Danazol Treatment for Thrombocytopenia in Lower-Risk Myelodysplastic Syndromes: A Pilot Real Life Experience

Abstract Background: Severe thrombocytopenia is an uncommon event in patients (pts) with lower-risk MDS, but it may significantly affect the prognosis. No specific pharmacological approaches other than hypometilating agents (not licensed in Europe in lower-risk MDS), able to improve platelet count in this setting, are currently available. Trials testing efficacy and safety of Eltrombopag are ongoing (Oliva 2017). Few data were reported about danazol, an attenuated androgen, that seems to have also some effectiveness in this still unmet need (Wattel 1994; Chan 2002). Aims: To assess the efficacy and safety of danazol in improving the platelet count in low risk MDS pts with severe thrombocytopenia. Methods: We retrospectively reviewed 35 thrombocytopenic MDS pts treated with danazol. The initial and maximal dose was 600 mg/day for all pts, modulated according to response and toxicity. The response was evaluated according to IWG response criteria (Cheson 2006). The outcome was strictly observed every 3 months (mo) up to the 12th mo, and the platelets average number in each observation moment was described. The time to response, the response rate and the enduring of response were also recorded. Results: Of the 35 pts, according to 2016 WHO classification, 4 pts were MDS-ULD; 19 were MDS-MLD (3 of them with medullar hypocellularity), 7 were MDS-EB1 and 5 were affected by MDS/MPN. At baseline the platelet count was lower than 20x10^3/mL in 11 pts, the median was 23x10^3/mL . At starting time of danazol therapy the IPSS-R cytogenetic class of risk was very low in 2 cases, low in 28 cases, intermediate in 3 cases and very high in 1 case. Cytogenetic was not available in one patient. In the 30 MDS pts, the IPSS-R was "very low" in 1 patient, "low" in 16, "intermediate" in 7, "high" in 4 and "very high" in 1. In 1 case it was not evaluable due to the lack of cytogenetics. Two pts were not included in the analysis because they were treated for less than 3 mo (in 1 case danazol was withdraw to permit the beginning of another therapy and in 1 case due to death for other neoplastic disease). The response rate was 63,6% (21 responders on 33 evaluable). Median time to response was 3.5 mo (range 0.3 - 12.4 mo); the average response time was 5.09 mo. In the first year of treatment, the platelet count (evaluated at baseline, 3, 6, 9 and 12 mo) changed in a significant way (F test after repeated measures ANOVA: p < 0.001 as shown in Figure 1). Pairwise comparisons of platelet count according to Bonferroni showed a significant difference for baseline vs. 3 mo (p = 0.0013), baseline vs 6 mo (p = 0.0255), baseline vs 9 mo (p = 0.0047) and baseline vs 12 mo (p = 0.0014); however, no significant differences (p ≥ 0.05) in counts were seen for all the further pairwise comparisons at 3, 6, 9 and 12 mo. The median and average duration of the response for the entire population were respectively 12,5 and 32,5 mo. Only 6 of the 21 responders (28%) lost the response (the median and average duration of response were respectively 5.8 and 12.9 mo). Within the 21 responders, the median progression free survival was not reached after 24 mo. The probability to maintain the response after 50 mo was assessed at 58.2% (C.I. 24.1% to 81.4% - Figure 2). The overall survival showed a significant difference (logrank test: p = 0.0064) between responders and non-responders (Figure 3). Adverse events recorded were as follows: moderate (grade 1 and 2) increase in transaminases in 4 cases (with reduction of danazol to 400 mg/day); 1 case of severe but reversible liver toxicity (grade 3) (with subsequently drug suspension); severe (grade 3) but reversible renal failure in 1 case (the drug was stopped); moderate (grade 1 and 2) increasing of serum creatinine in 6 case (with reduction of danazol to 400 mg/day in 2 of these); reversible cutaneous rash in 3 cases; amenorrhea in 1 case (the only fertile woman in the series); weight loss and loss of appetite in 1 case, weight gain in 1 case. Conclusion: Even if the mechanism of action of danazol in pts with MDS is unclear, this series confirms its efficacy to improve platelet count in the most of MDS pts with severe thrombocytopenia. The response was often clinically significant. It may not be immediate but seems to be reachable after 3-6 mo of treatment. A responsive patient has a good probability to maintain a long-lasting response. The toxicity profile of this drug is acceptable. Waiting for more effective options, danazol may be a good therapeutic option for these pts. Disclosures Riva: Jannsen and Cilag: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Reda:Celgene: Consultancy; Janssen and Cilag: Consultancy; Gilead: Consultancy; ABBVIE: Consultancy. Molteni:AMGEN: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Celgene: Consultancy; Janssen and Cilag: Consultancy.

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Interleukin-10 Gene Polymorphism Reflects the Severity of Chronic Idiopathic Thrombocytopenic Purpura.

Blood ◽

10.1182/blood.v110.11.2111.2111 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2111-2111

Author(s):

Takayuki Saitoh ◽

Tetsuhiro Kasamatsu ◽

Madoka Inoue ◽

W.H.S. Al-ma’Quol ◽

Akihiko Yokohama ◽

...

Keyword(s):

Platelet Count ◽

Idiopathic Thrombocytopenic Purpura ◽

Response Rate ◽

Initial Diagnosis ◽

Control Group ◽

Severe Thrombocytopenia ◽

Bleeding Tendency ◽

Thrombocytopenic Purpura ◽

Chronic Itp ◽

Significant Difference

Abstract Introduction: Recent several cytokine studies have shown Th1 polarization of the immune response in Idiopathic thrombocytopenic purpura (ITP) patients. IL–10 is most important factor regulating Th1 and Th2 cytokine synthesis and IL–10 polymorphism has been implicated in autoimmunity and tumorigenesis. We examined the single nucleotide polymorphisms (SNPs) in the promoter regions of the IL–10 genes in patients with ITP, and analyzed the relationship between IL–10 SNPs and clinical features. Patients and methods: Seventy-eight patients (male/female; 19/59, median age; 59.4) diagnosed as chronic ITP and 202 healthy controls were included. ITP with severe thrombocytopenia was defined as thrombocytopenia (platelet count < 10×109/L) at initial diagnosis of ITP. ALL patients gave written informed consent about the study. The platelet count was ranged from 1×109/L to 100×109/L at an initial diagnosis. In addition, 53 patients (67.9%) had bleeding tendency, and 20 patients (25.6%) had severe thrombocytopenia. Steroid treatment was given to 48 patients (61.5%), while splenectomy was applied to only 9 patients (11.5%). Genotyping in IL-10-1082G/A, -819C/T, −592A/C was determined by PCR based technique. Genotype and allele frequencies were compared between the study groups using χ2-test. The characteristics and laboratory features of the ITP patients with each IL-10 promoter polymorphism were compared using X2-tests and student t-tests. Probability values <0.05 were considered statistically significant. Results: The frequencies of the genotypes were as follows: GG (0%), GA (6%), and AA (94%) for −1082; CC (12%), CT (51%), and TT (37%) for −812; CC (12%), CA (51%), and AA (37%) for −592 loci. The frequencies of each haplotype were as follows: ATA/ATA haplotype in 31 patients (40%), ATA/ACC haplotype in 35 patients (45%), ACC/ACC haplotype in 7 patients (9%). No significant differences in the genotype or haplotype frequencies demonstrated between chronic ITP patients and control group. However, patients with −592AA genotypes showed severe thrombocytopenic state at initial diagnosis compared to those with −592CA/CC genotypes (41.4% vs. 16.3%, p=0.01). Furthermore, patients with ATA/ATA haplotype showed severe thrombocytopenic state (38.7% vs. 17%, p=0.03) compared to those without ATA/ATA haplotype. In patients treated with steroids, the overall response rate was 71% with complete response rate of 23.2% and partial response rate of 47.8%. No significant difference was observed in treatment response according to IL-10 polymorphism. Conclusion: In previous investigations, −592AA genotype or ATA/ATA haplotype have been reported to be associated with the lower levels of IL-10 expression. Our data suggest that the group with low IL-10 inducibility (i.e. −592AA genotype, ATA/ATA haplotype) may have more severe thrombocytopenia compared to those with high IL-10 inducibility. It is also reported that low IL-10 inducibility type enhances Th1-type polarization in ITP. Furthermore, Panitsas et al. revealed that higher Th1/Th2 ratio in ITP patients correlate with lower platelet count. Thus, these findings suggest that IL-10 polymorphism reflect the severity of chronic ITP.

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Efficacy and Safety of Once-Weekly Bortezomib Infusion in the Treatment of Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.5141.5141 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5141-5141 ◽

Cited By ~ 1

Author(s):

Hyun-Kyung Kim ◽

Yeung-Chul Mun ◽

Eun-Sun Yoo ◽

Kyoung Eun Lee ◽

Eunmi Nam ◽

...

Keyword(s):

Overall Survival ◽

Cumulative Dose ◽

Overall Response Rate ◽

Response Rate ◽

Drug Discontinuation ◽

Line Treatment ◽

Efficacy And Safety ◽

Significant Difference ◽

Grade 3 ◽

Median Cumulative Dose

Abstract Abstract 5141 Incorporation of bortezomib in the treatment of multiple myeloma (MM) has significantly imporved patient outcome. Because peripheral neuropathy (PN) leading to dose modification and drug discontinuation seems to be dependent on dose and exposure of bortezomib, some schedules of botezomib therapy were reduced from twice-weekly to once-weekly infusion. We assessed the efficacy and safety of once-weekly bortezomib infusion in the treatment of relapsed/refractory MM. We compared the outcomes and safety of once- and twice-weekly bortezomib infusion as a second-line treatment for the patients of relapsed/refractory MM in our hospital between 2005 and 2010, retrospectively. Twenty-nine patients were enrolled including 12 patients who received once-weekly bortezomib infusion on day 1, 8, 15 and 22 of the cycles and 19 patients who received twice-weekly bortezomib infusion on day 1, 4, 8 and 11 of the cycles as a second-line treatment. Dexamethasone alone (n=18), melpahalan with prednisolone (n=4), and thalidomide with dexamethasone (n=7) were administered combined with bortezomib. Median cumulative dose of bortezomib were 32.4mg/m2 and 18.4mg/m2 in the once- and twice-weekly group, retrospectively (p=0.019). There were no significant difference in overall response rate (66.7% in once-weekly vs 47.1% in twice-weekly, p=0.451) and time-to-progression (median 17.2 months in once-weekly vs 7.1 months in twice-weekly, p=0.381). There was a significant difference in the median time-to-onset of grade 2 to 4 PN (4.5 months in once-weekly vs 2.0 months in twice-weekly, p=0.017). The incidence of grade 2–4 PN (50.0% vs 47.1%) and median cumulative dose to onset of grade 2–4 PN (17.9mg/m2 vs 15.3mg/m2) were not different. The incidence of any grade 3/4 toxicity except PN was similar (25.0% vs 41.2%, p=0.449). Progression-free survival in once-weekly bortezomib group was slightly longer than that in twice-weekly bortezomib (median 34.8 months vs median 22.8 months, p=0.074). Overall survival was similar (median 35.2 months vs median 25.1 months, p=0.118), while the overall survival of elderly patients (60 years or above) in once-weekly bortezomib group was slightly longer than that in twice-weekly bortezomib group by Kaplan-Meier analysis (median 38.1 months vs median 20.1 months, p=0.085). Our data suggest that the onset time of PN was delayed in once-weekly regimen and there was no significant difference overall response, rate of PN, cumulative dose to onset of PN, grade 3/4 toxicity and overall survival between both groups. Because of the larger cumulative dose and the lower rate of dose modification or drug discontinuation due to good tolerability in once-weekly bortezomib than twice-weekly bortezomib, once-weekly bortezomib infusion could be a potential therapeutic approach for patient with MM as a scond-line therapy. Disclosures: No relevant conflicts of interest to declare.

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Efficacy and Safety of Aidi Injection Combined with Transcatheter Arterial Chemoembolization on Primary Hepatic Carcinoma: A Systematic Review and Meta-Analysis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/6376429 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14

Author(s):

Weihao Chen ◽

Yurong Wang ◽

Qiuer Liang ◽

Yunfei Cai ◽

Xudong Chen ◽

...

Keyword(s):

Clinical Response ◽

Transcatheter Arterial Chemoembolization ◽

Response Rate ◽

Clinical Response Rate ◽

Efficacy And Safety ◽

Hepatic Carcinoma ◽

Primary Hepatic Carcinoma ◽

Significant Difference ◽

Aidi Injection ◽

Arterial Chemoembolization

Objectives. To evaluate the efficacy and safety of Aidi injection (ADI) combined with transcatheter arterial chemoembolization (TACE) for primary hepatic carcinoma (PHCC). Methods. We conducted a literature search in EMBASE, PubMed, CENTRAL, MEDLINE, CNKI, Wanfang, and VIP databases from the earliest possible year to April 2018. Randomized controlled trials (RCTs) involving ADI combined with TACE versus TACE alone for patients with PHCC were included. The Cochrane Risk of Bias tool was applied for quality assessment. Results. 22 studies involving 1611 participants were included. The clinical response rate (RR = 1.28, 95% CI: 1.17-1.40; P < 0.00001), KPS score (RR = 1.78, 95% CI: 1.59-2.00; P < 0.00001), survival rate (RR = 1.27, 95% CI: 1.16-1.39; P < 0.00001), immune function (MD = 1.24, 95% CI: 0.98-1.51; P < 0.00001), and adverse effects (RR = 0.62, 95% CI: 0.57-0.68; P < 0.00001) of ADI plus TACE showed significant difference when compared with TACE alone. Conclusions. ADI combined with TACE in the treatment of PHCC improved the clinical response rate and safety compared to TACE alone. However, due to poor methodological quality of many of the included RCTs, more rigorously designed and large-scale RCTs are warranted to examine this beneficial effect in the future.

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Efficacy and safety of combined androgen blockade with antiandrogen for advanced prostate cancer

Current Oncology ◽

10.3747/co.26.4203 ◽

2019 ◽

Vol 26 (1) ◽

Cited By ~ 1

Author(s):

Y. Yang ◽

R. Chen ◽

T. Sun ◽

L. Zhao ◽

F. Liu ◽

...

Keyword(s):

Prostate Cancer ◽

Meta Analysis ◽

Progression Free Survival ◽

Efficacy And Safety ◽

First Line ◽

Combined Androgen Blockade ◽

Hazard Ratios ◽

Significant Difference ◽

Grade 3 ◽

Androgen Blockade

Background Combined androgen blockade (cab) is a promising treatment modality for prostate cancer (pca). In the present meta-analysis, we compared the efficacy and safety of first-line cab using an antiandrogen (aa) with castration monotherapy in patients with advanced pca.Methods PubMed, embase, Cochrane, and Google Scholar were searched for randomized controlled trials (rcts) published through 12 December 2016. Hazard ratios (hrs) with 95% confidence intervals (cis) were determined for primary outcomes: overall survival (os) and progression-free survival (pfs). Subgroup analyses were performed for Western compared with Eastern patients and use of a nonsteroidal aa (nsaa) compared with a steroidal aa (saa).Results Compared with castration monotherapy, cab using an aa was associated with significantly improved os (n = 14; hr: 0.90; 95% ci: 0.84 to 0.97; p = 0.003) and pfs (n = 13; hr: 0.89; 95% ci: 0.80 to 1.00; p = 0.04). No significant difference in os (p = 0.71) and pfs (p = 0.49) was observed between the Western and Eastern patients. Compared with castration monotherapy, cab using a nsaa was associated with significantly improved os (hr: 0.88; 95% ci: 0.82 to 0.95; p = 0.0009) and pfs (hr: 0.85; 95% ci: 0.73 to 0.98; p = 0.007)—a result that was not achieved with cab using a saa. The safety profiles of cab and monotherapy were similar in terms of adverse events, including hot flushes, impotence, and grade 3 or 4 events, with the exception of risk of diarrhea and liver dysfunction or elevation in liver enzymes, which were statistically greater with cab using an aa.Conclusions Compared with castration monotherapy, first-line cab therapy with an aa, especially a nsaa, resulted in significantly improved os and pfs, and had an acceptable safety profile in patients with advanced pca.

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Bortezomib (Velcade ™) Observational Study in China: Efficacy and Safety of Bortezomib-Based Regimen in 395 Relapsed or Refractory Multiple Myeloma Patients

Blood ◽

10.1182/blood.v112.11.5179.5179 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5179-5179

Author(s):

Zhi-Xiang Shen ◽

Hua Yan ◽

Linna Wang

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Observational Study ◽

Response Rate ◽

Complete Response ◽

Chinese Patients ◽

Efficacy And Safety ◽

Female Ratio ◽

Bortezomib Treatment ◽

Grade 3

Abstract Introduction: Multiple myeloma (MM) is a plasma-cell malignancy and overall survival for patients who have relapsed after initial therapy is approximately 2 years. Bortezomib (VELCADE TM) is a first-in-class proteasome inhibitor that has demonstrated significant anti-tumor activity in MM patients. Here we report the results of an observational study of the efficacy and safety of bortezomib-based regimens in Chinese relapsed/refractory MM patients. Methods: This was a multi-center, open-label, phase IV observational study designed to enroll 550 patients with relapsed or refractory MM. From Mar 2006 to May 2008, 500 patients with relapsed or refractory MM were enrolled from 43 medical centers in China and 395 of them were evaluated. Bortezomib (0.7 to 1.6 mg/m2 i.v.) was given on days 1, 4, 8, and 11 in in a 21-day cycle, up to a maximum of 8 cycles, combined with other agents, mainly with the addition of dexamethasone (60.1%). Major endpoint included response rate, safety and time to response. Responses of 62% patients were determined by European Group for Blood and Marrow Transplantation criteria (EBMT). Bortezomib withheld if patients developed neutropenia fever, grade 4 haematologic adverse events (AEs), or grade 3 non-haematologic AEs, and re-administered at 75% of the initial dosage after recovery. Results: In 395 evaluable cases, the median age was 59 years (range 35–82) and the male/female ratio was 1.5:1. 90% of patients were in late stage(stage II/III) and 50% of them were IgG subtype. Patients had received various prior therapies before bortezomib treatment, including VAD (31.3%), VBMCP (M2, 15.1%) and thalidomide-based regimens(14.9%), with best response rate of 10.4% complete response (CR) and 42.3% partial response (PR) from prior therapies. 311 (82%) cases of patients received 1.0–1.4mg/m2 bortezomib-based regimens treatment and 38.5% of them received at least 4 cycles of treatment. 364 patients were evaluable for response, the overall response rate was 287/364 (78.8%), 89 patients (24.5%) achieved a CR, 30(8.24%) had a nearly complete response (nCR), 168 (46.2%) had a PR, 39 (10.7%) had minimal response (MR), 24 (6.6%) had stable disease (SD), and the other 14 (3.9%) had progressive disease (PD). Median time to response was 1 cycle of treatment (range 1–6). Patients who received 4 or more cycles of bortezomib treatment achieved a higher response rate (CR+PR: 81.5%) compared to those who received fewer cycles (partly due to adverse events). And prognosis-related analysis showed that the dosage of bortezomib at 1.0 mg/m2 or more had a significant influence on the time to response and response rate, but no obvious effect on response duration, time to progress or the survival time. Drug related adverse events (AEs) were reported in 50.4% of patients during treatment, including hematologic AEs (mainly thrombocytopenia, 22.5%), gastrointestinal AEs (24.8%), and peripheral neuropathy (22.5%). The rates of grade 3–4 AEs of them were 46.1%, 11.2% and 15.7%, respectively. Serious AEs occurred in 33 (8.4%) cases and 23 (70%) patients recovered finally. Most AEs were predictable and manageable. Conclusion: Bortezomib-based regimen is effective treatment with higher response rate and is well tolerated in most Chinese patients with relapsed and refractory MM patients. Long-term follow-up is continuing.

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Association of Interleukin-18 Gene Polymorphism with Severity of Chronic Immune Thrombocytopenia (ITP).

Blood ◽

10.1182/blood.v116.21.3693.3693 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3693-3693

Author(s):

Takayuki Saitoh ◽

Norihiko Moriyama ◽

Tomonori Takani ◽

Takeki Mitsui ◽

Takumi Hoshino ◽

...

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Initial Diagnosis ◽

Severe Thrombocytopenia ◽

Interleukin 18 ◽

Single Nucleotide ◽

Chronic Itp ◽

Significant Difference ◽

Haplotype Frequencies ◽

And Control

Abstract Abstract 3693 Introduction: Immune thrombocytopenia (ITP) is a chronic acquired organ-specific autoimmune disorder characterized by the production of antibodies against antigens on the membranes of platelets. Several cytokine studies have shown Th1 polarization in ITP patients. Interleukin-18 (IL-18) plays an important role in Th1 and Th2 immune response. Recent studies showed that single-nucleotide promoter polymorphisms influence the transcriptions of IL-18 mRNA. IL-18 polymorphism has been implicated in autoimmunity, including Crohn's disease, rheumatoid arthritis, and asthma. We examined the single nucleotide polymorphisms (SNPs) in the promoter regions of the IL-18 genes in patients with ITP, and analyzed the relationship between IL-18 SNPs and clinical features. Patients and Methods: One hundred patients (male/female; 22/78, median age; 54.5) diagnosed as chronic ITP and 151 healthy controls were included. Chronic ITP was defined as thrombocytopenia (platelet count < 100×109/L) persisting greater than 12 months, normal or increased marrow megakaryocytes, and no secondary immune or non-immune abnormality that could account for the thrombocytopenic state. ITP with severe thrombocytopenia was defined as thrombocytopenia (platelet count < 10×109/L) at presentation of ITP. The response criteria of the ITP International Working Group was used. A complete response (CR) is defined as any platelet count of at least 100×109/L, and a response (R) was defined as any platelet count between 30 and 100×109/L and at least doubling of the baseline count. Allparticipants gave written informed consent about the study. Genomic DNA was isolated from peripheral blood using the DNA Kit (QIAGEN, Hilden, Germany). An allele-specific polymerase chain reaction was used to analyze polymorphism in IL-18 –607A/C and -137G/C. Genotype and allele frequencies were compared between the study groups using Χ2-test. The characteristics and laboratory features of the ITP patients with each IL-10 promoter polymorphism were compared using X2-tests and student t-tests. Probability values <0.05 were considered statistically significant. Results: The platelet count was at an initial diagnosis ranged from 1×109/L to 98 ×109/L, with a median of platelet count of 15×109/L. Thirty-five patients (35%) had severe thrombocytopenia. Steroid treatment was given to 68 patients (68%), while splenectomy was used in 11 patients (11%).The frequencies of the genotypes were as follows: AA (34%), AC (57%), and CC (9%) for -607; GG (77%), GC (21%), and CC (2%) for -137 loci. The frequencies of each haplotype were as follows: C-G/C-G haplotype (9%), A-G/C-G haplotype (47%), A-C/C-G haplotype (10%), A-G/A-G haplotype (21%), A-G/A-C haplotype (11%) and A-C/A-C haplotype (2%). No significant differences in the genotype or haplotype frequencies demonstrated between chronic ITP patients and control group. However, patients with -137CC genotypes showed severe thrombocytopenia at initial diagnosis compared to those with -137GG/GC genotypes (5×109/L vs. 22×109/L, p=0.002). Furthermore, patients with A-C/A-C haplotype showed severe thrombocytopenic state (5×109/L vs. 22×109/L, p=0.002) compared to those without A-C/A-C haplotype. No significant difference of treatment response was observed according to IL-18 polymorphism. Conclusion: No significant differences in the genotype or haplotype frequencies demonstrated between chronic ITP patients and control. However, -137CC genotypes or AA/CC haplotype was associated with severity of chronic ITP. Our data suggest that the group with low IL-18 inducibility (i.e. -137CC genotype, A-C/A-C haplotype) may have more severe thrombocytopenia. Disclosures: No relevant conflicts of interest to declare.

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Bortezomib-Dexamethasone Alone or Plus Cyclophosphamide or Lenalidomide As Second-Line Treatment for Patients with Multiple Myeloma: Final Results From a Phase 2 Study

Blood ◽

10.1182/blood.v118.21.1861.1861 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1861-1861

Author(s):

Meletios Athanasios Dimopoulos ◽

Meral Beksac ◽

Lotfi Benboubker ◽

Huw Roddie ◽

Nathalie Allietta ◽

...

Keyword(s):

Response Rate ◽

Stage Migration ◽

Second Line ◽

Phase 2 ◽

Efficacy And Safety ◽

Second Line Therapy ◽

Line Therapy ◽

Phase 2 Study ◽

Grade 3 ◽

Line Of Therapy

Abstract Abstract 1861 Background: Bortezomib plus dexamethasone (VD) has been shown to be effective and well tolerated in patients (pts) with multiple myeloma (MM) as frontline induction therapy and in relapsed pts; however, no studies have prospectively assessed VD as second-line therapy. The addition to VD of cyclophosphamide (VDC) or lenalidomide (VDR) may improve efficacy, but with increased toxicities. This phase 2 study evaluated the efficacy and safety of VD, with the addition of C or R for pts with stable disease (SD) after 4 cycles, in pts with relapsed or refractory MM following 1 prior line of therapy. This is the first prospective study of VD as second-line therapy for MM. Methods: Bortezomib-naïve pts aged ≥18 years with measurable MM and no grade ≥2 peripheral neuropathy (PN) who had relapsed/progressed after 1 previous line of therapy received four 21-day cycles of VD (bortezomib 1.3 mg/m2, days 1, 4, 8, 11; Dex 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12). Pts achieving at least partial response (PR) then received a further 4 cycles of VD. Pts with SD were randomized to a further 4 cycles of VD, or 4 cycles of VDC (VD + C 500 mg, days 1, 8, 15), or VDR (VD + R 10 mg, days 1–14) for Cycles 5–8. Pts with progressive disease (PD) discontinued treatment. The primary end point was response rate; secondary end points included time to response, duration of response (DOR), safety, and improvement in renal function (defined by the Cockcroft-Gault glomerular function rate [GFR], assessed prior to treatment on day 1, Cycles 1–5). Results: A total of 189 pts were enrolled; 26 did not receive therapy and were excluded from the safety/ITT population (N=163). Median age was 63 years (range 34–86), 53% were male, 20% had KPS ≤70; median time from prior therapy was 13.9 months. In the ITT population, 52% of pts (84/163) experienced an OR by Cycle 4 as validated by IDMC. Discontinuations were due to toxicity (N=10), death, PD, and other reasons (6 each). Of 135 remaining pts who started Cycle 4 treatment, 120 pts had a response assessment at Cycle 4; according to investigators, 82% of these pts experienced an overall response (OR) and 2.5% had PD; median time to first and best response was 49 and 85 days, respectively. Nineteen pts had SD and were randomized: 7 to VD, 8 to VDC (1 did not continue treatment), 4 to VDR. Only 11 pts received a third drug, C or R, in addition to VD. Due to the high response rate for the first four cycles, the second randomization arm was not completed. 47% (77/163) had continued treatment up to Cycle 8. Based on IDMC response validation as of June 2011, 122 patients had a Best Confirmed Response: 75% OR, 20% SD, and 4% PD. GFR results at Cycle 8 are shown in the Table. In pts who had baseline and on-study assessments, median GFR was 62.2 mL/min at baseline and increased after Cycles 1, 2, 3, 4, 5, 6, 7, and up to Cycle 8 by 4.5, 5.7, 9.4, 8.7, 6.0, 9.6, 8.9, and 5.5 mL/min, respectively. Of the 26 pts with stage migration from baseline GFR to best GFR at Cycle 4, 12 had a renal response (MR renal). Of the 24 pts with baseline GFR <50 ml/min and renal response with stage migration from baseline GFR to best GFR at Cycle 8, 13 had CR renal, 11 had MR renal. Grade 3/4 adverse events (AEs) occurred in 64% of pts; the most common were thrombocytopenia (17%), anemia (10%), and constipation (6%). 40% of pts had serious AEs, and 46%/29%/12% had AEs resulting in dose reductions/discontinuation/death. Overall rates of sensory PN, polyneuropathy, PN (neuropathy peripheral), and motor PN in Cycles 1–8 were 20%, 18%, 13%,and 1% respectively, including 5%, 5%, 4%, and 1% grade 3/4, respectively; 55% of PN events were reversible, with resolution in 43%. Conclusions: This is the first prospective trial which assessed VD as second-line treatment in MM. VD is effective and well tolerated with less than 10% of pts receiving subsequent C or R added to VD. Overall renal function was shown to improve with treatment. PN was manageable with good reversal rates. VD represents a feasible, active treatment option for pts with relapsed MM. Final efficacy and safety data will be presented. Disclosures: Dimopoulos: Ortho Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc: Consultancy, Honoraria. Beksac:Celgene: Honoraria, Speakers Bureau; Janssen-Cilag: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Allietta:Covance for Janssen-Cilag: Employment. Broer:Janssen-Cilag: Employment. Couturier:Janssen-Cilag: Employment. Angermund:Janssen-Cilag: Employment. Facon:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

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Outcome of Lower Risk Non Del 5q MDS after Failure of Erythropoiesis Stimulating Agents (ESA), and Impact of Post-ESA Treatment on Survival: A Retrospective European Study

Blood ◽

10.1182/blood.v126.23.1665.1665 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1665-1665 ◽

Cited By ~ 1

Author(s):

Sophie Park ◽

Jean-François Hamel ◽

Andrea Toma ◽

Charikleia Kelaidi ◽

Maria Campelo Diez ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Cooperative Groups ◽

Second Line ◽

Advisory Committees ◽

Primary Resistance ◽

Investigational Drugs ◽

Significant Difference ◽

Very High

Abstract Background : Most non-del 5q lower risk MDS patients (pts) are first treated with ESA, with about 50% (generally transient) responses, and second line treatments (TX) including hypomethylating agent (HMA), Lenalidomide (LEN) and investigational drugs are then often proposed, but their effect on overall survival (OS) is unknown. In a previous work on 253 such pts, we found worse OS with early failure to ESA, i.e. primary resistance (RES) or relapse (REL) < 6 months after ESA onset (Kelaidi, Leukemia, 2013), but only few pts had received, after ESA failure, TX other than RBC transfusions. In the present study, we gathered non-del 5q lower risk MDS treated with ESA from several EU MDS cooperative groups, and analyzed their outcome after ESA failure, and the effect of second line TX on survival. Methods : 1611 IPSS low and int-1 (lower risk) non del 5q MDS pts included in the French (GFM), Italian (FISM), Spanish (GESMD), Greek, Düsseldorf and Munich registries between 1997 and 2014, and treated by ESA were studied. Survival was assessed from failure of ESA (i.e. from primary failure evaluated after 12 to 24 weeks of ESA treatment, or from relapse after a response). Progression at ESA failure was defined upon progression to a higher IPSS-R class at ESA failure as compared with ESA onset. Results : At ESA onset, the 1611 pts were reclassified by IPSS-R in 16% very low, 54% low, 13% int, 6% high, 1% very high and 10% ND. HI-E (using IWG 2006 criteria) to ESA treatment was 66.9%, and the median duration of response was 15 months. The cohort of 1038 pts with ESA failure included 521 RES and 517 REL. Median OS was 4.2 years in REL and 3.7 years in RES pts (p=0.56), and no significant difference was seen, even after restricting the analysis to very low and low IPSS-R pts (p=0.81), or when analyzing "early" vs "late" failures, with cut-off points at 6 or 12 months, as we previously reported (Kelaidi, Leukemia, 2013). 336 (32%) pts received second line treatment (TX2) other than RBC transfusions, including HMA in 88 pts, LEN in 169 pts, and other TX (OT) in 79 pts (including 11 chemotherapy, 17 thalidomide, 11 immunosuppressors (ATG, cyclosporine), or investigational drugs), with response rates of 46%, 39% and 33% respectively (p=0.4). 87 pts had a third line TX (mostly a new drug, but also 7 pts who received HMA after LEN, and 33 pts LEN after HMA). Pts treated with LEN as TX2 were younger (median age 70 vs 75 for BSC, and 70 for HMA p<10-4), had more RARS (67% vs 28% for BSC and 27% for HMA, p<10-4), while pts treated with HMA as TX2 had more RAEB-1 (34% vs 10% for BSC and 12% for LEN, p<10-4) and more high and very high IPSS-R at onset of TX2 (48% vs 4.6% for BSC and 3.1% for LEN, p<10-4). Median OS for pts receiving BSC, LEN, HMA and OT as TX 2 was 4.3y, 3.7y (HR 1.1 [0.81-1.50] p=0.5), 2.1y (HR 1.59 [1.12-2.72], p=0.01) and 2.2y (HR1.17 [0.81-1.68], p=0.41) respectively (Figure). However, in a multivariate analysis adjusted on age, gender, and IPSS-R progression at ESA failure, OS difference became not significant. Analysis of AML progression in the different TX2 groups is currently being finalized. C onclusion: In this large multicenter retrospective cohort of non-del 5q lower risk MDS pts having failed ESA treatment, OS from failure was similar in RES and REL pts, contrary to our previous smaller experience. About 1/3 of the pts received second line treatments other than RBC transfusion, mainly LEN or HMA. However, none of those treatments was able to improve OS compared to BSC. Newer treatments are required in this situation, possibly including allogeneic SCT in younger pts. Figure 1. OS since ESA failure according to TX2 (Simon-Makuch method). Figure 1. OS since ESA failure according to TX2 (Simon-Makuch method). Disclosures Park: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Celgene: Research Funding. Off Label Use: Lenalidomide in non del 5q MDS. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Cony-Makhoul:BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Cheze:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wattel:PIERRE FABRE MEDICAMENTS: Research Funding; CELGENE: Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; NOVARTIS: Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Fenaux:Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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Single-agent bortezomib in previously untreated multiple myeloma (MM): Results of a phase II multicenter study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7504 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7504-7504 ◽

Cited By ~ 15

Author(s):

K. Anderson ◽

P. Richardson ◽

A. Chanan-Khan ◽

R. Schlossman ◽

N. Munshi ◽

...

Keyword(s):

Response Rate ◽

Axonal Neuropathy ◽

Single Agent ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Time To Progression ◽

Large Fiber ◽

Grade 3 ◽

Dose Modifications

7504 Background: Bortezomib is effective in relapsed and/or refractory MM. This trial evaluated its efficacy and safety as monotherapy in previously untreated MM. Methods: Pts with untreated, symptomatic MM were eligible, with pts receiving concomitant steroids, platelet count < 30 × 109/L, or grade > 2 peripheral neuropathy [PN] excluded. Endpoints included response rate (RR) [Bladé criteria], time to progression, safety, incidence/severity of PN, and effect of dose modifications on PN. Pts received bortezomib 1.3 mg/m2 (d1, 4, 8, 11 every 21d) for 8 cycles. Comprehensive neurologic evaluation including electrophysiologic testing [NCS] and skin biopsy was performed in a subset of pts (n = 34). Results: Sixty-six pts (47% with stage III MM) were treated and 60 pts are evaluable for response, with an overall RR of 38% (CR 10%, PR 28%). PN was reported in 55% (36/65) pts (23 grade 1, 12 grade 2). One pt with grade 3 PN was discontinued. Other common treatment-associated adverse events reported to date include grade 1–2 fatigue in 21% (6/29), and rash in 17% (5/29) pts. Preliminary analysis shows PN improved or resolved in 75% (6/8 pts, with available follow-up data) with dose reduction. At baseline, small-fiber neuropathy (SFN) was seen in 52% (17/33) and large fiber axonal neuropathy (LFN) occurred in 9% (3/34) pts by NCS. SFN worsened in 41% (7/17) pts with baseline SFN. After completion of treatment, new SFN was seen in 33% (8/24) pts and LFN in 17% (4/24) pts by NCS. Conclusion: Single agent bortezomib is active in newly diagnosed MM pts (CR 10%), has manageable toxicity and offers a steroid-sparing approach. Underlying SFN appears more common in MM than previously appreciated and can also develop during bortezomib therapy, with symptomatic PN improving with dose modification. [Table: see text]

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Multi-institutional phase II study of carboplatin-gemcitabine combination chemotherapy in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.18179 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 18179-18179

Author(s):

J. Sasaki ◽

H. Uramoto ◽

K. Kashiwabara ◽

H. Kishi ◽

E. Moriyam ◽

...

Keyword(s):

Phase Ii ◽

Combination Chemotherapy ◽

Advanced Nsclc ◽

Response Rate ◽

Group Performance ◽

Phase Ii Study ◽

Single Agent ◽

Objective Response ◽

Efficacy And Safety ◽

Grade 3

18179 Background: Because elderly pts may tolerate platinum-based combination chemotherapy poorly, single-agent chemotherapy is selected for the treatment regimen. However, retrospective subgroup analyses have consistently indicated that elderly pts indeed benefit from platinum-based combination chemotherapy as well as their younger counterparts. This phase II study evaluated the efficacy and safety of carboplatin-gemcitabine combination chemotherapy in elderly pts with advanced NSCLC. Methods: Fifty-four pts aged more than 70 years old (median, 77; range, 70–88) with previously untreated advanced NSCLC were enrolled on this trial. Additional criteria included the presence of measurable lesions, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Pts received carboplatin at an area under the curve of 4 mg/ml/min on the first day and gemcitabine at 1000 mg/m2 on the first and eighth day of consecutive 3 week periods. The primary endpoint was to determine the objective response rate of this platinum-doublet regimen. The RECIST criteria were used to measure response. Results: Enrolled pts included 15/39 with stage IIIB/IV diseases. Fifty-one out of enrolled pts were eligible for efficacy and safety analyses. The median number of treatment cycles was 4 (range, 1–7). Fifteen partial responses (response rate: 29%) were obtained. The median TTP was 118 days. Hematological toxicities of grade 3/4 included leukopenia (46%), neutropenia (72%) and thrombocytopenia (50%). Non-hematological toxicities of grade 3/4 included nausea (6%), appetite loss (7%), fatigue (7%) and infection (9%). Conclusions: The combination carboplatin-gemcitabine at these doses has shown activity with a favorable toxicity profile for fit elderly pts with advanced NSCLC. No significant financial relationships to disclose.

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