Carboplatin alone or in combination in high-risk acute nonlymphoblastic leukemia

Annals of Oncology 3 (Suppl.3): S39-S42, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Carboplatin alone or in combination in high-risk acute nonlymphoblastic leukemia M. A. Sanz, G. F. Sanz, J. A. Martinez, L. Senent, F. Lopez, J. Palau, G. Martin & I. Jarque Hematology Service, Hospital Universitario La Fe, Valencia, Spain

Introduction

Anthracyclines and platinum derivatives are probably the major contributions to the available anticancer drug armamentarium in the last decade. Based on their proven efficacy in an increasing number of tumor types, platinum compounds have been incorporated into several first-line chemotherapy regimens. The gastrointestinal, renal, and neurologic toxicities of firstgeneration platinum drugs (i.e. cisplatin), as with anthracyclines, have limited their extensive use. Consequently, the investigation of less toxic platinum derivatives has led to the development of a number of second- and third-generation platinum compounds. More than a hundred organoplatins have been synthesized and tried in experimental models, but very few have been studied in clinical trials: carboplatin [cis-diammine-l,l-cyclobutane dicarboxylate platinum (II)], iproplatin [cis-dichloro bis(isopropylamine) trans-dihydroxy platinum (IV)], and diaminocyclo hexanes platinum (spiroplatin, oxaliplatin, tetraplatin). Carboplatin is a second-generation platinum drug, which, unlike cisplatin, has prominent myelotoxicity and considerably less nephrotoxicity and ototoxicity

[1-3]. It is also associated with less nausea and vomiting [1-3], and is possibly less mutagenic and carcinogenic [4]. Despite the initially unknown cytotoxic activity of carboplatin in vivo against human acute leukemia (although data demonstrating cytotoxic effects of platinum derivatives against the L1210 leukemia cell line were available [5]), the pattern of toxicity of carboplatin suggested it be tried in very high-risk patients with acute leukemia [6, 7]. Preliminary results showed a striking effectiveness in inducing complete remission (CR) in high-risk patients with acute nonlymphoblastic leukemia (ANLL) with a highly selective myelotoxicity and minimal extramedullary toxicity. This article reviews information that has recently emerged concerning the use of carboplatin alone or in combination in high-risk leukemia patients. We also speculate about future applications of this drug in myeloid malignancies. Carboplatin alone in ANLL

The first clinical trials using carboplatin to treat acute leukemia patients were reported by Meyers et al. [6]

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Summary. The use of newly developed antileukemic agents tic leukemia (ANLL) and (2) carboplatin/etoposide has been is one of the therapeutic options available to overcome clini- extensively tested in patients with small and non-small cell cal resistance in refractory or other high-risk acute leuke- lung cancer, and therefore the toxicity and maximum toleratmias. Carboplatin is a second-generation platinum com- ed dose are known. The complete remission rate achieved pound that has demonstrated significant activity against was somewhat higher (40%) than with carboplatin alone deacute leukemia, particularly when administered via contin- spite the increased incidence of extrahematologic toxicities, uous intravenous infusion in phase 1 clinical trials. Based on particularly gastrointestinal bleeding. At present, carboplatin the preliminary reports of these trials, we designed a phase II should be considered as a new effective agent for the treatclinical trial to evaluate the efficacy and toxicity of carbopla- ment of ANLL. Its myeloablative potential coupled with its tin via continuous infusion (300 mg/mVd for 5 days) for re- scanty extrahematologic toxicity warrant the trial of carbomission induction in adult patients with high-risk acute leu- platin as a conditioning agent in bone marrow transplantakemia. Because of the significant antileukemic activity and tion for myeloid malignancies. It could also be incorporated the scarce extrahematologic toxicity noted in this trial, in into front-line regimens as part of intensive postremission order to increase the response rate, we were encouraged to therapy, and its role should be carefully addressed in hightry carboplatin in combination in a similar set of patients. A risk myelodysplastic syndromes (refractory anemia with phase II study of carboplatin 300 mg/m2/d for 5 days in excess blasts [RAEB| and RAEB in transformation). combination with etoposide 100 mg/m2/d for 3 to 4 days was designed by our group to treat patients with high-risk acute leukemia. This combination was chosen because (1) Key words: carboplatin, treatment, acute nonlymphoblastic each drug has independent activity in acute nonlymphoblas- leukemia

40 Table I. Phase I/I I clinical trials of carboplatin in acute leukemia. Reference

Clinical trial i.v. infusion No. days Dose escalation (mg/m2)

[9|

[13J

|10]

Phase I Continuous

Phase 1 Bolus

Phase II Continuous

Phase II Continuous

5 Yes 875

5 Yes

5 No

5 No

200 x 5 d 250 x 5 d 300 x 5 d

1,575

1,500

28 8 6 2

17 2 0 2

46 8 8

27 12 8 4

Severe Mild or severe

Mild Mild or severe (ototoxicity)

Severe Mild or minimal"

Severe Mild or minimal

1,000 1,175 1,550 1,800 2,100 No. patients Responses Complete Partial Toxicity Myelosuppression Nonhematologic

" Renal and auditory toxicities appeared to be cumulative.

and Lee et al. [7]. Preliminary results of these reports were eventually confirmed and published more extensively [8, 9]. Both studies showed the effectiveness of carboplatin in inducing CR in refractory and relapsed acute leukemia patients without significant toxicity, particularly when this drug was administrated via continuous infusion [8]. The study by Meyers et al. [8] also demonstrated that the myelotoxicity was dose-limiting, and the maximum tolerated dose was estimated to be about 1,500 mg/m 2 . Interestingly, extrahematologic side effects were mild or minimal in both trials, but 3 of 9 patients treated with carboplatin 300 mg/m 2 /d for 5 days by bolus injection developed significant ototoxicity [9]. In order to evaluate the efficacy and toxicity of carboplatin administered via continuous infusion in patients with refractory leukemias, we designed a phase II clinical trial. In this trial, we administered carboplatin 1,500 mg/m2 by continuous intravenous (i.v.) infusion over 5 days. The results of this study have been published recently [10], demonstrating that carboplatin is an active drug in the treatment of high-risk acute leukemia. The total response rate of 44% (7 CRs and 5 partial remissions) seems to be similar to other efficacious salvage regimens in ANLL [11]. In our study, carboplatin was well tolerated and toxicity was mainly hematologic. The pattern of toxicity was different from that of other platinum derivatives, with much less nephrotoxicity, ototoxicity, and emetic activity and demonstrating prominent myelotoxicity. Nevertheless, despite the severe and prolonged neutropenia, the mild extramedullary toxicity and the absence of overt deterioration of skin and mucosal barriers may be responsible for both the low rate of severe infections and the low incidence of gram-negative bacteriemia observed. As with cisplatin administration [12], differences in toxicity as a result of administering carboplatin via bolus or contin-

uous infusion could be due to pharmacokinetic considerations. Recently, the Eastern Cooperative Oncology Group [13] carried out a phase II clinical trial of carboplatin alone in patients with relapsed and refractory leukemia, including ANLL and acute lymphoblastic leukemia. Preliminary results of this study also demonstrate that carboplatin is an active agent in acute leukemia with a particular pattern of toxicity. Table 1 compares the main characteristics and results of the only four clinical trials reported to date using carboplatin in acute leukemia.

Carboplatin in combination in ANLL

To our knowledge, clinical studies of carboplatin in combination with other cytotoxic drugs in the treatment of patients with acute leukemia have not been reported until now. However, because of significant antileukemia activity and the scarce extrahematologic toxicity noted in our previous study [10], we were encouraged to conduct a phase II clinical trial of combination carboplatin/etoposide in a similar set of patients with high-risk ANLL. The main aim of this study was to increase response rate. This combination was chosen because (1) each drug has independent activity in ANLL, and (2) this combination has been tested extensively in patients with small and non-small cell lung cancer, and therefore the toxicity and maximum tolerated dose are known. Criteria for trial entry, supportive care, and response were essentially the same as those previously reported for carboplatin alone and have been described in detail elsewhere [10]. The regimen consisted of carboplatin 300 mg/mVd for 5 days (total dose 1,500 mg/m2) administered by continuous infu-

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[8]

41

The comparison of the main clinical characteristics, therapeutic results, and toxicities in both trials conducted in our unit to treat high-risk ANLL with carboplatin alone or carboplatin/etoposide are shown in Table 2. Responses observed in relapsed and refractory ANLL, and particularly in ANLL secondary to myelodysplastic syndrome, are encouraging. The most striking difference in toxicity between both regimens was the increased gastrointestinal involvement, particularly hemorrhagic enterocolitis in the carboplatin/etoposide study.

Conclusions and future directions

In light of current experience, carboplatin appears to be an effective agent with scanty extrahematologic toxicity, which can be used in the treatment of ANLL and should be considered for evaluation as first-line treatment either alone or in combination with other active drugs. The addition of etoposide seems to offer some

Table 2. Characteristics of patients with high-risk ANLL and results of carboplatin-based regimens.

No. patients Sex Male Female Age (yr) Median Range Response to induction (%) CR Failure Stage of disease (CR) Primary resistant ANLL Relapsed ANLL Secondary ANLL Myelodysplastic syndrome Solid tumor" Blastic-phase (CML)

Carboplatin

Carboplatin/ Etoposide

27

20

16 11

13 7

50 16-71

43 20-67

8 (30) 19

8 (40) 12

6 (2) 1 3 (2) 33% 9 (2) J 7 (2) 2 (0) 9(2)

8 (3) ] 3(1) 47% 4 (3) J 4 (3) 0 5(1)

a

One lung oat cell carcinoma and one cavum lymphoepithelioma. CML = chronic myelogenous leukemia.

advantage over carboplatin alone in high-risk ANLL, as it produces a slightly higher CR rate despite causing more toxic side effects. Due to the marrow-specific toxicity of carboplatin i.v. and its scanty nonhematologic toxicity, this drug could be incorporated into bone marrow transplantation programs where drug administration is limited only by extramedullary toxicity. The encouraging preliminary results of carboplatin in ANLL secondary to myelodysplastic syndrome warrants further testing of this drug in a larger series of these patients with a particularly poor prognosis, and also in high-risk myelodysplastic syndrome patients before transformation into acute leukemia occurs. Finally, carboplatin could be included in the postremission strategy of intensive chemotherapy protocols for ANLL. References 1. Rose WC, Schurig J. Preclinical antitumor and toxicologic profile of carboplatin. Cancer Treat Rev 1985; 12: 1-19. 2. Calvert AH, Harland SJ, Newell DR et al. Early clinical studies with cis-diamine-ll cyclobutane dicarboxylate platinum II. Cancer Chemother Pharmacol 1982; 2: 140-7. 3. Barnard CFS, Cleare MS, Hydes PC. Second generation anticancer platinum compounds. Chem Britain 1986; 22: 1001-4. 4. Chibber R, Ord MJ. The mutagenic and carcinogenic properties of three second generation antitumor platinum compounds: a comparison with cisplatin. Eur J Cancer Clin Oncol 1989; 25: 27-33. 5. Prestayko AW, Bradner WT, Huftalen JB et al. Antileukemic (1210) activity and toxicity of cis-dichlorodiammine platinum (II) analogs. Cancer Treat Rep 1979; 63: 1503-8. 6. Meyers MJ, Welborn J, Lewis JP et al. A phase I trial of carboplatin (CBDCA) in relapsed acute leukemia. Evidence of efficacy with limited toxicity (abstr 575). Proc Am Soc Clin Oncol 1987; 6: 146.

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sion in combination with etoposide 100 mg/m 2 /d on days 1 through 3 in the first 10 patients and through day 4 in the remaining patients. Patients entering CR were given consolidation with a 25% carboplatin dose reduction and the same dose of etoposide; no further maintenance chemotherapy was administered. When suitable, some patients were considered for autologous bone marrow transplant. Currently, 20 patients have entered the study (median age, 43 years; range, 20 to 67). Fifteen patients had ANLL (8 refractory, 3 relapsed, 4 secondary to myelodysplastic syndrome), and 5 patients were in the myeloid blastic phase of chronic myelogenous leukemia. Eight patients (40%) achieved CR (3 refractory ANLL, 3 ANLL secondary to myelodysplastic syndrome, 1 relapsed ANLL, and 1 blasticphase chronic myelogenous leukemia). Seven patients showed leukemic resistance and 5 died during hypoplasia. Median duration of neutropenia (polymorphonuclear leukocytes <1 x 109/L) and thrombocytopenia (platelets <50 x 10VL) in patients who achieved CR were 25 days (range, 16 to 35) and 30 days (range, 22 to 44), respectively. All 20 patients had fever. In 17 patients with infection the cause was documented either microbiologically (9 patients) or clinically (8 patients). The major nonhematologic toxicity involved the gastrointestinal tract, with severe bleeding in 5 patients. Moderate hepatic toxicity (9 cases), nausea and vomiting (7 cases), and diarrhea (11 cases) were also observed. Only 1 patient showed ototoxicity. The concurrent use of antibiotics and other drugs makes it difficult to determine the degree to which carboplatin or etoposide was responsible for these toxicities. However, it should be noted that most patients treated with carboplatin at dose levels exceeding 1,500 mg/m2 administered via bolus injection and combined with etoposide developed at least grade 2 enterocolitis [14]. Other characteristic side effects of platinum derivatives were not seen or were very infrequent in our series.

42 Lee EJ, Tait N, Egorin M et al. Phase I trial of carboplatin (CBDCA) in relapsed/refractory adult leukemia (abstr 617). Proc Am Soc Clin Oncol 1987; 6: 157. Meyers FJ, Welborn J, Lewis JP et al. Infusion carboplatin treatment of relapsed and refractory acute leukemia: evidence of efficacy with minimal extramedullary toxicity at intermedial doses. J Clin Oncol 1989; 7: 173-8. Lee EJ, Egorin MJ, Van Echo DA et al. Phase I and pharmacokinetic trial of carboplatin in refractory adult leukemia. J Natl Cancer Inst 1988; 80: 131-5. 10. Martinez JA, Martin G, Sanz GF et al. A phase II clinical trial of carboplatin infusion in high-risk acute nonlymphoblastic leukemia. J Clin Oncol 1991; 9: 39-43. Lazzarino M, Morra E, Alessandrino EP et al. Treatment of relapsed and refractory acute myeloid leukemia in adults. Bone Marrow Transplant 1989;4(suppl 1): 121-3. 12. Reece PA, Stafford I, Abbot RL et al. Two- versus 24-hour

infusion of cisplatin: pharmacokinetic considerations. J Clin Oncol 1989; 7: 270-5. 13. Vogler WR, Lazarus HM, Winton EF et al. A phase II clinical trial of carboplatin in relapsed and refractory leukemia by the Eastern Cooperative Oncology Group (abstr 1319). Blood 1990;76(suppl 1): 332. 14. Nichols CR, Tricot G, Williams SD et al. Dose-intensive chemotherapy in refractory germ cell cancer. A phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation. J Clin Oncol 1989; 7: 932-9. Correspondence to: Dr. Miguel A. Sanz Seccion de Hematologia Chnica Hospital La Fe AvdaCampanar 19 46009 Valencia, Spain

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