Clinical Experience of Decitabine in Elderly Patients with Myelodysplastic Syndromes (MDS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2792-2792 ◽  
Author(s):  
George F. Geils
Keyword(s):  
Elderly Patients ◽  
Subgroup Analysis ◽  
Response Rate ◽  
De Novo ◽  
Treatment Options ◽  
Group Versus ◽  
International Prognostic Scoring System ◽  
Hematological Toxicity ◽  
Age Group ◽  
Transfusion Independence

Abstract 2792 Poster Board II-768 Background: Decitabine, a potent DNA hypomethylating agent, has demonstrated efficacy in MDS patients. The incidence of MDS increases with age, with limited treatment options for these patients. With advancing age, patients are generally less tolerant of treatment and suffer from more comorbidities. Important goals of therapy are to improve transfusion dependence and to delay progression of disease, with favorable toxicity. This subgroup analysis evaluated the effect of decitabine on overall response rate (ORR), duration of response, time to response, transfusion independence, and tolerability in subgroups of older patients (65-75 and >75 years of age). Methods: Data used in these analyses were from two previously published clinical trials (Steensma et al. J Clin Oncol, 2009 [DACO-020] and Kantarjian et al. Cancer 2006 [DACO-007]). In both trials, eligible patients were ≥18 years of age and had MDS (de novo or secondary) of any French-American-British subtype and an International Prognostic Scoring System score ≥0.5. In DACO-020, patients were treated with decitabine 20 mg/m2 IV daily for 5 consecutive days every 4 weeks. Response rate was assessed with the International Working Group (IWG 2006) criteria in DACO-020. In DACO-007, patients were treated with decitabine 15 mg/m2 IV over 3 hours every 8 hours for 3 consecutive days every 6 weeks. Response rate was assessed with the IWG 2000 criteria in DACO-007. Results: In DACO-020, baseline disease characteristics were generally similar between groups, except more patients in the 65-75 age group (n = 58) had RARS (19% vs. 4%) or RAEB (50% vs. 38%) and fewer had RA (12% vs. 38%) compared to patients in the >75 age group (n = 26). Further, more patients in the >75 group were transfusion dependent at baseline (77% vs. 57%). Grade 3-4 anemia, leukopenia, neutropenia, and thrombocytopenia were less frequent (22, 5, 35, and 22%, respectively) in patients in the 65-75 age group versus patients in the >75 age group (27, 8, 46, and 35%, respectively). Remarkably, however, there were no reports of febrile neutropenia in >75 age group (26% in the 65-75 age group). Conclusions: In this subgroup analysis, decitabine is an effective and generally well tolerated treatment strategy, even in elderly patients with MDS. Despite the advanced age, responses were more rapid and more durable in the mature elderly than younger patients. The slightly higher hematological toxicity did not translate into increased infectious risk, with no febrile neutropenic episodes in patients over age 75 in these studies. These data suggest that the goals of therapy do not need to be stratified by age, and support future trials of decitabine in elderly and other at-risk populations with MDS. Disclosures: Geils: Eisai Inc. : Speakers Bureau.

Low Toxicity Profile of the Combination of Bendamustine Plus Rituximab (BR) in Elderly FRAIL Patients with Newly Diagnosed DLBCL

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4429-4429
Author(s):  
Michele Spina ◽  
Stefano Luminari ◽  
Flavia Salvi ◽  
Francesco Passamonti ◽  
Alberto Fabbri ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
Hematological Toxicity ◽  
High Risk Population ◽  
Toxicity Profile ◽  
Newly Diagnosed ◽  
Frail Patients ◽  
Low Toxicity ◽  
Grade 3

Abstract Introduction: R-CHOP is the gold standard for the treatment of elderly patients with DLBCL. However, unfit and frail patients frequently do not qualify for CHOP-based chemotherapy. Alternatives are an urgent medical need. Bendamustine plus rituximab (BR) has been established as a standard treatment of indolent lymphomas and preliminary data have shown a promising activity in DLBCL, both in the relapsing and upfront setting. Methods: Within the Fondazione Italiana Linfomi (FIL), we started a phase II study (R-BENDA frail study, EUDRACT2011-001421-24) in elderly patients (>70 years) with a newly diagnosed DLBCL not suitable for R-CHOP-based chemotherapy. All patients were evaluated according to ADL, IADL and CIRS-G and were considered FRAIL if the following criteria were meet: in patients aged 70-80 ADL<4 or IADL<5 or one grade 3 comorbidity or >8 grade 2 comorbidities; in patients older than 80 years ADL>5 or IADL>6 or 5-8 grade 2 comorbidities. Patients received bendamustine at a dose of 90 mg/m2 daily on days 1 and 2 of each 28-day cycle along with rituximab on day 1 for up to 6 cycles. Results: From February 2012 to February 2014, 49 patients were enrolled in 24 Italian centers. The majority (57%) were male and 57% had stage III-IV with 41% elevated LDH. The median age was 82. Overall, 83% of the planned cycles were delivered without dose reduction or delay; grade 3/4 neutropenia was reported in 25% of cycles followed by anemia 21%, and thrombocytopenia 20%. One case of febrile neutropenia was observed. Grade 3-4 non-hematological toxicity was mild and reported in 6% of cycles including 3 episodes of cardiovascular events and 7 other cases of different toxicities (one creatinine increase, one fatigue, one bleeding, one peripheral neurotoxicity, one hyponatriemia, one hyperglycemia and one liver toxicity). Two deaths during treatment have been observed (cardiac failure and sudden death). At the interim analysis (23 patients) the overall response rate was 56% with a complete response rate of 39%. Conclusions: Combination therapy with BR demonstrates low toxicity profile in this high risk population. The promising results on activity can encourage clinicians to considered BR for the treatment of FRAIL elderly patients with DLBCL not eligible for R-CHOP. Disclosures No relevant conflicts of interest to declare.

Cytogenetic responses to the hypomethylating agent, decitabine (DAC), in a phase III trial of DAC vs supportive care (SC) in patients (pts) with myelodysplastic syndromes (MDS)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6501-6501
Author(s):  
J. Issa ◽  
H. M. Kantarjian ◽  
H. I. Saba
Keyword(s):  
Response Rate ◽  
De Novo ◽  
Complete Blood Count ◽  
Cytogenetic Response ◽  
Phase Iii ◽  
International Prognostic Scoring System ◽  
Open Label ◽  
Hypomethylating Agent ◽  
Eligibility Requirements ◽  
A Minor

6501 Background: Clonal cytogenetic abnormalities are detected in 40%-70% of cases of de novo MDS and 95% of cases of therapy-related MDS, and the incidence increases with poor risk. DAC is a cytosine analog that reverses aberrant DNA methylation, leading to re-expression of silenced tumor suppressor genes. In this analysis, we asked whether the hypomethylating agent DAC leads to cytogenetic response in MDS. Methods: We report cytogenetic response data from a Phase III randomized, open-label trial of DAC vs SC in 170 MDS pts. Eligibility requirements included confirmed MDS (de novo or secondary) fitting any of the recognized French-American-British classifications and an International Prognostic Scoring System (IPSS) score of 0.5 or more as determined by complete blood count, cytogenetics, and bone marrow assessment. Cytogenetics was assessed as a secondary endpoint, whereas primary endpoints were response rate (CR+PR) and time to AML or death. For pts with clonal abnormalities at baseline, follow-up cytogenetic evaluations at study end were available for 26 pts in the DAC arm and 21 pts in the SC alone arm. Results: As previously reported, overall response rate according to International Working Group MDS criteria was 17% (15/89) for DAC vs 0% for SC (p<0.001). Responses occurred in all IPSS groups and were also seen in pts with 5q and 7 deletions. Response rate was 13% (2/16) in pts with 5q deletions and 21% (4/19) in pts with 7 deletions. In pts without 5q or 7 deletions, response rates were 16% (11/67) and 14% (9/64), respectively. Complete cytogenetic responses were observed in 35% (9/26) of DAC pts vs 10% (2/21) of SC pts (p=0.08, Fisher’s exact). Also, 1 pt receiving DAC had a minor cytogenetic response. 10/10 DAC pts with cytogenetic response had clinical benefit (6 CR, 2 PR, 1 hematologic improvement, and 1 with normalization of marrow blast count). The primary toxicity was myelosuppression. Conclusion: DAC induces a substantial rate of cytogenetic responses in pts with MDS, suggesting that the clinical improvements induced by this agent are related to elimination of the neoplastic clone rather than to pure differentiation effects. [Table: see text]

Phase II Study of VNP40101M (Cloretazine®) in Elderly Patients with De Novo Poor Risk Acute Myelogenous Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 917-917 ◽  
Author(s):  
Gary J. Schiller ◽  
Daniel J. DeAngelo ◽  
Arnaud Pigneux ◽  
Norbert Vey ◽  
Jonathan Kell ◽  
...  
Keyword(s):  
Risk Factors ◽  
Elderly Patients ◽  
Phase Ii ◽  
Response Rate ◽  
De Novo ◽  
Single Agent ◽  
Poor Risk ◽  
De Novo Aml ◽  
Ecog Ps ◽  
Confirmatory Phase

Abstract VNP40101M (Cloretazine®) is a novel sulfonylhydrazine alkylating agent which preferentially targets the O6 position of guanine resulting in DNA cross-links. Data from a previously reported phase II multi-center single agent study (CLI-033) in patients ≥60 years old with newly diagnosed AML or high risk MDS showed an overall response rate of 31% after VNP40101M induction (Giles, 2007). Subgroup analysis showed significant activity in 54 elderly patients with de novo AML with 24 patients (45%) achieving a complete response (CR) or CRp (CI: 30.9;58.6). Subsequently a confirmatory phase II study of single agent VNP40101M was conducted in elderly patients with poor risk de novo AML (CLI-043). Patients received induction therapy with 600 mg/m2 VNP40101M as a 60-minute infusion on day 1. A second induction cycle could be administered to patients with a partial response or hematologic improvement. Patients with CR or CRp received consolidation with cytarabine 400mg/m2/day CIV for 5 days. Patients were eligible if they were ≥60 yrs and had one of the following poor risk factors: age ≥70 yrs, ECOG PS 2, unfavorable cytogenetics, or cardiac, pulmonary or hepatic dysfunction. Patients with a prior diagnosis of MDS or favorable cytogenetics were excluded. A 2-stage optimal minimax design was employed with a target response rate of 35%. The study proceeded to the 2nd stage when >8 responses were confirmed. At least 22 responses in 77 patients are required to accept the hypothesis of a 35% target response rate. Eighty-five patients were treated as of August 14, 2007. Median age (range): 73 yrs (61– 86 y); male: 59%. The majority of patients (79%) had 2 or more risk factors. The most common risk factors were age ≥70 (78%), unfavorable cytogenetics (45%, half with complex karyotype), ECOG PS 2 (41%) and cardiac dysfunction (38%). Thirty VNP40101M-related serious adverse events (SAE) have been reported to date in 22 of 85 patients. The most common SAEs are myelosuppression or complications thereof (pancytopenia (10%), infection (47%)). Non-hematologic SAEs consist of the following gr.3 events: left ventricular dysfunction (1), transaminitis (1), confusion (1), seizure (1), rash (1), hypokalemia (1), weakness (1) and hypoxia/pleural effusion (2). Seventy-nine patients are currently evaluable for early death analysis. Of these, 12 patients (15%) and 16 patients (20%) died at ≤30 days and ≤42 days from first induction therapy, respectively. The most common causes of induction death were progression of disease (6) and infection (6). Other causes were tumor lysis syndrome (1), acute renal failure (1), and respiratory failure (2). A confirmatory Phase II single-agent study of VNP40101M shows anti-leukemia activity in elderly patients with de novo AML and multiple poor-risk features. Major toxicities include myelosuppression. Severe drug-related non-hematological toxicity is uncommon. Patients continue in follow up, and additional safety and response data is pending.

AZA In the Treatment of Therapy Related MDS and AML (tMDS/AML): a Report on 60 Patients by the Groupe Francophone Des Syndromes Myelodysplasiques (GFM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2911-2911
Author(s):  
Jehane Fadlallah ◽  
Cecile Bally ◽  
Bruno Quesnel ◽  
Norbert Vey ◽  
Francois Dreyfus ◽  
...  
Keyword(s):  
Response Rate ◽  
De Novo ◽  
Early Death ◽  
Poor Response ◽  
Female Gender ◽  
Median Number ◽  
Hematological Toxicity ◽  
Similar Response ◽  
Best Response ◽  
Wbc Count

Abstract Abstract 2911 Background: AZA gives 50–60% responses and improves OS in higher-risk MDS but its role in t MDS/AML, characterized by a high frequency of unfavorable karyotypes and poor response to available treatments, remains unknown. Methods: An AZA compassionate program (ATU) was opened in France between Dec 2004 and Jan 2009 for higher risk MDS, and for AML not candidates to or refractory to intensive chemotherapy (IC). We analyzed t MDS/AML included in this program and having received at least 1 cycle of AZA, excluding patients (pts) previously treated with chemotherapy (CT) for their tMDS/AML. Results: 60 tMDS/AML were included: M/F:24/36, median age 69 (range 20–87). Primary disease was Breast Carcinoma (n=17), CLL (n=6), Hodgkin's disease (n=4), NHL (n=7), ALL (n=2), ovarian (n=2), liver(n=2), prostate carcinoma (n=2), other cancers (n=16), immunosuppressive therapy for lupus or Lung transplant in the last 2 pts. Treatment of primary neoplasm consisted in C×T in 86% and R×T in 61%. Diagnosis (WHO) was RCMD+/− RS in 4 pts, RAEB-1 in 10 pts, RAEB-2 in 28 pts MDS with myelofibrosis in 1 pt, and AML in 17 pts (including 12 FAB RAEBt). IPSS cytogenetics were fav in 4 (6.7%), int in 11 (18.3%), and unfav in 45 (75%, including 71% Complex karyotypes). Patients received a median of 4 cycles (range 1–24) of AZA, at FDA/EMEA-approved schedule (75 mg/m2/d ×7d/4 week) in 73% patients and a less intensive schedule (5d/4w, or <75mg/m2/d) in 27% patients. 25 (41.6%) pts received < 4 cycles, mainly due to early death (32%), failure (28%) or hematological toxicity (16%). Best response according to IWG 2006 criteria was CR in 9 pts (15%), marrow CR (mCR) in 8 (13%), PR in 1, stable disease (SD) with HI in 5 (8%) ie an overall response rate (ORR) of 38%. In pts who received >4 cycles, ORR was 21/35 (60%). Age, WBC count, baseline platelet count, % marrow blasts, karyotype (whatever the categorization) and ECOG status had no impact on ORR. 1, 2 and 3 year survival was 35%, 15% and 7%. Female gender (p=0.02), achievement of response (p=0.003) and ECOG status (0-1 vs 2–4) (p=0.04) had significant impact on OS while karyotype and % marrow blasts had no impact. However, there was a trend for lower OS in patients with chrom 5 abn (2y 0S 7.7% vs 23 %, p=0.08). 9 (15%) patients, all females, median age 55 (range 35–66) were allografted after a median number of 6 AZA cycles (range 2–17), including 3 pts, 4 pts and 2 pts who had achieved CR, mCR and no response to AZA, respectively. 4 (44%) of them were alive after 5+,17+,32+ and 42+ months. By comparison to the 232 pts with de novo MDS/AML included in the same program, tMDS/AML had a higher frequency of complex karyotype (71 vs 29.5, p<0.01), received fewer cycles of AZA (4 vs 6, p=0.0014) due to more frequent discontinuation of AZA before 4 cycles (41.6% vs 25%, p=0.025) mainly related to a higher incidence of early deaths. tMDS/AML had a similar response rate (38% vs 45% in de novo MDS/AML, p=0.67), but significantly shorter OS (2yOS 15% vs 33.3, p=0.003, figure 1). Conclusion: In this cohort of tMDS/AML, survival with AZA was shorter than in de novo MDS/AML, probably largely due to their more severe baseline characteristics. Only 15% of tMDS/AML could be allografted, half of them with so far a favorable outcome. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Phase II Study of Clofarabine and Cytosine Arabinoside in Adult Patients with Relapsed AML and in Elderly Patients with Untreated AML Who Are at High Risk of Anthracycline Toxicity.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1951-1951 ◽  
Author(s):  
Edward Agura ◽  
R. Brian Berryman ◽  
Laura Brougher ◽  
Barry Cooper ◽  
Andrew De Leon ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Phase Ii ◽  
Response Rate ◽  
De Novo ◽  
High Risk Patient ◽  
Early Death ◽  
Poor Response ◽  
Adult Patients ◽  
Open Label

Abstract PURPOSE: To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in adult patients with refractory or relapsed acute myeloid leukemia and in selected elderly patients with untreated AML and heart disease. PATIENTS AND METHODS: In a phase II, open-label trial, 23 patients with de-novo AML, AML evolved from MDS or relapsed AML received a 5 day regimen consisting of clofarabine 40 mg/m2 intravenously over 1 hour followed within 4 hours by Ara-C 1000 mg/m2. The median age was 68 years (range 39–79 years). Fifteen (65%) had received at least one prior cytotoxic regimen (excluding 5-AZA). Significant cardiovascular disease (history of myocardial infarction, bypass grafting, cardiomyopathy) was present in 52% (12/23) prior to therapy. RESULTS: 22/23 received at least one cycle of therapy and 5 received 2 cycles. One early death was due to disease progression. Grade 4 neutropenia developed in all patients. There were no cases of regimen-related cardiac toxicity. Most patients had some degree of edema and third-spacing syndrome. Several developed a significant but reversible acral rash. 20 patients are evaluable for response. The histologic response rate (defined as marrow blasts <5%) is 60% (12/20) consisting of 10 (50%) complete remissions and 2 (10%) partial responses. Complete cytogenetic remissions occurred in 9 patients. Durable remissions and low toxicity allowed some patients to proceed to nonablative allogeneic stem cell transplantation. CONCLUSION: Clofarabine (40mg/m2) and Ara-C (1000mg/m2) x 5 days is an active and well tolerated regimen in myeloid malignancies including “elderly AML”—a distinct entity usually associated with poor response rate and high treatment-related toxicities. Other drug combinations with clofarabine are being explored for use in allogeneic transplant regimens and with other high-risk patient groups.

scholarly journals Treatment of low-risk myelodysplastic syndromes

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 462-469 ◽  
Author(s):  
Valeria Santini
Keyword(s):  
Clinical Trials ◽  
Lower Risk ◽  
Safety Concern ◽  
Treatment Options ◽  
International Prognostic Scoring System ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Endogenous Erythropoietin ◽  
Transfusion Independence ◽  
Prognostic Stratification

Abstract The majority of myelodysplastic syndrome (MDS) patients belong to the International Prognostic Scoring System (IPSS) and IPSS-revised (IPSS-R) lower-risk categories. Their precise diagnostics and prognostic stratification is often a challenge, but may ensure the optimization of therapy. The availability of diverse treatment options has significantly improved the quality of life and survival of this group of patients. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk MDS, and may be treated successfully with erythropoietic stimulating agents, provided a careful selection is performed on the basis of IPSS-R, endogenous erythropoietin levels, and transfusion independence. Doses and duration of therapy of erythropoietic-stimulating agents (ESAs) are critical to determine efficacy. In case a patient fails ESA treatment, the available options may include lenalidomide (approved for del5q positive cases), hypomethylating agents, and a rather large number of experimental agents, whose clinical trials should be offered to a larger number of MDS patients. The choice for second-line treatment must take into account biologic, cytogenetic, and molecular-identified characteristics of individual patients, as well as frailty and comorbidities. Other cytopenias are less frequently presenting as isolated. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Although neutropenia is targeted symptomatically with growth factor supportive care, the immunosuppressive treatments are indicated mainly for pancytopenic, hypoplastic lower-risk MDS; they are not widely used because of their toxicity, despite the fact that they may induce responses. Finally, hematopoietic stem cell transplant is the curative option also for lower-risk MDS and timing should be carefully evaluated, balancing toxicity and the possibility of survival advantage. Finally, even when considered suitable for lower-risk MDS, transplant application is limited to the rarer fit and younger MDS patient.

Efficacy and Safety Of Bendamustine In Combination With Rituximab For Elderly Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia. A Retrospective Multicenter Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5309-5309 ◽  
Author(s):  
Luca Laurenti ◽  
Barbara Vannata ◽  
Idanna Innocenti ◽  
Francesco Autore ◽  
Francesco Ghio ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Elderly Patients ◽  
Response Rate ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Hematological Toxicity ◽  
Efficacy And Safety ◽  
Front Line ◽  
Good Safety Profile ◽  
Standard Risk

Abstract Chronic Lymphocytic Leukemia (B-CLL) is the most prevalent adult leukemia in western countries, with a median age of onset of 65 years. Front-line therapy for B-CLL young patients is chemo-immunotherapy with Fludarabine-Cyclophosphamide and Rituximab (FCR). However, many B-CLL patients are elderly and with comorbidities. FCR regimen can result in a significant myelosuppression and a high rate of early and late infections, suggesting that it may be too toxic and therefore unsuitable for this large subpopulation of patients. Data from the CLL 5 phase III trial of the German CLL study group (GCLLSG) comparing Fludarabine vs Chlorambucil (Chl) in patients older than 65 years showed no differences in overall survival and progression free survival (PFS) between Fludarabine and Chl. Recently, Bendamustine as single agent showed superiority in comparison to Chl in terms of overall response rate (ORR) and PFS, with a good safety profile. Later, the addition of Rituximab (RTX) to Bendamustine (Benda-R) was shown to be efficacious and safe in the same treatment-naïve setting. Insufficient data are available in patients older than 70 years regarding the efficacy and safety, nevertheless increased incidence of extra-hematological toxicity was noted in this subgroup. Here we report our multicentre retrospective study focusing on responses and toxicities rate in elderly patients with B-CLL. We report data on 24 elderly patients with previously untreated B-CLL observed in 7 Italian Centers from November 2000 to June 2012. All patients were treated with a median of 6 cycles of Bendamustine (range, 3-6) at the median dose of 90 mg/m2 (range, 70-90 mg/m2) for 2 consecutive days every 28 days plus RTX (375 mg/m2 for the first course and 500 mg/m2 for subsequent cycles every 28 days). The median number of RTX cycles was 6 (range, 3-6). The mean dose of RTX was 4500 mg (range, 1500-6200 mg). The primary end points were the ORR (complete response CR and partial response PR) and hematological-extrahematological toxicities rate. Twenty male and four female with a median age of 72 years (range, 65-87 years) were included in the study. Only one patient was unfit with a CIRS score of 7. All patients had ECOG less than 2. Two B-CLL patients had A/I progressive stage according Binet and Rai, 10 patients had B/II and 12 patients had C/III or C/IV. The median lymphocytes count at diagnosis was 37.040/mmc (range, 2.200-140.000). FISH analysis was performed in 19/25 patients: 12 patients were classified as standard risk (normal karyotype, del13q14 or +12) and 7 patients as high risk (del11q and del17p). The analysis of the IgVH, available in 12 patients, showed 7 patients with somatic mutation and 5 patients with germ-line sequences. Only one patient was admitted to the hospital and one received reduced bendamustine dose for neutropenia. Fifteen patients received bendamustine at the dosage of 90 mg/m2 while 9 were treated with 70 mg/m2. The ORR rate was 87.5%: ten patients (41.7%) obtained a complete response and eleven patients (45.8%) obtained a partial response. Among biological features the presence of standard risk FISH karyotype showed a statistical significance in terms of better response to therapy (p= 0.013) and progression (p=0.034). Hematological toxicity was recorded in 7 patients (29%) (neutropenia grade III/IV), 5 of them required G-CSF. Extra-hematological toxicity grade I-III was noticed in 8 patients (3 skin reactions, 3 infusion related reactions, 2 nausea and vomiting). At the present only four patients showed a progressive disease with a PFS of 92% at 12 months. Only one unresponsive patient died from Richter disease 6 months after the end of therapy. When we stratified patients in two groups according to the age, we found that patients younger than 75 years (15 patients) showed a better response (p=0.004) and a delayed time to progression (p=0.027) in comparison to patients more than 75 years. Retrospective data from this group of elderly B-CLL patients indicate Benda-R front-line provide a high response rate and a good safety profile. Also in a subgroup of very elderly patients (age > 75 years) the association of bendamustine 90 mg/m2 and rituximab at standard dose is recommended because of a low rate of dose delay/reduction and acceptable hematological/extrahematological toxicities. Disclosures: No relevant conflicts of interest to declare.

Preliminary Results of a Multicenter Phase II Trial of 5-Day Decitabine as Front-Line Therapy for Elderly Patients with Acute Myeloid Leukemia (AML)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 560-560 ◽  
Author(s):  
Amanda F Cashen ◽  
Gary J. Schiller ◽  
Margaret R. O’Donnell ◽  
Julie S. Larsen ◽  
Akhil Baranwal ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Elderly Patients ◽  
Phase Ii ◽  
Patient Population ◽  
Overall Response Rate ◽  
Response Rate ◽  
De Novo ◽  
Phase Ii Trial ◽  
Newly Diagnosed ◽  
Prior Therapy

Abstract Introduction: More than half of patients diagnosed with AML are over 60 years old and have few effective treatment options due to both patient-related factors such as co-morbidities and poor performance status, and high-risk disease features such as complex cytogenetics and preceding myelodysplastic syndrome (MDS). Decitabine, a potent DNA hypomethylating agent, has been approved for the treatment of patients with all FAB subtypes of MDS, including those with secondary MDS and those who have received prior therapy for MDS. In AML, decitabine may target the frequent aberrant DNA methylation patterns and is a lower intensity therapy that may be better tolerated in this challenging patient population. Study: The primary objective of this multicenter, open label Phase II trial was establishing the morphologic complete response (CR) rate in patients 60 years and older with newly diagnosed, untreated AML, who were not candidates for standard induction chemotherapy. Decitabine was administered at a dose of 20 mg/m2 intravenously over 1-hour for 5 consecutive days every 4 weeks. Results: Fifty-five patients were enrolled in the trial [27 men, 28 women; median age: 74 years (range, 61–87); ECOG Score: 0 (47%), 1 (35%), or 2 (18%)]. Most patients had intermediate (53%) or poor (42%) risk cytogenetics. Fifty-six percent had de novo AML, 35% were transformed from MDS, 7% had AML secondary to prior therapy, and 2% had other. According to the AML response criteria (Cheson, JCO 2003), the expert-reviewed overall response rate in the intent-to-treat (ITT) population was 26%, with 13 (24%) morphologic complete responses (CR) and 1 (2%) CR with incomplete blood count recovery (CRi) (Table). The median time to response was 3 months (range, 51–164 days). Responses were seen in all subgroups of patients, including 5 of 19 patients with a prior history of MDS (CR or CRi, 26%) and 5 of 23 patients with poor-risk cytogenetics (22%). A median of 3 cycles (range, 1–25) was administered to the ITT population. Sixty-four percent of patients received 3 or more cycles of therapy. Twenty-four patients (44%) maintained stable disease during a median 5 cycles of therapy. With 1-year duration of follow-up, the overall median survival was 9.6 months. Besides myelosuppression, the most commonly reported adverse events considered possibly related to decitabine treatment were febrile neutropenia (24%), fatigue (24%), pneumonia (11%), sepsis (9%), dyspnea (9%), and bacteraemia (7%). Three deaths occurred on study and were attributed to sepsis. The 30-day mortality rate on this trial was 4%, which compares favorably to the ~20% mortality rate typically seen in this population treated with standard induction therapy (Stone RM. CA Cancer J Clin.2002;52(6):363). Conclusion: These preliminary results suggest that decitabine given daily for 5 days demonstrates efficacy in patients with newly diagnosed AML, with a toxicity profile that was manageable in this elderly patient population. This study supports the investigation of decitabine in an ongoing Phase III survival trial (n=480) of the 5-day regimen in elderly patients with AML. Table N CR CRi Overall Response Rate % All Patients 55 13 1 26% AML Diagnosis De novo 31 7 0 23% Transformation from MDS 19 4 1 26% Secondary to Prior Therapy 4 2 0 50% Other 1 0 0 0% Cytogenetic Risk Poor 23 5 0 22% Intermediate 29 6 1 24%

Ruxolitinib Plus Pomalidomide in Myelofibrosis: Updated Results from the Mpnsg-0212 Trial (NCT01644110)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1939-1939 ◽  
Author(s):  
Frank Stegelmann ◽  
Holger Hebart ◽  
Markus Bangerter ◽  
Denise Wolleschak ◽  
Martin Griesshammer ◽  
...  
Keyword(s):  
Septic Shock ◽  
Clinical Benefit ◽  
Research Funding ◽  
Response Rate ◽  
Objective Response ◽  
International Prognostic Scoring System ◽  
Study Cohort ◽  
Transfusion Independence ◽  
Treatment Interruptions ◽  
Rbc Transfusion

Abstract Background: Although ruxolitinib (RUX) reduces constitutional symptoms and splenomegaly in myelofibrosis (MF) therapy options for anemia are limited. In our prior MPNSG-0109 trial of pomalidomide (POM) in MF with cytopenia, anemia responses were reported in 14% and 29% of subjects receiving POM 0.5 mg/d and 2 mg/d, respectively (Schlenk RF et al., ASH 2013, abstract #2822). We designed a phase-Ib/-II combination study of RUX plus POM to evaluate synergistic effects in subjects with anemia and splenomegaly (MPNSG-0212 trial, NCT01644110; Stegelmann et al., ASH 2015, abstract #826). Study Design: Primary endpoints are response rate after 12 treatment cycles (28 days each) according to IWG-MRT criteria (Tefferi et al., Blood 2006) and achievement of RBC transfusion independence (Gale et al., Leuk Res 2011). Secondary endpoints are safety, quality-of-life, progression-free survival (PFS) and survival. Main inclusion criterion is pre-treated or untreated MF with anemia (Hb <10 g/dL and/or RBC transfusion dependence). Key exclusion criteria are transplant-eligibility, platelets <100x10E+9/L and neutrophils <0.5x10E+9/L). POM is given at 0.5 mg/d QD. RUX is started at 10 mg BID with dose modifications to optimize efficacy and to manage toxicity. According to a 2-stage design, 37 subjects will be tested in the 1st cohort before starting a 2ndcohort of 38 subjects. Results: Data from 37 subjects are reported. Median age was 73 years (range, 49-83 years). 17 subjects (46%) previously received therapy such as hydroxyurea, ruxolitinib, EPO, pomalidomide, and/or steroids. Median hemoglobin at study entry was 8.6 g/dL (range, 5.4-11.7 g/dL); 11 subjects (30%) were RBC-transfusion-dependent. Median spleen size by ultrasound was 18 cm (range, 13-28 cm). 29 subjects (78%) had constitutional symptoms at baseline; 25 (68%) were intermediate-2 risk and 9 (24%) high-risk according to the ´Dynamic International Prognostic Scoring System´ (DIPSS). Adverse prognosis of the study cohort was underlined by the detection of one or more high-molecular risk markers in 21 subjects (57%) [i.e. mutation in ASXL1, EZH2, IDH1/2 and/or SRSF2]. Median time on-treatment is 11 cycles (range, 1-26 cycles). 563 adverse events (AE) of any grade (CTCAE 1-5) were recorded. Worsening of anemia within the first 6 cycles was the most frequent AE occurring in 13 subjects (35%) followed by fatigue in 11 (30%). Treatment interruptions and dose reductions of RUX and/or POM were rare. There were 26 serious AE (SAE) CTCAE grade 2-5. Pneumonia (N=3), leukemia transformation (N=3), thoracic pain (N=3), abdominal pain (N=2) and septic shock (N=2) occurred in 13 subjects (35%) of which 4 were fatal (cardiac decompensation, pneumonia, and septic shock [N=2]). Only 2 SAE (hemoglobin, grade 4 and neuropathy, grade 3) were considered therapy-related. 18 subjects (49%) are on-study treatment; 19 (51%) discontinued because of AE (N=5), leukemia transformation (N=3), stable disease (SD) without objective response after 12 cycles (N=4), death (N=3) or withdrawal of consent (N=3). 6 subjects (16%) responded with spleen reduction (N=3) or ≥2 mg/dL hemoglobin increase / RBC transfusion independence (N=3). Mean hemoglobin increased from 8.6 g/dL at baseline to 9.3 g/dL at the end of cycle 12. 12 subjects (32%) continued treatment after cycle 12 because of response or SD plus clinical benefit (hemoglobin increase <2g/dL or prolongation of RBC-transfusion intervals and/or improvement of symptoms). 3 subjects (8%) are on treatment for >24 cycles. Conclusions: Combined RUX and POM was safe and feasible and achieved an objective response rate of 16%. One third of the subjects had clinical benefit with the combination therapy. Based on these results and our MPNSG-0109 data a step-wise increase of POM dose to 2 mg QD is intended for the 2nd study cohort to further improve anemia response. Disclosures Koschmieder: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. von Bubnoff:Amgen: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria. Hochhaus:Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Scheid:Janssen: Other: funding outside this work; Celgene: Other: funding outside this work; Novartis: Other: funding outside this work. Schlenk:Pfizer: Honoraria, Research Funding; Amgen: Research Funding.

Phase II study of clofarabine and cytosine arabinoside in adult patients with relapsed AML and in elderly patients with untreated AML who are at high risk of anthracycline toxicity

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7064-7064 ◽  
Author(s):  
E. D. Agura ◽  
R. Berryman ◽  
B. Cooper ◽  
J. Fay ◽  
H. Holmes ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Phase Ii ◽  
Response Rate ◽  
De Novo ◽  
Poor Response ◽  
Chromosome Analysis ◽  
Open Label ◽  
Elderly Aml ◽  
History Of

7064 Purpose: To evaluate the efficacy/safety of a novel AML regimen in elderly patients with heart disease or in patients with a contraindication to ‘standard‘ anthracycline-containing regimens. Patients and Methods: Phase II, open-label design. Eligible pts had elderly de-novo or relapsed AML or would not benefit from 7+3 or simlar therapy. Treatment was CLOF 40 mg/m2, Ara-C 1,000 mg/m2. (d1–5). Results: Patients were accrued and treated from April 2005 through Oct 2006. All pts signed IRB-approved consents. The median age was 67 years (range 38–82 years). Twenty (67%) subjects had received at least one prior cytoxic regimen (excluding 5-AZA). Significant cardiovascular (history of MI, bypass grafting, cardiomyopathy) was present in 43% (13/30) prior to therapy. Thirty pts were enrolled and all recieved at least one day of therapy. 1 pt died within 24 hours of starting treatment due to disease progression. Of the remaining, 29/30 received at least one complete cycle of therapy and 5 received 2 cycles. None received more than 2 cycles. Toxicities were greater in those receiving a second cycle. Grade 4 neutropenia developed in all patients. There were no cases of regimen-related cardiac toxicity. Most patients had some degree of edema and third-spacing syndrome. Several developed a significant but reversible acral rash. 25 patients survived >28 days and are evaluable for hematologic response. The histologic response rate (RR) is 68% (17/25) consisting of 14 (56%) complete remissions (marrow blasts <5%) and 3 (12%) partial responses (PR). There were 13 subjects with known cytogenetic abnormalities, 1 favorable and 12 unfavorable. Complete cytogenetic remissions (CytoCR) occurred in 4 of those patients, by chromosome analysis and/or FISH. Durable remissions and low toxicity allowed some patients to proceed to nonablative allogeneic stem cell transplantation. Conclusion: Clofarabine and Ara-C is an active and well tolerated regimen in myeloid malignancies including “elderly AML” a distinct entity usually associated with poor response rate and high treatment-related toxicities. Other drug combinations with clofarabine are ongoing in hematopoietic transplant and other high risk subgroups. No significant financial relationships to disclose.

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