השתלת תאי גזע לעומת תרופות לטרשת נפוצה: מה שחולים צריכים לדעת

תוכן עניינים

• מבוא: הבנת אפשרויות הטיפול
• עיצוב המחקר ושיטות
• מאפייני החולים
• ממצאים עיקריים: השוואות טיפוליות
• מידע בטיחותי
• השלכות קליניות עבור חולים
• מגבלות המחקר
• המלצות לחולים
• מידע מקור

מבוא: הבנת אפשרויות הטיפול

השתלת תאי גזע המטופויאטיים עצמית (AHSCT) היא גישת טיפולית חזקה לטרשת נפוצה פעילה מאוד הכרוכה בשימוש בתאי הגזע של החולה עצמו לאתחול מחדש של מערכת החיסון. פרוצדורה אינטנסיבית זו מתחילה בכימותרפיה לדיכוי מערכת החיסון, ולאחריה השתלה של תאי גזע שנאספו מראש לבניית מערכת חיסון חדשה שאינה תוקפת את מערכת העצבים.

הטיפול כרוך בסיכונים משמעותיים, כולל שיעור תמותה הקשור לטיפול של 0.3% עד 2%, אם כי סיכון זה ירד בשנים האחרונות בשל בחירת חולים טובה יותר וניסיון מצטבר של מרכזים. החוקרים תכננו מחקר זה כדי להשוות AHSCT מול שלוש תרופות מקובלות לטרשת נפוצה: פינגולימוד (טיפול בעל יעילות בינונית), ונטליזומב ואוקרליזומב (שתיהן טיפולים בעלי יעילות גבוהה).

הבנת אופן ההשוואה בין AHSCT לתרופות חזקות אלה היא קריטית עבור חולים ורופאים המקבלים החלטות טיפוליות עבור טרשת נפוצה פעילה מאוד מסוג התקפי-הפוגתי. מחקר זה מייצג אחת ההשוואות המקיפות ביותר עד כה, הכוללת כמעט 5,000 חולים ממרכזים מומחים ברחבי העולם.

עיצוב המחקר ושיטות

מחקר תצפיתי זה חיקה ניסויים קליניים על ידי השוואת AHSCT מול שלוש התרופות באמצעות שיטות סטטיסטיות מתוחכמות להבטחת השוואות הוגנות. החוקרים אספו נתונים ממאי 2006 עד דצמבר 2021 משישה מרכזים מומחים לטרשת נפוצה עם תוכניות AHSCT ו-94 מרכזים ב-27 מדינות המשתתפים ב-MSBase - הרישום הבינלאומי לטרשת נפוצה.

המחקר כלל 4,915 חולים עם טרשת נפוצה התקפית-הפוגתית שקיבלו AHSCT (167 חולים), פינגולימוד (2,558 חולים), נטליזומב (1,490 חולים), או אוקרליזומב (700 חולים). לכל החולים היה מעקב של לפחות שנתיים עם הערכות נכות מרובות. החוקרים השתמשו בהתאמת ניקוד נטייה, טכניקה סטטיסטית המסייעת להבטיח שהקבוצות המושוות דומות במאפייניהן הקליניים, מה שהופך את ההשוואות לתקפות יותר.

פרוצדורת ה-AHSCT עקבה אחר פרוטוקולים ספציפיים בכל מרכז. חולים קיבלו בדרך כלל כימותרפיה בציקלופוספמיד (2-4.5 גרם/מ"ר) עם גורם גרנולוציט-מושבת מגרה (G-CSF) לגיוס תאי גזע, אשר נאספו והוקפאו. כשליש מהחולים עברו טיהור תאי גזע באמצעות סלקציית CD34. משטרי התניית ההשתלה כללו:

• פרוטוקול BEAM (קרמוסטין, אטופוסיד, ציטרבין ומלפאלן)
• בוסולפן עם ציקלופוספמיד
• ציקלופוספמיד עם גלובולין אנטי-תימוציט

חולים בקבוצות התרופות קיבלו מינון סטנדרטי: פינגולימוד (0.5 מ"ג יומי דרך הפה), אוקרליזומב (600 מ"ג תוך ורידי כל 6 חודשים), או נטליזומב (300 מיקרוגרם תוך ורידי כל 4 שבועות). החוקרים ניתחו תוצאות כולל שיעורי התקפים שנתיים, חופש מהתקפים, ושינויים בנכות שנמדדו בסולם המצב הנכות המורחב (EDSS).

מאפייני החולים

לפני התאמה, חולי AHSCT נטו להיות צעירים יותר ולסבול מנכות גדולה יותר מאלה בקבוצות התרופות. לאחר התאמה סטטיסטית, הקבוצות היו מאוזנות היטב עם מאפיינים דומים:

הקבוצות המושוות כללו:

• AHSCT לעומת פינגולימוד: 144 חולי AHSCT לעומת 769 חולי פינגולימוד
• AHSCT לעומת נטליזומב: 146 חולי AHSCT לעומת 730 חולי נטליזומב
• AHSCT לעומת אוקרליזומב: 110 חולי AHSCT לעומת 343 חולי אוקרליזומב

בכל הקבוצות, נשים ייצגו 65-70% מהחולים. הגיל הממוצע נע בין 35.3 ל-37.1 שנים, משך המחלה בין 7.9 ל-8.7 שנים, וציוני EDSS בין 3.5 ל-3.9 (נכות בינונית). החולים חוו 0.77-0.86 התקפים בשנה שלפני הטיפול, מה שמעיד על מחלה פעילה מאוד.

בין חולי AHSCT, עוצמת ההתניה השתנתה: 26% קיבלו עוצמה גבוהה, 29% מיאלואבלציה בעוצמה בינונית, 38% לימפואבלציה בעוצמה בינונית, ו-7% פרוטוקולים בעוצמה נמוכה עד בינונית.

ממצאים עיקריים: השוואות טיפוליות

המחקר חשף הבדלים חשובים ביעילות בין AHSCT לשלוש התרופות:

AHSCT לעומת פינגולימוד (5 שנות מעקב)

AHSCT הדגימה יעילות עדיפה משמעותית בהשוואה לפינגולימוד. שיעור ההתקפים השנתי היה נמוך משמעותית עם AHSCT: 0.09 (סטיית תקן 0.30) לעומת 0.20 (סטיית תקן 0.44) עם פינגולימוד. זה מייצג ירידה של 55% בשיעור ההתקפים שהייתה מובהקת סטטיסטית (P < 0.001).

היחס הסכני (hazard ratio) עבור התקפים היה 0.26 (רווח בר-סמך 95%, 0.18-0.36), כלומר לחולי AHSCT היה סיכון נמוך ב-74% לחוות התקפים. בעוד ששני הטיפולים הראו סיכון דומה להחמרת נכות (יחס סכני 1.70; רווח בר-סמך 95%, 0.91-3.17), AHSCT היה קשור בסיכוי גבוה משמעותית לשיפור נכות (יחס סכני 2.70; רווח בר-סמך 95%, 1.71-4.26) - כמעט פי שלושה יותר מאשר עם פינגולימוד.

AHSCT לעומת נטליזומב (5 שנות מעקב)

AHSCT הראה עליונות שולית על פני נטליזומב. שיעור ההתקפים השנתי היה נמוך במעט עם AHSCT: 0.08 (סטיית תקן 0.31) לעומת 0.10 (סטיית תקן 0.34) עם נטליזומב, הבדל שהיה מובהק סטטיסטית (P = 0.03).

היחס הסכני עבור התקפים היה 0.51 (רווח בר-סמך 95%, 0.34-0.74), המצביע על סיכון נמוך ב-49% להתקפים עם AHSCT. הסיכון להחמרת נכות היה דומה בין הטיפולים (יחס סכני 1.06; רווח בר-סמך 95%, 0.54-2.09), אך AHSCT שוב הראה תוצאות שיפור נכות טובות יותר משמעותית (יחס סכני 2.68; רווח בר-סמך 95%, 1.72-4.18).

AHSCT לעומת אוקרליזומב (3 שנות מעקב)

עם תקופת המעקב הקצרה יותר הזמינה, AHSCT ואוקרליזומב הראו יעילות דומה באופן מרשים. שיעורי ההתקפים השנתיים היו דומים: 0.09 (סטיית תקן 0.34) עבור AHSCT לעומת 0.06 (סטיית תקן 0.32) עבור אוקרליזומב, ללא הבדל סטטיסטי (P = 0.86).

היחס הסכני עבור התקפים היה 0.75 (רווח בר-סמך 95%, 0.36-1.57), המצביע על אין הבדל משמעותי בסיכון להתקפים. שני הטיפולים הראו תוצאות דומות עבור החמרת נכות (יחס סכני 1.77; רווח בר-סמך 95%, 0.61-5.08) ושיפור נכות (יחס סכני 1.37; רווח בר-סמך 95%, 0.66-2.82).

מידע בטיחותי

המחקר סיפק נתוני בטיחות מפורטים עבור חולי AHSCT. מבין 159 חולי AHSCT מותאמים, החוקרים דיווחו על הסיבוכים הבאים:

• נויטרופניה חום במהלך גיוס: 23.3% (37 חולים)
• מחלת נסיוב: 11.3% (18 חולים)
• אשפוז ביחידה לטיפול נמרץ: 8.8% (14 חולים)

לאחר שחרור בעקבות AHSCT, אירעו 82 אירועים חריגים חמורים ב-58 חולים. רוב אלה (59.8%) היו זיהומים, עם זיהומים נגיפיים המייצגים 41.5% מכלל האירועים החריגים החמורים.

באופן טרגי, אירע מוות אחד הקשור לטיפול (שיעור תמותה 0.6%) עקב מחלה ונו-אוקלוסיבית של הכבד לאחר התניית בוסולפן. שיעור תמותה זה נמצא בטווח הצפוי לפרוצדורות AHSCT ומדגיש את הסיכונים החמורים הקשורים לטיפול זה.

השלכות קליניות עבור חולים

מחקר זה מספק תובנות יקרות ערך עבור חולים השוקלים אפשרויות טיפול עבור טרשת נפוצה פעילה מאוד מסוג התקפי-הפוגתי. הממצאים מצביעים על כך ש-AHSCT מציעה יתרונות משמעותיים להפחתת פעילות התקפים בהשוואה לפינגולימוד ונטליזומב, עם יעילות דומה לאוקרליזומב לאורך תקופת המעקב הזמינה.

אולי החשוב ביותר, AHSCT הדגימה שיעור גבוה משמעותית של שיפור נכות בהשוואה הן לפינגולימוד והן לנטליזומב. כ-30% מחולי AHSCT חוו החלמה מדידה מנכות, במיוחד במהלך השנה הראשונה לאחר הטיפול. ממצא זה בולט במיוחד מכיוון שנטליזומב עצמו ידוע בשיעור גבוה יחסית (25%) של שיפור נכות shortly after treatment initiation.

התוצאות הדומות בין AHSCT לאוקרליזומב בולטות במיוחד, מכיוון שאוקרליזומב נחשבת לאחת התרופות היעילות ביותר הזמינות כיום לטרשת נפוצה. עם זאת, תקופת המעקב הקצרה יותר להשוואות אוקרליזומב (3 שנים לעומת 5 שנים עבור התרופות האחרות) משמעה שנדרשות השוואות ארוכות טווח.

מגבלות המחקר

בעוד שמחקר זה מספק מידע יקר ערך, חולים צריכים להבין את מגבלותיו. כמחקר תצפיתי ולא ניסוי קליני אקראי מבוקר, עשויים להיות גורמים לא מדודים שהשפיעו על התוצאות למרות התאמה סטטיסטית מתוחכמת.

תקופת המעקב עבור אוקרליזומב הייתה קצרה יותר (3 שנים) מאשר עבור התרופות האחרות (5 שנים), מה שמגביל השוואות ישירות. אוקרליזומב היא תרופה חדשה יותר, כך שנתונים ארוכי טווח פשוט לא היו זמינים עדיין.

החלטות טיפוליות התקבלו על ידי רופאים וחולים ולא בהקצאה אקראית, מה שיכול להכניס הטיית בחירה. חולים הבוחרים ב-AHSCT עשויים להיות בעלי מאפיינים שונים או חומרת מחלה שונים מאלה הבוחרים בתרופות, גם לאחר התאמות סטטיסטיות.

המחקר לא כלל תוצאות הדמיית תהודה מגנטית (MRI), המספקות מידע חשוב על פעילות מחלה שאינה תמיד ניכרת באמצעים קליניים בלבד.

המלצות לחולים

על בסיס מחקר זה, חולים עם טרשת נפוצה פעילה מאוד מסוג התקפי-הפוגתי צריכים לשקול את הדברים הבאים:

1. דונו בכל האפשרויות עם הנוירולוג שלכם, כולל AHSCT ותרופות בעלות יעילות גבוהה כמו נטליזומב ואוקרליזומב
2. שקלו AHSCT אם יש לכם מחלה פעילה מאוד שלא הגיבה באופן מספק לטיפולים אחרים
3. הבינו את הסיכונים - AHSCT כרוכה בסיכונים קצרי טווח משמעותיים כולל זיהום ותמותה נדירה (0.6% במחקר זה)
4. שקלו תזמון - יתרונות שיפור הנכות של AHSCT היו בולטים ביותר בשנה הראשונה לאחר הטיפול
5. פנו למרכזים מומחים - AHSCT צריכה להתבצע רק במרכזים מנוסים עם צוותים רב-מקצועיים
6. קחו בחשבון את משך המעקב - בעוד ש-AHSCT הראתה יעילות דומה לאוקרליזומב, אנו זקוקים לנתונים ארוכי טווח להשוואה מלאה

מחקר זה מספק עדות חזקה לכך ש-AHSCT יכולה להיות אפשרות טיפולית יעילה מאוד עבור חולים מתאימים עם טרשת נפוצה פעילה מאוד מסוג התקפי-הפוגתי. ההחלטה בין AHSCT לתרופות בעלות יעילות גבוהה צריכה להתקבל through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through through 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כתב עת: JAMA Neurology

תאריך פרסום: 15 במאי 2023

כרך וגיליון: כרך 80, גיליון 7

עמודים: 702-713

DOI: 10.1001/jamaneurol.2023.1184

מאמר ידידותי זה למטופל מבוסס על מחקר שעבר ביקורת עמיתים ופורסם במקור ב-JAMA Neurology. הוא שומר על כל הממצאים המשמעותיים, נקודות הנתונים והמסקנות מהמחקר המקורי, תוך הפיכת המידע לנגיש עבור מטופלים ומטפלים.