Med. Oncol. & Tumor Pharmacother, Vol. 8, No. 4, pp. 261-263, 1991 Printed in Great Britain
0736-0t18/91 $3.00 + .00 Pergamon Press Ltd
LATE COMPLICATIONS OF ALLOGENEIC BONE MARROW TRANSPLANTATION A. B A C I G A L U P O , M. T. V A N LINT, F. F R A S S O N I , D. O C C H I N I , F. G U A L A N D I , T. L A M P A R E L L I and A. M. M A R M O N T Department of Hematology, Ospedale San Martino, Genova, Italy (Received 5 May 1991; accepted 7 May 199t) This report underlines the occurrence of multiple early and late complications after allogeneic BMT. Most of these are caused by the conditioning regimen, and especially by the use of total body irradiation. This should discourage the use of radiation for patients with non-malignant disorders such as aplastic anemia. We have shown that interstitial pneumonia is greatly reduced after fractionated TBI, and this should also be considered when designing transplant protocols. Prolonged immunodeficiency post-BMT is responsible for a high rate of infections: this suggests that long-term prophylactic antibiotic therapy should be considered. Great attention should be given to the quality of life of long-term survivors: to this respect a specific program for monitoring and treating gonadal complication can be extremely useful.
Key words: Bone marrow transplantation, Leukemia, Long-term effects. Table 1. Clinical data of patients
INTRODUCTION
Allogeneic bone marrow transplantation (BMT) is a biologically complex procedure, currently considered one important option in the clinical management of patients with leukemia and lymphoma. In spite of the considerable number of patients transplanted and the consequent growing experience of transplant teams, many problems remain to be solved, and the procedure still has a high incidence of early and late complications. In the present report we will summarize such early and late sequelae occurring in some 500 patients who received an allogeneic BMT at San Martino Hospital.
Number
Mismatched
SAA ANLL ALL CGL Inb.errors Lymphomas Myelodysplasia
67 135 112 107 6 15 13
3 3 4 5 4 3 1
Total
456
22
Abbreviations: SAA = severe aplastic anemia, ANLL = acute non-lymphoid leukemia, ALL = acute lymphoid leukemia, CGL = chronic granulocytic leukemia.
PATIENTS
Clinical data of patients are outlined in Tables 13. The large majority of our leukemia patients were conditioned with fractionated total body irradiation, and received cyclosporin A (CyA) alone or in combination with MTX for graft vs host disease G v H D prophylaxis. For the purpose of this study patients can be divided into 3 major groups: (a) patients prepared with chemotherapy alone (cyclophosphamide, CY with or without busulfan, BU); (b) patients prepared with CY and single dose total body irradiation;
Table 2. Conditioning regimens Cyclophosphamide (CY) alone CY and busulfan (BU) CY and nodal irradiation (TAI) CY and total body irradiation (TBI) Single dose TBI (sTBI) Fractionated TBI (fTBI) 3.3 Gy/day x 3 2.0 Gy • 2/day x 3 Other regimens 261
n n n n
= = = =
42 23 19 372
n = 19 n = 229 n = 103 n = 2I
262
A. Bacigalupo et al. Interstitial pneumonitis (IP)
Table 3. CvHD Prophylaxis regimens Methotrexate (MTX) alone MTX + Cyclosporin A (CyA) CyA alone T-cell depletion
n n n n
= = = =
41 51 307 62
(c) patients prepared with CY and fractionated total body irradiation.
IP occurs more frequently in patients receiving single-dose TBI (37%), less so in patients receiving fractionated TBI (10%) and still less in patients given chemotherapy only (9%). The incidence of lethal IP was 21%, 6% and 4% in these 3 groups respectively. We have also seen obstructive lung disease occurring late post-BMT: the important role of radiation is underlined by a 4% incidence in irradiated patients and none in patients given cyclophosphamide alone.
RESULTS AND DISCUSSION
Immunodeficiency This is the major problem encountered after allogeneic BMT. It has a multiple pathogenesis: recapitulation of the ontogeny of the immune system, emergence of specific and non-specific suppressor cells, immunosuppressive therapy with CyA and steroids, and GvHD all contribute to a profound and persistent inability of these patients to respond normally to bacterial, fungal and viral infections. This exposes patients to a significant risk of potentially lethal infections mostly in the first 100 days post-BMT, but, if chronic GvHD also thereafter. The degree of immunodeficiency can be shown by greatly diminished in vitro response of peripheral blood lymphocytes to mitogens (such as PHA), fungal antigens (candida), and to CD3: lowest T cell proliferation and cytoplasmic hydrolase expression (a marker of cell maturation) is seen between day 50and +100 and correlates with the severity of acute GvHD.
Amenorrhoea The occurrence of significant gonadal toxicity in patients undergoing allogeneic BMT has prompted us to open a specific program to monitor and treat this complication. In females TBI causes amenorrhoea: 100% of females irradiated after menarch enter menopause with amenorrhoea and local modifications of vaginal epithelium. Early treatment with low-dose estrogen/progesterone is successful in controlling menopausal symptoms and in ameliorating the trophism of vaginal epithelium. We feel this program has significantly improved the quality of life of our female patients: they have reported a reduction of dispareunia and an improvement of sexual relationship. When females are given TBI before menarch the incidence of amenorrhoea is only 33% and requirement for low-dose estrogen/progesterone treatment is much less. We are currently monitoring these young females for long-term effects and outcome. Females given cyclophosphamide alone have little or no gonadal complications, and successful pregnancies have been reported.
Cytomegalovirus (CMV) infections CMV infection is a major cause of morbidity and mortality in BMT recipients. In our program detection of immediate early antigen HCMV-IEA by immunoperoxidase on peripheral blood (PB) huffy coat cells and urine showed that 24% of our patients have evidence of CMV infection between 7-10 weeks post-BMT. Treatment with DHPG (Gancyclovir) of such patients has significantly improved their prognosis, and has shown promising results, also, in cases of interstitial pneumonitis. Often CMV infection is associated with a drop in neutrophil and platelet counts, and this, too, is a cause of concern. Donor-recipient HCMV serostatus (IgG) pre-BMT is helpful in predicting the risk of developing a CMV infection post-BMT: this risk is 7% in seronegative donor-recipient pairs, and 21-35% in other combinations.
Ophthalmic complications Sjogren syndrome is a typical symptom of chronic GvHD. We have had only one patient with severe Sjogren syndrome, causing severe damage to the conjunctiva: in our hands this complication has been poorly responsive to immunosuppressive therapy. Cataract formation is another frequent complication of patients given TBI. The overall incidence of cataracts is 11% (95% confidence limits 3-35%) at 15 yr, Most such patients have been operated on.
Secondary turnours Perhaps the most important long-term sequela of high-dose irradiation is secondary tumours. The role of radiation is underlined by the fact that in the
Allogeneic bone marrow transplantation European series of 500 patients with aplastic anemia receiving an allogeneic BMT without radiation in the conditioning regimen, and given long-term CyA therapy, there has been no case of secondary cancer. In our present series of 400 evaluable patients
263
receiving BMT after chemo/radiotherapy the actuarial 12-yr incidence of secondary turnouts is 7% (95% confidence limits 1-34%). There has been one glioblastoma and one cancer of the oesophagus. The latter was successfully operated on 1 yr ago.
0736-0t18/91 $3.00 + .00 Pergamon Press Ltd
LATE COMPLICATIONS OF ALLOGENEIC BONE MARROW TRANSPLANTATION A. B A C I G A L U P O , M. T. V A N LINT, F. F R A S S O N I , D. O C C H I N I , F. G U A L A N D I , T. L A M P A R E L L I and A. M. M A R M O N T Department of Hematology, Ospedale San Martino, Genova, Italy (Received 5 May 1991; accepted 7 May 199t) This report underlines the occurrence of multiple early and late complications after allogeneic BMT. Most of these are caused by the conditioning regimen, and especially by the use of total body irradiation. This should discourage the use of radiation for patients with non-malignant disorders such as aplastic anemia. We have shown that interstitial pneumonia is greatly reduced after fractionated TBI, and this should also be considered when designing transplant protocols. Prolonged immunodeficiency post-BMT is responsible for a high rate of infections: this suggests that long-term prophylactic antibiotic therapy should be considered. Great attention should be given to the quality of life of long-term survivors: to this respect a specific program for monitoring and treating gonadal complication can be extremely useful.
Key words: Bone marrow transplantation, Leukemia, Long-term effects. Table 1. Clinical data of patients
INTRODUCTION
Allogeneic bone marrow transplantation (BMT) is a biologically complex procedure, currently considered one important option in the clinical management of patients with leukemia and lymphoma. In spite of the considerable number of patients transplanted and the consequent growing experience of transplant teams, many problems remain to be solved, and the procedure still has a high incidence of early and late complications. In the present report we will summarize such early and late sequelae occurring in some 500 patients who received an allogeneic BMT at San Martino Hospital.
Number
Mismatched
SAA ANLL ALL CGL Inb.errors Lymphomas Myelodysplasia
67 135 112 107 6 15 13
3 3 4 5 4 3 1
Total
456
22
Abbreviations: SAA = severe aplastic anemia, ANLL = acute non-lymphoid leukemia, ALL = acute lymphoid leukemia, CGL = chronic granulocytic leukemia.
PATIENTS
Clinical data of patients are outlined in Tables 13. The large majority of our leukemia patients were conditioned with fractionated total body irradiation, and received cyclosporin A (CyA) alone or in combination with MTX for graft vs host disease G v H D prophylaxis. For the purpose of this study patients can be divided into 3 major groups: (a) patients prepared with chemotherapy alone (cyclophosphamide, CY with or without busulfan, BU); (b) patients prepared with CY and single dose total body irradiation;
Table 2. Conditioning regimens Cyclophosphamide (CY) alone CY and busulfan (BU) CY and nodal irradiation (TAI) CY and total body irradiation (TBI) Single dose TBI (sTBI) Fractionated TBI (fTBI) 3.3 Gy/day x 3 2.0 Gy • 2/day x 3 Other regimens 261
n n n n
= = = =
42 23 19 372
n = 19 n = 229 n = 103 n = 2I
262
A. Bacigalupo et al. Interstitial pneumonitis (IP)
Table 3. CvHD Prophylaxis regimens Methotrexate (MTX) alone MTX + Cyclosporin A (CyA) CyA alone T-cell depletion
n n n n
= = = =
41 51 307 62
(c) patients prepared with CY and fractionated total body irradiation.
IP occurs more frequently in patients receiving single-dose TBI (37%), less so in patients receiving fractionated TBI (10%) and still less in patients given chemotherapy only (9%). The incidence of lethal IP was 21%, 6% and 4% in these 3 groups respectively. We have also seen obstructive lung disease occurring late post-BMT: the important role of radiation is underlined by a 4% incidence in irradiated patients and none in patients given cyclophosphamide alone.
RESULTS AND DISCUSSION
Immunodeficiency This is the major problem encountered after allogeneic BMT. It has a multiple pathogenesis: recapitulation of the ontogeny of the immune system, emergence of specific and non-specific suppressor cells, immunosuppressive therapy with CyA and steroids, and GvHD all contribute to a profound and persistent inability of these patients to respond normally to bacterial, fungal and viral infections. This exposes patients to a significant risk of potentially lethal infections mostly in the first 100 days post-BMT, but, if chronic GvHD also thereafter. The degree of immunodeficiency can be shown by greatly diminished in vitro response of peripheral blood lymphocytes to mitogens (such as PHA), fungal antigens (candida), and to CD3: lowest T cell proliferation and cytoplasmic hydrolase expression (a marker of cell maturation) is seen between day 50and +100 and correlates with the severity of acute GvHD.
Amenorrhoea The occurrence of significant gonadal toxicity in patients undergoing allogeneic BMT has prompted us to open a specific program to monitor and treat this complication. In females TBI causes amenorrhoea: 100% of females irradiated after menarch enter menopause with amenorrhoea and local modifications of vaginal epithelium. Early treatment with low-dose estrogen/progesterone is successful in controlling menopausal symptoms and in ameliorating the trophism of vaginal epithelium. We feel this program has significantly improved the quality of life of our female patients: they have reported a reduction of dispareunia and an improvement of sexual relationship. When females are given TBI before menarch the incidence of amenorrhoea is only 33% and requirement for low-dose estrogen/progesterone treatment is much less. We are currently monitoring these young females for long-term effects and outcome. Females given cyclophosphamide alone have little or no gonadal complications, and successful pregnancies have been reported.
Cytomegalovirus (CMV) infections CMV infection is a major cause of morbidity and mortality in BMT recipients. In our program detection of immediate early antigen HCMV-IEA by immunoperoxidase on peripheral blood (PB) huffy coat cells and urine showed that 24% of our patients have evidence of CMV infection between 7-10 weeks post-BMT. Treatment with DHPG (Gancyclovir) of such patients has significantly improved their prognosis, and has shown promising results, also, in cases of interstitial pneumonitis. Often CMV infection is associated with a drop in neutrophil and platelet counts, and this, too, is a cause of concern. Donor-recipient HCMV serostatus (IgG) pre-BMT is helpful in predicting the risk of developing a CMV infection post-BMT: this risk is 7% in seronegative donor-recipient pairs, and 21-35% in other combinations.
Ophthalmic complications Sjogren syndrome is a typical symptom of chronic GvHD. We have had only one patient with severe Sjogren syndrome, causing severe damage to the conjunctiva: in our hands this complication has been poorly responsive to immunosuppressive therapy. Cataract formation is another frequent complication of patients given TBI. The overall incidence of cataracts is 11% (95% confidence limits 3-35%) at 15 yr, Most such patients have been operated on.
Secondary turnours Perhaps the most important long-term sequela of high-dose irradiation is secondary tumours. The role of radiation is underlined by the fact that in the
Allogeneic bone marrow transplantation European series of 500 patients with aplastic anemia receiving an allogeneic BMT without radiation in the conditioning regimen, and given long-term CyA therapy, there has been no case of secondary cancer. In our present series of 400 evaluable patients
263
receiving BMT after chemo/radiotherapy the actuarial 12-yr incidence of secondary turnouts is 7% (95% confidence limits 1-34%). There has been one glioblastoma and one cancer of the oesophagus. The latter was successfully operated on 1 yr ago.
