A New Option for Pain Prevention Using a Therapeutic Virtual Reality Solution for Bone Marrow Biopsy (REVEH Trial): Open-Label, Randomized, Multicenter, Phase 3 Study.

BACKGROUND: Evidence regarding the analgesic effect of distraction through immersion in virtual reality (VR) for care-induced pain has been documented in several phase 2 trials, but comparison with standard treatments in large, randomized studies is needed. OBJECTIVE: In this open-label, multicenter, randomized, phase 3 trial, we evaluated the safety and efficacy of a novel VR therapy solution for distraction in the context of bone marrow biopsy. METHODS: Bliss is a VR software with 4 imaginary interactive environments in 3 dimensions with binaural sound (head-mounted display). Efficacy regarding pain intensity was evaluated using a visual analog scale (VAS; score from 0 to 10) immediately after the biopsy. Secondary end points were anxiety and tolerance. Modified intention-to-treat analysis was performed. RESULTS: Overall, 126 patients with previously documented untreated or suspected malignant hemopathy between September 6, 2018, and May 18, 2020, were randomly assigned in a 1:1 ratio to receive pain prevention with a mixture of nitrous oxide/oxygen (MEOPA; n=63) or VR (n=63) before and during the bone marrow biopsy. We excluded 8 patients from the final analysis (3 in the MEOPA group and 5 in the VR group). All patients received local anesthesia (lidocaine) before biopsy. Follow-up was limited to 1 month after the biopsy. Participants' median age was 65.5 (range 18-87) years, and 54.2% (64/118) of patients were male. The average pain intensity was 3.5 (SD 2.6, 95% CI -1.6 to 8.6) for the MEOPA group and 3.0 (SD 2.4, 95% CI -1.7 to 7.7) for the VR group, without any significant differences in age, sex, center, and hemopathy (P=.26). Concerning anxiety, 67.5% (79/117; fear of pain questionnaire) of the patients were afraid before the biopsy, and anxiety scores were moderate to very high in 26.3% (30/114; revised Spielberger State-Trait Anxiety Inventory questionnaire) of the patients before the biopsy and 9.0% (10/114) after the biopsy for all patients, without a significant difference between the 2 groups (P=.83). Immersion in VR was well tolerated by the majority (54/57, 95%) of patients in the VR group. CONCLUSIONS: The intensity of pain did not significantly differ between both arms. VR was well tolerated, and the satisfaction of patients, nurses, and physicians was very high. VR could be an alternative treatment in case of contraindication or intolerance to MEOPA. TRIAL REGISTRATION: ClinicalTrials.gov NCT03483194; https://clinicaltrials.gov/ct2/show/NCT03483194.

Dyserythropoiesis evaluated by the RED score and hepcidin:ferritin ratio predicts response to erythropoietin in lower-risk myelodysplastic syndromes.

Erythropoiesis-stimulating agents are generally the first line of treatment of anemia in patients with lower-risk myelodysplastic syndrome. We prospectively investigated the predictive value of somatic mutations, and biomarkers of ineffective erythropoiesis including the flow cytometry RED score, serum growth-differentiation factor-15, and hepcidin levels. Inclusion criteria were no prior treatment with erythropoiesis-stimulating agents, low- or intermediate-1-risk myelodysplastic syndrome according to the International Prognostic Scoring System, and a hemoglobin level <10 g/dL. Patients could be red blood cell transfusion-dependent or not and were given epoetin zeta 40 000 IU/week. Serum erythropoietin level, iron parameters, hepcidin, flow cytometry Ogata and RED scores, and growth-differentiation factor-15 levels were determined at baseline, and molecular analysis by next-generation sequencing was also conducted. Erythroid response (defined according to the International Working Group 2006 criteria) was assessed at week 12. Seventy patients, with a median age of 78 years, were included in the study. There were 22 patients with refractory cytopenia with multilineage dysplasia, 19 with refractory cytopenia with unilineage dysplasia, 14 with refractory anemia with ring sideroblasts, four with refractory anemia with excess blasts-1, six with chronic myelomonocytic leukemia, two with del5q-and three with unclassifiable myelodysplastic syndrome. According to the revised International Prognostic Scoring System, 13 had very low risk, 47 had low risk, nine intermediate risk and one had high-risk disease. Twenty patients were transfusion dependent. Forty-eight percent had an erythroid response and the median duration of the response was 26 months. At baseline, non-responders had significantly higher RED scores and lower hepcidin:ferritin ratios. In multivariate analysis, only a RED score >4 (P=0.05) and a hepcidin:ferritin ratio <9 (P=0.02) were statistically significantly associated with worse erythroid response. The median response duration was shorter in patients with growth-differentiation factor-15 >2000 pg/mL and a hepcidin:ferritin ratio <9 (P=0.0008 and P=0.01, respectively). In multivariate analysis, both variables were associated with shorter response duration. Erythroid response to epoetin zeta was similar to that obtained with other erythropoiesis-stimulating agents and was correlated with higher baseline hepcidin:ferritin ratio and lower RED score. ClinicalTrials.gov registration: NCT 03598582.

Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study.

Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56dim subset than had relapsing patients, while CD56bright natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56dim natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors, BCR-ABL1+ leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies. (ClinicalTrial.gov Identifier NCT00478985).

Impact of ELN recommendations in the management of first-line treated chronic myeloid leukaemia patients: a French cross-sectional study.

The availability of tyrosine kinase inhibitors has extended therapeutic options for chronic myeloid leukaemia (CML) patients. Monitoring recommendations and clinical response goals have recently been updated. The objective of this study was to describe the profile of CML patients in chronic phase currently receiving first-line therapy, including treatment, monitoring and response kinetics. A multicentre, cross-sectional, epidemiological survey in unselected chronic phase CML patients in France attending consultations during a one-month period was performed. 438 of 697 (62·8%) reported patients were currently receiving first-line treatment and were analysed. Imatinib was the most frequently received treatment (72·4% of patients). Retrospective cytogenetic and molecular assessments at 3, 6, 12 or 18 months were available in 88·4% of patients. At the 12-month assessment, 32·2% were not in major molecular response (MMR). At last assessment, among 355 patients with duration of treatment ≥ 12 months, 91·5% had achieved MMR and 66·5% were in deep molecular response. This study, performed in everyday practice population of CML patients, suggests that monitoring of molecular responses in real-life practice is aligned with European LeukaemiaNet recommendations. The majority of patients still receiving first-line treatment are in optimal response, with a few being classified as in the warning area or responding to failure.

Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma.

Because interleukin-6 (IL-6) is considered important in the proliferation of early multiple myeloma (MM), we hypothesized that the addition of the anti-IL-6 monoclonal antibody siltuximab to the bortezomib-melphalan-prednisone (VMP) regimen would improve outcomes in transplant-ineligible patients with newly diagnosed MM. One hundred and six patients were randomized to receive 9 cycles of VMP or VMP plus siltuximab (11 mg/kg every 3 weeks) followed by siltuximab maintenance. Baseline characteristics were well balanced except for immunoglobulin A subtype and 17p deletions. With a complete response (CR) rate of 27% on siltuximab plus VMP (S+VMP) and 22% on VMP, the study did not confirm its hypothesis that the addition of siltuximab would increase the CR rate by at least 10%. Overall response rate was 88% on S+VMP and 80% on VMP, and at least very good partial response rates were 71% and 51% (P = .0382), respectively. Median progression-free survival (17 months) and 1-year overall survival (88%) were identical in the 2 arms. Grade ≥3 adverse-event incidence was 92% on S+VMP and 81% on VMP (P = .09), with trends toward more hematologic events and infections on S+VMP. Maintenance therapy with siltuximab was well tolerated. In conclusion, the addition of siltuximab to VMP did not improve the CR rate or long-term outcomes. This study was registered at http://clinicaltrials.gov as #NCT00911859.

Rituximab therapy for hairy cell leukemia: a retrospective study of 41 cases.

The purine analogs (PAs) cladribine and pentostatin have transformed the prognosis of hairy cell leukemia (HCL). However, some patients still relapse after PAs, or fail to reach an optimal response, and new agents are needed to further improve treatment outcome. We retrospectively studied 41 HCL patients from 10 centers in France and Belgium, who received 49 treatment courses with the anti-CD20 monoclonal antibody rituximab. Most of the patients were treated at relapse (84 % of cases) and rituximab was combined to a PA in 41 % of cases. Overall, response rate is 90 % including 71 % complete hematologic responses (CHRs). Frontline treatment, combination therapy, and absolute neutrophil count were associated with response in multivariate analysis. Three-year relapse-free and overall survivals are 68 and 90 %, respectively. When combined to a PA, rituximab yields a 100 % response rate, even beyond frontline therapy. In contrast, response rate is only 82 % (59 % CHR) when rituximab is used alone. In this latter setting, relapse rate is 56 % and median time to relapse is 17.5 months. All eight patients who were treated two times with the antibody responded again to re-treatment. We confirm the high efficacy of the combination rituximab + PA. However, when rituximab is used as monotherapy, response rate is lower and the high relapse rate is a concern. Prospective clinical trials are needed to confirm the superiority of the combination rituximab + PA over PA alone, both as frontline therapy and at relapse.

Incidence of ATRX mutations in myelodysplastic syndromes, the value of microcytosis.

Acquired α-thalassemia myelodysplastic syndrome (MDS) (ATMDS) is an acquired syndrome characterized by a somatic point mutation or splicing defect in the ATRX gene in patients with myeloid disorders, primarily MDS. In a large MDS patient series, the incidence of ATMDS was below 0.5%. But no large series has yet assessed the incidence of ATMDS in microcytic MDS. In this study, we focused on patients with MDS and unexplained microcytosis, which was defined as absence of iron deficiency, inflammatory disease, or history of inherited hemoglobinopathy. Our data confirm the low frequency of ATRX mutations in MDS: 0% in an unselected clinical trial cohort of 80 low risk MDS, 0.2-0.8% in a multicenter registry of 2,980 MDS and 43% of MDS with unexplained microcytosis in this same registry. In addition, we reported four novel mutations of the ATRX gene in ATMDS. This study further determines the frequency of ATRX mutations and highlights the importance of microcytosis to detect ATRX mutations within MDS patients.

BiOsimilaRs in the management of anaemia secondary to chemotherapy in HaEmatology and Oncology: results of the ORHEO observational study.

BACKGROUND: The approval of epoetin biosimilars in the European Union requires extensive scientific evaluation and stringent regulatory procedures, including post-marketing studies. The ORHEO (place of biOsimilaRs in the therapeutic management of anaemia secondary to chemotherapy in HaEmatology and Oncology) study was an observational, longitudinal, multicentre study performed in France to evaluate the efficacy and safety of biosimilar epoetins for the treatment of chemotherapy-induced anaemia (CIA) in the clinical setting. METHODS: Patients >18 years with CIA (haemoglobin [Hb] <11 g/dL) in association with solid tumours, lymphoma or myeloma and eligible for treatment with an epoetin biosimilar were included in this study. Patient characteristics were recorded at baseline along with anaemia-related information, such as observed and target Hb (as chosen by the treating clinician), brand and dose of epoetin biosimilar prescribed, and details of any other treatments. Patients were then followed-up at 3 and 6 months. The primary endpoint was Hb response (defined as Hb reaching ≥10 g/dL, an increase of Hb ≥1 g/dL since inclusion visit or reaching physician-defined target Hb, with no blood transfusions in the 3 weeks prior to measurement). Other endpoints included adverse events, achievement of target Hb and associated treatments. RESULTS: Overall, 2333 patients >18 years (mean age 66.5 years) with CIA (haemoglobin [Hb] <11 g/dL) in association with solid tumours, lymphoma or myeloma and eligible for biosimilar epoetin treatment were included. 99.9% of patients received epoetin zeta (median dose 30,000 IU/week). Mean baseline Hb was 9.61 g/dL, with 35.6% of patients having moderate anaemia (Hb 8-9.5 g/dL). Hb response was achieved in 81.6% and 86.5% of patients at 3 and 6 months, respectively. Overall mean change in Hb level was 1.52 ± 1.61 and 1.72 ± 1.61 g/dL at 3 and 6 months, respectively. Transfusion and thromboembolic event rates were 9.4% and 2.4% at 3 months, and 5.8% and 1.5% at 6 months, respectively. CONCLUSIONS: Epoetin zeta was effective and well tolerated in the management of CIA in patients with solid tumours, lymphoma and myeloma. TRIAL REGISTRATION NUMBER: NCT02140736 (date of registration: 14 May 2014).

Recommendations of the SFH (French Society of Haematology) for the diagnosis, treatment and follow-up of hairy cell leukaemia.

Hairy cell leukaemia (HCL) is a rare haematological malignancy, with approximately 175 new incident cases in France. Diagnosis is based on a careful examination of the blood smear and immunophenotyping of the tumour cells, with a panel of four markers being used specifically to screen for hairy cells (CD11c, CD25, CD103 and CD123). In 2011, the V600E mutation of the BRAF gene in exon 15 was identified in HCL; being present in HCL, it is absent in the variant form of HCL (HCL-v) and in splenic red pulp lymphoma (SRPL), two entities related to HCL. The management of patients with HCL has changed in recent years. A poorer response to purine nucleoside analogues (PNAs) is observed in patients with more marked leukocytosis, bulky splenomegaly, an unmutated immunoglobulin variable heavy chain (IgVH) gene profile, use of VH4-34 or with TP53 mutations. We present the recommendations of a group of 11 experts belonging to a number of French hospitals. This group met in November 2013 to examine the criteria for managing patients with HCL. The ideas and proposals of the group are based on a critical analysis of the recommendations already published in the literature and on an analysis of the practices of clinical haematology departments with experience in managing these patients. The first-line treatment uses purine analogues: cladribine or pentostatin. The role of BRAF inhibitors, whether or not combined with MEK inhibitors, is discussed. The panel of French experts proposed recommendations to manage patients with HCL, which can be used in a daily practice.

Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia.

BACKGROUND: Imatinib (400 mg daily) is considered the best initial therapy for patients with newly diagnosed chronic myeloid leukemia (CML) in the chronic phase. However, only a minority of patients treated with imatinib have a complete molecular remission. METHODS: We randomly assigned 636 patients with untreated chronic-phase CML to receive imatinib alone at a dose of 400 mg daily, imatinib (400 mg daily) plus cytarabine (20 mg per square meter of body-surface area per day on days 15 through 28 of each 28-day cycle) or pegylated interferon (peginterferon) alfa-2a (90 µg weekly), or imatinib alone at a dose of 600 mg daily. Molecular and cytogenetic responses, time to treatment failure, overall and event-free survival, and adverse events were assessed. An analysis of molecular response at 12 months was planned. A superior molecular response was defined as a decrease in the ratio of transcripts of the tyrosine kinase gene BCR-ABL to transcripts of ABL of 0.01% or less, corresponding to a reduction of 4 log(10) units or more from the baseline level, as assessed by means of a real-time quantitative polymerase-chain-reaction assay. RESULTS: At 12 months, the rates of cytogenetic response were similar among the four groups. The rate of a superior molecular response was significantly higher among patients receiving imatinib and peginterferon alfa-2a (30%) than among patients receiving 400 mg of imatinib alone (14%) (P=0.001). The rate was significantly higher among patients treated for more than 12 months than among those treated for 12 months or less. Gastrointestinal events were more frequent among patients receiving cytarabine, whereas rash and depression were more frequent among patients receiving peginterferon alfa-2a. CONCLUSIONS: As compared with other treatments, the addition of peginterferon alfa-2a to imatinib therapy resulted in significantly higher rates of molecular response in patients with chronic-phase CML. (Funded by the French Ministry of Health and others; ClinicalTrials.gov number, NCT00219739.).

Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC.

Long-term responses have been reported after autologous stem cell transplantation (ASCT) for chronic lymphocytic leukemia (CLL). We conducted a prospective, randomized trial of ASCT in previously untreated CLL patients. We enrolled 241 patients < 66 years of age with Binet stage B or C CLL. They received 3 courses of mini-CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone/prednisolone) and then 3 courses of fludarabine. Patients in complete response (CR) were then randomized to ASCT or observation, whereas the other patients were randomized to dexamethasone, high-dose aracytin, cisplatin (DHAP) salvage followed by either ASCT or 3 courses of fludarabine plus cyclophosphamide (FC). The primary end point was event-free survival (EFS). After up-front treatment, 105 patients entered CR and were randomized between ASCT (n = 52) and observation (n = 53); their respective 3-year EFS rates were 79.8% and 35.5%; the adjusted hazard ratio was 0.3 (95% CI: 0.1-0.7; P = .003). Ninety-four patients who did not enter CR were randomized between ASCT (n = 46) and FC (n = 48); their respective 3-year EFS rates were 48.9% and 44.4%, respectively; the adjusted hazard ratio was 1.7 (95% CI: 0.9-3.2; P = .13). No difference in overall survival was found between the 2 response subgroups. In young CLL patients in CR, ASCT consolidation markedly delayed disease progression. No difference was observed between ASCT and FC in patients requiring DHAP salvage.

Study design: two long-term observational studies of the biosimilar filgrastim Nivestim™ (Hospira filgrastim) in the treatment and prevention of chemotherapy-induced neutropenia.

BACKGROUND: Nivestim™ (filgrastim) is a follow-on biologic agent licensed in the EU for the treatment of neutropenia and febrile neutropenia induced by myelosuppressive chemotherapy. Nivestim™ has been studied in phase 2 and 3 clinical trials where its efficacy and safety was found to be similar to its reference product, Neupogen®. Follow-on biologics continue to be scrutinised for safety. We present a design for two observational phase IV studies that are evaluating the safety profile of Nivestim™ for the prevention and treatment of febrile neutropenia (FN) in patients treated with cytotoxic chemotherapy in general clinical practice. METHODS/DESIGN: The NEXT (Tolérance de Nivestim chez les patiEnts traités par une chimiothérapie anticancéreuse cytotoXique en praTique courante) and VENICE (VErträglichkeit von NIvestim unter zytotoxischer Chemotherapie in der Behandlung malinger Erkrankungen) trials are multicentre, prospective, longitudinal, observational studies evaluating the safety profile of Nivestim™ in 'real-world' clinical practice. Inclusion criteria include patients undergoing cytotoxic chemotherapy for malignancy and receiving Nivestim as primary or secondary prophylaxis (NEXT and VENICE), or as treatment for ongoing FN (NEXT only). In accordance with European Union pharmacovigilance guidelines, the primary objective is to evaluate the safety of Nivestim™ by gathering data on adverse events in all system organ classes. Secondary objectives include obtaining information on patient characteristics, efficacy of Nivestim™ therapy (including chemotherapy dose intensity), patterns of use of Nivestim™, and physician knowledge regarding filgrastim prescription and the reasons for choosing Nivestim™. Data will be gathered at three visits: 1. At the initial inclusion visit, 2. At a 1-month follow-up visit, and 3. At the end of chemotherapy.Recruitment for VENICE commenced in July 2011 and in November 2011 for NEXT. VENICE completed recruitment in July 2013 with 407 patients, and NEXT in September 2013 with 2123 patients. Last patient, last visit for each study will be December 2013 and March 2014 respectively. DISCUSSION: The NEXT and VENICE studies will provide long-term safety, efficacy and practice pattern data in patients receiving Nivestim™ to support myelosuppressive chemotherapy in real world clinical practice. These data will improve our understanding of the performance of Nivestim™ in patients encountered in the general patient population. TRIAL REGISTRATION: NEXT NCT01574235, VENICE NCT01627990.

Comparative analysis of rituximab or obinutuzumab combined with CHOP in first-line treatment of follicular lymphoma.

PURPOSE: Rituximab (R) or obinutuzumab (G) combined with CHOP chemotherapy are used in previously untreated follicular lymphoma (FL). The aim is to compare in real life setting the efficacy and safety of these therapeutic strategies and assess the economic impact of introducing G. METHODS: This retrospective study, performed in 3 centers, included data from all patients who received R-CHOP or G-CHOP for previous untreated FL from June 1st, 2016 to December 31st, 2020. Progression-Free Survival (PFS) were estimated according to the Kaplan-Meier method. A budgetary impact model was performed from the French health care system's perspective. RESULTS: N = 124 patients were included (58 G-CHOP; 66 R-CHOP). Fifty-one and 57 patients achieved a complete response at the end of induction in the G-CHOP and R-CHOP group, respectively. PFS was not significantly longer in the G-CHOP group (HR 0.28; 95% CI 0.08-0.97; p value = 0.14). Hematological toxicity occurred more frequently with G-CHOP than R-CHOP during induction treatment (n = 58; 100% vs. n = 61; 92%), including higher severe neutropenia (grade ≥ 3) (n = 26; 45% vs. n = 23; 35%). Infusion-related reactions during the first infusion occurred more frequently with G-CHOP (n = 19; 33% vs. n = 16; 24%). The introduction of a completed G treatment (induction and maintenance) results in an additional cumulative cost per patient estimated at more than €30,000. CONCLUSION: Similar results were found in the GALLIUM subgroup analysis study, suggesting that at this time there is no absolute benefit to administer G-CHOP instead of R-CHOP in all patients with previously untreated FL and may encourage clinical and economic trials including quality of life data.

Low-dose vs. high-dose thalidomide for advanced multiple myeloma: a prospective trial from the Intergroupe Francophone du Myélome.

This multicentre prospective randomised trial compared the efficacy and safety of two doses of thalidomide in patients with relapsed or refractory myeloma. The study was designed to test the non-inferior efficacy and to confirm the better tolerability of low-dose thalidomide as compared to a higher dose. Four hundred patients were randomly assigned to receive either 100 or 400 mg/day of thalidomide. Dexamethasone treatment was added in both arms for patients with stable disease or treatment failure at 12 weeks. The primary endpoint was 1-year overall survival (OS). Thalidomide 100 mg/day was better tolerated than 400 mg/day with less high-grade somnolence, constipation, nausea/vomiting and peripheral neuropathy (P < 0.001, P = 0.007, P = 0.03 and P = 0.007, respectively). In the per-protocol population (PP), the estimated 1-year OS rates were of 74.5% (n = 149) and 67.3% (n = 156) in the 400 and 100 groups, respectively. The upper limit of the difference between these rates was of 15.6% higher than the non-inferiority acceptable limit of 12.75%, and the hypothesis of non-inferiority of 100 could not be established (P = 0.14). On the other hand, when intent-to-treat (ITT) population was analysed, the non-inferiority was demonstrated because the 1-year OS rates were of 72.8% (n = 195) and 68.8% (n = 205) in the same groups, leading to an upper limit of the difference of 11.49% lower than the non-inferiority acceptable limit. In addition, in patients alive 12 weeks postrandomisation and those who received thalidomide plus dexamethasone, there were no significant differences in response rates, time to progression, progression-free survival and OS between the two groups. Collectively, low-dose thalidomide 100 mg/day has significant activity in advanced myeloma with an improved safety profile and can be a good salvage therapy in combination with dexamethasone.

Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial.

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.

The role of haematopoietic growth factors granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the management of drug-induced agranulocytosis.

Drug-induced agranulocytosis (neutrophil count <0.5 x 10(9)/l) is a rare haematological complication with an incidence of no more than 10 cases per million inhabitants per year in Europe. Over the past few years there has been a steady decline in mortality rate, (currently at <5%), which can be partly explained by earlier recognition and the improved clinical management of associated intercurrent infections that may lead to severe sepsis if left untreated. The true impact of the use of haematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), on the decreased mortality rate remains unknown. Yet, most studies show that these molecules, especially G-CSF, reduce the duration of agranulocytosis, antibiotic course and length of hospital stay. Their use is particularly recommended in patients with poor prognostic factors, such as a neutrophil count <0.1 x 10(9)/l, age over 65 years, severe infection or multiple co-morbidities. In all cases, the drug responsible for causing the agranulocytosis must be discontinued and remain permanently contraindicated. The appropriate Medicines Regulatory Agency must also be notified of the adverse event.

Upfront VIP-reinforced-ABVD (VIP-rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95.

Peripheral T-Cell lymphomas (PTCL) are relatively rare diseases but appear to be highly aggressive and display worse remission and survival rates than B-cell lymphomas. Despite unsatisfactory results with the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen, it remains the reference front-line therapy in these diseases, but has not been challenged in phase III trials. The Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang (GOELAMS) devised an alternative therapeutic schedule including etoposide, ifosfamide, cisplatin alternating with doxorubicin, bleomycin, vinblastine, dacarbazine (VIP-reinforced-ABVD; VIP-rABVD) and compared it to CHOP/21 as front-line treatment in non-cutaneous PTCL. All newly diagnosed patients were eligible. The primary objective was to improve the 2-year event-free survival (EFS) rate. Secondary objectives were to compare the response rate, overall survival, and toxicities as well as identify prognostic factors. Eighty-eight patients were identified between 1996 and 2002. Both arms were well balanced for patients' characteristics in terms of histological and clinical presentation. No significant difference was observed between the two arms in terms of 2-year EFS. Anaplastic large cell lymphoma type and Ann Arbor stage I-II were identified as two independent favourable prognostic factors influencing survival. VIP-rABVD was not superior to CHOP/21 in terms of EFS as first-line treatment of PTCL, confirming that CHOP/21 remains the reference regimen in these lymphomas.

Severe Neutropenia and Agranulocytosis Related to Antithyroid Drugs: A Study of 30 Cases Managed in A Single Reference Center.

BACKGROUND: The most important series devoted to antithyroid drug-induced severe neutropenia and agranulocytosis are Japanese studies, almost specifically in relation to the intake of methimazole. The clinical data of 30 Caucasian patients followed up for antithyroid drug-induced neutropenia at a third-level hospital are reported. Methods: The data of 30 patients with idiosyncratic antithyroid drug-induced neutropenia and agranulocytosis from a cohort study on drug-induced neutropenia and agranulocytosis conducted at the University Hospital of Strasbourg (France) were retrospectively reviewed. Results: The mean patient age was 61.7 years old (range: 20-87), and the gender ratio (F/M) was 4. Several comorbidities were reported in 23 patients (76.7%), with the mean Charlson comorbidity index of 1. The causative drugs were carbimazole and benzylthiouracil, in 28 (93.3%) and 2 cases, respectively, prescribed primarily for multi-hetero-nodular goiter or thyroid nodule to 18 patients (60%). Sore throat and acute tonsillitis (40%), isolated fever (20%), septicemia (13.3%), documented pneumonia (6.7%), and septic shock (6.7%) were the main clinical features upon admission. The mean neutrophil count at nadir was 0.02 and 0 × 109/L (range: 0-0.3). Regarding the patients' hospital course: 13 cases (43.3%) worsened during hospitalization, severe sepsis was found in 26.7%, systemic inflammatory response syndrome-in 13.3%, and septic shock-in 3.3% of the cases, respectively. Broad-spectrum antibiotics were indicated for all the patients, and 21 (73.3%) of them received hematopoietic growth factors. Hematological recovery (neutrophil count ≥ 1.5 × 109/L) was seen at 8.3 days (range: 2-24), but faster in those receiving hematopoietic growth factors (4.9 days, p = 0.046). Two patients died during hospitalization, and the rest had a favorable clinical outcome. Conclusions: Antithyroid drug-induced neutropenia represents a serious complication resulting from the rates of severe infections especially in those cases severe neutropenia. In this setting, an established procedure for the management of patients seems useful or even indispensable in view of potential mortality.

Tuberculosis and atypical mycobacterial infections in ruxolitinib-treated patients with primary or secondary myelofibrosis or polycythemia vera.

Ruxolitinib is a JAK-1/JAK-2 inhibitor indicated for the treatment of polycythemia vera and primary or secondary myelofibrosis. Only one patient (0.2%) was diagnosed with tuberculosis among the 485 patients receiving ruxolitinib in the four pivotal trials. Fourteen cases of tuberculosis have since been reported. We observed two (3%) mycobacterial infections (one due to Mycobacterium tuberculosis and one due to Mycobacterium avium complex) in our cohort of 65 patients receiving ruxolitinib. This observation suggests that the rate of mycobacterial infection might be higher than that observed in the pivotal trials and that atypical mycobacterial infections can also occur.

High efficacy with five days schedule of oral fludarabine phosphate and cyclophosphamide in patients with previously untreated chronic lymphocytic leukaemia.

A multicentre single-arm study testing the efficacy and toxicity of the oral combination of fludarabine and cyclophosphamide (FC) over 5 d in 75 patients with untreated B cell-chronic lymphocytic leukaemia. Oral FC demonstrated high efficacy with overall (OR) and complete response (CR) rates of 80% and 53%, respectively. Out of the 30 CR patients studied for Minimal Residual Disease (MRD) using 4-colour flow-cytometry and the 22 using Clonospecific polymerase chain reaction, 22 (66%) and 16 (68%), respectively, were MRD negative. Median survival and median treatment-free interval had not been reached at 7 years of follow-up. Median progression-free survival (PFS) was 5 years. Toxicity was acceptable, with 52% and 16% of National Cancer Institute grade 3/4 neutropenia and infections, respectively. Gastrointestinal toxicity was mild. Oral FC demonstrated a high efficacy and an acceptable safety profile and may be considered as the standard first line treatment in chronic lymphocytic leukaemia.