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  • 1
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    The PROSIT Cohort of Infliximab Biosimilar in IBD: A Prolonged Follow-up on the Effectiveness and Safety Across Italy
    Oxford University Press (OUP) ; 2019
    In:  Inflammatory Bowel Diseases Vol. 25, No. 3 ( 2019-02-21), p. 568-579
    Details
    In: Inflammatory Bowel Diseases, Oxford University Press (OUP), Vol. 25, No. 3 ( 2019-02-21), p. 568-579
    Type of Medium: Online Resource
    ISSN: 1078-0998 , 1536-4844
    URL: Article
    DOI: 10.1093/ibd/izy264
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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  • 2
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    Eltrombopag for the Treatment of Thrombocytopenia of Low and Intermediate-1 IPSS Risk Myelodysplastic Syndromes: Interim Results on Efficacy, Safety and Quality of Life of an International, Multicenter Prospective, Randomized, Trial
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 91-91
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 91-91
    Abstract: Background: About 10% of low risk patients with myelodysplastic syndromes (MDS) experience severe thrombocytopenia. Bleeding and the scarce efficacy of platelet (PLT) transfusions drive research in novel treatments. Eltrombopag is an oral agonist of the thrombopoetin-receptor (TPO-R). Its potential in increasing platelet (PLT) counts in low risk MDS has not been evaluated. We present interim results on the efficacy and safety of eltrombopag in inducing PLT responses in patients with low and intermediate-1 International Prognostic Scoring System (IPSS) risk MDS with severe thrombocytopenia in a Phase II, multicentre, prospective, placebo-controlled, single-blind study (EQoL-MDS). Methods: Primary endpoints are safety and efficacy of eltrombopag. Secondary endpoints include changes in quality of life (QoL), PLT transfusion requirement, incidence and severity of bleeding, and survival. Inclusion criteria are adult age; PLT 〈 30 Gi/L; ECOG performance status 〈 4; ineligibility for, relapsed or refractory to other treatments; and naive to TPO-R agonists. Eltrombopag/placebo (2:1) is administered at a 50 mg daily starting dose with 50 mg increases every 2 weeks to maximum 300 mg to target PLT 100 Gi/L. Dose interruptions or reductions are required for PLT 〉 200 Gi/L or adverse events. Study design is shown in the figure. PLT response, assessed at each visit, is defined as Response if: 1) baseline PLT 〉 20 Gi/L: absence of bleeding and increase by at least 30 Gi/L from baseline; 2) baseline PLT 〈 20 Gi/L: PLT 〉 20 Gi/L and increase by at least 100%, not due to PLT transfusions; and Complete Response if PLT≥100 Gi/L and absence of bleeding. QoL scores are analysed by MDS-specific instrument, QOL-E v. 3. Results: Seventy patients (46 on eltrombopag - Arm A, 24 on placebo -Arm B) have been randomized at the time of this report. Mean age is 68.3 (SD 13.0) years, M/F 38/32. ECOG performance status was 0 in 47 cases, 1 in 16 cases, 2 in 7 cases. Ten patients had comorbidities. According to the WHO 2008 classification, 22 patients had refractory cytopenia with unilineage dysplasia, 9 had refractory anemia with ringed sideroblasts, 31 had refractory cytopenia with multilineage dysplasia (of which 15 with ringed sideroblasts), 6 had refractory anemia with excess blasts-1 and 2 were unclassified. IPSS score was low in 48 cases. Mean baseline platelet (PLT) count was 17.1 (SD 8.2) Gi/L, mean hemoglobin level 10.8 (SD 2.5) g/dL and mean white blood cell count was 5.0 (SD 3.8) Gi/L. Twenty-five (36%) patients were red blood cell transfusion-dependent. Thirty-three had a WHO bleeding scale of 1, 2 experienced mild blood loss, 4 a gross blood loss and 1 a debilitating blood loss. Fourteen patients in Arm A and 8 in Arm B had required PLT transfusions in the 8 weeks prior to randomization. Twenty-three cases (50%) in Arm A have responded versus 2 (8%) in Arm B (p=0.001). Thirty-three patients have completed at least 24 weeks of study. Median time to response was 14 days (IQR 7-46 days) at a median daily dose of 75 (IQR 50-162.5 mg). PLT count increased by mean 53.2 (SD 68.1) Gi/L (p=0.001) in Arm A versus no significant changes in Arm B by week 24. QOL-E scores at baseline and 12 weeks in 47 cases in both arms are shown in the table. There was an increase in treatment outcome index,mainly experienced in the first 3 weeks (p=0.034). Fatigue improved from baseline to 12 weeks associated with response (p=0.016). Related Grade III-IV adverse events (AE) occurred in 10 patients (22%) in Arm A and consisted in: nausea (4), hypertransaminasemia (3), hyperbilirubinemia (1), sepsis (1), pruritis (1), heart failure (1), asthenia (1), vomit (1), while in Arm B 1 patient (4 %) experienced grade 3 bone marrow fibrosis. MDS disease progression occurred in 5 (11%) in Arm A versus 2 (8%) in Arm B, p=ns. Conclusions: Preliminary data indicate that lower risk MDS patients with severe thrombocytopenia undergoing treatment with eltrombopag experience significant improvements in PLT counts accompanied by improvements in fatigue. The drug appears to be well-tolerated and not associated with MDS progression. Further follow-up is required to evaluate the impact on survival. Figure 1. Study design Figure 1. Study design Figure 2. QOL-E domains at baseline and 12 weeks between Arm A (eltrombopag) and Arm B (placebo) Figure 2. QOL-E domains at baseline and 12 weeks between Arm A (eltrombopag) and Arm B (placebo) Disclosures Oliva: Novartis: Speakers Bureau; Celgene: Other: Advisory Board, Speakers Bureau; Amgen: Consultancy. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Palumbo:Novartis: Honoraria, Other: Advisory Board. Fenaux:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.91.91
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 3
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    High-Throughput Sequencing For The Identification Of NOTCH1 mutations In Early Stage Chronic Lymphocytic Leukemia: Biological and Clinical Implications
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 1622-1622
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1622-1622
    Abstract: NOTCH1 mutations have recently emerged as new genetic lesions significantly correlated with survival in chronic lymphocytic leukemia (CLL). NOTCH1 c.7541_7542delCT is by far the most frequently observed NOTCH1 mutation in the disease. To estimate the prevalence and clonal evolution of NOTCH1 c.7541_7542delCT mutation, and prospectively investigate its clinical significance in early stage CLL and clinical monoclonal B cell lymphocytosis (cMBL), we analyzed by next generation sequencing (NGS) 384 cases at diagnosis enrolled in the GISL O-CLL1 multicenter trial. The patient cohort included 100 cMBL and 284 Binet stage A CLL cases, 48 of whom were also longitudinally investigated at progression or during follow-up (32 and 16, respectively) in absence of treatment. Deep sequencing of the NOTCH1 mutation hotspot was performed by Roche 454 pyrosequencing on the Genome Sequencer Junior instrument. NOTCH1 mutation was validated by an extremely sensitive PCR-based approach and Sanger sequencing. The association between NOTCH1c.7541_7542delCT and clinical, molecular and biological variables, as well as its impact on progression free survival (PFS), were tested. Deep sequencing analysis of NOTCH1 mutation hotspot in our cohort (median depth of coverage 1510x, ranging from 605 to 2842) revealed a mutant allele frequency ranging from 0.02% to 75% of total reads in 145 cases. The occurrence of the mutation was subsequently assessed by an extremely sensitive ARMS (amplification refractory mutation system)-PCR, which allowed to confirm the presence of delCT in the 49 cases with frequency of mutated sequencing reads greater than 0.7%, specifically in 11% of cMBL (11/100) and 13.4% of CLL patients (38/284). Furthermore, mutated samples were subjected to DNA Sanger sequencing: in line with the expected sensitivity of the method, the mutation was identified only in samples with higher mutation loads according to NGS (mutant allele frequency ≥ 7%, n=25). Our data revealed that often NOTCH1 mutational activation affected a neoplastic sub-clone, especially in cMBL patients. NOTCH1 mutated patients utilized unmutated IGHV genes more frequently, and had higher expression of CD38 and ZAP-70 (P=3.2e-11, P=2.6e-08, P=3.4e-05, respectively). Trisomy 12 was more frequent in this patient group (P=5.4e-04), whereas 13q14 deletion was less represented than in the NOTCH1 wild-type patients (P=2.8e-03). NOTCH1 mutation was associated with the occurrence of stereotyped HCDR3 (P=5.6e-03); in addition, compared with other major BCR subsets, CLL subset #10 was significantly enriched in NOTCH1 mutations (P=0.032). The prevalence of the analyzed dinucleotide deletion was not significantly different between cMBL and CLL patients, even if only Rai 0 cases (28/197 cases, 14.2% mutation frequency) were considered. The percentages of variant sequencing reads in NOTCH1-mutated cases were slightly higher in CLL (median 19.6%) than in cMBL (median 4.2%), a finding confirmed by a regression analysis that highlighted the association of the CLL presentation with higher percentages of NOTCH1 delCT reads (P=0.033). NOTCH1-mutated cases, both at sub-clonal and clonal levels, displayed a significant reduction in median PFS (P=0.0018), although NOTCH1 mutation prognostic value, in multivariate analysis, was not independent if 11q and/or 17p deletion, IGHV mutational status, and cMBL or CLL status were considered. Finally, sequential analyses in a representative fraction of cases of our dataset indicated that (i) NOTCH1 mutation did not occur during the course of the disease and that (ii) the mutational load in positive cases was stable over time. These findings highlight the importance of using high sensitive methods for an accurate detection of NOTCH1 mutation in cMBL/early stage CLL. This is required for a better prognostic stratification and also to obtain useful information for potential therapeutic approaches, since sub-clonal mutations in untreated CLL can possibly anticipate the dominant genetic composition of the relapsing tumor. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.1622.1622
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 4
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    Allogeneic Hematopoietic Cell Transplantation For Patients With Mycosis Fungoides and Sezary Syndrome: The Experience Of The EBMT Lymphoma Working Party With An Extended Five-Year Follow Up
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 2094-2094
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2094-2094
    Abstract: In 2010 the EBMT Lymphoma Working Party reported our experience on allogeneic HCT in patients with mycosis fungoides and SŽzary syndrome (MF/SS) in what remains the largest series on this topic published to date [JCO 2010; 28: 4492-4499]. Despite the encouraging results, the main shortcoming of our initial report was a limited follow up of 36 months; in particular, for a series in which 73% of the cases received a reduced-intensity conditioning prior to HCT. The purpose of this study is to analyze our experience in this setting with an extended follow up, including standard outcomes of non-relapse mortality (NRM), incidence of relapse/progression (R/P), progression-free survival (PFS) and overall survival (OS), as well as to identify factors associated with patient outcome 5 years after allogeneic HCT. Patients and Methods Sixty patients with MF (n=36) and SS (n=24) who received a first allogeneic HCT from matched related (mRD, n=45) or unrelated (mUD, n=15) donors between 1997 and 2007, included in our original series were analyzed: 37 men and 23 women, median age 46.5 years (22-66). Forty-four patients (73%) had TNM stage IV, and 40 (67%) were at advanced disease phase at transplantation, defined as either those on third or later complete response (CR), partial response (PR) or relapse/progression, or those primary refractory to systemic therapy. Forty-four patients (73%) received reduced-intensity (RIC) and only 16 (27%) myeloablative (MAC) conditioning regimens, with 25 (42%) undergoing T-cell depletion (TCD). Extended follow up data was collected from the EBMT Registry and closed in July 2013. Results With an extended median follow up in survivors of 60 months (4–117), allogeneic HCT continues to offer patients with MF/SS an advantageous estimated OS of 66% at 1 year, 54% at 3 years and 48% at 5 years (95% CI: 36% - 64%), and a first PFS of 41% at 1 year, 35% at 3 years and 33% at 5 years (95% CI: 23% - 48%). Disease R/P remains the main complication, with a total of 26 cases (43%) at a median of 3.8 months (1-37) after HCT. While 16 of them died from disease R/P, it is worth noting that at present 10 of these patients (38%) remain alive at last follow up, suggesting that after R/P, patients can be successfully rescued with donor lymphocyte infusions and other lines of therapy. Indeed, at last follow up, a total of 31 patients remain alive, and of these only 2 have active disease, while 29 of them are also in sustained or re-attained CR from their MF/SS. NRM has remained stable at 22% (13 cases; median 52 days from HCT, 8-403) in this analysis. As described in Table 1, the outcome of MF/SS patients 5 years after allogeneic HCT is primarily driven by the type of donor, the intensity of conditioning, and the status of the disease at the time of transplant. In addition, patients with a poor performance status (Karnofsky 〈 70) have a higher risk of NRM, and patients receiving TCD, a higher incidence of disease R/P, none of which translate into a significant impact on OS. Conclusions Our data with a prolonged patient follow up provides a clearer picture of the value of allogeneic HCT as a therapeutic strategy for high-risk patients with advanced-stage MF/SS. They further suggest the existence of a clinically relevant graft-versus-MF/SS effect that provides prolonged survival with no evidence of disease to patients with advance phase at the time of transplant and even to many of those who relapse/progress after allogeneic HCT. This study identifies as well factors that may influence the overall outcome of these patients at a longer 5-year term after transplant. Disclosures: Dreger: Riemser Pharma : Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.2094.2094
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 5
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    Peripherally Inserted Central Catheters (PICCs) Implantation in the Clinical Management of Oncohematologic Patients: Results of a Large Multicenter, Retrospective Study of the REL Group (Rete Ematologica Lombarda - Lombardy Hematologic Network, Italy)
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 5611-5611
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    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 5611-5611
    Abstract: Background: PICCs are vascular devices inserted from a peripheral vein of the upper third of the arm under ultrasound guide, and provide a central venous access (CVA) with an intermediate duration between short term central venous catheters (CVCs), such as jugular or subclavian CVCs, and long term ones (port-a-caths). PICC insertion is ease and safe with no pneumothorax or hemothorax risk. Their extremity reaches a central vein, and can be used for cytostatic drugs, hyperosmolar solutions, and antibiotics infusion. Furthermore, patients (pts) at high risk of hemorrhage for thrombocytopenia or coagulopathy are eligible for PICC insertion. Nevertheless, some concern exists about the risk of infectious and thrombotic complications associated with PICC use in immunocompromised cancer pts characterized by a prothrombotic state. In particular, few clinical data from large oncohematologic pts series are available on PICCs' implants and their complications. Aims: To analyze the results of a large multicenter, retrospective study of the REL group (Rete Ematologica Lombarda-Lombardy Hematologic Network, Italy) aimed at clinically characterizing PICC use in oncohematologic patients management. Methods: Four REL Hematology Centers participate to the study. The clinical data of 453 implanted PICCs from January 2010 to June 2015, were retrospectively collected, for a total of 44,577 catheter days. Pts median age was 61 yrs (range 10-88). Patients' diagnoses were 197 non-Hodgkin's lymphoma, 10 chronic lymphocytic leukemia, 105 acute myeloid leukemia, 45 acute lymphoblastic leukemia, 33 Hodgkin's lymphoma, 39 multiple myeloma, 12 myelodysplastic/myeloproliferative syndrome, 6 miscellaneous. All pts received intravenous chemotherapy, long term anti infectious drugs (antibiotics and antifungals), and hypertonic solutions. PICCs were inserted by ultrasound-guided puncture of a peripheral vein of the arm, by microintroducer technique, under strict asepsis. Chest X-ray was performed to verify correct tip location (ideally in the proximity of cavo-atrial junction). Data on PICCs' lumen number are available in 423 cases: 292 (69%) were single-lumen and 131 were double-lumen (31%). Results: Median PICC life-span was 90 days (range 1-760, Kaplan-Meier method). No major insertion-related complications were observed. Late complications occurred in 172/453 PICCs (38%, 3.8/1000 catheter days): 93 infectious (20%, 2/1000 catheter days), 38 thrombotic (8%, 0.8/1000 catheter days), 37 mechanical (8%, 0.8/1000 catheter days), 5 (1%, 0.1/1000 catheter days) miscellaneous complications (patient intolerance, local pain and hematoma). Among infectious complications, we reported 24 cases (5%, 0.5/1000 catheter days) of fever of unknown origin (FUO) and 69 (15%, 1.5/1000 catheter days) catheter-related bloodstream infections. Mechanical complications consisted of 3 (1%) catheter dislocations, 19 accidental removals (4%), 16 (3%) lumen occlusions and 3 (1%) breakages of the external section of PICC. In 376/453 (83%) cases PICC was removed due to end of intravenous therapy in 160 patients (35%), death in 98 (22%) and to various complications in 118 (26%) cases. Specifically, FUO lead to PICC removal in 10 (2%), infection in 40 (9%), venous thrombosis in 25 (5%) cases, catheter dislocation or accidental removal in 22 (5%), lumen occlusion in 13 (3%), breakage of the external section of PICC in 2 (0,5%), other mechanical complication in 4 (1%), local pain and miscellaneous 2 (0,5%) each. In the case of a complication occured, the incidence of PICC removal was 68% (118/172): FUO/infections represented the removal cause in 50/172 (29%), mechanical complications in 40/172 (23%), thrombosis in 25/172 (14%) cases. Conclusions: Traditional CVCs are associated with significant complications, reported at varying frequencies in highly heterogeneous oncohematologic pts series: infections are reported from 4.6 to 23% and thromboses from 1.2 to 30.2% of the cases. We have clinically characterized a large series of PICCs in oncohematologic patients. Our data suggest that their implant, as an alternative to traditional CVCs, is a safe and effective way to provide oncohematologic patients at high risk of hemorrhagic and infective complications with a CVA. PICCs compare favorably with traditional CVCs reported complications, and facilitate the proper management of complex and prolonged therapeutic programs. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.5611.5611
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 6
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    Fludarabine, Cyclophosphamide, Ofatumumab (FC-O2) As Front-Line Treatment for Young and Fit Patients with Chronic Lymphocytic Leukemia (CLL): Preliminary Results of the Prospective Phase 2 LLC0911 Gimema Study
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 2946-2946
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2946-2946
    Abstract: Introduction. The fludarabine, cyclophosphamide, rituximab (FCR) regimen is associated with high complete response (CR) rates and a negative residual disease status in a significant proportion of cases and is considered the optimal front-line treatment for fit patients with chronic lymphocytic leukemia (CLL). In addition, long-term follow-up of patients treated with FCR at the MD Anderson Cancer Center, in the multicenter German CLL8 study and at Italian institutions indicate that a sizable fraction of patients characterized by a favorable biologic profile remains free from progression in excess of 10 years. FC combined with ofatumumab (FC-O), a human monoclonal antibody which targets an epitope of the CD20 molecule, has also been associated with a high CR rate. The aim of this study was to evaluate whether a double dose of ofatumumab (O2) combined with FC could improve the CR rate in young (≤65 yrs) and fit patients with CLL. Methods. Sixty-one fit CLL patients from 15 Italian institutions were enrolled in this front-line study and treated with the FC-O2 regimen based on the FC schedule (F 25 mg/sqm i.v. d1-3, C 250 mg/sqm i.v. d1-3) combined with 13 doses of O (300 mg i.v. d14; 1000 mg d21 at the first cycle; 1000 mg d1 and d15 at cycles 2-6 and d28 at cycle 6). As infection prophylaxis, patients received bactrim and peg-filgrastim in order to prevent granulocytopenia. CLL diagnosis, treatment requirement and response were assessed according to the 2008 iwCLL guidelines. Minimal residual disease (MRD) was evaluated by flow cytometry in the peripheral blood (PB) and bone marrow (BM), and also by RQ-PCR in flow negative cases. CT scan evaluation was included in the response assessment. Adverse events (AEs) were graded according to the NCI-CTCAE. Results. The median age of patients was 60 years (range 36-65), Binet stages B and C were recorded in 86% of cases, B-symptoms in 21%, increased β2M values in 74% and bulky nodes (≥5 cm) in 10%. An IGVH unmutated status was recorded in 60% of cases, deletion 13q in 37%, no aberrations in 33%, deletion 11q in 14%, trisomy 12 in 12%, 17p deletion and/or TP53 mutation were found in 10% of cases. At present, the median follow-up of patients is 7 months (range 1-20). Response to treatment has been assessed in 29 patients after a median number of 6 courses of treatment (range 2-6). The overall response rate is 90%, with a CR rate of 69% (20 patients). No evidence of MRD was observed by flow cytometry in both PB and BM in 15/20 CR patients (75%). To date, 11 patients with cytometric MRD negative CR have been evaluated by RQ-PCR and no residual disease was detected in 3. Grade 3-4 granulocytopenia was recorded in 4 patients (7%), a severe infection in 4 (7%) and 5 patients (8%) experienced a severe infusion-related reaction during ofatumumab administration. Treatment was discontinued in 8 patients as a result of toxicity (infection, 2 cases; FUO, 1; infusion-related toxicity, 1; autoimmune hemolytic anemia, 1; recurrent granulocytopenia, 1; tachyarrhythmia, 1; non-specified toxicity,1). A non-treatment-related death (traumatic aortic transaction due to a dislocated aortic endoprostheses) has been recorded in a patient after 2 months from treatment discontinuation and 1 showed a disease progression after 4 courses of FC-O2. Conclusions. Taken together, the first analysis of this ongoing front-line study suggests that the combination of FC with an increased dose of ofatumumab is well tolerated with acceptable and no unexpected toxicity. Our preliminary results show that the FC-O2 treatment is associated with a high rate of cytometric MRD-negative CR in young and fit patients with previously untreated CLL. Disclosures Carella: Seattle Genetics Inc.: Research Funding. Foà:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.2946.2946
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 7
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    What Numbers Don't Say: Immunogenetic Evidence Shows That High-Count MBL Resembles Rai 0 CLL While Low-Count MBL Does Not.
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 2883-2883
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2883-2883
    Abstract: Abstract 2883 CLL-like monoclonal B-cell lymphocytosis (MBL) shares common immunophenotypic features and cytogenetic abnormalities with CLL and is generally perceived as its premalignant state. The World Health Organization has set a consensus cut-off of 5×109/L circulating B cells to discriminate between what constitutes ‘disease’ and what not. However, the clonal size within MBL is extremely variable. High-count (HC), clinical MBL is associated with absolute lymphocytosis and progresses to CLL requiring treatment at a rate of 1–2% per year, whereas low-count (LC) MBL is found in the general population through high-sensitivity techniques and carries a risk of progression that is limited if any. Given the high frequency of CLL-like MBL in the general population, it is important to understand the underlying mechanisms and also identify biological markers endowing malignant potential that may distinguish between the different forms. To this end, we performed a detailed immunogenetic profiling of 334 CLL-like MBL cases (78 LC and 256 HC) for a total of 355 productive VDJ rearrangements (including double rearrangements), 91 from LC MBL and 264 from HC MBL. We also compared the immunoglobulin (IG) gene repertoires of MBL to 544 CLL Rai Stage 0 (CLL-0) that were part of an IG sequence dataset of 7424 CLL cases previously analyzed by our group. LC and HC MBL had distinct IG gene repertoires, with over-representation of the IGHV1–69 and IGHV4–34 genes in HC and the IGHV4–59/61 genes in LC MBL, respectively (p 〈 0.001). The HC MBL repertoire exhibited clear similarities to CLL-0 in terms of IGHV gene usage (similar frequencies of IGHV1–69 and IGHV4–34). Regarding somatic hypermutation, no differences were identified between LC MBL versus HC MBL versus CLL-0, in that the frequency of mutated rearrangements ( 〈 98% identity to the germline) was overall similar (LC MBL: 72.5%, HC MBL: 76.1%, CLL-0: 75%). In this respect, all the aforementioned subgroups differed significantly (p 〈 0.001) from the frequency previously reported by us in CLL where only 55% of rearrangements carried mutated IGHV genes. We finally analyzed the expression of stereotyped B cell receptor (BcR) IGs, identified through a cluster analysis of the MBL sequences together with all CLL sequences from our cohort and 5494 non-CLL IG sequences retrieved from public databases. Overall, only 6/91 (5.5%) LC MBL rearrangements could be clustered with other sequences in subsets with stereotyped BcRs. Two of these six LC MBL cases were clustered together with IG sequences from various entities, including CLL, other lymphomas and autoimmune diseases; thus, they were considered to carry ‘public’ BcR stereotypes. In contrast, HC MBL showed a significantly (p=0.0002) higher frequency of ‘CLL-specific’ BcR stereotypes versus LC MBL, with 60/264 (22.7%) HC MBL cases carrying stereotyped VH CDR3s. This frequency was comparable to the one observed in CLL-0 (20.2%). Notably, a gradation was observed in the frequency of BcR IG stereotypy depending on the absolute count of CLL-like cells, starting with 5.5% in LC MBL, raising to 22.7–20.2% in in HC MBL/CLL-0 and, finally, peaking at 30.4% in the entire CLL cohort as previously reported. Altogether, these findings suggest that rather than a true premalignant condition, LC MBL may merely reflect immune senescence or result from persistent antigen stimulation. On the other hand, HC MBL appears to be a continuum with Rai stage 0 in the evolution to clinically overt CLL, being maybe one step behind where it requires either additional genetic hits or simply extra time to cross the numerical border that discriminates it from CLL. Hence, the identification of molecular genetic markers that may predict progression of HC MBL/CLL-0 into full-fledged CLL is strongly warranted. Disclosures: Shanafelt: Genentech: Research Funding; GlaxoSmith Klein: Research Funding; Teva/Cephalon: Research Funding; Celgene: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.2883.2883
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 8
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    Quality of Life in Elderly Patients with Acute Myeloid Leukemia Undergoing Induction Chemotherapy
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 2120-2120
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2120-2120
    Abstract: Aims: In elderly patients with acute myeloid leukemia (AML), complete remission (CR) rate following intensive chemotherapy is approximately 45%, considerably lower than in younger patients, with a shorter duration of remission and high treatment-related mortality (30-50%). Median survival is about 12 months. Intensive chemotherapy is indicated in a small proportion of "fit" elderly patients. In a phase III, prospective, randomized, open-label, multicenter trial designed to assess the efficacy of post-remission treatment with 5-Azacitidine versus best supportive care (BSC) in patients 〉 60 years of age with AML in CR after conventional induction ("3+7") and consolidation chemotherapy, quality of life (QoL) was assessed from diagnosis. We present interim results of changes of QoL. Methods: Patients with newly diagnosed AML with 〉 30% myeloid marrow blasts, either "de novo" or evolving from myelodysplastic syndrome without contraindications for intensive chemotherapy and with an ECOG performance status 〈 3 are included. Induction chemotherapy consists of two courses of "3+7": Daunorubicin 40 mg/m2 daily days 1-3 and cytarabine 100 mg/m2 daily continuous IV infusion days 1-7. Patients in CR receive consolidation (cytarabine 800 mg/m2 3 hour infusion bid days 1-3) and are randomized 1:1 to receive BSC or 5-Azacitidine maintenance therapy up to 4 years and six months until AML recurrence. QoL assessment was performed using the EORTC QLQ-C30 and the QOL-E v.3 questionaires. Results: QoL results assessed at 3 time points are reported: 1) baseline; 2) at hematological recovery immediately after the first "3+7" course; and 3) after consolidation at randomization. Ninety-nine patients (male/female 50/49) of median age 70 (IQR 65-74) years have been enrolled. At diagnosis, mean hemoglobin was 9.2 (SD ± 2.4) g/dL, leukocytes were 7.9 (2.3-29.6)/µL, platelet count was 54 (IQR 29-85) Gi/L and bone marrow blasts were 70 (IQR 50-85)%. Seventy-five patients had "de novo" AML. Twenty-three patients had comorbidities. Forty-three patients had an ECOG PS 1 and 28 had ECOG PS 2. Baseline median QOL-E scores were poor (≤60) in all dimensions, except for fatigue (76, IQR 52-85). EORTC QLQ-C30 confirmed that fatigue was not prevalent at diagnosis (median 33, IQR 22-56). Median baseline EORTC QLQ-C30 scores were good in all domains except for global health status (GHS, median 50, IQR 33-67). Gender, comorbidities, bone marrow blasts and secondary AML were not related to QoL. Baseline Hb levels correlated with QOL-E functional (r=0.0216, p=0.14), fatigue (r=0.256, p=0.002) and disease-specific (r=0.247, p=0.010) scores and with EORTC QLQ-C30 GHS (r=0.270, p=0.001), physical (r=0.304, p 〈 0.0001), role (r=0.281, p=0.001), cognitive (r=0.262, p=0.003), social (r=0.229, p=0.010) functions and fatigue (r=-0.280, p=0.001), dyspnea (r=-0.287, p=0.001) and appetite loss (r=0.244, p=0.007). Age correlated with QOL-E disease specific scores (r=0.242, p=0.012). There were no changes in QOL-E scores following 1st "3+7". However, the EORTC QLQ-C30 detected deterioration in physical function from median 80, IQR 60-93, to 67, IQR 52-87 (p=0.008), in role function from median 83, IQR 67-100, to 67, IQR 33-83 (p=0.023) and in GHS from median 50, IQR 33-69, to 67, IQR 50-75 (p=0.002) and improvement in dyspnea (p=0.023). Forty patients obtained a CR. Interestingly, baseline role function was better (median 83, IQR 67-100) in cases obtaining a CR than in resistant patients (median 67, IQR 33-83, p=0.007). Patients obtaining CR experienced improvements after consolidation in median QOL-E physical scores from 56, IQR 41-72 to 63, IQR 50-84 (p=0.033), disease-specific domain scores from 59, IQR 48-67 to 74, IQR 67-85 (p=0.003) and treatment-outcome index scores from 55, IQR 32-77, to 79, IQR 41-86 (p=0.026). Median EORTC QLQ-C30 emotional function improved after consolidation therapy from 83, IQR 67-92, to 92, IQR 77-100 (p=0.015) as well as GHS from median 50, IQR 33-65 to 67, IQR 58-83 (p=0.002). Dyspnea and insomnia regressed while financial problems increased. Conclusions: Elderly patients with AML at diagnosis identified as fit for chemotherapy generally do not present fatigue, though health status is poor and is mainly correlated with Hb levels. Role function may predict response to induction chemotherapy. Patients obtaining CR perceive improvements in global health, including physical and emotional QoL and symptoms. Disclosures Oliva: Celgene: Other: Advisory Board, Speakers Bureau; Amgen: Consultancy; Novartis: Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.2120.2120
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 9
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    Insulin Growth Factor 1 Receptor Expression Is Associated with NOTCH1 Mutation, Trisomy 12 and Aggressive Clinical Course in Chronic Lymphocytic Leukemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3314-3314
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    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3314-3314
    Abstract: Insulin growth factor 1 receptor (IGF1R) is emerging as an important gene in many solid and hematological cancers and its over expression has been reported to be associated with aggressive disease and pharmacologic resistance. Specifically, the IGF1R-IGF1-2 interaction was recently described to be involved in the constitutive activation of many important cell signaling such as NOTCH1 and PI3K/Akt pathways that play a key role in many solid and hematological cancers. In this study we performed a clinical and biological investigations about the role of IGF1R expression in a large and representative prospective series of chronic lymphocytic leukemia (CLL) in Binet A clinical stage enrolled in observation O-CLL1 protocol (clinicaltrial.gov identifier NCT00917540). Total RNA extraction, preparation of DNA single-stranded sense target, and hybridization to gene expression profiling arrays were carried out according to manufacturer’s protocols in 217 CLL patients enrolled in the multicentre O-CLL1 protocol. Gene expression data has been deposited in the National Centre for Biotechnology Information’s Gene Expression Omnibus database http://www.ncbi.nlm.mih.gov/geo and are accessible through series accession number GSE51529. High IGF1R expression was significantly associated with IGHV unmutated (IGHV-UM) status (p 〈 0.0001), high ZAP-70 and CD38 expression (p 〈 0.0001) and unfavorable cytogenetic deletion [i.e. del(11)(q23) and del(17)(p13)], particularly with del(11)(q23) (p=0.03). Cases with del(13)(q14) as single lesion were characterized by the lowest IGF1R gene levels. On the contrary, among the most common cytogenetic aberrations, trisomy 12 showed stronger IGF1R expression compared with the other patients (p 〈 0.0001) and this association was independent from IGHV mutational status. Patients with stereotyped HCDR3 sequences showed a greater IGF1R expression compared to not stereotyped HCDR3 (p=0.001) even if this can be related to the high frequency of IGHV-UM among stereotyped HCDR patients. Interestingly, subset #4 patients, who are known to exhibit an indolent clinical course and distinct biological profile, were also characterized by lower IGF1R expression compared to other M-IGHV and UM-IGHV patients. NOTCH1 c.7541_7542delCT mutation was investigated by next generation sequencing Roche 454 technology in 199 (92%) patients (Lionetti et al, BJH 2014). Globally, median depth of coverage was 1510x, ranging from 605 to 2842. Mutant allele frequency estimated by NGS ranged from 0.02% to 75% of total reads per sample. The presence of NOTCH1 mutation was confirmed by ASO-PCR and Sanger sequencing in all patients with allele burden higher 〉 0.7% (31; 15.5%) and 7% (19; 9.5%) respectively. We considered as mutated only the 31 patients in whom the presence of the dinucleotide deletion was confirmed by ARMS-PCR. Patients carrying NOTCH1 mutation were characterized by a greater IGF1R expression compared with wild type cases (p=0.002). In addition high IGF1R expression was not significantly different comparing patients with low and high NOTCH1 mutation burden. In order to avoid the bias represented by the strong association between NOTCH1 and trisomy 12, we compared the IGF1R expression between NOTCH1 mutated and wild type cases excluding trisomy 12, and confirmed the previous association (p=0.004). IGF1R expression represented a strong clinical prognostic factor in our CLL cohort: by Kaplan-Maier analysis we observed a significant time to first treatment stratification in all CLLs, in all IGHV-UM and in all IGHV-M patients (p 〈 0.0001). Furthermore, IGF1R retained its significance in multivariate analysis with most important clinical and molecular prognostic factors (CD38 expression, unfavorable FISH and IGHV mutational status). Overall, our study shows the importance of IGF1R expression in CLL and its strong association with specific clinical and biological features, confirming the interest for the study of this gene as a potential prognostic factor and its possible role as a therapeutic target in a specific group of CLL patients carrying trisomy 12 and NOTCH1 mutations. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3314.3314
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 10
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    Clinical-Biological Characterization of Variant B Chronic Lymphocytic Leukemia, Characterized by a Mantle Cell Lymphoma-Like Immunophenotype, t(11;14)(q13;q32) Negative.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1259-1259
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    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1259-1259
    Abstract: Abstract 1259 Poster Board I-282 We describe the clinical-biological features of 63 cases of variant B chronic lymphocytic leukemia (v-B-CLL), characterized by a mantle cell lymphoma-like immunophenotype, atypical cytomorphology in absence of t(11;14)(q13;q32) in FISH analysis. A historical series of 130 B-CLL was used as comparison. The v-B-CLL were significantly different from the B-CLL in terms of the following clinico-hematological variables: age 〈 70 yrs (p 〈 .001), lymphocytosis 〈 20 × 109/ (p 〈 .001), lymphocyte doubling time 〈 12 months (p = .02), high serum β2-microglobulin levels (p 〈 .001), and splenomegaly (p = .002). Considering immunophenotipic features, CD38 and CD49d expression were significantly more expressed in v-B-CLL than B-CLL (p 〈 .001); whereas, no statistical difference was observed for ZAP-70 reactivity. Considering the IgVH mutation status, there were more patients mutated in the v-B-CLL group than in the B-CLL group (p = .001). Other significant differences were found about the frequency of the recurrent chromosome alterations, evaluated by means of FISH analysis: trisomy 12 was more frequent in v-B-CLL ( p 〈 .001), while del13q14, considered as a single alteration, was more frequent in B-CLL (p=.008). Gene expression profiling of a panel of 9 v-B-CLL compared with 60 B-CLL samples indicated that the variant group is characterized by a specific molecular pattern of gene expression. In particular we observed the upregulation of tumor protein D52 (TPD52), and that of 6 genes (AFF1, GMPS, PICALM, JUN, REL, RAC2) known to be protooncogenes. Furthermore, we found that upregulated genes with apoptosis related functions (IL-7, HSP90B1, NOTCH2, BECN1, ANXA4, MCL1) are all negative regulators of apoptosis. Microarray analysis revealed that various genes (TRIM38, EEF1D, CASP1, MALT1, RHOH0) involved in the I-kB kinase/NF-kB cascade of the canonical NF-kB signaling pathway, are furtherly upregulated in v-B-CLL. Furthermore, among the genes found differentially expressed in SAM analysis, we observed also the upregulation of CD1c (according to the surface expression of this antigen), OSBPL3 and ITGA4. After a median follow-up of 55 months (range 4-196) and 60 months (range 6-180), 25/42 (59%) v-CLL and 55/93 (59 %) CLL pts were treated. TTT was significant different between 2 groups when the IgVH mutational status was considered (p= .006). Median OS of v-CLL subset was 112 months vs 171 months of CLL subset. When the IgVH mutational status was considered, mutated cases showed a worse OS even if a statistical difference was not observed (p= 0.062). In conclusion, our study identifies, on the basis of a defined CFM-FISH diagnostic approach, a variant form of B-CLL that shows peculiar biological and clinical features that should be considered in the future clinical and prognostic studies. The inclusion of this form in B-CLL study could alter the interpretation of results, especially related to biological markers. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1259.1259
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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