EHA Library - The official digital education library of European Hematology Association (EHA)

A RANDOMIZED PHASE II STUDY OF STANDARD DOSE AZACITIDINE ALONE OR IN COMBINATION WITH LENALIDOMIDE IN HIGH-RISK MDS WITH A KARYOTYPE INCLUDING DEL(5Q)
Author(s): ,
Bengt Rasmussen
Affiliations:
Department of Medicine,School of Medical Sciences, Örebro University,Örebro,Sweden
,
Lars Nilsson
Affiliations:
Department of Hematology,Oncology and Radiation Physics, Skåne University Hospital,Lund,Sweden
,
Martin Jädersten
Affiliations:
Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge,Karolinska Institutet, Karolinska University Hospital,Stockholm,Sweden
,
Magnus Tobiasson
Affiliations:
Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge,Karolinska Institutet, Karolinska University Hospital,Stockholm,Sweden
,
Hege Garelius
Affiliations:
Section for Haematology and Coagulation, Department of Medicine,Sahlgrenska University Hospital,Gothenburg,Sweden
,
Jan Maxwell Nørgaard
Affiliations:
Department of Haematology,Aarhus University Hospital,Aarhus,Denmark
,
Ingunn Dybedal
Affiliations:
Department of Hematology,Oslo University Hospital,Oslo,Norway
,
Kirsten Grønbaek
Affiliations:
Department of Hematology,Rigshospitalet,Copenhagen,Denmark
,
Astrid Olsnes Kittang
Affiliations:
Division for Hematology, Department of Medicine,Haukeland University Hospital,Bergen,Norway
,
Fryderyk Lorenz
Affiliations:
Department of Medical Biosciences,Umeå University,Umeå,Sweden
,
Freja Eberling
Affiliations:
Deptartment of Medicine, Division of Haematology,Helsinki University Central Hospital,Helsinki,Finland
,
Max Flogegård
Affiliations:
Department of Medicine,Falu Lasarett,Falun,Sweden
,
Claus Werenberg Marcher
Affiliations:
Odense University Hospital,Odense,Denmark
,
Elisabeth Ejerblad
Affiliations:
Department of Medical Science, Section of Hematology,Uppsala University,Uppsala,Sweden
,
Annette Öster Fernström
Affiliations:
Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine (HERM),Karolinska Institutet,Stockholm,Sweden
,
Elsa Bernard
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Gudrun Göhring
Affiliations:
Department of Human Genetics,Hannover Medical School,Hannover,Germany
,
Elli Papaemmanuil
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Leoni Saft
Affiliations:
Department of Pathology,Karolinska University Hospital, Solna, and Karolinska Institutet,Stockholm,Sweden
,
Eva Hellström-Lingberg
Affiliations:
Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge,Karolinska Institutet, Karolinska University Hospital,Stockholm,Sweden
Lars Möllgård
Affiliations:
Section for Haematology and Coagulation, Department of Medicine,Sahlgrenska University Hospital,Gothenburg,Sweden
(Abstract release date: 05/17/18) EHA Library. Rasmussen B. 06/17/18; 214575; S1556
Bengt Rasmussen
Bengt Rasmussen
Contributions
Abstract

Abstract: S1556

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 08:15 - 08:30

Location: Room A4

Background
Patients with high-risk MDS with 5q deletion have a poor prognosis and there is a need for improvement of the current standard azacitidine (AZA) treatment. Lenalidomide (LEN) is an effective treatment for patients with lower-risk MDS with del(5q), and we previously showed that monotherapy with high-dose LEN may have antitumor effects also in high-risk del(5q) myeloid disease. We hypothesized that an upfront combination of AZA and high-dose LEN would be more effective than AZA alone for patients with del(5q) and an approved indication for azacitidine treatment according to the EMA label.

Aims
We designed a Nordic MDS group prospective multicentre randomized phase II trial and evaluated the efficacy and safety of AZA +/- LEN.

Methods
Consecutive patients with high-risk MDS (IPSS INT-2 and high) and AML with multilineage dysplasia and 20-29 % blasts (previous RAEB-t) with a karyotype including del(5q) were included. Patients were randomized to standard dose of AZA 5-2-2 (75 mg/m2/ d sc.) q 4 weeks for 6 cycles, or the same schedule of AZA+LEN. The initial dose of LEN was 10 mg daily 21/28 days. If well tolerated the dose was increased to 25 mg daily during cycle 4-6. The primary end point was response according to international working group (IWG) criteria. Secondary endpoints encompassed safety, AZA cycle interval between groups and survival. Informed consent was obtained.

Results
Seventy-two patients, from 12 centers in Sweden, Denmark, Norway and Finland were included between March 2012 and Jan 2017. Thirty-six patients were randomized to each arm. Median age was 71.5 years (35-84 yrs.). Thirty patients (41%) were female. Fifty-two (75%) patients were diagnosed with MDS and 18 (25%) patients with AML. According to IPSS the cytogenetic risk group was good in 8 patients (11%), intermediate in 4 patients (6%) and poor in 60 patients (83%). Serious adverse events were similar in the two groups. 47 patients (65%) completed 3 cycles and 40 patients (56%) completed the total treatment period. There was no difference in AZA cycle interval between the two groups. In the AZA+LEN arm, 7 out of 36 patients (19%), increased the lenalidomide dose to 25 mg/day during cycle 4-6.

The overall response rate (ORR) was 36% for patients receiving AZA alone and 28% for AZA+LEN (P=0.85) and the corresponding marrow CR rates were 28% and 36%, respectively (P=0.45). At follow-up at 7 months (range, 0 to 36 months) after the last patient completed the trial the median survival was 14 months for patients receiving AZA and 10 months for the AZA+LEN arm (P=0.18). Nine patients (25%) in the AZA arm and eight patients (22%) in the AZA+LEN arm had a hematological improvement (P=0.81).

Cytogenetic response (karyotype showing CR and PR) was achieved in 17% in the AZA arm and 28% in the AZA+LEN arm (P=0.13). Corresponding FISH analysis showed 39% in each group. After 3 cycles there was a trend towards a better cytogenetic response rate (FISH) in the AZA+LEN arm, 50% and 36%, respectively (P=0.052).

Conclusion
This is the first prospective randomized clinical trial in higher-risk MDS with a defined cytogenetic lesion.  In this study with high-risk MDS and AML patients with del(5q) and a dismal prognosis the addition of LEN to standard AZA treatment did not improve overall response or survival but may indicate a stronger antitumor response after three cycles.

Session topic: 10. Myelodysplastic syndromes – Clinical

Keyword(s): Acute Myeloid Leukemia, Azacitidine, Immunomodulatory thalidomide analog, Myelodysplasia

Abstract: S1556

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 08:15 - 08:30

Location: Room A4

Background
Patients with high-risk MDS with 5q deletion have a poor prognosis and there is a need for improvement of the current standard azacitidine (AZA) treatment. Lenalidomide (LEN) is an effective treatment for patients with lower-risk MDS with del(5q), and we previously showed that monotherapy with high-dose LEN may have antitumor effects also in high-risk del(5q) myeloid disease. We hypothesized that an upfront combination of AZA and high-dose LEN would be more effective than AZA alone for patients with del(5q) and an approved indication for azacitidine treatment according to the EMA label.

Aims
We designed a Nordic MDS group prospective multicentre randomized phase II trial and evaluated the efficacy and safety of AZA +/- LEN.

Methods
Consecutive patients with high-risk MDS (IPSS INT-2 and high) and AML with multilineage dysplasia and 20-29 % blasts (previous RAEB-t) with a karyotype including del(5q) were included. Patients were randomized to standard dose of AZA 5-2-2 (75 mg/m2/ d sc.) q 4 weeks for 6 cycles, or the same schedule of AZA+LEN. The initial dose of LEN was 10 mg daily 21/28 days. If well tolerated the dose was increased to 25 mg daily during cycle 4-6. The primary end point was response according to international working group (IWG) criteria. Secondary endpoints encompassed safety, AZA cycle interval between groups and survival. Informed consent was obtained.

Results
Seventy-two patients, from 12 centers in Sweden, Denmark, Norway and Finland were included between March 2012 and Jan 2017. Thirty-six patients were randomized to each arm. Median age was 71.5 years (35-84 yrs.). Thirty patients (41%) were female. Fifty-two (75%) patients were diagnosed with MDS and 18 (25%) patients with AML. According to IPSS the cytogenetic risk group was good in 8 patients (11%), intermediate in 4 patients (6%) and poor in 60 patients (83%). Serious adverse events were similar in the two groups. 47 patients (65%) completed 3 cycles and 40 patients (56%) completed the total treatment period. There was no difference in AZA cycle interval between the two groups. In the AZA+LEN arm, 7 out of 36 patients (19%), increased the lenalidomide dose to 25 mg/day during cycle 4-6.

The overall response rate (ORR) was 36% for patients receiving AZA alone and 28% for AZA+LEN (P=0.85) and the corresponding marrow CR rates were 28% and 36%, respectively (P=0.45). At follow-up at 7 months (range, 0 to 36 months) after the last patient completed the trial the median survival was 14 months for patients receiving AZA and 10 months for the AZA+LEN arm (P=0.18). Nine patients (25%) in the AZA arm and eight patients (22%) in the AZA+LEN arm had a hematological improvement (P=0.81).

Cytogenetic response (karyotype showing CR and PR) was achieved in 17% in the AZA arm and 28% in the AZA+LEN arm (P=0.13). Corresponding FISH analysis showed 39% in each group. After 3 cycles there was a trend towards a better cytogenetic response rate (FISH) in the AZA+LEN arm, 50% and 36%, respectively (P=0.052).

Conclusion
This is the first prospective randomized clinical trial in higher-risk MDS with a defined cytogenetic lesion.  In this study with high-risk MDS and AML patients with del(5q) and a dismal prognosis the addition of LEN to standard AZA treatment did not improve overall response or survival but may indicate a stronger antitumor response after three cycles.

Session topic: 10. Myelodysplastic syndromes – Clinical

Keyword(s): Acute Myeloid Leukemia, Azacitidine, Immunomodulatory thalidomide analog, Myelodysplasia

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies