Tolerability of 2-Weekly CHOP+Rituximab Followed by Yttrium-90 Ibritumomab Tiuxetan (Zevalin) In Patients with Previously Untreated Diffuse Large B Cell Lymphoma (DLBCL): Final Analysis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4918-4918 ◽  
Author(s):  
Andrew Manson ◽  
Reem Karmali ◽  
Irene Dehghan-Paz ◽  
Eduardo Braun ◽  
Teresa O'Brien ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Left Ventricular ◽  
Neutropenic Fever ◽  
Left Ventricular Ejection ◽  
Organizing Pneumonia ◽  
Off Label ◽  
Grade 3 ◽  
Dose Dense

Abstract Abstract 4918 Background: Improved outcomes have been demonstrated in DLBCL with dose dense CHOP (CHOP-14), the addition of immunotherapy to CHOP, and radioimmunotherapy consolidation following CHOP chemotherapy. A prospective, single-arm, open-label, nonrandomized phase II trial was conducted using a combination of the above with dose dense CHOP+R, every 2 weeks, followed by radioimmunotherapy consolidation to evaluate its efficacy and safety in untreated DLBCL patients. Patients and Methods: 20 eligible patients (measurable disease, age >18 years, performance status 0–2, adequate marrow, liver and kidney function) with previously untreated DLBCL were enrolled. Patients with transformed lymphoma were excluded. Patients received standard CHOP along with rituximab 375mg/m2 IV on day 1, every two weeks for 6 cycles, followed by Zevalin 6–8 weeks later. Efficacy of Study: In 20 treated patients, ORR was 100% with 90% CR and 10% PR. 16 patients received the entire treatment regimen as intended. 3 patients (15%) relapsed. All relapses were retreated with one patient now in CR and 2 deceased. One other patient, who did not receive Zevalin, is also deceased from organizing pneumonia 2 years after last chemotherapy. Safety Results: The most common adverse effects of this regimen were hematological. All patients (n=20) had anemia during CHOP+R pre-Zevalin, 15 (75%) patients with grade 1/2 and 5 (25%) with grade 3 anemia. 11 patients had thrombocytopenia, 4 with grade 3/4 toxicity. Neutropenia was present during CHOP+R therapy in 14 patients (70%), 2 cases of grade 2 and 12 cases of grade 4 toxicity. However, neutropenic fever only occurred in 4 patients, all with grade 1/2 neutropenia. Neuropathy was also a common toxicity (15 patients), with grade 3 toxicity occurring in 4 patients. Less common adverse effects, all ≤ grade 2, included anorexia, constipation, nephrolithiasis, diarrhea, urinary frequency, dysgeusia and rhinitis. With completion of dose dense chemotherapy, one patient had organizing pneumonia, one had grade 2 pneumonitis, and one had bronchiectasis, all precluding the use of Zevalin. Pre and post chemotherapy MUGA scans demonstrated stable left ventricular ejection fractions in all but one patient, who remains in CR. Zevalin was completed by 16 patients (80%). Zevalin induced grade 3/4 cytopenias occurred in 8 patients (50%), the most common being neutropenia (all 8 patients) with no cases of neutropenic fever. 12 (75%) patients experienced thrombocytopenia, though only 2 had grade 3/4 effects. Grade 3 syncope occurred in one patient. All other non-hematologic effects were ≤ grade 2 and included neuropathy, sinus and yeast infections, folliculitis, rash, diarrhea, nausea, and urinary incontinence. Conclusion: Consolidation with Zevalin radioimmunotherapy following dose dense CHOP+R therapy is well tolerated, safe and non-life threatening among our sample population of untreated DLBCL. Disclosures: Off Label Use: Chemotherapy with R-CHOP every 21 days is the standard of care for DLBCL in the front-line setting. We are administering R-CHOP every 14 days for dose intensification followed by zevalin (radioimmunotherapy) consolidation for untreated DLBCL. This regimen is off-label. Gregory: Amgen: Consultancy; Astellas: Research Funding; Celgene: Research Funding; Cephalon: Research Funding, Speakers Bureau; Genentech (Roche): Consultancy, Research Funding, Speakers Bureau; Glaxo-Smith-Kline: Research Funding; Immunomedics: Research Funding; NCIC CTG: Research Funding; Novartis: Consultancy, Research Funding; Onyx (Proteolix): Research Funding; Spectrum Pharmaceuticals: Consultancy.

Can a Dose-Dense RCHOP-Like Regimen Be Effectively Used In a Community Setting? Results of a Phase II Study Employing Pegylated Liposomal Doxorubicin In Elderly (> age 60) or Cardiac Compromised (LVEF <45%) Patients with Diffuse Large B Cell Lymphoma (DLBCL).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2797-2797
Author(s):  
Stephen J. Noga ◽  
Judith Bosley ◽  
Pamela Nickoles
Keyword(s):  
Phase Ii ◽  
Survival Data ◽  
Research Funding ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Dose Intensity ◽  
B Cell Lymphoma ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Dose Dense

Abstract Abstract 2797 Chemotherapy employing the RCHOP every 21 day regimen has become the standard of care for patients with DLBCL. Although the GELA study did include older patients, NHL incidence rises more steeply with age, with a third of cases occurring in patients over 75 years of age. Community oncologists see an ever-increasing NHL age group with multiple co-morbidities. There is also debate whether DLBCL is more aggressive/chemo-resistant at the higher age range. For many, cardiac issues exclude them from an adriamycin-based regimen and possible cure. Since pegylated liposomal doxorubicin (PLD) has a reported lower cardiac toxicity profile even at higher overall doses than doxorubicin, it was substituted into a dose-dense RCHOP regimen. To this end, we developed a phase II dose-dense/dose escalation study of PLD (Doxil®,20 mg/m2: cohort I, 25 mg/m2: cohort II, 30 mg/m2: cohort III), cyclophosphamide (CY, 750 mg/m2), vincristine (1.4 mg/m2: 2 mg max), prednisone (100 mg PO days 1–5) and rituximab (375 mg/m2) on day 1 followed by pegfilgrastim (Neulasta®, 6 mg, SC) on day 2 of a 14 day cycle. Patients received a planned 6 cycles of chemotherapy or 2 cycles past best response. Patients >60 years or with left ventricular ejection fractions (LVEF) <45% were enrolled with ECOG performance status (PS) of 0 – 3. Three, 6 and 8 patients (17 total) were enrolled on cohorts I – III, respectively, Intent to treat (ITT) data included all patients. Response/survival data excluded 2 patients who deteriorated by start of cycle 1 chemotherapy. Safety and SAE's were assessed with each cohort. Quantitative LVEF was obtained with each cycle, CT's every 3 cycles and PET/CT at baseline and within 60 days of chemotherapy completion. Median age was 78 (62-87), 59% were female and baseline LVEF from 12% (with AICD but ECOG PS1) to 87% (median 60%). There was no reduction in LVEF for patients receiving >1 cycle of chemotherapy. Patients who were hospitalized (PS>2) or who's PS declined rapidly between study entry and cycle 1 initiation rapidly became too moribund to complete planned therapy. Relative dose intensity [RDI: (delivered chemotherapy/time to complete)/(planned chemotherapy/planned time to complete)] for the entire group averaged 96 (83 – 100)% for PLD, median 100%, and 97 (86 – 100)%, median 100%, for cyclophosphamide. Nearly all patients (92%) achieved a CR/nCR with a 77% CR rate. Despite an every 14 day anthracycline regimen, Grade >2 hematologic toxicities were manageable and others were low. Overall Survival in the ITT population was 65% and 37% at 12 and 24 months, respectively. Censoring for patients removed in or after cycle 1 yielded a survival rate of 73% at 12 months and 42% at 24 months. This elderly patient population had significant long term morbidities, post-chemotherapy, leading to mortality from cardiac disease, ARF and liver failure besides lymphoma related causes. Adjusting for the non-lymphoma deaths gave adjusted survivals of 85% and 71% at 12 and 24 months, respectively. We conclude that it is feasible to deliver a dose-dense anthracycline regimen to geriatric patients with acceptable toxicity. Indeed, 71% of study patients were ≥ 70 years and 47% were ≥ 80 years. Microarray analysis may pinpoint which elderly patients may require a more intensive regimen to effect cure. Grade (%) N F/N Hosp F/N Tpenia PPE Cardiac Stomatitis All 88 24 24 82 65 24 47 3 24 12 12 24 6 12 6 4 41 12 12 6 6 - - Neutropenia =N, Febrile Neutropenia =F/N, Hospitalization for F/N = Hosp F/N, Thrombocytopenia = Tpenia, Palmar- Plantar erythrodysesthesia = PPE Disclosures: Noga: Amgen: Honoraria, Research Funding, Speakers Bureau, none; Millenium Takada: Consultancy, Honoraria, Research Funding, Speakers Bureau, none; Ortho-Centicor: Research Funding, Speakers Bureau, none; Cephalon: Honoraria, Speakers Bureau, none; Pfizer: Speakers Bureau, none; Cellgene: Honoraria, Research Funding, Speakers Bureau, none. Off Label Use: Doxil (pegylated liposomal doxorubicin) in place of adriamycin in a CHOP-R regimen for DLBCL.

Phase II Study of 2-Weekly CHOP+Rituximab Followed by Yttrium-90 Ibritumomab Tiuxetan (Zevalin) In Patients with Previously Untreated Diffuse Large B Cell Lymphoma (DLBCL): Final Analysis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3947-3947 ◽  
Author(s):  
Reem Karmali ◽  
Andrew Manson ◽  
Katherine Bueschel ◽  
Kathryn Shell ◽  
Stephanie A. Gregory ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Performance Status ◽  
B Cell Lymphoma ◽  
Final Analysis ◽  
The Other ◽  
Organizing Pneumonia ◽  
Nodal Disease ◽  
Off Label ◽  
Dose Dense

Abstract Abstract 3947 Background: Dose dense CHOP (CHOP-14), the addition of rituximab to CHOP-21 and consolidation with radioimmunotherapy following CHOP chemotherapy have all been shown to improve the outcome of DLBCL. We report the results of final analysis of a phase II clinical trial using a combination of the above with dose dense CHOP+R, every 2 weeks, followed by radioimmunotherapy consolidation in untreated DLBCL patients. Patients and Methods: Patients with previously untreated DLBCL with measurable disease, age >18 years, performance status 0–2, and adequate marrow, liver and kidney function were eligible. Those with transformed lymphoma were excluded. Patients received standard CHOP along with rituximab 375mg/m2 IV on day 1, repeated every two weeks for 6 cycles, followed by Zevalin consolidation 6–8 weeks later. Results: 20 patients were enrolled. The median age was 60 years (range 33–81 years). 8 patients were men and all patients had an ECOG performance status of 0 or 1. 4 (20%) had stage II, 11 (55%) stage III and 5 (25%) stage IV disease. The majority of patients had an IPI of 2 (40%) or 3 (55%). 14 patients (70%) had extra-nodal disease. 18 patients completed 6 cycles of CHOP+R, 16 of whom went onto Zevalin consolidation. Of the 2 patients who did not complete 6 cycles of CHOP+R, one patient with multiple lung masses could not tolerate further therapy and the other withdrew consent after 5 cycles. Of the 2 patients who completed 6 cycles of chemotherapy but did not receive Zevalin, one was excluded due to abnormal biodistribution on dosimetry with Zevalin and the other because of organizing pneumonia. Following CHOP+R alone in patients who received 4 or more cycles (n=20), ORR was 100% with a 75% CR (n=15) and a 25% PR (n=5). All 4 patients who stopped treatment with dose dense CHOP+R remained in CR. With Zevalin, 3 patients converted from PR to CR, maintaining an ORR of 100% (n=20) with an improved CR of 90% and a PR of 10%. The most common grade 3/4 toxicity with Zevalin was neutropenia in 8 patients (n=50%) with no cases of neutropenic fever. At a median follow-up of 42.4 months, median PFS and OS were not reached. 3 patients relapsed (15%), all of whom had extra-nodal disease, 2 had an IPI of 3, and 2 had bulky disease. All relapses were retreated with one patient now in CR and 2 deceased. One other patient died of organizing pneumonia, in CR at the time of death. To date, 17 patients remain alive, all in CR. Conclusion: Consolidation with Zevalin radioimmunotherapy following dose dense CHOP+R therapy converts PRs to CRs and maintains durable responses with acceptable toxicity in patients with untreated DLBCL. Disclosures: Off Label Use: Chemotherapy with R-CHOP every 21 days is the standard of care for DLBCL in the front-line setting. We are administering R-CHOP every 14 days for dose intensification followed by zevalin (radioimmunotherapy) consolidation for untreated DLBCL. This regimen is off-label. Gregory:Amgen: Consultancy; Astellas: Research Funding; Celgene: Research Funding; Cephalon: Research Funding, Speakers Bureau; Genentech (Roche): Consultancy, Research Funding, Speakers Bureau; Glaxo-Smith-Kline: Research Funding; Immunomedics: Research Funding; NCIC CTG: Research Funding; Novartis: Consultancy, Research Funding; Onyx (Proteolix): Research Funding; Spectrum Pharmaceuticals: Consultancy.

Non-Pegylated Liposomal Encapsulated Doxorubicin Reduces Cardiotoxicity in 1st Line Treatment of Diffuse Large B-Cell Lymphoma (DLBCL). Final Results of a Randomized Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2676-2676 ◽  
Author(s):  
Michael A. Fridrik ◽  
Andreas L Petzer ◽  
Felix Keil ◽  
Wolfgang Willenbacher ◽  
Ulrich Jaeger ◽  
...  
Keyword(s):  
Heart Failure ◽  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Line Treatment ◽  
Advisory Committees ◽  
End Of Treatment ◽  
Clinical Heart Failure

Abstract Abstract 2676 Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) has improved the treatment results in DLBCL substantially. With more patients being cured from the lymphoma long term toxicity becomes an even more important issue. By replacing doxorubicin with non-pegylated liposomal encapsulated doxorubicin in the R-CHOP regimen (R-COMP) we tried to reduce the cardiotoxicity of R-CHOP in the 1st line treatment of DLBCL. We randomized 88 patients with untreated DLBCL to one of two treatment arms. R-CHOP consisted of rituximab 375 mg/sqm, cyclophosphamide 750 mg/sqm, doxorubicin 50 mg/sqm, vincristine 2 mg, each iv. day 1 and prednisolone daily po for 5 consecutive days. Six cycles of chemotherapy and 8 cycles of rituximab were planned. In the R-COMP arm doxorubicin was replaced with non-pegylated liposomal encapsulated doxorubicin 50 mg/sqm iv day 1. Forty and 39 patients were eligible in the R-COMP and R-CHOP arm, respectively. The two arms were well balanced with respect to age, smoking status, heart function, hypertension, and international prognostic index. The primary endpoint of the study was the left ventricular ejection fraction (LVEF) measured by the Simpson method at randomization, after each cycle and 8 weeks after the end of treatment. Mean and standard error were compared by the two-sample t test. Mean LVEF was significantly lower in the R-CHOP arm (62.29%) than in the R-COMP arm (63.56%) (P=.0333). Out of all LVEF measurements 10 (4.6%) vs. 31 (15.8%) were <55% in the R-COMP arm and R-CHOP arm, respectively (P<.001). The N-terminal proB-type of the natriuretic peptide (NT-proBNP) is a strong marker for heart failure. Levels of NT-proBNP began to rise in the R-CHOP arm after the 5th cycle and were significantly different after the end of treatment (median 73 pg/ml vs. 188.2 pg/ml) in the R-COMP arm and R-CHOP arm, respectively. Three (7.5%) and 12 (33.3%) patients had a NT-proBNP >450 pg/ml in the R-COMP arm and R-CHOP arm, respectively (P=.005). Side effects were lower in the R-COMP arm. We observed 26 and 40 severe adverse events in the R-COMP and R-CHOP arm, respectively (P=.029). Most of those were due to infection. The rate of grade 3 and 4 neutropenias was comparable in both arms giving evidence, that non-pegylated liposomal encapsulated doxorubicin was not under-dosed. Although the study was not powered to show differences in efficacy, we had no signal of lower efficacy. The remission rate was 97.5% (CR+CRu 75.0%) and 82.0% (CR+CRu 69.2%) with R-COMP and R-CHOP, respectively. The 3 cases progressing during treatment were in the R-CHOP arm. Clinical heart failure usually appears after several years of treatment. The difference in LVEF may translate in a lower rate of clinical heart failure with longer follow-up. Disclosures: Fridrik: Cephalon: Research Funding. Off Label Use: Non-pegylated liposomal encapsulated doxorubicin in the treatment of lymphoma. Willenbacher:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AESCA: Honoraria, Research Funding. Jaeger:Cephalon: Membership on an entity's Board of Directors or advisory committees. Greil:Cephalon: Research Funding.

scholarly journals Dose-Dense Doxorubicin and Cyclophosphamide Followed by Weekly Paclitaxel With Trastuzumab and Lapatinib in HER2/neu–Overexpressed/Amplified Breast Cancer Is Not Feasible Because of Excessive Diarrhea

2010 ◽  
Vol 28 (18) ◽  
pp. 2982-2988 ◽  
Author(s):  
Chau Dang ◽  
Nancy Lin ◽  
Beverly Moy ◽  
Steven Come ◽  
Steven Sugarman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Left Ventricular ◽  
High Rate ◽  
Left Ventricular Ejection ◽  
Her2 Positive ◽  
Ventricular Ejection Fraction ◽  
Grade 3 ◽  
Dose Dense

PurposeDose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel and trastuzumab (PT) is feasible. Lapatinib is effective in the treatment of human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer. We conducted a pilot study of dose-dense AC followed by PT plus lapatinib (PTL) followed by trastuzumab plus lapatinib (TL).Patients and MethodsPatients with stages I to III, HER2-positive breast cancer and left ventricular ejection fraction (LVEF) of ≥ 50% were enrolled. Treatment consisted of AC (60 mg/m2and 600 mg/m2) for 4 cycles every 2 weeks (with pegfilgrastim 6 mg on day 2) followed by paclitaxel (80 mg/m2) for 12 doses weekly plus trastuzumab and lapatinib. Trastuzumab (4 mg/kg loading dose, then 2 mg/kg weekly during paclitaxel then 6 mg/kg every 3 weeks after paclitaxel) and lapatinib (1,000 mg daily) were given for 1 year. The primary end points were feasibility defined as ≥ 80% patients completing the PTL phase without a dose delay/reduction and a cardiac event rate of ≤ 4%.ResultsFrom March 2007 to April 2008, we enrolled 95 patients. Median age was 46 years (range, 28 to 73 years). At a median follow-up of 22 months, 92 were evaluable. Of the 92 patients, 41 patients (45%) withdrew for PTL-specific toxicities. Overall, 40 (43%) of 92 patients had lapatinib dose reductions, and 27 (29%) of 92 patients had grade 3 diarrhea. Three patients (3%) had congestive heart failure; three patients dropped out because of significant asymptomatic LVEF decline during PTL followed by TL.ConclusionDose-dense AC followed by PTL and then followed by TL was not feasible because of a high rate of lapatinib dose reduction, mostly caused by unacceptable grade 3 diarrhea. Lapatinib (1,000 mg/d) was not feasible combined with weekly PT.

Pegylated Liposomal Doxobubicin (PLD) Can Be Escalated in a Dose-Dense, 14 Day CDOP-Rituximab Regimen without Affecting Relative Dose Intensity (RDI) in Patients with Diffuse Large B Cell Lymphoma (DLBCL) Who Are Elderly or Have Compromised Cardiac Status.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2692-2692
Author(s):  
Stephen J Noga ◽  
Judy Bosley ◽  
Pamela Nickoles ◽  
Pallavi Kumar ◽  
Erica Monfred
Keyword(s):  
Cardiac Function ◽  
Dose Intensity ◽  
B Cell Lymphoma ◽  
The Elderly ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Poor Performance Status ◽  
Term Survival ◽  
Full Dose ◽  
Dose Dense

Abstract Abstract 2692 Poster Board II-668 Anthracycline/rituximab based chemotherapy such as CHOP-R has become the standard of care for DLBCL where cure is the primary goal. There is a direct correlation between long term survival and the delivery of on time, full dose chemotherapy. Several studies in DLBCL now indicate that this concept of dose intensity may be further exploited by compacting therapy cycles from the usual 21 days to the 14 day “dose dense” regimens. It is hoped that this will result in higher cure rates. Community oncologists often face tough decisions when deciding how to treat the increasing numbers of DLBCL patients who are elderly and have multiple co-morbidities including declining cardiac function and poor performance status (PS). Since PLD has a reported lower cardiac toxicity profile even at higher overall doses than doxorubicin, it was substituted into a dose-dense CHOP-R regimen. Patients >60 years or with left ventricular ejection fractions (LVEF) <45% were enrolled in a phase II dose escalation study of PLD (Doxil*®,20 mg/m2: cohort I, 25 mg/m2: cohort II, 30 mg/m2: cohort III), cyclophosphamide (CY, 750 mg/m2), vincristine (1.4 mg/m2: 2 mg max), prednisone (100 mg PO days 1-5), rituximab (375 mg/m2) on day 1 followed by pegfilgrastim (6 mg, SC) on day 2 of a 14 day cycle. Patients received a planned 6 cycles of chemotherapy or 2 cycles past best response. Safety and SAE's were assessed with each cohort or every 6 patients. Quantitative LVEF was obtained with each cycle, CT's every 3 cycles and PET/CT at baseline and within 60 days of chemotherapy completion. Median age was 76 (62-87) years, 59% were female with baseline LVEF from 12% (with AICD but ECOG PS1) to 75% (PS3). There was no diminution in LVEF for patients receiving >1 cycle of chemotherapy. AE's >grade 2 were neutropenia/fever (n=3), neutropenia (n=1), thrombocytopenia (n=1), chest pain (n=1), hyperglycemia (n=2), CHF (n=1) and worsening pleural effusion (n=1). PPE related to PLD was manageable and minimally delayed therapy. . Patients who were hospitalized (PS >2) or who's PS declined rapidly between study entry and cycle 1 initiation rapidly became too moribund to complete planned therapy. Escalation of the PLD dose from 20 mg/m2 to 30 mg/m2 did not alter the ability to deliver on time, full dose chemotherapy. Decreasing cycle length to 2 weeks actually increased the RDI to 150% over the standard 3 week regimen. This may be beneficial in the elderly where it is still uncertain if lower survival is due to substandard treatment regimens or a more chemo-resistant NHL phenotype. In the first 12 evaluable patients completing full course chemotherapy, 10 patients were in CR (CR +nCR), and 1 in PR within 60 days of chemotherapy completion. At 1 year, 6 patients were in CR and 2 had progressive disease. We conclude that CDOP-R 14 warrants further study in the elderly population and in those DLBCL patients with compromised cardiac function. Disclosures: Noga: Tibotec, Inc: Honoraria, Research Funding, Speakers Bureau; Amgen, Inc: Honoraria, Speakers Bureau. Off Label Use: Doxil. Substitutes for the standard anthracycline, doxorubicin, in the CHOP regimen for agressive NHL.

Pre-Phase Chemotherapy Followed By Ofatumumab (OFA) and Reduced Dose CHOP (OFA-mini-CHOP) for Patients over 80 Years with Diffuse Large B-Cell Lymphoma (DLBCL) – a Lymphoma Study Association (LYSA) Prospective Phase II Study (LNH09-7B)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3042-3042 ◽  
Author(s):  
Frédéric Peyrade ◽  
Bologna Serge ◽  
Vincent Delwail ◽  
Jean François Emile ◽  
Christian Rose ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Significant Prognostic Factor ◽  
Free Survival ◽  
Grade 3

Abstract Introduction: R-miniCHOP is the standard chemotherapy for patients over 80 years (y) with DLBCL. In the LNH 03-7B trial, the 2-year overall survival was 58.9% [95% CI: 49.3-67.2%]. Grade III/IV toxicity and deaths occurred during the two first cycles mainly (Lancet Oncol. 2011 May;12(5):460-8). In order to improve overall survival (OS) rituximab (R) was replaced by Ofatumumab (OFA), a humanised anti-CD20 monoclonal antibody. In vitro data suggest that OFA induces more potent complement-mediated cytotoxicity than rituximab, and clinical data demonstrate activity of OF in rituximab-refractory lymphomas). In addition, to reduce early toxicity a pre-phase (PP) with vincristine and prednisone (P) was tested. Patients and methods: Patients older than 80 y with untreated CD20+ DLBCL, Ann Arbor stage I to IV, left ventricular ejection fraction > 50%, and a performance status (PS) of 0 to 4 were eligible. Patients received a PP with vincristine (1 mg TD D-7) and P (60 mg TD D-7 to D-4) before the first cycle of OF-miniCHOP. PP was followed by miniCHOP chemotherapy (cyclophosphamide: 400 mg/m² D1; doxorubicine: 25 mg/m² D1; vincristine: 1 mg total dose D1 and prednisolone 40 mg/m² by oral route from D1 to D5) plus OFA (1000 mg TD) every 21 days for 6 cycles. GCSF was optional. The primary objective was to evaluate the efficacy of PP OF-mini-CHOP as measured by the OS. Secondary endpoints were response rate (RR), progression free survival (PFS), event-free survival (EFS), disease-free survival (DFS) for complete responders and toxicities. Survival results are presented for all included patients on an intend-to-treat basis (n=120). Response to treatment was evaluated according to 1999 Cheson criteria. Results: From June 2010 to November 2011, One-hundred-twenty-patients (male, female) were included in 41 centers of the LYSA. The median age was 83 years (range 89-95). Seventy-seven percent of patients had a stage III/IV. LDH level was elevated in 58% of patients. Age-adjusted (aa) IPI was 2-3 in 57% of patients. One-hundred-twenty patients completed the PP, 107 the first three cycles and 89 received the whole regimen. For patients who started the first cycle, the mean relative Dose-Intensity during trial was 98%, 97% and 96 % for OFA, doxorubicine and cyclophosphamide respectively. Seventy-eight percent of patient received at least one injection of GCSF. The overall RR was 67.5%, including 35.8% of complete response and 20 % of unconfirmed complete response. At the time of this analysis, in September 2013, the median follow-up time was 26.6 months. The 2-year overall survival was 64.7% [95% CI: 55.3-72.7%]. The two-year PFS, EFS and DFS were 57.2% [95% CI: 47.7-65.6%], 53.1% [95% CI: 43.7-61.6%] and 66.6% [95% CI: 54.0-76.5%] respectively. Haematological toxicity was the most common side effect. Grade 3-4 neutropenia was observed in 20.8% of the patients and grade 3-4 thrombocytopenia in 1.7%. Seven patients (5.8%) experienced at least one episode of febrile neutropenia. Infusion reaction related to OFA was reported in 12.5% of patients. Prolonged hospitalization (> or = 10 days) was observed in 17 cases (14.1%) and mainly occurred during cycle 1 to cycle 3. Forty-five patients died during the treatment evenly distributed between lymphoma (62.2%), intercurrent and other causes (22.2%), and concurrent illness (15.6 %). No toxic death was reported. Six patients died during treatment (1 during PP, 4 during cycle 1 to cycle 3, 1 during cycle 4 to cycle 6) Thirty-nine patients died during follow-up. In univariate analysis, low aaIPI (0 /1) is the unique statistically significant prognostic factor of prolonged OS (OR 3.083, [1.458-6.517] CI95%). Instrumental Activities of Daily Living (IADL) score equal to 4 is associated with a longer PFS. By contrast, low Albuminemia level, undernutrition according to buzby index and high Charlson comorbidity index (CCI) were not predictive of survival. Conclusion: In DLCBL patients over 80 y, immunochemotherapy with PP OFA-mini-CHOP appears to be safe and effective, confirming that a substantial proportion of very old patients can be cured. The use of a PP seems to reduce the early death risk. OFA and PP seems to improve OS comparing with the previous reported data. The combination of a PP, monoclonal antibody against CD20 and miniCHOP can be the new standard regimen for DLBCL patients over 80 y. Disclosures Off Label Use: Use of ofatumumab in high grade lymphoma..

Phase I-II Study of Dose Dense PEG-Filgrastim and GM-CSF as Support for Dose Dense CHOP-R Front Line Therapy for Aggressive Non-Hodgkin's Lymphoma (NHL).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2789-2789
Author(s):  
Maribel Cotto ◽  
Fernando Cabanillas ◽  
Idalia Liboy ◽  
Ezequiel Rivera ◽  
Orestes A. Pavia ◽  
...  
Keyword(s):  
Phase I ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Front Line ◽  
Free Survival ◽  
Gm Csf ◽  
Line Therapy ◽  
Short Course ◽  
Grade 3 ◽  
Dose Dense

Abstract Abstract 2789 Background: Standard front line therapy for large B cell lymphoma is R-CHOP every 21 days. However, a randomized study by Pfreundschuh comparing CHOP every 21 vs. CHOP every 14 days showed an advantage in favor of CHOP-14 (Pfreundschuh et al. Blood 104:626–33, 2004). Growth factor support is necessary in CHOP-14. Preclinical studies have shown that low dose GM-CSF augments the effect of Rituximab by enhancing various effector functions such as ADCC and upregulation of CD 20 antigen expression. We proposed to investigate in a phase I-II study, the standard combination of CHOP-Rituximab plus PEG-Filgrastim (PEG-F, Neulasta..), and a short course of GM-CSF (Leukine..). Rituximab 375 mg/m2 was given on day 1, CHOP on day 2. The phase I portion had shown that PEG-F at 4 mg SC on day 3 combined with a short course (4 doses) of GM-CSF 250 mcg given on days 6, 8, 10 and 13 was capable of supporting recovery from myelosuppression so as to allow repetition of chemotherapy cycles every 14 days (Cabanillas et al. JCO. 25: abstr 18501, 2007). We now report the results of the antitumor activity of this combination, which was designed to generate preliminary pilot data as to the effectiveness in regards to complete response (CR) rate and event free survival (EFS). Methods: We had proposed in the protocol a CR rate of >50%, using the modified IWC criteria which includes FDG-PET scan, as interesting enough to justify a larger study to be planned for the future. As an additional endpoint, EFS at 2 years was also included. Between January 2006 and June 2010, a total of 59 pts of a planned accrual of 60 pts, with previously untreated aggressive NHL have been enrolled. Eligibility criteria included age>18 (no top age limit), stages I-IV NHL, HIV negative. A total of 6 courses of CHOP-R-Peg-F-GM-CSF every 14 days were planned. Results: 54 patients (pts) are currently evaluable and 5 too early. Among these patients, histologies were: DLCL-B= 83%, Follicular grade 3= 8%, others 9%. Risk factors were distributed as follows: median age 56 (25-87); 40% were > 60 years, IPI ≥ 3 =30%, Stage III-IV= 54%. Metabolic CR rate (by PET criteria) was 88%. Pts < 60 years of age (y/o) had a CR rate= 91% vs. 82% for ≥ 60 y/o. At a median follow up of 27 months, 3 yr progression free survival (PFS) was 77%, EFS was 74% and 3 yr overall survival (OS) 76%. No pts have relapsed beyond 18 months. Pts < 60 y/o had 3 yr EFS of 77%, while those older than 60 y/o had EFS of 71%, p=0.42. Pts > 60 y/o had an OS at 3 yrs= 65%, while pts < 60 y/o had a OS= 85%, p=0.18. Pts with IPI > 3 had 3 yr PFS= 61% and EFS of 58% as compared with low IPI who had a PFS= 83%, EFS of 81%, p=0.11. Febrile neutropenia occurred in 7 pts and toxic death in 1 pt. Grade 3/4 leukopenias at any cycle were present in 44 pts (grade 3=19, and grade 4=25) and grade 3 anemia in 8 pts. Conclusions: R-CHOP-14-GMCSF-Peg-F achieved a CR of 88% which surpassed the planned primary endpoint which had been set at 50%. In an unplanned subset analysis, for the first time we have noticed the same outcome in pts ≥ 60 and <60 y/o (Fig. 1). This could mean that treatment has erased age as an adverse prognostic factor, possibly suggesting a favorable impact of GM-CSF on pts ≥60 y/o. A randomized trial in this particular age group is justified to test this hypothesis. Disclosures: Cabanillas: Bayer Pharmaceuticals: Research Funding; Genentech: Research Funding. Off Label Use: Leukine,neutrophil recovery for NHL, and possible augmentation of rituximab effect. Rivera:Genentech: Stocks.

Update on a Prospective Study Evaluating the Safety and Efficacy of Combination Therapy with Fludarabine, Mitoxantrone and Rituximab Followed by Yttrium-90 Ibritumomab Tiuxetan and Maintenance Rituximab as Front Line Therapy for Patients with Indolent Lymphomas

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3946-3946
Author(s):  
Reem Karmali ◽  
Mohamad Kassar ◽  
Antonio M. Jimenez ◽  
Parameswaran Venugopal ◽  
Jamile M. Shammo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Effects ◽  
Alternative Treatment ◽  
Research Funding ◽  
First Line ◽  
Ibritumomab Tiuxetan ◽  
Off Label ◽  
Rituximab Maintenance ◽  
Grade 3 ◽  
Indolent Lymphomas

Abstract Abstract 3946 Background: The First Line Indolent Trial (FIT) recently reported the superiority of consolidation therapy with 90Y-ibritumomab tiuxetan (Zevalin) versus observation in patients with advanced stage follicular lymphoma (FL) after induction with chemotherapy. The benefit of rituximab maintenance has also been shown in indolent lymphomas. We report the updated results of a single institution phase II clinical trial using a combination of the above in indolent lymphomas, namely chemo-immunotherapy followed by radioimmunotherapy and rituximab maintenance. Patients and Method: Patients with previously untreated indolent lymphomas including FL and marginal zone lymphomas (MZL), age ≥ 18, PS 0–2, measurable disease, with adequate bone marrow, liver and kidney function were eligible. Previous treatment with rituximab alone was allowed. Initial treatment consisted of 4–6 cycles of FM (fludarabine 25 mg/m2 on days 1–3, mitoxantrone 12 mg/m2 on day 1 of each 28-day cycle). The protocol was amended after enrolling the first four patients to include rituximab 375 mg/m2 on day 1 of each cycle. After 6 to 8 weeks, responding patients received Zevalin followed by maintenance rituximab (375 mg/m2 weekly × 4, repeated every 6 months for 2 years). Results: 22 patients were enrolled between July 2003 and May 2007. The median age was 55 years (range 32–79 years). 11 patients were men. One patient had stage II, 7 had stage III, and 14 had stage IV disease. 20 patients had FL and 2 had MZL. In the FL group, 18 (90%) patients were intermediate or high risk. All but one patient had 4 or more cycles of chemotherapy with an ORR of 100%, a CR of 45% (n=10), a PR of 50% (n=11) and stable disease in one patient. 19 patients underwent therapy with Zevalin. With Zevalin, 6 patients with PR post chemotherapy converted to CR, resulting in an improved CR of 79% (n=15) and a PR of 21% (n=4). Of the 19 patients that underwent Zevalin, 16 proceeded to rituximab maintenance. Of those excluded from rituximab maintenance, one patient refused maintenance, one had prolonged cytopenias after Zevalin and one transformed to DLBCL just prior to rituximab maintenance, requiring alternative treatment. The decision was made to give rituximab maintenance on a different schedule at 375 mg/m2, 1 dose every 3 months, to 2 patients for mild cytopenias. With rituximab maintenance, 2 patients in PR converted to CR. All patients who received chemotherapy and Zevalin were included in the survival analysis (n=19). At a median follow up of 47.7 months, median PFS was 47.2 months and median OS was not reached. 7 patients relapsed and 1 patient transformed to DLBCL, with 6 patients requiring alternative treatment. 3 of these relapses occurred while on rituximab maintenance and one occurred 2 months after receiving Zevalin prior to the initiation of immunotherapy maintenance. Of all relapses/transformations, 2 patients are deceased. In the remainder of patients, 4 (24%) are in stable relapse and 13 (76%) in CR. The most common adverse effects of this regimen were hematological. With chemotherapy, 7 patients had grade 3/4 neutropenia and 4 patients had grade 3/4 thrombocytopenia. Post Zevalin, 11 patients experienced one or more grade 3/4 cytopenias: 8 patients had neutropenia, 8 had thrombocytopenia, and 4 had anemia with time to recovery of counts ranging between 2–4 weeks. 8 of these patients had bone marrow involvement at the start of treatment. One patient developed treatment related MDS that evolved to AML 4 years after the start of therapy. This patient died. Other grade 3/4 adverse effects included: grade 3 hypoxia and pneumonia post chemotherapy in a patient with grade 1 neutropenia and grade 2 cellulitis after Zevalin in a patient with grade 3/4 neutropenia. Conclusion: Chemoimmunotherapy followed by consolidation with radioimmunotherapy and rituximab maintenance is well tolerated and able to improve complete remission rates and maintain durable responses in patients with untreated indolent lymphomas. The use of this approach in indolent NHL patients may become a new standard of care. Disclosures: Off Label Use: Both radioimmunotherapy consolidation with zevalin and rituximab (immunotherapy) maintenance have been used in indolent lymphomas first line post chemo-immunotherapy. However, in this study, we looked at the combination of chemo-immunotherapy followed by zevalin consolidation and rituximab maintenance. This combination is off-label. Kassar:Alexion: Honoraria. Gregory:Amgen: Consultancy; Astellas: Research Funding; Celgene: Research Funding; Cephalon: Research Funding, Speakers Bureau; Genentech (Roche): Consultancy, Research Funding, Speakers Bureau; Glaxo-Smith-Kline: Research Funding; Immunomedics: Research Funding; NCIC CTG: Research Funding; Novartis: Consultancy, Research Funding; Onyx (Proteolix): Research Funding; Spectrum Pharmaceuticals: Consultancy.

Dose-Dense Chemoimmunotherapy and Early Central Nervous System Prophylaxis For High-Risk Diffuse Large B-Cell Lymphoma. –Preliminary Results From a Nordic Phase II Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 849-849 ◽  
Author(s):  
Sirpa Leppa ◽  
Anne Maria Tierens ◽  
Judit Jorgensen ◽  
Mats Jerkeman ◽  
Magnus Bjorkholm ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Progression Rate ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Dose Dense ◽  
Large B Cell

Abstract Background Despite the advent of rituximab (R)-based chemoimmunotherapy, outcome for patients with high-risk diffuse large B-cell lymphoma (DLBCL) continues to be suboptimal, and the risk of central nervous system (CNS) progression is high. In a previous Nordic phase II study with dose-dense chemoimmunotherapy followed by systemic CNS prophylaxis, the CNS progression rate was lower than expected (4.5%), but all events occurred within 6 months after initiation of therapy (Holte et al., Ann Oncol 2013). Hence, in the present study, systemic CNS prophylaxis was moved to the beginning of therapy and CNS targeted therapy was further intensified by adding intrathecally administered liposomal AraC. Methods Inclusion criteria are age 18-65 years, primary DLBCL or grade 3B follicular lymphoma without clinical or radiological signs of CNS disease and cytology negative cerebrospinal fluid (CSF), age adjusted IPI 2-3, WHO performance score ≤3, and/or site specific risk factors for CNS recurrence. Treatment consists of two courses of high dose (HD)-Mtx in combination with R-CHOP14, four courses of R-CHOEP14 and a course of HD-AraC with R. In addition, liposomal AraC is administered intrathecally in courses 1, 3 and 5. All courses are administered with support of pegfilgastrim. Indications for radiotherapy are bulky masses at diagnosis and localized PET positive residual disease not eligible for biopsy. Primary endpoints are failure-free survival at 3 years, and CNS progression rate at 18 months. A secondary aim is to elucidate if CSF cytology negative/flow cytometry (FC) positive cases carry an increased risk of CNS progression with the present regimen. Results Of the accrued 84 patients by July 22, 2013, 70 had a complete set of baseline data. Median age was 55 years (range 20-64). The majority presented with DLBCL (96%), advanced-stage disease (94%), elevated LDH (94%), B-symptoms (67%), and 49% with >1 extranodal site. Seven CSF-samples were FC positive. Data on toxicity, response and relapse rates were registered for 45 patients. One toxic death due to pneumonia was reported. Grade 4 hematological toxicity and infections were observed in 78% and 11% of the patients, grade 3-4 mucositis and gastrointestinal toxicity in 27% and 42%, and grade 3 arachnoiditis in 2.2% of the patients. CR, CRu, PR and PD rates at the end of chemoimmunotherapy were 69.0%, 14.3%, 14.3% and 2.4 %, respectively. After a median follow up time of 19 months, four patients have relapsed, two of whom with fatal CNS manifestations. Conclusions Preliminary results indicate highly satisfactory response rates and reasonable toxicity despite intensive therapy. HD-Mtx in combination with R-CHOP in the beginning of therapy and further intensification of treatment with CNS targeted liposomal AraC seem feasible and safe. ClinicalTrials.gov Identifier: NCT01325194 Disclosures: Leppa: Amgen: Research Funding; Mundipharma: Honoraria, Research Funding. Holte:Mundipharma: Honoraria, Research Funding; Amgen: Research Funding.

Preliminary Phase II Study Results of BBR2778 in Combination with Cyclophosphamide, Vincristine, and Prednisone in Patients with Relapsed Aggressive Non-Hodgkin’s Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2489-2489 ◽  
Author(s):  
Raoul Herbrecht ◽  
Peter Borchmann ◽  
Martin Wilhelm ◽  
Franck Morschhauser ◽  
Georg Hess ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Cumulative Dose ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Grade 3

Abstract Background: Pixantrone (BBR 2778) is a novel aza-anthracenedione with superior activity compared to doxorubicin and mitoxantrone in various tumor models including hematological malignancies. Pixantrone single agent therapy led to major responses in patients (pts) with aggressive lymphoma including diffuse large B-cell lymphoma (DLCL). The safety of a CHOP-like regimen with pixantrone replacing doxorubicin (CPOP) was assessed in a dose-ranging study indicating a recommended dose of 150 mg/m² for pixantrone. Method: In this phase II study the primary objective was to assess the efficacy of the CPOP regimen (cyclophosphamide 750 mg/m² d1, pixantrone 150mg/m² d1, vincristine 1.4mg/m² d1, limited to 2mg, and prednisone 100mg d1 to 5) in pts with relapsed DLCL, transformed follicular lymphoma (tFL) and mantle cell lymphoma (MCL) for a total of 6 cycles given every 3 weeks. Hematopoietic growth factors were not permitted for the first cycle and used thereafter according to the ASCO guidelines. Inclusion/exclusion criteria included at least one but not more than two previous chemotherapy lines containing an anthracycline/anthracenedione with a cumulative dose of less than 450mg/m² doxorubicin equivalent, a left ventricular ejection fraction (LVEF) &gt;50%, no meningeal involvement, and HIV negative serology. Results: 21 pts have currently been included. Data is available for the first 15 pts. Main baseline characteristics are: median age 65 y [35 – 76]; DLCL 10 cases, tFL 2 cases, MCL 3 cases; stage I/II 4 cases, stage III/IV 11 cases; median number of previous therapy lines 2 [1–5], median prior cumulative dose of anthracyclines 320 mg/m² [104 – 452 mg/m²]. 48 cycles of CPOP have been administered to date, with a median number of 4 per pt. Most common grade 3 or 4 adverse events were neutropenia [39 episodes in 10 (67%) pts], leucopenia [37 episodes in 10 (67%) pts], thrombocytopenia [3 episodes in 3 (20%) pts] and febrile neutropenia [8 episodes in 4 (27%) pts]. There was no treatment related death and no grade 3 or 4 organ toxicity. Treatment was delayed in 6 pts and the doses of pixantrone and cyclophosphamide were reduced in 5 pts for a grade 4 hematological toxicity or infection. Only one patient had a decrease of ≥10% of LVEF from 72% at screening to 56% after 6 cycles without clinical symptoms. Out of 12 pts currently evaluable for response, 6 (50%) responded to CPOP therapy: 5 CR and 1 PR (responses maintained for ≥8 weeks). Conclusion : These early results of the CPOP regimen with 150 mg/m² of pixantrone indicates a high response rate in pts with relapsed aggressive B cell lymphoma with an acceptable and manageable safety profile.

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