Effect of gender on the outcome of patients receiving nivolumab for metastatic renal cancer: Results from a large study population.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16087-e16087
Author(s):  
Giuseppe Procopio ◽  
Serena Di Cosimo ◽  
Ugo De Giorgi ◽  
Giacomo Cartenì ◽  
Enrico Cortesi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Median Number ◽  
Metastatic Renal Cancer ◽  
Expanded Access Programme ◽  
Check Point Inhibitors ◽  
Access Programme ◽  
Study Population ◽  
Grade 3 ◽  
Metastatic Rcc

e16087 Background: Several studies, the majority on melanoma and lung cancer, have addressed the value of gender with respect to immune check point inhibitors outcome as compared to standard therapy, showing conflicting results. Nevertheless, few focused on gender-related clinical outcome and toxicity in renal cell carcinoma (RCC) patients. Methods: This analysis evaluated the effect of gender on overall survival and adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 in an expanded access programme of nivolumab 3 mg/kg once every 2 weeks in second-line and beyond metastatic RCC. Only patients assuming at least one dose of nivolumab were analyzed. Results: Of 389 patients analyzed, 25.2% were female. On study entry, no differences were found in women as compared to men in terms of age, on average 64 years, p = 0.91; overweight/obesity, 45 versus (vs) 49%, p = 0.47; LDH , mean U/L 391 vs 32, p = 0.17); and neutrophils/lymphocytes ratio> 3 (62 vs 63%, p = 0.87). Disease presentation was similar according to gender, although women tended to present less lung (66% vs 76%, p = 0.06) and bone metastases (42% vs 52%, p = 0.07). Notably, there was no differences in the IDMC prognostic model by gender (p = 0.94). Any drug related AEs (38 vs 30%, p 0.15), grade 3-4 (6% vs 6%) and median number of drug doses 12 (53% vs50%, p = 0.58 ) did not differ between gender. After adjusting for known prognostic variables, multivariate analysis showed that women had similar overall survival as compared to men (hazard ratio 0.81, 95% confidence interval 0.56-1.17, p = 0.26). Conclusions: Women demonstrate similar overall survival than men in metastatic RCC treated with secondal line and beyond nivolumab, with no differences observed in serious AEs and dose administered.

Correlation between efficacy and toxicity in pts with pretreated advanced melanoma treated within the Italian cohort of the ipilimumab expanded access programme (EAP).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9065-9065 ◽  
Author(s):  
Anna Maria Di Giacomo ◽  
Antonio M Grimaldi ◽  
Paolo Antonio Ascierto ◽  
Paola Queirolo ◽  
Michele Del Vecchio ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Therapeutic Option ◽  
Stage Iv ◽  
Phase Iii ◽  
Expanded Access Programme ◽  
Fast Progression ◽  
Phase Iii Trials ◽  
Access Programme ◽  
Overall Survival Benefit

9065 Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma that showed an overall survival benefit in randomised phase III trials. Early clinical studies explored the potential relationship between immune-related adverse events (irAEs) associated with ipilimumab and antitumor activity but no definitive conclusion has been reached. Here, we evaluated the possible correlation between efficacy of ipilimumab treatment and irAEs in patients (pts) enrolled in the EAP in Italy. Methods: Ipilimumab was available upon physician request for pts aged ≥16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. Pts were monitored for adverse events (AEs), including immune-related AEs (irAEs), using Common Terminology Criteria for Adverse Events v.3.0. Results: In total, 855 Italian pts participated in the EAP from June 2010 to April 2012 across 55 centres. Among 833 evaluable pts, 278 pts (33.4%) reported an irAE and 555 (66.6%) did not. As of December 2012, the disease control rates among pts with or without irAEs were 35.3% and 33.9% respectively. We noted that there was a difference in the distribution of pts with or without irAEs among pts who experienced a fast progression, thus not being able to receive at least 3 cycles, and pts with slow progression. In fact, due to the mechanism of action of the drug and consequent delayed onset of irAEs, pts with irAEs among fast and slow progressors were 22% and 37% respectively. Therefore, median overall survival was evaluated by adjusting the 2 groups for this factor and results showed a comparable survival between pts who reported an irAE and pts who did not (10.0 vs 9.7 months respectively). Conclusions: This exploratory analysis of EAP data suggest that activity and efficacy of ipilimumab is not related with the occurrence of irAEs.

287 Safety and antitumor activity of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor KHK2455 in combination with anti-CCR4 monoclonal antibody mogamulizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A313-A314
Author(s):  
Solmaz Sahebjam ◽  
Jameel Muzaffar ◽  
Timothy Yap ◽  
David Hong ◽  
Olivier Rixe ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
Antitumor Activity ◽  
Combination Therapy ◽  
Adverse Events ◽  
Solid Tumors ◽  
Ex Vivo ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Dose Dependent

BackgroundIDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Mogamulizumab is an anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody that has shown synergy with KHK2455 in preclinical models. Mogamulizumab is approved in the US and EU for treatment of mycosis fungoides and Sézary syndrome.MethodsIn this first-in-human study, patients with advanced solid tumors received escalating oral doses of KHK2455 alone (0.3, 1, 3, 10, 30 and 100 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV mogamulizumab for 4 weeks (Cycle 1), and then on Days 1 and 15 (from Cycle 2 onward) in a standard 3+3 Phase I design. Safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production) were evaluated.ResultsThirty-six patients were enrolled across all cohorts. One patient with lower esophageal cancer in the 100 mg cohort exhibited dose-limiting toxicity (Grade 3 gastrointestinal necrosis). The most frequent (≥10%) treatment-emergent adverse events (TEAEs) are presented in table 1. Overall numbers of TEAEs, ≥Grade 3 TEAEs, and serious TEAEs related to KHK2455 and mogamulizumab are presented in table 2. Serious KHK2455-related TEAEs included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, five drug-related TEAEs in combination therapy led to discontinuation; there were no fatal outcomes related to either study drug. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated by plasma Kyn concentration and Kyn/Trp ratio (median inhibition 70.5% and 70.8%, respectively, at 100 mg dose on Day 15, compared to baseline) and ex vivo Kyn production (>95% inhibition at ≥10 mg KHK2455), confirming target modulation. Six of 26 evaluable patients from all dosing groups achieved durable disease stabilization (≥6 months, RECIST 1.1), and one patient with bevacizumab-resistant glioblastoma demonstrated confirmed partial response (43.5% tumor reduction over a 2-year observation period). Median overall survival was 13.4 months, with 30% of subjects surviving for 2 years or longer (figure 1).Abstract 287 Table 1Study 2455-001: Treatment-Emergent Adverse Events (≥10% by Preferred Term)Abstract 287 Table 2Abstract 287 Figure 1Study 2455-001: Overall SurvivalConclusionsKHK2455 in combination with mogamulizumab was well-tolerated and manageable at all doses tested, suppressed Kyn production in a dose-dependent and sustained manner, and demonstrated signals of antitumor activity. These data support the continued development of this combination.AcknowledgementsMedical writing assistance was provided by Susan E. Johnson, PhD, S.E. Johnson Consulting, LLC, New Hope, PA, USA.Trial RegistrationNCT02867007 (www.clinicaltrials.gov)Ethics ApprovalThis study was approved by Ethics Committees at all participating study institutions.

scholarly journals Safety of switching between rituximab biosimilars in onco-hematology

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Silvana A. M. Urru ◽  
Stefania Spila Alegiani ◽  
Anna Guella ◽  
Giuseppe Traversa ◽  
Annalisa Campomori
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Prospective Observational Study ◽  
Randomized Trials ◽  
Lymphocytic Leukemia ◽  
Safety Signal ◽  
Efficacy And Safety ◽  
Clinical Safety ◽  
Study Population ◽  
Grade 3

AbstractComparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin’s Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3–4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.

scholarly journals The Outcomes of Nivolumab Fixed Dose 40 Mg Therapy in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-6
Author(s):  
Liudmila Fedorova ◽  
Kirill Lepik ◽  
Polina Kotselyabina ◽  
Elena Kondakova ◽  
Yuri Zalyalov ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Median Number ◽  
Fixed Dose ◽  
Published Data ◽  
High Dose ◽  
Efficacy And Safety ◽  
Classical Hodgkin Lymphoma ◽  
Grade 3

Background Currently, the recommended dose of nivolumab for patients with relapsed or refractory classical Hodgkin lymphoma (r/r сHL) is 3 mg/kg. Nevertheless, published clinical cases indicate the possible efficacy of lower doses of nivolumab. Moreover, experimental studies provided the rationale for possible reduction of nivolumab dose in patients with solid tumors (Agrawal et al. 2016). The presented data creates prerequisites for studying the lower nivolumab doses efficacy and safety in the r/r cHL therapy. Patients and Methods This study included 42 patients (14 male/28 female) with r/r cHL who were treated with nivolumab 40 mg every 2 weeks. The median age of patients was 36 (22-53) years. The median number of prior therapy lines was 4 (2-7). Prior treatment contained high dose chemotherapy with ASCT in 9 pts (21%), brentuximab vedotin in 14 pts (33%) and allo-HSCT in 1 pt (2%). Four pts (9,5%) had the partial response (PR) and the remaining 38 pts (90,5%) had the disease progression (PD) at the moment of nivolumab initiation. B-symptoms were present in 23 pts (55%), ECOG status was grade 0-I in 25 pts (59,5%), grade II in 12 pts (29%), grade III in 4 pts (9,5%) and grade IV in 1 pt (2%). The primary endpoint was the overall response rate (ORR) determined by positron-emission tomography/computed tomography (PET/CT) using LYRIC criteria every 3 months. Key secondary endpoints included progression-free survival (PFS) and overall survival (OS). Adverse events (AE) were evaluated according to CTCAE 4.03. The patient group characteristics were evaluated using descriptive statistics methods, the survival analysis was performed using Kaplan-Meyer method (SPSS Statistics v.17). Results The median number of nivolumab cycles was 24 (2-38). The response was evaluated in 41 out of 42 pts. The ORR was 66%. The best response included complete response (CR) in 39%, PR in 27%, stable disease in 5%, PD in 2%, indeterminate response (IR) in 27% of pts. With a median follow-up of 27,5 mo (11,3-34,5) 41 pts (97,6%) were alive, the median OS was not reached. The 2-year PFS was 44,5% (95% CI, 28,2-59,6) The nivolumab therapy was discontinued in 39 pts (93%) due to scheduled discontinuation in 14 pts (33%), PD in 13 pts (31%), grade 3-4 AE in 2 pts (5%), change of therapy because of insufficient response in 6 pts (14%) and other reasons in 4 pts (10%). The progression of disease during nivolumab therapy was present in 14 (33%) pts and after nivolumab discontinuation in 6 (14%) pts. After disease progression 30 pts (71%) were retreated with nivolumab monotherapy or in combination with chemotherapy. The median time to additional therapy was 14,5 mo (4,2 -32,9). The adverse events of any severity were observed in 30 pts (71%). Grade 3 or higher AE were present in 4 pts (9,5%), including grade 3 arthralgia, grade 3 anemia, grade 4 pneumonia and pneumonitis, grade 4 increased level of alanine aminotransferase and grade 5 MDS in 1 pt. A significant reduction of PD1+CD3+ cell population of peripheral blood lymphocytes was observed after first nivolumab cycle (median 0.7% (0-1.7) versus 33% (15.7-80.1) before therapy initiation, p = 0.02, Wilcoxon signed-rank test). Conclusion Our study demonstrated the efficacy and safety of nivolumab 40 mg therapy. The presented results are comparable to previously published data of nivolumab 3 mg/kg therapy in patients with r/r cHL. Thus, this creates a basis for further direct comparative study of nivolumab efficacy in different doses Disclosures No relevant conflicts of interest to declare.

The Role of Nanoliposomal Irinotecan Plus Fluorouracil and Folinic Acid as Second-Line Treatment Option in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Se Jun Park ◽  
Hyunho Kim ◽  
Kabsoo Shin ◽  
Tae Ho Hong ◽  
Ja Hee Suh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Adverse Events ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Real World ◽  
Median Overall Survival ◽  
Ductal Adenocarcinoma ◽  
Nanoliposomal Irinotecan ◽  
Previously Treated ◽  
Grade 3

Abstract BackgroundAccording to the NAPOLI-1 trial, nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) showed improved overall survival compared to fluorouracil alone for patients with metastatic pancreatic cancer who previously treated gemcitabine-based therapy. In that trial, Asian patients had frequent dose modification due to hematological toxicity. There has been limited information on the clinical benefit and toxicity of this regimen in a real-world setting. Herein, we assessed real-world experience of nal-IRI plus 5-FU/LV in patients with advanced pancreatic cancer after gemcitabine failure.MethodsWe conducted a single institution retrospective analysis of response, survival and safety in patients who had been treated with nal-IRI with 5-FU/LV. Patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy received nal-IRI (80mg/m2) with 5-FU/LV every 2 weeks. ResultsFifty-one patients received nal-IRI plus 5-FU/LV between January 2015 and December 2020. The median age was 67 years, and males were 58.8%. A total of 40 (78.4%) and 11 (21.6%) patients had received one and two lines of prior chemotherapy before enrollment, respectively. Median progression-free survival was 2.8 months (95% confidence interval [CI] 1.8-3.7) and median overall survival was 7.0 months (95% CI 6.0-7.9). Chemotherapy doses were reduced or delayed in 33 (64.7%) patients during the first 6 weeks and median relative dose intensity was 0.87. Thirty-six (70.6%) patients experienced any grade 3 or 4 adverse events. Most common grade 3 or 4 adverse event was neutropenia (58.8%) and most non-hematologic adverse events were under grade 2. Since the start of first-line chemotherapy, median overall survival was 16.3 months (95% CI 14.1-18.4).ConclusionsNal-IRI plus 5-FU/LV seems to be effective, with manageable toxicities, after gemcitabine-based treatment in patients with metastatic pancreatic ductal adenocarcinoma. Trial registration Retrospectively registered

scholarly journals EPID-07. HEMATOLOGICAL ADVERSE EVENTS IN GLIOBLASTOMA PATIENTS TREATED WITH TEMOZOLOMIDE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi75-vi76
Author(s):  
Catherine Garcia ◽  
Zin Myint ◽  
Rani Jayswal ◽  
Allison Butts ◽  
Heidi Weiss ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Protective Factor ◽  
Significant Proportion ◽  
Progression Free Survival ◽  
Free Survival ◽  
Significant Difference ◽  
History Of ◽  
Grade 3 ◽  
Severe Grade

Abstract BACKGROUND Temozolomide (TMZ) is the cornerstone for glioblastoma (GBM) treatment. A significant proportion of patients develops hematologic toxicities with limited investigations on outcomes and risk factors for their development. METHODS Our study combines data from the two largest group trials, RTOG 0525 and RTOG 0825, to analyze serious hematologic adverse events (HAE) associated with TMZ therapy for GBM. We analyzed frequency and outcomes of HAE during chemoradiation. RESULTS 1154 patients were evaluated with a median age of 57 years. Over 79% of patients developed HAE during the entire course of GBM treatment. During chemoradiation the most common HAE during chemoradiation was lymphopenia (41.5%), followed by thrombocytopenia (39.0%), and anemia (35.3%). Of these, 34.1% were severe (Grade 3 or 4) and 65.9% were mild (grade 1 or 2). During maintenance the most common HAE was leukopenia (50.7%), followed by neutropenia (50.4%), and lymphopenia (45.3%). MGMT methylation was not associated with HAEs. A history of HAEs during chemoradiation was a protective factor for developing HAEs during maintenance. MGMT methylated and age younger than 50 were protective factors for mortality. Patients that presented HAEs anytime during treatment had a longer overall survival and progression free survival. There was no significant difference in survival between mild or severe HAEs. CONCLUSION HAE are common during chemoradiation with TMZ for GBM, but are more commonly grade 1 or 2 per CTCAE. HAE during GBM treatment is associated with decreased progression free survival and overall survival.

scholarly journals Subcutaneous Administration of Bortezomib in Combination with Thalidomide and Dexamethasone for Treatment of Newly Diagnosed Multiple Myeloma Patients

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Shenghao Wu ◽  
Cuiping Zheng ◽  
Songyan Chen ◽  
Xiaoping Cai ◽  
Yuejian Shi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Adverse Events ◽  
Subcutaneous Administration ◽  
Progression Free Survival ◽  
The Other ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Grade 3

Objective. To investigate the efficacy and safety of the treatment of the newly diagnosed multiple myeloma (MM) patients with the therapy of subcutaneous (subQ) administration of bortezomib and dexamethasone plus thalidomide (VTD) regimen.Methods. A total of 60 newly diagnosed MM patients were analyzed. 30 patients received improved VTD regimen (improved VTD group) with the subQ injection of bortezomib and the other 30 patients received conventional VTD regimen (VTD group).The efficacy and safety of two groups were analyzed retrospectively.Results. The overall remission (OR) after eight cycles of treatment was 73.3% in the VTD group and 76.7% in the improved VTD group (P>0.05). No significant differences in time to 1-year estimate of overall survival (72% versus 75%,P=0.848) and progression-free survival (median 22 months versus 25 months;P=0.725) between two groups. The main toxicities related to therapy were leukopenia, neutropenia, thrombocytopenia, asthenia, fatigue, and renal and urinary disorders. Grade 3 and higher adverse events were significantly less common in the improved VTD group (50%) than VTD group (80%,P=0.015).Conclusions. The improved VTD regimen by changing bortezomib from intravenous administration to subcutaneous injection has noninferior efficacy to standard VTD regimen, with an improved safety profile and reduced adverse events.

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

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

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

5-Azacitidine In Patients with Myelodysplasia and Acute Myeloid Leukemia: a Single Centre Experience

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4969-4969 ◽  
Author(s):  
Capodanno Isabella ◽  
Paolo Avanzini ◽  
Francesco Merli
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Progression Free Survival ◽  
Median Number ◽  
Study Population ◽  
Blast Count ◽  
Acute Myeloid

Abstract Abstract 4969 Introduction Hypomethylating agents have recently been shown to prolong overall survival and improve quality of life in patients with INT-2 and high IPSS risk myelodysplasia (MDS) and low bone marrow blast count acute myeloid leukemia (AML). Patients and Methods Since September 2008 we have been treating 26 patients affected by acute myeloid leukemia (13 patients), MDS (11 patients) or chronic myelomonocytic leukemia (2 patients) with 5-azacitidine. According to recent guidelines, most of myelodysplastic patients eligible for treatment belonged to the IPSS INT-2 or high risk groups. Patients with acute myeloid leukemia had a medullary blast count of 20–30%, except for four cases. Patients with chronic myelomonocytic leukemia had a medullary blast count > 10% and < 20%. The median age of patients when treatment was started was 69,5 years (range: 51–82). Azacitidine was administered subcutaneously (75 mg/m2/d) for 7 days of every 28-day cycle until loss of response or disease progression. Patients received a median number of 5,5 cycles of therapy (range 1–24). We evaluated overall improvement (CR + PR+ HI), the best response obtained and adverse events in the overall study population, according to International Working Group MDS and LMA criteria. In the subgroup of patients who received at least 6 cycles of therapy (10 patients) we also evaluated overall survival (OS) and progression free survival (PFS). Results The results of 5-azacitidine therapy in our cohort of patients are described in Table 1. In the AML cohort, after a median number of 4 cycles (range 1–10), we observed a hematological improvement (HI) in 15% of the patients, a stable disease (SD) in 31% of patients and a lack of response in 38% of patients. In the MDS cohort, after a median number of 7 cycles (range 2–24), we observed a complete response (CR) (including a cytogenetic response) in 36.5% of patients, a partial response (PR) in 9% of patients, a hematological improvement in 45.5% of patients and a stable disease in 18% of patients. The overall improvement (CR + PR + HI) was 15% in the AML cohort and 91% in the MDS cohort. In the LMMC cohort, after a median number of 2.5 cycles (range 1–4), we observed a hematological improvement in 50% of the patients. In the subgroup of patients who received at least six cycles of therapy, the overall survival was 11.5 months and the progression free survival was 9 months. In the overall study population, two patients (8%) discontinued treatment as a result of adverse events. In four non-responder patients (15%) death was due to a rapid progression of disease. Discussion In this analysis we have reported good response rates in MDS patients, with 36.5% of complete response (including a complete cytogenetic response). No CR or PR were observed in AML patients; however, in this subgroup of patients the median follow-up was short (median number of cycles of therapy: four). Furthermore, in these patients even a stable disease with no need of hospitalization and a good quality of life can be considered an important result. Due to the short period of follow-up, 57.5% of our patients received fewer than 6 cycles of 5-azacitidine and their therapy is still ongoing. Conclusions The limited number of cases and the short period of follow-up did not allow us to evaluate overall survival and progression free survival in the overall study population. We will update these data as time progresses. We reported these data in the subgroup of patients who received at least six cycles of therapy. According to current evidence, we observed that 5-azacitidine plays an important role in the treatment of patients with MDS (both with high- and low-IPSS risk) and low bone marrow blast counts AML. In these subgroups of patients, 5-azacitidine prolongs survival and is well tolerated. In our limited experience, this drug had no efficacy when a higher degree of bone marrow blasts (> 30%) was present. Further trials should assess the number of cycles required for treatment, the role of hypometilating agents in low-risk MDS and in patients with AML and a bone marrow blasts counts > 30%. Disclosures: No relevant conflict of interest to declare. Disclosures: No relevant conflicts of interest to declare.

Cyclophosphamide, Adriamycin, Vincristine and Prednisone Plus Rituximab (CHOP-R) in Fludarabine (F) Refractory Chronic Lymphocytic Leukemia (CLL) or CLL with Autoimmune Cytopenia (AIC) or Richter's Transformation (RT): Final Analysis of a Phase II Study of the German CLL Study Group

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2860-2860
Author(s):  
Petra Jenke ◽  
Barbara Eichhorst ◽  
Raymonde Busch ◽  
Nadine Anheier ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Research Funding ◽  
Progression Free Survival ◽  
Response Rates ◽  
Median Number ◽  
Response Evaluation ◽  
Free Survival ◽  
Richter's Transformation ◽  
Grade 3

Abstract Abstract 2860 Introduction: In the last decade, important progress has been achieved in the treatment of CLL through the use of purine analog-based chemoimmunotherapies. Several conditions remain a challenge, often with a poor outcome. Amongst these therapeutic problems are Richter's transformation (RT), refractoriness to F-based therapies (Fref), and the occurrence of AIC, which are sometimes induced by F. Fref and RT pts have a very poor prognosis with an estimated overall survival (OS) of only 10 and 8 months (mos), respectively. Therefore, therapeutic alternatives are urgently warranted. CHOP-R has improved the outcome of pts with aggressive non-Hodgkin's lymphoma. To test the efficacy and tolerability of the CHOP-R regimen in CLL patients with RT, Fref, or AIC, the GCLLSG initiated a prospective phase II trial. Material and Methods: 62 patients were included in the study. Due to protocol violations, 2 patients were excluded. Within the group of Fref pts, the medical review detected 11 patients who had received pre-treatment with F (Fpret), but were not refractory according to the updated guidelines (Hallek et al., Blood 2008). Thus, 26 pts were classified as Fref/pret, 19 pts as AIC and 15 pts as RT. All patients received CHOP every 3 weeks (cyclophosphamide 750mg/m2, adriamycin 50mg/m2 and vincristine 1, 4mg/m2 d1; prednisone 100mg/m2 d1–5). Rituximab was added starting with the 2nd cycle (375mg/m2 on each d0, and 21 days after the last CHOP-R). RT pts received up to 8, Fref/pret and AIC up to 6 courses of CHOP-R. In case of PD after 3 cycles, pts went off-study. The primary endpoints were remission rate, quality and duration of response. Results: 79%, 73%, and 40% of AIC, Fref/pret, and RT pts were male, respectively. The median age was 65 years (y) for Fref/pret-pts, 66y in the AIC and 69y in the RT group. Binet stages for Fref/pret pts were: A: 8%; B: 27% C: 65 %. All but 3 AIC pts were at Binet stage C. Initial RT stages according to Ann Arbor were: II: 13%, III: 13%, IV 73%. The median number of previous therapies were 3 for Fref/pret, 2 for AIC and 2 for RT. A total of 314 cycles were administered, with a median number of 3 cycles for AIC and Fref pts and a median number of 4 cycles for the RT group. Due to toxicity 73% of cycles in the Fref/pret group, 66% in the AIC and 87% in the RT group were dose-reduced. 69% of Fref/pret-pts and 58% of AIC-pts received full 6 cycles of therapy and only 40% of RT-pts completed 8 cycles of therapy. Treatment was stopped in 6 pts because of PD. Due to treatment related toxicity treatment was stopped in 16 pts (27%). Treatment related mortality was 3% (2 pts). Treatment toxicity was reported according to NCI common toxicity criteria (CTC) version 2.0. Adverse events grade 3 or 4 for anemia, neutropenia and thrombocytopenia were documented in 75%, 55% and 65% of patients, respectively. Infections were the most common non-hematologic toxicity and occurred in 67%; severe infections CTC grade 3 or 4 occurred in 28%. All 26 Fref/pret-pts were available for response evaluation. CHOP-R achieved 54% PR, 35% SD and 12% PD. The median progression-free survival (PFS) and median treatment-free survival (TFS) were 11 and 14 mos. OS was 27 mos with a significant difference concerning F-ref (n=15) and F-pret (n=11) pts (17 vs. 35m; p=0.05). We evaluated the response of all 15 RT-pts with 60% PR, 7% CR, 13% SD and 20% PD. The PFS was 15 mos, TFS was 17 mos and OS 27 mos. 17 AIC pts were available for response evaluation with 82% PR, 6% SD and 12% PD. The PFS and TFS were only 14 and 16 mos. The OS was 50 mos. The population had a high incidence of unfavourable genetic markers: deletion of chromosome 17p [del(17p)] was detected in 24%, del(11q) in 34% and unmutated IGHV in 70%. 85% had high levels of serum thymidine kinase (sTK > 10 U/l), and 49% had high levels of ß2-microglobulin (ß2M > 3.5 mg/l). Patients with del(17p) had an unfavourable response rate and achieved significant less a PR or CR (36% vs. 76%; p=0.03). Multivariate analyses showed that del(17p) and ECOG performance status had a negative prognostic impact on OS (p<0.0001). Moreover the presence of a del(17p) predicted a short PFS (6 vs. 16.9 mos; p=0.001). Conclusion: CHOP-R achieves promising response rates in CLL patients with Fref and RT and very good response rates in patients with AIC. However, the progression-free survival and overall survival remain unsatisfactory. Therefore, CHOP-R might be used as induction therapy prior to allogeneic stem cell transplantation in physically fit patients. Disclosures: Eichhorst: Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Dreyling:Roche: Research Funding, Scientific advisory board, Speakers Bureau. Bergmann:Celgene: Honoraria. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fink:Hoffmann La Roche: travel grants. Fischer:Hoffmann La Roche:. Wendtner:Hofmann-La Roche: Consultancy, Honoraria, Research Funding. Hallek:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria.

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