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  • 1
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 2829-2829
    Abstract: Introduction: CD20 expression is classically considered to be associated with inferior survival in adults with B-cell precursor acute lymphoblastic leukemia (ALL) but this notion is not strongly sustained in the literature. A recent pediatric study performed at St Jude’s Children’s Research Hospital reports that CD20 expression does not appear to be associated with inferior outcome in a cohort of 359 patients treated with contemporary regimens. This question is of importance notably since favorable experience has been reported for the use of rituximab, a chimeric monoclonal antibody to CD20, in combination with chemotherapy in mature B-cell lymphoma and leukemia, and possibly also in adult B-cell precursor ALL. Method: To determine the prognostic impact of CD20 expression in adult patients with B-cell precursor ALL and therefore the potential utility of rituximab in this subset of patients, we studied 143 patients treated in the GRAALL-2003 trial, designed to offer a dose-intensive pediatric-like approach in adults with Ph-negative ALL until 55 years of age. Results: CD20 positivity, defined as expression of CD20 in more than 20% of leukemia blasts, was observed in 49 patients (34%). There was no association between CD20 expression and patient age, white blood cell count at diagnosis, E2A-PBX, or ploidy. None of 21 patients with MLL-AF4 expressed CD20 (p 〈 0.001). Even if CD20 expression tended to be associated with corticoresistance (24% in CD20+ cases vs. 14% in others, p=0.16), it was not associated with chemoresistance, overall early response (cortico- and/or chemoresistant ALL), CR rate, or post-induction MRD 〉 10-3, as assessed by clonal Ig rearrangements quantification. However, the cumulative incidence of relapse at 30 months was significantly higher in CD20+ cases (39% [95% CI, 25 to 55] vs. 20% [95% CI, 13 to 31] , p=0.02). Interestingly, a negative impact of corticoresistance and high white blood cell count at diagnosis on the cumulative incidence of relapse was only observed in this population of CD20+ patients (p=0.05 and p 〈 0.001, respectively), but not in CD20neg patients (p=0.85 and 0.67). These data suggest either an intrinsic resistance of CD20+ leukemic cells or a lack of impact on these cells of the dose intensification (reinforcement of the induction course with a sequential bolus administration of cyclophosphamide) applied to corticoresistant patients. Disease-free survivals at 30 months were of 57% [95% CI, 40 to 70] and 64% [95% CI, 52 to 74] in CD20+ and CD20neg groups, respectively (p=0.36). Conclusion: In contrast to pediatric ALL, CD20 expression appears to be associated with inferior outcome in adult ALL with a significantly higher cumulative incidence of relapse in this group of patients. This reinforces the interest of evaluating the effect of rituximab combined to chemotherapy in adult ALL.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 27, No. 6 ( 2009-02-20), p. 911-918
    Abstract: Retrospective comparisons have suggested that adolescents or teenagers with acute lymphoblastic leukemia (ALL) benefit from pediatric rather than adult chemotherapy regimens. Thus, the aim of the present phase II study was to test a pediatric-inspired treatment, including intensified doses of nonmyelotoxic drugs, such as prednisone, vincristine, or l-asparaginase, in adult patients with ALL up to the age of 60 years. Patients and Methods Between 2003 and 2005, 225 adult patients (median age, 31 years; range, 15 to 60 years) with Philadelphia chromosome–negative ALL were enrolled onto the Group for Research on Adult Acute Lymphoblastic Leukemia 2003 protocol, which included several pediatric options. Some adult options, such as allogeneic stem-cell transplantation for patients with high-risk ALL, were nevertheless retained. Results were retrospectively compared with the historical France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) trial experience in 712 patients age 15 to 55 years. Results Complete remission rate was 93.5%. At 42 months, event-free survival (EFS) and overall survival (OS) rates were 55% (95% CI, 48% to 52%) and 60% (95% CI, 53% to 66%), respectively. Age remained an important bad prognostic factor, with 45 years of age as best cutoff. In older versus younger patients, there was a higher cumulative incidence of chemotherapy-related deaths (23% v 5%, respectively; P 〈 .001) and deaths in first CR (22% v 5%, respectively; P 〈 .001), whereas the incidence of relapse remained stable (30% v 32%, respectively). Complete remission rate (P = .02), EFS (P 〈 .001), and OS (P 〈 .001) compared favorably with the previous LALA-94 experience. Conclusion These results suggest that pediatric-inspired therapy markedly improves the outcome of adult patients with ALL, at least until the age of 45 years.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2009
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  • 3
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1166-1166
    Abstract: Abstract 1166 Poster Board I-188 Introduction: The complement system consists of several serum proteins and cell membrane receptors that can be activated by three possible pathways leading to the production of pro-inflammatory factors such as the anaphylatoxins C3a and C5a and the formation of the membrane attack complex. The complement system has been implicated in the pathophysiology of several immune diseases and we previously reported that it was activated after allogeneic haematopoietic stem cell transplantation (HSCT) both in humans and mice. It's activation after allogeneic HSCT following a myeloablative conditioning could predict the development of gastrointestinal (GI) GVHD in humans. We now present updated data with long term follow up on an enlarged series of patients who did or did not activate complement after allogeneic HSCT. We also discuss the preliminary results of the inhibition of complement activation on experimental models of GVHD. Materials and methods: Complement activation was determined by measurment of complement proteins before and once a week up to 3 months after allogeneic HSCT in 34 patients allografted for diverse haematological malignancies in our institution following conventional myeloablative conditioning. Results were correlated to the clinical evolution of allogeneic HSCT. Preclinically, inhibition of mouse complement activation by C1 inhibitor esterase or an anti-C5 monoclonal antibody was tested in a parent (C57BL/6, H-2b) to F1 [(C57BL/6xDBA2), H-bd] GVHD mouse model. Lethally irradiated (9.75 to 11 Gy) mice reconstituted with either syngeneic or allogeneic bone marrow cells and splenocytes (107 and 13 to 20 ×106 cells/recipient, respectively) were treated with complement inhibitors between day-7 to Day 21 or day 1 to Day 28 post-HSCT. Clinical Results: Fifteen (44%) patients showed an activation of the classical pathway, as defined by a decrease of C3 and C4 proteins below normal values and of at least 50% of their pre-HSCT levels. Activation occurred during the 4 first weeks following HSCT in 11 patients, between 6 and 8 weeks in 2 cases and later, after withdrawal of immunosuppression, in 2 patients. Pre-transplant characteristics (age at transplant, sex, underlying haematological disease, conditioning regimen, use of ATG, type of donor and CMV risk) of patients who showed an activation of complement were comparable to those who did not. We confirmed that activation of complement was significantly associated with acute GI GVHD (80 % in the activated group versus 5.3% in the non activated, p=0.0028) and occurred from 1 to 3 weeks before the appearance of clinical GVHD. Patients in the activated group had a significantly increased incidence of capillary leak syndrome concomitant to the conditioning toxicity or GVHD (66.7% in the activated group vs 10.5% in the non activated, p=0.019). There was no significant difference between the groups in terms of skin or hepatic acute GVHD, TMA, VOD and chronic GVHD. In a landmark analysis by day 100 post-HSCT, overall survival was significantly impaired in the group of patients with complement activation (p=0.008) because of increased toxicity related mortality (p=0.02) and relapse (p=0.01) risks in comparison to the patients without complement activation. Preclinical Results: Complement inhibitors capable of blocking the first pathway (C1 inhibitor esterase) or terminal complement activation (anti-C5 mAb) were used in a mouse model of GVHD. These inhibitors were administrated before and/or during the phase of activation of complement which starts on day 4 post-HSCT. However, GVHD clinical signs and mortality did not appear to be improved following complement inhibitor administration in this mouse model. Conclusion: Activation of complement after allogeneic HSCT following a myeloablative conditioning appears as a predictive marker of acute GI GVHD and a pejorative prognostic factor of transplant outcome. However, inhibition of complement activation in a mouse experimental model of allogeneic HSCT did not allow the control of GVHD. It is not clear, therefore, that this mouse model is useful as a model of human GVHD. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 4
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4560-4560
    Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used for the treatment of various hematological conditions with poor outcome. However, despite its effectiveness opportunistic infection, graft versus host disease (GVHD), drug toxicity and relapse frequently lead to life threatening complications and 15-20% of HSCT recipients ultimately require life sustaining therapies. Nowadays, a trend toward the use of less toxic conditioning regiments, different graft sources and better management of GVHD is observed. Also recent finding emphasize advances in the ICU management and triage policies of hematological patients. However, it is not known whether these changes altered the typology and outcomes of HSCT recipient admitted to ICU. We then performed a multicenter study to assess the impact of these changes. Methods All adults admitted in 3 ICU in Paris France from 1997 to 2011 were included if they previously received an HSCT. Data from medical charts were retrospectively retrieved and analyzed after the patients gave written informed consent. 497 patients were included, among whom 209 were admitted in the 1997-2003 period (this cohort was already published)1 and 288 in the 2004-2011 period. This corresponded to 2286 HSCT procedures over the same centers and period of time. Patients, HSCT characteristics and outcomes of the 2 cohorts were compared and prognostic factors analysis was performed in the recent period cohort. Results Over the time, HSCT recipients were more likely to be older (48 vs. 41 years old p 〈 0.001), transplanted with a reduced intensity conditioning (46% vs. 10% p 〈 0.001), peripheral blood mobilized stem cell (67% vs. 28% p 〈 0.001) and an unrelated donor (37% vs. 29% p 〈 0.001). ICU admission rate was 22% and remain stable over time (p=0,17). ICU admission triage was more frequent with less patients admitted with graft versus host disease (GVHD) stade over 2 (27% vs. 52% p 〈 0,0001) and absence of hematological remission (33% vs. 56% p 〈 0,0001). Admission occurred with a median time of 72 vs. 75 days after HSCT procedure with no difference over time p=0.68. Finally, organ dysfunction severity scores were not different between the 2 cohorts. We observed a significant survival improvement over the time as ICU, Day 90 and 1 year survival in the 2004-2011 cohort was respectively 71%, 49% and 37% vs. 48%, 31% and 21% previously. This was mainly due to improvements in the subset of patients requiring mechanical ventilation as shown in Figure 1. Also non-invasive ventilation use was similar between the 2 cohorts but more frequently successful (not followed by invasive ventilation) in the 2004-2011 cohort (51% vs. 33%). In the recent cohort, univariate analysis of Day 90 mortality showed that no demographic or HSCT parameter was associated with mortality. Only graft versus host disease (p 〈 0.001) and life sustaining therapies use (p 〈 0.001) CMV reactivation (p 〈 0.001) and invasive fungal infection (p=0.03) were found as mortality determinant. We then tested whether the strength of prognostic factors were changing with time using Gail and Simon interaction test and revealed that renal and respiratory failure and CMV reactivation were all three most strongly associated with mortality in the recent cohort. Logistic regression analysis revealed that, in the 2004-2011 cohort, the presence of acute GVHD stade 〉 2, mechanical ventilation and renal replacement therapy were independently associated with day 90 mortality. Conclusion Despite improvement of ICU care in HSCT patients with no GVHD, this study show that life-sustaining therapy still remains mostly unsuccessful when used in patients with GVHD and deep immunosuppression. These data argue for a more rational policy of ICU admission triage in HSCT recipient 1Pene, Aubron, Azoulay et al. J. Clin. Oncol. February 1, 2006; 24(4): 643 - 649. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 5
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 974-974
    Abstract: Patients (pts) suffering from mature (peripheral) T-cell lymphoma are known to have a poor outcome compared to pts with aggressive B-cell lymphoma when receiving conventional therapies. However, case reports and single centre experiences show promising results of allogeneic stem cell transplantation (allo SCT) for these pts. We here present a retrospective analysis of 103 pts with mature T-cell lymphoma who received an HLA-identical allo SCT in EBMT centres between 2000 and 2005. Histological subtypes of the patients were anaplastic large cell lymphoma (n=25; 4 anaplastic lymphoma kinase [ALK] positive, 11 ALK negative, 10 ALK unknown), peripheral T-cell lymphoma unspecified (n=51), angioimmunoblastic T-cell lymphoma (n=18) and aggressive T-cell lymphoma unspecified (n=9). Patients with primary cutaneous T-cell lymphoma or T-lymphoblastic lymphoma were excluded. Median follow up for surviving patients was 40 months (6–98), median age at allo SCT 42 years (18–68) and median time to allo SCT 17 months (3–233). 39 pts had failed a prior autologous SCT; 68 pts had chemosensitive disease at allo SCT (of these 15 in CR1) and 30 pts had chemorefractory or untested relapsed or progressive disease. Donors were HLA identical siblings for 73 and matched unrelated donors for 30 pts; 82 pts received peripheral blood stem cells. 54 pts were treated with reduced intensity conditioning before SCT. The cumulative incidence (CI) of acute graft versus host disease (GvHD) 100 days after SCT was 52% and had no effect on non-relapse mortality (NRM) or relapse rate (RR). 34 of 74 evaluable pts experienced chronic GvHD (14 limited, 20 extensive), CI 46% at 2 years. Introducing chronic GvHD as a time dependent covariate, this factor was associated with a higher NRM (p 〈 0.001) and a lower RR (statistically not significant), resulting in a lower progression free survival (PFS) (p=0.001). For all patients CI of NRM and RR at 3 years were 36.7% and 24.9%, respectively, resulting in 41.4% PFS and 46.9% OS. Median time to relapse / progression was 4 (1–18) months. In multivariate COX analysis for PFS refractory disease (relative risk 3.4, p=0.001), prior failed auto SCT (relative risk 2.6, p=0.001) and poor performance status at SCT (relative risk 2.5, p=0.04) were significant adverse factors. Additionally, there were trends for T-cell depleted grafts (p=0.1), CMV status other than negative-negative (p=0.1) and reduced intensity conditioning (p=0.2) to be adverse factors. A subgroup of 39 good risk pts (good performance status, chemosensitive disease, no prior autologous SCT) had a PFS of 59%. This retrospective analysis on allo SCT in peripheral T-cell lymphoma shows an encouraging low RR but efforts have to be made to reduce NRM. Prospective studies are warranted to further define pts who will profit from an early allo SCT.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 6
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3794-3794
    Abstract: Abstract 3794 Background: CMML is a heterogeneous disease with overall survival (OS) ranging from 12 mo to several years, where few series of allo-SCT have been published. This retrospective study aimed at determining prognostic factors for OS after allo-SCT in a group of consecutive 73 CMML patients reported to the SFGM-TC registry between 1992 and 2009. Methods: For this analysis, in addition to classical demographic and transplant characteristics, patient data at diagnosis and at transplant, including WHO classification in CMML 1 and 2, IPSS in patients with WBC 〈 13G/L, and prognostic factors published by the Groupe Francophone des Myélodysplasies (GFM) in CMML with WBC 〉 13G/l (unfavorable factors included: palpable splenomegaly (SPM), Hb 〈 10g/dl, Platelets 〈 100G/l, marrow blasts 〉 5%, abnormal karyotype, extramedullary disease) (Wattel et al, Blood 1996, 88:2480, Braun T., Blood 2011, online), interval between diagnosis and allo-SCT, and prior treatment were analyzed. Results: Patient characteristics at diagnosis were as follows: M/F 49/26, median age 53 yrs (range, 27–66). 30% pts had palpable SPM, 70% WBC 〉 13×10^9/L. 48/12/9 pts had good/int/poor risk karyotype according to IPSS, including normal (n=47), monosomy 7 (n= 7) and abn 8 (n= 5). 61%pts had CMML1, and 39% CMML-2. Of the 22 patients with WBC 〈 13G/l, six had int-2 and 1 had high risk IPSS, while of the 45 patients with WBC 〉 13G/l, 37 had at least 2 of the GFM poor prognostic factors (see above). Before allo-SCT, 26 pts had received intensive anthracycline-cytarabine chemotherapy (CT), 21 low dose CT (18 HY, 3 VP16) and, 6 hypomethylating agents. Forty pts (56%) developed infection (bacterial or fungal) between diagnosis and allo-SCT. Median interval from diagnosis to allo-SCT was 10.6 mo (range 2.8–80). At time of allo-SCT, 26 pts (49%) had responded to therapy (19 CR and 7 PR), while 42 pts were treatment failure or in relapse, or had not been treated, including 5 AML progressions, (80% CMML1 and 13% CMML 2, while, in 52 pts with WBC 〈 13 G/L, 8 and 6 had IPSS int-2 and high respectively, and, in 16 pts with WBC 〉 13G/l, 9 had at least 2 GFM poor prognostic factors).19 pts still had palpable SPM before allo-SCT. The donor was an HLA-identical, unrelated and haploidentical sibling in 41/31/1 cases respectively. 30pts (41%) received a myeloablative conditioning (MAC) regimen, while 43pts (59%) received reduced-intensity conditioning (RIC). With a median follow-up of 23 mo (1–145), grade 0–1 acute GVHD developed in 23 pts, grade 2–4 in 21 pts. Chronic GVHD was present in 25 pts (35%) (limited:15, extensive: 10; cum incidence: 37% at 3 yrs).The 2- and 3-yr OS were 42% and 32%, respectively. 45 patients had died (23 NRM, 19 disease progression, and 3 unrelated). The 3-yr cum incidence of NRM was 36%. The 3-yr relapse-free survival was 30%. OS was not influenced by the disease status at allo-SCT, including CMML1 vs CMML2, IPSS score (WBC 〈 13G/l) and GFM score (WBC 〉 13G/L), the number of prior treatments, HLA matching, cGVHD. However, palpable SPM at diagnosis was a negative prognostic factor for OS (2-yr OS: 57% vs.15%, p=0.009). 3-yr OS was 33% after MAC conditioning vs 49% after RIC conditioning (p=0.17). In multivariate analysis, the strongest prognostic factor for OS was palpable SPM at diagnosis (HR=2.79 95% CI: 1.38–5.68; p=0.005). Conclusion: Allo-SCT is a valid treatment option for CMML patients eligible to this treatment. Palpable SPM at diagnosis was the only independent negative prognostic factor. Most pts were however treated before the advent of hypomethylating agents. The use of RIC regimens combined to those agents (and possibly to other novel agents) prior and after allo-SCT may further improve outcome. Disclosures: Park: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Yakoub-Agha:celgene: Honoraria, Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 7
    In: Blood, American Society of Hematology, Vol. 118, No. 19 ( 2011-11-10), p. 5099-5107
    Abstract: Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/Blow) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/Blow in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/Blow and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 8
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 1965-1965
    Abstract: MCL is a relatively rare, but aggressive subtype of non-Hodgkin’s lymphoma. The current standard therapeutic approach for MCL combines rituximab–containing chemotherapy, followed by autologous stem cell transplantation. Using such approach, most patients will achieve complete remission (CR). However, almost all patients will experience relapse with MCL being an uncurable disease. With this background, and given its curative potential, reduced intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) may represent an attractive strategy in MCL. Here, we report a large multicenter retrospective analysis including 60 MCL patients who underwent RIC-allo-SCT. In this series, 43 patients were males. All patients but one, received at least one line of chemotherapy prior to RIC-allo-SCT including auto-SCT in 37 cases. The median number of previous therapies was 2 (range, 0–5). At time of RIC-allo-SCT, 26 patients were in CR, 20 in PR, while 14 were in stable/progressive or refractory disease. Median age at time of transplantation was 56 years (range, 33–67). Median time between diagnosis and transplantation was 3.5 years (range, 0.5–10). PBSCs were used in the majority of cases (n=56). HLA-identical sibling donors were used in 25 cases. HLA-mismatched or HLA-matched unrelated donors were used in the remaining 35 cases. Different RIC regimens were also used: fludarabine-busulfan-ATG in 17 cases, fludarabine and low-dose TBI in 10 cases, fludarabine-melphalan-ATG-rituximab in 6 cases, and other various regimens in 27 cases. In all, the RIC regimen included low-dose TBI in 14 cases, fludarabine in 56 cases and ATG in 34 cases. The median follow-up for surviving patients was 2 years (range, 0.1–8.5). Fifteen patients died of non-relapse-related causes, while 6 patients did not engraft. Disease-related deathes accounted for 6 cases. The 3-years OS estimate was 47% (95%CI, 31–60). According to disease status at transplantation, the 3-years OS estimates for patients who reached CR were 59% (95%CI, 34–77) as compared to 36%(95%CI, 8–65.5) for patients who reached PR and 17% (95%CI, 1– 49) for all others (P=0.001). According to disease status at transplantation (excluding those patients who failed to engraft), the 3-years EFS estimates for patients who reached CR were 68.5% (95%CI, 42–85) as compared to 45% (95%CI, 15–72) for patients who reached PR and 21% (95%CI, 1–57) for all others (P=0.005). Interestingly, the number of lines of chemotherapy administered prior to RIC-allo-SCT had no significant impact on OS and EFS Despite its retrospective nature, and the heterogeneity of the patients included in this analysis, these results suggest that RIC-allo-SCT may be an effective therapy in MCL, especially in those patients with a chemo-sensitive disease at time of transplantation, irrespective of the number of lines of prior therapy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 9
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 1494-1494
    Abstract: Background: In recent years, oncogenic understanding of T-ALL has led to the identification of multiple molecular markers. However, each molecular abnormality accounts for a small proportion of cases and risk stratification at diagnosis still relies on age, clinical presentation, and early response to therapy. NOTCH1 and/or FBXW7 mutations have been recently reported to be a recurrent abnormality in T-ALL, both leading to activation of the NOTCH pathway. Studies in pediatric series have suggested a favorable outcome for NOTCH1 mutated T-ALL, but this has not been evaluated in large series of adult cases. Furthermore, FBXW7 prognostic impact remains unknown in both populations. Methods: In order to evaluate the incidence of these mutations and their prognostic impact in adults, we performed a retrospective analysis of 141 patients (median age, 28 years) with T-ALL treated within the LALA-94 (N=87) or the more recent GRAALL-2003 (N=54) French trials. These patients were representative of the overall population since their outcome did not differ from the overall T-ALL cases treated in either LALA-94 (estimated 3-year OS, 41%) or GRAALL-2003 (estimated 3-year OS, 66%) trial. Furthermore, the patients from the LALA-94 and the GRAALL-2003 trials did not differ with respect to sex ratio, age, WBC, and initial complete remission rate (92% and 98%, respectively). Exons 26 (HD N-terminal), 27 (HD C-terminal), 28 (juxtamembrane domain) and 34 (transactivation domain TAD and the PEST domain) of NOTCH1 and exons 9, 10 and 12 of WD40 domain of FBXW7 were sequenced. Results: We identified 101 cases with NOTCH1 and/or FBXW7 mutations (72%) and 40 wild type (WT) samples (28%). NOTCH1 was mutated in 88 patients (59 HD only, 15 HD+PEST, 9 PEST only, 5 other). FBXW7 was mutated in 34 patients, alone in 13 cases or in association with NOTCH1 mutations in 21 cases. There was no significant correlation between NOTCH1 and/or FBXW7 mutations and immunophenotypic or oncogenetic features. There was a trend for a higher WBC and more frequent CNS involvement in patients demonstrating WT NOTCH1 and FBXW7. Similarly, high-risk MRC/ECOG criteria (age & gt;35y and/or WBC & gt;100G/L) were found in 56% of patients from the mutated subgroup versus 73% in the WT subgroup (P=0.06). The prognostic impact of NOTCH1 mutations alone did not reach statistical significance on multivariate analysis (P=0.09). On the other hand, multivariate analysis showed that the GRAALL-2003 trial and the presence of NOTCH1 and/or FBXW7 mutations were the only factors associated with a longer EFS (P=0.001 and 0.035, respectively). Median EFS was 36 months for patients with NOTCH1 and/or FBXW7 mutations versus 17 months for WT patients. Conclusions: These data demonstrate that NOTCH pathway activation by either NOTCH1 or FBXW7 mutation identifies a large group of T-ALL adult patients (72%) with a favorable outcome that could be used for treatment stratification.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 10
    In: Blood, American Society of Hematology, Vol. 109, No. 4 ( 2007-02-15), p. 1408-1413
    Abstract: The combination of imatinib with chemotherapy has been recently reported as very promising in patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). During 2004 and 2005, 45 patients with newly diagnosed Ph+ ALL were treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAAPH) 2003 study, in which imatinib was started with HAM (mitoxantrone with intermediate-dose cytarabine) consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). Imatinib was then continuously administered until stem cell transplantation (SCT). Overall, complete remission (CR) and BCR-ABL real-time quantitative polymerase chain reaction (RQ-PCR) negativity rates were 96% and 29%, respectively. All of the 22 CR patients (100%) with a donor actually received allogeneic SCT in first CR. At 18 months, the estimated cumulative incidence of relapse, disease-free survival, and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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