Azacytidine (AZA) in MDS (including RAEB-t and CMML) in Patients (pts) ≥ 80 Years: Results of the French ATU Program.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1773-1773 ◽  
Author(s):  
Raphael Itzykson ◽  
Sylvain Thépot ◽  
Bechir Achour ◽  
Bruno Quesnel ◽  
Francois Dreyfus ◽  
...  
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Overall Response Rate ◽  
Best Supportive Care ◽  
Poor Survival ◽  
Overall Response ◽  
Number Of Patients ◽  
Ortho Biotech ◽  
Study Population

Abstract Abstract 1773 Poster Board I-799 Background Patients aged ≥ 80 years account for as many as 30 to 35% of MDS in large registries (Rollison Blood 2008; Germing Ann Hematol 2008). Those patients (pts), when they have high risk MDS, are rarely candidates for chemotherapy (CT), even at low dose like low-dose araC, due to the risk of myelosuppression, and generally receive best supportive care (BSC) only, with very poor survival. Azacytidine (AZA) improves survival in higher-risk MDS pts, including RAEB-t and in pts aged > 75, with more limited myelosuppression than CT (Lancet Oncol 2009). Methods An AZA compassionate program (ATU) was opened in France between Dec 2004 and Dec 2008 for higher risk MDS, and for AML not candidates or refractory to intensive chemotherapy (IC). We retrospectively analyzed the outcome of MDS (including RAEB-t and CMML) pts ≥ 80 years from the 42 centers with complete patient (pt) reporting, and having received ≥ 1 cycle of AZA. Results The study population included 41 pts (M/F: 22/19; median age 83y, range 80-91) WHO diagnosis was RMCD in 2, RAEB-1 in 12, RAEB-2 in 16, and RAEB-t in 8, CMML in 3; IPSS cytogenetic risk favorable (fav) in 16, intermediate (int) in 10, and unfavorable (unfav) in 9 (karyotype failure/not done in 6); IPSS was int-1 in 8, int-2 in 18 and high in 13, undetermined in 2. Six pts had previously been treated unsuccessfully with low-dose AraC. With a median follow-up of 12 months, pts had received a median of 4 cycles (1-12) of AZA, at FDA/EMEA-approved schedule (75 mg/m2/d x7d/4 w) in 54% or a less intensive schedule (5d/4w, or <75 mg/m2/d) in 46%. Dose reduction was more frequent than in pts < 80y (30%, p=0.04). Febrile neutropenia was reported in 36% pts, 67% of whom required hospitalization. Both rates were comparable to those observed in pts < 80 years (p=0.2 and p=0.5, respectively), and were not lower in pts treated by less intensive AZA dosing (p=0.7; and p=0.6 respectively). 5 pts (12%) died before completion of 4 cycles, compared to 10% below the age of 80y (p=0.7). According to IWG 2006 criteria, the overall response rate (ORR) was 34%, including CR in 6 pts (15%), PR in 2 (5%), marrow CR (mCR) in 3 (7%), stable disease (SD) with HI in 3 (7%), SD without HI in 9 (21%), progression in 12 (29%), and AZA discontinuation before 4 cycles in 6 (16% including 5 deaths, 1 SAE). The ORR did not significantly differ from that of pts < 80y (45% p=0.6). Median OS was 17.1 months and 1-y and 2-y OS were and 59.7% and 49.8% respectively, not significantly different from OS of pts < 80y (median OS: 15 months, p=0.27). The number of patients was too small to analyze prognostic factors of response to AZA and survival. Conclusion Although this cohort of higher risk MDS aged 80 or greater obviously included a selected population of relatively “fit” very old persons, our results suggest that treatment with AZA in this age group is associated with significant overall response rates and OS rates at 1 or 2 years. There was no clear evidence of increased toxicity such as a higher hospitalization rate for infection or increased death rate before 4 cycles, when compared to similar patients aged less than 80. Disclosures Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Decitabine Low-Dose Schedule (100 mg/m2/Course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2522-2522 ◽  
Author(s):  
Hagop Kantarjian ◽  
Susan O’Brien ◽  
Francis Giles ◽  
Farhad Ravandi-Kashani ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Optimal Schedule ◽  
Dose Schedule ◽  
Overall Response ◽  
Transfusion Independence ◽  
Secondary Mds ◽  
To Receive

Abstract Background Decitabine (DAC), a hypomethylating agent, has shown activity in MDS. DAC 150 mg/m2 by continuous infusion has been associated with CR rates of 10% to 20%. We investigated optimizing the dose schedule of DAC in MDS. Study Group and Methods Patients (pts) with IPSS intermediate 1–2 & high risk MDS were randomized to one of 3 schedules of DAC: 1) 20 mg/m2 IV over 1 hour daily x 5; 2) 10 mg/m2 IV over 1 hour daily x 10; or 3)10 mg/m2 subcutaneously (SQ) BID x 5. A total of 95 pts are to be treated; Bayesian randomization is implemented based on CR rates. Courses were given every 28 days. Delays to allow counts recovery were permitted every 3 courses, or if myelosuppression without disease, or severe myelosuppression complications. Pts were allowed to receive erythropoietin 40,000 units weekly for anemia, or GCSF if needed. Response criteria for CR & PR were as for AML (PR requiring also ↓ blasts by &gt;50%). Clinical benefit (CB) referred to one or more of: platelets î by ≥ 50% and &gt;30 x 109/L, or granulocytes increase by ≥ 100% and to &gt;109/L, or hemoglobin î by ≥ 2 g/dl or transfusion independence, or splenomegaly ↓ by 50% or more, or monocytes ↓ by 50% or more (pretreatment &gt;5 x 109/L). Results 92 pts have been treated; median age 65 (31–90) yrs; 66% &gt;60 yrs old. IPSS: intermediate-1 25%; intermediate-2 38%; high 19%; CMML 17% Cytogenetic abnormalities 57%; secondary MDS 17%; marrow blasts &gt; 10% in 31%. 27 pts had prior erythropoietin; 17 had prior GCSF; 22 had other prior therapies. Presently, 89 pts have received 1 course. Results: 32 CR (36%); 7 PR (8%); 13 marrow CR + CB (15%); 16 CB (18%); overall response 68/89=76%. Median courses to CR 3 (range 1 to 6). Median follow-up of 9 months; 48 pts continue on DAC. Compared with a 114 pts with MDS who received intensive chemotherapy (2000–2004), CR rate was lower with DAC (36% vs. 45%), overall response rate was favorable; 6-week mortality was lower with DAC (1% vs. 21%); and estimated survival favorable (p = 0.00007). CR rates by schedule: 5 days IV 24/58 (41%); 5 days SQ 4/14 (28%); 10 day IV 4/17 (24%). There was more myelosuppression with 10 day IV. After 55 patients were randomized, the 5 day IV arm was determined statistically superior, therefore, remaining patients were not randomized, but were treated with 5 days IV therapy. Conclusions DAC has significant anti-MDS activity; 2) optimal schedule: 20 mg/m2 IV over 1 hour daily x 5; 3) timely repeated courses needed for optimal response.

Lenalidomide and Rituximab For The Treatment Of Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia: Results Of Planned Interim Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5299-5299 ◽  
Author(s):  
Michael Y. Choi ◽  
Januario E. Castro ◽  
Sheila Hoff ◽  
Hongying Li ◽  
Laura Rassenti ◽  
...  
Keyword(s):  
Partial Response ◽  
Interim Analysis ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Free Survival ◽  
Safety And Efficacy ◽  
Overall Response ◽  
Grade 3

Abstract Based on data previously presented by our group demonstrating the safety and efficacy of lenalidomide (L) and rituximab (R) in the upfront setting, we are conducting an open-label, phase 2 trial single center trial to evaluate this combination as treatment for patients with relapsed or refractory CLL. Methods Patients started L at 5 mg per day and could escalate to 25 mg/day if tolerated. Patients received L for 21 of 35 days for cycle 1, then 21 of 28 days for cycles 2 to 7. Rituximab was started at the end of C1 at 50 mg/m2 on Day 29, 325 mg/m2 on day 31 and 33, then 375mg/m2 weekly x4 for cycle 2, and on day 1 for cycles 3-7. Patients who achieved a response but had residual disease after 7 cycles were given the option to continue single-agent L in a consolidative manner for 6 additional cycles. All patients received allopurinol 300mg daily and aspirin 81mg daily, unless contraindicated. The primary endpoint was overall response rate by iwCLL guidelines following 7 cycles. This abstract reports on the planned interim analysis of the safety and efficacy. Results By April 2013, 24 patients were enrolled and received treatment. 63% of patients were male (15/24). The median age at the start of study treatment was 67 years (range 53-83), with median 2.5 prior therapies (range 1-7). 75% (18/24) had CLL cells that expressed unmutated IgVH genes or high levels of ZAP-70. 25% (6/24) had unfavorable cytogenetics (del 17p or del 11q). 5 patients stopped therapy early due to toxicity. 2 patients stopped treatment due to grade 3 tumor flare reaction. 1 patient developed grade 4 tumor lysis requiring hemodialysis. 1 patient had grade 4 neutropenia within days of starting L. 1 patient developed a deep vein thrombosis during cycle 2 while off aspirin for transient thrombocytopenia. These patients tended to have a higher baseline absolute lymphocyte count, but this association did not meet statistical significance. Treatment was otherwise well tolerated. Neutropenia was the most common adverse event (AE), with grade 4 (by CTCAE 4) in 9 patients, and grade 3 in 6 patients out of 21 evaluable patients. There was a single instance of grade 4 thrombocytopenia, and 4 patients had grade 3 thrombocytopenia. 3 patients had grade 3 anemia. The only other grade 3 or higher AE was fatigue (5%). Of note, grade 2 superficial thrombophlebitis occurred in 3 patients. Out of the 20 patients whose primary endpoints were assessed, the overall response rate (ORR) was 70% (14/20) with 15% nodular partial response (3 patients) and 55% partial response (PR) (11 patients). 30% (6/20) were non-responders (NR). Only 1 of the 6 patients with NR had objective progressive disease (PD). The other 5 patients stopped treatment early due to toxicity and were designed as non-responders. Of the responder patients, 8 elected to receive an additional 6 months of consolidation lenalidomide. All maintained the same response without meeting objective criteria for either PD or complete response. After a median follow-up of 17 months from the start of treatment, there have been no deaths among the 24 patients. For the 20 evaluable patients, the median progression free survival (PFS) was 18.4 months and the median treatment free survival was 13.5 months.We did not find any significant association between response, toxicity, or PFS and any demographic or prognostic variable analyzed, including age, ZAP-70, IgVH mutation, cytogenetics, splenomegaly, or CLL cell immunophenotype. Conclusions The combination of lenalidomide and rituximab is an effective regimen for the treatment of patients with relapsed or refractory CLL with an ORR and PFS that rivals novel CLL therapies, especially for patients continued on lenalidomide consolidation therapy. The median PFS for all patients is in excess of 1.5 years after a median follow-up of 17 months. A subset of patients encountered adverse events requiring early treatment cessation, but only 1 patient progressed on treatment. Continued accrual will facilitate the identification of biologic or clinical factors that may predict such outcomes. Disclosures: Choi: Celgene: Research Funding. Castro:Celgene: Research Funding. Kipps:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

scholarly journals Clofarabine Plus Low-Dose Cytarabine for the Treatment of Patients with Higher-Risk Myelodysplastic Syndrome (MDS) Who Have Been Relapsing after, or Are Refractory to, Hypomethylating Agent (HMA) Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3166-3166 ◽  
Author(s):  
Elias J. Jabbour ◽  
Hagop M. Kantarjian ◽  
Koji Sasaki ◽  
Tapan M. Kadia ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Group Performance ◽  
Performance Status ◽  
Advisory Board ◽  
Cell Transplant ◽  
Complex Karyotype ◽  
Overall Response ◽  
Low Dose Cytarabine

Abstract Background: HMA therapy is standard of care for patients with MDS. Outcome post HMA failure is poor with a median survival of 4-6 months. Clofarabine is a second generation nucleoside analog with single agent activity in MDS. The objective of this phase II trial is to evaluate the safety and activity of the combination of clofarabine and low dose cytarabine in the treatment of patients with high risk MDS who failed prior HMA therapy. Methods: Eligible patients were adults older than 18 years with MDS intermediate-1 and higher by the IPSS, who have had no response, progressed, or relapsed following at least 4 cycles of therapy with either azacitidine and/or decitabine. Patients were required to have an Eastern Cooperative Oncology Group performance status of </=2 at the time of study entry. Responses were defined according to International Working Group 2006 criteria. Induction therapy consisted of clofarabine 10-15 mg/m2 IV daily X 5 days (days 1-5) and cytarabine 20 mg SC twice daily X 7 days (days 1-7). Patients could receive up to 3 induction cycles as long as they tolerated the therapy and had stable disease. Responding patients proceeded with consolidation therapy with clofarabine 10-15 mg/m2IV daily X 3 days (days 1-3) and cytarabine 20 mg SC twice daily X 5 days (days 1-5) for a maximum of 12 cycles. Cycles were repeated every 4 to 8 weeks depending on hematopoietic recovery and resolution of toxicities. Results: From January 2012 to August 2015, 80 eligible patients were enrolled in this prospective study (NCT01444742) and received a median of 2 cycles (range, 1-12) (Table 1). The overall response rate (ORR) was 46% (16 [20%] achieved complete remission (CR), 17 [21%] marrow CR, 1 [1%] partial response (PR), 3 [4%] hematological improvement (HI)) with a median response duration of 7 months. The median time to response was 42 days (range, 9-191). By multivariate analysis, complex karyotype was the only independent factor predicting for response (hazard ratio [HR] 0.13; 95% confidence interval [CI]: 0.03- 0.62; p=0.01). Of the 37 patients with diploid karyotype, the overall response was 68% (7 [19%] achieved CR, 15 [41%] marrow CR, 1 [3%] PR, 3 [4%] HI). Nine of the responding patients received subsequent allogeneic stem cell transplant (ASCT). With a median follow-up of 24 months (range: 1-51 months), the median event-free survival (EFS) and overall survival (OS) times were 5 months (95% CI: 2.7-6.3) and 11 months (95% CI: 6.5-14.9), respectively (Figure 1). The median OS for responding and non-responding patients was 24 months (95% CI: 11.7-35.6) and 5 months (95% CI: 2.8-6.2), respectively (p<0.001). There was no difference in OS whether patients were censored or not at the time of ASCT (p=0.463). At last follow-up, 22 patients (28%) remained alive: 1 is receiving low-dose clofarabine and cytarabine, 5 are alive in response after ASCT, 9 are receiving salvage therapy, 1 went to hospice, and 6 were lost to follow-up. By multivariate analyses, complex karyotype, platelet count less than 30 x 109/L, and poor performance status were independently associated with poor survival. In addition, the response to the combination of low-dose clofarabine and cytarabine was independently associated with better OS (HR 0.17; 95% CI 0.09-0.36; p<0.001). Grade ≥ 3 therapy-related toxicity included infections (34%), increased liver functional tests (8%), acute renal failure (3%), skin rash (3%), syncope (1%), and rectal bleeding (1%). Twenty-two (28%) patients had clofarabine dose reduction after a median of 2 courses. After 47 patients were enrolled and several patients experienced infections during induction, the protocol was amended to reduce the dose of clofarabine to 10 mg/m2 per day for 5 and 3 days during the induction and consolidation phases, respectively. There was no difference in responses before and after the modification to the protocol's dosing schedule (p=0.314). Conclusion: The combination of low-dose clofarabine and cytarabine in patients with higher-risk MDS after HMA failure resulted in an ORR of 46% and median OS of 11 months and may be particularly effective in patients with diploid karyotype. Our results also indicate that the combination of low-dose clofarabine and cytarabine may be useful as a bridge to ASCT in eligible patients. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jain:Abbvie: Research Funding; Infinity: Research Funding; Servier: Consultancy, Honoraria; Incyte: Research Funding; Genentech: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Novimmune: Consultancy, Honoraria; BMS: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

A Phase II Study (Biov-121) of Clofarabine Monotherapy First Line in Patients Aged 65 Years or Older with Acute Myeloid Leukemia for Whom Standard Intensive Chemotherapy Is Not Considered Suitable.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 425-425 ◽  
Author(s):  
Alan K. Burnett ◽  
M. Baccarani ◽  
Peter Johnson ◽  
John Yin ◽  
Andrew Saunders ◽  
...  
Keyword(s):  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Intensive Treatment ◽  
Intensive Chemotherapy ◽  
Secondary Aml ◽  
Overall Response ◽  
Number Of Patients ◽  
Cytogenetic Profile ◽  
Acute Myeloid

Abstract Background: The treatment of older patients with AML is unsatisfactory and not improving. A substantial proportion of patients are not offered a standard intensive (“3+7”) chemotherapy approach because they are not considered medically fit (Juliusson et al, Leukemia, 2006 (20):42-7). Such patients are usually treated with best supportive care or low-dose Ara-C with a median survival of approximately 3 months. BIOV-121 is an open-label non-randomised multicentre international study of clofarabine, a next generation purine nucleoside analogue, in elderly patients (≥ 65 yrs) with previously untreated acute myeloid leukaemia (AML) who are unsuitable for standard (“3+7”) treatment. Methods: 66 patients aged ≥ 65 with untreated AML (WHO classification) were enrolled in study BIOV-121. Clofarabine was administered at a dose of 30mg/m2 for 5 days repeated every 28–42 days (1 course) for a maximum of 3 courses. All patients were considered unsuitable for standard intensive treatment based primarily on age, comorbidity and/or performance status. The primary endpoint of the study was overall response rate defined as the number of patients achieving a CR, CRi or PR according to the international working group guidelines. Results: 66 patients were recruited with a median age of 71 (range 64–81). 48 patients had de novo and 16 had secondary AML. 72% had an ECOG performance sore of &lt;2; 74% had one or more comorbidities. 31% had an adverse cytogenetic profile; 69% had intermediate cytogenetics (Grimwade D et al Blood 1998). The principal reasons patients were considered unsuitable for standard intensive chemotherapy were age and comorbidity. Nineteen patients achieved a CR; 10 CRi and 3 PR, giving an overall response rate of 48%. 14 patients died (any cause) within 30 days of study start date. The CR/CRi rate in patients over 70 years (49%) was similar to that observed for younger patients (36%). 42% (8/19) of patients with adverse cytogenetics and 31% (5/16) of patients with secondary AML achieved a CR/CRi. The median times to recovery of neutrophils to 1.0 x 109/L and platelets to 100 x 109/L following course 1 were 18 and 27 days respectively. 26% of patients developed neutropenic sepsis. Liver and renal adverse events (NCI CTC grade 3+) were both observed in 23% of patients. The median duration of remission is 6 months; 12 patients have relapsed to date. The median overall survival for all patients is 5 months with a 1 year survival of 26%. Conclusion: A complete response rate of 44% achieved with clofarabine in older AML patients unsuitable for standard intensive treatment is encouraging and potentially superior to the current standard of care, low dose Ara-C. Of note a good proportion of patients with an adverse cytogenetic profile and/or secondary disease achieved a CR/CRi when treated with clofarabine.

Prospective observational trial of low-dose skin electron therapy in mycosis fungoides using rotational technique.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22077-e22077
Author(s):  
Neil Newman ◽  
Austin Noah Kirschner ◽  
Chirayu Patel
Keyword(s):  
Treatment Response ◽  
Mycosis Fungoides ◽  
Clinical Benefit ◽  
Low Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Time To Treatment ◽  
Overall Response ◽  
Electron Therapy

e22077 Background: Low dose total skin electron therapy (TSET) utilizing 12 Gy in 12 fractions has been shown to provide a durable treatment response for dermal lesions caused by mycosis fungoides secondary to cutaneous T cell lymphoma (CTCL). We sought to prospectively assess the durability of response and quality of life (QOL) for patients receiving low dose TSET using the rotational technique technique. Methods: We prospectively enrolled patients with CTCL on an IRB approved study from 2016 to 2019 who had pathologically confirmed CTCL from stage IB-III. Patients completed a baseline validated Skindex-29 survey encompassing 29 questions assessing QOL. Physicians graded the appearance of the skin using the modified severity-weighted assessment tool (mSWAT) at baseline. Patients received 12 Gy in 12 Fractions on consecutive dates and patients were treated with a dual field rotational technique. The mSWAT was reassessed on ensuing follow-up visits along with the Skindex. The primary outcome was overall response rate with the secondary outcomes being time to treatment response, duration of clinical benefit (time to requiring an additional intervention), as well as improvements in Skindex questionnaire items. Results: We enrolled 20 patients and recorded an overall response rate (ORR) of 90% with four complete responses. The time to treatment response was 9.7 weeks. While the baseline mSWAT was 55.6 it declined to a median mSWAT of 2.2 at last follow-up (p < 0.001) with there being a median decline of nearly 97% in the scores. The median duration of clinical benefit was 15.7 months. There was a precipitous decline in the Skindex total score and every subdomain when comparing each follow-up visit (p = 0.004) with post-hoc analysis demonstrating the decline between the baseline visit and first follow-up as the primary driver of the decline (p < 0.0001). Conclusions: This prospective study demonstrates the subjective and objective clinical benefits of utilizing low dose TSE with a dual beam rotational technique. This control rates and QOL will continue to be observed for ongoing feasibility as a treatment modality.

scholarly journals B Cell Maturation Antigen-Specific CAR T Cells for Relapsed or Refractory Multiple Myeloma: A Meta-Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3113-3113 ◽  
Author(s):  
Nico Gagelmann ◽  
Francis Ayuketang Ayuk ◽  
Djordje Atanackovic ◽  
Nicolaus Kroeger
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Overall Response ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Background Cellular immunotherapies represent an enormously promising strategy for relapsed/refractory multiple myeloma (RRMM). Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have shown impressive results in early-phase clinical studies. Here, we summarize the current body of evidence on the role of anti-BCMA CAR T cell therapy for RRMM. Methods We performed a systematic literature review to identify all publicly available prospective studies. We searched Medline, Cochrane trials registry, and www.clinicaltrials.gov. To include the most recent evidence, meeting abstracts from international hematology congresses were added. A conventional meta-analysis was conducted using meta and metafor packages in R statistical software. Pooled event rates and 95% confidence intervals (CIs) were calculated using the inverse variance method within a random-effects framework. Main efficacy outcomes were overall response, complete response (CR), and minimal residual disease (MRD). Furthermore, relapse rates, progression-free survival, and overall survival were evaluated. In terms of safety, outcomes were cytokine release syndrome (CRS), neurotoxicity, and hematologic toxic effects. Results Fifteen studies comprising a total of 285 patients with heavily pretreated RRMM were included in quantitative analyses. Patients received a median of seven prior treatment lines (such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, stem cell transplantation) which included autologous stem cell transplantation in 90% of patients. The median age of patients was 59 years and median follow-up duration ranged from 1.1 to 11.3 months. Most studies used 4-1BB (or CD137), a member of the TNF receptor superfamily, as an activation-induced T-cell costimulatory molecule. Most studies used fludarabine and cyclophosphamide for lymphodepletion while one study used busulfan and cyclophosphamide and one study used cyclophosphamide only. Most studies used the former Lee criteria for CRS grading. Anti-BCMA CAR T cells resulted in a pooled overall response of 82% (95% CI, 74-88%). The pooled proportion of CR in all evaluable patients was 36% (95% CI, 24-50%). Within responders, the pooled proportion of MRD negativity was 77% (95% CI, 67-85%). Higher dose levels of infused CAR+ cells were associated with higher overall response rates resulting in a pooled proportion of 88% (95% CI, 78-94%). In addition, peak CAR T cell expansion appeared to be associated with responses.The presence of high-risk cytogenetics appeared to be associated with lower overall response rates resulting in a pooled proportion of 68% (95% CI, 47-83%). The presence of extramedullary disease at time of infusion did not influence outcome and was associated with similar response rates compared with RRMM patients who did not have extramedullary disease, resulting in a pooled proportion of 78% (95% CI, 47-93%). The pooled relapse rate of all responders was 45% (95% CI, 27-64%) and the median progression-free survival was 10 months. In terms of overall survival, pooled survival rates were 84% (95% CI, 60-95%) at last follow-up (median, 11 months). In terms of safety, the pooled proportion of CRS of any grade was 69% (95% CI, 51-83%). Notably, the pooled proportions of CRS grades 3-4 and neurotoxicity were 15% (95% CI, 10-23%) and 18% (95% CI, 10-31%). Peak CAR T cell expansion appeared to be more likely in the setting of more severe CRS in three studies. Most hematologic toxic effects of grade 3 or higher were neutropenia (85%), thrombocytopenia (70%), and leukopenia (60%). Conclusion Anti-BCMA CAR T cells showed high response rates, even in high-risk features such as high-risk cytogenetics and extramedullary disease at time of CAR T cell infusion. Toxicity was manageable across all early-phase studies. However, almost half of the patients who achieved a response eventually relapsed. Larger studies with longer follow-up evaluating the association of response and survival are needed. Disclosures Ayuk: Novartis: Honoraria, Other: Advisory Board, Research Funding. Kroeger:Medac: Honoraria; Sanofi-Aventis: Honoraria; Neovii: Honoraria, Research Funding; Riemser: Research Funding; JAZZ: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; DKMS: Research Funding.

scholarly journals Time to Progression Post-Induction Predicts Outcomes of Ixazomib Based Therapy for Relapsed/Refractory Myeloma: Real World Data from a Multi-Site Israeli Registry Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1972-1972
Author(s):  
Yael C Cohen ◽  
Hila Magen ◽  
Noa Lavi ◽  
Moshe E. Gatt ◽  
Evgeni Chubar ◽  
...  
Keyword(s):  
Research Funding ◽  
Overall Response Rate ◽  
Target Organ Damage ◽  
Progression Free Survival ◽  
Organ Damage ◽  
Real World Data ◽  
Free Survival ◽  
Grade 3 ◽  
Indolent Disease

Abstract Introduction Ixazomib is an orally available proteasome inhibitor, shown to be safe and efficacious in combination with lenalidomide and dexamethasone (IRd regimen) in patients with relapsed and refractory multiple myeloma (RRMM) with 1-3 prior lines, demonstrating a progression free survival (PFS) benefit which was similar across cytogenetic risk groups (Tourmaline-MM1 phase 3 trial). A European real world data analysis of an IRd named patient program (NPP) outcomes in Greece (n=35), UK (n=46) and Check republic (n=57) showed similar favorable outcomes (Terpos et al, Blood 2017 130:3087). We aimed to analyze outcomes of ixazomib combinations among a multi-site cohort in the Israeli Myeloma registry. Overall response rate (ORR) was classified according to IMWG criteria. Primary endpoint was PFS, secondary endpoints included ORR, overall survival (OS), safety and tolerability. Patients A total of 78 patients across 7 sites, who received at least one cycle of ixazomib combination between June 2013 and June 2018 for treatment of RRMM were retrospectively included. Median age was 68 (range: 38-90). Male/Female ratio was 42/36. ISS (rISS) I/II/II was 30%/42%/27% (25%/54%/15%). Patient received between 1 and 7 prior lines of therapy, 66% received ixazomib in 2nd line, 18% in 3rd line. Overall, 89% of patients had been exposed to PIs (bortezomib 86%) prior to IRd, 41% to IMiDs (thalidomide 28% lenalidomide 22% and pomalidomide 6%), and 35% had undergone autologous transplantation (ASCT). Induction treatment was mostly bortezomib based (85%), most frequently VCD (62%). FISH cytogenetics were available for 60 patients, 29 (48%) had high or intermediate risk aberrations (t(4:14) 12 pts, amp 1q21 12 pts, del17p 9 pts). Disease aggressiveness was classified by treating physician as indolent (rapid control to protect from target organ damage not required) vs aggressive (imminent target organ damage) in 63% vs 27%, respectively. 60 (77%) of the 78 patients received ixazomib via a named patient program, the rest via national or private healthcare provider. Results Median time of follow up from first ixazomib dose was 22 months (range: 1-39 months), and 54 months from diagnosis of myeloma. Treatment is ongoing in 44 (56%) patients with a median duration of 19 months (range: 1-29). Among patients who discontinued treatment, the median duration was 9 months (1-31). Ixazomib was combined with lenalidomide, pomalidomide, and daratumumab in 69%, 9% and 4%, respectively. Overall response rate was 88% - CR 10%, VGPR 36%, PR 42%. Progression free survival was 78% and 54% at 12 and 24 months, respectively (fig1a). A worse PFS was found with physician assessment of aggressive vs indolent disease (14.5 vs 25.9 months, p=0.001), and with post induction progression free period (PFS1) ≤ 24 months vs. >24 months (23.9 vs 31.5 months, p=0.038) (fig 1b); age >=65 trended towards a worse PFS (p=0.058). Poor cytogenetic risk, prior exposure to bortezomib, prior auto transplant, and number of prior lines of therapy did not affect PFS or ORR. OS from first ixazomib administration was 90% and 81% at 12 and 24 months, respectively; median OS was not reached (fig1a). Any (grade 3-4) toxicity considered by investigator as related to ixazomib was reported in 70% (18% grade 3-4), including neutropenia 14% (6%), anemia 19% (6%), thrombocytopenia 17% (5%), nausea and vomiting 17% (1%), DVT/PE 4% (1%), neutropenic infection 0 (4%), peripheral neuropathy 14% (3%), diarrhea 14% (3%), rash 10% (4%), pneumonia 5% (3%). There were no ixazomib related deaths. Dose reduction or discontinuation due to toxicity occurred in 28% and 12%, respectively. Conclusion Our data shows ixazomib-based combinations are efficacious and safe regimens for patients with RRMM, achieving ORR of 88%, at 2nd as well as later lines of therapy, regardless to cytogenetic risk. Over a median follow up of almost 2-years, 54% remained progression free at 24 months. An ixazomib based regimen may be particularly attractive for patients who remain progression free for more than 24 months after a bortezomib induction and for patients with a more indolent disease phenotype. Disclosures Cohen: Neopharm Israel: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Medisson Israel: Consultancy, Honoraria, Research Funding. Tadmor:NOVARTIS: Consultancy; PFIEZER: Consultancy; ABBVIE: Consultancy; JNJ: Consultancy; ROCHE: Research Funding.

Hydrocortisone Therapy for Patients with Septic Shock

2018 ◽  
pp. 301-306
Author(s):  
Ryan J. Horvath ◽  
Edward Bittner
Keyword(s):  
Septic Shock ◽  
Study Design ◽  
Steroid Therapy ◽  
Clinical Case ◽  
Low Dose ◽  
Vasopressor Therapy ◽  
Surviving Sepsis Campaign ◽  
Number Of Patients ◽  
Study Intervention

This chapter provides a summary of the landmark study known as the CORTICUS trial. Among patients suffering from septic shock, does low dose hydrocortisone improve mortality? Starting with that question, it describes the basics of the study, including funding, study location, the population studies, number of patients, study design, study intervention, follow-up, endpoints, results, and criticism and limitations. The chapter briefly reviews other relevant studies and information, discusses implications, and concludes with a relevant clinical case. The CORTICUS trial failed to demonstrate a benefit on mortality with steroid therapy among patients with septic shock. Based on CORTICUS and other studies, the Surviving Sepsis Campaign guidelines no longer recommend steroids for all patients with septic shock. Corticosteroids should be considered, however, for patients with septic shock who do not respond to fluids and vasopressor therapy.

Decitabine Low-Dose Schedule (100 mg/m2/course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1437-1437 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Susan O’Brien ◽  
Francis Giles ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Low Dose ◽  
Optimal Dose ◽  
Dose Schedule ◽  
Overall Response ◽  
Transfusion Independence ◽  
Historical Group ◽  
Secondary Mds ◽  
To Receive

Abstract Decitabine, a hypomethylating agent, has shown activity in MDS, acute myeloid leukemia (AML), and chronic myeloid leukemia. In this study, we investigated optimizing the dose schedule. Patients with IPSS intermediate 1–2 and high risk were randomized to one of 3 schedules of decitabine: 1) 20 mg/m2 IV over 1 hour daily x 5; 2) 10 mg/m2 IV over 1 hour daily x 10; or 3) 10 mg/m2 subcutaneously (SQ) BID x 5. A total of 90 patients are to be treated. Randomization is equal until the 45th patient after which a Bayesian (play by the winner) randomization is implemented based on CR rates. Courses were given every 28 days regardless of counts, as long as counts recovered to pretreatment + evidence of disease on repeat marrow + no significant myelosuppression complications. Delays to allow for recovery of counts were permitted every 3 courses, or in the presence of myelosuppression without disease or severe myelosuppression-related complications. Patients were allowed to receive erythropoietin 40,000 units weekly for anemia, or GCSF if needed during febrile neutropenia. Response criteria for CR and PR were as for AML (PR requiring also decrease blasts by >50%). Clinical benefit (CB) referred to one or more of the following: platelets increase by 50% and above 30 x 109/L, or granulocytes increase by 100% and to above 109/L, or hemoglobin increase by 2 g/dl or transfusion independence, or splenomegaly decrease by 50% or more, or monocytes decrease by 50% or more (pretreatment >5 x 109/L). 43 patients have been treated; median age 63 years (range 39 to 90); 60 (26%) were ≥ 60 years old. IPSS risk: intermediate 1 –13 (30%); intermediate 2–13 (30%); high-(23%); CMML-7(16%). Cytogenetic abnormalities were present in 56%; secondary MDS in 23%; marrow blasts ≥ 10% in 30%. 22 patients had prior erythropoietin; 9 had prior GCSF; 12 had other prior therapies (thalidomide 6, azacytidine 2, other 4). Presently, 36 patients have received at least 1 course of therapy. Results were: 10 CR (28%); 3 PR (9%); 18 CB (50%); overall response 31/36=86%. 22(51%) patients required hospitalizations for fever and neutropenia. Median courses to CR was 1 (range 1 to 3); 5 patients (50%) needed 2 or more courses to achieve CR. With a median follow-up of 4 months, 5 have evolved into AML; 4 have died (2 AML; 2 MDS); 35 patients continue on decitabine therapy. Compared with a historical group of 54 patients with MDS who received intensive chemotherapy (2000–2003) and matched for age, cytogenetics and IPSS/FAB, the CR rate was lower with decitabine (28% vs 47%), but the overall response rate was favorable; the 8-week mortality was also lower with decitabine (7% vs 26%); and estimated survival favorable (6-month rates 80% vs 67%). CR rates by schedule were: 5 days IV 6/15 (40%); 5 days SQ 2/11 (18%); 10 day IV 2/10 (20%). There was more myelosuppression with the 10 day IV schedule. We conclude that 1) decitabine at this low-dose schedule has major anti- MDS activity in the setting of poorer risk MDS; 2) the optimal dose schedule is being defined; 3) side effects are acceptable; 4) timely and repeated courses of decitabine therapy is required for optimal response results.

Survival Benefits of Patients with Non-Hodgkin’s Lymphoma Treated with Rituximab Combined with Chemotherapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4625-4625
Author(s):  
Zhixiang Shen ◽  
Junmin Li ◽  
Aihua Wang ◽  
Yu Chen
Keyword(s):  
B Cell ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Free Survival ◽  
Overall Response ◽  
Large B Cell

Abstract Purpose: Rituximab combined with chemotherapy has been recommended as first-line or second-line standard regimen in most subtypes of B-cell lymphoma in China by the 2004 National Comprehensive Cancer Network lymphoma therapy guideline. We have conducted a multicenter trial to evaluate the efficacy and safety of rituximab in combination with standard chemotherapy (CHOP) in patients with previously untreated or relapsed indolent and aggressive NHL. Methods: Patients received 4–8 cycles of rituximab plus CHOP every 21 days. For each cycle, rituximab (375mg/m2) was given on day 1 and CHOP started on day 3. CHOP consisted of cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, and vincristine 1.4mg/m2 (maximum 2mg/dose) given intravenously on day 3, and oral prednisone 100mg on days 3–7. Results: A total of 221 patients were enrolled on the trial, 128 males and 93 females with a mean age of 49 years (range 10–83 years). The main lymphoma subtypes were small lymphocytic (15 patients, 7%), follicular (27 patients, 12%), and diffuse large B-cell (160 patients, 72%). In total, 56 patients had indolent NHL and 165 aggressive NHL. The overall response rate for all patients was 86% with 57% complete responses. In patients with indolent NHL the overall and complete response rates were 95% and 55% respectively. After a median 12 months follow up, progression-free survival in patients with indolent NHL was 88%±5% at 1 year and 83%±6% at 2 years. In the 160 patients with diffuse large B-cell lymphoma, the overall response rate was 88% with 61% complete responses, and after a mean follow-up of 6 months, predicted 1-year and 2-year progression-free survival were 88%±5% and 83%±7% respectively. Infusion-related adverse events occurred in 4% of patients, associated with the first infusion of rituximab. Subanalyses according to subtype, stage, IPI and other factors will be presented. Conclusion: Rituximab plus chemotherapy is an effective, well-tolerated treatment that achieves high response rates and long progression-free survival in both indolent and aggressive NHL.

Sign in / Sign up

Export Citation Format

Share Document