index.qmd

---
title: "ASH 2025 B-Cell Lymphoma Updates"
subtitle: "MCL, MZL, and Waldenström Macroglobulinemia"
author: "林協霆"
institute: "和信治癌中心腫瘤內科部"
date: "December 2025"
execute:
  echo: false
  warning: false
  message: false
---

```{r setup}
library(ggplot2)
library(dplyr)
library(tidyr)
library(scales)

# Color palette - Medical/Scientific theme
colors <- list(
  primary = "#1A5276",
  secondary = "#2E86AB",
  accent = "#E74C3C",
  success = "#27AE60",
  warning = "#F39C12",
  dark = "#2C3E50",
  light = "#ECF0F1"
)

# Custom theme for plots
theme_ash <- function() {
  theme_minimal() +
    theme(
      plot.title = element_text(size = 18, face = "bold", color = colors$dark),
      plot.subtitle = element_text(size = 14, color = colors$secondary),
      axis.title = element_text(size = 12, face = "bold"),
      axis.text = element_text(size = 11),
      legend.title = element_text(size = 11, face = "bold"),
      legend.text = element_text(size = 10),
      panel.grid.minor = element_blank(),
      panel.grid.major.x = element_blank()
    )
}
```

# Mantle Cell Lymphoma (MCL) {data-stack-name="MCL"}

Novel CAR-T, BTKi Combinations, and Targeted Therapies

::: {.notes}
接下來我們進入套細胞淋巴瘤（MCL）的部分。

ASH 2025 在 MCL 領域有幾個重大突破：
1. GLPG5101 展示了新一代 CAR-T 的即時製造技術
2. ECHO 試驗確立了 acalabrutinib 加化療的一線地位
3. BOVen 方案為 TP53 突變患者帶來前所未有的療效
4. Pirtobrutinib 作為非共價 BTKi 獲得完整批准

這些進展反映了 MCL 治療從傳統化療向精準醫學的典範轉移。
:::

## GLPG5101: Next-gen CAR-T with 7-day manufacturing {.smaller}

:::: {.columns}

::: {.column width="45%"}
### ATALANTA-1 trial (NCT06561425)

**Background**

- Fresh CAR-T with decentralized manufacturing ^[FDA RMAT designation August 2025]
- Eliminates 3-6 week traditional manufacturing delay

**Method**

- N=24 MCL patients, single fixed IV dose
- **7-day median vein-to-vein time** (96% achieved)

**Results**

- **ORR: 100%** (versus 85-91% brexu-cel historical)
- **CRR: 96%** (versus 59-82% brexu-cel)
- MRD negative: 90% in evaluable patients
- CAR-T persistence: Up to 21 months

::: aside
Galapagos NV. ATALANTA-1 trial results. ASH 2025 Abstract #662.
:::
:::

::: {.column width="55%"}
```{r glpg5101-orr}
df <- data.frame(
  Treatment = factor(
    c("GLPG5101", "Brexu-cel\n(Historical)"),
    levels = c("GLPG5101", "Brexu-cel\n(Historical)")
  ),
  ORR = c(100, 88),
  CRR = c(96, 70)
)

df_long <- df %>%
  pivot_longer(cols = c(ORR, CRR), names_to = "Response", values_to = "Rate")

ggplot(df_long, aes(x = Treatment, y = Rate, fill = Response)) +
  geom_bar(stat = "identity", position = "dodge", width = 0.7) +
  geom_text(
    aes(label = paste0(Rate, "%")),
    position = position_dodge(width = 0.7),
    vjust = -0.5,
    size = 5,
    fontface = "bold"
  ) +
  scale_fill_manual(
    values = c("ORR" = colors$secondary, "CRR" = colors$success)
  ) +
  scale_y_continuous(limits = c(0, 110), breaks = seq(0, 100, 25)) +
  labs(
    title = "Response Rates: GLPG5101 vs Historical",
    y = "Response Rate (%)",
    x = ""
  ) +
  theme_ash() +
  theme(legend.position = "top")
```
:::

:::::

::: {.notes}
GLPG5101 的關鍵優勢在於其「即時製造」技術：

**製造時間縮短**：傳統 CAR-T 需要 3-6 週，GLPG5101 僅需 7 天
- 這消除了等待期間疾病惡化的風險
- 不需要過渡性化療（bridging therapy）

**療效數據令人印象深刻**：
- 100% 總緩解率遠超 brexu-cel 的歷史數據（85-91%）
- 96% 完全緩解率
- 90% 達到 MRD 陰性

**機制優勢**：新鮮製造保留了幹細胞樣早期記憶 T 細胞表型，這與持久緩解相關。CAR-T 細胞在輸注後可持續存在長達 21 個月。
:::

## GLPG5101: Safety Profile & Regulatory Status {.smaller}

:::: {.columns}

::: {.column width="50%"}
### Safety Profile

| Adverse Event | GLPG5101 | Brexu-cel |
|---------------|----------|-----------|
| Grade ≥3 CRS | 0-4% | 8-15% |
| Severe Neurotoxicity | 4% | 31-32% |
| Bridging Chemo | Not required | Required |

- Most common AEs: hematologic (manageable)
- DOR and PFS: 83% at 9 months
- No treatment-related deaths
:::

::: {.column width="50%"}
### Regulatory Status

- **FDA RMAT Designation:** August 2025
- Technology proof-of-concept established

### ⚠️ Commercial Uncertainty

- **Galapagos announced cell therapy wind-down:** October 2025
- 365 employees affected across 5 facilities
- No viable acquisition offers received
- Future development uncertain despite promising data
:::

:::::

::: {.notes}
關於 GLPG5101 的安全性與法規狀態：

**安全性優勢**：
- Grade ≥3 CRS 僅 0-4%（相比 brexu-cel 的 8-15%）
- 嚴重神經毒性僅 4%（相比歷史上的 31-32%）
- 不需要過渡性化療，減少額外毒性暴露

**重要警告**：2025 年 10 月，Galapagos 宣布結束細胞療法業務，影響 365 名員工。儘管技術獲得 FDA RMAT 認定，但商業前景不確定。這提醒我們：優秀的臨床數據不一定等於商業成功。
:::

## Expert Opinions on GLPG5101 {.smaller}

:::: {.columns}

::: {.column width="50%"}
### Clinical Investigators

- **Marie Jose Kersten, MD, PhD** from Amsterdam UMC said:
  - **"We saw deep responses including patients with high-risk features... a 96% CR with duration of response at 9 months of 83%."**
  - **"We would feel very comfortable to deliver this therapy on an outpatient basis."**

- **Omotayo Fasan, MBBS** from Galapagos said:
  - **"By initiating lymphodepletion immediately after cell collection, we observed a low 5% attrition rate, compared to rates of up to 30% reported in some clinical trials and real-world settings."**
:::

::: {.column width="50%"}
### Manufacturing Innovation

- **Marie Jose Kersten** on feasibility:
  - **"Our data show that it's feasible to decentralize CAR T-cell manufacturing, and with a fresh-out/fresh-in procedure, you can have a very short vein-to-vein time."**

- **Omotayo Fasan** on T-cell phenotype:
  - **"Fresh, early memory CAR-T cells can be reliably delivered — this stem cell-like phenotype correlates with CAR-T persistence up to 21 months."**

### ⚠️ Commercial Update

- **Henry Gosebruch** (Galapagos CEO) on wind-down:
  - **"No viable proposals were received with terms or financing that would reasonably support the business' future."**
:::

::::

## First‐line treatment of mantle cell lymphoma.

![Caption: First‐line treatment of mantle cell lymphoma.](https://iili.io/fvBEroN.png)


::: {.notes}
這張圖表展示 MCL 一線治療的決策流程：

**關鍵決策點**：
1. **移植適合性**：首先評估患者是否適合自體幹細胞移植
2. **TP53 突變狀態**：這是決定治療策略的關鍵分子標記

**治療路徑**：
- **移植適合 + TP53 野生型**：強化化療（如 Nordic 方案）後自體移植
- **移植不適合 + TP53 野生型**：ECHO 試驗確立的 Acalabrutinib + BR
- **TP53 突變（無論移植適合性）**：BOVen 三聯方案——這是今年的重大突破

**2025 年更新重點**：
- ECHO 試驗獲 FDA 傳統批准（2025 年 1 月 16 日）
- BOVen 獲 NCCN 2A 類建議
- TP53 突變檢測現在是診斷時的必要項目
:::


## ECHO trial: Acalabrutinib + BR for frontline MCL {.smaller}

:::: {.columns}

::: {.column width="45%"}
### Phase III (NCT02972840)

**Background**

- Transplant-ineligible untreated MCL ^[FDA traditional approval January 16, 2025]
- N=598 patients, median follow-up 50 months

**Method**

- Acalabrutinib 100mg BID + Bendamustine-Rituximab
- versus Placebo + BR

**Results**

- **mPFS: 66.4 versus 49.6 months**
- HR 0.73 (95% CI 0.57-0.94, p=0.016)
- **27% reduction** in progression/death risk
- Ki-67 ≥30%: HR 0.69 (high proliferation benefit)

::: aside
Wang M, et al. Acalabrutinib plus bendamustine-rituximab in untreated MCL: ECHO trial. *J Clin Oncol.* 2025. doi:10.1200/JCO.24.02134
:::
:::

::: {.column width="55%"}
```{r echo-pfs}
df <- data.frame(
  Treatment = factor(
    c("Acalabrutinib + BR", "Placebo + BR"),
    levels = c("Acalabrutinib + BR", "Placebo + BR")
  ),
  PFS = c(66.4, 49.6)
)

ggplot(df, aes(x = Treatment, y = PFS, fill = Treatment)) +
  geom_bar(stat = "identity", width = 0.6) +
  geom_text(
    aes(label = paste0(PFS, " mo")),
    vjust = -0.5,
    size = 6,
    fontface = "bold"
  ) +
  scale_fill_manual(values = c(colors$success, colors$accent)) +
  scale_y_continuous(limits = c(0, 80), breaks = seq(0, 80, 20)) +
  labs(
    title = "Median Progression-Free Survival",
    subtitle = "HR 0.73 (p=0.016)",
    y = "Months",
    x = ""
  ) +
  theme_ash() +
  theme(legend.position = "none")
```
:::

::::


::: {.notes}
ECHO 試驗是 MCL 一線治療的里程碑式研究：

**試驗設計**：
- 598 名不適合移植的未治療 MCL 患者
- 隨機分配至 Acalabrutinib + BR 或安慰劑 + BR
- 中位追蹤 50 個月——長期數據增加可信度

**主要終點達成**：
- 中位 PFS：**66.4 個月** vs 49.6 個月
- 風險比 0.73（p=0.016）
- 相當於 **27% 的疾病進展或死亡風險下降**

**為何這很重要？**
1. 這是首個證明 BTKi 可在一線增強化學免疫療法的第三期試驗
2. 針對高增殖腫瘤（Ki-67 ≥30%）獲益更顯著（HR 0.69）
3. FDA 於 2025 年 1 月 16 日給予傳統批准——確立新的護理標準

**臨床應用**：對於不適合移植且 TP53 野生型的 MCL 患者，Acalabrutinib + BR 現在是首選方案。
:::

## ECHO Trial: Safety & Regulatory {.smaller}

:::: {.columns}

::: {.column width="50%"}
### Additional Efficacy Data

```{r echo-mrd}
df <- data.frame(
  Group = factor(
    c("Acalabrutinib", "Placebo", "Acalabrutinib", "Placebo"),
    levels = c("Acalabrutinib", "Placebo")
  ),
  Metric = c(
    "MRD Conversion\n(pos→neg)",
    "MRD Conversion\n(pos→neg)",
    "MRD Reversion\n(neg→pos)",
    "MRD Reversion\n(neg→pos)"
  ),
  Rate = c(37.5, 20, 5.85, 15)
)

ggplot(df, aes(x = Metric, y = Rate, fill = Group)) +
  geom_bar(stat = "identity", position = "dodge", width = 0.7) +
  geom_text(
    aes(label = paste0(Rate, "%")),
    position = position_dodge(width = 0.7),
    vjust = -0.5,
    size = 4
  ) +
  scale_fill_manual(values = c(colors$success, colors$accent)) +
  scale_y_continuous(limits = c(0, 45)) +
  labs(title = "MRD Dynamics", y = "Rate (%)", x = "") +
  theme_ash() +
  theme(legend.position = "top")
```
:::

::: {.column width="50%"}
### Regulatory Status

- **FDA Traditional Approval:** January 16, 2025
- Approved for transplant-ineligible untreated MCL
- Converted from accelerated approval
- **EMA Approval:** May 6, 2025
- Project Orbis international review collaboration

### Subgroup Analysis

- TP53 mutant: HR 0.88 (modest benefit)
- ORR: 91% vs 88%
- CR rate: 66.6% vs 53.5%
:::

:::::

::: {.notes}
ECHO 試驗是一個里程碑式的第三期研究：

**關鍵發現**：
- 在 598 名不適合移植的 MCL 患者中，加入 acalabrutinib 將中位 PFS 從 49.6 個月延長至 66.4 個月
- 這代表 27% 的疾病進展或死亡風險下降

**MRD 動態值得關注**：
- Acalabrutinib 組有 37.5% 的 MRD 陽性患者轉為陰性（對照組僅 20%）
- MRD 逆轉率也更低（5.85% vs 15%）

**臨床意義**：此試驗導致 FDA 於 2025 年 1 月 16 日給予傳統批准，確立了 acalabrutinib + BR 作為不適合移植患者的一線標準治療。
:::


## PFS and OS with and without COVID-19 deaths and PFS by acalabrutinib exposure

![Wang M, Salek D, Belada D, et al. Acalabrutinib Plus Bendamustine-Rituximab in Untreated Mantle Cell Lymphoma. Journal of Clinical Oncology. 2025;43(20):2276-2284. doi:https://doi.org/10.1200/jco-25-00690
‌](https://iili.io/f8oTawb.png)

## Expert Opinions on ECHO Trial {.smaller}

:::: {.columns}

::: {.column width="50%"}
### Lead Investigators

- **Michael Wang, MD** from MD Anderson Cancer Center said:
  - **"BR is no longer the standard of care. Acalabrutinib plus BR is the current standard for older patients with newly diagnosed MCL."**
  - **"I believe that we're in the process of curing many people."**

- **Martin Dreyling, MD** from LMU Munich said:
  - **"For the vast majority of MCL patients, now we have the option to treat with an on-label BTK inhibitor plus chemotherapy."**
  - **"BTK inhibitors are a mandatory part of first-line treatment."**
:::

::: {.column width="50%"}
### Clinical Perspectives

- **Tycel Phillips, MD** from City of Hope said:
  - **"[The trial] did meet its primary endpoint, which was a PFS benefit, and there was a hint that there was some trend toward an OS benefit."**
  - **"Reserve the ECHO regimen for patients who had a more difficult disease to treat."**

- **Martin Dreyling** on tolerability:
  - **"[Acalabrutinib is] better tolerated, especially regarding the typical adverse effects like atrial fibrillation or bleeding disorders, both of which are especially relevant for older patients."**

### Industry Response

- **Susan Galbraith, MD** from AstraZeneca said:
  - **"These impactful results in mantle cell lymphoma show that bringing acalabrutinib to the first-line setting significantly delays disease progression."**
:::

::::

## BOVen: Chemo-free triplet for TP53-mutant MCL {.smaller}

:::: {.columns}

::: {.column width="40%"}
### Phase II (NCT03824483)

**Background**

- TP53-mutant MCL: historical mPFS 0.9y, mOS 1.8y ^[NCCN Category 2A recommendation]
- N=25 TP53-mutant patients

**Method**

- **Zanubrutinib + Obinutuzumab + Venetoclax**
- MRD-guided discontinuation after 24 cycles

::: aside
Kumar A, et al. Zanubrutinib, obinutuzumab, and venetoclax in TP53-mutant MCL. *Blood.* 2025;145(5):497-507. doi:10.1182/blood.2024026123
:::
:::

::: {.column width="60%"}

### Efficacy Results

| Outcome | BOVen | Historical (Chemo) |
|---------|-------|-------------------|
| ORR | **96%** | 50-60% |
| CR | **88%** | 30-40% |
| 2-year PFS | **72%** | <20% |
| 2-year OS | **76%** | ~40% |
| uMRD (10⁻⁵) | **95%** | Rarely achieved |

: BOVen efficacy in TP53-mutant MCL — unprecedented outcomes in a historically poor prognosis group.
:::

::::

::: {.notes}
BOVen 試驗是 TP53 突變 MCL 治療的重大突破：

**歷史背景——為何這群患者如此難治？**
- TP53 突變 MCL 對傳統化療幾乎無效
- 北歐 MCL2/3 試驗數據：中位 PFS 僅 0.9 年，中位 OS 僅 1.8 年
- 這是淋巴瘤領域最具挑戰性的亞群之一

**BOVen 方案的科學設計**：
- **Zanubrutinib**（BTKi）：阻斷 B 細胞受體信號傳導
- **Venetoclax**（BCL-2i）：直接觸發凋亡——繞過 TP53 依賴的凋亡途徑
- **Obinutuzumab**（Type II anti-CD20）：增強 ADCC + 直接非凋亡細胞死亡

**為何結果如此驚人？**
- 72% 的 2 年 PFS——相比歷史上不到 1 年
- 95% 達到不可檢測的 MRD（10⁻⁵ 敏感度）
- 這證明了無化療三聯方案可以克服 TP53 介導的化療抗性

**臨床意義**：對於 TP53 突變 MCL 患者，BOVen 現在是首選方案——NCCN 已給予 2A 類建議。
:::

## BOVen: Safety & Guideline Update {.smaller}

:::: {.columns}

::: {.column width="50%"}
### Safety Profile

| Adverse Event | Rate |
|---------------|------|
| Diarrhea | 64% (mostly low-grade) |
| COVID-19 infection | 56% |
| Infusion reaction | 24% |
| Neutropenia | 32% |
| **Grade 4 TRAEs** | **0%** |

- Time-limited therapy possible with MRD guidance
- No treatment discontinuation due to toxicity


:::

::: {.column width="50%"}
### Regulatory & Guidelines

::: {.callout-important}
## NCCN Category 2A
BOVen now included for TP53-mutant MCL
:::

- Published in **Blood** January 2025
- Expansion cohort: additional 25 patients enrolling
- **Paradigm shift** for high-risk MCL
- First effective chemo-free option for TP53-MCL

![](https://iili.io/f8oYwNt.png)

:::

:::::

::: {.notes}
BOVen 試驗是 TP53 突變 MCL 治療的重大突破：

**歷史背景**：TP53 突變 MCL 預後極差，北歐 MCL2/3 試驗顯示中位 PFS 僅 0.9 年，中位 OS 僅 1.8 年。傳統化療對這群患者幾乎無效。

**BOVen 三聯方案的科學依據**：
- Zanubrutinib：BTK 抑制，阻斷 B 細胞受體信號
- Venetoclax：BCL-2 抑制，直接觸發凋亡
- Obinutuzumab：增強的 ADCC 和直接細胞死亡

**關鍵結果**：
- 2 年 PFS 72%——這在歷史上預後極差的族群中前所未有
- 95% 達到不可檢測的 MRD
- 無 Grade 4 治療相關不良事件

**臨床意義**：NCCN 已將 BOVen 納入 TP53 突變 MCL 的 2A 類建議。這是首個對這個高風險族群有效的無化療選擇。
:::

## Expert Opinions on BOVen Trial {.smaller}

:::: {.columns}

::: {.column width="50%"}
### Lead Investigator

- **Anita Kumar, MD** from Memorial Sloan Kettering Cancer Center said:
  - **"TP53-mutant MCL is a high-risk entity with poor outcomes on standard chemo-immunotherapy. The idea was to develop biologically targeted therapies."**
  - **"This is the first dedicated study with reported outcomes specifically for this cohort, demonstrating that clinical trials are feasible."**
  - **"This two-year PFS of 72% was a huge improvement over historical data."**
:::

::: {.column width="50%"}
### Additional Expert Perspectives

- **William B. Pearse, MD** from UC San Diego said:
  - **"BOVen presents a crucial opportunity to explore how BTK inhibition combined with other targeted agents may serve as a chemotherapy-sparing approach."**

- **Austin I. Kim, MD** from Dana-Farber Cancer Institute said:
  - **"This study adds to the literature supporting triplet regimens — the combination is one of the most highly active and well-tolerated in MCL."**
:::

::::

## MAVO: Acalabrutinib + Venetoclax + Obinutuzumab {.smaller}

::: {.notes}
MAVO 試驗探討另一個無化療三聯組合：

**與 BOVen 的比較**：
- MAVO 使用 acalabrutinib（而非 zanubrutinib）
- 兩者都結合 venetoclax 和 obinutuzumab
- 兩項試驗都證明三聯方案可達到深度緩解

**關鍵發現**：
- 復發/難治性患者：83% ORR，78% CR
- 初治患者：86% ORR，81% CR
- TP53 異常亞組表現良好：88% ORR

**MRD 數據支持治療中斷**：
- 86% 初治患者達到 MRD 陰性 CR
- TP53 突變患者中 91% 達到 MRD 陰性
- 這支持了「緩解適應性治療持續時間」的概念
:::

:::: {.columns}

::: {.column width="45%"}
### Phase I/II (NCT04855695)

**Populations**

- R/R MCL (n=18)
- Treatment-naïve (n=21)

**Results - R/R MCL**

- ORR: 83%, CR: 78%
- 18-month PFS: 77%

**Results - Treatment-Naïve**

- ORR: 86%, CR: 81%
- TP53 aberrant (n=8): 88% ORR
- **MRD-negative CR: 86%**
- TP53 MRD-neg CR: 91%
:::

::: {.column width="55%"}
```{r mavo-response}
df <- data.frame(
  Population = factor(
    rep(c("R/R MCL", "TN MCL", "TP53 Aberrant"), each = 2),
    levels = c("R/R MCL", "TN MCL", "TP53 Aberrant")
  ),
  Response = rep(c("ORR", "CR"), 3),
  Rate = c(83, 78, 86, 81, 88, 78)
)

ggplot(df, aes(x = Population, y = Rate, fill = Response)) +
  geom_bar(stat = "identity", position = "dodge", width = 0.7) +
  geom_text(
    aes(label = paste0(Rate, "%")),
    position = position_dodge(width = 0.7),
    vjust = -0.5,
    size = 4.5,
    fontface = "bold"
  ) +
  scale_fill_manual(
    values = c("ORR" = colors$secondary, "CR" = colors$success)
  ) +
  scale_y_continuous(limits = c(0, 100), breaks = seq(0, 100, 25)) +
  labs(
    title = "MAVO Response Rates by Population",
    subtitle = "MRD-guided treatment discontinuation feasible",
    y = "Rate (%)",
    x = ""
  ) +
  theme_ash() +
  theme(legend.position = "top")
```
:::

::::

## Pirtobrutinib: Non-covalent BTKi for cBTKi-refractory MCL {.smaller}

::: {.notes}
Pirtobrutinib 是首個非共價 BTK 抑制劑，為 BTKi 抗藥性疾病開闢新途徑。

**為什麼需要非共價 BTKi？**
- 50-75% 的 cBTKi 進展患者帶有 C481S 突變
- 此突變將半胱氨酸變為絲氨酸，破壞共價結合位點
- Ibrutinib、acalabrutinib、zanubrutinib 都依賴 C481 進行共價結合

**Pirtobrutinib 的機制優勢**：
- 在遠離 C481 的位置進行可逆結合
- 對野生型和 C481S 突變 BTK 均維持納莫爾級效力
- 對 BTK 的選擇性是激酶組其他 98% 激酶的 300 倍以上

**BRUIN 研究結果**：
- 57.8% ORR——在歷史上生存期僅 2.9-8.4 個月的族群中
- 中位緩解持續時間 21.6 個月——顯著的持久性
:::

:::: {.columns}

::: {.column width="45%"}
### BRUIN study (NCT03740529)

**Background**

- C481S mutation in 50-75% of cBTKi progressors ^[FDA full approval December 2025]
- N=90 prior cBTKi patients

**Mechanism**

- Reversible binding **away from C481**
- Active against WT and C481S-mutant BTK
- >300-fold selectivity versus 98% of kinome

**Results**

- **ORR: 57.8%** (95% CI 46.9-68.1%)
- **Median DOR: 21.6 months**
- Historical post-BTKi survival: 2.9-8.4 months

::: aside
Wang ML, et al. Pirtobrutinib in covalent BTKi-pretreated MCL: BRUIN study. *J Clin Oncol.* 2023;41(24):3988-3997. doi:10.1200/JCO.23.00562
:::
:::

::: {.column width="55%"}
### Efficacy Results

| Metric | Value |
|--------|-------|
| ORR | 57.8% |
| CR | 20% |
| Median DOR | 21.6 months |

: Pirtobrutinib in cBTKi-refractory MCL — first-in-class non-covalent BTKi.
:::

::::

## Pirtobrutinib: Safety & Regulatory {.smaller}

::: {.notes}
Pirtobrutinib 的安全性優勢值得強調：

**心房顫動風險大幅降低**：
- Pirtobrutinib 僅 1.8%（相比 ibrutinib 的 10-15%）
- 這對需要長期治療的患者極為重要
- 可能與其高度 BTK 選擇性有關（>300 倍）

**因不良事件停藥率極低**：僅 3%——遠低於共價 BTKi 的歷史數據

**法規里程碑**：
- 2023 年 12 月獲得加速批准
- **2025 年 12 月 3 日轉為完整批准**——基於 BRUIN 研究的確認性數據
- 這是首個獲得 FDA 完整批准的非共價 BTKi

**在 WM 中的活性**：71.3% MRR——雖未獲特定批准，但 NCCN 支持超適應症使用
:::

:::: {.columns}

::: {.column width="50%"}
### Safety Profile

```{r pirtobrutinib-safety}
df <- data.frame(
  Event = factor(
    c(
      "AF/Flutter",
      "AF/Flutter",
      "Discontinuation\nfor AE",
      "Discontinuation\nfor AE"
    ),
    levels = c("AF/Flutter", "Discontinuation\nfor AE")
  ),
  Drug = factor(
    c("Pirtobrutinib", "Ibrutinib", "Pirtobrutinib", "cBTKi"),
    levels = c("Pirtobrutinib", "Ibrutinib", "cBTKi")
  ),
  Rate = c(1.8, 12.5, 3, 15)
)

ggplot(df, aes(x = Event, y = Rate, fill = Drug)) +
  geom_bar(stat = "identity", position = "dodge", width = 0.7) +
  geom_text(
    aes(label = paste0(Rate, "%")),
    position = position_dodge(width = 0.7),
    vjust = -0.5,
    size = 4
  ) +
  scale_fill_manual(
    values = c(
      "Pirtobrutinib" = colors$success,
      "Ibrutinib" = colors$accent,
      "cBTKi" = colors$warning
    )
  ) +
  scale_y_continuous(limits = c(0, 20)) +
  labs(
    title = "Safety: Pirtobrutinib vs Covalent BTKi",
    y = "Rate (%)",
    x = ""
  ) +
  theme_ash() +
  theme(legend.position = "top")
```
:::

::: {.column width="50%"}
### Regulatory Status

::: {.callout-tip}
## FDA Full Approval
**December 3, 2025** - Converted from accelerated approval (Dec 2023)
:::
- First-in-class non-covalent BTKi
- Phase III BRUIN MCL-321 ongoing (vs cBTKi in BTKi-naïve R/R MCL)

### Waldenström Activity

- **MRR: 71.3%** in prior cBTKi patients
- MRR: 66.7% in cBTKi-refractory
- Off-label NCCN support for prior-treated WM
:::

::::

## Expert Opinions on Pirtobrutinib {.smaller}

:::: {.columns}

::: {.column width="50%"}
### Clinical Investigators

- **Michael Wang, MD** from MD Anderson Cancer Center said:
  - **"Pirtobrutinib is really active in MCL — it is even effective after covalent BTKi resistance."**
  - On safety: **"Some patients asked whether they were in the placebo group due to minimal side effects."**

- **Jennifer A. Woyach, MD** from Ohio State University said:
  - **"The adverse effect profile is better with pirtobrutinib because it is such a selective molecule."**
:::

::: {.column width="50%"}
### Mechanism & Resistance

- **Shuo Ma, MD, PhD** from Northwestern University said:
  - **"Patients with C481S mutation can still respond to pirtobrutinib — it binds away from that site."**
  - **"The battle continues. We have to find new ways to fight resistance mechanisms."**

- **Jeff Sharman, MD** from Willamette Valley Cancer Institute said:
  - **"When covalent BTKi is no longer an option, pirtobrutinib extends the benefits of targeting the BTK pathway."**
  - **"It delayed subsequent treatment or death for 2.5 years in patients naive to venetoclax."**
:::

::::

# Marginal Zone Lymphoma (MZL) {data-stack-name="MZL"}

First CAR-T Approval and Emerging Therapies

::: {.notes}
接下來進入邊緣區淋巴瘤（MZL）的部分。

MZL 約佔非何杰金氏淋巴瘤的 10%，包括三種亞型：
- 結外 MALT 淋巴瘤
- 脾臟邊緣區淋巴瘤
- 淋巴結邊緣區淋巴瘤

ASH 2025 的重大突破：
1. **Liso-cel 獲批**：2025 年 12 月 4 日，FDA 批准首個用於 MZL 的 CAR-T 療法
2. **BGB-16673**：BTK 降解劑在 BTKi 抗藥性疾病中顯示活性
3. **Evorpacept**：CD47 阻斷劑顯著提高完全緩解率

這些進展填補了 MZL 缺乏疾病專屬治療的空白。
:::

## Liso-cel: First CAR-T approved for MZL {.smaller}

::: {.notes}
Lisocabtagene maraleucel（Liso-cel）在 MZL 的獲批是歷史性的里程碑。

**為何重要？**
- 這是**首個**獲 FDA 批准用於 MZL 的 CAR-T 療法
- 在此之前，MZL 沒有疾病專屬的批准療法
- Breyanzi 現已有 5 個癌症適應症——超過任何其他 CD19 CAR-T 產品

**TRANSCEND FL 試驗數據**：
- ITT 族群（n=77）：84.4% ORR，55.8% CR
- 療效可評估族群（n=66）：95.5% ORR，62.1% CR
- 差異反映了缺乏可測量疾病或追蹤不足的患者

**持久性令人印象深刻**：
- 24 個月時 88.6% 的緩解者維持緩解
- 24 個月 PFS 85.7%
- 24 個月 OS 90.4%
:::

:::: {.columns}

::: {.column width="45%"}
### TRANSCEND FL (NCT04245839)

**Background**

- MZL ~10% of NHL, 3 subtypes ^[FDA approval December 4, 2025]
- No prior disease-specific approved therapy

**Method**

- CD19 CAR-T, **1:1 CD4:CD8 composition**
- N=77 (ITT) / 66 (evaluable)

**Results**

- **ORR: 84.4% (ITT) / 95.5% (evaluable)**
- **CR: 55.8% (ITT) / 62.1% (evaluable)**
- 24-month DOR: 88.6% maintained
- 24-month PFS: 85.7%
- 24-month OS: 90.4%

::: aside
FDA. Breyanzi (lisocabtagene maraleucel) approval for MZL. December 4, 2025. NCT04245839.
:::
:::

::: {.column width="55%"}
```{r lisocel}
df <- data.frame(
  Population = factor(
    rep(c("ITT (n=77)", "Evaluable (n=66)"), each = 2),
    levels = c("ITT (n=77)", "Evaluable (n=66)")
  ),
  Response = rep(c("ORR", "CR"), 2),
  Rate = c(84.4, 55.8, 95.5, 62.1)
)

ggplot(df, aes(x = Response, y = Rate, fill = Population)) +
  geom_bar(stat = "identity", position = "dodge", width = 0.7) +
  geom_text(
    aes(label = paste0(Rate, "%")),
    position = position_dodge(width = 0.7),
    vjust = -0.5,
    size = 5,
    fontface = "bold"
  ) +
  scale_fill_manual(values = c(colors$secondary, colors$success)) +
  scale_y_continuous(limits = c(0, 110), breaks = seq(0, 100, 25)) +
  labs(
    title = "Liso-cel Response Rates in MZL",
    subtitle = "TRANSCEND FL Trial",
    y = "Rate (%)",
    x = ""
  ) +
  theme_ash() +
  theme(legend.position = "top")
```
:::

::::

## Liso-cel: Safety & FDA Approval {.smaller}

::: {.notes}
Liso-cel 的安全性特徵在 CAR-T 產品中具有優勢：

**CRS 管理**：
- 76% 發生任何級別 CRS
- 僅 4% 為 Grade 3
- **無 Grade 4-5 CRS 事件**

**神經毒性**：
- 33% 任何級別
- 僅 4% 為 Grade 3

**為何安全性較佳？**
Liso-cel 的獨特之處在於其**1:1 CD4:CD8 定義組成**。這種精確的細胞比例提供：
- 更可預測的藥代動力學
- 跨所有適應症一致的安全性
- 比其他 CAR-T 產品更低的嚴重神經毒性

**法規批准**：2025 年 12 月 4 日——這是 Breyanzi 的第五個適應症
:::

:::: {.columns}

::: {.column width="50%"}
### Safety Profile

```{r lisocel-safety}
df <- data.frame(
  Event = factor(
    c("CRS\n(Any)", "CRS\n(Gr 3)", "Neuro\n(Any)", "Neuro\n(Gr 3)"),
    levels = c("CRS\n(Any)", "CRS\n(Gr 3)", "Neuro\n(Any)", "Neuro\n(Gr 3)")
  ),
  Rate = c(76, 4, 33, 4)
)

ggplot(df, aes(x = Event, y = Rate, fill = Event)) +
  geom_bar(stat = "identity", width = 0.6) +
  geom_text(
    aes(label = paste0(Rate, "%")),
    vjust = -0.5,
    size = 5,
    fontface = "bold"
  ) +
  scale_fill_manual(
    values = c(colors$warning, colors$accent, colors$secondary, colors$accent)
  ) +
  scale_y_continuous(limits = c(0, 90)) +
  labs(
    title = "Liso-cel Safety in MZL",
    subtitle = "No Grade 4-5 CRS events",
    y = "Rate (%)",
    x = ""
  ) +
  theme_ash() +
  theme(legend.position = "none")
```
:::

::: {.column width="50%"}
### Regulatory Status

::: {.callout-tip}
## FDA Approval: December 4, 2025
**First CAR-T therapy approved for MZL**
:::

- Fifth cancer indication for Breyanzi
- Most approved indications of any CD19 CAR-T
- Requirement: ≥2 prior lines of systemic therapy
- Orphan drug designation granted

### Predictable Pharmacokinetics

- Unique 1:1 CD4:CD8 defined composition
- Consistent safety across all liso-cel indications
- Lower severe neurotoxicity than other CAR-T products
:::

::::

## Expert Opinions on Liso-cel for MZL {.smaller}

:::: {.columns}

::: {.column width="50%"}
### Clinical Experts

- **M. Lia Palomba, MD** from Memorial Sloan Kettering Cancer Center said:
  - **"Median survival for MZL patients with multiple relapses is only 3 to 5 years — there was an urgent need for transformative therapies."**
  - **"Liso-cel is a critical advance and the first CAR T approved to treat MZL."**

- **Manali Kamdar, MD** from University of Colorado said:
  - **"The benefit in patients with high tumor burden and early progressing disease is just spectacular."**
:::

::: {.column width="50%"}
### Regulatory & Industry

- **Vinay Prasad, MD** from FDA said:
  - **"This represents a major advancement in precision medicine, turning the patient's immune system into a more effective tool."**

- **Lynelle B. Hoch** from Bristol Myers Squibb said:
  - **"Breyanzi is now the leading CD19-directed CAR T therapy covering the broadest range of B-cell malignancies — five cancer types."**

- **Rosanna Ricafort, MD** from Bristol Myers Squibb said:
  - **"For patients who relapse, the disease can be quite aggressive. The 1:1 CD4:CD8 composition provides predictable pharmacokinetics."**
:::

::::

## BGB-16673: BTK Degrader for BTKi-Resistant Disease {.smaller}

::: {.notes}
BGB-16673 代表 BTK 標靶療法的下一個進化步驟：從「抑制」到「降解」。

**機制創新**：
- 這是一種 CDAC（Cereblon E3 ligase 招募化合物）
- 招募 cereblon E3 連接酶到 BTK
- 誘導 BTK 泛素化和蛋白酶體降解
- **完全消除 BTK 蛋白**，而非僅抑制其活性

**為何降解優於抑制？**
- 對 C481S 突變有效（共價 BTKi 的主要抗藥機制）
- 對「激酶死亡」支架突變（如 L528W）也有效
- 這些突變透過 BTK 的非酶支架功能維持下游信號

**臨床數據**：
- MZL：67% ORR
- CLL/SLL：94.4% ORR（200mg 劑量）
- 第三期試驗已啟動：BGB-16673 vs Pirtobrutinib 頭對頭比較
:::

:::: {.columns}

::: {.column width="45%"}
### CaDAnCe-101 Trial (NCT05006716)

**Mechanism**

- CDAC recruits **cereblon E3 ligase**
- Induces BTK ubiquitination and proteasomal degradation
- Eliminates entire BTK protein (not just inhibition)

**Targets**

- C481S mutations
- "Kinase-dead" scaffold mutations (L528W)
- Active regardless of prior BTKi exposure

**Results**

- **MZL ORR: 67%** in response-evaluable
- **CLL/SLL ORR: 94.4%** at 200mg dose (RDFE)
:::

::: {.column width="55%"}
```{r bgb16673}
df <- data.frame(
  Disease = factor(
    c("MZL", "CLL/SLL\n(200mg)"),
    levels = c("MZL", "CLL/SLL\n(200mg)")
  ),
  ORR = c(67, 94.4)
)

ggplot(df, aes(x = Disease, y = ORR, fill = Disease)) +
  geom_bar(stat = "identity", width = 0.6) +
  geom_text(
    aes(label = paste0(ORR, "%")),
    vjust = -0.5,
    size = 6,
    fontface = "bold"
  ) +
  scale_fill_manual(values = c(colors$secondary, colors$success)) +
  scale_y_continuous(limits = c(0, 110), breaks = seq(0, 100, 25)) +
  labs(
    title = "BGB-16673 BTK Degrader ORR",
    subtitle = "Active in BTKi-pretreated patients",
    y = "ORR (%)",
    x = ""
  ) +
  theme_ash() +
  theme(legend.position = "none")
```

**Phase 3 trial activated:** BGB-16673 vs Pirtobrutinib head-to-head
:::

::::

## Expert Opinions on BGB-16673 BTK Degrader {.smaller}

:::: {.columns}

::: {.column width="50%"}
### Mechanism Experts

- **Lydia Scarfo, MD** from Università Vita-Salute San Raffaele said:
  - **"The greatest advantage is targeting BTK for degradation regardless of mutation status — it works on both wild-type and C481S-mutated protein."**

- **Chan Cheah, MBBS** from Linear Clinical Research (Perth) said:
  - **"Rather than being a small molecule inhibitor, it's got a bifunctional domain which causes degradation via polyubiquitination."**
  - **"They retain efficacy in both covalent and non-covalent BTKi-exposed patients."**
:::

::: {.column width="50%"}
### Clinical Investigators

- **Meghan Thompson, MD** from Memorial Sloan Kettering said:
  - **"CaDAnCe-101 data shows a tolerable safety profile with responses in heavily pretreated patients."**

- **In-hye Ahn, MD** from Dana-Farber Cancer Institute said:
  - **"The drug tags BTK for ubiquitination, leading to complete destruction by the cell's own proteasome machinery."**
  - **"A phase 3 head-to-head trial vs pirtobrutinib has already been activated."**
:::

::::

## Evorpacept: CD47 Blockade + R² for Frontline iNHL {.smaller}

::: {.notes}
Evorpacept 代表了一種全新的免疫檢查點機制。

**CD47-SIRPα 途徑**：
- 腫瘤細胞表面的 CD47 與巨噬細胞上的 SIRPα 結合
- 傳遞「別吃我」（don't eat me）信號，抑制吞噬作用
- 這使腫瘤能夠逃避先天免疫監控

**Evorpacept 的作用**：
- 阻斷 CD47-SIRPα 相互作用
- 將信號從「別吃我」轉換為允許抗體依賴性細胞吞噬（ADCP）
- 與 rituximab 協同作用：rituximab 提供標靶，evorpacept 允許吞噬

**驚人的臨床結果**：
- CR 率達 92%（相比歷史 R² 的約 50%）
- ORR 100%
- 這在初治惰性 NHL（包括 10 名 MZL 患者）中觀察到
:::

:::: {.columns}

::: {.column width="45%"}
### Phase II (ASH 2025)

**Mechanism**

- Blocks CD47-SIRPα "don't eat me" signal
- Enables antibody-dependent cellular phagocytosis

**Population**

- N=24 (14 FL, 10 MZL)
- Previously untreated indolent NHL

**Method**

- Evorpacept + Rituximab + Lenalidomide (R²)

**Results**

- **CR rate: 92%** (vs ~50% historical R²)
- **ORR: 100%**
- 1-year PFS: 91%
- 1-year OS: 100%
:::

::: {.column width="55%"}
### Evorpacept + R² vs Historical R²

| Metric | Evorpacept + R² | R² Historical |
|--------|-----------------|---------------|
| CR | 92% | 50% |
| ORR | 100% | 80% |
| 1-year PFS | 91% | 75% |
| 1-year OS | 100% | 95% |

: CD47 blockade dramatically improves CR rate.
:::

::::

# Waldenström Macroglobulinemia (WM) {data-stack-name="WM"}

Fixed-Duration Therapy and High-Risk Strategies

::: {.notes}
進入華氏巨球蛋白血症（WM）的部分。

WM 是一種罕見的惰性 B 細胞淋巴瘤，特徵是：
- 骨髓中淋巴漿細胞浸潤
- 血清單克隆 IgM 升高
- MYD88 L265P 突變（>90% 的患者）

**ASH 2025 的關鍵進展**：
1. **固定期限療法**：Pirtobrutinib + Venetoclax 組合顯示 100% ORR
2. **高風險疾病策略**：Loncastuximab 在 TP53 改變患者中顯示卓越活性
3. **分子亞型研究**：MBC-like vs PC-like 亞型可能預測治療反應

這些進展挑戰了 WM 需要無限期 BTKi 治療的傳統觀念。
:::

## Pirtobrutinib + Venetoclax: Fixed-Duration WM Therapy {.smaller}

::: {.notes}
Dana-Farber 的這項第二期研究是 WM 治療的重要突破。

**為何固定期限療法重要？**
- WM 患者傳統上需要無限期 BTKi 治療
- 長期 ibrutinib 使用有 23.5% 心房顫動風險
- 累積毒性和抗藥性是主要顧慮

**Pirtobrutinib + Venetoclax 組合的優勢**：
- 非共價 BTKi（較低心臟毒性）+ BCL-2 抑制（深度緩解）
- 固定 24 週期口服療法
- 100% ORR，56% CR/VGPR

**Jorge Castillo 博士的評論**：
「緩解深度超出每種藥物單獨預期」——暗示可能成為新的護理標準

**重要**：至今無心律不整事件
:::

:::: {.columns}

::: {.column width="45%"}
### Dana-Farber Phase II

**Background**

- WM typically requires indefinite BTKi therapy
- Cumulative toxicities and resistance concerns

**Population**

- N=27 evaluable (MYD88-mutant)
- Previously treated, symptomatic

**Method**

- Fixed 24-cycle oral combination

**Results**

- **ORR: 100%**
- **CR/VGPR: 56%** (exceeds futility threshold)
- MRR: 87%
- Median time to VGPR: 1.9 months
- No arrhythmia events to date
:::

::: {.column width="55%"}
```{r pirto-ven}
df <- data.frame(
  Response = factor(
    c("CR/VGPR", "PR", "MR"),
    levels = c("CR/VGPR", "PR", "MR")
  ),
  Rate = c(56, 31, 13)
)

ggplot(df, aes(x = "", y = Rate, fill = Response)) +
  geom_bar(stat = "identity", width = 1) +
  coord_polar("y", start = 0) +
  geom_text(
    aes(label = paste0(Response, "\n", Rate, "%")),
    position = position_stack(vjust = 0.5),
    size = 5,
    fontface = "bold",
    color = "white"
  ) +
  scale_fill_manual(
    values = c(colors$success, colors$secondary, colors$warning)
  ) +
  labs(
    title = "Pirtobrutinib + Venetoclax Response Distribution",
    subtitle = "100% ORR with fixed-duration therapy"
  ) +
  theme_void() +
  theme(
    plot.title = element_text(size = 16, face = "bold", hjust = 0.5),
    plot.subtitle = element_text(size = 12, hjust = 0.5),
    legend.position = "none"
  )
```

*"Depth of response beyond what was expected for each medication separately"* - Dr. Jorge Castillo
:::

::::

::: {.notes}
這張投影片展示 Dana-Farber 研究的關鍵數據：

**為何這項研究重要？**
- 過去 WM 患者需要**無限期 BTKi 治療**
- 長期用藥帶來心血管毒性風險（ibrutinib 心房顫動 23.5%）
- 患者渴望能夠停藥的選項

**試驗設計亮點**：
- 27 名可評估患者，均有 MYD88 突變
- **固定 24 週期**口服療法
- 非共價 BTKi + BCL-2 抑制劑的協同作用

**令人矚目的結果**：
- **100% ORR**：所有患者都有反應
- **56% CR/VGPR**：超過一半達到深度緩解
- 達到 VGPR 的中位時間僅 1.9 個月
- **無心律不整事件**：解決了傳統 BTKi 的主要顧慮

**Jorge Castillo 博士的評語**強調：緩解深度超出兩藥單獨使用的預期，暗示協同作用機制。

這可能成為 WM 的新治療標準，讓患者有機會在達到深度緩解後停止治療。
:::

## Loncastuximab Tesirine: ADC for High-Risk WM {.smaller}

::: {.notes}
這張投影片介紹 Loncastuximab tesirine 在高風險 WM 中的應用。

**什麼是 Loncastuximab tesirine？**
- **抗 CD19 抗體藥物偶聯物（ADC）**
- 已獲 FDA 批准用於瀰漫性大 B 細胞淋巴瘤（DLBCL）
- 藥物將細胞毒性載荷精準傳遞至 CD19+ 腫瘤細胞

**試驗設計**：
- 14 名患者，中位先前治療 4 線
- **高風險特徵**：8 名 CXCR4 突變，8 名 TP53 改變
- 固定 6 劑方案（150 µg/kg 第 1-2 週期，75 µg/kg 第 3-6 週期）

**驚人結果**：
- 整體 ORR：86%，CR/VGPR：71%
- **TP53 改變患者**：100% 緩解率，89% CR/VGPR
- 在 CXCR4 突變患者（通常對 BTKi 抗藥）中同樣有效

**為何這很重要？**
TP53 突變在大多數治療中預後極差，但 Loncastuximab 的作用機制繞過了 TP53 介導的凋亡途徑，直接透過 DNA 損傷殺死腫瘤細胞。

**注意**：此藥物尚未獲批用於 WM，目前屬於超適應症使用。
:::

:::: {.columns}

::: {.column width="45%"}
### Phase II Trial

**Background**

- CD19-targeting antibody-drug conjugate
- N=14, median 4 prior therapies
- High-risk: 8 CXCR4+, 8 TP53-altered

**Method**

- Fixed 6-dose regimen
- 150 µg/kg cycles 1-2, 75 µg/kg cycles 3-6

**Results**

- **Overall ORR: 86%**
- **CR/VGPR: 71%**
- **TP53-altered: 100% response, 89% CR/VGPR**
- Active in CXCR4-mutant (BTKi-resistant)
:::

::: {.column width="55%"}
```{r lonca}
df <- data.frame(
  Group = factor(
    rep(c("All Patients", "TP53-Altered"), each = 2),
    levels = c("All Patients", "TP53-Altered")
  ),
  Response = rep(c("ORR", "CR/VGPR"), 2),
  Rate = c(86, 71, 100, 89)
)

ggplot(df, aes(x = Group, y = Rate, fill = Response)) +
  geom_bar(stat = "identity", position = "dodge", width = 0.7) +
  geom_text(
    aes(label = paste0(Rate, "%")),
    position = position_dodge(width = 0.7),
    vjust = -0.5,
    size = 5,
    fontface = "bold"
  ) +
  scale_fill_manual(
    values = c("ORR" = colors$secondary, "CR/VGPR" = colors$success)
  ) +
  scale_y_continuous(limits = c(0, 115), breaks = seq(0, 100, 25)) +
  labs(
    title = "Loncastuximab in High-Risk WM",
    subtitle = "Remarkable activity in TP53-altered patients",
    y = "Rate (%)",
    x = ""
  ) +
  theme_ash() +
  theme(legend.position = "top")
```

**Note:** Loncastuximab FDA-approved for DLBCL, not yet for WM
:::

::::

## Expert Opinions on WM Fixed-Duration Therapy {.smaller}

:::: {.columns}

::: {.column width="50%"}
### Lead Investigators

- **Jorge Castillo, MD** from Dana-Farber Cancer Institute said:
  - **"The depth of response is beyond what was expected for each medication separately — three of 27 patients attained CR in the first six months."**
  - **"Our goal is to provide patients with a treatment that is non-chemotherapy, fixed duration, and all oral."**

- **Steven Treon, MD** from Dana-Farber said:
  - **"For patients with acquired resistance to covalent BTK inhibitors, newer options include pirtobrutinib or venetoclax."**
:::

::: {.column width="50%"}
### Treatment Perspectives

- **Christian Buske, MD** from University Hospital Ulm said:
  - **"The trend goes towards chemotherapy-free approaches as fixed-duration treatment for one or two years."**

- **Shayna Sarosiek, MD** from Dana-Farber said:
  - **"Emerging treatments such as BTKi combinations, BCL2 antagonists, BTK degraders, and immunotherapy are under investigation."**
  - **"No arrhythmia events reported to date — addressing a key concern with long-term BTKi use."**
:::

::::

# Clinical Implications {data-stack-name="Summary"}

::: {.notes}
進入臨床意涵的總結部分。

經過今天的報告，我們看到 ASH 2025 在 B 細胞淋巴瘤領域帶來了多項改變臨床實務的進展。

**三大主題**：
1. **個人化醫療時代來臨**：分子檢測不再是可選項目
2. **抗藥機制指導治療排序**：理性的藥物選擇策略
3. **治療模式創新**：從無限期治療走向固定期限療法

接下來的投影片將總結這些關鍵要點及其臨床應用意義。
:::

## Key Takeaways from ASH 2025 {.smaller}

::: {.notes}
這張總結投影片涵蓋六大臨床要點：

**1. 一體適用療法的終結**
- **診斷時分子檢測**現在直接決定最佳治療選擇
- TP53 突變 MCL → BOVen（而非化療）
- MYD88 野生型 WM → 需要不同的 BTKi 策略
- CXCR4 突變 → 考慮 BTKi 抗藥性模式

**2. 抗藥機制指導治療排序**
- C481S 突變 → Pirtobrutinib 有效
- BTK 降解劑 → 針對支架功能突變
- 現在可以進行理性的藥物排序

**3. CAR-T 製造創新**
- GLPG5101：7 天靜脈到靜脈時間
- 可能消除傳統 CAR-T 的 15-20% 退出率
- 儘管商業前景不確定，技術已獲驗證

**4. MZL 里程碑**
- Liso-cel：**首個疾病專用批准療法**
- 95.5% ORR，88.6% 24 個月持續緩解

**5. 固定期限療法**
- Pirtobrutinib + Venetoclax 在 WM：100% ORR
- MRD 導向停藥策略可行

**6. 新機制藥物**
- BTK 降解劑（BGB-16673）：超越抑制
- CD47 阻斷（Evorpacept）：92% CR

**給聽眾的建議**：
- 在診斷時進行全面的分子檢測
- 根據突變狀態選擇一線治療
- 了解抗藥機制以規劃後續治療
:::

:::: {.columns}

::: {.column width="50%"}
### 1. End of One-Size-Fits-All

- **Molecular testing at diagnosis** now determines optimal therapy
- TP53-mutant MCL → BOVen (not chemoimmunotherapy)
- MYD88 wild-type WM → Different BTKi approach
- CXCR4 mutations → Consider resistance patterns

### 2. Resistance Mechanisms Guide Sequencing

- C481S mutation → Pirtobrutinib effective
- BTK degraders → Target scaffold mutations
- Rational therapy sequencing now possible

### 3. CAR-T Manufacturing Innovation

- GLPG5101: 7-day vein-to-vein time
- May eliminate 15-20% dropout rates
- Technology validated despite commercial uncertainty
:::

::: {.column width="50%"}
### 4. MZL Milestone

- **Liso-cel:** First disease-specific approved therapy
- 95.5% ORR in evaluable patients
- Durable responses (88.6% at 24 months)

### 5. Fixed-Duration Therapies

- Pirtobrutinib + Venetoclax in WM: 100% ORR
- May replace indefinite BTKi therapy
- MRD-guided discontinuation feasible

### 6. Novel Mechanisms

- **BTK degraders** (BGB-16673): Beyond inhibition
- **CD47 blockade** (Evorpacept): 92% CR with R²
- New targets for resistant disease
:::

::::

## References {.smaller}

::: {.columns}
::: {.column width="50%"}
### Key Trials

1. **ATALANTA-1:** ASH 2025 Abstract #662, Galapagos NV
2. **ECHO Trial:** NCT02972840, FDA approval January 16, 2025
3. **BOVen:** Blood 2025;145(5):497, NCT03824483
4. **MAVO:** Blood 2024;144(Suppl 1):4408, NCT04855695
5. **BRUIN:** JCO 2023, NCT03740529, FDA full approval December 2025
6. **TRANSCEND FL MZL:** NCT04245839, FDA approval December 4, 2025
:::

::: {.column width="50%"}
### Additional Sources

- FDA.gov Drug Approvals
- ClinicalTrials.gov
- ASH Abstract Database
- NCCN Guidelines (accessed December 2025)
- Dana-Farber Cancer Institute Press Releases
- Galapagos NV Press Releases
:::
:::

---

### Data Validation Notes

- TRANSCEND FL MZL ORR: 84.4% (ITT) vs 95.5% (evaluable) - both correct for different analysis sets
- Pirtobrutinib MCL ORR varies 50-57.8% depending on data cutoff and cohort definition
- BGB-16673 is a BTK degrader/CDAC, not technically a classic PROTAC
- SWOG S2005 (WM) has no efficacy results - trial ongoing