Leukemia (1998) 12, 1457–1460 1998 Stockton Press All rights reserved 0887-6924/98 $12.00 http://www.stockton-press.co.uk/leu Biweekly THP-COPBLM (pirarubicin, cyclophosphamide, vincristine, prednisone, bleomycin and procarbazine) regimen combined with granulocyte colony-stimulating factor (G-CSF) for intermediate- and high-grade non-Hodgkin’s lymphoma N Niitsu and M Umeda First Department of Internal Medicine, Toho University School of Medicine, 6-77-7 Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan Biweekly THP-COPBLM including pirarubicin (THP), which is relapse and refractory NHL is treated by high-dose chemo- thought to be less toxic than doxorubicin, was used to treat therapy with peripheral blood stem cell transplantation non-Hodgkin’s lymphoma (NHL) and the remission rate and adverse events were studied in 42 patients younger than 69 (PBSCT), decreased cardiac function also not infrequently years. Complete remission (CR) was achieved in 37 patients poses a problem. (88.1%) and partial remission in five (11.9%). Classified by inter- In the present study, we used a biweekly THP-COPBLM national prognostic index, CR was achieved in 16 out of 17 low– regimen including a new anthracycline anticancer agent, pira- intermediate-risk patients, 14 out of 16 high–intermediate-risk rubicin (THP), which is considered to be less cardiotoxic than patients and seven out of nine high-risk patients. The 3-year DXR, to increase the dose intensity, and we assessed the effi- survival rate was 72.1% and the 3-year event-free survival rate was 58%. Grade 3 or higher adverse events included granulocy- cacy and occurrence of adverse events. topenia in 39 patients (92.9%) and thrombocytopenia in seven (16.7%). The biweekly THP-COPBLM regimen appears useful for the treatment of aggressive intermediate- and high-grade NHL, and G-CSF made it possible to shorten the interval Patients and methods between courses of chemotherapy. Further studies regarding adverse events on organs, other than on bone marrow are required to improve the long-term results of combination ther- Patients apy on NHL. Keywords: non-Hodgkin’s lymphoma; pirarubicin; granulocyte col- Forty-two Japanese patients with previously untreated NHL ony-stimulating factor; international prognostic index who received combination therapy between April 1994 and August 1997 are included in this report. The median age was 56 years (range 18–69). There were 24 males and 18 females. Introduction According to the Ann Arbor classification,8 staging was determined by bone marrow aspiration, bone marrow biopsy, In recent years, non-Hodgkin’s lymphoma (NHL) has been computerized tomography (CT) of the chest, abdominal son- treated successfully in an increasing number of patients. ography, abdominal CT, gastrointestinal endoscopy and gal- Third-generation chemotherapy has achieved complete lium scintigraphy as well as routine examinations. Their per- remission in 80–85% of the patients treated, and long-term formance status (PS) was between 0 and 3 according to the survival in 60–70%.1,2 According to Fisher et al,3 however, Eastern Cooperative Oncology Group (ECOG).9 Of the 42 intensified chemotherapy with third-generation multiple patients, 12 had stage II, 17 had stage III and 13 had stage IV. anticancer agents is not significantly different in efficacy from Histopathology of the NHLs was classified according to the the CHOP regimen, but it causes more adverse effects. When Working formulation.10 They were of the diffuse large cell patients treated mainly with the CHOP regimen were classi- type in 22 patients, the diffuse mixed cell type in 15, the dif- fied into prognostic groups according to the international fuse small non-cleaved cell type in three, and the follicular prognostic index,4 the 5-year survival rate was 73% for the large cell type in two. All patients tested negative for human low-risk group, while the rates for the low–intermediate (L-I), T cell lymphotropic virus type-I (HTLV-I) antibody. The score high–intermediate (H-I), and high (H)-risk groups were 51, 43 system of the International Non-Hodgkin’s Lymphoma Prog- and 26%, respectively. This indicates that the CHOP regimen nostic Factors (INHLPF) Project4 was used to evaluate thera- is satisfactorily effective for low-risk group non-Hodgkin’s peutic effects by age-adjusted risk group. The three prognostic lymphoma, but is inadequate when the prognosis is poorer. In factors employed were: Ann Arbor stages III and IV, a PS score order to improve the effectiveness of chemotherapy for these of 2 or higher as determined according to the ECOG criteria, poorer prognostic groups, a biweekly dose-intensified CHOP and an increased lactate dehydrogenase (LDH) level. They regimen has been used, in which CHOP is administered with were of the L-I risk group in 17, the H-I group risk in 16, and G-CSF to increase the doses of the key agents the H risk group in nine. (cyclophosphamide (CPA) and doxorubicin (DXR)).5,6 The total dose of DXR is limited by cardiotoxicity. When given alone, the dose limit is 450–550 mg/m2. Our previous study Treatment showed that cardiotoxicity appeared when the total dose of DXR in the COP-BLAM regimen was 350–400 mg/m.2,7 If it is All patients were treated with THP-COPBLM chemotherapy remembered that 40–50% of patients with NHL can usually plus recombinant human granulocyte colony-stimulating fac- achieve long-term survival, cardiotoxicity associated with pro- tor (G-CSF). THP-COPBLM regimen consisted of CPA longed administration of DXR should be considered. When 750 mg/m2, THP 50 mg/m2 and vincristine 1.4 mg/m2 (maximum dose, 2 mg) on day 1, and prednisone 40 mg/m2, procarbazine 100 mg/m2 on days 1–7 and bleomycin 10 mg Correspondence: N Niitsu; Fax: +81 03 3763 8298 on day 10 for six cycles every 2 weeks if absolute neutrophil Received 23 March 1998; accepted 27 May 1998 count (ANC) was у2 × 109/l and platelets у10 × 109/l. Dose Biweekly THP-COPBLM combined with G-CSF for NHL N Niitsu and M Umeda 1458 modification was planned for CPA and THP as follows: Table 1 Therapeutic effects decrease of 25% if ANC count was Ͻ2 × 109/l or platelet count Ͻ100 × 109/l on the planned day of treatment; decrease CR (%) PR (%) P value of 50% if the leukocyte count was Ͻ1.5 × 109/l or platelet count Ͻ70 × 109/l; and chemotherapy delay until hematologic Overall 37/42 (88.1) 5/42 (11.9) Ͻ × 9 Stage recovery if the leukocyte count was 1 10 /l or platelet Ͻ × 9 II 12/12 (100) — NS count 50 10 /l. Doses were not adjusted for patient’s age. III, IV 25/30 (83.3) 5/30 (16.7) G-CSF (lenograstim) was administered as a daily subcutaneous Histology dose of 2 ␮g/kg from day 5 up to day 13 without day 10 or Diffuse large 21/22 (95.5) 1/22 (4.5) ANC Ͼ5 × 109/l. Diffuse mixed 12/15 (80) 3/15 (20) Diffuse small non-cleaved 2/3 (66.7) 1/3 (33.3) NS Follicular large 2/2 (100) — Phenotype Analysis and statistics T cell 14/16 (87.5) 2/16 (12.5) B cell 23/26 (88.5) 3/26 (11.5) NS Performance status Response to treatment was documented on completion of 0, 1 28/31 (90.3) 3/31 (9.7) chemotherapy. Complete remission (CR) was defined as 2, 3 9/11 (81.8) 2/11 (18.2) NS absence of detectable disease on clinical, radiologic and his- LDH; Ͼ1 × normal 33/37 (89.2) 4/37 (12.1) NS у Ͻ tologic criteria. Partial remission (PR) required a Ͼ50% Soluble IL-2R; 1000 U/ml 9/14 (64.3) 5/14 (35.7) 0.01 Bone marrow involvement 2/5 (40) 3/5 (60) Ͻ0.01 reduction of tumor volume. Duration of CR was calculated Bulky mass (diameter у10 cm) 2/4 (50) 2/4 (50) Ͻ0.01 from completion of chemotherapy to relapse or last follow- AAII up. Overall survival (OS) was the interval from initiation of L-I 16/17 (94.1) 1/17 (5.9) therapy to the time of death or last follow-up. Survival analysis H-I 14/16 (87.1) 2/16 (12.5) NS was performed according to Kaplan–Meier.11 The generalized H 7/9 (77.8) 2/9 (22.2) Wilcoxon test (rank sum test) was used to compare mean dif- ference between the two groups. A level of P Ͻ 0.05 was accepted as statistically significant. WHO criteria12 were used to define adverse events. Dose intensity (DI) was evaluated according to Hryniuk and Bush.13 The actual DI of CPA, THP were calculated by dividing the actual total amount of each drug by the time needed for delivery. The expressions of the actual DI as fractions of the stated protocol dosages were defined as relative DI. The calculation was made for the whole treatment course and separately for the initial cycles needed to achieve maximal response (either CR or maximal degree of partial remission) or to determine the progression of disease. Results Therapeutic effects Figure 1 Survival time and event-free survival of non-Hodgkin’s All patients were evaluated for response and survival. Of the lymphoma patients treated with biweekly THP-COPBLAM therapy. 42 patients treated, 37 (88.1%) achieved a CR and five (11.9%) achieved a PR, for a response rate of 100%. The response rate was 100% for stage II disease and 83.3% for stage III and IV disease. With respect to histopathology, the response rate was 95.5% for diffuse large cell type, 80% for diffuse mixed cell type, 66.7% for diffuse small non-cleaved cell type and 100% for follicular large cell type, with no sig- nificant difference observed among histologic subsets.