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Unexpected Outbreak of Epstein-Barr Virus Post-Transplantation Lymphoproliferative Disorder after Hematopoietic Stem Cell Transplantation Conditioning with Thymoglobulin
L. Yáñez et al. / Biol Blood Marrow Transplant 20 (2014) 1455e1458
1457
Unexpected Outbreak of Epstein-Barr Virus Post-Transplantation Lymphoproliferative Disorder after Hematopoietic Stem Cell Transplantation Conditioning with Thymoglobulin Lucrecia Yáñez*, Arancha Bermúdez, Andrés Insunza, Iñigo Romón, Carlos Richard Hematology Department, Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain
Dear Editor, We have read with great interest the “Bottom line” by Dr. Andrea Bacigalupo titled “Antithymocyte Globulin in the Conditioning Regimen: Why Not?” on the advantages of the use of antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prevention in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Several studies have shown that ATG reduces the incidence and severity of acute and chronic GVHD, improving survival [1], but other studies have alerted us to an increased risk of infectious complications, especially caused by cytomegalovirus and Epstein-Barr virus, including post-transplantation lymphoproliferative disorders (PTLD) [2]. We agree that ATG reduces the incidence of GVHD but it often has undesirable consequences, some of them difficult to explain. From January 1, 2000 to June 30, 2012, 470 patients underwent an allo-HSCT in our center. Of them, 101 received ATG as part of GVHD prophylaxis (ATGAM [Pfizer, New York, NY], 21 patients, median total dose 40 mg/kg; Thymoglobulin [Genzyme-Sanofi, Lyon, France] 80 patients, median total dose, 7.5 mg/kg). All patients received acyclovir prophylaxis, and Epstein-Barr virus DNAemia was determined by an inhouse assay. According to the World Health Organization definition [3], 8 patients developed PTLD (7 proven, 1 probable) at a median of 63 days (interquartile range, 48 to 96) after transplantation, with a surprising temporal aggregation: all cases were diagnosed after 2010, with a peak incidence of 71% (5 of 7 patients) between December 2011 and June 2012. The age at transplantation, diagnosis, stem cell source, and conditioning regimen were heterogeneous. Among the 7 patients with proven PTLD, 6 were monomorphic and 1 was polymorphic. Two patients suffered an aggressive course with multiorgan failure. Chimerism analyses showed that tumor cells were from donor origin in 6 of 7 evaluated cases. Despite early treatment with rituximab and/ or chemotherapy, 50% of patients died because of PTLD. These facts prompted us to stop using Thymoglobulin and to shift to ATG Fresenius (Neopharm, Bad Homburg, Germany).
DOI of original article: http://dx.doi.org/10.1016/j.bbmt.2014.03.011. Financial disclosure: See Acknowledgments on page 1458. * Correspondence and reprint requests: Lucrecia Yáñez, Hematology Department, Hospital Universitario Marqués de Valdecilla-IDIVAL, Avda. de Valdecilla s/n, 39008 Santander, Spain. E-mail address: [email protected] (L. Yáñez) 1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.06.012
Because all cases appeared after 2010 without any change in the ATG dose and regimen or in the transplantation procedure, we compared patients who received Thymoglobulin (Genzyme-Sanofi) before January 2010 with those who received it from this date to July 2012. Except for the percentage of patients who underwent transplantation with a mismatched donor, there were no other significant differences regarding gender, age at transplantation, diagnosis, disease status, previous lines of treatment, previous HSCT, stem cell source, or use of fludarabine as part of the conditioning regimen. It is unlikely that the aforementioned single factor could explain the PTLD outbreak. We also analyzed a risk score for PTLD development (1 point for each item: T cell depletion, cord blood, haploidentical SCT, recipient age 50, matched unrelated donor, mismatched donor, and second allogeneic SCT) based on previously published risk factors [4-6], and no statistically significant differences were found between groups. It could be argued that some previous PTLD cases could have remained undiagnosed, but this is unlikely because of the high rate of necropsies carried out in our group (46% of patients who underwent transplantation). We then considered the possibility of a variation in Thymoglobulin (Genzyme-Sanofi) itself as the cause of the outbreak. ATG is a biological product, not a drug, and, as such, is highly dependent on the manufacturing process. The experience with other biological agents demonstrates that small changes in the manufacturing process can have unexpected clinical consequences [7]. Surprisingly, in 2007 a change in the quantity of the thymic source for rabbit immunization for Thymoglobulin production was allowed, without clinical validation. The in vitro tests used for Thymoglobulin potency testing only cover a small part of its broad biological activities and considerable variation is permitted. Moreover, on August 2012 and March 2014, several lots of Thymoglobulin were recalled after marketing because of an unexpected stability failure before the labeled expiration date. Interestingly, all of our PTLD patients, except patient number 4, had received 1 of these recalled lots. It is also significant that the switch from Thymoglobulin to ATGFresenius made after July 2012 was correlated with a decline of PTLD cases, without any differences in patient characteristics, transplantation procedure, or in the PTLD risk score. These events were communicated to Spanish Drug Agency and the manufacturer. In conclusion, ATG is an effective in vivo T celledepletion method for graft rejection and GVHD prevention, but it is a complex biological agent with broad immune effects and with potential variability [8]. Apart from unanswered questions, such as the best regimen and dose [9,10], we add
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L. Yáñez et al. / Biol Blood Marrow Transplant 20 (2014) 1455e1458
another question to Bacigalupo’s about ATG: Is the same ATG (Thymoglobulin) always the same? In our experience, the answer is “no.” This adds confusion in the ATG landscape and strengthens the need for caution with its use. ACKNOWLEDGMENTS Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report. REFERENCES 1. Yu ZP, Ding JH, Wu F, et al. Quality of life of patients after allogeneic hematopoietic stem cell transplantation with antihuman thymocyte globulin. Biol Blood Marrow Transplant. 2012;18:593-599. 2. Bacigalupo A. Antilymphocyte/thymocyte globulin for graft versus host disease prophylaxis: efficacy and side effects. Bone Marrow Transplant. 2005;35:225-231. 3. Swerdlow SH, Webber SA, Chadburn A, Ferry J. Post-transplant lymphoproliferative disorder. In: Swerdlow S, Campo E, Harris N, editors. Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th
4.
5.
6.
7. 8. 9.
10.
ed. Lyon, France: Interantional Agency for Research on Cancer; 2008. p. 342-349. Uhlin M, Wikell H, Sundin M, et al. Risk factors for Epstein Barr virus related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. Haematologica. 2014;99: 346-352. Landgren O, Gilbert ES, Rizzo JD, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. 2009;113:4992-5001. Rashke L, Kapp M, Einsele H, Mielke S. EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoietic SCT. Bone Marrow Transplant. 2014;49: 163-167. Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med. 2004;351:1403-1408. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007;21:1387-1394. Appelbaum FR, Bacigalupo A, Soiffer R. Anti-T cell antibodies as part of the preparative regimen in hematopoietic cell transplantation e a debate. Biol Blood Marrow Transplant. 2012;18:S111-S115. Siddiqui T, Blaise D. Does antithymocyte globulin have a place in reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation? Hematology Am Soc Hematol Educ Program. 2012; 2012:246-250.
1457
Unexpected Outbreak of Epstein-Barr Virus Post-Transplantation Lymphoproliferative Disorder after Hematopoietic Stem Cell Transplantation Conditioning with Thymoglobulin Lucrecia Yáñez*, Arancha Bermúdez, Andrés Insunza, Iñigo Romón, Carlos Richard Hematology Department, Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain
Dear Editor, We have read with great interest the “Bottom line” by Dr. Andrea Bacigalupo titled “Antithymocyte Globulin in the Conditioning Regimen: Why Not?” on the advantages of the use of antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prevention in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Several studies have shown that ATG reduces the incidence and severity of acute and chronic GVHD, improving survival [1], but other studies have alerted us to an increased risk of infectious complications, especially caused by cytomegalovirus and Epstein-Barr virus, including post-transplantation lymphoproliferative disorders (PTLD) [2]. We agree that ATG reduces the incidence of GVHD but it often has undesirable consequences, some of them difficult to explain. From January 1, 2000 to June 30, 2012, 470 patients underwent an allo-HSCT in our center. Of them, 101 received ATG as part of GVHD prophylaxis (ATGAM [Pfizer, New York, NY], 21 patients, median total dose 40 mg/kg; Thymoglobulin [Genzyme-Sanofi, Lyon, France] 80 patients, median total dose, 7.5 mg/kg). All patients received acyclovir prophylaxis, and Epstein-Barr virus DNAemia was determined by an inhouse assay. According to the World Health Organization definition [3], 8 patients developed PTLD (7 proven, 1 probable) at a median of 63 days (interquartile range, 48 to 96) after transplantation, with a surprising temporal aggregation: all cases were diagnosed after 2010, with a peak incidence of 71% (5 of 7 patients) between December 2011 and June 2012. The age at transplantation, diagnosis, stem cell source, and conditioning regimen were heterogeneous. Among the 7 patients with proven PTLD, 6 were monomorphic and 1 was polymorphic. Two patients suffered an aggressive course with multiorgan failure. Chimerism analyses showed that tumor cells were from donor origin in 6 of 7 evaluated cases. Despite early treatment with rituximab and/ or chemotherapy, 50% of patients died because of PTLD. These facts prompted us to stop using Thymoglobulin and to shift to ATG Fresenius (Neopharm, Bad Homburg, Germany).
DOI of original article: http://dx.doi.org/10.1016/j.bbmt.2014.03.011. Financial disclosure: See Acknowledgments on page 1458. * Correspondence and reprint requests: Lucrecia Yáñez, Hematology Department, Hospital Universitario Marqués de Valdecilla-IDIVAL, Avda. de Valdecilla s/n, 39008 Santander, Spain. E-mail address: [email protected] (L. Yáñez) 1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.06.012
Because all cases appeared after 2010 without any change in the ATG dose and regimen or in the transplantation procedure, we compared patients who received Thymoglobulin (Genzyme-Sanofi) before January 2010 with those who received it from this date to July 2012. Except for the percentage of patients who underwent transplantation with a mismatched donor, there were no other significant differences regarding gender, age at transplantation, diagnosis, disease status, previous lines of treatment, previous HSCT, stem cell source, or use of fludarabine as part of the conditioning regimen. It is unlikely that the aforementioned single factor could explain the PTLD outbreak. We also analyzed a risk score for PTLD development (1 point for each item: T cell depletion, cord blood, haploidentical SCT, recipient age 50, matched unrelated donor, mismatched donor, and second allogeneic SCT) based on previously published risk factors [4-6], and no statistically significant differences were found between groups. It could be argued that some previous PTLD cases could have remained undiagnosed, but this is unlikely because of the high rate of necropsies carried out in our group (46% of patients who underwent transplantation). We then considered the possibility of a variation in Thymoglobulin (Genzyme-Sanofi) itself as the cause of the outbreak. ATG is a biological product, not a drug, and, as such, is highly dependent on the manufacturing process. The experience with other biological agents demonstrates that small changes in the manufacturing process can have unexpected clinical consequences [7]. Surprisingly, in 2007 a change in the quantity of the thymic source for rabbit immunization for Thymoglobulin production was allowed, without clinical validation. The in vitro tests used for Thymoglobulin potency testing only cover a small part of its broad biological activities and considerable variation is permitted. Moreover, on August 2012 and March 2014, several lots of Thymoglobulin were recalled after marketing because of an unexpected stability failure before the labeled expiration date. Interestingly, all of our PTLD patients, except patient number 4, had received 1 of these recalled lots. It is also significant that the switch from Thymoglobulin to ATGFresenius made after July 2012 was correlated with a decline of PTLD cases, without any differences in patient characteristics, transplantation procedure, or in the PTLD risk score. These events were communicated to Spanish Drug Agency and the manufacturer. In conclusion, ATG is an effective in vivo T celledepletion method for graft rejection and GVHD prevention, but it is a complex biological agent with broad immune effects and with potential variability [8]. Apart from unanswered questions, such as the best regimen and dose [9,10], we add
1458
L. Yáñez et al. / Biol Blood Marrow Transplant 20 (2014) 1455e1458
another question to Bacigalupo’s about ATG: Is the same ATG (Thymoglobulin) always the same? In our experience, the answer is “no.” This adds confusion in the ATG landscape and strengthens the need for caution with its use. ACKNOWLEDGMENTS Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report. REFERENCES 1. Yu ZP, Ding JH, Wu F, et al. Quality of life of patients after allogeneic hematopoietic stem cell transplantation with antihuman thymocyte globulin. Biol Blood Marrow Transplant. 2012;18:593-599. 2. Bacigalupo A. Antilymphocyte/thymocyte globulin for graft versus host disease prophylaxis: efficacy and side effects. Bone Marrow Transplant. 2005;35:225-231. 3. Swerdlow SH, Webber SA, Chadburn A, Ferry J. Post-transplant lymphoproliferative disorder. In: Swerdlow S, Campo E, Harris N, editors. Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th
4.
5.
6.
7. 8. 9.
10.
ed. Lyon, France: Interantional Agency for Research on Cancer; 2008. p. 342-349. Uhlin M, Wikell H, Sundin M, et al. Risk factors for Epstein Barr virus related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. Haematologica. 2014;99: 346-352. Landgren O, Gilbert ES, Rizzo JD, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. 2009;113:4992-5001. Rashke L, Kapp M, Einsele H, Mielke S. EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoietic SCT. Bone Marrow Transplant. 2014;49: 163-167. Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med. 2004;351:1403-1408. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007;21:1387-1394. Appelbaum FR, Bacigalupo A, Soiffer R. Anti-T cell antibodies as part of the preparative regimen in hematopoietic cell transplantation e a debate. Biol Blood Marrow Transplant. 2012;18:S111-S115. Siddiqui T, Blaise D. Does antithymocyte globulin have a place in reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation? Hematology Am Soc Hematol Educ Program. 2012; 2012:246-250.