Allogeneic marrow transplantation for acute non-lymphoblastic leukemia in relapse using fractionated total body irradiation

Leukemia Re.searcfi Vol 6, No. 3. pp. 389-394. 1982. Printed in Great Britain.

0145-2126/82/'030389-06503.00~0 © 1982 Pergamon Press Lld,

ALLOGENEIC MARROW TRANSPLANTATION FOR ACUTE NON-LYMPHOBLASTIC LEUKEMIA IN RELAPSE USING FRACTIONATED TOTAL BODY IRRADIATION* C. DEAN BUCKNER, REGINALD A. CLIFT, E. DONNALL THOMAS, JEAN E. SANDERS, PATRICIA S. STEWART, RAINER STORB, KEITH M. SULLIVAN and ROBERT HACKMAN Fred Hutchinson Cancer Research Center and University of Washington School of Medicine, Seattle. Washington. U.S.A.

Al~traet--Twenty-three patients with acute non-lymphoblastic leukemia in relapse were treated with cyclophosphamide, fractionated total body irradiation (200 rad/day for six days) and allogeneic marrow transplantation. Six patients are alive in remission 756-1306 days following transplantation. One patient died of infection on day 17 without evidence of engraftment: all others achieved sustained engraftment. Eight patients died of recurrent leukemia, four of interstitial pneumonitis, two of infection, one of veno-occlusive disease of the liver and one of cardiac failure. The median survival time was 181 days, Key words: Marrow transplantation, acute non-lymphoblastic leukemia, fractionated total body irradiation.

INTRODUCTION PATIENTS with acute leukemia who fail induction therapy or who relapse after achieving a complete response have an extremely poor prognosis with conventional or experimental chemotherapy [-6]. Marrow transplantation provides the opportunity for aggressive antileukemic therapy without regard to marrow toxicity. We have previously reported the results of marrow transplantation using 120 mg/kg of cyclophosphamide (Cy) with and without other chemotherapeutic agents and a single exposure of 1000 rad total body irradiation (TBI) in patients with refractory acute non-lymphoblastic leukemia (ANL) [,14]. Six of 54 patients are without evidence of disease 69-111 months after transplantation and probably are cured [,1 I, 17]. More intensive regimens using additional chemotherapy were evaluated in an attempt to improve results [1, 16]. An analysis of these attempts has demonstrated that the addition of various chemotherapeutic agents to the basic Cy and TBI regimen did not improve survival or decrease the frequency of relapses [1]. More recently, transplant results in patients with ANL have been improved by performing the transplant in first remission [15]. However, not all patients will achieve a remission, and many will not have had an opportunity for or will have refused transplantation in first remission. The majority of patients with ANL in relapse transplanted following Cy and TBI (1000rad) died within 100 days of non-leukemic causes [1, 14]. However, it can be predicted that 64°,0 would have relapsed if they had not died of non-leukemic causes [1]. *This investigation was supported by grants CA 18029, CA 18579. CA 15704, CA 09319 and CA 18221 from the National Cancer Institute, DHHS. Dr. Thomas is the recipient of a Research Career Award AI 02425 from the National Institute of Allergy and Infectious Diseases. Drs. Stewart and Sullivan are supported in part by a Junior Faculty Clinical Fellowship from the American Cancer Society. Abbreriations: ANL, acute non-lymphoblastic leukemia: Cy, cyclophosphamide; GVHD, graft-vs-host disease: MTX, methotrexate: TBI, total body irradiation. ('orrespondence to: Dr. C D. Buckner. Fred Hutchinson Cancer Research Center. 1124 Columbia Street. Seattle. WA 98104, U.S.A. 389

37 18 15 25 17

18 38 27

18 13 10 20 26

25 17

36 52 17

19

19 12

27

21

756 788 791 812 819

883 907 924

930 933 962 972 981

988 992

991 998 995

1033

1070 1071

1188

1193

5

4

5 52

11

21 48 2

4 35

2 7 11 39 3

14 25 16

2 10 17 8 16

M o n t h s from diagnosis to transplantation

- -

AMML

AML

AUL AMML

AML

AMoL AML AML

AMoL AML

AML APML AML AML AML

AML AMML AML

AML AMML AML AML AML

Diagnosis

1

1

I 3

1

I 2 l

I 2

1 I 1 2 0

I 2 1

0* 2 I 1 0

Marrow relapse No.

0

0

0 CNS(Hx)

0 CNS(Tx) CNS Skin (Txj 0

0 Test. lTx)

0 0 0 C N S {Hx] 0

C N S (Hx) 0 C N S (TxJ

0 C N S (Tx) 0 0 0

Extramedullary involvement

2

I

0 0

0

0{CI 3IC) 0(C)

2 1 IC)

2IC) 0 3~C) 0 0

3 (C) 0 0

I (C~ 0 I 1 3

Clinical grade of G V H D

30

199

167

144

132

249 57 619

Day leukemia recurred

40

26

116 30

18

210 >756 >756

173 411

>888 167 >817 199 39

> 997 33 17

> 1306 297 181 714 57

Post-transplant survival (days) (6/I/811

Interstitial p n c u m o n i a u n k n o w n etiology, dcath Leukcmia, death Veno-occhlsive discase of liver, death Interstitial pneumonia, idiopathic, dcath Interstitial pneumonia, idiopathic, death

Alive, 90',',,,t Leukemia, death Leukemia, death Leukemia, death Interstitial pneumonilis (CMV), death Alive, chronic G V H D, 60",, Aspergillosis, death Infection before engraftment, death Alive, chronic G V H D , 90% Leukemia, death Alive, chronic G V H D , 90'!, Leukemia, death Septicemia, renal failure, death Leukemia, death Cardiac failure and chronic G V H D Leukemia, death Alive, chronic G V H D , 80~, Alive, 100~o

Outcome

G V H D = graft-vs-host disease. AML = acute myelocytic leukemia; A M M L = acute myelomonocytic leukemia; A M o L = acute monocytic leukemia', A U L = acute undilfercntiatcd leukemia; A P M L = acute promyelocytic leukemia. * 0 = failure to achieve a remission with chemotherapy. [C) = chronic grafl-vs-host disease. t "~, = Karnofsky score of physical activity. Hx = history of; Tx = involvement at transplant. ('MV : cvhmlc~ah~virl~s:Tt!sl Icslictll:lr invnl,.cmcnl

Age (yr)

Unique patient No.

TABLE 1. D A T A ON 23 PATIENTS WITH A N L TRANSPLAN'I'ED IN RELAPSE AFTER PREPARATION WITIt 2 0 0 r a d / D A Y FOR SIX DAYS

Z

(")

Marrow transplantation, non-lymphoblastic leukemia in relapse

391

Time-dose relationships have been of major interest in radiobiology [22], and fractionated irradiation regimens developed empirically are commonly used by irradiation therapists. Fractionation of the total dose of irradiation could offer the possibility of less toxicity without compromising the antileukemic effects and thus offer the possibility of increasing the total dose of irradiation. An evaluation of fractionated TBI regimens was begun in 1977 and the results in 23 consecutive patients with ANL in relapse are presented here. MATERIALS AND METHODS Twenty-three patients with ANL in relapse were transplanted between November of 1977 and May of 1978 and were analyzed as of 1 June, 1981 (Table 11. The protocol was approved by the Human Subjects Review Committee of the Fred Hutchinson Cancer Research Center. The procedures and risks were explained in detail to the patients and family members. Particular emphasis was placed on the option of treatment with chemotherapy. Prior chemotherapy given to patients before referral for marrow transplantation varied according to protocols of the referring institution. All patients had received an anthracycline and cytosine arabinoside. The technique of marrow transplantation has been described [18]. Preparation for engraftment consisted of intrathecal methotrexate (MIX)(12 mg on days - 12 and -61, Cy (60 mg/kg of body wt on days - 10 and -91 and TBI, a 1200-rad midpoint total tissue dose from opposing cobalt 60 sources, as 200 rad/day on day - 5 to day 0, the day of marrow transplantation [8]. The dose rate was 5-8 rad/min. All patients received allogeneic marrow from a sibling determined to be HLA-identical by study of the family with serologic typing and mixed leukocyte culture [19]. In an attempt to prevent graft-vs-host disease (GVHDI. all patients were given MTX, 15 mg/m: of body surface area on day 1. 10mg'm 2 on days 3, 6 and I1. and then weekly to day 102 [12,19]. In an effort to prevent central nervous system relapse, alternate MTX doses were given as 12 mg intrathecally from days 32 to 102. In patients with a history of central nervous system leukemia, intrathecal MTX was given every six weeks for an additional one and a half years. No other antileukemic therapy was given after grafting. The grading of acute G V H D and the description of chronic G V H D have been discussed elsewhere [13, 19]. These patients were also entered on protocols involving prophylactic granulocyte transfusion [3], laminar air flo~ isolation [2] and prophylactic antithymocyte globulin [20].

RESULTS Table 1 summarizes patient characteristics and results. Figure 1 shows the survival and probability of remaining in remission as calculated by the method of Kaplan and Meier [7]. One patient died of infection on day 17 without evidence of engraftment; all other patients achieved engraftment. Eight patients relapsed between 30 and 619 days after transplantation and died of leukemia-related problems. Nine patients died of transplant complications: four of interstitial pneumonitis, three of infection, one of veno-occlusive disease of the liver and one of cardiac failure. Six of the 23 patients (26°,,;) are alive and i

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YEARS

FKL 1. Kaplan Meier product limit estimate of the fraction of surviving patients < i ,--~ and of tile probabilit3 of being in remission (O---+O). Solid circles represent living patients without relapse of leukemia

392

C. DEANBUCKNERet

al.

free of disease 756-1306 days following transplantation. Four patients are well with Karnofsky scores of 90-1000/o, and two patients have mild to moderate chronic GVHD with Karnofsky scores of 60-80°/,o. Of the 22 patients with sustained engraftment, seven developed significant acute GVHD (grade 2 or greater). Fifteen patients survived longer than 100 days, and eight of these developed significant chronic GVHD. Of the 11 patients with significant GHVD (acute, chronic or bothl, two relapsed and died of leukemia, two died of interstitial pneumonitis, one died of the complications of GVHD, and six are long-term survivors. Eleven patients with sustained engraftment had no significant GVHD, and there are no survivors from this group. Six patients relapsed and died of leukemia, two died of interstitial pneumonia, two of other infections, and one of veno-occlusive disease of the liver. Sixteen patients had cytogenetic studies of marrow before transplantation to detect leukemia-associated chromosomal abnormalities. In two patients such abnormalities could not be detected, and a variety of chromosomal rearrangements was present in the other 14 patients. All eight patients who relapsed after transplantation had leukemia-associated chromosomal markers before transplantation, and four of them had donors of opposite sex. After relapse, five patients were studied, and in all cases the recurrent leukemia cells were of host type. DISCUSSION Experiments in radiobiology have established the rationale for fractionated or lowdose irradiation [22, 23]. Recent reviews have summarized the radiobiological data and suggested the possible application of those data to marrow transplantation I-5+9, 10]. We have documented that long-term survival of dogs given marrow grafts after fractionated TBI was superior to that of dogs given single-dose TBI [4]. Although many useful insights have been obtained from these studies, the complexity of the events initiated by TBI in man dictates great caution in designing irradiation regimens. The regimen must accomplish a delicate balance between three important effects. There must be adequate immunosuppression to permit successful allogeneic engraftment, non-marrow toxicity must be tolerable, and the antileukemic effect must be maximal. The balance of these effects achieved by the use of 1000 rad in one exposure is well understood, and this was the starting point for our investigations of dosage modification. We guessed that six consecutive daily exposures of 200 rad would be sufficiently equivalent to 1000 rad in a single exposure to achieve consistent engraftment and permit evaluation of the nonmarrow toxicity and antileukemic effects. We have performed a randomized trial comparing this fractionated TBI regimen with 1000 rad single exposure in patients with ANL in first remission (personal observations). That study and the results published here clearly establish that, when used with 120 mg/kg Cy, 1200 rad fractionated over six days is adequately immunosuppressive for allogeneic marrow engraftment. A comparative evaluation of the non-marrow toxicities and antileukemic effects is difficult to obtain in the setting of ANL in relapse. The non-leukemic mortality associated with allogeneic marrow transplantation regimens incorporating TBI is due mainly to interstitial pneumonitis, GVHD and associated infection. This mortality is strongly age-related, being low in children and high in older patients. It is clustered principally in the first t00 days after transplantation. The very high actuarial relapse incidence after transplantation for patients receiving the unfractionated TBI has been consistent at 60-70°(, since we started using 1000 rad in 1969, and this favours the use of historical controls in evaluating the antileukemic effect of the fractionated regimen.

Marrow transplantation, non-lymphoblastic leukemia in relapse

393

From 1971 to 1977, 31 patients with ANL in relapse were transplanted following Cy and 1000 rad of TBI given in one exposure [1]. Patients who had received other chemotherapeutic agents in addition to Cy were excluded from analysis. The median survival was 99 days; the last death occurred on day 571. Three patients are alive and free of disease 1943. 2625 and 3331 days following transplantation. In the current study the median survival was 181 days, the last death occurred on day 714, and six patients are alive and free of disease from 756 to 1306 days. The fraction of survivors was not significantly different between the current study and the historical control group (p = 0.10). However, the increase in median survival from 99 to 181 days was encouraging, and despite the increase in median survival there was no increase in the relapse rate as calculated by the Kaplan-Meier method [7]. These results have encouraged us to increase the dose of irradiation. Currently we are treating patients with ANL in relapse using a preparative regimen which consists of Cy 60 mg/kg on two consecutive days followed by seven consecutive daily TBI exposures of 225 rad each. These data also confirm previous observations that patients with significant GVHD are less likely to die of recurrent leukemia and have a better survival than patients without significant GHVD [21]. There is obviously an infinite variety of time-dosage relationships in the delivery of any one total TBI dose. Exploration of the therapeutic possibilities which can be achieved will require careful and prolonged empirical studies.

REFERENCES I. BADGERC., BUCKNER C. D., THOMASE. D., CLiff R. A., SANDERSJ. E., STEWART P. S., STORB R,, SULLIVAN K. M., SHULMAN H. & FLOURNOY N. (1982) Allogeneic marrow transplantation for acute leukemia in relapse. Leukemia Res. 6, 383. 2. BUCKNER C. D., CLIFT R. A., SANDERS J. E., MEYERS J. D , COUNTS G. W., FAREWELL V. T., THOMASE. D. & THE SEATTLEMARROW TRANSPLANT TEAM (1978) Protective environment for marrow transplant recipients. A prospective study. Ann, intern. Med. 89, 893. 3. CLIFT R. A., SANDERS J. E., THOMAS E. D., WILLIAMS B. & BUCKNER C. D. (1978) Granulocyte transfusions for the prevention of infection in patients receiving bone-marrow transplants. N. Engl. d. Med. 298, 1052. 4. DEEG H. J., STORB R., WEIDEN P. L., SCHUMACHER D., SHULMANS., GRAHAMT. & THOMASE. D. (1981) High dose total body irradiation and autologous marrow reconstitution in dogs: Dose rate related acute toxicity and fractionation dependent long-term survival. Radiat. Res. 88, 385. 5. DUTREIXJ., WAMBERSIEA., LOIRETTE M. & BOISSER1EG. (1979) Time factors in total body irradiation. Path. Biol. 27, 365, 6. FREIREICH E. J., KEATING M. J., GEHAN E. A., MCCREDIE K. B., BODEY G. P. & SMITH T. (1978) Therapy of acute myelogenous leukemia. Cancer 42, 874. 7. KAPLAN E. L. & MEmR P (1958) Nonparametric estimation from incomplete observations. J. Am. statist. Ass. 53, 457. 8. 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. J. Radiat. Oncol. Biol. Phys. 6, 245. 9. LICHTER A. S., TRACY D., LAM W.-C. & ORDER S. E. (1980) Total body irradiation in bone marrow transplantation : The influence of fractionation and delay of marrow infusion. Int. J. Radiat. Oncol. Biol. Phys. 6, 301. 10. PETERSL. F., WITHERS H. R., CUNDIFF J. H. & DICKE K. A. (1979) Radiobiological considerations in the use of total-body irradiation for bone-marrow transplantation. Radiology 131,243. 11. STEWART P. S., BUCKNER C. D., CLIFF R. A., SANDERS J. E., STORB R., LEONARD J. M. & THOMAS l~. D. (1979) Allogeneic marrow grafting for acute leukemia: A follow-up of long-term survivors. Expl Hemat. 7, 509. 12. STORB R, EPSTEIN R. B., GRAHAM T. C. & THOMAS E. D. (1970) Methotrexale regimens for control of graft-vs-host disease in dogs with allogeneic marrow grafts. Transplantation 9, 240. 13. SULLIVAN K. M.~ SHULMAN H. M., WEIDEY P. L., STORB R, TSOl M. S. & THOMAS E D. (1980) The spectrum of chronic graft-vs-host disease in man. In Biology of Bone Marrow Transplantation (GALE R. P~ & FOX C. F., Eds.), p. 69. Academic Press, New York. 14 THOMASE. D.. BUCKNER C~ D., BANAJI M., CLIFT R. A,. FEFER A.. 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 ailogeneic marrow transplantation. Blood 49, 51 I.

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C. DEAN BUCKNER et al.

15. THOMASE. D.. BUCKNER C. D., CLIFT R. A., FEEER A., JOHNSON F L., NEIMAN P. E., SALE G. E.. SANDERSJ E., SINGER J. W.. SHULMAN H., STORB R. d~, WEIDEN P L. (1979} Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N. Engl. J. Med. 301. 597. 16. THOMAS E. D.. BUCKNER C. D., FEFER A,, SANDERS J. E. & STORB R. (1978) Efforts to prevent recurrence of leukemia in marrow graft recipients. Tran,splanm Proc. 10, 163. 17. THOMASE. D.. FLOURNOY N., BUCKNER C. D., CLIFT R. A., FEFER A., NEIMAN P. E. & STORB R. [1977} Cure of leukemia by marrow transplantation, Leukemia Res. I, 67. 18. THOMAS E, D. & STORa R. (1970) Technique for human marrow grafting. Blood 36, 507. 19, THOMASE. D., STORB R., CLIFT R. A., FEVER A., JOHNSON F. L.. NEIr*tAN P. E.. LERNER K~ G., GLL'CKSBERG H. & BUCKNER C. D. (1975) Bone-marrow transplantation..\'. Emjl. J. ),led. 292, 832, 895, 20. WEIDEN P. L., DONEY K., S'rORB R. & THOMAS E. D. (1979] Antihuman thymocyte globulin for prophylaxis of graft-vs-host disease. A randomized trial in patients with leukemia treated with HLA-identical sibling marrow grafts. Transplantation 27, 227. 21. WEIDEN P. L., FLOURNOY N., SANDERSJ. E., SULLIVAN K, M. & THOMAS E. D. J1981) Antileukemic effect of graft-vs-host disease contributes to improved survival after allogeneic marrow transplantation. Transpla*Ttt~ Proc. 13, 248. 22 WIERNtK G. (1973)The significance.of the time-dose relationship in radiotherapy. Br. reed. Bull. 29. 39. 23. WITHERS H. R., THAMES H. D., PETERS L. J. & FLETCHER G. H (1982) Normal tissue radioresistance in clinical radiotherapy, In Bioloqical Bases and Clinical Implications of Tumor Radioresistance. Proc. 2nd Rome Int. Syrup., September 1980.