Validation of Recently Proposed Risk and Prognostic Factors for Thrombotic Microangiopathy after Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia
Authors: Min Gi June , Kim Hee-Je , Park Sung-Soo , Park Silvia , Jeon Young-Woo , Yahng Seung-Ah , Shin Seung-Hwan , Yoon Jae-Ho , Lee Sung-Eun , Cho Byung Sik , Eom Ki-Seong , Kim Yoo-Jin , Lee Seok , Min Chang-Ki , Cho Seok-Goo , Kim Dong-Wook , Lee Jong-Wook 
Published: November 2019

Background
Transplantation-associated thrombotic microangiopathy (TA-TMA) is a significant complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may affect 20% of recipients on average. A few groups have proposed risk or prognostic factors for TA-TMA, including a recent prospective study in a cohort that included both children and young adults (Jodele et al. Blood 2014), yet there has been no reproduced or validated data for consensus. Furthermore, with rapid advances in transplantation technology such as an increased variety of donors, conditioning regimens, and graft-versus-host disease (GVHD) prophylaxis, currently used diagnostic criteria and risk factors for TA-TMA must be re-evaluated using recent large cohorts.
Patients and method
The purpose of this study is to investigate risk and prognostic factors for TA-TMA in adult patients with acute myeloid leukemia (AML). TA-TMA was primarily diagnosed with previously published diagnostic criteria proposed by our group (Cho et al. Transplantation 2010). Then, we analyzed TA-TMA incidence, risk, and prognostic factors in two independent cohorts for training (n = 382, 2012-2015, retrospective) and validation (n = 231, 2016-2017, prospective). In particular, predictive factors for TA-TMA in a prospective cohort, including children and young adults as recently suggested by Jodele et al., were evaluated in our adult AML patients.
Results
In the entire cohort (n = 613), the median TA-TMA onset was 66 (range, 5-511) days from allo-HSCT. Among TA-TMA patients, 33.6% and 32.6% of them suffered from proteinuria and AKI, respectively. Also, 33.2% suffered from preceding or concurrent hemorrhagic cystitis (any grade), and 12.7% suffered from VOD/SOS at the time of TA-TMA diagnosis. Regarding the treatment of TA-TMA, 87.3% of patients discontinued or reduced the calcineurin inhibitor with supportive care, while 12.7%, 5.6%, and 4.2% were treated with total plasma exchange, t-PA, and defibrotide addition to calcineurin inhibitor dose modification, respectively. Thirty percent of patients achieved complete remission, and TA-TMA was related to poor three-year OS.
There were no significant clinical characteristic differences between the training and validation cohorts with the exception of more haploidentical allo-HSCT in the validation cohort (training vs. validation; 26.7% vs. 36.4%, p = 0.012), and the cumulative incidence of TA-TMA was significantly (p < 0.001) higher among the validation cohort (18.8%) than the training cohort (8.9%). For the risk factors of TA-TMA, univariate and multivariate analyses revealed that LDH > 1.5 x upper normal limit (training p = 0.042 and validation p = 0.0042), proteinuria ≥30 mg/dL (training p = 0.0019 and validation p = 0.0012), and ≥Grade I hemorrhagic cystitis (training p = 0.0460 and validation p = 0.0049) were significantly associated with an increased risk of TA-TMA in both the training and validation cohorts. Among patients with TA-TMA, concurrent hemorrhagic cystitis upon diagnosis of TA-TMA was a significant factor for inferior overall survival in the entire cohort (32.3% vs. 5.9%, p = 0.031).
Conclusions
This study validates the feasibility of diagnostic criteria for TA-TMA proposed by our group with a recent large cohort consisting of training and validation cohorts and points out the role of preceding hemorrhagic cystitis as a risk and prognostic factor for TA-TMA in AML. Of note, proteinuria and elevated LDH prior to the appearance of MAHA proposed by Jodele et al. with a younger population were proven to be useful for predicting the occurrence of TA-TMA among adult populations with AML.

Disclosures
Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding. Kim:BMS: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Il-Yang co.: Research Funding; Novartis: Research Funding. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Research Funding.