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Purpose To evaluate randomly the role of hyperfractionated cyclophosphamide (hyper-C) dose intensification in adults with newly diagnosed Philadelphia chromosome–negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol and to determine the upper age limit for treatment tolerability in this context. Patients and Methods A total of 787 evaluable patients (B/T lineage, 525 and 262, respectively; median age, 36.1 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyper-C during first induction and late intensification. Compliance with chemotherapy was assessed by median doses actually received during each treatment phase by patients potentially exposed to the full planned doses. Results Overall complete remission (CR) rate was 91.9%. With a median follow-up of 5.2 years, the 5-year rate of event-free survival (EFS) and overall survival (OS) was 52.2% (95% CI, 48.5% to 55.7%) and 58.5% (95% CI, 54.8% to 61.9%), respectively. Randomization to the hyper-C arm did not increase the CR rate or prolong EFS or OS. As a result of worse treatment tolerance, advanced age continuously affected CR rate, EFS, and OS, with 55 years as the best age cutoff. At 5 years, EFS was 55.7% (95% CI, 51.8% to 59.4%) for patients younger than 55 years of age versus 25.8% (95% CI, 19.9% to 35.6%) in older patients (hazard ratio, 2.16; P < .001). Patients ≥ 55 years of age, in whom a lower compliance to the whole planned chemotherapy was observed, benefited significantly from hyper-C, whereas younger patients did not. Conclusion No significant benefit was associated with the introduction of a hyper-C sequence into a frontline pediatric-like adult acute lymphoblastic leukemia therapy. Overall, tolerability of an intensive pediatric-derived treatment was poor in patients ≥ 55 years of age.

Intensive care unit (ICU) admission is associated with high mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Whether mortality has decreased recently is unknown. The 497 adult allogeneic HSCT recipients admitted to three ICUs between 1997 and 2011 were evaluated retrospectively. Two hundred and nine patients admitted between 1997 and 2003 were compared with the 288 patients admitted from 2004 to 2011. Factors associated with 90-day mortality were identified. The recent cohort was characterized by older age, lower conditioning intensity, and greater use of peripheral blood or unrelated-donor graft. In the recent cohort, ICU was used more often for patients in hematological remission (67% vs 44%; P

Resume Introduction Les differents plans cancer en France visent notamment a garantir a tout patient âge atteint de cancer une prise en charge specifique. Methode Nous avons utilise les donnees PMSI 2012 pour identifier les hospitalisations des personnes ≥ 75 ans liees a la prise en charge du cancer. Resultats On denombre 358 721 personnes avec 1 492 935 hospitalisations, respectivement avec chimiotherapie (32,4 %), radiotherapie (23,0 %), chirurgie (10,6 %), prise en charge palliative (3,9 %) ou autre prise en charge (30,9 %). L’activite est realisee dans les centres hospitaliers (36,3 %), les etablissements prives commerciaux (23,4 %), les centres hospitaliers universitaires (20,9 %), les centres de lutte contre le cancer (11,8 %). Leur part differe selon la prise en charge. Le volume total d’activite et la dispersion dans les etablissements varient beaucoup selon la region. Conclusion Ces donnees devraient aider a la mise en œuvre d’une politique oncogeriatrique, notamment par les unites de coordination en oncogeriatrie, permettant de cibler la formation des professionnels et la diffusion de bonnes pratiques dans les etablissements de leur region prenant en charge un nombre important de ces patients.

Resume La mesure des delais apparait comme un element de la qualite de prise en charge des patients atteints de cancer et pourrait s'averer etre un marqueur potentiel des inegalites d'acces aux soins. Objectif Faire un etat des lieux dans plusieurs regions de France des delais de prise en charge les plus representatifs du parcours de soins pour les cancers du sein, du poumon, du colon et de la prostate et analyser ces delais en fonction des elements individuels, medicaux et organisationnels de la prise en charge et selon la region. Methodes L'etude, pilotee par l'Institut national du cancer et operee par la Federation nationale des Observatoires regionaux de sante, a ete menee sur le terrain par les Reseaux regionaux de cancerologie avec l'appui des Observatoires regionaux de sante. Elle a permis d'analyser les delais a partir des fiches de reunion de concertation pluridisciplinaire et des dossiers medicaux dans huit regions de France metropolitaine lors de la premiere phase de l'etude en 2011, pour 2 530 cas de cancer du sein et 1 945 cas de cancer du poumon, et dans 13 regions de France dont deux regions d'outre-mer lors de la seconde phase en 2012, pour 3 248 cas de cancer du colon et 4 207 cas de cancer de la prostate. Resultats Les delais mesures pour le cancer du sein etaient en moyenne de 17,7 jours (± 15,9 jours) entre la mammographie et le diagnostic anatomopathologique et de 22,9 jours (± 13,9 jours) entre le diagnostic ou la proposition therapeutique et l'intervention chirurgicale. Pour le cancer du poumon, ils etaient en moyenne de 21,5 jours (± 17,6 jours) entre la premiere imagerie suspecte et le diagnostic anatomopathologique et de 13,5 jours (± 10,7 jours) entre le diagnostic et la proposition therapeutique. Pour le cancer du colon, les delais etaient en moyenne de 4,5 jours (± 4,1 jours) entre la coloscopie et le diagnostic anatomopathologique et de 18,9 jours (± 14,9 jours) entre le diagnostic et l'intervention chirurgicale. Pour le cancer de la prostate, ils etaient en moyenne de 36,5 jours (± 26,5 jours) entre le diagnostic anatomopathologique et la proposition therapeutique et de 45,2 jours (± 30,1 jours) entre la proposition therapeutique et l'intervention chirurgicale. Il ressort de cette etude une grande heterogeneite dans les pratiques de recueil et de mise en commun des informations rendant la methode employee difficilement utilisable en routine. Une variabilite relativement importante des delais pour les quatre localisations a ete constatee. l'âge, le mode de decouverte, le stade de la tumeur, les caracteristiques de la structure de premiere prise en charge jouaient un role sur les delais observes. Une fois ces differents facteurs pris en compte, des differences importantes entre regions persistaient, allant d'un facteur 2a 4pour certains delais. Des differences dans l'organisation des soins au sens large (repartition de l'offre de prise en charge, cooperation entre etablissements…) peuvent etre la source majeure de cette heterogeneite, sans que l'etude ne permette, en l'absence d'indicateur specifique, d'objectiver leur role. De meme, les indicateurs de contexte individuel n'etaient pas suffisamment disponibles (precarite, situation vis-a-vis de l'emploi et categorie socioprofessionnelle) pour discriminer leur role sur les delais. Enfin, les delais observes etaient comparables a ceux rapportes dans la litterature ou dans les recommandations internationales. Conclusion Les resultats de l'etude suggerent que les delais de prise en charge des cancers peuvent constituer des marqueurs potentiels de l'acces aux soins et de mesure des inegalites de prise en charge. Leur etude et leur suivi systematique en tant qu'indicateur pourraient donc permettre de mieux caracteriser ces inegalites, d'identifier des pistes d'action pour ameliorer les prises en charge, puis de mesurer leur impact.

Invariant natural killer T (iNKT) cells can experimentally dissociate GVL from graft-versus-host-disease (GVHD). Their role in human conventional allogeneic hematopoietic stem cell transplantation (HSCT) is unknown. Here, we analyzed the post-HSCT recovery of iNKT cells in 71 adult allografted patients. Results were compared with conventional T- and NK-cell recovery and correlated to the occurrence of GVHD, relapse, and survival. We observed that posttransplantation iNKT cells, likely of donor origin, recovered independently of T and NK cells in the first 90 days after HSCT and reached greater levels in recipient younger than 45 years (P = .003) and after a reduced-intensity conditioning regimen (P = .03). Low posttransplantation iNKT/T ratios (ie, < 10−3) were an independent factor associated with the occurrence of acute GVHD (aGVHD; P = .001). Inversely, reaching iNKT/T ratios > 10−3 before day 90 was associated with reduced nonrelapse mortality (P = .009) without increased risk of relapse and appeared as an independent predictive factor of an improved overall survival (P = .028). Furthermore, an iNKT/T ratio on day 15 > 0.58 × 10−3 was associated with a 94% risk reduction of aGVHD. These findings provide a proof of concept that early postallogeneic HSCT iNKT cell recovery can predict the occurrence of aGVHD and an improved overall survival.

Allogeneic haematopoietic stem-cell transplantation (HSCT) is the only curative treatment for myelofibrosis. We report an analysis of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) registry including patients with myelofibrosis transplanted between 1997 and 2008. Potential risk factors affecting engraftment, non-relapse mortality (NRM), overall survival (OS) and progression-free survival (PFS) were analysed. One hundred and forty-seven patients, aged 20-68 (median 53) years, diagnosed with primary (53%) or secondary myelofibrosis underwent HSCT; 59% of patients were transplanted from a matched sibling donor. The conditioning regimen was myeloablative in 31% of patients. Ninety percent of the patients engrafted. Factors affecting favourably engraftment were splenectomy before HSCT, human leucocyte antigen (HLA) matched sibling donor, peripheral stem cell use as source of stem cells and absence of pre-transplant thrombocytopenia. Four-year OS, PFS and NRM survival were 39% (95%confidence interval [CI]: 31-50), 32% (95%CI: 24-43) and 39% (95%CI 30-48), respectively. Multivariate analysis indicated that HLA-identical sibling donor, chronic phase disease and splenectomy in men had favourable impact on OS.

International audience; This retrospective report assessed the impact of rabbit antithymocyte globulins (ATG), incorporated within a standard myeloablative conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT) using human leukocyte antigen-matched unrelated donors (HLA-MUD), on the incidence of acute and chronic graft-vs-host disease (GVHD). In this series of leukemia patients, 120 patients (70%) did not receive ATG ('no-ATG' group), whereas 51 patients received ATG ('ATG' group). With a median follow-up of 30.3 months, the cumulative incidence of grade 3-4 acute GVHD was 36% in the no-ATG group and 20% in the ATG group (P = 0.11). The cumulative incidence of extensive chronic GVHD was significantly lower in the ATG group as compared to the no-ATG group (4 vs 32%, respectively; P = 0.0017). In multivariate analysis, the absence of use of ATG was the strongest parameter associated with an increased risk of extensive chronic GVHD (relative risk) = 7.14, 95% CI: 1.7-33.3, P = 0.008). At 2 years, the probability of nonrelapse mortality, relapse, overall and leukemia-free survivals was not significantly different between the no-ATG and ATG groups. We conclude that the addition of ATG to GVHD prophylaxis resulted in decreased incidence of extensive chronic GVHD without an increase in relapse or nonrelapse mortality, and without compromising survival after myeloablative allo-SCT from HLA-MUD.

Presidente du college de la Haute Autorite de sante (HAS) en 2016-2017, apres avoir preside le conseil d’administration de l’Institut de radioprotection et de surete nucleaire, puis l’Institut national du cancer, le Pr Agnes Buzyn, hematologue, evoque les missions de l’institution et ses futures orientations. Elle est actuellement ministre des Solidarites et de la Sante.

Extramedullary plasmacytomas (EMP) rarely occur during the course of multiple myeloma (MM). Most frequent reported sites are superior respiratory airways, pleura, lung, lymph nodes, skin, subcutaneous and soft tissues, testicles and liver. EMP involving the urinary tract are very uncommon and have been ill-described in the literature. We report two unusual cases of obstructive urinary tract EMP revealing a relapse of MM after allogeneic stem cell transplantation. Clinicians must be aware that EMP may be responsible for urinary tract obstruction even in the absence of medullary progression of MM.

Detection of galactomannan antigen (GMA) in serum is the standard assay for the diagnosis of invasive aspergillosis (IA) in high-risk patients with hematological disorders. Detection of Aspergillus DNA in serum has been proposed, but its sensitivity is lower than that of GMA when small serum volumes (SSV) are used. In this study, we investigated whether extraction of DNA from large serum volumes (LSV) improves diagnostic yield. In a 13-month prospective study, we compared the performances of twice-weekly screening of serum for GMA by an enzyme immunoassay and weekly screening for Aspergillus fumigatus DNA by a real-time PCR (RT-PCR) assay of 1.0 ml (LSV) or 100 μl (SSV) of serum. We included 124 patients (138 treatment episodes), with 17 episodes of EORTC (European Organization for Research and Treatment of Cancer)/MSG (Mycoses Study Group)-documented IA. In all, 1,870 samples were screened for GMA. The sensitivity (Se), specificity (Sp), and positive and negative predictive values (PPV and NPV, respectively) of GMA for IA were 88.2%, 95.8%, 75%, and 98.3%, respectively. We screened 938 samples for Aspergillus DNA by using LSV; 404 of these samples were also tested with SSV. The Se, Sp, PPV, and NPV of RT-PCR were 100%, 96.7%, 81%, and 100%, respectively, with LSV and 76.5%, 96.7%, 81.3%, and 95.6%, respectively, with SSV. DNA detection gave a positive result when performed on LSV in two cases of IA where the GMA assay result remained negative. Furthermore, in four IA cases, DNA was detected earlier than GMA. The use of LSV for extraction improved the performance of the RT-PCR, which appears highly sensitive and specific for the early diagnosis of IA in high-risk patients with hematological disorders.

Purpose This retrospective multicenter study assessed the outcome of 51 patients with myeloid sarcoma (MS) who underwent allogeneic hematopoietic stem-cell transplantation (alloHSCT). Patients and Methods Most patients had MS presenting in conjunction with acute myeloid leukemia (AML) or after AML. Six patients had isolated MS. The median time between diagnosis and alloHSCT was 8 months (range, 2.8 to 67). Forty patients were in complete remission (CR) at time of alloHSCT. Results With a median follow-up of 33 (range, 1 to 182) months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival were 47% (95% CI, 33% to 61%) and 36% (95% CI, 24% to 50%) at 5 years. Twenty patients (39%) relapsed at a median of 204 (range, 35 to 1151) days after alloHSCT, with relapse being the major cause of death. In a Cox multivariate analysis, age ≥ 15 years and remission status at time of alloHSCT (CR v other) were associated with improved OS (hazard ratio [HR], 0.27; 95% CI, 0.12 to 0.65; P = .003; and HR, 0.22; 95% CI, 0.08 to 0.57; P = .002, respectively). Conclusion We conclude that first-line alloHSCT performed early in the course of MS is a valid therapeutic option.

Purpose Aggressive T-cell lymphomas (ATCLs) represent 10% to 15% of non-Hodgkin's lymphomas (NHLs) in adults. ATCLs show a worse prognosis than B-cell lymphomas. Patients and Methods On behalf of the Société Française de Greffe de Moëlle et de Thérapie Cellulaire, we conducted a retrospective analysis including 77 ATCL patients who underwent allogeneic stem-cell transplantation (alloSCT). Results The different diagnosis included anaplastic large-cell lymphoma (ALCL; n = 27), peripheral T-cell lymphoma not otherwise specified (PTCL-NOS; n = 27), angioimmunoblastic T-cell lymphoma (AITL; n = 11), hepatosplenic γ/δ lymphoma (HSL; n = 3), T-cell granular lymphocytic leukemia (T-GLL; n = 1), nasal natural killer (NK)/T-cell lymphoma (nasal-NK/L; n = 3) or non-nasal NK/T-cell lymphoma (non-nasal-NK/L; n = 2), enteropathy-type T-cell (n = 1), and human T-lymphotropic virus (HTLV)-1 lymphoma (n = 2). Fifty-seven patients received a myeloablative conditioning regimen. Donors were human leukocyte antigen (HLA)-matched in 70 cases and related in 60 cases. Thirty-one patients were in complete remission (CR) at the time of alloSCT, whereas 26 were in partial response (PR). Five-year toxicity-related mortality (TRM) incidence was 33% (95% CI, 24% to 46%). The 5-year overall survival (OS) and event-free survival (EFS) rates were 57% (95% CI, 45% to 68%) and 53% (95% CI, 41% to 64%), respectively. In multivariate analysis, chemoresistant disease (stable, refractory, or progressing disease) at the time of alloSCT and the occurrence of severe grade 3 to 4 acute graft-versus-host disease (aGVHD) were the strongest adverse prognostic factors for OS (P = .03 and .03, respectively). Disease status at transplantation significantly influenced the 5-year EFS (P = .003), and an HLA-mismatched donor increased TRM (P = .04). Conclusion We conclude that alloSCT is a potentially efficient therapy for NK/T lymphomas and is worth further investigation through prospective clinical trials.

Rituximab is used in the treatment of lymphoma and autoimmune diseases, for which late-onset neutropenia (LON) were reported. LON-related mechanisms remain unclear. To obtain insights into the mechanisms, we assessed serum, peripheral blood and bone marrow (BM) samples of a patient with LON. Factors classically associated with neutropenia such as anti-neutrophil antibodies, T-LGL, soluble Fas Ligand were not detectable. We then evaluated the kinetics of various cytokines involved in B-cell and granulocyte homeostasis. We found that LON is related to a lack of granulopoiesis in the BM that coincides with a very high level of BAFF, a strong stimulator of B-cell recovery, and hypothesized a hematopoietic lineage competition due to an excessive B-cell recovery in the BM by promotion of B-cell lymphopoiesis over granulopoiesis within common developmental niches. Assessment of serum BAFF levels following rituximab could detect patients at risk of developing LON.

Systemic steroids are the standard treatment for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) despite their poor efficacy and disabling side effects.To evaluate the effectiveness and tolerance of budesonide/formoterol as an alternative treatment for BOS after HSCT.In this randomized, double-blind, placebo-controlled study, we randomly assigned 32 HSCT recipients with mild/severe BOS to receive budesonide/formoterol or placebo for 6 months. The primary outcome was the change in the FEV1 after 1 month of treatment (M1) compared with the baseline value. Patients were unblinded at M1 if there was no improvement in the FEV1. Those who had initially received placebo were switched to budesonide/formoterol. Intention-to-treat analysis was performed to assess the primary outcome. Additional analyses took scheduled treatment contamination into account.At M1, the median FEV1 increased by 260 ml in the budesonide/formoterol arm compared with 5 ml in the placebo arm (P = 0.012). The median increases in the FEV1 at M1 relative to the baseline value for the treated and placebo groups were 13 and 0%, respectively (P = 0.019). Twenty-five patients received budesonide/formoterol during the study. The median difference in the FEV1 between the baseline and after 1 month of treatment for these patients was +240 ml (P = 0.0001). The effect of budesonide/formoterol on the FEV1 was maintained in the 13 patients who completed 6 months of treatment.Budesonide/formoterol administration led to a significant improvement in the FEV1 in patients with mild/severe BOS after allogeneic HSCT. Clinical trial registered with www.clinicaltrials.gov (NCT00624754).

Because the indication of allograft (allogeneic stem cell transplantation [alloSCT]) for multiple myeloma (MM) has widened in recent years, thanks to the development of reduced-intensity conditionings (RIC), it is still unclear if myeloablative conditioning (MAC) remains appropriate. This study compares retrospectively outcomes of patients undergoing either RIC or MAC regimens for MM. Based on the SFGM-TC registry, we included 446 MM patients receiving alloSCT between 1999 and 2009 for whom a minimal data set was available. Median follow-up for the entire cohort was 33.6 months (range, 0 to 164.5). RIC and MAC populations were different regarding age (53.5 versus 47.1 years, respectively), number of prior autologous (auto)SCTs (93.2% versus 79.6% had at least 2 autoSCTs), and stem cell source (90.2% versus 61.2% received peripheral blood). For RIC and MAC populations the nonrelapse mortality at 2 years was 24.6% and 22.4%, respectively, progression-free survival 35.5% and 51.1%, and overall survival 59.5% and 66.7% (not significant). These outcomes were not affected by conditioning intensity either on univariate or multivariate analysis. Despite some limitations in the study design, these results indicate that MAC should remain a valuable option in alloSCT for MM, especially for young and less-treated patient with no comorbidity. The constant progress in induction treatments of MM and supportive care after alloSCT could improve these results in the near future.

Acute lymphoblastic leukemia ( ALL) in the elderly is characterized by its ominous prognosis. On the other hand, imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL), which prompted us to assess the use of imatinib in previously untreated elderly patients. ALL patients aged 55 years or older were given steroids during 1 week. Ph+ve cases were then offered a chemotherapy-based induction followed by a consolidation phase with imatinib and steroids during 2 months. Patients in complete response (CR) after consolidation were given 10 maintenance blocks of alternating chemotherapy, including two additional 2-month blocks of imatinib. Thirty patients were included in this study and are compared with 21 historical controls. Out of 29 assessable patients, 21 (72%, confidence interval (CI): 53 - 87%) were in CR after induction chemotherapy vs 6/21 (29%, CI: 11 - 52%) in controls (P = 0.003). Five additional CRs were obtained after salvage with imatinib and four after salvage with additional chemotherapy in the control group. Overall survival ( OS) is 66% at 1 year vs 43% in the control group ( P = 0.005). The 1-year relapse-free survival is 58 vs 11% ( P = 0.0003). The use of imatinib in elderly patients with Ph+ ALL is very likely to improve outcome, including OS.

Chronic myeloid leukemia (CML) relapse after allogeneic stem cell transplantation (SCT) is a relatively frequent situation, which is correlated to disease status, time from diagnosis to transplant and T-cell depletion. We evaluated the potential for early minimal residual disease (MRD) BCR-ABL quantification to predict relapse of CML patients receiving allogeneic SCT. Minimal residual disease was analyzed by real-time quantitative reverse transcriptase-polymerase chain reaction (RQ-PCR) at day 100 (d100) in 38 patients with >1 year follow-up after conventional non-T-cell-depleted SCT. Normal ABL control values from 1724 follow-up blood samples were used to define an RQ-PCR amplifiability index and the limits of reliable use of BCR-ABL ratios. We then compared the 14 patients with a high-level d100 BCR-ABL/ABL ratio (> or = 10(-4)) to that of the 24 patients with a negative/low-level ratio (

Purpose Because the overall outcome of critically ill hematologic patients has improved, we evaluated the short-term and long-term outcomes of the poor risk subgroup of allogeneic hematopoietic stem-cell transplantation (HSCT) recipients requiring admission to the intensive care unit (ICU). Patients and Methods This was a retrospective multicenter study of allogeneic HSCT recipients admitted to the ICU between 1997 and 2003. Results Two hundred nine critically ill allogeneic HSCT recipients were included in the study. Admission in the ICU occurred during the engraftment period (≤ 30 days after transplantation) for 70 of the patients and after the engraftment period for 139 patients. The overall in-ICU, in-hospital, 6-month, and 1-year survival rates were 48.3%, 32.5%, 27.2%, and 21%, respectively. Mechanical ventilation was required in 122 patients and led to a dramatic decrease in survival rates, resulting in in-ICU, in-hospital, 6-month, and 1-year survival rates of 18%, 15.6%, 14%, and 10.6%, respectively. Mechanical ventilation, elevated bilirubin level, and corticosteroid treatment for the indication of active graft-versus-host disease (GVHD) were independent predictors of death in the whole cohort. In the subgroup of patients requiring mechanical ventilation, associated organ failures, such as shock and liver dysfunction, were independent predictors of death. ICU admission during engraftment period was associated with acceptable outcome in mechanically ventilated patients, whereas patients with late complications of HSCT in the setting of active GVHD had a poor outcome. Conclusion Extensive unlimited intensive care support is justified for allogeneic HSCT recipients with complications occurring during the engraftment period. Conversely, initiation or maintenance of mechanical ventilation is questionable in the setting of active GVHD.

Intravascular lymphoma (IVL) is a rare and aggressive disorder, characterised by frequent cutaneous and neurological involvement and medullary infiltration. In rare cases particularly in Asia, IVL can be associated with haemophagocytic syndrome (IVL-HS). Here, we report the case of a 61-year-old Caucasian female who presented with IVL-HS. Bone marrow biopsy showed haemophagocytic features and medullary localisation of a diffuse large B-cell lymphoma. Liver biopsy showed exclusive sinusoidal infiltration by large B cells. Treatment by polychemotherapy associated with rituximab induced a rapid complete remission. Unfortunately, death occurred as a consequence of septic shock. Early recognition of IVL-HS by performing bone marrow biopsy is critical to start rapidly appropriate treatment. The role of rituximab in the management of IVL-HS remains to be established.

Class I MHC complexes (MHCI) are essential in mediating immune response. The transport of antigenic peptides (TAP) to MHCI and the stable expression of MHCI on the cell surface require the presence of a dedicated TAP. In this study we report that IFN-γ and thrombopoietin (TPO) strongly increase TAP1 protein expression in megakaryocytes, followed by an enhanced expression of MHCI on the cell surface. This expression parallels the enhanced TAP1 promoter activity and TAP1 mRNA expression, which are independent of protein synthesis. We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-γ target cells tested. Interaction of IRF-2 and STAT1 on the promoter depends on the DNA-binding domain of IRF-2. Overall, our data indicate that TPO and IFN-γ activate the expression of TAP1 via a new mechanism that involves functional cooperation between STAT1 and IRF-2 on the TAP1 promoter.

Purpose We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL. Patients and Methods A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT. Results Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3. Conclusion Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.

In chronic myelogenous leukemia (CML) imatinib mesylate has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr-abl fusion protein. Using this agent alone high rates of cytogenetic responses were recorded. However, several mechanisms of resistance have been described. In vitro studies examining the effects of imatinib mesylate plus cytarabine have shown synergistic antiproliferative effects of this combination. Thus, the CML French Group decided to perform a phase 2 trial testing a combination of imatinib mesylate and low-dose cytarabine in 30 previously untreated patients in chronic phase. Treatment was administered on 28-day cycles. Patients were treated continuously with imatinib mesylate orally at a dose of 400 mg daily. Cytarabine was given on days 15 to 28 of each cycle at an initial dose of 20 mg/m2/d via subcutaneous injection. Adverse events were frequently observed with grade 3 or 4 hematologic toxicities and nonhematologic toxicities in 53% (n = 16) and 23% (n = 7) of patients, respectively. The cumulative incidence of complete cytogenetic response (CCR) at 12 months was 83% and at 6 months 100% of the patients achieved complete hematologic response (CHR). We concluded that the combination was safe and promising given the rates of response. (Blood. 2003;102:4298-4305)

Purpose: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO. Patients and Methods: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response. Results: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity. Conclusion: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.

The t(10;11)(p13-14;q14-21) associated with CALM-AF10 is considered to be rare and associated with a variety of acute lymphoid and myeloid leukemias. Twelve (9%) of 131 unselected T-cell acute lymphoid leukemias (T-ALLs) expressed CALM-AF10 by reverse transcription-polymerase chain reaction or fluorescence in situ hybridization (or both), including 8% of children and 10% of adults, of whom only half demonstrated a t(10;11) by classical cytogenetics. CALM-AF10 was not found in T-cell-receptor alphabeta (TCRalphabeta) lineage T-ALLs, as defined by expression of TCRalphabeta, cytoplasmic TCRbeta, or TCRbetaVDJ rearrangement in immature cytoplasmic TCRbeta- cases, compared with 19% of TCRgammadelta T-ALLs and 33% of immature delta/gamma T-ALLs. The latter differed from their CALM-AF10- immature counterparts by a CD5+/CD2-phenotype, as found in TCRgammadelta but not TCRalphabeta T-ALLs and in their TCRgamma and TCRdelta configurations, altogether suggesting that CALM-AF10+ immature delta/gammaT-ALLs are TCRgammadelta precursors and that, within T-ALL, CALM-AF10 is specific for this lineage. Nine of 12 immature CALM-AF10 T-ALLs demonstrated 3' fusion transcripts, whereas 6 of 7 TCRgammadelta T-ALLs demonstrated 5' fusion transcripts. The latter retain the AF10 extended LAP/PHD domain necessary for homo-oligomerization. All 8 patients with CALM-AF10+TCRgammadelta T-ALLs are alive, compared with only 3 of 12 with immature CALM-AF10+ T-ALLs. Six CALM-AF10+ non-T acute leukemias all expressed CD7 and demonstrated T-restricted TCRdelta rearrangements, suggesting that they may also be related to the TCRgammadelta lineage. CALM-AF10 is therefore the most common fusion protein in T-ALL. It requires molecular and immunophenotypic characterization for appropriate prognostic evaluation and should be included in diagnostic screening panels of T-ALL and immature acute leukemias. Analysis of immature CALM-AF10+ leukemias will also facilitate analysis of the early stages of development of the TCRgammadelta lineage.

The authors report two cases of hypereosinophilia as the major presenting sign of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Tissue biopsies of the skin, salivary gland, gut, and liver showed evidence of acute GVHD (aGVHD). In one case, further investigations have been performed. Elevated levels of interleukin (IL)-5 and soluble IL-2 receptor were found in the blood, and skin biopsy specimens demonstrated high levels of IL-5 messenger ribonucleic acid (mRNA). In contrast, skin biopsy specimens from other patients with aGVHD but without eosinophilia were negative for IL-5 mRNA. The authors also demonstrated the presence of IL-4 and interferon(IFN)-gamma mRNA within the same skin biopsy specimen, suggesting that this case of aGVHD was mediated by both Th1 and Th2 cell type. These two patients were treated by glucocorticoids with resolution of the hypereosinophilia and the symptoms of GVHD. The authors briefly discuss the possible mechanisms of this hypereosinophilia with respect to aGVHD.

French national cancer plans were rolled out oncogeriatric coordination units in France in particular to enable all elderly people with cancer in each region to benefit from a specific care management.The national hospital discharge database was analyzed in order to analyze hospitalizations related to cancer care in ≥75 years patients for year 2012.A total of 358,721 patients with 1,492,935 hospitalizations were recorded, respectively with chemotherapy (32.4%), radiotherapy (23.0%), surgery (10.6%), palliative care (3.9%), or other care (30.9%). Hospital activity was distributed in hospitals (36.3%), clinics (23.4%), academic hospitals (20.9%), cancer centers (11.8%). Their respective share varied according to care. Total activity volume and number of health care facilities involved were highly variable in the different regions.These data would permit development of a national oncogeriatric policy through the action of regional oncogeriatric coordination units. These units should prioritize training actions and good practice guidelines dissemination in health care institutions with a high activity volume in this domain.

With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.

Background: Treatment of younger adults with Ph-negative ALL has markedly evolved since the early 2000s. Survivals have substantially improved using pediatric or pediatric-inspired protocols with higher doses of steroids, vincristine (VCR), methotrexate (MTX) and L-asparaginase (L-Aspa), as was done in the GRAALL-2003 trial (Huguet et al. JCO 2009). However, the upper age limit for a pediatric-like strategy remained undetermined. In the GRAALL-2005 study (NCT00327678), we aimed to address this age issue in a larger trial and to randomly evaluate a reinforced hyper-fractionated (hyperC) vs standard (standardC) dose of cyclophosphamide (CPM) during induction and late intensification. Patients with CD20-positive B-cell precursor (BCP) ALL were also randomized in the rituximab GRAALL-2005/R study, as specifically reported last year (Maury et al. ASH 2015). Patients and Methods: Patients aged 18-59 years old with newly-diagnosed Ph-negative ALL were eligible. Chemotherapy comprised a steroid prephase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance (Beldjord et al. Blood 2014). Allogeneic transplantation was offered in first complete remission (CR) to patients with conventional high-risk factors (Dhédin et al. Blood 2015). During induction and late intensification, CPM was given at 750 mg/m2 on day 1 followed by 750 mg/m2 on day 15 (standardC) or 300 mg/m2/12h on day 15 to 17 (hyperC), according to randomization arm. The primary endpoint was event-free survival (EFS). Secondary endpoints were cumulative incidences of failure (CIF, including primary refractoriness and relapse) and CI of non-refractoriness/relapse mortality (CINRM, including toxic death during induction and death in first CR), overall survival (OS), compliance and safety. Compliance was assessed by comparing the median doses of specific drugs actually received by patients who completed specific treatment phases. Results: Between 2006 and 2014, 787 evaluable patients were randomized (398 standardC, 389 hyperC; 525 BCP-ALL, 262 T-ALL). Median age was 36y, with 200, 172, 171, 151 and 93 patients in the 18-24y, 25-34y, 35-44y, 45-54y and 55y+ age subgroups, respectively. Overall CR rate was 91.9% and 278 patients were transplanted in first CR. With a median follow-up of 5.2 years, 5y-EFS and OS were 52% (48-56) and 58% (55-62), respectively, confirming previous GRAALL-2003 results. No difference in outcome was observed in T- vs BCP-ALL patients. At 5 years, EFS was 60%, 58%, 54%, 50% and 26% in the youngest to the oldest age subgroup, respectively (HR, 2.2 [1.7-2.8]; p Conclusions: Taken together, these results indicate that 55 years is likely to be the upper age limit for a pediatric-like strategy in younger adults with ALL, because of excessive toxicity and worse treatment compliance observed above this age. Older adults could probably benefit from alternative front-line approaches such as hyper-fractionated CPM or new agents such asinotuzumabozogamicin. Disclosures Rousselot: BMS: Research Funding; Ariad: Research Funding; Pfizer: Research Funding.

Purpose The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. Patients and Methods In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). Results N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). Conclusion These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.

In this retrospective multicentre study, we analysed the results of 82 consecutive second early allogeneic transplants for primary (n = 28) or secondary ([n = 54) graft failures performed between 1985 and 1997 in patients with acute leukaemia (n = 33), aplastic anaemia (n = 29) or chronic myeloid leukaemia (n = 20). HLA-matched siblings were used in 64 cases. The same donors were used for both transplants in 56 cases and the first transplant was T-cell depleted in 30 cases. The median age at transplant was 25 years and the median intertransplant time interval was 2 months. Estimates of the 3-year overall survival and day 100 transplant-related mortality were 30% and 53% respectively. A recipient age or = 80 d and a positive recipient cytomegalovirus serology were predictors of a better outcome. The use of cyclosporin A (CsA) after second transplant had a dramatic impact on outcome, the best results being observed with CsA alone. The day 40 probability of neutrophil recovery was 73%. The use of peripheral blood progenitor cells (PBPCs) was associated with a higher and faster neutrophil recovery. Other factors associated with neutrophil recovery were an intertransplant time interval > or = 80 d and a positive recipient cytomegalovirus serology. Therefore, second early allogeneic transplantation for graft failure is an effective treatment, especially if patients can receive CsA for graft-versus-host disease prevention and are retransplanted more than 80 d from first transplant.

B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) are increasingly treated on risk-adapted protocols based on presenting clinical and biological features. Residual molecular positivity of clonal immunoglobulin (IG) and T-cell receptor (TCR) rearrangements allows detection of patients at an increased risk of relapse. If these rearrangements are to be used for universal follow-up, it is important to determine the extent to which they are informative in different BCP-ALL subsets. We show thatIGH V-D-J rearrangements occur in 89% of 163 BCP-ALL, with no significant variation according to age or genotype (BCR-ABL, TEL-AML1, MLL-AF4, and E2A-PBX1). In contrast,TCRG rearrangements, which occur in 60% of patients overall, are frequent in BCR-ABL and TEL-AML1, are less so in MLL-AF4, and are virtually absent in infants aged predominantly from 1 to 2 years and in E2A-PBX1 ALLs. Incidence of the predominant TCRD Vδ2-Dδ3 rearrangement decreases with age but is independent of genotype. These differences are not due to differential recombination activating gene activity, nor can they be explained adequately by stage of maturation arrest. Analysis of MLL-AF4 BCP-ALL is in keeping with transformation of a precursor at an early stage of ontogenic development, despite the adult onset of the cases analyzed. We postulate that the complete absence of TCRG rearrangement in E2A-PBX1 cases may result from deregulated E2A function. These data also have practical consequences for the use ofTCR clonality for the molecular follow-up of BCP-ALL.

BACKGROUND: The optimal dose of post-chemotherapy granulocyte-colony-stimulating factor (G-CSF) administration before peripheral blood progenitor cell (PBPC) collection has not been determined as yet, although 5 microg per kg per day has been recommended as the standard dose. This study retrospectively analyzed the effect of G-CSF dose on peripheral blood CD34+ cell collection from 91 patients with hematologic malignancies. STUDY DESIGN AND METHODS: Various doses of G-CSF were administered after several chemotherapeutic PBPC mobilization regimens. According to the dose of G-CSF administered, patients were assigned to two groups. Group 1 included 46 patients who received a low dose of G-CSF (median, 3.6 [range, 2.8-4.6] microg/kg/day). Group 2 included 45 patients who received a standard G-CSF dose of 6.0 (5.5-8. 1) microg per kg per day. Patients in the two groups were matched for age, diagnosis, previous therapy, and chemotherapeutic PBPC mobilization regimens. RESULTS: No difference was observed in the median number of CD34+ cells harvested from each group. The number of leukapheresis procedures necessary to obtain a minimum of 3 x 10(6) CD34+ cells per kg was the same in both groups, and the percentage of patients who failed to achieve adequate PBPC collections was similar in the two groups. CONCLUSION: The administration of low-dose G-CSF after chemotherapy appears equivalent to administration of the standard dose in achieving satisfactory PBPC collection. This approach could allow significant savings in medical cost. A randomized and prospective study is necessary, however, to assess the validity of these conclusions.

Coexistence and Parallel Evolution of Hypereosinophilic Syndrome, Autoimmune Hepatitis, and Ulcerative Colitis Suggest Common Pathogenic Features

Agnogenic myeloid metaplasia is a rare indication for allogeneic bone marrow transplantation (BMT). We have retrospectively studied 12 patients allografted for this disease within the French BMT group. Prior to BMT, the mean age was 40 years (range 14-49). Diagnosis was based on the Polycythaemia Vera Study Group criteria. Before BMT, 10 patients had been splenectomized, eight required transfusions, and four had received at least two lines of chemotherapy. Cyclophosphamide and total body irradiation was the main conditioning regimen used (n=8). The donor was an HLA-identical sibling except in one case where there was one HLA-DR mismatch. Acute graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporine A. 11 patients engrafted with median times to achieve absolute neutrophil count > 0.5 x 10(9)/l and platelet count > 50 x 10(9)/l of 17 (range 12-44) and 29 (range 12-196) days respectively. One primary graft failure occurred. 10 patients developed grade II-IV acute GVHD, four developed extensive chronic GVHD. One patient relapsed 16 months post-BMT and was untreated and well 14 months later. Three patients died from the BMT procedure. In May 1996 the median follow-up was 25 months and the 4-year overall and event-free survivals were 71% and 59%, respectively. Thus, we conclude that extensive myelofibrosis is not associated with delayed engraftment, and that HLA-identical sibling allogeneic BMT can be considered in a small proportion of patients with agnogenic myeloid metaplasia.

Chronic myeloid leukemia (CML) is characterized cytogenetically by a t(9;22) translocation which generates a hybrid bcr-abl gene, encoding a p210(bcr-abl) fusion protein. The induction in vitro of leukemia-specific T cells reactive with p210(bcr-abl) is a strategy developed for an immunological therapeutic approach in CML. Peptides from the junction region of this chimeric protein have been considered as potential targets for a cytotoxic response against leukemic cells. However, only a few peptides encompassing the two p210(bcr-abl) breakpoints have been shown to bind to the most common HLA class I molecules, which limits the number of patients who could benefit from this approach. We assume that the presence of chimeric BCR-ABL protein in leukemic cells may affect processing and delivery of peptides, possibly giving rise to new epitopes at the cell surface. We selected 162 peptides from the whole sequence of this protein, including 14 peptides of the b2a2 and b3a2 junctions, which had an anchor motif for a common HLA class I molecule. We tested their ability to bind to eight HLA class I molecules (HLA-A1, -A2, -A3, -A11, -B7, -B8, -B27, -B44). We identified 48 peptides from outside the junction region, with intermediate or strong binding capacities to these HLA class I molecules contrasting with only six junction peptides with a moderate binding capacity to HLA-A3/A11, -B8, or -B44 molecules. Moreover, cytotoxic T lymphocyte lines specific for various peptides outside the junction were generated from peripheral blood mononuclear cells of HLA-A2 or -B7 healthy donors and from one CML patient. These results contribute to evaluation of immunity to the BCR-ABL chimeric protein. Further studies are required to investigate whether such epitopes are correctly processed and presented by leukemic cells.

Measuring waiting times is a good indicator of quality of cancer care and could reveal inequalities in cancer care access.To determine the most representative waiting times in breast, lung, colon and prostate cancer care in several regions of France. To analyze the influence of individual, medical or health care system factors on those waiting times.This study was piloted by the French Cancer Institute in partnership with the National Federation of the Regional Health Observatories and was driven by the Regional Oncology Networks and the Regional Health Observatories. In 2011, 2,530 women with breast cancer and 1,945 patient with lung cancer were included in eight regions, and in 2012, 3,248 patients with colon cancer and 4,207 men with prostate cancer were included in 13 regions, two of which were overseas departments. Data were analyzed from multidisciplinary discussion reports and from medical records.The mean time intervals (± standard deviation) for the various components of access to care were as follows in breast cancer: mammography to pathologist diagnosis, 17,7 days (±15,9); diagnosis (or treatment proposal) to surgery, 22,9 days (±13,9). In lung cancer: first suspect medical image to pathologist diagnosis, 21,5 days (±17,6); diagnosis to treatment proposal, 13,5 days (±10,7). In colon cancer: coloscopy to pathologist diagnosis, 4,5 days (±4,1); diagnosis to surgery, 18,9 days (±14,9). In prostate cancer: pathologist diagnosis to treatment proposal, 36,5 days (±26,5); treatment proposal to surgery, 45,2 days (±30,1). Data collection was particularly difficult because of very heterogeneous way in medical records filling by care centers, so the data collection method used in the study could not be used in routine procedures. Waiting times measured in the four cancers had an important variability. In fact, age, circumstance of diagnosis, tumor stage and category of care center had an influence. After considering those different factors, differences between regions remained from range 2 to 4. Those regional differences could be explained by organizational factors but were not explored in our study. In the same way, data on individual factors (social vulnerability, category of employment) were not available to measure their effects on this study. Besides, our results were comparable to those in international publications or national recommendations in other countries.These results suggest that waiting times could be good indicators and could reveal inequalities in cancer care access. Measuring them would lead to characterize those inequalities and to propose actions to improve access to cancer care whose impact could be measured.

The incidence of cancer will increase dramatically among elderly people in the 21st century. The first French National Cancer Plan (2003-2006) with the French Ministry of Health supported the creation of 15 pilot coordination units in oncogeriatrics (UPCOG) in 13 out of the 27 French regions. The second French National Cancer Plan (2009-2013) continues to support oncogeriatrics. Based on evaluation of the pilot experiment in 2010, requirement specifications for an oncogeriatric coordination unit were defined and rolled out nationwide. The following missions were set out: to adjust cancer treatment in elderly people and enable all elderly cancer patients to benefit from this oncogeriatric approach; to stimulate specific research in oncogeriatrics; to promote training of health professionals, and to promote information. The clinical use of a geriatric prescreening tool as a routine procedure needs to become more widespread. Lastly, recommendations for treatment strategies tailored to elderly persons with high-incidence cancer must be developed. Fifteen oncogeriatrics coordination units were founded since 2011, covering 11 regions. Roll-out continues in 2012.

The incidence of cancer will increase dramatically among elderly people in the 21st century. The first French National Cancer Plan (2003–2006) with the French Ministry of Health supported the creation of 15 pilot coordination units in oncogeriatrics (UPCOG) in 13 out of the 27 French regions. The second French National Cancer Plan (2009–2013) continues to support oncogeriatrics. Based on evaluation of the pilot experiment in 2010, requirement specifications for an oncogeriatric coordination unit were defined and rolled out nationwide. The following missions were set out: to adjust cancer treatment in elderly people and enable all elderly cancer patients to benefit from this oncogeriatric approach; to stimulate specific research in oncogeriatrics; to promote training of health professionals, and to promote information. The clinical use of a geriatric prescreening tool as a routine procedure needs to become more widespread. Lastly, recommendations for treatment strategies tailored to elderly persons with high-incidence cancer must be developed. Fifteen oncogeriatrics coordination units were founded since 2011, covering 11 regions. Roll-out continues in 2012.

TPS11620Background: Vemurafenib (V) is registered in monotherapy for the treatment of adult patients (pts) with BRAF V600 mutation (mut) unresectable or metastatic melanoma but responses were obser...

Background The impact of cytogenetic abnormalities in multiple myeloma after allogeneic stem cell transplantation has not been clearly defined. This study examines whether allogeneic stem cell transplantation could be of benefit for myeloma patients with high-risk cytogenetic abnormalities.Design and Methods This is a retrospective multicenter analysis of the registry of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire, including 143 myeloma patients transplanted between 1999 and 2008.Results The incidences of cytogenetic abnormalities were 59% for del(13q), 25% for t(4;14), 25% for del(17p) and 4% for t(14;16). When comparing the population carrying an abnormality to that without the same abnormality, no significant difference was found in progression-free survival, overall survival or progression rate. Patients were grouped according to the presence of any of the poor prognosis cytogenetic abnormalities t(4;14), del(17p) or t(14;16) (n=53) or their absence (n=32). No difference in outcomes was observed between these two groups: the 3-year progression-free survival, overall survival and progression rates were 30% versus 17% (P=0.9), 45% versus 39% (P=0.8) and 53% versus 75% (P=0.9), respectively.Conclusions These data indicate that allogeneic stem cell transplantation could potentially be of benefit to high-risk myeloma patients.

Purpose To analyze the outcome, including nonrelapse mortality (NRM), relapse rate (RR), progression-free survival (PFS), and overall survival (OS), of patients with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) relapsed after an autologous stem-cell transplantation (ASCT) and treated with an allogeneic stem-cell transplantation (allo-SCT). Patients and Methods The European Group for Blood and Marrow Transplantation database was scanned for a first allo-SCT in relapsed DLBCL after a previous ASCT between 1997 and 2006. Other inclusion criteria were age at allo-SCT ≥ 18 years and availability of an HLA-identical sibling or a matched unrelated donor. A total of 101 patients (57 males; median age, 46 years) were included. Median follow-up for survivors was 36 months. Results Myeloablative conditioning regimen was used in 37 patients and reduced intensity conditioning (RIC) was used in 64 patients. Three-year NRM was 28.2% (95% CI, 20% to 39%), RR was 30.1% (95% CI, 22% to 41%), PFS was 41.7% (95% CI, 32% to 52%), and OS was 53.8% (95% CI, 44% to 64%). NRM was significantly increased in patients ≥ 45 years (P = .01) and in those with an early relapse (< 12 months) after ASCT (P = .01). RR was significantly higher in refractory patients (P = .03). A time interval to relapse after ASCT of < 12 months was associated with lower PFS (P = .03). The use of RIC regimens was followed by a trend to a lower NRM (P = .1) and a trend to a higher RR (P = .1), with no differences in PFS and OS. No differences were seen between HLA-identical siblings and matched unrelated donors. Conclusion Allo-SCT in relapsed DLBCL after ASCT is a promising therapeutic modality. Patients with a long remission after ASCT and with sensitive disease at allo-SCT are the best candidates for this approach.

Antigen-independent adhesion of resting adult CD4+ CD45RO+ T cells to B lymphocytes has been shown to be transient and can be down-regulated by CD4 major histocompatibility complex (MHC) class II molecule interactions. Conversely, adhesion of adult CD4+ CD45RA+ subpopulation to B cells is not regulated by ligands of CD4. We have investigated the regulation of adhesion of cord blood CD45RA+ CD4+ T lymphocytes. In contrast to adult CD45RA+ CD4+ T cells, cord blood CD45RA+ CD4+ T cells were strongly sensitive to the down-regulation of adhesion mediated by the CD4-HLA class II interaction, since adhesion to MHC class II(+) B cells was transient and inhibited by an anti-CD4 antibody. In addition, human immunodeficiency virus gp160, synthetic gp106-derived peptides encompassing a CD4 binding site inhibited conjugate formation between cord blood CD45RA+ CD4+ T cells and B cells. Following activation of the cord blood CD4 T cells by an anti-CD3 antibody, a conversion from a transient to a stable adhesion pattern of cord blood CD4 T cells to B cells occurred in 2 days. The reversal to a transient adhesion occurred at day 8 following anti-CD3 activation in correlation with a complete shift to a CD45RO phenotype of the cord blood CD4 T cells. These data suggest that CD4 T cell adhesion can be developmentally regulated.

The prognostic significance of CD20 expression in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been mostly studied in children and yielded conflicting results. In 143 adults with Philadelphia chromosome-negative BCP-ALL treated in the multicentric GRAALL 2003 trial, CD20 positivity over 20% was observed in 32% of patients. While not influencing complete remission achievement, CD20 expression was associated with a higher cumulative incidence of relapse (CIR) at 42 months (P=0.04), independently of the ALL high-risk subset (P=0.025). Notably, the negative impact of CD20 expression on CIR was only observed in patients with a white blood cell count (WBC) over 30x10(9)/L (P=0.006), while not in those with a lower WBC. In the former subgroup, this impact translated into lower event-free survival (15% vs. 59% at 42 months, P=0.003). CD20 expression thus appears to be associated with a worse outcome, which reinforces the interest of evaluating rituximab combined to chemotherapy in CD20-positive adult BCP-ALL. ClinicalTrials.gov ID, NCT00222027.

Background Rapamycin, an inhibitor of mammalian target of rapamycin kinase, is a potent immunosuppressive drug that also displays antineoplastic properties and expands regulatory T cells. Steroid-refractory acute graft-versus-host disease (GVHD) remains a significant cause of mortality after allogeneic stem-cell transplantation and therapeutic options are not codified. We retrospectively evaluated the role of rapamycin in this setting. Methods In this retrospective single-center study, 22 patients were identified, from October 2004 to February 2008, as having received rapamycin for acute GVHD refractory to one or more lines of treatment. We analyzed the efficacy and tolerance of rapamycin and the outcome of these 22 patients in this setting. Results Rapamycin resulted in a rapid and sustained complete remission of GVHD in 72% of heavily pretreated patients. Cytopenias were frequent but did not require treatment interruption. Thrombotic microangiopathy developed in 36% of patients when rapamycin was associated with calcineurin inhibitors and frequently resolved after interruption of one or both drugs. At a median follow-up of 13 months, overall survival was 41%. Previous treatment with high-dose steroid pulses was associated with a worse outcome (survival 12% vs. 69%). The major cause of death was infectious complications (77%). Conclusion Despite a small and heterogeneous population of patients, these results are encouraging and provide a rationale for prospective studies that use rapamycin in steroid-refractory acute GVHD as a second- or third-line agent.