1870
Letters to the Editor / Biol Blood Marrow Transplant 20 (2014) 1869e1871
only study we are aware of that compared different durations of MMF. They demonstrated a significant decrease in grade II to IV GVHD in a small cohort of patients who received extended administration; this study may provide preliminary evidence of the potential differences in a longer course of MMF [10]. MMF remains a well-tolerated and important immunosuppressive agent in our already limited arsenal of GVHD prevention. Although newer and alternative GVHD prophylaxis regimens are certainly needed, the use of MMF should not be abandoned until the optimal dosing and duration is studied in larger prospective trials. ACKNOWLEDGMENTS Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report. REFERENCES 1. Al-Kadhimi Z, Gul Z, Chen W, et al. High incidence of severe acute graftversus-host disease with tacrolimus and mycophenolate mofetil in a large cohort of related and unrelated allogeneic transplantation patients. Biol Blood Marrow Transplant. 2014;20:979-985. 2. Eapen ML, Horowitz BR, Zhong MM, et al. Transplantation of peripheral blood progenitor cells (PBPC) as compared to bone marrow (BM) from unrelated related donors for hematologic cancers using fludarabinealkylating agent reduced intensity conditioning regimens. American Society of Hematology Annual Meeting. Blood. 2013;2013:122 [abstract].
3. Hamilton BK, Rybicki L, Tench S, et al. Mycophenolate mofetil is a suitable substitute for methotrexate for graft versus host disease prevention in myeloablative allogeneic hematopoietic cell transplantation with sibling donors. American Society of Hematology Annual Meeting. Blood. 2012;2012:120 [abstract]. 4. Nash RA, Johnston L, Parker P, et al. A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft-versus-host disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2005;11:495-505. 5. Jacobson PA, Huang J, Wu J, et al. Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease treatment from the Blood and Marrow Transplant Clinical Trials Network. Biol Blood Marrow Transplant. 2010;16:421-429. 6. McDermott CL, Sandmaier BM, Storer B, et al. Nonrelapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013;19:1159-1166. 7. Wakahashi K, Yamamori M, Minagawa K, et al. Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation. Int J Hematol. 2011;94:193-202. 8. Bejanyan N, Rogosheske J, Defor T, et al. Less acute graft-versus-host disease with higher mycophenolate dose in double umbilical cord blood transplant recipients. Biol Blood Marrow Transplant. 2014;20: S28-S29. 9. Sabry W, Le Blanc R, Labbe AC, et al. Graft-versus-host disease prophylaxis with tacrolimus and mycophenolate mofetil in HLA-matched nonmyeloablative transplant recipients is associated with very low incidence of GVHD and nonrelapse mortality. Biol Blood Marrow Transplant. 2009;15:919-929. 10. Nishikawa S, Okamura A, Yamamori M, et al. Extended mycophenolate mofetil administration beyond day 30 in allogeneic hematopoietic stem cell transplantation as preemptive therapy for severe graftversus-host disease. Transplant Proc. 2009;41:3873-3876.
What Do Cytogenetic Abnormalities after Autotransplant Really Mean? Giuseppe Rossi 1, Robert Peter Gale 2, * 1 2
Hematology Division and Department of Clinical Oncology, A.O. Spedali Civili, Brescia, Italy Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom
Article history: Received 6 August 2014 Accepted 7 August 2014
To the Editor: We read with interest the report by Showel et al. [1] and commentary by Gerber [2] describing the lack of a correlation in some people between isolated clonal cytogenetic abnormalities after autotransplant and leukemia recurrence. The authors reasonably speculated this might be because most subjects lacked abnormalities such as del(5/5q) or del(7/7q), which alone might have been sufficient to cause acute myelogenous leukemia, because the clonal DOI of original article: http://dx.doi.org/10.1016/j.bbmt.2014.03.033. Financial disclosure: See Acknowledgments on page 1871. * Correspondence and reprint requests: Dr. Robert Peter Gale, MD, PhD, DSc(hc), FACP, Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 OHS, United Kingdom. E-mail address: [email protected] (R.P. Gale) 1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.08.006
abnormalities occurred in only a few metaphases, suggesting no proliferative advantage for the new clone and/or because of brief follow-up. The issue arises whether their observation applies only to isolated clonal cytogenetic abnormalities or is a more general phenomenon. We and others reported diverse oligo- and polyclonal abnormalities in autotransplant hrecipients, sometimes accompanied by nonclonal abnormalities, especially indels and aneuploidy. New translocations are especially favored when ionizing radiation is given pretransplant because of the tendency of photons to cause synchronous and contiguous double-strand breaks in interphase cells. These abnormalities can represent a substantial proportion of metaphases in some instances and appear to wax and wane over many years, even decades. Sometimes this is an illusion resulting from imperfect sensitivity of our detection techniques. A study of 20 metaphases has a substantial likelihood of missing an abnormality present in 5% to 10% of cells, for example. Also, conventional cytogenetics capture only dividing cells; florescence in situ hybridization can reduce this bias. Sometimes these complex cytogenetic abnormities are a harbinger of leukemia recurrence, although they may seem
Letters to the Editor / Biol Blood Marrow Transplant 20 (2014) 1869e1871
to differ, in whole or part, from abnormalities detected at diagnosis. However, in other instances there is no leukemia recurrence. Similar findings were reported in A-bomb survivors, their progeny, and radiation accident victims. (Random, nonclonal abnormalities are even detected in normal healthy persons, including neonates, when large numbers of metaphases are studied.) Because of the uncertain biological importance of these cytogenetic abnormalities and because of limited effective therapy options, physicians should refrain from starting therapy until they are certain there is a high probability of leukemia recurrence and until there are convincing data early intervention produces a better outcome than waiting for relapse. Whether the cytogenetic abnormalities we discuss are inherent to the original leukemia or the result of exposing normal and/or leukemia cells to DNA-damaging drugs and to ionizing radiation, or both, cannot be presently determined but may be
1871
possible using more sophisticated techniques such as whole genome sequencing. However, one should consider that sometimes a new mutation may cripple rather than enable the leukemia clone(s) and need not eventuate in relapse. ACKNOWLEDGMENTS Financial disclosure: R.P.G. is a part-time employee of Celgene Corp. Conflict of interest statement: There are no conflicts of interest to report. REFERENCES 1. Showel MM, Brodsky RA, Tsai H-L, et abnormalities after high-dose therapy. 2014;20:1130-1138. 2. Gerber JM. Isolated clonal cytogenetic therapy: do they matter? Biol Blood 1077-1078.
al. Isolated clonal cytogenetic Biol Blood Marrow Transplant. abnormalities after high-dose Marrow Transplant. 2014;20:
Letters to the Editor / Biol Blood Marrow Transplant 20 (2014) 1869e1871
only study we are aware of that compared different durations of MMF. They demonstrated a significant decrease in grade II to IV GVHD in a small cohort of patients who received extended administration; this study may provide preliminary evidence of the potential differences in a longer course of MMF [10]. MMF remains a well-tolerated and important immunosuppressive agent in our already limited arsenal of GVHD prevention. Although newer and alternative GVHD prophylaxis regimens are certainly needed, the use of MMF should not be abandoned until the optimal dosing and duration is studied in larger prospective trials. ACKNOWLEDGMENTS Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report. REFERENCES 1. Al-Kadhimi Z, Gul Z, Chen W, et al. High incidence of severe acute graftversus-host disease with tacrolimus and mycophenolate mofetil in a large cohort of related and unrelated allogeneic transplantation patients. Biol Blood Marrow Transplant. 2014;20:979-985. 2. Eapen ML, Horowitz BR, Zhong MM, et al. Transplantation of peripheral blood progenitor cells (PBPC) as compared to bone marrow (BM) from unrelated related donors for hematologic cancers using fludarabinealkylating agent reduced intensity conditioning regimens. American Society of Hematology Annual Meeting. Blood. 2013;2013:122 [abstract].
3. Hamilton BK, Rybicki L, Tench S, et al. Mycophenolate mofetil is a suitable substitute for methotrexate for graft versus host disease prevention in myeloablative allogeneic hematopoietic cell transplantation with sibling donors. American Society of Hematology Annual Meeting. Blood. 2012;2012:120 [abstract]. 4. Nash RA, Johnston L, Parker P, et al. A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft-versus-host disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2005;11:495-505. 5. Jacobson PA, Huang J, Wu J, et al. Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease treatment from the Blood and Marrow Transplant Clinical Trials Network. Biol Blood Marrow Transplant. 2010;16:421-429. 6. McDermott CL, Sandmaier BM, Storer B, et al. Nonrelapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013;19:1159-1166. 7. Wakahashi K, Yamamori M, Minagawa K, et al. Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation. Int J Hematol. 2011;94:193-202. 8. Bejanyan N, Rogosheske J, Defor T, et al. Less acute graft-versus-host disease with higher mycophenolate dose in double umbilical cord blood transplant recipients. Biol Blood Marrow Transplant. 2014;20: S28-S29. 9. Sabry W, Le Blanc R, Labbe AC, et al. Graft-versus-host disease prophylaxis with tacrolimus and mycophenolate mofetil in HLA-matched nonmyeloablative transplant recipients is associated with very low incidence of GVHD and nonrelapse mortality. Biol Blood Marrow Transplant. 2009;15:919-929. 10. Nishikawa S, Okamura A, Yamamori M, et al. Extended mycophenolate mofetil administration beyond day 30 in allogeneic hematopoietic stem cell transplantation as preemptive therapy for severe graftversus-host disease. Transplant Proc. 2009;41:3873-3876.
What Do Cytogenetic Abnormalities after Autotransplant Really Mean? Giuseppe Rossi 1, Robert Peter Gale 2, * 1 2
Hematology Division and Department of Clinical Oncology, A.O. Spedali Civili, Brescia, Italy Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, United Kingdom
Article history: Received 6 August 2014 Accepted 7 August 2014
To the Editor: We read with interest the report by Showel et al. [1] and commentary by Gerber [2] describing the lack of a correlation in some people between isolated clonal cytogenetic abnormalities after autotransplant and leukemia recurrence. The authors reasonably speculated this might be because most subjects lacked abnormalities such as del(5/5q) or del(7/7q), which alone might have been sufficient to cause acute myelogenous leukemia, because the clonal DOI of original article: http://dx.doi.org/10.1016/j.bbmt.2014.03.033. Financial disclosure: See Acknowledgments on page 1871. * Correspondence and reprint requests: Dr. Robert Peter Gale, MD, PhD, DSc(hc), FACP, Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 OHS, United Kingdom. E-mail address: [email protected] (R.P. Gale) 1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.08.006
abnormalities occurred in only a few metaphases, suggesting no proliferative advantage for the new clone and/or because of brief follow-up. The issue arises whether their observation applies only to isolated clonal cytogenetic abnormalities or is a more general phenomenon. We and others reported diverse oligo- and polyclonal abnormalities in autotransplant hrecipients, sometimes accompanied by nonclonal abnormalities, especially indels and aneuploidy. New translocations are especially favored when ionizing radiation is given pretransplant because of the tendency of photons to cause synchronous and contiguous double-strand breaks in interphase cells. These abnormalities can represent a substantial proportion of metaphases in some instances and appear to wax and wane over many years, even decades. Sometimes this is an illusion resulting from imperfect sensitivity of our detection techniques. A study of 20 metaphases has a substantial likelihood of missing an abnormality present in 5% to 10% of cells, for example. Also, conventional cytogenetics capture only dividing cells; florescence in situ hybridization can reduce this bias. Sometimes these complex cytogenetic abnormities are a harbinger of leukemia recurrence, although they may seem
Letters to the Editor / Biol Blood Marrow Transplant 20 (2014) 1869e1871
to differ, in whole or part, from abnormalities detected at diagnosis. However, in other instances there is no leukemia recurrence. Similar findings were reported in A-bomb survivors, their progeny, and radiation accident victims. (Random, nonclonal abnormalities are even detected in normal healthy persons, including neonates, when large numbers of metaphases are studied.) Because of the uncertain biological importance of these cytogenetic abnormalities and because of limited effective therapy options, physicians should refrain from starting therapy until they are certain there is a high probability of leukemia recurrence and until there are convincing data early intervention produces a better outcome than waiting for relapse. Whether the cytogenetic abnormalities we discuss are inherent to the original leukemia or the result of exposing normal and/or leukemia cells to DNA-damaging drugs and to ionizing radiation, or both, cannot be presently determined but may be
1871
possible using more sophisticated techniques such as whole genome sequencing. However, one should consider that sometimes a new mutation may cripple rather than enable the leukemia clone(s) and need not eventuate in relapse. ACKNOWLEDGMENTS Financial disclosure: R.P.G. is a part-time employee of Celgene Corp. Conflict of interest statement: There are no conflicts of interest to report. REFERENCES 1. Showel MM, Brodsky RA, Tsai H-L, et abnormalities after high-dose therapy. 2014;20:1130-1138. 2. Gerber JM. Isolated clonal cytogenetic therapy: do they matter? Biol Blood 1077-1078.
al. Isolated clonal cytogenetic Biol Blood Marrow Transplant. abnormalities after high-dose Marrow Transplant. 2014;20:
