Letters to the Editor 731 To assess the frequency of LSC in the SP by the conventional 5Clinical Research Division, Fred Hutchinson Cancer Research Center, definition of ‘scid repopulating cells’, we performed engraftment Seattle, WA, USA and experiments in NODscid IL2Rgc À / À mice with 1700–120 000 SP 6Division of Medical Oncology, Department of Medicine, cells per mouse from patients 32, 34, 37, 56, 67 and 69. At 12–24 University of Washington, Seattle, WA, USA weeks, the bone marrow samples exhibited 1–35.6% (mean 7.8%), E-mail: [email protected] the spleen 0.4–38.3% (mean 10.2%) and the blood 0.3–27.4% (mean 10.1%) human CD45 þ cells. The cells from one patient demonstrated significant engraftment of 70 000 human SP cells REFERENCES per mouse resulting in 24.1% human CD45 þ cells in the blood 1 Bhatia M, Wang JC, Kapp U, Bonnet D, Dick JE. Purification of primitive human and 35.6% human CD45 þ cells in the bone marrow, comparable hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl to the level obtained from 1 000 000 CD34 þ cells per mouse from Acad Sci USA 1997; 94: 5320–5325. the same patient. 2 Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that In summary, SP cells can be derived from the majority of patient originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737. AML blast populations and can exhibit robust dye exclusion and 3 van Rhenen A, Feller N, Kelder A, Westra AH, Rombouts E, Zweegman S et al. High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal variable expression of CD38. They usually have the same residual disease and poor survival. Clin Cancer Res 2005; 11: 6520–6527. cytogenetic abnormality as the parent leukemia and are capable 4 Witte KE, Ahlers J, Schafer I, Andre M, Kerst G, Scheel-Walter HG et al. High pro- À / À of variable engraftment in the NODscid IL2Rgc mouse. portion of leukemic stem cells at diagnosis is correlated with unfavorable prognosis However, the frequency of this population does not correlate in childhood acute myeloid leukemia. Pediatr Hematol Oncol 2011; 28:91–99. with any known prognostic features in AML, in contrast to the 5 Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ et al. The frequency of CD34 þ CD38low or neg cells. We therefore favor the ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a phenotype of putative LSCs as CD34 þ CD38low or neg rather than molecular determinant of the side-population phenotype. Nat Med 2001; 7: 1028–1034. SP, as an increased proportion of CD34 þ CD38low or neg cells is 6 Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional correlated with increased age, unfavorable cytogenetics, properties of murine hematopoietic stem cells that are replicating in vivo. JExp Med 1996; 183: 1797–1806. chemotherapy resistance and short duration of CR1. Targeting 7 Challen GA, Little MH. A side order of stem cells: the SP phenotype. Stem Cells this population will likely be critical to eradication of leukemia. 2006; 24: 3–12. 8 Ho MM, Ng AV, Lam S, Hung JY. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res 2007; 67: 4827–4833. CONFLICT OF INTEREST 9 Christgen M, Geffers R, Ballmaier M, Christgen H, Poczkaj J, Krech T et al. The authors declare no conflict of interest. Down-regulation of the fetal stem cell factor SOX17 by H33342: a mechanism responsible for differential gene expression in breast cancer side population cells. J Biol Chem 2010; 285: 6412–6418. ACKNOWLEDGEMENTS 10 Oates JE, Grey BR, Addla SK, Samuel JD, Hart CA, Ramani VA et al. Hoechst 33342 side population identification is a conserved and unified mechanism in urological This project was supported by a grant from the Leukemia and Lymphoma Society cancers. Stem Cells Dev 2009; 18: 1515–1521. Translational Research Program (to PSB). We thank Ms Caroline Stamato for her 11 Feuring-Buske M, Hogge DE. Hoechst 33342 efflux identifies a subpopulation of assistance with the manuscript. cytogenetically normal CD34 þ CD38 À progenitor cells from patients with acute myeloid leukemia. Blood 2001; 97: 3882–3889. 1 2 3 4 4,5 M Roshal , S Chien , M Othus , BL Wood , M Fang , 12 Wulf GG, Wang RY, Kuehnle I, Weidner D, Marini F, Brenner MK et al. A leukemic 5,6 2,5 2 2 FR Appelbaum , EH Estey , T Papayannopoulou and PS Becker stem cell with intrinsic drug efflux capacity in acute myeloid leukemia. Blood 1Department of Pathology and Laboratory Medicine, 2001; 98: 1166–1173. Weill-Cornell Medical College, New York, NY, USA; 13 Moshaver B, van Rhenen A, Kelder A, van der Pol M, Terwijn M, Bachas C et al. 2Division of Hematology, Department of Medicine, Identification of a small subpopulation of candidate leukemia-initiating cells in Institute for Stem Cell and Regenerative Medicine, the side population of patients with acute myeloid leukemia. Stem Cells 2008; 26: University of Washington, 3059–3067. 14 Essers MA, Trumpp A. Targeting leukemic stem cells by breaking their dormancy. Seattle, WA, USA; 3 Mol Oncol 2010; 4: 443–450. Division of Public Health Sciences, 15 Gentles AJ, Plevritis SK, Majeti R, Alizadeh AA. Association of a leukemic stem cell Fred Hutchinson Cancer Research Center, Seattle, WA, USA; gene expression signature with clinical outcomes in acute myeloid leukemia. 4 Seattle Cancer Care Alliance, Seattle, WA, USA; JAMA 2010; 304: 2706–2715.

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Prognostic features in acute megakaryoblastic leukemia in children without Down syndrome: a report from the AML02 multicenter trial and the Children’s Oncology Group Study POG 9421

Leukemia (2013) 27, 731–734; doi:10.1038/leu.2012.223 prognostic and therapeutic implications of megakaryoblastic differentiation remain controversial, with some groups treating such disease as high risk and recommending hematopoietic While increased treatment intensity has improved outcomes stem cell transplantation (HSCT) during first remission, while for children with acute megakaryoblastic leukemia (AMKL), the others treat as standard risk in the absence of unfavorable

Accepted article preview online 3 August 2012; advance online publication 24 August 2012

& 2013 Macmillan Publishers Limited Leukemia (2013) 718 – 757 Letters to the Editor 732 Table 1. AML02 and POG 9421 patient characteristics and response

AML02 POG 9421

AMKL Other AML subtypes P-value AMKL Other AML subtypes P-value

Total patients, n 26 192 49 516

Gender, n (%) Male 14 (54) 108 (56) 0.84 29 (59) 269 (52) 0.3 Female 12 (46) 84 (44) 20 (41) 247 (48)

Age at diagnosis (years) Median 1.2 10.4 o0.01 1.8 9.6 o0.001 Range 0.2–11.3 0.01–21.4 0.1–16.2 0.0–20.4

Cytogenetics, n (%) t(1;22) 5 (19) 0 (0) o0.01 1 (2) 0 (0) o0.001 Normal 3 (11) 50 (26) 13 (27) 131 (25) t(8;21)/inv(16) 0 (0) 57 (30) 1 (2) 96 (19) 11q23 0 (0) 42 (22) 1 (2) 83 (16) Miscellaneous 16 (62) 40 (21) 24 (48) 122 (24) Not reported 2 (8) 3 (1) 9 (18) 84 (16)

FLT3 status, n (%) ITD 0 28 (15) o0.01 NA PM 0 8 (4) Wild type 17 (65) 150 (78) Not available 9 (35) 6 (3) 49 (100) 516 (100)

WBC at diagnosis ( Â 103) Median 11.7 22.2 0.06 13.5 24.7 0.004 Range 2.3–72.9 0.3–286.2 0.3–98.4 0.5–667

Induction therapy, n (%) Standard cytarabine 12 (46) 98 (51) 0.26 26 (53) 258 (50) 0.7 High-dose cytarabine 13 (50) 93 (48) 23 (47) 258 (50) Not randomized 1 (4) 1 (1) 0 (0) 0 (0)

Induction response, n (%) CR (after induction 1) 20 (81) 154 of 190 (81) 40.99 NA NA Induction 1 MRD X0.1% 10 of 24 (42) 65 of 180 (36) 0.65 NA NA CR (after induction 2) 26 (100) 174 of 183 (95) 61 39 (80) 436 (85) PR (after induction 2) 0 0 5 (10) 21 (4) Induction 2 MRD X0.1% 6 of 24 (25) 33 of 171 (19) 0.59 NA NA 0.2 Induction failure 0 11 (6) 0.37 2 (4) 43 (8) Toxic death 0 2 (1) 40.99 2 (4) 12 (2) Not evaluable 0 0 1 (2) 4 (1)

Survival, % (s.e.)a EFSa 48.7 (10.5) 64.8 (4.4) 0.21 34.7 (7.5) 37.9 (2.3) 0.7 OSa 53.9 (10.6) 73.1 (4.0) 0.023 36.3 (7.5) 51.8 (2.4) 0.1 Abbreviations: AML, acute myeloblastic leukemia; AMKL, acute megakaryoblastic leukemia; CR, complete response; EFS, event-free survival probability; FLT3, fms- related tyrosine kinase 3; ITD, internal tandem duplication; MRD, minimal residual disease; NA, not available; OS, overall survival probability; PM, point mutation; POG, Pediatric Oncology Group; PR, partial response; WBC, white blood cell count. aFor AML02, 3-year EFS/OS reported; for POG 9421, 5-year EFS/OS reported.

cytogenetics and/or a poor response to induction therapy.1–5 The difference between standard and high-dose cytarabine regimens, t(1;22)(p13;q13) translocation leads to the RBM15(OTT)-MKL1(MAL) which was similar to the non-AMKL cohort (84.5%). After fusion protein and predominates in infants with AMKL.6,7 induction, 44 patients with at least partial response continued Retrospective studies have reported conflicting data on long- on study; 6 underwent protocol-specified HSCT from a human term outcomes for the t(1;22) subgroup.8,9 We report the leukocyte antigen (HLA) matched sibling donor (4 remain in first outcomes of children with AMKL treated on the multicenter CR), while 38 received consolidation chemotherapy (13 remain in AML02 protocol (2002–2008) and on Pediatric Oncology Group first CR). The outcomes for patients with AMKL (5-year rates: event- protocol 9421 (1995–1999).5,10 Details of patient eligibility and free survival (EFS), 34.7±7.5%; overall survival (OS), 36.3±7.5%) treatment have been previously reported; written informed were similar to those of patients with other AML subtypes who consent was obtained from patients or their guardians in lacked favorable cytogenetic features (5-year rates: EFS accordance with supervising Institutional Review Boards. 33.9±2.5%; OS, 45.8±2.6%). Of the 565 patients enrolled on Pediatric Oncology Group 9421, Of the 39 AMKL patients with available cytogenetics, the single 49 (8.7%) had AMKL (Table 1). The complete response (CR) rate patient with the t(1;22) was a long-term survivor after chemother- after two cycles of induction therapy was 79.6%, with no apy without HSCT. As specific cytogenetic abnormalities in

Leukemia (2013) 718 – 757 & 2013 Macmillan Publishers Limited Letters to the Editor 733 childhood AML have been associated with poor prognosis, 100% patients were categorized based on the presence or absence of 90% high-risk cytogenetic features as defined by analysis of large Medical Research Council and Berlin-Frankfurt-Munster childhood 80% 11,12 AML cohorts. The 5-year OS rate was similar between patients 70% with or without high-risk cytogenetic abnormalities as defined by 60% Berlin-Frankfurt-Munster (high-risk n ¼ 11) or Medical Research Council (high-risk n ¼ 3) criteria. With regard to the prognostic 50% impact of HSCT during the first remission, statistical comparison is 40% limited by the small number of patients undergoing trans- ± 30% plantation. The 5-year OS rate was 66.7 22% for patients who t(1;22) (n=5) 20% received a protocol-specified, human leukocyte antigen-matched t(8;21)/inv16 (n=57) sibling HSCT in CR or partial response, but only 33.5±8.5% 10% Other AML (n=135) AMKL, non-t(1;22) (n=21) for those receiving chemotherapy (P ¼ 0.2). Probability of Event-free Survival (%) 0% Of the 232 patients enrolled on the AML02 protocol, 26 (11%) 012345678 had AMKL (Table 1). They lacked favorable cytogenetic features Years and had a high frequency of miscellaneous cytogenetic abnorm- alities. Five patients had the t(1;22). The FLT3 gene was wild-type 100% in the 17 cases analyzed. Twenty-five patients were randomized (12 standard-dose cytarabine, 13 high-dose cytarabine) for 90% induction 1. All patients had morphologic remission after two 80% cycles of induction chemotherapy. 70% MRD was measured in 24 of the 26 AMKL patients after induction 1 and 2: 10 (42%) patients had positive MRD (X0.1%) 60% after induction 1 and 6 (25%) after induction 2. There was no 50% significant difference in the MRD-positive rates between patients 40% with AMKL and those without AMKL (Table 1). Remission induction rates and MRD-negative rates for the AMKL cohort did not differ 30% between the high- and standard-dose cytarabine arms. Of the six 20% t(1;22) (n=5) t(8;21)/inv16 (n=57) patients with positive MRD (0.12–3.92%) after induction 2, Other AML (n=135)

Probability of Overall Survival (%) 10% five underwent HSCT, and two are alive in first remission at AMKL, non-t(1;22) (n=21) last follow-up. Of the 18 patients without MRD after the 0% 012345678 second induction, 10 are alive in first remission, including 4 of Years the 9 patients who underwent HSCT and 6 of the 9 patients who received chemotherapy only. Notably, of the 12 patients with Figure 1. (a) Event-free survival according to leukemia subtypes in MRDo0.1% at both measurements (that is, post induction 1 patients treated on AML02. The 3-year rates were 100% for the five and 2), eight are alive in first remission, including five who patients with the t(1;22) AMKL, 85.8±6.1% for the 57 patients with ± received only chemotherapy. favorable cytogenetics (t(8;21) or inv(16)), 56.1 5.3% for the 135 patients with other AML subtypes, and 36.3±10.9% for the 21 AMKL The five AMKL patients with the t(1;22) had excellent outcomes: patients without the t(1;22) (P ¼ 0.023) (b) Overall survival according all experienced complete remission, the four with evaluable MRD to leukemia subtypes in patients treated on AML02. The 3-year rates samples were negative. All were treated with consolidation were 100% for the five patients with t(1;22) AMKL, 90.6±5.1% for chemotherapy without HSCT; two participated in the St Jude the 57 patients with favorable cytogenetics (t(8;21), inv(16)), Pilot Study of Haploidentical Natural Killer Cell Transplantation 66.1±5% for the 135 patients with other AML subtypes, and for Acute Myeloid Leukemia (NKAML) trial of low-dose immuno- 42.4±11.4% for the 21 AMKL patients without t(1;22) (Po0.001). suppression followed by donor-recipient inhibitory, killer immunoglobulin-like receptor (KIR) HLA mismatched, natural kill cell infusion.13 All are alive in first remission with a median follow- up of 3.5 years (range, 1.4–6.1 years). Other than the t(1;22), there were no recurring cytogenetic (69.9±6.3%, P ¼ 0.01), but not significantly different from abnormalities, although complex karyotypes (X3 independent that of high-risk patients (60.4±8.5%, P ¼ 0.11). Of the 21 abnormalities) were common. According to the Medical Research AMKL patients without the t(1;22), 14 were treated with Council cytogenetic criteria, no AMKL patient on the AML02 HSCT in first remission, with 3-year EFS 41.7±13% and 3-year protocol would have been classified as having high-risk disease; OS 49±13.2%; these outcomes did not differ significantly however, based on karyotypes with three3 or more independent from the seven patients treated with consolidation chemotherapy abnormalities, 10 patients would have been classified as having only (3-year EFS, 28.6±17.1%, P ¼ 0.78; 3-year OS, 25±15.3%, high-risk cytogenetics by Berlin-Frankfurt-Munster criteria, includ- P ¼ 0.43). ing two of the cases with the t(1;22).11,12 Outcomes for patients CD36 expression was documented by flow cytometric immuno- with high-risk Berlin-Frankfurt-Munster cytogenetics were similar phenotyping of diagnostic bone marrow samples in 16 of 26 to those of patients without such characteristics. patients. Of the six patients with unequivocal positive The 3-year EFS probability for patients with non-t(1;22) AMKL CD36 expression on 490% of blasts all experienced treated on AML02 (36.3±10.9%) did not significantly differ from MRD-negative remission after induction 1, and five remain that of non-AMKL patients without favorable cytogenetics alive in first remission, four after HSCT and one after chemother- (56.1±5.3%, P ¼ 0.19, Figure 1a). However, OS was significantly apy only. Nine patients had leukemic blasts that did not express inferior for patients with non-t(1;22) AMKL compared with those CD36; two of these patients had the t(1;22) and had good with AML without favorable cytogenetics (3-year rates, 42.4±11.4 outcomes as noted previously. In contrast, for the seven patients vs 66.1±5%, P ¼ 0.02, Figure 1b). Furthermore, the OS rate for without the t(1;22) and without CD36 expression, five had patients with non-t(1;22) AMKL (42.4±11.4%) was significantly detectable MRD after induction 1, and only two are alive in first worse than that for patients considered to be standard risk remission.

& 2013 Macmillan Publishers Limited Leukemia (2013) 718 – 757 Letters to the Editor 734 The results of AML02 suggest that the t(1;22) may confer 2Department of Biostatistics, St Jude Children’s Research Hospital a favorable prognosis compared with other subtypes of AMKL and the University of Tennessee Health Science Center, in the context of intensive chemotherapy and adequate Memphis, TN, USA; supportive care, as the five infants with this karyotype had 3Department of Pathology, St Jude Children’s Research Hospital and excellent outcomes. These results support the findings of a the University of Tennessee Health Science Center, Memphis, TN, USA; retrospective series of 30 pediatric AMKL patients in which 6 of the 4Division of Pediatric Hematology/Oncology, Children’s Hospital of 11 patients with the t(1;22) were long-term survivors while none Michigan, Detroit, MI, USA; of the AMKL patients without the t(1;22) survived.9 Based on the 5Department of Statistics, University of Florida, Gainesville, FL, USA; AML02 results, the t(1;22) is considered a standard-risk feature in 6Department of Pediatrics, Massachusetts General Hospital for the successor AML08 trial (NCT00703820). On the AML08 trial, Children, Boston, MA, USA and patients with non-t(1;22) AMKL continue to be regarded as high 7Department of Oncology, St Jude Children’s Research Hospital and risk and are recommended to undergo HSCT in first remission. the University of Tennessee Health Science Center, Memphis, TN, USA Given the report of detection of the RBM15(OTT)-MKL1(MAL) fusion E-mail: [email protected] or transcript in a patient with normal metaphase cytogenetics,9 we [email protected] suggest that infants presenting with AMKL but without the t(1;22) should be evaluated for the fusion transcript by reverse transcription-PCR. REFERENCES Descriptive analyses suggest that MRD of at least 0.1% 1 Athale UH, Razzouk BI, Raimondi SC, Tong X, Behm FG, Head DR et al. Biology and after induction 2 and lack of CD36 expression on leukemic outcome of childhood acute megakaryoblastic leukemia: a single institution’s blasts may be associated with inferior outcome. Although experience. 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Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421. Blood 2006; 107: CONFLICT OF INTEREST 1315–1324. The authors declare no conflict of interest. 11 Harrison CJ, Hills RK, Moorman AV, Grimwade DJ, Hann I, Webb DK et al. Cyto- genetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment trials AML 10 and 12. J Clin Oncol 2010; 28: 2674–2681. ACKNOWLEDGEMENTS 12 von Neuhoff C, Reinhardt D, Sander A, Zimmermann M, Bradtke J, Betts DR et al. Prognostic impact of specific chromosomal aberrations in a large group of We thank Cherise Guess for expert editorial review. This work is supported in part by pediatric patients with acute myeloid leukemia treated uniformly according to grant CA21765 from the National Institutes of Health and by the American Lebanese trial AML-BFM 98. J Clin Oncol 2010; 28: 2682–2689. Syrian Associated Charities. 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Leukemia (2013) 718 – 757 & 2013 Macmillan Publishers Limited