Prognostic Factors for Overall Survival in Relapsed Acute Myeloid Leukemia
Authors: Heinicke Thomas , Krahl Rainer , Kahl Christoph , Scholl Sebastian , Wolf Hans-Heinrich , Hähling Detlev , Hegenbart Ute , Peter Norma , Schulze Antje , Florschütz Axel , Reifenrath Kolja , Zojer Niklas , Jakob Christian , Junghanss Christian , Sayer Herbert G. , Maschmeyer Georg , Hochhaus Andreas , Fischer Thomas , Niederwieser Dietger , Al-Ali Haifa Kathrin 
Published: October 2019

Abstract
Purpose: To define prognostic factors for overall survival in adult patients (pts) with relapsed acute myeloid leukemia (AML).
Introduction: Prognostic factors for overall survival after AML relapse are poorly defined. Here, we investigate patient and disease related factors in terms of their impact on prognosis after AML relapse in a cohort of 495 adult AML relapse patients treated in two prospective AML trials of the East German Society of Hematology and Oncology (OSHO).
Patients and methods: We retrospectively evaluated all consecutive relapsed AML pts treated in two OSHO trials (OSHO #61 (pts < 60 years) and OSHO #69 (pts > 60 years)). Age, cytogenetic risk at initial diagnosis, FLT3/NPM1 mutational status, type of AML (de novo versus secondary to myelodysplastic syndrome or myeloproliferative neoplasia (MDS/MPN) versus therapy related), time interval from first complete remission (CR1) to relapse and allogeneic stem cell transplantation (alloSCT) as consolidation in CR1 were evaluated in univariate and multivariate analysis.
Results: Between March 2002 and July 2014, a total of 862 and 968 patients (pts) were enrolled in the OSHO #61 and #69 trial, respectively. Five hundred and thirty two of 690 (77%) documented pts achieved first complete remission in the #61 and 501 of 813 (62%) pts in the #69 trial. Of these, 495 pts (252 male, 243 female) experienced AML relapse, 207(39%) pts in #61 and 288(57%) pts in #69. Median age at relapse was 63 years (range 18 to 86 years). Initial diagnoses were de novo AML, secondary AML to MDS/MPN and therapy related AML in 332(67%) pts, 129 (25.9%) pts and 30 (6%) pts, respectively. Time from CR1 to relapse was < = 6 months in 198 (40%) pts, 7 to 18 months in 226 (45.7%) pts and > 18 months in 71 (14.3%) pts. Initial karyotpe was available for 449 pts (90.7 %). It was favorable, intermediate and poor in 20 (4.5%) pts, 301(67%) pts and 128(28.5%) pts, respectively. Sixty two (13.9%) relapsed pts had a monosomal karyotype at initial diagnosis. NPM1/FLT3 mutational status at initial diagnosis was available in 354 (78.8%) pts, 378 (71%) pts in #61 and 370 (74%) pts in #69. One hundred and three (20.8%) had allogeneic stem cell transplantation as consolidation in CR1 (56 pts) in #61 and (47 pts) in #69.
Relapse therapy was documented in 450 (91%) pts. Six pts that had immunosuppression withdrawn as the only therapy and nine pts that had received a tyrosine kinase inhibitor as monotherapy were excluded from further analysis due to small numbers. All other treatments were as follows: intensive chemotherapy (INT) n=225, alloSCT with or without prior INT n=50, donor lymphocyte infusions (DLi) with or without prior chemotherapy n=22, palliative mild cytoreductive chemotherapy (mCT) n=66, azacitidine (Aza) n=52, best supportive care (BSC) n=20. With these, CR was achieved in 78 (36%), 34 (68%), 8 (36%), 6 (9%), 1 (2%), 0 (0%), respectively.
Median overall survival probability (OS) for all 495 relapsed patients was 6 months. It was 11.3 months, 5.7 months, 4.5 months and 4.6 months for patients aged 18 to 50 years, 51 to 60 years, 61 to 70 years and 71 to 86 years, respectively (p<0.0005). Initial cytogenetics also influenced OS, it was 10.4 months, 7.5 months and 3.8 months for patients with a favorable, intermediate and poor karyotype, respectively (p<0.0005). Having a monosomal karyotype at initial diagnosis was associated with a median OS of only 2.3 months (p<0.001). Initial FLT3/NPM1 mutational status had no impact on OS after relapse. OS was 4 months, 7.1 months and 16.9 months for pts with a time interval from CR1 to relapse of <= 6 months, 7 to 18 months and > 18 months, respectively (p<0.0005).
In univariate analysis age (p<0.0005), initial cytogenetic risk (p<0.0005), type of AML (p=0.01), interval from CR1 to relapse (p<0.0005), alloSCT in CR1 (p=0.03) and type of relapse therapy (p<0.0005) had a significant impact on OS. In multivariate analysis favorable prognostic factors for OS were lower age (p<0.0005), favorable initial cytogenetics (p=0.01), longer interval from CR1 to relapse (p<0.0005) and not having undergone alloSCT in CR1.
Conclusions:
Our study shows that outcome of relapsed AML pts is poor. Younger age, favorable cytogenetics at initial diagnosis, a longer interval from CR1 to relapse and not having undergone alloSCT as consolidation in CR1 are positive prognostic factors, whereas type of AML and FLT3/NPM1 mutational status have no significant impact on survival after relapse.

Disclosures
Off Label Use: Azacitidine is licensed in Germany for the treatment of adult patients with the following conditions, who are not eligible for haematopoietic stem cell transplantation:  intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS),  chronic myelomonocytic leukaemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder,  acute myeloid leukaemia (AML) with 20-30% blasts and multi-lineage dysplasia,according to World Health Organisation (WHO) classification.. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria. Sayer:Takeda: Other; Medac: Other. Al-Ali:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding.