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Is there immune surveillance against chronic myeloid leukaemia? Possibly, but not much
Leukemia Research 57 (2017) 109–111
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Letter to the Editor Is there immune surveillance against chronic myeloid leukaemia? Possibly, but not much Reality is the leading cause of stress among those in touch with it. Lily Tomlin Immune surveillance is defined as the ability of the immune system to identify and destroy nascent neoplasms [1,2]. In recent years this concept has been refined to a concept termed immune editing whereby the innate and adoptive immune systems recognize cancer cells on the basis of cancer-specific antigens or molecules [2]. Substantial data support the concept of immune surveillance or immune editing in rodents (reviewed in reference [2]). However, most of these models involve carcinogen- or virus-induced or related cancers with questionable relevance to most cancers in humans. Data supporting immune surveillance in humans with congenital or acquired immune deficiency syndromes or receiving prolonged immune suppression after solid organ transplants are discussed below. In a 2012 review we interrogated concepts of immune suppression and immune surveillance in the context of acute myeloid leukaemia [3]. To estimate whether immune surveillance operates we used 3 models looking for increased risks of developing AML: (1) persons with congenital immune deficiencies; (2) persons with acquired immune deficiencies; and (3) persons receiving immune suppression for a prolonged interval. Our model of the latter was persons receiving kidney and heart transplants. Although none of these settings is a perfect test of immune surveillance, we reasoned we should see an increased incidence of AML if immune surveillance was a powerful preventive force. We concluded although there was a modest increase in AML in persons receiving prolonged immune suppression (50 excess cases in about one-quarter million subjects followed for 10 years), this modest increase was mostly explained by increased cancer surveillance in transplant recipients, early detection of bone marrow failure resulting in a diagnosis of MDS rather than AML and by exposures to high doses of ionizing radiations. Also, we found no evidence of an increased AML risk in persons with congenital or acquired immune deficiencies. Consequently, we concluded immune surveillance was probably not a terribly strong force in preventing AML. In contrast to AML, several cancers more closely-linked to immune surveillance in humans are markedly increased in these populations such as melanoma, nonmelanoma skin cancers, kidney cancer, Kaposi sarcoma, vulvar and cervical cancer, neuroblastoma and lymphomas with SIRs often in excess of 5–10 [4–6]. Several of these cancers are caused by viruses including cervical cancer, Epstein-Barr virus-related lymphomas and probably Kaposi sarcoma. The small if any role of immune surveillance against common cancers such as lung, breast, colorectal, pancreas and prostate is reasonable from an evolutionary perspective as cancer is a relatively recent disease in humans occurring at ages which most people did not attain until the past century, too short an interval http://dx.doi.org/10.1016/j.leukres.2017.03.003 0145-2126/© 2017 Elsevier Ltd. All rights reserved.
for evolutionary pressures to operate and because cancer mostly occurs after reproduction. For example, median age at cancer diagnosis in 2012 in the US was 70 years with 90 percent of cancers occurring after age 50 years (https://seer.cancer.gov/statfacts/ html/all.html). These factors make immune surveillance to common, non-virus infection-related cancers unlikely. Nevertheless, the notion of immune surveillance and immune editing of cancer in humans remains popular and is recently buoyed by success of immune interventions to treat diverse cancers, a concept distinct from immune surveillance. There is great interest in the concept of immune surveillance for chronic myeloid leukaemia (CML). Some of this enthusiasm is prompted by substantial data showing immune-mediated antileukaemia mechanisms operate in persons with CML receiving allogeneic haematopoietic cell transplants. Most of this antileukaemia effect is concordant with graft-versus-host disease (GvHD) but there may also be a leukaemia-specific anti-leukaemia effect independent of GvHD best-termed graft-versus-leukaemia [7,8]. However, these immune-mediated anti-leukaemia effects operate in the setting of genetic-disparity between donor and recipient, different than the concept underlying immune surveillance. Many other clinical observations related to CML are hypothesized to result from immune surveillance. For example, latency to develop CML after the A-bomb explosions is <2 years in some persons but >10–15 years in others despite reasonably-convincing evidence of the causative gene, BCR/ABL1, being formed at the time of A-bomb exposure [9]. Some interpret these data to indicate immune surveillance operated in persons who developed CML after many years and possibly in others never developing CML. Another interesting observation derives from studies of discontinuing tyrosine kinase therapy in persons with CML in a sustained deep molecular response (>MR4) after >2–3 years (reviewed in Ref. [10]). Although about 60 percent of people relapse rapidly, 40 percent do not despite the high likelihood there are many residual CML cells in these persons [11–13]. Again, some people interpret these data to reflect the role of immune surveillance in controlling residual CML cells. A third observation is some normals have BCR/ABL1 but do not have CML, at least not in the interval over which they have been observed [14]. Whether the mutation is in a cell with the biological capacity to cause CML is unproved. A common theme of these observations in CML is whenever there are unexplained phenomena immune surveillance or immune editing is invoked as a possible explanation. But do these processes really operate? We decided to study this question using the same strategy we used to study immune suppression and immune surveillance for AML. Our review of the bio-medical literature found no convincing reports of an increased risk of CML in persons with congenital and acquired immune deficiencies [4–6]. We next used data from the Collaborative Transplant Study (CTS) which collects information on recipients of solid organ transplants since 1985 from >300
110
Letter to the Editor / Leukemia Research 57 (2017) 109–111
transplant centers worldwide. Cancer incidence data were checked annually by questionnaire. Only CML in persons with a functioning graft were included so our data may under-estimate CML incidence slightly. Data for expected CML incidence were obtained from a cohort of identical size matched for age and sex from Cancer Incidence in Five Continents monitored for the same duration as the transplant cohort. The most appropriate regional reference registry was used for each transplant recipient. Data collection and processing were approved by the Data Protection Agency in Germany and all participating centers complied with local ethical and privacy regulations. Details of our analytical techniques are presented in our prior report [3]. The dataset consisted of 441,332 recipients of kidney (N = 355,606), liver (N = 47,846) and heart (N = 37,880) transplants. Amongst kidney transplant recipients the SIR for developing CML was 1.54 (95% confidence interval, 1.1, 2.1; p = 0.01) representing 39 cases in 1,682,491 person-years at-risk vs. 25 expected (14 excess cases). Amongst liver transplant recipients the SIR was 1.72 (0.6, 4.0; P = 0.34) representing 5 cases in 182,833 person-years at-risk vs. 3 expected (2 excess cases). Amongst heart transplant recipients the SIR was 3.47 (1.8, 6.1; p = 0.0005) representing 12 cases in 173,015 person-years at-risk vs. 3 expected (9 excess cases). The data from recipients of kidney and liver transplants suggest immune-suppression does not increase risk of developing CML or does so very slightly. The increase in SIR in kidney graft recipients is generally-attributed to increased cancer surveillance including blood testing, especially for a disease like CML where many diagnoses are based on an increased WBC detected on routine blood-testing and prompting further investigation. Although the SIR of CML was substantially-increased after heart transplants, these persons receive high doses of ionizing radiations in the context of diagnostic radiological procedures such as computer tomography (CT)-angiography pre- and posttransplant. Ionizing radiations are a proved cause of CML which might explain the increased SIR. Also, heart transplant recipients are more strongly immune suppressed than kidney transplant recipients. One potentially confounding issue in prior analyses of AML is inhibition of DNA-mismatch repair by azathioprine commonly used after solid organ transplants [15]. However, this is not a confounder in CML which results from a reciprocal translocation unaffected by DNAmismatch repair. Our data, 25 excess cases of CML in 2,038,339 person-years atrisk observation, suggest failure of immune-suppression per se does not explain most cases of CML implying, along with data from persons with congenital and acquired immune deficiencies, immune surveillance is not a strong component of prevention of new cases of CML in most instances. Whether the immune system operates to prevent recurrence of CML in other setting such as in some, but not most persons achieving a deep molecular remission following therapy with tyrosine kinase-inhibitors, is unknown but again seems unlikely. Humans have about 10E+12 bone marrow cells. The lower limit of detection of a typical revers transcription-qualitative polymerase chain reaction test (RT-qPCR) is about 5-logs at best. Consequently, a person with a deep sustained complete molecular remission (MR4.5 ) might have as many as 10E+6 residual CML cells. It seems most unlikely if immune surveillance did not prevent CML from developing when there was 1 or a few CML cells that it would be effective against 100s, 1000s or a million residual CML cells. Some cases of CML are caused by exposure to ionizingradiations. However, in contrast to AML, exposure to alkylating drugs (such as busulfan, melphalan and nitrosoureas) and chemicals (such as benzene) are not convincingly shown to cause CML. Consequently, the cause(s) of most cases of CML is unknown but, for reasons we discuss, is unlikely to result from failed immune surveillance. To the contrary, in the thousands of years before antibiotics were developed having chronic phase CML with excess
granulocytes may have conferred a survival advantage to affected persons until they progressed to acute phase. Our conclusion, immune surveillance probably does not operate for CML, or if it does, operates only weakly, has implications for understanding the biology and therapy of this leukaemia. For example, it is unlikely to explain the diverse latencies of persons developing CML after A-bomb exposures, of patterns of molecular relapse after discontinuing tyrosine kinase-inhibitor therapy or why some normals with BCR/ABL don’t develop CML. Other explanations should be sought. It’s time to given immune surveillance and immune editing a rest for CML and perhaps for many cancers in humans.
Contributions The authors contributed equally to conception, execution and writing of the typescript. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.
Conflict of interest None. RPG is a part time employee of Celgene Corp.
References [1] G.P. Dunn, A.T. Bruce, H. Ikeda, L.J. Old, R.D. Schreiber, Cancer immunoediting: from immunosurveillance to tumor escape, Nat. Immunol. 11 (2002) 991–998, Review. [2] J.B. Swann, M.J. Smyth, Immune surveillance of tumors, J. Clin. Invest. 117 (2007) 1137–1146. [3] R.P. Gale, G. Opelz, Commentary: Does immune suppression increase risk of developing acute myeloid leukemia, Leukemia 26 (2012) 422–423. [4] J. Adami, H. Gäbel, B. Lindelöf, K. Ekström, B. Rydh, B. Glimelius, Cancer risk following organ transplantation: a nationwide cohort study in Sweden, Br. J. Cancer 89 (2003) 1221–1227. [5] C.M. Vajdic, S.P. McDonald, M.R. McCredie, M.T. van Leeuwen, J.H. Stewart, M. Law, Cancer incidence before and after kidney transplantation, JAMA 296 (2006) 2823–2831. [6] P.J. Villeneuve, D.E. Schaubel, S.S. Fenton, F.A. Shepherd, Y. Jiang, Y. Mao, Cancer incidence among Canadian kidney transplant recipients, Am. J. Transplant. 7 (2007) 941–948. [7] M.M. Horowitz, R.P. Gale, P.M. Sondel, J.M. Goldman, J. Kersey, H.J. Kolb, Graft-versus-leukemia reactions after bone marrow transplantation, Blood 75 (1990) 555–562. [8] R.P. Gale, E.J. Fuchs, Is there really a specific graft-versus-leukaemia effect, Bone Marrow Transplant. 51 (2016) 1413–1415. [9] W.L. Hsu, D.I. Preston, M. Soda, H. Sugiyama, S. Funamoto, K. Kodama, The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 1950–2001, Radiat. Res. 179 (2013) 361–382. [10] S. Saussele, J. Richter, A. Hochhaus, F.-X. Mahon, The concept of treatment-free remission in chronic myeloid leukemia, Leukemia 30 (2016) 1638–1647. [11] F.-X. Mahon, D. Rea, J. Guilhot, F. Guilhot, F. Huguet, F. Nicolini, Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicenter STOP imatinib (STIM) trial, Lancet Oncol. 11 (2010) 1029–1035. [12] P. Rousselot, A. Charbonnier, P. Cony-Makhoul, P. Agape, F.E. Nicolini, B. Varet, Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetected disease, J. Clin. Oncol. 32 (2013) 424–430. [13] D.M. Ross, S. Branford, J.F. Seymour, A.P. Schwarer, C. Arthur, D.T. Yeung, Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study, Blood 122 (2013) 515–522. [14] S. Bose, M. Deininger, J. Gora-Tybor, J.M. Goldman, J.V. Melo, The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: Biologic significance and implications for the assessment of minimal residual disease, Blood 92 (1998) 3362–3367. [15] J. Offman, G. Opelz, B. Doehler, D. Cummins, O. Halil, N.R. Banner, Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation, Blood 104 (2004) 822–828.
Letter to the Editor / Leukemia Research 57 (2017) 109–111
Robert Peter Gale ∗ Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, UK Gerhard Opelz Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany
111
∗ Corresponding author. E-mail addresses: [email protected], [email protected] (R.P. Gale).
19 January 2017 28 February 2017 2 March 2017 Available online 6 March 2017
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Letter to the Editor Is there immune surveillance against chronic myeloid leukaemia? Possibly, but not much Reality is the leading cause of stress among those in touch with it. Lily Tomlin Immune surveillance is defined as the ability of the immune system to identify and destroy nascent neoplasms [1,2]. In recent years this concept has been refined to a concept termed immune editing whereby the innate and adoptive immune systems recognize cancer cells on the basis of cancer-specific antigens or molecules [2]. Substantial data support the concept of immune surveillance or immune editing in rodents (reviewed in reference [2]). However, most of these models involve carcinogen- or virus-induced or related cancers with questionable relevance to most cancers in humans. Data supporting immune surveillance in humans with congenital or acquired immune deficiency syndromes or receiving prolonged immune suppression after solid organ transplants are discussed below. In a 2012 review we interrogated concepts of immune suppression and immune surveillance in the context of acute myeloid leukaemia [3]. To estimate whether immune surveillance operates we used 3 models looking for increased risks of developing AML: (1) persons with congenital immune deficiencies; (2) persons with acquired immune deficiencies; and (3) persons receiving immune suppression for a prolonged interval. Our model of the latter was persons receiving kidney and heart transplants. Although none of these settings is a perfect test of immune surveillance, we reasoned we should see an increased incidence of AML if immune surveillance was a powerful preventive force. We concluded although there was a modest increase in AML in persons receiving prolonged immune suppression (50 excess cases in about one-quarter million subjects followed for 10 years), this modest increase was mostly explained by increased cancer surveillance in transplant recipients, early detection of bone marrow failure resulting in a diagnosis of MDS rather than AML and by exposures to high doses of ionizing radiations. Also, we found no evidence of an increased AML risk in persons with congenital or acquired immune deficiencies. Consequently, we concluded immune surveillance was probably not a terribly strong force in preventing AML. In contrast to AML, several cancers more closely-linked to immune surveillance in humans are markedly increased in these populations such as melanoma, nonmelanoma skin cancers, kidney cancer, Kaposi sarcoma, vulvar and cervical cancer, neuroblastoma and lymphomas with SIRs often in excess of 5–10 [4–6]. Several of these cancers are caused by viruses including cervical cancer, Epstein-Barr virus-related lymphomas and probably Kaposi sarcoma. The small if any role of immune surveillance against common cancers such as lung, breast, colorectal, pancreas and prostate is reasonable from an evolutionary perspective as cancer is a relatively recent disease in humans occurring at ages which most people did not attain until the past century, too short an interval http://dx.doi.org/10.1016/j.leukres.2017.03.003 0145-2126/© 2017 Elsevier Ltd. All rights reserved.
for evolutionary pressures to operate and because cancer mostly occurs after reproduction. For example, median age at cancer diagnosis in 2012 in the US was 70 years with 90 percent of cancers occurring after age 50 years (https://seer.cancer.gov/statfacts/ html/all.html). These factors make immune surveillance to common, non-virus infection-related cancers unlikely. Nevertheless, the notion of immune surveillance and immune editing of cancer in humans remains popular and is recently buoyed by success of immune interventions to treat diverse cancers, a concept distinct from immune surveillance. There is great interest in the concept of immune surveillance for chronic myeloid leukaemia (CML). Some of this enthusiasm is prompted by substantial data showing immune-mediated antileukaemia mechanisms operate in persons with CML receiving allogeneic haematopoietic cell transplants. Most of this antileukaemia effect is concordant with graft-versus-host disease (GvHD) but there may also be a leukaemia-specific anti-leukaemia effect independent of GvHD best-termed graft-versus-leukaemia [7,8]. However, these immune-mediated anti-leukaemia effects operate in the setting of genetic-disparity between donor and recipient, different than the concept underlying immune surveillance. Many other clinical observations related to CML are hypothesized to result from immune surveillance. For example, latency to develop CML after the A-bomb explosions is <2 years in some persons but >10–15 years in others despite reasonably-convincing evidence of the causative gene, BCR/ABL1, being formed at the time of A-bomb exposure [9]. Some interpret these data to indicate immune surveillance operated in persons who developed CML after many years and possibly in others never developing CML. Another interesting observation derives from studies of discontinuing tyrosine kinase therapy in persons with CML in a sustained deep molecular response (>MR4) after >2–3 years (reviewed in Ref. [10]). Although about 60 percent of people relapse rapidly, 40 percent do not despite the high likelihood there are many residual CML cells in these persons [11–13]. Again, some people interpret these data to reflect the role of immune surveillance in controlling residual CML cells. A third observation is some normals have BCR/ABL1 but do not have CML, at least not in the interval over which they have been observed [14]. Whether the mutation is in a cell with the biological capacity to cause CML is unproved. A common theme of these observations in CML is whenever there are unexplained phenomena immune surveillance or immune editing is invoked as a possible explanation. But do these processes really operate? We decided to study this question using the same strategy we used to study immune suppression and immune surveillance for AML. Our review of the bio-medical literature found no convincing reports of an increased risk of CML in persons with congenital and acquired immune deficiencies [4–6]. We next used data from the Collaborative Transplant Study (CTS) which collects information on recipients of solid organ transplants since 1985 from >300
110
Letter to the Editor / Leukemia Research 57 (2017) 109–111
transplant centers worldwide. Cancer incidence data were checked annually by questionnaire. Only CML in persons with a functioning graft were included so our data may under-estimate CML incidence slightly. Data for expected CML incidence were obtained from a cohort of identical size matched for age and sex from Cancer Incidence in Five Continents monitored for the same duration as the transplant cohort. The most appropriate regional reference registry was used for each transplant recipient. Data collection and processing were approved by the Data Protection Agency in Germany and all participating centers complied with local ethical and privacy regulations. Details of our analytical techniques are presented in our prior report [3]. The dataset consisted of 441,332 recipients of kidney (N = 355,606), liver (N = 47,846) and heart (N = 37,880) transplants. Amongst kidney transplant recipients the SIR for developing CML was 1.54 (95% confidence interval, 1.1, 2.1; p = 0.01) representing 39 cases in 1,682,491 person-years at-risk vs. 25 expected (14 excess cases). Amongst liver transplant recipients the SIR was 1.72 (0.6, 4.0; P = 0.34) representing 5 cases in 182,833 person-years at-risk vs. 3 expected (2 excess cases). Amongst heart transplant recipients the SIR was 3.47 (1.8, 6.1; p = 0.0005) representing 12 cases in 173,015 person-years at-risk vs. 3 expected (9 excess cases). The data from recipients of kidney and liver transplants suggest immune-suppression does not increase risk of developing CML or does so very slightly. The increase in SIR in kidney graft recipients is generally-attributed to increased cancer surveillance including blood testing, especially for a disease like CML where many diagnoses are based on an increased WBC detected on routine blood-testing and prompting further investigation. Although the SIR of CML was substantially-increased after heart transplants, these persons receive high doses of ionizing radiations in the context of diagnostic radiological procedures such as computer tomography (CT)-angiography pre- and posttransplant. Ionizing radiations are a proved cause of CML which might explain the increased SIR. Also, heart transplant recipients are more strongly immune suppressed than kidney transplant recipients. One potentially confounding issue in prior analyses of AML is inhibition of DNA-mismatch repair by azathioprine commonly used after solid organ transplants [15]. However, this is not a confounder in CML which results from a reciprocal translocation unaffected by DNAmismatch repair. Our data, 25 excess cases of CML in 2,038,339 person-years atrisk observation, suggest failure of immune-suppression per se does not explain most cases of CML implying, along with data from persons with congenital and acquired immune deficiencies, immune surveillance is not a strong component of prevention of new cases of CML in most instances. Whether the immune system operates to prevent recurrence of CML in other setting such as in some, but not most persons achieving a deep molecular remission following therapy with tyrosine kinase-inhibitors, is unknown but again seems unlikely. Humans have about 10E+12 bone marrow cells. The lower limit of detection of a typical revers transcription-qualitative polymerase chain reaction test (RT-qPCR) is about 5-logs at best. Consequently, a person with a deep sustained complete molecular remission (MR4.5 ) might have as many as 10E+6 residual CML cells. It seems most unlikely if immune surveillance did not prevent CML from developing when there was 1 or a few CML cells that it would be effective against 100s, 1000s or a million residual CML cells. Some cases of CML are caused by exposure to ionizingradiations. However, in contrast to AML, exposure to alkylating drugs (such as busulfan, melphalan and nitrosoureas) and chemicals (such as benzene) are not convincingly shown to cause CML. Consequently, the cause(s) of most cases of CML is unknown but, for reasons we discuss, is unlikely to result from failed immune surveillance. To the contrary, in the thousands of years before antibiotics were developed having chronic phase CML with excess
granulocytes may have conferred a survival advantage to affected persons until they progressed to acute phase. Our conclusion, immune surveillance probably does not operate for CML, or if it does, operates only weakly, has implications for understanding the biology and therapy of this leukaemia. For example, it is unlikely to explain the diverse latencies of persons developing CML after A-bomb exposures, of patterns of molecular relapse after discontinuing tyrosine kinase-inhibitor therapy or why some normals with BCR/ABL don’t develop CML. Other explanations should be sought. It’s time to given immune surveillance and immune editing a rest for CML and perhaps for many cancers in humans.
Contributions The authors contributed equally to conception, execution and writing of the typescript. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.
Conflict of interest None. RPG is a part time employee of Celgene Corp.
References [1] G.P. Dunn, A.T. Bruce, H. Ikeda, L.J. Old, R.D. Schreiber, Cancer immunoediting: from immunosurveillance to tumor escape, Nat. Immunol. 11 (2002) 991–998, Review. [2] J.B. Swann, M.J. Smyth, Immune surveillance of tumors, J. Clin. Invest. 117 (2007) 1137–1146. [3] R.P. Gale, G. Opelz, Commentary: Does immune suppression increase risk of developing acute myeloid leukemia, Leukemia 26 (2012) 422–423. [4] J. Adami, H. Gäbel, B. Lindelöf, K. Ekström, B. Rydh, B. Glimelius, Cancer risk following organ transplantation: a nationwide cohort study in Sweden, Br. J. Cancer 89 (2003) 1221–1227. [5] C.M. Vajdic, S.P. McDonald, M.R. McCredie, M.T. van Leeuwen, J.H. Stewart, M. Law, Cancer incidence before and after kidney transplantation, JAMA 296 (2006) 2823–2831. [6] P.J. Villeneuve, D.E. Schaubel, S.S. Fenton, F.A. Shepherd, Y. Jiang, Y. Mao, Cancer incidence among Canadian kidney transplant recipients, Am. J. Transplant. 7 (2007) 941–948. [7] M.M. Horowitz, R.P. Gale, P.M. Sondel, J.M. Goldman, J. Kersey, H.J. Kolb, Graft-versus-leukemia reactions after bone marrow transplantation, Blood 75 (1990) 555–562. [8] R.P. Gale, E.J. Fuchs, Is there really a specific graft-versus-leukaemia effect, Bone Marrow Transplant. 51 (2016) 1413–1415. [9] W.L. Hsu, D.I. Preston, M. Soda, H. Sugiyama, S. Funamoto, K. Kodama, The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 1950–2001, Radiat. Res. 179 (2013) 361–382. [10] S. Saussele, J. Richter, A. Hochhaus, F.-X. Mahon, The concept of treatment-free remission in chronic myeloid leukemia, Leukemia 30 (2016) 1638–1647. [11] F.-X. Mahon, D. Rea, J. Guilhot, F. Guilhot, F. Huguet, F. Nicolini, Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicenter STOP imatinib (STIM) trial, Lancet Oncol. 11 (2010) 1029–1035. [12] P. Rousselot, A. Charbonnier, P. Cony-Makhoul, P. Agape, F.E. Nicolini, B. Varet, Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetected disease, J. Clin. Oncol. 32 (2013) 424–430. [13] D.M. Ross, S. Branford, J.F. Seymour, A.P. Schwarer, C. Arthur, D.T. Yeung, Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study, Blood 122 (2013) 515–522. [14] S. Bose, M. Deininger, J. Gora-Tybor, J.M. Goldman, J.V. Melo, The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: Biologic significance and implications for the assessment of minimal residual disease, Blood 92 (1998) 3362–3367. [15] J. Offman, G. Opelz, B. Doehler, D. Cummins, O. Halil, N.R. Banner, Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation, Blood 104 (2004) 822–828.
Letter to the Editor / Leukemia Research 57 (2017) 109–111
Robert Peter Gale ∗ Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, UK Gerhard Opelz Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany
111
∗ Corresponding author. E-mail addresses: [email protected], [email protected] (R.P. Gale).
19 January 2017 28 February 2017 2 March 2017 Available online 6 March 2017