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Very late relapse of Philadelphia chromosome positive acute megakaryoblastic leukemia a
a
a
a
Jeffery M. Patterson , Lauren Bolster , Loree Larratt , Marlene Hamilton & Joseph a
Brandwein a
Division of Hematology, University of Alberta, Edmonton, Alberta, Canada Accepted author version posted online: 11 Dec 2014.Published online: 21 Jan 2015.
Click for updates To cite this article: Jeffery M. Patterson, Lauren Bolster, Loree Larratt, Marlene Hamilton & Joseph Brandwein (2015) Very late relapse of Philadelphia chromosome positive acute megakaryoblastic leukemia, Leukemia & Lymphoma, 56:7, 2203-2205, DOI: 10.3109/10428194.2014.994178 To link to this article: http://dx.doi.org/10.3109/10428194.2014.994178
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Leukemia & Lymphoma, July 2015; 56(7): 2203–2205 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.994178
LETTER TO THE EDITOR
Very late relapse of Philadelphia chromosome positive acute megakaryoblastic leukemia Jeffery M. Patterson, Lauren Bolster, Loree Larratt, Marlene Hamilton & Joseph Brandwein
Downloaded by [Stockholm University Library] at 12:59 05 September 2015
Division of Hematology, University of Alberta, Edmonton, Alberta, Canada
Twenty-two years later, at age 55, the patient re-presented with fatigue, chest pain and dyspnea. The CBC revealed hemoglobin 55 g/L, platelets 161 ⫻ 109/L, WBC 6.1 ⫻ 109/L with 21% neutrophils and 49% blasts. He had had normal blood counts 1 year previously. Bone marrow biopsy (Figure 1) revealed acute megakaryoblastic leukemia (M7), with 66% blasts, and cytogenetics showing two abnormal cell lines, one with 45,X,⫺ Y,t(9;22)(q34;q11.2) and the other 45,sl,dup(1)(q23q44). The Ph breakpoint was identified at b3a2; no FLT3 mutation was detected. In April 2009, he underwent 3 ⫹ 7 induction chemotherapy with idarubicin and cytarabine, in addition to imatinib 300 mg twice a day (BID). His induction course was complicated by disseminated fungal infection and delayed count recovery. Recovery marrow day 36 post-chemotherapy revealed mild fibrosis with 30% cellularity, reduced megakaryocytes and 1% blasts; cytogenetics were normal. He remained BCR–ABL positive, with 2–3-log reductions versus baseline on polymerase chain reaction (PCR) testing of his peripheral blood over the next year, maintained on single-agent imatinib 300–400 mg daily. Repeat transplant was initially delayed due to severe deconditioning, and concern for exacerbating his fungal infection, but 441 days after starting induction chemotherapy he received a second HLA-matched allogeneic stem cell transplant. This time he received etoposide, antithymocyte globulin (ATG) and total body irradiation conditioning; the donor was a different sibling. His post-transplant course was again complicated by GVHD involving the skin and eyes, and avascular necrosis of the left humerus. By day 23 post-transplant his neutrophil count recovered; he was platelet transfusion independent by day 30, and red cell transfusion independent by day 85. On follow-up peripheral blood monitoring his BCR–ABL transcripts remained undetectable by revere transcription (RT)-PCR, and therefore no tyrosine kinase treatment was instituted. At day 782 post-second transplant, his BCR–ABL transcripts again reappeared, showing a 3.18-log reduction versus baseline, and by day 872 his hemoglobin and platelets slowly began to fall; he once again became neutropenic
Very late relapses of acute myeloid leukemia (AML), defined as occurring ⬎ 5 years from the date of achievement of complete remission (CR), are rare; previous reports have indicated that these constitute 0.002–3% of all relapses [1–3]. Cytogenetic results in such cases have frequently been either normal, not available or different at relapse [1–3]. This raises the question of whether some of these constitute new cases of AML rather than relapses. We report one of the latest relapses yet reported, with a common cytogenetic marker and rare histologic subtype. In 1985, a previously healthy 33-year-old male presented with a month-long history of dizzy spells, malaise, weight loss and headache. Physical examination was normal. A complete blood count (CBC) revealed hemoglobin 121 g/L, platelets 107 ⫻ 109/L and white blood cell count (WBC) 2.0 ⫻ 109/L, with a differential containing 4% blasts. Bone marrow biopsy revealed 25–28% myeloblasts, periodic acid–Schiff (PAS) negative and Sudan Black positive, and he was diagnosed with an aggressive myelodysplastic syndrome. Further history revealed he had worked in a gas plant and was exposed to a number of acids and solvents over the previous 4–5 years. He was maintained initially on only red cell transfusion support. His disease progressed to AML 18 months later, with his marrow demonstrating sheets of abnormal megakaryocytes. The cytogenetics revealed two cytogenetic clones, both containing the Philadelphia chromosome (Ph); one also contained ⫺ Y. He did not receive induction chemotherapy, rather undergoing myeloablative conditioning with busulphan and cyclophosphamide followed by allogeneic stem cell transplant from a human leukocyte antigen (HLA) and ABO compatible matched sibling donor in May 1987. The early post-transplant course was complicated by Escherichia coli septicemia, oral herpes simplex infection, candidal endophthalmitis, mild skin but severe eye graft-versus-host disease (GVHD) and arachnoiditis secondary to intrathecal chemotherapy. A follow-up marrow at day 100 was free of leukemia, and showed no cytogenetic abnormalities. BCR–ABL transcript monitoring was unavailable at that time; he was discharged from hematology follow-up 10 years after the transplant, declared cured.
Correspondence: Dr. Jeffery M. Patterson, MD, FRCPC, Assistant Clinical Professor, Division of Hematology, University of Alberta, 4-112 Clinical Sciences Building, 11350 83rd Ave, Edmonton, Alberta T6G 2G3, Canada. Tel: 780-407-1584. Fax: 780-407-2680. E-mail: [email protected] Received 18 August 2014; revised 8 November 2014; accepted 26 November 2014
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Figure 1. Relapsed bone marrow aspirate.
on day 1009. Bone marrow biopsy on day 1019 post-second transplant, and over 9400 days post-first transplant, showed relapsed leukemia. The morphological findings were consistent with his previous M7 leukemia (16% blasts). Cytogenetics again showed two cell lines, both positive for the previously identified t(9;22)(q34;q11.2), and this time both showing loss of the Y chromosome. One line also showed a new trisomy 8 and t(18;20), and the other a new 5q rearrangement and t(2;3). At relapse he was initially started on imatinib for 2 months, then switched to nilotinib. He did not respond to treatment, however, and died 3 months later. Previous case reports of very late relapses in AML have included cases with first CR (CR1) durations of 5–12 years [1–5]. Incidence rates of late relapse ⬎ 5 years post-transplant are unknown, but leukemia-free survival at 15 years for patients who are leukemia-free at 3 years is reported at 72.8% [6]. The present case represents, to our knowledge, the latest relapse reported to date. This case is also, to our knowledge, the first reported case of very late relapse with this morphologic subtype, acute megakaryoblastic leukemia (M7). M7 is a rare entity, representing ⬍ 1% of AML seen in adults [7]; prognosis is considered poor, largely due to a high rate of relapse. Median overall survival is estimated at only 40 weeks, with a disease-free survival of 17% at 5 years [8,9]. Allogeneic stem cell transplant offers the best chance of cure, with reported overall survival of 43% at 3 years [7]. In our case, the presence of the Philadelphia chromosome at both diagnosis and relapse, and the recurrence of the same rare histologic subtype, provide compelling evidence of true relapse, rather than the emergence of a secondary AML. The acquisition of additional cytogenetic abnormalities at relapse is consistent with clonal evolution. How did this patient, with such an aggressive subtype of leukemia, manage to stay in remission for over 20 years before relapse? One hypothesis suggests that pre-malignant clones with malignant potential retain viability after chemotherapy treatments, and may re-emerge as AML through the acquisition of new genetic mutations (clonal evolution). Alternatively, a small malignant leukemic clone may be kept under control by the host immune system, particularly after an allograft. This clone may undergo reactivation via
an external stressor such as a viral infection or acquired immunodeficiency state which results in removal of host surveillance. It is also possible that residual malignant cells persisted after chemotherapy in a prolonged quiescent (G0) state, undergoing reactivation in relation to changes in the microenvironment [10]. It appears that the second CR (CR2) rate is higher in patients with later relapse [1–3,11]. Medeiros et al. found a CR2 rate of 87% in their series [1] and Watts et al. 57% [2], but Verma et al. reported only a 45% CR2 rate [3]. The latter series, however, included cases with different cytogenetic profiles at relapse, suggesting the possibility that some of those may have represented therapy related AML (t-AML). The CR2 rate may also hinge on the aggressiveness of the initial consolidation regimen; those having more intense initial chemotherapy may have subsequently developed more resistant disease, rendering them less sensitive to the second chemotherapy regimen [12]. The fact that our patient never received induction chemotherapy when he initially presented, instead going directly to transplant, may have contributed to the success of attaining remission when he was subsequently exposed to the standard 3 ⫹ 7 induction regimen at relapse. Although he did achieve a lengthy CR2 with the transplant, the leukemia ultimately did return, this time off any tyrosine kinase inhibitor (TKI). Whether maintenance therapy with a TKI may have prolonged the remission in this setting is unknown. Papageorgiou et al. published a case of Ph positive acute megakaryoblastic leukemia that failed two attempts at induction but achieved remission on only dasatinib, subsequently relapsing in the central nervous system (CNS) [13]. Since responses to such agents in Ph positive acute leukemias are generally transient, particularly in second remission, transplant still offers the best chance of cure. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Medeiros B, Minden MD, Schuh AC, et al. Characteristics and outcomes of acute myelogenous leukemia patients with very late relapse (⬎ 5 years). Leuk Lymphoma 2007;48:65–71. [2] Watts JM, Wang XV, Litzow MR, et al. Younger adults with acute myeloid in remission for ⱖ 3 years have a high likelihood of cure: the ECOG experience in over 1200 patients. Leuk Res 2014;38:901–906. [3] Verma D, Kantarjian H, Faderl S, et al. Late relapses in acute myeloid leukemia: analysis of characteristics and outcomes. Leuk Lymphoma 2010;51:778–782. [4] Schiffer CA , Dodge R, Larson RA . Long-term follow-up of Cancer and Leukemia Group B studies in acute myeloid leukemia. Cancer 1997;80:2210–2214. [5] Preisler HD, Anderson K, Rai K, et al. The frequency of longterm remission in patients with acute myeloid leukemia treated with conventional maintenance chemotherapy: a study of 760 patients with a minimal follow-up time of 6 years. Br J Haematol 1989;71:189–194. [6] Pant S, Hamadani M, Dodds AJ, et al. Incidence and reasons for late failure after allogeneic haematopoietic cell transplantation following BuCy2 in acute myeloid leukemia. Br J Hematol 2009;148:623–626. [7] Garderet L, Labopin M, Gorin NC, et al. Hematopoietic stem cell transplantation for de novo acute megakaryocytic leukemia in first
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complete remission: a retrospective study of the European Group for Blood and Marrow Transplantation (EBMT). Blood 2005;105:405–409. [8] Pagano L , Pulsoni A , Vignetti M, et al. Acute megakaryoblastic leukemia: experience of GIMEMA trials. Leukemia 2002; 16:1622–1626. [9] Ruiz-Arguelles GJ, Lobato-Mendizabal E, San-Miguel JF, et al. Long-term treatment results for acute megakaryoblastic leukemia patients: a multicenter study. Br J Haematol 1992;82:671–675. [10] Indraccolo S, Stievano L, Minuzzo S, et al. Interruption of tumor dormancy by a transient angiogenic burst within the tumor microenvironment. Proc Natl Acad Sci USA 2006;103:4216–4221.
[11] Kantarjian HM, Keating MJ, Walters RS et al. The characteristics and outcome of patients with late relapse acute myelogenous leukemia. J Clin Oncol 1988;6:232–238. [12] Norkin M, Uberti JP, Schiffer CA . Very late recurrences of leukemia: why does leukemia awake after many years of dormancy? Leuk Res 2011;35:139–144. [13] Papageorgiou SG, Pappa V, Economopoulou C, et al. Dasatinib induces long term remission in imatinib-resistant Philadelphia chromosome-positive acute megakaryoblastic leukemia but fails to prevent development of central nervous system progression. Leuk Res 2010;34:254–256.
Leukemia & Lymphoma Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ilal20
Very late relapse of Philadelphia chromosome positive acute megakaryoblastic leukemia a
a
a
a
Jeffery M. Patterson , Lauren Bolster , Loree Larratt , Marlene Hamilton & Joseph a
Brandwein a
Division of Hematology, University of Alberta, Edmonton, Alberta, Canada Accepted author version posted online: 11 Dec 2014.Published online: 21 Jan 2015.
Click for updates To cite this article: Jeffery M. Patterson, Lauren Bolster, Loree Larratt, Marlene Hamilton & Joseph Brandwein (2015) Very late relapse of Philadelphia chromosome positive acute megakaryoblastic leukemia, Leukemia & Lymphoma, 56:7, 2203-2205, DOI: 10.3109/10428194.2014.994178 To link to this article: http://dx.doi.org/10.3109/10428194.2014.994178
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Leukemia & Lymphoma, July 2015; 56(7): 2203–2205 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.994178
LETTER TO THE EDITOR
Very late relapse of Philadelphia chromosome positive acute megakaryoblastic leukemia Jeffery M. Patterson, Lauren Bolster, Loree Larratt, Marlene Hamilton & Joseph Brandwein
Downloaded by [Stockholm University Library] at 12:59 05 September 2015
Division of Hematology, University of Alberta, Edmonton, Alberta, Canada
Twenty-two years later, at age 55, the patient re-presented with fatigue, chest pain and dyspnea. The CBC revealed hemoglobin 55 g/L, platelets 161 ⫻ 109/L, WBC 6.1 ⫻ 109/L with 21% neutrophils and 49% blasts. He had had normal blood counts 1 year previously. Bone marrow biopsy (Figure 1) revealed acute megakaryoblastic leukemia (M7), with 66% blasts, and cytogenetics showing two abnormal cell lines, one with 45,X,⫺ Y,t(9;22)(q34;q11.2) and the other 45,sl,dup(1)(q23q44). The Ph breakpoint was identified at b3a2; no FLT3 mutation was detected. In April 2009, he underwent 3 ⫹ 7 induction chemotherapy with idarubicin and cytarabine, in addition to imatinib 300 mg twice a day (BID). His induction course was complicated by disseminated fungal infection and delayed count recovery. Recovery marrow day 36 post-chemotherapy revealed mild fibrosis with 30% cellularity, reduced megakaryocytes and 1% blasts; cytogenetics were normal. He remained BCR–ABL positive, with 2–3-log reductions versus baseline on polymerase chain reaction (PCR) testing of his peripheral blood over the next year, maintained on single-agent imatinib 300–400 mg daily. Repeat transplant was initially delayed due to severe deconditioning, and concern for exacerbating his fungal infection, but 441 days after starting induction chemotherapy he received a second HLA-matched allogeneic stem cell transplant. This time he received etoposide, antithymocyte globulin (ATG) and total body irradiation conditioning; the donor was a different sibling. His post-transplant course was again complicated by GVHD involving the skin and eyes, and avascular necrosis of the left humerus. By day 23 post-transplant his neutrophil count recovered; he was platelet transfusion independent by day 30, and red cell transfusion independent by day 85. On follow-up peripheral blood monitoring his BCR–ABL transcripts remained undetectable by revere transcription (RT)-PCR, and therefore no tyrosine kinase treatment was instituted. At day 782 post-second transplant, his BCR–ABL transcripts again reappeared, showing a 3.18-log reduction versus baseline, and by day 872 his hemoglobin and platelets slowly began to fall; he once again became neutropenic
Very late relapses of acute myeloid leukemia (AML), defined as occurring ⬎ 5 years from the date of achievement of complete remission (CR), are rare; previous reports have indicated that these constitute 0.002–3% of all relapses [1–3]. Cytogenetic results in such cases have frequently been either normal, not available or different at relapse [1–3]. This raises the question of whether some of these constitute new cases of AML rather than relapses. We report one of the latest relapses yet reported, with a common cytogenetic marker and rare histologic subtype. In 1985, a previously healthy 33-year-old male presented with a month-long history of dizzy spells, malaise, weight loss and headache. Physical examination was normal. A complete blood count (CBC) revealed hemoglobin 121 g/L, platelets 107 ⫻ 109/L and white blood cell count (WBC) 2.0 ⫻ 109/L, with a differential containing 4% blasts. Bone marrow biopsy revealed 25–28% myeloblasts, periodic acid–Schiff (PAS) negative and Sudan Black positive, and he was diagnosed with an aggressive myelodysplastic syndrome. Further history revealed he had worked in a gas plant and was exposed to a number of acids and solvents over the previous 4–5 years. He was maintained initially on only red cell transfusion support. His disease progressed to AML 18 months later, with his marrow demonstrating sheets of abnormal megakaryocytes. The cytogenetics revealed two cytogenetic clones, both containing the Philadelphia chromosome (Ph); one also contained ⫺ Y. He did not receive induction chemotherapy, rather undergoing myeloablative conditioning with busulphan and cyclophosphamide followed by allogeneic stem cell transplant from a human leukocyte antigen (HLA) and ABO compatible matched sibling donor in May 1987. The early post-transplant course was complicated by Escherichia coli septicemia, oral herpes simplex infection, candidal endophthalmitis, mild skin but severe eye graft-versus-host disease (GVHD) and arachnoiditis secondary to intrathecal chemotherapy. A follow-up marrow at day 100 was free of leukemia, and showed no cytogenetic abnormalities. BCR–ABL transcript monitoring was unavailable at that time; he was discharged from hematology follow-up 10 years after the transplant, declared cured.
Correspondence: Dr. Jeffery M. Patterson, MD, FRCPC, Assistant Clinical Professor, Division of Hematology, University of Alberta, 4-112 Clinical Sciences Building, 11350 83rd Ave, Edmonton, Alberta T6G 2G3, Canada. Tel: 780-407-1584. Fax: 780-407-2680. E-mail: [email protected] Received 18 August 2014; revised 8 November 2014; accepted 26 November 2014
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Figure 1. Relapsed bone marrow aspirate.
on day 1009. Bone marrow biopsy on day 1019 post-second transplant, and over 9400 days post-first transplant, showed relapsed leukemia. The morphological findings were consistent with his previous M7 leukemia (16% blasts). Cytogenetics again showed two cell lines, both positive for the previously identified t(9;22)(q34;q11.2), and this time both showing loss of the Y chromosome. One line also showed a new trisomy 8 and t(18;20), and the other a new 5q rearrangement and t(2;3). At relapse he was initially started on imatinib for 2 months, then switched to nilotinib. He did not respond to treatment, however, and died 3 months later. Previous case reports of very late relapses in AML have included cases with first CR (CR1) durations of 5–12 years [1–5]. Incidence rates of late relapse ⬎ 5 years post-transplant are unknown, but leukemia-free survival at 15 years for patients who are leukemia-free at 3 years is reported at 72.8% [6]. The present case represents, to our knowledge, the latest relapse reported to date. This case is also, to our knowledge, the first reported case of very late relapse with this morphologic subtype, acute megakaryoblastic leukemia (M7). M7 is a rare entity, representing ⬍ 1% of AML seen in adults [7]; prognosis is considered poor, largely due to a high rate of relapse. Median overall survival is estimated at only 40 weeks, with a disease-free survival of 17% at 5 years [8,9]. Allogeneic stem cell transplant offers the best chance of cure, with reported overall survival of 43% at 3 years [7]. In our case, the presence of the Philadelphia chromosome at both diagnosis and relapse, and the recurrence of the same rare histologic subtype, provide compelling evidence of true relapse, rather than the emergence of a secondary AML. The acquisition of additional cytogenetic abnormalities at relapse is consistent with clonal evolution. How did this patient, with such an aggressive subtype of leukemia, manage to stay in remission for over 20 years before relapse? One hypothesis suggests that pre-malignant clones with malignant potential retain viability after chemotherapy treatments, and may re-emerge as AML through the acquisition of new genetic mutations (clonal evolution). Alternatively, a small malignant leukemic clone may be kept under control by the host immune system, particularly after an allograft. This clone may undergo reactivation via
an external stressor such as a viral infection or acquired immunodeficiency state which results in removal of host surveillance. It is also possible that residual malignant cells persisted after chemotherapy in a prolonged quiescent (G0) state, undergoing reactivation in relation to changes in the microenvironment [10]. It appears that the second CR (CR2) rate is higher in patients with later relapse [1–3,11]. Medeiros et al. found a CR2 rate of 87% in their series [1] and Watts et al. 57% [2], but Verma et al. reported only a 45% CR2 rate [3]. The latter series, however, included cases with different cytogenetic profiles at relapse, suggesting the possibility that some of those may have represented therapy related AML (t-AML). The CR2 rate may also hinge on the aggressiveness of the initial consolidation regimen; those having more intense initial chemotherapy may have subsequently developed more resistant disease, rendering them less sensitive to the second chemotherapy regimen [12]. The fact that our patient never received induction chemotherapy when he initially presented, instead going directly to transplant, may have contributed to the success of attaining remission when he was subsequently exposed to the standard 3 ⫹ 7 induction regimen at relapse. Although he did achieve a lengthy CR2 with the transplant, the leukemia ultimately did return, this time off any tyrosine kinase inhibitor (TKI). Whether maintenance therapy with a TKI may have prolonged the remission in this setting is unknown. Papageorgiou et al. published a case of Ph positive acute megakaryoblastic leukemia that failed two attempts at induction but achieved remission on only dasatinib, subsequently relapsing in the central nervous system (CNS) [13]. Since responses to such agents in Ph positive acute leukemias are generally transient, particularly in second remission, transplant still offers the best chance of cure. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Medeiros B, Minden MD, Schuh AC, et al. Characteristics and outcomes of acute myelogenous leukemia patients with very late relapse (⬎ 5 years). Leuk Lymphoma 2007;48:65–71. [2] Watts JM, Wang XV, Litzow MR, et al. Younger adults with acute myeloid in remission for ⱖ 3 years have a high likelihood of cure: the ECOG experience in over 1200 patients. Leuk Res 2014;38:901–906. [3] Verma D, Kantarjian H, Faderl S, et al. Late relapses in acute myeloid leukemia: analysis of characteristics and outcomes. Leuk Lymphoma 2010;51:778–782. [4] Schiffer CA , Dodge R, Larson RA . Long-term follow-up of Cancer and Leukemia Group B studies in acute myeloid leukemia. Cancer 1997;80:2210–2214. [5] Preisler HD, Anderson K, Rai K, et al. The frequency of longterm remission in patients with acute myeloid leukemia treated with conventional maintenance chemotherapy: a study of 760 patients with a minimal follow-up time of 6 years. Br J Haematol 1989;71:189–194. [6] Pant S, Hamadani M, Dodds AJ, et al. Incidence and reasons for late failure after allogeneic haematopoietic cell transplantation following BuCy2 in acute myeloid leukemia. Br J Hematol 2009;148:623–626. [7] Garderet L, Labopin M, Gorin NC, et al. Hematopoietic stem cell transplantation for de novo acute megakaryocytic leukemia in first
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complete remission: a retrospective study of the European Group for Blood and Marrow Transplantation (EBMT). Blood 2005;105:405–409. [8] Pagano L , Pulsoni A , Vignetti M, et al. Acute megakaryoblastic leukemia: experience of GIMEMA trials. Leukemia 2002; 16:1622–1626. [9] Ruiz-Arguelles GJ, Lobato-Mendizabal E, San-Miguel JF, et al. Long-term treatment results for acute megakaryoblastic leukemia patients: a multicenter study. Br J Haematol 1992;82:671–675. [10] Indraccolo S, Stievano L, Minuzzo S, et al. Interruption of tumor dormancy by a transient angiogenic burst within the tumor microenvironment. Proc Natl Acad Sci USA 2006;103:4216–4221.
[11] Kantarjian HM, Keating MJ, Walters RS et al. The characteristics and outcome of patients with late relapse acute myelogenous leukemia. J Clin Oncol 1988;6:232–238. [12] Norkin M, Uberti JP, Schiffer CA . Very late recurrences of leukemia: why does leukemia awake after many years of dormancy? Leuk Res 2011;35:139–144. [13] Papageorgiou SG, Pappa V, Economopoulou C, et al. Dasatinib induces long term remission in imatinib-resistant Philadelphia chromosome-positive acute megakaryoblastic leukemia but fails to prevent development of central nervous system progression. Leuk Res 2010;34:254–256.
