- Email: [email protected]
Treatment of post-transplant lymphoproliferative disease with rituximab monoclonal antibody after lung transplantation
1 2
3
4
5
Clinical Standards Advisory Group. Cleft lip and/or palate. London: Stationery Office, 1998. Witt PD, Wahlen JC, Marsh JL, Grames LM, Pilgram TK. The effect of surgeon experience on velopharyngeal functional outcome following palatoplasty: is there a learning curve? Plast Reconstr Surg 1998; 102: 1375–84. Marrinan E, LaBrie R, Mulliken J. Velopharyngeal function in nonsyndromic cleft palate: relevance of surgical technique, age at repair and cleft type. Cleft Palate Craniofac J 1998; 35: 95–100. Ross RB. Treatment variables affecting facial growth in unilateral cleft lip and palate. Part 2: presurgical orthopaedics. Cleft Palate J 1987; 24: 24–32. Sell D, Harding A, Grunwell P. GOS.SP.ASS.’98: an assessment for speech disorders associated with cleft palate and/or velopharyngeal dysfunction (revised). Int J Lang Commun Disord 1999; 34: 17–33.
Division of Child Dental Health, Lower Maudlin Street, Bristol BS1 2LY, UK (A C Williams FDSRCS , J R Sandy FDSRCS, S Thomas FDSRCS, D Sell PhD ); and Department of Social Science, University of Bristol, Bristol (J A C Sterne PhD) Correspondence to: Mr A C Williams
Treatment of post-transplant lymphoproliferative disease with rituximab monoclonal antibody after lung transplantation Richard C Cook, Joseph M Connors, Randy D Gascoyne, Guy Fradet, Robert D Levy Three patients with diffuse large B-cell type of post-transplant lymphoproliferative disease after lung transplantation were treated with rituximab, an anti-CD2O monoclonal antibody. Treatment resulted in two complete remissions and one nonresponse.
Post-transplant lymphoproliferative disorder (PTLD) is usually a catastrophic complication and can be an important cause of death in organ-transplant patients.1 Standard treatment consists of reduction in immunosuppression.1,2 Antiviral agents, surgery, and radiation have had only variable success.1 Multi-agent chemotherapy has been helpful for a few well-selected patients but is commonly either ineffective or too toxic.1 We treated three patients with aggressive pulmonary PTLD with a novel treatment using a monoclonal anti-CD20 anti-B-cell antibody. All three patients received initial and maintenance cyclosporine, azathioprine, and methylprednisolone. No patients were given anti-lymphocyte antibodies. The first patient was a 36-year-old Epstein-Barr-virus (EBV)seropositive man who underwent bilateral lung transplantation from an EBV-seropositive donor. By day 49, he developed hilar and mediastinal lymphadenopathy, lung nodules (figure, A) and a solid mass occluding the superior segmental bronchus of the left lower lobe. Multiple biopsies showed PTLD consisting of a diffuse infiltrate of histiocytes, plasma cells, rare multinucleate giant cells, and large neoplastic lymphoid cells that were strongly positive for CD20 and EBV and showed light-chain restriction (/ ratio 20/1). Oral aciclovir, reduced immunosuppression, and cyclophosphamide had no effect on the tumour. On the suggestion of the oncologist, and after informed consent, rituximab (Rituxin, IDEC Pharmaceuticals, San Diego, CA, USA) was given in standard doses over 4 weeks without sideeffects. The masses resolved over the next 3 months (figure, B). 6 months later the patient succumbed to bronchiolitis obliterans. Necropsy showed no evidence of PTLD. A 67-year-old EBV-seropositive woman underwent rightlung transplantation from an EBV-seronegative donor. 19 months later she developed a right upper-lung nodule.
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Chest radiographs taken just before rituximab, showing bilateral hilar lymphadenopathy and left lower lobe consolidation with nodular opacities scattered throughout the left lower lobe (A), and 6 months later showing nearly complete tumour regression (B)
Immunosuppression was reduced but the lung mass grew. Rituximab (Rituxin, Hoffmann-La Roche Canada, Mississauga, Canada) was given in standard doses without toxic effects. The mass regressed modestly then grew. She died 4 months later. A necropsy showed a diffuse large-cell EBV-positive lymphoma with large CD20-positive malignant cells showing moderate plasmacytoid differentiation. An EBV-seronegative 16-year-old girl underwent bilateral lung transplantation from an EBV-seropositive donor. A seizure caused a change in immunosuppressants to tacrolimus and mycophenolate. 2 months later she developed mediastinal lymphadenopathy and lung nodules that progressed despite reduced immunosuppression and aciclovir therapy. A peripheral lung nodule was resected showing a diffuse largecell PTLD with malignant cells expressing light chains, CD19, CD20, CD11c, and CD23. Immunoglobulin heavychain PCR was clonal and EBV-PCR positive. Rituximab was given without significant toxic effects. Within 4 weeks all masses had regressed. She remained free of disease 8 months later. The incidence of PTLD after lung transplantation is 5–7% with mortality up to 70% if the tumour does not respond to reduced immunosuppression.1 Immunotherapy is an appealing therapeutic option. One previously reported patient
THE LANCET • Vol 354 • November 13, 1999
responded completely to a CD22-directed immunotoxin.3 Of 58 patients treated with a mixture of anti-CD21 and antiCD24 antibodies, 80% of the patients with oligoclonal and 48% of patients with monoclonal diseases had a complete response.4 A patient who developed PTLD 6 months after bone-marrow transplantation responded to rituximab.5 Interpretation of maintenance of this response is difficult because the patient later received donor lymphocytes. The rituximab therapy that we gave to three patients with progressive, treatment-refractory PTLD was well tolerated. Two had radiological evidence, and one of those proof on necropsy, of complete sustained responses to rituximab. Further testing of rituximab for lymphoid malignant disease arising in the setting of immunosuppression should be undertaken. 1
2
3
4
5
Magrath IT, Shad AT, Sandlund JT. Lymphoproliferative disorders in immunocompromised individuals. In: Magrath IT, ed. The nonHodgkin’s lymphomas. 2nd edn. London: Oxford University Press, 1997: 955–74. Starzl TE, Nalesnik MA, Porter KA, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1984; ii: 583–87. Senderowicz AM, Vitetta E, Headlee D, et al. Complete sustained response of a refractory, post-transplantation, large B-cell lymphomato an anti-CD22 immunotoxin. Ann Intern Med 1997; 126: 882–85. Benekerrou M, Jais J-P, Leblond V, et al. Anti-B-cell antibody treatment of severe posttransplant B-lymphoproliferative disorder: prognostic factors and long-term outcome. Blood 1998; 92: 3137–47. Faye A, Abeele TVD, Peuchman M, Mathieu-Boue A, Vilmer E. Anti-CD20 monoclonal antibody for post-transplant lymphoproliferative disorders. Lancet 1998; 352: 1285.
University of British Columbia Lung Transplant Program (R C Cook MD, G Fradet MD, R D Levy MD), and Division of Medical Oncology (J M Connors MD) and Pathology (R D Gascoyne MD), British Columbia Cancer Agency, University of British Columbia and Vancouver General Hospital, Vancouver, 100 West 10th Avenue, Vancouver, BC, V5Z 4E6 Canada Correspondence to: Dr Joseph M Connors (e-mail: [email protected])
Influence of vaccination coverage on pertussis transmission in France Emmanuel Grimprel, Sabine Baron, Daniel Lévy-Bruhl, Jean Marc Garnier, Elisabeth N’jamkepo, Nicole Guiso, Pierre Bégué Older children still contribute to the transmission of pertussis to infants in French regions with low booster coverage at 2 years of age. Booster vaccination seems crucial for protection against symptomatic pertussis in childhood.
In countries with sustained and widespread use of pertussis vaccination, resurgence of the disease has been reported. Although the highest risk of severe disease is still in infants, incidence of pertussis is increasing in adolescents and adults.1 By contrast, in countries with low coverage, pertussis remains endemic with a unique peak of incidence in children less than 7 years old.2 In France, pertussis whole-cell vaccine has been used since 1957, and combined in the diphtheria-tetanus-pertussis inactivated poliomyelitis vaccine since 1966. The schedule DTP coverage*
Paris Marseille
4 doses
3 doses
91% 61%
98% 89%
Number of Index cases 80 30
recommends three doses at 2 months, 3 months, and 4 months, with one booster dose at 18 months. Since the early 1990s, the national immunisation coverage has been above 90% for three doses and had risen from 82% in 1990 to 89% in 1997 for four doses. A national survey done in 1993–94 in 22 paediatric hospitals shows a high incidence of pertussis among infants.3 A household transmission study carried out within this survey pointed out that infants were equally contaminated by siblings and parents.3 These results contrasted with preliminary data from a single hospital in Paris in which infants were mainly contaminated by their parents.4 The hypothesis of a possible relation between vaccination coverage and the pattern of transmission led us to reanalyse the data from the national survey and to compare pertussis household transmission between two administrative districts (“departments”) of contrasted vaccination coverage. The analysis was done in four hospitals in Paris (a department by itself) and in one hospital in Marseille (45% of the population of the Bouches-du-Rhone department). Ascertainment of cases was done as described previously 3 through an active and prospective collection of pertussis cases among inpatients and outpatients. Index cases were defined as either confirmed cases (paroxysmal cough ⭓8 days and either positive culture or serological confirmation or epidemiological link to a bacteriologically or serologically confirmed case) or probable cases (paroxysmal cough ⭓21 days without confirmation by culture or serology). Repeated interviews and consultations were conducted to identify all contact cases according to the same case definition—ie, family members coughing in the month before and after the onset of the index case disease. A primary case was defined as a case with onset of cough within 30 days to 7 days before the index case. Proportions were compared with the 2 test, and continuous variables with the Kruskal-Wallis test (Epi-Info, version 6.1). In Paris (four hospitals accounting for 22 000 paediatric hospital admissions per year in 1994) 80 index cases were found leading to the identification of 67 contact cases, and in Marseille (one hospital accounting for 1900 paediatric hospitalisations per year) 30 index cases were found leading to the identification of 28 contact cases. In the absence of a welldefined hospital catchment area, no incidence data can be calculated. However, pertussis seems to be more common in Marseille, as could be expected in a region with a low vaccination coverage. A similar ratio of contact/index cases was found in each centre, which suggests that the search for contact cases was similarly conducted. The patterns of transmission were significantly different between the two departments (table). The proportion of adults as source of contamination was higher in the high coverage department (Paris). The low percentage of adults as primary cases found in Marseille is similar to that found in West Germany, where immunisation rates were even lower,2 and also similar to those in Denmark5 where only three doses of vaccine are administrated. These data suggest that, in French regions with low pertussis-booster coverage at 2 years of age, children are still a major source of infection for unimmunised infants, and younger adults seem to be protected against clinical pertussis, probably as a consequence of previous infection and natural boosters in childhood. Therefore, in a four-dose schedule, the booster injection seems to be crucial to insure protection against
Contact cases
Primary cases
n (%)
Age (mean/median, years)
n (%)
Age (mean/median, years)
67 (59·7%) 28 (35·7%)†
22·0‡/25 13·1‡/5
30 (66·6%)§ 14 (14·3%)§
23·3¶/25·5 7·4¶/3
*Mean immunisation rates for 1986–1992 (source: French Ministry of Health). †p=0·03; ‡p=0·006; §p=0·001; ¶p=0·0008. DTP=diphtheria-tetanus-pertussis vaccine.
Age and proportion of adults among contact cases and primary cases by place and vaccination coverage in the pertussis study, France, 1993–94
THE LANCET • Vol 354 • November 13, 1999
1699
3
4
5
Clinical Standards Advisory Group. Cleft lip and/or palate. London: Stationery Office, 1998. Witt PD, Wahlen JC, Marsh JL, Grames LM, Pilgram TK. The effect of surgeon experience on velopharyngeal functional outcome following palatoplasty: is there a learning curve? Plast Reconstr Surg 1998; 102: 1375–84. Marrinan E, LaBrie R, Mulliken J. Velopharyngeal function in nonsyndromic cleft palate: relevance of surgical technique, age at repair and cleft type. Cleft Palate Craniofac J 1998; 35: 95–100. Ross RB. Treatment variables affecting facial growth in unilateral cleft lip and palate. Part 2: presurgical orthopaedics. Cleft Palate J 1987; 24: 24–32. Sell D, Harding A, Grunwell P. GOS.SP.ASS.’98: an assessment for speech disorders associated with cleft palate and/or velopharyngeal dysfunction (revised). Int J Lang Commun Disord 1999; 34: 17–33.
Division of Child Dental Health, Lower Maudlin Street, Bristol BS1 2LY, UK (A C Williams FDSRCS , J R Sandy FDSRCS, S Thomas FDSRCS, D Sell PhD ); and Department of Social Science, University of Bristol, Bristol (J A C Sterne PhD) Correspondence to: Mr A C Williams
Treatment of post-transplant lymphoproliferative disease with rituximab monoclonal antibody after lung transplantation Richard C Cook, Joseph M Connors, Randy D Gascoyne, Guy Fradet, Robert D Levy Three patients with diffuse large B-cell type of post-transplant lymphoproliferative disease after lung transplantation were treated with rituximab, an anti-CD2O monoclonal antibody. Treatment resulted in two complete remissions and one nonresponse.
Post-transplant lymphoproliferative disorder (PTLD) is usually a catastrophic complication and can be an important cause of death in organ-transplant patients.1 Standard treatment consists of reduction in immunosuppression.1,2 Antiviral agents, surgery, and radiation have had only variable success.1 Multi-agent chemotherapy has been helpful for a few well-selected patients but is commonly either ineffective or too toxic.1 We treated three patients with aggressive pulmonary PTLD with a novel treatment using a monoclonal anti-CD20 anti-B-cell antibody. All three patients received initial and maintenance cyclosporine, azathioprine, and methylprednisolone. No patients were given anti-lymphocyte antibodies. The first patient was a 36-year-old Epstein-Barr-virus (EBV)seropositive man who underwent bilateral lung transplantation from an EBV-seropositive donor. By day 49, he developed hilar and mediastinal lymphadenopathy, lung nodules (figure, A) and a solid mass occluding the superior segmental bronchus of the left lower lobe. Multiple biopsies showed PTLD consisting of a diffuse infiltrate of histiocytes, plasma cells, rare multinucleate giant cells, and large neoplastic lymphoid cells that were strongly positive for CD20 and EBV and showed light-chain restriction (/ ratio 20/1). Oral aciclovir, reduced immunosuppression, and cyclophosphamide had no effect on the tumour. On the suggestion of the oncologist, and after informed consent, rituximab (Rituxin, IDEC Pharmaceuticals, San Diego, CA, USA) was given in standard doses over 4 weeks without sideeffects. The masses resolved over the next 3 months (figure, B). 6 months later the patient succumbed to bronchiolitis obliterans. Necropsy showed no evidence of PTLD. A 67-year-old EBV-seropositive woman underwent rightlung transplantation from an EBV-seronegative donor. 19 months later she developed a right upper-lung nodule.
1698
Chest radiographs taken just before rituximab, showing bilateral hilar lymphadenopathy and left lower lobe consolidation with nodular opacities scattered throughout the left lower lobe (A), and 6 months later showing nearly complete tumour regression (B)
Immunosuppression was reduced but the lung mass grew. Rituximab (Rituxin, Hoffmann-La Roche Canada, Mississauga, Canada) was given in standard doses without toxic effects. The mass regressed modestly then grew. She died 4 months later. A necropsy showed a diffuse large-cell EBV-positive lymphoma with large CD20-positive malignant cells showing moderate plasmacytoid differentiation. An EBV-seronegative 16-year-old girl underwent bilateral lung transplantation from an EBV-seropositive donor. A seizure caused a change in immunosuppressants to tacrolimus and mycophenolate. 2 months later she developed mediastinal lymphadenopathy and lung nodules that progressed despite reduced immunosuppression and aciclovir therapy. A peripheral lung nodule was resected showing a diffuse largecell PTLD with malignant cells expressing light chains, CD19, CD20, CD11c, and CD23. Immunoglobulin heavychain PCR was clonal and EBV-PCR positive. Rituximab was given without significant toxic effects. Within 4 weeks all masses had regressed. She remained free of disease 8 months later. The incidence of PTLD after lung transplantation is 5–7% with mortality up to 70% if the tumour does not respond to reduced immunosuppression.1 Immunotherapy is an appealing therapeutic option. One previously reported patient
THE LANCET • Vol 354 • November 13, 1999
responded completely to a CD22-directed immunotoxin.3 Of 58 patients treated with a mixture of anti-CD21 and antiCD24 antibodies, 80% of the patients with oligoclonal and 48% of patients with monoclonal diseases had a complete response.4 A patient who developed PTLD 6 months after bone-marrow transplantation responded to rituximab.5 Interpretation of maintenance of this response is difficult because the patient later received donor lymphocytes. The rituximab therapy that we gave to three patients with progressive, treatment-refractory PTLD was well tolerated. Two had radiological evidence, and one of those proof on necropsy, of complete sustained responses to rituximab. Further testing of rituximab for lymphoid malignant disease arising in the setting of immunosuppression should be undertaken. 1
2
3
4
5
Magrath IT, Shad AT, Sandlund JT. Lymphoproliferative disorders in immunocompromised individuals. In: Magrath IT, ed. The nonHodgkin’s lymphomas. 2nd edn. London: Oxford University Press, 1997: 955–74. Starzl TE, Nalesnik MA, Porter KA, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1984; ii: 583–87. Senderowicz AM, Vitetta E, Headlee D, et al. Complete sustained response of a refractory, post-transplantation, large B-cell lymphomato an anti-CD22 immunotoxin. Ann Intern Med 1997; 126: 882–85. Benekerrou M, Jais J-P, Leblond V, et al. Anti-B-cell antibody treatment of severe posttransplant B-lymphoproliferative disorder: prognostic factors and long-term outcome. Blood 1998; 92: 3137–47. Faye A, Abeele TVD, Peuchman M, Mathieu-Boue A, Vilmer E. Anti-CD20 monoclonal antibody for post-transplant lymphoproliferative disorders. Lancet 1998; 352: 1285.
University of British Columbia Lung Transplant Program (R C Cook MD, G Fradet MD, R D Levy MD), and Division of Medical Oncology (J M Connors MD) and Pathology (R D Gascoyne MD), British Columbia Cancer Agency, University of British Columbia and Vancouver General Hospital, Vancouver, 100 West 10th Avenue, Vancouver, BC, V5Z 4E6 Canada Correspondence to: Dr Joseph M Connors (e-mail: [email protected])
Influence of vaccination coverage on pertussis transmission in France Emmanuel Grimprel, Sabine Baron, Daniel Lévy-Bruhl, Jean Marc Garnier, Elisabeth N’jamkepo, Nicole Guiso, Pierre Bégué Older children still contribute to the transmission of pertussis to infants in French regions with low booster coverage at 2 years of age. Booster vaccination seems crucial for protection against symptomatic pertussis in childhood.
In countries with sustained and widespread use of pertussis vaccination, resurgence of the disease has been reported. Although the highest risk of severe disease is still in infants, incidence of pertussis is increasing in adolescents and adults.1 By contrast, in countries with low coverage, pertussis remains endemic with a unique peak of incidence in children less than 7 years old.2 In France, pertussis whole-cell vaccine has been used since 1957, and combined in the diphtheria-tetanus-pertussis inactivated poliomyelitis vaccine since 1966. The schedule DTP coverage*
Paris Marseille
4 doses
3 doses
91% 61%
98% 89%
Number of Index cases 80 30
recommends three doses at 2 months, 3 months, and 4 months, with one booster dose at 18 months. Since the early 1990s, the national immunisation coverage has been above 90% for three doses and had risen from 82% in 1990 to 89% in 1997 for four doses. A national survey done in 1993–94 in 22 paediatric hospitals shows a high incidence of pertussis among infants.3 A household transmission study carried out within this survey pointed out that infants were equally contaminated by siblings and parents.3 These results contrasted with preliminary data from a single hospital in Paris in which infants were mainly contaminated by their parents.4 The hypothesis of a possible relation between vaccination coverage and the pattern of transmission led us to reanalyse the data from the national survey and to compare pertussis household transmission between two administrative districts (“departments”) of contrasted vaccination coverage. The analysis was done in four hospitals in Paris (a department by itself) and in one hospital in Marseille (45% of the population of the Bouches-du-Rhone department). Ascertainment of cases was done as described previously 3 through an active and prospective collection of pertussis cases among inpatients and outpatients. Index cases were defined as either confirmed cases (paroxysmal cough ⭓8 days and either positive culture or serological confirmation or epidemiological link to a bacteriologically or serologically confirmed case) or probable cases (paroxysmal cough ⭓21 days without confirmation by culture or serology). Repeated interviews and consultations were conducted to identify all contact cases according to the same case definition—ie, family members coughing in the month before and after the onset of the index case disease. A primary case was defined as a case with onset of cough within 30 days to 7 days before the index case. Proportions were compared with the 2 test, and continuous variables with the Kruskal-Wallis test (Epi-Info, version 6.1). In Paris (four hospitals accounting for 22 000 paediatric hospital admissions per year in 1994) 80 index cases were found leading to the identification of 67 contact cases, and in Marseille (one hospital accounting for 1900 paediatric hospitalisations per year) 30 index cases were found leading to the identification of 28 contact cases. In the absence of a welldefined hospital catchment area, no incidence data can be calculated. However, pertussis seems to be more common in Marseille, as could be expected in a region with a low vaccination coverage. A similar ratio of contact/index cases was found in each centre, which suggests that the search for contact cases was similarly conducted. The patterns of transmission were significantly different between the two departments (table). The proportion of adults as source of contamination was higher in the high coverage department (Paris). The low percentage of adults as primary cases found in Marseille is similar to that found in West Germany, where immunisation rates were even lower,2 and also similar to those in Denmark5 where only three doses of vaccine are administrated. These data suggest that, in French regions with low pertussis-booster coverage at 2 years of age, children are still a major source of infection for unimmunised infants, and younger adults seem to be protected against clinical pertussis, probably as a consequence of previous infection and natural boosters in childhood. Therefore, in a four-dose schedule, the booster injection seems to be crucial to insure protection against
Contact cases
Primary cases
n (%)
Age (mean/median, years)
n (%)
Age (mean/median, years)
67 (59·7%) 28 (35·7%)†
22·0‡/25 13·1‡/5
30 (66·6%)§ 14 (14·3%)§
23·3¶/25·5 7·4¶/3
*Mean immunisation rates for 1986–1992 (source: French Ministry of Health). †p=0·03; ‡p=0·006; §p=0·001; ¶p=0·0008. DTP=diphtheria-tetanus-pertussis vaccine.
Age and proportion of adults among contact cases and primary cases by place and vaccination coverage in the pertussis study, France, 1993–94
THE LANCET • Vol 354 • November 13, 1999
1699