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  • 1
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    Online Resource
    Updating Long-Term Outcome of Intermittent Imatinib (INTERIM) Treatment in Elderly Patients with Ph+-CML
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 1794-1794
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1794-1794
    Abstract: BACKGROUND: The INTERIM study (ClinicalTrials.gov NCT 00858806) showed that in elderly ( 〉 65 years) Ph+ CML patients selected for a stable complete cytogenetic response (CCgR) lasting 〉 2 years, the policy of intermittent imatinib treatment (one month on/one month off) may affect the markers of residual disease (CCgR and major molecular response, MMR or MR3.0), but not the clinical outcomes (overall survival and progression-free survival) (Russo D et al, Blood 2013; 121(26):5138-44). AIMS: To update the results of the INTERIM Study, with a follow up ≥ 5 years. METHODS: After 4 years of follow up, patients continouing INTERIM treatment were monitored with peripheral blood RT-Q-PCR every 3 months according to the ELN-2013 guidelines. RESULTS: At 48thmonth, out of 76 patients enrolled in the INTERIM study, 13 (17%) had lost CCgR and MMR, 14 (18%) had lost MMR only and 50 patients (75%) continued INTERIM. The patients who had lost CCgR and/or MMR resumed imatinib continuously and all of them regained the CCgR and the MMR, within 3 to 12 months. No patient progressed to accelerated or blastic phase, or developed clonal chromosomal abnormalities in Ph+ cells, or BCR-ABL mutations. No patient complained of new or more severe side effects during the months “on”. After a follow up ≥ 5 years, 45/76 (59%) enrolled patients are on INTERIM, with a probability of maintaining intermittent administration of 59% (95% CI: 46-69). No patient lost the CCgR and only 9 additional patients lost the MMR while on intermittent treatment. All these patients resumed continuous imatinib treatment and regained the MMR. Thus, at ≥ 5 years, the probability of maintaing CCgR is 80% (95% CI 68-87) and the probability of maintaining the MMR is 61% (95% CI: 48-71). From start of INTERIM, 6 patients died but no deaths were related to CML progression (3 cases of other non haematological neoplasms, 1 stroke, 1 myocardial infarction, 1 chronic obstructive pulmonary disease).The PFS at ≥ 5 years is 94% (95% CI: 89-100) CONCLUSIONS: In summary, with a follow up ≥ 5 years, intermittent imatinib administration (INTERIM) confirmed to be safe, to produce a reversible increase of residual molecular disease in about one third of patients, but not to affect the long-term outcome. Aknowledgments: This work was supported in part by EuropeanLeukemiaNet (contract LSHC-CT-2004-503216) through the European Treatment and Outcome Study (EUTOS), supported by Novartis Oncology Europe, and COFIN 2009 Disclosures Russo: Celgene: Research Funding; Gilead: Research Funding; Novartis: Consultancy. Martinelli:Novartis: Speakers Bureau; Bristol-Meyers and Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Soverini:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Speakers Bureau. Turri:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Abruzzese:Novartis: Consultancy. Tiribelli:Novartis: Consultancy, Honoraria; Bristol-Meyers and Squibb: Consultancy, Honoraria. Rosti:Consultant: Consultancy, Speakers Bureau; Bristol-Meiers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.1794.1794
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 2
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    Final Report of Bendamustine and Alemtuzumab (BEN CAM) Combination in Relapsed and Refractory Chronic Lymphocytic Leukemia.
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 2898-2898
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2898-2898
    Abstract: Abstract 2898 Background: Notwithstanding the improved results with first-line therapy, CLL remains incurable, and patients are destined to relapse after primary treatment. The management of relapsed CLL pts is then dependent on several factors, including age, performance status, previous therapy, response and duration of response to therapy, and time from last therapy. Currently, the optimal treatment for pts with relapsed disease is not known. Bendamustine (BEN) demonstrated clinical activity in pre-treated hematological malignancies due to its unique mechanism of action distinct from standard alkylating agents. Alemtuzumab (CAM) is active in previously treated pts with CLL refractory to alkylating agents and purine nucleoside analogs. We designed a multicentric, single arm, dose escalation study to determine maximum tolerated dose (MTD) and to evaluate the efficacy and safety of Ben Cam combination in refractory/relapsed CLL pts. Methods: Previously treated CLL pts requiring therapy were enrolled. In the first part of the study, the tolerability of a stepwise dose-escalation schedule of BEN along with an increasing dose of CAM has been determined. BEN was given at a starting dose of 50 mg/sqm for 2 consecutive days along with CAM 20 mg sc on days 1 to 3; if MTD was not reached within the 1st cohort, the 2nd cohort received an increased dose of CAM 30 mg with a subsequent further increase of BEN 70 mg/sqm if MTD was not reached. Treatment was repeated every 28 d up to 4 course. If one of 3 pts at each dose level experienced DLT three additional pts were added (max 6). If 5 of the 6 subjects were able to complete the first 2 courses without experiencing DLT, this level was considered tolerable and dose-escalation continued initiating the following cohort. Results: Between July 2008 and March 2012, 50 pts with previously treated CLL requiring therapy according to IWCLL criteria were enrolled in 9 Italian centres. The median age of our population was 67 years (range 46–82), 64% were male and all pts presented with Binet stage B or C. Pts' population was characterized by high risk biological and clinical disease profile: 44% were in Binet stage C, bulky lymph nodes were present in 24% of pts, refractory pts represented 26% of our population. According to hierarchical model, del17p was present in 28% and del11q in 24%; 66% were IGVH unmutated, 40% ZAP70+ and 36% CD38+. Median number of prior regimens was 2 (range, 1–4): 84% had previously received fludarabine-based treatment and 70% monoclonal antibodies in monotherapy or in combination. Twelve pts have been enrolled in the Phase I of this trial: 3 pts in each of the first 2 cohorts, 6 in the third cohort. BEN 70 mg/sqm and CAM 30 mg sc resulted as the MTD. Median number of courses administered was 4 (range, 1–4), 72% of pts completed treatment program being progression the major cause of discontinuation. At the time of writing 43 pts (86%) are evaluable for response, evaluation is pending in 7 pts who completed in all cases treatment program. Overall response rate resulted of 70% including 26% of CRs and 44% of PRs; 18% of pts maintained a stable disease; 12% showed a progression. Significant difference in response rate (P=0.009) was observed among pts with relapsed versus refractory disease. Previous treatment and unfavourable biological features did not affect response achievement. None of the variables considered showed to be significant in reaching a CR. In the whole series of treated pts grade III-IV hematological toxicity was: neutropenia in the 33% of courses, thrombocytopenia and anemia in 7 and 4% respectively. Febrile neutropenia developed in the 15% of courses. CMV reactivation occurred in 10% of courses without any organ involvement. We recorded 8 major infections: 3 sepsis, 4 pneumonias and 1 enteritis. Extra-hematological toxicity was mild. Median time to progression in responders was reached after a median follow-up of 15,5 months. Conclusions: Analysis of results data collected on 43/50 pts treated with 4-weekly dosing BENCAM regimen suggests that this combination is effective in relapsed and refractory CLL pts, most of them carrying adverse prognostic factors. Hematologic toxicity was the only serious adverse event observed with a manageable myelosuppression. Major infections recorded were not superior in quantity and quality to those observed using other immuno-chemotherapeutic regimens in the same setting. No toxic deaths were recorded while on treatment. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.2898.2898
    RVK:
    XA 33000
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 3
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    Therapy-Related Myeloid Neoplasms: Report Of The Italian Network On Secondary Leukemias
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 2659-2659
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2659-2659
    Abstract: In 2001, the World Health Organization (WHO) recognized therapy-related myeloid neoplasms (t-MN) as a distinct entity including acute myeloid leukemia (AML) and myelodisplastic syndromes (MDS). At present, about 10% of all AML patients have a previous history of exposure to chemotherapy and/or radiation for a primary malignancy or autoimmune disease. In 2009, we initiated a Web-based epidemiological registry, with the purpose of collecting t-MN diagnosed at Italian Hematological or Oncological Divisions. Methods Demographic and clinical information on t-MN patients were included in the database whose access was restricted to selected users and was password-protected. Between May 2009 and June 2013, 279 t-MN patients [121 males and 158 females; median age 64 years (range 23-88 years)], observed at 22 Italian Centers between 1999 and 2012, were registered in the web-database. Results The primary malignancy (PM) was a hematological neoplasm (HM) in 123 cases (44%), a solid tumor in 145 cases (52%), and an autoimmune disease in 11 patients (4%). Twenty patients (7%) had a history of two or more previous cancers. Among hematological malignancies, the most frequent PM were lymphoproliferative diseases (92/122 cases), while breast cancer (65/146 cases) was the most frequent primary solid tumor. In particular, hematological PM were: 92 lymphoprolipherative diseases (68 Non Hodgkin and 18 Hodgkin lymphoma, 6 chronic lymphocytic leukemia); 12 Multiple myeloma; 14 myeloproliferative neoplasms (7 Myelofibrosis; 3 polycitemia vera; 3 essential thrombocythemia; 1 Hypereosinophilic syndrome.); 1 Acute lymphoblastic leukemia; 4 Acute myeloid leukemia (acute promielocytic leukemia in 2 cases). Sites of primary solid tumors were: 65 Breast; 32 Uro-genital (14 prostate; 5 bladder; 8 uterus; 5 ovarium); 17 Colon-rectal; 8 Lung; 8 Thyroid; 15 others (2 stomach; 5 CNS; 2 skin, 4 oropharynx; 2 sarcoma). Eleven patients had previously received immunosuppressive therapy for an autoimmune disease (5 with mitoxantrone, 5 with methotrexate, 1 with chlorambucil). Two-hundred-thirty-six patients had previously received chemotherapy for their primary malignancy, associated to radiotherapy (RT) in 94 cases. RT represented the only primary treatment in 43 cases. Median latency between PM and t-MN was 5.6 years (range 0.5-48). There were no differences between t-MN after lymphoprolipherative diseases or after breast cancer when considering patients’ age (p=0.09) or median latency (p 0.20) between PM and t-MN. According to morphology, t-MN were classified as 164 AML, 108 MDS and 7 ALL. Karyotype was available for 204 patients and was unfavorable in 81 patients (complex in 54 patients including del(7) in 19 cases; 15 cases with isolated del(7)]. A recurrent chromosomal translocation was present in 13 patients [1 t(8;21), 8 t(15;17) and 1 inv(16); 3 t(9;22)] , while 75 patients had a normal karyotype. One-hundred-thirty-five patients received chemotherapy for t-MN, while the hypomethylating drug Azacitidine was administered to 63 patients. Fifty-six patients underwent bone marrow transplantation (45 allogeneic and 11 autologous). Median OS from the t-MN diagnosis was 7.7 months (range 0.2-158+). Conclusions The incidence of t-MN is rising as a result of the increasing number of cancer survivors. Lymphoprolipherative diseases and breast cancer are the most common primary malignancies at risk of developing a therapy-related myeloid neoplasm. Disclosures: Santini: Novartis: Honoraria; Janssen : Honoraria; Celgene: Honoraria; gsk: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.2659.2659
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 4
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    ATRA and Arsenic Trioxide (ATO) Versus ATRA and Idarubicin (AIDA) for Newly Diagnosed, Non High-Risk Acute Promyelocytic Leukemia (APL): Results of the Phase III, Prospective, Randomized, Intergroup APL0406 Study by the Italian-German Cooperative Groups Gimema-SAL-AMLSG
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 6-6
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 6-6
    Abstract: Abstract 6 Background Simultaneous ATRA and chemotherapy (CHT) is the current gold standard for newly diagnosed APL resulting in ∼80% cure rates, while arsenic trioxide (ATO) is the treatment of choice for relapsed patients. ATO in variable combinations including ± ATRA ± CHT has also been tested as front-line therapy yielding encouraging results in several pilot studies as well as in two phase III studies conducted in China and the US. So far, no randomised studies have compared front-line CHT-free ATO+ATRA combination against the standard ATRA+CHT approach. Patients and Methods The phase III, randomised, prospective APL0406 trial was started in October 2007 by the Italian GIMEMA group and joined in November 2008 by the German SAL and AMLSG multicenter groups. Eligible patients were adults aged 18- 〈 71 years with newly diagnosed, genetically confirmed, non-high-risk (WBC≤10×109/L) APL. Patients were randomized to receive the ATO+ATRA combination originally reported by the MD Anderson group (Estey et al. Blood 2006, arm A), or the Italian AIDA2000 risk-adapted protocol for non high-risk disease (arm B). Patients in arm A received ATO 0.15/kg plus ATRA 45 mg/m2 daily until CR, then ATO 5 days/week, 4 weeks on 4 weeks off, for a total of 4 courses and ATRA 2 weeks on and 2 weeks off for a total of 7 courses. Patients in arm B received the standard AIDA (ATRA+Idarubicin) induction followed by 3 cycles of anthracycline-based plus ATRA consolidation and low dose CHT and ATRA for maintenance as reported (Lo-Coco et al., Blood 2011). The primary study objective was EFS at 2 years. The study was designed to show that the rate of patients alive event-free at two years in the experimental treatment arm is at least 80%. Secondary objectives included OS, DFS, CIR rates, molecular response and toxicity profile. Results From October 2007 to September 2010, the required sample size of 162 enrolled patients was completed. Median age was 45.3 years (18.7–70.2 years) and median WBC 1.50 × 109/L. As to the Sanz's risk score, 61.8% and 38.2% of patients were in the intermediate- and low-risk categories, respectively. The two treatment arms were well balanced for main baseline characteristics including age, sex, median WBC and Sanz's score. Eight patients were not evaluable for induction due to ineligibility or protocol violation. Of 154 patients evaluable for response to induction, CR was achieved in 150 (97.4%): 75/75 (100%) in arm A vs 75/79 (95%) in arm B (P=0.12). After a median follow-up of 31 months (range 0.07–50.4) the 2 year EFS (primary objective) was 97% (C.I.95%: 93.1–100) and 86.7% (C.I.95%: 80.3–93.6) in arms A and B respectively (P=0.03). There were 1 death in CR and 2 relapses in arm A, and 7 deaths (4 in induction, 3 in CR) and 4 relapses in arm B. As to secondary objectives, OS, DFS, and CIR rates were 98.7% vs. 91.1% (P=0.03), 97% vs. 91.6% (P=0.19) and 1.6% vs. 4.3% (P=0.41) in arm A and B, respectively. Fever episodes, prolonged ( 〉 15 d) grade ≥ 3 neutropenia and thrombocytopenia were significantly more frequent in patients in arm B as compared to those in arm A (P 〈 .001 for all comparisons). Other side effects including differentiation syndrome and increase of liver enzymes were recorded with similar frequency in the two study arms. Two patients in arm A had QTc prolongation requiring ATO discontinuation with final withdrawal in one case. PCR analysis of PML/RARA (sensitivity 10−4) was centrally performed in Rome (F. Lo-Coco) and Dresden (C. Thiede) and showed molecular CR in 141/142 (99%) of evaluable patients after completion of 3rd consolidation. One patient in arm B who tested PCR-positive at this time point was considered resistant and taken off protocol as per study design. Conclusions For patients with newly diagnosed non-high-risk APL, as compared to the standard AIDA regimen, the front-line CHT-free ATO+ATRA combination is at least not inferior for 2 year EFS. Disclosures: Lo-Coco: Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Cephalon: Speakers Bureau. Off Label Use: Arsenic Trioxide (ATO) is currently approved for therapy of relapsed APL in the US and Europe. In this study the role of ATO in front-line therapy of APL is explored. Fiedler:Pfizer Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Breccia:Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria. Platzbecker:GlaxoSmithKline: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Amgen: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.6.6
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 5
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    Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP
    American Society of Hematology ; 2001
    In:  Blood Vol. 97, No. 12 ( 2001-06-15), p. 3867-3874
    Details
    In: Blood, American Society of Hematology, Vol. 97, No. 12 ( 2001-06-15), p. 3867-3874
    Abstract: X-linked lymphoproliferative disease (XLP) is a rare immune disorder commonly triggered by infection with Epstein-Barr virus. Major disease manifestations include fatal acute infectious mononucleosis, B-cell lymphoma, and progressive dys-gammaglobulinemia. SAP/SH2D1A, the product of the gene mutated in XLP, is a small protein that comprises a single SH2 domain and a short tail of 26 amino acids. SAP binds to a specific motif in the cytoplasmic tails of the cell surface receptors SLAM and 2B4, where it blocks recruitment of the phosphatase SHP-2. Here it is reported that Ly-9 and CD84, 2 related glycoproteins differentially expressed on hematopoietic cells, also recruit SAP. Interactions between SAP and Ly-9 or CD84 were analyzed using a novel yeast 2-hybrid system, by COS cell transfections and in lymphoid cells. Recruitment of SAP is most efficient when the specific tyrosine residues in the cytoplasmic tails of Ly-9 or CD84 are phosphorylated. It is concluded that in activated T cells, the SAP protein binds to and regulates signal transduction events initiated through the engagement of SLAM, 2B4, CD84, and Ly-9. This suggests that combinations of dysfunctional signaling pathways initiated by these 4 cell surface receptors may cause the complex phenotypes of XLP.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V97.12.3867
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2001
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  • 6
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    Alterations of the X-linked lymphoproliferative disease geneSH2D1A in common variable immunodeficiency syndrome
    American Society of Hematology ; 2001
    In:  Blood Vol. 98, No. 5 ( 2001-09-01), p. 1321-1325
    Details
    In: Blood, American Society of Hematology, Vol. 98, No. 5 ( 2001-09-01), p. 1321-1325
    Abstract: X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency caused by a defect in the SH2D1A gene. At least 3 major manifestations characterize its clinical presentation: fatal infectious mononucleosis (FIM), lymphomas, and immunoglobulin deficiencies. Common variable immunodeficiency (CVID) is a syndrome characterized by immunoglobulin deficiency leading to susceptibility to infection. In some patients with CVID, a defective btk orCD40-L gene has been found, but most often there is no clearly identified etiology. Here, 2 unrelated families in whom male members were affected by CVID were examined for a defect in theXLP gene. In one family previously reported in the literature as having progressive immunoglobulin deficiencies, 3 brothers were examined for recurrent respiratory infections, whereas female family members showed only elevated serum immunoglobulin A levels. A grandson of one of the brothers died of a severeAspergillus infection secondary to progressive immunoglobulin deficiency, FIM, aplastic anemia, and B-cell lymphoma. In the second family, 2 brothers had B lymphocytopenia and immunoglobulin deficiencies. X-linked agammaglobulinemia syndrome was excluded genetically, and they were classified as having CVID. The occurrence of FIM in a male cousin of the brothers led to the XLP diagnosis. Because the SH2D1A gene was found altered in both families, these findings indicate that XLP must be considered when more than one male patient with CVID is encountered in the same family, and SH2D1A must be analyzed in all male patients with CVID. Moreover, these data link defects in the SH2D1A gene to abnormal B-lymphocyte development and to dysgammaglobulinemia in female members of families with XLP disease.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V98.5.1321
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2001
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  • 7
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    Intermittent Imatinib (INTERIM) Treatment of Patients with Ph+ Chronic Myeloid Leukemia in Complete Cytogenetic Response: Cytogenetic and Molecular Data At One Year
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1682-1682
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1682-1682
    Abstract: Abstract 1682 Background: The introduction of Imatinib has significantly improved the outcome for patients with Ph+ CML. The complete cytogenetic response (CCgR) is a strong and confirmed predictor of improved long-term outcome. According to current recommendations, Imatinib (IM) should be continued indefinitely. However, optimal responders can be eligible for investigational trials of treatment discontinuation. AIMS: This study (ClinicalTrials.gov NCT 00858806) describes the effects of a policy of intermittent Imatinib (INTERIM) treatment (one month on/one month off) on cytogenetic and molecular responses in a selected population of patients ≥ 65 years old who were receiving treatment with Imatinib for 〉 2 years and were in stable complete cytogenetic response (CCgR). The primary endpoint of the study was the proportion of patients who maintained CCgR after 1 year of INTERIM. The secondary endpoint was the level of BCR-ABL transcripts during INTERIM METHODS: Cytogenetic and molecular responses were monitored by FISH and RT-Q-PCR every 3 months. The definition of CCgR, and of CCgR loss was based on CBA of marrow metaphases which was performed at baseline and in all the patients who became FISH positive (BCR-ABL–positive nuclei 〉 1%). Major molecular response (MMR), corresponding to a 3-log reduction in BCR-ABL transcript level from the standardized baseline, was defined as BCR-ABL ≤0.1%IS and was indicated as MR3.0. For the purposes of this study, complete molecular response (CMR) was defined as a 4-log reduction in BCR-ABL transcript level ( 〈 0.01%IS), with a sensitivity of at least 10,000 ABL copies, and is indicated as MR4.0. In case of loss of CCgR or MMR, Ph+ additional cytogenetic abnormalities (ACA) and BCR-ABL kinase domain (KD) point mutation analysis were also performed. RESULTS: Seventy-six patients have been enrolled. Six patients (8%) lost CCgR (CBA positive), and 3 other patients became FISH positive while remaining CBA negative. At 12 months, the probability of maintaining CBA negativity was 92% (95% CI 86–98%), while the probability of maintaining FISH negativity was 87% (95% CI 79–94%). None of the factors that were examined by univariate and multivariate analysis were found to be associated with an higher probability of either loosing the CCgR (CBA) or showing a FISH positivity ( 〉 1%), with the exception of the duration of imatinib therapy (HR = 0.23, 95% CI 0.008–0.73, P =.01). Among patients with prior Imatinib treatment longer or shorter than 48 months, the probability of maintaining FISH negativity was 94% (95% CI 88–100%) vs 71% (95% CI 53–89%), respectively, HR = 0.23 (P =.007). All the 6 patients who lost CCgR regained the CCgR with daily Imatinib, at the same dose, defined by FISH negativity after 3 to 9 months (4/6 also CBA negative, 2 patients refused bone marrow aspiration). At baseline, all but one patient (99%) were in MMR (MR3.0, BCR-ABL ≤0.1%IS), and 63 patients (83%) were in MR4.0 ( 〈 0.01%IS). After one year of intermittent Imatinib, 18/76 patients (24%) lost MR3.0 and 25/63 (39%) patients lost MR4.0. No patient lost complete hematologic response, progressed to accelerated or blastic phase, developed ACA in Ph+ cells, or developed BCR-ABL mutations. After one year, the remaining 70 patients were allowed to go back to continuous treatment, or to continue the intermittent treatment. During the first six months of follow-up (month 13 to 18), 1 of 70 discontinued Imatinib for atrial fibrillation and 9 of 70 went back to continuous treatment because FISH negativity loss (1 patient) or MMR (MR3.0) loss (8 patients). All the patients continue to be regularly observed and monitored and the first twelve months of follow-up will be presented. CONCLUSIONS: The intermittent use of imatinib in older patients in stable CCgR after continuous imatinib treatment results in the transient loss of the CCgR in a minority (8%) of the patients. However, the disease burden at the molecular level significantly increased. A policy of intermittent treatment may be an alternative both to chronic continuous treatment and to treatment discontinuation, particularly in the elderly. However, a longer follow up is required before drawing final conclusions. Acknowledgments: This work was supported in part by EuropeanLeukemiaNet through the European Treatment and Outcome Study (EUTOS) and by Cofin 2009. Disclosures: Baccarani: Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Castagnetti:Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Di Raimondo:celgene: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.1682.1682
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 8
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    The Dose and the duration of frontline therapy with Imatinib does not affect response to Dasatinib in Imatinib-Resistant or -intolerant patients with chronic myeloid leukemia (CML). Results from a real Life-Based Italian Multicenter retrospective study on 124 Patients.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1124-1124
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1124-1124
    Abstract: Abstract 1124 Poster Board I-146 Background Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC with significant activity in patients with CML resistant or intolerant to front-line Imatinib (IM). However, the information so far available are to great extent limited to controlled clinical trials, which usually recruited patients with acceptable performance status, and no major organ dysfunction. Noteworthy, this fact, although essential for ethical reasons in clinical trials, may somehow determine an overestimation of the clinical benefit of new compounds. Thus, further studies based on non selected populations are indeed opportune. Patients and Methods A total of 124 patients (61 male and 63 females) with CML resistant or intolerant to IM received Dasatinib as second line therapy outside from clinical trials. 91 patients had a resistant disease, 19 were intolerant to IM and 14 patients were both resistant and intolerant to IM. Median age at switching to Dasatinib was 56.5 years (range 21-82). 62/124 patients escalated IM before switching from 400 to 600 mg/day and 26/62 patients received an additional dose escalation from 600 to 800 mg/day. Median time on IM prior to the switch to Dasatinib was 36 months (range 2-99), whereas median time on IM after dose escalation was 9 months (range: 1-43). Dasatinib was given at 100 mg once daily in 54/124 patients (43%), at 70 mg twice daily in 43/124 patients (35%) and at 50 mg once daily in the remaining patients (22%). Response (hematologic, cytogenetic and molecular), toxicities according to NCI-CTC, discontinuation/dose reduction of Dasatinib, event-free survival (EFS) and overall survival (OS) were evaluated. Results With a median follow-up of 12 months, 94% of patients attained a complete hematological response (CHR), whereas 69% and 51% achieved a major (MCyR) or a complete cytogenetic response and 32% attained a major molecular response (MMR). Cumulative EFS and OS at 12 months were 91 and 93% respectively. These data are in line with those of clinical trials, but the population of the present study was not selected. The commonest grade III/IV adverse events were thrombocytopenia and neutropenia, occurring in around half of patients. Only 3% of the patients suffered from a grade III-IV pleural effusion or dyspnea. The achievement of CHR, MCyR, CCyR and MMR significantly influenced EFS (p=0.006; 0.04; 0.008 and 0.003 respectively) and OS (p=0.002; 0.02; 0.004 and 0.001 respectively) both in univariate and in multivariate analysis. Intriguingly, neither the dose nor the duration of prior IM affected the response to Dasatinib, neither before switching to Dasatinib (p= 0.9 and p=0.4) nor after it (p=0.4 and 0.7). Moreover, dose escalation to IM 600 or 800 mg/day did not influence negatively the subsequent response to Dasatinib (p=0.8). In addition, we did not observe any difference in the response rate (CHR, MCyR, CCyR, MMR) between patients who received prior IM for more than 3 years with respect to those patients who received it for less than 3 years (p=0.9). Regarding Dasatinib therapy, we observed a statistically significant better outcome in term of both DFS and OS for those patients receiving lower doses continuously without interruption (p=0.05 and p=0.04) with respect to patients who received higher doses but were forced to stop the treatment due to grade III-IV toxicity. This observation clearly indicate the necessity of administer dasatinib continuously to patients in order to override possible mechanisms of resistance due to the reduction of the plasma level of the drug. Conclusions We confirm the safety and efficacy of Dasatinib as second line therapy for unselected patients with CML either resistant or refractory to IM even outside from clinical trials. Neither the dose nor the duration of Imatinib affects the response to Dasatinib. As well, patients receiving continuously Dasatinib, even at low doses, perform better. In conclusion, these findings show an increase possibility of cure for unselected patients resistant or intolerant to Imatinib submitted to second line therapy with Dasatinib in everyday clinical practice. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1124.1124
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 9
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    Bendamustine and Rituximab Combination Is Safe and Effective As Salvage Regimen in Waldenstrom's Macroglobulinemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3072-3072
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3072-3072
    Abstract: Introduction: Accordingto National Comprehensive Cancer Network (NCCN) and ESMO guidelines on Waldenstrom’s Macroglobulinemia (WM) bendamustine may be considered as a therapeutic option in first line treatment or in relapsed refractory disease. Even though there are only two clinical trials including a limited number of patients addressing the role of bendamustine and rituximab (BR) treatment in WM. Patients and Methods: To define the efficacy and tolerability of BR combination as salvage regimen in WM patients, we retrospectively analyzed the outcome of symptomatic refractory relapsed patients treated with BR in 14 Italian centres. All patients receiving at least one day of treatment were included in the study. Treatment consisted of: R 375 mg/sqm iv day 1 and B iv days 1, 2. Therapy was administered every 4 weeks up to 6 courses. Results: Seventy-one patients are included in the study. As regards B dosage; 45 patients (63%) received the highest dose of 90 mg/sqm while 22 (31%) were treated with 70 mg/sqm. The 4 patients (6%) with a cumulative illness rating scale ≥ 6, received the lowest dose of 50 mg/sqm. At treatment, median age was 72 years (49-88), sex ratio M/F 46/25. Mediannumber of prior regimens was 2 (range 1-6). Twenty-four patients (34%) presented with refractory disease. The majority (90%) of patients had been previously treated with alkylating agents, 30% had also received purine analogues based treatments. Previous R was administered in the 77% of cases. The main reason (62%) for starting treatment was anemia followed by adenopathy and/or splenomegaly (35%). Median IgM level at treatment was 3815 mg/dL.Overall 361 courses of BR treatment were administered, median number 6 (range 1-6) with 47 (66%) of patients completing the 6 planned courses. Toxicity was discontinuation cause in 10 patients (14%): 4 infection, 1 fatal, 6 myelosuppression. In the remaining 14 treatment was discontinued for clinical clinical decision after disease reassessment. No difference in terms of treatment discontinuation was observed according to B dosage and age. Overall response rate (ORR) was 80.3% including: 7% complete remissions (CR), 15.5 % very good partial remissions (VGPR), 52.2% partial remissions (PR) and 5.6% of minor responses. A stable disease was observed in 16.9% of patients. One (1.4%) disease progression and one death were recorded. A progressive decrease of IgM level was observed during follow-up leading to an amelioration of response in 4 cases leading to a final ORR of 84.5%. None of the clinical and biological characteristics considered (age, sex, disease status, previous lines of treatment, previous fludarabine, bulky disease, Hb and IgM level, beta 2 microglobulin, B dosage) had an impact on ORR achievement. A better quality of response (CR plus VGPR) was observed in patients with an IgM level 〈 3000 mg/dL and in those treated with the higher dosage of B (90 mg/sqm). After a median follow-up of 19 months (3-54) 11 of the 57 responding patients met the criteria for disease progression. No difference was observed when patients were stratified according to the quality of response. B dosage did not impact disease progression. Considering that most of the patients received prophylactic growth factors, grade 3-4 neutropenia developed in only 13% of courses, 36% of patients. Dose modification or delayed treatment administration was necessary in 4 and 10% of courses respectively. During treatment we recorded 14 episodes of FUO and 5 major infections, leading death in one case. After a median follow up of 19 months none of the patients developed secondary myelodisplastic syndrome, acute leukemia or diffuse large B-cell lymphoma. In 3 cases a solid cancer was observed. Conclusion: BR combination showed to be as effective as more intensive salvage regimens in pretreated WM patients. Treatment showed to be well tolerated even in elderly patients with limited episodes of myelosuppression and infections when compared to purine analogues including regimens. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3072.3072
    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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    IgA and IgG Hypogammaglobulinemia Does Not Predict for Recurrent Infection Risk and Persists Despite Therapeutic Response in Patients with Waldentrom's Macroglobulinemia.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 1947-1947
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1947-1947
    Abstract: Abstract 1947 Poster Board I-970 Recurrent infections are commonly observed among patients with WM, and may be related to the presence of IgA and IgG hypogammaglobulinemia. The etiology for this finding remains unclear, and has been speculated to be on the basis of tumor-induced suppression. We therefore evaluated the incidence of IgA and IgG hypogammaglobulinemia in 207 untreated WM patients and addressed the associated clinicopathological findings, and impact of therapy. The median age of these patients was 60, median IgM was 2,910, and median bone marrow (BM) infiltration was 40%. Of these patients, 131 (63.3%) and 120 (58.0%) patients demonstrated decreased serum IgA and IgG levels respectively, while 102 (49.3%) of these patients were abnormally low for both. BM infiltration, serum IgM levels, complete blood counts, absolute lymphocyte counts, b2-microglobulin, or the WM International Prognostic Scoring System score had no impact on the odds ratio of having IgA or IgG, or both IgA or IgG hypogammaglobulinemia by logistic regression analysis. The presence of adenopathy and/or splenomegaly was surprisingly associated with a lower incidence of hypogammaglobulinemia (p≤0.03). The presence of IgA, IgG or both IgA and IgG hypogammaglobulinemia did not predict for the occurrence of recurring infections, which were nearly all respiratory in nature and consisted of sinus (n=53; 25.85%), bronchial (n=16; 7.80%), unspecified upper respiratory tract (n=14; 6.83%), and pneumonic (n=7; 3.41%) infections. Lower IgA and IgG levels were however associated with disease progression in watch and wait patients. To understand the impact of WM directed therapeutic intervention on uninvolved immunoglobulin levels, we analyzed changes in IgA and IgG levels in a cohort of 93 patients who underwent treatment for WM. With a median follow-up of 12 months, no significant recovery in the median IgA and IgG levels was observed with any therapy during the course of follow-up, including in those patients who had follow-up in excess of 1 (n=46), 2 (n=25), and 3 (n=8) or more years post-therapy, and in those achieving a major remission including complete response. Lastly, we sequenced 8 genes (AICDA; BTK; CD40; CD154; NEMO, TACI, SH2D1A, UNG) implicated in immunoglobulin deficiency in 19 WM patients with IgA and/or IgG hypogammaglobulinemia. We observed an intronic variation at position c.1056-6T 〉 C in 2 patients, and a hemizygous missense mutation at c.337G 〉 A in another patient for NEMO, as well as a heterozygous missense mutation at c.425A 〉 T in the highly conserved catalytic site of UNG for one patient. The results of these studies demonstrate that IgA and IgG hypogammaglobulinemia is common, and does not predict for recurrent infection risk in WM. Moreover, IgA and IgG hypogammaglobulinemia persists despite therapeutic intervention and response. These studies highlight the importance for further investigations into the IgA and IgG hypogammaglobulinemia of WM, as well as the signaling pathways involved in B-cell differentiation and immunoglobulin heavy chain class switching in the pathogenesis of WM. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.1947.1947
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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