Real-world Data From the Swiss Lenalidomide in MDS del(5q) (SLIM)—Registry Identify New Chances and Challenges in Lenalidomide Treatment of Patients With MDS del(5q)

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1
Letter
Open Access
Real-world Data From the Swiss Lenalidomide in
MDS del(5q) (SLIM)—Registry Identify New Chances
and Challenges in Lenalidomide Treatment of
Patients With MDS del(5q)
AxelRüfer1, HubertAngermann2, RudolfBenz3, NicolasBonadies4, AntonelloCalderoni5, NathanCantoni6,
AnnaEfthymiou7, RobertEscher8, GenevièveFavre9, DorotheaFriess10, AndreasGschwend11,
AndreasHimmelmann12, AndreasHolbro13, PeterKeller14, EiriniKouroupi15, ThomasLehmann16, NikolausPedarnig17,
VéroniqueRigamonti18, KavehSamii19, AdrianSchmidt20, Hans-PeterSchäfer21, RolandSperb22, GeorgStüssi23,
AnnetteWinkler24, ReinhardZenhäusern25, Jeroen S.Goede26; on behalf of the SLIM-Registry Investigators*
Correspondence: Axel Rüfer (axel.ruefer@luks.ch).
Myelodysplastic syndromes (MDS) constitute a het-
erogeneous group of clonal hematopoietic disor-
ders characterized by ineffective hematopoiesis,
persistent peripheral blood cytopenias, and an
increased risk of transformation to acute myeloid leukemia
(AML).1 Treatment with lenalidomide has been recommended
for patients with MDS and 5q deletion with symptomatic ane-
mia and a high-transfusion burden with red blood cells (RBC)
by several guidelines.2–4 Little is known about usage, chances,
and challenges in daily clinical practice to comply with these
guidelines. To close this informative gap an observational,
multicenter, national registry, involving the whole spectrum of
hematologists and oncologists from primary to tertiary health
care centers in Switzerland—the Swiss Lenalidomide in MDS
del(5q)-Registry (SLIM-Registry)—was established.
The SLIM-Registry is a web-based clinical data management
application. Data entry was performed retrospectively, after at
least one cycle of lenalidomide has been applied, and locally by
each participating center via a password-protected log-in at the
website (www.slim-registry.ch). Eligible patients were 18 years
of age or older and had a MDS and a del(5q) with or with-
out additional cytogenetic abnormalities. Patients were either
treated with lenalidomide in the past or treatment with lenalid-
omide was ongoing at entry into the registry. All living patients
provided written informed consent. Patients with MDS without
a conrmation of del(5q) were not eligible. The SLIM-Registry
was carried out according to all applicable national and local
regulatory requirements. There was a regular review and veri-
cation of recorded data. From March 1, 2014, until December
31, 2019, patients were included. Data cleaning was performed
thereafter, and nal database lock was on October 31, 2021.
Totally 83 patients (57 females, 26 males) with MDS and
del(5q) have been registered in 25 health care centers across
Switzerland, which included minimum 1 and maximum 10
patients per center. The majority, 63 patients (75.9%), had a
hemoglobin-level below 100 g/L. At diagnosis of MDS, in
all patients, a bone marrow (BM) aspirate (with dry tap in 8
patients), and in 78 patients (94%) additionally a BM biopsy
was done. Conventional karyotyping was performed in 45
patients, both conventional karyotyping and uorescence in situ
1Department of Hematology, Luzerner Kantonsspital, Luzern, Switzerland
2Unidata Geodesign GmbH, Vienna, Austria
3Oncology/Hematology, Kantonsspital Münsterlingen, Münsterlingen, Switzerland
4Department of Hematology and Central Hematology Laboratory, Inselspital Bern,
Switzerland
5Oncologia Verini Calderoni Christinat, Lugano, Switzerland
6Division of Hematology, University Clinic of Medicine, Kantonsspital Aarau AG,
Switzerland
7Department Hemato-Oncology, HFR Hôpital Fribourgeois, Fribourg,
Switzerland
8Department of Medicine, Hematology, Spital Emmental, Burgdorf, Switzerland
9Hematology-Oncology-Immunotherapy, Kantonsspital Baselland, Liestal, Switzerland
10Department of Hematology, Kantonsspital Olten, Switzerland
11Oncology/Hematology, Zuger Kantonsspital, Baar, Switzerland
12Hematology, Klinik St. Anna, Luzern, Switzerland
13Department of Hematology, University Hospital Basel, Switzerland
14Hematology/Oncology, Spital Langenthal, Switzerland
15Department Oncology-Hematology, Hôpital Neuchâtelois, Neuchâtel,
Switzerland
16Department of Medical Oncology and Hematology, Kantonsspital St. Gallen,
Switzerland
17Unidata Geodesign GmbH, Vienna, Austria
LWW
18Praxis Bubenberg, Bern, Switzerland
19Service Hématologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland
20Department of Internal Medicine, Clinic for Medical Oncology and Hematology,
Municipal Hospital Zürich Triemli, Zürich, Switzerland
21Department of Internal Medicine, Kantonsspital Schaffhausen, Switzerland
22Department of Medicine, Oncology, Luzerner Kantonsspital, Sursee, Switzerland
23Istituto Oncologico della Svizzera Italiana, Ospedale Regionale Bellinzona e Valli,
Bellinzona, Switzerland
24Center of Oncology Thun-Berner Oberland, Spital Thun, Switzerland
25Oncology-Hematology, Spitalzentrum Oberwallis, Brig, Switzerland
26Medical Oncology and Hematology, Kantonsspital Winterthur, Switzerland
*All the authors of this article belong to the SLIM-Registry Investigators group.
Supplemental digital content is available for this article.
Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.
on behalf of the European Hematology Association. This is an open-access
article distributed under the terms of the Creative Commons Attribution-Non
Commercial License 4.0 (CCBY-NC), where it is permissible to download, share,
remix, transform, and buildup the work provided it is properly cited. The work
cannot be used commercially without permission from the journal.
HemaSphere (2022) 6:7(e741).
http://dx.doi.org/10.1097/HS9.0000000000000741.
Received: March 7, 2022 / Accepted: May 16, 2022

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Rüfer et al Real-world Data From the Swiss Lenalidomide in MDS del(5q) (SLIM)–Registry
hybridization (FISH) were performed in 26 patients, and in 12
patients only FISH was done. In 72 patients, there was exqui-
sitely del(5q) detected. With regard to RBC-transfusion depen-
dence (TD) at diagnosis, 41 patients (49.4 %) had RBC-TD
with a median hemoglobin of 81 g/L (range, 50–110 g/L). In 55
patients (66.3%), the diagnosis was myelodysplastic syndrome
with isolated del(5q) according to WHO Classication 2008.
Prognostic stratication was done according to IPSS, IPSS-R,
and WPSS (Figure1A–C).
In total, 1714 cycles of treatment with lenalidomide were
recorded. In all patients, at least one cycle of treatment with
lenalidomide was given. At start of the rst cycle, median hemo-
globin was 87 g/L (range, 51–119 g/L), with 45 patients (54.2%)
in need of RBC transfusions. Treatment with lenalidomide was
initiated within 6 months after the diagnosis of MDS with a 5q
deletion in 55 patients (66.3%).
With regard to onset and duration of treatment response,
in cycle 2 of treatment with lenalidomide, 22 patients (26.5%
of the total cohort and 48.8% of the patients with RBC-TD
at treatment start) had RBC-transfusion independence (TI),
another 5 (6% and 11.1%, respectively) each in cycle 3
and in cycle 4, 2 patients (3.6% and 4.4%, respectively) in
cycle 5, and 1 patient (1.2% and 2.2%, respectively) in cycle 6.
Of 61 patients with at least 6 documented treatment cycles
48 patients (78.7%) had RBC-TI for ≥8 weeks. Of those, 36
patients (75%) had a diagnosis of MDS with isolated del(5q).
Analyzing those 61 patients with regard to erythroid response,
there were 28 patients (45.9%) with RBC-TD and a hemo-
globin <90 g/L before start of treatment with lenalidomide, 16
patients (57.1%) had an erythroid response, that is, a reduc-
tion of at least 4 RBC transfusions with treatment with lena-
lidomide over a period of 2 months. In those 43 patients with
at least 12 documented treatment cycles, 34 patients (79.1%)
had RBC-TI for ≥26 weeks.
The recommended dosage of lenalidomide 10 mg daily on
days 1–21 of a 28-day cycle was administered in 21 patients
(25.3%) without adjustments. Venous thromboembolism pro-
phylaxis was given in 33 patients (39.8%). Of note, there were 5
patients with a treatment-free interval (TFI) for various reasons
and durations (Suppl. Table S1). There was a patient who had
a complete cytogenetic remission after 6 and after 12 cycles of
treatment with lenalidomide. Therefore, treatment was stopped
with regular monitoring of blood count and del(5q) by FISH.
This patient remains in complete hematologic and cytogenetic
remission 3 years after stopping treatment.
Median overall survival (OS) in a multivariate analysis was
signicantly longer in patients who received no RBC transfu-
sions during the rst treatment cycle of 6.7 years (95% CI, 3.9-
9.6) compared with patients who did receive RBC transfusions
during that time of 3.34 years (95% CI, 2.56-4.12; P = 0.014),
and was signicantly longer in patients with MDS with isolated
del(5q) of 6.7 years (95% CI, 3.0-10.4) compared with 2.4
years (95% CI, 1.99-2.9) in other entities of MDS (P = 0.004)
(Figure2A,B). With regard to Lenalidomide-emergent adverse
events, there were no new safety signals identied.
In conclusion, treatment with lenalidomide was initiated
within 6 months after the diagnosis of MDS with 5q deletion
in about two-thirds of patients, reecting the uncertainty with
regard to the optimal time point to start disease directed treat-
ment, especially in patients who are not—yet—RBC-transfusion
dependent, as lenalidomide is formally approved only for
patients with a transfusion-dependent anemia—and not for
preventing it. In all patients, cytogenetic analysis at diagnosis
was done. However, in 12 patients (14.5%), only FISH was
performed at diagnosis, which is insufcient at initial work up.
A minority of patients—14.5%—had higher-risk disease, and
treatment with lenalidomide in this patient group would not
entirely be in line with current guidelines. With the start of treat-
ment with lenalidomide, 45 patients (54.2%) had RBC-TD, 22 of
those patients (48.8%) were free of RBC transfusions in cycle 2,
with 5 patients (11.1 %) each in cycle 3 and 4. This rapid onset
of response and high efcacy with regard to RBC-TI is in line
with the results of the MDS-003- and MDS-004-studies.5,6
Analyzing 61 patients with at least 6 documented cycles of lena-
lidomide treatment, RBC-TI for ≥8 weeks was more common
in patients with a diagnosis of MDS with isolated del(5q) com-
pared with other entities of MDS. Analyzing 43 patients with
Figure 1. Prognostic scoring systems at diagnosis of MDS. (A) IPSS at
diagnosis of MDS, (B) IPSS-R at diagnosis of MDS, and (C) WPSS at diagno-
sis of MDS. IPSS = International Prognostic Scoring System; IPSS-R = Revised International
Prognostic Scoring System; MDS = myelodysplastic syndromes; WPSS = WHO Classification-
based Prognostic Scoring System.

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(2022) 6:7 www.hemaspherejournal.com
at least 12 documented cycles of lenalidomide treatment, 34
patients (79.1%) had RBC-TI for ≥26 weeks. This conrms the
high efcacy of lenalidomide with regard to RBC-TI in patients
with MDS and 5q deletion also in daily clinical practice.5,6 Two
months before start of treatment with lenalidomide, 25 patients
(30.1%) of the whole cohort had no RBC-TD. Although off-la-
bel, commencing disease directed treatment at that time reects
daily clinical practice of not waiting for a patient with MDS to
become RBC-transfusion dependent. Whether this practice will
alter the natural course of the disease and has an impact on
long-term outcome is not known, as is the optimal time of start-
ing therapy. However, interim analyses of the SINTRA-REV
trial (ClinicalTrials.gov Identier: NCT01243476) in non-TD
LR MDS del(5q) patients suggest that early treatment with lena-
lidomide at low doses (5 mg) prolongs the time to and decreases
the risk of TD with cytogenetic responses.7 This is supported
by our data—although not corrected for disease duration and
risk stratication—as patients with no RBC transfusions during
the rst cycle of treatment with lenalidomide had a signicant
improvement of median OS (P = 0.014).
Renal failure in this elderly population was the most preva-
lent condition and is possibly the explanation for the fact, that in
only 21 patients (25.3%) the recommended lenalidomide dose
was given without alterations. Diagnostic evaluation with BM
analysis was done in about half of the patients who received 12
treatment cycles, in all other patients treatment with lenalidomide
Figure 2. Median OS. (A) Kaplan-Meier curve for median OS as of start of treatment with lenalidomide according to RBC transfusions during cycle 1 of treat-
ment with lenalidomide in 61 patients with at least 6 documented treatment cycles. There was a significant longer median OS in those 30 patients who received
no RBC transfusions during the first cycle of treatment with lenalidomide of 6.7 y (95% CI, 3.9-9.6) compared with 31 patients who did receive RBC transfusions
during that time of 3.34 y (95% CI, 2.56-4.12; P = 0.014). (B) Kaplan-Meier curve for median OS as of start of treatment with lenalidomide according to initial
diagnosis of MDS. There was a significant longer median OS of 6.7 y (95% CI, 3.0-10.4) in those 55 patients with MDS with isolated del(5q) compared with 2.4 y
(95% CI, 1.99-2.9) in 28 patients with other entities of MDS (P = 0.004). CI = confidence intervals; MDS = myelodysplastic syndromes; OS = overall survival; RBC = red blood cells.

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Rüfer et al Real-world Data From the Swiss Lenalidomide in MDS del(5q) (SLIM)–Registry
was continued when peripheral blood values were (near) normal
without morphological BM or cytogenetic response assessment.
Response assessment beyond peripheral blood values seems to
be of particular importance, as deep genetic responses are pos-
sible and could potentially lead to a treatment-free remission.
Clarication on when and how response assessment has to be
done is necessary. And there is a clear need for dening patient
and disease characteristics with the possibility of a TFI.8 Median
OS is signicantly longer in lenalidomide-treated patients with
MDS and isolated del(5q) compared with patients with other
entities of MDS. This is longer compared with the MDS-004
study, which allowed recruitment of all subgroups of patients
with MDS and del(5q), including patients with additional chro-
mosomal abnormalities and blasts in BM of up to 10%, but all
these patients had RBC-TD, which is in contrast to the SLIM-
Registry.6 Observation time in our registry was too short to
comment on the long-term safety of lenalidomide and on the
possible occurrence of secondary malignancies. There is also a
clear need for dening a diagnostic and therapeutic approach
after stopping lenalidomide treatment due to intolerance or
resistance to the drug with disease progression.
ACKNOWLEDGMENTS
We thank Mrs Gaby Fahrni, Clinical Research Coordinator at the Clinical
Trial Unit Hematology, Luzerner Kantonsspital, Switzerland, for her contri-
butions to data management. Additionally, the authors thank all data man-
agers of the participating study centers in Switzerland contributing to enter
data into the SLIM-Registry. The SLIM-Registry is sponsored by the Clinical
Trial Unit Hematology, Luzerner Kantonsspital, Luzern, which was funded
by an unrestricted grant from Celgene Switzerland.
AUTHORS CONTRIBUTIONS
AR and JSG designed the clinical data management application, per-
formed research, and contributed as well as analyzed patient data. AR
wrote the article. HA and NP developed, validated, and approved the clini-
cal data management application and analyzed data. All authors performed
research, contributed patient data, reviewed the article, and approved it for
submission.
DISCLOSURES
AR received advisory from Amgen, AOP OrphaSwiss, Celgene/BMS,
Janssen, Novartis, Sobi, Takeda. HA received current employment Unidata
Geodesign GmbH, Vienna, Austria. RB received from advisory board,
travel grants Abbvie, AOP OrphaSwiss, Janssen, Novartis, Sobi, Taked. NB
received funding from Alexion, Astellas, Celgene/BMS, Novartis, Roche,
Sandoz, Servier, Takeda and consultancy honoraria from Amgen, Celgene/
BMS, Janssen, Novartis, Roche: travel grants; Celgene/BMS, Novartis. NC
received advisory board and consultancy honoraria from AbbVie, Amgen,
AOP OrphaSwiss, Astra Zeneca, Celgene/BMS, Gilead, Incyte, Janssen,
Novartis, Pzer, Takeda. AE received advisory board from Abbvie, Jazz
Pharmaceuticals, Teva. TL received consultancy honoraria from AbbVie,
Amgen, BMS, Incyte, Janssen, Swedish Orphan Biovitrum AG; research
funding from Celgene, Novartis; and travel grants from AbbVie, Amgen.
NP received current employment from Unidata Geodesign GmbH, Vienna,
Austria. KS received advisory board from Amgen, AOP OrphaSwiss, Celgene/
BMS, Janssen, Novartis. AS received advisory board, consultancy honoraria,
travel grants, educational grants from Amgen, Celgene/BMS, Incyte, Janssen,
Novartis, Sano, Takeda. H.-P. S received travel grants from Amgen, Celgene/
BMS. GS received advisory board, consultancy honoraria, travel grants,
educational grants, research funding from Amgen, Celgene/BMS, Gilead,
Janssen, Novartis. JSG received advisory board, consultancy honoraria from
Amgen, AOP OrphaSwiss, Celgene/BMS, Janssen, Novartis, Sobi, Takeda.
The remaining authors have no conicts of interest to disclose.
SOURCES OF FUNDING
Work at the Swiss Lenalidomide in MDS del(5q) (SLIM)—Registry
was sponsored by Clinical Trial Unit Hematology, Luzerner Kantonsspital,
Switzerland, which was funded by an unrestricted grant of Celgene
Switzerland.
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