In! J. Radio/ion Oncolo,qy Biol. Phys Vol. Printed in the U.S.A. All rights reserved.
23, pp.
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??Phase I/II Clinical Trials MARROW TRANSPLANTATION FOLLOWING ESCALATING DOSES OF FRACTIONATED TOTAL BODY IRRADIATION AND CYCLOPHOSPHAMIDE-A PHASE I TRIAL F. B. PETERSEN, M.D., H. J. DEEG, M.D., C. D. BUCKNER, M.D., F. R. APPELBAUM, M.D., R. STORB, M.D., R. A. CLIFT, FIMLS, J. E. SANDERS, M.D., W. I. BENSINGER, M.D., R. P. WITHERSPOON, M.D., K. M. SULLIVAN, M.D., K. DONEY, M.D. AND J. A. HANSEN, M.D. Departments
of Medicine
and Pediatrics, University of Washington, School of Medicine and the Clinical Research Fred Hutchinson Cancer Research Center, Seattle, WA
Division,
Thirty-six patients with advancedhematologicmalignancywere enteredinto a Phase I study designedto define the maximum tolerated dose of unshielded total body irradiation delivered from dual 60Cobalt sources at an exposure rate of 8 cGy/min and given in fractions twice daily for total doses rangingfrom 12 Gy to 17 Gy. All patients received cyclophosphamide, 120 mg/kg administered over 2 days before total body irradiation. Allogeneic marrow was infused from HLA-identical siblings (n = 29) or one locus HLA incompatible family members (n = 3); three patients received cryopreserved autologous marrow and one patient received syngeneic marrow. The maximum tolerated dose of total body irradiation given as 2 Gy fractions twice a day was 16 Gy. One of eight patients receiving 12 Gy, none of four receiving 14 Gy, three of 20 receiving 16 Gy, and two of four receiving 17 Gy developed severe (Grade 3-4) regimen-related toxicity. The primary dose limiting toxicity was pneumonitis, followed by venoocclusive disease of the liver, renal impairment, and mucositis. Five patients (14%) are alive, four disease-free 7981522 days posttransplant. Twenty (56%) relapsed posttransplant. Further investigation of regimens containing 16 Gy of hyperfractionated total body irradiation is warranted to assess anti-tumor efficacy. Hyperfractionated TBI, Total body irradiation (TBI), Bone marrow transplantation, Preparative regimen, Radiation toxicity. 7, 12, 18, 19, 2 1, 23). However, few attempts have been made to determine the maximum tolerated dose (MTD) of any given TBI regimen in man. In this study the MTD of TBI that could be administered in 2 Gy fractions, given twice daily at an exposure rate of 8 cGy/min preceded by 120 mg/kg cyclophosphamide (CY) was determined.
INTRODUCTION Total
body irradiation (TBI) is incorporated into many treatment regimens used in preparation for marrow transplantation for patients with hematologic malignancies (25). Most regimens have been developed by extrapolating results from animal models ( 13). The first studies of marrow transplantation employed TBI administered as a single dose at relatively low dose rates (26). Studies in animal models demonstrated that increased doses of TBI resulted in increased leukemic cell kill, albeit at the expense of increased toxicity (4). Toxicity could be reduced by radiation dose fractionation (6, 7, 10, 12, 18, 19,2 1,23). Based on these observations, subsequent clinical TBI regimens employing one to three fractions a day were developed (8,9,27). Fractionation of TBI given once daily and hyperfractionation given several times daily theoretically results in an improved therapeutic index by allowing normal tissues to recover between fractions (6,
METHODS
AND
MATERIALS
Patients Thirty-six patients, three to 40 (median 18) years of age, with advanced hematologic malignancies were entered into this study. Patients with active hepatitis or abnormal renal function were excluded. In addition, patients transplanted through November 1986 were excluded if they had received mediastinal radiotherapy to a dose of 20 Gy or more before transplant. Patients transplanted after November 1986 were ineligible for the study if they
18221, CA 18029, CA 15704, CA 47748, CCA-8510/019, CA 095 15 from the National Cancer Institute, DHHS. Accepted for publication 2 October 199 1.
Reprint requests to: F. B. Petersen, M.D., Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98 104. This investigation was supported by PHS Grant Numbers CA 1027
and
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I. J. Radiation Oncology 0 Biology 0 Physics
had received any chest radiotherapy before transplant. Marrow was obtained from genotypically HLA-identical (29 patients) or HLA-heploidentical family member who were matched for two to three HLA loci on the nonshared haplotype (three patients), or from an identical twin in one patient and for three patients autologous marrow was used. The protocol was approved by the Institutional Review Board of the Fred Hutchinson Cancer Research Center. Consent was obtained from all patients or their guardians. Results were evaluated as of November 1, 1990. Preparative regimen All 36 patients received intravenous CY, 60 mg/kg/day on two consecutive days. Following a day of rest, TBI was given at an exposure rate of 8 cGy/min in fractions of 2 Gy twice a day with a 6 hr interval to a midline calculated total tissue dose of between 12 and 16 Gy. Four patients received an additional fraction of 1 Gy for a total dose of I7 Gy. TBI was administered without using shields to any organ from dual opposing 60Cobalt sources ( 17). Marrow was infused on day 0, 24 hr after the last dose of TBI. The schedule for the 17 Gy preparative regimen is shown below:
Volume 23, Number 5, 1992
Toxicity grading A standard grading system for evaluating regimen-related toxicity (RRT) was used ( 1). Attempts were made to distinguish symptoms from infections, toxicity from drugs administered after the transplant, or signs of acute and chronic GVHD from toxicity of the preparative regimen. Patients were prospectively evaluated for RRT by a single observer (F.B.P.) on days 0, 7, 14, 21, 28, and 100 posttransplant. Grade 1 RRT was defined as not lifethreatening and reversible without specific treatment. Grade 2 RRT was not life-threatening, but required specific medical intervention. Grade 3 RRT was life-threatening and required life-support measures (i.e., dialysis, ventilatory support). Grade 4 was fatal with RRT being the principal cause of death. The highest grade in any single organ system determined the overall grade of RRT. Organs evaluated were heart, CNS, gastro-intestinal system, bladder, lungs, kidneys, liver, and oral cavity (mucositis). All patients had a clinical performance score determined according to the Karnofsky system at the time the pretransplant cytotoxic therapy was started and at the time of last contact for surviving patients (16). I
Day ______________~~_________~~_________~~_____________~~_______________~~________________~~_______ CY
CY
Rest
TBI x 2
TBI X 2
Patients at high risk of central nervous system (CNS) relapse received two doses of methotrexate (MTX) intrathecally before and six doses after transplant starting on day 32 after marrow infusion. Males with lymphoid malignancies other than Hodgkin’s disease, received an additional 6 Gy irradiation to the testicles delivered as electrons from a linear accelerator in a single exposure during the preparative regimen. Patients were given increased hydration at twice the calculated volume of maintenance, diuretics, and continuous bladder irrigation, during CY administration to prevent hemorrhagic cystitis. Children did not receive bladder irrigation, but were urged to void frequently. Mesna was not given to any patient. Marrow transplantation, posttransplant immunosuppression, and supportive care The technique of marrow transplantation and posttransplant care have been described (28). Cyclosporine (CSP) and MTX were given for graft-versus-host disease (GVHD) prophylaxis in recipients of allogeneic grafts (20). The diagnosis and grading of acute and chronic GVHD have been described (11,22). Patients were entered on studies investigating the use of prophylactic systemic antibiotics, laminar airflow isolation, and prophylactic IV immunoglobulin infusions. Patients in this study did not receive hematopoietic growth factor or pentoxifylline.
TBI X 2
TBI X 2
TBI x 1
BMT
Patient allocation In a previous analysis of RRT in patients receiving CY (120 mg/kg) followed by daily fractions of 2.25 Gy for seven or 2.0 for six consecutive days, Grades 3-4 RRT was observed in 20%-30% of patients. On that background, attempts were made to define the highest dose of TBI associated with an incidence of Grade 3-4 RRT < 25%. To achieve this, a modification of Hsi’s method was used to allocate consecutive patients to higher or lower dose levels ( 14). Accordingly, patients were treated in groups of four. Doses were escalated or de-escalated with one fraction of 2 Gy per dose level at total doses between 12 Gy and 16 Gy. Further dose escalations involved a single one Gy fraction. The first four patients were treated with 12 Gy. Treatment of subsequent groups of four patients was at the next higher dose level, at the same dose level, or at the next lower dose level if the previous group had none, one, or more than one case of severe RRT, respectively. Patients were not placed in a higher dose level if estimates indicated a greater than 80% probability that the incidence of Grade 3-4 RRT would exceed 25% at that dose level. Statistics The probabilities of survival, relapse of leukemia, and non-relapse deaths were computed according to the method of Kaplan and Meier (15).
Marrow transplantation following TBI and cyclophosphamide 0 F. B. PETERSENet al.
RESULTS
Patient characteristics and treatment outcome are shown in Table 1. Eight patients (22%) were treated with a total TBI dose of 12 Gy, four patients ( 11%) with 14 Gy, 20 patients (56%) with 16 Gy and four patients ( 11%) with 17 Gy. Two of the 32 patients who received allogeneic marrow and who were given 12 and 16 Gy of TBI respectively died on day 14, too early to assess hematopoietic engraftment, and the remaining 30 patients transplanted with allogeneic marrow achieved engraftment. This was documented by cytogenetic analysis or HLA typing in 16 patients in whom a sex-mismatch or HLA difference with the donor existed. All three autologous and one syngeneic patient achieved hematopoietic reconstitution within 28 days of marrow infusion. Toxicity and graft-versus-host-disease
One of the first four patients in the 12 Gy group [UPN 30841 developed grade 4 toxicity of lungs and liver and died on day 22 of presumably radiation-induced interstitial pneumonitis. According to study design, the next four patients also received 12 Gy of TBI and none developed Grades 3-4 RRT. Therefore, in the next four patients the dose was escalated to 14 Gy, and none of these patients developed Grades 3-4 RRT. Consequently the next four patients were given 16 Gy of TBI. Since one of these patients developed grade 3 toxicity, the next four patients also received a total dose of 16 Gy. None of the second group of four patients developed Grade 3-4 toxicity (for a total of l/8), and thus the TBI dose was escalated in the next four patients to 17 Gy. Two of the first four patients in the 17 Gy group developed Grades 3-4 RRT. Consequently, the total TBI dose was decreased to 16 Gy in the remaining 12 patients. Two of the 12 patients developed Grades 3-4 RRT and this dose level was designated the MTD. Overall, three of 20 patients (UPN’s 3301, 3686, and 4036) receiving 16 Gy of TBI developed grades 3 (two patients) or 4 (one patient) RRT. Organs predominantly affected were lungs (three patients) and kidneys (one patient). All three patients died, one as a direct consequence of radiation toxicity to the lungs, one from cytomegalovirus (CMV) pneumonitis and one from candida septicemia. Two of four patients (UPN’s 3524 and 3534) receiving 17 Gy of TBI developed grades 3 and 4 toxicity, respectively. Both patients died, one from combined cytomegalovirus (CMV) and Pneumocystis carinii pneumonitis and one from radiation pneumonitis. The actuarial probability of death from non-relapse causes (defined as RRT, GVHD, infections, and bleeding) was 44% for all 36 patients, and 36% for the 20 patients receiving 16 Gy. All 36 patients developed mucositis of grades 1 (n = 9) or 2 (n = 27) severity. Sixteen patients developed pulmonary toxicity: nine grade 1, three grade 2 and four
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grade 4. Nineteen patients developed veno-occlusive-disease of the liver (VOD) with a median serum bilirubin of 6.3 (2.6-24.5) mg/lOO ml; however, this was mild (Grade 1) in eight patients. Ten patients developed grade 2 and one patient developed grade 3 VOD. Of the 32 allogeneic patients, 14 (44%) did not receive the prescribed schedule of acute GVHD prophylaxis throughout the first 28 days after transplant due to toxicity: two of these patients died on day 14 without signs of engraftment or GVHD. Thus, 12 of 30 evaluable patients (40%) did not receive the full schedule of acute GVHD prophylaxis. Eleven of the 12 patients had one or more doses of MTX omitted because of mucositis (n = 7) decreased renal function (n = 2) or both (n = 2). Six of the 12 patients had CSP stopped before day 28 due to renal impairment. Six of the 12 patients (50%) developed grades 2-4 acute GVHD compared to five of 18 patients (27%) who received all scheduled GVHD prophylaxis within the first 28 days from transplant. Survival, response, and causes of death
Outcome for individual patients is summarized in Table 1. The actuarial probability of disease-free survival at two years was 11% for all 36 patients, and 15% for the 20 patients who received the MTD of 16 Gy. Twenty patients (56%) relapsed from 14 to 5 16 (median 8 1) days posttransplant. The actuarial probability of relapse was 80% for all patients and 76% for the 20 patients who received 16 Gy. Currently four patients survive disease-free; all four have Karnofsky scores of 100% and no chronic GVHD. One patient is alive but is being treated for posttransplant relapse. Thirty-one patients died; seventeen (55%) from complications related to recurrence of the original malignancy. The remaining 14 patients (45%) died from non-relapse causes, although two of these were found to have recurrent leukemia at autopsy. Nine patients (29%) died from infectious complications: four from CMV interstitial pneumonitis, three from fungal infections (one of these combined with severe acute GVHD), and two from gramnegative septicemia. Four patients (13%) died from “idiopathic” alveolar/interstitial pneumonitis. At autopsy, all four patients had non-infectious pulmonary changes compatible with radiation injury. One patient died from an intracerebral hemorrhage secondary to thrombocytopenia. DISCUSSION
At least four variables determine the effects of TBI: total dose, dose rate, size of fraction, and fractionation interval. In a previous study from this institution, a regimen of cyclophosphamide followed by six daily 2.0 Gy fractions of TBI was compared to a single fraction of 10.0 Gy (8, 27). The fractionated regimen led to an improved survival that was associated with fewer relapse and nonrelapse deaths in patients with acute myeloblastic leuke-
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Volume 23, Number 5, 1992
Table 1. Patient characteristics
UPN years
Age
Diagnosis subtype
Disease phase
Source of marrow
Kamofsky score pretreatment
Maximum acute GVHD
RRT score
Day relapse
2 2
438 dead-relapse 27 I dead-relapse 119 dead-relapse I4 dead-sepsis 2 I dead-relapse 22 dead-pneumonitis 146 dead-relapse 117 dead-relapse
Day after transplant outcome
12 Gy total TBI dose 3013 3044 3045 3064 3078 3084 3089 3090
27 19 4 15 12 35 35 3
AML, FAB M3 ALL, Calla+ ALL, Calla+ ALL, Calla+ ALL, T cell CML, Phlf ALL, Calla+ ALL, Calla+
REM 2 REL 2 REL 0 REM 3 REL 2 AP REM 2 REL 2
HLA HLA HLA HLA HLA HLA HLA HLA
identical identical identical identical identical identical identical mismatch
90 90 80 90 70 90 100 90
2 0 0 0 0 0 0 0
2 2 4 2 1
420 91 76 11 80 27
REL I REM 2 REL 2 REM 4
HLA HLA HLA HLA
identical identical identical identical
80 100 90 80
I 3 2 1
2 2 1 1
59 325
29 dead-cerebral bleed > 1522 alive in rem, KS = 100% Dead-relapse 7 I3 dead-relapse
I
I I 3 2 2 2 2 2
3 0 2 0
2 4 2 2 2 2 1 2 2 4 2
58 516 103 564 103 139 82 14 155 68 44 -
340 dead-relapse 537 dead-relapse 65 dead-CMV pneumonia 143 dead-relapse 6 I4 dead-relapse > 1270 alive in REM, KS = 100% 85 dead-CMV pneumonia 250 dead-relapse 165 dead-relapse 126 dead-relapse 14 dead-idiopathic pneumonia, RRT 26 dead-sepsis 103 dead-CMV pneumonia 37 dead-aspergillosis 18 I dead-relapse >924 alive in REM, KS = 100% 68 dead-GVHD, fungemia I 16 dead-relapse 38 dead-RRT, pneumonia >798 alive in REM, KS = 100%
1 0 2 2
3 4 2 2
21
106 dead-pneumonia, RRT 29 dead-RRT, pneumonia 72 dead-CMV pneumonia > I 102 alive in REL, KS = 70%
1
I4 Gy total TBI dose 3094 3106 3124 3 139
23 26 15 11
ALL, Calla+ AML, FAB M2 ALL, Calla+ ALL, Calla+
I6 Gy total TBI dose 3178 325 I 3301 3309 3407 3419 3447 3474 3647 3665 3686 3733 3791 3805 3849 3854 3991 4030 4036 4082
3 1I 35 10 15 17 16 23 14 13 34 16 27 I3 23 40 29 32 22
ALL, Calla+ ALL, Calla+ AML, FAB M3 CML, PHI+ AML, FAB M2 ALL, Calla+ ALL, T cell ALL, T cell ALL, Dr+ ALL, T cell IGL ALL, T cell CML, Phlf ALL, Calla+ ALL, Calla+ LGL ALL, Calla+ ALL. T cell ALL, Calla+ AML. FAB M3
REL 2 HLA identical REM 3 Purged autologous REM 2 HLA identical BC HLA identical REM 2 HLA mismatch REL 0 HLA identical REL 1 HLA identical REL 2 HLA identical REL 1 Purged autologous REM 3 Unpurged autologous REL 0 HLA identical REL 0 HLA identical HLA identical BC REL I HLA identical REL I HLA identical REL 0 Syngeneic REL 3 HLA mismatch REL I HLA identical REL 0 HLA identical REM 2 HLA identical
80 90 100 70 90 80 70 100 100 100 90 80 70 80 80 80 80 90 90 100
4 I 0 2 1 0 0 2 2 0 1
I
I7 Gy total TBI dose 3524 3534 3573 3639
13 22 18 35
ALL, Ph+ HGL, T cell ALL, Calla+ LGL
REM 3 REL 0 REL 2 REL 0
HLA identical HLA-mismatch HLA identical HLA identical
80 90 80 80
Note: Patients are listed in UPN order within each dose level. REM = Remission; REL = Relapse; GVHD = Graft-versus-host disease; CMV = Cytomegalovirus; AML = Acute myeloblastic leukemia; IGL = Intermediate grade lymphoma; LGL = low grade lymphoma; HGL = High grade lymphoma; ALL = Acute lymphoblastic leukemia; CML = Chronic myelogenous leukemia; REL 0 = Never achieved remission; AP = Accelerated phase; BC = Blast phase; RRT = Regimen related toxicity; KS = Kamofsky score: FAB = French-American-British classification.
mia (AML) in remission. However, fractionated TBI did not improve transplanted in relapse (2, 3). In patients transplanted for ALL using Gy TBI, the MTD was determined The 15.75 Gy regimen compared
the same regimen of survival for patients subsequent studies in daily fractions of 2.25 to be 15.75 Gy (5). to one of 12.0 Gy re-
sulted in a significant reduction in the probability of posttransplant relapse in patients with AML in first remission or chronic myelogenous leukemia (CML) in chronic phase, but not in patients with more advanced disease. Radiobiologic studies in murine models or in ex vivo tissue sections suggest that normal non-hemopoietic cells,
Marrow transplantation following TBI and cyclophosphamide 0 F. B. PETERSEN et al.
in particular intestinal crypt cells, can be spared relative to lympho-hemopoietic cells with irradiation fractions spaced 3 to 6 hr apart (24). Hence, this approach theoretically should allow the use of high total doses of irradiation with an increased cumulative killing of lymphohemopoietic cells (both normal and malignant) and with less injury to most tissues than with the same total dose administered in fewer fractions (29). Results in animal models indicate that such an approach reduces delayed and long-term toxicity and thereby improves survival (6). In the present study, the interval between fractions on a given day was 6 hr (somewhat longer than those used in murine and canine studies) and pulmonary toxicity was dose-limiting. It is of interest, however, that we observed no more toxicity in patients receiving 16 Gy over four days than in the previous study in which patients
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received 15.75 Gy over seven days (5). This suggests that the shorter interval between fractions was indeed sufficient for repair of acute injury to the same extent as observed with 24 hr intervals. The probability of relapse observed at the MTD of 16.0 Gy was 76% and, compared to the probability of relapse observed following 15.75 Gy given over seven days, (72%) was not significantly different (5). However, since this was a Phase I study, only patients with a hematologic malignancy at an advanced stage were entered. Thus, conclusions about the relative anti-leukemic effect of this regimen are difficult to draw. A definitive analysis of the effectiveness of this (or any other) regimen can be carried out only in controlled randomized studies. Such a study would probably be best conducted in patients with relatively uniform disease and disease stage.
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21. Storb, R.; Raff, R. F.; Appelbaum, F. R.; Graham, T. C.; Schuening, F. G.; Sale, G.; Pepe, M. Comparison of fractionated to singledose total body irradiation in conditioning canine littermates for DLA-identical marrow grafts. Blood 74: 1139-l 143; 1989. 22. Sullivan, K. M.; Witherspoon, R.; Deeg, H. J.; Doney, K.; Appelbaum, F.; Sanders, J.; Lum, L.; Loughran, T.; Hill, R.; Anasetti, C.; Shields, A.; Nims, J.; Shulman, H.; Storb, R.; Thomas, E. D. Chronic graft-versus-host disease in man. In: Gale, R. P. Champlin, R., eds. Progress in bone marrow transplantation, UCLA Symposia on Molecular and Cellular Biology, New Series, Vol. 53. New York: Alan R. Liss, Inc.; 1987: 473-487. 23. Tarbell, N. J.; Amato, D. A.; Down, J. D.; Mauch, P.; Hellman, S. Fractionation and dose rate effects in mice: a model for bone marrow transplantation in man. Int. J. Radiat. Oncol. Biol. Phys. 13: 1065-1069: 1987. 24. Thames, H. D., Jr.; Withers, R.; Mason, K. A.; Reid, B. 0. Dose-survival characteristics of mouse jejunal crypt cells. Int. J. Radiat. Oncol. Biol. Phys. 7: 1591-157: 198 1.
Volume 23, Number 5, 1992 25. Thomas, E. D. High-dose therapy and bone marrow transplantation. Semin. Oncol. 12(Suppl. 6): 15-20; 1986. 26. Thomas, E. D.; Buckner, C. D.; Rudolph, R. H.; Fefer, A.; Storb, 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. Allogeneic marrow grafting for hematologic malignancy using HL-A matched donor-recipient sibling pairs. Blood 38: 267-287: 1971. 27. Thomas, E. D.; Clift, R. A.; Hersman, J.; Sanders, J. E.; Stewart, P.; Buckner, C. D.; Fefer, A.; McGuffin, R.; Smith, J. W.; Storb, R. Marrow transplantation for acute nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation. Int. J. Radiat. Oncol. Biol. Phys. 8: 817-821; 1982. 28. Thomas, E. D.; Storb, R.; Clift, R. A.; Fefer, A.; Johnson, F. L.; Neiman, P. E.; Lerner, K. G.; Glucksberg, H.; Buckner, C. D. Bone-marrow transplantation. N. Engl. J. Med. 292: 832-843, -895-902; 1975. 29. Withers, H. R. The four R’s of radiotherapy. Adv. Radiol. Biol. 5: 241-269; 1975.
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??Phase I/II Clinical Trials MARROW TRANSPLANTATION FOLLOWING ESCALATING DOSES OF FRACTIONATED TOTAL BODY IRRADIATION AND CYCLOPHOSPHAMIDE-A PHASE I TRIAL F. B. PETERSEN, M.D., H. J. DEEG, M.D., C. D. BUCKNER, M.D., F. R. APPELBAUM, M.D., R. STORB, M.D., R. A. CLIFT, FIMLS, J. E. SANDERS, M.D., W. I. BENSINGER, M.D., R. P. WITHERSPOON, M.D., K. M. SULLIVAN, M.D., K. DONEY, M.D. AND J. A. HANSEN, M.D. Departments
of Medicine
and Pediatrics, University of Washington, School of Medicine and the Clinical Research Fred Hutchinson Cancer Research Center, Seattle, WA
Division,
Thirty-six patients with advancedhematologicmalignancywere enteredinto a Phase I study designedto define the maximum tolerated dose of unshielded total body irradiation delivered from dual 60Cobalt sources at an exposure rate of 8 cGy/min and given in fractions twice daily for total doses rangingfrom 12 Gy to 17 Gy. All patients received cyclophosphamide, 120 mg/kg administered over 2 days before total body irradiation. Allogeneic marrow was infused from HLA-identical siblings (n = 29) or one locus HLA incompatible family members (n = 3); three patients received cryopreserved autologous marrow and one patient received syngeneic marrow. The maximum tolerated dose of total body irradiation given as 2 Gy fractions twice a day was 16 Gy. One of eight patients receiving 12 Gy, none of four receiving 14 Gy, three of 20 receiving 16 Gy, and two of four receiving 17 Gy developed severe (Grade 3-4) regimen-related toxicity. The primary dose limiting toxicity was pneumonitis, followed by venoocclusive disease of the liver, renal impairment, and mucositis. Five patients (14%) are alive, four disease-free 7981522 days posttransplant. Twenty (56%) relapsed posttransplant. Further investigation of regimens containing 16 Gy of hyperfractionated total body irradiation is warranted to assess anti-tumor efficacy. Hyperfractionated TBI, Total body irradiation (TBI), Bone marrow transplantation, Preparative regimen, Radiation toxicity. 7, 12, 18, 19, 2 1, 23). However, few attempts have been made to determine the maximum tolerated dose (MTD) of any given TBI regimen in man. In this study the MTD of TBI that could be administered in 2 Gy fractions, given twice daily at an exposure rate of 8 cGy/min preceded by 120 mg/kg cyclophosphamide (CY) was determined.
INTRODUCTION Total
body irradiation (TBI) is incorporated into many treatment regimens used in preparation for marrow transplantation for patients with hematologic malignancies (25). Most regimens have been developed by extrapolating results from animal models ( 13). The first studies of marrow transplantation employed TBI administered as a single dose at relatively low dose rates (26). Studies in animal models demonstrated that increased doses of TBI resulted in increased leukemic cell kill, albeit at the expense of increased toxicity (4). Toxicity could be reduced by radiation dose fractionation (6, 7, 10, 12, 18, 19,2 1,23). Based on these observations, subsequent clinical TBI regimens employing one to three fractions a day were developed (8,9,27). Fractionation of TBI given once daily and hyperfractionation given several times daily theoretically results in an improved therapeutic index by allowing normal tissues to recover between fractions (6,
METHODS
AND
MATERIALS
Patients Thirty-six patients, three to 40 (median 18) years of age, with advanced hematologic malignancies were entered into this study. Patients with active hepatitis or abnormal renal function were excluded. In addition, patients transplanted through November 1986 were excluded if they had received mediastinal radiotherapy to a dose of 20 Gy or more before transplant. Patients transplanted after November 1986 were ineligible for the study if they
18221, CA 18029, CA 15704, CA 47748, CCA-8510/019, CA 095 15 from the National Cancer Institute, DHHS. Accepted for publication 2 October 199 1.
Reprint requests to: F. B. Petersen, M.D., Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98 104. This investigation was supported by PHS Grant Numbers CA 1027
and
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had received any chest radiotherapy before transplant. Marrow was obtained from genotypically HLA-identical (29 patients) or HLA-heploidentical family member who were matched for two to three HLA loci on the nonshared haplotype (three patients), or from an identical twin in one patient and for three patients autologous marrow was used. The protocol was approved by the Institutional Review Board of the Fred Hutchinson Cancer Research Center. Consent was obtained from all patients or their guardians. Results were evaluated as of November 1, 1990. Preparative regimen All 36 patients received intravenous CY, 60 mg/kg/day on two consecutive days. Following a day of rest, TBI was given at an exposure rate of 8 cGy/min in fractions of 2 Gy twice a day with a 6 hr interval to a midline calculated total tissue dose of between 12 and 16 Gy. Four patients received an additional fraction of 1 Gy for a total dose of I7 Gy. TBI was administered without using shields to any organ from dual opposing 60Cobalt sources ( 17). Marrow was infused on day 0, 24 hr after the last dose of TBI. The schedule for the 17 Gy preparative regimen is shown below:
Volume 23, Number 5, 1992
Toxicity grading A standard grading system for evaluating regimen-related toxicity (RRT) was used ( 1). Attempts were made to distinguish symptoms from infections, toxicity from drugs administered after the transplant, or signs of acute and chronic GVHD from toxicity of the preparative regimen. Patients were prospectively evaluated for RRT by a single observer (F.B.P.) on days 0, 7, 14, 21, 28, and 100 posttransplant. Grade 1 RRT was defined as not lifethreatening and reversible without specific treatment. Grade 2 RRT was not life-threatening, but required specific medical intervention. Grade 3 RRT was life-threatening and required life-support measures (i.e., dialysis, ventilatory support). Grade 4 was fatal with RRT being the principal cause of death. The highest grade in any single organ system determined the overall grade of RRT. Organs evaluated were heart, CNS, gastro-intestinal system, bladder, lungs, kidneys, liver, and oral cavity (mucositis). All patients had a clinical performance score determined according to the Karnofsky system at the time the pretransplant cytotoxic therapy was started and at the time of last contact for surviving patients (16). I
Day ______________~~_________~~_________~~_____________~~_______________~~________________~~_______ CY
CY
Rest
TBI x 2
TBI X 2
Patients at high risk of central nervous system (CNS) relapse received two doses of methotrexate (MTX) intrathecally before and six doses after transplant starting on day 32 after marrow infusion. Males with lymphoid malignancies other than Hodgkin’s disease, received an additional 6 Gy irradiation to the testicles delivered as electrons from a linear accelerator in a single exposure during the preparative regimen. Patients were given increased hydration at twice the calculated volume of maintenance, diuretics, and continuous bladder irrigation, during CY administration to prevent hemorrhagic cystitis. Children did not receive bladder irrigation, but were urged to void frequently. Mesna was not given to any patient. Marrow transplantation, posttransplant immunosuppression, and supportive care The technique of marrow transplantation and posttransplant care have been described (28). Cyclosporine (CSP) and MTX were given for graft-versus-host disease (GVHD) prophylaxis in recipients of allogeneic grafts (20). The diagnosis and grading of acute and chronic GVHD have been described (11,22). Patients were entered on studies investigating the use of prophylactic systemic antibiotics, laminar airflow isolation, and prophylactic IV immunoglobulin infusions. Patients in this study did not receive hematopoietic growth factor or pentoxifylline.
TBI X 2
TBI X 2
TBI x 1
BMT
Patient allocation In a previous analysis of RRT in patients receiving CY (120 mg/kg) followed by daily fractions of 2.25 Gy for seven or 2.0 for six consecutive days, Grades 3-4 RRT was observed in 20%-30% of patients. On that background, attempts were made to define the highest dose of TBI associated with an incidence of Grade 3-4 RRT < 25%. To achieve this, a modification of Hsi’s method was used to allocate consecutive patients to higher or lower dose levels ( 14). Accordingly, patients were treated in groups of four. Doses were escalated or de-escalated with one fraction of 2 Gy per dose level at total doses between 12 Gy and 16 Gy. Further dose escalations involved a single one Gy fraction. The first four patients were treated with 12 Gy. Treatment of subsequent groups of four patients was at the next higher dose level, at the same dose level, or at the next lower dose level if the previous group had none, one, or more than one case of severe RRT, respectively. Patients were not placed in a higher dose level if estimates indicated a greater than 80% probability that the incidence of Grade 3-4 RRT would exceed 25% at that dose level. Statistics The probabilities of survival, relapse of leukemia, and non-relapse deaths were computed according to the method of Kaplan and Meier (15).
Marrow transplantation following TBI and cyclophosphamide 0 F. B. PETERSENet al.
RESULTS
Patient characteristics and treatment outcome are shown in Table 1. Eight patients (22%) were treated with a total TBI dose of 12 Gy, four patients ( 11%) with 14 Gy, 20 patients (56%) with 16 Gy and four patients ( 11%) with 17 Gy. Two of the 32 patients who received allogeneic marrow and who were given 12 and 16 Gy of TBI respectively died on day 14, too early to assess hematopoietic engraftment, and the remaining 30 patients transplanted with allogeneic marrow achieved engraftment. This was documented by cytogenetic analysis or HLA typing in 16 patients in whom a sex-mismatch or HLA difference with the donor existed. All three autologous and one syngeneic patient achieved hematopoietic reconstitution within 28 days of marrow infusion. Toxicity and graft-versus-host-disease
One of the first four patients in the 12 Gy group [UPN 30841 developed grade 4 toxicity of lungs and liver and died on day 22 of presumably radiation-induced interstitial pneumonitis. According to study design, the next four patients also received 12 Gy of TBI and none developed Grades 3-4 RRT. Therefore, in the next four patients the dose was escalated to 14 Gy, and none of these patients developed Grades 3-4 RRT. Consequently the next four patients were given 16 Gy of TBI. Since one of these patients developed grade 3 toxicity, the next four patients also received a total dose of 16 Gy. None of the second group of four patients developed Grade 3-4 toxicity (for a total of l/8), and thus the TBI dose was escalated in the next four patients to 17 Gy. Two of the first four patients in the 17 Gy group developed Grades 3-4 RRT. Consequently, the total TBI dose was decreased to 16 Gy in the remaining 12 patients. Two of the 12 patients developed Grades 3-4 RRT and this dose level was designated the MTD. Overall, three of 20 patients (UPN’s 3301, 3686, and 4036) receiving 16 Gy of TBI developed grades 3 (two patients) or 4 (one patient) RRT. Organs predominantly affected were lungs (three patients) and kidneys (one patient). All three patients died, one as a direct consequence of radiation toxicity to the lungs, one from cytomegalovirus (CMV) pneumonitis and one from candida septicemia. Two of four patients (UPN’s 3524 and 3534) receiving 17 Gy of TBI developed grades 3 and 4 toxicity, respectively. Both patients died, one from combined cytomegalovirus (CMV) and Pneumocystis carinii pneumonitis and one from radiation pneumonitis. The actuarial probability of death from non-relapse causes (defined as RRT, GVHD, infections, and bleeding) was 44% for all 36 patients, and 36% for the 20 patients receiving 16 Gy. All 36 patients developed mucositis of grades 1 (n = 9) or 2 (n = 27) severity. Sixteen patients developed pulmonary toxicity: nine grade 1, three grade 2 and four
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grade 4. Nineteen patients developed veno-occlusive-disease of the liver (VOD) with a median serum bilirubin of 6.3 (2.6-24.5) mg/lOO ml; however, this was mild (Grade 1) in eight patients. Ten patients developed grade 2 and one patient developed grade 3 VOD. Of the 32 allogeneic patients, 14 (44%) did not receive the prescribed schedule of acute GVHD prophylaxis throughout the first 28 days after transplant due to toxicity: two of these patients died on day 14 without signs of engraftment or GVHD. Thus, 12 of 30 evaluable patients (40%) did not receive the full schedule of acute GVHD prophylaxis. Eleven of the 12 patients had one or more doses of MTX omitted because of mucositis (n = 7) decreased renal function (n = 2) or both (n = 2). Six of the 12 patients had CSP stopped before day 28 due to renal impairment. Six of the 12 patients (50%) developed grades 2-4 acute GVHD compared to five of 18 patients (27%) who received all scheduled GVHD prophylaxis within the first 28 days from transplant. Survival, response, and causes of death
Outcome for individual patients is summarized in Table 1. The actuarial probability of disease-free survival at two years was 11% for all 36 patients, and 15% for the 20 patients who received the MTD of 16 Gy. Twenty patients (56%) relapsed from 14 to 5 16 (median 8 1) days posttransplant. The actuarial probability of relapse was 80% for all patients and 76% for the 20 patients who received 16 Gy. Currently four patients survive disease-free; all four have Karnofsky scores of 100% and no chronic GVHD. One patient is alive but is being treated for posttransplant relapse. Thirty-one patients died; seventeen (55%) from complications related to recurrence of the original malignancy. The remaining 14 patients (45%) died from non-relapse causes, although two of these were found to have recurrent leukemia at autopsy. Nine patients (29%) died from infectious complications: four from CMV interstitial pneumonitis, three from fungal infections (one of these combined with severe acute GVHD), and two from gramnegative septicemia. Four patients (13%) died from “idiopathic” alveolar/interstitial pneumonitis. At autopsy, all four patients had non-infectious pulmonary changes compatible with radiation injury. One patient died from an intracerebral hemorrhage secondary to thrombocytopenia. DISCUSSION
At least four variables determine the effects of TBI: total dose, dose rate, size of fraction, and fractionation interval. In a previous study from this institution, a regimen of cyclophosphamide followed by six daily 2.0 Gy fractions of TBI was compared to a single fraction of 10.0 Gy (8, 27). The fractionated regimen led to an improved survival that was associated with fewer relapse and nonrelapse deaths in patients with acute myeloblastic leuke-
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Volume 23, Number 5, 1992
Table 1. Patient characteristics
UPN years
Age
Diagnosis subtype
Disease phase
Source of marrow
Kamofsky score pretreatment
Maximum acute GVHD
RRT score
Day relapse
2 2
438 dead-relapse 27 I dead-relapse 119 dead-relapse I4 dead-sepsis 2 I dead-relapse 22 dead-pneumonitis 146 dead-relapse 117 dead-relapse
Day after transplant outcome
12 Gy total TBI dose 3013 3044 3045 3064 3078 3084 3089 3090
27 19 4 15 12 35 35 3
AML, FAB M3 ALL, Calla+ ALL, Calla+ ALL, Calla+ ALL, T cell CML, Phlf ALL, Calla+ ALL, Calla+
REM 2 REL 2 REL 0 REM 3 REL 2 AP REM 2 REL 2
HLA HLA HLA HLA HLA HLA HLA HLA
identical identical identical identical identical identical identical mismatch
90 90 80 90 70 90 100 90
2 0 0 0 0 0 0 0
2 2 4 2 1
420 91 76 11 80 27
REL I REM 2 REL 2 REM 4
HLA HLA HLA HLA
identical identical identical identical
80 100 90 80
I 3 2 1
2 2 1 1
59 325
29 dead-cerebral bleed > 1522 alive in rem, KS = 100% Dead-relapse 7 I3 dead-relapse
I
I I 3 2 2 2 2 2
3 0 2 0
2 4 2 2 2 2 1 2 2 4 2
58 516 103 564 103 139 82 14 155 68 44 -
340 dead-relapse 537 dead-relapse 65 dead-CMV pneumonia 143 dead-relapse 6 I4 dead-relapse > 1270 alive in REM, KS = 100% 85 dead-CMV pneumonia 250 dead-relapse 165 dead-relapse 126 dead-relapse 14 dead-idiopathic pneumonia, RRT 26 dead-sepsis 103 dead-CMV pneumonia 37 dead-aspergillosis 18 I dead-relapse >924 alive in REM, KS = 100% 68 dead-GVHD, fungemia I 16 dead-relapse 38 dead-RRT, pneumonia >798 alive in REM, KS = 100%
1 0 2 2
3 4 2 2
21
106 dead-pneumonia, RRT 29 dead-RRT, pneumonia 72 dead-CMV pneumonia > I 102 alive in REL, KS = 70%
1
I4 Gy total TBI dose 3094 3106 3124 3 139
23 26 15 11
ALL, Calla+ AML, FAB M2 ALL, Calla+ ALL, Calla+
I6 Gy total TBI dose 3178 325 I 3301 3309 3407 3419 3447 3474 3647 3665 3686 3733 3791 3805 3849 3854 3991 4030 4036 4082
3 1I 35 10 15 17 16 23 14 13 34 16 27 I3 23 40 29 32 22
ALL, Calla+ ALL, Calla+ AML, FAB M3 CML, PHI+ AML, FAB M2 ALL, Calla+ ALL, T cell ALL, T cell ALL, Dr+ ALL, T cell IGL ALL, T cell CML, Phlf ALL, Calla+ ALL, Calla+ LGL ALL, Calla+ ALL. T cell ALL, Calla+ AML. FAB M3
REL 2 HLA identical REM 3 Purged autologous REM 2 HLA identical BC HLA identical REM 2 HLA mismatch REL 0 HLA identical REL 1 HLA identical REL 2 HLA identical REL 1 Purged autologous REM 3 Unpurged autologous REL 0 HLA identical REL 0 HLA identical HLA identical BC REL I HLA identical REL I HLA identical REL 0 Syngeneic REL 3 HLA mismatch REL I HLA identical REL 0 HLA identical REM 2 HLA identical
80 90 100 70 90 80 70 100 100 100 90 80 70 80 80 80 80 90 90 100
4 I 0 2 1 0 0 2 2 0 1
I
I7 Gy total TBI dose 3524 3534 3573 3639
13 22 18 35
ALL, Ph+ HGL, T cell ALL, Calla+ LGL
REM 3 REL 0 REL 2 REL 0
HLA identical HLA-mismatch HLA identical HLA identical
80 90 80 80
Note: Patients are listed in UPN order within each dose level. REM = Remission; REL = Relapse; GVHD = Graft-versus-host disease; CMV = Cytomegalovirus; AML = Acute myeloblastic leukemia; IGL = Intermediate grade lymphoma; LGL = low grade lymphoma; HGL = High grade lymphoma; ALL = Acute lymphoblastic leukemia; CML = Chronic myelogenous leukemia; REL 0 = Never achieved remission; AP = Accelerated phase; BC = Blast phase; RRT = Regimen related toxicity; KS = Kamofsky score: FAB = French-American-British classification.
mia (AML) in remission. However, fractionated TBI did not improve transplanted in relapse (2, 3). In patients transplanted for ALL using Gy TBI, the MTD was determined The 15.75 Gy regimen compared
the same regimen of survival for patients subsequent studies in daily fractions of 2.25 to be 15.75 Gy (5). to one of 12.0 Gy re-
sulted in a significant reduction in the probability of posttransplant relapse in patients with AML in first remission or chronic myelogenous leukemia (CML) in chronic phase, but not in patients with more advanced disease. Radiobiologic studies in murine models or in ex vivo tissue sections suggest that normal non-hemopoietic cells,
Marrow transplantation following TBI and cyclophosphamide 0 F. B. PETERSEN et al.
in particular intestinal crypt cells, can be spared relative to lympho-hemopoietic cells with irradiation fractions spaced 3 to 6 hr apart (24). Hence, this approach theoretically should allow the use of high total doses of irradiation with an increased cumulative killing of lymphohemopoietic cells (both normal and malignant) and with less injury to most tissues than with the same total dose administered in fewer fractions (29). Results in animal models indicate that such an approach reduces delayed and long-term toxicity and thereby improves survival (6). In the present study, the interval between fractions on a given day was 6 hr (somewhat longer than those used in murine and canine studies) and pulmonary toxicity was dose-limiting. It is of interest, however, that we observed no more toxicity in patients receiving 16 Gy over four days than in the previous study in which patients
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received 15.75 Gy over seven days (5). This suggests that the shorter interval between fractions was indeed sufficient for repair of acute injury to the same extent as observed with 24 hr intervals. The probability of relapse observed at the MTD of 16.0 Gy was 76% and, compared to the probability of relapse observed following 15.75 Gy given over seven days, (72%) was not significantly different (5). However, since this was a Phase I study, only patients with a hematologic malignancy at an advanced stage were entered. Thus, conclusions about the relative anti-leukemic effect of this regimen are difficult to draw. A definitive analysis of the effectiveness of this (or any other) regimen can be carried out only in controlled randomized studies. Such a study would probably be best conducted in patients with relatively uniform disease and disease stage.
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21. Storb, R.; Raff, R. F.; Appelbaum, F. R.; Graham, T. C.; Schuening, F. G.; Sale, G.; Pepe, M. Comparison of fractionated to singledose total body irradiation in conditioning canine littermates for DLA-identical marrow grafts. Blood 74: 1139-l 143; 1989. 22. Sullivan, K. M.; Witherspoon, R.; Deeg, H. J.; Doney, K.; Appelbaum, F.; Sanders, J.; Lum, L.; Loughran, T.; Hill, R.; Anasetti, C.; Shields, A.; Nims, J.; Shulman, H.; Storb, R.; Thomas, E. D. Chronic graft-versus-host disease in man. In: Gale, R. P. Champlin, R., eds. Progress in bone marrow transplantation, UCLA Symposia on Molecular and Cellular Biology, New Series, Vol. 53. New York: Alan R. Liss, Inc.; 1987: 473-487. 23. Tarbell, N. J.; Amato, D. A.; Down, J. D.; Mauch, P.; Hellman, S. Fractionation and dose rate effects in mice: a model for bone marrow transplantation in man. Int. J. Radiat. Oncol. Biol. Phys. 13: 1065-1069: 1987. 24. Thames, H. D., Jr.; Withers, R.; Mason, K. A.; Reid, B. 0. Dose-survival characteristics of mouse jejunal crypt cells. Int. J. Radiat. Oncol. Biol. Phys. 7: 1591-157: 198 1.
Volume 23, Number 5, 1992 25. Thomas, E. D. High-dose therapy and bone marrow transplantation. Semin. Oncol. 12(Suppl. 6): 15-20; 1986. 26. Thomas, E. D.; Buckner, C. D.; Rudolph, R. H.; Fefer, A.; Storb, 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. Allogeneic marrow grafting for hematologic malignancy using HL-A matched donor-recipient sibling pairs. Blood 38: 267-287: 1971. 27. Thomas, E. D.; Clift, R. A.; Hersman, J.; Sanders, J. E.; Stewart, P.; Buckner, C. D.; Fefer, A.; McGuffin, R.; Smith, J. W.; Storb, R. Marrow transplantation for acute nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation. Int. J. Radiat. Oncol. Biol. Phys. 8: 817-821; 1982. 28. Thomas, E. D.; Storb, R.; Clift, R. A.; Fefer, A.; Johnson, F. L.; Neiman, P. E.; Lerner, K. G.; Glucksberg, H.; Buckner, C. D. Bone-marrow transplantation. N. Engl. J. Med. 292: 832-843, -895-902; 1975. 29. Withers, H. R. The four R’s of radiotherapy. Adv. Radiol. Biol. 5: 241-269; 1975.
