Clinical Trials

Mitoxantrone and High-Dose Etoposide for Patients With Relapsed or Refractory Acute Leukemia Susan O’Brien, MD, Hagop Kantarjian, MD, Elihu Estey, MD, Charles Koller, MD, Miloslav Beran, MD, PhD, Kenneth McCredie, MB, ChB, and Michael Keating, MB, BS

Among 35 patients with relapsed or refractory acute myelogenous leukemia (AML) who received salvage chemotherapy, 28 were treated with mitoxantrone (7.5 mg/ m2/d intravenously [IV] over 1 hour for 5 days) and etoposide (VP-16) (2 g/mZ over 4 days either as a daily infusion or as two daily doses). Seven patients received mitoxantrone (6 mg/m2/d for 5 days) and VP-16 (1500 mg/mz over 3 days). The median duration of the initial complete remission (CR) was 6 months and 83% of the patients had initial CR that lasted 12 months or less. Forty-six percent of the patients were undergoing a second or subsequent salvage attempt. Eight patients (23%) achieved CR; seven of these CR were obtained after one course of therapy. Twelve patients (33%) died and 15 patients (42%) had disease that was resistant to treatment. Patients undergoing a first salvage attempt had a higher incidence rate of CR than those undergoing a second or subsequent salvage attempt (37% versus 6%; P = 0.03). CR rates were also higher in patients with a favorable (translocation 8;21 or 15;17) or diploid karyotype compared with other patients (32% versus 8%; P = 0.10). The median survival time was 2 months for all patients and 8 months for patients achieving CR. Mucositis occurred in 74% of the patients and was severe in 32%. Diarrhea and rash occurred in less than 33% of the patients. Fever was noticed in all but 1 of the patients and documented infections occurred in 65% of the patients. Six patients had pancytopenia or thrombocytopenia that lasted more than 42 days from the initiation of treatment. Although mitoxantrone and high-dose VP-16 is an effective antileukemic regimen, it is associated with a high incidence of mucositis. Strategies that are used to limit mucosal damage may improve the tolerance of this combination. Cancer 68:691-694,1991.

LTHOUGH induction chemotherapy for acute my- A elogenous leukemia (AML) results in complete re- mission (CR) in 65% to 75% of the patients, disease will recur in most responders and they will subsequently die of their disease.’ New drugs or new combinations of drugs are needed to increase the likelihood of obtaining a second

From the Department of Hematology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Address for reprints: Susan OBrien, MD, Department of Hematology, Box 6 1, The University of Texas M.D. Anderson Cancer Center, 15 15 Holcombe Boulevard, Houston, TX 77030.

Accepted for publication May 17, 199 1.

remission. Drugs effective in relapse might then be in- corporated into front-line regimens.

Mitoxantrone produces a CR rate of 10% to 40% when used as a single agent for patients with AML whose disease has relapsed or never responded.24 Etoposide (VP- 16) at doses of 100 mg/m2/d for 5 days is similarly effective in patients with recurrent AML.5-7 Mitoxantrone and VP- 16 have been used in combination for relapsed AML by various groups. Ho et al. gave 10 mg/m2/d of mitoxan- trone concurrently with 100 mg/m2/d of VP- I6 for 5 days to 6 1 patients. Twenty-six patients (42.6%) attained CR.8 When treating 23 patients, Lazzarino et al. used the same

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dosages of mitoxantrone and VP- 16 but gave the VP- 16 in two daily doses, attaining a CR rate of 6 1%.' Although these investigators used an amount of mitoxantrone close to the maximally tolerated dosage (MTD), their dosage of VP- 16 might be considered low because some Phase I studies have shown VP-16 to have an MTD of 2.7 to 3.5 g/m2'07'1 and there is in vitro and in vivo evidence of the increasing effectiveness of VP-16 as the dosage is raised.I2-I5 This study investigates higher dosages of VP- 16 in combination with mitoxantrone.

Patients and Methods

Thirty-five adult patients with relapsed or refractory AML entered the study after giving written informed con- sent. Thirty-four patients had 30% or greater blasts in the bone marrow, and 1 patient had disseminated leukemia cutis but a normal bone marrow. Criteria for entry in- cluded a Zubrod performance status of 3 or less and nor- mal hepatic and renal functions. CR was defined as the presence of 5% or less blasts in normocellular or hyper- cellular bone marrow and normal peripheral counts and differential, including a hemoglobin (Hb) value of greater than 10 g/dl, a granulocyte count of greater than 1500 cells/gl, and a platelet count of greater than 100 X lo3 cells/gl. Other forms of response were called failures and were categorized as follows: (1) early death, which oc- curred within 2 weeks of the start of therapy; (2) aplastic death, which occurred 2 weeks after the start of therapy, with hypocellular marrow and a marrow leukemic infil- trate (LI) (marrow cellularity X percentage of blasts) of less than 10%; (3) primary resistance in which the patient never achieved a marrow LI of less than 10%; and (4) secondary resistance in which the marrow LI of the patient decreased to less than 10% with subsequent leukemic re- growth. Survival was calculated from the date chemo- therapy began. The duration of remission was calculated from the time of CR until relapse. Differences among subgroups were compared using the chi-square test. Sur- vival and remission duration curves were plotted using the Kaplan-Meier method.16

Patient characteristics are outlined in Table 1. The me- dian age of the patients was 35 years (range, 20 to 76 years). All patients had received cytosine arabinoside (ara- C) in one of the following dosages: (1) a continuous in- fusion of 1.5 g/m2/d for 2 to 4 days (28 patients); (2) 500 mg/m2 every 12 hours for 12 to 15 doses (4 patients); or (3) 100 to 200 mg/m2/d for 7 days (3 patients). Ten pa- tients had not previously received anthracyclines. Fifty- four percent of the patients were undergoing first salvage therapy. The median duration of the first remission was 6 months and 83% of the patients had an initial CR that lasted 12 months or less. The diagnosis and classification of AML were made according to the French-American- British (FAB) criteria.'7 Cytogenetic studies were per-

TABLE 1. Patient Characteristics

No. Percent

Total no. of patients Sex

Female Male

Age t 60 yr Performance status

0 1

3 Previous anthracycline therapy Cytogenetics

Favorable [t(8;21),t( 15;17)] Diploid Unfavorable [-5, -7, +8] Other

Duration of first complete remission

35 100

13 37 22 63

8 23

9 26 17 49 3 9 6 17

25 72

7 20 15 43 I 20 6 17

Patients in first salvage

0-11 mo t 12mo

salvage 0-11 mo t 12mo

Patients in second or subsequent

< 50 50-64 2 65

10 5 2 1 0 1

7 2 1 4 1 1

formed using trypsin-Giemsa banding techniques and at least 25 metaphases were analyzed.'*

Eighteen patients received mitoxantrone at a dosage of 7.5 mg/m2/d intravenously (IV) over 1 hour for 5 days and VP- 16 at 500 mg/m2/d over 3 hours for 4 days. Based on the suggestion that mucositis was related to high peak levels of VP- 16, we gave 10 patients the same dosages but with a VP-16 schedule of 250 mg/m2 every 12 hours for 8 doses. Seven patients received mitoxantrone at a dosage of 6 mg/rn2/d for 5 days and VP-16 at 500 mg/m2/d for 3 days (- 1 dose level) because of the high incidence of mucositis seen in the initial patients.

Results Response and Survival

All patients were evaluable for response to therapy. Eight CR occurred (23%; 95% confidence limits, 10% to 40%), 7 after 1 course. One CR was that of the patient with cutaneous, but not medullary, disease. The responses of the remaining patients were as follows: early death, 4 patients (1 1%); aplastic death, 8 patients (23%); primary resistance, 4 patients ( 1 1 %); and secondary resistance, 1 1 patients (31%). Five of 18 patients who received VP-16 at 500 mg/m2/d for 4 days entered CR, as did 3 of 10 patients who received VP- 16 at 250 mg/m2 every 12 hours for 8 doses and 0 of 7 patients treated with the lower doses (P = 0.27); deaths occurred in 9 of 18, 3 of 10, and 0 of 7, respectively.

No. 4 MITOXANTRONE AND VP- 16 FOR LEUKEMIA * O’Brien et a[. 693

Patients undergoing their first salvage attempt re- sponded better than those who were undergoing a second or subsequent one (37% versus 6%; P = 0.03). CR rates were also better among patients whose marrow meta- phases showed a favorable (translocation 8;2 l or 15; 17) or diploid karyotype compared with the other categories (32% versus 8%; P = 0.10). Four of 10 patients who had not previously received anthracycline achieved CR versus 4 of 25 who had received such treatment (P = 0.13).

Six of the eight patients who achieved CR received fur- ther therapy. One patient with acute promyelocytic leu- kemia received consolidation treatment consisting of three courses of daunorubicin as a single agent; this patient re- mains in remission at 23+ months. Three patients who had donors were referred for allogeneic bone marrow transplantation. One patient continued the treatment with a 50% dose reduction for six courses and another patient received a consolidation course but died of pseudomonas sepsis during aplasia. Two patients experienced a relapse soon after achieving remission and were not eligible for maintenance therapy. Fourteen of I5 patients with disease resistant to mitoxantrone and VP- 16 received further sal- vage therapy but attained no remissions.

The overall median survival time was 2 months (range, 1 to 23+ months). For patients achieving CR, the median survival time was 8 months. The median duration of re- mission was 7 months (range, 3 to 23+ months). At the time of this analysis, one patient was alive and disease- free.

Toxicity The toxicities of the regimen are outlined in Table 2.

Four patients were not evaluable for toxicity: three because

TABLE 2. Toxicity of Mitoxantrone and High-Dose Etoposide

Toxicity No. of patients* (%)

Mucositis Mild to moderate Severe

Diarrhea Mild to moderate Severe

Mild Moderate

Rash

Elevated bilirubin value Elevated creatinine Febrile episodes

Fever of undetermined origin Documented infections

Bacterial Viral Fungal Pneumonia

Prolonged myelosuppressiont (z 42 days) Hypoplastic marrow (5 5% cellular) Thrombocytopenia alone

* Thirty-one patients were evaluable. t Twenty-five patients were evaluable.

TABLE 3. Incidence of Mucositis According to Schedule

Mucositis grade

Dosage schedule total (%) 1 2 3 No. with mucositis/

~

MITOX (5 or 6 mg/m2/d X 5) 5/6 (83) 3 0 2 VP- 16 ( 1500 mg/m2)

VP-16 (250 mg/m2 every 12 h X 8) MlTOX (7.5 mg/m2/d X 5) 13/15(87) 0 9 4 VP- I6 (500 mg/m2/d X 4)

MITOX (7.5 mg/m2/d X 5) 7/10 (70) 1 2 4

MITOX: mitoxantrone; VP-16: etoposide.

of their early death and one because of a lack of infor- mation. Nausea and vomiting were mild, but most pa- tients had been pretreated with antiemetics. The most common side effect was mucositis; this occurred in 74% of the patients and was severe in 32%. Neither the inci- dence nor severity of mucositis was dose related (Table 3). Other side effects were diarrhea in 29% of the patients (this was severe in 6%) and rash in 13%. All but one of the patients had febrile episodes. Documented infections were noticed in 65% of the patients. Disturbed hepatic function occurred in 45% of the patients and an elevated creatinine in 16%. All of these patients had fever or known infections, which made it difficult to assess the individual contributions of each. One patient experienced cardiac arrhythmias that required intensive care monitoring and treatment, but this patient had had cardiac arrhythmias before. No congestive heart failure was seen.

Myelosuppression

All patients required platelet and packed erythrocyte transfusions. Prolonged myelosuppression (a platelet count of -= 100 X lo3 cells/pl and a granulocyte count of < 1000 cells/pl42 days after the start of treatment despite a marrow with less than 5% blasts) occurred in 6 of 25 evaluable patients (Table 2). Three of these patients had pancytopenia and three had isolated thrombocytopenia. Of the three patients with hypocellular marrows, one ex- perienced progressive leukemia and received other treat- ment, one died of infection during aplasia, and one sub- sequently achieved CR. Two of the patients with throm- bocytopenia died of complications from multiorgan failure (these patients were 69 and 71 years of age). The third patient who had thrombocytopenia experienced central nervous system and cutaneous relapse and died.

Comparison With Expected CR Rate

Keating et al. l9 developed a proportional hazards model to predict the probability of response when using ara-C- based regimens for patients undergoing their first salvage attempt. In our study, 7 of 19 patients undergoing first salvage therapy attained CR; this number compares fa-

694 CANCER August 15 1991 Vol. 68

vorably with an expected number of 4.8. Among 16 pa- tients treated with second or subsequent salvage therapy, 1 (6%) achieved CR; this rate compares with the expected rate of 8% to 11% based on the Keating et al. model.

Discussion

The administration of mitoxantrone and high-dose VP- 16 resulted in a CR rate of 23% in a group of patients who had relapsed or refractory AML. Mucositis occurred in most patients and was severe in 32%, probably prohib- iting any further dosage increment. The CR rate reported here is similar to rates reported by others using one quarter the dosage of VP- 16. More precise comparison between treatments is difficult because of differences in the distri- bution of known and unknown prognostic factors among patients treated with the various regimens. The most im- portant prognostic factor in attaining CR after first relapse is the duration of the first remission.’9320 The patients in our study might be considered relatively poor risks because only 19 patients (54%) were undergoing a first salvage attempt, and only 2 of the 19 had had an initial CR that lasted longer than 1 year. In the study by Lazzarino et ~ l . , ~ the median duration of the patients’ first CR was 10.5 months; 10 of 23 patients were categorized as having AML M3, and 8 of 10 CR occurred in that subset. Sixty- seven percent of the patients treated by Ho et a1.* were refractory to treatment or had experienced a relapse within 6 months of attaining CR. Their CR rate of 42.6% had 95% confidence limits of 30% to 57%, which overlap with those seen in our study.

To assess this salvage regimen, we compared the out- come of our patients with an expected outcome based on the salvage model derived by Keating et al.I9 Using du- ration of first CR, age, and lactate dehydrogenase levels, we calculated an expected response rate for patients un- dergoing the first salvage attempt. In this group of 19 pa- tients, for whom the expected number of remissions is 4.8, 7 attained CR. Keating et al. demonstrated that, in patients undergoing a second or subsequent salvage at- tempt, only the duration of the initial CR has prognostic value. In that study 132 patients had a CR rate of 8% to 1 1% (95% confidence limits, 3% to 14%). Among our 16 patients undergoing second or subsequent salvage therapy, 1 attained remission, yielding a CR rate of 6%. This anal- ysis shows that the combination of mitoxantrone and high- dose VP- 16 seems to be as effective as, and perhaps slightly better than, ara-C-based salvage regimens in patients with poor prognoses.

The major complication of this regimen was mucositis and it was experienced by the majority of patients. Viral cultures of the oral mucosa, which were performed in some cases, grew herpes simplex. However, since this was not done routinely we cannot say that the reactivation of

herpes simplex and the severity of mucositis are correlated. Although mucositis was frequent in this study, its inci- dence and severity were similar to those seen by Lazzarino et al. with a lower dosage of VP- 16.

Mitoxantrone and high-dose VP- 16 have significant activity in patients with relapsed AML who have a poor prognosis. Mucositis is the major drug-related toxicity. Strategies that are used to limit mucosal injury may im- prove the tolerance of this combination.

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