scholarly journals Real Life Use of Bendamustine in Elderly Patients with Lymphoid Neoplasia

2021 ◽  
Vol 11 (4) ◽  
pp. 249
Author(s):  
Irene Dogliotti ◽  
Simone Ragaini ◽  
Francesco Vassallo ◽  
Elia Boccellato ◽  
Gabriele De Luca ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Rating Scale ◽  
Single Agent ◽  
Multivariable Analysis ◽  
Real Life ◽  
Lymphocytic Leukemia ◽  
Factors Affecting ◽  
Lymphoid Neoplasia ◽  
Baseline Factors ◽  
Grade 3

Background. Bendamustine is a cytotoxic alkylating drug with a broad range of indications as a single agent or in combination therapy in lymphoid neoplasia patients. However, its tolerability in elderly patients is still debated. Methods: An observational, retrospective study was carried out; patients with chronic lymphocytic leukemia (CLL) or lymphoma, aged ≥ 65 years old, treated with bendamustine-based regimens in first or subsequent lines between 2010 and 2020 were considered eligible. Results: Overall, 179 patients aged ≥ 65 years were enrolled, 53% between 71 and 79 years old. Cumulative Illness Rating Scale (CIRS) comorbidity score was ≥6 in 54% patients. Overall survival (OS) at 12 months was 95% (95% confidence interval [CI]: 90–97%); after a median follow up of 50 months, median OS was 84 months. The overall response rate was 87%, with 56% complete responses; the median time to progression (TTP) was 61 months. The baseline factors affecting OS by multivariable analysis were sex, histological diagnosis, renal function, and planned bendamustine dose, while only type of lymphoma and bendamustine dose impacted on TTP. Main adverse events were neutropenia (grade ≥ 3: 43%) and infections (any grade: 36%), with 17% of patients requiring hospital admission. Conclusions: The responses to bendamustine, as well as survival, are relevant even in advanced age patients, with a manageable incidence of acute toxicity.

Retrospective Analysis of the Experience with Rituximab and Methylprednisone In Elderly Patients with CLL

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4636-4636
Author(s):  
Xavier Badoux ◽  
Ali M Al-Ameri ◽  
Susan O'Brien ◽  
William G. Wierda ◽  
Jan A. Burger ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Partial Response ◽  
Elderly Patients ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Chromosome 17 ◽  
High Dose ◽  
Β2 Microglobulin ◽  
Grade 3

Abstract Abstract 4636 Background: Single agent rituximab has limited activity in chronic lymphocytic at standard doses; however, the addition of rituximab to purine analogues, monoclonal antibodies or steroids has been shown to improve responses and response duration in patients with untreated and relapsed chronic lymphocytic leukemia (CLL). The combination of rituximab and high dose methylprednisone has shown activity in patients with untreated and fludarabine-refractory CLL (Castro 2008, Castro 2009); however, there is limited reported experience with this regimen in elderly patients. These data prompted us to review our center's experience with rituximab in combination with high dose methylprednisone in elderly patients with CLL. Patients and Methods: We retrospectively identified 24 patients 65 years or older with CLL who received rituximab and methylprednisone between July 2002 and April 2010 at MD Anderson Cancer Center. Six patients received this treatment as initial therapy and 18 patients as salvage treatment. Rituximab 375–750 mg/m2 and methylprednisone 500–2000 mg were administered i.v. weekly for 4 weeks. Three patients received further maintenance treatment with rituximab 375–750 mg/m2 and methylprednisone 500 mg/m2 every month or every 3 months until failure of response. Responses were assessed according to 2008 NCI-WG criteria. Estimated progression free survival and OS were analyzed from time of treatment to progression or death using Kaplan-Meier survival curves. Results: The median age was 71 (65 – 87) years and 17 of 24 (71%) had Rai stage III or IV disease. Two patients had concomitant autoimmune hemolytic anemia (AIHA), one patient had immune thrombocytopenic purpura and AIHA was the indication for therapy in one patient. Median β2-microglobulin was 7.7 (2.3 – 21) mg/l and 5 patients had chromosome 17 abnormalities. Previously treated patients had received a median of 3 (1 – 7) prior treatments and 6 (32%) pts were refractory to fludarabine. Responses were observed in 4 of 6 untreated patients (ORR 67%) and included 3 clinical complete responses unconfirmed by bone marrow biopsy (CRu, 50%) and 1 partial response. The estimated median PFS and OS in this group were 13 and 55 months, respectively. Among patients who received rituximab and methylprednisone as salvage therapy, 7 patients achieved a partial response (ORR 39%), 10 (50%) patients failed treatment, 1 patient (6%) received another therapy after 1 cycle for lack of response and 1 patient (6%) was lost to follow-up. In the salvage group, estimated median PFS and OS were 4 and 18 months, respectively. Four deaths occurred 3, 5, 11 and 12 months after rituximab and methylprednisone without further therapy; 3 patients had progressive CLL and the cause of death was unknown in 1 patient. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in 6 (33%), 3 (14%) and 1 (5%) of evaluable patients. Four patients (17%) experienced grade 3 or 4 infections (3 pneumonia and 1 colonic abscess), 5 patients experienced minor infections and 3 patients experienced viral reactivations (1 CMV, 1 HSV, 2 VZV). There were four grade 3 or 4 non-hematological adverse events including grade 4 gastrointestinal and pulmonary hemorrhage (1), colitis (1), steroid myopathy (1) and peripheral edema (1). All grade 3 or 4 complication occurred in salvage patients. Conclusions: Based on our experience, rituximab and methylprednisone therapy can be safely administered to older patients with CLL. As previously reported by Castro et al, higher response rates were seen in untreated patients, whereas responses were less frequent and shorter lasting in patients with relapsed disease, although this group had high risk disease based on β2-microglobulin levels. Additional studies are required to explore the benefit of this regimen in elderly patients with CLL. Disclosures: Off Label Use: Ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia. O'Brien:Celgene: Consultancy; Genentech BioOncology: Consultancy. Wierda:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Advisory Board, Consultancy, Speakers Bureau. Estrov:Celgene: Consultancy. Keating:Celgene: Consultancy; Genentech: Consultancy. Ferrajoli:Celgene: Research Funding; Genentech: Research Funding.

Outcome of Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and/or 17p Deletion/TP53 Mutations Treated with Ibrutinib According to a Named Patient Program (NPP) in Italy: Preliminary Analysis of a Real Life Retrospective Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2038-2038 ◽  
Author(s):  
Francesca Romana Mauro ◽  
Alessandra Tedeschi ◽  
Alfonso Piciocchi ◽  
Marina Motta ◽  
Emilia Iannella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Real Life ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Tp53 Mutations ◽  
Prospective Trials ◽  
Grade 3

Abstract Introduction. Observational studies from patients treated outside controlled clinical trials offer real life information and are relevant to understand whether data derived from prospective trials are reproducible in the clinical practice. A retrospective observational study was carried out by the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) group in order to evaluate the clinical characteristics and outcome of patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib in Italy within a Named Patient Program (NPP). The NPP was intended to offer free and early drug access to CLL patients until ibrutinib became available on the Italian market. Methods. Patients included in the NPP program had refractory or relapsed (R/R) disease with progression within 24 months after prior chemo-immunotherapy, and/or 17p deletion/TP53 mutations. Patients were also required to have an ECOG performance status ≤2; serum creatinine ≤2 times, liver enzymes ≤3 times and total bilirubin ≤1.5 times the upper limit of normal. Key exclusion criteria were: the need of a concomitant treatment with a strong CYP3A inhibitor or warfarin, an allogeneic stem cell transplantation within the past 6 months or an ongoing active infection. All patients included in the program received ibrutinib orally as a single agent at the standard dose of 420 mg daily. Clinical data of 110 patients included in the NPP program between January 2014 and November 2014 have so far been collected and analyzed using the Research Electronic Data Capture (REDCap) system. Patients were managed at 20 Italian centers and received at least one dose of ibrutinib. Clinical data were reported by the treating physicians. Results. The median age of patients was 69.9 years (range 49.8-83.3); 53% were in Rai stage III-IV, 32% in stage II and 15% in stage 0-I. Sixty-two percent of patients had relapsed disease, 38% were refractory to prior treatment. The presence of a 17p deletion and/or TP53 mutations was recorded in 51 R/R patients. Eighty-six percent of patients had an unmutated IGHV gene profile. The median number of prior treatments was 3 and included allogeneic stem cell transplantation in 4 cases. Two or more comorbidities were reported in 57 patients (52%) and included atrial fibrillation (AF) in 10 (9.1%) and hypertension in 40 (36.4%). After a median follow-up of 12.1 months (range, 1.6-24.6), 87 patients (79%) were still on ibrutinib. A response to ibrutinib was reported in 98/110 patients (89.1%). The best recorded response was a CR/CRi in 19 patients (17.3%), while a PR was reported in 79 patients (72%; PR-L 21.1%). Similar response rates were observed in patients with unmutated IGHV genes (91.9%) and in those with 17p deletion/TP53 mutations (90.3%). At 12 months, the progression-free survival (PFS) and overall survival (OS) were 92.9% (95%CI: 87.9-98.2) and 95.2% (95%CI: 91.1-99.4), respectively. PFS at 12 months of patients who achieved a response was 96.3%, 98.9% in unmutated IGHV patients, 90.7% in those with 17p deletion/TP53 mutations. Five patients (4.5%) died during the NPP program (1 patient each for sepsis, heart failure, ileus perforation, cancer, unknown cause). Adverse events (AE) were recorded in 75 patients (68.2%); in 47 (42.7%) they were grade ≥3. Any grade AEs recorded in ≥5% of patients were: infections (35%; grade ≥3, 22%), granulocytopenia (18.8%; grade ≥3, 17.2%), bleeding (15.5%; grade ≥3, 2.7%), fever of unknown origin or febrile neutropenia (12%; grade ≥3, 5.4%), AF (10.9%; grade ≥3, 4.5%), diarrhoea (8.3; grade ≥3, 2%), hypertension (7.2%; grade ≥3, 5.4%). A new event of AF occurred in 1/10 patients with a prior history of AF. Warfarin was required in 1 patient with AF and this was the reason for ibrutinib discontinuation. Conclusions. The results of the first interim analysis of this retrospective, real life study confirms that ibrutinib, as a single agent, is an effective treatment for patients with poor-prognosis CLL. Our data also suggest that ibrutinib given to unselected patients, in a compassionate-use program, shows a clinical activity and a safety profile comparable to those reported in prospective trials. Data collection is ongoing in order to complete the analysis of this large NPP cohort in Italy. Disclosures Marasca: Roche: Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria. Coscia:Karyopharm: Research Funding; ROCHE: Honoraria, Other: Advisory board; Janssen: Honoraria; Gilead: Honoraria; Mundipharma: Honoraria. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees. Molica:Jansen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche Italy: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Speakers Bureau. Orlandi:Ariad: Honoraria; BMS: Honoraria; Novartis: Honoraria. Ghia:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Adaptive Biotechnology: Consultancy; Roche: Honoraria, Research Funding. Foà:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy; Genentech: Consultancy; Pfizer: Speakers Bureau; Ariad: Speakers Bureau.

Efficacy and safety of surgery for spontaneous pneumothorax in elderly patients

2019 ◽  
Author(s):  
Shunichi Nagata ◽  
Mitsugu Omasa ◽  
Kosuke Tokushige ◽  
Takao Nakanishi ◽  
Hideki Motoyama
Keyword(s):  
Risk Factors ◽  
Surgical Treatment ◽  
Postoperative Complications ◽  
Elderly Patients ◽  
Spontaneous Pneumothorax ◽  
Performance Status ◽  
Multivariable Analysis ◽  
Efficacy And Safety ◽  
Air Leaks ◽  
Grade 3

Abstract OBJECTIVES There is no clear consensus on the surgical indications for spontaneous pneumothorax in elderly patients. In this study, we aimed to assess the efficacy and safety of surgical treatment of spontaneous pneumothorax in patients aged ≥70 years. We also sought to identify the risk factors for postoperative prolonged air leaks and complications in such patients. METHODS Data pertaining to 104 elderly patients who underwent surgery out of 206 patients (aged ≥70 years) who were diagnosed with spontaneous pneumothorax at our institution between 1994 and 2018 were retrospectively reviewed. The incidences of postoperative persistent air leaks (≥2 days) and postoperative complications (≥grade 3; Clavien–Dindo classification) were analysed for efficacy and safety assessment, respectively. RESULTS Median postoperative air leaks continued for 0 days (range 0–25); 14.4% patients developed ≥grade 3 postoperative complications. On the basis of results of multivariable analysis, it was observed that a higher PaCO2 level was significantly associated with prolonged postoperative air leaks [odds ratio (OR) 1.08, 95% confidence interval (CI) 1.00–1.17; P = 0.047]. Poorer performance status was associated with a significantly increased risk of postoperative complications, as assessed by multivariable analysis (OR 6.13, 95% CI 1.38–27.3; P = 0.017). The recurrence rate was 4.8%; mortality rate of patients was 2.9%. Three-year survival rate after surgery was 73.8%. CONCLUSIONS Surgical treatment of spontaneous pneumothorax may be effective and safe in selected elderly patients. Moreover, higher PaCO2 and poorer performance status were independent risk factors for postoperative persistent air leaks and complications, respectively.

A Pilot Study of Genasense® (Oblimersen Sodium, Bcl-2 Antisense Oligonucleotide), Fludarabine and Rituximab in Previously Treated and Untreated Subjects with Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4827-4827 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Blanche Mavromatis ◽  
Kanti R. Rai ◽  
Philomena Casey ◽  
Steven Novick ◽  
...  
Keyword(s):  
Adverse Events ◽  
Lymphocyte Count ◽  
Alkylating Agents ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Serious Adverse Events ◽  
Reduced Dose ◽  
Previously Treated ◽  
Grade 3

Abstract Bcl-2 is an anti-apoptotic protein closely linked to chemotherapy resistance and inferior survival in patients (pts) with CLL. Genasense(GNS) enhances apoptosis induced by fludarabine (F), dexamethasone, and rituximab (R) in vitro, and has limited single-agent activity in heavily pre-treated CLL pts. Down-regulation of Bcl-2 may further sensitize CLL cells to apoptosis induced by F and R without exposing subjects to the toxicity of alkylating agents. CLL and NHL pts occasionally exhibit a “cytokine release syndrome” (spiking fever, back pain, and occasional hypotension) with GNS treatment. We hypothesized that a “step dosing” approach with GNS, similar to that sometimes used for R, could ameliorate these effects and allow safe and effective combination of this agent with F and R. We are currently evaluating this combination in pts with either previously untreated (UT) or relapsed, previously treated (PT) CLL who require systemic treatment. Eligibility includes: plts ≥ 50,000/mm3; serum Cr ≤ 1.5 mg/dL; adequate organ function; negative Coombs; no history of autoimmune hemolytic anemia. In cycle 1, GNS is given by continuous intravenous infusion at 1.5 mg/kg/d days 1 to 7. R is given on a dose-escalating schema (day 4, 125 mg/m2; day 6, 250 mg/m2). F (25 mg/m2/d) is given on days 6 to 8. In subsequent 28-day cycles (up to 6), the dose of GNS is escalated to 3 mg/kg/d days 1 to7 days, with R 375 mg/m2 on day 5 and F days 5 to7. To date, 20 pts have been enrolled (17 PT and 3 UT). Characteristics included: median age, 62 yrs (range 39 to 82 yrs); Rai stage III (2 pts) and IV (6 pts). Prior to administration of either F or R, single-agent GNS treatment at the initial reduced dose in Cycle 1 resulted in a median decrease in lymphocytes of 15% (among all patients regardless of decline in lymphocyte count) (Baseline: 48.3 cells x 103/ml; day 4: 40.1 cells x 103/ml). For the 13 pts who experienced a decline in lymphocyte count in cycle 1 prior to F and R, the median percentage change was 17%, with 4 pts having a > 25% decrease. Three PT pts discontinued from study treatment prior to completing 6 cycles, 2 due to disease progression, and 1 with Grade 3 thrombocytopenia that was unresolved after 4 weeks. Among the 20 pts treated to date (9 ongoing), the most common grade 3 or higher adverse events have been neutropenia, pyrexia and thrombocytopenia. Serious adverse events have been noted in only 6 of 20 pts (all PT pts) and have included 2 pts with fever (1 neutropenic), 2 R infusion reactions, 1 lymph node abscess and 1 tumor lysis syndrome (with sepsis). Conclusions: 20 pts have been treated with combination GNS, F and R. Single-agent activity with GNS has been observed at a reduced dose of 1.5 mg/kg/d in cycle 1. The “step dosing” approach appears to be a well-tolerated, alternative approach to the administration of GNS. Further details of safety and efficacy will be presented.

Results of a Phase I Trial of SGN-40 (Anti-huCD40 mAb) in Patients with Relapsed Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3576-3576 ◽  
Author(s):  
Mohamad A. Hussein ◽  
James R. Berenson ◽  
Ruben Niesvizky ◽  
Nikhil C. Munshi ◽  
Jeffrey Matous ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Aseptic Meningitis ◽  
Dose Escalation ◽  
Single Agent ◽  
Objective Response ◽  
Lymphocytic Leukemia ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Grade 3

Abstract SGN-40 is a humanized anti-CD40 monoclonal antibody that has demonstrated potent in vitro and in vivo efficacy against cell lines expressing CD40, a member of the tumor necrosis factor receptor family. CD40 is widely expressed on tumors of B-cell origin, including myeloma, non-Hodgkin’s lymphoma, Hodgkin’s disease, and chronic lymphocytic leukemia. SGN-40 has been evaluated in a phase I, multi-dose, single-agent, dose escalation study for patients with relapsed or refractory multiple myeloma. This single-arm trial was designed to evaluate safety, pharmacokinetics, immunogenicity, and antitumor activity. Thirty-two patients were treated at five clinical sites. Patients had been heavily pretreated with a median of four prior regimens and 4.8 years since diagnosis. Initially, patients were treated with four weekly infusions at a cohort-specific dose. This schedule was well-tolerated at 0.5, 1.0 and 2.0 mg/kg/wk; however, two of three patients experienced dose-limiting toxicities following the first dose at 4 mg/kg. One patient had aseptic meningitis (grade 3) and another had headache (grade 3) and aseptic meningitis (grade 4); both patients fully recovered after several days of symptom management. Subsequently, the protocol was amended to allow intra-patient dose-loading, which resulted in successful dose escalation to 8 mg/kg, the highest dose tested. There was neither recurrence of grade 3 neurotoxicity nor evidence of cumulative toxicity. Drug-related adverse events were mostly grade 1 or 2 and included: fatigue (38%), headache (34%), nausea (16%), conjunctivitis (13%), diarrhea (13%), vomiting (13%), anemia (9%), anorexia (9%), chills (9%), and pyrexia (9%). Transient grade 3 elevation of hepatic transaminases (1) and grade 3 neutropenia (1) were observed. Overall, toxicity did not appear to increase in incidence or severity at higher doses. Patients were evaluated at baseline and end of treatment for development of anti-SGN-40 antibodies. Of 30 patients for whom appropriate samples were available for testing, only one low-titer immune response (16 ng/mL) was detected, suggesting that immunogenicity does not appear to be a significant problem in this patient population. Pharmacokinetic analysis demonstrates dose-proportional changes in Cmax and AUC with a relatively short terminal half-life, similar to that seen in non-human primates. Final analysis of SGN-40 serum levels is ongoing. Although several patients demonstrated decreased M-protein and improvement in subjective symptoms, no patients met criteria for objective response. Five patients (16%) had stable disease at the time of restaging. In summary, dose-dependent toxicity was established only in relation to the first dose of SGN-40, which may be due to partial agonistic signal transduction. Using a dose-loading schedule, SGN-40 was administered up to 8 mg/kg without reaching a maximum tolerated dose. Some patients with advanced myeloma appeared to derive clinical benefit from therapy, and further development of this antibody, either as monotherapy or in combination with other anti-myeloma therapies, is indicated.

Frontline Combined Chemoimmunotherapy with Fludarabine, Cyclophosphamide, Alemtuzumab and Rituximab (CFAR) in High-Risk Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 208-208 ◽  
Author(s):  
Sameer A Parikh ◽  
Michael Keating ◽  
Susan O'Brien ◽  
Alessandra Ferrajoli ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Frontline Therapy ◽  
Grade 3 ◽  
Tract Infections ◽  
Cmv Reactivation

Abstract Abstract 208 Background: Combined chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has excellent clinical activity as frontline therapy for patients (pts) with chronic lymphocytic leukemia (CLL). In a subset of pts who exhibited high-risk features, such as serum beta-2 microglobulin (B2M) ≥4 mg/L; the complete remission (CR) was lower and time to progression (TTP) and overall survival (OS) were shorter; therefore characterizing these pts as high-risk. Alemtuzumab (A) has activity as a single-agent and in combination with F in pts with relapsed/refractory CLL. To improve the CR and OS for pts with high-risk CLL, we added A to the FCR regimen (CFAR) as frontline therapy in a Phase II clinical trial. Methods: All pts who met NCI-WG criteria to initiate therapy, were < 70 years and had a B2M ≥4 mg/L were eligible for the study. Frontline CFAR consisted of C-200 mg/m2 D3-5, F-20mg/m2 D3-5, A-30mg IV D1,3,5, and R-375–500 mg/m2 D2. Courses were repeated every 28 days for a total of 6 courses. All pts received pegylated filgrastim 6mg SC with each course of therapy. All pts received allopurinol for tumor lysis prophylaxis. Antibiotic prophylaxis with TMP/SMX DS and valacyclovir or valganciclovir was also given to all pts. CMV antigenemia was monitored before each course. Results: A total of 60 pts were enrolled from July 2005 through August 2008 (Table). One pt was lost to follow-up. The median age was 59 yrs (range 42–69) and 44 (75%) were male. Median B2M was 5.1 mg/L (4–11.6); HGB was 11.5gm/dL (5.5–15.1); PLT was 139 k/μL(41–446); WBC was 100k/μL (5–665); ALC was 92k/μL (4–619); and 30 pts (51%) were Rai stage III-IV. The median number of courses administered was 4 (2–6); reasons for not completing 6 courses included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and pt. choice (2). CR was achieved in 70%, nPR in 3%, PR in 18%, and 7% pts did not respond, leading to an ORR of 92% (Table). There was no significant correlation between CR or OR with Rai Stage, IgVH mutation status, FISH status, ZAP70 and CD38 expression. After a median follow-up of 24 months (3–49), 19(32%) pts have progressive disease. Patients with 17p deletion and unmutated IgVH had significantly shorter TTP as shown in the >Table. Eleven (19%) pts have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 transformed into AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. In a historic cohort of high-risk pts treated with FCR, grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 10% courses; and major and minor infections were seen in 15% and 23% pts respectively, all comparable to that seen with frontline CFAR. A-associated infusion reactions occurred in 42 (71%) pts. CMV reactivation occurred in 7 (12%) pts, all of whom were on valacyclovir prophylaxis. There was 1 death due to CMV pneumonia; all other episodes of CMV reactivation were promptly treated with valaganciclovir leading to resolution of fever and/or antigenemia. The median OS for all pts has not been reached (49+mo) and the median TTP is 38 months. Conclusion: CFAR is an active frontline regimen in high-risk pts with CLL. Although CR rates in pts with other high-risk features such as 17p deletion and unmutated IgVH were >50%, TTP was significantly shorter for these pts than for pts without these features. With current follow-up, OS, TTP, infectious complications and grade 3/4 hematologic toxicity are comparable to historic high-risk pts treated with FCR. Disclosures: Keating: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Genentech: Consultancy, Honoraria; Genzyme: Research Funding.

Phase II Trial of Ofatumumab (OFA) for Older Patients and Patients Who Refuse Fludarabine-Based Regimens with Previously Untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 719-719 ◽  
Author(s):  
Ian W. Flinn ◽  
William N. Harwin ◽  
Patrick Ward ◽  
Habib H. Doss ◽  
Steven W. Papish ◽  
...  
Keyword(s):  
Overall Survival ◽  
Nk Cell ◽  
Single Agent ◽  
Age Groups ◽  
Progression Free Survival ◽  
Response Rates ◽  
Lymphocytic Leukemia ◽  
Induction Treatment ◽  
Front Line ◽  
Grade 3

Abstract Abstract 719 Background: Fludarabine (FLU), cyclophosphamide and rituximab or other FLU based regimens have shown improvement in response rates, progression-free survival, and in some studies overall survival in patients (pts) with previously untreated CLL or SLL. However, the value of FLU based therapies in older pts is less clear with both clinical trial and retrospective analyses showing no improvement in progression-free and overall survival with FLU based therapy. In contrast, regimens that contain rituximab appear to provide benefit across all age groups. OFA is a fully human Immunoglobulin G1 kappa, monoclonal antibody that targets a unique epitope on the CD20 molecule. Pre-clinical data indicate that OFA has greater NK cell and monocyte mediated killing, complement dependent cytotoxicity, and direct killing against CLL cells. Based on pre-clinical and clinical studies indicating possible increased efficacy of OFA in pts with CLL, our aim was to develop an antibody-only regimen for older pts and pts who refuse FLU-based regimens. Methods: Eligible pts had previously untreated CD20+ B-cell CLL(B-CLL) or SLL according to NCI criteria, ECOG PS of ≤2, and were either ≥ 65 years of age, or pts 18–64 years of age who had declined FLU-based regimens. All pts in this study received OFA as an IV infusion once weekly for a total of 8 weeks. To reduce the possibility of infusion reactions, the first dose of OFA was administered at a dose of 300mg. If the initial 300mg dose of OFA was well tolerated, without occurrence of any infusion associated AEs of ≥ grade 3, subsequent doses of OFA (i.e., Week 2 through Week 8) were given at a dose of 2000mg for cohort 1 and 1000mg for cohort 2. Eight weeks after the 8-week induction treatment (tx) ended; pts were assessed for response to the tx. Pts who progressed received no further tx. Pts who responded to the tx or who did not have disease progression received maintenance therapy - OFA at a dose of 2000mg IV for cohort 1 and 1000mg for cohort 2 every 2 months for 2 years (for a total of 12 doses, in the absence of PD or intolerable toxicity) beginning 3 months after the last dose of OFA. Results: Between 8/2010 and 12/2011, 77 pts were accrued (44 pts on cohort 1, 33 pts on cohort 2), median FU for Cohort 1 was 16.1 months (11.6–20.9) and Cohort 2 7.2 months (3.6–10.7). Median age of cohort 1 was 69 (range 47–88) and cohort 2 was 75 (range 50–93). Rai stage at study entry was I/II/III/IV (cohort 1 15/5/11/14 and cohort 2 9/10/7/7). All pts have completed induction therapy. The most common reason for early discontinuation was due to progressive disease (7 pts). Neutropenia was the most common grade 3/4 hematologic adverse event (10 pts). There were no G3 related non-hematologic AEs in either cohort. Two pts have died (1 due to MI, 1 due to CVA). Response by NCI 1996 criteria and IWCLL 2008 criteria and FISH category are shown below; at the time of this analysis 44 pts on C1 and 22pts on C2 were evaluable for response. Kaplan-Meier estimate of PFS is 74% at 15 months for cohort 1. Time to event data for cohort 2 are immature at this analysis but PFS but will be presented at the meeting. Conclusions: OFA, when given as a single agent, is well tolerated as front-line therapy in pts with CLL/SLL. Response rates and PFS compare favorably to our previous studies with rituximab using the same response criteria, particularly when differences in the age of pts entered onto the study are considered. The optimal single-agent dose of OFA in the front-line setting remains to be determined. Further follow-up of these data my provide insight in the dose/response relationship. Disclosures: Off Label Use: Ofatumumab as front-line treatment for CLL/SLL.

Ibrutinib In Combination With Rituximab (iR) Is Well Tolerated and Induces a High Rate Of Durable Remissions In Patients With High-Risk Chronic Lymphocytic Leukemia (CLL): New, Updated Results Of a Phase II Trial In 40 Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 675-675 ◽  
Author(s):  
Jan A. Burger ◽  
Michael J. Keating ◽  
William G. Wierda ◽  
Julia Hoellenriegel ◽  
Ghayathri Jeyakumar ◽  
...  
Keyword(s):  
High Risk ◽  
Subdural Hematoma ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Single Agent ◽  
Infectious Complications ◽  
Lymphocytic Leukemia ◽  
High Rate ◽  
Grade 3

Abstract The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is a promising new targeted therapy for patients with mature B cell malignancies, especially CLL and mantle cell lymphoma (MCL). Single agent ibrutinib induces an overall response rate (ORR) of 71% in relapsed CLL, based on the Phase 1/2 experience. To accelerate and improve responses to ibrutinib in high-risk CLL, ibrutinib was combined with rituximab; we update this Phase 2 single-center clinical trial with a median follow-up of 14 months. Methods Patients were treated with ibrutinib 420 mg PO daily continuously throughout the study Rituximab (375 mg/m2) was administered weekly for the first four weeks (cycle 1), then monthly until cycle 6.at which point patients continued on ibrutinib monotherapy. Study inclusion required high-risk disease (del17p or TP53 mutation [treated or untreated]), PFS < 36 months after frontline chemo-immunotherapy, or relapsed CLL with del11q. Results Characteristics of the 40 patients enrolled included median age of 65 (range 35–82) with a median of 2 prior therapies. There were14 female and 26 male patients. 20 patients had del17p or TP53 mutation (4 without prior therapy), and 13 patients had del11q. 32 patients had unmutated IGHV, only one patient mutated IGHV, the remaining patients had inconclusive IGHV results. The median β2 microglobulin was 4.2 mg/L (2.2 – 12.3), At a median follow up of 14 months, 32 of 40 patients continue on therapy (16 out of 20 with del17p or TP53 mutation) without disease progression. 39 patients were evaluable for response assessment per 2008 IWCLL guidelines; 34 (87%) achieved partial remission (PR), and three (8%) complete remission (CR), accounting for an ORR of 95%. One CR was negative for MRD by flow cytometry, The ORR in the 20 patients with del17p or TP53 mutation was 90% (16 PR, 2 CR). Among the 8 patients that came off study, 3 patient died from unrelated infectious complications (2 cases of sepsis, 1 case of pneumonia), and 1 died from unrelated respiratory and cardiovascular failure. Two patients came off study because of possibly ibrutinib-related toxicity (one subdural hematoma, one grade 3 mucositis), one patient had progressive disease, and one proceeded to stem cell transplantation. Treatment generally was well tolerated, with infectious complications (6 cases of pneumonia and 3 cases of upper respiratory infections) being the most common complication. There were two Grade 3, possibly related AEs: mucositis (n=1), and peripheral neuropathy (n=1). Milder toxicities included Grade 1-2 bruising (n=7), Grade 1 subdural hematoma (n=1), fatigue (n=2), bone pain, myalgias, and arthralgia (n=5), or diarrhea (n=1). Questionnaires revealed significantly improved overall health and quality of life (QOL) after 6 months, based on the EORTC-QOL-v.3 questionnaire, which coincided with a significant weight gain at 3 and 6 months. Conclusion Ibrutinib in combination with rituximab is a safe, well tolerated regimen for high-risk CLL patients, which induces high rates of durable responses. Responses were associated with significant improvements in QOL. Compared to ibrutinib monotherapy, the redistribution lymphocytosis resolves more rapidly and completely (see Figure), and consequently the ORR is higher. Whether the addition of rituximab to ibrutinib therapy translates into longer progression-free and overall survival will be addressed in an upcoming larger, randomized trial of ibrutinib versus iR in relapsed/refractory CLL. Disclosures: Burger: Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Ibrutinib (PCI-32765) for treatment of high-risk CLL patients. O'Brien:Pharmacyclics: Research Funding.

Toxicity Is Not Associated with Age or Comorbidity Score in a Randomised Study of Oral Fludarabine and Cyclophosphamide and IV Rituximab (FCR) As First-Line Therapy of Fit, Elderly Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4695-4695 ◽  
Author(s):  
Stephen P. Mulligan ◽  
Devinder Gill ◽  
Paul Turner ◽  
William E. P. Renwick ◽  
Maya Latimer ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Adverse Events ◽  
Research Funding ◽  
Rating Scale ◽  
Lymphocytic Leukemia ◽  
Early Stopping ◽  
First Line ◽  
Significant Difference ◽  
Skin Allergy ◽  
Grade 3

Abstract BACKGROUND Fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free (PFS) and overall survival (OS) versus (vs) FC in the CLL8 Study. The median age in CLL8 was 61 years compared to 72 years for CLL overall. There has been considerable debate regarding the tolerability and toxicity of FCR based therapy in older patients (pts) and those with comorbidities. METHODS Previously untreated fit pts with progressive CLL aged ≥65 were randomised to one of 3 therapy arms: (i) FR5: F 24mg/m2 po D1-5 + R iv D1 (375mg/m2 cycle 1, 500mg/m2 cycles 2-6), (ii) FCR3: F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 or (iii) FCR5: F 24mg/m2 po+ C 150mg/m2 po D1-5 + R iv D1 all at 4 weekly intervals for an intended 6 cycles. Cycles could be delayed up to 2 weeks for grade 3+ toxicity, and if unresolved by 2 weeks, pts were taken off study. Fitness was assessed using the Cumulative Illness Rating Scale (CIRS) score with eligibility restricted to CIRS ≤6. RESULTS Recruitment of 120 pts was completed in July 2012. 117 fulfilled eligibility and 1 had no treatment or follow-up reducing the cohort to 116. Median age was 71 (range 65-82) years (yrs) with 78 males (67%) and 39 females (33%). Patient registration by age was 65-69 yrs – 44, 70-74 yrs – 44, 75-79 yrs – 20 and 80-84 yrs – 8 pts, and by CIRS score was 0-2 – 61, 3-4 – 38, 5-6 – 17 pts. Toxicity data by age and CIRS score are shown in tables 1 and 2 respectively. All 6 protocol cycles were completed in 69% but less on FCR5 44% vs FR5 89% and FCR3 76% (p<0.001). Selected toxicity and early stopping rates in table 3. Overall response and toxicity are presented separately. Table 1:Grade 3+ Adverse Events by AgeAgeTotal65-6970-7475-7980-84(n=116)(N=44)(N=44)(N=20)(N=8)Hematological28 (64%)29 (66%)10 (50%)3 (38%)70 (60%)Neutropenia24 (55%)21 (48%)10 (50%)3 (38%)58 (50%)Thrombocytopenia9 (20%)9 (20%)1 (5%)0 (0%)19 (16%)Anaemia7 (16%)6 (14%)2 (10%)0 (0%)15 (13%)Haemolytic Anaemia1 (2%)2 (5%)1 (5%)1 (12%)5 (4%)Febrile Neutropenia / Infection9 (20%)5 (11%)8 (40%)2 (25%)24 (21%)Skin/Allergy/Fatigue/hypersensitivity3 (7%)2 (5%)4 (20%)2 (25%)11 (9%)Other (Card / resp / neuro / metabolic)13 (30%)10 (23%)3 (15%)1 (12%)27 (23%)At least 1 grade 3+ AE37 (84%)34 (77%)13 (65%)6 (75%)90 (78%) There was no statistically significant difference by age (p=0.429). Table 2:Grade 3+ Adverse Events by CIRS scoreCIRS scoreTotal0-23-45-6(n=116)(N=61)(N=38)(N=17)Hematological38 (62%)21 (55%)11 (65%)70 (60%)Neutropenia31 (51%)16 (42%)11 (65%)58 (50%)Thrombocytopenia11 (18%)6 (16%)2 (12%)19 (16%)Anaemia7 (11%)5 (13%)3 (18%)15 (13%)Haemolytic Anaemia1 (2%)4 (11%)0 (0%)5 (4%)Febrile Neutropenia / Infection11 (18%)9 (24%)4 (24%)24 (21%)Skin/Allergy/Fatigue/hypersensitivity6 (10%)4 (11%)1 (6%)11 (9%)Other (Card / resp / neuro / metabolic)12 (20%)9 (24%)6 (35%)27 (23%)At least 1 grade 3+ AE78 (79%)27 (71%)15 (88%)90 (78%) There was no statistically significant difference by CIRS score (p=0.355). Table 3:Abbreviated Grade 3+ Adverse Events by Treatment ArmTreatment armTotal (n=116)FR5 (N=37)FCR3 (N=41)FCR5 (N=38)Hematological15 (41% )26 (63% )29 (76% )70 (60%)At least 1 grade 3+ AE21 (57%)34 (83%)35 (92%)90 (78%)Early cessation due to toxicity2 (5.6%)1 (2.4%)13 (34%)16 (14%) Early cessation due to toxicity was significantly more common with FCR5 (p<0.001). However, of the 13 patients on FCR5 arm that stopped early due to toxicity, there was no difference by age or CIRS score: by age, 5 were 65-69 yrs, 3 were 70-74 yrs, 4 were 75-79 yrs and 1 was 80-84 yrs and by CIRS score, 3 were 0-2, 6 were 3-4 and 4 were 5-6. CONCLUSIONS Final analysis in this randomised dose de-escalation study shows oral FCR therapy is generally safe and well tolerated in CLL pts aged ≥65 years requiring first-line treatment, when early stopping is utilised if prolonged toxicity occurs. Early cessation due to toxicity was more common with full dose FCR5, but not associated with age or CIRS score within this arm. Overall in this relatively fit elderly CLL cohort, neither age nor CIRS score were associated with toxicity, or early cessation of therapy due to toxicity. The results highlight the difficulty of predicting toxicity based on age and comorbidity in elderly CLL pts. Disclosures Mulligan: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria. Gill:Roche: Research Funding; Sanofi Aventis: Research Funding. Turner:Roche: Research Funding; Sanofi Aventis: Research Funding. Renwick:Roche: Research Funding; Sanofi: Research Funding. Latimer:Roche: Research Funding; Sanofi: Research Funding. Mackinlay:Roche: Research Funding; Sanofi: Research Funding. Berkahn:Roche: Research Funding; Sanofi: Research Funding. Simpson:Roche: Research Funding; Sanofi: Research Funding. Forsyth:Roche: Research Funding; Sanofi: Research Funding. Harrup:Roche: Research Funding; Sanofi: Research Funding. Kuss:Roche: Research Funding; Sanofi: Research Funding.

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