A PROOF OF CONCEPT OF LSD1-INHIBITON IN A PHASE I/II PILOT TRIAL OF TCP AND ATRA IN REFRACTORY / RELAPSED AML PATIENTS NOT ELIGIBLE FOR INTENSIVE THERAPY
Author(s): ,
Maxi Wass
Affiliations:
Department of Internal Medicine IV,University of Halle,Halle,Germany
,
Richard F Schlenk
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany
,
Joachim Göthert
Affiliations:
Department of Hematology,University Hospital Essen,Essen,Germany
,
Richard Noppeney
Affiliations:
Department of Hematology,University Hospital Essen,Essen,Germany
,
Christoph Schliemann
Affiliations:
Department of Medicine A,University Hospital Münster,Münster,Germany
,
Jan-Henrik Mikesch
Affiliations:
Department of Medicine A,University Hospital Münster,Münster,Germany
,
Martin Dugas
Affiliations:
Department of Medicine A,University Hospital Münster,Münster,Germany
,
Martin Wermke
Affiliations:
Medical Clinic I,University Hospital Carl Gustav Carus,Dresden,Germany
,
Christoph Röllig
Affiliations:
Medical Clinic I,University Hospital Carl Gustav Carus,Dresden,Germany
,
Martin Bornhäuser
Affiliations:
Medical Clinic I,University Hospital Carl Gustav Carus,Dresden,Germany
,
Hubert Serve
Affiliations:
Department of Medicine II, Hematology/Oncology,Goethe University,Frankfurt/Main,Germany
,
Mascha Binder
Affiliations:
Department of Internal Medicine IV,University of Halle,Halle,Germany
,
Lutz P Müller
Affiliations:
Department of Internal Medicine IV,University of Halle,Halle,Germany
,
Stefanie Göllner
Affiliations:
Department of Internal Medicine V,University of Heidelberg,Heidelberg,Germany
,
Caroline Pabst
Affiliations:
Department of Internal Medicine V,University of Heidelberg,Heidelberg,Germany
Carsten Müller-Tidow for the SAL study group
Affiliations:
Department of Internal Medicine V,University of Heidelberg,Heidelberg,Germany
EHA Library. Wass M. Jun 15, 2019; 266650; PS1033
Maxi Wass
Maxi Wass
Contributions
Abstract

Abstract: PS1033

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
In cancer, epigenetic alterations occur much more frequently than genetic mutations. Targeting epigenetic regulators constitutes a promising approach in leukemia treatment. Lysine-specific demethylase 1 (LSD1) is a histone demethylase that modifies histone 3 methylation (H3K4me1/2) status, and is highly expressed in AML patients. In Acute Promyelocytic Leukemia (APL), all-trans-retinoic acid (ATRA) induces differentiation of leukemic blasts, but is not effective in non-APL AML. Recently, we showed that LSD1 inhibition by Tranylcypromine (TCP) has a synergistic effect with ATRA inducing myeloid differentiation in primary AML blasts (Schenk et al., Nature Med 2012).  

 

Aims
This phase I/II study evaluated feasibility, safety and efficacy of combination treatment of the LSD1 inhibitor TCP and ATRA as salvage therapy for patients with relapsed/refractory (r/r) AML, ineligible for intensive treatment.

Methods
The trial was conducted at four centers in Germany on behalf of the SAL (Study Alliance Leukemia). TCP (starting at 10 mg/d with daily increases up to 60 mg/d) and ATRA (starting on day +7 with a fixed dose of 45mg/m²) were administered as 28-day cycles up to 12 cycles. The primary endpoint was the cumulative response rate.

Results
Between December 2014 and February 2017, 18 Patients (median age 73 [range, 22-79] years) were enrolled (Tab 1). Four patients were refractory and among the 14 relapsed patients, 8 patients had relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) and 9 patients had at least two or more previous therapy lines. A median of 1.4 cycles (range, 0.5-3.5) were administered. 16 patients were available for efficacy analyses. The overall response rate was 18.75%; 2 patients (12.5%) achieved complete remission without hematological recovery (CRi) and 1 patient achieved a partial response (PR). One patient had reduction of blasts in the bone marrow without fulfilling PR criteria and one patient, who also achieved stable disease with improved clinical status underwent HCST after two cycles and is still alive. The most frequently reported treatment-related adverse events (AE) were fatigue and vertigo. One patient developed a severe differentiation syndrome. None of the 13 serious AEs (SAEs) were related to the study treatment. At the end of follow-up, 17 out of 18 Patients had died, no cases of treatment related mortality occurred.

Conclusion
The current study provides evidence that LSD1 inhibition coupled with ATRA can induce differentiation of AML in vivo with clinical benefit. The combination has acceptable toxicity in heavily pretreated patients with r/r AML, warranting further trials in randomized studies. More specific LSD1 inhibitors might be even more effective when combined with ATRA.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Acute myeloid leukemia

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