33

Phase I-II study of achrubicin for treatment of acute myeloid leukaemia

David Machover t Julio Castiaburu t Michel Delgado', Emma Goldschmidt', R ~ i n a l ~ H ~ l h ~ ~ e n ~ , Manuel Benavides Jean-Pierre Lotz: Jean-Louis Misset', Francoise d e Vassal , H a m Tapiero', Patricia Ribaud', L&n Schwarzenberg'and Georges Math&'

' Service des Maladies Sanguines et Tumorales et ICIG, CNRS UA 04-1 163, Hopital Paul-Brousse, 94804-Villejuif, F rance 'Service d e Pharmacothc!rapie, Cliniques Saint-Luc, Universitc! Cathol ique d e Louvain, 1200-Bruxelles, Belgique

SUMMARY

Aclarubicin (ACM) was administered as induction t r e a t m e n t to 38 evaluable pa t i en t s with a c u t e myeloid leukaemia (AML) who were e i the r r e f r ac to ry to in i t ia l chemotherapy or in relapse. Thi r teen pa t i en t s received daily doses of ACM while t h e remaining 2 5 were given 10-day courses with 10-day in te rva ls be tween courses. The overall C R r a t e was 34% and t h e incidence and sever i ty of t h e tox ic e f f e c t s were re la ted to t h e dose of ACM adminis te red per cour se of therapy. Our resu l t s ind ica te t h a t ACM is a major new drug fo r t h e t r e a t m e n t of AML.

INTRODUCTION

Aclarubicin (ACM) is one of t h e an t i tumoura l an thracyc l ines produced by fe rmenta t ion of S t rep tomyces gali leus MA-144-MI (1). If d i f fe rs f rom daunorubicin (DNR) and doxorubicin (ADM) in severa l subs t i tu t ions on t h e hydrophobic rings (aklavinone) and in t h e t h r e e hexopyranoses which a r e a t t a c h e d to aklavinone by glycosidic linkage. In t h e Ames test ACM, unlike DNR and ADM, was found to b e non-mutagenic (2). The drug exe r t s a wide spec t rum of ac t iv i ty aga ins t an imal tumours (3, 4, 5) and i t h a s been shown to b e less cardiotoxic than ADM and DNR (6, 7).

Initial phase I s tud ies have been repor ted previously by o the r s ( 8 , 9 , 10). The toxic e f f e c t s no ted w e r e t rans ien t d i s turbances of hepa t i c function, mild gas t ro in tes t ina l toxicity, and dose-dependent myelosuppression. Alopecia was minimal, and minor EKG abnormal i t ies were seldom observed. No case of conges t ive h e a r t fa i lure was reported. In these phase I studies, tumour regression was observed in a smal l pe rcen tage of pa t ien ts with lymphomas and with various carcinomas.

In our own preliminary s tudies w e observed an t i tumoura l ac t iv i ty of ACM in a c u t e lymphocytic leukaernia (AML) (11, 12, 13). These ear ly s tud ies have ne i ther fully explored t h e degree of ac t iv i ty of ACM in AML nor c la r i f ied t h e opt imal dose schedule when t h e drug is used o n a daily adminis t ra t ion basis. In t h e present r epor t w e descr ibe a phase 1-11 s tudy of ACM for AML using two d i f fe ren t t r e a t m e n t modalities. This study was conducted f rom September 1978 to Oc tobe r 1982.

34

PATIENTS AND METHODS

Pa t i en t s with ove r t AML were eligible fo r en t ry in this study e i the r a f t e r init ial fa i lure to respond to s tandard induction chemotherapy or upon relapse. For ty pa t i en t s were en te red in t h e study. Two of t hese were l a t e r excluded because of protocol violations. The 38 evaluable pa t ien ts (Table 1) were f rom 2 to 80 years old (mean 3.2 years); 23 were male and 15 were female . None of t h e pa t i en t s had any history of previous

SE, 35.0

TABLE 1 Charactertstics of the 38 AM patients treated with aclarubicin

I No. o f patients treated I

I Regimen I I Regimen I1 I I I I

Patient characteristics I with I All patients

Age range (years) 2-10 11-39 40-80

2 5 6

1

3 i 5 12 I 17 10 I 16

I I I I I I

Sex I I I Male I 10 I 13 I 23 Female 1 3 I 12 I 15

I I I Cytologic type I I I Acute myelocytic I 10 I 18 I 28

1 Acute promyel ocytic l - I 1 Acute myelomonocytic 1 3 ‘ 9 I 6 I I

I I I

0 1 2 i 1 3 i 5 I No. o f previous remissions I

1 1 6 I 18 I 24 a

i 1 2 i 4 i 4 3 l l I - I

Prior resistance to i daunorubicin or doxorubicin I Yes * 1 7 Unknown 1 6

I I

10 I 17 15 I 21

Patients who received ACM after an unsuccessful attempt had been made to obtain a CR with various intensive regimens including doxorubicin or dauno- rubicin.

rnyeloproliferative or rnyelodysplastic syndromes. All cases were subclassified according to t h e World Heal th Organization (WHO) classification of neoplastic haematopoie t ic diseases (14); cytologic types included 28 cases of a c u t e rnyelocytic leukaernia, 1 case of a c u t e promyelocytic leukaemia, and 9 cases of a c u t e myelornonocytic leukaernia. All pa t i en t s had received previous chemotherapy fo r AML including DNR or ADM o r both. Five pa t i en t s had shown primary res i s tance to 1-3 courses of a n intensive regimen combining ADM (50 mg/rn2, day I) , vincrist ine (VCR) (1 mg/rn2, day 2) and cy ta rab ine (Ara-C) (160 mg/m2/day, days 2-81,

35

and 33 pa t ien ts were t r e a t e d with ACM a f t e r 1-3 relapses. Of t h e 33 pa t ien ts in relapse, 12 received ACM a f t e r a n unsuccessful a t t e m p t had been made to obta in another remission with various intensive reg imens t h a t included ADM or DNR: 8 pa t ien ts received t h e s a m e chemotherapy described above, 3 pa t i en t s were t r e a t e d with a reg imen combining DNR (45 m /m2/day, days I-3), cytarab ine (100 mg/m2/day, days 1-5) and thioguanine (100

DNR. The remaining 21 pa t i en t s received ACM immedia te ly a f t e r t h e diagnosis of relapse; their s t a tus in regard to res i s tance to ADM or DNR was thus unknown.

ACM was given daily by rapid i.v. injection. T h e following 2 therapeut ic reg imens were used: in Regimen 1, groups of 2-4 pa t i en t s were t r e a t e d with increasing daily doses, unti l a maximum total dose of 300 mg/m2 was reached or until unacceptab le toxicity appeared. The s ta r t ing daily dose was 10 mg/m2. Each of t h e 1 3 pa t i en t s t r e a t e d f rom September 1978 t o March 1980 received a single course of ACM according to one of t h e four following schedules: a) ,2 pa t i en t s reze ived 10 mg/m2/day, b) 4 pa t i en t s rece ived 15 mg/m2/day, C) 3 pat ien ts received 20 mg/m /day, and d) 4 pa t ien ts received 30 mg/m2/day. By May 1980, t h e t r ea tmen t modality was modified because t h e tox ic i ty with Regimen I was high. In Regimen 2, 25 pa t i en t s received a cyc l ic t r e a t m e n t with ACM. They were given 10-day courses at a daily dose of 15 mg/m2; t h e in te rva ls be tween courses were fixed at 10 days. For t h e s e 2 5 patients, courses of ACM were repea ted until t h e blast ce l l s were c leared f rom peripheral blood and bone marrow, o r un t i l progressive disease became evident.

Before en ter ing t h e tr ial , a l l pa t i en t s were eva lua ted by physical examination, marrow aspirate, blood count , t h e usual biochemical profile, EKG, and ches t roentgenograms. During t h e t r ea tmen t , bone marrow smear s were examined weekly, blood counts were per formed daily and liver function tests, serum e lec t ro ly tes , BUN, and crea t in ine w e r e de te rmined a t least twice a week. An EKG was per formed before each dose of ACM, and QRS vol tages were compared according to t h e method of Minow et al. (15). All of t h e pa t i en t s rece ived intensive haematological suppor t ive t r ea tmen t .

The CALCG remission c r i t e r i a were used (16) and only comple t e remissions (CR) were considered to b e significant. Af t e r a t ta in ing a CR, t h e pa t ien ts rece ived various main- t enance chemotherapy regimens. Toxicity was scored according to WHO recommendat ions (1 7). S t a t i s t i ca l comparisons were per formed with t h e chi-square test.

mg/m 9 /day, days 1-5). Therefore , a t o t a l of 17 pa t i en t s were considered res i s tan t to ADM o r

RESULTS

Response to therapy

Of t h e 13 pa t ien ts subjected to Regimen 1, four received a to t a l dose of 300 mg/m2 and 9 rece ived lower doses ranging f rom 150 t o 280 mg/m2. In th i s group, a C R was a t t a ined by 2 pa t ien ts (15%) who received a total dose of 300 mg/m2. Duration of C R s was 6 and 17 weeks (Table 2). Of t h e 25 pa t i en t s who received Regimen 2, e leven (44%) a t t a ined a CR. Comple t e remissions were a t t a ined a f t e r 1 course (150 m g / d ) by 3 pat ien ts , a f t e r 2 courses (300 mg/m2) by 5, a f t e r 3 cour ses (450 mg/m2) by 1, and a f t e r 4 cour ses (600 m g / d ) by 2 patients. Duration of C R s were 5 , 8, 9, 10, 22, 26, 30, 30, 34, 38 and 86 weeks. T h e overall C R r a t e fo r t h e 38 pa t i en t s was 34%. Upon relapse, 3 of t h e I 1 comple t e responders to Regimen 2 were submi t ted to a second induction t r e a t m e n t with ACM and 2 again a t t a ined a C R of 6 and 13 weeks. Fur thermore , as indicated in Table 3 , 6 pa t ien ts who had previously shown res i s tance to a regimen including vincristine, cy ta rab ine and modera t e doses of ADM, a t t a ined a C R with ACM.

36

TABLE 2 Response t o ac la rub ic in according t o regimens and t o the t o t a l dose administered

Regimen and t o t a l dose (mg/m'

I Nlonber o f I N d e r o f I Durat ion I p a t i e n t s I p a t i e n t s I o f CRs*

I i n CR (2) I i n weeks I I I I

I I I Reaimen 1 I I I

150-200 201-280

300

i 3 i o I 1 6 I 0 I

1 2 I 6, 17 l 4 I i 13 i 2 (15) i I I I I I

I Regimen 2 I I I 26, 38, 86 150 1 7 1 3

300 I 11 1 5 I 9, 10, 30, 30, 34 450 1 3 1 1 I 22 600 1 4 1 2 I 5, 8

1- I I I

I A l l p a t i e n t s I 38 I 13 (34) I

I I I

A f t e r a t t a i n i n g a CR. t h e pa t ien ts received var ious maintenance chemotherapy regimens

No s t a t i s t i ca l d i f fe rence was found in comparisons of t h e incidence of CR according to age, cy to logic type of AML, or number of previous remissions ( for da t a , see Table 2). In most of t h e pa t ien ts no cy togenet ic s tud ies were per formed and the re fo re t h e results could not b e analysed fo r t h e incidence of CR.

TABLE 3 Response t o ac la rub ic in according t o p a t i e n t c h a r a c t e r i s t i c s

P a t i e n t c h a r a c t e r i s t i c s Response t o therapy CR I F a i l u r e P value

Age range (years) 2-39

40-80 I I

I I I I Cy to log ic type I I I I

I 0.95 I 3 1 6 I

Acute myelocyt ic I 9 I 19 Acute myelomonocytic I

I I 1** 1 0 i Acute promyel o c y t i c

I No. o f previous remissions I

I I

P r i o r res is tance t o I daunorubicin o r doxorubic in I

0 o r 1 9 2 or 3 I 4 I

Yes*** Unknown I

I I I I I 0.74 I

5 I I I

I I I I I I

11 I I 14 I

20

I

* S t a t i s t i c a l comparisons o f t h e incidence o f CR w i t h c h a r a c t e r i s t i c s o f p a t i e n t s were performed w i t h t h e chi-square t e s t .

Pa t ien ts who were r e s i s t a n t t o previous induc t ion t reatment inc lud ing ADM or DNR (only doses o f anthracycl ines are given): 13 p a t i e n t s received ADM (50 mg/m', day 11, VCR and Ara-C; 3 p a t i e n t s were t r e a t e d w i t h DNR (45 mg/mz, days 1-3). 6-TG and Ara-C; and 1 p a t i e n t received DNR alone (25 mg/m', days 1 - 5 ) . **** Two p a t i e n t s were t rea ted w i t h Regimen 1, and 4 w i t h Regimen 2. A l l had prev ious ly shown resistance t o co lb ined treatment w i t h A H , VCR and Ara-C.

** Not included i n s t a t i s t i c a l comparisons. ***

37

Toxicity

The incidence and sever i ty of t h e toxic e f f e c t s were re la ted to t h e to t a l dose of A C M administered during each course of therapy (Table 4). Toxic e f f e c t s led to discontinuation of therapy in 9 pa t i en t s subjected to Regimen 1, at t5tal doses ranging f rom 150 to 280 mg/rr?. In this regimen, only t h e 4 pa t ien ts who rece ived 30 mg/m2/day could a t t a i n t h e total planned dose of 300 mg/m2. This was explained by t h e delayed appearance of toxicity induced by ACM (occurring in most cases a f t e r t h e 10th day of t r e a t m e n t ) which only allowed completion of t h e shor te r courses. Al l pa t i en t s t r ea t ed with Regimen 2 received t h e total planned dose of 150 mg/m2 per course.

TABLE 4 T o x i c i t y according t o dose o f a c l a r u b i c i n per course

I No. o f p a t i e n t s w i t h t o x i c e f f e c t s I I according t o dose pe r course (mg/m') I I I I I 1 150** I 170-200 I 201-250 251-300 I I (N = 26) I (N = 2 ) I (N = 3 ) I (N = 7 I I I I I I

O r a l mucos i t i s * 1 I 1 I 0 1 0 1 0 1 2 1 5 I l l 2 1 4 1

Tox ic e f f e c t

3 1 2 i o i o i o i 4 I 0 1 0 1 1 1 1 1

i 8 i i i j i S i I I I I I

Diarrhoea 2 1 4 I l l 2 1 1 1 3 I 0 I l l 0 1 5 1

Nausea /vmi t i ng 1 i 3 i i i i i z i 2 1 2 I 0 1 2 1 4 1

I I 1 1 I I n fec t i on* * * I I I I

Non-documented f e v e r I 3 I 0 I 1 I 1 I Septicaemia I 7 ( 2 ) 1 1 I 2 I 4 I Pneumoni t i s I l ( 1 ) I 0 I 0 I 1 I Septicaemia & pneumonitis I 0 I 1 (111 0 I 1 I

I 1 1 I 2 1 3 1 7 ! I I I I

I I Renal dys func t i on I None I

I I

L i v e r dys func t i on I 4**** I 0 1 0 1 0 1

A lopec ia I None i n 14 eva luab le p a t i e n t s I

* T o x i c i t y score according t o WHO recommendations (17). ** Th is group inc ludes 1 p a t i e n t who rece ived Regimen 1 and a l l p a t i e n t s

t r e a t e d w i t h Regimen 2. *** Numbers i n parentheses denote p a t i e n t s who d i e d o f i n f e c t i o n .

**** Trans ien t , m i l d i nc rease o f serum transaminases, ma in l y SGPT (150 t o 200 U/1; normal values 15-35 U / l ) .

Chi-square t e s t showed a h i g h l y s i g n i f i c a n t d i f f e r e n c e when we compared t h e incidence o f mucos i t i s d iarrhoea, vomi t i ng and i n f e c t i o n between p a t i e n t s who rece ived 150 mg/m' pe r course and those who rece ived doses equal t o or grea te r than 170 mg/m' pe r course. P values were(0.02, 10-6 , (0.001, and (0.01, r e s p e c t i v e l y .

38

All pa t i en t s had granulocytopenia with less than 200 granulocytes /mm3 and t h e number of p l a t e l e t s was less t han 30,00O/mm requiring p la te le t transfusions. The t i m e required for recovery of myelopoiesis f rom t h e end of t r e a t m e n t was 25-35 days in responders t r ea t ed with Regimen 1 and 10-15 days in those t r ea t ed with Regimen 2.

Diarrhoea, mucosit is , and infec t ion complicating granulocytopenia were t h e most prominent tox ic e f fec ts . Nausea and vomiting were less prevalent. The incidence of these tox ic e f f e c t s in t h e 12 pa t ien ts who received doses of A C M above 150 m g / d per course was significantly higher than observed in t h e 26 pa t ien ts who rece ived a dose of 150 mg/m per cour se ( fo r da ta , see Table 2). A t rans ien t , mild increase in serum transaminases, mainly SGPT, was observed in 4 patients. However, hepa t i c tox ic i ty was difficult to assess because these 4 pa t i en t s were heavily transfused and were receiving concurren t an t ib io t ic therapy which could explain the i r mild liver dysfunction.

Alopecia did not occur in any of t h e 14 pa t iens evaluable fo r hair loss.

A s shown in Table 5, t h ree pa t i en t s developed t rans ien t inversion of T-wave and one had one episode of a t r i a l f lu t te r . None of these pa t i en t s had any underlying ca rd iac disease or hypertension. No significant dec rease in t h e QRS ampl i tude was observed. Congestive hea r t fa i lure did not occur during t h e observation period.

Loca l phlebit is at t h e injection s i t e was not observed and drug ex t ravasa t ion did not occur in any of t h e patients.

TABLE 5 Cardiac t o x i c i t y according t o cumulative dose o f aclarubicin administered (N = 38)

Type o f cardiac I No. o f I Cumulative dose I Previous amount I t o x i c i t y I pat ients I o f ACU a t which I o f daunorubicin I

I I t o x i c i t y appeared I and/or doxorubicinl I 1 (mg/m') I (mg/m') I I 1 I I I I 1 I

Transient inversion I I I I o f T-wave I 3 I 450, 510, 690 I 300, 140, 100 I

I I I I Reversible a t r i a l I I I

I I I I None I 34* I I

I I I I

f l u t t e r I l l I 300 I 290 I

270 (mean) I

The 34 pa t ien ts without cardiac t o x i c i t y received doses o f ACM ranging f r o m 150 t o 600 mg/m' (mean 310 mg/m'). rub ic in or daunorubicin, or both.

Al l had previously been t rea ted with doxo-

39

DISCUSSION

The results of this study ind ica te t h a t ACM induced a high r a t e of C R (34% overall) in previously t r e a t e d AML patients. With Regimen I , t h e C R r a t e was 15%. This t r e a t m e n t modality produced a high incidence of severe tox ic e f f e c t s which usually appeared a f t e r t h e 10th day of t r e a t m e n t at t o t a l doses above 150 mg/m2, leading, in most cases, t o discontinuation of therapy. In Regimen 2, we were ab le to avoid severe toxicity in most of t h e patients. With t h e cyc l ic schedule employed in th i s regimen, t h e C R r a t e was also improved: 44% of t h e pa t i en t s a t t a ined a C R a f t e r 1-4 t r e a t m e n t courses.

From th is s tudy it was n o t possible to de te rmine t h e minimal total dose of ACM required fo r pa t i en t s to achieve a CR. Some pa t ien ts a t t a ined a C R a f t e r receiving 150 mg/mz, which was t h e lowest t o t a l dose adminis te red during t h e study. However, t h e cumula ted dose required fo r t h e majority of t h e pa t ien ts to achieve a C R was equal o r superior to 300 mg/m2. W e believe t h a t t h e low response r a t e obtained wi th Regimen 1 could b e explained, in pa r t , by t h e insufficient amount of ACM adminis te red to most pa t i en t s because of t h e major tox ic e f f e c t s induced by th i s t r ea tmen t . Regimen 2, a much less toxic schedule, allowed t h e administration of higher t o t a l doses of ACM, and therefore , improved t h e therapeut ic e f f icacy of t h e drug.

Yamada et al. (18) repor ted CR r a t e s of 35% in 20 previously unt rea ted and 18% in 33 previous t r e a t e d AML patients. The schedule of ACM used in the i r t r i a l consisted of daily administration of 15 mg/m2 until tox ic i ty developed. Warrell et al. (19) adminis te red ACM a t doses of 100-120 mg/rn2/day for 2-3 days to 34 pa t iens with a c u t e non-lymphocytic leukaemia. Of these, only 4 (11%) a t t a ined a CR.

The schedules used in t h e present s tudy were se lec ted on t h e basis of exper imenta l d a t a obta ined with tumour-bearing mice (3, 4, 5, 20). The opt imal dose and schedule of ACM for t r e a m e n t of AML a r e still uncertain. Our results and those obtained by o the r s (18, 19, 21) suggest t h a t daily adminis t ra t ion of smal l doses of ACM over a n ex tended period is more e f f e c t i v e than adminis t ra t ion o f high doses fo r a shor t t ime. However, our resu l t s a l so ind ica te t h a t in t h e cases of prolonged t r e a t m e n t with smal l daily doses, t h e total amoun t of ACM per course should no t exceed 150 mg/m2, in order to avoid seve re drug-induced toxicity. For these reasons, w e recommend fo r fur ther clinical t r ia l s t h e administration of ACM at t h e daily dose of 15 mg/m2 over 10 days wi th 10-day in te rva ls be tween courses.

Moreover, 6 pat ien ts previously res i s tan t to an intensive regimen comprising vincrist ine, cy ta rab ine and modera t e doses of ADM, a t t a ined a C R with ACM. These resu l t s support previous clinical s tud ies (18, 22, 23) which suggest t h a t t h e r e is no cross-resistance be tween ADM o r DNR, and ACM. Absence of cross-resistance has been experimentally demonst ra ted in Friend leukaemia cell l ines (24). However, o the r s tud ies per formed with DNR-resistant L1210 and ADM-resistant P388 leukaemias have shown t h a t t hese ce l l s were a l so res i s tan t to ACM (3, 5).

Dose-related ora l mucosit is and diarrhoea were prominent toxic e f f e c t s observed during th i s study. Other inves t iga tors (18, 19) have repor ted mucosit is in 32-53% and d ia r rhoea in 12- 26% of pa t i en t s with a c u t e leukaemia t r ea t ed with ACM.

Alopecia was no t observed in t h e present study. This is in ag reemen t with exper imenta l resu l t s obtained in ACM-treated hams te r s (6 ) .

40

In t h e present study, ca rd iac toxicity was l imited to t rans ien t T-wave inversion in 3 pa t i en t s and to a single episode of a t r i a l f lu t te r . O the r clinical s tud ies have shown t h a t ACM c a n induce ca rd iac dysrythmias and repolarisation d is turbances (18, 19, 25, 26). Conges t ive h e a r t fa i lure a t t r i bu tab le to ACM has n o t been repor ted thus far. However, a n assessment of t h e risk of chronic an thracyc l ine cardiomyopathy will no t b e possible until a c c u r a t e ca rd iac monitoring is ca r r i ed ou t on a much la rger number of pa t i en t s t r e a t e d with higher cumula t ive doses of ACM.

W e conclude t h a t ACM appea r s to b e a major new drug for t h e t r e a t m e n t of AML. Its use as a single agen t and in combination reg imens mer i t s fur ther clinical trials.

ACKNOWLEDGEMENTS

W e thank Pr. H. Rappaport , Drs. L. Berumen and R. Maral and Miss L. Pr i tchard fo r the i r support and cons t ruc t ive comment s and Mrs. Nicole Vriz and Elisabeth Couv6 for prepar- a t ion of t h e manuscript.

Aclarubicin was supplied by Labora to i res Roger Bellon, Neuilly s/Seine, France.

This work was supported in p a r t by t h e Simone and Cino Del Duca Foundation.

41

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