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    Home > Active Ingredient News > Blood System > Rucotinib combination therapy provides a new solution for the treatment of intolerant or drug-resistant MF patients

    Rucotinib combination therapy provides a new solution for the treatment of intolerant or drug-resistant MF patients

    • Last Update: 2021-10-21
    • Source: Internet
    • Author: User
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    In the first three phases, we combed and summarized the survival benefits of rucotinib in the treatment of myelofibrosis (MF) patients and real-world data, and also discussed the best timing of rucotinib treatment
    .

    It has been established that rucotinib treatment in MF patients can not only shrink the spleen and improve systemic symptoms, but also significantly prolong the overall survival of MF patients and reverse myelofibrosis, and it is safe and effective in real clinical practice; and early and first-line initiation of rucotinib The treatment benefit is significant
    .

    However, during the treatment of Rucotinib, the blood cells will decrease
    .

    In addition, in the course of treatment, some MF patients are insensitive or resistant to the treatment of rucotinib
    .

    Researchers have found that the combination of rucotinib therapy can support patients with MF to receive a stable dose of rucotinib treatment and maximize the benefits of patients
    .

    In this issue, let’s take a look at the exploration of the combination therapy of rocotinib to solve various specific problems! The new dosage regimen and the combination regimen of rucotinib for MF patients with cytopenias are well tolerated.
    Rucotinib is the standard treatment method for MF patients.
    However, the management and control of cytopenias during the treatment is still a challenge.
    Some patients are not affected by adverse events.
    Treatment is not interrupted
    .

    In order to minimize the impact of rucotinib treatment on blood cells, while ensuring the therapeutic effect, researchers have explored new rucotinib dosage regimens and combinations of rucotinib and new drugs.
    These explorations may give MF patients Provide excellent disease control and transformative clinical benefits [1]
    .

    The safe and effective treatment of rucotinib in patients with low platelet MF The EXPAND study evaluated the maximum safe start of rucotinib in MF patients with low baseline platelet counts (50-74×109/L or 75-99×109/L) Dose [2]
    .

    Data suggest that for patients with platelets between 50 and 99 × 109/L, 10 mg bid is the maximum safe starting dose of rucotinib [2]
    .

    At this dose, the spleen of patients with different platelet counts responded well [2]
    .

    Figure 1 Waterfall diagram of the best spleen response in patients with different platelet counts at the maximum safe starting dose.
    The new dosage regimen of rucotinib for anemia patients with MF is well tolerated.
    Rucotinib treatment-related anemia mainly occurs in the first 12 weeks [3]
    .

    The REALISE study evaluated the efficacy and tolerability of the new dosage regimen of receiving 10 mg bid rucotinib in the first 12 weeks and then increasing it to a maximum of 25 mg bid based on platelet count and efficacy in baseline anemic MF patients [3]
    .

    A total of 51 adult patients with MF with splenomegaly and hemoglobin <10g/dL (excluding other causes) were enrolled [3]
    .

    The median daily dose of rucotinib is 20 mg (range 8-36 mg).
    As the study time goes by, the proportion of patients with a daily dose ≥ 30 mg gradually increases [3]
    .

    Figure 2 The results of the study on the proportion of patients with different daily doses show that the rucotinib dosage regimen has a significant effect on spleen shrinkage and symptom improvement in patients with anemic MF.
    The palpable spleen length is reduced by ≥50% in 70% of patients, and no new findings have been found.
    The adverse events were well tolerated [3]
    .

    Figure 3 Changes in the length of the patient's spleen throughout the treatment period, the hemoglobin level and platelet count remained stable, and the need for blood transfusion in transfusion dependent patients was reduced (Figure 4) [3]
    .

    Figure 4 Realise study of blood transfusion requirements shows that MF patients with splenomegaly and/or systemic symptoms do not need to delay or suspend rucotinib treatment due to baseline anemia or anemia during treatment [3]
    .

    In patients with cytopenic MF, the combination of rucotinib and PTD has significant benefits.
    Tianjin Hematology Hospital conducted a retrospective cohort study to evaluate the efficacy and efficacy of rucotinib combined with prednisone, thalidomide and danazol in the treatment of MF.
    Tolerance [4]
    .

    A total of 49 MF patients were included in the study
    .

    Figure 5 Rucotinib and PTD regimen dosing results show that during the treatment period, the hemoglobin (Hb) level of 67.
    3% of patients increased from baseline, with the highest increase of 20 (7-64) g/L [4]
    .

    Figure 6 The change in average Hb level during treatment from baseline (Figure A) and the change in Hb of patients (Figure B) During the treatment period, the platelet count (PLT) of 77.
    6% of patients increased, with the highest increase of 143 (14-489)×109/ L[4]
    .

    Figure 7 Changes in the average PLT level during the treatment period from baseline (Figure A) and changes in patients' PLT (Figure B) Hb and PLT increased in 55.
    1% of patients
    .

    In 88.
    9% (40/45) of patients, the length of the spleen was reduced to below the costal margin in the first 12 weeks [4]
    .

    It can be seen that the treatment of rucotinib combined with PTD regimen can improve the tolerance of MF patients to rucotinib, improve blood cell reduction, and bring significant benefits to MF patients [4]
    .

    In patients with drug-resistant MF, Rucotinib has a significant effect on combined treatment.
    Rucotinib shows good spleen shrinkage and improvement of physical symptoms in most MF patients.
    It can also significantly prolong the survival period of patients and delay or reverse the process of myelofibrosis.

    .

    However, some patients do not respond well or are resistant to rucotinib, which is reflected in the loss of spleen shrinkage, enlargement of the spleen, or disease progression.
    At this time, it is necessary to consider discontinuing rucotinib
    .

    However, some patients face the situation that there is no drug to choose after discontinuing rucotinib, and discontinuing rucotinib will inevitably face the problem of worsening symptoms
    .

    In drug-resistant patients, Rucotinib combined with BCL-2 inhibitors has a significant therapeutic effect.
    Navitoclax is an oral small molecule B-cell lymphoma 2 family protein (BCL-XL, BCL-2 and BCL-W) inhibitor.
    Cell lines derived from tumors show cytotoxic activity [5]
    .

    Will its combination with Rucotinib overcome the drug resistance of JAK inhibitors and provide a new treatment plan for MF patients? Figure 8 The potential mode of action of rucotinib and navitoclax in the TAK/STAT signaling pathway.
    REFINE (NCT03222609) This single-arm, multi-center phase 2 study analyzed patients who had been treated with rucotinib for ≥12 weeks and had persistent splenomegaly Adult patients with MF who are in need of new treatments receive rucotinib combined with navitoclax for spleen shrinkage, symptom improvement, adverse reactions and safety [5]
    .

     Figure 9 Study design The 2020 EHA meeting reported the interim results of 34 patients receiving rucotinib + navitoclax treatment [5]
    .

    The results showed that 43% of patients had a reduction of spleen volume ≥35% from baseline (SVR 35), and 30% of them reached SVR35 at week 24 [5]
    .

    The grade of myelofibrosis decreased in 25% of patients by ≥1 grade
    .

    Of the 17 evaluable patients, 11 had a total symptom score (TSS) reduction at week 24, and 6 patients (35%) had a TSS reduction ≥50% [5]
    .

    The updated results at the EHA meeting in 2021 showed that the median response duration of SVR35 was 13.
    8 months (95%CI: 8.
    2-not reached) [6]
    .

    The median OS was not reached at a median follow-up of 105 weeks (Figure 10), and the estimated OS at 24 months was 84% ​​(95% CI: 63.
    0%-93.
    9%) [6]
    .

    Figure 10 The most common adverse event reported by the Kaplan-Meier curve of overall survival is thrombocytopenia, which can be controlled and reversed by dose adjustment, without significant bleeding events [5]
    .

    Studies have shown that the combination regimen of rucotinib and navitoclax has significant efficacy and is well tolerated.
    It is expected to become an important treatment option for MF patients to prevent or reverse JAK2 inhibitor resistance and change the biology of MF [6]
    .

    In patients with poor response, rucotinib combined with PI3Kδ inhibitor has a good therapeutic effect.
    In the process of rucotinib's continuous inhibition of the JAK pathway, due to continuous PI3K/AKT activation, some patients may have a poor response [7]
    .

    The highly selective PI3Kδ inhibitor parsaclisib targets PI3K/AKT.
    Will its combination with rucotinib have clinically relevant effects on the diseases of MF patients with poor response to rucotinib [7-9]? A phase 2 study (NCT02718300) evaluated the poor response of rucotinib combined with parsaclisib in rucotinib (recotinib treatment for ≥6 months, the left subcostal spleen> 10cm, or the left subcostal palpable The spleen is 5-10 cm and is accompanied by 1 symptom score ≥ 5 points, or two symptom scores ≥ 3 points) the best dose and efficacy in patients [7]
    .

    The patient maintains a stable dose of rucotinib (5-25mg bid), and the dose and flow of parsaclisib are shown in the following figure [7]
    .

    Figure 11 Dosage and procedure of rucotinib combined with parsaclisib Note: QD, once a day; QW, once a week; RUX: Rucotinib combined with parsaclisib can further relieve the effects of the EHA meeting in 2020.
    QD parsaclisib administration seems to be more effective than QD/QW for splenomegaly and myelofibrosis in MF patients with poor response to cotinib [7]
    .

    Moreover, the safety of combination therapy is tolerable [7]
    .

    Figure 12 The average change of palpable spleen length in the two groups over time.
    Two randomized double-blind placebo-controlled phase 3 studies LIMBER-304 (NCT04551053) and LIMBER-313 study (NCT04551066) at the EHA meeting in 2021 are designed to explore ruginib The efficacy and safety of combining Parsaclisib compared with Rucotinib combined with placebo in MF patients with poor response to Rucotinib [8-9]
    .

    The current studies are in progress, and it is expected that the results of the two large studies will bring hope to patients with MF who do not respond well to rucotinib treatment
    .

    In the newly treated MF patients, the combination of rucotinib and spleen contraction is effective.
    Rucotinib and BETi are synergistically effective in the JAK inhibitor-naive patients.
    The bromodomain and extra-terminal domain (BET) protein family are involved in the regulation of a variety of pro-fibrosis The transcription of pathway target genes is a potential new therapeutic target to reduce the degree of fibrosis in MF patients [10]
    .

    Pelabresib is an oral BET inhibitor (BETi) that has shown clinical activity in severely treated MF patients.
    In preclinical studies, BETi combined with rucotinib treatment can synergistically reduce spleen volume [10-11]
    .

    Therefore, the combination of rucotinib and pelabresib is expected to achieve a higher splenic response in MF patients [10]
    .

    The EP1085 study at the EHA meeting in 2021 reported the efficacy of rocotinib combined with pelabresib in 78 MF patients who had not previously received JAK inhibitor treatment.
    The baseline characteristics of the patients are as follows [10]
    .

    Table 1 Baseline characteristics of patients At the 24th week, 67% (42/63) of the patients reached SVR35 [10]
    .

    Subgroup analysis showed that in each subgroup such as risk score, MF subtype, baseline platelet count, and baseline spleen size, the combination therapy consistently showed a good spleen shrinking effect (Figure 13) [10]
    .

    In addition, regardless of the mutation status, patients benefited significantly, including the ASXL1 mutation subgroup, which usually has a poor prognosis [10]
    .

    Figure 13 Subgroup analysis of the percentage decrease in spleen volume from baseline at week 24.
    Conclusion MF is a myeloproliferative tumor.
    In addition to megakaryocyte proliferation and progressive myelofibrosis, it also has splenomegaly and bone marrow caused by extramedullary hematopoiesis Clinical features such as blood cell reduction and systemic symptoms caused by failure [12]
    .

    At the time of diagnosis, nearly 40% of patients have hemoglobin <10 g/dL, the patient’s survival period is shortened, and the quality of life is reduced [12]
    .

    Rucotinib has a significant effect in improving splenomegaly, MF-related symptoms and quality of life in patients with MF, and it can also bring survival benefits to patients
    .

    However, the reduction of blood cells in the treatment of rucotinib is still a challenge in the management of MF
    .

    In addition, not all patients respond to rucotinib, some patients lose their response during treatment, and some patients do not respond well to rucotinib
    .

    Existing studies have shown that: ①the patients with hemocytopenia who changed the dosage regimen of rucotinib or combined with the PTD regimen are well tolerated; ②the patients who are resistant to or not responding to rucotinib have a significant combined treatment effect; ③the patients who are newly treated with MF are well tolerated by the combination therapy.
    The combined treatment of tinib has obvious effect on spleen contraction
    .

    Researchers are still further exploring the best combination of treatments for rucotinib into patients with rucotinib or drug-resistant MF.
    It is hoped that these studies will benefit more MF patients in the future
    .

    References: [1] Ross D, et al.
    2021 EHA.
    Abstract: PB1723.
    [2] Vannucchi AM, Boekhorst P, Harrison CN, et al.
    EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis[J].
    Haematologica, 2018, 104(5):947-954.
    [3] 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.
    [4] Zefeng Xu, et al.
    2020 EHA.
    Abstract: EP1116.
    [5] Harrison C, et al.
    2020 EHA.
    Abstract : EP1081.
    [6] Harrison C, et al.
    2021 EHA.
    Abstract: EP1078.
    [7] Yacoub A, et al.
    2020 EHA.
    Abstract: S216.
    [8] Yacoub A, et al.
    2021 EHA.
    Abstract: PB1715 .
    [9] Yacoub A, et al.
    2021 EHA.
    Abstract: PB1716.
    [10] Kremyanskaya M, et al.
    2021 EHA.
    Abstract: EP1085.
    [11] Kleppe M, Koche R, Zou L, et al.
    Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms[J].
    Cancer Cell.
    2018;33(4):785–787.
    [12] Perkins AC, Burbury K, Lehmann T, et al.
    Adore: A Randomized, Open-Label, Phase 1/2 Open-Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Patients with Myelofibrosis[J].
    Blood, 2020, 136(Supplement 1):52-53.
    The article involves some products or adaptations The disease has not been approved in China, and the relevant content is for academic exchanges only52-53.
    Some products or indications involved in the article have not been approved in China, and the relevant content is for academic exchanges only52-53.
    Some products or indications involved in the article have not been approved in China, and the relevant content is for academic exchanges only
    .

    The MCC number JAK2110583 is valid for 2022-10-13, the information is expired and deemed invalid.
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