3

Click here to load reader

Clinical benefits of lenograstim in patients with neutropenia due to chemotherapy for multiple myeloma (MM)

Embed Size (px)

Citation preview

Page 1: Clinical benefits of lenograstim in patients with neutropenia due to chemotherapy for multiple myeloma (MM)

Support Care Cancer (2001) 9 :397–399DOI 10.1007/s005200000223 SHORT COMMUNICATION

T. TakagiM. SawamuraT. SezakiM. KashimuraJ. TsuchiyaT. HottaN. OgawaK. Hirashima

Clinical benefits of lenograstim in

patients with neutropenia due to

chemotherapy for multiple myeloma (MM)

Published online: 3 April 2001Q Springer-Verlag 2001

K. Hirashima for the Lenograstim/MMStudy Group

T. Takagi (Y)Chiba Cancer Center Hospital,Nitona-cho 666–2, Chuo-ku, Chiba City,Chiba, JapanE-mail: ttakagi6chiba-cc.pref.chiba.jpPhone: c81-43-2645431Fax: c81-43-2659515

M. SawamuraNational Nishigunma Hospital,Kanai 2854, Shibukawa City, Gunma,Japan

T. SezakiNational Okayama Hospital,13–1, Minamikata 2-chome,Okayama City, Okayama, Japan

M. KashimuraMatsudo Municipal Hospital,Uehongo 4005, Matsudo City, Chiba,Japan

J. TsuchiyaGunma University School of Medicine,39–15, Shouwamachi 3-chome,Maebashi City, Gunma, Japan

T. HottaSchool of Medicine, Tokai University,Bouseidai, Isehara City, Kanagawa, Japan

N. OgawaEhime University School of Medicine,Ooaza Shizugawa, Shigenobu-cho,Onsen-gun, Ehime, Japan

K. HirashimaSaitama Medical School, Morohongo 38,Moroyama-cho, Iruma-gun, Saitama,Japan

Abstract The object of this studywas to determine the efficacy andsafety of glycosylated recombinanthuman granulocyte colony-stimu-lating factor (rHuG-CSF; leno-grastim) after combination chemo-therapy consisting of ranimustine,vindesine, melphalan and predniso-lone (MCNU-VMP). One hundredthirty-nine consecutive patientswith newly diagnosed multiplemyeloma (MM) were allocated atrandom to a lenograstim group(np70) or a placebo group(np69). Patients were treated withtwo cycles of MCNU-VMP, andeither lenograstim (2 mg/kg daily,s.c.) or placebo was administeredfrom the day neutrophils decreasedto less than 1,000/ml and wasdiscontinued when neutrophilsexceeded 5,000/ml. The medianduration of neutropenia (neutro-phils under 1,000/ml)was signifi-cantly shorter for the lenograstimgroup than the placebo group(2 days vs 9 days in the first cycle;1 day vs 13 days in the secondcycle). The incidence of febrileneutropenia in the first cycle wassignificantly lower in the leno-grastim group than in the placebogroup (9.2% vs 30.4%). No life-threatening infections wereobserved in either group. The twocycles of MCNU-VMP therapywere completed in 90.8% of thepatients, and a higher average rela-tive dose intensity (ARDI; 0.94)

was achieved in the lenograstimgroup. The tumor response rate ofthe lenograstim group (57.8%) washigher than that of the placebogroup (43.1%), but the differencewas not statistically significant(x2p2.634, dfp1, Pp0.105). Leno-grastim was well tolerated, and nounexpected adverse eventsoccurred. Lenograstim provedeffective in controlling chemo-therapy-induced neutropenia inMM patients under MCNU-VMPtherapy.

Keywords Lenograstim 7 Multiplemyeloma 7 Neutropenia 7MCNU-VMP therapy 7Compliance of the treatment 7Average dose intensity

Page 2: Clinical benefits of lenograstim in patients with neutropenia due to chemotherapy for multiple myeloma (MM)

398

Introduction

Although melphalan combined with prednisolone (MP)has been the standard treatment for multiple myeloma(MM) [1], alternative intensive combination chemo-therapies such as VAD [2] or VMCP/ABVP therapy [3]have long been investigated. Ranimustine (MCNU) is anew nitrosourea derivative developed in Japan [9], andrecently a new combination chemotherapy whichincludes MCNU, vindesine, melphalan and predniso-lone (MCNU-VMP) has shown a high response ratewith such clinical benefits as rapid alleviation of bonepain and improvement of QOL [6, 10]. Unfortunately,the substantial bone marrow suppression attained withMCNU-VMP therapy has frequently impeded theplanned treatment schedule.

Glycosylated recombinant human granulocytecolony-stimulating factor (rHuG-CSF, lenograstim) isknown to stimulate the differentiation and proliferationof neutrophils and to enhance their function [7]. It iswell known that lenograstim is an effective treatmentfor neutropenia in patients undergoing intensivechemotherapy [8]. We conducted a placebo-controlledstudy to evaluate the efficacy of lenograstim againstchemotherapy-induced neutropenia and related infec-tions in MM patients receiving MCNU-VMP therapy.We also assessed compliance and tumor responserates.

Patients and methods

This was a randomized, double-blind, placebo-controlled studyconducted at 55 institutions in Japan. The inclusion criteria were:(1) newly diagnosed MM with no history of combination chemo-therapy, (2) stage II or III according to the Durie and Salmonclassification, (3) expected survival of more than 5 months, (4)age 15–79 and (5) neutrophil counts over 2,000/ml. Exclusioncriteria were: (1) severe complications affecting hepatic, renal,cardiac and/or pulmonary functions, (2) obvious infection,concurrent active cancer, or hypersensitivity to lenograstim, (3)pregnancy. Written informed consent was obtained from allpatients before they entered the study.

Patients were treated with two cycles of MCNU-VMP therapy[10]: ranimustine 50 mg/m2 i.v. on day 1, vindesine 2 mg/m2 i.v. ondays 1 and 22, melphalan 8 mg/m2 p.o. and prednisolone 40 mg/m2 p.o. on days 1–4 and 22–25. On entry to the study and beforethe start of chemotherapy, patients were randomized to the leno-grastim or the placebo group. Patients received either lenograstim(rHuG-CSF; Chugai Pharmaceutical Co.) at a dose of 2 mg/kgdaily (lenograstim group) or placebo (placebo group). Leno-grastim or placebo was given s.c. from the day on which neutro-phil counts decreased to less than 1,000/ml and discontinued whenneutrophils exceeded 5,000/ml.

Tumor response was evaluated according to Imamura’smodified evaluation criteria at the end of the two cycles ofMCNU-VMP therapy [5]: complete response (CR) was defined asthe disappearance of M protein in serum and urine for more than4 weeks and partial response (PR) as a decline (650%) in thelevel of M protein in serum or urine that was sustained for more

Table 1 Patients’ characteristics (BJP Bence Jones protein, PSperformance status)

Placebo Lenograstim Total

No. of patients 69 70 139Sex

Male 38 38 76Female 31 32 63

AgeMedian 63 64 64Range (44–79) (44–78) (44–79)

PS0 16 25 411 12 17 292 17 12 293 15 12 274 9 4 13

Type of M proteinIgG 37 50 87IgA 14 13 27IgD 4 0 4IgE 1 0 1BJP 13 7 20

Clinical stageII 14 19 33III 55 51 106

Creatinine (mg/dl)~2 60 62 12262 9 8 17

than 4 weeks. Febrile neutropenia was defined as a temperaturehigher than 38 7C during the period of neutropenia (~1,000/ml).Tumor response rate was defined as the sum of the CR and PRrates.

Relative dose intensity (RDI) and average relative dose inten-sity (ARDI) were calculated using the method of Hryniuk andBush [4]. Statistical analysis of differences between the leno-grastim and placebo group was performed using the x2 test,Student’s t-test and the Wilcoxon test.

Results

Between December 1994 and December 1997, 139newly diagnosed MM patients were entered in thisstudy. Six patients were excluded from the assessmentsfor efficacy and safety for the following reasons: inade-quate administration of the test drug (np5) and breachof inclusion criteria (np1). One hundred thirty-threepatients were evaluated for the safety and 121 patients,for the efficacy of the test drug. Response to theMCNU-VMP therapy was evaluated in 102 patients.

There were no significant differences between thetwo groups in terms of sex, age, performance status(PS), clinical stage or serum creatinine (Table 1). Themedian duration of neutropenia was shorter and theincidence of febrile neutropenia lower during the firstcycle in the lenograstim group (Table 2). No life-threat-ening infections were observed in either group. The

Page 3: Clinical benefits of lenograstim in patients with neutropenia due to chemotherapy for multiple myeloma (MM)

399

Table 2 Clinical benefit of lenograstim

No. ofpatients

Duration of neutropenia (neutrophils ~1000/ml) Incidence of febrile neutropenia

Median Range Wilcoxon-test Yes (%) No (%) Chi-squared test

First cyclePlacebo 56 9 days 1F32 Zp6.971 17 (30.4) 39 (69.6) x2p8.721

dfp1Lenograstim 65 2 days 0F28 P~0.001 6 (9.2) 59 (90.8) Pp0.003

Second cyclePlacebo 44 13 days 0F29 Zp6.065 3 (6.8) 41 (93.2) x2p0.643

dfp1Lenograstim 61 1 day 0F10 P~0.001 7 (11.5) 54 (88.5) Pp0.422

tumor response rate (57.8%) in the lenograstim groupwas higher than that (43.1%) in the placebo group,although the difference was not statistically significant(xp2.634, dfp1, Pp0.105). The two courses ofMCNU-VMP therapy were completed in 59 of the 65(90.8%) patients receiving lenograstim and in 40 of the56 (71.4%) patients receiving placebo (xp7.564, dfp1,Pp0.006). The mean value of ARDI was 0.94 in thelenograstim group and 0.80 in the placebo group(Wilcoxon test, Zp4.703, P~0.001).

Minor adverse drug reactions in the lenograstimgroup were observed: muscle/skeletal pains (4patients); fatigue (1 patient); elevation of lactic dehy-drogenase (LDH, 6 patients), and alkaline phosphatase(ALP, 7 patients).

Discussion

In the present study, we demonstrated some clinicalbenefits of lenograstim: the duration of neutropeniawas shorter, and the frequency of febrile neutropeniawas lower. Tumor response rate was higher in the leno-grastim group because of the higher chemotherapycompliance in this group. But, longer follow-up will beneeded to determine whether the higher response rateis associated with longer survival. As for safety, leno-grastim was well tolerated and no clinically significantadverse drug reactions were observed.

In conclusion, administration of lenograstim at adaily dose of 2 mg/kg s.c. after MCNU-VMP therapy forMM proved useful for controlling chemotherapy-induced neutropenia and related infections. Patients’compliance and tumor response rate were improved bylenograstim.

References

1. Alexanian R, Dimopoulos M (1994)The treatment of multiple myeloma.N Engl J Med 330 :484–489

2. Barlogie B, Smith L, Alexanian R(1984) Effective treatment ofadvanced multiple myeloma refrac-tory to alkylating agents. N Engl JMed 310 :1353–1356

3. Boccardo M, Marmount F, TribaltoM, et al (1999) Multiple myeloma:VMCP/VBAP alternating combina-tion chemotherapy is not superior tomelphalan and prednisolone even inhigh-risk patients. J Clin Oncol9 :444–448

4. Hryniuk W, Bush H (1984) Theimportance of dose intensity inchemotherapy of metastatic breastcancer. J Clin Oncol 2 :1281–1288

5. Imamura Y (1981) Effect criteria ofchemotherapy: myeloma (in Japanesewith English abstract). Jpn J CancerClin 27 :1067–1074

6. Imamura Y, Takagi T, Isobe T, et al(1994) Combination chemotherapywith MCNU, vindesine, melphalan,and prednisolone (MCNU-VMPtherapy) in induction therapy formultiple myeloma. Int J Hematol59 :113–123

7. Nomura H, Imazeki I, Oheda M, et al(1986) Purification and characteriza-tion of human granulocyte colony-stimulating factor (rG-CSF). EMBO J5 :871–876

8. Ohno R, Tomonaga M, Ohshima T,et al (1993) A randomized controlledstudy of granulocyte colony-stimu-lating factor after intensive inductionand consolidation therapy in patientswith acute lymphoblastic leukemia.Int J Hematol 58 :73–81

9. Sekido S, Ninomiya K, Iwasaki M(1979) Biologic activity of MCNU: anew antitumor agent. Cancer TreatRep 63 :961–970

10. Takagi T, Sakai C, Goto S, et al(1996) MCNU-VMP therapy: a newnitrosourea-based combinationchemotherapy for multiple myeloma(abstract). Br J Haematol 93 [Suppl2] :302