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Allogeneic Transplantation for Unfavorable-Risk Acute Myeloid Leukemia
SOHO Supplement 2015
Allogeneic Transplantation for Unfavorable-Risk Acute Myeloid Leukemia Hugo F. Fernandez Abstract Acute myeloid leukemia (AML) is a complex, heterogeneous disorder that can have devastating effects. Although control of AML can be attained with various induction regimens, long-term cure is much more difficult to maintain. This is understated in patients with unfavorable-risk AML, who are usually older and have prior myeloid and/or therapyrelated disease and more challenges in curing this disease. Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. S1, S70-2 ª 2015 Elsevier Inc. All rights reserved. Keywords: Acute myeloid leukemia, Allogeneic hematopoietic cell transplantation, Consolidation therapy, Maintenance therapy, Unfavorable risk
Introduction Several prognostic guidelines have been developed for acute myeloid leukemia (AML) based on cytogenetic and more recently molecular profiles. The European Leukemia Network classification has defined unfavorable-risk prognostication based on published cytogenetic and molecular results and their impact in the disease. Unfavorable risk includes deletions of chromosome 5 or 7, inversion or translocation of chromosome 3, translocation 6;9, MLL rearrangements (11q23), 17p abnormalities (TP53), complex karyotypes, and FLT3-ITD.1 Whole-genome sequencing has led to the discovery of molecular mutations in DNMT3A, PHF6, ASXL1, RAS, and WT1, which portend a worse prognosis.2 Although these somatic mutations can help redefine cytogenetically normal disease, they are considered investigational because of the small numbers studied, and they require long-term validation of the preliminary results. In addition, they often do not change the prognosis in cytogenetically unfavorable-risk AML.3 Other clinical presentations of AML including patients with antecedent hematological disorders (myelodysplastic and myeloproliferative) or patients whose disease has failed to respond to induction also carry a poor prognosis (Table 1).
Therapy for Unfavorable-Risk Disease Current therapy for all patients AML induction include 7 þ 3 (anthracycline and cytarabine), high-dose cytarabine-containing
Moffitt Cancer Center, Tampa, FL Submitted: Dec 6, 2014; Accepted: Feb 3, 2015; Epub: Feb 18, 2015 Address for correspondence: Hugo F. Fernandez, MD, Moffitt Cancer Center, 12902 Magnolia Drive, FOB3, Tampa, FL 33612 E-mail contact: hugo.fernandez@moffitt.org
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regimens (with and without anthracycline), and others.4-6 In these studies, complete remission (CR) was experienced by 50% to 70% of patients with unfavorable-risk disease. However, chemotherapy alone is not enough to adequately control unfavorable-risk AML because remissions are not sustained and are not affected by regimen intensification. High-dose cytarabine, long a standard in consolidation, is less effective in unfavorable-risk AML in maintaining the CR.7 Multiple trials have demonstrated long-term survival of less than 20%, regardless of consolidation regimens excluding allogeneic hematopoietic cell transplantation (HCT). The subsets of patients with a monosomal karyotype, defined as presence of at least 2 autosomal monosomies or a single autosomal monosomy with at least 1 structural abnormality, have a very poor prognosis, with overall survival of < 5% because of its association with prior therapy, advanced age, complex karyotype unfavorable molecular markers, and antecedent hematological disorders.8
Immunotherapy Because standard chemotherapy is not enough, other approaches have been developed to aggressively treat this disease. Allogeneic HCT was the first immunologic therapy that provided a better approach to the treatment of unfavorable risk AML. The Eastern Cooperative Oncology Group led an intergroup trial that allocated patients using genetic criteria to allogeneic HCT or autologous HCT versus chemotherapy; results showed no survival difference between the groups.9 A subsequent subset analysis of cytogenetic risk showed that allogeneic HCT improved overall survival for unfavorable-risk patients treated on the trial.10 The small numbers in the analysis was a concern; however, 2 recent meta-analyses and 1 Markov analysis have solidified the concept that unfavorable-risk AML in first CR benefits from allogeneic HCT and is superior to chemotherapy consolidation.11-13 Until a better approach is developed, this remains the current standard of care for these high-risk patients.
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2015.02.014
Table 1 Definition of Unfavorable-Risk Acute Myeloid Leukemia Unfavorable risk cytogenetics Monosomal karyotype 5 or del(5q) or 7. Complex karyotype. inv(3)(q21q26.2) or t(3;3)(q21;q26.2) RPN1-EVI1. t(6;9)(p23;q34) DEK-NUP214. t(v;11)(v;q23) MLL rearranged. abnl(17p). Unfavorable molecular markers FLT3-ITD, MLL, TP53. Future: DNMT3A, PHF6, ASXL1, RAS, WT1. Other Primary induction failure. Antecedent hematological disorder. Adapted from Dohner et al.1
Because overall survival is improved for patients in first CR, patients need to be human leukocyte antigen (HLA) typed early in the course of disease (before induction, if possible) and a donor search initiated as soon as the HLA information is available. Ongoing intergroup trial S1203 (NCT01802333), in addition to comparing 3 induction regimens, will be testing the hypothesis of taking unfavorable-risk patients forward to immediate allogeneic HCT upon attainment of remission in order to improve the overall survival of these patients. Finally, patients with primary induction failure have benefited by immediate allogeneic HCT and should be considered for this approach over other chemotherapy.14,15
The Allogeneic Conundrum Although allogeneic HCT can provide long-term survival for some high-risk AML patients, it does not benefit all. Patients who are not in CR do not have adequate outcomes. Even with the advances and improvements in HCT,16 there are still challenges in getting patients to their ultimate goal. Patents with this disease are usually older, have significant comorbidities, and are often not thought of as candidates for transplantation. Even older patients should be considered and consulted, as there is evidence that those who receive transplants benefit.17 Concerns regarding treatmentrelated mortality often scare patients and physicians away from this definitive therapy.18,19 Also, delays in referrals, particularly in this subgroup, can affect outcomes, as they worsen with relapse. Moreover, some patients die of disease if a donor cannot be found in time. Another aspect of the HCT conundrum is that older patients often have more comorbidities, and to compensate for this, they are treated with a reduced-intensity transplantation regimen, which in turn leads to poorer outcomes from relapse of disease.14 Many centers are now using maintenance therapy to counteract the reduction in conditioning; however, this has been built on scant phase 1/2 data,20 and these findings need to be confirmed in phase 3 trials. Newer approaches with targeted immunotherapy are being evaluated in this setting. Ongoing trials are evaluating FLT3 inhibitors midostaurin (NCT01883362) and sorafenib (NCT01578109); hypomethylating agents (azacitidine; NCT01747499), and immunotherapy (WT1 with T cell receptor therapy; NCT01621724).
Finally, the act of curing the disease often leaves behind a lifelong aftermath: chronic graft versus host disease can negatively affect quality of life, and patients should understand that they may be trading a deadly disease for a chronic one. Survivorship is a new concept for these patients once cured. These patients are now at a higher risk of cardiac and other malignancies. Follow-up should include addressing these long-term needs.21,22
Clinical Practice Points Unfavorable risk AML is a deadly disease which needs to
be treated aggressively. Conventional chemotherapy is not sufficient. Allogeneic HCT benefits this group of patients. Ongoing trials are investigating targeted therpy in these patients. Survivorship post allogeneic HCT is still an issue.
Disclosure The author has stated that he has no conflicts of interest.
References 1. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115:453-74. 2. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366:1079-89. 3. Patel JP, Levine RL. How do novel molecular genetic markers influence treatment decisions in acute myeloid leukemia? Hematology 2012; 2012:28-34. 4. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009; 361:1249-59. 5. Garcia-Manero G, Tambaro FP, Bekele NB, et al. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol 2012; 30: 2204-10. 6. Pautas C, Thomas X, Merabet F, et al. Randomized comparison of standard induction with daunorubicin (DNR) for 3 days vs idarubicin (IDA) for 3 or 4 days in AML pts aged 50 to 70 and of maintenance with interleukin 2. Final analysis of the ALFA 9801 study. ASH Annual Meeting Abstracts 2007; 110:162. 7. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994; 331:896-903. 8. Estey E. High cytogenetic or molecular genetic risk acute myeloid leukemia. Hematology 2010; 2010:474-80. 9. Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998; 339: 1649-56. 10. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96:4075-83. 11. Koreth J, Schlenk R, Kopecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and metaanalysis of prospective clinical trials. JAMA 2009; 301:2349-61. 12. Cornelissen JJ, van Putten WL, Verdonck LF, et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middleaged adults: benefits for whom? Blood 2007; 109:3658-66. 13. Kurosawa S, Yamaguchi T, Miyawaki S, et al. A Markov decision analysis of allogeneic hematopoietic cell transplantation versus chemotherapy in patients with acute myeloid leukemia in first remission. Blood 2011; 117:2113-20. 14. Krejci M, Doubek M, Dusek J, et al. Combination of fludarabine, amsacrine, and cytarabine followed by reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with high-risk acute myeloid leukemia. Ann Hematol 2013; 92:1397-403. 15. Fung HC, Stein A, Slovak M, et al. A long-term follow-up report on allogeneic stem cell transplantation for patients with primary refractory acute myelogenous leukemia: impact of cytogenetic characteristics on transplantation outcome. Biol Blood Marrow Transplant 2003; 9:766-71. 16. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363:2091-101. 17. Estey E, de Lima M, Tibes R, et al. Prospective feasibility analysis of reducedintensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HSCT) in elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Blood 2007; 109:1395-400.
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Allogeneic Transplantation for AML 18. Mawad R, Gooley TA, Sandhu V, et al. Frequency of allogeneic hematopoietic cell transplantation among patients with high- or intermediate-risk acute myeloid leukemia in first complete remission. J Clin Oncol 2013; 31:3883-8. 19. Pidala J, Craig BM, Lee SJ, et al. Practice variation in physician referral for allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2013; 48:63-7. 20. de Lima M, Giralt S, Thall PF, et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute
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myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer 2010; 116:5420-31. 21. Majhail NS, Rizzo JD. Surviving the cure: long term followup of hematopoietic cell transplant recipients. Bone Marrow Transplant 2013; 48:1145-51. 22. Majhail NS, Tao L, Bredeson C, et al. Prevalence of hematopoietic cell transplant survivors in the United States. Biol Blood Marrow Transplant 2013; 19:1498-501.
Allogeneic Transplantation for Unfavorable-Risk Acute Myeloid Leukemia Hugo F. Fernandez Abstract Acute myeloid leukemia (AML) is a complex, heterogeneous disorder that can have devastating effects. Although control of AML can be attained with various induction regimens, long-term cure is much more difficult to maintain. This is understated in patients with unfavorable-risk AML, who are usually older and have prior myeloid and/or therapyrelated disease and more challenges in curing this disease. Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. S1, S70-2 ª 2015 Elsevier Inc. All rights reserved. Keywords: Acute myeloid leukemia, Allogeneic hematopoietic cell transplantation, Consolidation therapy, Maintenance therapy, Unfavorable risk
Introduction Several prognostic guidelines have been developed for acute myeloid leukemia (AML) based on cytogenetic and more recently molecular profiles. The European Leukemia Network classification has defined unfavorable-risk prognostication based on published cytogenetic and molecular results and their impact in the disease. Unfavorable risk includes deletions of chromosome 5 or 7, inversion or translocation of chromosome 3, translocation 6;9, MLL rearrangements (11q23), 17p abnormalities (TP53), complex karyotypes, and FLT3-ITD.1 Whole-genome sequencing has led to the discovery of molecular mutations in DNMT3A, PHF6, ASXL1, RAS, and WT1, which portend a worse prognosis.2 Although these somatic mutations can help redefine cytogenetically normal disease, they are considered investigational because of the small numbers studied, and they require long-term validation of the preliminary results. In addition, they often do not change the prognosis in cytogenetically unfavorable-risk AML.3 Other clinical presentations of AML including patients with antecedent hematological disorders (myelodysplastic and myeloproliferative) or patients whose disease has failed to respond to induction also carry a poor prognosis (Table 1).
Therapy for Unfavorable-Risk Disease Current therapy for all patients AML induction include 7 þ 3 (anthracycline and cytarabine), high-dose cytarabine-containing
Moffitt Cancer Center, Tampa, FL Submitted: Dec 6, 2014; Accepted: Feb 3, 2015; Epub: Feb 18, 2015 Address for correspondence: Hugo F. Fernandez, MD, Moffitt Cancer Center, 12902 Magnolia Drive, FOB3, Tampa, FL 33612 E-mail contact: hugo.fernandez@moffitt.org
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regimens (with and without anthracycline), and others.4-6 In these studies, complete remission (CR) was experienced by 50% to 70% of patients with unfavorable-risk disease. However, chemotherapy alone is not enough to adequately control unfavorable-risk AML because remissions are not sustained and are not affected by regimen intensification. High-dose cytarabine, long a standard in consolidation, is less effective in unfavorable-risk AML in maintaining the CR.7 Multiple trials have demonstrated long-term survival of less than 20%, regardless of consolidation regimens excluding allogeneic hematopoietic cell transplantation (HCT). The subsets of patients with a monosomal karyotype, defined as presence of at least 2 autosomal monosomies or a single autosomal monosomy with at least 1 structural abnormality, have a very poor prognosis, with overall survival of < 5% because of its association with prior therapy, advanced age, complex karyotype unfavorable molecular markers, and antecedent hematological disorders.8
Immunotherapy Because standard chemotherapy is not enough, other approaches have been developed to aggressively treat this disease. Allogeneic HCT was the first immunologic therapy that provided a better approach to the treatment of unfavorable risk AML. The Eastern Cooperative Oncology Group led an intergroup trial that allocated patients using genetic criteria to allogeneic HCT or autologous HCT versus chemotherapy; results showed no survival difference between the groups.9 A subsequent subset analysis of cytogenetic risk showed that allogeneic HCT improved overall survival for unfavorable-risk patients treated on the trial.10 The small numbers in the analysis was a concern; however, 2 recent meta-analyses and 1 Markov analysis have solidified the concept that unfavorable-risk AML in first CR benefits from allogeneic HCT and is superior to chemotherapy consolidation.11-13 Until a better approach is developed, this remains the current standard of care for these high-risk patients.
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2015.02.014
Table 1 Definition of Unfavorable-Risk Acute Myeloid Leukemia Unfavorable risk cytogenetics Monosomal karyotype 5 or del(5q) or 7. Complex karyotype. inv(3)(q21q26.2) or t(3;3)(q21;q26.2) RPN1-EVI1. t(6;9)(p23;q34) DEK-NUP214. t(v;11)(v;q23) MLL rearranged. abnl(17p). Unfavorable molecular markers FLT3-ITD, MLL, TP53. Future: DNMT3A, PHF6, ASXL1, RAS, WT1. Other Primary induction failure. Antecedent hematological disorder. Adapted from Dohner et al.1
Because overall survival is improved for patients in first CR, patients need to be human leukocyte antigen (HLA) typed early in the course of disease (before induction, if possible) and a donor search initiated as soon as the HLA information is available. Ongoing intergroup trial S1203 (NCT01802333), in addition to comparing 3 induction regimens, will be testing the hypothesis of taking unfavorable-risk patients forward to immediate allogeneic HCT upon attainment of remission in order to improve the overall survival of these patients. Finally, patients with primary induction failure have benefited by immediate allogeneic HCT and should be considered for this approach over other chemotherapy.14,15
The Allogeneic Conundrum Although allogeneic HCT can provide long-term survival for some high-risk AML patients, it does not benefit all. Patients who are not in CR do not have adequate outcomes. Even with the advances and improvements in HCT,16 there are still challenges in getting patients to their ultimate goal. Patents with this disease are usually older, have significant comorbidities, and are often not thought of as candidates for transplantation. Even older patients should be considered and consulted, as there is evidence that those who receive transplants benefit.17 Concerns regarding treatmentrelated mortality often scare patients and physicians away from this definitive therapy.18,19 Also, delays in referrals, particularly in this subgroup, can affect outcomes, as they worsen with relapse. Moreover, some patients die of disease if a donor cannot be found in time. Another aspect of the HCT conundrum is that older patients often have more comorbidities, and to compensate for this, they are treated with a reduced-intensity transplantation regimen, which in turn leads to poorer outcomes from relapse of disease.14 Many centers are now using maintenance therapy to counteract the reduction in conditioning; however, this has been built on scant phase 1/2 data,20 and these findings need to be confirmed in phase 3 trials. Newer approaches with targeted immunotherapy are being evaluated in this setting. Ongoing trials are evaluating FLT3 inhibitors midostaurin (NCT01883362) and sorafenib (NCT01578109); hypomethylating agents (azacitidine; NCT01747499), and immunotherapy (WT1 with T cell receptor therapy; NCT01621724).
Finally, the act of curing the disease often leaves behind a lifelong aftermath: chronic graft versus host disease can negatively affect quality of life, and patients should understand that they may be trading a deadly disease for a chronic one. Survivorship is a new concept for these patients once cured. These patients are now at a higher risk of cardiac and other malignancies. Follow-up should include addressing these long-term needs.21,22
Clinical Practice Points Unfavorable risk AML is a deadly disease which needs to
be treated aggressively. Conventional chemotherapy is not sufficient. Allogeneic HCT benefits this group of patients. Ongoing trials are investigating targeted therpy in these patients. Survivorship post allogeneic HCT is still an issue.
Disclosure The author has stated that he has no conflicts of interest.
References 1. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115:453-74. 2. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366:1079-89. 3. Patel JP, Levine RL. How do novel molecular genetic markers influence treatment decisions in acute myeloid leukemia? Hematology 2012; 2012:28-34. 4. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009; 361:1249-59. 5. Garcia-Manero G, Tambaro FP, Bekele NB, et al. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol 2012; 30: 2204-10. 6. Pautas C, Thomas X, Merabet F, et al. Randomized comparison of standard induction with daunorubicin (DNR) for 3 days vs idarubicin (IDA) for 3 or 4 days in AML pts aged 50 to 70 and of maintenance with interleukin 2. Final analysis of the ALFA 9801 study. ASH Annual Meeting Abstracts 2007; 110:162. 7. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994; 331:896-903. 8. Estey E. High cytogenetic or molecular genetic risk acute myeloid leukemia. Hematology 2010; 2010:474-80. 9. Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998; 339: 1649-56. 10. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96:4075-83. 11. Koreth J, Schlenk R, Kopecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and metaanalysis of prospective clinical trials. JAMA 2009; 301:2349-61. 12. Cornelissen JJ, van Putten WL, Verdonck LF, et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middleaged adults: benefits for whom? Blood 2007; 109:3658-66. 13. Kurosawa S, Yamaguchi T, Miyawaki S, et al. A Markov decision analysis of allogeneic hematopoietic cell transplantation versus chemotherapy in patients with acute myeloid leukemia in first remission. Blood 2011; 117:2113-20. 14. Krejci M, Doubek M, Dusek J, et al. Combination of fludarabine, amsacrine, and cytarabine followed by reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with high-risk acute myeloid leukemia. Ann Hematol 2013; 92:1397-403. 15. Fung HC, Stein A, Slovak M, et al. A long-term follow-up report on allogeneic stem cell transplantation for patients with primary refractory acute myelogenous leukemia: impact of cytogenetic characteristics on transplantation outcome. Biol Blood Marrow Transplant 2003; 9:766-71. 16. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363:2091-101. 17. Estey E, de Lima M, Tibes R, et al. Prospective feasibility analysis of reducedintensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HSCT) in elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Blood 2007; 109:1395-400.
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Allogeneic Transplantation for AML 18. Mawad R, Gooley TA, Sandhu V, et al. Frequency of allogeneic hematopoietic cell transplantation among patients with high- or intermediate-risk acute myeloid leukemia in first complete remission. J Clin Oncol 2013; 31:3883-8. 19. Pidala J, Craig BM, Lee SJ, et al. Practice variation in physician referral for allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2013; 48:63-7. 20. de Lima M, Giralt S, Thall PF, et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute
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myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer 2010; 116:5420-31. 21. Majhail NS, Rizzo JD. Surviving the cure: long term followup of hematopoietic cell transplant recipients. Bone Marrow Transplant 2013; 48:1145-51. 22. Majhail NS, Tao L, Bredeson C, et al. Prevalence of hematopoietic cell transplant survivors in the United States. Biol Blood Marrow Transplant 2013; 19:1498-501.