improved survival from acute lymphoblastic leukemia in adolescents and adults

5
Improved Survival from Acute L ymphoblastic Leukemia in Adolescents and Adults HILARY A. BLACKLOCK, FRACP, FRCPA, JOHN R. D. MATTHEWS, FRACP, FRCPA. JOHN G. BUCHANAN, B. MEO Sc, FRACP, FRCPA, PAUL A. OCKELFORD, MB, CHB. AND ROGER S. HILL, FRACP, FRCPA Nineteen adult patients with acute lymphoblastic leukemia were treated with combination chemotherapy to induce remission in the period from 1971 to 1979. Those patients achieving remission received intensive post-remission therapy with central nervous system (CNS) prophylaxis, followed by two-drug maintenance therapy, and reinduction courses of chemotherapy every six months. Remissions were achieved in 17 of the 19 patients (89%). Twelve patients (63%) are alive, 11 currently in complete remission. Two patients who experienced relapses i n recent months have successfully undergone trans- plantation with allogeneic marrow from sex-matched, HLA-compatible sibling donors. The median survival and median duration rates of first remissions have not yet been reached, but to date are 36+ months and 29+ months, respectively with a predicted five-year survival rate of 61 9i . These results not only are significantly better than those achieved in the years 1968 to 1971 in our institution, but also are superior to others reported in the world medical literature. The combination of optimal treatment protocols with allogeneic marrow transplantation for patients with poor prognoses is expected to improve the survival of adult patients even further in the next decade. Cancer 48: 193 1 - 1935. 198 I. EMISSION AND SURVIVAL RATES in adult patients R with acute lymphoblastic leukemia (ALL) had not improved by 1970." Recognizing the advances made in childhood ALL (particularly with the use of combination chemotherapy, prophylactic measures for the prevention of central nervous system (CNS) leu- kemia, and maintenance therapy),*.'' and because of our poor results in adults with ALL, modifications were made in our treatment protocol in 197 1. These changes included the addition of daunorubicin to the induction regimen, the introduction of CNS prophylaxis when hematologic remission was achieved, the use of two drugs for remission maintenance therapy, and reinduc- tion courses of combination chemotherapy every six months. The purpose of this paper is to review the re- sults obtained in our patients since the institution of this protocol, in comparison with patients previously treated in our department, and with comparable adult series reported in the medical literature. From the Department of Haematology, Auckland Hospital, Auck- Suported in part by the Medical Research Council of New Zealand. Address for reprints: Dr. t I. Blacklock, Department of Haematol- ogy, Royal Free Hospital, Pond Street, London, N W3 2QC. England. The authors thank Associate Professor J. D. Wilson for the lym- phoid marker testing, Mrs. Svea Gulbis for assisting with data col- lection. and Mrs. Valerie Matejka for her editorial assistance. land, New Zealand. Accepted for publication September 29, 1980. Materials and Methods Twenty-two patients presented to Auckland Hospital with ALL between May 1971 and May 1978. Three patients were excluded from analysis, two dying within 24 hours of admission (one with C N S disease, one with acute liver failure) and a third referred from overseas who was not treated with this protocol. The diagnosis of ALL was based on the examination of peripheral blood and bone-marrow smears (or tre- phine trails) using Romanowsky, periodic acid-Schiff and myeloperoxidase stains. The marrow material at presentation was reviewed retrospectively by the group and reclassified according to the French, American and British Cooperative (FAB) classification.' Additional information was obtained from chest radiographs and serum murimidase estimations. Later in the period of study, tests for lymphoid markers were performed on eight patients. These included examination of the lym- phoid cells for B- and T-surface markers-those with absent markers being designated as null leukemia. Spe- cific ALL antisera were not used, and tests for pre-B cell markers were not performed. The diagnosis of CNS leukemia was established on the basis of clinical signs and/or the presence of leukemic cells in the cerebro- spinal fluid (CSF). Patient age ranged in years from 14% to 45, with a mean of 24 years. There were 11 male and 8 female OOOX-543X/Xl/l1O1/1931 $0.75 CJ American Cancer Society 1931

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Page 1: Improved survival from acute lymphoblastic leukemia in adolescents and adults

Improved Survival from Acute L ymphoblastic Leukemia in Adolescents and Adults

HILARY A. BLACKLOCK, FRACP, FRCPA, JOHN R. D. MATTHEWS, FRACP, FRCPA. JOHN G. BUCHANAN, B. MEO Sc, FRACP, FRCPA, PAUL A. OCKELFORD, MB, CHB.

AND ROGER S. HILL, FRACP, FRCPA

Nineteen adult patients with acute lymphoblastic leukemia were treated with combination chemotherapy to induce remission in the period from 1971 to 1979. Those patients achieving remission received intensive post-remission therapy with central nervous system (CNS) prophylaxis, followed by two-drug maintenance therapy, and reinduction courses of chemotherapy every six months. Remissions were achieved in 17 of the 19 patients (89%). Twelve patients (63%) are alive, 11 currently in complete remission. Two patients who experienced relapses in recent months have successfully undergone trans- plantation with allogeneic marrow from sex-matched, HLA-compatible sibling donors. The median survival and median duration rates of first remissions have not yet been reached, but to date are 36+ months and 29+ months, respectively with a predicted five-year survival rate of 61 9i . These results not only are significantly better than those achieved in the years 1968 to 1971 in our institution, but also are superior to others reported in the world medical literature. The combination of optimal treatment protocols with allogeneic marrow transplantation for patients with poor prognoses is expected to improve the survival o f adult patients even further in the next decade.

Cancer 48: 193 1 - 1935. 198 I .

EMISSION A N D S U R V I V A L RATES in adult patients R with acute lymphoblastic leukemia (ALL) had not improved by 1970." Recognizing the advances made in childhood ALL (particularly with the use of combination chemotherapy, prophylactic measures for the prevention of central nervous system (CNS) leu- kemia, and maintenance therapy),*.'' and because of our poor results in adults with ALL, modifications were made in our treatment protocol in 197 1. These changes included the addition of daunorubicin to the induction regimen, the introduction of CNS prophylaxis when hematologic remission was achieved, the use of two drugs for remission maintenance therapy, and reinduc- tion courses of combination chemotherapy every six months. The purpose of this paper is to review the re- sults obtained in our patients since the institution of this protocol, in comparison with patients previously treated in our department, and with comparable adult series reported in the medical literature.

From the Department of Haematology, Auckland Hospital, Auck-

Suported in part by the Medical Research Council of New Zealand. Address for reprints: Dr. t I . Blacklock, Department of Haematol-

ogy, Royal Free Hospital, Pond Street, London, N W3 2QC. England. The authors thank Associate Professor J . D. Wilson for the lym-

phoid marker testing, Mrs. Svea Gulbis for assisting with data col- lection. and Mrs. Valerie Matejka for her editorial assistance.

land, New Zealand.

Accepted for publication September 29, 1980.

Materials and Methods

Twenty-two patients presented to Auckland Hospital with ALL between May 1971 and May 1978. Three patients were excluded from analysis, two dying within 24 hours of admission (one with C N S disease, one with acute liver failure) and a third referred from overseas who was not treated with this protocol.

The diagnosis of ALL was based on the examination of peripheral blood and bone-marrow smears (or tre- phine trails) using Romanowsky, periodic acid-Schiff and myeloperoxidase stains. The marrow material at presentation was reviewed retrospectively by the group and reclassified according to the French, American and British Cooperative (FAB) classification.' Additional information was obtained from chest radiographs and serum murimidase estimations. Later in the period of study, tests for lymphoid markers were performed on eight patients. These included examination of the lym- phoid cells for B- and T-surface markers-those with absent markers being designated as null leukemia. Spe- cific ALL antisera were not used, and tests for pre-B cell markers were not performed. The diagnosis of CNS leukemia was established on the basis of clinical signs and/or the presence of leukemic cells in the cerebro- spinal fluid (CSF).

Patient age ranged in years from 14% to 45, with a mean of 24 years. There were 11 male and 8 female

OOOX-543X/Xl/l1O1/1931 $0.75 CJ American Cancer Society

1931

Page 2: Improved survival from acute lymphoblastic leukemia in adolescents and adults

1932 CANCER November I 1981 Vol. 48

patients. The patients were numbered 1 to 19, from the longest to the shortest current survivor. Patient 1 had received prior therapy with vincristine and prednisone, and was admitted to this protocol after experiencing a relapse seven months after presentation. Patient 5 had received previous therapy for presumed acute m yeloid leukemia.

Treatment Protocol

Induction therapy: Remissions were achieved using vincristine 2.0 mg/m2 (maximum dose 2 mg) admin- istered intravenously once a week; daunorubicin 45 mg/ m’ administered intravenously once a week; and pred- nisone 150 mg/m2 administered orally daily. These drugs were continued until complete remission was achieved.

Intensive post-remission induclion or consolidation therapy including CNS prophylaxis: Once remission was achieved three five-day courses of methotrexate at a dosage of 10 mg/m2 daily (intrathecally on two days and orally on three) were instituted, allowing peripheral blood recovery between courses. Beginning at the same time, the skull was irradiated with laterally opposed fields in 12 fractions, a midline dose of 2,400 rads being administered over a period of two and a half weeks.

Maintenance lherapy: Therapy was then begun to maintain remission using 6-mercaptopurine 90 mg/m2 daily orally, and methotrexate 10 mg/m2 weekly orally. If peripheral blood depression occurred during therapy, a bone-marrow examination was performed to exclude relapse, and the dosage reduced to allow recovery. Every 12 weeks, the methotrexate was administered intrathe- cally rather than orally.

Reinduction therapy: Every six months during the remission period, four doses of vincristine 2 mg/m2 (maximum dose 2 mg/m’) were administered intrave- nously once a week; four doses of daunorubicin 45 mg/ m2 were administered intravenously once a week; and 28 days of prednisone 150 mg/m2. Daunorubicin was excluded after a total of 10 doses i.e., 450 mg/m2, in- cluding the amount given during remission induction.

Specific toxicity related to therapy included periph- eral neuropathy secondary to vincristine (four patients), methotrexate-induced hepatitis (two patients), steroid myopathy (one patient) and symptomatic glycosuria (two patients). Patient 5 , who had received daunorub- icin prior to entering this protocol, experienced an ill- ness associated with fever, tachycardia, and non-specific electrocardiographic changes after receiving ten doses, which resolved after some weeks. Three patients had one or two doses of daunorubicin withheld in the re- mission induction phase of therapy because of treat-

ment-induced severe neutropenia (<0.5 X 109/L) as- sociated with infection.

Supportive Treatment

Anemia was treated by transfusions of packed eryth- rocytes. Platelet transfusions from random donors were used prophylactically in instances of severe thrombo- cytopenia (<20 X 109/L), or in situations of hemor- rhage associated with thrombocytopenia. An in-dwell- ing subcutaneous right atrial catheter was used in some patients who required intensive ~ u p p o r t . ~ Combination antibiotic therapy, and since 1975, granulocyte trans- fusions, were administered when appropriate. Allopu- rinol was prescribed during remission induction, con- solidation, and reinduction therapy.

Relapses

Remission was attempted in those patients who had experienced relapses (except patient 17) with combi- nations of cytotoxic drugs including those already de- scribed and others such as cyclophosphamide, cytosine arabinoside and doxorubicin. After achieving a second and third remission, respectively, two patients (no. 4 and no. 10) received sex-matched, HLA-compatible allogeneic marrow transplants from sibling donors as described by Thomas et dZ4

Definitions

Complete remission was defined as a normocellular marrow with less than 5% blasts and 25% lymphocytes with no identifiable lymphoblasts, a peripheral blood smear with neutrophils > 2.0 X 109/L, and platelets > 100 X 109/L, while maintaining a normal hemoglobin level without tranfusion, with no symptoms or signs of leukemia. Relapse was defined as the appearance of leukemic cells in the bone marrow, peripheral blood, and/or CNS. Bone-marrow examinations were per- formed when the peripheral blood became abnormal, when clinical signs or symptoms developed, and prior to each six-month reinduction course of treatment. Cy- tologic examination of the CSF was undertaken when symptoms or signs appeared, and every three months at the time of the intrathecal methotrexate injections. The duration of survival was defined as the period be- tween bone-marrow diagnosis and death, or to January 31, 1980 when this review was undertaken. The dura- tion of remission was defined as the period between complete remission and relapse. Therapy was stopped after four years in the first three patients, and after three years in the other patients.

Page 3: Improved survival from acute lymphoblastic leukemia in adolescents and adults

No. 9 AILIT ACUTE LYMPHOBLASTIC LEUKEMIA . B/aCk/OCk et al. I933

60 -

50 - 40 -

30 -

20 -

10 -

0 'f

TABLE 1 . Clinical Data of the Nineteen Patients

Duration of tirst

Data at presentation

Patient Spleen Leukocytes Platelets Marrow Lymphoid Remission No. remission Current Survival No. Sex/age (cm) X 109/1. X 109/I. morphology markers achieved courses (months) status (months)

i n I I 1 I I and no response to other agents using doxorubicin, cy- clophosphamide, and vinblastine; and Patient 19 died from candida septicemia after two weeks of therapy when he was neutropenic.

To date, the duration of first remission ranges from three to 94 months (median: 29 months+) for the whole group, and 23 to 94 months for those still in their first remission.

1971 - 79 n=19

p < . 001

1968 - 71 n=12

, 1 I , I I I 1 I I Relapse

1 F/15 4 0.7 R 1- I Yes 4 94'* RM; S 104' 2 M/14'h 5 4 16 LZ Yes 2 98' RM; S 99' 3 M/l6 3 20.6 21 Ll Yes 4 90' RM; S 91' 4 F/14% I 4.7 120 Lz Null Yes 4 47.5 RM; BT 60'

- Yes 7* 43' RM; S 50 Yes 6 40' R M : S 42'

5 F/21 0 20.1 310 Ll

- Yes 6 39' RM; S 42' 6 F/24 0 43 I59 L2 7 MI34 I 5 I80 L,

Null Yes 6 33 RI 41' 8 F/36 0 3 310 L, 9 34/20 0 I .8 R 1-2

10 >M/14'/2 0 I .2 344 L2 Yes 6 11.5 RM; BT 36* I I MI18 4 12.1 16 1 - 2 Null Yes 6 29+ RM; MT 31' I2 F/44 4 4.1 56 L2 Null Yes 6 25+ R.M; M T 27'

Null Yes 8 23 RM; M T 25' - Yes 4 6 D I 9D

Null Yes 6 8 D I 7D

-

- Yes 6 23 D 39D

13 MI32 2 5 I76 L2 14 F/24 3 3.6 10 L, 15 F/31 5 65 30 L, 16 MI45 0 170 57 L2 B N o 5* 17 MI15 0 4 129 L,3 B Yes 4 3 D 5D

Yes 8 3 D 5D 18 MI32 7 177 60 LZ 19 M/18 5 10.3 5 L2 No 2

- 1) 5 . P

- D .8"

Abbreviations: BT 7 marrow transplant; D = deceased: M T R L = relapse; R M - remission; S - treatment stopped; * = see text. = maintenance therapy; R reduced; RI = remission induction;

Results of which had greater than 50% lymphoblasts) according to the FAB rite ria,^ showed that seven patients had type L, ALL, 1 1 had type L2, and one L3. Of the eight patients whose lymphoblasts were assessed with respect to lymphoid markers, six were null and two had B-cell disease with surface immunoglobulin.

Clinical data of the 19 patients are recorded in Table 1. Twelve had splenomegaly; none had mediastinal en- largement radiologically or CNS disease clinically. Classification of the bone-marrow preparations (each

Page 4: Improved survival from acute lymphoblastic leukemia in adolescents and adults

1934 CANCER November I 1981 Vol. 48

T A H I . ~ ; 2. Review of Adult ALL Series in the World Vediciil Literature

Cumplelc Medtan Ihralion Pdllelll.; remission (months)

Age Remission Consolidaiiun CNS Prophy- Maintenance Kcinduction Complelc

_____. - -. -

Xu ()ears) induction drugs N u T drugs laxir drugs drugs remission Survival Reference ~ ~ ~

1') >Id': V . P . D 17 89 MT R. MI Mp, MI V . P 7 D 29' 36' Ours 14 > I 6 V. P r Ca f D 10 7 1 None K, MI Mp. MI. Cp hone 25' 14 I 75 > I h V. P 2 D 3h h l Ca, Cp or none R, MI. De Mp. MI v. P 24 10 19 12 >I? V. P + I) + Cp 2 5 7X None K. MI. Ca Mp. MI + v -r P ?? 13.5' 18 5 I > I5 v 1'. 1)U. I.:, 36 7 I V. 1'. 1)u. I..r R, MI Mp, MI, c p None 18.5 21 I5 17 > I 7 V . P . 1 . a 12 72 Mp. MI. +[>or MI Mp. MI, Cn. P. Uone I x- No1 stated 29

D U 1, V. +D or DO

Drug5 cycled 7 q >IJ V. P t D o r Do 63 X3 None MI It K or none Mp. MI or 7 V. P or nune I? 27 25

I 4 > I h v. P 11 91 cp. Mp K, M I Mp. MI. ! Cp None 9' 1 1 ' 20 2 5 >I c \ . 1'. Ih I X l? None K. MI or none Mp. MI v. P 10 Not siaied 21 7 3 > I 5 V. P. D I 8 7X B. Ca. Ld. T. V .MI 7 drugs cycled None 25 33 9 17 2 1 V . T. Py. I k 9 53 V. T. Py. De Cc. Py. De Cc. Py. T. V . De Xone 6 13 23

17 Ih >I< v. P. D I4 87 >one None A: Mp. MI v. 1'. D A ' l 4 . 3 R: MI R: 16.6

X > I X C d . C p . W i . I . e 5 h? None None Ca, Cp. MI hone 4.5 22 Z? <JY , I T V. P. Mt 79 8 0 Ca, L A , T. V. P 2 R, MI Cp. Mp, MI v. P I h.9 24 I6a .

marrow relapse and death; one testicular (Patient 9 ) and two CNS, despite prophylaxis (Patients 14 and 17). Of five who had bone-marrow relapses, three achieved a second remission (Patients 4, 10, and 15) of five+, 11.5, and one months duration; one is undergoing fur- ther remission induction (Patient 8), and one failed with further chemotherapy (Patient 18). Patients 4 (in sec- ond remission) and 10 (in third remission) have recently received successful marrow transplants from sex- matched, HLA-compatible siblings, and are currently in remission at 152 and 131 days, respectively after transplant.

Survival

With the small number of patients, no significant difference in survival can be demonstrated with respect to L , versus L2 morphology, leukocyte count, age at presentation, or sex. Twelve of the patients are currently alive, 1 1 in remission with current survival rates ranging from 25 to 104 months. The median survival for the whole group is to date 36 months, and using standard methods of life-table analysis, the predicted five-year survival rateis61%." Using thelogrank test, theseresults are significantly better ( P < 0.001) than those for the 12 patients between 1968-71 who were treated with vincristine and prednisone alone for induction, and maintained with met hotrexate and 6-mercaptopurine, without daunorubicin, CNS prophylaxis, or reinduction cytotoxics (Fig. I ).

Discussion

The survival of adult patients with ALL treated in our institution has greatly improved this decade, and

our results compare favorably with other series reported in the literature within recent years (Table 2).'*9.1s.'6a.- 17 23.22.29 Once remission is achieved, the prognosis for adults may be similar to that reported in childhood ALL,',' with the realistic hope for long-term survival in a significant proportion of those treated.

Several changes were made to our treatment regimen including improved supportive measures, the addition of daunorubicin, C N S prophylaxis, and further rein- duction therapy every six months. Thus, i t is difficult to apportion the contribution that each of these factors may have played in the improved survival of our pa- tients. As the frequency of CNS disease in adult ALL patients not given prophylaxis may reach as high as 50% clinically, or greater than 65% p o ~ t m o r t e r n , ~ . ~ ~ , ~ ' . ~ ~ and because of the proven efficacy of CNS prophylaxis in children,2,16 and now in a controlled trial in adults,I6" we are inclined to attribute the major improvement to that component of the treatment protocol. However, on review of the series reported (Table 2), duration of sur- vival is not clearly separated into long- and short-term whether CNS prophylaxis was given or not, suggesting that other factors may be important. On the other hand, prophylaxis using intrathecal methotrexate and cranial irradiation appears to have reduced the incidence of CNS disease in individual series,','5-20 and more recently in a controlled, randomized study (with no improvement in and seems superior either to intrathecal rnethotrexate alone,' or oral pyremethamine with dexa- methasone and CCNU." CNS prophylaxis did not pre- vent the development of CNS leukemia in two of our patients, one of whom had Burkitt's-type leukemia (L3, B-surface markers), which is associated with a high

Page 5: Improved survival from acute lymphoblastic leukemia in adolescents and adults

KO. 9 ADULT ACUTE L Y M P ~ i o B L A S T I C LELKEMIA Blacklock et a/ . 1935

incidence of CNS involvement with or without prophy- laxis. 15.28

The relative importance of other treatment compo- nents in improving survival is difficult to assess in our series and in others reported, with the variation in type and intensity of the chemotherapy used and the small numbers of patients. The benefits of consolidation ther- apy and the optimal length of maintenance therapy have yet to be determined in adult ALL by controlled studies.

Although considerable progress has been made in the last decade, the remission rate for adults remains lower than for children. Also, a different therapeutic approach is needed for the now identified poor prognosis patients which include those with for B-cell disease, Burkitt’s or L3 type ALL,5,8 CNS involvement, relapsed disease, and perhaps Lz disease.” A second remission can be achieved in a high proportion of patients (70%) who experience relapse, but its duration is short in most patient^.^' In this context, the results of allogeneic mar- row transplantation in this group are of interest with a 50% two-year survival rate for those transplanted in remission, compared with only a 15% two-year survival for those transplanted in relapse.z4 Thus, the combi- nation of optimal remission induction chemotherapy protocols, with CNS prophylaxis and maintenance ther- apy, reserving allogeneic marrow transplantation pref- erably in remission for poor prognosis patients fortunate to have compatible siblings, should be expected to im- prove the survival of adult ALL patients even further in the next decade.

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