Azacitidine in Relapsed and Refractory AML: Efficacy for Patients Relapsing As MDS Post AML

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4332-4332
Author(s):  
Sarah Ivanoff ◽  
Emilie Lemasle ◽  
Berengere Gruson ◽  
Lavinia Merlusca ◽  
Amandine Charbonnier ◽  
...  
Keyword(s):  
Overall Survival ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Regulation Of Gene Expression ◽  
Complete Response ◽  
Allogeneic Transplantation ◽  
Dna Methyltransferases ◽  
Duration Of Response ◽  
Myeloid Neoplasia ◽  
Refractory Aml

Abstract Abstract 4332 Background: Azacitidine (Aza), inhibitor of DNA methyltransferases, plays an important role in epigenetic regulation of gene expression and tumorogenesis, and is active in myeloid neoplasia such as myelodysplasia (MDS) and de novo acute myeloid leukemia (AML). Efficacy of Aza for relapsed and refractory AML has not been so far reported. Methods: We report in 2 french centers (Amiens, Rouen) retrospective study, the results of Aza for relapsed or refractory patients. All patients received Aza (75 mg/m2 per day over 7 days for 4 weeks cycles), until progression, and at least one cycle. Leukocyte blood count was < 10109/l. The primary endpoint was overall response rate (ORR), according to IWG 2006: complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD), hematological improvement (HI). Secondary endpoints were duration of response and overall survival (OS). Results: 41 patients (26 males and 15 females) with a median age of 59 years (range 28–78) were studied from August, 2007 and November, 2011 (Table): 15 had refractory and 26 relapsed AML. At relapse 11/26 had MDS, defined by blast count <20% and cytological morphology of MDS in bone marrow aspirate, and 15/26 AML. Patients received in average 6 cycles (1–30): 4 (1–7) for refractory; 7 (1–30) for relapsed (11 (3–30) for MDS post AML; 3 (3–5) for relapsed AML). Overall, the ORR was 34% (7 CR, 5 RP, and 9 HI). For patients with MDS post AML OR was 82% (7 CR, 2 RP, 7 HI), 13% (1 RP, 1 HI) for relapsed AML, and 13% (2 PR and 1HI) for refractory AML. The average duration of response was 4 months (0–39) for the 41 patients: 14 months (0–39) for MDS post AML, 0.3 for relapsed AML, and 0.5 for refractory. Overall survival from diagnosis was 29 months (6.9–87): 38.2 (12–57) for MDS post AML, 30.1 (6.9–87) for relapsed AML and 13.3 (6.9–35.5) for refractory (no significant differences). Overall survival from initiation of Aza was 9.4 months (1.1–39.2): 22.6 (4.8–39.2) for MDS post relapsed and 3.9 (0.3–11.3) for relapsed AML and 6.2 (1.1–13.3) for refractory patients. The differences are not statically significant probably due to small effective of our study. Contrarily to the others 2 groups, 6 patients (55%) with MDS post AML are alive in CR at the latest report; moreover three of them underwent an allogeneic transplantation. Conclusion: Aza seems to efficient for relapsed AML patient, especially for MDS post AML, but inappropriate for refractory patients. Disclosures: No relevant conflicts of interest to declare.

Efficacy and Safety of 5-Azacytidine Based Regimens in Old AML patients: a Retrospective Study of 29 Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4148-4148
Author(s):  
France Roszkiewicz ◽  
Berengere Gruson ◽  
Ioana Vaida ◽  
Gandhi Damaj ◽  
Bruno Royer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Retrospective Study ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Overall Response ◽  
Co Morbidity ◽  
Significant Difference ◽  
Wbc Count

Abstract Abstract 4148 Background 5-azacytidine (AZA) is an hypomethylating drug. The international multicenter AZA-001 trial established that AZA significantly improves overall survival (OS) in patients with high risk myelodysplastic syndromes (MDS) compared with conventional care regimens (Fenaux, Lancet Oncol 2009). Some recent reports have raised the question of a possible efficacy of AZA in selected patients with acute myeloid leukaemia (AML). In this study we retrospectively analysed the safety and efficacy of a 7 days-schedule of AZA alone or in combination with an HDAC inhibitor, Valproic acid (VA) and with All-trans retinoic acid (ATRA) in patients with newly-diagnosed and refractory/relapsed AML not eligible for intensive chemotherapy. Patients and Methods A monocentric retrospective study from October, 2006 until March, 2009 analysed 29 patients with AML. Among these patients. There were 11 males and 18 females, median age 70,8 years (range 51,2-84,1), AML de novo in 15 patients (3 relapse) and secondary in 14 patients (2 post MPD and 12 post MDS). Median WBC count was 2,5 (range 0,7-140).109/L, 4 patients had WBC more than 10.109/L. The median rate of bone marrow blasts is 30%. 12/27 (44%) patients and 15/26 (56%) have respectively an intermediate and poor risk caryotype. Fifteen (54%) were newly-diagnosed patients, 14 (46%) were refractory/relapsed patients. Median co morbidity index (Sorror, J Clin Oncol 2007) of patients is 2 (0-7). Patients received daily AZA 75mg/m2 J1-J7, ± VA 35 to 50 mg/kg J1-J7 and ATRA 45mg/m2 J8-J28 every 4 weeks. Results 5 azacytidine was used alone for 6/29 (21%) patients and in combination with VA and ATRA for 23/29 (79%) patients. Compliance to the planned therapy was good. Average number of AZA administration was 6 days. To date a total 150 treatment-cycles with a median of 5 cycles/patient were applied (1-14). Treatment was well tolerated. Neutropenia grade3III and thrombopenia grade3III occurred respectively in 26/150 cycles (17%) and in 31/150 (20%). Infections grade3III were observed in 14/150 cycles (9,3 %). Overall response was 62% (17/29): 9 complete response (CR=31%), 3 partial response (PR=10%), 5 haematological improvement (HI=21%), There were 2 stable diseases (SD=7%). 28% of responses were obtained after 1 cycle, 56% after 3 and 89% after 4. Median overall survival (OS) was 13,2 months (0.3-26). We did not observe any significant difference on OS regarding: age, cytogenetics, de novo vs secondary AML, newly diagnosed vs refractory/relapsed patients. OS for patients with SD was similar to patients with CR, PR or HI. WBC >10.109/L before treatment was not correlated with a shorter survival (7.73 months vs 13.2 months p=0,6). Correlation was found between OS and clearance of the creatinine (p=0.005). In conclusion, AZA based regimens seems well tolerated and an effective treatment in AML, with an overall response of 62% and an OS of 13,2 months. A minimum of 4 cycles of treatment is necessary to evaluate the efficacy. OS of patients achieving CR, PR or HI is not significantly different of those with SD. Treatment should be continued until progression of the disease. Disclosures: No relevant conflicts of interest to declare.

Count Recovery in AML Patients Achieving a Complete Response.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2062-2062 ◽  
Author(s):  
Steven Lawrence Rosinski ◽  
Farhad Ravandi ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Sherry Pierce ◽  
...  
Keyword(s):  
Recovery Time ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Platelet Recovery ◽  
Neutrophil Recovery ◽  
Secondary Aml ◽  
Recovery Times ◽  
Md Anderson ◽  
Count Recovery

Abstract Abstract 2062 Poster Board II-39 AML is typically defined as “de novo” or “secondary”, the latter referring to patients diagnosed only after persistent blood count abnormalities (AHD) or after prior “chemotherapy” (PCT) for other illnesses. Patients with secondary AML may have a different bone marrow microenvironment leading to prolonged neutrophil and platelet recovery times following induction chemotherapy. Accordingly, we compared time from start of chemotherapy to neutrophil recovery (>1,000/μl) and platelet recovery (>100,000/μl) in 424 patients who achieved a complete response (CR) following treatment with ara-C-containing induction therapy at MD Anderson Hospital from 1995 to 2008. We divided the 424 patients as follows: (1) no AHD, no PCT (236 patients); (2) AHD, no PCT (131 patients); (3) PCT, no AHD (28 patients); and (4) AHD and PCT (29 patients). Because time to recovery may also be influenced by cytogenetics and age we subdivided patients in each of the four groups according to age (< vs. ≥ 60) and cytogenetics (normal vs. complex or -5/-7). Despite very differing CR rates, time to neutrophil recovery in patients achieving CR while statistically longer in PCT patients (p=0.05) was from a medical standpoint essentially uninfluenced by AHD and PCT status (table, median delays 2 days with PCT). Platelet recovery was affected by such status (p<0.001) being delayed by a median of 6-8 days in patients who had received PCT. Age had no effect on time to neutrophil (p=0.42) or platelet (p=0.23) recovery, while complex or -5/-7 cytogenetics had a statistically significant (p=0.002 neutrophils, 0.009 platelets) but medically insignificant (median delays of 2 days) effect on recovery time. There was no interaction between age or cytogenetics and AHD or PCT status. A similar analysis in patients who do not achieve CR would be of interest, but might be confounded by the difficulty in distinguishing between the effects of chemotherapy and those of residual AML on count recovery. Our data suggest that older patients, patients with complex or -5/-7 cytogenetics, and patients with secondary AML should not be excluded from clinical trials because of concern about prolonged time to count recovery. Group CRs CR Rate Median Days to > 1000 Neut Median Days to > 100,000 Plt No AHD no PCT 236 68% 27 28 AHD no PCT 131 50% 27 30 PCT no AHD 28 44% 29 34 AHD + PCT 29 35% 30 36 Age < 60 255 64% 28 29 Age ≥ 60 169 48% 26 30 Normal cyto 281 69% 27 29 Complex cyto or -5/-7 143 41% 29 31 Disclosures: No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Cell Transplantation with FLAMSA-RIC Can Overcome the Poor Prognosis of Primary Refractory or Relapsed AML

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1938-1938
Author(s):  
Dominik Schneidawind ◽  
Birgit Federmann ◽  
Christoph Faul ◽  
Wichard Vogel ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Overall Survival ◽  
Salvage Therapy ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Free Survival ◽  
Secondary Aml ◽  
Off Label ◽  
Dismal Prognosis ◽  
De Novo Aml ◽  
Refractory Aml

Abstract Abstract 1938 Introduction: Patients with relapsed or primary refractory AML have a dismal prognosis. Even salvage therapy with allogeneic hematopoietic cell transplantation (HCT) could not improve outcome due to high incidence of relapse and high non-relapse mortality (NRM). Recently, promising results in patients with unfavorable karyotype or treatment refractory AML have been reported using a sequential treatment with aplasia inducing chemotherapy consisting of Fludarabine, Ara-C and Amsacrine (FLAMSA) followed within 3 days by reduced intensity conditioning (RIC) for allogeneic HCT (Schmid et al., Blood 2006 Aug 1;108(3):1092–9). Methods: We report a retrospective analysis of our single center experience with FLAMSA-RIC in primary refractory or relapsed AML patients. We searched our database for patients receiving FLAMSA-RIC in the past 10 years. Details on characteristics and clinical course of the patients were confirmed by retrospective chart review. Results: We retrospectively identified and analyzed 51 consecutive patients (f=22, m=29) transplanted after FLAMSA-RIC at our institution from 2006–2011. At time of HCT patients were refractory after chemotherapy (n=22) or had an untreated relapse (n=29). Data on molecular and cytogenetic markers were available in 36 and 44 patients, respectively. 34 were initially high-risk because of unfavorable karyotype (n=25) or molecular genetic alterations (n=9). Median age of patients was 56 years (range, 20–72) and diagnosis of all patients was acute myeloid leukemia (de-novo AML, n=27, secondary AML, n=24). FLAMSA (Fludarabine 30 mg/m2 day −12 to −9, AraC 2000 mg/m2 day −12 to −11 and Amsacrine 100 mg/m2 day −12 to −9) was used as salvage therapy followed by RIC (Fludarabine 30 mg/m2 day −5 to −4/Busulfan 0.8 mg/kg day −6 to −4, n=10; TBI 4Gy on day −5/Cyclophosphamide 60 mg/kg on day −4 to −3, n=28; Busulfan 0.8 mg/kg day −6 to −4/Cyclophosphamide 60 mg/kg for matched and mismatched unrelated donors (MUD/MMUD) or 40 mg/kg for matched related donors (MRD) on day −3 to −2, n=13). As GVHD prophylaxis calcineurin inhibitor combined with mycophenolate mofetil and anti-thymocyte globuline (ATG-Fresenius®, 10 mg/kg for MRD and 20 mg/kg for MUD/MMUD) was used. 10 patients were transplanted from MRD, 16 from MUD, 21 from a MMUD and 4 from a MMRD. 14 patients received DLI (2 × 106 - 1 × 108 /kg after a median of 186 days, range 72–922) in absence of GVHD in case of mixed chimerism or relapse after HCT. Current overall survival (OS) was 18/51 patients with a median follow-up of 410 days (range, 179–1557) of patients alive resulting in a Kaplan-Meier estimated 2-year OS and event-free-survival (EFS) of 34% and 29%, respectively. There was no significant difference between the different RIC regimens with 50% Fludarabine / Busulfan vs. 26% TBI 4Gy / Cyclophosphamide and 40% Fludarabine / Busulfan (p=0.37). Causes of death were relapse (n=19), infections (n=5), GVHD (n=2), multi-organ-failure (n=5), cerebral hemorrhage (n=1) and progressive multifocal leukencephalopathy (n=1). Cumulative incidence of relapse at 2 years with death due to NRM as competing risk was 40% and cumulative incidence at 2 years of NRM with death due to relapse as competing risk was 27%. 2-year OS was inferior in patients with secondary AML compared to patients with de-novo AML (28% vs. 38% p=0.79). The outcome in the elderly subgroup defined by age ≥60 years (median age 67, n=22) was similar to the group of younger patients (median age 46, n=29) with 2-year OS of 31% vs. 37% (p=0.87). Patients with a blast count < 10% in the bone marrow at time of HCT had a better outcome with 64% vs. 25% OS (p=0.09). 2-year-OS was inferior in patients being refractory after chemotherapy (25% vs 38%, p=0.78). Incidence of acute GVHD (aGVHD) ≥II and chronic GVHD (cGVHD, limited, n=11, extensive, n=3) was 22% and 27%, respectively. Presence of aGVHD did not influence survival while presence of cGVHD was associated with an improved overall survival after HCT (58% vs 24%, p=0.009). Conclusion: FLAMSA-RIC followed by allogeneic HCT enables long-term disease free survival, even in primary refractory or relapsed AML patients. The sequential approach of this regimen seems to overcome the dismal prognosis of these patients. Its moderate toxicity allows the application of this curative salvage therapy option even in an elderly patient population. Disclosures: Off Label Use: The use of some agents in the conditioning is off-label.

Cytogenetic and Molecular Characterization of Extramedullary Disease (EMD) in Patients (pts) with Acute Myeloid Leukemia (AML).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2592-2592
Author(s):  
Naveen Pemmaraju ◽  
Hagop M. Kantarjian ◽  
Kathy M. Tran ◽  
Syed M. Kazmi ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lymph Node ◽  
Molecular Characterization ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Neck Lymph Node ◽  
Total Group ◽  
Molecular Abnormalities ◽  
Organ Systems

Abstract Abstract 2592 Background: The phenomenon of EMD in pts with AML has been previously noted. However, little is known about the cytogenetic and molecular characterization of these pts in the modern era of AML prognostic cytogenetic and molecular markers. Methods: We conducted a retrospective review of 2,181 consecutive pts with AML who underwent induction chemotherapy and were treated at our institution from 2000–2011. All pts included in this analysis had histologically-proven EMD-AML. Chi-squared test was used to assess complete response (CR) probability and Kaplan-Meier method was used to assess CR duration and overall survival (OS) outcomes. Results: Overall, 1,120 pts underwent biopsies/tissue sampling during the study period to evaluate for EMD-AML. 244 pts (11% of total group, 22% of those biopsied) were diagnosed (dx) with histologically proven EMD. 47 pts (2% of total group, 4% of pts biopsied, 19% of EMD pts) had EMD-AML at multiple sites. Median age of AML dx was 57 years (range 14–82 years). 135 pts were male (55%). Baseline CBC parameters at AML dx: WBC 9.5 (0–433), platelets 53 (0–581), Hb 8.7 (0–15.6). Median blasts at baseline AML dx: Peripheral 22% (0–99%) and bone marrow 56% (0–98%). EMD occurred at all phases of AML therapy course, with majority of EMD dx occurring at or after time of relapse (n=112, 46%), followed by concomitant at AML dx (28%), during induction therapy (15%) and prior to AML dx (11%). EMD sites were found throughout all major organ systems (Table 1). The specific sites most commonly affected by EMD included skin (n=84), CSF (n=76), pleural fluid (n=41), ascitic fluid (n=7), abdominal wall soft tissue (n=6), pelvic/inguinal lymph node (n=6), stomach (n=5), liver (n=5), cervical/neck lymph node (n=5), and bone (n=5). Cytogenetic abnormalities and molecular mutations were frequent features of EMD pts (Table 2, Table 3). Pts with EMD (n=156, 64%) were more likely to achieve CR than pts without EMD (n=1079, 56%, p=0.01). For those pts with EMD, CR duration was 59.0 months (95% CI 54.8–63.2 months), which was longer than for pts without EMD (CR duration, 43.5 months, 95% CI 40.7–46.4 months, p<0.0001). Overall survival (OS) of EMD pts (30.9 months, 95% CI 25.3–36.6 months) was significantly less than OS of non-EMD pts (43.5 months, 95% CI 40.7–46.4 months, p=0.04). Conclusion: Incidence of EMD in AML pts is common (11%) and occurs at all phases of disease course. Almost every organ system/tissue demonstrates involvement with EMD AML. Cytogenetic and molecular abnormalities are commonly associated with EMD AML pts, with FLT3 mutation being the most common molecular abnormality in this cohort (30% of evaluable pts) and deletion of chromosome 7 being most common chromosomal abnormality (14% of pts). While pts with EMD-AML had significantly longer CR duration, interestingly these pts were noted to have significantly shorter OS in this analysis, suggesting the unique biologic and clinical features of this subset of AML pts. Disclosures: No relevant conflicts of interest to declare.

ASXL1 Mutations in AML: Molecular Biomarker for Secondary AML?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2343-2343
Author(s):  
Jingmei Hsu ◽  
Anita J. Kumar ◽  
Martin P. Carroll ◽  
Noelle V. Frey ◽  
Nirav N. Shah ◽  
...  
Keyword(s):  
Overall Survival ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Myeloproliferative Neoplasm ◽  
Molecular Characteristics ◽  
Intermediate Risk ◽  
Kaplan Meier ◽  
The Impact

Abstract Background: Additional sex combs like transcription factor 1 (ASXL1) is a member of the polycomb group protein. ASXL1 mutation has been implicated in myeloid malignancy transformation. It is hypothesized that mutated ASXL1 leads to the loss of polycomb repressive complex 2 (PRC2) mediated gene repression and subsequent transforming events. Recent studies identify ASXL1 mutation as a poor prognostic marker in patients (pts) with de novo acute myeloid leukemia (AML) who present with intermediate–risk cytogenetic lesions (Patel, NEJM 2012; Schnittger, Leukemia2013). To study the impact of ASXL1 mutations in an unselected AML population, we analyzed clinical and molecular characteristics of patients with untreated AML who express ASXL1 mutation at presentation. Methods: Using next generation sequencing, 254 adult patients with AML seen at the Hospital of the University of Pennsylvania were analyzed for mutations, including ASXL1, using a 33-gene hematologic malignancy panel. Clinical characteristics were obtained from retrospective chart review. Kaplan-Meier estimates were used to calculate overall survival (OS) from time of diagnosis. Living patients were censored at date last seen. Results: ASXL1 mutations were detected in 36/254 (14%) AML pts. There were 29 known pathologic mutations, 1 benign, 1 probable pathologic, and 9 variants of unknown clinical significance (VUS). In 6/36 (16.7%) pts, ASXL1 was the sole mutation identified. Of the 30 pts with additional mutations (Figure 1), 6/30 (20%) pts harbored 2 independent ASXL1 mutations. When the 27 patients with pathologic ASCL mutations were analyzed for co-mutations, TET2 (13/27, 48%) was the most frequent ASXL1 co-mutation. FLT3 (0/27, 0%) and NPM1 (1/27, 3.7%) were notable for their absence. Median age of pts at diagnosis was 69 years (range 23-80). Prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) was noted in 9/36 (25%) and 11/36 (30.6%) pts, respectively. Four pts (11.1%) had received chemotherapy and/or radiation therapy for a prior non-myeloid neoplasm. Karyotype was normal in 18/36 (50%) pts, and 7 additional pts had intermediate cytogenetic lesions. There were 7 pts (19.4%) with unfavorable cytogenetics (complex karyotype (3 pts), 7q- (3 pts), and 5q- (1 pt)). Four pts (11.1%) had a favorable karyotype, with t(8;21) in 3 pts and t(15;17) in 1 pt. At presentation, median white blood cell count (WBC) was 6.4x103/uL (1.0 x -103). In pts whose AML transformed from prior MPN, median WBC was 50 X103/uL (3.3-140). Standard induction chemotherapy with an anthracycline and cytarabine was given to 17/36 (47%) pts. An additional 3/36 (8.3%) pts underwent induction therapy with clofarabine. Complete remission (CR) was documented in 14/20 (70%) evaluable pts. Of the remaining pts, 11 received a hypomethylating agent, and 5 received other therapies. Thirty-day treatment mortality for all 36 pts and for 27 pts with known ASXL1 pathologic mutation was 13.4% and 18.5% respectively. Kaplan-Meier estimate showed a median overall survival of 349 days (median follow up of 107 days (range 15-1570)). For the 27 pts with a pathologic ASXL1 mutation, the OS was 276 days (Figure 2, median follow up of 145 days (range 18-1570)). Conclusion: ASXL1 mutations in de novo AML with intermediate-risk cytogenetics is associated with poor clinical outcome in cooperative group trials. Strikingly we demonstrate in a single institution, retrospective analysis that 66.7% of pts who present with ASXL1 mutations in the setting of previously untreated AML had documented MDS, MPN and/or prior chemotherapy/radiation. Further studies are necessary to evaluate if ASXL1 mutation has independent prognostic significance in AML or if it is primarily a marker for secondary leukemia. Figure 1: ASXL1 and co-mutations Figure 1:. ASXL1 and co-mutations Figure 2: Overall survival for AML patients with ASXL1 pathologic mutation Figure 2:. Overall survival for AML patients with ASXL1 pathologic mutation Disclosures No relevant conflicts of interest to declare.

Clinicopathologic Characteristics and Outcome of Diffuse Large B-Cell Lymphomas Presenting With an Associated Low-Grade Component at Diagnosis

2006 ◽  
Vol 24 (33) ◽  
pp. 5234-5241 ◽  
Author(s):  
Hervé Ghesquières ◽  
Françoise Berger ◽  
Pascale Felman ◽  
Evelyne Callet-Bauchu ◽  
Paul-André Bryon ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
De Novo ◽  
Complete Response ◽  
Progression Rate ◽  
Low Grade ◽  
Control Analysis ◽  
B Cell Lymphomas ◽  
Response To Chemotherapy ◽  
Large B Cell

Purpose Some diffuse large B-cell lymphomas (DLBCL) present at diagnosis with associated morphologic features of small B-cell non-Hodgkin's lymphoma (NHL) and may arise from the transformation of a previously unknown indolent low-grade lymphoma. The characteristics and prognosis of these particular DLBCL are not well known. Patients and Methods The strict morphologic review of consecutive DLBCL patients diagnosed over 12 years in our department (Hematology Department, Centre Hospitalier Lyon-Sud, Lyon, France) allowed to retrieve 60 DLBCL that could be have occurred from the transformation of marginal zone B-cell NHL (32 patients), follicular NHL (22 patients), and small lymphocytic NHL (6 patients). We compared them to 180 matched patients of de novo DLBCL. Results Patients median age was 55 years and presented the following clinical characteristics: poor performance status in 33%, disseminated disease in 97%, more than one extranodal site in 50%, and increased lactate dehydrogenase level in 55%. Complete remission with multidrug chemotherapy regimens was achieved in 60% of the patients, but 48% relapsed: 28% with aggressive and 20% with indolent histology, respectively. Overall survival (OS) and freedom-from-progression rates at 5 years were 57% and 33%, respectively. The matched-control analysis showed that patients with transformed NHL at diagnosis had lower complete response to chemotherapy (P = .004) and higher progression rate (P = .03), whereas no difference was observed in OS (P = .21). Conclusion Compared to de novo DLBCL, transformed NHL at diagnosis have similar overall survival but lower complete response to initial treatment and higher risk of indolent relapses.

scholarly journals De Novo Nethyltransferases, DNMT3a and DNMT3b Are Underexpressed in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4818-4818 ◽  
Author(s):  
Pavla Latalova ◽  
Jiri Minarik ◽  
Katerina Smesny Trtkova
Keyword(s):  
Dna Methylation ◽  
Multiple Myeloma ◽  
Cell Lines ◽  
Plasma Cells ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Myeloma Cell ◽  
Dna Methyltransferases ◽  
Rt Pcr ◽  
Cpg Dinucleotides

Abstract Background and aims: Presently, there is growing evidence that along with the important role of genetic abnormalities, epigenetic aberrations are relevant factors in multiple myeloma (MM). As was recently found, genome-wide analysis of DNA methylation reveals epigenetic alterations in plasma cells from patients with MM and individuals with monoclonal gammopathy of undetermined significance (MGUS). MGUS is characterized by predominant hypomethylation. Transformation into MM is accompanied by progressive hypermethylation with maximum methylation seen in relapsed disease. DNA methyltransferases (DNMTs) catalyze DNA methylation through transfer of methyl group to cytosine of the CpG dinucleotides, resulting in 5-methylcytostine. DNMT1 maintains patterns of methylated cytosine residues in human genome. DNMT3A and DNMT3B are de novo DNA methyltransferases, whose role is to maintain new methylation pattern that forms due to formation of the cancer. Methods: 30 bone-marrow aspirates from individuals with MGUS or MM patients before the treatment initiation were used. The cDNA was synthesized using 100 ng of total RNA in a 20 µl reaction volume (Roche, Diagnostics, Basel, Switzerland). Quantification of DNMT1, DNMT3a and DNMT3b levels by TaqMan® probes (Life Technologies, Grand Island, NY) with Xceed qPCR Master Mix (IAB, BioTech-Europe, Czech Republic) was performed. For normalization, the GAPDH was used. Results: Although MM is characterized by widespread alterations in DNA methylation, we observed that DNMT3a and DNMT3b de novo methyltransferases were underexpressed in both, MGUS individuals and MM patients when compared to DNMT1 expression level (Figure 1). The transcribed genes have increased levels of 5-hydroxymethylcytosine, then the DNMTs activities might compensate for active hydroxymethylation - demethylation. Conclusions: Our results confirm that the expression of de novo DNA methyltransferases is deregulated in MM cell lines. The presented analysis is first of its kind that was performed on human myeloma cell lines, especially with the focus on the residual expression of Dnmt3a. With support of the grant NT14393. Figure 1. Quantitative RT-PCR for DNMT1, DNMT3a and DNMT3b in MGUS individuals and MM patients. Figure 1. Quantitative RT-PCR for DNMT1, DNMT3a and DNMT3b in MGUS individuals and MM patients. Disclosures No relevant conflicts of interest to declare.

The Optimal Initiation Timing for Cyclosporine in Allogeneic Transplantation, Earlier Is Better with the Price of Higher Rate of Chronic Gvhd.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1143-1143
Author(s):  
Liliane Dray ◽  
Aliza Matusevich ◽  
Igor Resnick ◽  
Memet Aker ◽  
Simcha Samuel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Allogeneic Transplantation ◽  
Hazard Ratio ◽  
Blood Levels ◽  
Kaplan Meier ◽  
Donor Type

Abstract Abstract 1143 Poster Board I-165 Introduction Cyclosporine (CSA) is the backbone of graft vs. host disease (GVHD) prophylaxis in the last decades. It is established that CSA levels in the 1st weeks after transplant are critical for the rate and severity of GVHD. Initially, we gave CSA starting on day -1 in all our protocols. However, 8 years ago, we have changed CSA initiation in most of our protocols to day -4 in order to have stable, controlled therapeutic blood levels of CSA prior to transplant. Since nowadays the use of CSA is the most widespread prophylaxis of GVHD, we found it essential to compare the initiation of CSA on day -4 to day -1, consecutively determining the preferred initiating timing of CSA for patients who undergo allogeneic transplantations. Methods Out of 1716 patients that underwent allogeneic transplantation, we identified 2 groups of patients that received T-cell repleted grafts in which only CSA was used for GVHD prevention, starting on days -1 or -4 (n=219 and 261 respectively). The guidelines for CSA cessation and DLI were uniform in both groups. Both groups were compared for age, sex, donor type and matching, disease, disease status upon transplant, graft type, engraftment, GVHD (both acute and chronic), GVHD associated death and overall survival. Results The groups were found to be equal for age (p=0.83), sex (p=0.58), donor type (p=0.54), matching (p=0.98), disease type (malignant or non-malignant; p=0.25), graft type (PBSC or BM; p=0.45) and disease status (remission or active; p=0.42). The median time to ANC>500 was 16 and 15 days in the CSA -1 and -4 groups respectively with a trend toward better engraftment with initiation of CSA on day -4 (figure 1A, P=0.07). However, platelet engraftment was significantly better with CSA -4, with a median of 14 and 12 days in the CSA -1 and -4 groups respectively (figure 1B, p=0.0005). 112 and 138 patients developed acute GVHD (aGVHD) of any grade, respectively. Out of them 54% and 44% had severe (grade 3-4) aGVHD (p=0.45). The median time to aGVHD was similar, with a median of 29 and 28.5 days in the CSA -1 and -4 groups respectively (p=0.54). However, 64 patients developed cGVHD in the CSA -1 group, while 102 did so in the CSA -4 group (figure 2A, p=0.0002. Hazard ratio 0.59, 95% CI 0.37 to 0.73). Of these patients, 46.8% and 40.2% of the patients had extensive cGVHD (p=0.70), respectively. Additionally, despite lower GVHD rate in the CSA -1 group, GVHD associated death occurrence was more frequent then in the CSA -4 group (41/148 and 17/132 patients, p=0.02). Kaplan Meier analysis of all cause mortality showed higher mortality in the CSA -1 group (67.6% and 50.5%, figure 2B, p=0.074. Hazard ratio 1.24, 95% CI 0.98 to 1.58). Conclusions The initiation of CSA on day -4 improves engraftment, conversely increases the risk for cGVHD of any grade (possibly through prevention of tolerance), but reduces the risk of GVHD associated death and improves overall survival. Disclosures No relevant conflicts of interest to declare.

Overall Survival by Prognosis Score in High-Risk Myelodysplastic Syndromes (MDS) Patients Receiving Decitabine Treatment: Results From Clinical Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5024-5024
Author(s):  
Marcelo Iastrebner ◽  
Jun Ho Jang ◽  
Kihyun Kim ◽  
Chul W. Jung ◽  
Elsa Nucifora ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Life Expectancy ◽  
Stable Disease ◽  
Myelodysplastic Syndromes ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Prognosis Score

Abstract Abstract 5024 Background The DNA-targeted hypomethylating agent, decitabine, has made a real impact on response rate in Myelodysplastic Syndromes (MDS) patients, and may improve overall survival in high-risk patients. Aim: To describe overall survival by prognosis score in decitabine-treated MDS patients. Methods: From May 2007 to January 2011, MDS patients who received decitabine were followed at centers in Argentina and South Korea. Patients ≥18 years of age with de novo MDS (all WHO Subtypes and CMML type-1 and type-2) were included, provided they had received ≥4 cycles of decitabine (recommended dose, 20 mg/m2 IV over 1 hour × 5 days every 4 weeks) and had stable disease or better by IWG 2006 criteria. Median life expectancy was determined according different categories of the MD Anderson and International Prognostic Scoring Systems (MDAPSS and IPSS). Decitabine treatment was effective when the patient outlived the median life expectancy. Results: Sixty-one patients received ≥4 cycles of decitabine and had stable disease or better. Median age was 61 years and 69% were male. All patients had de novo MDS with ECOG ≤2. Median time from MDS diagnosis was 24 months. Baseline WHO classification was: RA (0%); RARS (2%); RCMD (18%); RCMDRS (3%); RAEB-1 (13%); RAEB-2 (30%); MDS/MPD (2%); AML/MDS (5%); CMML type-1 (21%); and CMML type-2 (6%). Forty one percent had comorbidities. Patients received a median of 8 cycles of decitabine (range, 4–18). Forty four percent died during the study and 31% progressed to AML. Median overall survival was higher than life expectancy among patients with high-risk MDS by MDAPSS (Kantarjian H. et al. Cancer 2008; 113: 1351) and by IPSS (Greenberg P. et al. Blood 1997; 89: 2079). Survival exceeded life expectancy for 90%, 100%, and 86% of patients with MDAPSS 7–8, MDAPSS ≥9, and IPSS Int-2 + High, respectively. Conclusion: High-risk MDS patients who received ≥4 cycles of decitabine and had stable disease or better showed improvement in survival compared with predicted life expectancy published in literature.Median OS, MonthsPredictedActual*p-ValueMDAPSS (N=61)0–454395–625697–81431> 96230.014IPSS (N=58)Int-14237Int-2 + High14 to 5290.001*Kaplan-Meier and log-rank Test (Mantel-Cox). Disclosures: No relevant conflicts of interest to declare.

Outcome of BEAM-Autologous and BEAM-Alemtuzumab Allogeneic Transplantation in Relapsed Advanced Stage Follicular Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2022-2022
Author(s):  
Victor Noriega ◽  
Anjum Bashir Khan ◽  
Stephen Devereux ◽  
Robert E. Marcus ◽  
Michelle Kenyon ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
High Grade ◽  
Advanced Stage

Abstract Abstract 2022 Introduction: Follicular Lymphoma is the most common indolent lymphoma, characterized by an indolent course, multiple recurrence, responses to chemotherapy, risk of transformation into a high grade lymphoma and with a median overall survival of 10–12 years. Transplantation (autologous and allogeneic) has improved the overall outcome of this disease, however a continuous pattern of relapse is observed essentially in the autologous setting. Allogeneic transplant has shown encouraging results in terms of long term overall survival (OS) and disease free survival (DFS), with acceptable transplant related mortality (TRM) and with significantly lower relapse rate. Objective: To analyse retrospectively the outcome of relapsed follicular lymphoma patients who received BCNU (carmustine), cytarabine, etoposide, melphalan-alemtuzumab allogeneic HSCT (BEAM-C allo) or BEAM-autologous HSCT (BEAM-auto). Results: The study includes 74 consecutive patients with relapsed advanced stage follicular lymphoma who received BEAM-C allo (n=38) and BEAM-auto (n=36) between 1992 and 2010. Patients characteristics are summarized in Table 1. Median follow-up of surviving patients was 6.1 years. Patients undergoing allo transplants were younger than those who unbderwent and autologous procedure (50 vs 54 years, p=0.018). 1y and 5y TRM was higher in the allo transplant group (27% and 27% vs 6% and 6%; p=0,011). The Cumulative incidence of relapse (CIR) was lower in the allo at 1, 2 and 5 years (11%, 14% and 18% vs 28%, 49% and 60%, p=0,000). Significant differences were not observed in 1, 2 and 5 years OS between allo and auto transplant groups (74%, 74% and 69% vs 85%, 69% and 51%; p=0,217), but we found a strong trend in DFS difference between both groups at 1, 2 and 5 years (65%, 61% and 58% vs 69%, 43% and 33%; p=0.089) observing a plateau around 60% after 2 years in the allograft group. The rate of graft versus host disease (GvHD) was low with 14% acute GvHD (2.6% grade 3–4 GvHD) and 28% chronic GvHD (10% of extensive chronic GvHD). Analysis of the whole cohort (n=74) showed that patients in CR before transplant (n=28) had better 1, 2 and 5 years DFS following a allotransplant (69%, 69% and 69% vs 79%, 36% and 18%; p=0.012). These differences did not affect the 1, 2 and 5 years OS (76%, 76% and 76% vs 93%, 76% and 56%; p=0,214). TRM for the allo transplant group was 24% and 0% R in the auto (p=0,064) in patients when achieved CR before transplant. There were no difference in OS (p=0,785) and DFS (p=0,954) between allo or auto patients in partial response (PR) before transplant. A subgroup analysis of patients with high grade transformation before transplant did not show any differences in OS (p=0,823) or EFS (p=0,526).between allo and auto groups. Conclusions: Long term follow-up of Follicular Lymphoma patients has shown a continuous pattern of relapse when patients receive an autologous transplant, after 5 years. whereas patients undergoing allo transplant, despite a higher mortality, have a 5 year OS and DFS of 60% with a plateau been achieved in both curves after 2 years suggesting that these patients may be cured. Prospective randomised studies are still required to answer the the role of these two approaches in follicular Lymphoma. Disclosures: No relevant conflicts of interest to declare.

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