT signaling by FIL and are consistent with the observed clinical efficacy of FIL in these pts.

THU0095 IMPACT OF BASELINE EROSION SCORE ON RESPONSE TO TREATMENT AND FUTURE RADIOLOGICAL DAMAGE IN AVERT-2, A RANDOMISED PHASE IIIB STUDY OF ABATACEPT IN MTX-NAÏVE, ANTI-CITRULLINATED PROTEIN ANTIBODY–POSITIVE (ACPA+) PATIENTS WITH EARLY RA

Background: Bone erosions are associated with poor prognosis in patients (pts) with RA. They can be associated with subclinical inflammation and independently predict future radiological damage.1 The Phase IIIb Assessing Very Early RA Treatment (AVERT)-2 (NCT02504268) trial evaluated abatacept (ABA)+MTX in MTX-naive, ACPA+ pts with early RA.2 Objectives: To explore the impact of baseline (BL) X-ray erosion scores (ES) on clinical response and future radiological damage over 1 yr in different groups of pts from AVERT-2. Methods: BL and Wk 52 X-ray data were evaluated using Sharp/van der Heijde score. SDAI remission rates (RRs; ≤3.3), unadjusted mean changes from BL (CfB) and duration of/time to sustained remission over 52 wks were evaluated. Radiographic progression was assessed at Wk 52 using CfB in ES. A range of BL ES cut-offs were evaluated to highlight key findings through comparison of pts with low and high ES. Results: Of 994 pts in the study, 964 (97%) had BL (median 2.0, interquartile range [IQR] 0.5–5.1) and 792 (80%) had BL and Wk 52 (median 2.5, IQR 1.0–6.5) ES. Results in Table 1 are based on ES cut-offs of 2 and 5, resulting in 53% and 75%, respectively, of pts in low ES groups. In pts who received ABA+MTX, those with low ES had higher SDAI RRs over 52 wks vs pts with high ES. The relationship was more pronounced for higher cut-offs. This was not observed with ABA placebo+MTX (MTX). Greater reduction of mean CfB in SDAI was achieved in pts with high vs low ES who received ABA+MTX. This was not observed with MTX. Pts who received ABA+MTX had longer duration and shorter time to sustained SDAI remission vs MTX. With ABA+MTX, pts with low ES had longer duration and shorter time to sustained SDAI remission vs high ES. This was not observed with MTX. Mean CfB in ES at Wk 52 was lower in the ABA+MTX arm vs the MTX arm. ABA seemed to equally protect pts with low and high ES; with MTX, pts with high ES had higher mean CfB in ES at Wk 52 than pts with low ES. Conclusion: This erosion-based stratification of the AVERT-2 early seropositive RA population emphasizes the importance of treating pts prior to the accumulation of erosive disease. Abatacept+MTX led to higher SDAI RRs in pts with low vs high ES and provided further protection vs MTX alone against future radiological damage in pts with high ES. Additional statistical modelling and adjustment for confounding factors at BL is warranted.

Methotrexate in Early Chikungunya Arthritis: A 6 Month Randomized Controlled Open-label Trial.

Evidence for treating chikungunya arthritis early in the course of illness is scarce. This study assesses the efficacy of Methotrexate in early Chikungunya arthritis. It is a randomized controlled open-label assessor-blinded trial with a crossover design. Sixty patients with persistent post chikungunya arthritis with at least 3 or more tender or swollen joints (28 joint count) were recruited. MTX arm was given oral Methotrexate and NSAID arm was given NSAIDs (Naproxen 1 gm/day or Etoricoxib 120 mg/day). Patients were followed at 1, 2, 4 and 6 months. After 2 months patients in NSAID arm who have not achieved remission were given MTX. The primary endpoint was remission (no tender or swollen joints by 28 joint count) at 6 months. Secondary endpoints were change in CDAI, Indian HAQ, total steroid use, total NSAID use, and serious adverse effects. Intention to treat analysis was used. TJC, SJC, CDAI and HAQ were matched between two at baseline. Remission was achieved by 28 patients (93%, CI- 78%-98%) in the NSAID arm and 26 patients (86%, CI-70%- 94%) in MTX arm (p=0.18). There was no significant difference in steroid need, change in HAQ, CDAI, TJC or SJC. Those who have not achieved remission had higher disease activity at baseline. A protocol-based approach with steroid and NSAIDs helped to achieve remission in most patients with early subacute phase of post-Chikungunya arthritis and the effect was comparable to that of early initiation of methotrexate.

Radiographic joint damage in early rheumatoid arthritis patients: comparing tocilizumab- and methotrexate-based treat-to-target strategies.

To evaluate the progression of erosions and joint space narrowing (JSN) in feet and hands in the U-Act-Early trial. In this trial, 317 newly diagnosed DMARD-naïve RA patients initiated randomly tocilizumab, or step-up MTX or a combination of the two. Radiographs were scored at baseline and after 52 and 104 weeks using the Sharp-van der Heijde erosion and JSN score. Between the strategy arms, changes from baseline and the proportions of patients without radiographic progression (change from baseline ≤0) were compared. Mean changes from baseline in erosion and JSN scores for the whole study population were after 52 weeks 0.59 and 0.18 and after 104 weeks 0.70 and 0.50, respectively. For JSN, at both time points no differences in progression were found between strategies (P ⩾ 0.09). For erosions, the progression was significantly lower at week 104 in both tocilizumab arms when compared with the MTX arm ((p≤0.023). Less progression of erosions in the feet was found after 104 weeks in both tocilizumab arms (P ⩽ 0.046); this was not significant for the hands (P ⩾ 0.11). The proportion of patients without progression in erosions was higher in the tocilizumab arms at week 52 (tocilizumab plus MTX: 87%, P = 0.038; tocilizumab: 81%, P = 0.29) and 104 (tocilizumab plus MTX: 85%, P = 0.001; tocilizumab: 77%, P = 0.028), compared with the MTX arm (74 and 60%, respectively). In DMARD-naïve early RA patients, initiating a tocilizumab-based treat-to-target strategy inhibits the progression of erosions, especially in the feet, more compared with initiation of a step-up MTX strategy. ClinicalTrials.gov, https://clinicaltrials.gov, NCT01034137.

Patient-reported outcomes in newly diagnosed early rheumatoid arthritis patients treated to target with a tocilizumab- or methotrexate-based strategy.

To evaluate the effect of initiation of tocilizumab, with or without MTX, compared with MTX alone on patient-reported outcomes (PROs), in DMARD-naïve patients with early RA. In U-Act-Early, patients initiated treat-to-target step-up MTX, tocilizumab or tocilizumab plus MTX therapy. PROs assessed included the Functional Assessment of Chronic Illness Therapy-Fatigue, 36-item Short Form (SF-36), five dimensional EuroQol (EQ-5D) and the Revised Illness Perception Questionnaire. Differences between strategy groups over time and proportions of patients exceeding minimum clinically important differences (MCID) were evaluated. During the 2-year study period, significant improvements were found in the tocilizumab strategies in the SF-36 physical component score (tocilizumab, P = 0.012; tocilizumab plus MTX, P = 0.044) and EQ-5D score (tocilizumab plus MTX, P = 0.020) when compared with the MTX strategy. No significant differences were noted in other PROs (P ⩾ 0.052, except for the domain 'identity' in the Illness Perception Questionnaire; tocilizumab vs MTX, P = 0.048). The proportions of patients achieving MCID in SF-36 physical component score were significantly higher at 12 and 52 weeks (P ⩽ 0.049) in the tocilizumab arms when compared with the MTX arm. At week 24, the proportion achieving MCID in EQ-5D was significantly higher in the tocilizumab plus MTX arm vs the MTX arm (P = 0.045). Initiation of treat-to-target tocilizumab therapy resulted in significantly improved PROs, especially within the first 24 weeks, when compared with initiation of MTX therapy. Also on the patients' level, initiating tocilizumab may be considered as a valuable strategy in DMARD-naïve patients with early RA. ClinicalTrials.gov, http://clinicaltrials.gov, NCT01034137.

Brief Report: Clinical Trials Aiming to Prevent Rheumatoid Arthritis Cannot Detect Prevention Without Adequate Risk Stratification: A Trial of Methotrexate Versus Placebo in Undifferentiated Arthritis as an Example.

Prevention of rheumatoid arthritis (RA) was the aim of several trials in undifferentiated arthritis (UA), with overall negative results. As preparatory work has revealed that only ∼30% of UA patients progress to having RA, we hypothesized that inclusion of patients without imminent RA could lead to false-negative results. We undertook this study to evaluate this hypothesis by reinvestigating the Probable Rheumatoid Arthritis: Methotrexate versus Placebo Treatment (PROMPT) trial (a 1-year course of methotrexate [MTX] versus placebo in UA) after excluding patients without a high risk of developing RA. A validated prediction model was used to determine the risk of RA in all patients included in the PROMPT trial. Patients with a prediction score of ≥8 (positive predictive value of ≥84% for developing RA) were considered to have a high risk of developing RA. The effect of a 1-year course of MTX during 5 years of follow-up was reinvestigated in these patients. Twenty-two of the 110 patients in the PROMPT trial had a high risk of RA at baseline. In the MTX arm, 6 of 11 patients (55%) developed RA, compared to 11 of 11 patients (100%) in the placebo arm (P = 0.011). Time to RA development was longer in the MTX arm than in the placebo arm (median 22.5 months versus 3 months; P < 0.001). Drug-free remission was achieved by 4 of 11 patients (36%) in the MTX arm compared to 0 of 11 patients (0%) in the placebo arm (P = 0.031). These beneficial effects of MTX were observed both in anti-citrullinated protein antibody (ACPA)-positive and in ACPA-negative UA patients with a high risk of RA, but not in UA patients without a high risk of RA. In retrospect, 43 of 110 patients fulfilled the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria for RA at baseline. In addition, beneficial effects were observed only in patients with a high prediction score. A 1-year course of MTX delayed and prevented RA development in high-risk UA patients. This emphasizes the importance of adequate risk prediction in trials that aim to prevent RA.

Improvement in insulin resistance is greater when infliximab is added to methotrexate during intensive treatment of early rheumatoid arthritis-results from the IDEA study.

To determine the change in established biomarkers of cardiovascular (CV) risk, namely, total cholesterol/high-density lipoprotein cholesterol ratio (TC/HDL-C), N-terminal pro-brain natriuretic peptide (NT-proBNP) and insulin resistance (IR) in patients with early RA treated with two different treat-to-target strategies. Fasting glucose, lipids, insulin and NT-proBNP were measured at baseline, weeks 26 and 78 in 79 DMARD-naïve RA patients, free of CV disease, as part of a double-blind randomized controlled trial of MTX with either infliximab (IFX) or methylprednisolone as induction therapy. Homeostasis model assessment-estimated IR (HOMA-IR) (glucose*insulin/405) was used to measure IR. Multiple imputation was employed, and linear regression analyses were adjusted for baseline values. Changes in DAS44-CRP did not differ between the treatment arms at weeks 26 and 78. Mean TC/HDL-C, HOMA-IR and NT-proBNP improved in both groups at weeks 26 and 78, although change in NT-proBNP was not statistically significant at week 78. Changes in TC/HDL-C and NT-proBNP were similar between treatment arms, but HOMA-IR values in the IFX + MTX arm were 42% lower than those treated with MTX + methylprednisolone at week 78 (P = 0.003); the difference remained significant after adjustment for baseline BMI, ACPA positivity, smoking status and intramuscular glucocorticoid use (P = 0.007). When implementing a treat-to-target approach, treatment of early RA was associated with improvement in TC/HDL-C, HOMA-IR and NT-proBNP, and a greater long-term improvement in HOMA-IR was seen in those treated with IFX. EU Clinical Trials Register, http://www.clinicaltrialsregister.eu, Eudract-2005-005013-37; ISRTCNregisrty, http://www.isrctn.com, ISRCTN48638981.

OP0006 Long-Term Safety and Effectiveness of Adalimumab in Children with Moderately to Severely Active Polyarticular or Polyarticular-Course Juvenile Idiopathic Arthritis

BackgroundJuvenile idiopathic arthritis (JIA) is one of the most common rheumatic diseases of childhood. Adalimumab (ADA) is approved for use in moderate to severe polyarticular JIA (pJIA) patients (pts) ≥4...

OP0026 Induction of Clinical Remission Followed by Drug-Free Withdrawal with Abatacept Combination and Monotherapy in Early RA: Results from the AVERT Study over 18 Months

BackgroundAVERT (Assessing Very Early Rheumatoid arthirits Treatment) is a Phase IIIb, randomized, active-controlled study to evaluate the efficacy and safety of subcutaneous (SC) abatacept (ABA) in pts with early RA.ObjectivesTo...

SAT0210 X-Ray and MRI Results from A Phase Iib Study of Subcutaneous Anti-Interleukin-6 Monoclonal Antibody Clazakizumab with or without MTX in Adults with Moderate-To-Severe Active RA and Inadequate Response to Conventional DMARDS Including Methotrexate

BackgroundClazakizumab (CLZ) is a potent, neutralizing anti-interleukin (IL)-6 monoclonal antibody that is being studied in RA. CLZ in combination with MTX (+ MTX) or as monotherapy demonstrated efficacy in controlling...

SAT0244 A Phase Iib Study of the Efficacy and Safety of Subcutaneous Clazakizumab (ANTI-IL-6 Monoclonal Antibody) with or without Methotrexate in Adults with Moderate-To-Severe Active Rheumatoid Arthritis and an Inadequate Response to Methotrexate

BackgroundClazakizumab (CLZ) is a humanized anti-interleukin-6 (IL-6) monoclonal antibody that potently neutralizes IL-6 signalling.ObjectivesThis study evaluated the safety and efficacy of subcutaneous CLZ with or without MTX versus placebo (pbo)...

AB0459 Analysis of integrated radiographic data for two long-term, open-label extension studies of adalimumab

BackgroundAccurate analysis of radiographic progression in rheumatoid arthritis (RA) has been challenging because most evaluations use change in Sharp score either between only 2 time points or between multiple time...

THU0190 Long-Term Impact of Delaying Combination Therapy with Adalimumab Plus Methotrexate by 2 Years in Patients with Early Rheumatoid Arthritis: Final 10-Year Results of the Premier Trial

BackgroundThe PREMIER trial demonstrated the superiority of initial adalimumab (ADA)+MTX vs the individual monotherapies in MTX-naïve patients (pts) with early, aggressive rheumatoid arthritis (RA)1.ObjectivesTo assess long-term outcomes in pts treated...

B cells in rheumatoid arthritis: from hypothesis to the clinic

Rituximab (MabThera/Rituxan) is a therapeutic monoclonal antibody against CD20, an antigen expressed by B cells but not B-cell progenitor or plasma cells. It is currently approved for the treatment of relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) and is well tolerated and efficacious. A small open-label study (conducted by Edwards and Cambridge) indicated that selective depletion of B cells using rituximab led to sustained benefits for patients with active rheumatoid arthritis. A 24-week, double-blind, randomized controlled trial was carried out to confirm these initial observations. In total, 161 patients with active rheumatoid arthritis were randomized to one of four treatment groups: rituximab monotherapy; rituximab plus methotrexate (R+MTX); rituximab plus cyclophosphamide (R+CTX); or methotrexate alone (MTX). Rituximab was administered as two 1000 mg infusions on days 1 and 15. An analysis at 24 weeks showed that the proportion of patients achieving an ACR20 response was significantly greater (P < or = 0.025 for all three comparisons) in all the rituximab groups compared with the MTX control group (rituximab alone, 65%; R+CTX, 76%; R+MTX, 73%; MTX alone, 38%). Both ACR50 (43 vs 13%; P = 0.005) and ACR70 (23 vs 5%; P = 0.048) responses were also significantly higher for the R+MTX group compared with the MTX group. The rituximab groups showed no significant safety differences compared with the MTX arm. The majority of adverse events were of mild to moderate intensity. Rituximab is a novel targeted therapy for the treatment of rheumatoid arthritis and it appears to be highly effective, safe and well tolerated.

Treatment of High Risk T-Cell Acute Lymphoblastic Leukemia (T-ALL): Comparison of Recent Experience of the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG).

Recent CCG and POG treatment stategies for patients with T-ALL are significantly different. POG treats T-ALL patients on a separate protocol from that used for B precursor ALL (B-ALL) while CCG treats T-ALL patients on the same protocols utilized for B-ALL patients with protocol assignment determined by the NCI risk classification. We recently reviewed the outcome of patients with T-ALL and high-risk features (age ≥ 10 years and/or initial WBC > 50,000/ul) treated on either the CCG-1961 or POG-9404 clinical trials. POG utilized an intensive anthracycline based multidrug regimen based on the DFCI treatment program and randomized patients at registration to receive or not receive additional high dose methotrexate(HDMTX) with leucovorin rescue. All patients received cranial irradiation (CRT). CCG therapy for high risk T-ALL was based on CCG modified BFM(S-BFM) and Augmented BFM(A-BFM). Patients with <25% blasts on day 7 bone marrow(RER) who achieved remission were randomized in a 2X2 design to standard or augmented intensity and standard duration(1 interim maintenance(IM) and 1 delayed intensification(DI) phase or prolonged duration (2 IM and DI phases). Only RER patients with CNS-3 status received CRT. Patients with a slow response(SER) to induction therapy received A-BFM therapy +/− idarubicin/cyclophosphamide courses during DI phases. All SER patients received CRT. In the POG trial, HDMTX produced a significant improvement in event free survival (EFS). In the CCG trial, for RER patients, augmented intensity regimens produced a better EFS than standard intensity regimens. There was no difference in outcome for patients receiving standard or prolonged duration therapy. Thus we compared the high dose MTX arm from POG 9404 to a composite EFS result for CCG l961 based on induction failure/toxic death rate, augmented intensity therapy(1 or 2 DI phases) for RER patients and A-BFM therapy for SER patients. POG 9404, (opened 6/1996; closed 9/2001) and enrolled 363 T-ALL patients, with 77% having high risk features of which 155 were randomized to HDMTX arms. 5 yr EFS for patients on these arms was 75% and overall survival (S) of 84%. CCG 1961(opened 11/1996;closed 5/2002) entered 2077 patients of which 410 had T-cell disease with 263 RERs. The projected composite 5 year EFS and S estimated for high risk T-ALL patients treated on CCG l961 was 76.9% and 82.5% respectively. Isolated CNS relapse accounted for approximately 2/3 of the relapses in RER patients patients.CNS 3 patients treated on 9404 demonstrated 75% 5 yr EFS as compared to 82% for patients on 1961. Outcome for higher risk T-ALL patients treated by POG and CCG were quite similar. However, the BFM based strategy utilizes significantly less anthracycline and appears to produce a lower rate of bone marrow relapse. We postulate that incorporating low dose cranial RT(1200 cGy) will significantly reduce the incidence of CNS relapse and improve the overall EFS rate. Therefore, COG will utilize an augmented intensity BFM backbone for the first T-ALL protocol.

Result of two randomized trials comparing nolatrexed (Thymitaq™) versus methotrexate in patients with recurrent head and neck cancer

We report on two randomized trials performed in the USA and Europe, which compared methotrexate and nolatrexed as treatment for patients with recurrent head and neck cancer. Eligibility criteria included: histologically confirmed squamous-cell carcinoma, measurable disease, adequate hematological, renal and hepatic functions, failure of a first-line chemotherapy, and informed consent. Methotrexate 40 mg/m2 was weekly given by short infusion, and nolatrexed 725 mg/m2 per day was administered as a five-day continuous infusion, every three weeks. A total of 139 patients (63 in the USA. 76 in Europe) were randomized based on a ratio of 2/1: 93 and 46 received nolatrexed and methotrexate, respectively. Patient characteristics included 115 males and 24 females; median age 60 years. In the nolatrexed arm, the following grade 3-4 toxicities occurred: neutropenia (29.9%) with 3.1% of febrile neutropenia, mucositis (33.3%), and vomiting (10.3%). In the MTX arm, the grade 3-4 toxicities were neutropenia (7.1%) and mucositis (6.9%). There was no difference in activity between the nolatrexed and the methotrexate treatment: 3.3% and 10.8% of objective responses, 1.9 versus 1.5 months of disease-free progression and 3.5 versus 3.7 months of overall survival, respectively. Nolatrexed has demonstrated a similar activity to methotrexate.