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Treating classical Hodgkin lymphoma: Spotlight on targeted therapies
with Gilles Salles, Paul Bröckelmann, and Ann S. LaCasce
Saturday, November 2, 2024
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While not all cases of myelodysplastic syndromes (MDS) require treatment, the development of symptomatic anemia is common indication for initiating therapy. The current standard of care is recombinant erythropoietin, however, this treatment is only effective in a small subset of patients. It has been shown that the lipid raft in which the erythropoietin receptor is located is inherently unstable in MDS, and therefore addition of erythropoietin cannot increase signal transduction. The addition of lenalidomide (lenalidomide) to erythropoietin is a promising strategy, as lenalidomide has been shown to trigger the assembly of lipid rafts enriched with Janus kinase-2 and erythropoietin-receptor complexes, which in turn leads to increased development of erythroid precursors.
In an article published in the Journal of Clinical Oncology, Alan List and colleagues describe the results of a phase III study (NCT00843882) in which patients with low-risk, non-5q deletion [del(5q)] MDS were treated with lenalidomide and epoetin alfa (Len + Epo) and compared with patients treated with lenalidomide alone.1 Patients with non-del(5q) MDS were included, as lenalidomide has been shown to be cytotoxic in patients with the deletion. Lenalidomide causes lethal degradation of the casein kinase 1A1 encoded within the region. The Sintra-REV phase III trial assessing the impact of lenalidomide in patients with del(5q) was reported on recently by the MDS Hub, and can be found here.
Patients were excluded if they presented with therapy-related MDS. Patients with del(5q) were enrolled but only received lenalidomide and were not included in the analysis.
The key primary endpoint was major erythroid response (MER) at Week 16, defined as:
A total of 195 patients were found to be evaluable in this trial. Patients were randomly assigned to receive Len + Epo (n = 99) or lenalidomide alone (n = 96). Baseline characteristics were similar between treatment groups (Table 1). Over two-thirds of patients included in this study were male, and over 90% had received erythropoietin treatment previously. Patients were mostly transfusion dependent (85%) and receiving a median of 4 units/8 weeks.
Table 1. Baseline patient characteristics1
ANC, absolute neutrophil count; BM, bone marrow; CMML, chronic myelomonocytic leukemia; EPO, epoetin alfa; IPSS, International Prognostic Scoring System; LEN, lenalidomide; MDS, myelodysplastic syndromes; MDS-U, MDS unclassified; RA, refractory anemia; RAEB-1, refractory cytopenia with excess blasts-1; RARS, refractory anemia with RS; RBC, red blood cell; RCMD, refractory cytopenia with multilineage dysplasia; RS, ring sideroblasts; WHO, World Health Organization. |
|||
Characteristic |
Len + Epo |
Len only |
Total |
---|---|---|---|
Median age, years (range) |
73 (47−92) |
74 (49−89) |
74 (47−92) |
Male, % |
74.7 |
67.7 |
71.3 |
Median years from diagnosis (range) |
1.7 (0−18) |
1.5 (0−17) |
1.6 (0−18) |
Median RBC transfusions, units/28 days (range) |
2 (0−8) |
2 (0−7) |
2 (0−8) |
Median hemoglobin, g/dL (range) |
8.3 (6.0−10) |
8.6 (6.0−10) |
8.4 (6.0−10) |
Prior erythropoietin treatment, % |
92.9 |
92.7 |
92.8 |
Prior azanucleoside therapy, % |
12.1 |
24 |
17.9 |
Median no. of prior treatments (range) |
1 (0−4) |
1 (0−4) |
1 (0−4) |
IPSS risk, % |
|
|
|
Low |
48.5 |
37.5 |
43.1 |
Intermediate-1 |
49.5 |
61.5 |
55.4 |
IPSS karyotype risk type, % |
|
|
|
Good |
84.8 |
79.2 |
82.1 |
Intermediate |
13.1 |
17.7 |
15.4 |
Poor |
0 |
3.1 |
1.5 |
MDS WHO category, % |
|
|
|
RA |
7.1 |
6.3 |
6.7 |
RARS |
29.3 |
25 |
27.2 |
RCMD-RS |
23.2 |
16.7 |
20 |
RCMD |
17.2 |
24 |
20.5 |
RAEB-1 |
1.0 |
10.4 |
5.6 |
MDS-U |
16.2 |
11.5 |
13.8 |
CMML |
2.0 |
4.2 |
3.1 |
Median BM blasts, % (range) |
2 (0−15) |
2 (0−15) |
2 (0−15) |
Median ANC/mm3 |
2,410 |
2,200 |
2,320 |
Median platelet count × 103 mm3 |
222,000 |
215,000 |
218,00 |
Median serum erythropoietin, mU/mL (range) |
151 (19−3264) |
160 (11−3048) |
156 (11−3264) |
MER was significantly increased in the Len + Epo treatment group compared with those receiving lenalidomide alone (28.3% vs 11.5%; p = 0.004). Of the patients who completed 16 weeks of treatment (n = 136), 38.9% of patients in the Len + Epo group and 15.6% in the lenalidomide-only group achieved MER (p = 0.004).
A median maximum hemoglobin concentration of 12.4 g/dL (range, 10.2−15.5) was reached in the study, with a median rise in hemoglobin of 4.1 g/dL compared with the mean pretransfusion value. This was similar between the two treatment arms (p = 0.79).
The time between start of treatment and reaching MER was also comparable across the study (3.7 months [range, 2.1−5.5] and 3.6 months [range, 1.0−10.6], in the combination arm and the monotherapy arm, respectively). In patients reaching MER, the median duration of epoetin alfa treatment was 14.9 months. In patients receiving lenalidomide as part of the combined treatment, the median duration of lenalidomide treatment was 17.4 months in patients who achieved MER. MER was maintained for a median of 23.8 months in the Len + Epo cohort compared with 13 months in the lenalidomide only group (p = 0.24).
Targeted deep sequencing was performed on 103 patients (76 non-MER and 27 MER). Of the nine genes that were commonly found to be mutated, none were significantly associated with response to treatment. However, multivariate analysis demonstrated that the distribution of signaling gene and kinase mutations approached significance (p = 0.08). Non-responders consisted of a significantly increased proportion of patients without mutation or with few mutations, compared with those reaching MER (p = 0.031), however this was not confirmed in multivariate analysis.
The frequency of Grade ≥ III adverse events (AEs) was not significantly different between treatment arms. Anemia was the most common Grade III AE recorded, and neutropenia was the most frequently noted Grade IV event. Only four cases of Grade V AEs were recorded: one case each of lung infection, sepsis, soft-tissue infection, and ‘other neoplasm’ (Table 2).
Table 2. Grade 3 or higher adverse events affecting > 1% of study population1
ALL, acute lymphoblastic leukemia; EPO, epoetin alfa; LEN, lenalidomide. |
|||||
|
Len + Epo (n = 99) |
Len only (n = 96) |
|||
---|---|---|---|---|---|
Toxicity, % |
Grade III |
Grade IV |
Grade III |
Grade IV |
|
Anemia |
56.6 |
3 |
56 |
1 |
|
Neutropenia |
30 |
34 |
32 |
31 |
|
Febrile neutropenia |
3 |
1 |
2.1 |
0 |
|
Thrombocytopenia |
17 |
11 |
14.6 |
16.7 |
|
Fatigue |
8 |
0 |
3.1 |
0 |
|
Creatinine rise |
3 |
3 |
2.1 |
0 |
|
Diarrhea |
3 |
0 |
2.1 |
0 |
|
Rash maculopapular |
3 |
0 |
4.2 |
0 |
|
Pruritis |
1 |
0 |
2.1 |
0 |
|
Dyspnea |
3 |
0 |
1 |
0 |
|
ALL |
0 |
0 |
0 |
2.1 |
In the lenalidomide-only group, two patients progressed to acute lymphoblastic leukemia and four patients developed acute myeloid leukemia while on follow-up following study completion. In total, four treatment-related deaths occurred: half of which in the combined treatment cohort and half in the monotherapy group.
Similar rates of treatment discontinuation were recorded (Len + Epo, 20.2% vs lenalidomide only, 16.7%).
In this study, for patients with low-risk, non-del(5q) MDS, treatment with the combination Len + Epo increased the chance of a positive and durable MER compared to lenalidomide alone. The combination treatment did not result in a decreased safety profile compared to the single agent. The results of this study indicate that lenalidomide could be used to restore treatment sensitivity to patients with growth factor-insensitive, lower-risk, non del(5q) MDS.
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