Allogeneic Hematopoietic Stem Cell Transplantation
for Adults with Therapy-Related Acute Myeloid
Leukemia: a Retrospective Multicentre Study on
behalf of the SFGM-TC

Emmanuelle Tavernier ( ✉ emmanuelle.tavernier@chu-st-etienne.fr )

CHU Saint-Etienne

Gaëlle Rey

CHU Saint-Etienne

Elisabeth Daguenet

CHU Saint-Etienne

Paul Bonjean

CHU Saint-Etienne

Raynier Devillier

Institut Paoli-Calmettes https://orcid.org/0000-0002-4045-8310

Nathalie Fegueux

hopital lapeyronnie

Edouard Forcade

Bordeaux University Hospital https://orcid.org/0000-0002-8873-2868

micha srour

CHRU Lille https://orcid.org/0000-0002-8519-4187

patrice chevalier

Universite de Nantes - INSERM UMR U892

marie robin

Saint-Louis Hospital

Felipe Suarez

Hôpital Necker

Jean-Baptiste Micol

Institut Gustave Rousy https://orcid.org/0000-0003-0934-294X

helene labussiere

Centre Hospitalier Lyon Sud

Karin Bilger

CHU Strasbourg

Etienne Daguindau

CHRU de Besançon
**Jacques Olivier Bay**

CHU Clermont-Ferrand

**Amandine Fayard**

CHU Estaing

**Claude-Eric BULABOIS**

Université Grenoble Alpes

**Stéphanie Nguyen-Quoc**

Hopital Pitie Salpetriere, Service d'Hématologie Clinique

**Alexis Genthon**

Hopital Saint-Antoine

**Corentin Orvain**

Angers University Hospital https://orcid.org/0000-0002-8717-0824

**Pascal TURLURE**

CHU Limoges

**Michael Loschi**

CHU Nice https://orcid.org/0000-0002-4460-5939

**Xavier Poire**

Cliniques Universitaires U.C.L. de Mont-Godinne

**Gaella Guillerm**

CHU Morvan

**Yves Beguin**

University of Liege

**Natacha Maillard**

Hôpital la Mileterie

**jean-baptiste Mear**

university hospital of Rennes

**Emilie Chalayer**

CHU de Saint-Etienne

**Jerome Cornillon**

CHU de Saint-Etienne

**Article**

**Keywords:**

**Posted Date:** March 1st, 2023

**DOI:** https://doi.org/10.21203/rs.3.rs-2570049/v1
**License:** © Ⓟ This work is licensed under a Creative Commons Attribution 4.0 International License.

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**Version of Record:** A version of this preprint was published at Bone Marrow Transplantation on August 31st, 2023. See the published version at https://doi.org/10.1038/s41409-023-02082-5.
**Abstract**

We report the results from a multicentre retrospective study of 220 adult patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) for therapy-related acute myeloid leukemia (t-AML). Median age at t-AML diagnosis was 56 years, with a prior history of haematological (45%) or gynaecological neoplasia (37%). Median time from cytotoxic exposure to t-AML diagnosis was 54.7 months. At transplant, around 20% of patients had measurable residual disease and 3% of patients were not in complete remission. The median follow-up was 21.4 months (Q1-Q3, 5.9-52.8). At 12 months, overall survival (OS), event-free survival (EFS), and graft-versus-host-disease (GVHD)-free-relapse-free survival (GRFS) were 60.7% (95% CI 54.6-67.5), 52.8% (95% CI 46.5-68.4), and 44.1% (95% CI 37.6-51.8), respectively. At 5 years, OS, EFS, and GRFS were 44.1% (95% CI 37.4-52.1), 40.4% (95% CI 33.9-48.1), and 35.3% (95% CI 28.8-43.3), respectively. At last follow-up, 44% of patients were in complete remission (n = 96) and transplant-related mortality accounted for 39% of all deaths (n = 119).
Multivariable analysis revealed that uncontrolled t-AML at transplant was associated with lower EFS (HR 1.94, 95% CI 1.0-3.7, p = 0.041). In conclusion, alloHSCT for t-AML shows encouraging results and offers additional opportunity with the emergence of novel pre-graft therapies.

**Introduction**

Therapy-related acute myeloid leukaemia (t-AML) is defined as a clonal proliferation and expansion of abnormal differentiated myeloid blasts, as a consequence of exposition to cytotoxic therapy [1]. It results from mutational events induced by radiotherapy or chemotherapy. Indeed, cytotoxic therapies have the ability to induce mutagenic and clastogenic DNA damage, thus leading to genomic instability. Given that the bone marrow is highly sensitive to mutagenic effects, there are 4.7 times greater risk to develop leukaemia after therapy [2-4]. Among chemotherapies, the best known agents are alkylating agents and topoisomerase II inhibitors, and immunosuppressive therapies, methylating agents and thiopurines are also proven to be in cause [2, 3].

In recent years, the incidence of t-AML increased due to the improvement of survival and greater life expectancy in patients treated for cancer [5-8]. Based on a Swedish study, the incidence of t-AML almost doubled between 1997 and 2015, from a mean of 0.39 cases per 100,000 adult inhabitants between 1997 and 2006 to 0.63 between 2007 and 2015 [9]. In adults, t-AML accounts for approximately 5 to 10% of all AMLs [10, 11]. Despite recent advances, t-AMLs remain of poor prognosis. The median survival for t-AML patients treated with standard chemotherapy is about 8 to 14 months [3, 12]. In this context, allogeneic hematopoietic stem cell transplantation (alloHSCT) provides a curative approach for these patients. Unfortunately, little data is available in literature on alloHSCT in t-AML patients, mainly because these patients were excluded from clinical trials. Moreover, the existing literature on t-AML is often confounded by the inclusion of therapy-related myelodysplastic syndromes (t-MDS) and/or secondary AML (transformed from MDS or myeloproliferative neoplasms, s-AML) [13]. Here, we report the results of a retrospective, multicentre study to describe clinical outcomes of t-AML patients who underwent alloHSCT.
# Methods

# Data sources

This study was approved by the scientific committee of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Data were collected from the SFGM-TC transplant registry, the ProMIS database, from 24 transplantation centres in France and Belgium. Centres contributed detailed clinical, pathological, and outcome data to the registry as well as additional characteristics on primary tumor. All patients were included in the registry and gave their written informed consent for data acquisition and analysis.

# Patient selection

Patients with t-AML who were ≥ 18 year old and underwent alloHSCT between 2013 and 2019 were studied. Patients with prior malignancy but without exposure to cytotoxic agents or radiotherapy were excluded, as well as secondary AML (occurring after a myeloid disease, e.g. myelodysplastic syndrome or myeloproliferative disorder) with no cytotoxic therapy exposure. Based on the cytogenetic and molecular results, patients were stratified into favourable, intermediate, and poor risk categories following the MRC classification [14] and ELN-2017 risk stratification system [15].

# Study endpoints

Clinical outcomes included overall survival (OS), event-free survival (EFS), therapy-related mortality (TRM), and survival free from grade III-IV acute graft - versus - host disease (GVHD), chronic GVHD, and relapse (GRFS). OS was defined as the time from alloHSCT to death from any cause. EFS was defined as the time to t-AML relapse or death from any cause and surviving patients in continuous complete response (CR) were censored at the time of last contact. Relapse was defined as detection of the disease from any biological evidence, including cytology, flow cytometry, cytogenetic and molecular data. TRM was defined as death in remission from specific cause: infection, GVHD and other causes related to alloHSCT (including organ dysfunction). GRFS was defined as survival without grade III-IV acute GVHD, systemic therapy-requiring chronic GVHD, or relapse.

# Statistical analyses

Patient characteristics were described using numbers and proportions for categorical variables and using mean, standard deviation, median and interquartile range for continuous variables. OS, EFS and GRFS were estimated with the Kaplan-Meier method. Univariate analyses with Cox regression models were conducted to assess the association of baseline characteristics with OS and EFS. Patients with missing data on at least one variable of interest were excluded from the multivariable model and their characteristics were compared with those included in the models to detect potential attrition bias. All results were expressed as hazard ratios (HR) with 95% confidence intervals (95% CI) and all tests were performed with a two-sided alpha risk of 5%. Statistical analyses were performed with R software version 3.6.2.
# Results

## Baseline patient, disease, and treatment characteristics

A total of 220 t-AML patients who underwent alloHSCT between 2013 and 2019 were included. Patient and prior tumour characteristics are detailed in Table 1. Median age at diagnosis of AML was 56 years [range, 18–74], with a majority of women (61%). Patients mainly presented history of haematological (45%) and gynaecological (37%) neoplasia, among which breast cancer and Non-Hodgkin Lymphomas (NHLs) were the most frequent. Most patients received multiple drug chemotherapy and radiotherapy. There was a predominance of alkylating agents (71%) followed by topo-isomerase inhibitors (61%), spindle poison agents (49%), radiotherapy (47%) and anti-metabolites (46%). Median time from cytotoxic exposure to t-AML diagnosis was 54.7 months. Cytogenetic scores showed that 51% had intermediate risk or 43% had poor risk. Of note, 41 patients had monosomic and/or complex karyotype, including 19 patients with abnormality of the short arm of chromosome 17. At the molecular level, 14% had favourable profile, 36% had intermediate risk and 51% had adverse risk genetic profile. All patients received at least one induction therapy.
<table><caption>Table 1

Patient and Tumor Characteristics at Baseline (n=220)*.</caption><thead><tr><th>Characteristics</th><th></th></tr></thead><tbody><tr><td>Median age, y (range), N = 220</td><td>56 (18-74)</td></tr><tr><td>Sex, female no. (%), N = 220</td><td>133 (61)</td></tr><tr><td><strong>Prior tumour</strong></td><td></td></tr><tr><td>Organ system, no. (%), N = 219</td><td></td></tr><tr><td>Haematological</td><td>98 (45)</td></tr><tr><td>Lymphoid neoplasia</td><td>67 (31)</td></tr><tr><td>Acute leukaemia</td><td>13 (6)</td></tr><tr><td>Myeloproliferative neoplasia</td><td>8 (4)</td></tr><tr><td>Myeloma</td><td>5 (2)</td></tr><tr><td>Other</td><td>5 (2)</td></tr><tr><td>Gynaecological</td><td>82 (37)</td></tr><tr><td>Breast cancer</td><td>74 (34)</td></tr><tr><td>Urological</td><td>13 (6)</td></tr><tr><td>Digestive</td><td>11 (5)</td></tr><tr><td>Others</td><td>15 (7)</td></tr><tr><td><strong>Cytotoxic agent, no. (%)<sup>‡</sup></strong></td><td></td></tr><tr><td>Alkylating agents, N = 207</td><td>147 (71)</td></tr><tr><td>Nitrogen mustard</td><td>113 (55)</td></tr><tr><td>Platins</td><td>35 (17)</td></tr><tr><td>Others</td><td>33 (16)</td></tr><tr><td>Antimetabolite, N = 207</td><td>95 (46)</td></tr><tr><td>Purine analog</td><td>16 (7)</td></tr><tr><td>Antifolate</td><td>13 (6)</td></tr><tr><td>Pyrimidine analog</td><td>77 (37)</td></tr><tr><td>Topoisomerase inhibitors, N = 207</td><td>127 (61)</td></tr><tr><td>Topoisomerase inhibitor type I</td><td>30 (15)</td></tr><tr><td>Topoisomerase inhibitor type II</td><td>122 (59)</td></tr></tbody></table>
<table><tr><td>Spindle poison, N = 207</td><td>102 (49)</td></tr><tr><td>Vinca alkaloids</td><td>63 (30)</td></tr><tr><td>Taxanes</td><td>40 (19)</td></tr><tr><td>Other drugs, N = 210</td><td>65 (31)</td></tr><tr><td>Radiotherapy, no. (%), N = 217</td><td>102 (47)</td></tr><tr><td><strong>t-AML</strong></td><td></td></tr><tr><td>Median time between cytotoxic exposure and diagnosis of t-AML, months (range), N = 217</td><td>54.7 (2.3-441.8)</td></tr><tr><td>Karyotype risk category, no. (%)<sup>†</sup>, N = 213</td><td></td></tr><tr><td>Favourable</td><td>13 (6)</td></tr><tr><td>Intermediate</td><td>109 (51)</td></tr><tr><td>Adverse</td><td>91 (42.7)</td></tr><tr><td>Molecular risk category, no. (%)<sup>§</sup>, N = 197</td><td></td></tr><tr><td>Favourable</td><td>27 (14)</td></tr><tr><td>Intermediate</td><td>70 (35)</td></tr><tr><td>Adverse</td><td>100 (51)</td></tr></table>

Abbreviations: no., number; t-AML, therapy-related acute myeloid leukemia; y, years. * Percentages are calculated out of the amount of data available. ‡ Most patients received several drugs from the same antineoplastic class. † Categorized according to MRC¹⁵. § Categorized according to ELN2017¹⁴.

## Transplant characteristics and clinical outcomes

Median time from t-AML diagnosis to alloHSCT was 5.5 months. Transplant characteristics are summarized in Table 2. At the time of transplant, 3.1% of patients had uncontrolled disease. For 18% of patients, disease was still detectable on the pre-graft myelogram. The Karnofsky score at diagnosis was ≥ 90 in 62% of patients. Preparative regimen was either myeloablative (MAC) (30%), non-myeloablative / reduced intensity (NMA/RIC) (62%) or sequential (9%). Most patients received a 10/10 HLA-matched graft (58%). Mobilized peripheral blood was the stem cell source in 85% of patients and umbilical cord blood (UCB) for 5% of them. Median time of engraftment was 17 days.
<table><caption>Table 2
Transplant-related characteristics and AlloHSCT outcomes*.</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td><strong>AlloHSCT characteristics</strong></td><td></td></tr><tr><td><strong>Prior tumor status at transplantation, no. (%), N = 193</strong></td><td></td></tr><tr><td>Complete response</td><td>178 (92)</td></tr><tr><td>Stable/untreated</td><td>8 (4)</td></tr><tr><td>Uncontrolled</td><td>6 (3)</td></tr><tr><td>Partial response</td><td>1 (1)</td></tr><tr><td><strong>t-AML status at the time of transplant, no. (%), N = 218</strong></td><td></td></tr><tr><td>CR</td><td>178 (82)</td></tr><tr><td>Not in CR</td><td>40 (18)</td></tr><tr><td><strong>Karnofsky at transplantation, no. (%), N = 181</strong></td><td></td></tr><tr><td>≥ 90%</td><td>113 (62)</td></tr><tr><td>&lt; 90%</td><td>68 (38)</td></tr><tr><td><strong>Stem cells source, no. (%), N = 207</strong></td><td></td></tr><tr><td>Peripheral blood</td><td>176 (85)</td></tr><tr><td>Bone marrow</td><td>20 (10)</td></tr><tr><td>Cord blood</td><td>11 (5)</td></tr><tr><td><strong>HLA match, no. (%), N = 207</strong></td><td></td></tr><tr><td>Matched sibling</td><td>64 (31)</td></tr><tr><td>Matched unrelated</td><td>56 (27)</td></tr><tr><td>Mismatched unrelated</td><td>54 (26)</td></tr><tr><td>Mismatched sibling</td><td>33 (16)</td></tr><tr><td><strong>Conditioning therapy, no. (%), N = 220</strong></td><td></td></tr><tr><td>RIC/NMA</td><td>136 (62)</td></tr><tr><td>MAC</td><td>65 (30)</td></tr><tr><td>Sequential</td><td>19 (9)</td></tr></tbody></table>

Abbreviations: CR, complete response; D100, Day 100 after transplant; GVHD, graft-versus-host disease; MAC, myeloablative conditioning; NMA, non-myeloablative conditioning; no., number; RIC, reduced-intensity conditioning; t-AML, therapy-related acute myeloid leukemia; UK, unknown. * Percentages are calculated out of the amount of data available.
<table><thead><tr><th>AlloHSCT characteristics</th><th></th></tr></thead><tbody><tr><td>Median time of hematopoietic recovery, day (range), N = 208</td><td>17 (0-37)</td></tr><tr><td>Acute GVHD, no. (%), N = 213</td><td>101 (47)</td></tr><tr><td>Grade I</td><td>34 (34)</td></tr><tr><td>Grade II</td><td>43 (43)</td></tr><tr><td>Grade III-IV</td><td>20 (20)</td></tr><tr><td>UK</td><td>4 (4)</td></tr><tr><td>Chronic GVHD, no. (%), N = 205</td><td>67 (32)</td></tr><tr><td>Limited</td><td>33 (49)</td></tr><tr><td>Extensive</td><td>30 (45)</td></tr><tr><td>UK</td><td>4 (6)</td></tr><tr><td>Response at D100, no. (%), N = 95</td><td></td></tr><tr><td>CR</td><td>84 (88)</td></tr><tr><td>Cytological relapse</td><td>10 (11)</td></tr><tr><td>Molecular relapse</td><td>1 (1)</td></tr><tr><td>Chimerism at D100, no. (%), N = 113</td><td></td></tr><tr><td>Full donor</td><td>83 (74)</td></tr><tr><td>Partial</td><td>26 (23)</td></tr><tr><td>Failure</td><td>4 (4)</td></tr><tr><td>Post-graft treatments, no. (%), N = 215</td><td></td></tr><tr><td>None</td><td>137 (64)</td></tr><tr><td>Anti-leukemic treatments</td><td>61 (28)</td></tr><tr><td>Pre-emptive treatment</td><td>11 (5)</td></tr><tr><td>Palliative care</td><td>4 (2)</td></tr><tr><td>UK</td><td>2 (1)</td></tr><tr><td>Second alloHSCT, no. (%), N = 220</td><td>17 (8)</td></tr></tbody></table>

Abbreviations: CR, complete response; D100, Day 100 after transplant; GVHD, graft-versus-host disease; MAC, myeloablative conditioning; NMA, non-myeloablative conditioning; no., number; RIC, reduced-intensity conditioning; t-AML, therapy-related acute myeloid leukemia; UK, unknown. * Percentages are calculated out of the amount of data available.
Median follow-up time of the cohort was 21.4 months (IQ [5.9–52.8]). At day 100, 88% of evaluated patients were in CR (n = 84) and 74% of evaluated patients had a full donor chimerism (n = 83). Acute GVHD occurred in 47% of patients, including mostly grade I-II (76%) and cGVHD occurred in 32% of patients with 49% of them having limited cGVHD. Relapse of t-AML was detected in 38% of patients at a median onset of 4 months. Among them, 7% also had a progressive prior tumour after transplantation. Post-graft treatments were introduced for 35% patients, i.e. for t-AML relapse (28%) and pre-emptive therapy (5%). Palliative care was provided for 2% of patients.

At last follow-up, 44% patients were in CR (n = 96), 2% were alive with t-AML relapse, 1% were alive with relapse of prior tumour and 54% died. The main cause of death was t-AML relapse (52%), followed by infectious complications (22%), GVHD (9%), other HSCT-related toxicities (8%), and relapse of prior tumour (4%). Of note, three patients died from another neoplasia following transplantation.

## Survival endpoints

Median OS was 31 months (95% CI 8.1-NR). One-year and 5-year OS post-transplant were respectively 60.7% (95% CI 54.6–67.5) and 44.1% (95% CI 37.4–52.1) (Fig. 1). Univariate analysis showed a significant association between adverse cytogenetics (HR 1.70, 95% CI 1.2–2.5, p = 0.005), molecular risk categories (HR 1.90, 95% CI 1.0–3.6, p = 0.049), uncontrolled t-AML at transplantation (HR 1.78, 95% CI 1.2–2.7, p = 0.007), sequential conditioning regimen (HR 2.03, 95% CI 1.2–3.9, p = 0.009) and OS (Table 3). A pre-transplantation Karnofsky score at diagnosis ≥ 90 was associated with better OS (HR 0.59, 95% CI 0.4–0.9, p = 0.011). However, in multivariable analysis, no variable was independently associated with OS (Table 4).
<table><caption>Table 3
Univariate analysis of OS and EFS.</caption><thead><tr><th rowspan="2">Variable</th><th colspan="3">OS</th><th colspan="3">EFS</th></tr><tr><th>N</th><th>HR (95% CI)</th><th>p value</th><th>N</th><th>HR (95% CI)</th><th>p value</th></tr></thead><tbody><tr><td>Prior tumour</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Haematological</td><td>98</td><td></td><td></td><td>96</td><td></td><td></td></tr><tr><td>Gynaecological</td><td>82</td><td>1.14 (0.76-1.69)</td><td>0.529</td><td>80</td><td>1.08 (0.73-1.60)</td><td>0.683</td></tr><tr><td>Urological</td><td>13</td><td>1.00 (0.43-2.34)</td><td>0.995</td><td>13</td><td>1.50 (0.76-2.94)</td><td>0.243</td></tr><tr><td>Digestive</td><td>11</td><td>0.83 (0.33-2.07)</td><td>0.683</td><td>11</td><td>0.69 (0.28-1.73)</td><td>0.432</td></tr><tr><td>Others</td><td>15</td><td>1.08 (0.53-2.19)</td><td>0.833</td><td>15</td><td>1.00 (0.49-2.01)</td><td>0.990</td></tr><tr><td>Cytotoxic agent</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Alkylating agents</td><td>147</td><td>0.95 (0.63-1.43)</td><td>0.804</td><td>145</td><td>0.95 (0.64-1.41)</td><td>0.789</td></tr><tr><td>Antimetabolites</td><td>95</td><td>1.10 (0.76-1.59)</td><td>0.615</td><td>94</td><td>0.93 (0.65-1.33)</td><td>0.706</td></tr><tr><td>Topoisomerase inhibitors</td><td>127</td><td>1.08 (0.69-1.69)</td><td>0.728</td><td>125</td><td>1.11 (0.77-1.61)</td><td>0.571</td></tr><tr><td>Spindle poison</td><td>102</td><td>1.33 (0.92-1.93)</td><td>0.130</td><td>101</td><td>1.35 (0.95-1.93)</td><td>0.098</td></tr><tr><td>Radiotherapy</td><td>102</td><td>1.03 (0.71-1.47)</td><td>0.895</td><td>99</td><td>0.85 (0.60-1.21)</td><td>0.373</td></tr><tr><td>Time between cytotoxic exposure and diagnosis of t-AML</td><td>217</td><td>0.99 (0.99-1.01)</td><td>0.552</td><td>213</td><td>0.99 (0.99-1.01)</td><td>0.867</td></tr><tr><td>Age at diagnosis</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 60 years</td><td>127</td><td></td><td></td><td>126</td><td></td><td></td></tr></tbody></table>
<table><thead><tr><th rowspan="2">Variable</th><th colspan="3">OS</th><th colspan="3">EFS</th></tr><tr><th>N</th><th>HR (95% CI)</th><th>p value</th><th>N</th><th>HR (95% CI)</th><th>p value</th></tr></thead><tbody><tr><td>≥ 60 years</td><td>93</td><td>0.89 (0.61-1.29)</td><td>0.544</td><td>90</td><td>0.76 (0.53-1.10)</td><td>0.149</td></tr><tr><td>Karyotype risk category</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Favourable/intermediate</td><td>122</td><td></td><td></td><td>120</td><td></td><td></td></tr><tr><td>Adverse</td><td>91</td><td>1.70 (1.18-2.45)</td><td>0.005</td><td>89</td><td>1.60 (1.12-2.28)</td><td>0.009</td></tr><tr><td>Molecular risk category</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Favourable</td><td>27</td><td></td><td></td><td>27</td><td></td><td></td></tr><tr><td>Intermediate</td><td>70</td><td>1.11 (0.56-2.20)</td><td>0.763</td><td>68</td><td>1.08 (0.57-2.04)</td><td>0.809</td></tr><tr><td>Adverse</td><td>100</td><td>1.90 (1.00-3.61)</td><td>0.0496</td><td>98</td><td>1.79 (0.99-3.25)</td><td>0.055</td></tr><tr><td>Karnofsky score at transplantation</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 90%</td><td>68</td><td></td><td></td><td>65</td><td></td><td></td></tr><tr><td>≥ 90%</td><td>113</td><td>0.59 (0.39-0.88)</td><td>0.011</td><td>113</td><td>0.70 (0.47-1.05)</td><td>0.082</td></tr><tr><td>t-AML status at the time of transplant</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>CR</td><td>178</td><td></td><td></td><td>175</td><td></td><td></td></tr><tr><td>Not in CR</td><td>40</td><td>1.58 (0.9-2.9)</td><td>0.007</td><td>39</td><td>1.97 (1.30-3.00)</td><td>0.001</td></tr><tr><td>Stem cell source</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Peripheral blood</td><td>176</td><td></td><td></td><td>173</td><td></td><td></td></tr><tr><td>Bone marrow</td><td>20</td><td>1.19 (0.63-2.22)</td><td>0.593</td><td>20</td><td>0.95 (0.51-1.78)</td><td>0.876</td></tr><tr><td>Cord blood</td><td>11</td><td>0.93 (0.38-2.29)</td><td>0.875</td><td>11</td><td>0.82 (0.34-2.03)</td><td>0.673</td></tr></tbody></table>
<table><thead><tr><th rowspan="2">Variable</th><th colspan="3">OS</th><th colspan="3">EFS</th></tr><tr><th>N</th><th>HR (95% CI)</th><th>p value</th><th>N</th><th>HR (95% CI)</th><th>p value</th></tr></thead><tbody><tr><td>HLA match</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>10/10</td><td>87</td><td></td><td></td><td>85</td><td></td><td></td></tr><tr><td>Haplo-identical and others</td><td>120</td><td>0.97<br>(0.66-1.43)</td><td>0.882</td><td>119</td><td>0.96<br>(0.66-1.39)</td><td>0.833</td></tr><tr><td>Conditioning regimen</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>RIC/NMA</td><td>136</td><td></td><td></td><td>132</td><td></td><td></td></tr><tr><td>MAC</td><td>65</td><td>1.18<br>(0.79-1.77)</td><td>0.425</td><td>65</td><td>1.07<br>(0.72-1.59)</td><td>0.728</td></tr><tr><td>Sequential</td><td>19</td><td>2.03<br>(1.16-3.56)</td><td>0.013</td><td>19</td><td>2.39<br>(1.41-4.07)</td><td>0.001</td></tr></tbody></table>
<table><caption>Table 4
Multivariable analysis of OS and EFS.</caption><thead><tr><th rowspan="2">Variable</th><th colspan="3">OS</th><th colspan="3">EFS</th></tr><tr><th>N</th><th>HR (95% CI)</th><th>p value</th><th>N</th><th>HR (95% CI)</th><th>p value</th></tr></thead><tbody><tr><td>Age at diagnosis</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 60 years</td><td>-</td><td></td><td></td><td>126</td><td></td><td></td></tr><tr><td>≥ 60 years</td><td>-</td><td>-</td><td>-</td><td>90</td><td>0.69 (0.42-1.13)</td><td>0.137</td></tr><tr><td>Karyotype risk category</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Favourable/intermediate</td><td>122</td><td></td><td></td><td>120</td><td></td><td></td></tr><tr><td>Adverse</td><td>91</td><td>2.08 (0.60-7.26)</td><td>0.251</td><td>89</td><td>1.53 (0.55-4.25)</td><td>0.412</td></tr><tr><td>Molecular risk category</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Favourable</td><td>27</td><td></td><td></td><td>27</td><td></td><td></td></tr><tr><td>Intermediate</td><td>70</td><td>1.01 (0.43-2.37)</td><td>0.984</td><td>68</td><td>0.81 (0.37-1.77)</td><td>0.601</td></tr><tr><td>Adverse</td><td>100</td><td>1.02 (0.26-4.04)</td><td>0.975</td><td>98</td><td>1.00 (0.32-3.12)</td><td>0.996</td></tr><tr><td>Karnofsky score at transplantation</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; 90%</td><td>68</td><td></td><td></td><td>65</td><td></td><td></td></tr><tr><td>≥ 90%</td><td>113</td><td>0.73 (0.47-1.15)</td><td>0.173</td><td>113</td><td>0.83 (0.53-1.29)</td><td>0.408</td></tr><tr><td>t-AML status at the time of transplant</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>CR</td><td>178</td><td></td><td></td><td>175</td><td></td><td></td></tr><tr><td>Not in CR</td><td>40</td><td>1.58 (0.95-2.60)</td><td>0.082</td><td>39</td><td>1.94 (1.03-3.67)</td><td>0.041</td></tr><tr><td>Conditioning regimen</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>RIC/NMA</td><td>136</td><td></td><td></td><td>132</td><td></td><td></td></tr><tr><td>MAC</td><td>65</td><td>0.71 (0.40-1.25)</td><td>0.230</td><td>65</td><td>0.59 (0.34-1.03)</td><td>0.066</td></tr></tbody></table>

<footnote>* Only variables with univariate p-value < 0.2 were included in the multivariable analysis.</footnote>
<table><thead><tr><th rowspan="2">Variable</th><th colspan="3">OS</th><th colspan="3">EFS</th></tr><tr><th>N</th><th>HR (95% CI)</th><th>p value</th><th>N</th><th>HR (95% CI)</th><th>p value</th></tr></thead><tbody><tr><td>Sequential</td><td>19</td><td>1.39 (0.65-2.99)</td><td>0.394</td><td>19</td><td>1.30 (0.60-2.84)</td><td>0.500</td></tr></tbody><tfoot><tr><td colspan="7">* Only variables with univariate p-value &lt; 0.2 were included in the multivariable analysis.</td></tr></tfoot></table>

Median EFS was 16.3 months (95% CI 9.9-40.8). One-year and 5-year EFS were respectively estimated at 52.8% (95% CI 46.5-68.4) and 40.4% (95% CI 33.9-48.1), with most relapse events occurring in the first 2 years (Fig. 2). Univariate analysis showed a significant association between adverse cytogenetics (HR 1.60, 95% CI 1.1-2.3, p = 0.009), uncontrolled t-AML at transplantation (HR 1.97, 95% CI 1.3-3.0, p = 0.001), sequential conditioning regimen (HR 2.39, 95% CI 1.4-4.1, p = 0.001), and EFS (Table 3). In multivariable analysis, uncontrolled t-AML at transplantation was the only independent variable associated with lower EFS (HR 1.94, 95% CI 1.0-3.7, p = 0.041) (Table 4). Furthermore, myeloablative conditioning regimen was non-significantly associated with EFS (HR 0.59, 95% CI 0.3-1.0, p = 0.066) in multivariable analysis.

Overall, 39% of all deaths were transplant-related. TRM was non-significantly lower in the RIC/NMA group (33%) compared to MAC (47%) and sequential conditioning (53%) (p = 0.157). Median GRFS was 6.3 months (95% CI 4.7-13.4). One-year and 5-year GRFS were respectively estimated at 44.1% (95% CI 37.6-51.8) and 35.3% (95% CI 28.8-43.3), with most events occurring during the first two years (Fig. 3).

## Discussion

AML is a highly heterogeneous disease, requiring individualized treatment approaches. Of note, t-AML has a unique pathogenesis and clinical course, and its prognosis is usually poor. According to the 2022 WHO classification of Myeloid Neoplasms, t-AML is part of the distinct entity called "therapy-related myeloid neoplasms (t-MN)", alongside therapy-related myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPN) [16]. Based on the Surveillance, Epidemiology and End Results (SEER) database, the risk for t-AML after chemotherapy treatment is 4.7-fold higher than in the general population [5]. While the incidence of t-AML has been increasing for the last 50 years, it was recently shown that the use of targeted-immunotherapy in some cancers, such as non-small cell lung cancer or melanoma, was associated with a decrease in the incidence of t-AML [17].

AlloHSCT offers a potentially curative treatment for t-AML patients. However, the subsequent toxicities of this procedure, as is the difficulty to obtain CR often prevent from choosing this therapeutic option. Although outcomes after alloHSCT have improved [18], it remains poor for t-AML patients due to their neoplasia history, comorbidities and poor prognosis of t-AML *per se*. The present study spanned a six-
year period and included patients from 22 French centres and 2 Belgian centres, which gives a broad perspective on the management and outcome of alloHSCT in t-AML patients.

Several months, or several years, may elapse between primary tumour diagnosis and t-AML. This latency depends on the exposure to specific agent, the cumulative dose or dose intensity of the cytotoxic therapy [2, 19]. Alkylating agents are usually responsible for late t-AML, with a maximum frequency between the 5th and 10th year, whereas topoisomerase inhibitors induce early t-AML in the 2–3 years following exposure [4]. In our study, median time to onset of t-AML was 54.7 months at a median age of 56 years. Moreover, t-AML mostly affected women, as the main anterior neoplasm was breast cancer, followed by NHLs. Previous cancer therapies mostly included alkylating agents and topoisomerase inhibitors. These features are consistent with other published cohorts [20–22]. Most patients had intermediate cytogenetics risk, followed by adverse cytogenetics. A recent study by Kayser and collaborators showed that there was no difference in the frequency of favourable-risk cytogenetics abnormalities between *de novo* and t-AMLs. However, the latter were underrepresented in intermediate-risk abnormalities and more frequently exhibited adverse-risk karyotypes [21], which is consistent with previous studies [19, 23, 24]. It has also been shown that t-AML is an adverse prognosis factor for EFS and OS, independently of the favourable or unfavourable genetic profile [21, 23, 25–27]. Moreover, recent studies described that specific cytotoxic agent promoted t-AMLs-associated abnormalities. Two unfavourable karyotype patterns are well-described: losses and deletions of chromosomes 5 and 7 associated with the use of alkylating agent, and rearrangement of *MLL/KMT2A* gene following topoisomerase inhibitors [2, 19, 28–31]. The frequency of specific mutations in t-AML suggests a distinct mechanism of leukemogenesis as compared to *de novo* AML, and hence a different outcome after alloHSCT.

In this cohort, 5-year OS and 5-year EFS were respectively of 44.1% and 40.4%. In a CIBMTR study analysing data of t-AML patients who underwent alloHSCT between 2000 and 2014, Metheny *et al.* reported a 5-year OS and 5-year EFS of 25% and 23%, respectively [32]. In an EBMT study, 535 t-AML patients who received alloHSCT between 2000 and 2016 were analysed with a 5-year OS and 5-year EFS of 40.4% and 36.4% [26]. Both studies reported that active AML at the time of transplantation and adverse-risk cytogenetics were associated with worse OS and EFS. In the present study, there was no independent prognosis factor associated with OS, while EFS was significantly lower in patients with an active AML at the time of transplantation. Several factors could explain these differences. First, both studies enrolled more patients, suggesting that our study might be lacking sufficient statistical power. Secondly, the reported cohorts were treated 5 years earlier, while novel therapies and post-engraftment treatment have since emerged possibly improving OS and EFS [33]. Moreover, there were significant differences between populations regarding performance status, age, disease status at transplantation and conditioning regimens. Therefore, clinical practices may be influenced by differences between centres, especially criteria for alloHSCT eligibility and graft management, which can affect OS and EFS.

Whereas the main cause of death was relapse of t-AML, we report a TRM of 38.8%, which is consistent with other studies [32, 34]. Despite a low frequency of MAC conditioning, this rate remained higher than TRM reported in studies including *de novo* AML [35–38]. Moreover, the 1-year and 5-year GRFS were
44.1% and 35.3%, thus reflecting more accurately the proportion of patients who benefited from alloHSCT. It is interesting to note that the GRFS curve was not modified after 18–24 months. This result is comparable with GRFS of *de novo* AML[39–41] but is better than GRFS of sAML patients (including t-AML and AML following other myeloid neoplasm, treated or not) who underwent alloHSCT before 2016 [40, 42, 43]. However, in a cohort evaluating trends in post-alloHSCT outcome for sAML patients, the 2-year GRFS was 38.2% for patients transplanted between 2011 and 2020 [44], which is concordant with this cohort. This result suggests that alloHSCT is beneficial for t-AML patients.

Eligibility for alloHSCT partially relies on scoring systems to assess pre-transplant comorbidity, as the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) [45, 46]. Based on HCT-CI, a prior history of solid tumour (excluding non-melanoma skin cancer) should be scored with 3 points. Indeed, HCT-CI score ≥ 3 was associated with a two-year OS of 39%. However, as observed in this cohort, the 5-year OS was 44.1%. Since the elaboration of this score, several changes in clinical practice and patient management may explain this difference. Moreover, HCT-CI was not applicable to alternative graft source [47, 48], and a most recent study showed that cancer comorbidity did not impair 2-year OS [49]. These data suggest that this comorbidity score may be not applicable to all AML patients, especially in those with t-AML patient for whom alloHSCT is the only therapeutic option. Indeed, despite high levels of TRM in our cohort, 40% of these high-risk patients were alive and leukaemia-free at five years. These are encouraging results, even if there was a bias as only most fit patients and patients in remission received alloHSCT. However, considering recent advances in pre-graft therapy, such as CPX-351 [50–52] and the association of azacytidine and venetoclax [53, 54], there are still opportunities that more t-AML patients will be able to achieve CR and benefit from alloHSCT.

In conclusion, we reported data of 220 t-AML patients who underwent alloHSCT between 2013 and 2019. This study showed an improvement in the management and the outcome of these patients, although alloHSCT was undertaken in older patients. However, t-AML prognosis remains poorer compared to *de novo* AML. With future pre-emptive anti-leukemic targeted therapies following alloHSCT and a better understanding of physiopathology, there are further options to improve the survival of t-AML patients.

# Declarations

## Author contributions

Conceptualization, E.T.; Methodology, G.R., E.D., E.T.; Patients care, G.R, R.D., N.F., E.F., M.S., P.C., M.R., F.S., J.B.M., H.L.W., K.B., E.D., J.O.B., A.F., C.E.B., S.N.Q., A.G., C.O., P.T., M.L., X.P., G.G., Y.B., N.M., J.B.M., E.C., J.C., E.T.; Collected the data, G.R, E.D., R.D., N.F., E.F., M.S., P.C., M.R., F.S., J.B.M., H.L.W., K.B., E.D., J.O.B., A.F., C.E.B., S.N.Q., A.G., C.O., P.T., M.L., X.P., G.G., Y.B., N.M., J.B.M., E.C., J.C., E.T.; Analysed data, G.R., E.D., P.B., E.T.; Writing – original draft, G.R., E.D., E.T.; Review and editing, all the authors.

## Compliance with ethical standards

## Conflict of interest
References

1. McNerney ME, Godley LA, Beau MML. Therapy-Related Myeloid Neoplasms: When Genetics and Environment Collide. 2018; 35.

2. Allan JM, Travis LB. Mechanisms of therapy-related carcinogenesis. Nat Rev Cancer 2005; 5: 943–955.

3. Larson RA. Etiology and Management of Therapy-Related Myeloid Leukemia. *Hematology* 2007; 2007: 453–459.

4. Nenova I, Grudeva-Popova J. Carcinogenic potential of antitumor therapies - is the risk predictable?; : 7.

5. Morton LM, Dores GM, Tucker MA, Kim CJ, Onel K, Gilbert ES et al. Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975–2008. Blood 2013; 121: 2996–3004.

6. Borthakur G, Estey EE. Therapy-related acute myelogenous leukemia and myelodysplastic syndrome. Curr Oncol Rep 2007; 9: 373–377.

7. Cancer Survivorship — United States, 1971–2001. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5324a3.htm (accessed 20 Sep2021).

8. Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM et al. Cancer treatment and survivorship statistics, 2019. CA: A Cancer Journal for Clinicians 2019; 69: 363–385.

9. Nilsson C, Linde F, Hulegårdh E, Garelius H, Lazarevic V, Antunovic P et al. Characterization of therapy-related acute myeloid leukemia: increasing incidence and prognostic implications. *haematol* 2022. doi:10.3324/haematol.2022.281233.

10. Granfeldt Østgård LS, Medeiros BC, Sengeløv H, Nørgaard M, Andersen MK, Dufva IH et al. Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study. *JCO* 2015; 33: 3641–3649.

11. Churpek JE, Larson RA. The evolving challenge of therapy-related myeloid neoplasms. Best Practice & Research Clinical Haematology 2013; 26: 309–317.

12. Hulegårdh E, Nilsson C, Lazarevic V, Garelius H, Antunovic P, Derolf ÅR et al. Characterization and prognostic features of secondary acute myeloid leukemia in a population-based setting: A report from the Swedish Acute Leukemia Registry. American Journal of Hematology 2015; 90: 208–214.

13. Nampoothiri RV. Predictors of outcomes of therapy-related acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation.; : 9.

14. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116: 354–365.
15. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129: 424–447.

16. Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 2022; 36: 1703–1719.

17. Singh A, Herr MM, Griffiths EA, Przespolewski A, Faber MG, Mrad C et al. Emerging trends of therapy related myeloid neoplasms following modern cancer therapeutics in the United States. Sci Rep 2021; 11: 23284.

18. McDonald GB, Sandmaier BM, Mielcarek M, Sorror M, Pergam SA, Cheng G-S et al. Survival, Nonrelapse Mortality, and Relapse-Related Mortality After Allogeneic Hematopoietic Cell Transplantation: Comparing 2003–2007 Versus 2013–2017 Cohorts. Ann Intern Med 2020; 172: 229.

19. Smith SM, Le Beau MM, Huo D, Karrison T, Sobecks RM, Anastasi J et al. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 2003; 102: 43–52.

20. Metheny L, Callander NS, Hall AC, Zhang M-J, Bo-Subait K, Wang H-L et al. Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults. Transplantation and Cellular Therapy 2021; S2666636721011465.

21. Kayser S, Döhner K, Krauter J, Köhne C-H, Horst HA, Held G et al. The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood 2011; 117: 2137–2145.

22. Litzow MR, Tarima S, Pérez WS, Bolwell BJ, Cairo MS, Camitta BM et al. Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood 2010; 115: 1850–1857.

23. Schoch C, Kern W, Schnittger S, Hiddemann W, Haferlach T. Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML. Leukemia 2004; 18: 120–125.

24. Mauritzson N, Albin M, Rylander L, Billström R, Ahlgren T, Mikoczy Z et al. Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976–1993 and on 5098 unselected cases reported in the literature 1974–2001. Leukemia 2002; 16: 2366–2378.

25. Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS et al. The Role of TP53 Mutations in the Origin and Evolution of Therapy-Related AML. Nature 2015; 518: 552–555.

26. Bloomfield CD, Archer KJ, Mrózek K, Lillington DM, Kaneko Y, Head DR et al. 11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: Report from an International Workshop†: Balanced 11q23 Aberrations in t-MDS/t-AL. *Genes Chromosom Cancer* 2002; 33: 362–378.
27. Antonijevic N, Suvajdzic N, Terzic T, Jakovljevic B, Jankovic G, Elezovic I *et al*. Favourable prognostic factors in therapy related acute myeloid leukaemia. Srp Arh Celok Lek 2011; 139: 347–352.

28. Le Beau MM, Albain KS, Larson RA, Vardiman JW, Davis EM, Blough RR *et al*. Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of chromosomes no. 5 and 7. *JCO* 1986; 4: 325–345.

29. Godley LA, Larson RA. Therapy-Related Myeloid Leukemia. Seminars in Oncology 2008; 35: 418–429.

30. Pedersen-Bjergaard J, Andersen MK, Andersen MT, Christiansen DH. Genetics of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 2008; 22: 240–248.

31. Larson RA, Le Beau MM. Therapy-related myeloid leukaemia: A model for leukemogenesis in humans. Chemico-Biological Interactions 2005; 153–154: 187–195.

32. Metheny L, Callander NS, Hall AC, Zhang M-J, Bo-Subait K, Wang H-L *et al*. Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults. *Transplantation and Cellular Therapy* 2021; 27: 923.e1-923.e12.

33. Döhner H, Wei AH, Löwenberg B. Towards precision medicine for AML. Nat Rev Clin Oncol 2021; 18: 577–590.

34. Lee CJ, Labopin M, Beelen D, Finke J, Blaise D, Ganser A *et al*. Comparative outcomes of myeloablative and reduced-intensity conditioning allogeneic hematopoietic cell transplantation for therapy-related acute myeloid leukemia with prior solid tumor: A report from the acute leukemia working party of the European society for blood and bone marrow transplantation. Am J Hematol 2019; 94: 431–438.

35. Bastida JM, Cabrero M, Lopez-Godino O, Lopez-Parra M, Sanchez-Guijo F, Lopez-Corral L *et al*. Influence of donor age in allogeneic stem cell transplant outcome in acute myeloid leukemia and myelodisplastic syndrome. Leukemia Research 2015; 39: 828–834.

36. Tomizawa D, Tanaka S, Kondo T, Hashii Y, Arai Y, Kudo K *et al*. Allogeneic Hematopoietic Stem Cell Transplantation for Adolescents and Young Adults with Acute Myeloid Leukemia. Biology of Blood and Marrow Transplantation 2017; 23: 1515–1522.

37. Takami A. Hematopoietic stem cell transplantation for acute myeloid leukemia.; : 6.

38. Goyal SD, Zhang M-J, Wang H-L, Akpek G, Copelan EA, Freytes C *et al*. Allogeneic hematopoietic cell transplant for AML: no impact of pre-transplant extramedullary disease on outcome. Bone Marrow Transplant 2015; 50: 1057–1062.

39. Yokohama Cooperative Study Group for Hematology (YACHT), Ando T, Fujisawa S, Teshigawara H, Ogusa E, Ishii Y *et al*. Impact of treatment-related weight changes from diagnosis to hematopoietic stem-cell transplantation on clinical outcome of acute myeloid leukemia. Int J Hematol 2019; 109: 673–683.

40. Schmaelter A-K, Labopin M, Socié G, Itälä-Remes M, Blaise D, Yakoub-Agha I *et al*. Inferior outcome of allogeneic stem cell transplantation for secondary acute myeloid leukemia in first complete
remission as compared to de novo acute myeloid leukemia. Blood Cancer J 2020; 10: 26.

41. Salas MQ, Chen S, Lam W, Pasic I, Gerbitz A, Michelis FV et al. Less Is More: Superior Graft-versus-Host Disease-Free/Relapse-Free Survival with Reduced-Intensity Conditioning and Dual T Cell Depletion in Acute Myelogenous Leukemia. Biology of Blood and Marrow Transplantation 2020; 26: 1511-1519.

42. Gatwood KS, Labopin M, Savani BN, Finke J, Socie G, Beelen D et al. Transplant outcomes for patients with therapy-related acute myeloid leukemia with prior lymphoid malignancy: an ALWP of EBMT study. Bone Marrow Transplant 2020; 55: 224-232.

43. Sengsayadeth S, Labopin M, Boumendil A, Finke J, Ganser A, Stelljes M et al. Transplant Outcomes for Secondary Acute Myeloid Leukemia: Acute Leukemia Working Party of the European Society for Blood and Bone Marrow Transplantation Study. Biology of Blood and Marrow Transplantation 2018; 24: 1406-1414.

44. Nagler A, Ngoya M, Galimard J-E, Labopin M, Kröger N, Socié G et al. Trends in outcome of transplantation in patients with secondary acute myeloid leukemia: an analysis from the Acute Leukemia Working Party (ALWP) of the EBMT. Bone Marrow Transplant 2022. doi:10.1038/s41409-022-01825-0.

45. Sroror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106: 2912-2919.

46. ElSawy M, Storer BE, Pulsipher MA, Maziarz RT, Bhatia S, Maris MB et al. Multi-centre validation of the prognostic value of the haematopoietic cell transplantation- specific comorbidity index among recipient of allogeneic haematopoietic cell transplantation. Br J Haematol 2015; 170: 574-583.

47. Jullien M, Orvain C, Berceanu A, Couturier M, Guillaume T, Peterlin P et al. Impact of allogeneic stem cell transplantation comorbidity indexes after haplotransplant using post-transplant cyclophosphamide. Cancer Med 2021; 10: 7194-7202.

48. Elsawy M, Storer BE, Milano F, Sandmaier BM, Delaney C, Salit RB et al. Prognostic Performance of the Augmented Hematopoietic Cell Transplantation-Specific Comorbidity/Age Index in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation from Alternative Graft Sources. Biology of Blood and Marrow Transplantation 2019; 25: 1045-1052.

49. D'Angelo CR, Novitsky B, Mee Lee S, Godley LA, Kline J, Larson RA et al. Characterization of cancer comorbidity prior to allogeneic hematopoietic cell transplantation. Leukemia & Lymphoma 2019; 60: 629-638.

50. Alfayez M, Kantarjian H, Kadia T, Ravandi-Kashani F, Daver N. CPX-351 (vyxeos) in AML. Leukemia & Lymphoma 2020; 61: 288-297.

51. Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK et al. CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. JCO 2018; 36: 2684-2692.
52. Lancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK et al. CPX-351 versus 7 + 3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. The Lancet Haematology 2021; 8: e481–e491.

53. Cherry EM, Abbott D, Amaya M, McMahon C, Schwartz M, Rosser J et al. Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia. Blood Advances 2021; 5: 5565–5573.

54. DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med 2020; 383: 617–629.

## Figures

<figure><img src="image_1.png" /></figure>

<figure><img src="image_2.png" /></figure>

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /><figcaption>Figure 1</figcaption></figure>

### Figure 1

**Overall survival after transplant within the entire cohort and subgroups of patients.** (A), entire cohort (N=220). (B), subgroup analysis by molecular risk category. (C), subgroup analysis by AML status at transplantation. (D), subgroup analysis by graft conditioning.
<figure><img src="image_5.png" /></figure>

Number at risk (number of events)
216 (0) 134 (83) 113 (102) 98 (109) 87 (113) 76 (117) 68 (117) 60 (121) 52 (122) 41 (122) 37 (123) 31 (124) 21 (125) 15 (125) 9 (125) 5 (126)

<figure><img src="image_6.png" /></figure>

Number at risk (number of events)
175 (0) 117 (59) 100 (74) 87 (79) 79 (82) 68 (86) 63 (86) 55 (90) 48 (91) 38 (91) 34 (92) 28 (93) 20 (94) 14 (94) 8 (94) 4 (95)
39 (0) 16 (23) 12 (27) 10 (29) 8 (30) 8 (30) 5 (30) 5 (30) 4 (30) 3 (30) 3 (30) 3 (30) 1 (30) 1 (30) 1 (30) 1 (30)

<figure><img src="image_7.png" /></figure>

Number at risk (number of events)
27 (0) 19 (8) 16 (11) 15 (11) 13 (11) 11 (12) 10 (12) 8 (13) 7 (13) 4 (13) 4 (13) 3 (13) 1 (13) 1 (13) 1 (13) 0 (13)
68 (0) 48 (20) 42 (26) 35 (30) 34 (31) 32 (32) 30 (32) 26 (34) 23 (34) 19 (34) 17 (34) 13 (35) 10 (35) 5 (35) 4 (35) 3 (35)
98 (0) 50 (49) 40 (57) 35 (59) 30 (62) 24 (64) 19 (64) 18 (64) 15 (64) 13 (64) 11 (65) 10 (65) 7 (66) 6 (66) 3 (66) 1 (67)

<figure><img src="image_8.png" /></figure>

Number at risk (number of events)
132 (0) 87 (46) 73 (58) 62 (63) 54 (66) 44 (70) 41 (70) 38 (71) 33 (71) 24 (71) 22 (71) 17 (72) 12 (72) 8 (72) 4 (72) 3 (72)
65 (0) 39 (26) 36 (29) 33 (30) 30 (31) 30 (31) 25 (31) 20 (34) 17 (35) 16 (35) 14 (36) 13 (36) 9 (36) 7 (36) 5 (36) 2 (37)
19 (0) 8 (11) 4 (15) 3 (16) 3 (16) 2 (16) 2 (16) 2 (16) 2 (16) 1 (16) 1 (16) 1 (16) 0 (17) 0 (17) 0 (17) 0 (17)

<caption>Figure 2</caption>

Figure 2

**Event-free survival after transplant within the entire cohort and subgroups of patients.** (A), entire cohort (N=216). (B), subgroup analysis by molecular risk category. (C), subgroup analysis by AML status at transplantation. (D), subgroup analysis by graft conditioning.
<figure><img src="image_9.png" /><figcaption>Figure 3</figcaption></figure>

Figure 3

Graft-versus-host disease-free relapse-free survival within the entire cohort. N=188.