Peritransplantation treatment with rucotinib improves the prognosis of MF patients

In the first four 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
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It has been clear: ①The treatment of MF patients with Rucotinib can not only shrink the spleen and improve the systemic symptoms, but also significantly prolong the overall survival of MF patients and reverse myelofibrosis; ②In actual clinical practice, Rucotinib is equally safe and effective; ③Early And the first-line start-up of rucotinib treatment has significant benefits; ④The blood cell decline in the process of rucotinib treatment can be solved by the combination of rucotinib
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Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for MF patients, but the patient's physical status, spleen load, and constitutional symptoms will affect the patient's outcome [1]
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What is the effect of receiving Rucotinib before transplantation on HSCT in MF patients? Do I need to stop rocotinib before transplantation? In this issue, we sorted out the latest evidence and guidelines for the use of rucotinib in the peri-transplantation period to guide the management of MF patients
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Rucotinib bridging therapy before transplantation can improve the outcome of MF patients.
The improvement of physical symptoms and physical status of patients before HSCT may improve the results after HSCT, increase the implantation rate, reduce adverse reactions, and reduce mortality [2]
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Rucotinib can just improve these symptoms of MF patients, and can reduce the rate of patients undergoing splenectomy before HSCT [2]
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For this reason, many researchers have explored the results of bridging treatment with rucotinib before HSCT
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1.
Rucotinib bridging treatment before transplantation has a high transplant rate JAK ALLO (NCT01795677) This multi-center prospective phase II trial analyzed the results of 76 MF patients who received rucotinib treatment for 6 months before transplantation [2]
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In the initial study design, Rucotinib was gradually reduced within 15 days before the start of pretreatment, and then revised to stop the drug directly before the melphalan treatment
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Among them, 64 patients found a suitable donor [2]
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Among the 64 patients with donors, 31% achieved partial remission before transplantation, and 92% could be transplanted after rucotinib treatment [2]
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All patients who received HSCT were successfully implanted at 4 months
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It is suggested that receiving rocotinib treatment before transplantation increases the proportion of patients who can be transplanted, and the success rate of transplantation is high [2]
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Figure 1 Transplantable patients after rucotinib treatment 2.
Rucotinib bridging therapy before transplantation improves the survival of MF patients [3]
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The median administration time of rucotinib was 7 months (range 2-36 months), and the drug was discontinued 4 days before HSCT [3]
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With a median follow-up of 12.
5 months, the results showed that the overall 1-year OS was 93% (95% CI 73%-98%) and the 2-year OS was 86% (95% CI 61%-96%), indicating that the pre-transplantation Cotinib treatment can obtain good survival results [3]
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Figure 2 OS curve of MF patients after transplantation Another report of the results of 37 MF patients who received HSCT in a single center from 2009 to 2018, 32 patients received rucotinib before transplantation, and all patients received it.
Porting [4]
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The median follow-up time was 40.
2 months, and the 3-year OS and recurrence-free survival (RFS) were 81.
1% and 78.
4%, respectively [4]
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Only 2 patients relapsed/progressed after transplantation
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The 2-year non-relapse mortality (NRM) was 16.
2%
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The results show that MF patients can be treated with rucotinib before transplantation to obtain good transplant results [4]
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Fig.
3 Kaplan-Meier of OS after transplantation Fig.
3.
Clinical remission patients benefited best in rocotinib bridge transplantation EBMT-Chronic Malignant Tumor Working Group at the 2021 European Association for Blood and Bone Marrow Transplantation (EBMT 2021) Annual Meeting (EBMT 2021) CMWP) A study of 551 patients with MF who underwent HSCT between 2012 and 2016 showed that on the 45th day, the overall leukocyte implantation rate was 92%, and the implantation rate of patients who responded to rucotinib was significant It is higher than that of patients who do not respond or fail to respond to rucotinib (94% vs 85%, p=0.
05) [5]
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Multivariate analysis showed that compared with early treatment with rucotinib, patients who were treated with rucotinib in the early stage and had sustained splenic response at the time of transplantation had a significantly lower risk of recurrence (p = 0.
04), and the 2-year event-free survival rate Significantly improved (68.
9% vs 53.
7%, p = 0.
02) [5]
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Figure 4 Implantation rate after transplantation in patients with different early treatments.
The results of this study are consistent with previous reports
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In a retrospective multi-center study conducted in 2009-2014, the OSCT in patients who had achieved clinical remission with rucotinib treatment was significantly higher than those in patients who had failed treatment or had disease progression at 2 years (91% vs 55% vs 32%).
, P=0.
010) [6]
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Figure 5 The optimal duration of bridging treatment with rucotinib before OS transplantation in different treatment groups of MF patients and the way of discontinuation.
Rucotinib bridging transplantation can shrink the spleen and improve the constitutional symptoms, so as to increase the implantation rate.
The results of reducing the recurrence-free mortality and improving the survival rate have shown good benefits in MF patients [3]
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However, there is a risk of immunosuppression in patients treated with rucotinib for HSCT, which may lead to delayed transplantation and increased susceptibility to infection [1,7]
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How to grasp the continuous use time of rucotinib bridge transplantation and the way to reduce and stop? A review in 2020, based on a detailed review of published literature data, proposed specific management recommendations for bridging treatment with rucotinib before transplantation
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1.
A tapering strategy should be used to stop rucotinib treatment.
Some studies reported that rucotinib was gradually reduced from 14 days to 1 day before HSCT pretreatment, and there were also studies that started 6 days before rucotinib pretreatment.
Gradually reduce the dose by 5mg every 2 days, and add prednisone during the rucotinib reduction period [1]
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The reduction time reported in the literature ranges from 4 days to 14 days, and there are cases of sudden drug withdrawal [1]
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In patients with an interval of 6 days between the last dose of rucotinib and the start of the pretreatment regimen, adverse events are more common [1]
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Taking into account the risk of cytokine rebound when JAK inhibitors are stopped suddenly, combined with the reported dose reduction studies of rucotinib before transplantation, rucotinib should be gradually reduced before the start of pretreatment
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If you are worried about severe withdrawal syndrome, you can add hormones during the tapering period [1]
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2.
Rucotinib can continue to be used until the day before pretreatment.
Reviewing the MF patients who received rucotinib treatment until the day before the start of pretreatment, no significant delay in HSCT implantation, NRM, acute graft versus host disease (aGVHD) ) Or the incidence of chronic graft-versus-host disease (cGVHD) has not increased significantly, but studies have reported an increase in the reactivation rate of cytomegalovirus (CMV) [1]
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It is suggested that rucotinib can be used continuously until the day before pretreatment, but the risk of cytokine rebound should be paid attention to [1]
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3.
Rucotinib continued to be used until the implantation was well tolerated.
In a prospective study, 12 patients continued to use Rucotinib during the pretreatment period until the implantation was stable.
Rucotinib was reduced on the 20th day.
To 5mg per day, stop the drug on the 28th day [8]
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The median time of implantation was 12 days
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The overall incidence of grade II-IV aGVHD on day 100 was 8%
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All patients survived for 1 year
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CMV reactivation was observed in 5 patients (41%)
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The onset of CMV reactivation was earlier than that of the cohort that had not received rucotinib treatment [8]
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In a prospective single-center study, MF patients were treated with rucotinib before transplantation and continued until the 30th day after hematopoietic stem cell transplantation, and the dose was gradually reduced and stopped on the 33rd day [9]
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All patients underwent transplantation, with a median time of 19 days
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CMV reactivation occurred in 1 patient [9]
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The above data shows that MF patients are well tolerated by rucotinib treatment until implantation, and will not cause a significant delay in transplantation time, but during use, cytomegalovirus reactivation and blood cell reduction must be closely monitored [1]
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The 2021 version of the Chinese Society of Clinical Oncology (CSCO) Diagnosis and Treatment Guidelines for Hematological Malignancies recommends that patients with high-risk and very high-risk primary myelofibrosis (PMF) can be treated with rocotinib before and after HSCT, but the specific method currently lacks evidence-based medicine Evidence
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The choice of HSCT timing also lacks evidence-based medical evidence.
If rucotinib and other drugs achieve the desired effect, it may be appropriate to postpone the timing of transplantation until the efficacy of rucotinib begins to lose [10]
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The 2019 European Society for Blood and Bone Marrow Transplantation (EBMT) Hematopoietic Stem Cell Transplantation and Cell Therapy Manual recommends the use of rocotinib at least 2 months before HSCT, and caution to stop the drug before pretreatment to avoid rebound [11]
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Rucotinib maintains the safety of treatment after transplantation and can improve the results of transplantation The previous studies have shown that rucotinib bridging therapy can improve the HSCT results of MF patients
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What is the role of Rucotinib in the maintenance after HSCT? A retrospective study evaluated the feasibility and toxicity of rucotinib bridging and maintenance therapy before and after HSCT in MF patients [12]
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The patients were divided into 3 cohorts.
3 patients in cohort A had never received recotinib, 9 patients in cohort B received only recotinib bridging therapy, and 4 patients in cohort C received both pre-transplant bridging and Maintenance treatment after transplantation
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All patients had systemic symptoms and splenomegaly at the time of diagnosis
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The median duration of rucotinib treatment before transplantation was 8 months, and the median duration of rucotinib maintenance treatment after transplantation was 20 months [12]
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The results showed that compared with cohorts A and B, patients in cohort C had significantly reduced spleen, improved fibrosis, and could achieve rapid implantation
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At the time of the last data collection, all patients were alive
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In cohort A, 2 patients had stable disease and 1 patient had disease progression
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In cohort B, 2 patients achieved complete remission, 2 patients achieved partial remission, and 5 patients had stable disease
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All patients in cohort C achieved complete remission at a median time of 11.
5 months
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Moreover, the proportion of aGVHD patients in cohort C was significantly lower than cohort A or B (P=0.
0365), and there were no obvious side effects
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The study showed that the results of rucotinib treatment before and after HSCT in MF patients were improved, and rucotinib maintenance treatment after HSCT was safe and tolerable
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Conclusion As the treatment of MF enters the era of JAK inhibitors, the selection and bridging of JAK inhibitors and HSCT has become the key to MF management
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The results of studies on early acceptance of HSCT and JAK inhibitors suggest that early HSCT treatment has no significant benefit, and patients who respond to JAK inhibitors such as rucotinib can delay transplantation [10,13]
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Rucotinib bridging treatment can continue until the time of implantation
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If it is considered to discontinue rucotinib before HSCT pretreatment, the discontinuation should be gradually reduced
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In addition, Rucotinib maintenance treatment after transplantation can also improve the outcome of MF patients
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This is the end of the content of this issue, hoping to provide some reference for the management of MF patients
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References: [1] Ibrahim U, Petrone G, Mascarenhas J, et al.
Peri-transplant Use of Ruxolitinib in Myelofibrosis[J].
Biology of Blood and Marrow Transplantation, 2020, 26: 2177-2180.
[2] Robin M , Porcher R, Orvain C, et al.
Ruxolitinib before allogeneic hematopoietic transplantation in patients with myelofibrosis on behalf SFGM-TC and FIM groups[J].
Bone Marrow Transplant.
2021, 56(8): 1888-1899.
[3] Salit RB, Scott BL, Stevens EA, et al.
Pre-hematopoietic cell transplant Ruxolitinib in patients with primary and secondary myelofibrosis[J].
Bone Marrow Transplant.
2020, 55(1): 70-76.
doi: 10.
1038/s41409-019 -0523-3.
[4] Chhabra S, Narra RK, Wu R, et al.
Fludarabine/Busulfan Conditioning-Based Allogeneic Hematopoietic Cell Transplantation for Myelofibrosis: Role of Ruxolitinib in Improving Survival Outcomes[J].
Biol Blood Marrow Transplant.
2020 , 26(5):893-901.
doi: 10.
1016/j.
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[5] Kröger N, Sbianchi G, Sirait T, et al.
Impact of prior JAK-inhibitor therapy with ruxolitinib on outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis : a study of the CMWP of EBMT[J].
Leukemia, 2021.
[6] Shanavas M, Popat U, Michaelis LC, et al.
Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors[J].
Biol Blood Marrow Transplant 2016, 22(3): 432-40.
[7] Tiribelli M, Palandri F, E Sant'Antonio, et al.
The role of allogeneic stem-cell transplant in myelofibrosis in the era of JAK inhibitors: a case-based review[J].
Bone Marrow Transplantation, 2020, 55:708-716.
[8] Kroger N, Shahnaz Syed Abd Kadir S, Zabelina T, et al.
Peritransplantation ruxolitinib prevents acute graft-versus-host disease in patients with myelofifibrosis undergoing allogenic stem cell transplantation[J].
Biol Blood Marrow Transplant.
2018, 24: 2152–2156.
[9] Ali H, Snyder D, Stiller T, et al .
Peri-transplant administration of ruxolitinib is safe and feasible in patients with myelofifibrosis: primary results of a pilot open-label study of ruxolitinib administration in combination with reduced intensity conditioning[J].
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2019, 134(suppl_1): 669.
[ 10] Chinese Society of Clinical Oncology Guidelines Working Committee, Chinese Society of Clinical Oncology (CSCO) Guidelines for Diagnosis and Treatment of Hematological Malignancies 2021[M].
Beijing: People's Medical Publishing House, 2021:309-311.
[11] Carreras E, Dufour C, Mohty M, et al.
The EBMT Handbook Hematopoietic Stem Cell Transplantation and Cellular Therapies: Hematopoietic Stem Cell Transplantation and Cellular Therapies[M].
2019.
[12] Pu JJ, Poulose J, Malysz J, et al.
Impact of Ruxolitinib on Myelofibrosis Patients Post Allogeneic Stem Cell Transplant---A Pilot Study[J].
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[13] Maze D , Arcasoy MO, Henrie R, et al.
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RECOMMEND Recommended reading 1.
Repost "Good News": Rucotinib prolongs the survival of MF patients 2.
Real-world data helps Rucotinib medication practice 3.
Early and first-line initiation of Rucotinib treatment benefits significantly 4.
Rucotinib combination therapy, why not For patients with tolerant or drug-resistant MF, the new solution MCC number JAK2111879 will be provided.
The validity period is 2022-11-11.
The data is out of date and deemed invalid.
Another "good" report: Rucotinib prolongs the survival of MF patients 2.
Real-world data helps Rucotinib medication practice 3.
Early and first-line initiation of Rucotinib treatment benefits significantly 4.
Rucotinib combination therapy, Provide a new solution for the treatment of intolerant or drug-resistant MF patients.
The MCC number JAK2111879 is valid for 2022-11-11.
The data is out of date and deemed invalidAnother "good" report: Rucotinib prolongs the survival of MF patients 2.
Real-world data helps Rucotinib medication practice 3.
Early and first-line initiation of Rucotinib treatment benefits significantly 4.
Rucotinib combination therapy, Provide a new solution for the treatment of intolerant or drug-resistant MF patients.
The MCC number JAK2111879 is valid for 2022-11-11.
The data is out of date and deemed invalid
.

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.

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