干擾素先驅提出干擾素的長期定位
https://www.onclive.com/publications/milestones-in-medicine/2019/history-and-evolving-role-of-interferon-in-myeloproliferative-neoplasms/mpns-pioneer-highlights-long-lasting-role-of-interferon
發表日期：2019年2月21日
Despite the rise of newer, effective therapies since the inception of interferon 30 years ago, there is still a biologic basis for its use in the treatment of patients with myeloproliferative neoplasms (MPNs), according to Richard T. Silver, MD.
Richard T. Silver醫師提到：自30年前干擾素用於治療以來，新型療法越來越多，但他的生物學基礎仍可用於治療骨髓增生性腫瘤（MPNs）病患。
In polycythemia vera (PV), for example, patients typically develop symptomatic iron deficiency and thrombotic events. Interferon, which inhibits PDGF, TGFβ, and other critical pathways, reduces the risk of these events, explained Silver, who is a professor of medicine at Weill Cornell Medical College/NewYork-Presbyterian.
Silver醫生提到：在PV病患通常會出現缺鐵症狀和血栓事件。干擾素治療能夠抑制PDGF，TGFβ和其他關鍵途徑降低了這些事件的風險。
“There is evidence that interferon will also reduce the cellularity of the bone marrow, which is responsible for producing the number of white and red blood cells and platelets that we see in PV,” added Silver.
Silver補充說明：有證據顯示出，干擾素也會降低骨髓的細胞構成，而骨髓的細胞構成會產生我們在PV中看到的白血球和紅血球以及血小板。”
The phase III PROUD-PV study, which compared ropeginterferon alfa-2b with hydroxyurea in patients with PV, further established the role for interferon in the treatment paradigm. Results showed that ropeginterferon alfa-2b was noninferior to hydroxyurea, with a 12-month complete hematologic remission rate of 43.1% versus 45.6%, respectively. The need for phlebotomy for patients treated with interferon dropped from 86% to 6%, and 37% of patients achieved a JAK2 molecular response with the therapy.
臨床三期PROUD-PV研究針對HU和P1101用於PV病患進行比較。結果進一步確定了干擾素在治療中的作用。結果顯示，新一代長效型干擾素不劣於HU，12個月完全血液學緩解率分別為43.1％和45.6％。用干擾素治療的患者對靜脈切開術的需求從86％下降到6％，並且37％的患者在治療中獲得了JAK2分子反應。
In an interview with OncLive, Silver provided the history of interferon and shared insight on why the drug still holds its place in the treatment of patients with MPNs.
在接受OncLive訪問時，Silver醫生說明了干擾素的歷史，並分享了為什麼該藥物仍然在治療MPN病患中佔有一席之地。
OncLive: How has interferon been used traditionally for the treatment of patients with MPNs?
OncLive：傳統上干擾素如何用於治療MPN病患？
Silver: The use of interferon was first reported by me in 1988. Since that time, we have developed extensive experience using it at Weill Cornell Medicine. We use it preferentially to any other agent because there is a biologic basis for its use. In comparison with the most commonly used drug—hydroxyurea, which is a nonspecific cell poison—there is a biologic basis for its use. It interferes with cell development and marrow fibrosis by interfering with PDGF and VEGF; it also affects JAK signaling. As I said, interferon is a drug for which there is a meaningful use—it is not a nonspecific myelosuppressive.
我在1988年首次報導了干擾素的使用。從那時起，我們在使用它已經累積了豐富的經驗。比起最常用的藥物HU，我們優先將使用這種藥物，因為它為生物用藥。它通過干擾PDGF和VEGF阻止細胞發育和骨髓纖維化；它也會影響JAK信號。正如我所說，干擾素是有意義的藥物，它並非特殊用於骨髓抑制的藥物。
In our clinic, we don't believe in the "watch and wait" approach that is recommended by some [physicians] because it develops iron deficiency in patients; this has been getting a lot more attention now both in men and women. Most women become iron deficient because of menstruation. Phlebotomy will obviously add to that in men, irrespective of the fact that they don't menstruate. The average patient with PV we see requires about 8 phlebotomies. The maintenance thereof should not be phlebotomy only, even in so-called good-risk patients. This is because the phlebotomy rate is higher in those patients than in the normal population and because it doesn't suppress disease. It is sort of like treating a diabetic and letting their blood sugar rise while the patient has blood in the urine. You can't just treat their symptoms without giving them insulin.
在我們的診所，我們認同某些醫生推薦的“觀察和等待”，因為它會導致病患缺鐵。現在，男性和女性都受到了越來越多的關注。大多數女性因月經而缺鐵。無論是否有月經，男性放血顯然會比女性增加。我們看到PV的普通病患需要大約8次放血。即使在所謂的高風險患者中，也不應僅是放血。這些病患的靜脈切開率高於正常人群，並且因為它不能抑制疾病。這有點像治療糖尿病患者，當病患尿液中有血液時讓他們的血糖升高，你不能只是給他們胰島素治療他們的症狀。
We believe that there are 2 reasons for using interferon. First, there is a biologic basis for its use, and secondly, it avoids the development of iron deficiency. In addition, there is evidence that interferon can reduce thrombotic risk, which is significant for patients who are only treated with phlebotomy. We also have evidence from more than 300 patients with PV that the fibrosis we see in this disease will have a delayed onset of disease when they are treated with interferon; this is because interferon affects PDGF and TGFβ, as well as other cytokines that are responsible for the development of myelofibrosis. This is very exciting, and it is new information; it has never been shown in any population of patients. We presented a poster on this at the 2018 ASH Annual Meeting.
我們認為使用干擾素有兩個原因。首先，它為生物用藥，其次，它避免了缺鐵。此外，有證據顯示出干擾素可降低血栓風險，這對僅接受放血的病患俱有重要意義。
來自300多名PV病患的證據表明，我們在這種疾病中看到的纖維化在用干擾素治療時會延遲發病；這是因為干擾素影響PDGF和TGFβ，以及負責骨髓纖維化發展的其他細胞因子。這非常令人興奮，最新數據顯示它從未在任何病患群體中顯示出來。我們在2018年血液年會上發表。
Could you expand on the use of interferon in today’s landscape?
能否說明干擾素的現今概況
We believe that in the long-term—not the short-term use—that hydroxyurea can cause leukemia in about 8% to 10% of patients. In a 15-year span, this number increases to about 15%. A patient can no longer use the drug if he/she develops secondary leukemia. There has never been a controlled study evaluating hydroxyurea over the long-term compared with phlebotomy because most patients cannot stay on phlebotomy.
我們認為，長期使用HU會導致約8％至10％的病患得到血癌。在15年的時間裡，這一數字增加到約15％。如果病患惡化為繼發性白血病，則病患不能再使用該藥物。與放血相比，長期以來從未有過對照HU的研究，因為大多數病患不能持續放血。
Interferon will significantly reduce the risk of developing secondary leukemia—this is very important. I might say that the reason there has not been a controlled trial for this is because of 1 trial conducted by French [researchers], which compared the use of hydroxyurea with pipobroman. Thank goodness this drug is not available in the United States because it is very leukemogenic in patients with PV, even more so than hydroxyurea. There is evidence that interferon will also reduce the cellularity of the bone marrow, which is responsible for producing the number of white blood cells, red blood cells, and platelets that we see in PV. We reported on that a couple of years ago as well.
干擾素將顯著降低繼發性白血病的風險，這非常重要。法國研究人員進行了一項試驗，比較了HU與pipobroman的使用。感謝老天這種藥在美國無法使用，因為它對PV病患會導致白血病，甚至比HU比例更高。證據顯示出，干擾素會降低骨髓的細胞構成，這是造成我們在PV中看到的白血球，紅血球和血小板數量的原因，幾年前我們也報導了這一點。
We also have evidence that interferon will reduce JAK2, the genetic abnormality that characterizes PV. We are not quite sure what that means, because we can see marrow reduction in patients that don't have significant decreases in JAK2. Anyway, there is evidence that interferon will certainly affect significant parameters of the disease. Lastly, the data from an Austrian group suggest that in a controlled trial, interferon can lead to significant differences in remission rates compared with hydroxyurea [at 1 year]. I would imagine this study will be published relatively soon. Those are the reasons that we believe interferon should have preference over other options in patients with PV.
我們也有證據表明干擾素會減少JAK2，這是PV的異常特徵。我們不太清楚這意味著什麼，因為我們可以看到骨髓減少的病患JAK2沒有顯著下降。無論如何，有證據顯示干擾素肯定會影響疾病。最後，來自奧地利的數據顯示出，在對照試驗中，與HU相比，干擾素在一年療程可顯著在分子緩解率上產生差異。我想這項研究將很快公佈。這些是我們認為干擾素在PV病患應優先於其他選擇的原因。
Where does ruxolitinib (Jakafi) play into this?
JAKAFi 扮演了甚麼角色？
We think ruxolitinib is a useful drug. As you know, it has been FDA approved for its efficacy in intermediate- and high-risk disease. Many doctors prescribe it for patients with earlier-stage myelofibrosis if a patient is symptomatic. Ruxolitinib is very helpful in these patients, but I don't believe it definitively changes the disease from the standpoint of bone marrow remission. It will make the spleen smaller in a significant number of patients with myelofibrosis at about 30% to 40%. At the end of 5 years, more than 60% are off this drug.
我們認為JAKAFi是有用的藥物。FDA已批准用在中高風險疾病中的治療。如果病患有症狀，許多醫生會為患有早期骨髓纖維化的病患開立處方。JAKAFi對這些病患非常有幫助，但我不認為它能改善骨髓緩解。它將使大量骨髓纖維化病患的脾臟變小約30％至40％。在5年療程後，超過60％的人停用這種藥物。
In my view, ruxolitinib retreats constitutional symptoms such as fatigue, weight loss, and bone pain. I believe it should be used in combination with interferon for the treatment of PV. There are studies from Weill Cornell Medicine about the early use of interferon for biologic abnormalities and the use of ruxolitinib for symptomatic improvement. There is also, perhaps, biologic synergy between these 2 agents.
以我的觀點，JAKAFi可以緩解疲勞、體重減輕和骨痛等症狀。我認為它應該與干擾素聯合用藥用於治療PV，目前也有干擾素早期應用於生物學異常以及使用合併JAKAFi進行症狀改善的研究。也許，這兩種藥物之間也存在生物學協同作用。
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JAKAFi 合併療法應用在MPN相關疾病的探討
Brandon Scalea
Published: Monday, May 06, 2019
發表日期：2019年5月6日
One of the biggest challenges in patients with myeloproliferative neoplasms (MPNs) is managing associated symptoms, but a myriad of ongoing studies evaluating ruxolitinib (Jakafi) in combination are hoping to address this, said Laura Michaelis, MD.
Laura Michaelis提到：骨髓增生性腫瘤（MPNs）病患面臨的最大挑戰之一是管理病患症狀，但無數正在進行的Jakafi合併療法的相關研究希望能夠解決這個問題。
Anemia is a common presenting symptom of myelofibrosis, one that can worsen when treatment with ruxolitinib is started, said Michaelis, an associate professor of the Medical College of Wisconsin. In an effort to overcome this issue, ruxolitinib is being combined with agents such as erythropoietin and danazol.
Michaelis提到：貧血是骨髓纖維化的常見症狀，當開始使用JAKAFi治療時可能會惡化。為了克服這個問題，JAKAFi與紅血球生成素(erythropoietin)和達爾諾等藥物合併用藥治療。
“Sometimes we need to combine ruxolitinib with erythroid-stimulating agents like that in order to prevent some of the anemia,” she explained.
她提到“有時我們需要將JAKAFi與紅血球生成刺激劑結合起來以防止貧血”。
The FDA-approved JAK inhibitor is also being studied in combination with hypomethylating agents, such as azacytidine, as well as PI3K inhibitors, such as TGR-1202. Beyond these combinations, newer-generation JAK inhibitors momelotinib and fedratinib are also progressing through the pipeline.
FDA批准用藥JAK抑制劑也與去甲基化藥物如VIDAZA以及PI3K抑制劑如TGR-1202合併用藥進行研究。除了這些組合，新一代JAK抑制劑momelotinib和fedratinib也正在進行相關研究。
All the while, the role of interferon in the treatment paradigm remains in place, she added.
她提到，干擾素一直持續用於治療。
“Where the MPN field in general is going, when we are looking at essential thrombocythemia and polycythemia vera (PV) in particular, there is growing information on how to use interferon in the frontline [setting],” said Michaelis. “The question of whether or not interferon should be used early on in the disease rather than when patients become high-risk is one that is being vigorously debated in the community.”
Michaelis提到：MPN領域包含ET和PV，關於使用干擾素治療用於一線用藥的討論越來越多。干擾素是否應該在疾病早期使用而不是在高風險時使用的問題是論壇中激烈爭論的問題。”
In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Michaelis highlighted the many ruxolitinib combinations under investigation and provided insight into the role of interferon in the space.
2019年OncLive®關於血液惡性腫瘤的一次採訪中，Michaelis提到了JAKAfi的合併用藥治療，並提供了干擾素在該領域中的作用。
OncLive: What recent developments have been made in MPNs?
目前MPN領域有那些進展
Michaelis: It's been 6 years since ruxolitinib has been FDA approved in myelofibrosis, but there are additional nuances in MPNs and PV. One of the things I spoke about [in my presentation] was how to deal with patients with myelofibrosis who also have anemia. Anemia is a common presenting symptom of myelofibrosis, and it can sometimes worsen once patients start treatment with ruxolitinib.
自從JAKAFi取得FDA批准用於MF用藥以來已有6年了，但在骨髓增生性腫瘤領域以及PV仍有差別。我演講中談到的一件事是如何處理也患有貧血的MF病患。貧血是MF的常見症狀，一旦病患使用JAKAFi治療，它有時會惡化。
I also spoke about some combination therapies developed to help overcome this. That includes ruxolitinib in combination with approved agents like erythropoietin, for example. We could also combine it with some of the older therapies, such as danazol. Some individuals who present with MPNs and anemia can see their hemoglobin dip and then it will come back up. One of the things we see is that if patients with myelofibrosis have a lot of hemolysis, we can see that when the spleen shrinks on the ruxolitinib, their anemia can improve despite the suppressive effects of the agent.
為了克服這個問題我們提到了一些合併療法。這包括JAKAFi與紅血球生成素的合併療法。我們還可以將它合併用在一些較老的藥物如達爾諾。一些罹患MPN相關疾病的病患和貧血的人可以看到他們的血紅蛋白下降然後恢復。其中如果MF病患有溶血反應，我們可以看到儘管有藥物的抑制作用，但JAKAFi可以改善貧血且讓脾臟縮小。
The second question is what to do with the patients who present with myelofibrosis with increased blasts. This is a more dire situation, and it's definitely one of those [factors] that speaks to a more accelerated phase of the disease. Another thing I discussed was how to safely combine ruxolitinib with hypomethylating agents. That [approach] is new and it's something that many of us have been doing off-label because we not only have evidence that it can increase the blast count, but it may also reverse the fibrosis.
第二個問題是如何治療MF伴隨芽細胞增加病症。這是更加可怕的情況，它肯定是那些與疾病加速惡化的原因之一。因此我們探討如何安全地將JAKAFi與去甲基化藥物合併用藥。這種嘗試式新型的且我們都用於仿單外用藥因為我們不僅有證據顯示出它可以增加芽細胞數量，而且還可以修復纖維化。
I also spoke to the studies conducted by The University of Texas MD Anderson Cancer Center with ruxolitinib plus azacitidine. Most of the trials being performed in MPNs, and myelofibrosis in particular, are looking at what we can combine ruxolitinib with. Many of those trials are geared toward improving patient symptoms, either the spleen hasn't shrunk enough on ruxolitinib alone or pervasive fatigue is occurring. A wide variety of agents [are being] combined with ruxolitinib [to counter that]. I focused on a PI3K-delta inhibitor and a BET inhibitor in my talk, both of which are being used to augment the effectiveness of ruxolitinib as well as potentially provide additional symptom management.
德州大學癌症中心用JAKAFi合併Azacitidine進行研究。大多數在骨髓增生性腫瘤中的試驗，特別是MF我們可以運用JAKAFi進行合併用藥治療。許多試驗都是為了改善病患的症狀，如單獨使用JAKAFi時脾臟沒有縮小，或是疲勞。各種藥物都正在嘗試與JAKAFi合併治療。我專注於PI3K-delta抑制劑和BET抑制劑的治療上，兩者都被有助於增加JAKAFi的療效，並可能提供額外的症狀管理。
There are also next-generation JAK inhibitors that are making it further along in clinical development; momelotinib is one of those. Fedratinib, which is now moving a little bit closer to registration, was initially put on hold due to some adverse events that are now being reexamined in the context of their clinical trials. We think that fedratinib may be available to patients before too long.
下一代JAK抑制劑正在下一階段臨床開發中，如momelotinib。目前正在接近藥證的Fedratinib先前因為一些不良事件而暫時被中止，這些不良反應現在正在臨床試驗中重新審查。我們認為Fedratinib可能在不久可以提供病患使用。
Could you expand on the data exploring the use of ruxolitinib in combination with hypomethylating agents?
能否說明JAKAFi與去甲基化藥物合併用藥的數據？
One of the most interesting things about the study out of The University of Texas MD Anderson Cancer Center was the way that the investigators devised their treatment plan. People came into the study on ruxolitinib already, or they were started on it. They had individuals stay on ruxolitinib and then the azacitidine rolled in later; it was cycle 4 where they started to use azacitidine. They also dose-reduced the azacitidine from 75 mg to 50 mg. That could be adjusted up later. In practice, when I've had somebody with high blast counts, I've often used it without that ramp up of [more than] 50 mg. However, it's great to see that actually be spelled out when you go to patients and say, “These are published data and we can do it like this.”
研究中最有趣的事情之一就是調查人員設計治療的方式。我們已經開始研究JAKAFi了。病患使用JAKAFi進行治療，接著注射Azacitidine。在治療第4週期時，他們開始使用Azacitidine。他們還將Azacitidine劑量從75毫克減少到50毫克，以便之後可以再調整。在實際上，當病患處於急性期時，我通常不會用超過50毫克。但我們樂於跟病患說明這些是已公佈的數據，我們可以這樣做。
We know that hypomethylating agents are good for low blast count acute myeloid leukemia, but they are not necessarily good for everyone. I'm feeling increasingly supported by the data in using that combination. There's a point where medicine moves from science to craft, but every time there are new data, you feel that you are on firmer ground in terms of that particular therapy. [I should note that] there was significant concern about cytopenia with this combination.
我們知道去甲基化藥物對於慢性期的急性骨髓性白血病病患是有益的，但它們並不一定對每個人都有好處。這種合併療法的數據越來越受到我的支持。在醫學治療的進展中，這些數據會讓你覺得你在這個特定的治療方法上更穩固。但我需要說明這種合併療法需擔憂對病患的血球數量減少。
What other ruxolitinib combinations are under investigation?
還有哪些JAKAFi的合併療法正在研究中？
There have been predominately phase I and some phase II results for using ruxolitinib in combination with PI3K inhibitors and with HDAC inhibitors, but none of these are close to registration. We've been involved in a study out of Vanderbilt University Medical Center that's combining ruxolitinib with TGR-1202, a PI3K-delta inhibitor. This has some extremely favorable and encouraging symptom responses that we found. TGR-1202 is being utilized in other hematologic malignancies, such as lymphoma. However, these [combinations] are still in the hypothesis-testing stage rather than the true move-to-registration stage.
JAKAFi合併PI3K抑制劑和HDAC抑制劑有臨床一期和二期成果，但這些都沒有接近登記。Vanderbilt大學醫學中心的一項研究，該研究將JAKAFi與PI3K-delta抑制劑TGR-1202合併用藥。我們發現一些令人興奮的成果。TGR-1202正用於其他血液系統惡性腫瘤，如淋巴瘤。然而，這些合併療法仍然處於假設驗證階段，尚未接近藥證申請。
How would you define the role of interferon today?
你如何定義目前的干擾素角色？
As you know, most of the randomized data for the past 3 decades in PV has utilized hydroxyurea as one of the primary arms. However, there is increasing use of interferon, especially in patients who are JAK2-positive. We have early hints that over time, patients' molecular mutation burden might decline with the use of interferon. One of the big landmarks in MPNs was the publication in the National Comprehensive Cancer Network guidelines of treatment recommendations for these diseases. They did indicate that interferon was an appropriate frontline choice for some individuals.
如您所知，PV過去30年的大多數隨機數據都使用HU作為主要對照組之一。然而，干擾素對於JAK2呈現陽性的病患治療上使用比例持續增加。隨著時間的推移，病患的分子突變負擔可能隨著干擾素的使用而下降。骨髓增生性腫瘤中的一個重要標竿是NCCN針對這些疾病的治療建議指南的出版物。他們明確表示干擾素是某些人適當的一線用藥選擇。
In my practice, I tend to use interferon in younger patients because it's a little bit better tolerated. I use it in individuals where fertility is a concern because it's less likely to cause significant concerns in either male or female patients. Also, if I'm contemplating treatment for decades, the skin toxicities for hydroxyurea can be a problem over time. I do prefer to start with interferon since it can be well tolerated, especially in pegylated form. A novel interferon- alpha has been introduced in Europe, and we hope that will be the kind of agent that American patients have access to in the future.
依照我的實際經驗，我傾向在年輕病患中使用干擾素，因為他們的耐受性稍好一些。我在懷孕的個體中會使用干擾素治療，因為它不太可能引起男性或女性病患的擔憂。此外，如果長期治療情況下，HU的皮膚毒性可能會是一個問題。我個人更傾向使用干擾素開始治療，因為它耐受度更佳，尤其是長效型干擾素。一種新型干擾素(藥華藥新一代干擾素P1101)已經在歐洲導入，我們希望美國病患未來也可以獲得使用。
Pegasys interferon shortage
長效型干擾素(羅氏Pegasys) 短缺
https://healthunlocked.com/mpnvoice/posts/140672434/pegasys-interferon-shortage?uid=c8bfda7f-c70a-4f22-a4bb-ade56c670522&utm_campaign=mpnvoice&utm_medium=email&utm_source=notification&utm_term=new-daily+digest
Spam1979：
Hi,
Had my monthly haematology check up the other day and my consultant advised that there is a manufacturing shortage of peg interferon at the moment so they couldn’t prescribe my normal 4 weeks supply. Has anyone else heard this or is it maybe just a Scotland thing?
I’ve to go back on Friday as they could only prescribe 1 week last time, and if they haven’t managed to source it yet I may need to move over to hydroxycarbamide until they can source more which worries me a bit. Has anyone else made this transition and what was your experience? I’m a 39 year old female with PV.
Hi, 我每個月進行血液檢查, 我的顧問提到目前長效型干擾素(羅氏Pegasys)短缺，所以他們無法正常開出四周療程的治療用藥。有沒有人聽過這個還是它只發生在蘇格蘭？我將在周五回去，因為他們只能開立一周處方，如果仍沒有辦法取得的話，我可能要轉到HU。有無其他人曾這樣轉變，而你們的經驗是什麼？我是一名39歲罹患PV的女性。
Cja1956：
I have PV but have never done interferon. I also have ET so I take hydroxyurea for the ET and jakafi for PV which works pretty well. Hydroxy stopped working on my platelets after eight years on it so That’s why my doctor put me on Jakafi which helps a lot. But I’m older than you and I’ve heard on this site that doctors treat us differently due to our ages.
Hope this helps.
我是真性紅血球增生症(PV)病患，但從未使用干擾素治療。我也同時也罹患血小板增生症(ET)，所以我用HU治療血小板增生症(ET)，而JAKAFi用於治療真性紅血球增生症(PV)，療效很好。八年後，HU對我的血小板增生症(ET)治療無效，因此醫生將Jakafi治療用於我身上，這對我有很大的幫助。我年紀比你大，我曾在這個網站上聽說過，醫生會根據我們的年齡採用不同的用藥建議。
希望這可以幫助妳。
MPort
19 hours ago
Hi, that's sounds worrying. But I wonder and HOPE if it is a supply problem. For the past year I haven't been given my full perscription. This has only been on 4 occasions and I get the next 4 months so I need about 12 injections. I get to pharmacy after 12 and they can only give me 1 or 2. I go back when they phone me and get the remainder. I always ask them why but they have no interest in giving a reason. I will bring it up at next appointment. Let's hope it is just a blip.
Mairead
這聽起來很令人擔憂。我也想知道供應是否是個問題。在過去的一年裡，我從未得到完整的處方。我只能注射4次，但我接下來的4個月大約需要12次注射。在12次注射後我去了藥局但他們只能給我1或2劑。當他們給我打電話的時候我才能回去拿剩餘的。我問他們為什麼，但他們都沒給出理由。我會在下次預約看診時提出來。
希望這只是偶發現象。
Jocko
19 hours ago
Hi,
I am on Peg and aspirin. I get prescription for Peg every 3 months. Peg is working really well for me and I do not want to go on HU. If that were to happen I think I would ask my consultant if I could stick to aspirin until Peg was available. It must take a while for the platelet count to rise back up so I guess it wouldn't be too bad for a few weeks.
I hope it works out for you whatever you decide.
Good luck
Hi，
我使用長效型干擾素(羅氏Pegasys)和阿斯匹靈治療。我每隔3個月取得長效型干擾素(羅氏Pegasys)處方一次。長效型干擾素(羅氏Pegasys)對我來說非常好，我不想繼續使用HU。如果發生這種情況，我想我會請教我的顧問，我是否可以堅持使用阿斯匹靈直到長效型干擾素(羅氏Pegasys)恢復供應。血小板數字要回升也需要一段時間，所以我想這幾週應該不會太糟糕。
我希望無論你決定什麼，上述資訊都對妳有幫助。
Susana7
18 hours ago
That’s really worrying... Pegasys availability is an ongoing source of concern for me in the current situation. If it were me, I would ask to take a short Pegasys break rather than transition to HU. I had no problems with my last Peg prescription in February, but am due in clinic in 2 weeks so will know more then. Ask your haemo if you can keep a couple of extra injections for situations such as this. Maybe they can source interferon from a different manufacturer or buy vials rather than pre-filled syringes, if there is more availability. Good luck and let us know how you get on. Susana x
這真的令人擔心，長效型干擾素(羅氏Pegasys)能否使用一直是我關注的焦點。如果是我，我會要求短暫停止使用長效型干擾素(羅氏Pegasys)，而不是轉換到HU。我在今年2月最近一次的長效型干擾素(羅氏Pegasys)處方並沒有問題，而我需要在2週內就診，到時會了解更多資訊。妳可以問你的血液科醫生是否可以針對這種情況進行一些額外的採購。也許他們可以從不同的製造商採購干擾素或購買小罐裝的而非預先填充的注射器。
祝你好運，讓我們知道妳後來如何處理。
蘇珊娜
SueWhelan
17 hours ago
The hospital pharmacy will only give me 4 weeks at a time even though I have a prescription for 3 months. I have to go back each time to collect. They only order it in the week I am due. Not sure why. If it is shortage or hospital policy?
I know there was a shortage of interferon a while ago as I was on that, couldn’t get it for a few days and the pharmacy had to source from another hospital.
I have been told that pegalated interferon will no longer be prescribed (ie not licensed) for MPNs, though those people already on it can continue. Also not sure of the reasons?
It is a little worrisome.
即使我的處方為3個月，醫院藥局也只會給我4個星期。我每次都要回去重新取得。他們只在我到期的那一周訂購。不知道這是短缺或醫院政策？我知道前一段時間長效型干擾素(羅氏Pegasys)短缺，因為我曾有幾天不能得到它，藥局不得不從另一家醫院採購。有人告訴我骨髓增生性腫瘤病患(MPNs)不再使用長效型干擾素(羅氏Pegasys)治療因為沒有取得藥證批准，但已經使用它的人可以繼續使用。我還不確定原因？
這有點令人擔憂。
swimswam
17 hours ago
I was told Pegasys wasn’t approved for ET, so I have to use the old fashioned Interferon, I suppose that could be an alternative if you can’t get Peg.
我被告知長效型干擾素(羅氏Pegasys)沒有被批准用於ET，所以我必須使用舊型干擾素，我想如果你不能取得長效型干擾素(羅氏Pegasys)，那可能是另一種選擇。
Anag
14 hours ago
Hi Spam, there are sometimes shortages. My husband’s meds were out for 9 months last year in Austria. Not funny. I always try to keep a 4 month stock at home. Just in case.
Hi, Spam, 有時會短缺。我丈夫在奧地利的藥局去年已經有9個月沒貨了。我總是試著把4個月的庫存留在家裡以防萬一。
Charlieapple2018
14 hours ago
I was only allowed 4 wks supply and had to return to the hospital to collect the 5th week between consultant meetings. I think the hospital only has a certain number in and has to order. I didn’t consider that there was a shortage, I thought it was just policy.
我只被允許一次取得4週的用量，所以不得不在第五周和顧問會議時回醫院取得。我認為醫院只有一定數量並且必須訂購。我並沒有考慮到短缺現象，我想這是政策。
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6.2Therapiemodalitäten
6.2 治療方式
6.2.1 Allgemeine Maßnahmen
6.2.1 一般措施
Gewichtsnormalisierung, regelmäßige Bewegung, Vermeiden von Exsikkose und langem Sitzen (ggf. Kompressionsstrümpfe, insbesondere bei Reisen), Reduktion von Risikofaktoren und effektive Behandlung kardiovaskulärer Erkrankungen, kein Nikotinkonsum.
標準體重，定期運動，避免外傷和長時間久坐（必要時選擇彈力襪，特別在旅行時），減少危險因素和有效治療心血管疾病，不使用尼古丁。
6.2.2Aderlass
6.2.2放血
Aderlässe sind die schnellste und einfachste Maßnahme zur Absenkung des Hämatokrit und der Beseitigung der Hyperviskosität. Empfohlen werden isovolämische Aderlässe von 500 ml (bei Beginn evtl. von 300 ml) je nach individueller Verträglichkeit ein- bis zweimal pro Woche, bis der Hämatokrit (geschlechtsunabhängig) unter 45% eingestellt ist [27]. Wie durch eine randomisierte Studie belegt wurde (CYTO-PV Studie), konnte durch eine stringente Einstellung des Hämatokrit unter 45% und eine Kontrolle der Leukozytenzahl eine signifikante Absenkung der Thromboembolierate erreicht werden. Damit verbunden war auch eine Reduktion der kardiovaskulären und durch andere größere thrombotische Ereignisse verursachten Mortalität [28, 29]. Die im Verlauf erforderliche Aderlassfrequenz ist den Hämatokrit-Werten individuell anzupassen. Gelegentliche Aderlässe können ergänzend zur zytoreduktiven Therapie erforderlich sein, um den Hämatokrit im gewünschten Bereich zu halten, falls eine Änderung der zytoreduktiven Therapie nicht möglich oder geboten erscheint.
Der immer eintretende Eisenmangel ist „erwünscht“ und wird nicht substituiert. In Ausnahmefällen, keinesfalls routinemäßig, kann bei symptomatischem Eisenmangel unter strenger Indikationsstellung und engmaschiger Laborkontrolle eine vorsichtige, orale Eisensubstitution durchgeführt werden. Der zunehmende Eisenmangel ist nicht selten von einem Thrombozytenanstieg begleitet.
Als Alternative zu Aderlässen kann die Erythrozytapherese eingesetzt werden. Ihre Durchführung ist nur an dafür ausgestatteten Einrichtungen möglich.
放血是降低血容比和消除血液高度黏稠最快速且最簡單的方法。根據個體耐受性，建議每週一次或兩次放血500毫升（初期可能為300毫升），直到血容比（與性別無關）低於45％。
如臨床隨機研究（CYTO-PV研究）所證實的那樣，通過嚴控血容比低於45％並控制白血球數量，可以顯著降低血栓發生率，而這與心血管死亡率和其他主要血栓形成事件的減少有關。
放血頻率須根據個體調整。如果細胞減滅治療無法有所保證，則除了細胞減滅治療外，可能還需要偶爾放血將血容比維持在所需範圍內。
永遠存在的缺鐵是無法被替代。在特殊情況下，絕不是常規，在嚴格適應症和嚴密的實驗室控制下，可以通過症狀性鐵缺乏進行仔細的口服鐵替代。增加缺鐵通常伴隨著血小板的增加。
病患會經常性的缺鐵，在非常規狀態下以及嚴格控制下，可以通過缺鐵症狀進行口服鐵替代。缺鐵通常伴隨著血小板的增加。放血的替代方案，可以使用紅血球血液分離術。只有在為此目的有相對應的設施中才能實行。
6.2.3Thrombozytenaggregationshemmer
6.2.3抗凝血藥物
Niedrig dosierte Azetylsalizylsäure (‚low dose Aspirin‘, ASS) 100 mg/Tag, ist bei Patienten ohne Kontraindikationen gegen das Medikament (Ulkusanamnese, vorausgegangene Blutungskomplikationen u.a.) zur Primärprophylaxe von Thrombosen indiziert, unabhängig davon ob gleichzeitig eine zytoreduktive Therapie durchgeführt wird [4]. Periphere und zerebrale Mikrozirkulationsstörungen sind eine symptombezogene Indikation für ASS [30].
Bei einer Thrombozytenzahl über 1 Million/µl sollte ASS wegen des erhöhten Blutungsrisikos erst nach einer medikamentösen Absenkung der Thrombozytenzahl (wünschenswert unter 600 000/µl) verabreicht werden. Manche Institutionen schließen die Höhe der von Willebrand Faktor-Aktivität in die Entscheidung bzgl. des Therapiebeginns von ASS ein.
Zum Einsatz anderer Thrombozytenaggregationshemmer (z.B. ADP-Antagonisten) gibt es positive Erfahrungen an individuellen Fällen, aber keine gesicherten Daten.
無論是否進行了細胞減滅治療，低劑量阿斯匹靈，100毫克/天）適用於對該藥物無禁忌的病患（潰瘍病史，先前出血併發症）。同時腦部、胃粘膜出血是乙醯水楊酸(ASA)的症狀相關特徵。
當血小板數量超過1百萬/ul時，乙醯水楊酸(ASA)應僅在血小板數量降低後降低藥物劑量（最好低於600,000 /μl），因為出血風險增加。一些機構在關於乙醯水楊酸(ASA)治療開始前會參考vWF activity的基準。其他抗血小板藥物（例如，ADP抗凝血藥物）對個體病例具有很好的效果，但沒有可靠數據支持。
6.2.4Zytoreduktive Therapie
6.2.4 細胞減滅療法
Bereits stattgehabte Thromboembolien und höheres Lebensalter (über 60 bzw. 65 Jahre) sind gesicherte Risikofaktoren für das Auftreten von Gefäßkomplikationen. Jeder dieser Parameter stellt primär eine Indikation zur Einleitung einer zytoreduktiven Therapie dar (Hochrisiko-Patienten).
Auch bei Niedrig-Risiko-Patienten können sich im Krankheitsverlauf Gründe ergeben, eine zytoreduktive Therapie zu beginnen oder diese in Betracht zu ziehen. Diese umfassen insbesondere die Progression der Myeloproliferation, ein steigendes Risiko für Thromboembolien und Blutungen sowie anderweitig nicht kontrollierbare belastende klinische Symptome [26, 27, 31]. Mit Ausnahme von neu aufgetretenen Thrombosen stellen die im Kapitel 6.2.4.1 dargestellten Parameter jedoch keine zwingende Indikation für die Einleitung einer zytoreduktiven Therapie dar. Auch hinsichtlich der Zeichen der Progression der Myeloproliferation gibt es keine exakten Schwellenwerte für den Beginn einer zytoreduktiven Therapie, sodass hier auch die individuelle Proliferationskinetik zu berücksichtigen ist. Die in der Praxis empfohlenen Parameter sind nachfolgend zusammengefasst [27].
曾有血栓栓塞病史和年齡較大（超過60或65歲）的病患是有血管併發症的高危險群。這些高風險病患主要為細胞減滅治療族群。
即使在低風險病者，也可能有原因考慮細胞減滅治療，包括骨髓增生性疾病的惡化、血栓栓塞和出血的風險增加以及其他不可控的臨床症狀。然而，除了新發生的血栓外，第6.2.4.1章中的參數並不是開始細胞減滅治療的強制性要件。沒有明確採用細胞減滅療法的方式，必須考慮個體增殖動力學。實際中推薦的參數總結如下。
6.2.4.1Parameter zur Einleitung einer zytoreduktiven Therapie
6.2.4.1 使用細胞減滅療法的參數
Zeichen der Progression der Myeloproliferation
• Zunahme der Milzgröße oder symptomatische Splenomegalie
• Thrombozytenanstieg auf > 1 000 000/µl
• Leukozytenanstieg auf > 10 000/µl bis > 15 000/µl oder höher
• Häufige bzw. zunehmende Aderlassfrequenz
骨髓增生的惡化跡象
• 脾臟變大或症狀性脾腫大
• 血小板增加至> 1000000 /μl
• 白血球增加至> 10 000 /μl 至 > 15 000 /μl或更高
• 頻率增加
Gesteigertes/zunehmendes Risiko für Thromboembolien und Blutung und nicht kontrollierbare belastende klinische Symptome
• Im Verlauf neu aufgetretene Thromboembolien
• Hämorrhagische Komplikationen
• Mikrozirkulationsstörungen trotz ASS
• Eingeschränkte Durchführbarkeit von Aderlässen
• Symptomatischer Eisenmangel, der eine Fortführung der Aderlässe nicht erlaubt
• Unkontrollierter Hämatokritanstieg, falls Eisensubstitution unumgänglich ist
• Schwere bzw. den Patienten belastende krankheitsbedingte Symptome
血栓出血風險的增加以及其他不可控的臨床症狀
• 新發生的血栓
• 出血性併發症
• 儘管使用乙醯水楊酸(ASA)仍有微血管循環障礙
• 放血可行性不佳
• 持續缺鐵，不允許放血
• 如果缺鐵不可避免，血容比不受控地增加
• 病患嚴重的疾病相關症狀
6.2.4.2Zytoreduktive Therapieformen
6.2.4.2 細胞減滅療法
6.2.4.2.1Primärtherapie
6.2.4.2.1 主要治療方式
Die von Seiten der ELN-Expertengruppe empfohlene zytoreduktive Primärtherapie ist Hydroxyurea (Hydroxycarbamid) oder Interferon alpha (siehe Abbildung 1) [27]. Die (insbesondere anfänglich) ggf. notwendige Fortführung der Aderlasstherapie ist von den individuellen Blutwerten abhängig zu machen.
歐洲白血球網絡ELN主要推薦細胞減滅原始療法是HU或干擾素。是否需要持續放血取決於個體血液值。
Hydroxyurea (Anfangsdosis: 15-20 mg/kg KG/Tag). Eine individuelle Anpassung an die Blutwerte ist vorzunehmen. Im Rahmen des European LeukemiaNET wurden Kriterien zur Bewertung des Therapieansprechens auf zytoreduktive Therapie sowie von Resistenz und Intoleranz von Hydroxyurea erarbeitet (siehe Tabelle 7). Diese stellen Konsensusempfehlungen dar und sollen Hilfestellung bei der Bewertung des Therapieansprechens und bei eventuell erforderlichem Therapiewechsel geben [32, 33].
HU（起始劑量：15-20mg / kg體重/天）。需針對血液值進行個別調整劑量。歐洲白血病網站制定了評估細胞減滅治療反應的標準，以及HU的有效性和耐受性。這些代表為共識，主要在幫助評估對治療的反應和可能的治療變化。
Interferon alpha (IFN): IFN wird von der ELN-Expertengruppe für die Primärtherapie der PV ohne definiertes Alterslimit alternativ zu Hydroxyurea empfohlen [27]. Eine besondere Zielgruppe für IFN sind jüngere Patienten mit Kinderwunsch. Die herkömmliche Form von IFN (Anfangsdosis: 3 x 3 Mio. IE/Woche s.c.) wurde weitgehend von der pegylierten Form abgelöst. Die Anpassung der IFN-Dosis erfolgt nach Blutbild und Verträglichkeit [34]. Bisher im Handel verfügbares pegyliertes Interferon wird nur einmal wöchentlich verabreicht (IFN alfa 2a, Pegasys®, durchschnittliche Dosierung 90µg pro Woche) Hauptproblem von IFN ist die oft eingeschränkte Verträglichkeit, die nicht selten zum Therapieabbruch führt [34, 35]. Eine neue, bisher nur in Studien eingesetzte Form des pegylierten IFN (Ropeginterferon alfa-2b) mit längerer Wirkdauer erlaubt eine Applikation in 14-tägigem Abstand [36, 37]. Die Dreijahresdaten der randomisierten Zulassungsstudie bei unbehandelten oder mit Hydroxyurea vorbehandelten Patienten zeigten eine signifikante Überlegenheit von Ropeginterferon gegenüber Hydroxyurea oder bester verfügbarer Therapie (BAT) hinsichtlich der Rate an kompletter hämatologischer Remission sowie der Reduktion der Allel-Last. Ropeginterferon alfa-2b ist das derzeit einzige für die Therapie der PV zugelassene Interferon-Präparat (Zulassung in der EU im Februar 2019, siehe Anlage Zulassungsstatus).
干擾素α（IFN）：ELN專家小組建議將干擾素用來取作HU，作為PV的主要治療方式，這種治療沒有明顯的年齡限制。干擾素的特殊目標群體是想要懷孕的年輕病患。一般干擾素大部分已被長效型干擾素形式取代。干擾素劑量的調整基於紅血球數量和耐受性。
目前被批准的長效型干擾素每週僅施打一次（羅式Pegasys，平均劑量每週90μg）。干擾素的主要問題是通常耐受度不佳，這常導致病患中斷治療。
一種新一代的長效型干擾素P1101（ropeginterferon alfa-2b）具有較長的作用持續時間，僅用於研究，允許每14天的施打一次。
尚未治療的病患或預先使用HU治療的病患, 三年期臨床隨機試驗數據顯示，就完全血液學反應和等位基因負荷減少而言，P1101相較於HU或最佳治療方式（BAT）具有顯著優勢。
新一代的長效型干擾素P1101（ropeginterferon alfa-2b）是目前唯一批准用於治療PV的干擾素產品（2019年2月獲得歐盟批准）。
Tabelle 7: ELN-Definition der Resistenz oder Intoleranz gegenüber Hydroxyurea (HU) bei PV [32]
表7：HU在PV適應症中的無效或不耐受的ELN定義
# Aderlassbedürftigkeit nach 3-monatiger Therapie mit mindestens 2g HU/Tag, um den Hämatokrit unter 45% zu halten oder
在每天 2g的 HU治療3個月後，仍須要放血才能使血細胞比容保持在45％以下
# Unkontrollierte Myeloproliferation (d.h. Thrombozyten >400 000/µl oder Leukozyten >10 000/µl) nach 3 Monaten Therapie mit mindestens 2g HU/Tag oder
在每天 2g的 HU治療3個月後仍有不受控制的骨髓增生症狀（血小板> 400,000 /μl或白血球> 10,000 /μl）
# Milzgrößenreduktion unter 50% bei massiver1 Splenomegalie (Beurteilung durch Palpation) oder unvollständiges Verschwinden von durch die Splenomegalie bedingten Symptomen nach 3-monatiger Therapie mit mindestens 2g HU/Tag oder
在每天 2g的 HU治療3個月後，脾腫大縮小程度小於50%或治療3個月後脾腫大相關症狀沒有完全消失
# Absolute Neutrophilenzahl <1 000/µl oder Thrombozytenzahl <100 000/µl oder Hämoglobin <10g/dl mit der niedrigsten Dosis von HU, die erforderlich ist, um ein komplettes2 oder partielles3 klinisch-hämatologisches Ansprechen zu erzielen oder
用最低劑量的HU後，嗜中性白血球數量<1000 /μl或 血小板數量<100,000 /μl或 血紅蛋白<10克/ dl
# Ulcera an den Beinen oder andere inakzeptable HU-bedingte nicht-hämatologische Toxizitäten, wie andere Manifestationen an Haut oder Schleimhäuten, gastrointestinale Symptome, Pneumonitis oder Fieber unabhängig von der Dosierung von HU.
無論HU的劑量如何，腿部潰瘍或其他不可接受的HU相關的非血液學毒性，如其他皮膚或粘膜表現、腸胃道症狀，肺炎或發熱。
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