REALISE Study: A new dosage regimen of Rucotinib in the treatment of MF patients with anemia

Anemia is one of the common manifestations of myelofibrosis (MF) and an important factor in risk assessment.
It will aggravate as the disease progresses and adversely affect the prognosis.
There is an unmet need for the existing treatment of MF with anemia.

Rucotinib is a potent JAK1/JAK2 inhibitor and the first targeted drug approved by the FDA/EMA for the treatment of MF.

The instructions suggest that the starting dose of rucotinib is based on platelet counts, regardless of baseline hemoglobin levels.

Rucotinib treatment-related anemia mainly occurs in the first 12 weeks and is usually manageable, with no adverse effects on the patient's prognosis.

With clinical experience, using a low starting dose (10 mg bid) and gradually increasing the dose can reduce the effect of rucotinib treatment on anemia, while ensuring the therapeutic effect of anemia patients.

Based on this, some researchers initiated a study to evaluate the effectiveness and safety of this new dosage regimen (10 mg bid starting and gradually increasing the dose) in MF patients with anemia.

The main results of the study are summarized as follows for readers' reference.

 A quick overview of key results The new dosage regimen of Lucotinib in the treatment of MF patients with anemia can significantly reduce the spleen, improve symptoms, and is safe.
Throughout the treatment period, the hemoglobin level and platelet count remain stable, and the need for blood transfusion in patients with blood transfusion dependence is reduced without cause Baseline with anemia or anemia during treatment and delay or suspension of rucotinib treatment Study method: 10 mg bid starting dose, gradually increasing the dose REALISE study is an open-label, single-arm, phase 2 study, in Europe, Asia and North America Of the 20 centers enrolled 51 adult patients with PMF (66.
7%), PET-MF (21.
6%) and PPV-MF (11.
8%), accompanied by splenomegaly and hemoglobin <10g/dL (others need to be excluded before admission Causes of anemia), and the Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, peripheral blood blasts <10%.

The patient received rucotinib 10 mg bid in the first 12 weeks, and then increased to a maximum of 25 mg bid based on platelet count and efficacy.

Patients with absolute neutrophil value (ANC)>0.
5×109/L and hemoglobin (Hb)≥6.
5g/dL can increase the dose.
The specific dose adjustment plan is shown in Figure 1.

Figure 1 Dose up-regulation flow chart BSL baseline spleen length, SL spleen length, PLT platelet count, RUX rocotinib The primary endpoint of this study is the proportion of patients with a reduction of ≥50% in SL at week 24.

Secondary endpoints include blood transfusion requirements, safety, hemoglobin changes, and patient-reported outcomes.

Results of the study: Spleen, patient-reported outcomes, and safety.
Before the data deadline, 50 patients had completed or stopped treatment (1 patient was undergoing treatment), and a total of 28 (54.
9%) patients completed the study.

During the study period, the median daily dose of rucotinib was 20 mg (range 8-36 mg).

By the 24th week, 26.
2% of patients had received treatment with a total daily dose of ≥30 mg.
By the 48th week, the proportion had increased to 32.
4%.

At the end of the final data cutoff, 12% of patients had increased the dose, and 30% had maintained the starting dose.

as shown in picture 2.

Figure 2 The proportion of patients with different daily doses was compared with those who did not receive the dose increase.
The patients who received the dose increase had a larger baseline spleen (median SL 14cm vs 9cm) and a higher median white blood cell count (14×10 9/L vs.
8.
7×10 9/L).

In addition, patients who did not receive a dose increase had a higher incidence of low platelet counts (27.
8% vs 6.
7%).

The shrinkage of the spleen was significant.
70% of patients had a reduction of spleen length of ≥50%.
As of the 24th week, a total of 56% of patients had a reduction of spleen ≥50%, reaching the primary endpoint.

70% of patients achieved a SL reduction of ≥50% at any time (Figure 3).

Among them, the proportion of patients with transfusion dependent (TD) and non-transfusion dependent patients whose SL decreased ≥50% was 66.
7% (6/9) and 52.
5% (21/40), respectively.

According to the stratification of DIPSS status, the proportions of patients with intermediate-risk-1, intermediate-risk-2, and high-risk patients who achieved a SL reduction of ≥50% at 24 weeks were 55.
6%, 57.
1%, and 40%, respectively.

Figure 3 The value of SL changes in patients.
Among the 15 patients who received a dose increase in the 12th week, 7 patients (47%) had a spleen shrinkage of ≥50% at the 24th week.

Most (11/15) patients who maintained the initial dose achieved a SL reduction of ≥50% on or after the 12th week.

Significantly improve the symptoms of patients, >70% of patients have a symptom score reduction of ≥50%.
According to the DIPSS status, 75% of intermediate-risk-1 patients, 84.
6% of intermediate-risk-2 patients, and 75% of high-risk patients are in the entire study At any time during this period, the MF-7 TSS total symptom score decreased by ≥50%.

According to the MF-S AF score results, 75% of intermediate-risk-1 patients, 84.
6% of intermediate-risk-2 patients, and 50% of high-risk patients had a score reduction of ≥50% at any time during the entire study period (Figure 4).

According to the results of the PGIC score, the proportion of patients with improved symptoms was 82.
9% at the 24th week and 87.
9% at the 48th week.

Figure 4 The safety of patients' MFSAF score changes.
No new adverse events were found.
86.
3% (44/51) of subjects reported at least one adverse event (AE), of which 51% were considered to be related to treatment.

A total of 25 patients (49.
0%) had at least one dose reduction, and 16 patients (31.
4%) had at least one dose interruption.

The most common AEs leading to dose interruption/adjustment were thrombocytopenia (17.
6%) and anemia (11.
8%).

5 patients discontinued treatment due to AE, and 8 patients died.

Compared with previous trials of rucotinib in the treatment of MF, no new AEs were observed in the REALISE trial.

Changes in hematology parameters and blood transfusion requirements were observed in 82.
4% of patients with a decrease in Hb, of which 54.
9% were grade 3.

Throughout the study, with the support of red blood cell (RBC) infusion, the average Hb level remained stable.

66.
7% of patients had thrombocytopenia, of which 17.
6% were grade 3 or 4.

During the study period, 11.
8% of patients required platelet transfusion.

In patients whose baseline initial platelet count decreased and were still enrolled in the study, the median platelet count remained stable throughout the study period.

During the study, the platelet counts and Hb levels of patients who received and did not receive the dose increase were similar.

Overall, the RBC infusion requirement of TD patients decreased, while the RBC infusion requirement of non-TD patients remained stable throughout the study (Figure 5).

Whether it is patients with or without splenic remission, the demand for blood transfusion is showing a decreasing trend.

In patients who had TD at baseline but did not achieve splenic remission, a trend toward a decrease in the need for red blood cell transfusion was also observed.

Figure 5 Conclusion of the study on blood transfusion requirements: individualized starting dose selection, no need to delay/interrupt treatment due to anemia.
Based on the above results, the new administration strategy of rucotinib may be more suitable for splenomegaly and/or symptoms accompanied by anemia (Hb <10g/dL) MF patients.

It is worth noting that the study found that the spleen of patients who need to increase the dose of rucotinib is often larger than that of patients who do not need to increase the dose.
Therefore, the starting dose of rucotinib can be selected based on the need for rapid spleen shrinkage.

For anemia patients with physical symptoms but no obvious splenomegaly, a lower starting dose of rucotinib (ie 10 mg bid) can be selected.

In summary, the results of the REALISE study show that the alternative dosing regimen of rucotinib (starting at 10 mg bid and gradually increasing the dose after 12 weeks) is effective and well tolerated in MF patients with anemia.

This also shows that in MF patients with splenomegaly and/or systemic symptoms, there is no need to delay or suspend rucotinib treatment due to baseline anemia or anemia during treatment.

References: Cervantes F, Ross DM, Radinoff A, et al.
Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study.
Leukemia.
2021 May 20.
doi: 10.
1038 /s41375-021-01261-x.
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The information in this document is for reference only, please follow the advice or guidance of doctors or other medical and health professionals.

The MCC number JAK21052743 is valid for 2022-05-28, and the information is expired and deemed invalid.

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