IDH1 and IDH2 Mutations in Myelodysplastic Syndromes and Role in Disease Progression

Home , IDH2

Letters to the Editor 980 3 Lohr JG, Stojanov P, Carter SL, Cruz-Gordillo P, Lawrence MS, Auclair D et al. 11 Durie BGM, Harousseau J-L, Miguel JS, Bladé J, Barlogie B, Anderson K et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted International uniform response criteria for multiple myeloma. Leukemia 2006; 20: therapy. Cancer Cell 2014; 25:91–101. 1467–1473. 4 Bolli N, Avet-Loiseau H, Wedge DC, Van Loo P, Alexandrov LB, Martincorena I et al. 12 Annunziata CM, Hernandez L, Davis RE, Zingone A, Lamy L, Lam LT et al. Heterogeneity of genomic evolution and mutational proﬁles in multiple myeloma. A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade Nat Commun 2014; 5: 2997. of MAF oncogene expression. Blood 2011; 117: 2396–2404. 5 Walker BA, Wardell CP, Melchor L, Brioli A, Johnson DC, Kaiser MF et al. Intraclonal 13 Barlogie B, Shaughnessy JD. Early results of total therapy II in multiple heterogeneity is a critical early event in the development of myeloma and myeloma: implications of cytogenetics and FISH. Int J Hematol 2002; 76 (Suppl 1): precedes the development of clinical symptoms. Leukemia 2014; 28: 384–390. 337–339. 6 Andrulis M, Lehners N, Capper D, Penzel R, Heining C, Huellein J et al. Targeting 14 Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M et al. the BRAF V600E mutation in multiple myeloma. Cancer Discov 2013; 3:862–869. Incorporating bortezomib into upfront treatment for multiple myeloma: early 7 Garnett MJ, Rana S, Paterson H, Barford D, Marais R. Wild-type and mutant B-RAF results of total therapy 3. Br J Haematol 2007; 138:176–185. activate C-RAF through distinct mechanisms involving heterodimerization. Mol 15 Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D et al. Total Cell 2005; 20:963–969. therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 8 Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R et al. RAF 1999; 93:55–65. inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010; 464: 431–435. 9 Gilmartin AG, Bleam MR, Groy A, Moss KG, Minthorn EA, Kulkarni SG et al. This work is licensed under a Creative Commons Attribution- GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with NonCommercial-NoDerivs 4.0 International License. The images or favorable pharmacokinetic properties for sustained in vivo pathway inhibition. other third party material in this article are included in the article’s Creative Commons Clin Cancer Res 2011; 17: 989–1000. license, unless indicated otherwise in the credit line; if the material is not included under 10 Shaughnessy JD, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I et al. Avalidated the Creative Commons license, users will need to obtain permission from the license gene expression model of high-risk multiple myeloma is deﬁned by deregulated holder to reproduce the material. To view a copy of this license, visit http:// expression of genes mapping to chromosome 1. Blood 2007; 109:2276–2284. creativecommons.org/licenses/by-nc-nd/4.0/

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IDH1 and IDH2 mutations in myelodysplastic syndromes and role in disease progression

Leukemia (2016) 30, 980–984; doi:10.1038/leu.2015.211 sequencing confirmation (analytical sensitivity: 10–20%) as has been previously described.11 Beginning in September 2012, IDH1/2 testing was performed within a Clinical Laboratory Recurrent pathogenic mutations in IDH1 and IDH2 at the Improvements Ammendments-certified next-generation sequen- conserved amino acid sites IDH1-R132, IDH2-R140 and IDH2-R172 cing platform (analytical sensitivity: 2.5–5%). Statistical analyses 1 occur in ~ 20% of patients with acute myeloid leukemia (AML). were conducted in Statistica v12.0 (StatSoft Inc, Tulsa, OK, USA) A recent analysis of AML patients at our institution identified and significance defined as Po0.05. Overall survival (OS) was IDH1/2 mutations in 20% (n = 167) of 826 AML patients, with measured as the time from presentation to date of death or last IDH1/2 mutations occurring most frequently in the setting of follow-up, and progression-free survival from presentation to date diploid karyotype or other intermediate-risk cytogenetics, parti- of death, last follow-up, or date of progression to AML. Informed cularly trisomy 8 (77 vs 53%, Po0.0005). AML patients with IDH1/2 consent was obtained following institutional guidelines and in mutations were overall less likely to have a diagnosis of therapy- accordance with the Declaration of Helsinki. related AML (8 vs 17%, P = 0.003).2 Of the 1042 MDS patients, 60 patients (5.7%) had IDH1/2 Compared with their frequency in AML, IDH1/2 mutations are mutations identified. Specifically, 17 patients (1.6%) were IDH1- less common in myelodysplastic syndromes (MDS), occurring in R132 mutated and 43 patients (4.1%) had IDH2-R140 (n = 42) or ~ 5% of MDS patients, although an incidence as high as 12% has IDH2-R172 (n = 1) mutations, respectively. The clinicopathological – been reported.3 8 Although IDH1/2 mutations are thought to characteristics of patients with and without IDH1/2 mutations are represent early ‘driver’ events in leukemogenesis with mutational shown in Table 1. Within this cohort, 701 patients (67%) were stability over time, reports of IDH1/2 acquisition at the time of untreated and 341 (33%) had received systemic MDS therapy leukemic transformation in patients with myeloproliferative before presentation. MDS patients with IDH1/2 mutations had a neoplasms and MDS have been described.3,9,10 lower absolute neutrophil count (1.15 × 109/l vs 1.71 × 109/l, The purpose of this analysis is to evaluate the overall prevalence P = 0.02), higher bone marrow blast percentage (6 vs 4%, of IDH1/2 mutations in MDS patients treated at our institution, as P = 0.001), and a trend for higher platelet counts (99 × 109/l vs well as determine the incidence and frequency of IDH1/2 75 × 109/l, P = 0.07). mutations identified at the time of leukemic transformation in Of the 60 IDH1/2 mutations, 17 (28%) were present in the very MDS patients. low or low-risk IPSS-R groups, 15 (25%) intermediate, and 27 (45%) Eligible patients comprised all adults with histologically in the high or very-high IPSS-R prognostic score categories confirmed MDS treated at MD Anderson Cancer Center from (Table 1). While the distribution of IPSS-R categories among January 2010 to January 2015. A total of 1042 MDS patients with IDH1/2-mutants versus wild-type patients was similar, we identi- known IDH1 and IDH2 status were included. From January 2010 to fied a conspicuously different underlying pattern of cytogenetics September 2012, IDH1/2 molecular analysis was performed by and bone marrow blasts. Consistent with karyotypic patterns in high-resolution melting curve analysis followed by Sanger IDH1/2-mutant AML,2 the majority of IDH1/2-mutant MDS patients

Accepted article preview online 31 July 2015; advance online publication, 21 August 2015

Table 1. Clinicopathological characteristics of MDS study cohort (n = 1042)

Characteristic IDH wild-type (n = 982) IDH-mutated (n = 60) P-valuea IDH1-mutated (n = 17) IDH2-mutated (n = 43) P-valuea

Median age (range) 70 (17–90) 68 (32–85) 0.36 68 (57–78) 68 (32–85) 0.84 Male sex (%) 642 (65) 44 (73) 0.21 14 (82) 30 (70) 0.32 WBC count (×109/l) 3.6 (0.4–223.1) 2.5 (0.7–67.5) 0.12 2.1 (1.2–67.5) 3.2 (0.7–58.6) 0.08 ANC (×109/l) 1.71 (0.008–118.3) 1.15 (0.064–60.07) 0.02 0.97 (0.098–60.075) 1.23 (0.064–33.9) 0.31 PLT count (×109/l) 76 (3–1552) 99 (11–441) 0.07 99 (30–194) 101 (11–441) 0.98 BM blasts (%) 4 (0–38) 6 (1–18) 0.001 5(1–18) 7 (1–18) 0.41 PB blasts (%) 0 (0–29) 0 (0–14) 0.12 0 (0–3) 1 (0–14) 0.006 LDHb 536 (24–9329) 550 (278–2321) 0.37 534 (322–963) 580 (278–2321) 0.37 Cytogenetics; n (%) 0.023 0.97 Diploid or –Y 420 (43) 36 (60) 10 (59) 26 (60) Isolated del(5q) 23 (2) 0 (0) 0 (0) 0 (0) Double del(5q) 14 (1) 0 (0) 0 (0) 0 (0) Complex del(5q) 56 (6) 0 (0) 0 (0) 0 (0) Trisomy 8 73 (7) 6 (10) 2 (12) 4 (9) -7/7q or complex 135 (14) 3 (5) 1 (6) 2 (5) Isolated del(20q) 29 (3) 0 (0) 0 (0) 0 (0) Other intermediate 174 (18) 14 (23) 4 (24) 10 (23) -Not done,Inad. 58 (6) 1 (2) 0 (0) 1 (2) WHO category; n (%) 0.330 0.073 5q- 19 (2) 0 (0) 0 (0) 0 (0) CML Ph- 8 (1) 0 (0) 0 (0) 0 (0) CMML-1 100 (10) 6 (10) 0 (0) 6 (14) CMML-2 36 (4) 4 (7) 0 (0) 4 (9) MDS/MPD 23 (2) 1 (2) 1 (6) 0 (0) MDS-U 39 (4) 1 (2) 1 (6) 0 (0) RA 88 (9) 0 (0) 0 (0) 0 (0) RAEB-1 215 (22) 19 (32) 5 (29) 14 (33) RAEB-2 199 (20) 14 (23) 4 (24) 10 (23) RARS 35 (4) 3 (5) 0 (0) 3 (7) RCMD 196 (20) 11 (18) 5 (29) 6 (14) RCMD-RS 24 (2) 1 (2) 1 (6) 0 (0) IPSS-R 0.792 0.334 Very high 188 (19) 13 (22) 4 (24) 9 (21) High 195 (20) 14 (23) 1 (6) 13 (30) Intermediate 195 (20) 15 (25) 6 (35) 9 (21) Low 247 (25) 12 (20) 4 (24) 8 (19) Very low 91 (9) 5 (8) 2 (12) 3 (7) N/A 66 (7) 1 (2) 0 (0) 1 (2) Molecular KRAS/NRAS 73 (8) 7 (12) 0.25 1 (6) 6 (14) 0.37 JAK2 25 (3) 2 (3) 0.76 1 (6) 1 (2) 0.50 FLT3-ITD or D835 21 (2) 0 (0) 0.006 0 (0) 0 (0) n/a NPM1 9 (1) 1 (2) 0.54 0 (0) 1 (3) 0.54 TP53 73 (17) 0 (0) 0.006 0 (0) 0 (0) n/a RUNX1 24 (40) 3 (13) 0.015 1 (25) 2 (10) 0.41 ASXL1 37 (44) 5 (21) 0.039 2 (50) 3 (15) 0.12 TET2 53 (35) 2 (8) 0.008 0 (0) 2 (10) 0.51 DNMT3a 26 (6) 3 (7) 0.89 1 (7) 2 (6) 0.93 CEBPA 52 (6) 4 (8) 0.64 1 (7) 3 (8) 0.93 EZH2 13 (1) 0 (0) 0.36 0 (0) 0 (0) n/a Abbreviations: ANC, absolute neutrophil count; BM, bone marrow; LDH, lactate dehydrogenase; MDS, myelodysplastic syndromes; MPD, myeloproliferative disease; PB, peripheral blood; PLT, platelet; RA, refractory anemia; RARS, refractory anemia with ringed sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia; RCMD-RS, refractory cytopenia with multilineage dysplasia ring sideroblasts; WBC, white blood cell; WHO, World Health Organization. aP-valueso0.1 are depicted in bold font. bInstitutional normal reference range for LDH is 313 to 618 IU/l.

demonstrated favorable or intermediate-risk cytogenetics (93%, At presentation, IDH1/2-mutated patients had higher bone n = 56), with diploid karyotype in 60%, isolated trisomy 8 in 10%, marrow blast percentage than IDH wild-type patients (6 vs 4%, and other intermediate cytogenetics in 23%; significantly different P = 0.001) and were more frequently classified as RAEB-1 or RAEB2 than the cytogenetic distribution in the IDH1/2 wild-type MDS morphology. By WHO classification, 55% of IDH1/2 mutants were patients (P = 0.023) as per Table 1. Of interest, there were no MDS classified as RAEB-1 (32%) or RAEB-2 (23%), compared to 42% IDH patients with an IDH1/2-mutation and isolated del(20q), and no wild-type (P = 0.051). Additionally, 17% of IDH-mutants were IDH1/2-mutated patients with the presence of a del(5q) chromo- classified as CMML-1 or CMML-2. Interestingly while 10 of the 43 somal abnormality were identified, as also demonstrated by (23%) IDH2 mutations occurred in CMML patients, no IDH1 Papaemmanuil et al.12 Only 5% of IDH1/2-mutated patients had mutations were detected in CMML patients, suggesting a chromosome 7 abnormalities or complex cytogenetics, compared particular genotype-phenotype correlation with IDH2 mutations to 14% of IDH wild-type patients (Table 1). and CMML. As SRSF2 mutations, which are not analyzed within our

© 2016 Macmillan Publishers Limited Leukemia (2016) 947 – 1002 Letters to the Editor 982 different based on IDH1 vs IDH2 mutation status; 22.2 months for IDH1 and 21.0 months for IDH2 mutants (P = 0.44). Progression- free survival for treatment-naive MDS patients was 19.9 months (range 0–47.4 months); 22.2 months for IDH1/2-mutated and 19.7 months for IDH1/2 wild-type (P = 0.77). Progression-free survival among patients with IDH mutations was similar, 16.9 months in IDH1-mutated patients and 17.4 months IDH2- mutated patients (P = 0.18). Of the 214 treatment-naive patients receiving HMA therapy for which response assessments are available, 18 (8.4%) had IDH1/2 mutations (Supplementary Table 1). No significant difference in the rate of responses was seen based on the presence of IDH1/2 mutations, with complete remission (CR) in 7 out of 18 IDH1/2- mutant (39%) versus 63 out of 196 (32%) IDH wild-type patients (P = 0.56). OS was similarly not dependent on IDH1/2-mutation status in this HMA-treated group, with a median OS of 20.0 months in IDH1/2-mutant patients and 15.0 months in IDH wild-type patients, P = 0.64 (Supplementary Figure 1). During the treatment course of the complete n = 1042 cohort, 150 MDS patients transformed to AML. This includes 11 out of the 60 patients with IDH1/2-mutation identified at MDS diagnosis (1 IDH1 and 10 IDH2; 18% of IDH1/2-mutated patients), and 138 (14%) IDH1/2 wild-type MDS patients. In addition, seven confirmed IDH1/2 wild-type patients at MDS diagnosis had an identified IDH1 or IDH2 mutation at the time of AML transformation (n =5) or progression to RAEB-2 MDS (n = 2; one subsequently progressed to AML within another 6 weeks), with an allelic frequency ranging from 10–37%. Specific details of these seven patients are provided in Table 2. Of interest, patient #5 had both an IDH1-R132H and IDH2-R140Q mutation at the time of AML transformation. In the patients with apparent IDH1/2 acquisition, IDH1/2 mutations were detected a median of 1.3 years from original presentation, at the time of disease progression. In these seven patients, OS was universally poor, with 3 month median OS from time of IDH1/2 detection. Thus of the 150 MDS patients transforming to AML, 17 (11.3%) were identified to have an IDH1/2-mutation at the time of AML progression. We acknowledge several study limitations. Given the limits of Figure 1. (a) Overall Survival and (b) Progression-Free Survival of treatment-naive patients with MDS by IDH1/2-mutant versus wild- sequencing technology, we cannot fully rule out the presence of a type status. small IDH1/2 clone in some MDS patients at presentation, undetected at diagnosis which increased in size at the time of progression, thus more accurately representing clonal expansion rather than molecular acquisition. Additionally, selection bias, molecular panel, are enriched within CMML patients and also including more frequent molecular testing among MDS patients frequently co-occur with IDH2 mutations, the IDH2/CMML asso- with transformation and proliferative disease in this retrospective ciation may be related to underlying SRSF2 co-mutations.13,14 fi study may have exaggerated the overall frequency of IDH1/2 Notably also, no patients with the WHO classi cation of MDS with acquisition. However this is unlikely the case, as only 42 out of 150 refractory anemia (RA) were IDH1/2-mutated, although RA patients (28%) MDS patients transforming to AML had repeated compre- comprised 9% of the total MDS cohort. hensive molecular sequencing performed within 8 weeks The frequency of other somatic mutations among IDH1/2- of transformation, and thus the frequency of IDH1/2 acquisition mutated versus wild-type patients is displayed in Table 1. No or expansion, particularly in MDS patients with diploid or IDH1/2-mutated MDS patient also had a TP53 mutation at intermediate cytogenetics, may be even higher than reported. presentation, compared to 17% of the IDH1/2 wild-type MDS We have previously reported on the dynamic acquisition of FLT3 cohort (P = 0.006). While rare overall, no IDH1/2-mutated patients and RAS mutations in lower-risk patients at the time of MDS had concomitant FLT3-ITD or FLT3-D835 mutation (0 vs 2%, disease progression,15 specifically in 20 out of 278 IPSS low or P = 0.006). Patients with IDH1/2 mutations were also significantly intermediate-1 risk MDS patients, of whom 18 (90%) then less likely to have a RUNX1 (13 vs 40%, P = 0.015), ASXL1 (21 vs transformed to AML. Our findings suggest we can also consider 44%, P = 0.039), or TET2 mutation (8 vs 35%, P = 0.008). While TET2 IDH1/2 mutations as molecular ‘drivers’ of leukemic transformation mutations are frequently thought to be mutually exclusive with in some MDS patients. It will be most interesting to evaluate the IDH1/2 mutations, 2 patients with IDH2-R140 mutations did have efficacy of targeted IDH-inhibitors in the secondary/transformed concurrent TET2 mutations identified. While the subsets are small, AML setting, specifically whether responding patients revert back the distribution of KRAS, NRAS, JAK2, NPM1, DNMT3A, EZH2 and to a prior MDS state, or whether complete remissions CEBPA mutations were similar between IDH1/2-mutated and wild- with full count recovery are attainable. This further advocates a type patients. role for rational combination studies of IDH-inhibitors with other OS among the 701 treatment-naïve MDS patients (including 45 effective MDS strategies such as hypomethylating agents for these IDH1/2-mutants) was 21.2 months; 22.2 months for IDH1/2- patients. mutated patients and 21.1 months for IDH1/2 wild-type patients To conclude, IDH1/2 mutations were found in 5.7% of MDS (P = 0.67). [Figure 1] Within IDH1/2 mutants, survival was not patients at presentation; 1.6% IDH1-R132 and 4.1% IDH2-mutated.

Leukemia (2016) 947 – 1002 © 2016 Macmillan Publishers Limited Letters to the Editor 983 Only one MDS patient with an IDH2-R172 mutation was identified, the IDH2-R140 mutation comprised all other IDH2 mutants. The notable low frequency of IDH1-R132 and IDH2-R172 mutations is consistent with recent data by Molenaar et al.,10 suggesting IDH1-R132 and IDH2-R172 mutations are less frequently involved in the ancestral neoplastic clone. IDH1/2 mutations occurred more frequently in patients with diploid or other intermediate-risk Died 3.6 months from AML dx RAEB-2 dx Died 3.0 months from AML dx Died 3.3 months from RAEB-2 dx Died 12 months from AML dx Died 1.1 months from AML dx Died 2.0 months from AML dx cytogenetics and RAEB classification by WHO, and were less frequent in patients with TP53, RUNX1, ASXL1 or TET2 mutations. At the time of leukemic transformation/secondary AML, 11.3% of MDS patients had an IDH1/2-mutation identified, suggesting the importance of molecular profiling at the time of progression for optimal characterization and treatment decisions for our

10% AF) IDH2- patients. o

CONFLICT OF INTEREST The authors declare no conﬂict of interest. DNMT3A R882H; same cyto Genetics at progression Status same cyto also acquired Del(20)(q11.2q13.3) R140Q (12% AF) NPM1still and present; NRAS same cyto same cyto still present; same cyto

ACKNOWLEDGEMENTS This work was supported in part by the MD Anderson Cancer Center Support Grant (CCSG) CA016672 and by the generous philanthropic contributions to MD Anderson’s MDS/AML Moon Shot Program. CDD is also supported by the Jeanne F. Shelby Time from Dx to progression 1 Year IDH2-R140Q (10% AF) TP53-E339K Scholarship Fund which has supported her R. Lee Clark Fellow award. This manuscript represents original research which has not been previously published and has not been submitted for publication elsewhere.

CD DiNardo1, E Jabbour1, F Ravandi1, K Takahashi1, N Daver1, M Routbort2, KP Patel2, M Brandt1, S Pierce1, H Kantarjian1 and G Garcia-Manero1 1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA and 7) AML (67% blasts) 2.5 Years IDH2-R1420Q (37% AF) FLT3-ITD progression RAEB-2 (15% blasts) 2.1 Years IDH2-R140Q (30% AF); same cyto Died 2.7 months from AML (28% blasts) 2.3 Years IDH1-R132G (17% AF) TP53-S240R; RAEB-2 (10% blasts) (further progressed to AML within 6 weeks) AML (60% blasts) 1.3 Years IDH1-R132H ( AML (24% blasts) 6 Months IDH1-R132C (11% AF) JAK2 V617F; AML (60% blasts) 6 Months IDH2-R140Q (18%2 AF) TP53 Y234C = Department of Hematopathology, The University of Texas MD n Anderson Cancer Center, Houston, TX, USA E-mail: [email protected]

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15,+22 5 Thol F, Weissinger EM, Krauter J, Wagner K, Damm F, Wichmann M et al. IDH1 − mutations in patients with myelodysplastic syndromes are associated with an 95 – r(7)(p12q11.2) +13, (5)(q22), unfavorable prognosis. Haematologica 2010; : 1668 1674. 6 Rocquain J, Carbuccia N, Trouplin V, Raynaud S, Murati A, Nezri M et al. Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC Cancer 2010; 10:401. 7 Lin CC, Hou HA, Chou WC, Kuo YY, Liu CY, Chen CY et al. IDH mutations are closely associated with mutations of DNMT3A, ASXL1 and SRSF2 in patients with myelodysplastic syndromes and are stable during disease evolution. Am J Hematol 2014; 89:137–144. Initial WHO Dx Cyto Molecular testing at Dx WHO Dx at 8 Patnaik MM, Hanson CA, Hodneﬁeld JM, Lasho TL, Finke CM, Knudson RA et al.

Clinicopathological details of patients with Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic study of 277 patients. Leukemia 2012; 26:101–105. Age/ sex 9 Green A, Beer P. Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med 2010; 362: 1 65/M RAEB-2 (15% blasts) Diploid Wild-type: FLT3, NPM1, RAS, CEBPA, 2 70/M RCMD (6% blasts) +8 Wild-type: FLT3, NPM1, RAS, CEBPA, 3 77/F RAEB-1 (7% blasts) Del(5)(q13q33), +6 Wild-type: FLT3, NPM1, RAS, CEBPA, 4 81/M RAEB-1 (7% blasts) Del(12)(p11.2p13), 5 65/F CMML-2 (15% blasts) +21 Mutant: NPM1 W288fs NRAS G12D; 6 60/M CMML-1 (6% blasts) Diploid Wild-type: FLT3, NPM1, RAS, CEBPA, 7 63/F RAEB-1 (7% blasts) Complex 50,XX,+2, add Table 2. Abbreviations: AF, allelic frequency; AML, acute myeloid leukemia; cyto, cytogenetics; Dx, diagnosis; WHO, World Health Organization. 369–370.

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Radioimmunotherapy in relapsed/refractory mantle cell lymphoma patients: ﬁnal results of a European MCL Network Phase II Trial

Leukemia (2016) 30, 984–987; doi:10.1038/leu.2015.215 following common laboratory parameters. Statistical methods can be found in Supplementary Materials. fi Between June 2004 and September 2008, 48 patients were Although rst-line treatment for mantle cell lymphoma (MCL) is enrolled (16 in group A, 32 in group B). Patient characteristics at nowadays effective in most of the cases, patients eventually enrollment are detailed in Table 1. In group B, reinduction therapy relapse. Of note, patients with relapsed lymphoma are often 1,2 consisted in three cycles of rituximab-bendamustin in 16 patients chemorefractory and die because of disease progression. (50%), fludarabine-cyclophosphamide-rituximab in 9 patients However, new molecules targeting crucial molecular pathways (28%) and other regimens in 7 patients (22%, including: of survival have improved the therapeutic perspectives of these – R-GEMOX=1, R-DHAP=2, R-ICE=1, rituximab=1, radiotherapy=1, patients.3 8 In the past, CD20-targeted radioimmunotherapy (RIT) rituximab+radiotherapy = 1). Overall, 46/48 patients completed demonstrated durable remissions in chemorefractory follicular the treatment and 44 (92%) could be evaluated for response: 2 did lymphoma, without significant toxicity.9 Owing to its simple not complete RIT because of patient refusal, 1 died because of ('one-day') administration schedule, RIT might represent an ideal toxicity before restaging and 1 was lost to follow-up. Main approach for elderly patients. Nevertheless, the application of registered toxicities were hematological, and they were managed CD20-targeted RIT in relapsed MCL is still limited: only one pilot, – single-center trial with yttrium-90 ibritumomab tiuxetan (90Y-IT) through blood and thrombocyte transfusions: grade (G) 3 4 10 thrombocytopenia occurred in 11/40 patients (28%), G3–4 has been published so far. – Therefore, the European MCL Network conducted a prospective, neutropenia in 13/40 (33%) and G3 4 anemia in 9/40 (23%). multicenter, phase II trial evaluating a single dose of 90Y-IT as One patient died in arm B because of severe thrombocytopenia salvage induction or consolidation therapy in patients with leading to a lethal central nervous system hemorrhage (this relapsed/refractory MCL after autologous stem-cell transplantation patient refused regular cell blood count examinations and or unsuitable for high-dose therapies. The aim was to validate the experienced a traumatic event, with a thrombocyte count of μ results obtained with CD20-targeted RIT in a multicentric, less 7000/ l). Only 1/48 patients (2%) developed a secondary – selected population. myelodysplasia (group B). G3 4 non-hematologic toxicities were Inclusion criteria were o25% bone marrow and no central gastrointestinal in 3/27 patients (11%), infections in 1/28 (4%) and nervous system involvement, absence of extensive pleural neurological symptoms in 1/27 (4%). Other G1–2 non-hematologic effusion or ascites and adequate bone marrow function (granu- toxicities are detailed in Supplementary Table 1S, and they include locytes 41000/μl, thrombocytes 4100 000/μl and hemoglobin gastrointestinal in 5/27 patients (19%), infections in 5/28 (18%), 48 g/dl). Patients received rituximab 250 mg/m2 (day 1) followed pulmonary in 3/23 (13%), neurological in 2/27 (7%) and skin rash by a sequential infusion of rituximab and 90Y-IT 14.8 MBq/kg in 2/27 (7%). Thus, our series confirmed the feasibility and the (0.4 mCi/kg); patients with thrombocytes o150 000/μlorprevious manageable toxicity of RIT after chemotherapy in a heavily autologous stem-cell transplantation (day 8) received 90Y-IT at a pretreated patient population. reduced dose of 11.1 MBq/kg (0.3 mCi/kg). Initially, patients received The overall response rate (ORR) was 61%, including a CR rate of this schedule as reinduction therapy (group A). Subsequently, the 32% and a partial response (PR) rate of 29%. In group A, the ORR protocol was amended, and patients with either ‘bulky disease’ was 40%, with a CR rate of 20%, whereas in group B the ORR was (45cm) or ‘multicentric relapse’ (43 localizations, each 43cm) 72% and the CR rate 38%. In particular, 24/29 patients (83%) (group B) could receive a short, prior immunochemotherapy (e.g. 3 responded to salvage chemotherapy, with 21% achieving a CR cycles of rituximab-bendamustin). For the efficacy assessment, (of note, 5/6 received rituximab-bendamustin); in this group, 90Y-IT computed tomography scans were performed 6 weeks after RIT, improved the quality of response: the CR rate increased from 21% then every 3 months for up to 1 year and later at least every (6/29) after salvage chemotherapy to 38% (11/29) after RIT 6 months. In our study, no positron emission tomography was (Figure 1a). Moreover, two patients with stable disease achieved a available, and both confirmed and unconfirmed complete responses PR and a CR, respectively. The need for RIT dose reduction was (CRs) were categorized as CRs.11 Safety was evaluated weekly during higher in group B (53% vs 25%), as expected. However, in this group the first 3 months and subsequently at the regular restaging visits no difference was recorded in terms of hematological recovery

Accepted article preview online 5 August 2015; advance online publication, 21 August 2015