Carboplatin plus cytarabine in the treatment of high-risk acute myeloblastic leukemia

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1 Leukemia (1999) 13, Stockton Press All rights reserved /99 $ Carboplatin plus cytarabine in the treatment of high-risk acute myeloblastic leukemia L Larrea, JA Martínez, GF Sanz, G Martín, J de la Rubia, C Jiménez, I Jarque, A Cid, A López and MA Sanz Hematology Service, University Hospital La Fe, Valencia, Spain Thirty-one patients (20 male and 11 female; median age 51 years (16 79)) with high-risk acute myeloblastic leukemia (AML) (20 refractory AML and 11 secondary AML (s-aml) (four to myelodysplastic syndrome, five to chemo/radiotherapy, one to aplastic anemia and one blastic chronic myelogenous leukemia (B-CML)) were treated with CBDCA (300 mg/m 2 /day 5 days in continuous i.v. infusion) plus intermediate-dose Ara-C (500 mg/m 2 /day 3 days in rapid i.v. infusion). Nine patients (29%) achieved CR (five s-aml (three myelodysplastic syndromes, one CML and one ALL) and four refractory AML) and 11 patients had resistant disease. There were 11 early deaths (35%). Median disease-free survival of the nine responders was 4 months. The main toxicity was hematological, febrile episodes took place in nearly all the patients (96%). The CBDCA plus Ara-C regimen showed an evident antileukemic activity in high-risk leukemia. However, the lack of long-term disease-free survivors shows the need for innovative postremission strategies. The high initial response rate seen in AML secondary to myelodysplastic syndromes (MDS) warrants further investigation of CBDCA in combination regimens for MDS patients. Keywords: acute myeloblastic leukemia; salvage therapy; carboplatin; high-risk AML Introduction Approximately 30% of adult patients with acute myeloblastic leukemia (AML) fail to obtain a complete remission and 60 70% of those who achieve CR relapse within 2 years. 1,2 The prognosis of refractory leukemia is poor In an attempt to overcome this feature, salvage therapy tends to be more intensive than standard induction therapy using, when possible, higher dose or other non cross-resistant drugs not previously delivered. These kind of treatments are also used as first-line therapy in other high risk leukemia, such as in the setting of secondary AML (s-aml). Carboplatin (CBDCA) is a second-generation platinum drug, which, unlike other platinum compounds like cisplatin, has less nephrotoxicity and ototoxicity, with a dose-limiting toxicity represented by myelosuppression. 11 In phase I II trials, CBDCA in continuous infusion has showed an evident antileukemic activity in the treatment of high-risk AML with acceptable toxicity, mainly hematological In our previously reported experience, 12,13 CBDCA as a single agent or in combination with etoposide led to a 30% and 40% complete remission (CR) rate, respectively. Some studies have demonstrated an increasing activity of Ara-C, one of the most active drugs in acute leukemia treatment, with the addition of platinum analogues. 21 Moreover, leukemic cells exhibiting the mdr1 phenotype or impaired intracellular levels of cytosine arabinoside (Ara-C) would still manifest sensitivity to the pharmacological effects of CBDCA, as has been clinically shown in a pilot study using CBDCA as augmentation of standard leukemia induction therapy with daunorubicin and Ara-C. 15 Correspondence: MA Sanz, Servicio de Hematología, Hospital Universitario La Fe, Av. Campanar 21, Valencia, Spain; Fax: Received 19 May 1998; accepted 20 October 1998 In this report we show the results obtained in a series of 31 patients with high-risk AML with a chemotherapy regimen combining CBDCA and intermediate-dose Ara-C. Materials and methods Patient selection Eligibility criteria for the study included AML that had failed induction remission, or had relapsed shortly (less than 12 months) after a first remission, blastic phase of CML and AML evolving from myelodysplastic syndromes and therapyrelated AML. Therapeutic protocol Treatment consisted of CBDCA (300 mg/m 2 /day 5 days administered as a continuous 24 h i.v. infusion) plus intermediate-dose Ara-C (500 mg/m 2 /day 3 days, in 2 h i.v. infusion). Definitions Although there are some controversies about the definition of refractory leukemia, the term of refractory AML has recently been defined as disease that responded to initial therapy for less than 2 years or that failed to respond to this therapy. 22 Secondary leukemia usually refers to leukemia that arises secondary to chemo- or radiotherapy (treatment-related leukemia), environmental or occupational exposure to several agents (eg benzene), and antecedent myelodysplasia. 23 CR was defined according to the criteria established by the Cancer and Leukemia Group B. 24 Failures were classified as resistant leukemia and early death. Early death was defined as death during induction therapy, or during the period of aplasia after chemotherapy. Toxicities were graded according to the WHO criteria. 25 Overall survival was calculated from the date of start of chemotherapy until death or last follow-up. The duration of disease-free survival was calculated from the time CR that was obtained until relapse, death in remission or last follow-up. Statistical methods Actuarial curves for disease-free survival and overall survival were plotted according to the Kaplan Meier method. 26 Statistical analyses were carried out using the SPSS (Statistical Package for Social Science) package, version 6.0 for Windows.

2 162 Table 1 Response to induction No. of patients CR (%) Resistant disease (%) Early deaths (%) Overall group 31 9 (29) 11 (35) 11 (35) Refractory AML 20 4 (20) 7 (35) 9 (45) s-aml 11 5 (45) 4 (36) 2 (18) Results Patient characteristics From May 1992 to June 1996, 31 patients with high-risk AML entered in this study. Twenty patients were male and 11 female; with a median age of 51 years (16 79). Twenty had refractory AML and 11 had s-aml (four to MDS, five to chemo/radiotherapy, one to aplastic anemia and one blastic chronic myelogenous leukemia (B-CML). Primary resistant or relapsed AML had previously been treated with different protocols based on the classical combination of anthracycline plus cytarabine in a 7+3 schedule. cases), new salvage chemotherapy after early relapse (two cases) and no further therapy (two). Six out of eight valuable patients have relapsed. Of the two remaining patients, one died in remission from a secondary astrocytoma and the other is still alive and disease-free (42 m+). These two last patients had received an allogeneic stem cell transplantation shortly after CR had been achieved with CBDCA plus Ara-C. The median overall survival was 3 months (Figure 2). Median survival of patients who achieved CR and those that were refractory for salvage therapy was 15.5 and 2 months respectively (Figure 3; P = ). Treatment outcome Treatment results are summarized in Table 1. Nine patients (29%) achieved CR, five s-aml (three MDS, one CML and one ALL) and four refractory AML. Among failures, 11 patients had resistant disease and 11 were early deaths (35%) due to infection (seven patients) and multiorgan failure (four patients). The CR rate in refractory AML was 4/20 (20%) with two CR occurring in eight relapsed AML patients (25%) while only two in 12 primary resistant AML patients (17%). The highest CR rate corresponded to AML evolving from MDS (3/4; 75%) whereas only one patient entered CR in the treatment-related AML group (16%). The median disease-free survival of the nine responders was 4 months (Figure 1). One patient, 4 months after achieving CR, went abroad (to Argentina, where she lived) and was lost to follow-up. Several therapeutic approaches were made after achieving CR: autologous hematopoietic stem cell transplantation (two cases), allogeneic hematopoietic stem cell transplantation (two Toxicity The main toxicity was hematological. All patients developed pancytopenia during therapy. The median length of neutropenia (neutrophil count /l) and thrombocytopenia (platelets /l) was 27 and 31 days, respectively. Febrile episodes took place in nearly all the patients (96%). Major hemorrhage occurred in two patients (massive gastrointestinal bleeding and hemoptisis). Minor episodes of hemorrhage occurred in 20 patients (epistaxis, hematuria and gingival bruising). Extramedullary toxicity was characteristic of platinum derivatives, especially renal toxicity, observed in 11 patients (eight grade 1, two grade 2 and one grade 3). Seventeen patients had skin rashes. Almost all patients had nausea and vomiting. Only six patients had mild mucositis and 19 had diarrhea. In 19 patients altered hepatic tests were seen. Toxicities are shown in Table 2. Figure 1 Actuarial disease-free survival for patients achieving CR.

3 163 Figure 2 Overall group survival. Figure 3 Survival of the responders to salvage therapy. Table 2 Toxicities Grade Infection Skin Mucositis Vomiting Diarrhea Liver Hyperglycemia WHO criteria for infection: 0 = no, 1 = microbiological with bacteriema; 2 = microbiological without bacteriemia, 3 = clinical, 4 = FUO. Discussion The therapeutic results of CBDCA-containing regimens in AML, reported in the literature reflect an enormous variation. Letendre et al, 27 obtained no response with a continuous infusion etoposide/cbdca regimen. Comparing our previous experience, 12,13 employing CBDCA alone or in combination with etoposide, the addition of Ara-C to CBDCA in a high-risk treatment schedule did not result in a higher CR rate (Table 3) and was associated with higher toxicity. Looking for differences in the CR rates in the different disease groups, CBDCA in combination both with etoposide and Ara-C yields better results than CBDCA alone for secondary AML, especially for myelodysplastic syndromes (75% vs 28.5% CR rate). With regard to refractory AML the combination with etoposide shows the best CR rates (47%), followed by CBDCA alone (33%), while the addition of Ara-C to CBDCA gives the poorest results (20%). Another topic of concern with this population of patients with high-risk AML is the short duration of remissions (4 months in our series). Regarding the approaches to prolong the length of remission, there is no consensus about the postremission therapy in high-risk AML. There are several studies reporting a number of patients gaining long-term disease-free survival after allogeneic hematopoietic stem cell transplantation. 28,29 In our series, this procedure was performed in two

4 164 Table 3 Characteristics of patients with high-risk AML and treated with CBDCA regimens Carboplatin 12 Carboplatin/etoposide 13 Carboplatin/Ara-C No. patients Sex M/F 16/11 13/7 20/11 Age (year) median (range) 50 (16 71) 43 (20 67) 51 (16 79) Response to induction: CR/failure (%) 8/19 (30) 8/12 (40) 9/22 (29) Primary resistant AML/CR (%) 6/2 (33) 8/3 (37.5) 12/2 (17) Relapsed AML/CR (%) 3/2 (33) 3/1 (33) 8/2 (25) Secondary to MDS/CR (%) 7/2 (28.5) 4/3 (75) 4/3 (75) Treatment-related AML/CR (%) 2/0 0 6/1 (16) B-CML/CR (%) 9/2 (22) 5/1 (20) 1/1 (100) patients with an HLA-identical sibling. One died in remission from a secondary astrocytoma (17 months after CR) and the remaining one is still alive and disease-free 38 months after peripheral blood stem cell transplantation. The increased toxicity of the combination of CBDCA + Ara- C reflects the high rate of early deaths (35%). This fact has clearly contributed to a decrease in the CR rate when compared with other CBDCA-containing regimens, eg CBDCA + etoposide with 40% CR rate and 25% early deaths, 13 and VAC regimen with 58% CR rate and 10% induction death rate, 17 although in the later combination CBDCA dose (150 mg/m 2 ) was halved and only patients under 50 years were included. The major toxicity seen during the induction therapy was bone marrow suppression and infection. The high incidence of febrile episodes (30/31 patients) seems to be related to the length of neutropenia. In comparison with other salvage regimens in AML, infectious mortality (7/30) is similar 12,30 or superior. 17,31 33 Nephrotoxicity is a serious cause of concern when using CBDCA. In order to avoid this problem, some authors 34 have recently recommended that the CBDCA dosage be based on renal function with promising results. The CBDCA + Ara-C regimen showed an evident antileukemic activity in high-risk leukemia. 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