American Journal of Hematology 41 :40-44 (1992)

Allogeneic Bone Marrow Transplantation for Hematological Malignancies Following Etoposide, Cyclophosphamide, and Fractionated Total Body Irradiation Jonathan C. Yau, Charles F. LeMaistre, Borje S. Andersson, Susan D. Huan, Ralph 0. Wallerstein, Shiao Y. Woo, Gary Spitzer, Jorge A. Spinolo, Verneeda Spencer, Lane J. Brunner, Meletios A. Dimopoulos, Sundar Jagannath, Sergio Giralt, Carole M. Meneghetti, Karel A. Dicke, and Albert B. Deisseroth Ottawa Regional Cancer Center, Ottawa, Ontario, Canada (J.C.Y., S.D.H.); University of Texas, San Antonio, Texas (C.F.L., C.M.M.); University of Texas M.D. Anderson Cancer Center, Houston, Texas (B.S.A., R.O.W., S.Y.W., L.J.B., M.A.D., S.G., A.B.D.); St. Louis University Medical Center, St Louis, Missouri (G.S., V.S.); University of Nebraska, Omaha, Nebraska (J.A.S., K.A.D.); and University of Arkansas for Medical Sciences, Little Rock, Arkansas (S.J.)

Forty-three patients received etoposide, cyclophosphamide, and fractionated total body irradiation before allogeneic marrow transplantation. Fifteen patients had chronic myelogenous leukemia in chronic phase or acute leukemia in first remission (standard risk) and twenty-eight patients with more advanced disease (high risk). All patients received etoposide 1,500 mg/m2 intravenously on day -8, cyclophosphamide 60 mg/kg/day intravenously on days -7 and -6, and total body irradiation at 170 cGy twice a day on days -3, -2, and -1. During the first 100 days 12 high risk patients (43%) died from causes unrelated to relapse while none of the standard risk patients died. Renal and hepatic dysfunction were also significantly increased during the first 14 days in the high risk group. The addition of 1,500 mg/m2of etoposide to the cyclophosphamide and total body irradiation was well tolerated for patients with standard risk. However, the regimen was poorly tolerated with high mortality in patients with more advanced disease. 0 1992 Wiley-Liss, Inc.

Key words: etoposide, cyclophosphamide, allogeneic, transplantation

INTRODUCTION

Allogeneic bone marrow transplantation from HLAmatched sibling donors has been shown to be curative for many patients with acute leukemia and chronic myelogenous leukemia. The early mortality of the allogeneic bone marrow transplantation has been steadily decreasing because of the improvement in supportive care and more effective prophylaxis against acute graft-versus-host disease (GVHD). The combination of cyclophosphamide and total body irradiation (TBI) has been considered as the standard preparatory regimen for allogeneic bone marrow transplantation [ 13. However, the actuarial relapse rate after this regimen is over 70% in advanced leukemia [*I' the Of etoposide and TBI was tested with promising in patients with relapsed acute leukemia [3,4]. The toxicities of cyclo0 1992 Wiley-Liss, Inc.

phosphamide and etoposide did not appear to be overlapping, as we demonstrated in the etoposide, cyclophosphamide, and carmustine combination [ 5 ] .We therefore initiated the study of a combination of etoposide, cyclophosphamide and TBI as conditioning regimen for allogeneic bone marrow transplantation starting April 1988.

Received for publication October 24, 1991; accepted January 30, 1992. Address reprint requests to Dr. Jonathan C. Yau, Ottawa Regional Cancer Center, 190 Melrose Avenue, Ottawa, Ontario, Canada KIY 4K7.

Etoposide, Cyclophosphamide, and TBI

MATERIALS AND METHODS

TABLE 1. Patient Characteristics

Between April 1988 and April 1990 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), non-Hodgkin’s lymphoma, or myelodysplastic syndrome undergoing allogeneic bone marrow transplantation with unpurged marrow from HLA-A, B, C, and DR-matched siblings were entered in the study. All patients must be less than 55 years old and had adequate renal and liver functions. All procedures were approved by the Institutional Review Boards of the University of Texas M.D. Anderson Cancer Center. Informed consent was obtained from each patient prior to the transplantation. The conditioning regimen included etoposide (VP-16) 1,500 mg/m2 intravenously at 500 mg/hr on day -8 , cyclophosphamide 60 mg/kg/day intravenously for two days on days -7 and -6, and TBI at 170 cGy twice a day, 6 hours apart, for 3 days from a 18-MV linear accelerator on days -3, -2, and - 1. On day 0 the allogeneic marrow was reinfused. The marrow was collected and processed as previously described [6]. Patients received several regimens for acute GVHD prophylaxis. Briefly 36 patients received a single dose methylprednisolone and a combination of low dose methotrexate and cyclosporine, two patients received the same regimen without methotrexate due to the presence of pleural effusion, and five patients received a combination of steroid and XomaZyme-H65 (Xoma, Berkeley, CA) [6,7]. The supportive care for these patients have been reported previously [6]. The diagnosis and grading of acute GVHD were determined by skin biopsy and according to the Glucksberg criteria [8]. Toxicities were assessed and graded according to the Eastern Cooperative Oncology Group scale 191. Serum creatinine and total bilirubin were performed three times a week during the hospitalization. Bone marrow aspirations were performed every three months during the first 2 years after transplantation. Cytogenetics and detection for DNA rearrangement with the bcr probe (Molecular Diagnostic Associates, Inc., Houston, TX) were obtained on the marrow aspirates for patients with CML. Patients were not evaluable for acute GVHD if survival was less than 21 days and not evaluable for chronic GVHD if survival was less than 120 days. Rate of engraftment, cumulative probability of acute GVHD, relapse, and survival data were analyzed as of January 15, 1991 by the method of Kaplan and Meier and log-rank test taking censored data into account [ 101. T-tests were used for the comparison of creatinine and total bilirubin between groups.

Number of patients Median age (range) Ma1e:Female Diagnosis Acute myelogenous leukemia First remission Second remission Relapse Primary refractory Acute lymphoblastic leukemia First remission Second or third remission Relapse Primary refractory Chronic myelogenous leukemia First chronic phase Accelerated phase Second chronic phase Myelodysplastic syndrome Non-Hodakin’s lymphoma

RESULTS

Forty-three patients (24 men and 19 women) with a median age of 30 (range 17-49) years were studied. The

41

43 30 (1 7-49) 24:19

14 5 1 6 2 10 2 5 2 1 12 8 3 1 2

5

TABLE II. Non-Hematological Toxicities of the Conditioning Regimen

Standard risk Total number of patients

> Grade 2 nausea and vomiting > Grade 2 diarrhea > Grade 2 mucositis Pre-transplant serum creatinine pmol/l (range) Median peak serum creatinine in 14 days pnol/l (range) Pre-transplant total bilirubin pmolll (range) Median peak total bilirubin in 14 days ~ m o l / (range) l

High risk

15 0.0% 0.6% 40.0% 80 (44-106)

28 10.7% 14.3% 50.0% 88 (44-168)

80 (53-177)

124 (44-566)*

13 (3-29)

14 (5-32)

22 (10-75)

36 (12-177)**

* P = 0.06. **P = 0.03

diagnosis and status of their disease at the time of transplantation are shown in Table I. There were 15 patients transplanted in chronic phase of CML or first remission of acute leukemia (standard risk) and 28 patients transplanted with more advanced disease (high risk). Patients with lymphoma were all refractory to standard dose combination chemotherapy. The non-hematological toxicities of the regimen are shown in Table 11. There was no significant difference in hematopoietic recovery, mucositis, diarrhea, nausea, and vomiting between the groups. In the standard risk group all 15 patients were evaluable for acute and chronic GVHD. Two patients developed Grade 2 acute GVHD and eight developed chronic GVHD (three with limited and five with extensive disease). In the high risk group 25 patients (89.3%) were evaluable for acute and 15 patients (63.6%) were evaluable for chronic GVHD. Three patients developed Grade 3 and one Grade 4 acute GVHD.

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Yau et al.

4 0.4

1 I

1 I

1 I

1 I

1 I

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0.2 -

0

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1

Five patients developed limited chronic GVHD. There is no significant difference in the probability of developing greater than Grade 2 acute GVHD or chronic GVHD between the groups. The peak serum creatinine and total bilirubin within the first 14 days of transplantation were higher in the high risk group ( P = 0.06 and P = 0.03, respectively). In the standard risk group none of the patients died within the first 100 days of transplantation. One patient developed cardiac failure 2 weeks after transplantation and was monitored in the intensive care unit before discharge. In the high risk group 12 patients (42.9%) died within the first 100 days of transplantation unrelated to the relapse of disease ( P = 0.01). Two patients with lymphoblastic lymphoma developed tumor lysis syndrome during etoposide infusion. One died from the complication of the tumor lysis and the other achieved a partial response after etoposide alone and was transplanted 4 weeks later with the full regimen but subsequently died of fungal pneumonia. Three patients developed diffuse alveolar hemorrhage within the first 2 weeks of transplantation and one of these patients also developed veno-occlusive disease. All three patients died from respiratory failure. One patient failed to engraft and received a second allogeneic marrow infusion and subsequently died of sepsis and veno-occlusive disease. One patient who was refractory to platelet transfusion died from central nervous system hemorrhage six days after marrow infusion. Five patients died of interstitial pneumonitis; three of these patients had positive culture for cytomegalovirus from bronchoal-

I

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1

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veolar lavage. None died from the complications of acute GVHD. After a median follow-up of 13.0 months (range 6.523.0) 23 patients are alive with a 52.0% (SE 7.9%) cumulative probability of survival. The cumulative probability of survival for patients with standard risk is 86.0% (SE 9.0%) and that of the high risk patients was 35.0% (SE 9.0%) (Fig. l).One patient in the standard risk group (AML in first remission) relapsed 6.5 months after transplantation. Five patients in the high risk group relapsed (one with primary refractory AML, one AML with refractory relapse, one AML in first relapse, one AML in second relapse, and one ALL in second remission). It is too early to determine the probability of relapse after this conditioning regimen. Twenty patients had died at the last follow-up (Table 111). In the standard risk group two patients died: one from relapse of leukemia and one from the complication of chronic GVHD. In the high risk group 18 patients had died. During the first 100 days of transplantation 12 patients died from causes unrelated to the relapse of disease as described above. Of the remaining six patients, three died from the relapse of malignancies and three from idiopathic interstitial pneumonitis. DISCUSSION

In an attempt to enhance the antileukemic effect of our preparatory regimen for patients with leukemia undergoing allogeneic bone marrow transplantation, we added

Etoposide, Cyclophosphamide, and TBI

43

TABLE 111. Diaanosis and Outcome of Hiah Risk Patients*

Diagnosis to BMT (days)

Relapse (days)

Survival (days)

UPN

Age

Sex

Diagnosis/stage

45 4 26 31 40 17 5 13

24 17 18 41 37 18 28 19

F M F M M M F M

AML Secondary AML refractory AML 1st relapse AML 1st relapse AML 1st relapse AML 1st relapse AML2ndCR AML 2nd relapse

95 112 158 35 1 366 800 591 I69

1

29 40 27 27

F M M M

AML 2nd relapse ALL refractory ALL 1st relapse ALL2ndCR

339 181 194 184

88 56 20 34

20 37

21 24 25 32 19 41 29 48 25 35

M M F F M F M M F F

ALL 2nd CR ALL 2nd CR ALL 2nd CR ALL 2nd relapse ALL 3rd CR CML AP CML AP CML AP CML 2nd CP Lymphoma refractory

310 83 612 695 718 553 1,496 2,186 74 161

>317 >382 317 76 30 >468 >377 189 >552 60

16

28

F

Lymphoma refractory

90

30

27

M

Lymphoma refractory

494

12

34 30 47 30

M M M F

Lymphoma 1st relapse Lymphoma 1st relapse Mvelodvsolastic Mvelodvsolastic

749 779 78 200

25 46 23 35 24 29 14 36 27 34 15

11

2 6

.

123 25 312 196

146

>I93 282 61 >426 7 >550 6 >362

>405 48 75 131 268

Outcome Alive Relapse Relapse Alive DAH Alive, in CR CNS hemorrhage Alive, CNS Relapse in CR IP (CMV) DAH, VOD DAH No engraftment, VOD Alive Alive Relapse IP (CMV) IP (CMV) Alive Alive IP (Idiopathic) Alive Tumor lysis, IP (candida) Tumor lysis, no BMT Alive, resolved IP (CMW IP (Idiopathic) IP (Idiopathic) IP (Idiopathic) IP (Idiooathic)

* AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myelogenous leukemia; CR, complete remission; AP, accelerated phase; CP, chronic phase; DAH, diffuse alveolar hemorrhage; VOD, veno-occlusive disease; IP, interstitial pneumonitis; CMV, cytomegalovirus; CNS, central nervous system. etoposide to the cyclophosphamide and fractionated TBI combination. Etoposide and TBI have been used as preparatory regimen for patients with relapsed acute leukemia with effective anti-leukemic effects [3,4]. Our experience with the combination of etoposide, cyclophosphamide, and carmustine showed that the toxicities of cyclophosphamide and etoposide are not overlapping [ 5 ] .Others using a combination of cyclophosphamide, cisplatin, TBI, and etoposide also showed that the regimen is well tolerated with the etoposide dose of 1,500 mg/m2 [ 1 11. Higher dose of etoposide was associated with severe mucositis and pneumonitis. We therefore chose a dose of 1,500 mg/m2 of etoposide for our combination. This combination has been evaluated in other centers [ 12-14]. In one study using etoposide 500 mg/m2/day for 3 days in a similar sequence as our study, the mortality unrelated to relapse was 33% in patients with advanced acute leukemia [ 131. In another study using cyclophos-

phamide and etoposide 30-65 mg/kg after fractionated TBI three of the 13 patients receiving allogeneic marrow died during the first 100 days unrelated to relapse of leukemia. There were only seven high risk patients and two (29%) died from causes unrelated to relapse during the first 100days [ 141. The authors from the second study suggested that the ability to escalate etoposide dose may be due to the difference in the scheduling or method of fractionation of TBI. However the number of patients in the study was too small to determine if similar dose escalation would be feasible in the high risk patients. This regimen was well tolerated in patients with standard risk. There were no early death in this group. Only one patient required intensive care support. Further escalation of the etoposide dose in this group of patients may be possible. However in patient with more advanced disease the peak serum creatinine and total bilirubin were both increased more than those with standard risk (Table 11). During the

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first 100 days of transplantation 12 of the high risk patients (42.9%)died of regimen related toxicities such as idiopathic interstitial pneumonitis, diffuse alveolar hemorrhage and veno-occlusive disease. These complications may be due to the pretreatment or the extent of the disease in the high risk patients. Several attempts have been made by other centers, including ours, to enhance the antitumor effect or conditioning regimens [ 15-19]. However, the overall survival has not changed significantly. In our study the addition of etoposide to the standard cyclophosphamide and TBI combination in the standard risk patients were well tolerated. A large prospective randomized study will be needed to compare this regimen with the standard cyclophosphamide and TBI regimen since the survival of these patients is high and the probability of relapse is relatively low. The major cause of failure in patients with advanced leukemia after allogeneic bone marrow transplantation is the relapse of leukemia. It is doubtful that further intensification of this regimen would improve the outcome in these patients as the regimen related toxicities at the current dose level were severe. Perhaps therapy given after transplantation to eliminate minimal residual disease would be more effective and less toxic. We are now investigating the feasibility of using a second high dose chemotherapy combination with allogeneic marrow after patient recovers from the toxicities of the first allogeneic transplantation as cross-over intensification for the elimination of minimal residual disease without increasing the early mortality. Other post-transplantation treatment of minimal residual disease such as enhancement of graftversus-leukemia effect or use of various biologic response modifiers such as interleukin 2, interferon, and monoclonal antibodies conjugated with drugs, radioactive agents, or other toxins may be considered. This study shows that intensification of the conditioning regimen may enhance the antileukemic effects but the therapeutic index of the current regimens would not permit significant intensification without enhancement of the toxicities in patients with advanced leukemia. REFERENCES I . Thomas ED, Storb R, Clift RA, et al.: Bone marrow transplantation. N Engl J Med 292332, 1975. 2. Gale RP, Champlin RE: Bone marow transplantation in leukemia: Critical analysis and controlled clinical trials. In RP Gale (ed): “Recent Advances in Bone Marrow Transplantation.” New York: Alan R Liss, lnc., 1983, p71. 3. Blume KG, Forinan SJ, O’Donnell MR, Doroshow JH, Krance RA, Nademanee AP, Snyder DS, Schmidt GM, Fahey JL, Metter GE, Hill LR, Findley DO, Sniecinski IJ: Total body irradiation and high-dose etoposide: a new preparatory regimen for bone marrow transplantation in patients with advanced hematologic malignancies. Blood 69: 1015, 1987.

4. Schmitz N, Gassmann W, Rister M, Johannson W, Suttorp M, Brix F, Holthuis JJM, Heit W, Hertenstein B, Schaub J , Loffler H: Fractionated total body irradiation and high-dose VP 16-213 followed by allogeneic bone marrow transplantation in advanced leukemias. Blood 72:1567, 1988. 5 . Jagannath S, Dicke KA, Armitage JO, Cabanillas FF, Horwitz LJ, Vellekoop L, Zander AR, Spitzer G: High-dose cyclophosphamide, carmustine, and etoposide and autologous bone marrow transplantation for relapsed Hodgkin’s disease. Ann Intern Med 104:163, 1986. 6. Yau JC, LeMaistre CF, Zagars GK, Williams LA, Meneghetti CM, Luke DR, Dunphy FR, Spinolo JA, Jagannath S , Spitzer G, Zander AR and Dicke KA: Methylprednisolone, cyclosporine and methotrexate for prophylaxis of acute graft-versus-host disease. Bone Marrow Transplant 5:269, 1990. 7 LeMaistre F, Yau J , Meneghetti C, Champlin R, Spitzer G, Huan S, Andersson B, Wallerstein R, Lomen P, Protopsaltis N, Jackson L, and Deisseroth A: linmunoprophylaxis of graft-vs-host disease with H65RTA is associated with accelerated engraftment. Blood 76:549a, 1990. 8 Glucksberg H, Storb R, Fefer A, Buckner CD, Neimdn PE, Clift RA, Lerner KG, Thomas ED: Clinical manifestation of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation 18:295, 1974. 9 Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol5:649, 1982. 10. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457, 1958. I I . Herzig RH: High-dose etoposide and marrow transplantation. Cancer 67:292, 1991. 12. Kletzel M, Becton DL, Hutchins L: Phase 1/11 trial of high dose cytoxan, continuous infusion vincristine, escalating doses of VP- 16 and TBI with autologous bone marrow transplant. J Cell Biochem 12C:90, 1988. 13. Bostrom B, Weisdorf DJ, Kim T, Kersey JH, Ramsay NK: Bone marrow transplantation for advanced acute leukemia: A pilot study of high-energy total body irradiation, cyclophosphamide and continuous infusion etoposide. Bone Marrow Transplant 5233, 1990. 14. Spitzer TR, Cottler-Fox M , Torrisi J , Cahill R, Greenspan A, Lynch M, Deeg HJ: Escalating doses of etoposide with cyclophosphamide and fractionated total body irradiation or busulfan as conditioning for bone marrow transplantation. Bone Marrow Transplant 4559, 1989. 15 Zander AR, Dicke KA, Keating M, Vellekoop L, Culbert S , Spitzer G, Kanojia M, Jagannath S, Schell S, Hester J, Ayyar Raji, Verma D, McCredie K , Peters L, Poynton CH, Freireich EJ: Allogeneic bone marrow transplantation for acute leukemia refractory to induction chemotherapy. Cancer 561374, 1985. 16 Tutscka PJ, Copelan FA, Klein JP: Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood 70:1382, 1987. 17 Riddell S , Appelbaum FR, Buckner CD, Stewart P, Clift R, Sanders J, Storb R, Sullivan K , Thomas ED: High dose cytarabine and total body irradiation with or without cyclophosphamide as a preparative regimen for marrow transplantation for acute leukemia. J Clin Oncol 6376, 1988. IS Petersen FB, Buckner CD, Appelbaum FR, Clift RA, Sanders JE, Bensinger WI, Storb R, Witherspoon RP, Sullivan KM, Bearman SI, Flournoy N, Thomas ED: Busulfan, cyclophosphamide and fractionated total body irradiation as a preparatory regimen for marrow transplantation in patients with advanced hematological malignancies: A phase I study. Bone Marrow Transplant 4517, 1989. 19. Broun ER, Tricot G, Akard L, Nichols C, Cheerva A, Jansen J: Treatment of refractory lymphoma with high dose cytarabine, cyclophosphamide and either TBI or VP-16 followed by autologous bone marrow transplantation. Bone Marrow Transplant 5:341, 1990.