Official Journal of the British Blood Transfusion Society
Transfusion Medicine
| LETTER TO THE EDITOR
Successful treatment of refractory pure red cell aplasia with bortezomib after allogeneic haematopoietic cell transplantation in a patient with alpha-beta subcutaneous panniculitis-like T cell lymphoma Dear Sir, Pure red cell aplasia (PRCA) is a possible complication of ABO-mismatched allogeneic haematopoietic cell transplantation (allo-HCT). This syndrome is characterised by anaemia, reticulocytopenia and the absence of erythroblasts in a normal appearing bone marrow biopsy. This condition is relatively rare, and has been attributed to the inhibitory effects of persisting recipient isoagglutinins on erythroid precursors as the result of long-lived recipient plasma cells surviving after transplant. It has been treated with mixed results using various approaches, including high-dose erythropoietin (EPO), plasma exchange, steroids, donor lymphocyte infusion (DLI), rituximab, and tapering and discontinuation of immunosuppression (Hirokawa et al., 2013). Here, we describe a patient with treatment refractory PRCA following major plus minor ABO mismatched allo-HCT from matched related donor, which eventually responded well to subcutaneous bortezomib administration. A 50-year-old Samoan male with a history of refractory alpha-beta subcutaneous panniculitis-like T cell lymphoma received reduced intensity conditioning with fludarabine 30 mg m−2 for days −6 to −2 and melphalan 140 mg m−2 on day −1, followed by allo-HCT with peripheral blood stem cells from his 8/8 human leukocyte antigen (HLA)-matched sister. Graft vs host disease (GVHD) prophylaxis consisted of cyclosporine A plus standard methotrexate on days 1, 3, 6 and 11. The patient’s ABO type was B Rh-positive, while the donor was A Rh-positive. ABO antibody screen at time of transplant was negative. The patient had an uneventful early post-transplant course and showed neutrophil engraftment on day +16 and platelet engraftment on day +12, with total white blood cell (WBC) peripheral blood chimerism on day 30 being of 100% donor origin. Haemoglobin recovery was somewhat sluggish, yet was not unexpected due to existing ABO mismatch. The patient did not require any transfusion in the first month post-transplant, and by day +21, haemoglobin had risen to 9·6 g dL−1 . However, he presented on day +33 with an unexpected sudden drop in his haemoglobin down to 6·9 g dl−1 . His direct Coombs testing on
Correspondence: Jaime Shahan, PA-C, Division of Hematology & Hematologic Malignancies, University of Utah, Huntsman Cancer Institute, 1950 Circle of Hope Drive, Salt Lake City, Utah 84112, USA. Tel.: +1 801 587 4474; fax: +1 801 587 5838; e-mail: [email protected]
First published online 6 July 2015 doi: 10.1111/tme.12216
day +33 was IgG positive and C3 negative. Reticulocyte counts were decreased at this time with a reticulocyte index of 0·1 compatible with insufficient red blood cell (RBC) production rather than increased RBC destruction. Vitamin B12 and folate were within normal limits. EPO levels were 1190 mU mL−1 on day +46, and 3270 mU mL−1 on day +220. Viral workup by polymerase chain reaction (PCR) was negative for Epstein Barr, cytomegalovirus, parvovirus and hepatitis B. Reticulocyte count remained decreased for another month, and a bone marrow biopsy (BMBx) on day +68 confirmed suspected PRCA in otherwise cellular marrow with a myeloid to erythroid (M : E) ratio of 122 : 1 and preserved bilineage engraftment of myeloand megakaryopoesis. As a first measure and in the absence of GVHD, cyclosporine taper was initiated on day +80, yet did not result in improvement in transfusion needs, and subsequently rituximab was given for four doses weekly at 375 mg m−2 , starting on day +111, also without success. BMBx on day +140 revealed a hypocellular marrow (20%) with relative erythroid hypoplasia and an M : E ratio of 24·5 : 1. Cyclosporine tapering was continued, and the patient developed isolated mild oral GVHD, which temporarily required topical dexamethasone solution rinses, before cyclosporine could be safely discontinued at day +220. BMBx on day +213 showed a hypocellular marrow (20%) with continued erythroid hypoplasia (M : E ratio of 9·1 : 1). Transfusion requirements remained unchanged, and a treatment attempt with pulse dose dexamethasone 40 mg × 4 days was initiated on day +244. This resulted in a transient reduction in RBC transfusion frequency for approximately 3 weeks, yet his haemoglobin did not recover and the patient continued to have transfusion dependent anaemia. Forward typing showed an ABO blood type of the patient being 0, reflecting status post-massive RBC type 0 transfusions, and reverse typing revealed blood type B, compatible with the plasmatic presence of recipient-derived anti-A isohemagglutinins. Unsorted bone marrow and peripheral blood chimerism were of 100% donor origin, and unfortunately CD138+ plasma cell sorted-chimerism studies were unsuccessful due to low cell numbers. We hypothesised, that nevertheless long-lived recipient plasma cells after HCT are the culprit producing anti-A isohemagglutinins, and that targeting these cells using the proteasome inhibitor bortezomib, commonly used in the treatment of plasma cell dyscrasias, may be beneficial in combating the patient’s treatment-refractory PRCA. We discussed the use of donor lymphocytes (DLI) as treatment alternative with the patient, but in light of his history
© 2015 British Blood Transfusion Society
Letter to the Editor
343
Fig. 1. Haemoglobin levels post allo-HCT displaying recovery of haemoglobin following bortezomib administration.
of mild oral GVHD and the associated risk of inducing severe GVHD, the decision was made to proceed with bortezomib first. This felt supported by the successful use of bortezomib for refractory PRCA, which so far has been reported in only two patients in the literature (Poon & Koh, 2012; Khan et al., 2014). Our decision was also persuaded by the patient’s frequent upper respiratory tract infections and associated hospital admissions, and the desire to avoid the increased risk of infection with repeating rituximab or steroids. Another concern about the repeat use of steroids was related to the possibility of losing the observed graft vs lymphoma (GVL) effect in this patient, considering that he was only in partial remission at time of transplant and at day +185 had showed a near complete resolution of previously noted fluorodeoxyglucose (FDG) uptake on positron emission tomography–computed tomography (PET-CT). Immediately prior to initiation of bortezomib, isohemagglutinin titer was 2 for anti-A antibodies, with a reticulocyte index of 0·2, and treatment was started on day +293 with bortezomib at 1·3 mg m−2 weekly for 4 weeks. Approximately 4 weeks post-initiation of bortezomib, the patient’s haemoglobin spontaneously recovered to 9·7 g dL−1 , and some A type red cells were found on ABO forward typing. However, he continued to have anti-A isohemagglutinins at two dilutions. Another 2 weeks later, the reticulocyte index had improved to 7·7, the isohemagglutinin titer no longer showed any anti A antibodies, and eventually the haemoglobin continued to increase to 14·0 g dL−1 by 9 weeks after bortezomib initiation (Fig. 1). Bortezomib was well tolerated and the patient is now 1 year after allo-HCT and infusion-independent, does not experience signs of acute or chronic GVHD, has an excellent Karnofsky performance status
© 2015 British Blood Transfusion Society
of 90% and on PET-CT performed at day +320 showed a complete remission, the latter possibly directly supported by the use of bortezomib (Zain & O’Connor, 2010; Evens et al., 2013; Chaoui et al., 2014). In conclusion, the use of bortezomib for refractory PRCA appears a promising tool in our armamentarium to combat this potentially life-threatening complication after ABO-mismatched allo-HCT. In addition, beneficial effects of proteasome inhibition on the prevention and treatment of acute and chronic GVHD (Li et al., 2013; Herrera et al., 2014; Pai et al., 2014a,2014b), and the growing knowledge of its anti-cancer effects in lymphoid B and T cell malignancies warrants expanded exploration of using bortezomib as well as next generation proteasome inhibitors in this field. We believe bortezomib to be the cause of the patient’s rapidly recovered haemoglobin and feel this is a promising, well tolerated regimen which may benefit others in refractory red cell aplasia following ABO mismatched allo-HCT.
ACKNOWLEDGMENTS J. L. S. prepared the manuscript. G. C. H. edited and revised the manuscript.
CONFLICT OF INTEREST The authors have no competing interests.
J. L. Shahan & G. C. Hildebrandt Division of Hematology & Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
Transfusion Medicine, 2015, 25, 342–344
344 Letter to the Editor
REFERENCES Chaoui, D., Bouallegue, S., Arakelyan, N., Genet, P., Aljijakli, A. & Sutton, L. (2014) Bortezomib, lenalidomide and dexamethasone (VRD) combination as salvage therapy in refractory angioimmunoblastic T cell lymphoma. British Journal of Haematology, 164, 750–752. Evens, A.M., Rosen, S.T., Helenowski, I. et al. (2013) A phase I/II trial of bortezomib combined concurrently with gemcitabine for relapsed or refractory DLBCL and peripheral T-cell lymphomas. British Journal of Haematology, 163, 55–61. Herrera, A.F., Kim, H.T., Bindra, B. et al. (2014) A phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease. Biology
Transfusion Medicine, 2015, 25, 342–344
of Blood and Marrow Transplantation, 20, 1737–1743. Hirokawa, M., Fukuda, T., Ohashi, K. et al. (2013) Efficacy and long-term outcome of treatment for pure red cell aplasia after allogeneic stem cell transplantation from major ABO-incompatible donors. Biology of Blood and Marrow Transplantation, 19, 1026–1032. Khan, F., Linden, M.A., Zantek, N.D. & Vercellotti, G.M. (2014) Subcutaneous bortezomib is highly effective for pure red cell aplasia after ABO-incompatible haematopoietic stem cell transplantation. Transfusion Medicine, 24, 187–188. Li, Z., Wu, Q., Yan, Z. et al. (2013) The protection and therapy effects of bortezomib in murine acute graft-versus-host disease. Transplantation Proceedings, 45, 2527–2535.
Pai, C.C., Chen, M., Mirsoian, A. et al. (2014a) Treatment of chronic graft-versus-host disease with bortezomib. Blood, 124, 1677–1688. Pai, C.C., Hsiao, H.H., Sun, K. et al. (2014b) Therapeutic benefit of bortezomib on acute graft-versus-host disease is tissue specific and is associated with interleukin-6 levels. Biology of Blood and Marrow Transplantation, 20, 1899–1904. Poon, L.-M. & Koh, L.-H. (2012) Successful treatment of isohemagglutinin-mediated pure red cell aplasia after ABO-mismatched allogeneic hematopoietic cell transplant using bortezomib. Bone Marrow Transplantation, 47, 870–871. Zain, J.M. & O’Connor, O. (2010) Targeted treatment and new agents in peripheral T-cell lymphoma. International Journal of Hematology, 92, 33–44.
© 2015 British Blood Transfusion Society
Transfusion Medicine
| LETTER TO THE EDITOR
Successful treatment of refractory pure red cell aplasia with bortezomib after allogeneic haematopoietic cell transplantation in a patient with alpha-beta subcutaneous panniculitis-like T cell lymphoma Dear Sir, Pure red cell aplasia (PRCA) is a possible complication of ABO-mismatched allogeneic haematopoietic cell transplantation (allo-HCT). This syndrome is characterised by anaemia, reticulocytopenia and the absence of erythroblasts in a normal appearing bone marrow biopsy. This condition is relatively rare, and has been attributed to the inhibitory effects of persisting recipient isoagglutinins on erythroid precursors as the result of long-lived recipient plasma cells surviving after transplant. It has been treated with mixed results using various approaches, including high-dose erythropoietin (EPO), plasma exchange, steroids, donor lymphocyte infusion (DLI), rituximab, and tapering and discontinuation of immunosuppression (Hirokawa et al., 2013). Here, we describe a patient with treatment refractory PRCA following major plus minor ABO mismatched allo-HCT from matched related donor, which eventually responded well to subcutaneous bortezomib administration. A 50-year-old Samoan male with a history of refractory alpha-beta subcutaneous panniculitis-like T cell lymphoma received reduced intensity conditioning with fludarabine 30 mg m−2 for days −6 to −2 and melphalan 140 mg m−2 on day −1, followed by allo-HCT with peripheral blood stem cells from his 8/8 human leukocyte antigen (HLA)-matched sister. Graft vs host disease (GVHD) prophylaxis consisted of cyclosporine A plus standard methotrexate on days 1, 3, 6 and 11. The patient’s ABO type was B Rh-positive, while the donor was A Rh-positive. ABO antibody screen at time of transplant was negative. The patient had an uneventful early post-transplant course and showed neutrophil engraftment on day +16 and platelet engraftment on day +12, with total white blood cell (WBC) peripheral blood chimerism on day 30 being of 100% donor origin. Haemoglobin recovery was somewhat sluggish, yet was not unexpected due to existing ABO mismatch. The patient did not require any transfusion in the first month post-transplant, and by day +21, haemoglobin had risen to 9·6 g dL−1 . However, he presented on day +33 with an unexpected sudden drop in his haemoglobin down to 6·9 g dl−1 . His direct Coombs testing on
Correspondence: Jaime Shahan, PA-C, Division of Hematology & Hematologic Malignancies, University of Utah, Huntsman Cancer Institute, 1950 Circle of Hope Drive, Salt Lake City, Utah 84112, USA. Tel.: +1 801 587 4474; fax: +1 801 587 5838; e-mail: [email protected]
First published online 6 July 2015 doi: 10.1111/tme.12216
day +33 was IgG positive and C3 negative. Reticulocyte counts were decreased at this time with a reticulocyte index of 0·1 compatible with insufficient red blood cell (RBC) production rather than increased RBC destruction. Vitamin B12 and folate were within normal limits. EPO levels were 1190 mU mL−1 on day +46, and 3270 mU mL−1 on day +220. Viral workup by polymerase chain reaction (PCR) was negative for Epstein Barr, cytomegalovirus, parvovirus and hepatitis B. Reticulocyte count remained decreased for another month, and a bone marrow biopsy (BMBx) on day +68 confirmed suspected PRCA in otherwise cellular marrow with a myeloid to erythroid (M : E) ratio of 122 : 1 and preserved bilineage engraftment of myeloand megakaryopoesis. As a first measure and in the absence of GVHD, cyclosporine taper was initiated on day +80, yet did not result in improvement in transfusion needs, and subsequently rituximab was given for four doses weekly at 375 mg m−2 , starting on day +111, also without success. BMBx on day +140 revealed a hypocellular marrow (20%) with relative erythroid hypoplasia and an M : E ratio of 24·5 : 1. Cyclosporine tapering was continued, and the patient developed isolated mild oral GVHD, which temporarily required topical dexamethasone solution rinses, before cyclosporine could be safely discontinued at day +220. BMBx on day +213 showed a hypocellular marrow (20%) with continued erythroid hypoplasia (M : E ratio of 9·1 : 1). Transfusion requirements remained unchanged, and a treatment attempt with pulse dose dexamethasone 40 mg × 4 days was initiated on day +244. This resulted in a transient reduction in RBC transfusion frequency for approximately 3 weeks, yet his haemoglobin did not recover and the patient continued to have transfusion dependent anaemia. Forward typing showed an ABO blood type of the patient being 0, reflecting status post-massive RBC type 0 transfusions, and reverse typing revealed blood type B, compatible with the plasmatic presence of recipient-derived anti-A isohemagglutinins. Unsorted bone marrow and peripheral blood chimerism were of 100% donor origin, and unfortunately CD138+ plasma cell sorted-chimerism studies were unsuccessful due to low cell numbers. We hypothesised, that nevertheless long-lived recipient plasma cells after HCT are the culprit producing anti-A isohemagglutinins, and that targeting these cells using the proteasome inhibitor bortezomib, commonly used in the treatment of plasma cell dyscrasias, may be beneficial in combating the patient’s treatment-refractory PRCA. We discussed the use of donor lymphocytes (DLI) as treatment alternative with the patient, but in light of his history
© 2015 British Blood Transfusion Society
Letter to the Editor
343
Fig. 1. Haemoglobin levels post allo-HCT displaying recovery of haemoglobin following bortezomib administration.
of mild oral GVHD and the associated risk of inducing severe GVHD, the decision was made to proceed with bortezomib first. This felt supported by the successful use of bortezomib for refractory PRCA, which so far has been reported in only two patients in the literature (Poon & Koh, 2012; Khan et al., 2014). Our decision was also persuaded by the patient’s frequent upper respiratory tract infections and associated hospital admissions, and the desire to avoid the increased risk of infection with repeating rituximab or steroids. Another concern about the repeat use of steroids was related to the possibility of losing the observed graft vs lymphoma (GVL) effect in this patient, considering that he was only in partial remission at time of transplant and at day +185 had showed a near complete resolution of previously noted fluorodeoxyglucose (FDG) uptake on positron emission tomography–computed tomography (PET-CT). Immediately prior to initiation of bortezomib, isohemagglutinin titer was 2 for anti-A antibodies, with a reticulocyte index of 0·2, and treatment was started on day +293 with bortezomib at 1·3 mg m−2 weekly for 4 weeks. Approximately 4 weeks post-initiation of bortezomib, the patient’s haemoglobin spontaneously recovered to 9·7 g dL−1 , and some A type red cells were found on ABO forward typing. However, he continued to have anti-A isohemagglutinins at two dilutions. Another 2 weeks later, the reticulocyte index had improved to 7·7, the isohemagglutinin titer no longer showed any anti A antibodies, and eventually the haemoglobin continued to increase to 14·0 g dL−1 by 9 weeks after bortezomib initiation (Fig. 1). Bortezomib was well tolerated and the patient is now 1 year after allo-HCT and infusion-independent, does not experience signs of acute or chronic GVHD, has an excellent Karnofsky performance status
© 2015 British Blood Transfusion Society
of 90% and on PET-CT performed at day +320 showed a complete remission, the latter possibly directly supported by the use of bortezomib (Zain & O’Connor, 2010; Evens et al., 2013; Chaoui et al., 2014). In conclusion, the use of bortezomib for refractory PRCA appears a promising tool in our armamentarium to combat this potentially life-threatening complication after ABO-mismatched allo-HCT. In addition, beneficial effects of proteasome inhibition on the prevention and treatment of acute and chronic GVHD (Li et al., 2013; Herrera et al., 2014; Pai et al., 2014a,2014b), and the growing knowledge of its anti-cancer effects in lymphoid B and T cell malignancies warrants expanded exploration of using bortezomib as well as next generation proteasome inhibitors in this field. We believe bortezomib to be the cause of the patient’s rapidly recovered haemoglobin and feel this is a promising, well tolerated regimen which may benefit others in refractory red cell aplasia following ABO mismatched allo-HCT.
ACKNOWLEDGMENTS J. L. S. prepared the manuscript. G. C. H. edited and revised the manuscript.
CONFLICT OF INTEREST The authors have no competing interests.
J. L. Shahan & G. C. Hildebrandt Division of Hematology & Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
Transfusion Medicine, 2015, 25, 342–344
344 Letter to the Editor
REFERENCES Chaoui, D., Bouallegue, S., Arakelyan, N., Genet, P., Aljijakli, A. & Sutton, L. (2014) Bortezomib, lenalidomide and dexamethasone (VRD) combination as salvage therapy in refractory angioimmunoblastic T cell lymphoma. British Journal of Haematology, 164, 750–752. Evens, A.M., Rosen, S.T., Helenowski, I. et al. (2013) A phase I/II trial of bortezomib combined concurrently with gemcitabine for relapsed or refractory DLBCL and peripheral T-cell lymphomas. British Journal of Haematology, 163, 55–61. Herrera, A.F., Kim, H.T., Bindra, B. et al. (2014) A phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease. Biology
Transfusion Medicine, 2015, 25, 342–344
of Blood and Marrow Transplantation, 20, 1737–1743. Hirokawa, M., Fukuda, T., Ohashi, K. et al. (2013) Efficacy and long-term outcome of treatment for pure red cell aplasia after allogeneic stem cell transplantation from major ABO-incompatible donors. Biology of Blood and Marrow Transplantation, 19, 1026–1032. Khan, F., Linden, M.A., Zantek, N.D. & Vercellotti, G.M. (2014) Subcutaneous bortezomib is highly effective for pure red cell aplasia after ABO-incompatible haematopoietic stem cell transplantation. Transfusion Medicine, 24, 187–188. Li, Z., Wu, Q., Yan, Z. et al. (2013) The protection and therapy effects of bortezomib in murine acute graft-versus-host disease. Transplantation Proceedings, 45, 2527–2535.
Pai, C.C., Chen, M., Mirsoian, A. et al. (2014a) Treatment of chronic graft-versus-host disease with bortezomib. Blood, 124, 1677–1688. Pai, C.C., Hsiao, H.H., Sun, K. et al. (2014b) Therapeutic benefit of bortezomib on acute graft-versus-host disease is tissue specific and is associated with interleukin-6 levels. Biology of Blood and Marrow Transplantation, 20, 1899–1904. Poon, L.-M. & Koh, L.-H. (2012) Successful treatment of isohemagglutinin-mediated pure red cell aplasia after ABO-mismatched allogeneic hematopoietic cell transplant using bortezomib. Bone Marrow Transplantation, 47, 870–871. Zain, J.M. & O’Connor, O. (2010) Targeted treatment and new agents in peripheral T-cell lymphoma. International Journal of Hematology, 92, 33–44.
© 2015 British Blood Transfusion Society
