Safety analysis of a phase II study of cyclophosphamide, vincristine, non-pegilated liposomal doxorubicin (Myocet), and prednisone + rituximab in biweekly regimen (R-COMP-14) as primary treatment of non-Hodgkin lymphoma

17532 Background: Gold standard treatment of CD20+ aggressive B-cell non-Hodgkin lymphoma, R-CHOP, has been suggested to improve outcome when administered as dose-dense regimen supported with G-CSF. The non-pegylated liposomal doxorubicin (Myocet) has an improved safety profile compared to standard formulations of doxorubicin. Standard R-CHOP regimen has been modified replacing doxorubicin with Myocet, administered on a biweekly basis (R-COMP-14) looking for an increase in efficacy without impairing tolerability Methods: Single arm, multicentric, 2-step (Simon design) phase II trial. Newly diagnosed, diffuse large B-cell lymphoma, stages III, IV or I, II with IPI ≥ 1, CD20+, eligible patients (Pt) were treated with Myocet 50 mg/m2, cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 (max. 2 mg), rituximab 375 mg/m2 and prednisone 100 mg/d d1–5 in biweekly cycles. Pegilated filgastrim (Neulasta™) was administered on day 2 of the cycle. Response was assessed after 3 cycles, and patients with PR or CR received 5 additional cycles. A safety analysis was planned by protocol with data of first patients included Results: The median age of the 13 Pt included was 59 (range 28–64). At baseline 53.9% Pt had III-IV stage and 41.7% had extraganglionar involvement. Median basal LVEF was 66% (range 44–79). A median of 7 cycles of R-COMP were administered. The median relative dose intensity per week for Myocet was 94.9%. 6.2% of the cycles were delayed and 8.6% of the cycles were dose reduced. There were 2 episodes of febrile neutropenia. G3 asthenia, G3 neurotoxicity and G3 related infection were found in one cycle each. One patient had G3 hepatic toxicity resolved with dose reduction. At the end of treatment the median LVEF was 65.52% (range 52–76), there was no cardiac event related to the treatment. 84.6% of Pt had complete or partial response (7 RC, 2 uRC, 2 PR, 1 SD, 1 PD) at the end of the study Conclusions: In this small safety group of Pt that received the dose-dense regimen, the preliminary results suggest that R-COMP-14 supported with Neulasta is a well tolerated and effective regimen. Recruitment will proceed as planned (75 Pt). No significant financial relationships to disclose.

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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 ◽

10.1182/blood.v116.21.2797.2797 ◽

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.

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A Phase II Clinical Study of Rituximab and High-Dose Biweekly THP-COP (Pirarubicin, Cyclophosphamide, Vincristine and Predonisolone) with G-CSF for Non-Hodgkin Lymphoma: Results of a Multicentric Study of NMLSG (Niigata Malignant Lymphoma Study Group).

Blood ◽

10.1182/blood.v106.11.4734.4734 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4734-4734

Author(s):

Jun Takizawa ◽

Sadao Aoki ◽

Kazue Takai ◽

Tohri Kurasaki ◽

Keiichiro Honma ◽

...

Keyword(s):

Clinical Study ◽

T Cell ◽

B Cell ◽

Hodgkin Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Dose ◽

Histological Subtypes ◽

Non Hodgkin Lymphoma

Abstract Introduction CHOP chemotherapy has been accepted as the standard treatment for patients with non-Hodgkin lymphoma (NHL), but in some histological or clinical subtypes the results are not satisfactory. We have shown the efficacy and safety of high-dose biweekly THP-COP with G-CSF support (HDBW-TCOP(G)) for NHL. In this regimen, we choose pirarubicin in stead of doxorubicin because it was proven high efficacy against NHL and the lower toxicity than doxorubicin. Recently, the combination of rituximab and standard CHOP has been shown to have a synergistic effect for NHL. We performed a phase II multicentric clinical study to assessed the feasibility and toxicity of the combination chemotherapy of rituximab and HDBW-TCOP(G) (HDBW-R-TCOP(G)) compared with those of HDBW-TCOP(G). Patients and methods Between August 1998 and December 2004, Forty-one Japanese patients with previously untreated NHL from whom informed consent was obtained were included in this study. Median age was 45 (range 19–63) years. There were 19 males and 22 females. According to WHO-classification diagnoses, histological subtypes included follicular lymphoma (FL) 15(37%); nodal marginal zone B-cell lymphoma (NMZBCL) 2(5%); mantle cell lymphoma (MCL) 3(7%); anaplastic large cell lymphoma (ALCL) 1(2%), diffuse large B-cell lymphoma (DLBCL) 18(44%); peripheral T-cell lymphoma (PTCL) 1(2%), angioimmunoblastic T-cell lymphoma (AILT) 1(2%). Of 41 patients, one patient was stage 1, stage 2, 11 stage 3 and 16 stage 4. International prognostic index (IPI) included L 6; LI 22; HI 7; H 6. HDBW-TCOP(G) consisted of pirarubicin 70 mg/m2 on day 1; cyclophosphamide 1000 mg/m2 on day 1; vincristine 1.4 mg/m2 on day 1; predonisolone 50 mg/m2 orally from day 1 to 5; lenograstim 2.0 μg/kg/day from day 3. Fifteen patients who enrolled after rituximab was approved in Japan received therapy combined HDBW-TCOP(G) with rituximab 375mg/ m2 on day -2 (HDBW-R-TCOP(G)). Six cycles were administered at intervals of two weeks. Results Of the 41 patients treated, 32 (78.0%) achieved a complete remission (CR) and nine (22.0%) achieved a partial remission (PR), for an overall response rate of 100%. After median follow-up of 36 months (range 2.9– 81.8), progression free survival (PFS) and overall survival (OS) were 68.2% and 97.5%, respectively. PFS was 90.9% for HDBW-R-TCOP(G), and 69.5% for HDBW-TCOP(G), but no significant differences was found among two regimen. There was no significant difference in the PFS and OS between aggressive and indolent histological subtypes. 76% of patients developed Grade4 leukopenia (according to NCI criteria) but no patients experienced febrile neutropenia. 15% of patients developed G4 anemia and 17% of patients G4 thrombocytopenia. Other adverse effects were minimal. Conclusion Both HDBW-TCOP(G) and HDBW-R-TCOP(G) are feasible for NHL with acceptable toxicity. The excellent result suggests they are effective for aggressive NHL patients with poor prognostic factors and advanced stage indolent NHL.

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Activity and toxicity of pegylated liposomal doxorubicin in combination regimen (DRCOP) for patients >60 years old with untreated diffuse large B cell lymphoma (DLBCL): A phase II study

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.20505 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 20505-20505

Author(s):

M. A. Rodriguez ◽

M. Fanale ◽

F. B. Hagemeister ◽

P. McLaughlin ◽

B. Pro ◽

...

Keyword(s):

B Cell ◽

Phase Ii ◽

Liposomal Doxorubicin ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Pegylated Liposomal Doxorubicin ◽

B Cell Lymphoma ◽

Combination Regimen ◽

Large B Cell Lymphoma ◽

Large B Cell

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Phase II study of RCHOP with pegylated liposomal doxorubicin (DRCOP) for patients older than age 60 with untreated diffuse large B-cell lymphoma (DLBCL).

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.8053 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 8053-8053

Author(s):

M. A. Rodriguez ◽

J. Durand ◽

A. B. Astrow ◽

M. J. Bury ◽

M. A. Fanale ◽

...

Keyword(s):

B Cell ◽

Phase Ii ◽

Liposomal Doxorubicin ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Pegylated Liposomal Doxorubicin ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Biweekly regimen of nonpegylated liposomal doxorubicin with cyclophosphamide, vincristine, and prednisone plus rituximab (R-COMP-14) as primary treatment for diffuse large B-cell lymphoma (DLBCL): Long-term follow-up of a phase II study.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8062 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8062-8062

Author(s):

Joaquin Herrero ◽

Jose Gómez-Codina ◽

Mariano Provencio ◽

Antonio Rueda ◽

Pilar Sabin ◽

...

Keyword(s):

B Cell ◽

Liposomal Doxorubicin ◽

Cardiac Toxicity ◽

Objective Response ◽

Pegylated Liposomal Doxorubicin ◽

B Cell Lymphoma ◽

Tolerability Profile ◽

Free Survival ◽

Dose Dense

8062 Background: To evaluate the efficacy and toxicity of dose-dense biweekly schedule of (R-COMP-14) in patients newly diagnosed of agrressive diffuse B cell lymphomas (DLBCL). Methods: In this single-arm, open-label, multicenter trial, 60 pts were included between 2004 to 2008. Received rituximab (375 mg/m2) D1 + cyclophosphamide (750 mg/m2)D1 + vincristine (1.4 mg/m2; max. 2 mg)D1 + prednisone (100 mg/d D1 and D5) and non-pegylated liposomal doxorubicin (50 mg/m2) every two weeks. Response was assessed at cycle 3, and patients with complete or partial response received 5 additional courses. Granulocyte colony-stimulating factor (G-CSF). Pegfilgrastim was administered on day 2. The primary efficacy endpoint was (CR) and objective response rate (ORR). Survival follow-up data were updated. Results: 59 evaluable patients with a median age of 50 years (21-65) were analyzed. Clinical Characteristics: 22 Pts stage I-II (aaIPI≥1 (37%), 17 (29%) stage III, and 19 (32%) in stage IV. aaIPI=1 41(67%), aaIPI2/3= 18(33%).LVEF basal: 65,5[50-93]. Extra-nodal disease: 42%. B symptoms: 44.1%. The mean calculated dose intensities of cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and rituximab were 98,7%, 98,7%, 76,1% and 98,3% respectively. Among 60 eligible patients (96,7% completed six cycles and 74,4% completed all eight cycles. ORR was 81%, and CR rate of 54,2%. IC 95% [40,7-67,8]. The main toxicity was neutropenia Gr=III-IV/ and febrile neutropenia in 20% of patients. Neurotoxicity Gr=III-IV in 3,4%. No cardiac toxicity Gr: III-IV was reported. No toxic deaths. After a median follow-up of 25-64m(44m) the 5-year overall survival (OS), event-free survival, (EFS) and disease free survival (DFS) were 80%, 67%, and 77% respectively. Forty two patients (71%) had (<60 y) and med. OS(p=0,017) and med EFS(p=0,014) was 72,3% and 68,1 in aaIPI=1 and 50,4% and 33,8 in aaIPI>1. Conclusions: Dose dense R-COMP-14 is an effective regimen in patients with (DLBCL) comparable o R- CHOP-14. Good tolerability profile with no Gr: III-IV cardiac toxicity or reduction of LVEF.

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