A fixed-duration immunochemotherapy approach in CLL: 5.5-year results from the phase 2 ICLL-07 FILO trial.

In previously untreated, medically fit patients with chronic lymphocytic leukemia (CLL), research is focused on developing fixed-duration strategies to improve long-term outcomes while sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach in which after obinutuzumab-ibrutinib induction for 9 months, patients (n = 10) in complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) <0.01% continued only ibrutinib 420 mg/day for 6 additional months (I arm), whereas the majority (n = 115) received up to 4 cycles of fludarabine/cyclophosphamide-obinutuzumab 1000 mg alongside the ibrutinib (I-FCG arm). Primary analysis at month 16 showed that 84 of 135 (62.2%) patients enrolled achieved CR with a BM MRD <0.01%. Here, we report follow-up at median 63 months. Peripheral blood (PB) MRD was assessed 6 monthly beyond the end of treatment using a highly sensitive (10-6) flow cytometry technique. In the I-FCG arm, the PB MRD <0.01% rate (low-level positive <0.01% or undetectable with limit of detection ≤10-4) in evaluable patients was still 92.5% (74/80) at month 40 and 80.6% (50/62) at month 64. No differences in the PB MRD status were apparent per to the IGHV mutational status. In the overall population, 4-year progression-free and overall survival rates were 95.5% and 96.2%, respectively. Twelve deaths occurred overall. Fourteen serious adverse events occurred beyond the end of treatment. Thus, our fixed-duration immunochemotherapy approach produced deep and sustained PB MRD responses, high survival rates, and low long-term toxicity. A randomized trial is needed to compare our immunochemotherapy approach with a chemotherapy-free strategy. This trial was registered at www.clinicaltrials.gov as #NCT02666898.

Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease-driven strategy in patients with chronic lymphocytic leukaemia (ICLL07 FILO): a single-arm, multicentre, phase 2 trial.

BACKGROUND: In patients with chronic lymphocytic leukaemia, achievement of a complete response with minimal residual disease of less than 0·01% (ie, <1 chronic lymphocytic leukaemia cell per 10 000 leukocytes) in bone marrow has been associated with improved progression-free survival. We aimed to explore the activity of induction therapy for 9 months with obinutuzumab and ibrutinib, followed up with a minimal residual disease-driven therapeutic strategy for 6 additional months, in previously untreated patients. METHODS: We did a single-arm, phase 2 trial in 27 university hospitals, general hospitals, and specialist cancer centres in France. Eligible patients were at least 18 years old and previously untreated, and had immunophenotypically confirmed B-cell chronic lymphocytic leukaemia; an Eastern Cooperative Oncology Group (ECOG) performance status score of less than 2; a Binet stage C according to IWCLL 2008 criteria or Binet stage A and B with active disease; no 17p deletion or absence of p53 mutation; and were considered medically fit. In the first part of the study (induction phase), all participants received eight intravenous infusions of obinutuzumab 1000 mg over six 4-weekly cycles and oral ibrutinib 420 mg once per day for 9 months. In part 2, after assessment on day 1 of month 9, patients with a complete response and bone marrow minimal residual disease of less than 0·01% received only oral ibrutinib 420 mg once per day for 6 additional months. Patients with a partial response, or with a complete response and bone marrow minimal residual disease of 0·01% or more, received 6 months of four 4-weekly cycles of intravenous fludarabine, cyclophosphamide, and obinutuzumab 1000 mg, alongside continuing ibrutinib 420 mg once per day. The primary endpoint was the proportion of patients achieving a complete response with bone marrow minimal residual disease less than 0·01% on day 1 of month 16 assessed by intention to treat (ITT). This trial is registered with ClinicalTrials.gov (number NCT02666898) and is still open for follow-up. FINDINGS: Between Oct 27, 2015, and May 16, 2017, 135 patients were enrolled. After induction treatment (day 1 of month 9), 130 patients were evaluable, of which ten (8%) achieved a complete response with bone marrow minimal residual disease of less than 0·01% and were assigned to ibrutinib, and 120 (92%) were assigned to ibrutinib plus fludarabine, cyclophosphamide, and obinutuzumab. After minimal residual disease-guided treatment (day 1 of month 16), 84 (62%, 90% CI 55-69) of 135 patients (ITT population) achieved a complete response with bone marrow minimal residual disease of less than 0·01%. The most common haematological adverse event was thrombocytopenia (in 45 [34%] of 133 patients at grade 1-2 in months 1-9 and in 43 [33%] of 130 patients at grade 1-2 in months 9-15). The most common non-haematological adverse events were infusion-related reactions (in 83 [62%] patients at grade 1-2 in months 1-9) and gastrointestinal disorders (in 62 [48%] patients at grades 1 and 2 in months 9-15). 49 serious adverse events occurred, most frequently infections (ten), cardiac events (eight), and haematological events (eight). No treatment-related deaths occurred. INTERPRETATION: Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease driven strategy is safe and active in patients with previously untreated chronic lymphocytic leukaemia. With longer follow-up, including assessing the evolution of minimal residual disease, if response is maintained, this strategy could be an option in the first-line setting in patients with chronic lymphocytic leukaemia, although randomised evidence is needed. FUNDING: Roche, Janssen.

Bendamustine-based conditioning prior to autologous stem cell transplantation (ASCT): Results of a French multicenter study of 474 patients from LYmphoma Study Association (LYSA) centers.

Carmustine shortage has led to an increase use of alternative conditioning regimens prior to autologous stem cell transplantation for the treatment of lymphoma, including Bendamustine-based (BeEAM). The aim of this study was to evaluate the safety of the BeEAM regimen in a large cohort of patients. A total of 474 patients with a median age of 56 years were analyzed. The majority of patients had diffuse large B-cell lymphoma (43.5%). Bendamustine was administered at a median dose of 197 mg/m2 /day (50-250) on days-7 and -6. The observed grade 1-4 toxicities included mucositis (83.5%), gastroenteritis (53%), skin toxicity (34%), colitis (29%), liver toxicity (19%), pneumonitis (5%), and cardiac rhythm disorders (4%). Nonrelapse mortality (NRM) was reported in 3.3% of patients. Acute renal failure (ARF) was reported in 132 cases (27.9%) (G ≥2; 12.3%). Organ toxicities and death were more frequent in patients with post conditioning renal failure. In a multivariate analysis, pretransplant chronic renal failure, bendamustine dose >160 mg/m2 and age were independent prognostic factors for ARF. Pretransplant chronic renal failure, hyperhydration volume, duration of hyperhydration, and etoposide dose were predictive factors of NRM. A simple, four-point scoring system can stratify patients by levels of risk for ARF and may allow for a reduction in the bendamustine dose to avoid toxicity. Drugs shortage may have dangerous consequences. Prospective, comparative studies are needed to confirm the toxicity/efficacy extents from this conditioning regimen compared to other types of high dose therapy.

Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Short intensive chemotherapy is the standard of care for adult patients with Burkitt's leukaemia or lymphoma. Findings from single-arm studies suggest that addition of rituximab to these regimens could improve patient outcomes. Our objective was to test this possibility in a randomised trial. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients older than 18 years with untreated HIV-negative Burkitt's lymphoma (including Burkitt's leukaemia) from 45 haematological centres in France. Exclusion criteria were contraindications to any drug included in the chemotherapy regimens, any serious comorbidity, poor renal (creatinine concentration >150 µmol/L) or hepatic (cirrhosis or previous hepatitis B or C) function, pregnancy, and any history of cancer except for non-melanoma skin tumours or stage 0 (in situ) cervical carcinoma. Patients were stratified into two groups based on disease extension (absence [group B] or presence [group C] of bone marrow or central nervous system involvement). Patients were further stratified in group C according to age (<40 years, 40-60 years, and >60 years) and central nervous system involvement. Participants were randomly assigned in each group to either intravenous rituximab injections and chemotherapy (lymphome malin B [LMB]) or chemotherapy alone by the Groupe d'Etude des Lymphomes de l'Adulte datacentre. Randomisation was stratified by treatment group and centre using computer-assisted permuted-block randomisation (block size of four; allocation ratio 1:1). We gave rituximab (375 mg/m(2)) on day 1 and day 6 during the first two courses of chemotherapy (total of four infusions). The primary endpoint is 3 year event-free survival (EFS). We analysed all patients who had data available according to their originally assigned group. This trial is registered with ClinicalTrials.gov, number NCT00180882. RESULTS: Between Oct 14, 2004, and Sept 7, 2010, we randomly allocated 260 patients to rituximab or no rituximab (group B 124 patients [64 no rituximab; 60 rituximab]; group C 136 patients [66 no rituximab; 70 rituximab]). With a median follow-up of 38 months (IQR 24-59), patients in the rituximab group achieved better 3 year EFS (75% [95% CI 66-82]) than did those in the no rituximab group (62% [53-70]; log-rank p stratified by treatment group=0·024). The hazard ratio estimated with a Cox model stratified by treatment group, assuming proportionality, was 0·59 for EFS (95% CI 0·38-0·94; p=0·025). Adverse events did not differ between the two treatment groups. The most common adverse events were infectious (grade 3-4 in 137 [17%] treatment cycles in the rituximab group vs 115 [15%] in the no rituximab group) and haematological (mean duration of grade 4 neutropenia of 3·31 days per cycle [95% CI 3·01-3·61] vs 3·38 days per cycle [3·05-3·70]) events. INTERPRETATION: Addition of rituximab to a short intensive chemotherapy programme improves EFS in adults with Burkitt's leukaemia or lymphoma. FUNDING: Gustave Roussy Cancer Campus, Roche, Chugai, Sanofi.

Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no-treatment study.

Intravascular hemolysis in Paroxysmal nocturnal hemoglobinuria (PNH) can effectively be controlled with eculizumab, a humanized monoclonal antibody that binds complement protein C5. We report here a retrospective comparison study between 123 patients treated with eculizumab in the recent period (>2005) and 191 historical controls (from the French registry). Overall survival (OS) at 6 years was 92% (95%CI, 87 to 98) in the eculizumab cohort versus 80% (95%CI 70 to 91) in historical controls diagnosed after 1985 (HR 0.38 [0.15 to 0.94], P = 0.037). There were significantly fewer thrombotic events (TEs) in the group of patients treated with eculizumab (4% [1-10]) as compared to the historical cohort (27% [20-34]). However, we found that TEs may still occur after the initiation of eculizumab treatment and that previous TEs still have a negative impact on survival. Evolutions to myelodysplastic syndrome or acute leukemia were similar in both cohorts. There was less evolution to aplastic anemia in the treatment group. In multivariate analysis, absence of a previous TE and treatment with eculizumab were associated with a better OS. Treatment with eculizumab improves overall survival in classic PNH patients without increasing the risk of clonal evolution.

Chronic Brucella infection of the humerus diagnosed after a spontaneous fracture.

Brucellosis is uncommon in humans and only rarely manifests as osteomyelitis. We report the case of a 57-year-old patient with chronic Brucella osteomyelitis of both humeri. The diagnosis was established upon evaluation of a spontaneous fracture of the right humerus. The organism was recovered in fluid draining to the skin from an abscess located in the bone and soft tissues.

C-reactive protein predicts tumor necrosis factor-alpha blocker retention rate in axial ankylosing spondylitis.

OBJECTIVE: In ankylosing spondylitis (AS), tumor necrosis factor (TNF) blockers are recommended for patients with high symptomatic disease activity. Few data are available about objective signs of inflammation such as increased C-reactive protein (CRP). We assessed the retention rate of TNF blockers in patients with axial AS, according to baseline CRP and other potentially predictive measures. METHODS: A retrospective study of all patients treated with TNF blockers for axial AS. Retention rate was evaluated using a survival-data analysis technique with discontinuation of the drug because of inefficacy (Kaplan-Meier method). Potential factors explaining the retention rates (demographic and clinical indicators and CRP) were evaluated using log-rank tests and a Cox proportional-hazards regression model. RESULTS: For axial AS, 175 patients received TNF blockers (men 78%, mean disease duration 12.4 +/- 9.1 yrs); 100 patients (of 143 with available data) had an increased CRP (> 10 mg/l). An increased CRP at baseline was the only variable explaining the retention rate in the Cox model (p = 0.003, hazard ratio = 3.3, 95% CI 1.5-7.3). CONCLUSION: Interruption for expert opinion of inefficacy was more frequent for patients with low baseline CRP; however, even in these patients retention was high. Increased CRP should not be considered mandatory for proposing TNF blocker treatment in axial AS.

Pregnancy-related hip diseases: incidence and diagnoses.

BACKGROUND: Pregnancy-related hip diseases epidemiology has been poorly evaluated. We report our experience of gestational and postpartum hip diseases and evaluate their incidence. METHODS: (1) Prospective survey: all pregnant or early postpartum women suspected to have hip involvement during their follow-up in an Obstetric unit were referred to a rheumatologist. If clinically confirmed, magnetic resonance imaging (MRI) and additional investigations as needed were performed. This survey had 2 years duration. (2) Retrospective study: all cases of definite (with MRI confirmation) pregnancy-related hip disease referred to our Rheumatology unit during the past 15 years were analyzed. RESULTS: During the 2-year prospective survey, 3 patients (4 hips) of pregnancy-related hip disease were observed over 4900 pregnancies (1 case of transient osteoporosis of the hip (TOH) and 2 cases of occult fracture of the femoral head). During the 15-year retrospective study, 12 patients (17 hips) with hip diseases during pregnancy or early postpartum were identified. There were 6 patients (9 hips) with TOH, 4 patients (6 hips) with occult fracture of the femoral head, 1 patient with osteonecrosis of the femoral head, and 1 coxitis in a patient with ankylosing spondylitis. Differentiating diagnosis between TOH and occult fractures could only be made by MRI. Five of the 6 women with TOH had osteopenia at the lumbar spine at dual energy X-ray absorptiometry (DEXA). The 4 women with occult fractures had either osteopenia or osteoporosis at the lumbar spine. CONCLUSION: Hip diseases are infrequent during pregnancy and early postpartum. Transient osteoporosis of the hip and occult stress fractures of the femoral head appear the main causes and those diagnoses justify evaluation for an underlying bone fragility. Osteonecrosis is very rare in this setting.

Gait recovery in a distal spinal muscular atrophy patient wearing a patellar tendon-bearing orthosis and orthopaedic shoes.

OBJECTIVE: To illustrate that a patient with distal spinal muscular atrophy can recover gait with a combination of orthoses and orthopaedic shoes. SUBJECT: A 28-year-old man with distal spinal muscular atrophy affecting only the distal muscles of the lower limbs. Clinical examination showed a bilateral pes cavus with a varus and a 90 degrees equinus of the ankle joint. METHODS: The patient was fitted with orthopaedic shoes and a patellar tendon-bearing orthosis. In order to assess the clinical effects of this fitting, a complete physical examination was performed and the patient's temporo-spatial gait parameters were assessed quantitatively using gait analysis tools (Gaitrite) both prior to treatment and after one month. RESULTS: Before the fitting, the patient was not able to walk alone or to maintain an upright position and he suffered from foot pain. One month after the fitting was applied, the patient was able to walk alone and to maintain an upright position for 1 hour. His pain disappeared. Quantified study of the patient's gait parameters shows that the temporo-spatial parameters are close to normal with fitting. CONCLUSION: Clinical and quantitative data both confirm the subjective improvements reported by the patient.

Retention rates of tumor necrosis factor blockers in daily practice in 770 rheumatic patients.

OBJECTIVE: Tumor necrosis factor (TNF) blockers are efficacious in clinical trials in rheumatic diseases. However, their efficacy in daily practice, depending on the specific diagnosis or the use of concomitant therapy, remains to be confirmed. Our objective was to evaluate TNF blocker retention rates and their predisposing factors in daily practice. METHODS: Retrospective evaluation of all TNF blocker therapies in one center. Retention rate was evaluated using a Kaplan-Meier survival data analysis technique in which the event was discontinuation of the drug due to inefficacy or toxicity with log-rank tests and a Cox proportional-hazards regression model. RESULTS: From 1997 to 2004, 770 patients with inflammatory rheumatism received at least one TNF blocker; 142 received more than one agent (975 treatment courses: 493 etanercept, 335 infliximab, 147 adalimumab). The underlying disease was mainly rheumatoid arthritis (RA), found in 57.1% of patients, and spondyloarthropathies (SpA) in 37.7%. The percentage of patients receiving the same treatment at Month 12, 24, and 36 was 64.0%, 50.3%, and 39.4%, respectively. No difference between the 3 TNF blockers was found (p = 0.48). The retention rate was longer for the first treatment course [hazard ratio (HR) 2.17, 95% confidence interval (95% CI) 1.82-2.58, p < 0.0001]; longer for patients with SpA (HR 1.60, 95% CI 1.20-2.13, p = 0.001); and longer without concomitant DMARD (HR 0.70, 95% CI 0.51-0.97, p = 0.03). CONCLUSION: Our results indicate a lower retention rate of TNF blockers in daily practice compared with clinical trials, with no difference between the 3 currently available agents. Moreover, results suggest greater benefit in SpA. The role of concomitant DMARD remains to be confirmed.

TNFalpha antagonist therapy in ankylosing spondylitis and psoriatic arthritis: recommendations of the French Society for Rheumatology.

OBJECTIVES: To develop recommendations for TNFalpha antagonist therapy in patients with spondyloarthropathies. METHODS: The Delphi consensus procedure was used to select questions, to which evidence-based answers were sought in the literature. Expert opinion was used when needed to estimate the risks and benefits of TNFalpha antagonists. TNFalpha antagonists exert potent antiinflammatory effects but fail to provide a definitive cure. RESULTS: Recommendations were developed for patients with ankylosing spondylitis (AS) or psoriatic arthritis (PsA). The following criteria for TNFalpha antagonist therapy were selected: definitive diagnosis of AS or PsA, active disease for at least 4 consecutive weeks documented during two physician visits, overall physician's assessment of disease activity>/=4/10 and BASDAI>/=4/10 in axial disease or at least three tender and swollen joints in peripheral disease, failure to respond adequately to at least three nonsteroidal antiinflammatory drugs given in optimal dosages for at least 3 months in axial disease or at least one disease-modifying antirheumatic drug (methotrexate, leflunomide, sulfasalazine) for at least 4 months, with local glucocorticoid injections if appropriate, in peripheral disease. Effectiveness and safety should be evaluated by a rheumatologist. The frequency of monitoring depends on the drug. Lack of effectiveness should be defined as inadequate improvement after 6-12 weeks, with a less than two-point decrease in the BASDAI in axial disease or a less than 30% decrease in the tender and swollen joint counts in peripheral disease. CONCLUSION: These clinical practice recommendations should help rheumatologists in their everyday decisions regarding the use of TNFalpha antagonist therapy in patients with AS or PsA.