Final Results of a Phase II Study of Sequential R-CHOP and Yttrium-90 Ibritumomab Tiuxetan (RIT) for Elderly High Risk Patients with Untreated Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1793-1793 ◽  
Author(s):  
Paul A. Hamlin ◽  
Maria Alma Rodriguez ◽  
Ariela Noy ◽  
Carol S. Portlock ◽  
David Straus ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
B Cell Lymphoma ◽  
Phase Iii ◽  
Ibritumomab Tiuxetan ◽  
Grade 5 ◽  
Yttrium 90

Abstract Abstract 1793 Introduction: Elderly patients (pts) with high risk DLBCL are one of the fastest growing demographics of pts, but advances over RCHOP21 have not been realized. These pts are often under-represented in clinical trial secondary to comorbidity, ageism, and eligibility requirements. By the age adjusted international prognostic index (aaIPI), pts >60 years (yrs) with high-intermediate (HI) and high (H) risk disease had 5 yr survival (OS) rates of 37% and 21%. Even in the RCHOP era, high risk elderly patients have event-free-survival of roughly 50%. We report the mature data from a phase II study investigating sequential RCHOP followed by yttrium-90 ibritumomab tiuxetan radioimmunotherapy (RIT) in an effort to improve these results. Methods: Untreated ASCT-ineligible pts >60 yrs, with aaIPI HI and H risk DLBCL were eligible for study. Pts received RCHOP21 × 6 cycles at standard doses with prophylactic GCSF and darbepoetin alfa. Pts with responding (CR/PR) or stable disease post RCHOP received RIT, given 6–9 weeks post chemotherapy at 0.4 mCi/kg for platelets (plt) ≥150K and 0.3 mCi/kg for plt 100–149K. Weekly CBCs were performed for 12–13 weeks or until count resolution. Rituximab levels were assessed pre-RIT in a subset of pts. Primary end-points were PFS and OS, with intent-to-treat (ITT) analysis performed for all patients. Statistics anticipated 2/3 of pts (n=43) receiving RIT, with power to demonstrate a 20% improvement in PFS/OS at 2 yrs. Results: 65 pts were consented, with 2 pts having progression prior to a single cycle on protocol, leaving 63 evaluable pts. The median age was 75 (62-86), median KPS 70% (50-100%), Stage III/IV 23/74%, LDH>ULN 91%, ENS>1=45%, BM positive=11%; aaIPI HI/H 45%/55%. Moderate or greater comorbidity was present in 86% of pts (n=65) by NIA/NCI scale. 86% of pts completed RCHOP, with overall response rate (ORR) of 83% (CR/Cru 75%, PR 8%) (Cheson 1999). Fifty pts by ITT were eligible for RIT following RCHOP chemotherapy, with 44 pts ultimately treated. Reasons for discrepancy included low bone marrow cellularity (2pt), AFIB/CHF post day 0 (1 pt), abnormal baseline FISH/cytogenetics (2 pts), withdrawal of consent (1pt). Rituximab levels in 30 pts are available pre-RIT: mean 112 mcg/ml (range 41–196) and did not correlate with outcome. The RIT dose was 0.4 mCi/kg in 38 patients and 0.3 mCi/kg in 6 patients. No patient had altered biodistribution on imaging. RIT was generally well tolerated with expected hematologic nadirs at weeks 6–7. Grade 3/4 non-heme toxicity during RIT included neutropenic fever (2), transient EF decline >20% (1), hip fracture (1), anthracycline induced cardiomyopathy (grade 5), suspected CNS bleed (grade 5). Response post RIT (n=44) was CR/CRu 86%, PR 2%. Response improvement (PR->CR or CRu->CR) occurred in 7 pts (16%). Median followup for surviving pts is 42 months, with median OS and PFS not reached (0.5-74.4). KM estimates of OS and PFS at 42 months by ITT: 64% and 62% respectively. OS and PFS at 42 months for RIT treated pts (n=44): 83.5% and 74.5%. There have been only two relapse >12 months after RIT. The aaIPI (HI vs H) predicted outcomes: OS 75% vs. 49% (p=.008), PFS 68% vs. 45% (p=.01). Conclusion: Sequential RCHOP21 × 6 cycles followed by RIT in an elderly, high comorbidity, high risk DLBCL cohort is associated with very encouraging outcomes by ITT and specifically in the RIT treated pts with long term follow-up. Therapy was well tolerated in this age group and given lack of late relapses, one may hypothesize RIT is addressing minimal residual disease typically associated with recurrence. Outcome is very favorable when compared to historical controls. A prospective Phase III study is needed to confirm these results. Disclosures: Hamlin: Genentech: Honoraria, Speakers Bureau; Biogen Idec: Honoraria, Speakers Bureau; Spectrum: Consultancy, Research Funding; CTI: Consultancy, Research Funding. Off Label Use: Y-90 ibritumumab tiuxetan is not approved for use in DLBCL; it is FDA approved for NHL/indolent lymphoma. Rodriguez:CTI: Research Funding. Noy:Spectrum: Consultancy. McLaughlin:Spectrum: Consultancy. Pandit Tasker:CTI: Research Funding; Spectrum: Research Funding. Zelenetz:GSK: Consultancy; CTI: advisory board.

Final Results of a Phase II Danish Trial Testing Low Dose Total Body Irradiation Following Six Bi-Weekly RCHOP-14 Plus 2 Extra Rituximab in Elderly High risk Patients with Aggressive CD20+ Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1013-1013
Author(s):  
Akmal Safwat ◽  
Lena Specht ◽  
Flemming Hansen ◽  
Mads Hansen ◽  
Jesper Jurlander ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Phase Ii ◽  
Total Body Irradiation ◽  
Low Dose ◽  
B Cell Lymphoma ◽  
Observation Time ◽  
Phase Iii ◽  
Total Body

Abstract Background: To further improve the results achieved by adding Rituximab (R) and shortening chemotherapy interval in elderly patients, an effective but relatively non-toxic treatment modality is needed. We tested therefore the addition of low dose total body irradiation (LTBI) of 1,6 Gy given after chemo-immunotherapy. Methods: A multicenter, phase II trial including patients >60 yrs with stage II-IV, CD20-positive DLBCL was performed between 2003 and 2007. Patients received 6x R-CHOP-14 + 2x R alone followed by LTBI given as 2 courses of 4 daily fractions of 0,2 Gy separated by 2 weeks of rest. Radiotherapy to sites of bulky (>7.5 cm) disease was given according to the local guidelines of the participating centres. Results: Forty two patients were included. Observation time ranged from 3 to 47 months with median follow up of 24 months. The median age was 67 years; 62% had stage III or IV; 48% had B symptoms and 36% had bulky (> 7.5 cm) disease; 50% had ECOG score ≥ 1; 76% had elevated LDH and 57% had IPI of >2. Twenty four patients (57%) achieved a CR or CRu at the end of chemotherapy, while 12 (28.5%) were in PR. One of the 12 PR patients refused LTBI. Of the remaining 11 PR patients who received LTBI, 8 (82%) achieved CR in the first follow up after LTBI while the remaining 3 patients had initially stable disease but progressed shortly after. One patient (2%) progressed under chemotherapy while seven patients (17%) relapsed after achieving CR. Six of these refractory/relapsed cases presented with IPI ≥ 3. The 3-yr event-free and progression-free survival values were 64.8% (SE: 8.7%) and 73.5% (SE: 8.9%), respectively, while the 3-yr overall survival was 85.4% (SE: 5.5%). There were 3 toxic deaths (7.1%) due to sepsis occurring during chemotherapy. Ninteen of 235 cycles of CHOP (8%) were given at reduced dose levels in 3 patients (7%), while 3 cycles (1.3%) were delayed but given at 100% dose level. None of the 305 injections of Rituximab were dose reduced. Only one of 31 patients (3%) got his second LTBI cycle at 75% of the planned dose because of thrombocytopenia. CTC Gr 3–4 neutropenia occurred following 50 of 250 R-CHOP-14 cycles (20%). CTC Gr. 3–4 thrombocytopenia was seen in 8 pts (22%) following LTBI. Conclusions: Despite the high risk profile of the patient cohort enrolled in this trial, the 3-yr outcome values match the results of the best performing recent phase III clinical trials designed for elderly patients with DLBCL. Adding LTBI to 6 cycles of R-CHOP-14 was well tolerated and effective in converting the majority of PRs into CRs. Therefore, it may provide survival benefit and should be tested in a randomised setting.

Analysis of the GeneXpert System on the International Multicentre ICORG 08–02 Phase II Study of Nilotinib 300mg BID as Frontline Treatment in Patients with Early Chronic Phase Chronic Myeloid Leukemia (ECPCML),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3774-3774 ◽  
Author(s):  
Michael E O'Dwyer ◽  
Ronan Swords ◽  
Francis Giles ◽  
Mary Frances McMullin ◽  
Philipp D. le Coutre ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Low Risk ◽  
Phase Iii ◽  
Additional Patient ◽  
Molecular Response ◽  
Grade Iii

Abstract Abstract 3774 BACKGROUND/METHODS: Data from the ENESTnd phase III trial showed superiority of nilotinib over imatinib leading to accelerated approval of nilotinib as initial treatment of ECPCML at a dose of 300mg BID. ICORG, the All-Ireland Cooperative Oncology Research Group, has been coordinating an international open-label, single stage, multicenter, investigator-initiated phase II study (ClinicalTrials.gov NCT00809211) of the safety and efficacy of nilotinib 300 mg BID in previously untreated patients with ECPCML. The primary study endpoint is the complete cytogenetic response (CCyR) rate at 6 months; secondary endpoints include the kinetics of molecular response, determined by RQ-PCR at baseline and 3 monthly from start of treatment as well as an evaluation of a novel rapid turnaround PCR system “GeneXpert” with IS BCR-ABL1/ABL1 RQ-PCR. The study closed to accrual with 61 patients (median age 54 years [range 20 –77]) enrolled; 53% have low risk Sokal score, 25% intermediate and 22% high risk. Median follow up is currently 12 months (range 1–30) and by November 2011 all patients will have had at least 6 months follow up. RESULTS: At the time of this analysis, 6 and 12 month follow up data were available in 43 and 31 patients, respectively. By intention to treat analysis, 41/43 (95%) have achieved CCyR within 6 months with all patients still on treatment at 12 months achieving CCyR. 26/43 (60%) and 25/31 (81%) of patients have achieved a major molecular response (MMR) (BCR-ABL1/ABL1 IS ≤ 0.1%) within 6 and 12 months, respectively, with 16/31 (52%) and 11/31 (35%) patients on treatment at least 12 months achieving BCR-ABL1/ABL1 IS ≤ 0.01% and ≤ 0.0032%, respectively. Sokal risk had no apparent effect on response with 12/16 (75%) low risk and 13/15 (87%) intermediate/high risk patients achieving MMR within 12 months, p=0.65. Thus far 4/6 (67%) high risk Sokal patients achieved BCR-ABL1/ABL1 IS ≤ 0.0032% within 12 months. No patients have suffered CML progression to date. 53 patients remain on study. Six patients have been removed from study due to adverse events: 4 patients due to persistent drug-related toxicity; 2 patients non drug-related events (death due to progressive multiple system atrophy and colorectal carcinoma, respectively). In addition, one patient was enrolled but never received study drug and an additional patient was lost to follow up. Treatment was generally well tolerated and toxicities easily managed. Haematologic toxicity was minimal with grade III/IV thrombocytopenia seen in 3 (5%) patients and only a single patient (2%) each with grade III/IV neutropenia and anemia, respectively. The most common grade III/IV non-haematologic toxicity was lipase elevation, seen in 14/61 (23%). No cases of acute pancreatitis were seen. Other grade III/IV non-hematologic toxicities were uncommon (< 5% patients). While treatment was interrupted at least once in 36/59 (61%) patients, the median duration of interruptions was short (5 days). At last follow up 49/59 (83%) of patients were taking ≥ 300mg BID. The study evaluation of the “GeneXpert” PCR system consisted of paired BCR-ABL1/ABL1 measurements performed by RQ-PCR methodologies aligned to International Standard (IS) and by the Xpert BCR-ABL Monitor system on 36 evaluable patients at diagnosis and at 128 subsequent three-monthly time-points. In patients expressing e13a2 or e14a2 BCR-ABL1 transcripts, both techniques had comparable results at diagnosis: IS median BCR-ABL1/ABL1 41.0% vs 44.0% median BCR-ABL1/ABL1 on the Xpert BCR-ABL Monitor. In the 122 paired analyses, correlation between methodologies, without automated system IS conversion, over a five log range (IS BCR-ABL1/ABL1 100–0.001%) was favourable (r2=0.845), however a progressive decline in correlation was noted with each decreasing log IS BCR-ABL1/ABL1 level. No significant difference was observed between the Xpert BCR-ABL Monitor and IS RQ-PCR in identifying MMR (44.3% vs 41.8%). CONCLUSION: In ECPCML, nilotinib 300mg BID induces high rates of CCyR and MMR with a substantial fraction of patients achieving responses in the range of complete molecular response (CMR). This regimen's toxicity is modest. The GeneXpert system provides a reliable and rapid means of assessing CML patients' response to tyrosine kinase inhibitor (TKI) therapy. Development of a reagent lot-specific conversion factor to the IS would enhance GeneXpert's applicability in monitoring TKI therapy in patients with CML. Disclosures: O'Dwyer: Novartis: Honoraria, Research Funding. Giles:Novartis: Consultancy, Honoraria, Research Funding. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau. Nagler:Novartis: Honoraria, Research Funding. Egan:Novartis: Employment. Conneally:Novartis: Honoraria.

Early Safety and Efficacy Analysis of a Phase II Study of Sequential R-CHOP and Yttrium-90 Ibritumomab Tiuxetan (Zevalin®) for Elderly High Risk Patients with Untreated DLBCL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 926-926 ◽  
Author(s):  
Paul A. Hamlin ◽  
Craig H. Moskowitz ◽  
Brett C. Wegner ◽  
Carol S. Portlock ◽  
David J. Straus ◽  
...  
Keyword(s):  
High Risk ◽  
Sudden Death ◽  
Elderly Patients ◽  
Hematologic Toxicity ◽  
Ibritumomab Tiuxetan ◽  
Safety And Efficacy ◽  
Grade 5 ◽  
Grade 3 ◽  
Yttrium 90

Abstract Introduction: Elderly patients (pts) with high risk DLBCL represent an increasing demographic, are often underserved in clinical trials, and need improved therapies. By the age-adjusted international prognostic index (aaIPI), pts &gt;60 years (yrs) with high-intermediate (HI) and high risk (H) disease had 5 yr survival (OS) rates of 37%, and 21%, respectively. Rituximab’s addition to CHOP has improved responses and outcomes, but &gt;50% of high risk pts still relapse. We are investigating the safety and efficacy of sequential RCHOP followed by Yttrium-90 ibritumomab tiuxetan (Zevalin ®) radioimmunotherapy (RIT) in an effort to improve these results. An early safety analysis of this sequential program is presented here. Methods: Untreated ASCT-ineligible pts &gt;60 yrs, with aaIPI HI or H risk DLBCL are eligible for study. Induction: pts receive R-CHOP chemotherapy at standard doses q 21 days x 6 cycles with prophylactic pegfilgrastim (or G-CSF) and darbepoetin alfa (Aranesp ®) support. Consolidation: pts with ≥ stable disease at post RCHOP restaging are eligible for 90Y-90 ibritumomab tiuxetan, given 6–9 weeks post RCHOP; For platelet (plt) counts ≥ 150K → 0.4 mCi/kg dose, plt counts of 100–149K → 0.3 mCi/kg. Weekly CBC’s are performed until week 12–13 restaging. Results: 26 pts have been enrolled as of July 12th, 2005. Median age is 75 (range 65–85; male:female 9:17); KPS &lt;80% in 55% (median 70%, range 60–90%); LDH &gt; nl: 89% (range 150–804); Stage III/IV: 11.5% / 88.5 %; Extranodal sites are &gt;1 in 50%; B symptoms in 54%; aaIPI HI (2 factors) = 46%, H (3 factors) = 54%; 18/26 pts have completed RCHOP; 8 pts are off study before RIT for: 4 cardiovascular events (1 CHF,1 Non-Q-wave MI, 1 sudden death, 1 V. Fib arrest), 3 neutropenic sepsis (1=grade 4, 2=grade 5), 1 leptomeningeal progression; 14 pts have received RIT. Median nadir counts during RIT occur at week 6–7: absolute neutrophil count (ANC) = 850 cells/mm3 (0.3–5.4), Hemoglobin (Hgb)= 10.1 gm/dl (6.6–14.6), plt = 28K cells/mm3 (7–103); Grade 3 and 4 ANC = 39%/39%, Hgb 39%/0%, Plt 46%/15%; During RIT, blood and Plt transfusion occurred for 46% and 31%, respectively; colony stimulating factor and erythropoietic support was used in 39% and 31%, respectively. One pt had delayed count recovery post RIT (448 days, transfusion independent from week 12→). Non-hematologic serious adverse events after RIT include: two grade 3 neutropenic infection (1 without fever), 1 grade 5 sudden death at week 7 (autopsy refused). OS and EFS for all pts by intent to treat is 60% and 55%, respectively, with 14 months median followup. Of pts post-RIT &gt;12 weeks (11 pts), none have relapsed with 21 months median follow-up. Conclusions: Treatment of elderly aaIPI HI and H risk DLBCL pts with sequential RCHOP followed by 90Y ibritumomab tiuxetan is feasible and associated with manageable toxicity. Hematologic toxicity with RIT is similar to single agent toxicity, with slightly greater thrombocytopenia that warrants careful follow-up. Toxicity during RCHOP induction is significant in high risk elderly patients and cycle one modification is being implemented. Accrual continues to evaluate the potential long term impact of RIT on EFS and OS.

scholarly journals Engine: Phase III Randomized Study of Enzastaurin/R-CHOP Versus Placebo/R-CHOP in Frontline High Risk Diffuse Large B Cell Lymphoma Patients with Novel Genomic Biomarker DGM1

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5330-5330 ◽  
Author(s):  
Jun Zhu ◽  
Grzegorz Nowakowski ◽  
Qingyuan Zhang ◽  
Joshua Brody ◽  
Xiuhua Sun ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Randomized Study ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Response Assessment ◽  
Phase Iii ◽  
Advisory Committees

Background: Progress in genome technology allows analysis of previously completed trials to identify subgroups potentially benefiting from therapy. Enzastaurin is a potent inhibitor of protein kinase C beta (PKC-β) and suppresses the phosphoinositide 3-kinase (PI3K)/AKT pathway. The safety and efficacy of Enzastaurin has been tested in more than 60 clinical trials including 2 major studies in DLBCL: (1) PRELUDE (A phase III maintenance trial of Enzastaurin vs Placebo, N=758) (Crump, 2016), and (2) S028 (A randomized phase II study of Enzastaurin/R-CHOP vs R-CHOP in frontline intermediate/high-risk DLBCL, N=101) (Hainsworth, 2016). DNA samples extracted from blood of patients from PRELUDE were retrospectively genotyped using whole genome SNP arrays. From the genome wide screening a novel genetic biomarker, DGM1, was identified showing high correlation with response to Enzastaurin treatment (Luo, ASH 2018). Importantly, these findings were replicated in the phase II S028 study. In the S028 study the hazard ratio (HR) for OS in high-risk (IPI ≥ 3) DGM1 positive (+) patients who received Enzastaurin/R-CHOP was 0.28 (0.1-0.81) when compared to subjects who received R-CHOP, a benefit favoring Enzastaurin (p=0.018). These data suggest that addition of Enzastaurin to R-CHOP may significantly improve outcome in frontline high-risk DGM1 (+) DLBCL. The ENGINE study was initiated to validate this finding in a prospective study. Study Design and Methods: Adult patients must have untreated CD20+ DLBCL, IPI ≥ 3. Patients are randomized 1:1 to Enzastaurin/R-CHOP or Placebo/R-CHOP for 6 cycles during combination phase. Each subject's treatment assignment will be unblinded after response assessment at the end of the combination phase. Subjects randomized to the investigational arm who have a complete or partial response will have the option to continue in the single agent phase to receive Enzastaurin for up to 2 additional years. The study intends to enroll approximately 235 patients with primary endpoint of OS in DGM1 (+) patients. The study is ongoing with 57 sites open in the US and China. As of 20 July 2019, 128 patients have been randomized. Clinical trial information: NCT03263026. Disclosures Nowakowski: Genentech, Inc.: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Brody:Acerta Pharma: Research Funding; Merck: Research Funding; Celldex Therapeutics: Research Funding; Genentech: Research Funding; Oncovir, Inc.: Research Funding; BMS: Research Funding; Kite Pharma: Research Funding. Lue:Kymera Therapeutics: Honoraria; Astex Pharmaceuticals: Honoraria. Luo:Denovo Biopharma LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Zhang:Denovo Biopharma LLC: Employment. Han:Denovo Biopharma LLC: Employment. Jivani:TRACON Pharmaceuticals, Inc.: Other: Stock; Denovo Biopharma LLC: Employment. Liu:Denovo Biopharma LLC: Employment. Li:Denovo Biopharma LLC: Employment. Sun:Novartis: Other: Stock; Denovo Biopharma LLC: Employment.

VNCOP-B (Etoposide, Mitoxantrone, Cyclophosphamide, Vincristine, Prednisolone, Bleomycin) Plus Rituximab Therapy in Elderly Patients with Aggressive B-Cell Non-Hodgkin Lymphoma: A Phase II Study of Efficacy and Safety

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3586-3586
Author(s):  
Kazuyoshi Ishii ◽  
Masahiro Manabe ◽  
Toshiya Yagi ◽  
Hirofumi Teshima ◽  
Yasuaki Nagare ◽  
...  
Keyword(s):  
Elderly Patients ◽  
B Cell ◽  
Phase Ii ◽  
Induction Therapy ◽  
Phase Ii Study ◽  
B Cell Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Grade 3

Abstract [Background and Objectives] CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) plus rituximab is a standard chemotherapy used to treat patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, among elderly patients, this regimen has not been completely satisfactory in its efficacy and safety because of agespecific comorbidity, increased toxicities of chemo-agents, and the more aggressive aspect of the lymphoma itself. Zinzani reported that a combination therapy including etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisolone, and bleomycin (VNCOP-B) was effective in elderly aggressive NHL patients (Blood1999;94:33–38). We conducted a phase II multicenter study in 8 collaborative institutions to determine if VNCOP-B plus rituximab was effective and safe to treat elderly patients with aggressive B-NHL. The primary endpoint was to detect overall survival (OS). The second endpoint was to detect the response rate (RR) and progression-free survival (PFS). [Patients and Treatment] Eligible patients were those aged over 60 years, with aggressive B-NHL documented as CD20 surface antigen positive, performance status (PS) 0 to 2, clinical stage over II or I with a bulky disease, measurable lesions, no prior chemotherapy nor radiation, no severe complications, no major organ dysfunction, no other active cancer, not a HBV carrier, no central nervous system involvement with lymphoma, and who gave the required written informed consent. VNCOP-B plus rituximab was administered as an induction therapy. This protocol was completed in 8 weeks and consisted of weekly doses of chemotherapy combined with rituximab every two weeks. During the 8 weeks of therapy, granulocyte colony-stimulating factor (G-CSF) was administered on a prophylactic base. Rituximab was administered weekly four times a month as a sequential therapy, following one month after the end of the induction therapy. [Results] Between September 2004 and December 2007, 23 patients, median age 73 years, 50.0% classified as high-intermediate/high risk on the age-adjusted International Prognostic Index (IPI), entered this trial and 21 were evaluated for feasibility, toxicity, and efficacy. Twenty-two patients (95.2%) were diagnosed with diffuse large B-cell lymphoma and one (4.8%) with mediastinal large B-cell lymphoma. The nineteen patients (90.5%) completed the induction therapy and all these then received a sequential rituximab therapy. Complete remission rate was 90.5%, with a 100% overall RR at the end of induction therapy; OS rate at 3 years was 76.4% (median follow-up 744days); with an 82.6% 3-year PFS rate (median follow-up 744days). Average Relative dose intensity (RDI) in MIT was 0.61, no significant difference in survival was found regarding RDI. Although IgG level decreased during the induction therapy, it recovered to the prior level after sequential rituximab (IgG means±standard error: pre-treatment 1355.2±146.4mg/dl, post-induction therapy 785.3±107.0mg/dl, post-sequential rituximab 1010.4±60.2mg/dl). According to the IPI, there was a trend suggesting a lower probability of OS and PFS in high/high-intermediate risk than in low/low-intermediate risk cases (3-year OS: 67.5% versus 100.0%, P=0.51; 3-year PFS: 66.7% versus 100.0%, P NA). The most common grade 3/4 toxicities were hematologic, including neutropenia in 75.0% of the 21 patients despite prophylactic administration of G-CSF, febrile neutropenia in 30.0%, and thrombocytopenia in 10.0%, respectively. Regarding non-hematologic grade 3/4 toxicities, hepatitis occurred in one patient (5.0%) from HCV reactivation, intestinal perforation involving the lymphoma in one patient (5.0%). There was no treatment-related mortality. We had conducted a phase II study of VNCOP-B therapy in 16 elderly patients with aggressive B-NHL (Gan To Kagaku Ryoho2005;32:39–44, in Japanese). Against this historical comparison, the present protocol seemed better in PFS than that without rituximab (3-year PFS: 82.6% versus 56.0%, P=0.11), although OS was almost the same (3-year OS: 76.4% versus 73.4%, P=0.22). [Conclusion] Although our enrolled patients were quite elderly with a median age of 73 years, and half of them had a poor prognosis index, VNCOP-B combined with rituximab was well tolerated and showed promise.

Sign in / Sign up

Export Citation Format

Share Document