REGULAR ARTICLE Treatment patterns and outcomes of 2310 patients with secondary acute myeloid leukemia: a PETHEMA registry study David Martınez-Cuadr anchez,5 Eduardo Rodrıguez-Arbolı,6 on,1,2 Juan E. Megıas-Vericat,3 Josefina Serrano,4 Pilar Martınez-S 7 8 9 Cristina Gil, Eliana Aguiar, Juan Bergua, Jose  L. Lo pez-Lorenzo, Teresa Bernal, Ana Espadana,12 Mercedes Colorado,13 10 11 Carlos Rodrıguez-Medina, Marıa Lo 14 pez-Pavıa, Mar Tormo,16 Lorenzo Algarra,17 Marıa-Luz Amigo,18 Marıa J. Sayas,19 15 Jorge Labrador, Juan I. Rodrıguez-Gutie 20 rrez,21 Celina Benavente,22 Lissette Costilla-Barriga,23 Raimundo Garcıa-Boyero,24 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 Esperanza Lavilla-Rubira, Susana Vives,26 Pilar Herrera,27 Daniel Garcıa-Belmonte,28 Marıa Mar Herr 25 aez,29 30 Graça Vasconcelos Esteves, Maria I. Go mez-Roncero, Ana Cabello, Guiomar Bautista, Amaia Balerdi,34 Jose 31 32 33  Mariz,35 1,2  2 Blanca Boluda, Miguel A. Sanz, and Pau Montesinos 1,2 1 ecnic La Fe, Valencia, Spain; 2Instituto de Investigaci Hospital Universitari i Polit  on Sanitaria La Fe (IISLAFE), Valencia, Spain; 3Servicio de Farmacia, Area del Medicamento. ecnic La Fe, Valencia, Spain; 4Hospital Universitario Reina Sofıa-IMIBIC, C Hospital Universitari i Polit ordoba, Spain; 5Hospital Universitario 12 de Octubre, Madrid, Spain; 6 Hospital Universitario Virgen del Rocıo, Sevilla, Spain; 7Hospital General Universitario de Alicante, Alicante, Spain; 8Centro Hospitalar S~ao Jo~ao, Porto, Portugal; 9Hospital San Pedro Alc aceres, Spain; 10Hospital Universitario Fundaci antara, C enez Dıaz, Madrid, Spain; 11Hospital Universitario Central de Asturias, Asturias, Spain; 12Centro on Jim 13 Hospitalar e Universitario de Coimbra, EPE, Coimbra, Portugal; Hospital Universitario Marqu es de Valdecilla, Santander, Spain; 14Hospital Universitario de Gran Canaria Doctor Negrın, Las Palmas, Spain; 15Hospital General Universitario de Valencia, Valencia, Spain; 16Hospital Clınico Universitario, INCLIVA Biomedical Research Institute, Valencia, Spain; 17Hospital General Universitario de Albacete, Albacete, Spain; 18Hospital General Universitario Morales Meseguer, Murcia, Spain; 19Hospital Universitario Doctor Peset, Valencia, Spain; 20Hospital Universitario de Burgos, Burgos, Spain; 21Basurtuko Unibertsitate Ospitalea, Bizkaia, Spain; 22Hospital Clınico San Carlos, Madrid, Spain; 23Hospital Universitario Miguel Servet, Zaragoza, Spain; 24Hospital General Universitario de Castell on, Spain; 25Hospital Lucus Augusti, Lugo, Spain; o, Castell 26 ICO-Hospital Germans Trias i Pujol, Badalona, Jos e Carreras Leukemia Research Institute, Universitat Aut onoma de Barcelona, Barcelona, Spain; 27Hospital Univeristario Ram on y Cajal, Madrid, Spain; 28Hospital Sanitas La Zarzuela, Madrid, Spain; 29Hospital Santa Barbara de Puertollano, Ciudad Real, Spain; 30Hospital de Santa Maria, Lisboa, Portugal; 31Hospital Virgen de la Salud, Toledo, Spain; 32Hospital Universitario Nuestra Se~ nora de Candelaria, Tenerife, Spain; 33Hospital Universitario Puerta De Hierro, Madrid, 34 35 Spain; Hospital Universitario Cruces, Bizkaia, Spain; and Instituto Portugu^ es de Oncologıa do Porto, Porto, Portugal Key Points Secondary acute myeloid leukemia (sAML) comprises a heterogeneous group of patients and is associated with poor overall survival (OS). We analyze the characteristics,  The large PETHEMA treatment patterns, and outcomes of adult patients with sAML in the Programa Espan ~ ol registry shows that de Tratamientos en Hematologıa (PETHEMA) registry. Overall, 6211 (72.9%) were de secondary AML novo and 2310 (27.1%) had sAML, divided into myelodysplastic syndrome AML (MDS- represents 27% of AML, 44%), MDS/myeloproliferative AML (MDS/MPN-AML, 10%), MPN-AML (11%), AML cases and confirms its therapy-related AML (t-AML, 25%), and antecedent neoplasia without prior chemother- independent adverse apy/radiotherapy (neo-AML, 9%). Compared with de novo, patients with sAML were older prognostic value. (median age, 69 years), had more Eastern Cooperative Oncology Group $2 (35%) or high-  risk cytogenetics (40%), less FMS-like tyrosine kinase 3 internal tandem duplication Subcategories of (11%), and nucleophosmin 1 (NPM1) mutations (21%) and received less intensive chemo- secondary AML were analyzed, including therapy regimens (38%) (all P , .001). Median OS was higher for de novo than sAML (10.9 MSD/MPN and vs 5.6 months; P , .001) and shorter in sAML after hematologic disorder (MDS, MDS/MPN, or therapy-related cases, MPN) compared with t-AML and neo-AML (5.3 vs 6.1 vs 5.7 months, respectively; P 5 .04). After with different features intensive chemotherapy, median OS was better among patients with de novo and neo-AML and outcomes. (17.2 and 14.6 months, respectively). No OS differences were observed after hypomethylating agents according to type of AML. sAML was an independent adverse prognostic factor for OS. We confirmed high prevalence and adverse features of sAML and established its independent adverse prognostic value. This trial was registered at www.clinicaltrials.gov as #NCT02607059. Submitted 21 May 2021; accepted 12 October 2021; prepublished online on Blood The full-text version of this article contains a data supplement. Advances First Edition 18 November 2021; final version published online 17 February © 2022 by The American Society of Hematology. Licensed under Creative Commons 2022. DOI 10.1182/bloodadvances.2021005335. Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permit- Requests for data sharing should be sent to Pau Montesinos (montesinos_pau@gva.es). ting only noncommercial, nonderivative use with attribution. All other rights reserved. 1278 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 Introduction Treatment schedules Patients were classified into five groups according to intensity of Secondary acute myeloid leukemia (sAML) includes therapy-related therapy: intensive chemotherapy (IC), nonintensive chemotherapy AML (t-AML) and antecedent hematologic disorders.1,2 The (non-IC), hypomethylating agents (HMA), clinical trial, and best sup- reported incidence of sAML ranges from 18% to 28% of all AML portive care (BSC). IC schedules included the following regimens: cases and is associated with poor outcomes, including lower com- 3 1 7 (idarubicin or daunorubicin and Ara-C), mitoxantrone plus Ara-C, FLAG-Ida (fludarabine, idarubicin, and Ara-C), FLAT (fludara- plete remission (CR), overall survival (OS), and relapse-free survival bine, Ara-C, and topotecan), or ICE (idarubicin, Ara-C, and etopo- rates than de novo AML.1,3-6 Consequently, the diagnosis of sAML side). HMA comprised decitabine or azacitidine at low doses. The has been considered a risk factor for early death and OS in some non-IC group included FLUGA (fludarabine and Ara-C), FLAGIDA- predictive models.7,8 Nevertheless, its independent prognostic value Lite (fludarabine, Ara-C, and idarubicin), or LDAC. Regardless of the has been questioned due to its association with older age, frequent Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 regimen intensity, all clinical trials were grouped in a separate treat- comorbidities/organ dysfunction, and unfavorable cytogenetic and ment category. BSC included patients receiving transfusions and molecular profile.9 On the other hand, whether patients with AML other supportive measures, including oral agents to control the with antecedent neoplasia who did not receive chemotherapy or white blood cell (WBC) counts (ie, hydroxyurea, melphalan, mercap- radiotherapy for the first malignancy (neo-AML) should be consid- topurine, or thioguanine). Treatment schedules are detailed in sup- ered as having sAML remains an unresolved issue. To our knowl- plemental Table 1. edge, it is unknown if these patients have differential characteristics and outcomes compared with other sAMLs. Study definitions and endpoints This study aims to analyze the incidence, clinical and biological char- sAML comprised patients derived from myelodysplastic syndrome acteristics, and outcome in a large series of patients with sAML (MDS-AML), myeloproliferative neoplasm (MPN-AML), myelodys- reported to the Programa Espan ~ol de Tratamientos en Hematologıa plastic/myeloproliferative neoplasm (MDS/MPN-AML), and t-AML. (PETHEMA) registry. These characteristics and outcomes will be For the purposes of this study, we also included the aforementioned compared with those of patients with de novo AML as well as patients with neo-AML. The remaining patients were classified as de between the different types of sAML and according to therapeutic novo AML. Latency period was the time between diagnosis of the primary disease or previous cytotoxic therapy and sAML. Cytogenet- approaches. ics was classified according to the Medical Research Council (MRC) classification.10 Methods According to the revised criteria by Cheson et al,11 CR required PETHEMA registry ,5% of blast cells in bone marrow (BM) and absence of them in The PETHEMA AML registry (NCT02607059) includes patients peripheral blood (PB), with neutrophil and platelet counts .1 3 diagnosed with AML, regardless of the treatment administered. 109/L and .100 3 109/L, respectively. If patients did not achieve Patient and disease characteristics, in addition to treatment these values of neutrophil and platelet counts in PB, response was approaches and outcomes, were collected retrospectively, including classified as CR with incomplete recovery (CRi). Both CR and CRi demographics (age and gender), cytomorphological subtype of had to be lacking in extramedullary disease. BM blasts between 5% AML, cytogenetics, details on treatment schedule, response assess- and 25% and reduction .50% compared with the basal value was ment, and disease follow-up (relapse or death). Optional forms were considered partial remission (PR). Independent of the therapeutic also collected, including baseline physical and laboratory examina- approach, response in patients who died before having been assessed was classified as induction death. Patients not meeting tion; prior neoplastic/hematologic diseases or exposure to radiation, the previous criteria were considered resistant. After achieving chemotherapy, or immunosuppressive drugs; molecular assessment CR/CRi, reappearance of disease in PB, blast cells in BM $ 5%, (according to the site’s routine practice); treatment-related toxicities; and development of extramedullary disease were criteria for relapse. and consolidation and post-consolidation schedules (eg, transplant and maintenance). Patient and disease baseline characteristics The primary end point was to compare baseline characteristics, were captured at the time of diagnosis (before starting treatment). CR/CRi, OS, and event-free survival (EFS) in all patients with reported sAML and according to therapeutic approaches. Other Eligibility secondary end points were to analyze the differences in baseline Adult patients (age $ 18 years) reported to the multinational characteristics and OS between patients with AML de novo and PETHEMA AML registry and diagnosed in Spanish and Portuguese sAML and between different sAML subsets. institutions from 1 January 1990 until 31 December 2019 were Statistical analysis included in the study. Patients with acute promyelocytic leukemia were excluded, just like those without information related to antece- To analyze the relationship between the characteristics of the dents of prior malignancies, preleukemic hematological disorders, patients’ subgroups, x-square with Yates’ correction, analysis of var- and leukemogenic or immunosuppressive therapies. The study was iance, Wilcoxon test, Student t test, and Kruskal-Wallis test were approved by Hospital Universitari i Polite cnic La Fe’s Research performed depending on the variable. Ethics Board according to the Declaration of Helsinki, and informed The Kaplan-Meier estimator12 was used to calculate unadjusted consent was a requisite for patients alive at the time of the analyses time-to-event variables and log-rank test13 to compare them. The (15 September 2020). corrected method of Kalbfleisch and Prentice was used for the 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 CHARACTERISTICS OF 2310 SECONDARY AML PATIENTS 1279 • Aged t18 years All AML patients (PETHEMA registry) • Spain and Portugal (n = 11224) • Diagnosed between 01/01/1990 and 31/12/2019 Missing data to classify as de novo or sAML (n = 2703) Eligible for the study (n = 8521) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 de novo AML patients (n = 6211) Overall survival (OS) sAML patients (n = 2310) Therapeutic approach not available (n = 158) Treatment patterns sAML and therapeutic approach (n = 2152) Best supportive care only (n = 544) Active therapy (n = 1608) Response not available (n = 119) Event-free survival (EFS) Response available (n = 1489) Figure 1. Consolidated Standards of Reporting Trials (CONSORT) diagram for secondary AML adult patients. estimation of medians and 95% confidence intervals (CI).14 OS de novo AML, patients with sAML were older (median age in years, was analyzed from the date of diagnosis of sAML until death and 69 vs 64; P , .001), were more frequently male (60% vs 53%; EFS from the date of diagnosis to death due to any cause, treat- P , .001), had performance status Eastern Cooperative Oncology ment failure, or relapse, whichever occurred first. Multivariate analy- Group (ECOG) $2 (35% vs 28%; P , .001), had lower median sis for OS was performed through a Cox proportional hazards WBC count in PB and blast cells percentage in BM (6.6 3 109/L model and through multinomial logistic regression for CR/CRi. Char- and 42% vs 10.4 3 109/L and 64%, respectively, both P , .001), acteristics with significant association in univariate analysis (P , .1) were more often classified with high-risk cytogenetics according to and those available variables with a possible relationship in previous MRC (40% vs 24%; P , .001), and had less FMS-like tyrosine studies were included in the multivariate analysis. Living patients at kinase 3 (FLT3) internal tandem duplication (ITD) and nucleophos- the time of the analysis were censored at the last known living day. min 1 (NPM1) mutations (11% and 16% vs 21% and 33%, Patient follow-up was updated on 31 December 2019. All P values respectively; P , .001). Patients with sAML were less commonly reported are 2-sided. Computations were executed using the R treated up front with IC (P , .001). 2.14.0 software package. Characteristics of sAML according to Results treatment approach Table 2 shows patient and disease features according to treatment Characteristics and treatment (sAML vs de approach in sAML. Among 2152 patients with sAML with available novo AML) front-line treatment, 876 (38%) received IC, 328 (14%) received Between January 1990 and December 2019, 11 224 patients with HMA, 325 (14%) received non-IC, 79 (3%) were in a clinical trial, AML were registered from several institutions in Spain and Portugal. and 544 (24%) received BSC. Patients who received BSC were Of these patients, 8521 (75.9%) could be classified as de novo older and had worse ECOG, higher uric acid, lactate dehydroge- AML (n 5 6211, 72.9%) or sAML (n 5 2310, 27.1%). A Consoli- nase (LDH), creatinine, and alkaline phosphatase serum levels, dated Standards of Reporting Trials (CONSORT) diagram is shown lower albumin levels, and higher WBC in PB and BM blast percent- in Figure 1. Characteristics and treatment patterns of de novo vs age. Patients who received IC were younger, with more frequent sAML patients are shown in Table 1. Compared with patients with t-AML or neo-AML, higher BM blast cells percentage, and more 1280  et al MARTINEZ-CUADRON 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 Table 1. Demographic and baseline characteristics of the study population (de novo vs sAML, n 5 8521) Overall De novo Secondary AML Characteristic Median (range) n (%) Median (range) n (%) Median (range) n (%) P value Total 8521 (100) 6211 (100) 2310 (100) Age, y 66 (18-104) 8507 (100) 64 (18-99) 6201 (100) 69 (18-104) 2306 (100) ,.001* 18-29 389 (5) 359 (6) 30 (1) ,.001 30-39 549 (6) 480 (8) 69 (3) 40-49 823 (10) 706 (11) 117 (5) 50-59 1285 (15) 998 (16) 287 (12) 60-69 2087 (25) 1421 (23) 666 (29) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 70-79 2333 (27) 1535 (25) 798 (35) 80-89 967 (11) 649 (10) 318 (14) $90 74 (1) 53 (1) 21 (1) Gender 8432 (100) 6127 (100) 2304 (100) Male 4643 (55) 3266 (53) 1377 (60) ,.001 Female 3788 (45) 2861 (47) 927 (40) ECOG 1 (0-4) 6640 (100) 1 (0-4) 4819 (100) 1 (0-4) 1821 (100) ,.001* 0 1949 (29) 1481 (31) 468 (26) ,.001 1 2740 (41) 2028 (42) 712 (39) 2 1239 (19) 852 (18) 387 (21) 3 538 (8) 336 (7) 202 (11) 4 174 (3) 122 (3) 52 (3) FAB subtype 8521 (100) 6211 (100) 2310 (100) M0/M6/M7 872 (10) 638 (10) 234 (10) ,.001 M1/M2 2301 (27) 1814 (29) 487 (21) M4/M5 2156 (37) 1764 (28) 392 (17) Not available 3192 (37) 1995 (32) 1197 (52) Hepatosplenomegaly 4380 (100) 3263 (100) 1117 (100) .63 Yes 962 (22) 723 (22) 239 (21) No 3418 (78) 2540 (78) 878 (79) WBC, 3109/L 9.2 (0-669) 7801 (100) 10.4 (0-669) 5762 (100) 6.6 (0.1-312) 2039 (100) ,.001* #5 3135 (40) 2199 (38) 936 (46) ,.001 5-10 883 (11) 651 (11) 232 (11) 10-50 2137 (27) 1574 (27) 563 (28) .50 1646 (21) 1338 (23) 308 (15) Hemoglobin, g/dL 9 (1.3-18.7) 7204 (100) 9 (1.3-18.7) 5353 (100) 9 (3.3-17.2) 1851 (100) .71* Platelet count, 310 /L 9 56 (0-1645) 7225 (100) 57 (0-1419) 5368 (100) 51 (1-1645) 1857 (100) ,.001* BM blasts, % 60 (0-100) 6612 (100) 64 (0-100) 4937 (100) 42 (0-100) 1675 (100) ,.001* Creatinine, mg/dL 0.9 (0.1-10) 4439 (100) 0.88 (0.1-10) 3022 (100) 0.94 (0.1-9.2) 1417 (100) ,.001* Urea, mg/dL 34 (2-267) 3931 (100) 33 (4-241) 2650 (100) 38 (2-267) 1281 (100) ,.001* Uric acid, mg/dL 4.9 (0-45) 3649 (100) 4.8 (0-45) 2443 (100) 5.3 (0-21) 1206 (100) ,.001* Bilirubin, mg/dL 0.6 (0.07-21) 4011 (100) 0.6 (0.1-21) 2692 (100) 0.67 (0.07-9.94) 1319 (100) ,.001* AST, U/L 22 (2-1085) 3869 (100) 22 (2-1085) 2599 (100) 22 (5-496) 1270 (100) .61* ALT, U/L 20 (1-743) 3987 (100) 20 (1-743) 2682 (100) 19 (2-623) 1305 (100) .004* AP, U/L 73 (2-3571) 3570 (100) 71 (4-1474) 2385 (100) 78 (2-3571) 1185 (100) ,.001 Albumin, g/dL 3.6 (0.5-8.5) 3520 (100) 3.6 (0.5-8.5) 2388 (100) 3.7 (1.7-7) 1132 (100) .03* LDH, U/L 480 (12-42 630) 4827 (100) 486 (16-42 630) 3342 (100) 460 (12-13 420) 1485 (100) .38* Fibrinogen, mg/dL 426 (1-1500) 3686 (100) 423 (1-1150) 2610 (100) 430 (1-1500) 1076 (100) .22* ALT, alanine transaminase; AP, alkaline phosphatase; AST, aspartate transaminase; FAB, French–American–British. *P compare continuous variables. 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 CHARACTERISTICS OF 2310 SECONDARY AML PATIENTS 1281 Table 1. (continued) Overall De novo Secondary AML Characteristic Median (range) n (%) Median (range) n (%) Median (range) n (%) P value Cytogenetics 8521 (100) 6211 (100) 2310 (100) Normal 2892 (34) 2299 (37) 593 (26) ,.001 Abnormal 3192 (37) 2201 (35) 991 (43) No metaphases 592 (7) 436 (7) 156 (7) Not available 1845 (22) 1275 (21) 570 (22) MRC cytogenetic risk 6099 (100) 4501 (100) 1598 (100) Favorable 474 (8) 420 (9) 54 (3) ,.001 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 Intermediate 3919 (64) 3014 (67) 905 (57) Adverse 1706 (28) 1067 (24) 639 (40) FLT3-ITD 4291 (100) 3301 (100) 990 (100) Positive 789 (18) 677 (21) 112 (11) ,.001 Negative 3502 (82) 2624 (79) 878 (89) NPM1 4024 (100) 3097 (100) 927 (100) Positive 1173 (29) 1023 (33) 150 (16) ,.001 Negative 2851 (71) 2074 (67) 777 (84) Therapeutic approach 8520 (100) 6210 (100) 2310 (100) Intensive 4620 (54) 3744 (60) 876 (38) ,.001 Nonintensive 974 (11) 649 (10) 325 (14) HMA 780 (9) 452 (7) 328 (14) Clinical trial 192 (2) 113 (2) 79 (3) BSC 1467 (17) 923 (15) 544 (24) Unknown 487 (6) 329 (5) 158 (7) ALT, alanine transaminase; AP, alkaline phosphatase; AST, aspartate transaminase; FAB, French–American–British. *P compare continuous variables. favorable cytogenetics, and they showed a trend to have more had better ECOG. Patients with MDS/MPN-AML had more frequent NPM1 mutations. hepatosplenomegaly, French–American–British M4/M5, and higher WBC counts in PB, creatinine, uric acid, and urea serum levels. Disease characteristics and treatment according to Patients with MPN-AML showed more hepatosplenomegaly and type of sAML higher LDH and fibrinogen levels. t-AML and neo-AML showed higher Information related to type of sAML was available in 2000 patients; blast percentage in BM, and more frequent favorable cytogenetics, 884 (44%) had MDS-AML, 209 (10%) had MDS/MPN-AML, 226 NPM1 and FLT3-ITD mutations. An adverse cytogenetic reaction was (11%) had MPN-AML, 502 (25%) had t-AML, and 179 (9%) had more frequent among MPN-AML and t-AML subgroups. IC was the neo-AML. Refractory cytopenia with excess blasts was the most fre- main therapeutic choice for patients with t-AML and neo-AML (52% quent condition preceding MDS-AML (Figure 2A), chronic myelomo- and 41%, respectively), whereas patients with MDS-, MDS/MPN-, and MPN-AML were more commonly treated with non-IC or HMA. nocytic leukemia for MDS/MPN-AML (Figure 2B), and essential thrombocythemia for MPN-AML (Figure 2C). Hematologic malignan- Response after front-line therapy in sAML cies and breast cancer were the most frequent conditions preceding t-AML (Figure 2D), and 65% of patients with t-AML were previously Response assessment after front-line therapy was available in 1486 treated with chemotherapy with or without radiotherapy (Figure 2E). (93%) patients with sAML actively treated (Figure 1). CR/CRi was Lung, prostate, and gynecologic cancer were the most frequent achieved in 619 (41%) patients, 117 (8%) showed PR, 561 (38%) antecedents for patients with neo-AML (Figure 2F). The median were resistant, and 189 (13%) died during induction (Table 4). CR/ CRi rate was higher after IC (55%) followed by clinical trial (31%), latency period in patients with sAML was 34.1 months (range, 0.07- non-IC (30%), and HMA (16%). Lower induction mortality was 471.7), 71.8 months for MPN-AML (range, 2.2-360.8) , 60.4 months observed after HMA (9%). Among 619 patients who achieved a for t-AML (range, 1.5-451.7), 59.2 months for neo-AML (range, 0.1- first CR/CRi, information about hematopoietic stem cell transplanta- 392.1), 20 months for MDS/MPN-AML (range, 0.1-272.6), and 16.2 tion (HSCT) was available in 582: 51 (9%) received autologous months for MDS-AML (range, 0.2-327.6) (P , .001). HSCT (49 after IC and 2 after non-IC), 152 (26%) received an allo- Table 3 shows characteristics and treatment according to the type of geneic HSCT (131 after IC, 18 after non-IC, and 3 after clinical sAML. Patients with neo-AML were older, and only among t-AML was trial), and no HSCT was performed in the remaining 379 (65%) female gender more frequent. Patients with MDS-AML and t-AML patients. 1282  et al MARTINEZ-CUADRON 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 Table 2. Characteristics of patients with sAML as per front-line treatment (n 5 2152) IC Non-IC HMA Clinical trial BSC Characteristic Median (range) n (%) Median (range) n (%) Median (range) n (%) Median (range) n (%) Median (range) n (%) P value Total 876 (100) 325 (100) 328 (100) 79 (100) 544 (100) Age, y 61 (18-85) 875 (100) 72 (24-91) 325 (100) 73 (29-88) 327 (100) 72 (31-89) 79 (100) 77 (23-104) 542 (100) ,.001* Gender 870 (100) 325 (100) 328 (100) 79 (100) 544 (100) Male 518 (59) 199 (61) 209 (64) 52 (66) 305 (56) .15 Female 352 (41) 126 (39) 119 (36) 27 (34) 239 (44) ECOG 1 (0-4) 726 (100) 1 (0-4) 256 (100) 1 (0-4) 273 (100) 1 (0-3) 75 (100) 2 (0-4) 433 (100) ,.001* 0 252 (34) 62 (24) 50 (18) 26 (35) 57 (13) ,.001 1 320 (44) 101 (40) 134 (49) 38 (51) 99 (23) 2 113 (16) 59 (23) 70 (26) 10 (13) 126 (29) 3 35 (5) 26 (10) 17 (6) 1 (1) 115 (27) 4 6 (1) 8 (3) 2 (1) 0 (0) 36 (8) Type of sAML 764 (100) 302 (100) 258 (100) 76 (100) 481 (100) MDS-AML, MDS/ 429 (56) 209 (69) 189 (73) 55 (72) 354 (74) ,.001 MPN, and MPN-AML 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 t-AML 261 (34) 68 (23) 51 (20) 14 (19) 83 (17) Neo-AML 74 (10) 25 (8) 18 (7) 7 (9) 44 (9) FAB subtype 658 (100) 252 (100) 189 (100) 50 (100) 341 (100) M0/M6/M7 100 (15) 37 (15) 26 (14) 6 (12) 59 (17) ,.001 M1/M2 233 (35) 86 (34) 40 (21) 18 (36) 103 (30) M4/M5 196 (30) 56 (22) 28 (15) 11 (22) 92 (27) Not available 129 (20) 73 (29) 95 (50) 15 (30) 87 (26) WBC, 3109/L 6.7 (0.1-289) 800 (100) 6.3 (0.4-312) 296 (100) 4.3 (0.5-214) 300 (100) 4.7 (0.5-158) 78 (100) 10.2 (0.2-310) 484 (100) ,.001* Hemoglobin, g/dL 9.1 (3.3-17.2) 730 (100) 8.8 (4.1-13.9) 287 (100) 8.9 (4.8-14.9) 293 (100) 9.0 (3.2-14.3) 76 (100) 8.9 (3.4-16.4) 393 (100) .02* 9 Platelet count, 310 /L 49 (2-1442) 731 (100) 50 (1-1645) 287 (100) 59 (3-870) 294 (100) 40 (7-350) 76 (100) 58 (1-1372) 396 (100) .15* BM blasts, % 50 (0-100) 676 (100) 39 (3-100) 270 (100) 32 (0-100) 286 (100) 34 (16-94) 74 (100) 47 (3-100) 324 (100) ,.001* Creatinine, mg/dL 0.87 (0.07-7.2) 613 (100) 0.99 (0.39-3.63) 220 (100) 0.99 (0.47-7) 185 (100) 0.96 (0.42-1.84) 69 (100) 1.12 (0.25-9.2) 281 (100) ,.001* #1.3 534 (87) 172 (78) 149 (81) 59 (86) 182 (65) ,.001 .1.3 79 (13) 48 (22) 36 (19) 10 (14) 99 (35) Urea, mg/dL 32 (4-255) 547 (100) 42 (1.9-162) 205 (100) 41 (12-195) 170 (100) 38 (12-117) 68 (100) 47 (10-267) 246 (100) ,.001* Uric acid, mg/dL 4.7 (0-14.4) 540 (100) 5.6 (0-17.1) 187 (100) 5.7 (1.7-13.6) 158 (100) 5.3 (0.1-11) 61 (100) 6.1 (0.6-21) 218 (100) ,.001* *P compare continuous variables. CHARACTERISTICS OF 2310 SECONDARY AML PATIENTS 1283 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 1284 Table 2. (continued) IC Non-IC HMA Clinical trial BSC Characteristic Median (range) n (%) Median (range) n (%) Median (range) n (%) Median (range) n (%) Median (range) n (%) P value Bilirubin, mg/dL 0.6 (0.1-8.1) 582 (100) 0.7 (0.1-9.9) 207 (100) 0.7 (0.2-5.3) 172 (100) 0.7 (0.2-3.9) 65 (100) 0.7 (0.2-8.1) 248 (100) .01* AST, U/L 22 (5-213) 565 (100) 22 (8-154) 204 (100) 20 (7-88) 163 (100) 22 (11-99) 56 (100) 23 (7-141) 238 (100) .18* MARTINEZ-CUADRON ALT, U/L 20 (3-498) 577 (100) 19 (2-233) 206 (100) 16 (3-91) 170 (100) 18 (4-623) 59 (100) 19 (3-168) 247 (100) .02*  et al AP, U/L 76 (2-1252) 533 (100) 75 (18-812) 186 (100) 73 (19-894) 159 (100) 75 (42-416) 55 (100) 95 (23-3571) 208 (100) ,.001* Albumin, g/dL 3.7 (2-5.8) 508 (100) 3.7 (2-5.2) 187 (100) 3.8 (2.7-5.9) 143 (100) 4.1 (2-5) 61 (100) 3.4 (1.7-7) 197 (100) ,.001* #3.5 212 (42) 86 (46) 53 (37) 18 (30) 107 (54) .001 . 3.5 296 (58) 101 (54) 90 (63) 43 (70) 90 (46) LDH, U/L 471 (12-9540) 602 (100) 437 (57-12 460) 253 (100) 385 (61-4266) 220 (100) 390 (144-3557) 63 (100) 617 (102-13 420) 302 (100) ,.001* Cytogenetics 876 (100) 325 (100) 328 (100) 79 (100) 544 (100) Normal 255 (29) 93 (29) 107 (33) 29 (37) 90 (17) ,.001 Abnormal 422 (48) 161 (50) 152 (46) 41 (52) 192 (35) No metaphases 76 (9) 27 (8) 19 (6) 2 (3) 31 (6) Not available 123 (14) 44 (14) 50 (15) 7 (9) 231 (42) MRC cytogenetic risk 690 (100) 256 (100) 263 (100) 71 (100) 277 (100) Favorable 40 (6) 8 (3) 2 (1) 0 (0) 4 (2) ,.001 Intermediate 386 (56) 147 (57) 150 (57) 46 (65) 148 (53) Adverse 264 (38) 101 (40) 111 (42) 25 (35) 125 (45) FLT3-ITD 467 (100) 174 (100) 118 (100) 70 (100) 122 (100) Positive 54 (12) 20 (11) 10 (8) 10 (14) 12 (10) .76 Negative 413 (88) 154 (89) 10108 (92) 60 (85) 110 (90) NPM1 427 (100) 169 (100) 113 (100) 67 (100) 113 (100) Positive 85 (20) 25 (15) 16 (14) 8 (12) 11 (10) .06 Negative 342 (80) 144 (85) 97 (86) 59 (88) 102 (90) Period 876 (100) 325 (100) 328 (100) 79 (100) 544 (100) 1990-1994 33 (4) 7 (2) 0 (0) 0 (0) 13 (2) ,.001 1995-1999 68 (8) 2 (1) 0 (0) 0 (0) 28 (5) 2000-2004 92 (11) 2 (1) 3 (1) 0 (0) 66 (12) 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 2005-2009 168 (19) 23 (7) 51 (16) 0 (0) 164 (30) 2010-2014 290 (33) 171 (53) 132 (40) 23 (29) 192 (35) 2015-2019 225 (26) 120 (37) 142 (43) 56 (71) 81 (15) *P compare continuous variables. Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 A B MDS-AML MDS/MPN-AML 6% 6% 6% 25% 15% RA RARS CMML RCMD U-MDS/MPN RCEB MDS 5q- 67% 75% RA: refractory anemia; RARS: refractory anemia with ringed sideroblasts; CMML: chronic myelomonocytic leukemia; RCMD: refractory cytopenia with multilineage dysplasia; RCEB: U-MDS/MPN: myelodysplastic/myeloproliferative refractory cytopenia with excess blasts; MDS 5q-: myelodysplastic diseases, unclassificable. Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 syndrome associated with isolated del(5q) chromosome abnormality. C MPN-AML D t-AML 2% 2% 5% ET 31% 40% 42% CHT MF PV RT 33% CHT + RT CNL CML IT 25% 20% CML: philadelphia negative chronic myelogenous leukemia; CHT: chemotherapy; RT: radiotherapy; CNL: chronic neutrophilic leukemia; PV: polycytemia vera; MF; IT: immunosuppressive agent. chronic idiopathic myelofibrosis; ET: essential thrombocytemia. E F t-AML Neo-AML 2% Breast 2% Gastrointestinal Gastrointestinal 2% 1% Prostate 11% 13% 12% Urinary 2% Prostate 6% Gynecologic 4% Skin 6% Lung 5% Urinary 12% Autoimmune disease 14% Hematologic 8% Nervous system 7% Breast 28% 3% Laryngeal Other solid tumors Renal 3% 4% NHL 14% Lung 8% HD 8% Gynecologic 5% 1% CLPS Laryngeal MM 10% Others 26% AL 12% Other hematologic NHL: Non-Hodgkin lymphoma; HD: Hodgkin disease; CLPS: Chronic lymphoproliferative syndrome; MM: multiple myeloma; AL: acute leukemia. Figure 2. Description of disorders diagnosed before AML. (A) Type of previous MDS in patients included in MDS-AML group. Patients with nonspecified and unclassifiable MDS were not included in this figure. (B) Type of previous MDS/MPN in patients included in MDS/MPN-AML group. (C) Type of previous MPN in patients included in MPN-AML group. (D) Type of previous therapy in patients included in t-AML group. (E) Type of previous neoplasm in treated patients included in t-AML group. (F) Type of previous solid neoplasm in patients with cancer antecedents without prior treatment. CR/CRi rate after IC was superior among patients with t-AML and favorable and intermediate cytogenetic risk were independent favor- neo-AML (64% and 63%, respectively), as compared with MDS- able prognostic factors for CR/CRi (all P , .001). MDS/MPN- and MPN-AML (52%, 44%, and 45%, respectively) Among patients with sAML, age (P , .001), ECOG (P 5 .004), (P , .001). Response after other therapies and HSCT rates were WBC count (P 5 .002), and bilirubin level .1.2 mg/dL (P 5 .03) similar among all sAML subgroups (supplemental Table 2). were independent prognostic factors for CR/CRi. NPM1 mutation (P , .001), favorable and intermediate cytogenetic risk (both P , Multivariate analyses for complete remission .001), t-AML (P , .001), and neo-AML (P 5 .01) were independent When all patients receiving IC were included (de novo and sAML) favorable prognostic factors for CR/CRi. in a multinomial logistic regression, sAML (P , .001), age (P , .001), ECOG (P , .001), WBC count (P , .001), and creatinine OS level .1.2 mg/dL (P 5 .003) were independent adverse prognostic The median OS of the 8521 patients included in the study was 9.1 factors for CR/Cri, whereas presence of NPM1 mutation and months (95% CI, 8.7-9.6). Median OS was higher in patients with 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 CHARACTERISTICS OF 2310 SECONDARY AML PATIENTS 1285 1286 Table 3. Disease and patient characteristics according to the type of sAML (n 5 2000) MDS-AML MDS/MPN-AML MPN-AML t-AML neo-AML Characteristic Median (range) n (%) Median (range) n (%) Median (range) n (%) Median (range) n (%) Median (range) n (%) P value Global 884 (100) 209 (100) 226 (100) 502 (100) 179 (100) Age, y 70 (19-97) 883 (100) 69 (31-92) 208 (100) 68 (31-92) 225 (100) 67 (18-104) 502 (100) 73 (26-93) 179 (100) ,.001* MARTINEZ-CUADRON Gender 882 (100) 209 (100) 226 (100) 502 (100) 179 (100)  et al Male 548 (62) 148 (71) 129 (57) 248 (49) 121 (68) ,.001 Female 334 (38) 61 (29) 97 (43) 254 (51) 58 (32) ECOG 1 (0-4) 670 (100) 1 (0-4) 165 (100) 1 (0-4) 188 (100) 1 (0-4) 435 (100) 1 (0-4) 169 (100) ,.001* 0 185 (28) 34 (21) 39 (21) 130 (30) 40 (24) ,.001 1 268 (40) 62 (38) 73 (39) 178 (41) 64 (38) 2 139 (21) 36 (22) 35 (19) 80 (18) 44 (26) 3 67 (10) 25 (15) 27 (14) 38 (9) 18 (11) 4 11 (2) 8 (5) 14 (7) 9 (2) 3 (2) FAB subtype 884 (100) 209 (100) 226 (100) 502 (100) 179 (100) M0/M6/M7 80 (9) 4 (2) 42 (19) 65 (13) 22 (12) ,.001 M1/M2 230 (26) 18 (9) 30 (13) 118 (24) 51 (28) M4/M5 100 (11) 79 (38) 15 (7) 121 (24) 54 (30) Not available 474 (54) 108 (52) 139 (61) 198 (39) 52 (29) Hepatosplenomegaly 419 (100) 114 (100) 112 (100) 290 (100) 142 (100) ,.001 Yes 77 (18) 37 (32) 44 (39) 52 (18) 24 (17) No 342 (82) 77 (68) 68 (61) 238 (82) 118 (83) 9 WBC, 310 /L 4.4 (0.1-310.4) 786 (100) 23.5 (0.1-300.2) 169 (100) 10.8 (0.3-312) 198 (100) 5.1 (0.1-289) 466 (100) 10.7 (0.-230.7) 173 (100) ,.001* Hemoglobin, g/dL 8.9 (3.3-17.2) 690 (100) 9.1 (4-15.1) 154 (100) 8.7 (4.7-15) 173 (100) 9.1 (3.2-15.2) 452 (100) 9.1 (4.4-14.4) 170 (100) .23* Platelet count, 3109/L 45 (1-1645) 691 (100) 55 (6-459) 155 (100) 74 (1-1372) 173 (100) 47 (2-1442) 456 (100) 58 (5-462) 171 (100) ,.001* BM blasts, % 36 (2-100) 653 (100) 40 (1-100) 136 (100) 35 (0-94) 148 (100) 55 (0-100) 408 (100) 58 (10-100) 160 (100) ,.001* Creatinine, mg/dL 0.97 (0.32-9.2) 500 (100) 1.07 (0.29-7.2) 133 (100) 0.95 (0.25-5.09) 141 (100) 0.9 (0.07-5.48) 416 (100) 0.97 (0.4-8.5) 163 (100) ,.001* Urea, mg/dL 38 (4-192) 456 (100) 44 (11-255) 121 (100) 39 (8-242) 126 (100) 35 (2-243) 391 (100) 41 (11-267) 146 (100) ,.001* Uric acid, mg/dL 5 (0.1-19) 413 (100) 6.5 (0.1-17.1) 119 (100) 5.8 (0-16.2) 121 (100) 4.9 (0-14.4) 366 (100) 5.3 (0-13) 143 (100) ,.001* Bilirubin, mg/dL 0.7 (0.14-7.5) 449 (100) 0.75 (0.22-7) 127 (100) 0.67 (0.2-5.5) 137 (100) 0.64 (0.07-9.94) 392 (100) 0.62 (0.1-4.57) 151 (100) .06* 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 AST, U/L 22 (7-171) 451 (100) 22 (6-496) 119 (100) 23 (8-151) 124 (100) 22 (5-213) 383 (100) 21 (8-338) 150 (100) .81* ALT, U/L 18 (2-272) 461 (100) 16 (3-515) 121 (100) 18 (3-160) 131 (100) 20 (3-623) 395 (100) 19 (5-328) 152 (100) .24* The type of sAML was not available in 310 patients. *P compare continuous variables. Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 Table 3. (continued) MDS-AML MDS/MPN-AML MPN-AML t-AML neo-AML Characteristic Median (range) n (%) Median (range) n (%) Median (range) n (%) Median (range) n (%) Median (range) n (%) P value AP, U/L 78 (29-702) 412 (100) 82 (14-1158) 115 (100) 80 (26-1525) 120 (100) 77 (19-3571) 354 (100) 75 (2-3402) 143 (100) .41* Albumin, g/dL 3.7 (2.1-7) 389 (100) 3.7 (1.7-5.8) 113 (100) 3.7 (1.9-5.2) 117 (100) 3.7 (1.8-5.8) 340 (100) 3.7 (2.6-4.9) 136 (100) .95* LDH, U/L 416 (13-9168) 571 (100) 612 (96-11380) 138 (100) 768 (102-10560) 147 (100) 436 (12-9540) 398 (100) 561 (112-13420) 149 (100) ,.001* Fibrinogen, mg/dL 423 (1-1033) 358 (100) 410 (1-940) 111 (100) 467 (3-889) 115 (100) 422 (3-983) 328 (100) 444 (2-1500) 137 (100) .04* Cytogenetics 884 (100) 209 (100) 226 (100) 502 (100) 179 (100) Normal 247 (28) 61 (29) 49 (22) 107 (21) 60 (34) ,.001 Abnormal 361 (41) 72 (34) 102 (45) 266 (53) 74 (41) No metaphases 65 (7) 10 (5) 12 (5) 45 (9) 14 (8) Not available 211 (24) 66 (32) 63 (28) 84 (17) 31 (17) MRC cytogenetic risk 612 (100) 134 (100) 152 (100) 382 (100) 137 (100) Favorable 4 (1) 1 (1) 2 (1) 31 (8) 11 (8) ,.001 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 Intermediate 377 (62) 94 (70) 64 (42) 172 (45) 88 (64) Adverse 231 (38) 38 (28) 86 (57) 179 (47) 38 (28) FLT3-ITD 340 (100) 104 (100) 86 (100) 288 (100) 114 (100) Positive 35 (10) 11 (11) 3 (3) 26 (9) 24 (21) ,.001 Negative 305 (90) 93 (89) 83 (97) 262 (91) 90 (79) NPM1 312 (100) 103 (100) 85 (100) 265 (100) 105 (100) Positive 34 (11) 13 (13) 7 (8) 50 (19) 28 (27) ,.001 Negative 278 (89) 90 (87) 78 (92) 215 (81) 77 (73) Therapeutic approach 884 (100) 209 (100) 226 (100) 502 (100) 179 (100) IC 294 (33) 66 (32) 69 (31) 261 (52) 74 (41) ,.001 Non-IC 149 (17) 35 (17) 25 (11) 68 (14) 25 (14) HMA 127 (14) 27 (13) 35 (15) 51 (10) 18 (10) Clinical trial 35 (4) 11 (5) 9 (4) 14 (3) 7 (4) BSC 234 (26) 50 (24) 70 (31) 83 (17) 44 (25) Not available 45 (5) 20 (10) 18 (8) 25 (5) 11 (6) The type of sAML was not available in 310 patients. *P compare continuous variables. CHARACTERISTICS OF 2310 SECONDARY AML PATIENTS 1287 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 Table 4. Response and HSCT rates, OS, and EFS according to therapeutic approach in patients with sAML Variable Overall IC Non-IC HMA Clinical trial BSC P value Response, n (%) 1489 (100) 844 (100) 303 (100) 274 (100) 68 (100) ORR (CR 1 CRi) 620 (41) 467 (55) 89 (30) 43 (16) 21 (31) ,.001 CR 559 (37) 437 (52) 71 (23) 33 (12) 18 (26) Cri 61 (4) 30 (4) 18 (6) 10 (4) 3 (4) PR 118 (8) 54 (6) 30 (10) 21 (8) 13 (19) Resistance 562 (38) 220 (26) 138 (46) 184 (67) 20 (30) Death 189 (13) 103 (12) 46 (15) 26 (9) 14 (21) HSCT in first CR/CRi, n (%)* 584 (100) 439 (100) 83 (100) 43 (100) 19 (100) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 Allogeneic HSCT rate, n (%) 151 (26) 130 (30) 18 (22) 0 (0) 3 (16) ,.001 Autologous HSCT rate, n (%) 51 (9) 49 (11) 2 (2) 0 (0) 0 (0) No HSCT, n (%) 382 (65) 260 (59) 63 (76) 43 (100) 16 (84) OS, n (%) 2310 (100)* 876 (100) 325 (100) 328 (100) 79 (100) 544 (100) Median (CI 95%), mo 5.6 (5.2-6.3) 9.9 (8.9-11.4) 5.5 (4.6-7.4) 9.0 (7.6-10.6) 7.7 (6.4-10.6) 1.2 (1.0-1.5) ,.001 1 y (CI 95%) 31.4 (29.3-33.4) 44.4 (41.1-48.0) 29.7 (24.9-35.5) 40.3 (35.0-46.3) 32.9 (22.8-47.5) 6.5 (4.7-9.0) 5 y (CI 95%) 8.2 (6.8-9.6) 15.7 (13.0-18.9) 6.4 (3.7-11.0) 3.7 (1.8-7.6) 7.1 (2.1-23.7) NA (NA-NA) EFS, n (%) 1394 (100) 810 (100) 288 (100) 230 (100) 66 (100) NA ,.001 Median (CI 95%), mo 3.6 (3.2-4.0) 4.1 (3.5-5.7) 1.7 (1.5-2.1) 4.8 (4.0-6.0) 3.3 (1.9-5.9) NA 1 y (CI 95%) 22.2 (20.0-24.5) 28.3 (25.3-31.7) 13.7 (10.2-18.4) 23.0 (18.2-29.2) 10.3 (4.7-22.6) NA 5 y (CI 95%) 8.4 (6.8-10.0) 11.3 (9.1-14.1) 6.0 (3.6-9.7) 2.5 (1.0-6.1) 6.2 (2.1-17.9) NA NA, not applicable; ORR, overall response rate; *Data from patients in CR/CRi after front-line therapy. Global OS results includes all patients with sAML (2310 patients), but in 162 patients the therapeutic approach was not available. Including only patients with therapeutic approach available (2148 patients), the median OS was 8.9 mo (8.0-9.6), 1 y OS was 40% (38-43), and 5 y OS was 11% (9-13). de novo than sAML (10.9 [95% CI, 10.3-11.5] vs 5.6 months [95% Table 4), but no differences were observed between neo-AML CI, 5.2-6.3], respectively; P , .001), with 1- and 5-year OS of and de novo AML (14.6 [95% CI, 10.3-42.4] vs 17.2 [95% CI, 47.8% (95% CI, 46.5-49.1) vs 31.4% (95% CI, 29.3-33.4), and 16.0-18.6], respectively; P 5 .63) (supplemental Figure 2A). No dif- 23.4% (95% CI, 22.2-24.7) vs 8.3% (95% CI, 6.7-9.7), respec- ferences were observed among patients treated with HMA (supple- tively (P , .001) (Figure 3A). mental Figure 2B) or non-IC according to the type of sAML although patients with nonsignificant, neo-AML aged ,60 years Patients with sAML who received IC or HMA had better median and those with intermediate cytogenetics had better 5-year OS OS than others (9.9 and 9.0 months, respectively), but the 5-year compared with other sAML subsets (supplemental Table 4). OS was better among the IC group (15.7%) (Figure 3B; Table 4). Favorable cytogenetic risk (Figure 3C) and NPM1 mutations (Figure Among 666 patients with MDS-AML, MDS/MPN-AML, and MPN- 3D) were associated with prolonged OS, whereas FLT3-ITD muta- AML with available information of prior HMAs exposure, OS was tions did not affect OS (Figure 3E). OS was significantly lower in significantly lower among those treated with HMAs before AML patients with sAML after hematologic disorders (together MDS- transformation (P , .001) (supplemental Figure 3A). We also AML, MDS/MPN-AML, and MPN-AML) as compared with t-AML explored the prognosis of 101 patients with t-AML who received and neo-AML (median OS 5.3 [95% CI, 5.0-6.1] vs 6.1 [95% CI, only prior radiotherapy as compared with other sAML types and de 5.1-7.8] vs 5.7 [95% CI, 4.1-7.8] months, respectively; P 5 .04) novo AML (supplemental Figure 3B). After including this new cate- (Figure 3F). Other risk factors for OS were identified in univariate gory in the multivariate analysis, prior administration of radiotherapy analyses (ie, age, ECOG, WBC count, or alkaline phosphatase) exclusively was not an independent prognostic factor: hazard ratio (HR) was 1.06 (95% CI, 0.84-1.35; P 5 .61). (supplemental Table 3). Patients who achieved CR/CRi had higher median OS as compared Multivariate analyses for OS with patients with PR or resistance (19.5 [95% CI, 16.7-23.8], 15.5 Among patients with sAML with an age between 30 and 59 years, [95% CI, 14.6-18.9], 10.8 [95% CI, 7.7-13.3], and 5.8 [95% CI, neo-AML, platelet count .20 3 109/L, albumin .3.5 g/dL, favor- 5.3-6.5] months, respectively; P , .001). Patients in first CR/CRi able and intermediate cytogenetic risk, and NPM1 mutation had a allocated to allogeneic HSCT had longer median OS than those positive impact on OS. ECOG $2, WBC count $10 3 109/L, assigned to autologous therapy or chemotherapy exclusively (44.9 blast cells in BM .70%, creatinine .1.3 mg/dL, and alkaline phos- [95% CI, 30.2-NA] vs 31.5 [95% CI, 23.1-59.8] vs 14.9 [13.7- phatase .150 U/L were independent adverse prognostic factors 16.9] months, respectively; P , .001) (supplemental Figure 1A-B). for OS (supplemental Table 5). After IC front-line, median OS was significantly better among When all patients were included (de novo and sAML) in a multivari- patients with neo-AML as compared with other sAML (supplemental ate Cox regression, sAML was an independent adverse prognostic 1288  et al MARTINEZ-CUADRON 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 A B 1.00 1.00 0.75 0.75 OS Probability OS Probability 0.50 0.50 0.25 0.25 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 0.00 0.00 0 6 12 18 24 30 36 42 48 54 60 Months after diagnosis 0 6 12 18 24 30 36 42 48 54 60 IC 876 502 332 227 180 141 114 101 83 74 64 Months after diagnosis non-IC 325 144 82 44 34 27 22 17 11 9 7 HMA 328 183 109 64 40 29 16 13 10 8 6 De novo 6211 3305 2298 1736 1378 1166 1034 909 823 733 650 Trial 79 38 14 6 4 3 2 2 2 2 1 Secondary 2310 969 578 360 268 208 159 138 111 96 80 BSC 544 86 33 14 6 4 3 3 3 1 0 C D 1.00 1.00 0.75 0.75 OS Probability OS Probability 0.50 0.50 0.25 0.25 0.00 0.00 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 54 60 Months after diagnosis Months after diagnosis Favourable 54 35 23 19 15 12 10 10 9 Intermediate 905 NPM1mut 150 87 55 40 35 27 22 17 14 11 9 492 319 201 159 120 96 82 65 Adverse 639 NPM1wt 777 356 207 117 90 72 56 49 40 34 26 254 136 74 50 38 27 23 18 E F 1.00 1.00 0.75 0.75 OS Probability OS Probability 0.50 0.50 0.25 0.25 0.00 0 6 12 18 24 30 36 42 48 54 60 0.00 Months after diagnosis 0 6 12 18 24 30 36 42 48 54 60 De novo 6211 3305 2298 1736 1378 1166 1034 909 823 733 650 Months after diagnosis MDS-AML 884 383 222 139 101 72 59 48 36 31 24 MDS/MPN-AML 209 75 40 25 18 10 6 4 4 3 1 FLT3ITDmut 112 52 27 20 16 11 9 7 6 4 4 MPN-AML 226 84 45 30 21 19 10 9 8 7 6 FLT3ITDwt 878 432 266 158 121 98 78 67 55 46 34 t-AML 502 217 133 77 59 54 41 38 29 25 21 Neo-AML 179 78 50 36 29 23 19 17 15 14 12 Figure 3. OS of the AML patients included in the study according to different disease characteristics or therapeutic approach. (A) OS in the entire cohort of 8521 patients with AML according to type of AML (P < .001). (B) OS in secondary AML according to therapeutic approach (P < .001). (C) OS in secondary AML according to cytogenetic risk (P < .001). (D) OS in secondary AML according to NPM1 mutation (P < .001). (E) OS in secondary AML according to FLT3-ITD mutation (P 5 .45). (F) OS in secondary AML according to the different subgroups (P 5 .04). 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 CHARACTERISTICS OF 2310 SECONDARY AML PATIENTS 1289 factor for OS (P 5 .01; HR 1.08 [95% CI, 1.02-1.15]). Because reported,25 in which breast cancer history was present in 25%. Sur- neo-AML had different prognosis than other sAML types, we per- prisingly, 28% of t-AML cases evolved from prior hematological formed a multivariate analysis, including neo-AML in the de novo malignancies (eg, lymphoma), highlighting an increased risk of devel- AML category, showing that sAML (without neo-AML) was a signifi- oping sAML in this setting. Another interesting finding was that cant predictor for OS (P 5 .008; HR 1.09 [95% CI, 1.02-1.16]). patients with MDS- and t-AML had less WBC and BM blasts at Other independent prognostic factors are detailed in supplemental diagnosis because they are usually less proliferative and can show Table 6. We analyzed the effect of cytogenetics with type of AML signs and symptoms of hematopoietic insufficiency due to prior anti- interaction, showing that in all MRC risk subgroups, the presence of neoplastic therapies.35 On the contrary, MPN- and MDS/MPN-AML sAML was accompanied by lower OS (supplemental Figure 4A). showed signs and symptoms related to the previous disorder, such as increased WBC, M4/M5 morphology, hepatomegaly, and spleno- We also analyzed the trend in OS across the study period, showing megaly.36 We found that low-risk karyotype was uncommon, espe- that OS improved gradually (90s vs 00s vs 10s decade) among cially for MDS-, MDS/MPN-, and MPN-AML,4 whereas high-risk patients with de novo AML, but such improvement was not Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 karyotype was frequent, especially in t-AML4,24 and MPN-AML. observed among patients with sAML (supplementary Figure 4B). Regarding molecular findings, we could only analyze NPM1 and EFS FLT3-ITD mutations, confirming previous studies showing that these lesions are less prevalent among sAMLs.37-39 Interestingly, although The median EFS of 1394 evaluable patients with sAML was 3.6 neo-AML and t-AML shared 8% core-binding factor (CBF) rear- months (95% CI, 3.2-4.0), with 1- and 5-year EFS of 22.2% (95% rangements, only neo-AML cases showed a prevalence for NPM1 CI, 20.0-24.5) and 8.4% (95% CI, 6.8-10.0), respectively (supple- and FLT3-ITD comparable to de novo AML, supporting that they mental Figure 5A). Higher median EFS was observed after IC, should not be considered sAML. HMA, and clinical trials compared with non-IC regimens (4.1 months [95% CI, 3.5-5.7], 4.8 months [95% CI, 4.0-6.0], 3.3 months [95% The optimal treatment options for patients with sAML are not yet CI, 1.9-5.9], and 1.7 months [95% CI, 1.5-2.1] respectively; established. This quandary comes from the lack of studies in this P , .001) (supplemental Figure 5B). subset of patients because they are generally excluded from trials and protocols.22,40 As expected, this study shows that few patients with sAML received up-front IC regimens (38%) compared with de Discussion novo (60%),3-5,16,21,24,27,28 curative approaches being the preferred In this study we reported the largest cohort of patients with sAML to option only in a subset of favorable risk sAML subjects (ie, younger, date and dissected their characteristics, treatment patterns, and main CBF, and NPM1). Only 8 sAML registry studies provided data outcomes. We showed in a real-life setting that sAML represents regarding CR/CRi after IC,3-5,17,22,24,27 obtaining a median of 50.7% roughly 25% of all AML cases, with worse prognosis and different (range: 21% to 63%), slightly lower than in our series (55%). As in baseline characteristics and patterns of care as compared with de other series, we found better CR/CRi rates among patients with t- novo AML (especially for those arising after MDS, MDS/MPN, and AML (63%) followed by MDS-AML (52%), and the worst rates were MPN). Nevertheless, we highlighted that patients with neo-AML have obtained among patients with MDS/MPN- and MPN-AML.3,4,41 Of similar outcomes and biology than patients with de novo AML. It note, 3 1 7 and FLAG-Ida regimens were administered in most IC should be noted that therapeutic results were equally poor for unfit patients in our historical sAML cohort, whereas only 6 patients patients with de novo and sAML; thus, the adverse prognostic impact received CPX-351. Our CR/CRi rate after IC was .48% in the of sAML is mainly applicable to the eligible for IC setting. CPX-351 and 33% in the 3 1 7 arm of a recently published phase 3 study.42 However, we should avoid comparisons because this clin- In our registry, 27.1% of patients with AML were classified as ical trial included patients $65 years and excluded those with MPN- sAML, which is superior to a median prevalence of 22.0% (range: AML. Scarce studies have analyzed the CR/CRi rates after HMA in 5.7% to 42.1%) previously reported.3-5,10,15-27 However, we have sAML, showing 12% to 36% CR/CRi, in line with 16% herein also considered as sAML those patients with AML following prior reported.43,44 Interestingly, we show 30% CR/CRi after non-IC for neoplasia without exposure to leukemogenic agents (namely unfit patients (ie, FLUGA regimen or similar), but this was not accom- neo-AML, 2.1%), which is uncommon in prior series.16 Regarding panied by improved survival compared with HMA.45 well-recognizedsAML subsets, our frequencies are in line with prior studies showing 13.1% (range: 5.7% to 26.5%) MDS-AML, 7.1% We reproduced significantly poorer median OS in sAML (5.6 months) (range:1.6% to 8.3%) MPN-AML, and 6.2% (range: 1.9% to as compared with de novo AML (10.9 months).3-5,16,19,21,24-28 We 13.7%) t-AML.3,4,15-31 As expected, we observed shorter median can affirm that median OS in different studies is affected by the pro- latency in MDS- and MDS/MPN-AML (,2 years),4 whereas leuke- portion of IC-treated patients in each series. As an example, two reg- mic transformation occurred over a 5-year period in t-AML4,25 and istries reported a median OS of 7 and 8.6 months,17,27 with even longer in MPN-AML.32 The latency period could depend on percentage of IC treatment of 56% and 57%, respectively, whereas median OS was 5.8 months in a study with only 28% IC24 (similar to the cumulative dose, dose intensity, and type of preceding chemo- our registry, in which 38% received IC). We confirmed that HMA therapy and/or radiation therapy,33,34 but those factors were not could lead to comparable median OS than IC strategies, but long- analyzed here. term survival might be improved after IC approaches.44 We hypothe- We confirm that sAML is closely associated with older age, comor- sized that sAML patients achieving a CR/CRi should be considered bidities (ie, renal and liver dysfunction), worse performance status, for allogeneic HSCT to prolong survival, but few data have been pub- and unfavorable genetic features.4,7-9 We also show that male gen- lished comparing patients with or without HSCT after induction ther- der was more predominant among patients with sAML compared apy in this setting.41 The population-based study in sAML by Nilsson with de novo AML. The exception was t-AML, as previously et al reported improved 5-year OS after allogeneic HSCT (18% to 1290  et al MARTINEZ-CUADRON 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 32%) compared with non-HSCT (2% to 10%). Here we show This study was supported in part by the Jazz Pharmaceuticals improved median OS in patients undergoing allogeneic or autologous and Cooperative Research Thematic Network (RTICC) grant HSCT in first CR/CRi (45 and 31 months, respectively) compared RD12/0036/014 (ISCIII and ERDF). with 65% who did not receive transplant (15 months). We should cautiously interpret these findings, acknowledging the inherent selec- Authorship tion bias and the fact that analyses were not time dependent. Contribution: D.M.-C. and P.M. conceived the study; D.M.-C., The dilemma about considering sAML an independent prognostic J.E.M.-V., and P.M. analyzed and interpreted the data and wrote the factor remains unsolved because published manuscripts revealed paper; D.M.-C. and P.M. performed the statistical analyses; D.M.-C., discrepant results.5,21,22,46 In this large study, we showed that J.E.M.-V., J.S., P.M.-S., E.R.-A., C.G., E.A., J.B., J.L.L.-L., T.B., A.E., sAML is an independent risk factor. Nevertheless, in line with a Ger- M.C., C.R.-M., M.L.-P., M.T., L.A., M.L.A., M.J.S., J.L., J.I.R.-G., C.B., man cohort of patients with t-MN,21 significantly worse OS was L.C.-B., R.G.-B., E.L.-R., S.V., P.H., D.G.-B., M.M.H., G.V.E., M.I.G.-R., A.C., G.B., A.B., J.M., B.B., M.A.S., and P.M. included data Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 observed only among patients receiving IC strategies, as compared with de novo AML, whereas therapeutic outcomes were as bad of patients treated in their institutions, reviewed the manuscript, and among all unfit patients. Some studies have shown a different prog- contributed to the final draft. nosis depending on the type of sAML; patients with MPN who Conflict-of-interest disclosure: The authors declare no competing develop a leukemic transformation could have dismal out- financial interests. comes.43,47 The population-based study by Hulegardh et al reported 1-year OS of 10% in MPN-AML, 20% in t-AML, and 43% A complete list of the institutions and clinicians participating in in MDS-AML.3 However, in our cohort, we observed lower OS the PETHEMA epidemiologic registry of acute myeloid leukemia and among patients with MDS/MPN-, MDS-, and MPN-AML compared acute promyelocytic leukemia appears in “Appendix.” with t-AML. As previously published, patients with sAML with CBF ORCID profiles: D.M-C., 0000-0001-7540-4091; J.E.M-V., had a longer OS than those with intermediate and adverse genetic 0000-0002-0369-5341; J.B., 0000-0001-8229-1208; C.B., risks.48 However, the prognostic impact of some well-established 0000-0002-0735-2602; L.C-B., 0000-0002-8359-6203; E.L-R., gene mutations in sAML remains unclear (eg, FLT3 and NPM1). 0000-0003-1490-0678; D.G-B., 0000-0002-0353-3457; J.M., Our study supports the favorable OS impact of NPM1 suggested 0000-0003-0240-4749; P.M., 0000-0002-3275-5593. by Sto€lzel et al,49 but we were unable to demonstrate any prognos- Correspondence: Pau Montesinos, Hematology Department, Hos- tic role of FLT3-ITD mutations in sAML. Our multivariable model cnic La Fe, Avinguda Fernando Abril Martorell pital Universitari i Polite confirmed previous risk factors for OS in sAML as age, ECOG, 106, CP 46026 Valencia, Spain; e-mail: montesinos_pau@gva.es. adverse cytogenetic risk, and lower platelet count,10,16,21,22,24,49-52 but we also found new independent variables such as higher WBC count and BM blast percentage, low albumin levels, creatinine Appendix .1.3 mg/dL, and increased alkaline phosphatase. We were not able to confirm an independent favorable risk of patients with t-AML PETHEMA GROUP who received only prior radiotherapy, as suggested by Nardi et al.53 Institutions and clinicians participating in the PETHEMA epidemio- Our study has some limitations: (1) This is a real-life analysis, but logic registry of acute myeloid leukemia and acute promyelocytic our registry was not capturing, by far, most patients with AML in leukemia. Spain and Portugal. (2) Molecular data (eg, P53 and IDH) were not Argentina (Grupo Argentino para el Tratamiento de la Leucemia analyzed. (3) The study period started in 1990, but most cases of Aguda [GATLA])—Hospital de Clınicas, Buenos Aires: F. Rojas; sAML were included after 2010 (Table 2). (4) For some variables, H. Longoni; Fundaleu, Buenos Aires: G. Milone, I. Fern andez, the proportion of missing data precluded granular analyses (eg, Clınica Conciencia, Neuqu en: R. Ramirez; Hospital Rossi, La Plata: impact of cumulative doses of cytotoxic agents). C. Canepa, S. Saba, G. Balladares, Hospital General San Martin, In conclusion, this large study confirms that the frequency of adverse Parana: G. Milone, C. Ventiurini, R. Mariano, P. Negri; Hospital Ital- features, such as older age, worse performance status, and adverse iano de La Plata, La Plata: M.V. Prates, J. Milone; Hospital General karyotype, is by far higher in sAML than in de novo AML. In addition, San Martın, La Plata: P. Fazio, M. Gelemur; Hospital Clemente Alva- sAML itself should be considered an independent risk factor, espe- rez, Rosario: G. Milone, S. Ciarlo, F. Bezares; Hospital de Cordoba, cially for patients treated with IC approaches. Although the best ther- Co rdoba: L. Lo pez, Hospital Privado de Co rdoba, Co rdoba: apeutic results are obtained after IC followed by an allogeneic HSCT, J.J. Garcıa; Instituto Privado Hematologıa, Paran a: P. Negri, this strategy is only accomplished in a minority of patients. Given the M. Giunta, G. Milone; Hospital Teodoro Alvarez, Buenos Aires: challenging condition that they represent, obtaining improvements in M. Kruss; Hospital Torn u, Buenos Aires: D. Lafalse, G. Milone; Hos- sAML should be a priority, warranting that this field become an active pital Gobernador Centeno, La Pampa: E. Marquesoni, M.F. Casale; area of basic and clinical research in the forthcoming years. Hospital Italiano de Buenos Aires, Buenos Aires: A. Gimenez, E.B. Brulc, M.A. Perusini; Complejo Me dico Policıa Federal, La Plata: G. Milone, L. Palmer; Colombia (Asociacio n Colombian de Acknowledgments Hematologıa y Oncologıa [ACHO])—Clınica La Estancia, Popay an: The authors would like to thank Marıa D. Garcıa, Carlos Pastor- M.E. Correa; Fundaci on Valle del Lili, Cauca: F.J. Jaramillo, ini, Mar Benlloch, and Alba Blazquez for data collection and J. Rosales; Instituto FOSCAL, Bucaramanga: C. Sossa, J.C. Herrera; management. Hospital Pablo Tobo n Uribe, Antioquia: M. Arango; Poland (Polish 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 CHARACTERISTICS OF 2310 SECONDARY AML PATIENTS 1291 Adult Leukemia Group [PALG])—City Hospital Legnica, Baja Silesia: C adiz: R. Saldan ~a, F. Rodrıguez, E. Martın, L. Hermosın; Hospital J. Holojda; IHIT Hematology and Transfusiology Institute, Warszawa: Universitario Puerta del Mar, C adiz: M.P. Garrastazul, I. Marchante, A. Golos, A. Ejduk; Wojewo dzki Szpital Specjalistyczny w Olsztynie, J.A. Raposo, F.J. Capote; Hospital U. Marque s de Valdecilla, Canta- Olsztyn: B. Ochrem; WIM (Military Institute of Medicine in Warsaw), bria: M. Colorado, A. Batlle, L. Ya~ nez, S. Garcıa, P. Gonz alez, Warszawa: G. Małgorzata; Poland Medical University of Warsaw E.M. Ocio, M. Briz, A. Berm udez, S. Garcıa; Consorcio Hospitalario Banacha, Warszawa: A. Waszczuk-Gajda, J. Drozd-Sokolowska, Provincial de Castello n, Castellon: C. Jime nez, S. Beltran; Hospital M. Czemerska, M. Paluszewska; Medical University School Gdansk, de Vinaroz: M. Montagud; Hospital Universitario de La Plana, Gdansk: E. Zarzycka; Wojewo dzki Szpital Specjalistyczny im. Sw. Castello n: I. Castillo; Hospital General de Castello n, Castellon:  Jadwigi Sla˛skiej, Opole: A. Masternak; Hospital Brzozow, Brzozow: R. Garcıa, A. Gasco n, J. Clavel, A. Lancharro, L. Lnares; Hospital Dr. Hawrylecka; Medical University Lublin, Lublin: M. Podhoreka, Santa B arbara, Ciudad Real: M.M. Herr aez, A. Milena; Hospital Vir- K. Giannopoulos, T. Gromek; Medical University Bialystok, Bialystok: gen de Altagracia, Ciudad Real: M.J. Romero, Hospital General de J. Oleksiuk; Silesian Medical University Katowice, Katowice: Ciudad Real, Ciudad Real: B. Hern andez, C. Calle, R. Benegas; nas, Ciudad Real: Dr. Bolıvar; Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 BA. Armatys, G. Helbig; Universitary Hospital Wroclaw, Wroclaw: Hospital Gutierrez Ortega de Valdepe~ M. Sobas; Poznan University of Medical Sciences, Pozna: Hospital General La Mancha Centro, Ciudad Real: M.A. Pozas; Hos- A. Szczepaniak; Rydigier City Hospital Krakow, Krakow: E. Rzenno, pital Reina Sofia, C ordoba: J. Serrano, F.J. Dorado, J. S anchez, M. Rodzaj; Collegium Medicum Jagiellonian University Krakow, M.C. Martınez; Hospital Virgen de la Luz, Cuenca: C.J. Cervero , Krakow: B. Piatkowska-Jakubas; City Hospital Rzeszo w, Rzeszo w: M.J. Busto; Hospitales HUVN-HC San Cecilio de Ganada, Granada: A. Skret; Medical University Lodz, Lodz: A. Pluta, M. Czemerska; M. Bernal, E. Lo pez, L. Moratalla, Z. Mesa, M. Jurado, A. Romero, Center of Oncology Kielce, Kielce: E. Baran ska; Medical University P. Gonz alez; Complejo Hospitalario Universitario Granada, Granada: of Warsaw, Warsaw: M. Paluszewska; Portugal—Hospital de Santa L. Moratalla, A. Romero, L. Lo pez; Hospital Universitario de Guadala- Maria-Lisboa, Lisboa: G. Vasconcelos, J. Brioso; IPOFG Lisboa, jara, Guadalajara: M. Dıaz, D. De Miguel, A.B. Santos, J. Arbeteta; Lisboa: A. Nunes, I. Bogalho; Centro Hospitalar e Universit ario de Hospital Donostia, Donosti: E. P erez, N. Caminos, N. Uresandi, Coimbra, Coimbra: A. Espadana, M. Coucelo, S. Marini, J. Azevedo, N. Argoitiaituart, T. Artola, J. Swen, A. Uranga, I. Olazaba, M. Lizuain, A.I. Crisostomo, L. Ribeiro, V. Pereira; Centro Hospitalar de Lisboa E. Gainza, P. Romero; Hospital Juan Ram on Jimenez Huelva, Huelva: Central E.P.E., Lisboa: A. Botelho; Instituto Portugue ^s Oncologia do E. Gil, A.J. Palma, K.G. Go mez, M. Sole , J.N. Rodrıguez; Hospital Porto Francisco Gentil, Porto: J.M. Mariz; Centro Hospitalar S~ ao San Jorge, Huesca: I.M. Murillo, J. Marco, J. Serena, V. Marco; Hospi- Jo~ao, Porto: J.E. Guimaraes, E. Aguiar; Centro Hospitalar do Porto tal de Barbastro, Huesca: M. Perella, L. Costilla; Hospital General E.P.E., Porto: J. Coutinho; Spain (Programa Espa~ nol de Tratamiento Ciudad de Jaen, Ja en: J.A. Lopez, A. Baena, P. Almagro; Hospital de las Hemopatıas Malignas [PETHEMA])—Complejo Hospitalario San Pedro de Logron ~o, La Rioja: M. Hermosilla, A. Esteban, Universitario A Corun ~a, A Corun ~a: V. Noriega, L. Garcıa, C. Varela, B.A. Campeny, M.J. N ajera, P. Herrra; Hospital Insular de Las Pal- G. Debe n, M. R. Gonzalez; Hospital Clınico Universitario de mas, Las Palmas: R. Fern andez, J.D. Gonz alez, L. Torres; Hospital Santiago, A Corun ~a: M. Encinas, A. Bendan ~a, S. Gonzalez, J.L. Bello, Dr. Negrın, Las Palmas: S. Jime nez; M.T. Go mez, C. Bilbao, M. Albors; Hospital General de Albacete, Albacete: L. Algarra, C. Rodrıguez; Hospital Doctor Jose  Molina Orosa, Las Palmas: J.R. Romero, J.S. Bermon, M.J. Varo; Hospital Vinalopo , Alicante: A. Hong, Y. Ramos de Lao n, V. Afonso; Hospital Universitario de V. Lopez, E. L opez; Hospital Virgen de los Lirios, Alcoy: C. Mora, Le on, Leon: F. Ramos, M. Fuertes; Hospital Comarcal del Bierzo, C. Amoro s; Hospital General Elche, Alicante: E. Lo pez, A. Romero; Leo n: E. de Cabo, C. Aguilera, M. Megido; Hospital Universitari Hospital Torrevieja Salud, Alicante: A. Jaramillo, N. Valdez, I. Molina, Arnau de Vilanova de Lleida, Leida: T. Garcıa; Hospital Lucus A. Fernandez, B. Sanchez; Hospital de la Marina Baixa Villajoyosa, Augusti, Lugo: E. Lavilla, M. Varela, S. Ferrero, M.J. S anchez, Alicante: A. Garcıa; Hospital General de Elda, Alicante: V. Casta~ no, L. L opez, J. Arias, L. Vizcaya; Hospital Infanta Sofıa, Madrid: T. Lopez, J. Bernabeu; Hospital de Denia-Marina Salud, Alicante: A. Rold an, A. Vilches, M.J. Penalva, J. V azquez; Hospital Central de M.J. S anchez; Hospital de la Vega Baja de Orihuela, Alicante: la Defensa G omez Ulla, Madrid: M.T. Calder on, A. Matilla, C. Serı, C. Fernandez; Hospital General de Alicante, Alicante: C. Gil, M.J. Otero, N. Garcıa, E. Sandoval; Hospital de Fuenlabrada, Madrid: C. Botella, P. Fernandez, M. Pacheco, F. Tarın; J.J. Verd u; Complejo C. Franco, R. Flores, P. Bravo, A. Lo pez; Hospital Fundacio n Jimenez Hospitalario Torrecardenas, Almeria: M.J. Garcıa, A. Mellado, Dıaz, Madrid: J.L. Lo pez, C. Blas, A. Dıez, J.M. Alonso, C. Soto, M.C. Garcıa, J. Gonzalez; Hospital Central de Asturias, Asturias: A. Arenas; Hospital U. Prıncipe de Asturias, Madrid: J. Garcıa, T. Castillo, E. Colado, S. Alonso; Complejo Asistencial Avila,  Avila: Y. Martın, P.S. Villafuerte, E. Magro; Hospital Puerta de Hierro, I. Recio, M. Cabezudo, J. Davila, M.J. Rodrıguez, A. Barez, B. Dıaz; Madrid: G. Bautista; A. De Laiglesia; Hospital Gregorio Maran ~o n, Hospital Don Benito-Villanueva, Badajoz: J. Prieto; Institut Catala Madrid: G. Rodrıguez, L. Sol an, M. Chicano, P. Balsalobre,  d'Oncologia LHospitalet, Barcelona: M. Arnan, C. Marın, M. Mansilla; S. Monsalvo, P. Font, D. Carbonell, C. Martınez; Hospital U. La Paz, Hospital de Cruces, Bizkaia: A. Balaberdi, M.E. Amutio, R.A. del Orbe, Madrid: K. Humala, A.E. Kerguelen, D. Hern andez, M. Gasior, I. Ancin, J.C. Ruız; Hospital Galdakao-Usansolo, Bizkaia: M. Olivalres, P. Go mez, I. Sanchez; Hospital Madrid Norte Sanchinarro, Madrid: C. G omez, I. Gonzalez, M. Celis, K. Atutxa, T. Carrascosa, T. Artola, S. Redondo, L. Llorente, M. Bengochea, J. P erez; Hospital Sanitas M. Lizuain; Basurtuko Ospitalea, Bizkaia: J.I. Rodriguez, O. Arce, Torrejon, Madrid: A. Sebrango, M. Santero, A. Morales; Hospital La J.A. Marquez, J. Atuch, F. Marco de Lucas, Z. Dıez, B. Davila; Hospi- Princesa, Madrid: A. Figuera, P. Villafuerte, A. Alegre, E. Fern andez; tal Santos Reyes, Burgos: R. Cantalejo, M. Dıaz; Hospital Universi- Hospital Ruber Internacional, Madrid: A. Alonso; Hospital 12 de tario de Burgos, Burgos: J. Labrador, F. Serra, G. Hermida, F.J. Dıaz, Octubre, Madrid: M.P. Martınez, J. Martınez, M. T. Cedena, L. Moreno;  P. de Vicente, R. Alvarez: Hospital Santiago Apo stol, Burgos: MD Anderson Cancer Center, Madrid: A. De la Fuente; Hospital C. Alonso, Hospital San Pedro de Alcantara, Caceres: J.M. Bergua; Sanitas La Zarzuela, Madrid: D. Garcıa; Hospital Universitario Hospital Campo Aran ~uelo, Caceres: N. Ugalde; Hospital Virgen del Quiron, Madrid: C. Chamorro, V. Pradillo, E. Martı, J. M. S anchez, Puerto, Caceres: E. Pardal; Hospital General Jerez de la Frontera, I. Delgado, A. Alonso; Hospital Rey Juan Carlos, Madrid: B. Rosado, 1292  et al MARTINEZ-CUADRON 22 FEBRUARY 2022 • VOLUME 6, NUMBER 4 A. Velasco, C. Miranda, G. Salvatierra, J.M. Alonso, J.L. Lo pez; Hospi- Hospital U. Virgen Macarena, Sevilla: O. Pe rez, J.A. Vera, C. Mun~oz, tal Infanta Leonor, Madrid: M. Foncillas, J.A. Hernandez; Hospital Uni- A. Rodriguez, N. Gonz alez; Hospital U. Virgen del Rocio, Sevilla: versitario de Getafe, Madrid: C. Escolano, L. Garcıa, I. Delgado; J.A. P erez, E. Soria, I. Espigado, J. Falantes, I. Montero, P. Garcıa, Hospital Clınico San Carlos, Madrid: C. Benabente, R. Martınez, E. Rodrıguez, E. Carrillo, T. Caballero, C. Garcıa; Hospital Virgen de M. Polo, E. Anguita; Hospital Universitario Severo Ochoa, Madrid: Valme, Sevilla: C. Couto, I. Simo n, M. Go mez; Hospital Virgen del R. Riaza, G. Amores, M.J. Requena; Hospital Universitario Fundaci on Miron de Soria, Soria: C. Aguilar; Hospital Universitario Canarias, Alcorco n, Madrid: F. Javier, L. Villaloo n; Hospital Universitario Mon- Tenerife: B.J. Gonz alez, S. Lakhwani, A. Bienert, B. Gonz alez; Hospi- cloa, Madrid: C. Alaez, V. Pradillo, S. Nistal, B. Navas; Hospital Uni- tal Universitario Nuestra Sen ~ora de Candelaria, Tenrife: A. Cabello, versitario de M ostoles, Madrid: J. Sanchez, M.A. Andreu; Hospital A.Y. Oliva, H. Gonz alez; Hospital Obispo Polanco, Teruel: Ramon y Cajal, Madrid: P. Herrera, J. Lo pez; Hospital U. Virgen de la N. Gonz alez, Hospital de Alcan ~iz, Teruel: L. Sancho, M. Paricio, Victoria, Malaga: M. Garcıa, M.J. Moreno, A. Fern andez, L. Perdiguer; Hospital General Nuestra Sen ~ora del Prado, Toledo: M.P. Queipo; Hospital Quir onsalud Malaga, Malaga: A. Hern andez; F. Solano, A. Lerma, M.D. Martınez; Hospital Virgen de la Salud de Hospital Regional de Malaga, Malaga: M. Barrios, A. Heiniger, mez, A. Yeguas; Hospital U. La Fe, Valencia: Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/4/1278/1872139/advancesadv2021005335.pdf by guest on 09 February 2023 Toledo, Toledo: M.I. Go A. Jime nez, A. Contento, F. Lo pez, M. Alcala; Hospital Vithas Xanit P. Montesinos, E. Barrag an, C. Sargas, R. Amigo, D. Martinez, Internacional, Malaga: S. Lorente, M. Gonzalez, E.M. Morales, B. Boluda, R. Rodrıguez, E. Acun ~a, I. Cano; Hospital de Requena, J. Gutierrez; Hospital Virgen del Castillo, Murcia: M.J. Serna, Valencia: A. Escriv a, M. Pedre~ no; Hospital de Lluis Alcanyis de V. Beltran; Hospital Santa Lucıa de Cartagena, Murcia: M. Romera, Xativa, Valencia: R. Renart; IVO (Instituto Valenciano de Oncologıa), M. Berenguer, A. Martınez, A. Tejedor; Hospital Morales Meseguer, Valencia: A. Navalo n; Hospital de Sagunto, Valencia: I. Castillo, Murcia: M. L. Amigo, F. Ortu~ no, L. Garcıa, A. Jerez, O. L opez; Hospi- M. Orts; Hospital Dr. Peset, Valencia: M.J. Sayas, M.J. Fern andez, tal U. Virgen de la Arrixaca, Murcia: J.M. Moraleda, P. Rosique, M.L. Juan, E. Go mez, M. Gimeno, E. Donato, M. Cejalvo, J. Marco; J. Go mez, M.C. Garay; Hospital Los Arcos Mar Menor, Murcia: Hospital Clınico Universitario, Valencia: M. Tormo, M. Calabuig, P. Cerezuela, C. Martınez, A.B. Martınez, A. Gonzalez; Hospital STa B. Navarro, I. Martin, E. Villamont, A. Miralles; Hospital de La Ribera, Ma del Rosell, Murcia: J. Iban ~ez; Clınica San Miguel, Navarra: Valencia: R. Lluch; Hospital Casa de la Salud, Valencia: J. Garcıa; M.J. Alfaro; Complejo Hospitalario de Navarra, Navarra: M. Mateos, Hospital de Gandıa, Valencia: M. Moragues, M.A. Ruiz; Hospital M.A. Gon ~i, M.A. Araiz, A. Gorosquieta, M. Zudaire, M. Viguria, Arnau de Vilanova, Valencia: A. Lo pez, C. Benet, M. Valero; Hospital A. Zabala, M. Alvarellos, I. Quispe, M.P. Sanchez, G. Hurtado, General de Valencia, Valencia: M. Linares, R. Collado, M. Orero, M. Pe rez, Y. Burguete, N. Areizaga, T. Galicia; Clınica Universitaria P. Iban ~ez, M.J. Lis, P.L. Perez, M. Roig, M. Lopez, A.V. Mena; Hospital de Navarra, Navarra: J. Rifo n, A. Alfonso, F. Pro sper, M. Marcos, Manises, Valencia: I. Pico n, V. Canovas, A. Palacios, E. Martı; Hospi- L.E. Tamariz, V. Riego. A. Manubens, M.J. Larrayoz, M.J. Calasanz, tal Clınico de Valladolid, Valladolid: R. Cuello, J. Borrego, M. Burgois; A. Man ~u , B. Paiva, I. Vazquez, L. Burgos; Complejo Hospitalario Hospital Rio Hortega, Valladolid: A. Cantalapiedra, O. Norberto, de Ourense (CHOU), Ourense: M. Pereiro, M. Rodrıguez, E. Angomas, B. Cidoncha; Hospital Universitario Araba, M.C. Pastoriza, J.A. Mendez, J.L. Sastre, M. Iglesias, C. Ulibarrena, Victoria: L. Cuevas, D. Robles, A. Mendiazabal, I. Oiartzabal, F. Campoy; Hospital Valdeorras, Ourense: D. Jaimes; Hospital Rio J.M. Guinea de Castro; Hospital Virgen de la Concha, Zamora: Carrion, Palencia: J. M. Alonso, B. Albarran, J. Solano, A. Silvestre; C. Montes, M. Pe rez, L. Garcıa; Hospital Royo Villanova, Zaragoza: Complexo Hospitalario Universitario de Vigo, Vigo: C. Albo, V. Carrasco, A. P erez, L. L opez, J.J. Moneva; Hospital Clınico S. Suarez, C. Loureiro, I. Figueroa, M. Rodrıguez, M.A. Fern andez, U. Lozano Blesa, Zaragoza: M. Olave, E. Bonafonte, L. Mayor, A. Martınez, C. Podero s, J. Vazquez, L. Iglesias, A. Nieto, T. Torrado, G. Azaceta, L. Palomera; Hospital Ernest Lluch Martin, Zaragoza: A.M. Martınez; Hospital Provincial de Pontevedra, Pontevedra: M. Malo, M.J. Escobar; Hospital Quiron Salud Zaragoza, Zaragoza: M.L. Amador, P. Oubi~ na, E. Feij o, A. Dios, I. Loyola, R. Roreno; Hos- J.M. Grasa; Hospital Miguel Servet, Zaragoza: B. De Rueda, A. Aul es,  pital POVISA, Pontevedra: A. Simiele, L. Alvarez, V. Turcu; Hospital C. Salvador, V. Anso , A. Iborra, P. Delagado, A. Rubio; and Uruguay— U. Salamanca, Salamanca: B. Vidriales, M. Gonzalez, R. Garcıa, Hospital de Clınicas, Montevideo: M. Stevenazzi, I. Alpire, V. Irigoin, A. Avenda~ no, C. Chill on, E. Perez, V. Gonzalez; Hospital General La L. Dıaz, C. Guillermo, R. Guadagna, S. Grille, C. Oliver, M. Boada, Palma, Santa Cruz de Tenerife: J.V. Govantes, S. Rubio, M. 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