In1 J Rudmrun Oneolo~y Bd Phrs Vol. I’). pp. 889-897 Pnnted in the U.S.A. All rights reserved.

Copyright

0360.3016/90 $3.00 + .OO 01 1990 Pergamon Press plc

??Original Contribution COMPARISON OF TWO TOTAL BODY IRRADIATION REGIMENS IN ALLOGENEIC BONE MARROW TRANSPLANTATION FOR ACUTE NON-LYMPHOBLASTIC LEUKEMIA IN FIRST REMISSION TAE H. KIM, M.D.,*# PHILIP B. MCGLAVE, M.D.,+ NORMA RAMSAY, M.D.,$ WILLIAM WOODS, M.D.,* BRUCE BOSTROM, M.D.,’ GREGORY VERCELLOTTI, M.D.,+ DAVID HURD, M.D.,+ WILLIAM KRIVIT, M.D.,$ MARK NESBIT, M.D.,** ROBERT HAAKE, PH.D.,” FAIZ KHAN, PH.D.* AND JOHN H. KERSEY, M.D.** Bone Marrow

Transplantation

Program,

the University

of Minnesota.

Minneapolis,

MN 55455

Between November 1976 and December 1987,84 patients with newly diagnosed acute non-lymphoblastic leukemia who had achieved complete remission underwent non T-cell depleted allogeneic bone marrow transplantation from Human Leukocyte Antigen-Mixed Lymphocyte Culture (HLA-MLC) matched sibling donors. The first 36 patients (November 1976-June 1983) were prepared with cyclophosphamide, 60 mg/kg/day, IV for 2 days and single fraction total body irradiation with 750 cGy at a dose rate of 26 cGy/minute (Group I). The next 48 patients (July 1983-December 1987) were prepared with similar chemotherapy, but received hyperfractionated total body irradiation with total 1320 cGy, 165 cGy twice a day at a dose rate of 10 cGy/minute (Group II). Patient characteristics between these two groups are similar except for the significantly older age distribution in Group II. Median followup of Groups I and II are 8 years and 11 months and 2 years and 3 months, respectively. The Kaplan-Meier relapsefree survival, survival, and relapse rates at 3 years are 56,58, and 19% in Group I and 69 (p = 0.22), 77 (p = 0.07), and 10% (p = 0.37) in Group II. There is no difference in the incidence of interstitial pneumonitis, viral or idiopathic, engraftment rate, or incidence of graft versus host disease (GVHD) between these two groups. The fractionated total body irradiation treated group had significantly less nausea and vomiting. Multivariate analysis shows that total body irradiation regimen is not a significant factor in regard to relapse rate, relapse-free survival, and survival. Bone marrow transplantation,

Total body irradiation

INTRODUCTION

To develop more effective TBI regimens, we conducted sequential allogeneic BMT studies using two different TBI regimens at the University of Minnesota. These studies have been previously reported with smaller patient numbers (18).

Allogeneic bone marrow transplant (BMT) from Human Leukocyte Antigen-Mixed Lymphocytic Culture (HLAMLC) matched sibling donor for acute non-lymphoblastic leukemia (ANLL) in first remission has been proven to be very effective in prolonging remission status and improving relapse-free survival ( 1, 3, 4, 6, 10, 18, 35). In most BMT regimens, conditioning of patients include high dose chemotherapy and total body irradiation (TBI) (1. 3, 6, 1.5, 38). At the present time there is no consensus as to which TBI regimen is the most effective in reducing the relapse rate and decreasing the incidence of the acute and the late effects of treatment.

METHODS

AND

MATERIALS

Patient characteristics Between November 1976 and December 1987, 84 patients with newly diagnosed ANLL who had achieved complete remission underwent non T-cell depleted allogeneic BMT from HLA-MLC matched sibling donors.

Presented in part at the Meeting of the American Society for Therapeutic Radiology and Oncology, Boston, Massachusetts, October 2 1, 1987. * Dept. of Therapeutic Radiology/Radiation Oncology. + Dept. of Medicine. * Dept. of Pediatrics. Reprint requests to: Tae H. Kim. M.D., Department of Radiation Oncology, Abbott Northwestern Hospital, 800 E. 28th Street at Chicago Avenue, Minneapolis, MN 55407-3799.

.4cknow/eclgPment-Supported in part by a grant from the National Cancer Institute (POl-CA21737) and Children’s Cancer Research Fund. Dr. John Kersey is the recipient of an Outstanding Investigator Award (CA49721) from the National Cancer Institute. Accepted for publication 26 April 1990.

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Age, sex distribution, time from diagnosis to achieve complete remission, time from diagnosis to BMT. and initial white blood count are summarized in Table 1. Analysis of results was performed as of September 1988. Follow-up ranges from 9 months to 11 years 11 months (median = 5 years 7 months).

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position, the distance from the radiation source to the sagittal axis of the patient was maintained at 4.1 1 meters. The held projected at the patient was large enough to include the entire body within the 95Y0 isodose profile of the beam. Individualized aluminum compensators were used for head and neck. lungs. and lower extremities. No attempt was made to shield the lungs. The upper arms were positioned at the center of the lateral chest. The compensator pieces for lungs were designed by determining equivalent thickness of lungs plus the arms, using simulator films and physical patient measurements. No additional compensation was provided for parts of the lungs not covered by the arms. The data obtained from Randophantom dosimetry using this compensator technique showed a dose uniformity of -t5% along the sagittal axis of the phantom (14). From computer generated dose distribution for a typical patient as well as TLD measurements of the transmitted dose on patients, we have estimated that the dose in the compensated part of the lungs (covered by arm) is 95105% of the prescribed midline TBI dose. In the uncompensated part of the lungs, the dose can be as high as 110%. A 1 cm thick lucite screen was used in the beam at a distance of about 20 cm from the patient’s proximal surface to act as a beam spoiler. that is, to build up the skin dose to the same dose as the midline dose. This was verified by phantom dosimetry as well as by thin TLD chips taped on the surface of selected patients. Four patients. two each in Groups I and II. received TBI under general anesthesia because they were not able to hold proper position during irradiation. One patient in Group II was

Between November 1976 and June 1983, 36 patients were prepared with cyclophosphamide, 60 mg/kg/day. I.V. (days -4. -3) and single fraction TBI (day ~ 1) with 750 cGy to the midplane of the patient at a dose rate of 26 cGy/minute (Group I). Between July 1983 and December 1987, 48 patients were prepared with similar cyclophosphamide, 60 mg/kg/day, I.V. (days -7, -6). but received hyperfractionated TBI consisting of a total dose of 1320 cGy to the midplane of the patient, delivering 165 cGy twice a day at a dose rate of 10 cGy/minute (days -4, -3, -2, - 1). The time interval between the two daily fractions of TBI was 4-6 hr (Group II). All patients received marrow from allogeneic sibling donors matched at the HLA-A and B loci and non-reactive in bidirectional MLC (day 0). Seventy patients received their TBI by 10 MV x-ray beam from a linear accelerator. Fourteen patients received all or part of their TBI by 4 MV or 6 MV X rays because the 10 MV X-ray machine was not available or their lateral thickness at the level of umbilicus was small ( 1,000 mm3 for 3 consecutive days following BMT. Seventy-seven out of 84 patients achieved engraftment at a median of 26 days (range 17-43 days). Seven patients, four in Group I and three in Group II, died at day +9 to +54 without peripheral blood evidence of engraftment. Six of these seven died of sepsis, whereas one died of hyperammonemia. There were no late graft failures in nonrelapsing patients. There was no difference in engraftment rate between the two groups.

Survival and relapse-free survival Fifty-seven of 84 patients are alive, of whom 54 are alive without relapse. The Kaplan-Meier estimates of survival and relapse-free survival are 64% (95% C.I. = 53-

892

I. J. Radiation Oncology

0 Biology 0 Physics

October

1990. Volume

19. Number

4

1OOr

80

- - - -

Cyclophosphamlda

+ Single

-

Cyclophosphamide

+ Fractionated

Fraction

Follow-up

TBI

TSI

Time (Year)

Fig. 1. Cumulative proportion of patients who relapsed following allogeneic bone marrow transplantation. according to the number of years after transplantation. [j = 0.37. p value represents the test comparing groups at 3 years.

76%) and 59% (95% C.I. = 47-72%) respectively. Comparison of survival and relapse-free survival between Groups I and II are summarized in Table 2 and Figure 2. There were no statistically significant differences in survival or disease-free survival between Groups I and II. An additional analysis of relapse-free survival comparing Groups I and II was performed using a “cure” model. The estimated fractions of patients that are alive and relapse-free (the “cure” fraction) are P = 53% (95%’ C.I. = 36-69%) for Group 1 and P = 70% (95%) C.I. = 5684%) for Group II. This difference is not statistically significant (X’ = 2.3 1, 1 d.f., p = 0.13). Likewise, there was no statistically significant difference in the median time to events for those not “cured” between Group I (M = 7.3 months, 95% C.I. = 4.9-14.2 months) and Group II (M = 5.7 months, 95% C.I. = 3.3-19.3 months) (X2 = 0.30. p = 0.58).

TBI without general anesthesia, radiation therapy was interrupted in 16 patients (47%) because of nausea and vomiting despite premeditation with prednisone and antiemetics (24). Most of the interruptions occurred in the second half of the treatment. The average total treatment time including interruption to care for nausea and vomiting and to change the position of the patient from right lateral to left lateral in this group of patients was 44.7 minutes (34 minutes-57.4 minutes). The actual midplane dose rate averaged over the overall treatment time including interruption was 16.7 cGy/minute. In the hyperfractionated TBI group, however, interruption of TBI from GI toxicities was seen in only 5 out of 46 patients ( 1 1%) who received TBI without general anesthesia (X’ = 1 I .42. p = 0.00 1). The actual midplane dose rate averaged over the overall time including interruption was 7.7 cGy/minute in this group. None of the four patients who received TBI under general anesthesia experienced nausea or vomiting during radiation. Chtaructs. Fifteen of 84 patients developed cataracts between 10 and 60 months with an estimated incidence of 52% (95% Confidence Interval (C.I.) = 31-74%) at 5

Complications und cuuw qf&utI~ Acute gastrointestinal to,vicit?1of’TBI. Acute gastrointestinal toxicity (GI) of TBI include nausea, vomiting, and diarrhea. Of 34 patients who received single fraction

Table 2. Survival and relapse-free Group Total patients Relapse Dead Dead without relapse Kaplan-Meier relapse free survival at 3 years Kaplan-Meier

survival rate at 3 years

survival by TBI regimen

I

36 6 I6 II 56%. (95Rr c.1. = 39-7X) 58% (95% C.I. = 39-7X)

Group

II

p value

48

If II

69% (95% C.I. = 54-84s) 77%, (95% C.I. = 65-89%1)

0.22 0.07

Two TBI regimens in bone marrow transplantation 0 T. H.

ffiM

----

Cyclophosphamide + Single

-

Cychqhosphamida

K48

893

et al

Fraction TBI

+ Fractiinated

TBI

pts. u

_-

I --I...-_,

(g-J_

------------AL-

N=36

I_--~--UI~--_UUI~___L-~

pts.

40 -

20

01

1

2

4

3

5

Follow-up

7

6

a

9

10

Time (Year)

Fig. 2. Cumulative proportion of patients who are alive and free of relapse, according to the number of years after transplantation. Tick marks indicate patients who are alive and relapse-free. p = 0.22. p value represents the test comparing groups at 3 years.

years (Fig. 3). Twelve of 36 patients in Group I and 3 of 48 patients in Group II developed cataracts, with a 3-year estimated

incidence

of 27% (95% C.I. = 9-46%)

and

(95% C.I. = O-2.5%), respectively. This difference statistically significant (p = 0.19).

(25%, 95% C.I. = lo-40%) and 9 of 48 patients in Group II (23%, 95% C.I. = 9-36%) developed I.P. (p = 0.76). Ten patients developed idiopathic interstitial pneumonitis (14%, 95% C.I. = 6-22%), five in Group I and five in Group II, with an estimated incidence of 16% (95% C.I. = 3-29%) and 14% (95% C.I. = 2-25%), respectively (p = 0.64). Cytomegalovirus (CMV) seropositivity of recipient was found to be significantly associated with the development of interstitial pneumonitis (p = 0.014). De-

12%

was not

Interstitial pneumonitis. Seventeen of 84 patients developed interstitial pneumonitis of viral or idiopathic etiology, with an estimated incidence of 23% (95% C.I. = 14-33%) at 8 years. Eight of 36 patients in Group I

loo-

80 -

- - - -

Cyclophosphamide

+ Single Fraction TBI

-

Cyclophosphamlde

+ Fractionated

TBI

I----

N=36

-------------

pts.

60 -

40 -

20 -

_i

N=46

pts.

, !__I$ 0’

I

1

2

3

4

5

Follow-up

Fig. 3. Cumulative proportion of patients who developed according to the number of years after transplantation. 3 years.

6 Time

7

a

9

10

(Year)

cataracts following allogeneic bone marrow transplantation, p = 0.19. p value represents the test comparing groups at

894

I. J. Radiation Oncology 0 Biology 0 Physics

velopment of interstitial pneumonitis was significantly associated with poor survival (p < 0.0001) and relapsefree survival (p < 0.0001). GVHD. Grade 2 or greater acute GVHD developed in 34 of the 84 patients, with an estimated incidence of 43% (95% C.I. = 32-54%). There was no significant difference in the incidence of grade 2 or greater acute GVHD between Group I (35%, 95% C.I. = 19-5 1%) and Group II (49%. 95% C.I. = 34-64%) (p = 0.32). Extensive chronic GVHD developed in 21 of the 84 patients, with an estimated incidence of 3 1% (95% C.I. = 20-42%). Although the difference was not statistically significant, there was a higher incidence of extensive chronic GVHD among Group II patients (39%. 95% C.I. = 24-53%) than among Group I patients (18%, 95% C.I. = 4-32%) (p = .06). Cause ofdeath. Principal causes of death are listed in Table 3. Five of six relapsed patients in Group I have died. Two relapsed patients in Group II are still alive.

‘4ssociation qfprognostic,factor.c and TBI regimen M’ithoutcome Various potential prognostic factors. including FrenchAmerican-British (FAB) classification, patient and donor age, time from diagnosis to complete remission, time from complete remission to transplantation, patient and donor sex, patient and donor CMV seropositivity, GVHD prophylaxis, preparative regimen, and initial white blood count were analyzed to determine their impact on relapsefree survival (Table 4). Univariate analyses revealed that initial white blood count greater than 20,000, patient’s CMV seropositivity, and male donor combined with male patient were poor prognostic factors for relapse-free survival. Additionally, FAB morphology of M4 or M5 was

Table 3. Principal

Cause Relapse Sepsis Aspergillus sp. Candida sp. Staphylococcus sp. Enterococcus sp. Escherichia coli CMV Pneumonitis CMV RSV Candida sp Pseudomomas Idiopathic B-cell lymphoproliferation Liver failure Hyperammonemia Total

cause of death

Group I 5

Group II 0

2 0 0 0 0 2 0 0

2

0 0 0

2 0

0

16

11

GVHD has been excluded as a principal cause of death but was implicated in 9 of 27 deaths. CMV = Cytomegalovirus; RSV = Respiratory syncitial virus.

October 1990. Volume 19. Number 4

associated with a higher relapse rate (43%. 95% C.I. = 1 l75%) than other morphologies combined (14%, 95% C.I. = O-29%) (p = 0.02). Stepwise multivariate analyses of prognostic factors and TBI regimen were performed using the Cox regression model. These results are summarized in Table 5. TBI regimen had no significant impact on survival. relapse-free survival. or relapse after adjusting for other significant prognostic factors.

DISCUSSION Although some investigators advocate conditioning regimens using chemotherapy alone for allogeneic BMT for ANLL (25). most investigators use a combination of high dose chemotherapy and TBI to prepare these patients (1, 3, 6). TBI in allogeneic BMT for ANLL is used (a) to reduce the tumor volume. and (b) to suppress immune function of the recipient to enhance the marrow graft. The most ideal TBI regimen in BMT for acute leukemia would be the regimen that achieves the maximum therapeutic ratio, that is. the maximum target cell kill with minimum damage to the normal tissue. Target cells include leukemic cells, leukemic stem cells, and cells responsible for immune function. The group at Fred Hutchinson Cancer Center pioneered BMT for acute leukemia using high dose chemotherapy and a single fraction of 1000 cGy TBI at a dose rate of 5 cGy/minute ( 1). Some investigators, however. contend that fractionated or hyperfractionated TBI is a better method than single fraction TBI because leukemic cells have a very narrow shoulder of the radiation cell survival curve, indicating that they have a very limited capability to repair sublethal damage (16. 20, 2 1, 22). These investigators postulate that fractionated or hyperfractionated TBI maximizes leukemic cell kill with minimal damage to the normal tissue. Other investigators, however, have demonstrated that the parameter Do, extrapolation number (N). or quasithreshold dose (Dq) of the survival curve for some acute leukemia cells are not different from those for normal or other malignant cells including human tumor cells, and these cells can repair sublethal damage as well as normal tissue or some other malignant cells (30, Uckun, F.: Ramsay, N.; Kim. T.; Song, C. Unpublished data: June 1989.) Some sub-population of acute leukemic cells survives the usual dose of TBI, and suppression of immune function with radiation is significantly decreased by fractionating radiation regimen (29). Thus they contend that fractionating TBI will not necessarily increase the leukemic cell kill unless the total dose is increased. When this is done. the therapeutic ratio will not necessarily increase because of increased normal tissue damage. We started our BMT program for patients with ANLL in first remission by using single fraction TBI with 750 cGy at a dose rate of 26 cGy/minutes. The choice of this TBI regimen was based on animal experiments which

Two TBI regimens in bone marrow transplantation

Table 4. Influence

Prognostic

of prognostic

factors and treatment

factor

Ml, 2, 3, 6. 7 M4. 5 Recipient age < 18 years > 18 years TBI regimen S.TBI FrTBI Time from diagnosis to complete remission t44 days >44 days Time from complete remission to transplant t82 days >82 days GVHD prophylaxis MAP MTX RFS = Relapse-free survival: CMV = Cytomegalovirus: S.TBI = Single fraction

895

ef al.

survival-univariate

Estimated RFS %

analysis

95% C.I. %

P

54 28

68 40

52-84 21-59

,005

26 58

36 71

13-60 59-83

,012

44 40

48 71

28-68 57-86

,123

45 39

51 70

33-69 55-85

.155

43 40

46 73

27-65 58-87

.037

30 52

70 53

51-88 37-69

.139

29 54

54 61

36-73 44-78

.149

65 13

62 43

47-76 15-58

.311

43 41

59 63

43-75 46-79

.99

36 48

56 69

39-72 54-84

0.22

42 42

50 69

29-70 54-84

.273

42 42

54 64

38-70 45-84

,196

45 33

68 61

53-82 43-78

,791

MAP = Methotrexate, TBI: Fr.TBI = Fractionated TBI.

showed LD 50/30 following TBI with 750 cGy at a higher dose rate is similar to that of TBI with 1000 cGy at a dose rate of 5 cGy/minute (7). We achieved 3-year actuarial relapse-free survival of 56% with a recurrence rate of 19% using this regimen. To decrease the recurrence rate and improve the overall result, we changed the TBI regimen to a hyperfractionated one in the subsequent study. The total dose was increased to 1320 cGy from 750 cGy. The chemotherapy regimen remained the same. Although these regimens were studied sequentially, the patients in these two studies have comparable patient characteristics except for age (Table 1). Initial white blood count, time from diagnosis to achieve remission, time from remission to BMT, number of patients with M4.5. and number of patients with positive CMV serology are similar between the two groups. The

KIM

on relapse-free

Number of patients

Initial WBC 20,000 Recipient-donor sex Male to male Other Recipient sex Male Female Donor sex Male Female Recipient CMV seropositivity Positive Negative Recipient-donor CMV seropositivity Both negative One or both positive Donor CMV seropositivity Positive Negative FAB classification

otrexate;

regimen

0 T. H.

antithymocyte

globulin, prednisone;

MTX = Meth-

patients in Group II are significantly older than the patients in Group I. However, current and previous univariate or multivariate analyses ( 18) show that age is not significantly associated with relapse rate, relapse-free survival, or overall survival. The results so far have shown only an insignificant trend of improvement. Kaplan-Meier relapse-free survival rate, overall survival, and relapse rate at 3 years being 69, 77, and lo%, respectively. The stepwise multivariate analysis shows that TBI regimen is not a significant factor affecting the relapse rate, relapse-free survival, or overall survival. The etiology of interstitial pneumonitis in allogeneic BMT is not clearly understood. CMV seropositivity of recipient, acute GVHD, age of recipient. and radiation dose rate have been implicated as possible etiologic factors (11, 32, 33). The fact that the incidence of interstitial

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896

Table 5. Influence of prognostic factors and treatment regimen on outcome-multivariate analysis

Covariate Survival Initial WBC > 20,000 CY + S. TBI Relapse free survival Initial WBC > 20.000 Male to male Recipient CMV + Cy + S. TBI Relapse FAB M4.5 Male recipient Cy + S. TBI

Relative risk

95% C.I.

P

3.2

1.5-7. I

,002 .36

2.9 2.2 2.2 -

1.4-6.0 1.1-4.7 I .o-4.7

,007 .022 ,042 .30

7.5 5.6 -

1.7-32.2 1.o-30.0 -

.035 ,029 .I9

Cy = Cyclophosphamide; S.TBI = Single fraction TBI; CMV = Cytomegalovirus; WBC = White blood cells.

pneumonitis in autologous or syngeneic BMT is significantly lower than in allogeneic BMT, in spite of the fact that these patients were prepared with the same amount of radiotherapy and chemotherapy, and that the incidence of interstitial pneumonitis increases with higher dose BCNU without TBI, strongly suggests that radiation may not be a major cause of interstitial pneumonitis (3 1, 34). Note that the incidences of overall and idiopathic interstitial pneumonitis are identical between the two TBl groups in spite of the difference in dose rate and total dose. This report again confirms our previous findings that initial white blood count independently predicted poor relapse-free survival and survival and FAB morphology M-4. M-5 subtype independently predicted higher relapse

October 1990. Volume 19. Number 4

rate. Age and GVHD prophylaxis method were not significant prognostic factors ( 18). Acute GI toxicity was significantly less in patients who received fractionated TBI. However, the overall impact of this difference on outcome would be very minimal. if any. The incidence of cataracts appears to be less with the hyperfractionated TBI regimen. however longer followup is needed to determine if such a decrease remains for this regimen. The results from this study are inconclusive in defining a better TBI regimen. The numbers of patients are too small and follow-up time of Group II is probably too short. If there really were a 15% relapse-free survival advantage at 3 years as shown in Figure 2, 230 patients in each arm would be needed to demonstrate a statistically significant difference with 90% power (8). A more innovative or aggressive fractionated TBI regimen might be able to show a statistically significant improved outcome with a smaller number of patients. However, addition of further radiation to our current fractionated TBI regimen may exceed the tolerance of normal tissues (2. 13). In conclusion, our study showed that allogeneic BMT is an effective treatment in prolonging relapse-free survival time in patients with ANLL in first remission. Relapse of leukemia is one of the major causes of failure. Our attempt to improve the result by reducing the recurrence rate by changing a single fraction TBI of 750 cGy at the dose rate of 26 cGy/minute to a fractionated TBI of 1320 cGy at the dose rate of 10 cGy/minute given over 4 days in 8 fractions on a small number ofpatients has not yet shown significant improvement, although there is a statistically insignificant trend of improvement in favor of hyperfractionated TBI. Further study will be needed to define better TBI regimens.

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Comparison of two total body irradiation regimens in allogeneic bone marrow transplantation for acute non-lymphoblastic leukemia in first remission.

Between November 1976 and December 1987, 84 patients with newly diagnosed acute non-lymphoblastic leukemia who had achieved complete remission underwe...
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