Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2601-2601

Abstract: Abstract 2601 Background: Tyrosine Kinase Inhibitors (TKI) have been shown to be very effective for the treatment of Acute Lymphoblastic Leukemia (ALL), with a Complete Hematologic Remission (CHR) rate close to 100%, and a high rate of Complete Cytogenetic and Molecular responses (CCgR and CMR). However, when they are used alone, as single agents, most patients relapse, so that they are currently used in combination with chemotherapy and as a preparation to allogeneic stem cell transplantation (SCT). Since Ph+ ALL is more frequent in the elderly, many patients cannot tolerate intensive chemotherapy and are not eligible for SCT. We have explored if the administration of two TKIs, Nilotinib (NIL) and Imatinib (IM) can improve the results without increasing the toxicity. Aims: To evaluate the response and the outcome of Ph+ ALL patients treated with the sequential administration of NIL and IM, to investigate the type and number of BCR-ABL kinase domain mutations developing during and after the study. Methods: We have designed a study (ClinicalTrials.gov. NCT01025505) in which patients more than 60 years old or unfit for intensive chemotherapy and SCT where treated with two TKIs, NIL 400 mg twice daily, and IM 300 mg twice daily, alternating for 6 weeks for a minimum of 24 weeks (study core) and indefinitely in case of response. The 6-weeks rotation schedule was respected, irrespectively of temporary discontinuations. The primary end-point was the rate of Disease Free Survival (DFS) at 24 weeks (4 courses of treatment); the secondary end points included the evaluation of CHR, CCgR and CMR rates. Mutation analysis was performed by nested RT-PCR amplification of the ABL kinase domain of the BCR-ABL transcript (codons 206 through 421). Amplified products were screened by denaturing-high performance liquid chromatography (D-HPLC). Samples scored positive for the presence of sequence variations were then subjected to direct automatic sequencing to characterize the mutation. Results: 39 patients have been enrolled in 15 Italian hematologic Centers (median age 66 years, range 28–84). Among these, 8 patients were unfit for standard chemotherapy or SCT (median age 50 years, range 28–59). 27 patients were p190, 5 were p210 and 7 were p190/p210. After 6 weeks of treatment, 36 patients were evaluable for response: 34 were in CHR (94%) and 2 in PHR (6%). 23 patients have already completed the study core (24 weeks), 87% were in CHR and 17 are currently continuing therapy in the protocol extension phase. Thus, the OS at 1 year is 79%, and 64% at 2 years. Overall, 1 patient was primarily resistant and 13 patients have relapsed, with a median time to relapse of 7.6 months (range 0.8–16.1 months), for a DFS of 51.3% at 12 months (Figure 1). Mutations detected were T315I in 2 cases, Y253H in 3 cases, T315I and Y253H in 1 case, E255K in 1 case, T315I and E255K in 1 case, E255V and Y253H in 1 case. Two patients were WT. A detailed kinetics of Molecular responses is shown in Table 1. Data on mutational analysis are reported in Table 2. Further details about Cytogenetic and Molecular responses, and about Adverse Events will be provided on site. Conclusions: In this small cohort of Ph+ ALL elderly/unfit patients, the rates of relapse and progression were not likely to be different from the rates observed with Imatinib alone (Vignetti et al, Blood 2007, May 1;109(9):3676-8) and Dasatinib alone (Foà, Blood 2011, Dec 15;118(25):6521-8). It's important to notice that the mutations that occurred at the time of relapse were sensitive to other TKIs (Dasatinib and Ponatinib). Acknowledgments: COFIN, Bologna University, BolognAIL, PRIN, Fondazione del Monte di Bologna e Ravenna, INPDAP. Disclosures: Pizzolo: Hoffmann-La Roche: Consultancy, Honoraria. Luppi:CELGENE CORPORATION: Research Funding. Vallisa:CELGENE CORPORATION: Research Funding. Martinelli:NOVARTIS: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; PFIZER: Consultancy; ARIAD: Consultancy. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.2601.2601

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2756-2756

Abstract: Abstract 2756 Background: Nilotinib is a potent and selective BCR-ABL inhibitor. The phase 3 ENESTnd trial demonstrated superior efficacy nilotinib vs. imatinib, with higher and faster molecular responses. After 24 months, the rates of progression to accelerated-blastic phase (ABP) were 0.7% and 1.1% with nilotinib 300mg and 400mg BID, respectively, significantly lower compared to imatinib (4.2%). Nilotinib has been approved for the frontline treatment of Ph+ CML. With imatinib 400mg (IRIS trial), the rate of any event and of progression to ABP were higher during the first 3–4 years. Consequently, a confirmation of the durability of responses to nilotinib beyond 3 years is extremely relevant. Aims: To evaluate the long term outcome of patients treated with nilotinib 400mg BID as frontline therapy. Methods: A multicentre phase 2 trial was conducted by the GIMEMA CML WP (ClinicalTrials.gov.NCT00481052). Median 48-month follow-up data for all patients will be presented. Definitions: MR3.0 (Major Molecular Response) as a BCR-ABL/ABL ratio 〈 0,1%IS; MR4.0, undetectable transcript levels with ≥10,000 ABL transcripts; failures: according to the revised ELN recommendations; events: failures and treatment discontinuation for any reason. All the analysis has been made according to the intention-to-treat principle. Results: 73 patients enrolled: median age 51 years; 45% low, 41% intermediate and 14% high Sokal risk. The cumulative incidence of CCgR at 12 months was 100%. CCgR at each milestone: 78%, 96%, 96%, 95%, 92% at 3, 6, 12, 18 and 24 months, respectively. The overall estimated probability of MR3.0 was 99%, while the rates of MR3.0 at 3, 6, 12, 18 and 24 months were 52%, 66%, 85%, 81% and 82%, respectively. Two out of 73 patients never achieved a MR3.0, 1 who progressed to AP/BP (see below) and 1 in stable and confirmed CCgR at 36 months. Three pts had a confirmed loss of MR3.0 due to low adherence (all 3 still on nilotinib). The overall estimated probability of MR4.0 was 79%, while the rates of MR4.0 at 12, 24 and 36 months were 12%, 27% and 25%, respectively. One third (21/73 pts) showed a stable MR4.0 (defined based on 3 consecutive MR4.0 samples 4 months apart). Only one patient progressed at 6 months to ABP and subsequently died (high Sokal risk, T315I mutation). Adverse events were mostly grade 1 or 2 and manageable with appropriate dose adaptations. During the first 12 months, the mean daily dose was 600–800mg in 74% of patients. The nilotinib last daily dose was as follows: 800mg in 46 (63%) patients, 600mg in 3 (4%) patients and 400mg in 18 (25%), 6 permanent discontinuations. Detail of discontinuation: 1 patient progressed to ABP; 3 patients had recurrent episodes of amylase and/or lipase increase (no pancreatitis); 1 patient had atrial fibrillation (unrelated to study drug) and 1 patient died after 32 months of mental deterioration and starvation (unrelated to study drug). Two patients are currently on imatinib second-line and 2 on dasatinib third-line. With a median follow-up of 39 months, the estimated probability of overall survival, progression-free survival and failure-free survival was 97%, the estimated probability of event-free survival was 91%. Conclusions: The rate of failures was very low during the first 3 years. Responses remain stable. The high rates of responses achieved during the first 12–18 months are being translated into optimal outcome for most of patients. Acknowledgments: European LeukemiaNet, COFIN, Bologna University, BolognAIL Disclosures: Gugliotta: Novartis: Honoraria; Bristol-Myers-Squibb: Honoraria. Castagnetti:Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Cuneo:Roche: Consultancy, Speakers Bureau. Soverini:Novartis: Consultancy; ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy. Saglio:Novartis Pharmaceutical: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfizer: Consultancy. 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.V118.21.2756.2756

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 334-334

Abstract: Abstract 334 Background: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease believed to be mediated by autoreactive lymphocytes that invade the Central Nervous System and cause oligodendrocyte, axonal and neuronal damage as well as glial scarring.to and resulting in demyelination, neuronal death and brain atrophy. Hematopoietic Stem Cell Transplantation (HSCT) has been tried in the last 15 years as a therapeutic option in patients with a poor prognosis autoimmune disease not responding to conventional treatments. Worldwide ≥600 patients with MS have been treated with HSCT, most of them having been recruited in small, single center, phase 1–2 uncontrolled trials. Clinical and MRI outcomes from case series reports or Registry-based analyses suggest that a major response is achieved in most patients; quality and duration of response are better in patients transplanted earlier in the relapsing-remitting phase. The intensity of the immunosuppression from transplant treatment may be determined by several factors, such as the use of chemotherapy in the mobilization regimen, the intensity of the conditioning regimen and ex-vivo T-cell depletion. Methods: We report here the Italian multi-center experience on 74 MS patients treated with AHSCT between 1996 and 2008, all mobilized with Cyclophosphamide/G-CSF and conditioned with BEAM and rabbit ATG. Clinical and MRI outcomes were reported to the Italian Registry; the median follow-up is 48.3 (range 30–210) months. All patients clinically deteriorated in the year prior to HSCT, with an increase of Extended Disability Scale (EDSS) of at least one point (average EDSS change=1.5 points, range=1–9), Results: Two patients (3.3%) died for transplant-related causes. At 5 years after the transplant, 66% of patients remained stable or improved. Progression free survival (PFS) was slightly better in relapsing-remitting (RR) (5 years PFS=71%) than in secondary-progressive (SP) forms (5 years PFS=62%, p=0.28). Amongst patients with a follow up longer than 1 year, 8 out of 25 RR subjects (31%) had a 6–12 months confirmed EDSS improvement 〉 1 point as compared to 1 out of 36 (3%) SP patients (p=0.009), Figure 1. Out of 18 cases with a follow up longer than 7 years, 8 (44%) remained stable or had a sustained improvement whilst 10 (56%), after an initial period of stabilization or improvement with a median duration of 3.5 years, showed a slow progression of disability. Conclusions: This study shows in a large cohort of patients with a long follow-up that AHSCT with BEAM/ATG conditioning regimen has a profound effect in suppressing disease progression in aggressive MS cases, unresponsive to conventional therapies. Indeed it results in a sustained improvement of the disability, free of immunosuppression, in a significant amount of RR patients. Clinical improvement is scarcely reported in MS literature as it is rather infrequent with conventional treatments; nevertheless it results in a stable increase of the quality of the life in this subset of young patients and should be considered in the choice of a therapeutic strategy in the early phase of MS. Disclosures: Cuneo: Roche: Consultancy, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.334.334

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 119, No. 10 ( 2012-03-08), p. 2310-2313

Abstract: It is unclear whether karyotype aberrations that occur in regions uncovered by the standard fluorescence in situ hybridization (FISH) panel have prognostic relevance in chronic lymphocytic leukemia (CLL). We evaluated the significance of karyotypic aberrations in a learning cohort (LC; n = 64) and a validation cohort (VC; n = 84) of patients with chronic lymphocytic leukemia with “normal” FISH. An abnormal karyotype was found in 21.5% and 35.7% of cases in the LC and VC, respectively, and was associated with a lower immunophenotypic score (P = .030 in the LC, P = .035 in the VC), advanced stage (P = .040 in the VC), and need for treatment (P = .002 in the LC, P = 〈 .0001 in the VC). The abnormal karyotype correlated with shorter time to first treatment and shorter survival in both the LC and the VC, representing the strongest prognostic parameter. In patients with chronic lymphocytic leukemia with normal FISH, karyotypic aberrations by conventional cytogenetics with novel mitogens identify a subset of cases with adverse prognostic features.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2011-11-395269

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3300-3300

Abstract: Background. Fludarabine, cyclophosphamide, and rituximab (FCR) has represented a significant advancement in the treatment of patients with chronic lymphocytic leukemia (CLL) and has the potential of inducing durable remissions of the disease. In the new scenario of targeted agents for CLL, there is an increasing interest in identifying patients who may gain the maximum benefit in terms of disease control by a single shot of FCR chemo-immunotherapy. Purpose. Here we aimed at identifying predictors of durable remission after first line FCR treatment. Methods. The study was based on 405 progressive and previously untreated CLL patients who consecutively received standard FCR (up to 6 cycles) as first line therapy in 19 hematologic centers between 2001 and 2010. According to an intention to treat approach, all patients who received at least one FCR cycle were registered in the study. This series was representative of a FCR treated CLL cohort with respect to baseline characteristics, including age (median: 61 years; 〉 65 years in 33% of patients), gender (male in 68% of patients), stage (progressive Binet A in 11% of patients; Binet B in 59%; Binet C in 30%) and number of FCR courses (median: 6; 〈 6 in 42% of patients). Most patients were evaluable for IGHV mutation status (unmutated in 192/296, 65%) and genomic aberrations at treatment requirement (17p deletion in 30/306, 9.8%; 11q deletion in 56/300, 19%; +12 in 70/298, 23%; 13q deletion in 108/301, 36%). Results. After a median follow-up of five years, 159 patients have progressed and 72 have died, accounting for a 5-year progression free survival (PFS) according to the IWCLL criteria of 47% (median: 58 months) and for a 5-year overall survival (OS) of 81% (median: not reached). When the demographic effects of age, gender and year of treatment were compensated, the 5-year and 10-year survival of the whole CLL cohort were 85% and 68%, respectively, of those expected in the matched normal general population (p 〈 0.001). By multivariate analysis, unmutated IGHV genes, 11q deletion and 17p deletion maintained independent association with both PFS and OS, thus providing the rationale to utilize them in the development of a model to predict remission duration after FCR. By recursive partitioning analysis, 17p deletion was the most important variable in predicting PFS after FCR, followed by 11q deletion and IGHV mutation status (Fig. 1A). Based on the application of an amalgamation algorithm, cases harboring unmutated IGHV genes and 11q deletion were grouped into a single category because they showed an identical drop of the PFS curve (Fig. 1A). By this approach, three CLL subgroups were hierarchically classified. Clinical features and treatment indication were superimposable across the three risk groups. The low risk category comprised patients harboring mutated IGHV genes but neither 11q or 17p deletion, and accounted for 26% of all cases. Most of the low risk patients (67%) remained free of progression after FCR (Fig. 1B), and their hazard of relapse dropped to zero after 5 years of follow-up. Consistently, the PFS curve of low risk patients plateaued after 5-years from FCR (Fig 1B). The life expectancy of low risk patients (91% at 5 year) was superimposable to that observed in the matched normal general population (Fig. 1D), indicating that neither the disease, nor complications of its treatment affected survival in this favorable group of CLL. Conversely, patients belonging to the intermediate risk (IGHV unmutated and/or 11q deleted) and high risk (17p deleted) categories showed a constant increase of the hazard of progression over time and almost all were projected to relapse after FCR, although at a different rate: 10% per year of follow-up in the intermediate risk group and 17% per year of follow-up in the high risk group (Fig. 1B-C). The 5-year life expectancy of intermediate and high-risk patients was significantly impaired compared to that observed in the matched general population (85% and 60%, respectively) (Fig. 1D), indicating an excess of deaths related to the disease or treatment complications in these unfavorable groups of CLL. Conclusions. The combination of three biomarkers that are routinely tested at treatment allows to segregate a subgroup of CLL (IGHV mutated without 17p or 11q deletion) that may achieve a durable remission after first line FCR treatment and experience an expected survival similar to that of the general population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3300.3300

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1782-1782

Abstract: Abstract 1782 The aims of LE.P.RE. study include the identification of clinical and biological factors associated with clinical response and toxicity of lenalidomide monotherapy in relapsed/refractory CLL patients enrolled from 9 Italian centers. Lenalidomide treatment schedule starts with 5 mg daily and increases of 5 mg daily every two weeks, up to 25 mg daily or maximum tolerated dose. Therapy is scheduled to be administered for 12 courses (1 course = 4 weeks) unless disease progression or excessive toxicity are observed. Here we show preliminary results about the first 20 enrolled patients up to the 4th treatment course. Patients received a mean daily lenalidomide dose of 8 mg in the 1st course, 10 mg in the 2nd, 14 mg in the 3rd and 4th. Four patients left the study at the 1st course (1 acute renal failure ARF, 1 infection, 1 second neoplasia likely related to CLL, 1 consent withdrawal) and 3 patients at the 3rd (1 Tumor Flare Reaction TFR, 1 infection, 1 thrombocytopenia). The observed toxicities are listed in Table 1. After the 4th course, 13 patients were evaluable for response: 9 partial response (PR), 3 progressive disease (PD) and 1 stable disease (SD) [ORR 69%]. Table 1 Hematological and extra hematological toxicities (n° tot cases=20) grade n° cases grade n° cases Thrombocytopenia 03/04/11 7 TLS 2 1 Neutropenia 03/04/11 14 TFR 1-2 4 Anemia 03/04/11 2 Second Neoplasia 1 Death 1 ARF 02/03/11 3 Infection 03/04/11 3 We compared the levels of several cytokines measured by ELISA in plasma of the 20 patients at baseline and day+8 of therapy. We observed a significant increase of IL2 Receptor (mean 55,31 vs 112,14 ng/ml; p 〈 0,001), IL2 (14,15 vs 17,27 pg/ml; p=0,019), CCL3 (5,21 vs 21,23 pg/ml; p 〈 0,001), CCL4 (24,76 vs 72,99 pg/ml; p=0,003), IL10 (2,65 vs 6,33 pg/ml; p=0,001), IL1b (0,94 vs 2,77 pg/ml; p=0,048), TNFa (35,00 vs 140,59 pg/ml; p 〈 0,001) and IL8 (0,31 vs 3,50 pg/ml; p=0,037) and a decrease of Thrombospondin 1 (693 vs 488 ng/ml; p=0,037). Interestingly, we found that IL1b level decreased from baseline to day+8 in the 4 non responder (PD+SD) patients while increasing in the 9 responder (PR) patients. Moreover, we found that the 5 patients that experienced TFR or tumor lysis syndrome TLS had significantly higher CCL3 level at baseline than the other 15 patients (p=0,025). We also studied peripheral blood cell subsets (T, B, NK, monocyte, dendritic and endothelial cells) in the 20 patients by flow cytometry. From baseline to day+8 we observed a significant increase of the Thelper1/Thelper2 ratio (p 〈 0,001), T cytotoxic1/Tcytotoxic2 ratio (p=0,001) and memory T cells % (p 〈 0,001) as well as a decrease of naïve T cells % (p 〈 0,001) and mean CD69 expression on T cells (p=0,016). Moreover, the expression of CD40 (p=0,001), CD80 (p=0,018), CD86 (p=0,003) and CD95 (p=0,008) were found to be increased on B-CLL cells. Finally, we observed a decrease of endothelial progenitors cells (EPC) (p=0,032) and live circulating endothelial cells (CEC) (p 〈 0,001) and an increase of dead CEC (p 〈 0,001). Interestingly, there was a significant difference in activated CEC (mean 53,57 vs 81,63 CEC %; p=0,031) and resting CEC (46,54 vs 18,37; p=0,031) at baseline between responders and non responders, respectively. Moreover, the patients exhibiting TFR or TLS showed a higher % of CD4+CD3+ cells (p=0,009) and CD4+CD8+ cells (p=0,036) at day+8 than the others. In conclusion: (i) the increase of inflammatory cytokines IL2R, IL2, CCL3, CCL4, IL10, IL1b and TNFa observed from baseline to day+8 suggests that lenalidomide can induce immune activation; (ii) the augmentation of IL2, IL2R and memory T cells and the decrease of naïve T cells noticed from baseline to day+8 indicate that lenalidomide can promote T cell activation; (iii) the shift toward Thelper1 and Tcytotoxic1 phenotypes and the increased expression of co-stimulatory molecules on B-CLL cells observed from baseline to day+8 suggest that lenalidomide can promote an active T cell response against leukemic cells; (iv) the alterations in EPC and CEC noticed from baseline to day+8 suggest that lenalidomide may also have an anti angiogenic action. Moreover, our preliminary data seem to show interesting biological differences among CLL patients that respond or do not respond to lenalidomide treatment, which if replicated in additional patients and with increasing time on therapy could give important information for predicting which patients may best respond to therapy or may experience TFR or TLS. Disclosures: Maffei: CELGENE CORPORATION: Research Funding. Off Label Use: Lenalidomide, a thalidomide analogue, is an immunomodulatory drug (IMiD) with antitumoural activity reported in various malignant disorders including multiple myeloma and myelodysplastic syndrome. At preclinical level, lenalidomide has shown to decrease the production of several prosurvival cytokines. This drug is also reported to modulate an effector cell immune response through the activation of T and natural killer cells, inducing apoptosis directly on tumour cells. Currently available data indicate that lenalidomide is active also in heavily pre-treated CLL patients. However, in order to reduce toxicity and to optimize the therapeutic index of lenalidomide treatment in CLL patients, it is necessary to identify features of tumour cells that differ between responder and non responder patients. Hence, we propose a multicenter, phase II study designed in order to identify potential predictive factors correlating with response and toxicity to Lenalidomide treatment in relapsed/refractory CLL patients. Martinelli:CELGENE CORPORATION: Research Funding. Debbia:CELGENE CORPORATION: Research Funding. Rigolin:CELGENE CORPORATION: Research Funding. Rizzotto:CELGENE CORPORATION: Research Funding. Castelli:CELGENE CORPORATION: Research Funding. Bonacorsi:CELGENE CORPORATION: Research Funding. Bulgarelli:CELGENE CORPORATION: Research Funding. Fiorcari:CELGENE CORPORATION: Research Funding. Zucchini:CELGENE CORPORATION: Research Funding. Santachiara:CELGENE CORPORATION: Research Funding. Forconi:CELGENE CORPORATION: Research Funding. Rossi:CELGENE CORPORATION: Research Funding. Laurenti:CELGENE CORPORATION: Research Funding. Palumbo:CELGENE CORPORATION: Research Funding. Vallisa:CELGENE CORPORATION: Research Funding. Cuneo:CELGENE CORPORATION: Research Funding. Gaidano:CELGENE CORPORATION: Research Funding. Luppi:CELGENE CORPORATION: Research Funding. Marasca:CELGENE CORPORATION: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.1782.1782

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2273-2273

Abstract: Abstract 2273 Background: While Imatinib (IM) has revolutionized treatment for chronic myeloid leukemia (CML), demonstrating outstanding survival figures, currently no data exist on mid to long term impact of disease burden and therapy from the patients’ perspective. Aim: The main objective of this study is to identify specific limitations of quality of life (QoL) in CML survivors who are undergoing first line treatment with IM in comparison with controls from the general population. Patient-reported symptom prevalence was also investigated. Patients and methods: Patients were recruited in 26 centers, randomly selected to geographically represent the whole study country. Patients selection criteria included: being in treatment with IM for at least three years and being in complete cytogenetic response at the time of study entry. All patients were invited by their treating physicians in the hospital to participate and all consenting patients were requested to complete a Health Survey Packet at home. Pre-paid reply envelopes were also provided with the request to send back completed Surveys to an independent National coordinating Data Center. Generic QoL was assessed with the SF-36 that consists of 36 items covering eight generic health status/QoL domains: physical functioning (PF), role limitations due to physical health (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and mental health (MH). All scales ranging between 0 and 100 with higher scores representing better outcomes. A previously devised patient-reported CML Symptom Checklist was used to investigate 9 symptoms of possible major concern in these patients. Mean SF-36 scores were compared to available national general population reference values and all analyses were adjusted for age and gender. Statistical comparisons were all adjusted for multiple testing. Differences in mean scores were expressed in Cohen effect sizes (ES; with 0.2, 0.5, and 0.8 indicating small, medium, and large ES, respectively) and clinical significance. Results: Between March and December 2009, 448 patients were recruited in a large national-based survivorship project. Patients’ compliance was optimal with 94% of patients (N=421) returning a valid Health Survey Packet to the National coordinating Data center. At study participation, mean age of patients was 56 years (59% male and 41% female) and median time of IM therapy was 5 years. Seventy-seven percent of patients were receiving standard dose of 400 mg and 43% had at least one comorbidity. Age and gender adjusted comparisons with general population norms revealed worse outcomes for the following scales: RP (P 〈 .001; ES=0.3), GH (P 〈 .001; ES=0.4) and RE (P=.01; ES=0.2). The largest clinically meaningful difference (Δ=12.3 points) was found for the RP domain with mean scores of 61.4 vs. 73.7 respectively for the CML and the general population. Age specific comparisons, adjusted by gender, (55-64; 65–74 and 〉 75 years) suggested an almost uniform pattern in all scales with worse outcomes between CML patients and population controls among the youngest groups. GH was significantly worse in younger patients (55-64) (P=.03; ES=0.4) and no differences were found in the older age groups compared with population norms. Prevalence of reported symptoms (with any level of concern) was: fatigue (82%); problems with muscular cramps (78%); problems with musculoskeletal pain (72%); problems with edema (70%); skin problems (47%); diarrhea (43%); headache (39%); abdominal discomfort and nausea (28%). Conclusion: This study suggests that while still being on treatment with IM for years, CML patients might expect to have a QoL profile broadly similar to that of general population in many areas. However, role limitations (i.e., in work or other regular daily activities) due to physical health seem the major constraint faced by these patients; there is also an indication that younger patients might be those experiencing major limitations. Additional analyses will be undertaken to ascertain the impact of symptoms and other laboratory and clinical data on specific QoL domains. Such unique patient-reported data supplements conventional information on clinical efficacy of IM and may support both clinicians and patients in making more informed treatment decisions in this area. Disclosures: Rosti: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol M. Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.2273.2273

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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detail.hit.zdb_id: 80069-7

In: American Journal of Hematology, Wiley, Vol. 89, No. 5 ( 2014-05), p. 480-486

Abstract: In a phase II trial, we evaluated chlorambucil and rituximab (CLB‐R) as first‐line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28‐day cycles of CLB (8 mg/m 2 /day, days 1–7) and R (day 1 of cycle 3, 375 mg/m 2 ; cycles 4–8, 500 mg/m 2 ). Responders were randomized to 12 8‐week doses of R (375 mg/m 2 ) or observation. As per intention‐to‐treat analysis, 82.4% (95% CI, 74.25–90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60–64 years, 92.3%; 65–69, 85.2%; 70–74, 75.0%; ≥75, 81.0%). CLB‐R was well tolerated. After a median follow‐up of 34.2 months, the median progression‐free survival (PFS) was 34.7 months (95% CI, 33.1–39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB‐R represents a promising option for elderly CLL patients. Am. J. Hematol. 89:480–486, 2014. © 2014 Wiley Periodicals, Inc.

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v89.5

DOI: 10.1002/ajh.23668

Language: English

Publisher: Wiley

Publication Date: 2014

detail.hit.zdb_id: 1492749-4

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 4 ( 2011-02-15), p. 762-770

Abstract: Purpose: To analyze the effect of the combination of Dasatinib, a multikinase inhibitor, plus Nutlin-3, a nongenotoxic activator of the p53 pathway, in primary B chronic lymphocytic leukemia (B-CLL) patient samples and B leukemic cell line models. Experimental Design: The induction of cytotoxicity was evaluated in both primary B-CLL cell samples (n = 20) and in p53wild-type (EHEB, JVM-2) and p53deleted/mutated (MEC-2, BJAB) B leukemic cell lines. The role of Akt in modulating leukemic cell survival/apoptosis in response to Dasatinib or Dasatinib + Nutlin-3 was documented by functional experiments carried out using specific pharmacological inhibitors and by overexpression of membrane-targeted constitutively active form of Akt. Results: The combination of Dasatinib + Nutlin-3 exhibited a synergistic cytotoxicity in the majority (19 out of 20) of B-CLL samples, including patients carrying 17p- (n = 4), and in both p53wild-type and p53deleted/mutated B leukemic cell lines. At the molecular level, Dasatinib significantly counteracted the Nutlin-3-mediated induction of the p53 transcriptional targets MDM2 and p21 observed in p53wild-type leukemic cells. Conversely, Nutlin-3 did not interfere with the ability of Dasatinib to decrease the phosphorylation levels of ERK1/2, p38/MAPK, and Akt in both p53wild-type and p53deleted/mutated B leukemic cell lines. A critical role of Akt downregulation in mediating the antileukemic activity of Dasatinib and Dasatinib + Nutlin-3 was demonstrated in experiments carried out by specifically modulating the Akt pathway. Conclusions: These findings suggest that Dasatinib + Nutlin-3 might represent an innovative therapeutic combination for both p53wild-type and p53deleted/mutated B-CLL. Clin Cancer Res; 17(4); 1–9. ©2010 AACR.

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1078-0432.CCR-10-2572

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2011

detail.hit.zdb_id: 1225457-5

detail.hit.zdb_id: 2036787-9

In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 1, No. S1 ( 2013-11)

Type of Medium: Online Resource

ISSN: 2051-1426

URL: Article

DOI: 10.1186/2051-1426-1-S1-P43

Language: English

Publisher: BMJ

Publication Date: 2013

detail.hit.zdb_id: 2719863-7