ORIGINAL ARTICLE: CLINICAL Phase II study of the tetrahydropyranyl adriamycin–cyclophosphamide, vincristine, and prednisolone regimen combined with rituximab as first-line treatment for elderly patients with diffuse large B-cell lymphoma SENJI KASAHARA1, TAKESHI HARA1, HISASHI TSURUMI1, NAOE GOTO1, JUN-ICHI KITAGAWA2, NOBUHIRO KANEMURA1, TAKESHI YOSHIKAWA1, HIDEKO GOTO3, KENJI FUKUNO4, TOSHIKI YAMADA1, MICHIO SAWADA2, TAKESHI TAKAHASHI4, TSUYOSHI TAKAMI5, & HISATAKA MORIWAKI1 1First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan, 2Department of Hematology, Gifu Red-Cross Hospital, Gifu, Japan, 3Department of Internal Medicine, Kisogawa Municipal Hospital, Kisogawa, Japan, 4Division of Hematology, Gifu Municipal Hospital, Gifu, Japan, and 5Department of Immunopathology, Gifu University Graduate School of Medicine, Gifu, Japan (Received 13 September 2010; accepted 6 January 2011) Abstract The anthracycline drug pirarubicin (tetrahydropyranyl adriamycin; THP) apparently has fewer cardiotoxic effects than doxorubicin. We previously described the benefit of the THP-COP regimen comprising cyclophosphamide, THP, vincristine, and prednisolone for elderly patients with diffuse large B-cell lymphoma (DLBCL). However, that study was completed before rituximab (R) was introduced into clinical practice. Here we report a phase II study of the THP-COP regimen combined with R (R-THP-COP) every 3 weeks. The complete response and 3-year overall survival rates was 63% and 53%, respectively, and no deaths were related to the regimen. We conclude that the R-THP-COP regimen is safe and effective for patients with DLBCL. Based on these results, a randomized controlled trial of rituximab–cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and R-THP-COP as a phase III study is ongoing. Keywords: R-CHOP, R-THP-COP, non-Hodgkin lymphoma, pirarubicin, elderly Introduction The number of elderly patients with non-Hodgkin lymphoma (NHL) is increasing as the proportion of elderly people in the general population increases [1]. However, organ function is reduced in elderly patients and the incidence of concurrent chronic or debilitating diseases also increases with age, which limits the choice of treatments for such patients with NHL [2]. Although anthracycline derivatives are effective against NHL, they have cardiotoxic and myelosuppressive effects that can be deleterious to the elderly. Pirarubicin (tetrahydropyranyl adriamycin; THP) is an anthracycline doxorubicin (DOX) derivative that is considered less cardiotoxic than DOX [3–5]. Accordingly, a THP-COP regimen [6] composed of THP, cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL) has been administered to elderly patients with NHL [7–9]. We have also described the value of the THP-COP regimen for treating elderly patients with diffuse large B-cell lymphoma (DLBCL) [10]. In the meantime ritux- imab, a chimeric monoclonal antibody against the CD20 B-cell antigen, combined with the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, Correspondence: Hisashi Tsurumi, MD, First Department of Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. Tel: þ81-58-230-6308. Fax: þ81-58-230-6310. E-mail:
[email protected] Leukemia & Lymphoma, April 2011; 52(4): 629–634 ISSN 1042-8194 print/ISSN 1029-2403 online � 2011 Informa UK, Ltd. DOI: 10.3109/10428194.2011.555024 L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y M cM as te r U ni ve rs ity o n 11 /0 6/ 14 Fo r pe rs on al u se o nl y. and prednisolone) has increased the complete response (CR) rate and prolonged progression-free and overall survival in previously untreated elderly patients with DLBCL [11,12]. Thus, a combination of rituximab and CHOP (R-CHOP) has become the current standard for treating DLBCL. Indeed, we recently reported the results of a phase II study of the R-THP-COP regimen for patients with DLBCL aged less than 70 years [13]. The present phase II study assessed the response rates, long-term effects, and toxicity of the R-THP-COP regimen as first-line treatment for previously untreated elderly patients with CD20þ DLBCL and evaluated its clinical effects. Patients and methods Study design The objective of this open, non-randomized, multi- center phase II trial, which was carried out at Gifu University Graduate School of Medicine (Gifu, Japan), was to assess the effect and safety of R-THP-COP. The local ethics committee approved the study, and all patients provided written informed consent to participate before enrollment. Patients Adults aged between 70 and 80 years were eligible for inclusion in the study if they were diagnosed with untreated CD20þ DLBCL that was then confirmed by biopsy and classified according to the World Health Organization classification [14]. All patients had clinical stage (CS) II, III, or IV DLBCL according to the Ann Arbor staging system [15]. The assignment of Ann Arbor stages was based on clinical findings and tumor measurements obtained before biopsy. Bulky disease was defined as a mediastinal mass with a maximum diameter exceed- ing one-third of the maximum chest diameter, or any other mass that was �10 cm. None of the patients was infected with human immunodeficiency virus or human T-cell lymphotropic virus type I. Clinical stage was evaluated by physical examina- tion, chest X-rays, computed tomography of the brain, neck, chest, abdomen, and pelvis, bone marrow aspiration and biopsy, gallium scintigraphy, and/or fluorodeoxyglucose positron emission tomo- graphy (FDG-PET). Laboratory measurements comprised serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase (ALP), creatinine, lactate dehy- drogenase (LDH), soluble interleukin-2 receptors (sIL-2R), C-reactive protein (CRP), and peripheral blood cell counts. All patients had almost normal cardiac function (left ventricular ejection fraction 450%), serum creatinine concentration 52.0 mg/ dL, no severe complications, no multiple malignan- cies, performance status (PS) ranging from 0 to 3, and evaluable lesions. Treatment strategy The R-THP-COP combination comprised rituximab (375 mg/m2) administered intravenously (i.v.) on day 1, CPA, THP, and VCR 750, 50, and 1.4 mg/m2 (maximum, 2.0 mg) i.v., respectively, on day 3, and 100 mg/day PSL administered orally on days 3–7. This treatment cycle was repeated every 3 weeks for a total of six cycles. Nausea and vomiting were prevented by a 5-hydroxytryptamine (5-HT3) recep- tor antagonist. Oral fluconazoles (200 mg/day) were administered as antifungal prophylaxis. Cardiac function was evaluated echocardiographically before and after every two courses of chemotherapy. Granulocyte colony-stimulating factor (G-CSF; 100 mg/m2) was administered subcutaneously when the peripheral neutrophil count reached516 109 cells/L. Patients with a bulky mass received local radiotherapy ranging from 30 to 40 Gy after chemotherapy. The daily radiotherapy dose varied from 1.8 to 2.0 Gy. Patients who relapsed or whose disease progressed after R-THP-COP and those who were resistant to the R-THP-COP regimen received the P-IMVP-16/CBDCA regimen compris- ing rituximab, methylprednisolone, ifosfamide, methotrexate, etoposide, and carboplatin as salvage chemotherapy [16]. Response criteria Tumor responses to chemotherapy were evaluated after the second, fourth, and sixth (final) courses of chemotherapy. Therapy was considered to have failed at these time points if tumors had progressed. Responses to treatment were categorized by repeated physical examinations, radiological studies, gallium scintigraphy, FDG-PET, and bone-marrow aspira- tion as defined by Cheson et al. [17]. We evaluated clinical stage or response to treatment (after the final course of chemotherapy) by gallium scintigraphy before the introduction of FDG-PET in February 2004. Endpoints The primary endpoint was to assess the effects of R-THP-COP as response rates. Secondary endpoints were assessments of survival and toxicity. Overall survival (OS) was measured from the time of assignment to a treatment group until death from 630 S. Kasahara et al. L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y M cM as te r U ni ve rs ity o n 11 /0 6/ 14 Fo r pe rs on al u se o nl y. any cause. Progression-free survival (PFS) was defined for all eligible patients, including non- responders, as the interval from the day of starting chemotherapy to the day upon which progression or death due to any cause was confirmed. Adverse effects were graded according to the National Cancer Institute Common Toxicity Criteria version 3.0 and were recorded as maximum grade during the period from the start of chemotherapy until recovery from the final course. Statistical analysis The sample size for the study was calculated from a predicted response rate of 80% and a minimum of 60% with an a error of 0.05 and a b error of 0.20 using Simon’s two-stage minimax design [18]. The estimated sample size was 43, with a further 10% being added to account for predicted ineligible patients. All follow-up data were updated on 1 March 2009. The patients’ characteristics were compared using the w2 test. The effects of several pretreatment factors on achieving CR or partial response (PR) were analyzed using the w2 test. The effects of several pretreatment factors on survival were examined using univariate analyses and the log-rank test based on the Kaplan–Meier method [19]. The prognostic signifi- cance of selected covariates was defined using multivariate analysis with the Cox regression techni- que [20]. Results Patients’ characteristics All of the 52 consecutive patients (30 males and 22 females) who enrolled in the study between December 2003 and December 2005 were eligible. The median follow-up period was 44.4 months. All of them provided written informed consent in accordance with our institutional guidelines and the Declaration of Helsinki. Table I shows that the clinical characteristics did not significantly differ between this patient population and those in our previous studies (data not shown). Eight patients with bulky disease received radiation therapy. Feasibility Of the 52 included patients, 16 received fewer than six courses of the R-THP-COP regimen. Reasons for discontinuing were disease progression (n¼ 7; 13.5%), independent complication with cerebral infarction (n¼ 2; 3.8%), adverse febrile neutropenia (n¼ 2; 3.8%), PS progression (n¼ 1; 1.9%), and patient’s personal choice (n¼ 4; 7.7%). Data from all of these patients were included in the toxicity analysis. We analyzed the dose intensity of che- motherapy during the six cycles for the 36 patients who received six courses; the median relative dose intensity (RDI) was 95.4% and 95.1% for THP and cyclophosphamide, respectively. The physician judged that a dose reduction was required after three courses in one patient with esophageal perforation. A total of 28 (10.6%) cycles were delayed due to non-hematological adverse events (n¼ 8), hematolo- gical adverse events (n¼ 14), presence of both types of toxicity (n¼ 2), and non-drug-related issues (n¼ 4). Responses to therapy Table II summarizes the patients’ responses to therapy. Of the 52 patients whose response to treatment was evaluated, 33 (63%) reached CR or CR uncertain (CRu). The CR/CRu rate was Table I. Clinical characteristics of the 52 patients. Number % Gender Male 30 58 Female 22 42 Age (years) 576 31 60 �76 21 40 PS 0, 1 33 63 2–4 19 37 LDH Normal 13 25 Increased 39 75 Extranodal sites 0, 1 31 60 �2 21 40 Clinical stage I/II 22 42 III/IV 30 58 B symptoms Absent 34 65 Present 18 35 sIL-2R 52000 22 42 �2000 30 58 IPI L/LI 21 40 HI/H 31 60 R-IPI Very good 0 0 Good 21 40 Poor 31 60 PS, performance status; LDH, lactate dehydrogenase; sIL-2R, soluble interleukin-2 receptors; IPI, International Prognostic Index; L/LI, low/low intermediate; HI/H, high intermediate/high; R-IPI, revised IPI. R-THP-COP regimen for elderly DLBCL 631 L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y M cM as te r U ni ve rs ity o n 11 /0 6/ 14 Fo r pe rs on al u se o nl y. significantly lower in patients with a poor PS (2–4) and elevated LDH, but the International Prognostic Index (IPI) [21] and revised IPI (R-IPI) [22] did not differ significantly. The CR/CRu/PR rate was sig- nificantly lower only in patients with a poor PS (2–4). Survival The OS and PFS rates were 63% and 53%, respectively, after 3 years [Figures 1(A) and 1(B)]. The OS rates did not differ significantly according to the IPI or R-IPI values, whereas significantly worse factors were poor PS, elevated LDH, and elevated sIL-2R (Table III). The 3-year PFS differed sig- nificantly according to IPI or R-IPI. Other signifi- cantly worse factors were poor PS, elevated LDH, multiple extranodal sites, advanced clincal stage, and elevated sIL-2R (Table III). Toxicity Table IV summarizes the adverse effects, of which hematological toxicity was the major type. Twelve (29%), 35 (85%), and six (14%) patients developed grade 3 or 4 anemia, neutropenia, and thrombocy- topenia, respectively. Non-hematological adverse effects were tolerable. Neutropenia developed in five (9.6%) patients and in 11 (4.2%) of 264 cycles (n¼ 1, 1, 2, 1, 3, and 3 patients at 1, 2, 3, 4, 5, and 6 cycles, respectively). Grade 3 infection and fever that occurred in seven patients improved after antibiotic therapy. Grade 3 neuropathy that occurred after the final chemotherapy course in one patient gradually improved. Therapy-related death was not observed. Discussion The CHOP regimen became the chemotherapeutic gold standard for NHL after a report published by Fisher et al. in 1993 [23]. Although the frequency of infections has decreased because G-CSF is adminis- tered to reduce the duration of neutropenia, ther- apeutic outcomes have not improved remarkably [8,24–26]. However, the combination of rituximab with the CHOP regimen has obviously improved therapeutic outcomes [11,12]. The RICOVER-60 (rituximab with CHOP for patients460 years old) Table II. Univariate analyses of response rates. CR CR/PR (%) p-Value (%) p-Value Total 63 96 Gender Male 61 NS 97 NS Female 67 95 Age 576 68 NS 94 NS �76 57 100 PS 0, 1 76 50.05 100 50.05 2–4 42 89 LDH Normal 100 50.0005 100 NS Increased 51 95 Extranodal sites 0, 1 68 NS 97 NS �2 57 95 Clinical stage I/II 73 NS 100 NS III/IV 57 93 B symptoms Absent 65 NS 97 NS Present 61 94 sIL-2R 52000 77 NS 100 NS �2000 53 93 IPI L/LI 76 NS 100 NS HI/H 55 94 R-IPI Very good – NS – NS Good 76 100 Poor 55 96 CR, complete response; PR, partial response; PS, performance status; LDH, lactate dehydrogenase; sIL-2R, soluble interleukin-2 receptors; IPI, International Prognostic Index; L/LI, low/low intermediate; HI/H, high intermediate/high; R-IPI, revised IPI; NS, not significant. Figure 1. Survival curves of elderly patients with diffuse large B-cell lymphoma who received R-THP-COP chemotherapy. (A) Overall survival; (B) progression-free survival. 632 S. Kasahara et al. L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y M cM as te r U ni ve rs ity o n 11 /0 6/ 14 Fo r pe rs on al u se o nl y. trial showed that adding rituximab to CHOP and dose-dense approaches (R-CHOP-14) could further improve the prognosis of elderly patients with NHL [27]. The MabThera International Trial Group (MInT) study then found that the combination with rituximab is also suitable for young patients [28]. Thus, R-CHOP or R-CHOP-14 might become a standard treatment for DLBCL. Because THP is a less cardiotoxic anthracycline derivative of DOX [3–5], its value in treating lymphoma has been reviewed mainly in elderly patients. Kitamura et al. showed that the THP– cyclophosphamide, vincristine, and prednisolone (THP-CVP) regimen, in which THP replaced DOX, safely and effectively treated patients aged�65 years with NHL [7]. Aoki et al. also showed that chemotherapy regimens containing THP were safe and effective for elderly patients with NHL and that THP conferred better outcomes compared with DOX [29]. We also described the value of the THP-COP regimen for patients with DLBCL [10]. Based on these results, rituximab combined with THP-COP should also be considered as a treatment for patients with CD20þ DLBCL. Indeed, we recently described that the feasibility and toxicity of the R-THP-COP regimen were similar to those of R-CHOP for treating younger patients (18–70 years old) with CD20þ DLBCL [13]. We found higher response rates and improved progression-free and overall survival among patients treated with rituximab plus THP-COP compared with THP-COP alone, as we previously reported. The addition of rituximab was tolerated well, and the incidence of severe or serious adverse events did not differ from that associated with THP-COP. Our long-term follow-up of a phase II study of the THP- COP regimen administered to elderly patients with DLBCL [10] confirmed the absence of exacerbated cardiac function by echocardiography. Neither that phase II study nor the present study was a randomized controlled trial; hence, we could not directly compare THP with DOX. However, we regard THP as having less cardiotoxicity. Adding rituximab to six cycles of THP-COP chemotherapy administered to elderly patients with recently diag- nosed DLBCL significantly increased the rate of achieving a complete response, decreased the rates of treatment failure and relapse, and improved progression-free and overall survival, as compared with standard THP-COP alone. When patients who have received CHOP relapse, they generally need to avoid anthracycline salvage therapy because of accumulated cardiotoxicity by DOX. However, anthracyclines can be administered again to patients who have received THP-COP. Thus, substituting THP for DOX might be more Table III. Univariate analyses of survival rates of all patients. 3-year OS 3-year PFS (%) p-Value (%) p-Value Total 63 53 Gender Male 61 NS 53 NS Female 65 55 Age 576 59 NS 46 NS �76 71 65 PS 0, 1 74 50.05 67 50.001 2–4 43 29 LDH Normal 92 50.05 79 50.05 Increased 53 45 Extranodal sites 0, 1 71 NS 62 50.05 �2 48 40 Clinical stage I/II 71 NS 72 50.05 III/IV 57 40 B symptoms Absent 62 NS 57 NS Present 63 46 sIL-2R 52000 86 50.05 74 50.05 �2000 45 38 IPI L/LI 75 NS 69 50.05 HI/H 53 43 R-IPI Very good – NS – 50.05 Good 75 69 Poor 53 43 OS, overall survivial; PFS, progression-free survival; PS, perfor- mance status; LDH, lactate dehydrogenase; sIL-2R, soluble interleukin-2 receptors; IPI, International Prognostic Index; L/ LI, low/low intermediate; HI/H, high intermediate/high; R-IPI, revised IPI; NS, not significant. Table IV. Toxicity. Grade 3 Grade 4 Total (%) Hematological toxicity Anemia 9 3 29 Neutropenia 15 20 85 Thrombocytopenia 5 1 14 Non-hematological toxicity Nausea 0 0 0 Stomatitis 0 0 0 Liver dysfunction 0 0 0 Renal dysfunction 0 0 0 Hematuria 0 0 0 Cardiac toxicity 0 0 0 Pulmonary toxicity 0 0 0 Neuropathy 1 0 2.4 Infection 2 0 4.8 Febrile neutropenia 5 0 10 R-THP-COP regimen for elderly DLBCL 633 L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y M cM as te r U ni ve rs ity o n 11 /0 6/ 14 Fo r pe rs on al u se o nl y. effective for elderly patients whose cardiac function is generally inferior to that of younger patients. Further clinical studies of the R-THP-COP regimen are warranted. Conclusion The addition of rituximab to the THP-COP regimen is effective against CD20þ DLBCL. The present findings indicate that the R-THP-COP and R- CHOP regimens should be compared in a phase III trial of elderly patients with CD 20þ DLBCL. 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L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y M cM as te r U ni ve rs ity o n 11 /0 6/ 14 Fo r pe rs on al u se o nl y. http://www.informahealthcare.com/doi/suppl/10.3109/10428194.2011.555024/suppl_file/disclosure.zip http://www.informahealthcare.com/lal