Allogeneic Hematopoietic Stem Cell Transplantation in Advanced Systemic Mastocytosis
Blood, vol. 142, pp. 3605
Abstract
Purpose Advanced systemic mastocytosis (AdvSM) is driven by the KIT D816V mutation in >90% of patients (pts.). Depending on subtype, median survival is between 1.5 and 4 years. Despite recent advances on responses and survival due to the availability of effective KIT inhibitors, allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative treatment option. Data on optimal timing, conditioning regimens, and pre- as well as post-alloHSCT treatments for maintenance or relapse are however scarce. Current recommendations mainly refer to a retrospective analysis published almost 10 years ago (Ustun et al., JCO 32, 2014). With the advent of new therapies and improved transplant procedures, more recently collected data on alloHSCT in AdvSM are needed for actual assessment of optimal treatment strategies. Patients & Methods This retrospective analysis identified 71 pts. with AdvSM who underwent alloHSCT at 20 German centers between 1999 and 2021. Data were collected via the 'German Stem Cell Transplantation Registry (DRST)' and the 'German Registry on Disorders of Eosinophils and Mast Cells (GREM)'. Additional baseline characteristics and response status prior to, during and post alloHSCT were provided by the participating centers. Results At time of alloHSCT, median age was 59 years (range 21-84); 55/71 (77%) pts. were male. Median time between diagnosis of AdvSM and alloHSCT was 1.2 years (range 0.1-16.7). Pts. were grouped into (i) aggressive systemic mastocytosis (ASM, n=6) and SM with an associated hematological neoplasm (SM-AHN, n=24), totaling 30/71 (42%) ASM/SM-AHN pts., (ii) SM with an associated acute myeloid leukemia (SM-AML; 28/71, 39%) and (iii) mast cell leukemia ± AHN (MCL±AHN; 13/71, 18%). The median follow-up time after alloHSCT was 1.4 years (range 0-20.4). PFS and OS were 52% (SD ± 6.1%) and 62% (SD ± 5.9%) at 1 year, and 39% (SD ± 6.3%) and 50% (SD ± 6.2%) at 3 years. Discrimination between the three cohorts allowed a three-tier risk stratification (median PFS, 4.5 vs. 0.7 vs. 0.3 years, P<0.001; median OS, 9.0 vs. 3.3 vs. 0.9 years, P=0.007, Figure 1). Overall non-relapse mortality rate was 30% (21/71) including infectious complications in 8/21 (38%), GvHD in 1/21 (5%), cardiotoxicity in 1/21 (5%) and ‘combinations/not further specified’ in 11/21 (52%) pts. The 100-day non-relapse mortality was 8% (6/71; ASM/SM-AHN, 0/30; SM-AML, 4/28, 14%; MCL±AHN, 2/13, 15%). OS was associated with response status of SM (17/41, 41%; median OS 4.6 vs. 1.1 years, P=0.029) or AHN (26/43, 60%, median OS not reached vs. 0.4 years, P=0.003) prior to alloHSCT ( Figure 2). Univariable analyses revealed absence of a KIT D816V mutation (HR 2.9 [1.2-6.5], P<0.001) and a complex karyotype (HR 4.2 [1.8-10.0], P=0.016) as adverse prognostic factors regarding OS. PFS was significantly impacted by diagnosis of MCL±AHN (HR 3.5 [1.7-7.5], P<0.001), absence of a KIT D816V mutation (HR 2.5 [1.2-5.4], presence of a complex karyotype (HR 4.2 [1.8-10.0], P=0.016), P=0.021) and absence of the use of tyrosine kinase inhibitors prior to alloHSCT (HR 0.461 [0.249-0.854], P=0.014). In contrast, HLA match (complete vs. incomplete), type of conditioning (myeloablative vs. dose-reduced intensity), use of total body irradiation (≥8 Gy yes vs. no) or the transplantation at high volume centers (≥7 patients yes vs. no) were not associated with significant differences in PFS or OS. During or after alloHSCT, 30/71 (42%) pts. showed either refractory (9/71, 13%) or relapsed (21/71, 29%) disease (R/R), being highest among MCL±AHN pts. (11/13, 85%; ASM/SM-AHN, 9/30, 30%; SM-AML, 10/28, 36%; P=0.002). R/R SM was predominantly observed in MCL±AHN (10/11, 91%) while R/R AHN was higher in SM-AML patients (6/10, 60%) and ASM/SM-AHN (5/9, 56%). The median time to relapse was 0.6 years (range 0.1-4.5). Post alloHSCT, a response to various treatment regimens was achieved in 13/30 (43%) pts. (ASM/SM-AHN, 3/9, 33%; SM-AML, 5/10, 50%; MCL±AHN, 5/11, 45%) with highest response rates in 9 pts. receiving midostaurin and/or avapritinib (7/9, 78%). Conclusions In pts. with AdvSM eligible for alloHSCT, i) baseline characteristics affect outcome of alloHSCT more than specific transplant procedures, ii) alloHSCT should not be performed in pts. without response prior to alloHSCT and iii) post-alloHSCT strategies such as preemptive or residual disease guided maintenance therapy should be considered to improve post-alloHSCT outcome.
Authors 26
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Affiliation as printed
1Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
2Center for Integrated Oncology - Aachen Bonn Cologne Duesseldorf (CIO-ABCD), Aachen, Germany
3contributed equally, ., Germany
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Heidelberg University · University Medical Centre Mannheim
Affiliation as printed
3contributed equally, ., Germany
4Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
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Affiliation as printed
1Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
2Center for Integrated Oncology - Aachen Bonn Cologne Duesseldorf (CIO-ABCD), Aachen, Germany
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Heidelberg University · University Medical Centre Mannheim
Affiliation as printed
4Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
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University of Freiburg · University Medical Center Freiburg · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
5Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany
6German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany
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University Hospital Leipzig · Leipzig University
Affiliation as printed
7Medical Clinic and Policlinic 1, for Hematology and Cellular Therapy, University of Leipzig Medical Center, Leipzig, Germany
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University Hospital Carl Gustav Carus · Technische Universität Dresden
Affiliation as printed
8Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
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Martin Luther University Halle-Wittenberg
Affiliation as printed
9Department of Internal Medicine IV, Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
10Department of Stem Cell Transplantation with Research Department Cell and Gene Therapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Affiliation as printed
11Department of Medicine A/Hematology and Oncology, University of Muenster, Münster, Germany
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Affiliation as printed
12Universitätsklinikum Jena, Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie, Jena, Germany
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Affiliation as printed
13Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
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Essen University Hospital · University of Duisburg-Essen
Affiliation as printed
14Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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Heidelberg University · University Hospital Heidelberg
Affiliation as printed
15Department of Internal Medicine V, Division of Hematology/Oncology/Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
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Affiliation as printed
16Department of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, Rostock University Medical Center, Rostock, Germany
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Affiliation as printed
17Klinikum Bremen-Mitte, Bremen, Germany
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Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz
Affiliation as printed
183rd Department of Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany
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University Hospital Regensburg
Affiliation as printed
19Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
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Affiliation as printed
20Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Erlangen, Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
21Department of Stem Cell Transplantation with Research Department Cell and Gene Therapy University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Heidelberg University · University Medical Centre Mannheim
Affiliation as printed
22Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
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Heidelberg University · University Medical Centre Mannheim
Affiliation as printed
4Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
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Affiliation as printed
1Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
2Center for Integrated Oncology - Aachen Bonn Cologne Duesseldorf (CIO-ABCD), Aachen, Germany
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Affiliation as printed
1Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
2Center for Integrated Oncology - Aachen Bonn Cologne Duesseldorf (CIO-ABCD), Aachen, Germany
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Affiliation as printed
1Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
2Center for Integrated Oncology - Aachen Bonn Cologne Duesseldorf (CIO-ABCD), Aachen, Germany
3contributed equally, ., Germany
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Heidelberg University · University Medical Centre Mannheim
Affiliation as printed
3contributed equally, ., Germany
4Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
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