Allogeneic marrow transplantation for acute leukemia in relapse

Leukemia Researcfi Vol. 6. No. 3. pp 383-387. 1982. Printed in Great Britain.

0145-2126/82/030383-051D3.00/0 © 1982 Pergamon Press Ltd.

ALLOGENEIC MARROW TRANSPLANTATION ACUTE LEUKEMIA IN RELAPSE*

FOR

CHRISTOPHER BADGER, C. DEAN BUCKNER, E. DONNALL THOMAS, REGINALD A, CLIFT, JEAN E. SANDERS, PATRICIA S. STEWART, RAINER STORB, KEITH M. SULLIVAN, HOWARD SHULMAN and NANCY FLOURNOY Fred Hutchinson Cancer Research Center and University of Washington School of Medicine, Seattle, Washington, U.S.A. ANtraet--The results of allogeneic marrow transplantation in 75 patients with acute lymphoblastic leukemia and 63 patients with acute non-lymphoblastic leukemia in relapse are reviewed. The effects of various chemotherapeutic regimens added to the basic regimen of cyclophosphamide (Cy) 60 mg/kg given on each of two successive days followed by 1000 rad of total body irradiation (TBII were evaluated. The regimens tested were dimethylbusulphan (DMB), 1,3-bis(2-chlorethyl)-l-nitrosourea (BCNU) and daunorubicin. Seventeen .of 138 patients are alive between three and nine and a half years from transplantation. The addition of otl',er chemotherapeutic agents to the basic Cy and TBI regimen did not decrease relapse frequency or prolong survival. Key words: Marrow transplantation, acute leukemia, total body irradiation.

INTRODUCTION

MARROW transplantation permits cytotoxic therapy causing irreversible damage to the patient's normal marrow. When used in the treatment of leukemia, the procedure removes the need for discrimination between leukemic and normal stem cells. While allogeneic marrow transplantation sometimes causes graft-vs-host disease (GVHD) which has been shown to reduce the incidence of relapse of leukemia [16], GVHD is unlikely to be effective in inducing remissions when treating patients with acute leukemia in relapse. In this circumstance the principal determinant of success in inducing remission is not the fact of marrow transplantation but the cytotoxic regimen which transplantation has made possible. When remission is achieved, the effectiveness of GVDH in preventing subsequent relapse is probably related to the number of residual leukemic stem cells, and this also is determined by the cytotoxic therapy used in the transplant procedure. Therefore it is important to evaluate conditioning regimens associated with marrow transplantation. We have reported results in patients with acute leukemia transplanted following a single dose of 1000 rad total body irradiation (TBI) [10], and following high doses of cyclophosphamide (Cy) and TBI with and without other chemotherapeutic agents [-3, 7.9, 13]. These regimens were designed in an attempt to improve remission induction rates, decrease relapse frequency, and improve survival. This report summarizes our experience in patients with acute leukemia in relapse treated with Cy and TBI with and without additional chemotherapeutic agents followed by allogeneic marrow transplantation. *This investigation was supported by grants CA 18029, CA 15704, CA 18579~ CA 09319 and CA 18221 awarded by the National Cancer Institute, DHHS. Dr. Thomas is a recipient of Research Career Award AI 02425 from the National Institute of Allergy and Infectious diseases. Abbreviations: ALL, acute lymphoblastic leukemia: A NL, acute non-lymphoblastic leukemia; Cy, cyclophosphamide; TBI, total body irradiation: BCNU, 1,3-bis(2-chlorethyl},l-nitrosourea; GVHD, graft-vs-host disease; M TX. methotrexate: CNS, central nervous system; IP, interstitial pneumonia; VOD, veno-occlusive disease. Correspondence to: Dr. C. Badger, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104. U.S.A. 383

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MATERIALS AND METHODS Case selection Records from all patients with acute leukemia in relapse who received allogeneic transplants from HLAmatched siblings between December 1971 and November 1978 were reviewed. Eleven patients were excluded from analysis because they were treated with regimens used for fewer than eight patients. Seventy-five patients with acute lymphocytic leukemia (ALL) and 63 patients with acute non-lymphocytic leukemia (ANL) were evaluated. All patients received Cy and TBI. Sixty-four patients received other chemotherapeutic agents in addition to Cy. This analysis includes patients reported in previous publications I-3.7. 9. 133. The technique of marrow transplantation has been described I-14]. Preparation for engraftment consisted of intrathecal methotrexate (MTX) (12 mg given on days - 8 and -4), Cy t60 mg/kg on days - 5 and - 4 ) and TBI on day 0, the day of marrow infusion. TBI was administered from two opposing cobalt 60 sources in a single exposure at a dose rate of 5-8 rad/min for a total midline dose of 920-1000rad [5]. When given. additional chemotherapy was administered before the first dose of Cy as outlined below. Each patient received allogeneic marrow from a sibling determined to be HLA-identical by family study using serologic typing and mixed leukocyte culture i"15]. In an attempt to prevent GVHD, all patients were given MTX, 15 mg/m 2 on day 1 and l0 mg/m 2 on days 3, 6 and I I and then weekly to day 102 [15]. In an effortto prevent central nervous system (CNS) relapse, most patients after 1976 received 12 mg of MTX intrathecally, instead of the i.v. dose. on alternate weeks from days 32 to 102. Patients with active CNS disease or a history of CNS disease received intrathecal MTX after day 102, usually every six weeks from day 102 for one and a half to two years. Some patients received additional pre-transplant irradiation to extramedullary sites of involvement including the CNS. No antileukemic therapy other than MTX was given after transplantation unless a relapse of leukemia occurred.

Preparation for en(lraftment All patients received the basic regimen of MTX, Cy and TBI as outlined above. The following regimens were evaluated. Regimen I. Thirty-one patients with ANL and 43 with ALL received no additional chemotherapy. Regimen 2. Dimethylbusulphan (DMB), 5 mg/kg was given in a single i.v. dose to eight patients with ANL and eight with ALL. Regimen 3. 1,3-bis-(2-chlorethyl)-l-nitrosourea (BCNU), a median total dose of 10 mg/kg (7.9-13.7) was given as a single i.v. dose or on two consecutive days to nine patients with ANL and 10 with ALL. Regimen 4. Daunorubicin, a median total dose of 4.8 mg/kg (2.1-12.7) was given i.v. over 3-5 days to 15 patients with ANL and 14 with ALL. Eight of these patients with ALL and three with ANL received one or more of the following additional drugs: cytosine arabinoside, median total dose 12.7 mg/kg (5.6--27.8) given as a continuous i.v. infusion over 3-5 days; 6-mercaptopurine or 6-thioguanine, median total dose 12.7 mg/kg (8.3-35.8) given orally over 3-5 days; or prednisone, median total dose 3 mg/kg (1.7-7.6) given orally over 3-7 days.

Statistics Kaplan-Meier estimates of survival, relapse and death from causes other than relapse were performed and differences among regimens were tested using log rank tests for censored observations 1,4]. All survival statistics are calculated as of 6/1/81.

RESULTS

Patient characteristics. The median age for the 63 patients with ANL was 23 years (range 1-55), and for the 75 patients with ALL was 17 years (range 2-36). Within the various disease and regimen categories the patient populations were similar with regard to age and clinical condition. An analysis of post-transplant results failed to reveal any statistical differences between the various pre-transplant treatment regimens 143. Therefore, the results are presented as a comparison of the basic Cy and TBI regimen alone and Cy and TBI with additional chemotherapy, i.e. regimens 2-4 are combined. Early deaths. Twelve patients died between days 3 and 20 without evidence of engraftment. Seven had ANL and five had ALL. Engraftment. One hundred and twenty-six patients had marrow engraftment demonstrated by marrow examination, a rise in peripheral blood counts, and survival greater than 21 days. When donors of opposite sex were used, engraftment was documented by cytogenetics.

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Marrow transplantation, acute leukemia in relapse

lnitial antileukemic effectiveness. One hundred and three of 132 patients who had marrow aspirations performed in the first 14 days had no blasts in the marrow. Twentythree patients (18 with ALL and five with ANL) had persistent leukemic cells in the marrow on examination between days 7 and 14 and cleared their marrows between days 14 and 41. Seventeen of these patients eventually relapsed 41-532 days following transplantation, five died of non-leukemic causes while in remission, and one patient is alive in continuing remission seven and a half years after transplant. Six patients failed to clear their marrows of blasts (five with ALL and one with ANL) and died between days 10 and 87. The five patients with ALL had received Cy and TBI alone and the patient with ANL had in addition received daunorubicin. Non-leukemic deaths. Table 1 shows the absolute percentages of death from causes other than leukemia. Actuarial analysis demonstrated a significant difference in the probability of non-leukemic death between patients with ALL and patients with ANL, 56 vs 72~o (p = 0.005) and this was a consequence of older patients with ANL having a high rate of non-leukemic death (82°'o for regimen 1, 76~o for regimens 2-4). In patients less than 21 years old at the time of transplantation there was no difference between patients with ANL and ALL in rates of survival, relapse or non-leukemic death. Causes of non-leukemic death (Table 2) were similar in all regimens, consisting predominantly of interstitial pneumonitis (IP), GVHD and infection. Four patients died of congestive heart failure, two patients with ANL who received BCNU died suddenly of TABLE 1. ACUTE LEUKEMIA.RESULTSOF ALLOGENEICTRANSPLANTATION

N

Survival (%)

Relapse of leukemia (%)

Non-leukemic mortality (%)

Cy + TBI ANL ALL ANL, age <21 ALL, age <21

31 43 12 36

3(10) 8 (19)* 2(17) 6(17)

8(26) 21 (49) 5(42) 17(47)

20(65) 14(35) 5(42) 12(33)

Other chemotherapy ANL ALL ANL, age <21 ALL, age <21

32 32 12 23

3 (9) 3(9) 0(0) 3(13)

8 (25) 13(41) 5(42) 8(35)

21 (66) 16(50) 7(58) 12(52)

*One patient survives seven and a half years after transplant in enduring remission six and a half years after isolated testicular relapse. TABLE 2. CAUSESOF NON=LEUKEMICDEATH Number of patients

N Cy + TBI ANL ALL

Interstitial pneumonia

GVHD

Infection

Other

20 15

13 9

4 3

3 1

0 2

ANL ALL

21 16

7 12

4 1

5 2

5 1

Total Co)

72

41 (57)

Additional ~ a p y

12(17)

II (15)

8(11)

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CHRISTOPHER BADGER et al.

unexplained causes, one patient with ANL who received DMB died of veno-occlusive disease (VOD) of the liver, and one patient with ANL who received daunorubicin died of respiratory failure 790 days post-transplant. One patient with ALL relapsed in the CNS on day 833 and died in remission of leukoencephalopathy on day 1500. There was a slight increase in IP in the patients with ALL who received BCNU which was not statistically significant. There were no significant differences between groups in incidence of GVHD or infection. Relapse of leukemia. Table 1 shows the absolute occurrence of death from leukemia. either residual or recurrent. Twenty-five per cent of patients with ANL and 45°.0 of patients with ALL died of leukemia. Using the method of Kaplan and Meier, which corrects for competing causes of death, the probability of relapse was 64°0 in patients with ANL and 72~o in patients with ALL. The differences in relapse rates for the various regimens were not significant when compared within diagnostic categories or for the population as a whole. There was a suggestion that the addition of daunorubicin prolonged time to relapse in ALL (median 304 days vs medians of 71-148 for the other regimens), and patients with ALL treated with BCNU had a 33°0 probability of relapsing; however, these were not statistically significant differences. The relationship between the development of GVHD and the occurrence of leukemic relapse was examined in the 126 patients with engraftment surviving more than 21 days. For this purpose grades 2-4 acute GVHD or any chronic GVHD were considered significant. Of the 57 patients with ANL, 21 did not develop significant GVHD. Eight of the 21 relapsed and two survive. Of 36 ANL patients with significant GVHD, eight relapsed and four survive. Of the 69 patients with ALL, 42 had no significant GVHD and 21 of these patients relapsed and four survive. Of the 27 ALL patients with significant GVHD, four relapsed and seven survive. Thus, six of 63 patients without significant GVHD and 11 of 63 patients with significant GVHD survive. Survival. The actuarial probability of long-term survival ranged from 7 to 17°o. There were no significant differences between any of the treatment groups or between ALL and ANL. Seventeen patients survive between three and nine and a half years after transplantation. DISCUSSION With current therapy most patients with newly diagnosed acute leukemia can be placed into complete remission, but, with the exception of patients with childhood ALL with good risk factors, almost all are destined to relapse. Marrow transplantation allows the delivery of doses of chemotherapy and radiation that are lethal to the marrow, and this has made it possible to produce long-term survivors even in late stages of the disease [6, 11] but relapse of leukemia and transplant-related deaths remain major problems. One approach to these problems is to undertake marrow transplantation while the leukemia is in remission when the clinical condition of the patient is better, the leukemic cell burden lower and drug resistance less likely. This approach has improved the results of marrow transplantation for patients with ANL [8] and ALL 1-12]. However. current therapy remains unsatisfactory for those patients who relapse before transplantation or who do not achieve primary remission. Transplantation with more aggressive chemotherapeutic conditioning regimens in addition to CY and TBI has been attempted at a number of centres. Gale has summarized the results from UCLA and other centres from the literature [2]. The actuarial probability of relapse appears to be the same for patients in relapse with ANL or ALL and is unaffected by patient age or treatment regimen. The greater incidence of non-leukemic death in older patients is seen in other settings in which allogeneic marrow transplantation is undertaken 1-1]. This mortality is mainly due to IP and

Marrow transplantation, acute leukemia in relapse

387

GVHD. The findings reported here also show that a reduction in deaths from nonleukemic causes would be accompanied by an increased absolute incidence of leukemic relapse. The present analysis suggests that a more intensive use of existing drugs with current TBI regimens is unlikely to affect relapse rates. The only manoeuvre we have found that has a major impact on relapse rates and survival is transplantation during first remission [8]. Clearly this option is not available to patients already in relapse and other treatment modifications are needed. Such modifications under study include evaluation of fractionated TBI regimens, attempts to manipulate a possible antileukemic effect of GVHD, and post-transplant antileukemic therapy with interferon and other agents. REFERENCES 1. CAMITTA B. M., THOMAS E. D., NATHAN D. G., GALE R. P., KOPECKY K. J., RAPPEPORT J. M., SANTOS G., GOROOr~-SMITH E. C. & STORB R. (1979) A prospective study of androgens and bone marrow transplantation for treatment of severe aplastic anemia. Blood 53, 504. 2. GALE R. P. (1980) Clinical trials of bone marrow transplantation in leukemia. In Biolo#y of Bone Marrow Transplantation (GALE R. P. & FOX C. F., Eds.L p. 11. Academic Press, New York. 3. HARRISON D. T., FLOURNOY N., RAMBERG R., BOYD C., ERNE K., BUCKNER C. D., FEFER A., SANDERS J. E., STORB R. & THOMAS E. D. (1978) Relapse following marrow transplantation for acute leukemia. Am. 3. Hemat. 5, 191. 4. KAPLAN E. L. & MEIER P. (1958) Nonparametric estimation from incomplete observations. 3. Am. statist. Ass. 53, 457. 5. LAM W.-C., ORDER S. E. & THOMAS E. D. (1980) Uniformity and standardization of single and opposing cobalt 60 sources for total body irradiation Int. d. Radiat. Oncol. Biol. Phys. 6, 245. 6. STEWART P. S., BUCKNER C. D., CLIFf R. A., SANDERS J. E., STORB R., LEONARD J. M. & THOMAS E. D. (19791 Allogeneic marrow grafting for acute leukemia: A follow-up of long-term survivors. Expl Haemat. 7, 509. 7. THOMASE. D., BUCKNERC. D., BANAJI M., CLIFf R. A., FEVERA., FLOURNOY N., GOODELL B. W., HICKMAN R. O., LERNER K. G., NEIMAN P. E., SALE G. E., SANDERS J. E., SINGER J., STEVENS M., STORB R. & WEIDEN P. L. (1977) One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 49, 511. 8. THOMASE. D., BUCKNER C. D., CLIFf R. A., FEVER A., JOHNSON F. L., NEIMAN P. E., SALE G. E., SANDERS J. E., SINGER J. W., SHULMAN H., STORB R. & WEIDEN P. L. (1979) Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N. Engl. J. Med. 301, 597. 9. THOMASE. D., BUCKNER C. D., FEVER A., SANDERS J. E. & STORB R. (1978) Effects to prevent recurrence of leukemia in marrow graft recipients. Transplantn Proc. 10, 163. 10. THOMAS E. D., BUCKNER C. D., RtJDOLPH R. H., FEVER A., SIORB R., NEIMAN P. E., BRYANT J. I., CHARD R. L., CLIFT R. A., EPSTEIN R. B, FIALKOW P. J., FUNK D. D., GIBLETT E. R., LERNER K. G., REYNOLDS F. A. & SLICHTER S. (1971) Allogeneic marrow grafting for hematologic malignancy using HL-A matched donorrecipient sibling pairs. Blood 38, 267. 11. THOMASE. D.. FLOURNOY N., BUCKNER C. D., CLIFT R. A., FEFER A., NElMAN P. E. & STORE R. (1977) Cure of leukemia by marrow transplantation. Leukemia Res. 1, 67. 12. THOMAS E. D., SANDERS J. E., FLOURNOY N., JOHNSON F. L., BUCKNER C. D., CLIFT R. A., FEFeR A., GOODELL B. W., STORB R. & WEIDEN P. L. (1979) Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood 54, 468. 13. THOMASE. D., SANDERSJ. E. & JOHNSON F. L. & THE SEATTLE MARROW TRANSPLANTTEAM (1979) Marrow transplantation in the therapy of children with acute leukemia. Proccedings of the National Conference on the Care of the Child with Cancer, Boston, 9/78. In Care of the Child with Cancer, p. 172. American Cancer Society, New York. 14. THOMASE. D~ & STORB R. (1970) Technique for human marrow grafting. Blood 36, 507. 15. THOMASE. D., STORB R., CLIFf R. A., FEVER A., JOHNSON F. L., NEtmAN P. E., LERN~ K. G., GLUCKSBERG H. & BUCKNER C. D. (1975) Bone-marrow transplantation. N. Engl. d. Med. 292, 832, 895. 16. WEIDEN P. L., FLOURNOY N., SANDERSJ. E., SULLIVANK. M. & THOMAS E. D. (1981) Antileukemic effect of graft-versus-host disease contributes to improved survival after allogeneic marrow transplantation. Transptantn Proc 13, 248.