American Journal of Hematology 4: 173-1 77 (1978)

Combination Chemotherapy for Haematological Relapse in Adult Acute Lymphoblastic Leukaemia (ALL) I?. K. Woodruff, T. A. Lister, A. M. Paxton, J. M. A. Whitehouse, and J. S. Malpas Imperial Cancer Research Fund Department of Medical Oncology, and the Department of Haematology, St Bartholornew's Hospital, London

Twenty-three adult patients (median age 22 years) with haematological relapse of acute lyrnphoblastic leukaemia were given reinduction therapy with vin-

cristine, adriamycin, prednisolone, and L-asparaginase. Complete remission (CR) was achieved in 16 patients (69%), and only one patient was completely unresponsive t o therapy. The duration of second remission was short except in three patients who had experienced long first remissions (> 2.5 years). The median duration of survival from first relapse was seven months. Key words: leukaernia, lymphoblastic, adult, relapse, therapy

I NTR OD UCTlON

The results of therapy in adult patients with acute lymphoblastic leukaemia (ALL) have shown considerable improvement over recent years, and this is partly attributable t o the inclusion of anthracycline antibiotics in induction therapy [I -31 . This report gives the results of therapy of haematological relapse in 23 adult patients with ALL, who were given reinduction therapy with a combination of vincristine, prednisolone, adriamycin, and L-asparaginase. The results of the therapy, and the features of prognostic significance, are discussed in the light of other reports.

A preliminary report o n a portlon of the data given here was presented at the Second International Symposium on Therapy of Acute Leukaemia, Rome, December 1977. Received for publication August 31, 1977; accepted February 18, 1978. J.M.A. Whitehouse is now at Southampton General Hospital, Southampton, England. Address reprint requests t o Dr T.A. Lister, Department of Medical Oncology, St Bartholomew's Hospital, London, EC1 A, UK.

0361-8609/78/0402-Ol73$01.40 0 1978 Alan R. Liss, Inc

174

Woodruff et al

MATERIALS AND METHODS Patients

Twenty-three adult patients (aged 15 years or more; median age 22 years) in haematological relapse of ALL were treated with a combination of vincristine, prednisolone, and adriamycin with or without L-asparaginase as reinduction therapy. All the patients were under the care of the Imperial Cancer Research Fund (ICRF) Department of Medical Oncology at St Bartholomew’s Hospital. All patients were evaluable. Seventeen patients (group 1) had been treated initially with the Same combination followed by central nervous system prophylaxis. Oral maintenance therapy was given, comprising daily 6-mercaptopurine with weekly cyclophosphamide and methotrexate, the dosages being adjusted to maintain a mild leucopenia. Six patients (group 2) were long survivors of previous studies. All had received vincristine and prednisolone, with the addition in four cases of cytosine arabinoside and/or an anthracycline. Four patients had received prophylactic CNS therapy, and all received the same continuous maintenance therapy as group 1 patients. The details of the patien,ts and their treatment are shown in Table I. Treatment Programme (OPAL)

Details of this programme used for initial induction therapy for ALLin adults have been published elsewhere [ 11 . It comprises vincristine 1.4 mg/m2 (max 2 mg) IV on day 1, adriamycin 30 mg/m2 IV on day 1 , L-asparaginase 10,000 IU/m2 IV on days 1L14, and prednisolone 40 mg/day orally on days 1-28. Except in patients who died or did not respond to therapy, four injections of vincristine and adriamycin were given at 14-21 -day intervals, with an additional one, or two injections in five cases. The exact interval between the injections of vincristine and adriamycin was determined by the cellularity of the bone marrow. The strain of L-asparaginase was changed from that used in the initial induction to prevent hypersensitivity. Four patients previously known t o be intolerant t o L-asparaginase received an identical programme with L-asparaginase omitted (OPA). Maintenance therapy for patients achieving second complete haematological remission consisted of daily 6-thioguanine and weekly pulses of methotrexate given orally. Three unselected patients (patients 3, 8, 19) were entered into a pilot study of consolidation therapy at the time of achieving second CR. This comprised vincristine (1 .5 mg, IV) and methotrexate (lgm/m* in six hours) follwed by folinic acid therapy, given each 14 days for three courses. Definition of Response

Complete remission (CR) was defined as peripheral white cell count 2 1.5 X 10g/liter, and no circulating blasts; bone marrow: normocellular with normal maturation of formed elements and no recognisable leukaemic blast cells. Partial remission (PR) was defined as having the peripheral blood findings of CR, and a bone marrow in which the leukaemic blast cell population is decreased by more than 50% of pretreatment level.

RESULTS

The results of reinduction chemotherapy are shown in Table I. CR was achieved in 16 patients (69%) and PR in one. Patients 1 and 2 showed response with clearing of all peripheral blast cells but subsequently died of septicaemia. Only patient 19 failed t o show

ALL Relapse Therapy

175

TABLE I. Detailsof Patients and Treatment Sex/

Patient

age

Group 1 1 M21 2 F47 3 M28 F 15 4 5b M29 6b M23 7 Y 16 8 M 19 9 F43 10 M 17 11 M 16 12 F 32 13 M 38 14 M 19 15 M27 16 F31 17 F18 Group 2 18 M23 19 20d

M23 M 20

2ld 22d 23

F 30 M 17 M 20

Primary induction therapy

Duration of initial CR (mo)

OPAL OPAL OPAL OPAL OPAL OPAL OPAL OPAL OPAL OPAL OPAL OPAL OPAL OPAL OPAL OPAL OPAL O,P,A,C Ara-C, L-asp O,P,D O,P,A Ara-C, L-asp 0,P O,P,Ara-C 0,P

Reinduction therapya

Result of reinduction therapy

Duration of second CR (mo)

Response Response CR CR Fail Fail CR CR Fail CR CR CR CR CR CR CR PR

1.5 2

9 9 10 11 11 12 12 13 19 34

OPA (X 2) OPAL ( X 2) OPAL(X6) OPAL(X4) OPAL (X 3) OPAL (X 3) OPAL(X4) OPAL(X4) OPA (X4) OPAL(X6) OPAL (X4) OPAL(X4) OPAL(X4) OPAL(X4) OPAL(X4) OPAL(X5) OPA (X 3)

12

OPAL(X4)

CR

19 33

OPAL (X4) OPAL (X6)

Fail CR

13

9+ 24+

35 36 72

OPAL(X4) OPAL(X5) OPA (X4)

CR CR CR

35+ 25+ 5

37+ 27+ 12

2 4.5 4.5 6 7 8

8.5

Survival from first relapse (mo)

1.5 0.5 7 4.5

-

1

-

2 12 8 6 6 11 14 7.5 4 7

5.5

2 -

2 5

4 4.5 1 1 5.5

14

-

4

2+

3+

-

aNumbers in parentheses indicate the number of vincristine + adriamycin injections given. bFailed to take maintenance therapy. CO = vincristine, P = prednisolone, A = adriamycin, A r a C = cytosine arabinoside, L-asp = L-asparaginase, D = daunorubicin. dMaintenance therapy electively stopped 9- 12 months prior to relapse.

any response to OPAL, and he subsequently achieved CR with cyclophosphamide, cytosine arabinoside, and 6-thoguanine. The other three patients listed in Table I as treatment failures all showed excellent response to the first two injections of vincristine and adriamycin, with clearing of peripheral blasts and significant reduction in the numbers of blast cells in the bone marrow, but this was followed by rapid marrow relapse and a quickly rising peripheral blast count shortly after the third injection. The overall response rate in this study was thus 97%. The CR rate was higher in those patients who had been in intial remission for a year or more (9/11) than in those in whom the initial remission lasted less than a year (7/12) (P not significant). The CR rate was also higher in patients receiving L-asparaginase (15/19) than in those not receiving it (1/4), but no conclusions may be drawn from this as the number of patients is small and there was no randomisation. Three patients (patients

176

Woodruff et a1

20-22) had had maintenance therapy stopped 9-12 months prior to relapse, and all responded well to reinduction therapy. Two other patients (5 and 6) failed t o take maintenance therapy and both failed t o respond to reinduction therapy. The duration of second CR (Table I) was short. Twelve patients relapsed within six months and one at thirteen months. The brevity of second CR was not influenced by concurrent development of meningeal leukaemia, as this occurred in one patient only. The attempt to improve the duration of second CR by employing consolidation therapy with vincristine and methotrexate infusions was unsuccessful. In the three patients in whom it was used, bone marrow relapse occurred at 2 , 4 , and 6 weeks respectively. Median survival from the time of first relapse was only seven months and survival was better in those patients who achieved a second complete remission. Only three patients survived more than two years, and all had experienced long (> 2.5 years) first remissions. Toxicity was primarily haematological and was similar to that observed during initial induction with the same protocol [ I ] . L-asparaginase had to be withdrawn in four patients because of hyperglycaemia. Four patients died during or immediately following initial reinduction therapy: Two patients (1 and 2) had responded to therapy and developed septicaemia while hypoplastic, and two others (5 and 6 ) with chemoresistant and rapidly advancing disease, died of septicaemia. DISCUSSION

Although results comparable to those seen in childhood ALL have not been achieved, the therapy of adult ALL has shown promising improvement [l-31. With the addition of an anthracycline antibiotic to the traditional combination of vincristine and prednisolone, initial remission rates of about 75% may be expected. The duration of initial CR has also improved, and this may be related to the use of intensive consolidation therapy early in remission [2]. There are few reports concerning the results of reinduction therapy in adults with haematological relapse. The present study demonstrates that OPAL, used as for initial induction, is an effective reinduction therapy with acceptable toxicity. CR was achieved in 69% of cases, and only one patient was completely unresponsive to therapy. Both the probability of achieving second CR and the duration of it were better in patients who experienced a long initial CR. The patients in group 1 are the first haematological relapses seen in a larger group of 35 patients with ALL in CR, and as such have had a much shorter initial CR (median nine months) than the group as a whole (1 8.5 months). The poor response seen in these patients with shorter initial CR is in keeping with other studies [4] and with the observation that children with ALL who relapse early and while they are on maintenance therapy comprise a bad prognosis group [51. In the present study, the best results were seen in three patients with long initial remissions who had been electively taken off maintenance therapy before relapse occurred. The results presented here are in agreement with the findings by Clarkson [6] that ALL is more chemosensitive than acute myeloid leukaemia. However, the problem is to prolong the duration of second CR in those patients who have not experienced a long initial remission. Varying the maintenance therapy has not altered this, and an attempt at consolidation therapy with methotrexate infusions in three patients was unsuccessful. More intensive programmes of consolidation and maintenance chemotherapy must be

ALL Relapse Therapy

177

explored in an attempt t o maintain the second remission in bad-prognosis patients (with short initial CR), and it is hoped that much longer survival will be seen as more patients with long initial remission are treated. ACKNOWLEDGMENTS

R.K.W. is the National Health and Medical Research Council of Australia Research Fellow in Clinical Science (Clinical Pharmacology). The authors are indebted t o other members of their departments who have contributed t o the management of the patients reported here, and in particular t o the late Professor Gordon Hamilton Fairley, under whose care most of the patients were admitted. REFERENCES 1. Lister TA, Whitehouse JMA, Beard MEJ, et al: Combination chemotherapy for acute lymphoblastic leukaemia in adults. Br Med J 1:199-203, 1978. 2. Gee TS, Haghbin M,Dowling YD, et al: Acute lyniphoblastic leukaemia in adults and children. Cancer 37:1256-1264, 1976. 3. Jacquillat C, Weil M , Gemon MF, et al: Combination therapy in 130 patients with acute lympho. blastic leukaeniia (Protocol 0 6 AL 66-Paris). Cancer Res 33:3278-3284, 1973. 4. Bloomfield CD, Brunning RD, Kennedy BJ: Daunorubicin therapy in adult acute lymphatic leukaemia. Cancer 30:47, 1972. 5. Mauer AM, Sinione JV: The current status of the treatment of childhood acute lyinphoblastic leukaemia. Cancer Treat Rev 3 : 1 7 - ~ 4 1 1976. , 6. Clarkson BD: Acute myelocytic leukaeniia in adults. Cancer 30:1572, 1972.