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Factors affecting risk of relapse and leukemia-free survival in HLA-identical sibling marrow transplant recipients with leukemia
ELSEVIER
Factors Affecting Risk of Relapse and Leukemia-Free Survival in HLA-Identical Sibling Marrow Transplant Recipients With Leukemia S. Cat-lens, 0. Ringden,
M. Remberger,
J. Mattsson,
D
ESPITE heavy myeloablative therapy, recurrent disease is a major problem after allogeneic bone marrow transplantation (BMT) in patients with leukemia.‘,* Previous studies have shown that a more advanced disease and the use of a more efficient GVHD prophylaxis (such as methotrexate (MTX) combined with cyclosporine (CyA) and T-cell depletion) correlates with increased risk of leukemic relapse. 3-5 Second, the choice of pretransplant conditioning-for instance, higher doses of irradiation or additive cytotoxic drugs-entails the risk of relapse.‘x6 Furthermore, recent studies have also concluded that certain cytogenetic abnormalities correlate with the risk of relapse.7 The purpose of the present study was to identify risk factors for relapse, and factors associated with a poor leukemia-free survival (LFS), in leukemic patients undergoing allogeneic bone marrow transplantation with HLA-A, -B, and -DR-identical sibling donors. MATERIALS
AND
METHODS
Patients Among 288 consecutive patients with leukemia
receiving allogeneic
bone marrow transplants between 1980 and November 1997, a total of 254 survived more than 3 months and were studied retrospectively. There were 89 patients with acute myeloid leukemia (AML), 89 with acute lymphoblastic leukemia (ALL), and 76 with chronic myeloid leukemia (CML). One hundred and sixty-two patients were in first remission/chronic phase, 77 were in second or greater remission/chronic phase (intermediate-risk disease), and 14 patients had advanced disease (high-risk disease, more than 30% blasts in the bone marrow). Patient age ranged from 1 year to 58 years, with a median age of 28 years. There were 162 male and 92 female patients.
J. Aschan,
H. Hagglund,
and P. Ljungman
Donors
The donors were all HLA-A, -B, and -DR-identical siblings. There were 134 male and 120 female donors. Age ranged from 2 to 67 years, with a median of 26 years. The number of nucleated cells infused in the patients (adjusted for white blood cell count in blood) ranged from 0.1 to 9.2 X 10s cells/kg body weight, with a median value of 2.4 X 10’. Conditioning All patients were conditioned with cyclophosphamide (CY) 120 mg/kg before BMT.’ In 215 patients this was combined with total
body irradiation (TBI), and essentially all these patients received 10 Gy as a single fraction, with lungs shielded to receive no more than 9 Gy.s Thirty-eight patients were given busulfan 16 mg/kg prior to CY treatment instead of TBI. One patient received CY conditioning alone. lmmunosuppression Fifty-two patients received monotherapy with MTX according to the Seattle protocol (MTX 15 mgim’ on day 1; 10 mg/m2 on days 3,6,11,18, and 25, and every 2 weeks until day 95).9 Twenty-seven patients received CyA as a single drug for GVHD prophylaxis. Cyclosporine was given daily, starting IV from day -1 (1 to 7.5 mg/kg per day) and thereafter orally from day 1 (3 to 12.5 mgikg per day). Combination therapy with MTX and CyA was given to 155 patients. Since August 1985 only the first four doses of MTX
From Depts of Transplantation Surgery (S.C., OR., J.M., H.H.), Clinical Immunology (MR., J.M., OR.), and Haematology (J.A., P.L.), Huddinge University Hospital, Huddinge, Sweden. Address reprint requests to S. Carlens, Department of Transplantation Surgery, Huddinge University Hospital, B56, S-141 86 Huddinge, Sweden.
Table 1. Significant Risk Factors for Relapse in Univariate Analysis Factor
No. of Patients (O/l)
Relative Hazard
P-value
GVHD prophylaxis: Monotherapy/combination MTX + CyA Low-risk/intermediate + high-risk disease Chronic GVHD (yes/no) CMUacute leukemia
79/l 75 163/91 102/l 52 76/l 78
3.35 2.05 2.05 1.QO
.0005 .0037 ,008 ,034
Nonsignificant risk factors: donor/recipient age, donor/recipient sex mismatch, female donor to male recipient, immunized female donor, donor/recipient seropositivity for O-2 herpes viruses vs 3-4, donor/recipient CMV serology, CMV infection/disease, marrow cell dose, total body irradiation vs busulfan, acute GVHD, herpes simplex virus infection, day of engraftment. ‘P < .05.
1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0
Transplantation Proceedings, 29, 3147-3149
(1997)
0041-l 345/97l$17.00 PII SO041 -1345(97)008181 -X
3147
RELAPSE AND LEUKEMIA-FREE SURVIVAL
3149
Table 4. Significant Risk Factors Associated With Poor Leukemia-Free Factor Intermediate + high-risk disease Acute GVHD grades II-IV Female donor-to-male recipient
Survival, Multivariats Analysis From Day 30 Post-BMT
beta
SE
RH
Cl
P-value
0.756 0.677 0.469
0.193 0.244 0.20
2.15 1.99 1.60
1.46-3.16 1.21-3.21 1.07-2.39
<.OOOl .0056 .02
Relativehazards (RH):95% confidence intervals (Cl); beta = beta coefficient; SE = standard error.
shown that the best LFS in patients with acute leukemia as well as CML was seen in patients with grade I acute GVHD.“*‘* Higher grades should be avoided because of the risk of increased transplantation-related mortality. We therefore conclude that an adequate GVHD prophylaxis is very important. The goal must be to prevent moderate-tosevere acute GVHD (grades II-IV), but at the same time seek the benefits from the GVL reaction.‘4.1s
5. Aschan J, Ringden 0, Sundberg B, et al: Bone Marrow Transplant 7:113, 1991
ACKNOWLEDGMENTS
10. Aschan J, Ringden 0, Andstrom E, et al: Bone Marrow Transplant 1479, 1994
This study was supported by grants from the Swedish Cancer Foundation (0070-B95-09XCC), the Children’s Cancer Foundation (1994-060), the BelvCn Foundation, the Swedish Medical Research Council (B96-16X-05971-16C), the FRF Foundation, and the Tobias Foundation. REFERENCES 1. Thomas ED, Storb R, Clift RA, et al: N Engl J Med 292832, 1975 2. Giralt SA, Champlin RE Blood 843603, 1994 3. Ringden 0, Zwaan FE, Hermans J, et al: Transplant Proc 19:2600, 1987 4. Goldman JM, Gale RP, Horowitz MM, et al: Ann Int Med 108:806, 1988
6. Clift RA, Buckner CD, Appelbaum FR, et al: Blood 761867, 1990 7. Gale RP, Horowitz MM, Weiner RS, et al: Bone Marrow Transplant 16:203, 1995 8. Ringden 0, Biryd I, Johansson B, et al: Acta Radio1 Oncol 22:423, 1983 9. Storb R, Epstein RB, Graham TC, et al: Transplantation 9:240, 1970
11. Cox DR: J R Stat Sot Ser B 34187, 1972 12. Enterline PE: J Occup Med 18:150, 1976 13. Kaplan EI, Meier P: J Am Stat Assoc 53:457, 1958 14. Weiden PL, Sullivan KM, Floumoy N, et al: N Engl J Med 304:1529, 1981 15. Horowitz MM, Gale RP, Sondel PM, et al: Blood 175:555, 1989 16. Weaver CH, Hansen JA, Martin PO, et al: Bone Marrow Transplant 14:885, 1994 17. Gratwohl A, Hermans J, Apperley J, et al: Blood 86:813, 1995 18. Ringden 0, Hermans J, Labopin M, et al: Leuk Lymphoma 24:71, 1996
Factors Affecting Risk of Relapse and Leukemia-Free Survival in HLA-Identical Sibling Marrow Transplant Recipients With Leukemia S. Cat-lens, 0. Ringden,
M. Remberger,
J. Mattsson,
D
ESPITE heavy myeloablative therapy, recurrent disease is a major problem after allogeneic bone marrow transplantation (BMT) in patients with leukemia.‘,* Previous studies have shown that a more advanced disease and the use of a more efficient GVHD prophylaxis (such as methotrexate (MTX) combined with cyclosporine (CyA) and T-cell depletion) correlates with increased risk of leukemic relapse. 3-5 Second, the choice of pretransplant conditioning-for instance, higher doses of irradiation or additive cytotoxic drugs-entails the risk of relapse.‘x6 Furthermore, recent studies have also concluded that certain cytogenetic abnormalities correlate with the risk of relapse.7 The purpose of the present study was to identify risk factors for relapse, and factors associated with a poor leukemia-free survival (LFS), in leukemic patients undergoing allogeneic bone marrow transplantation with HLA-A, -B, and -DR-identical sibling donors. MATERIALS
AND
METHODS
Patients Among 288 consecutive patients with leukemia
receiving allogeneic
bone marrow transplants between 1980 and November 1997, a total of 254 survived more than 3 months and were studied retrospectively. There were 89 patients with acute myeloid leukemia (AML), 89 with acute lymphoblastic leukemia (ALL), and 76 with chronic myeloid leukemia (CML). One hundred and sixty-two patients were in first remission/chronic phase, 77 were in second or greater remission/chronic phase (intermediate-risk disease), and 14 patients had advanced disease (high-risk disease, more than 30% blasts in the bone marrow). Patient age ranged from 1 year to 58 years, with a median age of 28 years. There were 162 male and 92 female patients.
J. Aschan,
H. Hagglund,
and P. Ljungman
Donors
The donors were all HLA-A, -B, and -DR-identical siblings. There were 134 male and 120 female donors. Age ranged from 2 to 67 years, with a median of 26 years. The number of nucleated cells infused in the patients (adjusted for white blood cell count in blood) ranged from 0.1 to 9.2 X 10s cells/kg body weight, with a median value of 2.4 X 10’. Conditioning All patients were conditioned with cyclophosphamide (CY) 120 mg/kg before BMT.’ In 215 patients this was combined with total
body irradiation (TBI), and essentially all these patients received 10 Gy as a single fraction, with lungs shielded to receive no more than 9 Gy.s Thirty-eight patients were given busulfan 16 mg/kg prior to CY treatment instead of TBI. One patient received CY conditioning alone. lmmunosuppression Fifty-two patients received monotherapy with MTX according to the Seattle protocol (MTX 15 mgim’ on day 1; 10 mg/m2 on days 3,6,11,18, and 25, and every 2 weeks until day 95).9 Twenty-seven patients received CyA as a single drug for GVHD prophylaxis. Cyclosporine was given daily, starting IV from day -1 (1 to 7.5 mg/kg per day) and thereafter orally from day 1 (3 to 12.5 mgikg per day). Combination therapy with MTX and CyA was given to 155 patients. Since August 1985 only the first four doses of MTX
From Depts of Transplantation Surgery (S.C., OR., J.M., H.H.), Clinical Immunology (MR., J.M., OR.), and Haematology (J.A., P.L.), Huddinge University Hospital, Huddinge, Sweden. Address reprint requests to S. Carlens, Department of Transplantation Surgery, Huddinge University Hospital, B56, S-141 86 Huddinge, Sweden.
Table 1. Significant Risk Factors for Relapse in Univariate Analysis Factor
No. of Patients (O/l)
Relative Hazard
P-value
GVHD prophylaxis: Monotherapy/combination MTX + CyA Low-risk/intermediate + high-risk disease Chronic GVHD (yes/no) CMUacute leukemia
79/l 75 163/91 102/l 52 76/l 78
3.35 2.05 2.05 1.QO
.0005 .0037 ,008 ,034
Nonsignificant risk factors: donor/recipient age, donor/recipient sex mismatch, female donor to male recipient, immunized female donor, donor/recipient seropositivity for O-2 herpes viruses vs 3-4, donor/recipient CMV serology, CMV infection/disease, marrow cell dose, total body irradiation vs busulfan, acute GVHD, herpes simplex virus infection, day of engraftment. ‘P < .05.
1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0
Transplantation Proceedings, 29, 3147-3149
(1997)
0041-l 345/97l$17.00 PII SO041 -1345(97)008181 -X
3147
RELAPSE AND LEUKEMIA-FREE SURVIVAL
3149
Table 4. Significant Risk Factors Associated With Poor Leukemia-Free Factor Intermediate + high-risk disease Acute GVHD grades II-IV Female donor-to-male recipient
Survival, Multivariats Analysis From Day 30 Post-BMT
beta
SE
RH
Cl
P-value
0.756 0.677 0.469
0.193 0.244 0.20
2.15 1.99 1.60
1.46-3.16 1.21-3.21 1.07-2.39
<.OOOl .0056 .02
Relativehazards (RH):95% confidence intervals (Cl); beta = beta coefficient; SE = standard error.
shown that the best LFS in patients with acute leukemia as well as CML was seen in patients with grade I acute GVHD.“*‘* Higher grades should be avoided because of the risk of increased transplantation-related mortality. We therefore conclude that an adequate GVHD prophylaxis is very important. The goal must be to prevent moderate-tosevere acute GVHD (grades II-IV), but at the same time seek the benefits from the GVL reaction.‘4.1s
5. Aschan J, Ringden 0, Sundberg B, et al: Bone Marrow Transplant 7:113, 1991
ACKNOWLEDGMENTS
10. Aschan J, Ringden 0, Andstrom E, et al: Bone Marrow Transplant 1479, 1994
This study was supported by grants from the Swedish Cancer Foundation (0070-B95-09XCC), the Children’s Cancer Foundation (1994-060), the BelvCn Foundation, the Swedish Medical Research Council (B96-16X-05971-16C), the FRF Foundation, and the Tobias Foundation. REFERENCES 1. Thomas ED, Storb R, Clift RA, et al: N Engl J Med 292832, 1975 2. Giralt SA, Champlin RE Blood 843603, 1994 3. Ringden 0, Zwaan FE, Hermans J, et al: Transplant Proc 19:2600, 1987 4. Goldman JM, Gale RP, Horowitz MM, et al: Ann Int Med 108:806, 1988
6. Clift RA, Buckner CD, Appelbaum FR, et al: Blood 761867, 1990 7. Gale RP, Horowitz MM, Weiner RS, et al: Bone Marrow Transplant 16:203, 1995 8. Ringden 0, Biryd I, Johansson B, et al: Acta Radio1 Oncol 22:423, 1983 9. Storb R, Epstein RB, Graham TC, et al: Transplantation 9:240, 1970
11. Cox DR: J R Stat Sot Ser B 34187, 1972 12. Enterline PE: J Occup Med 18:150, 1976 13. Kaplan EI, Meier P: J Am Stat Assoc 53:457, 1958 14. Weiden PL, Sullivan KM, Floumoy N, et al: N Engl J Med 304:1529, 1981 15. Horowitz MM, Gale RP, Sondel PM, et al: Blood 175:555, 1989 16. Weaver CH, Hansen JA, Martin PO, et al: Bone Marrow Transplant 14:885, 1994 17. Gratwohl A, Hermans J, Apperley J, et al: Blood 86:813, 1995 18. Ringden 0, Hermans J, Labopin M, et al: Leuk Lymphoma 24:71, 1996