Tuesday, March 28th
16:30-18:00
Oral 14: Acute leukemia
Autologous versus related versus unrelated hematopoietic stem cell transplantation for adult patients with
NPM1 mutated/FLT3-ITD negative acute myeloid leukemia in first remission: a study from the Acute
Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT).
Poiré, Xavier; Labopin, Myriam 1,2,3,4; Blaise, Didier 5; Chevallier, Patrice 6; Maertens, Johan 7; Deconinck, Eric 8;
Forcade, Edouard 9; Rambaldi, Alessandro 10; Baerlocher, Gabriela 11; Zuckerman, Tsila 12; Volin, Liisa 13;
Schouten, Harry; Ifrah, Norbert 14; Esteve, Jordi 15,1; Mohty, Mohamad 1,2,3,16; Nagler, Arnon 1,17
1
Acute Leukemia Working Party of the EBMT, 2Université Pierre et Marie Curie, 3INSERM UMR 938, 4Service
d’Hématologie, Hôpital Saint-Antoine, 5Institut Paoli Calmette, Programme de Transplantation&Therapie
Cellulaire, 6CHU Nantes, 7University Hospital Gasthuisberg, 8Hopital Jean Minjoz, 9CHU Bordeaux, Hôpital Hautleveque, 10University of Milan, Azienda Ospedaliera Papa Giovanni XXIII, 11Inselspital, 12Rambam Medical
Center, 13HUCH Comprehensive Cancer Center, 14CHRU, 15Hospital Clinic, 16Hôpital Saint-Antoine, 17Chaim
Sheba Medical Center
Abstract
Introduction: Acute myeloid leukemia (AML) in first remission (CR1) with intermediate-risk cytogenetics and
isolated NPM1 mutation carries a good prognosis and allogeneic stem cell transplantation (allo-SCT) is not
usually recommended in these patients. To evaluate the best consolidation strategy in AML with isolated
NPM1 mutation, we retrospectively compared auto-SCT, related (MRD) and fully matched (10/10) unrelated
(MUD) allo-SCT within the EBMT registry. Methods: We selected de novo adult AML with intermediate-risk
cytogenetics harbouring an isolated NPM1 mutation without FLT3-ITD and transplanted between 2005 and
2015. Results: Two hundred and fifty-six patients have been allocated. One hundred and twenty-five patients
received an auto-SCT, 72 a MRD and 59 a MUD. Median age at SCT was 52.5-year-old (range, 18.9-77) and
median follow-up was 30 months (range, 1.6-109.7). Molecular status was available in 55% of patients, with a
higher proportion of complete molecular remission (CMR) before auto-SCT than before allo-SCT (84% versus
63%, respectively, p=0.005). The majority of patients have a good performance status at the time of SCT.
Peripheral blood was more frequently used as stem cell source in auto-SCT. Among allo-SCT, a myeloablative
conditioning regimen was administered in 57% of the patients. In vivo T-cell depletion was more frequently in
MUD than in MRD (70 versus 40%, respectively, p=0.001). The 2-year leukemia-free survival (LFS) was 62% in
auto-SCT, 69% in MUD and 81% in MRD (p=0.02 for MRD versus auto-SCT or MUD). The 2-year overall survival
(OS) was not significantly different among auto-SCT, MUD and MRD, reaching 82%, 81% and 85%, respectively
(p=0.88). The 2-year non-relapse mortality (NRM) was 2.5% in auto-SCT and 7.5% in allo-SCT (p=0.04), without
any difference between MRD and MUD. The 2-year cumulative incidence of relapse (RI) was significantly higher
after auto-SCT (30%) than after MUD (22%) and MRD (12%, p=0.01). Among patients transplanted in CMR, RI
was higher after auto-SCT and LFS was superior after allo-SCT (RI: 21 vs. 11 vs 4%; LFS: 61 vs 74 vs. 91 after
auto-SCT, MUD, and MRD, respectively, p=0.04), although this difference did not translate into a different OS
(82 vs. 77 vs. 90 after auto-SCT, MUD, and MRD, respectively). In the 28 patients not transplanted in CMR who
received an allo-SCT, 2-year RI, LFS and OS were 33% (15-53), 63 (43-83), and 81 (65 – 96%), whereas only 10
patients with persistant MRD received an auto-SCT precluding firm conclusions. In multivariate analysis, MRD
versus auto-SCT but not MUD versus auto-SCT was significantly associated with a lower RI (p<0.01 and p=0.13,
respectively) and a better LFS (p=0.01 and p=0.31, respectively). Age correlated significantly with higher NRM
(p<0.01). Donor type, and age were not significantly associated with OS. Conclusion: Allo-SCT using a sibling
donor appears as a good consolidation therapy to prevent relapse for young patients with AML and isolated
NPM1 mutation in CR1. Auto-SCT was followed by higher relapse risk and inferior LFS, but similar OS to both
allo-SCT modalities. In patients with molecular persistence, allo-SCT was followed by a relatively favourable
outcome, but the low number of patients with molecular data included in this series precludes more firm
conclusions. The strategy for patients not transplanted in CMR remains to be further evaluated.
Disclosure of conflict of interest
All the authors declare no conflict of interest.
2
Umbilical cord blood transplantation versus unrelated donor transplantation in adults with relapsed or
primary refractory acute myeloid leukemia: a report from Eurocord, the Acute Leukemia Working Party and
the Cord Blood Committee of the Cellular Therapy & Immunobiology Working Party of the EBMT
Frédéric Baron1, Annalisa Ruggeri2,3, Myriam Labopin4, Mohamad Mohty3, Gerhard Ehninger5, Fransesca
Bonifazi6, Matthias Stelljes7, Jaime Sanz8, Gernot Stuhler9, Alberto Bosi10, Nicolaus Kröger11, Maria Teresa Van
Lint12, Arnold Ganser13, Noel Milpied14, Eliane Gluckman15, Arnon Nagler4,16
1
Laboratory of Hematology, GIGA-I3, University of Liege, Liege, Belgium; 2Eurocord, Hospital Saint Louis, AP-HP,
and IUH University Paris VII, France; 3AP-HP, Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine,
Paris, France; 4EBMT Paris Office, Hospital Saint Antoine, Paris, France; 5Universitaetsklinikum Dresden,
Medizinische Klinik und Poliklinik I, Dresden, Germany; 6Bologna University, S.Orsola-Malpighi Hospital,
Institute of Hematology & Medical Oncology, Bologna, Italy; 7University of Münster, Dept. of Hematol./Oncol.,
Münster, Germany; 8Servicio de Hematologia, Hospital Universitario La Fe, Valencia, Spain; 9Deutsche Klinik für
Diagnostik, KMT Zentrum, Wiesbaden, Germany; 10Hematology Unit, AOU Careggi, Florence, Italy; 11University
Hospital Eppendorf, Bone Marrow Transplantation Centre, Hamburg, Germany; 12Ospedale San Martino,
Department of Haematology II, Genova, Italy; 13Hannover Medical School, Department of Haematology,
Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany; 14CHU Bordeaux, Hôpital Hautleveque, Pessac, France; 15Eurocord, Hospital Saint Louis, AP-HP, and IUH University Paris VII, France
Monacord, Centre Scientifique de Monaco, Monaco; 16Division of Hematology and Bone Marrow
Transplantation, The Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel and the EBMT Paris Office,
Hospital Saint Antoine, Paris, France
Abstract
Background. A recent retrospective study demonstrated a better outcome of umbilical cord blood (UCB)
transplantation vs HLA-matched (MUD) or HLA-mismatched (MMUD) unrelated donor hematopoietic stem cell
transplantation (allo-HCT) in AML patients (pts) with positive pre-transplantation minimal residual disease
(MRD) (Milano et al., NEJM 2016). This prompted us to compare the outcomes of UCBT vs MUD or MMUD alloHCT in AML pts with active disease at transplantation. Methods. The study population consisted of patients
with either primary refractory or relapsed AML given UCBT, MUD or MMUD allo-HCT from 2004 to 2015 at
EBMT-affiliated centers. Results. Data from 2963 pts with primary or secondary AML were included in this
study. Two hundred eighty five pts underwent an UCBT, 2001 a MUD and 677 a 9/10 MMUD allo-HCT. In
comparison to MUD or MMUD recipients, UCBT pts were younger (48 vs 55 and 55 yrs, respectively, P<0.001),
were less frequently transplanted with primary refractory disease (37% vs 50% and 42%, respectively,
P<0.001), and were more frequently conditioned with a myeloablative regimen (52% vs 46% and 42%,
respectively, P<0.001). In multivariate Cox analyses, in comparison to UCBT, MUD recipients had a lower
incidence of relapse (HR=0.7, P=0.001), a lower incidence of nonrelapse mortality (HR=0.6, P<0.001), better
GVHD-free leukemia-free survival (GRFS, HR=0.8 , P<0.001) and better survival (HR=0.6, P<0.001). Further, in
comparison to UCBT, MMUD recipients had a lower incidence of relapse (HR=0.8, P=0.02), a lower incidence of
nonrelapse mortality (HR=0.7, P=0.008), better GRFS (HR=0.8 , P=0.01) and better survival (HR=0.7, P<0.001).
Similar qualitative observations were made in a propensity weighted Cox survey. Conclusions. These data
suggest that in AML pts with active disease at transplantation, allo-HCT with MUD or 9/10-antigen MMUD
results in better transplantation outcomes than UCBT.
Disclosure of conflict of interest
None
3
The Value of Allogeneic Stem Cell Transplantation in Patients with Intermediate Risk (ELN) Acute Myeloid
Leukemia with no FLT3-ITD, no NPM1 mutations and no CEBPA double mutations
Heidrich, Katharina 1; Thiede, Christian 1; Schäfer-Eckart, Kerstin 2; Schmitz, Norbert 3; Aulitzky, Walter E 4;
Krämer, Alwin 5; Rösler, Wolf 6; Hänel, Matthias 7; Einsele, Hermann 8; Baldus, Claudia D 9; Trappe, Ralf U 10;
Stölzel, Friedrich 1; Middeke, Jan Moritz; Röllig, Christoph; Taube, Franziska 1; Kramer, Michael 1; Serve,
Hubert11; Berdel, Wolfgang E 12; Ehninger, Gerhard 1; Bornhäuser, Martin 1; Schetelig, Johannes 1
1
Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany, 2Medical Clinic
5, Hematology and Oncology, Klinikum Nuernberg, Nuernberg, Germany, 3Hematology and Stem Cell
Transplantation, ASKLEPIOS Klinik St. Georg, Hamburg, Germany, 4Department of Hematology and Oncology,
Robert-Bosch-Hospital, Stuttgart, Germany, 5Department of Internal Medicine V, University Hospital of
Heidelberg, Heidelberg, Germany, 6Medizinische Klinik 5, Universitätsklinkum Erlangen, Erlangen, Germany,
7
Klinik für Innere Medizin III, Klinikum Chemnitz, Chemnitz, Germany, 8Department of Internal Medicine II,
University Hospital of Würzburg, Wuerzburg, Germany, 9Department of Hematology, Oncology and Tumor
Immunology, Charité, University Medical Center, Berlin, Germany, 10Hämatologisch-Onkologisches
Kompetenzzentrum, Evangelisches Diakonie-Krankenhaus Bremen, Bremen, Germany, 11Department of
Hematology/Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany;, 12Department of Medicine A,
University Hospital of Muenster, Muenster, Germany
Abstract
Introduction The value of allogeneic hematopoietic cell transplantation (alloHCT) in patients with intermediate
risk AML in the absence of FLT3-ITD and NPM1 mutations, called triple-negative AML by some authors,
referring to the absence of CEBPA double mutations, is poorly defined. The purpose of this analysis was to
evaluate the impact of alloHCT on the overall (OS) and relapse free survival (RFS) in this group of patients in
first remission (CR1) in comparison to post remission chemotherapy (CT). Patients and Methods We analyzed
data of 3041 AML patients who were enrolled into two large prospective, randomized trials (AML96,
NCT00180115 and AML2003, NCT00180102) of the Study Alliance Leukemia (SAL). The trials included patients
aged 16-60 years with newly diagnosed AML. In the AML2003 study, donor status was evaluated at study entry,
making this data eligible for a donor versus no-donor analysis. Within the subgroup of interest, alloHCT was
offered to all patients with an HLA-identical sibling donor in CR1 (donor group). Only patients with
relapsed/refractory AML were scheduled for matched unrelated alloHCT (UD-HCT). Within the intensified
treatment arm, patients who had >10% bone marrow blasts on day 15 after first induction were scheduled for
early UD-HCT. Selection criteria were documented CR1, the absence of FLT3-ITD, CEPBA double mutations and
NPM1 mutations, and a karyotype not defined as favorable or adverse according to ELN. Results For donor
versus no-donor analysis, 276 patients with a median age of 49 years were evaluable for the analysis of OS
from diagnosis while 252 patients had reached CR1 and were evaluable for RFS. The availability of an HLAidentical sibling had a significant impact on RFS (p=0.002) and a trend to better OS (p=0.08) in the control arm
where only patients with relapsed/refractory patients received UD-HCT. In the intensified arm with early UDHCT, the availability of an HLA-identical sibling had no impact on survival. Accordingly, in the subgroup of
patients with >10% day 15 marrow blasts or induction failure, patients who were randomized to the intensified
arm with early UD-HCT had a trend towards superior RFS and OS compared to patients in the control arm,
reflected by a hazard ratio (HR) of 0.5 (95%CI 0.3 to 1.0, p=0.06). Notably, the transplantation rate in the donor
group was only 53% while 15% of patients in the no-donor group received alloHCT. Therefore, and as donor
versus no-donor analysis was only possible within the AML 2003 patient cohort, we additionally performed astreated analyses with alloHCT as time-dependent intervention in both cohorts, AML96 and AML2003. Astreated analysis showed a substantial advantage in terms of OS (HR 0.58, 95%CI 0.37 to 0.9, p=.02) and RFS (HR
0.51 (95%CI 0.34 to 0.76, p=0.001) for patients who had received alloHCT in CR1. Conclusion Our analyses
suggest that medically fit intermediate-risk AML patients with no FLT3-ITD, no NPM1-mutation, and no double
CEBPA-mutations should proceed to alloHCT after induction chemotherapy. Legend to the figure Kaplan-Meier4
Plots on Relapse-free Survival and Overall Survival, by availability of a matched sibling donor at baseline and
treatment arm (early UD-HCT versus control). RFS, Relapse free survival; OS, Overall survival; UD, unrelated
donor; HCT, hematopoietic cell transplantation
Disclosure of conflict of interest
Nothing to declare.
5
Outcomes of Allogeneic Hematopoietic Cell Transplantation for Acute Myelogenous Leukemia (AML) with
Complex Karyotypes (CK): a Retrospective Study from the Acute Leukemia Working Party (ALWP) of the
European Society for Blood and Marrow Transplantation (EBMT) and MD Anderson Cancer Center (MDACC)
Ciurea, Stefan 1; Labopin, Myriam; Polge, Emmanuelle; Kongtim, Piyanuch; Rondon, Gabriela; Socie, Gerard;
Volin, Liisa; Passweg, Jakob; Chevallier, Patrice; Beelen, Dietrich; Milpied, Noel; Blaise, Didier; Cornelissen, Jan
J.; Fegueux, Nathalie; Mohty, Mohamad; Savani, Bipin; Champlin, Richard; Nagler, Arnon
1
Department of Stem Cell Transplantation and Cellular Therapy MD Anderson Cancer Center
Abstract
Introduction Allogeneic hematopoietic stem cell transplantation (AHSCT) is the only curative treatment for CK
AML which otherwise has dismal outcomes. However, relapse rate remains a major limitation and survival is
one of the worst amongst AML patients. Here we aimed to identify prognostic factors associated with survival
in adult patients with CK AML using combined data from the EBMT and MDACC. Methods We analyzed
outcomes of 1,342 consecutively transplanted patients with CK (> 3 cytogenetic abnormalities) AML reported
to EBMT (N=1,118) and at MDACC (N=224) between 01/2000-12/2015. The median age was 52 years (range
18-76 years), 335 patients (25%) were older than 60 years, 239 patients (17.8%) had secondary AML. Disease
status before transplant was CR1, CR2 and active disease in 877 (65.3%), 77 (5.7%) and 388 (29%), respectively.
Donors were matched related (MRD), matched unrelated (MUD) and mismatched unrelated (MMUD) in 749
(55.8%), 513 (38.2%) and 80 (6%), respectively. Conditioning regimens were various, mostly either busulfanbased (53.7%) or TBI-based (26.7%). Seven hundred and thirty-nine patients (55%) received myeloablative
conditioning (MAC). The main stem cell source was peripheral blood (81%). In vivo T-cell depleted (TCD)
methods were used in 665 patients (50%). The median follow-up duration was 35.5 months (range 8-174
months). Results At 2 year post-transplant, the cumulative incidence (CI) of acute GVHD grade II-IV and grade
III-IV was 26.3% and 8.4%, respectively, whereas CI of chronic GVHD was 30.9% with extensive chronic GVHD
17.8%. Leukemia free survival (LFS), overall survival (OS), CI of relapse, non-relapse mortality (NRM) at 2 years
for the whole group was 31.3%, 36.8%, 51.1% and 17.6%, respectively, whereas 2-year GVHD-free, relapse-free
survival (GRFS) was 19.8%. LFS, OS, GRFS, CI of relapse and NRM at 2 years for patients transplanted in CR1 was
38.4%, 44.5%, 23.8%, 46% and 15.7%, respectively. For patients with active disease, these outcomes were
14.6%, 18.5%, 9.6%, 63.5% and 21.9%, respectively (Figure A, B). Patients ages 40-60 years transplanted in CR1
with MAC demonstrated lower relapse (40.2% vs. 51% with RIC, p=0.005), offset by a higher NRM (18.2% vs
9.8% RIC, p=0.037), associated with higher incidence of acute GVHD, resulted in a non-significant difference in
LFS (Figure C, D). In multivariable analysis, advanced age, transplantation in active disease, secondary AML and
presence of deletion or monosomy 5 or 7 predicted poor LFS and OS. All of these factors as well as year of
transplant (before 2010) also predicted poor GRFS. Prognostic factors for relapse were age, secondary AML,
active disease at transplant and presence of deletion or monosomy 5, while prognostic factors for NRM were
older age, active disease, use of a MMUD and deletion or monosomy 7. Conclusions In this largest analysis of
complex karyotypes AML patients, relapse remains the most common cause of treatment failure with 45% for
patients in CR1 and 63.5% for patients not in remission relapsing after transplant. To maximize survival for
these patients, AHSCT should be considered in every CK AML patients in CR1 as soon as the donor is available.
Better control of GVHD might allow younger patients receiving MAC to have a lower NRM and improved LFS.
Novel approaches including maintenance therapy are needed to decrease relapse rate and improve survival in
these patients.
6
Disclosure of conflict of interest
No
7
Efficacy, Safety and Long Term Results of Prophylactic and Preemptive Donor Lymphocyte Infusion after
Allogeneic Stem Cell Transplantation (alloSCT) for Acute Leukemia – Final results from a Registry-based
Evaluation of 334 Patients by the Acute Leukemia Working Party (ALWP) of EBMT
Schmid, Christoph; Labopin, Myriam 1; Veelken, Hendrik 2; Schaap, Nicolaas 3; Schleuning, Michael 4; Stadler,
Michael 5; Finke, Juergen; Bug, Gesine 6; Ringden, Olle; Collin, Matthew; Blaise, Didier; Tischer, Johanna; Bloor,
Adrian 7; Esteve, Jordi; Ciceri, Fabio; Baron, Frederic; Gorin, Norbert-Claude 8; Savani, Bipin 9; Giebel, Sebastian;
Mohty, Mohamad; Nagler, Arnon
1
Hopital St. Antoine, Universite de Paris; ALWP office, 2Leiden University Medical Center, 3Radboud University
Medical Centre Dept. of Hematology, 4Department of Stem Cell Transplantation, Helios-Kliniken, Wiesbaden,
5
Medizinische Hochschule Hannover, Deparment of Haematolohy and Oncology, 6University of Frankfurt,
Department of Haematology and Oncology, 7The Christie NHS Foundation Trust, 8Hopital St. Antoine,
Universite de Paris, 9Vanderbilt University
Abstract
Background Infusion of donor lymphocytes (DLI) is of limited efficacy in haematological relapse after alloSCT
for acute leukaemia. Hence, DLI is frequently given in complete haematological remission (CHR), either as early
intervention for mixed chimerism (MC) or minimal residual disease (MRD, both summarized as preemptive DLI,
preDLI), or as maintenance without any evidence of disease (prophylactic DLI, proDLI). However, no systematic
analysis of this strategy is available so far. Patients and Methods 334 patients (AML:77%, ALL:23%; median
age:47.5y) received DLI in CHR after alloSCT. 65%/35% had a matched sibling/unrelated donor. Stage at SCT
was CR1/CR2/advanced in 68%/14%/18%. Patients had received standard/reduced conditioning in 51%/49%.
55% had received in vivo T-cell depletion (TCD), 16% ex vivo, 10% in vivo plus ex vivo, and 19% no TCD. Reason
for DLI were MC in 51%, persisting/recurrent MRD in 11%, and prophylaxis in 38%. Improvement of MC and
decrease of MRD were used efficacy in preDLI. A matched pair analysis investigated the effects of proDLI:
Inclusion criteria for the proDLI cohort comprised ≥1 DLI within 1y from SCT, no additional anti-leukemic
therapy, and neither leukemia relapse nor aGvHD ≥II° or cGvHD between SCT and DLI1. Controls were selected
from the ALWP registry among 13827 patients in CHR after SCT without proDLI. Controls had further to be alive
without relapse and GvHD ≥ the interval between SCT and proDLI in the respective matched case. Matching
variables were age (+/-5y), diagnosis (AML/ALL), stage at SCT, donor, patient-donor sex combination,
cytogenetics, conditioning (reduced/standard), and T-cell depletion (no/in vivo/ex vivo). Results Median followup from DLI1 was 6.5y (1.1-14.5), median interval from SCT to first DLI (DLI1) was 187d (15-1178). Patients
received a median of 2 infusions, median CD3+ cell count at DLI1 was 1x106/kg (0.1-163). GvHD was the major
complication after DLI: 5y incidence of aGvHD II-IV° and cGvHD were 12% and 30%, respectively. A multivariate
model identified a history of prior aGvHD ≥II° after SCT (p=0.001, HR: 4.6, 95%CI: 1.8-11.9), and a shorter
interval from SCT to DLI1 (p=0.001, HR: 0.994, 95%CI: 0.990-0.998), as risk factors for GvHD. 15 patients (5% of
the entire cohort) died from DLI-induced GvHD. 5y cumulative incidence of leukemia relapse was 44% and 28%
after preDLI for MRD and MC, and 28% after proDLI. Corresponding 5y-OS was 51%, 63% and 68%, 5y-LFS was
47%, 57% and 62%. Efficacy of preDLI could be demonstrated by decreasing MRD in 16/23 (70%), and
improvement of chimerism in 110/169 (65%) informative patients. 89 proDLI cases were pair-matched with 89
controls (p=.885 for age, p=1.0 for all other variables). Within the overall population, no outcome parameter
was influenced by proDLI. However, improved OS was seen in high-risk AML, as defined by unfavorable
cytogenetics and/or SCT in active disease (5y OS 69.8% (52.2-87.3) for proDLI recipients vs. 40.2% (19.3-61%)
for controls, p=.036; figure 1). In contrast, no difference was seen in standard-risk patients. Conclusion In this
large cohort, efficacy of preDLI cells was observed in 69% of patients. More than 50% of patients with MRD,
and >70% of patients with MC did not relapse during a follow-up of >5 years, suggesting a meaningful longterm effect. Significantly improved OS was seen after proDLI in high-risk AML. GvHD was the major
complication, leading to death in 5% of patients.
8
Disclosure of conflict of interest
None with respect to this study
9
Different outcome of allogeneic stem cell transplantation for transformed acute myeloid leukemia derived
from MDS, CMML or MPN. A retrospective study of the Chronic Malignancies Working Party (CMWP) of
EBMT
Kröger, Nicolaus 1; Eikema, Diderik-Jan 2; de Wreede, Liesbeth 3,4; van Biezen, Anja 5; Beelen, Dietrich 6; Finke,
Jürgen 7; Koenecke, Christian 8; Niederwieser, Dietger 9; Bornhäuser, Martin 10; Schönland, Stefan 11; Mufti,
Ghulam 12; Stuhler, Gernot 13; Maertens, Johan 14; Theobald, Matthias 15; Kobbe, Guido 16; Volin, Liisa 17; Wulf,
Gerald 18; Kahls, Peter 19; Milpied, Noel 20; Greinix, Hildegard 21; Masszi, Tamás; Nagler, Arnon 22; Chalandon,
Yves 23; Robin, Marie 24
1
University Medical Center Hamburg, Eppendorf, 2Depatment of Medical Statistics & Bioinformatics, Leiden,
Dept. Medical Statistics Bioinformatics, Leiden, 4DKMS, German Bone Marrow Donor Center, 5Dept. Medical
Statistics & Bioinformatics, Leiden, 6University Hospital Essen, 7University of Freiburg, 8Hannover Medical
School, 9University Hospital Leipzig, 10University Hospital Dresden, 11University of Heidelberg, 12GKT School of
Medicine, London, 13German Clinic for Diagnostics Wiesbaden, 14University Hospital Gasthuisberg, Leuven,
15
University Medical Center Mainz, 16University Hospital Düsseldorf, 17HUCH Comprehensive Cancer Center
Helsinki, 18University Hospital Göttingen, 19Medical University Vienna, 20CHU Bordeaux, Pessac, 21LKH University Hospital Graz, 22Tel Hashomer, 23Hôpitaux Universitaires de Genève, 24Hôpital St.Louis, Paris
3
Abstract
Introduction Myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic
myelomonocytic leukemia (CMML) can progress to acute myeloid leukemia (transformed AML). The aim of this
EBMT registry study was to compare 3 year outcome in patients with transformed AMLwho received allogeneic
stem cell transplantation according to the primary disease. Patients and Methods Within the European Society
of Blood and Marrow Transplantation (EBMT) registry, we found 4214 patients (female: 39%, male: 61%) with
transformed acute myeloid leukemia, who received allogeneic stem cell transplantation between 2000 and
2014. The primary disease was MDS (n=3541), CMML (n=251) or MPN (n=422). The median age at
transplantation was 58 years (range, 18-79) and 59% received a reduced intensity (RIC) conditioning regimen.
The majority of the patients received stem cells from an unrelated donor (62%) and 50% were in complete
remission at time of transplantation. Within the different groups of primary diseases, MDS patients were more
often in CR (53%) than patients with CMML (47%) or MPN (43%). RIC was also more frequently used in MDS
patients (65%), than in CMML (64%) and MPN patients (58%). Results After a median follow up of 46.5 months
, the estimated 3 year relapse-free (RFS) and overall survival (OS) for the entire group was 36% (95%CI: 34-38%)
and 40% (95% CI: 33-42%), respectively. The cumulative incidence of relapse and non-relapse mortality (NRM)
was 37% (95% CI: 35-39%) and 27% (95% CI: 26-29%), respectively. In a univariate analysis, patients with
primary disease MDS had a significant better 3 year OS and RFS (41% and 37%) than patients with CMML (36%
and 30) and MPN (32% and 25%) (p<0.001), due to a significant lower incidence of relapse at 3 years (35% vs
43% vs 50%, p<0.001). Other risk factors for worse OS were higher patient’s age (>60 years), unrelated donor,
not being in complete remission and low Karnofsky index (< 80%), while T-cell depletion, intensity of the
conditioning regimen and TBI as conditioning regimen did not influence survival significantly. In a multivariate
analysis for OS beside age >60 years (HR 1.31; 95% CI: 1.13-1.52, p<0.001), unrelated donor (HR 1.12; 95% CI:
1.04-1.23, p=0.005), CMV +/- constellation (HR 1.13; 95%CI: 0.99-1.28, p=0.05), Karnofsky index > 80 (HR 0.66;
95% CI: 0.58-0.74, p< 0.001), non CR (HR 1.50; 95% CI: 1.38-1.63, p<0.001) PBSC as stem cell source (HR 0.86;
95% CI:0.75-0.97, p=0.02) and transformed AML from MPN (HR 1.24; 95% CI: 1.085-1.41, p=0.002) remained a
significant factor in comparison to transformed AML from MDS, while outcome of transformed AML from
CMML did not reach statistical significance in comparison to MDS (HR 1.10; 95% CI: 0.933-1.30, p=0.25)
Conclusion This large EBMT registry study demonstrates that the primary underlying disease influences
outcome of transformed acute myeloid leukemia in addition to other risk factors.
Disclosure of conflict of interest
10
None
11
Post transplant cyclophosphamide (PT-Cy) in association to standard GVHD prophylaxis in sibling and
unrelated allogeneic stem cell transplantation (HSCT) for patients with acute leukemia, a survey from the
ALWP of EBMT
Ruggeri, Annalisa; Labopin, Myriam; Afanasyev, Boris; Cornelissen, Jan J; Glass, Bertram; Blaise, Didier; ItäläRemes, Maija; Kroeger, Nikolaus; Meijer, Ellen; Ciceri, Fabio; Milpied, Noel; Savchenko, Valery; Koc, Yener;
Mohty, Mohamad; Bacigalupo, Andrea; Nagler, Arnon
Service d’Hematologie, Hospital Saint Antoine, Paris, France
Abstract
Introduction: Post-transplant Cyclophosphamide (PT-Cy) as graft versus host disease (GVHD) prophylaxis,
pioneered in the setting of unmanipulated haploidentical transplantation, is effective reducing the incidence of
GVHD.Use of PT-Cy for GVHD prophylaxis from HLA matched sibling (MSD) or unrelated (UD) donors is less
established. Methods: With the aim to evaluate the applicability of PT-Cy as GVHD prophylaxis in MSD and UD
transplants we conducted a surveyon 625 patients (pts) transplanted from 2008-2015 for AML (n=471) and ALL
(n=154). Results: The majority of the pts were transplanted in CR1 (n=384, 61%), CR2/3 (n=106, 17%) or
advanced disease (n=135, 22%). Median age at transplant was 44 years, 14% of the pts had secondary leukemia
and 26% (n=151) had a Karnofsky performance status <90%. Donor type was MSD (n=255, 41%), 10/10 UD
(n=245, 39%) and 9/10 UD (n=125, 20%) with peripheral blood (PB) being used in 79% of cases (n=494). Median
follow up was 12 months. 52% of pts (n=316) received a myeloablative conditioning regimen (MAC) and 48%
(n=297) a reduced intensity conditioning (RIC). All pts received PT-Cy as GVHD prophylaxis, mainly in
combination with tacrolimus and MMF (n=110), CSA+MMF (n=95) or CSA+MTX (n=70), according to transplant
center policy. ATG was also used in 33% of pts (n=206). Ninety-six percent of patients achieved neutrophil
engraftment. The cumulative incidence (CI) of acute GVHD grade II-IV and grade III-IV were 27% and 10%,
respectively. At 2 years the CI of chronic GVHD was 32% with 14% being extensive. Overall CI of relapse and
NRM were 33% and 17%, respectively. Disease recurrence was the most common causes of death (52%),
followed by infection (19%) and GVHD (11%) as causes of NRM. Overall 2 year OS, LFS, GRFS were 59%, 50%
and 35%, respectively. In the univariate analysis outcomes were not different according to the different
combination of GVHD prophylaxis. LFS was not different for patients transplanted for AML (56%) or ALL (50%)
p=0.87 or for those transplanted with a MSD (51%), 10/10 UD 57% or 9/10 UD 56%, p=0.63. According to
disease status, LFS was 64%, 51% and 32% for patients transplanted in CR1, CR2 or in advanced disease status,
respectively, p<10-4. Patients with secondary leukemia had lower 2 year LFS (39% vs 57%, p<10-4). In the
multivariate analysis adjusted for type of diagnosis, disease status, secondary leukemia, age, type of donor,
stem cell source, CMV serostatus, conditioning regimen, center effect. Donor CMV serostatus was the sole
factor associated with an increased risk of grade II-IV acute GVHD (HR 4.5, 95%CI 1.6-12.4, p=0.03). Advanced
disease (HR 2.25, 95%CI 1.49-3.42, p<10-4), and donor CMV status (HR 1.51, 95%CI 1.02-1.32, p=0.03) were
associated with increased risk of relapse. Disease status remained the only factor associated with LFS (for CR2
or CR3: HR 1.49, 95%CI 1.00-2.23, p=0.04, and for advanced disease: HR 2.37, 95%CI 1.7-3.29, p<10-4). Disease
status was also significant for OS with type of diagnosis (AML vs ALL: HR 0.67, 95%CI 0.45-0.98, p=0.04) and
secondary leukemia (HR 1.64, 95%CI 1.08-2.48, p=0.01) as other independent factors. Conclusion: The use of
PT-Cy in the setting MSD or UD transplants for adults with acute leukemia is effective to avoid prohibitive acute
GVHD and GVHD related mortality. Although somewhat preliminary these results may serve as the basis for
prospective randomized trial aiming in better defining the package of GVHD prophylaxis in unrelated HSCT.
Disclosure of conflict of interest
None
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Second Allograft for Relapsed or Refractory Acute Myeloid Leukemia after First Allogeneic Stem Cell
Transplantation: a Study on behalf of the SFGM-TC
LOMBION, Naelle; Blaise, Didier 1; Milpied, Noël 2; Socié, Gérard 3; Delage, Jérémy 4; Yacoub-Agha, Ibrahim 5;
Chevallier, Patrice 6; Bourhis, Jean-Henri 7; Mohty, Mohamad 8; Couturier, Marie-Anne 9
1
Département d’Onco-Hématologie, Unité de transplantation et de Thérapie Cellulaire Institut Paoli Calmettes,
Service des Maladies du Sang G.H. du Haut Levêque, 3Fédération d’Hématologie Service de greffes de moelle
Hôpital Saint-Louis, 4Service d’Hématologie Clinique CHRU Saint-Eloi, 5Service des Maladies du Sang Hôpital
Claude Huriez CHRU, 6Service d’Hématologie Clinique Hotel Dieu CHU, 7Service d’Hématologie Institut Gustave
Roussy, 8Service d’Hématologie Clinique Hôpital Saint-Antoine, 9Service d’Hématologie clinique Hôpital
Morvan, bât 3
2
Abstract
Patients with relapsed or refractory acute myeloid leukemia (AML) after allogeneic hematopoietic stem-cell
transplantation (HSCT) have a poor prognosis. Retrospective studies showed that such patients experiment a
1
low rate and short duration of complete remission (CR). The therapeutic strategies in this situation are still
controversial: donor lymphocyte infusion, second HSCT (HSCT2), chemotherapy, tapering immune-suppression
2
or supportive care. We aimed to evaluate the tolerance and efficiency of a HSCT2 in patients with relapsed or
refractory AML after first HSCT (HSCT1). We performed a retrospective multicenter study on patients from the
SFGM-TC registry. From January 2004 to January 2014, patients with AML who received at least one allogeneic
HSCT were included. We discriminated three groups: group 1 contains patients who did not relapsed, group 2
contains patients treated with conventional drugs for relapse after HSCT1 and group 3 contains patients who
received a HSCT2 for relapsed/refractory AML after HSCT1. The decision of a HSCT2 was made by physicians
depending on patients’ general condition, comorbidities, disease status and graft availability. The tolerance
was evaluated on the outcome of graft versus host disease (GvHD). The efficiency was evaluated on the CR rate
and the overall survival (OS). During this period, 4033 AML patients were included: 2096 males and 1937
females (sex-ratio=1.08). The median age at diagnosis was 48 years (range 4-72). Among the
relapsed/refractory AML, 1216 patients (30.2%) received rescue conventional therapy, and 186 patients (4.6%)
received a HSCT2. Characteristics such as secondary AML, cytogenetic prognosis, conditioning regimen, HLAtype of donor, aGvHD outcome or failure to achieve a CR after HSCT1 were similar between patients of the
second and third groups. CR before HSCT1 was obtained in 73.6% of patients rescued by conventional
treatment and in 52.1% of patients treated by HSCT2 (p<0.0001). Chronic GvHD after HSCT1 was more
frequent in patients of the third group (39.5%) than in patients of the second group (21.6%) (p=0.003). Among
patients with HSCT2, 52.4% patients received a myeloablative conditioning (MAC). Peripheral stem cells were
transplanted in 75.8% patients, 9.3% patients received bone marrow cells and 14.8% patients received cord
blood cells. Most patients received HSCT2 with unrelated donor (59.2%). At d100, 94 of 186 patients (50.5%)
achieved CR and 98 of 186 patients (52.7%) showed a full donor chimerism. Early death after HSCT2 outcame
for 32 of 186 patients (17.2%). After HSCT2, cumulative incidence of grade 2-4 aGvHD was 34.3% of patients
and cGvHD occurred in 17.9% of patients (69.2% limited cGvHD and 30.8% extensive cGvHD). After a median
follow up of 53.4 months (range 14.3-92.5), we observed a gain of OS in favor of the group of patients treated
with a HSCT2 compared to patients of the second group: OS rate at 4 years and a half was 33.8% vs. 17.5% and
the median OS was 34.6 vs. 19.2 months respectively (p< 0.0001). Patients with relapsed/refractory AML after
HSCT1 could be rescued by HSCT2 with significant gain of survival and reasonable toxicity. HSCT2 feasibility
should be evaluated according to the comorbidities, the disease status and donor characteristics. However, the
rate of relapse remains strong. Strategies using new therapies such as CAR T-cells, targeted therapies or new
immune-suppressive agents with or without HSCT2 should be evaluated.
13
Disclosure of conflict of interest
No conflict of interest
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