Poster ash_4

A Phase II study with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin (Myocet™), and prednisone plus rituximab, administered
in a two weeks regimen (R-COMP-14) as primary treatment for agressive non-hodgkin’s lymphoma.
J. Herrero1, J. Gómez-Codina2, M. Provencio3, A. Rueda4, M. Llanos5, P. Sabín6, F. Lobo7, D. Vicente8, F. García-Arroyo9 and C. Iglesias10. 1H.Gen. Alicante, Alicante; 2H. La Fe, Valencia; 3H. Puerta de Hierro, Madrid ; 4H.Virgen de la Victoria, Málaga;5H. Unv. Canarias, Tenerife;
Gotel 6H. Gregorio Marañón, Madrid; 7Fun. Jiménez Díaz, Madrid; 8H.Juan Ramón Jiménez, Huelva; 9H.Pontevedra, Pontevedra and 10H.Virgen del Rocío, Sevilla, Spain.
Treatment and study procedures
Treatment delay and dose reductions
Abstract
Patients and methods
Treatment was administered on day one of biweekly courses, and consisted of Rituximab (375 mg/m2), Cyclophosphamide (750 mg/m2), Eleven cycles (4.8%) were delayed in 7 patients (19.4%). Haematological toxicity was the main reason for delay (6 cycles). Infection, Liposomal Doxorubicin, Myocet™, (50 mg/m2), Vincristine (1.4 mg/m2; up to a maximum dose of 2 mg) and oral prednisone liver toxicity, vomiting, mucositis and unrelated neumonia caused delay in one cycle each.
(100 mg daily on days one to five). Pegfilgrastrim, (6 mg s.c.) was administered on day two of each cycle.
Nine cycles (3.9%) were reduced in 6 patients (16.7%) due to haematological toxicity (6 cycles), and liver toxicity, diarrhoea or vomiting If neutropenia or trombocitopenia grade 2 were observed, course was administered, and cyclophosphamide and liposomal doxorubicin Background: R-CHOP every 21 days is the standard front line therapy for CD20+ aggressive B-cell non-Hodgkin lymphoma (DLBCL).
Eligibility criteria
doses were reduced by 10 percent; in case of neutropenia or trombocitopenia grade 3 or 4, or febrile neutropenia, chemotherapy course Intensification of R-CHOP from 21 to 14 days courses with growth factors prophylaxis has shown better outcome and acceptable Median intensity dose per week was 23.4 mg/m2 for Myocet and 351.5 mg/m2 for cyclophosphamide; Median relative intensity dose was delayed one week, then toxicities were again evaluated and 10 percent reduced dose or full dose was administered if grade 2 or Patients have to fulfil the following criteria to be included in the trial: tolerability. Liposomal doxorubicin (Myocet™) has demonstrated significant less cardiotoxicity than standard doxorubicin. The aim of fewer toxicity was found, respectively. More than 14 days delay or two dose reductions leaded to patient withdrawal.
the study is to assess the efficacy and safety of dose dense R-CHOP regimen modified with Myocet™ (R-COMP-14) in newly diagnosed • Newly diagnosed and histologically proven diffuse large B-cell lymphoma (DLBCL) or the morphologic variants according to WHO For grade 3 non haematological toxicities, chemotherapy administration was delayed until recovery, and cyclophosphamide and liposomal Toxicity
aggressive DLBCL. Prophylactic pegfilgrastim was administered on day two of each cycle to reduce neutropenia incidence and severity.
doxorubicin doses were reduced by 10 percent; grade 4 toxicity meant patient withdrawal.
The incidence of Grade 3 and 4 haematological and non haematological toxicities is indicated in Tables 3 and 4, respectively.
Methods: Between Dec 04 and Aug 07, 47 patients (pats.) were included in the trial. Interim analysis results of the first 36 evaluable
Toxicities were graded according to NCI-CTC v2.0 criteria at baseline and on day one of each cycle. Tumour assessment was performed Table 3. Grade 3 and Grade 4 Haematological Toxicity
pats. completing the study are reported. CD20+, newly diagnosed DLBC non-Hodgkin lymphoma pats. were treated with Rituximab • Ann Arbor Stage III , Stage IV, or Stages I and II with age adjusted IPI 1.
at baseline, after three cycles and at the end of study. Response was evaluated according to the International Workshop Response (375 mg/m2), Cyclophosphamide (750 mg/m2), Vincristine (1.4 mg/m2; max. 2 mg), Myocet™ (50 mg/m2) on day 1 and oral Prednisone Criteria Guidelines(7). Patients with objective response after third cycle received five additional cycles.
(100 mg) on days 1 to 5. Pegfilgrastim was administered on day 2 at standard dose. A maximum of 8 cycles, administered every 14 Toxicity
Number of cycles (%)
Number of patients (%)
• Age between 18 and 65 years old, both included.
days, were given. Response was assessed at cycle 3, and patients with complete or partial response received 5 additional courses.
Pats. characteristics at baseline were: Median age of 55 years (range 27-65); Ann Arbor stage I-II (IPI >1) 40%, III 28.6%, IV 31.4%; Extranodal involvement was present in 52.8% pats. ECOG 0: 44.4 %, ECOG 1: 41.7%; ECOG 2: 13.9%. Median basal LVEF was • Appropriate renal, hepatic, cardiac and haematological function, defined by: Results: The median relative intensity per week of the chemotherapy regimen was 93.7%. A total of 264 cycles were given, 11 (4.8%)
· Serum bilirubin 2 mg/dl; Serum ALT, AST and alkaline phosphatase 2,5 UNL (excepting increases caused by NHL were delayed and 9 cycles (3.9%) were dose reduced mainly due to haematological toxicity. Twenty-four patients (66.7%) completed · No significant abnormalities in EKG; Left ventricular ejection fraction 50% Efficacy
8 cycles of treatment. Patients withdrew the study because of investigator or patient decision (7 pats.), unrelated adverse events (2 · Neutrophil count (ANC) 1.5x109/L; platelet count 100x109/L (unless bone marrow involvement or auto-immune disease pats.), haematological or gastrointestinal toxicity (2 pats.) and progression disease (1 pat.). Tolerability: Haematological Grade 3-4
Treatment outcome is presented in Table 2.
toxicity was: Febrile neutropenia in 2.7% cycles; neutropenia in 3.0% cycles; anaemia in 0.8% cycles and thrombocytopenia in 0.4% The overall response to treatment at the end of the study was 83.4 % (95% Confidence interval: 67.2%-93.6%) Table 4. Grade 3 and Grade 4 Non Haematological Toxicity
cycles. Non-haematological G 3-4 toxicities were gastrointestinal, emesis, nausea/vomiting, hepatic, and asthenia observed in 1.1% • Written informed consent (signed before any specific procedure of the protocol).
Complete Response was achieved in 24 patients (66.7%) and Partial Response in 6 patients (16.7 %). Two patients had stable disease of the cycles each; G 3 neurotoxicity and infection were observed in one cycle each. No additional G 3-4 toxicities were recorded.
(5.5%) and four patients progression disease (11.1%).
Median LVEF at final visit was 63 % (range 52-76). No cardiac episode was observed. Efficacy: Overall response rate was 83.4%
Toxicity
Number of cycles (%)
Number of patients (%)
• Indolent lymphoma becoming an aggressive lymphoma; mantle cell lymphoma, peripheral T-cell lymphoma and their variants; Table 2. Efficacy
(95% CI: 67.2%-93.6%). 24 pts. (66.7%) achieved a complete response (CR) and 6 pts. (16.7%) a partial response (PR); 2 pats Myelodisplasic Syndrome and patient with prior allograft.
(5.5%) had stable disease and 4 (11.1%) progression disease.
Efficacy
Number of Patients (%)
95% Confidence Interval
Conclusions: Dose dense R-CHOP modified with liposomal doxorubicin (R-COMP-14) and supported with prophylactic pegfilgrastim
• Clinically significant cardiovascular disease.
is an effective treatment for DLBC non Hodgkin lymphoma, that shows good tolerability profile and no cardiac events. The good efficacy and safety results justify continuing until study completion.
• Severe active acute or chronic infection (Hepatitis B, C or HIV) • Active cancer, or history of any malignancy in the last five years.
• Hypersensitivity to the study drugs, to eggs or egg products.
Introduction
• Pregnant and childbearing women, and fertile patients not accepting the use of contraceptive methods during the study and three The protocol was approved by the ethics committee responsible for each centre involved in the trial.
This interim analysis reports data from 36 patients that completed the study, out of the 47 patients included from December 2004 to The standard treatment for patients with diffuse large B-cell non-Hodgkin´s lymphoma (DLBCL) has been cyclophosphamide, doxorubicin, Cardiac assessment
August 2007 in ten Spanish centers. Complete information on treatment, safety and outcome was obtained. Patient characteristics vincristine and prednisone (CHOP) regimen given every three weeks(1). The addition of Rituximab to patients with CD20 positive Left Ventricular Ejection Fraction was performed by MUGA or echocardiography at baseline, after cycle four and at the end of trial.
lymphomas substantially improved efficacy results(2,3).
Table 1. Patient Characteristics
Median decrease from baseline to the end of treatment was – 2 % (range – 15% to + 13.1%) (Figure 1).
Studies with dose dense regimens, including etoposide to CHOP regimen, or reducing cycles from three to two weeks achieved better Figure 1 Changes in Left Ventricular Ejection Fraction
Number of Patients
Number of Patients
Conclusions
The Spanish Group of Oncologist Treating Lymphoid Diseases (GOTEL) had already combined both strategies, Rituximab and biweekly Age, years
CHOP courses (R-CHOP-14), in the treatment of DLBCL(6). The study showed good efficacy results, and similar haematological and non haematological toxicities than three weeks regimen. GOTEL group proposed this new phase II trial to confirm the good efficacy The regimen R-CHOP, administered in a biweekly scheme, and modified replacing standard formulation of doxorubicin with Myocet™ (R-COMP-14) showed good efficacy in the primary treatment of aggressive diffuse large B-cell non-Hodgkin lymphoma. The combination, administered with prophylactic pegfilgrastim on day two of each cycle, showed an excellent tolerability and safety profile. Few courses With the aim of reducing toxicity, mainly the cardiac toxicity, maintaining the same efficacy, doxorubicin has been substituted by the ECOG performance status
Extranodal involvement
had to be dose reduced or delayed due to toxicities, which were low in frequency and intensity. No cardiac episode was observed, same dose of non-pegylated liposomal doxorubicin (Myocet™) in the R-CHOP-14 regimen (R-COMP-14). Patients also received and left ventricular ejection fraction values were maintained along the study.
Pegfilgrastim (Neulasta™) on day two of each cycle to reduce incidence and severity neutropenia.
Recruitment of patients in the study continues to confirm the results of this interim analysis, and follow up information is being collected to complete overall and disease free survival information.
References
Objective
1. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non Hodgkin´s lymphoma. N Engl J Med 1993; 328:1002-6.
Ann Arbor Stage
Treatment
2. Coiffier B, Lepage E, Brière J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B cell lymphoma. N Engl J Med 2002; 346:235-42.
3. Coiffier B, Feugier P, Mounier N, Franchi-Rezgui P, Van Den Neste E, Macro M, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. Proc Am Soc Clin Oncol 2007. Abs 8009.
A total of 264 cycles were given to the 36 patients, median 8 cycles, range (2-8). Twenty-four patients (66.7%) received 8 cycles.
4. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rudolph C, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive Reasons for not completing treatment were investigator or patient decision in seven patients (6 of them had achieved completed response lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood 2004; 104:626-633.
5. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rübe C, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the To assess the efficacy and safety of R-COMP (rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin; Myocet™, vincristine and one partial response); unrelated adverse events in two patients; haematological toxicity, gastrointestinal toxicity and progression NHL-B2 trial of the DSHNHL. Blood 2004; 104:634-641.
and prednisolone) administered in a biweekly regimen, with pegfilgrastim as prophylactic neutropenia support, in patients with newly disease in one patient each. Median intensity dose per week was 23.4 mg/m2 for Myocet and 351.5 mg/m2 for cyclophosphamide; 6. Rueda A, Sabín P, Rifá J, Llanos M, Gómez-Codina J., Lobo. et al. R-CHOP-14 in patients with diffuse large-B-cell lymphoma (DLBCL) younger than 70 years: A multicentric and prospective study. Proc Am Soc Clin Oncol 2006.
diagnosed diffuse large B-cell lymphoma.
Median relative intensity dose per week was 93.7% for both drugs.
7. Cheson D et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphoma. J Clin Oncol 1999;17:1244

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