Published Ahead of Print on March 11, 2016, as doi:10.3324/haematol.2015.140053. Copyright 2016 Ferrata Storti Foundation. Late thyroid complications in childhood acute leukemia survivors. An L.E.A. study by Claire Oudin, Pascal Auquier, Yves Bertrand, Philippe Chastagner, Justyna Kanold, Marilyne Poirée, Sandrine Thouvenin, Stephane Ducassou, Dominique Plantaz, Marie-Dominique Tabone, Jean-Hugues Dalle, Virginie Gandemer, Patrick Lutz, Anne Sirvent, Virginie Villes, Vincent Barlogis, André Baruchel, Guy Leverger, Julie Berbis, and Gérard Michel Haematologica 2016 [Epub ahead of print] Citation: Oudin C, Auquier P, Bertrand Y, Chastagner P, Kanold J, Poirée M, Thouvenin S, Ducassou S, Plantaz D, Tabone MD, Dalle JH, Gandemer V, Lutz P, Sirvent A, Villes V, Barlogis V, Baruchel A, Leverger G, Berbis J, and Michel. Late thyroid complications in childhood acute leukemia survivors. An L.E.A. study. Haematologica. 2016; 101:xxx doi:10.3324/haematol.2015.140053 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.
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Supplemental data Supplemental methods Data regarding disease type, treatment modalities, irradiation modalities, and transplantation procedure were collected from the medical records. The chemotherapy protocol and the conditioning regimen depended on the protocols used at the time of transplantation, the underlying disease, disease status, and history of central nervous system irradiation involvement. The central nervous system irradiation dose (18 or 24 grays), field (cranial or cranio-spinal) and indication depended on the protocol used at the time of treatment.
Gender Hypothyroidism evaluation Thyroid cancer evaluation Participants group (n=588) Non participants group (n=77) p- value Participants group (n=502) Non participants group (n=163) Male n (%) 340 (57.8) 38 (49.3) 0.16 284 (56.6) 94 (57.7) 0.81 Female n (%) 248 (42.2) 39 (50.7) 218 (43.4) 69 (42.3) Leukemia type Acute myeloid leukemia n (%) 146 (24.8) 15 (19.5) 0.30 118 (23.5) 43 (26.4) 0.46 Acute lymphoid leukemia n (%) 442 (75.2) 62 (80.5) 384 (76.5) 120 (73.6) Relapse p- value Yes 237 (40.3) 13 (16.9) <10-3 207 (41.2) 43 (26.4) 0.001 No 351 (59.7) 64 (83.1) 295 (58.5) 120 (73.6) Age at leukemia diagnosis (years) 6.5 (3.4-6.3 (3.4-0.81 7.4 ± 0.2 7.2 ± 0.4 0.72 Median (min-max) 11.2) 11.7) Treatment modality CNS irradiation, no HSCT n (%) 143 (24.3) 51 (66.2) <10-3 119 (23.7) 75 (46) <10-3 HSCT with TBI, with previous CNS irradiation n (%) 21 (3.6) 2 (2.6) 19 (3.8) 4 (2.5) HSCT with TBI, without previous CNS irradiation n (%) 289 (49.1) 8 (10.4) 255 (30.9) 42 (25.8) HSCT without TBI, with previous CNS irradiation n (%) 15 (2.6) 1 (1.3) 10 (2) 6 (3.7) HSCT without TBI, without previous CNS irradiation n (%) 120 (20.4) 15 (19.5) 99 (19.7) 36 (22.1) Age at transplantation/irradiation < 10 years n (%) 361 (61.4) 50 (64.9) 0.55 306 (61) 105 (64.4) 0.43 10 years n (%) 227 (38.6) 27 (35.1) 196 (39) 58 (35.6) Hematopoietic stem cell transplantation (HSCT) type Autologous n(% of transplanted patients) 91 (20.4) 1 (3.8) 0.04 70 (18.3) 22 (25) 0.15 Allogeneic n(% of transplanted patients) 354 (79.6) 25 (96.2) 313 (81.7) 66 (75) Age at transplantation (years) 8.8 ± 0.2 7.8 ± 1.0 0.32 8.9 ± 0.3 8.2 ± 0.5 0.26 Conditioning regimen before HSCT TBI-based n(% of transplanted patients) 310 (69.7) 10 (38.5) 0.001 274 (71.5) 46 (52.3) <10-3 Non-TBI based n(% of transplanted patients) 135 (30.3) 16 (61.5) 109 (28.5) 42 (47.7) Central nervous system (CNS) irradiation Yes n (%) 179 (30.4) 54 (70.1) <10-3 148 (29.5) 85 (52.1) <10-3 No n (%) 409 (69.6) 23 (29.9) 354 (70.5) 78 (47.9) Age at CNS irradiation (years) 8.5 ± 0.3 8.6 ± 0.7 0.84 8.6 ± 0.4 8.4 ± 0.5 0.70 CNS irradiation type Cranial irradiation n(% of CNS irradiation recipients) Cerebro spinal irradiation n(% of CNS irradiation recipients) Unknown n(% of CNS irradiation recipients) CNS irradiation dose 18 grays n(% of CNS irradiation recipients) 24 grays n(% of CNS irradiation recipients) 122 (68.2) 41 (75.9) 0.25 106 (71.6) 57 (67) 0.48 53 (29.6) 12 (22.2) 39 (26.4) 26 (30.6) 4 (2.2) 1 (1.9) 3 (2) 2 (2.4) 134 (74.9) 39 (72.2) 0.10 114 (77) 59 (69.4) 0.32 36 (20.1) 7 (13) 23 (15.5) 20 (23.5)
Other n(% of CNS irradiation recipients) 8 (4.5) 6 (11.1) 9 (6.1) 5 (5.9) Time from diagnosis to last visit (years) 12.6 [ 6.4-13.9 [6.0-12.5 [ 6.4-13.9 [6.3-0.49 Median (min-max) 18.8] 21.3] 19.1] 19.1] 0.45 Supplemental Table 1. Patients characteristics. Comparison between participant and non participant patients. CNS: central nervous system; HSCT: hematopoietic stem cell transplantation; TBI: total body irradiation
2162 patients with a new LEA evaluation during years 2004-2012 1497 patients treated with chemotherapy only (not eligible) 665 eligible patients treated with CNS irradiation and/or HSCT Thyroid function analysis Thyroid tumor analysis 77 patients who had no complete thyroid function evaluation (eligible not included in function analysis) 163 patients who had no thyroid tumor evaluation (eligible not included in tumor analysis) 588 patients with at least one thyroid function evaluation (included in thyroid function analysis) 502 patients with at least one thyroid tumor evaluation by ultrasound scan (included in thyroid tumor analysis) Supplemental figure: flow chart. CNS: central nervous system, HSCT: hematopoietic stem cell transplantation
Number (%) p-value 10 years Cumulative incidence (%) [95%CI] 20 years Cumulative incidence (%) [95%CI] Gender Male 49 (14.5) 15.0 [11.3-19.9] 18.4 [13.9-24.1] Female 50 (20.4) 0.16 18.5 [13.7-24.9] 28.8 [22.0-37.3] Leukemia type Acute myeloid leukemia 15 (10.3) 11.4 [6.9-18.7] 14.5 [8.2-24.9] Acute lymphoid leukemia 84 (19.2) 0.09 18.0 [14.3-22.5] 25.3 [20.5-31.0] Age at transplantation/irradiation < 10 years 71 (19.8) 18.6 [14.6-23.6] 26.2 [20.9-32.4] 10 years 28 (12.5) 0.13 13.2 [8.7-19.8] 16.9 [11.4-24.8] Hematopoietic stem cell transplantation type Autologous 22 (25.3) 20.6 [13.3-31.1] 25.3 [17.0-36.6] Allogeneic 71 (20.2) 0.46 22.8 [17.9-28.7] 32.5 [25.4-41.1] Treatment modality HSCT without TBI. without previous CNS irradiation 9 (7.5) 7.0 [3.5-13.5] 12.1 [4.9-28.4] CNS irradiation. no HSCT 6 (4.2) 1.0 [0.1-6.8] 5.0 [1.9-13.2] HSCT with TBI. with previous CNS irradiation 6 (33.3) <10-3 23.0 [9.3-50.3] 30.0 [13.6-58.1] HSCT with TBI. without previous CNS irradiation 72 (25.1) 28.4 [22.7-35.1] 34.7 [28.2-42.3] HSCT without TBI. with previous CNS irradiation 6 (42.9) 14.9 [3.9-47.7] 39.8 [18.7-71.2] CNS irradiation type Cranial irradiation 10 (8.4) 3.7 [1.4-9.5] 8.1 [3.8-16.6] Cerebro spinal irradiation 7 (13.5) 0.37 4.8 [1.2-17.7] 17.6 [8.1-35.8] CNS irradiation dose 18 grays 7 (5.4) 2.8 [0.9-8.6] 7.0 [3.1-15.2] 24 grays 8 (22.2) 6.8 [1.7-25.0] 23.9 [11.4-46.0] Other 3 (37.5) 0.01 25.0 [6.9-68.5] 25.0 [6.9-68.5]
Supplemental Table 2. Univariate analysis: risk factors for primary hypothyroidism (n=582). CNS: central nervous system; HSCT: hematopoietic stem cell transplantation; TBI: total body irradiation
Variables N % ahr 95%CI p-value Age at transplantation/irradiation < 10 years 358 61.5 1 10 years 224 38.5 0.58 0.37-0.91 0.02 Gender Male 337 57.9 1 Female 245 42.1 1.46 0.97-2.17 0.07 Leukemia type Acute lymphoid leukemia 437 75.1 1 Acute myeloid leukemia 145 24.9 0.60 0.31-1.13 0.12 Treatment modality HSCT without TBI, without previous CNS irradiation 120 20.6 1 CNS irradiation, no HSCT 143 24.6 0.26 0.09-0.80 0.02 HSCT with TBI, with previous CNS irradiation 18 3.1 2.15 0.69-6.64 0.18 HSCT with TBI, without previous CNS irradiation 287 49.3 2.69 1.22-5.91 0.01 HSCT without TBI, with previous CNS irradiation 14 2.4 3.04 1.05-8.78 0.04 Supplemental Table 3. Risk factors for primary hypothyroidism: multivariate analysis (n=582). CNS: central nervous system; HSCT: hematopoietic stem cell transplantation; TBI: total body irradiation. In bold: significant values
The L.E.A study group Marseille: ALLOIN Anne-Lise, AUQUIER Pascal, BARLOGIS Vincent, BERBIS Julie, CHAMBOST Hervé, CURTILLET Catherine, ESMIOL Sophie, GALAMBRUN Claire, GARNIER Floriane, MICHEL Gérard, ORBICINI Delphine, OUDIN Claire, THURET Isabelle, VERCASSON Camille, VILLES Virginie, Nancy: CHASTAGNER Pascal, CLEMENT Laurence, CONTET Audrey, FOUYSSAC Fanny, LEMELLE Irène, MANSUY Ludovic, PERNET Marjolaine, PERROT Aurore, PHULPIN Aurélie, POCHON Cécile, SCHMITT Claudine, SERRIER Caroline, Nice: BELLMANN-ROQUEPLAN Françoise, DEVILLE Anne, HATHROUBI Chokri, LE MEIGNEN-DIOP Marion, MONPOUX Fabrice, POIREE Maryline, ROHRLICH Pierre-Simon, SOLER Christine, Clermont-Ferrand: CHAMBON Fanny, DORE Eric, ISFAN Florentina, KANOLD Justyna, ROUEL Nadège, Grenoble: ADJAOUD Dalila, ARMARI-ALLA Corinne, CACACE Sophie, PAGNIER Anne, PLANTAZ Dominique, SCHIFF Isabelle, Lyon: BERTRAND Yves, GARNIER Nathalie, HALFON-DOMENECH Carine, HU Julie-Yi, KEBAÏLI Kamila, RENARD Cécile, Paris Trousseau: AUVRIGNON Anne, BOUAYAD AGHA Latéfa, DOLLFUS Catherine, DONADIEU Jean, FASOLA Sylvie, LANDMAN-PARKER Judith, LEVERGER Guy, PELLEGRINO Béatrice, PETIT Arnaud, TABONE Marie Dominique, St Etienne: BERGER Claire, DAVID Audrey, ODIER Françoise, STEPHAN Jean Louis, THOUVENIN-DOULET Sandrine, Rennes: BAYART Sophie, BONNEAU Jacinthe, CHAPPE Céline, GANDEMER Virginie, LAMOUR Anne- Marie, SOK-FEDELE Phaktra, TAQUE Sophie, TOUTAIN Fabienne, Montpellier: HAOUY Stéphanie, MOPHAWE Ornellia, SAUMET Laure, SIRVENT Nicolas, SIRVENT Anne, Paris St Louis Robert Debré: BARUCHEL André, BRETHON Benoît, LEBLANC Thierry, MOUKOKO Marie- Noelle, RAY-LUNVEN Anne-France, AVRAN David, AZARNOUSH Saba, CUINET Aurélie, DALLE Jean- Hugues, DUQUESNE Frédérique, FAHD Raymonda, LESCOEUR Brigitte, OUACHEE-CHARDIN Marie, YAKOUBEN Karima, Bordeaux: ALADJIDI Nathalie, ANSOBORLO Sophie, DE BOUYN-ICHER Céline, DUCASSOU Stéphane, JUBERT Charlotte, MERCHED Maria, NOTZ-CARRERE Anne, PEREL Yves, VERITE-GOULARD Cécile, Strasbourg: CERON-DURAN Sofia, LUTZ Patrick, PAILLARD Catherine, SPIEGEL Alexandra, Angers: BERARDI Elsa, BRASME Jean-François, COLIN Laure, DE CARLI Emilie, DUPLAN Mylène, PELLIER Isabelle, PROUST-HOUDEMONT Stéphanie.