scholarly journals Safety and Short-Term Efficacy of Venetoclax Combined with Azacitidine in Acute Myeloid Leukemia: A Single Institution Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4413-4413
Author(s):  
Wen-Jing Yu ◽  
Jinsong JIA ◽  
Jing Wang ◽  
Fei-Fei Tang ◽  
Lizhong Gong ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Active Infection ◽  
Standard Chemotherapy ◽  
Short Term ◽  
Poor Risk ◽  
The Poor ◽  
Grade 3

Abstract Introduction The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor (venetoclax) combined with hypomethylating agents (azacitidine) has shown promising activity in patients with acute myeloid leukemia (AML). However, there are no single center real-world research results with relatively large sample size in China. The purpose of this study is to explore the safety and short-term efficacy of venetoclax combined with azacitidine (Ven + AZA) in previously untreated patients who were ineligible for standard chemotherapy and patients with relapsed/refractory (R/R) AML in China. Methods A retrospective study was conducted on 60 previously untreated patients who were ineligible for standard chemotherapy and patients with R/R AML who received Ven + AZA (venetoclax，100mg D1、200mg D2、400mg D3-28；azacitidine, 75mg/m2 D1-7) in the Peking University Institute of Hematology from March 15, 2019 to May 20, 2021. The incidence of adverse events (AE), complete remission (CR)/CR with incomplete hematological recovery (CRi) rate, objective remission rate (ORR) and minimal residual disease (MRD) status in patients with different risk stratification and different gene subtypes were analyzed. Results Patient Characteristics The median age was 54 (18-77) years, 33 males (55.0%), and the median follow-up time was 4.8 (1.4-26.3) months. Among the 60 patients, 24 (40.0%) were previously untreated patients who were ineligible for standard chemotherapy and 36 (60.0%) were R/R patients. The median cycles of Ven + AZA in the two groups were both 1 (1-5). The median follow-up time of them were 2.9 (1.5-13.2) and 118 (1.4-26.3) months, respectively. In the previously untreated patients who were ineligible for standard chemotherapy, 2 were over 75 years old, 16 cases were diagnosed with active infection, 6 had organ dysfunction. According to the risk stratification of NCCN, it was divided into 8 cases of favorable-risk, 2 cases of intermediate-risk and 14 cases of poor-risk. According to the time from CR to hematological recurrence, the R/R group was divided into 12 cases in the favorable-risk group (CR to hematological recurrence ≥18 months) and 24 cases in the poor-risk group (CR to hematological recurrence <18 months, no remission after 1 cycle of therapy, no remission after ≥2 cycles of therapy). Efficacy In the previously untreated patients who were ineligible for standard chemotherapy, after the first cycle of Ven + AZA treatment, 17/24 (70.8%) cases achieved CR/CRi, 3/24 (12.5%) cases achieved partial remission (PR), and the ORR was 83.3%. Among the CR/CRi patients, 8/17 (47.1%) achieved MRD negative after 2 cycles of therapy. Four patients achieved CR/CRi after the first cycle of Ven + AZA, ineligible factors (active infection) were eliminated, followed by chemotherapy, and MRD achieved negative after 1-2 cycles of consolidation therapy. The median duration of induction therapy in R/R group was 28 (14-28) days, and the total CR/CRi rate was 58.3%. 11/24 (45.8%) cases achieved CR/CRi after one cycle of Ven + AZA in the poor-risk R/R group, and 10/12 (83.3%) cases achieved CR/CRi in the favorable-risk R/R group, which was significantly superior than that in the poor-risk group (P = 0.031). The efficacy in patients with different risk stratification and gene subtypes are displayed in Table. Safety The incidence of hematological AEs was 100%, and the incidence of neutropenic fever was 40.0% (24/60). The incidence of grade 3-4 leukopenia was 86.7% (52/60), of which 60.0% (36/60) occurred before therapy, and the incidence of grade 3-4 leukopenia caused by therapy was 26.7% (16/60). The incidence of grade 3-4 anemia was 71.7% (43/60), of which 51.7% (31/60) occurred before therapy, and the incidence of grade 3-4 anemia caused by therapy was 20.0% (12/60). The incidence of grade 3-4 thrombocytopenia was 76.7% (46/60), of which 60.0% (36/60) occurred before therapy, and the incidence of grade 3-4 thrombocytopenia caused by therapy was 16.7%. The most common non hematological AE was infection, followed by gastrointestinal AE. Infection mainly included pneumonia (13.3%) and soft tissue infection (6.7%), both of which were grade 3-4. Conclusion Ven + AZA has acceptable safety in previously untreated patients who were ineligible for standard chemotherapy and patients with R/R AML, can achieve a high response rate, and some patients can achieve MRD negative in China. It is effective in patients with NPM1, IDH1/IDH2 and TP53 positive. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Long-Term Prognostic Significance of Response in Hodgkin Lymphoma Before Autologous Stem Cell Transplantation :Results of the Prospective Multicenter H96 Trial by the GELA/SFGM-TC Study Group

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3070-3070
Author(s):  
David Sibon ◽  
Matthieu Resche-Rigon ◽  
Franck Morschhauser ◽  
Christophe Fermé ◽  
Isabelle Gaillard ◽  
...  
Keyword(s):  
Risk Group ◽  
Prognostic Significance ◽  
Salvage Chemotherapy ◽  
Secondary Malignancy ◽  
Intermediate Risk ◽  
Poor Risk ◽  
The Poor ◽  
Significant Difference

Abstract Abstract 3070 Introduction. The standard treatment for relapsed or refractory Hodgkin lymphoma (HL) is high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT). The prognostic significance of response to initial salvage therapy (i.e. prior to HDT/ASCT) has been shown in many studies. However, the existing results have been based either on retrospective studies or on prospective studies with a relatively short median follow-up, and long-term prospective data are missing. The aim of the present study was to establish the actual prognosis for the different response categories in a prospective cohort of HL patients (pts) treated with HDT/ASCT after long-term follow-up. Methods. The GELA/SFGM-TC H96 trial was a prospective, multicenter, phase II trial evaluating a risk-adapted salvage treatment with single or tandem HDT/ASCT for HL pts who experienced first-line treatment failure (Morschhauser F, J Clin Oncol 2008). Pts were stratified as follows: the poor-risk group included pts with primary refractory disease or at least two risk factors at relapse (time to relapse < 12 months, stage III or IV at relapse, or relapse within previously irradiated sites); the intermediate-risk group included pts with only one risk factor at relapse. Poor-risk and intermediate-risk pts were eligible for tandem and single HDT/ASCT, respectively. The primary end point was to evaluate the freedom from second failure (FF2F) rate in the poor- and intermediate-risk groups. Secondary end points included overall survival (OS) for both groups, FF2F and OS according to the response to salvage chemotherapy. Response was assessed according to 1999 standard guidelines: complete remission (CR), unconfirmed CR (CRu), partial remission (PR), stable disease (SD) or progressive disease (PD). Results. Between 1995 and 2002, 245 pts were enrolled. The pts characteristics at diagnosis and at time of treatment failure/relapse have been previously described (Morschhauser F, J Clin Oncol 2008). The median follow-up is now 9.2 years (yrs). In the poor-risk group (n=150 [77 pts with primary refractory HL and 73 pts with unfavorable relapse]), the 9-yr FF2F and OS were 41% and 50%, respectively, without significant difference between primary refractory HL and unfavorable relapse. In the intermediate-risk group (n=95), the 9-yr FF2F and OS were 61% and 70%, respectively. The response to salvage treatment was assessable for 243 pts. In the poor-risk group, the 9-yr FF2F according to each response category was 67% for CR/CRu (n=39), 45% for PR (n=55), 12% for SD (n=24), and 23% for PD (n=31). The 9-yr OS were 76% for CR/CRu, 60% for PR, 16% for SD, and 26% for PD. Significant differences in FF2F were found between CR/CRu and PR groups (p=0.02), between PR and SD groups (p=0.006), but not between SD and PD groups (p=0.82). For OS, no significant differences were found between CR/CRu and PR groups (p=0.09) and between SD and PD groups (p=0.89), but there was a significant difference between PR and SD groups (p=0.001). In the intermediate-risk group, the 9-yr FF2F was 66% for CR/CRu (n=65) and 60% for PR (n=26) [no SD and 3 PD]. The 9-yr OS was 71% for CR/CRu and 67% for PR. No significant differences in FF2F (p=0.98) and OS (p=0.96) were observed between the CR/CRu and PR groups. In all, 100 pts relapsed after HDT/ASCT (76 in the poor-risk group [primary refractory, n=44; unfavorable relapse, n=32] and 24 in the intermediate-risk group). Half of relapses occurred in the first yr following HDT/ASCT. In the poor-risk group, the cumulative incidence of relapse at 1, 2, 5 and 9-yr was 33%, 43%, 47% and 52%. In the intermediate-risk group, the cumulative incidence of relapse at 1, 2, 5 and 9-yr was 5%, 15%, 23% and 26%. Among relapsing pts, 21 (poor-risk group, n=16) underwent allogeneic transplantation (alloSCT). In all, 101 pts died (poor-risk group, n=76). The cause of death was PD in 78 pts (poor-risk group, n=65) or other cause in 23 pts (secondary malignancy, n=6; non-relapse mortality after alloSCT, n=5; infection, n=4; other, n=5; unknown, n=3). Secondary malignancy occurred in 11 pts (solid tumor, n=7; acute leukemia, n=4), including 2 pts in the poor-risk group (solid tumor only). Secondary cardiac toxicity occurred in 7 pts (2 pts in the poor-risk group). Conclusion. This prospective study emphasized the prognostic impact of response to salvage chemotherapy on the long-term outcome after HDT/ASCT for first relapsed/refractory HL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Venetoclax Combined with Daunorubicin and Cytarabine (DAV) As Induction Therapy in De Novo Young Adult Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2334-2334
Author(s):  
Huafeng Wang ◽  
Liping Mao ◽  
Wanzhuo Xie ◽  
Hongyan Tong ◽  
Min Yang ◽  
...  
Keyword(s):  
Young Adult ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Residual Disease ◽  
The Novel ◽  
Poor Risk ◽  
De Novo Aml ◽  
Grade 3

Abstract Background: Anthracycline and cytarabine ("3+7") have been the standard induction therapy for acute myeloid leukemia (AML) for almost 4 decades. Only 60%-70% patients can achieve complete remission (CR) with "3+7" induction treatment in de nove AML. The novel induction regimens with higher CR rate are urgent needed. Venetoclax, a b-cell lymphoma 2 (BCL-2) inhibitor combining with hypomethylation agents (HMA) or low dose cytarabine has showed a high response rate and safe in elder AML patients [Dinardo CD, N Engl J Med. 2020; Dinardo CD, Lancet Oncol 2018; Wei AH, J Clin Oncol 2019]. Recently, venetoclax combined with FLAG-IDA induction achieved 90% CR rate in newly diagnosed adult AML (Dinardo CD, J Clin Oncol. 2021). Whether venetoclax combined with standard 3+7 regimen (daunorubicin + cytarabine) as induction therapy can further improve the CR rate in adult AML patients need to be investigated in a well-designed trial. Objective: To evaluate the efficacy and safety of "3+7" (daunorubicin and cytarabine) combined with venetoclax induction regimen (DAV regimen) in young adult patients with de novo AML. Design, setting and participants: Single-arm, prospective clinical trial conducted in the First Affiliated Hospital, Zhejiang University College of Medicine, China. Eligible patients (18-60 years old) with de novo AML (exclude acute promyelocytic leukemia) were enrolled since December 25, 2020, with final follow-up in July 31,2021. Interventions: Patients were treated with daunorubicin 60mg/m 2 on days 1-3 (d1-3) and cytarabine 100 mg/m 2/d by continuous intravenous infusion daily on d1-7, combined with venetoclax (100mg d4, 200mg d5, 400mg d6-11). Main outcomes and measures: The primary endpoint was the percentage of patients who achieved CR/CR with incomplete count recovery (CRi) after once cycle of DAV regimen. Secondary endpoints included minimal residual disease (MRD), overall survival (OS), event-free survival (EFS) and adverse events. Results: Thirty-two patients were enrolled. Median age was 40 years old (range, 19-59), with poor-risk in 25% (8/32) of patients (European LeukemiaNet 2017 risk). Other characteristics of patients were listed in Table 1. The CR rate were 90.6% (29/32) (Table 1). Seven out eight (87.5%) patients with poor-risk achieved CR. Measurable residual disease-negative composite CR was attained in 65.5% (19 out 29) of total patients achieved CR, and 71.4% (5 out 7) of poor-risk patients achieved CR (Table 1). Common adverse events (&gt;30%) included fatigue, nausea, bleeding, febrile neutropenia, infection, neutropenia, anemia and thrombocytopenia. The main grade ≥ 3 hematologic toxicities during induction were neutropenia (100%), anemia (100%) and thrombocytopenia (100%). The main grade ≥ 3 nonhematologic toxicities during induction were infection (81.3%), bleeding (28.1%) and mucositis (3.1%) (Table 1). No tumor lysis syndrome was observed. After a median follow-up of 118.5 days, no patient relapsed or died, and 24.1% (7/29) received allogeneic hematopoietic stem-cell transplantation in CR1. Conclusions: The novel combination of "3+7" (daunorubicin and cytarabine) with venetoclax (DAV regimen) was effective and well tolerated in young adult patients with de novo AML, with high CR rate and deep remission. Trial registration: The trial was registered in the Chinese Clinical Trial Register, number ChiCTR2000041509. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A Phase II Trial of Azacitidine (NSC-102816) and Gemtuzumab Ozogamicin (NSC-720568) As Induction and Post-Remission Therapy in Patients of Age 60 and Older with Previously Untreated Non-M3 Acute Myeloid Leukemia (SWOG S0703): Report On the Poor Risk Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3584-3584 ◽  
Author(s):  
Sucha Nand ◽  
Megan Othus ◽  
John E. Godwin ◽  
Cheryl L Willman ◽  
Thomas Norwood ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Outpatient Setting ◽  
Induction Treatment ◽  
Standard Chemotherapy ◽  
Poor Risk ◽  
The Poor ◽  
Good Risk ◽  
Acute Myeloid

Abstract Abstract 3584 Background: Increasing age and worsening performance status (PS) are associated with low complete remission (CR) rates and high early death rates in patients (pts) with acute myeloid leukemia (AML). Data from 4 SWOG trials show that in patients ≥70 and PS of ≥ 2, the CR rate with standard chemotherapy is 29% and 30-day death rate 48%. Preliminary data suggest that a regimen combining azacitidine (AZA) and gemtuzumab ozogamicin (GO) has significant activity and low toxicity in this group of patients. The current trial was designed to test this regimen in a larger group of patients in a cooperative group setting. Methods: Newly diagnosed pts, ≥60 years of age, with de novo or secondary non-M3 AML were treated as follows: Induction: Hydroxyurea 1500 mg twice daily till WBC <10,000/mcL, followed by azacitidine 75 mg/m2/day s/cu or iv days 1–7, gemtuzumab ozogamicin 3mg/m2 D8. If D14 marrow showed residual disease, induction treatment was repeated. Those achieving CR received one consolidation treatment which was identical to the induction treatment. This was followed by 4 cycles of azacitidine 75/m2/day, D1–7, given every 4 weeks. Subsequent management was left to the treating physicians. Patients were prospectively entered into good risk (age 60–69 or PS 0–1) and poor risk (age ≥70 and PS 2 or 3) cohorts. Based on our previous experience, we concluded that the regimen would be worth further study if CR+CRi was ≥ 30% and a 30 day survival was ≥ 70%. Promoter and global methylation studies were performed at defined time points. Results: Data on 83 good risk pts were presented at ASCO 2012. The results presented here are from the poor risk cohort. A total of 54 poor risk pts were treated. Median age was 76 (70.3–87) and 33 were males. Five pts had pre-existing MDS. Of the 54 evaluable pts, 19 (35%) achieved a CR or CRi. One additional pt achieved a CR with continued AZA therapy after being removed from the study for persistent disease on D28. Median progression free survival is 7 mo and median overall survival 6 months. There were 31 grade 3 or 4 toxicities. Seven (14 %) pts died early, with a 30 day survival of 86%. An estimated 30% of the pts (in good risk and poor risk groups) were able to receive their induction therapy in the outpatient setting. Conclusions: The combination of hydroxyurea, azacitidine and GO is associated with lower induction mortality, can be given in the outpatient setting and results in a CR rate better than that seen in poor risk pts with AML treated with standard chemotherapy. These results are sufficiently encouraging to warrant further studies with this approach. Clinical Trials.govIdentifier: NCT00658814. Disclosures: Nand: Celgene: Research Funding.

Analysis of Efficacy and Prognostic Factors of CLAG Treatment in Chinese Patients with Refractory or Relapsed Acute Myeloid Leukemia

2018 ◽  
Vol 141 (1) ◽  
pp. 43-53 ◽  
Author(s):  
Li Wang ◽  
Jun Xu ◽  
Xiaolong Tian ◽  
Tingting Lv ◽  
Guolin Yuan
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Risk Stratification ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Median Overall Survival ◽  
Remission Rate ◽  
Chinese Patients ◽  
Acute Myeloid

Background/Aims: The aim of this work was to investigate the efficacy and predictive factors of CLAG treatment in refractory or relapsed (R/R) acute myeloid leukemia (AML) patients. Methods: Sixty-seven R/R AML patients were enrolled in this prospective cohort study and treated by a CLAG regimen: 5 mg/m2/day cladribine (days 1–5), 2 g/m2/day cytarabine (days 1–5), and 300 μg/day filgrastim (days 0–5). The median follow-up duration was 10 months. Results: A total of 57 out of 67 patients were evaluable for remission after CLAG therapy, of whom 57.9% achieved a complete remission (CR) and the overall remission rate was 77.2%. The median overall survival (OS) was 10.0 months, with a 1-year OS of 40.3 ± 6.0% and 3-year OS of 16.7 ± 5.7%. CR at first induction after the initial diagnosis was associated with a favorable CR. Age above 60 years, high risk stratification, second or higher salvage therapy, and bone marrow (BM) blasts ≥42.1% were correlated with an unfavorable CR. Secondary disease, age ≥60 years, high risk stratification, and second or higher salvage therapy were associated with worse OS. Patients developed thrombocytopenia (41, 61%), febrile neutropenia (37, 55%), leukopenia (33, 49%), neutropenia (18, 27%), and anemia (9, 13%). Conclusion: CLAG was effective and well tolerated for R/R AML. BM blasts ≥42.1%, age ≥60 years, high risk stratification, and second or higher salvage therapy were independent factors for a poor prognosis.

Sequential Combination of Gemtuzumab Ozogamicin and Standard Chemotherapy in Older Patients With Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase III Trial by the EORTC and GIMEMA Consortium (AML-17)

2013 ◽  
Vol 31 (35) ◽  
pp. 4424-4430 ◽  
Author(s):  
Sergio Amadori ◽  
Stefan Suciu ◽  
Roberto Stasi ◽  
Helmut R. Salih ◽  
Dominik Selleslag ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Standard Chemotherapy ◽  
Sequential Combination ◽  
Grade 3 ◽  
Acute Myeloid

Purpose This randomized trial evaluated the efficacy and toxicity of sequential gemtuzumab ozogamicin (GO) and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia (AML). Patients and Methods Patients (n = 472) age 61 to 75 years were randomly assigned to induction chemotherapy with mitoxantrone, cytarabine, and etoposide preceded, or not, by a course of GO (6 mg/m2 on days 1 and 15). In remission, patients received two consolidation courses with or without GO (3 mg/m2 on day 0). The primary end point was overall survival (OS). Results The overall response rate was comparable between the two arms (GO, 45%; no GO, 49%), but induction and 60-day mortality rates were higher in the GO arm (17% v 12% and 22% v 18%, respectively). With median follow-up of 5.2 years, median OS was 7.1 months in the GO arm and 10 months in the no-GO arm (hazard ratio, 1.20; 95% CI, 0.99 to 1.45; P = .07). Other survival end points were similar in both arms. Grade 3 to 4 hematologic and liver toxicities were greater in the GO arm. Treatment with GO provided no benefit in any prognostic subgroup, with the possible exception of patients age < 70 years with secondary AML, but outcomes were significantly worse in the oldest age subgroup because of a higher risk of early mortality. Conclusion As used in this trial, the sequential combination of GO and standard chemotherapy provides no benefit for older patients with AML and is too toxic for those age ≥ 70 years.

Comprehensive Geriatric Assessment-Adapted Chemotherapy in 100 Elderly Patients (>70 Years) with Diffuse Large B-Cell Non-Hodgkin’s Lymphoma (DLBCL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2440-2440 ◽  
Author(s):  
Michele Spina ◽  
Monica Balzarotti ◽  
Uziel Lilj ◽  
Ferreri Andres ◽  
Fratino Lucia ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Geriatric Assessment ◽  
Comprehensive Geriatric Assessment ◽  
Cardiac Toxicity ◽  
Skin Toxicity ◽  
Standard Chemotherapy ◽  
Highly Active ◽  
Good Score ◽  
Grade 3

Abstract Rituximab plus CHOP (R-CHOP) is the standard chemotherapy (CT) regimen for elderly patients (pts) with CD20 positive DLBCL. However, many pts aged 70 years (yrs) or more are often unable to received R-CHOP and the majority of them are excluded from clinical trials. Moreover, comprehensive geriatric assessment (CGA) has been demonstrated a useful instrument to predict the clinical outcome of elderly pts with cancer even if it has never been tested in a prospective way. Within the GOL (Gruppo Oncoematologico Linfomi) from June 2000 to March 2006 we started a phase II prospective study with the aim to evaluate the feasibility and activity of a CGA-driven CT for elderly pts with DLBCL. Rituximab was used in all pts after its introduction in the marketing in Italy (February 2002). Pts with no comorbidity received CHOP or R-CHOP; in pts with mild cardiopathy epirubicin was used instead of doxorubicin (CEOP or R-CEOP); in pts with moderate or severe cardiopathy the use of antracyclines was omitted (CVP or R-CVP); pts with diabetes didn’t receive prednisone (CHO,CEO or R-CHO,R-CEO); pts with neuropathy received CHP or R-CHP or CEP or R-CEP (vincristine was omitted). Moreover, the dosage of CT was decided according to the CGA: pts with a good score of CGA (i.e. ADL=6 and IADL>6) received full doses of CT; pts with an intermediate score (ADL=5 and IADL>4) received 75% of the planned dose; pts with a poor score (ADL<5 and IADL<5) received 50% of the planned dose. All pts received prophylactic filgrastim. One hundred pts (41 males and 59 females) have been treated and no patient was excluded from this approach. The median age was 75 yrs (range 70–89) and stages III–IV were diagnosed in 51% of pts. Sixty-one per cent of pts received full doses of CT; 25% of pts received 75% of planned dose and 14% of pts 50% reduced dose of CT. Overall, 86% of pts received an antracycline (doxorubicin in 56% and epirubicin in 30%) and 54% of pts received rituximab plus CT. The following regimens were used: R-CHOP 22%, CHOP 16%, 75%-R-CHOP 10%, 75%-CHOP 8%, CEOP 11%, R-CEOP 4%, 75%-R-CEOP 9%, 75%-CEOP 6%. The remaining pts received CVP in 5% of cases and reduced R-CVP in 9% of cases. The toxicity was quite acceptable. Grade 3–4 neutropenia was observed in 29% of pts, mucositis in 13%, peripheral neuropathy in 9%, febrile neutropenia in 13%, cardiac toxicity in 3% and skin toxicity in 1%. Four toxic deats were observed (2 septic shock, 1 acute respiratory failure and 1 acute myocardial infarction). Overall, 76% of pts achieved a complete remission (CR) and with a median follow-up of 24 months (range 1–71 months) only 16% of them have relapsed. Seventy-three pts are alive and 63% are alive in CR. Our results demonstrated that a CGA-driven approach is feasible and highly active in elderly pts with DLBCL. Moreover this strategy allows a potentially curative approach to all pts with aggressive NHL avoiding both to under-treat elderly pts with a curable disease and to over-treat elderly pts with comorbidities.

Randomized Study of Decitabine Versus Observation or Continued Cytotoxic Chemotherapy in Patients with Intermediate and Poor Risk Acute Myeloid Leukemia in First or Subsequent Complete Remission.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2859-2859 ◽  
Author(s):  
Farhad Ravandi ◽  
Jean-Pierre Issa ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Mary Hood ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Clin Oncol ◽  
Myeloid Leukemia ◽  
Cytotoxic Chemotherapy ◽  
Cytotoxic Agents ◽  
High Dose ◽  
Poor Risk ◽  
Grade 3 ◽  
Acute Myeloid

Abstract The role of maintenance therapy in acute myeloid leukemia (AML) remains unclear. Continued therapy with cytotoxic agents similar to those used for induction and consolidation is associated with toxicity but can improve disease free survival (DFS). (Buchner T, J Clin Oncol. 2006;24:2480 and Lowenberg B, J Clin Oncol. 1998;16:872) Immune modulation in this setting may also be effective in prolonging DFS.(Brune M, Blood2006;108:88). Methylation status of tumor suppressor genes in clinical remission predicts the relapse risk in AML with earlier relapse in patients with increased DNA promotor methylation.(Agrawal S, Cancer Res. 2007;67:1370) Therefore, hypomethylating therapy may be effective in maintaining remission and prolonging survival in these patients. We are conducting a clinical trial comparing decitabine to cytotoxic chemotherapy or observation in patients with AML in their first or subsequent complete remission (CR). Patients with non-favorable risk AML (including intermediate and poor risk) receive induction therapy with idarubicin and high dose cytarabine followed by at least 2 cycles of cytarabine based consolidation. They are then stratified by age (≤ 60 vs. > 60) and cytogenetics (intermediate vs. poor risk) and randomized to receive decitabine 20 mg/m2 IV daily × 5 every 4 to 8 weeks for 12 cycles, or to continue chemotherapy/observation. Patients in > first CR are randomized after completion of salvage therapy. Serial samples for methylation studies and determination of minimal residual disease by flow cytometry are collected. To date, 19 (8 M, 11 F) patients with AML (including 14 in first CR and 5 in subsequent CR) have been enrolled onto the study. Median age of the patients is 56 years (range 31 – 74). Fourteen patients are ≤ 60 years. Cytogenetics at diagnosis was intermediate in 10 patients, poor-risk in 8 patients, and favorable [inv(16)] in one relapsed patient. Eight patients were randomized to decitabine and have received a median of 3 cycles (range 1 – 6). Eleven patients were randomized to observation/continued therapy and all, except 2 patients, have received further cytarabine based therapy after consolidation. With a median duration of follow up for the entire group of 5 months (range 1 – 9), 7/8 patients on the decitabine arm and 9/11 patients on the other arm have remained in remission. Toxicity in the decitabine treated patients was limited to 4 episodes of grade 3 neutropenia, 2 episode of grade 3 thrombocytopenia, and 1 episodes of grade 3 anemia. All of these cytopenias were short in duration and reversed without any associated adverse events. We conclude that administration of decitabine in CR at the above schedule/dose is safe and well tolerated.

Impact of Cytogenetics Risk on Outcome after Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) from An HLA Identical Sibling for Patients with Acute Myeloid Leukemia (AML) in First Complete Remission (CR1)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 345-345
Author(s):  
Mohamad Mohty ◽  
Myriam Labopin ◽  
Noel-Jean Milpied ◽  
Jan J. Cornelissen ◽  
Didier Blaise ◽  
...  
Keyword(s):  
Stem Cell ◽  
Risk Group ◽  
Conditioning Regimen ◽  
Early Death ◽  
Risk Groups ◽  
New Drugs ◽  
Intermediate Group ◽  
Poor Risk ◽  
The Poor ◽  
The Impact

Abstract Allo-SCT is a well established therapy for adult patients with AML. In the setting of standard myeloablative allo-SCT, the fear of early death as a result of the procedure led to the restriction of allo-SCT in CR1 to patients who presented with high risk AML features, especially taking into account the impact of cytogenetics risk on outcome determining standard (good)-, intermediate-, and poor-risk populations. In the last decade, RIC allo-SCT has emerged as an attractive modality to decrease toxicity and widen the spectrum of AML patients who are candidate to allo-SCT. However, the issue of possible higher relapse rates after RIC allo-SCT, and continuous improvements in non-allo-SCT strategies, raise concern about the utility of this approach in AML patients in CR1 (e.g. in comparison to intensive chemotherapy and new drugs). Of note, no large studies have yet assessed the impact of cytogenetics risk on outcome in the context of RIC allo-SCT. This report describes the results of 378 AML patients (185 males) transplanted in CR1 using a RIC regimen and reported to the EBMT registry between 2000 and 2007, and for whom detailed cytogenetics data were available. All patients received RIC allo-SCT from an HLA identical sibling. RIC was defined as Busulfan conditioning regimens containing &lt; 8mg/kg total dose, or TBI &lt;6 Gy: The median age at time of allo-SCT was 55 (range, 18–74) y. The median intervals from AML diagnosis to CR1 and from CR1 to RIC allo- SCT were 45 and 155 days respectively. In this series, 21 patients (6%) belonged to the good cytogenetics risk group, while 304 patients (80%) and 53 patients (14%) belonged to the intermediate and poor cytogenetics risk groups respectively. Age, year of transplant, WBC at diagnosis, gender, CMV serostatus, stem cell source, and RIC regimen type were comparable between all three groups. The M5-6-7 FAB subgroup was significantly higher in the poor risk group (30% vs. 20% in the intermediate group). With a median follow-up of 24 (range, 1–93) months, the KM estimates of 2 years leukemia-free survival (LFS) were 64+/−4, 57+/-3 and 38+/−7% in the good-, intermediate-, and poor-risk subgroups respectively (P=0.003). In multivariate analysis, cytogenetics was not significantly associated with non-relapse mortality. However, relapse incidence was significantly influenced by the cytogenetics risk groups (P=0.0001) and a higher WBC at diagnosis (P=0.001). Finally, LFS was significantly influenced by the cytogenetics risk groups (P=0.004), a higher WBC at diagnosis (P=0.006), and year of transplant (P=0.04). Despite its retrospective nature, results from this large study strongly suggest that RIC allo-SCT from an HLA-matched sibling donor is a valid option for AML patients in CR1 not eligible for standard allo-SCT. As it has been shown in the setting of myeloablative conditioning allo-SCT, patients from the poor cytogenetics risk group had increased relapse incidence and decreased LFS rate after RIC allo-SCT. Therefore, prospective strategies such as use of new drugs, intensification of conditioning regimen, post HST immunotherapy should be investigate to improve current results in this group.

Nilotinib in Chronic Myeloid Leukemia Patients in Accelerated Phase (CML-AP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3229-3229 ◽  
Author(s):  
Philipp D. le Coutre ◽  
Francis Giles ◽  
Andreas Hochhaus ◽  
Jane F. Apperley ◽  
Gert Ossenkoppele ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Time To Progression ◽  
Phase 2 Study ◽  
Grade 3

Abstract Background: Nilotinib is a rationally designed, potent and highly selective BCR-ABL kinase inhibitor, and binds to ABL with higher affinity and improved topological fit compared to imatinib. Nilotinib is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myeloid leukemia pts in chronic (CML-CP) or accelerated phase (CML-AP) resistant or intolerant to prior therapy including imatinib. Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-AP pts who are resistant or intolerant to imatinib. Nilotinib was dosed at 400 mg twice daily with the option to dose escalate to 600 mg twice daily for lack of response. The primary endpoint was confirmed hematologic response (HR). Complete hematologic response (CHR) was defined as meeting all of the following criteria: myeloblast count &lt;5% in bone marrow, no myeloblast in peripheral blood, neutrophil count ≥1.5 × 109/L, platelet count ≥100×109/L, basophils &lt;5%, no evidence of extramedullary involvement. Secondary endpoints included major cytogenetic response (MCyR), time to progression, overall survival, and safety. Results: A total of 138 CML-AP pts (80% imatinib resistant; 20% imatinib intolerant) who received at least 1 dose of nilotinib were included in the analysis. Median age was 57 years (range, 22–82 years); median duration of prior imatinib treatment was 28 months. Seventy-nine percent of pts received prior imatinib doses ≥600 mg/day; overall, 45% received ≥800 mg/day imatinib. Median dose intensity of nilotinib was near planned dose at 775 mg/day with a median duration of exposure of 253 days (8.4 months). Of 134 pts with at least 6 months of follow-up included in the efficacy analysis, 56% had confirmed HR and 30% had CHR. Responses were rapid, with a median time to first HR of 1 month. Hematologic responses were durable at 1 year, with 78% of pts who achieved HR maintaining their response. MCyR and complete cytogenetic response (CCyR) occurred in 32% and 19% of pts, respectively. Cytogenetic responses were also durable, with 69% of pts maintaining MCyR at 18 months. Median time to progression was 16 months in this population of pts with advanced disease. Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-AP or blast crisis, loss of CHR, loss of MCyR. Estimated overall survival at 1 year is 82%. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 laboratory abnormalities were thrombocytopenia (40%), neutropenia (40%), anemia (25%), elevated serum lipase (17%), and hypophosphatemia (12%). Grade 3/4 non-hematologic adverse events were uncommon (&lt;1%) and included rash, nausea, fatigue, and diarrhea. Brief dose interruptions were sufficient to manage most adverse events. Conclusions: The long-term follow-up results of this phase 2 study confirm that nilotinib induces rapid and durable responses in pts with CML-AP who failed prior imatinib therapy due to intolerance or resistance, with a favorable toxicity profile.

Validation of Monosomal Karyotype Based Model In the Risk Stratification of Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2745-2745
Author(s):  
Murtadha K. Al-Khabori ◽  
Karen Yee ◽  
Vikas Gupta ◽  
Aaron Schimmer ◽  
Andre Schuh ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Structural Abnormality ◽  
Complex Karyotype ◽  
Poor Risk ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Abstract 2745 Background: The influence of cytogenetic abnormalities on the prognosis of acute myeloid leukemia (AML) has been well-documented; however, the relative impact of certain miscellaneous abnormalities remains controversial. Recently, monosomal karyotype-based risk stratification has been shown to further discriminate the prognosis within the poor-risk karyotype group (Breems et al. JCO 2008), but this finding requires further validation. Methods: We retrospectively reviewed 779 consecutive adult AML patients treated with standard induction chemotherapy, consisting of daunorubicin plus cytarabine (3+7), at our institution from 1998–2008. After excluding patients with favourable risk, normal, missing or failed karyotype, 290 patients remained and were included in the analysis. Results: The baseline characteristics of these 290 patients were as follows: median age 59 y (range 18–81), male 181, prior malignancy 110, median white cell count (WBC) 7.6 × 10^9/L (range 0–246). The karyotypic features included single monosomy in 42, 2 or more monosomies in 51, and non-monosomy structural and numerical abnormalities in 197 patients. Of the 290, 116 (40 %) had three or more abnormalities (complex karyotype, CK). A total of 141 patients (49 %) achieved complete remission (CR) with 3+7 induction chemotherapy. Sixty-four patients received allogeneic stem cell transplantation in CR. The median overall survival (OS) for all patients was 12 months (95% CI: 10–14 months). The median OS was 10 (95% CI: 6–18), 7 (95% CI: 6–10) and 14 months (95% CI: 12–16) in the single monosomy, 2+ monosomy and non-monosomy groups, respectively (p < 0.0001 by log-rank test comparing the three groups). Among the patients containing at least one monosomy, the OS was not significantly different between the CK and non-CK groups (p = 0.08 by log rank). Similarly, in the non-monosomy structural abnormality group, the OS was not significantly different between the CK and non-CK groups (p = 0.2). Conclusions: Our results provide validation for the monosomal karyotype-based risk stratification for AML, indicating that patients with at least one monosomy have an inferior OS compared to other poor-risk non-monosomy groups. Within each of the monosomy and non-monosomy groups, the presence of a complex karyotype does not significantly influence the OS. Disclosures: No relevant conflicts of interest to declare.

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