Impact of lenalidomide discontinuation in patients with MDS and del(5q) achieving transfusion independence: HARMONY Alliance study

Lenalidomide demonstrates successful clinical activity in patients with myelodysplastic syndrome (MDS) who harbor deletion 5q (del[5q]) and has been shown to achieve red blood cell transfusion independence (RBC-TI) as well as complete cytogenetic response (CCyR). However, lenalidomide is associated with high treatment costs, serious side effects such as thromboembolism or cytopenia, and impacts on patients’ quality of life.¹ The MDS Hub has previously covered several articles on lenalidomide.

During the European Hematology Association (EHA) 2023 congress, Elena Crisá presented the findings from the HARMONY Alliance investigating the impact of lenalidomide discontinuation in patients with MDS and del(5q) after achieving RBC-TI.¹ We are pleased to summarize the findings here.

Study design

This is a retrospective cohort study in patients aged ≥18 years, diagnosed with MDS with isolated del(5q) or a del(5q) with one additional abnormality (excluding chromosome 7 abnormalities), and who had achieved RBC-TI with lenalidomide. Patients who discontinued lenalidomide due to lack of response or disease progression, as well as those with transfusion-dependent anemia at lenalidomide stop, were excluded.    

The primary endpoint was event-free survival (EFS). Secondary endpoints included:

• RBC-TI duration
• Overall survival
• Progression-free survival
• Time to acute myeloid leukemia
• Response rate to lenalidomide re-challenge
• Biological and clinical predictors of response duration after discontinuation

Results

A total of 115 patients were included with a median age of 77 years (range, 42–93 years). The median follow-up period was 40 months (range, 2–213 months), and the median number of lenalidomide cycles was 12 (range, 1–72 cycles). Patient characteristics are shown in Table 1.

Table 1. Patient characteristics*

IPSS, International Prognostic Scoring System; IPSS-R, Revised International Prognostic Scoring System; MDS, myelodysplastic syndromes; MDS-EB, MDS with excess blasts; MDS-MLD, MDS with multilineage dysplasia; RA, refractory anemia; RAEB-I, refractory anemia with excess blasts-1; RAEB-II, refractory anemia with excess blasts-2; RBC, red blood cell; RCMD, refractory cytopenia with multilineage dysplasia. *Adapted from Crisá E.1
Characteristic	Total patients (N = 115), %
Sex
Female	80.9
Male	19.1
WHO 2008
RA	0.9
RCMD	1.7
MDS with 5Q syndrome	87.0
RAEB-I	9.6
RAEB II	0.9
WHO 2016
MDS-MLD	0.9
MDS-EB	10.4
MDS with isolated del(5q)	88.7
Therapy related
No	95.6
Yes	4.4
IPSS
Low	54.9
Intermediate I	45.1
IPSS-R
Very low	26.0
Low	51.0
Intermediate I	22.9
RBC-transfusion dependence (>2 units in 8 weeks)
No	17.4
Yes	82.6

Toxicity

Lenalidomide dose reduction due to toxicity was required in 40% of patients. In addition, in most patients who discontinued lenalidomide, this was due to toxicity (Figure 1).

*Adapted from Crisá E.¹

EFS after lenalidomide discontinuation

At the time of lenalidomide discontinuation, 115 patients had RBC-TI and 90 patients achieved a cytogenetic response. Overall, CCyR and partial CyR were achieved in 48.9% and 66.6% of patients, respectively. At a median duration of 34.6 months, 48% of patients achieved EFS. A total of 40.9% of patients lost RBC-TI, and 73% of patients lost CCyR. Progression to high-risk MDS, acute myeloid leukemia, clonal evolution, or chronic myelomonocytic leukemia-2 occurred in 21% of patients, and 38.3% patients died.

There was a significant association between EFS and transfusion dependence at the start of lenalidomide treatment (p = 0.008) and the number of lenalidomide cycles received (p < 0.001) (Figures 2A and 2B).

• The median duration of EFS was 79 months in patients who started lenalidomide earlier and had achieved RBC-TI versus 31 months in those who started lenalidomide later and were transfusion-dependent.
• The median duration of EFS was 58 months in patients who received >12 cycles versus 18 months in those who received ≤12 cycles of lenalidomide.

*Adapted from Crisá E.¹
EFS, event-free survival; RBC-TD, red blood cell transfusion dependent; RBC-TI, red blood cell transfusion independent.

The multivariate analysis showed that the following factors were significantly associated with EFS:

• RBC-TD versus RBC-TI (hazard ratio [HR], 2.919; p = 0.032)
• Revised International Prognostic Scoring System very low versus low/intermediate status (HR, 0.436; p = 0.027)
• Lenalidomide cycles <12 versus >12 (HR, 4.360; p < 0.001).

RBC-TI duration after lenalidomide discontinuation

The median RBC-TI duration after lenalidomide discontinuation was 56 months. Patients who achieved CCyR, received >12 cycles of lenalidomide, and achieved RBC-TI showed longer duration of RBC-TI (Table 2).

The median duration of survival was shorter in patients who lost RBC-TI compared with those who retained RBC-TI (71 vs 102 months; p = 0.029). Of the 46 patients re-treated with lenalidomide for response loss, 65% (26/40) of the evaluable patients achieved at least a hematological response, including 3 patients who achieved a CCyR.

Table 2. RBC-TI duration after lenalidomide discontinuation*

CCyR, complete cytogenetic response; NR, not reached; RBC-TD, red blood cell transfusion dependence; RBC-TI, red blood cell transfusion independence. *Adapted from Crisá E.1
Factors	Median duration of RBC-TI, months	RBC-TI at 3 years, %
CCyR (n = 44)	86	77
No CCyR (n = 46)	86	49
> 12 cycles (n = 54)	NR	87
≤ 12 cycles (n = 61)	86	39
RBC-TI (n = 20)	NR	85
RBC-TD (n = 95)	44	58

Conclusion

This retrospective study presented by Elena Crisá demonstrates that there is potential to stop lenalidomide after achieving RBC-TI, particularly after at least 12 months of treatment, while limiting toxicities, reducing utilization of healthcare, and improving patients’ quality of life. The authors hope that future studies will validate the findings of this study.