IntroductionCNS dissemination in patients with aggressive non-Hodgkin lymphoma (NHL) is a relatively rare but often fatal complication that occurs in the different subtypes of NHL with a frequency of 5% (ie, diffuse large B-cell lymphoma [DLBCL]) to 30% 1 (ie, Burkitt lymphoma [BL] and B-cell lymphoblastic lymphoma [B-LL]). Many CNS events occur early after diagnosis (4.7-9 months), during therapy, or shortly after completion of treatment, suggesting that initial CNS involvement could have been undetected in most cases. Prophylactic treatment likely reduces the incidence of CNS relapse, but may increase the toxicity of systemic chemotherapy; furthermore, the incidence of CNS dissemination is not high enough to suggest the use of prophylaxis treatment in all patients affected by aggressive NHL. Therefore, CNS prophylaxis is usually incorporated into protocols for the treatment of B-LL and BL, but it is not systematically warranted in patients with DLBCL. Therefore, the identification of patient subgroups for which CNS prophylaxis may be useful is important, especially for DLBCL patients who have no well-defined risk factors for CNS relapse. Risk models for DLBCL have been developed, but are mainly derived from analyses of retrospective studies. [2][3][4][5] An increased risk of CNS dissemination is associated with involvement of the BM and certain extranodal sites such as testis, paranasal sinuses, orbits, and paravertebral masses. Moreover, patients with a high to intermediate or high risk according to the International Prognostic Index (IPI), particularly those with high serum levels of lactate dehydrogenase (LDH) and involvement of more than 1 extranodal organ, are much more prone to develop CNS involvement than others and should receive CNS prophylaxis. 6 Nevertheless, CNS risk predictors and related prognostic scores have been identified in retrospective and heterogeneous series, including different lymphoma categories; however, resulting scores show a low sensitivity in predicting CNS involvement.The diagnosis of CNS dissemination is frequently suspected by the presence of related signs or symptoms and confirmed by examination of cerebrospinal fluid (CSF) and neuroimaging techniques. The diagnostic standard conventional cytology (CC) examination of CSF is considered as having low sensitivity and low specificity, with reported falsenegative rates of 20%-60%. 7 This has been ascribed to the paucity of neoplastic cells in the CSF of patients with minimal disease and to the presence of confounding reactive lymphocytes. Therefore, patients with low tumor burden in the CSF, who are more likely to benefit from CNS treatment, are actually more commonly exposed to false-negative [8][9][10][11][12][13][14] However, it is still unknown whether detecting occult leptomeningeal involvement and consequently changing treatment may improve outcome in these patients.In the present study, we compared prospectively FCM analysis versus CC examination of baseline samples of CSF to detect occult leptomeningeal disease in patie...

An updated strategy combining pediatric-based chemotherapy with risk-oriented allogeneic hematopoietic cell transplantation (HCT) was evaluated in Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph− ALL) and compared with a published control series. Following induction–consolidation chemotherapy, responsive patients were assigned to receive maintenance chemotherapy or undergo early HCT according to the risk stratification criteria and minimal residual disease (MRD) status. Of the 203 study patients (median age 41 years, range 17–67), 140/161 with Ph− ALL achieved complete remission (86.9%; 91.6% ≤55 years, P = 0.0002), with complete MRD clearing in 68/109; 55 patients were assigned to maintenance chemotherapy, and 85 to HCT due to very high-risk characteristics (hyperleukocytosis, adverse genetics, early/mature T-precursor ALL, and MRD persistence). The 5-year relapse incidence was 36%, and the treatment-related mortality rate was 18%. Median overall and relapse-free survival were 7.4 and 6.2 years, with rates of 54 and 53% at 5 years, respectively, which were significantly better than those obtained with the historical protocol (P = 0.001 and P = 0.005, respectively), without significant differences between maintenance and HCT cohorts. In prognostic analysis, MRD negativity and age ≤55 years were the most favorable independent prognostic factors. A reduction in treatment toxicity and further improvements in the risk definitions and risk-oriented design are the focuses of this ongoing research.

Introduction. The application of Pediatric-Type Therapy (PTT) programs to adults with ALL can improve outcome significantly despite higher age-related toxicity. Recent series reported survival rates ≥ 50%, but only few combined PTT with Minimal Residual Disease (MRD) study for risk-oriented Hematopoietic Cell Transplantation (HCT) and/or explored the value of specific PTT element such as higher dose, lineage-targeted MTX up to 5 g/m2. Methods. To improve over prior data, NILG protocol 10/07 (Clinical.Trials.gov NCT-00795756) for unselected adult patients aged 18-65 years combined PTT together with MRD study for risk/MRD-based HCT. The 8-course program consisted of a 5-drug complete remission (CR) induction (cycle no. 1; imatinib added if Ph+) followed by 3 modified BFM blocks (no. 2, 4 and 6), 3 lineage-targeted MTX blocks (no. 3, 5 and 7; MTX 5 g/m2 for T-ALL and 2.5 g/m2 for B-ALL [1.5 g/m2 if age > 55 years or Ph+]; no. 3 and 7 with high-dose Ara-C 2 g/m2 x4, no. 5 with L-Asp 10,000 IU/m2 x2) and reinduction (no. 8). CNS prophylaxis was with triple intrathecals or liposomal cytarabine (Haematologica 2015;100:786). MRD was studied molecularly with sensitive probe(s) (sensitivity 10-4 or greater) on marrow samples obtained at end of induction (week 4, w4) and after cycles 3 (w10), 5 (w16), 7 (w22) i.e. after 1st, 2nd and 3rd lineage-targeted MTX block. Patients were risk-stratified at diagnosis and after MRD analysis for the purpose of allocation to HCT or conventional maintenance. The HCT allocation cohort consisted of predefined very high-risk patients (vHR: WBC >100, highly adverse cytogenetics, pre-T/mature T-ALL) regardless of MRD, of HR patients without MRD study (HR: late CR; B-ALL with WBC >30 or pro-B phenotype), and of HR or standard-risk (SR) patients with MRD ≥ 10-4 at w10/16 or positive at w22. Conversely, the maintenance allocation cohort consisted of SR and HR patients with MRD < 10-4 at w10/16 and negative at w22 and of SR patients without MRD study. A family related/unrelated donor search was activated at diagnosis in order to proceed to HCT soon after cycle no. 3 when needed. Results. 205 patients were enrolled, with a median age of 41 years (range 17-67 years, 11% > 60 years). 55% were male, 42 had Ph+ ALL, 119 Ph- B-ALL and 44 T-ALL. Of 163 patients with Ph- ALL, 45% were SR, 13% HR and 42% vHR. CR rate was 98% in Ph+ ALL and T-ALL, and 83% in Ph- B-ALL (88% vs 58% in patients ≤ vs > 60 years, P .0013). The MRD study was successful in 109/142 CR patients with Ph- ALL (77%), contributing to the final risk classification in 63 patients, of whom 41 were MRD responsive (65%) and 22 MRD resistant (35%). Altogether, 55 CR patients constituted the maintenance allocation group (39%) and 87 the HCT allocation group (61%), which included mainly vHR patients (n=61, 43%) selected for HCT independently of MRD study results. According to intention-to-treat, median OS is not reached (53% at 5 years, figure) and median DFS is 4.8 years (48% at 5 years). In Ph- ALL, 5-year OS/DFS are 74%/61% in T-ALL (medians not reached) and 48% each in B-ALL (medians 3.9 and 4.7 years). Median OS is not reached in both HCT and maintenance allocation groups (58% and 73% at 5 years, respectively, P .078), with a median DFS of 4.7 years (48% at 5 years) versus not reached (59% at 5 years) (P .19). Treatment adherence was good with some exceptions in maintenance allocation group (6 HCT, 11%) and a transplant realization of 68% (53 allogeneic; 6 autologous) in HCT allocation group. With HCT, 5-year incidence of nonrelapse mortality was 17%. The MRD analysis proved that DFS of patients achieving an MRD response <10-4 at w4 (n=46/90, 51%) or w10 (n=76/107, 71%) was significantly improved compared to those with MRD ≥ 10-4, with median not reached and 5-year rate 67% versus 4.5 years and 41% (w4 MRD; P .041), and 7.2 years and 64% versus 1 year and 23% (w10 MRD; P .0001). Conclusion. The current PTT and MRD-based risk-oriented strategy was applicable to adults with ALL in a wide age range, with some limitations in patients > 60 years. 5-year OS and DFS of 55% and 52% respectively in Ph- patients aged up to 65 years represent an improvement over prior NILG study (5-year OS and DFS of 36% and 35% respectively). MRD was essential in orientating the HCT choice in SR and HR patients and retained a major prognostic role in all patients. Optimizing the early MRD response with new immunotherapeutics and clarifying the role of HCT in MRD responsive vHR patients are some relevant topics of future research. Figure Figure. Disclosures Ciceri: MolMed SpA: Consultancy. Vitolo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gallamini:Millenium Takeda: Membership on an entity's Board of Directors or advisory committees.

Febrile neutropenia (FN) represents a life-threatening complication in hematological malignancies. Its etiology is most often due to infections even though FN of other origins, such as tumor-related fever and non-infectious inflammation, should rapidly be ruled out. Initially, C-reactive protein and, more recently, procalcitonin (PCT) have been proposed as useful biomarkers for differential diagnosis. PCT was shown to be a good biomarker of bacterial infections and their clinical outcomes. Definition of standard cut-offs and design of PCT-guided treatment protocols remain however to be defined. Areas covered: In this review, highlights on the current clinical use of PCT and its potential role as a diagnostic tool have been discussed by a panel of physicians from different areas of expertise. We provide current clinical evidence that PCT has been shown to be a reliable biomarker to differentiate fever of bacterial origin from other causes. Moreover, the Authors convened to a round-table to discuss their 'real-life experience' and offer their recommendations by a Delphi survey. Expert commentary: PCT has an important clinical role in FN. Issues such as the validation of a specific decision algorithm that includes PCT to monitor antibiotic choice and treatment duration will be addressed in prospective studies.

Background: Expression of p190 BCR-ABL mRNA is generally considered to be confined to patients with acute lymphoid or more rarely myeloid leukemias, whereas p210 BCR-ABL mRNA is the hallmark of CML. In reality it is not uncommon the presence of p190 m-RNA in p210 CML in chronic phase, due to alternative or missplicing1. Its presence seems to have no impact on prognosis in the pre-TKI era, although it may be expression of genomic instability. Aim: Primary object of this study was to investigate if the co-expression might influence the rate of early outcome surrogate endpoints such as such as early complete cytogenetic response in patients treated with imatinib. The secondary endpoint was the evaluation of failure free survival (FFS) measured from the start of imatinib to the date of any of the following events: progression to accelerated or blastic phase, death for any cause and switch to nilotinib/dasatinib for resistance or intolerance. Methods: Were evaluated patients with CML in chronic phase treated with imatinib at our institution. We excluded cases with less than one year of treatment and/or treated with other TKIs or conventional chemotherapy.The fusion transcripts BCR-ABL were evaluated at diagnosis in peripheral blood by NESTED-PCR2 and the cytogenetic response were evaluated in bone marrow cells with G-banding technique and fluorescent in situ hybridization (FISH)3. The patients were divided into two groups, "double transcripts" (DT) and "single transcript" (ST). All patients received imatinib 400 mg/die. Results: A total of 56 patients were analyzed. The median age of patients was 58 years (range 28-80 years) and 35 (62%) were male. Twenty patients (36%) were DT and thirty-six (64 %) ST. The distribution according to Sokal score was: 7 (35%), 8 (40%) and 5 (25%) patients for low, intermediate and high risk in the DT, whereas 18 (50%), 15 (42%) and 3 (8%) low, intermediate and high risk in ST, respectively. The complete cytogenetic response at 3 months was achieved in 2 patients with DT and 7 patients with ST (10% vs 19% p 0.35), at 6-month complete cytogenetic response was achieved in 8 patients with DT and 27 patients with ST (40% vs 75% p 0.01) (Table 1). After median follow-up of 1966 days, the FFS was significantly different between the DT and ST (55% vs 5 % p< 0.001) (figure 1), 11 patients in the DT group and 5 patients in ST group had shift to TKI 2¡ generation (55% vs 14% p 0.001) and 4 patients in DT group not achieved complete cytogenetic response. Summary/Conclusion: In our study the co-expression of p190 and p210 BCR-ABL transcripts influences the early cytogenetic response to imatinib and suggesting the need for a larger validation study Reference 1). van Rhee F, Hochhaus A, Lin F, Melo JV, Goldman JM, Cross NC. : "p190 BCR-ABL mRNA is expressed at low levels in p210-positive chronic myeloid and acute lymphoblastic leukemias."Blood. 1996 15;87:5213-7. 2). Hermans A, Selleri L, Gow J, Wiedemann L, Grosveld G: "Molecular analysis of the Philadelphia translocation in chronic myelocytic and acute lymphocytic leukemia." Leukemia 2:628,1988. 3) Landstrom AP, Tefferi A.: "Fluorescent in situ hybridization in the diagnosis, prognosis, and treatment monitoring of chronic myeloid leukaemia".Leuk Lymphoma.2006;47:397-402. Figure 1: Failure Free Survival: Figure 1:. Failure Free Survival: Table 1 : Complete Cytogenetic response: Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.