🧬 cGFS vs GRFS after allo-HSCT — don’t confuse them! 🔵 cGFS = chronic GVHD–free survival Patient remains alive without moderate–severe chronic GVHD. ❌ Events: ☠️ Death 🔥 Moderate–severe chronic GVHD ⚠️ Relapse is NOT an event for cGFS. 🟣 GRFS = GVHD-free, relapse-free survival A stricter composite endpoint. ❌ Events: ☠️ Death 🎯 Relapse/progression 🔥 Grade III–IV acute GVHD 🔥 Moderate–severe chronic GVHD 🧠 Easy mnemonic: cGFS = Chronic GVHD + death GRFS = GVHD + Relapse + death 📌 Therefore: ➡️ GRFS is harder to achieve ➡️ It better reflects being alive without major GVHD AND without disease relapse ➡️ cGFS specifically evaluates freedom from clinically important chronic GVHD 🔬 Precision-T / Orca-T example: At 1 year: ✅ cGFS: 78.0% vs 38.4% ✅ GRFS: 63.1% vs 30.9% Orca-T vs Tac/MTX. (PubMed Central (PMC)) ⚠️ Important statistical pearl: in Precision-T, cGFS was the primary endpoint. GRFS was a hierarchically tested secondary endpoint; because interim OS did not cross its prespecified significance boundary, FDA noted that GRFS was not formally tested in the hierarchy, so the GRFS result should be interpreted descriptively. (U.S. Food and Drug Administration) #BMT #HSCT #GVHD #cGVHD #GRFS #OrcaT #TREGZI #Hematology #KFSHRC

🩸🧬 ABO SUBGROUP ANTIBODIES: transfusion pearls 🧵👇 1️⃣ The key antibody: anti-A₁ Some A₂ and A₂B individuals produce anti-A₁ against A₁ red cells. 📊 Reported frequency: 🔹 A₂: ~1–8% 🔹 A₂B: ~22–35% ⚠️ A₂ phenotype does NOT automatically mean anti-A₁ is present! 2️⃣ When does anti-A₁ matter? 🌡️ Usually naturally occurring, IgM and cold-reactive → clinically insignificant. 🚨 Reactivity at 37°C raises concern for hemolysis. Rare severe hemolytic transfusion reactions are documented. 🧠 Assess thermal amplitude—the temperature range of reactivity. 3️⃣ Classic laboratory clue 🔬 Forward grouping → A or AB. Reverse grouping → unexpected reaction with A₁ reagent cells. ✅ Patient plasma reacts with A₁ cells but not A₂ cells → supports anti-A₁. ⚠️ Investigate the ABO discrepancy before routine group-specific transfusion. 4️⃣ How to investigate 🧪 🔹 Repeat forward/reverse grouping. 🔹 Test patient RBCs with anti-A₁ lectin: Dolichos biflorus. 🔹 Test plasma against A₁ and A₂ cells. 🔹 Assess reactivity at 37°C. 🔹 Refer unresolved cases for specialist testing. 💡 Negative anti-A₁ lectin alone does not prove A₂; other A subgroups also test negative. 5️⃣ Selecting RBCs: cold-only anti-A₁ ❄️ Use ABO-compatible RBCs that are crossmatch-compatible by indirect antiglobulin testing at 37°C. ✅ A₂ or group O units are not automatically required merely because anti-A₁ is detected. 6️⃣ Selecting RBCs: clinically significant anti-A₁ 🔥 Choose A₁-negative, crossmatch-compatible RBCs: 🩸 A₂ recipient → A₂ or O. 🩸 A₂B recipient → A₂B, A₂, B or O. ✅ Respect RhD status and other clinically significant antibodies. ⚠️ These choices apply to RBC components—not automatically to plasma or whole blood. 7️⃣ A negative antibody screen can mislead! 🚩 Routine screening cells are group O and lack A₁ antigen. ➡️ Anti-A₁ may therefore coexist with a negative antibody screen. 🧠 Negative screen ≠ resolved ABO discrepancy! 8️⃣ Other ABO subgroups 🧬 🔹 A₃/B₃ → classically mixed-field reactions. 🔹 Aₓ/Aₑₗ and other weak variants → weak or absent routine reactions. ⚠️ Weak antigen expression alone does not determine antibody significance or transfusion selection. 9️⃣ Related exam trap: Bombay phenotype 🚨 Classical Bombay RBCs lack H antigen. Anti-H can react strongly with ordinary group O RBCs! ❌ O-negative is NOT universally compatible. ✅ These recipients require compatible H-deficient RBCs through specialist blood-bank support. 🔟 Memory pearl 🧠 ❄️ Anti-A₁ cold-only → usually insignificant. 🔥 Anti-A₁ at 37°C → assess hemolytic risk; select compatible A₁-negative RBCs. 🚨 Bombay anti-H → ordinary O blood is unsafe. #Hematology #TransfusionMedicine #BloodBank #ABO #PatientBloodManagement #KFSHRC

🧠💉 CNS PROPHYLAXIS IN DLBCL: DOES IT REALLY WORK? 📚 Evidence update through September 2026 💊 High-dose methotrexate = HD-MTX 💉 Intrathecal chemotherapy = IT A critical review of the major studies 🧵👇 1️⃣ 🎯 THE MAIN MESSAGE Routine HD-MTX ± IT has no established survival benefit in most high-risk DLBCL patients. 📉 Larger studies increasingly question meaningful CNS-relapse prevention. 🧬 Testicular and intravascular LBCL require separate consideration. (pmc.ncbi.nlm.nih.gov⁠, research.monash.edu⁠, onlinelibrary.wiley.com⁠) 2️⃣ 📈 THE POSITIVE MIYAZAWA STUDY 2025 online/2026 issue | Retrospective | n=178 HD-MTX + IT: 🧠 Two-year CNS relapse: 6.2% ❤️ Five-year OS: 93.2% No prophylaxis: 🧠 CNS relapse: 13.0% ❤️ OS: 58.0% Adjusted mortality HR: 0.160. (link.springer.com⁠) 3️⃣ ⚠️ HOW TO INTERPRET MIYAZAWA Pooled prophylaxis did not significantly reduce CNS relapse: 17.6% versus 13.0%. 🔍 My appraisal: an encouraging association requiring confirmation. Patient selection and unmeasured confounding can persist despite multivariable adjustment. (link.springer.com⁠) 4️⃣ 📚 EARLIER POSITIVE SIGNALS Cheah 2014: lower CNS relapse with systemic CNS-directed strategies. Ferreri 2015: 0/33 CNS relapses with IV prophylaxis versus 9/74 with none/IT only. ⚠️ Small retrospective comparisons with potential selection bias. (research.monash.edu⁠, pmc.ncbi.nlm.nih.gov⁠, onlinelibrary.wiley.com⁠) 5️⃣ 🧠 ONG 2021 | n=226 Three-year isolated CNS relapse: 💊 HD-MTX: 3.1% 🚫 Without HD-MTX: 14.6% 📊 p=0.032 📌 A positive signal for isolated CNS relapse. Always distinguish this endpoint from any CNS relapse and overall survival. (onlinelibrary.wiley.com⁠, pubmed.ncbi.nlm.nih.gov⁠) 6️⃣ 🌍 LEWIS 2023 | n=2,418 HD-MTX showed an adjusted association with fewer CNS events in the overall analysis. But: 📉 Five-year absolute difference: only 1.6 percentage points; CI crossed zero. ❌ No significant association in the complete-response cohort. (pubmed.ncbi.nlm.nih.gov⁠) 7️⃣ 🆕 WILSON 2026 | n=1,923 Ultra-high-risk LBCL Three-year CNS relapse: 🚫 No HD-MTX: 9.3% 💊 HD-MTX: 8.1% Adjusted HR 1.13; 95% CI 0.82–1.57. ❌ No significant benefit—even in this selected high-risk population. (research.monash.edu⁠) 8️⃣ 🔎 WHY THE 2026 STUDY MATTERS Included CNS-IPI 5–6, selected high-risk organs or ≥3 extranodal sites. Landmark analysis remained negative. ⚠️ Retrospective and derived from two previous datasets: avoid counting it as entirely independent evidence. (research.monash.edu⁠) 9️⃣ ⏳ PREVENTION OR DELAY? Bobillo 2021 | n=585: Early differences narrowed over time. Five-year CNS relapse: 💉 Prophylaxis: 5.6% 🚫 None: 7.5% 💡 Prophylaxis may delay some relapses rather than reliably prevent them. (nature.com⁠) 🔟 📉 OTHER NEGATIVE COHORTS Puckrin 2021: no clear HD-MTX benefit in high-risk patients. Jeong 2021 | n=258: No significant CNS-relapse benefit after propensity-based analyses. 📌 These findings challenge routine prophylaxis. (pubmed.ncbi.nlm.nih.gov⁠, ashpublications.org⁠, sciencedirect.com⁠) 1️⃣1️⃣ 💉 IV VERSUS IT? Orellana-Noia 2022 | n=1,162: 🧠 CNS relapse: IT 5.4% versus HD-MTX 6.8%; p=0.4. ⚠️ Similar outcomes between two prophylaxis strategies do not prove that either works compared with no prophylaxis. (sciencedirect.com⁠) 1️⃣2️⃣ 🎲 RANDOMIZED EVIDENCE Yahng/CISL1703 | 2023 abstract | n=142: Two-year CNS relapse: 💉 IT: 5.5% 💊 IV: 4.9% ❌ No significant difference. ⚠️ Limited power; no untreated randomized comparator. (pmc.ncbi.nlm.nih.gov⁠, onlinelibrary.wiley.com⁠) 1️⃣3️⃣ 🆕 CLSG-CNS-01 | 2026 Only 61 patients randomized: IV versus IT MTX. ❓ Efficacy inconclusive. 🦠 Grade ≥3 infections: 30% versus 6.45%. ⚠️ The untreated group contained nonrandomized low-risk patients—not a valid equivalent control. (onlinelibrary.wiley.com⁠, onlinelibrary.wiley.com⁠)

🩸 Relapsed CLL/SLL: treatment sequencing matters! 🧵 1️⃣ 📋 Preferred options shown on the slide: 💊 Venetoclax + obinutuzumab 💊 Acalabrutinib or zanubrutinib 💊 Pirtobrutinib after prior covalent BTK inhibitor resistance/intolerance Selection depends on previous exposure, response duration, toxicity and disease biology. 2️⃣ 🔄 BTKi intolerance ≠ resistance! ✅ Intolerance: another second-generation covalent BTKi may be considered, unless toxicity was life- or organ-threatening. 🚫 Progression on a covalent BTKi: switching to another covalent BTKi generally does not overcome resistance. Consider venetoclax-based treatment or pirtobrutinib. (ashpublications.org) 3️⃣ ⏳ Relapse after fixed-duration venetoclax: ➡️ Acalabrutinib or zanubrutinib if appropriate. ➡️ Venetoclax retreatment may be reasonable after a durable treatment-free remission and previous good tolerance. ⚠️ Progression during venetoclax is a different scenario. (pubmed.ncbi.nlm.nih.gov) 4️⃣ 🎯 Pirtobrutinib is a noncovalent BTKi. 🇺🇸 Since December 2025, its FDA indication includes R/R CLL/SLL previously treated with a covalent BTKi—prior venetoclax is no longer required. (fda.gov) 5️⃣ 🧬 After both BTKi and BCL2 inhibitor exposure: ➡️ Pirtobrutinib, if not previously used. ➡️ Lisocabtagene maraleucel: CD19 CAR-T; FDA indication requires ≥2 prior lines, including a BTKi and a BCL2 inhibitor. ➡️ Consider clinical trials and early cellular therapy referral. (pubmed.ncbi.nlm.nih.gov, fda.gov, ashpublications.org) 🧠 Memory pearl: “Which class? Why stopped? How long was remission?” 📚 NCCN Insights | Sequencing consensus | FDA CAR-T indication #CLL #Hematology #BTKi #CART #MedEd #KFSHRC

galleri.com/. Screening test for tumors including leukemia and lymphoma False positive only 0.4 % Epigenetics are key for the future of cancer screening.. Important note: The Galleri multi-cancer early detection test identifies *DNA in the bloodstream shed by cancer cells' and does not predict future genetic risk for cancer.*

🧵 Frontline CLL: fixed-duration therapy, survival & relapse predictors — 5 trial pearls 🩸 1️⃣ CLL14: who relapses earlier after venetoclax–obinutuzumab? 🧬 TP53 disruption: del(17p) and/or TP53 mutation 🧬 Unmutated IGHV 📏 Bulky lymph nodes ≥5 cm The slide’s univariate PFS hazard ratios are approximately 2.26, 2.26 and 1.92, respectively. 🧠 Remember “T–U–B”: TP53, Unmutated, Bulk. ⚠️ These are adverse prognostic factors—not proof that venetoclax–obinutuzumab provides no benefit. (pmc.ncbi.nlm.nih.gov) 2️⃣ GLOW: an all-oral, fixed-duration approach 💊 👥 211 previously untreated older/comorbid patients. 💊 Ibrutinib lead-in ×3 cycles → ibrutinib + venetoclax ×12 cycles. 📉 Versus chlorambucil–obinutuzumab: PFS HR 0.216 → approximately 78% lower hazard of progression/death at the primary analysis. ⚠️ Del(17p)/known TP53 mutation were exclusion criteria; avoid extrapolating these findings to TP53-disrupted CLL. (pmc.ncbi.nlm.nih.gov) 3️⃣ CLL17: fixed-duration vs continuous therapy ⏳ 📊 3-year PFS: 🔹 Venetoclax–obinutuzumab: 81.1% 🔹 Venetoclax–ibrutinib: 79.4% 🔹 Continuous ibrutinib: 81.0% ✅ Both fixed-duration regimens met the prespecified noninferiority criterion versus continuous ibrutinib. ⚠️ Noninferiority does not mean identical efficacy; no statistically significant OS difference was demonstrated at this analysis. (nejm.org) 4️⃣ FLAIR: MRD-guided ibrutinib–venetoclax 🧬 At median follow-up 62.2 months: 📈 5-year PFS: 🥇 Ibrutinib–venetoclax: 93.9% 🔹 Ibrutinib alone: 79.0% 🔹 FCR: 58.1% ❤️ OS also favored the combination: ➡️ Versus ibrutinib: HR 0.41 ➡️ Versus FCR: HR 0.26 ⚠️ FLAIR used MRD-guided treatment duration; it should not be treated as interchangeable with GLOW’s fixed schedule. (pubmed.ncbi.nlm.nih.gov) 5️⃣ AMPLIFY: better disease control ≠ automatic OS benefit 📊 💊 AV = acalabrutinib–venetoclax 💊 AVO = AV + obinutuzumab ❤️ 36-month OS: 🔹 AV: 94.1% 🔹 AVO: 87.7% 🔹 FCR/BR: 85.9% ✅ AV improved OS versus FCR/BR: HR 0.33 ⚠️ AVO did not demonstrate a significant OS advantage: HR 0.76; 95% CI 0.49–1.18. 🦠 COVID-related deaths were 10 / 25 / 21, respectively—essential context when interpreting survival. These results do not establish AV superiority over AVO. (doi.org, ashpublications.org) 📚 Sources: CLL14 • GLOW • CLL17 • FLAIR • AMPLIFY #CLL #Hematology #MedEd #MRD #KFSHRC

🧵 R/R CLL: practical sequencing from the Onkopedia algorithm 🩸💊 1️⃣ After venetoclax–obinutuzumab ⏳ 🔴 Refractory/early relapse → acalabrutinib or zanubrutinib, if BTKi-sensitive. 🟢 Late relapse → consider venetoclax–rituximab (VenR) retreatment or a suitable BTKi. 📌 This algorithm uses approximately 2–3 years to distinguish early from late relapse; retreatment remains individualized. 2️⃣ Progression ON a covalent BTKi 🔄 ➡️ VenR or pirtobrutinib. 🚫 Established resistance is not overcome by switching from one covalent BTKi to another. 🟠 If discontinuation was for intolerance, an alternative BTKi may remain appropriate. 3️⃣ After BTKi + venetoclax combinations 🧩 Ask: relapse after planned completion—or progression during treatment? ✅ A previously effective agent may be reused after a durable treatment-free interval. ⚠️ Progression on treatment requires a resistance-informed choice; do not interpret every arrow as permission to recycle a failed drug. 4️⃣ Treatment duration matters 📅 💊 BTKi monotherapy → generally continuous until progression/intolerance. ⏱️ VenR → venetoclax for 24 months, with rituximab during the initial six cycles—not rituximab for two years. 5️⃣ When options become limited 🧬 ➡️ Pirtobrutinib, if appropriate and not already failed. ➡️ Clinical trials. ➡️ Idelalisib–rituximab is a later option shown in the algorithm. 🌱 Allogeneic HSCT offers potential cure for selected fit, high-risk patients; discuss early with a transplant center and aim for disease control before transplantation. 6️⃣ Do not miss Richter transformation 🚨 Rapidly enlarging nodes, marked B symptoms or an unexpectedly aggressive relapse → PET-CT to guide biopsy. 🔬 Tissue establishes the diagnosis. 🤝 For patients with profound frailty and limited expected treatment benefit, prioritize supportive care and individual goals. (onkopedia-guidelines.info) 📚 Onkopedia CLL guideline #CLL #Hematology #BTKi #Venetoclax #HSCT #MedEd #KFSHRC

🩸 First-line CLL: match treatment to biology + comorbidities 🧬 TP53 mutation/del(17p) ➡️ Generally favor continuous acalabrutinib or zanubrutinib. ⏳ Time-limited therapy remains an option through shared decision-making. 🧬 No TP53 aberration ➡️ Favor time-limited targeted therapy when feasible—particularly with mutated IGHV. ✅ Unmutated IGHV also benefits from targeted combinations. (onlinelibrary.wiley.com⁠) ❤️ Cardiovascular disease ➡️ Often favors venetoclax–obinutuzumab. 💊 If choosing a BTK inhibitor, prefer acalabrutinib/zanubrutinib over ibrutinib. 🚫 Generally avoid BTK inhibitors with ventricular arrhythmias or uncontrolled heart failure. 🩸 Anticoagulation/bleeding risk ➡️ Favors venetoclax–obinutuzumab; carefully assess BTK inhibitor bleeding risk. (onlinelibrary.wiley.com⁠) 🦠 High infection risk ➡️ The slide favors BTK inhibitor monotherapy over obinutuzumab-containing regimens. ⚠️ Adding an antibody increases treatment and immune-suppression burden. 🫘 Renal impairment ➡️ Venetoclax requires careful tumor lysis syndrome risk assessment, prophylaxis and ramp-up monitoring. ⚠️ Renal dysfunction requires individualized planning with either drug class. 🏥 Treatment burden 💊 BTK inhibitor monotherapy: simpler initiation, ongoing treatment. ⏳ Venetoclax combinations: more initial monitoring, planned treatment completion. 💊 Always review drug interactions and patient preference. 🧠 Practical memory aid: “Genes → Heart → Bleeding → Kidneys → Infections → Preference” 📚 EHA CLL Guidelines 2026—Eichhorst et al., HemaSphere⁠ #CLL #Hematology #PrecisionMedicine #EHA2026 #KFSHRC

🩸 CLL: WHEN to treat, WHY targeted therapy works & WHAT to monitor 🧵👇 1️⃣ 🚦 WHEN TO TREAT? Start treatment when ≥1 iwCLL active-disease criterion is present: 🩸 Progressive marrow failure: Hb <10 g/dL or platelets <100 ×10⁹/L attributable to CLL. ⚠️ Stable thrombocytopenia below this threshold does not automatically require treatment. 2️⃣ 📏 BULK & KINETICS 🔹 Spleen ≥6 cm below left costal margin, progressive or symptomatic. 🔹 Nodes ≥10 cm, progressive or symptomatic. 🔹 Lymphocytes ↑≥50% in 2 months OR doubling time <6 months. 🔍 Exclude infection/steroid effects on lymphocyte counts. 3️⃣ 🚨 OTHER TREATMENT TRIGGERS 🛡️ Autoimmune anemia/thrombocytopenia poorly responsive to corticosteroids. 🫁 Symptomatic or functionally significant extranodal disease. 🌡️ Disease-related symptoms: • Weight loss ≥10% in 6 months • Significant fatigue: ECOG ≥2 • Fever ≥38°C for ≥2 weeks • Night sweats ≥1 month Exclude infection for fever/sweats. 💡 A high lymphocyte count alone is NOT an indication! (ashpublications.org⁠) 4️⃣ 🔬 THE CLL MICROENVIRONMENT Lymph-node proliferation centers provide survival signals through: 🤝 T cells, nurse-like cells & stromal cells 📡 B-cell receptor signaling: SYK, BTK & PI3K 🧭 CXCL12–CXCR4 and CXCL13–CXCR5: trafficking/retention 🔗 CD40–CD40L: supportive cellular interactions 🎯 Therapeutic targets: • BTK inhibitors → disrupt signaling and tissue support • Venetoclax → inhibits BCL2, restoring apoptosis • Anti-CD20 antibodies → target CD20⁺ B cells. (nejm.org⁠) 5️⃣ 📊 LANDMARK FRONTLINE TRIAL: E1912 Previously untreated patients ≤70 years; del(17p) excluded. 💊 Ibrutinib–rituximab vs fludarabine–cyclophosphamide–rituximab: ✅ 3-year progression-free survival: 89.4% vs 72.9% ✅ HR 0.35; P<0.001 🧠 These are the original 2019 results. Longer follow-up confirmed a PFS benefit in both mutated and unmutated IGHV disease. (nejm.org⁠, pmc.ncbi.nlm.nih.gov⁠) 6️⃣ 📊 ALLIANCE A041202 Previously untreated patients ≥65 years: 2-year progression-free survival: 💊 Ibrutinib: 87% 💊 Ibrutinib–rituximab: 88% 💉 Bendamustine–rituximab: 74% 💡 Adding rituximab to ibrutinib did NOT significantly improve PFS in this trial. (nejm.org⁠) 7️⃣ ⚠️ IBRUTINIB TOXICITY ❤️ Atrial fibrillation/flutter; serious ventricular arrhythmias can occur 📈 Hypertension 🩸 Bruising/major bleeding 🦠 Infections 🚽 Diarrhea 🦴 Arthralgia/musculoskeletal pain 🩺 Monitor BP, cardiac symptoms, bleeding, CBC & infections; review interacting medications and antithrombotic therapy. (dailymed.nlm.nih.gov⁠) 8️⃣ 📉 WHAT DOES “2.1 YEARS” ON THE SLIDE MEAN? In the E1912 update, 101 patients stopped ibrutinib for reasons OTHER than progression/death. ⏳ Median time from discontinuation to progression or death: 25 months ≈2.1 years. ⚠️ This is post-discontinuation PFS—not overall survival and not evidence supporting elective treatment cessation. (pmc.ncbi.nlm.nih.gov⁠) 📚 Sources: 🔗 iwCLL criteria⁠ 🔗 CLL biology & treatment⁠ 🔗 E1912⁠ 🔗 Alliance A041202⁠ 🔗 E1912 long-term follow-up⁠ 🔗 Ibrutinib prescribing information⁠ #CLL #Hematology #BTKi #Ibrutinib #MedEd #KFSHRC

🩸 Frontline CLL: does obinutuzumab timing matter? 🔬 MD Anderson randomized phase II trial: 84 patients, comparing acalabrutinib + venetoclax with delayed, response-adapted versus early obinutuzumab. ⏳ Delayed strategy: assess at cycle 14 → add 6 cycles of obinutuzumab from cycle 15 for detectable MRD or partial response. ➡️ 32/42 patients (76%) ultimately received it. 📊 Delayed vs early, as reported on the slide: 🎯 Bone marrow uMRD4 at cycle 26: 90% vs 94% 🦠 Year-1 grade ≥3 infections: 5% vs 26%; P=0.013 🩸 Year-1 grade ≥3 neutropenia: 12% vs 64%; P<0.00001 ✅ Completed 2 years: 93% vs 76% 🦠 COVID-19 deaths: 0 vs 3 🧠 Clinical pearl: Delaying obinutuzumab showed less first-year toxicity, with numerically similar final marrow MRD clearance. ⚠️ Small phase II study: similar MRD rates do not establish equivalent long-term PFS/OS or justify universal antibody omission. 🔎 uMRD4 = disease undetectable at a sensitivity of 10⁻⁴. The reported cycle-26 comparison had P=0.683. (openalex.org⁠) 📚 Swaminathan et al. ASH 2025, abstract 681. Blood abstract⁠ #CLL #Hematology #ASH25 #MRD #KFSHRC

🩸 Richter transformation in CLL: PET, pathology & the withdrawal trap! 🧵 1️⃣ 🔥 SUVmax ≥5 → strongly consider biopsy In suspected transformation, particularly during B-cell receptor inhibitor therapy, do not wait for SUVmax ≥10. 🎯 Target the most FDG-avid accessible lesion. 🔬 Excisional or adequate core biopsy establishes the diagnosis. (haematologica.org⁠) 2️⃣ 📊 Why use the lower threshold? In Wang et al.’s cohort of 54 biopsied patients: • SUVmax ≥5: sensitivity 96%, specificity 21% • SUVmax ≥10: sensitivity 56%, specificity 76% ⚠️ Higher thresholds miss transformation. ⚠️ High uptake also occurs with progressive CLL, inflammation or another malignancy. ⚠️ SUVmax <5 does not completely exclude Richter transformation when clinical suspicion remains high. (haematologica.org⁠) 3️⃣ 🔬 Accelerated CLL ≠ DLBCL transformation Accelerated CLL shows expanded/highly active proliferation centers. Classic histological criteria include: 🔹 Proliferation centers broader than a ×20 field 🔹 >2.4 mitoses per proliferation center 🔹 Ki-67 >40% within proliferation centers One or more may support accelerated CLL; a high Ki-67 alone does not establish DLBCL. Expert hematopathology review is essential. (haematologica.org⁠) 4️⃣ 🧩 “Pseudo-Richter” after BTKi interruption Rare reports—mainly with ibrutinib—describe reversible Richter-like changes during a treatment hold. 🚨 Even biopsy findings may resemble DLBCL. 🔄 Resolution after restarting ibrutinib has been reported. 📅 Always provide the pathologist with the drug interruption timeline. (pmc.ncbi.nlm.nih.gov⁠, pubmed.ncbi.nlm.nih.gov⁠) 5️⃣ 🛑 A withdrawal flare is a diagnostic consideration—not an assumption Evidence for pseudo-Richter comes from small reports. Suspected true transformation still requires urgent evaluation, expert pathology review and close reassessment; restarting a BTKi alone is not a general treatment strategy for confirmed Richter transformation. (pmc.ncbi.nlm.nih.gov⁠, pubmed.ncbi.nlm.nih.gov⁠) 🧠 Memory pearl: “PET guides the biopsy; pathology and clinical context establish the diagnosis.” 📚 Wang: PET thresholds⁠ | Giné: accelerated CLL⁠ | Hampel: BTKi interruption⁠ #CLL #RichterTransformation #Hematopathology #PETCT #BTKi #MedEd #KFSHRC

🩸 CAR-T FDA indications: hematology board guide 🎯 CD19: liso, axi, tisa, obe, brexu 🎯 BCMA: ide, cilta 2L = second-line; ≥2 prior lines = third-line or later. 1️⃣ Liso-cel — lisocabtagene maraleucel (Breyanzi) Adults with: 🔹 Large B-cell lymphoma (LBCL): 2L: primary refractory or relapse within 12 months of first-line chemoimmunotherapy. 2L: refractory/relapsed after first-line treatment and HSCT-ineligible because of age or comorbidities, including later relapse. 3L+: R/R after ≥2 prior systemic lines. Includes DLBCL, transformed indolent lymphoma, high-grade B-cell lymphoma, PMBCL and FL grade 3B. 🔹 CLL/SLL: ≥2 prior lines, including BTKi + BCL2 inhibitor. 🔹 FL: ≥2 prior lines. 🔹 MCL: ≥2 prior lines, including a BTKi. 🔹 MZL: ≥2 prior lines. 🧠 Liso = broadest list: LBCL + CLL + FL + MCL + MZL. 📚 FDA label⁠. 2️⃣ Axi-cel — axicabtagene ciloleucel (Yescarta) Adults with: 🔹 LBCL, 2L: primary refractory or relapse within 12 months of first-line chemoimmunotherapy. 🔹 LBCL, 3L+: R/R after ≥2 prior lines; includes DLBCL, PMBCL, high-grade B-cell lymphoma and DLBCL arising from FL. 🔹 FL: ≥2 prior lines. 🧠 Axi = aggressive lymphoma + follicular lymphoma. 📚 FDA label⁠. 3️⃣ Tisa-cel — tisagenlecleucel (Kymriah) 🔹 B-cell precursor ALL, age ≤25 years: refractory OR second/later relapse. 🔹 Adult LBCL: ≥2 prior lines; includes DLBCL, high-grade B-cell lymphoma and DLBCL arising from FL. 🔹 Adult FL: ≥2 prior lines. 🚨 No FDA second-line LBCL indication. 🧠 Tisa = young ALL + later-line lymphoma. 📚 FDA label⁠. 4️⃣ Obe-cel — obecabtagene autoleucel (Aucatzyl) 🔹 Adults with R/R B-cell precursor ALL. 🧠 Obe = adult B-ALL. 📚 FDA approval⁠. 5️⃣ Brexu-cel — brexucabtagene autoleucel (Tecartus) 🔹 Adult R/R MCL. 🔹 Adult R/R B-cell precursor ALL. 🚨 MCL label does not require previous BTKi or specify ≥2 prior lines—a key distinction from liso-cel. 🧠 Brexu = mantle + adult ALL. 📚 FDA label⁠. 6️⃣ Ide-cel — idecabtagene vicleucel (Abecma) 🔹 Adult R/R multiple myeloma after ≥2 prior lines, including: 💊 IMiD 💊 Proteasome inhibitor 💊 Anti-CD38 monoclonal antibody 🧠 Ide = 2 prior lines + 3 drug classes → 3L+. 📚 FDA indication⁠. 7️⃣ Cilta-cel — ciltacabtagene autoleucel (Carvykti) 🔹 Adult R/R multiple myeloma after ≥1 prior line, including: 💊 Proteasome inhibitor 💊 IMiD 🚨 Must be lenalidomide-refractory. 🧠 Cilta = 1 prior line + len-refractory → 2L+. 📚 FDA label⁠. 🎓 Rapid-recall exam traps ✅ Second-line LBCL: axi or liso. ✅ Late-relapse LBCL + HSCT-ineligible: remember liso’s specific indication. ✅ CLL/SLL or MZL: liso. ✅ MCL: brexu or liso—different prior-treatment requirements. ✅ Adult B-ALL: obe or brexu; tisa also overlaps at ages 18–25 when its disease criteria are met. ✅ FL: axi, tisa, liso—all after ≥2 prior lines. ✅ Myeloma: cilta 1 / ide 2 prior lines; remember the required drug exposures. #CART #Hematology #BoardExams #CellularTherapy #KFSHRC

🩸 Relapsed CLL: treatment-sequencing pearls 🎤 From Dr. Sameer Parikh’s presentation, with evidence updates. 1️⃣ 💊 After chemoimmunotherapy Move to targeted therapy: acalabrutinib, zanubrutinib, or venetoclax + anti-CD20. Fixed-duration venetoclax is an option; selection depends on prior exposure, comorbidities and patient preference. (pmc.ncbi.nlm.nih.gov) 2️⃣ 🔄 After covalent BTK inhibitor therapy Distinguish intolerance from progression: 🔹 Intolerance → another covalent BTKi may be reasonable. 🔹 Progression → change treatment strategy; venetoclax-based therapy is an established option. (pmc.ncbi.nlm.nih.gov) 3️⃣ 🚀 BRUIN CLL-322: randomized phase III Pirtobrutinib + venetoclax + rituximab versus venetoclax + rituximab; 639 patients. 📊 Overall 24-month PFS: 87% vs 72%. 📉 PFS HR 0.55: approximately 45% lower hazard of progression/death. ⏳ OS benefit remains unproven. (sciencedirect.com, lilly.gcs-web.com) 4️⃣ 🔍 What does the slide’s “88%” mean? In an exploratory second-line subgroup progressing after frontline covalent BTKi, 24-month PFS was 88% vs 52% with triplet versus doublet. ⚠️ This is a subgroup result, not the overall trial estimate. (lilly.gcs-web.com) 5️⃣ ♻️ After fixed-duration venetoclax Retreatment can be considered after a durable treatment-free remission—LRF consensus suggests ≥1 year off therapy, with prior good tolerability. 🚨 Progression during venetoclax is a different scenario; consider a class switch, such as a second-generation BTKi if BTKi-naïve. (pmc.ncbi.nlm.nih.gov) 📚 Sources: BRUIN CLL-322 | LRF sequencing consensus #CLL #Hematology #Lymphoma #PrecisionMedicine #KFSHRC

🩸 Hazard ratio (HR) in hematology—how to read it HR compares the instantaneous event rates between two groups among patients who have not yet experienced the event. It incorporates when events occur, not simply how many occur. 1️⃣ First identify the endpoint 🎯 💀 Overall survival (OS): event = death from any cause. 📉 Progression-free survival (PFS): event = progression or death. 🔄 Event-free survival (EFS): events depend on the trial definition—check the protocol. 2️⃣ Interpret the number 🔢 For experimental treatment versus control, when the event is unfavorable: 🟢 HR 0.70: 30% lower hazard. 🟢 HR 0.50: 50% lower hazard. ⚪ HR 1.00: equal hazards. 🔴 HR 1.30: 30% higher hazard. 🧠 Relative hazard reduction = (1 − HR) × 100%. Always check which group is the reference. 3️⃣ Example from your CLL slides 💊 In FLAIR, ibrutinib–venetoclax versus ibrutinib alone: ❤️ OS HR 0.41; 95% CI 0.20–0.83 ✅ Interpretation: 59% lower hazard of death during follow-up. ❌ It does not mean 59% fewer patients died, 59% longer survival, or a 59-percentage-point survival improvement. 4️⃣ Read the confidence interval 🔍 For a conventional two-sided superiority analysis: ✅ 95% CI entirely below 1: statistically significant lower hazard at the 5% level. ❓ 95% CI includes 1: superiority is not established; this does not prove equivalence. 📏 Narrower CI = greater precision. Example: HR 0.76, CI 0.49–1.18 suggests benefit numerically, but the uncertainty includes no difference and possible harm. 5️⃣ HR is not absolute benefit ⚖️ 🧮 Hypothetical example: 3-year PFS is 80% versus 70%. ➡️ Absolute PFS improvement = 10 percentage points. ➡️ Progression/death probability = 20% versus 30%. ➡️ Risk ratio at 3 years = 0.67. 🚫 You cannot determine the HR from those two percentages alone without additional assumptions. 6️⃣ Two hematology exam pearls 🎓 ⏳ A single HR is easiest to interpret when hazards are approximately proportional over time. Crossing curves or delayed effects can make it misleading; examine survival rates at specified times and restricted mean survival time. 🌱 After HSCT, relapse and nonrelapse mortality are competing events. A cause-specific HR and a Fine–Gray subdistribution HR answer different questions. 📚 NCI definition⁠ • HR primer in cancer trials⁠ #Hematology #ClinicalTrials #Biostatistics #MedEd #KFSHRC

🧵 Frontline CLL: how do I choose treatment for my patient? 🩸💊 1️⃣ Start with “WHY treat?” ✅ Confirm iwCLL treatment indications. 🧬 High-risk genetics alone do not justify treating asymptomatic CLL. Before therapy: 🔬 FISH for del(17p) + TP53 sequencing—repeat before each treatment line. 🧬 IGHV mutation status—usually tested once. (pmc.ncbi.nlm.nih.gov⁠) 2️⃣ Know the main treatment strategies ⏳ ♾️ Continuous: • Zanubrutinib • Acalabrutinib ± obinutuzumab → Until progression or intolerance. 📅 Fixed-duration: • Venetoclax–obinutuzumab: 12 cycles. • Acalabrutinib–venetoclax: 14 cycles of acalabrutinib, with venetoclax during cycles 3–14. ✅ Acalabrutinib–venetoclax received FDA approval in February 2026. (pubmed.ncbi.nlm.nih.gov⁠, fda.gov⁠) 3️⃣ Match treatment to disease biology 🧬 🔴 del(17p)/TP53 mutation: Often favor continuous acalabrutinib or zanubrutinib. Venetoclax–obinutuzumab remains an option after individualized discussion. 🟢 TP53-intact, mutated IGHV, nonbulky disease: The presented Mayo approach favors venetoclax–obinutuzumab. 📦 Bulky disease + preference for all-oral, time-limited therapy: The slide favors acalabrutinib–venetoclax. ⚠️ These are treatment preferences, not absolute eligibility rules. AMPLIFY excluded del(17p)/TP53-mutated disease. (pmc.ncbi.nlm.nih.gov⁠, fda.gov⁠) 4️⃣ Match treatment to comorbidities ❤️🩺 ❤️ AF, significant bleeding risk or anticoagulation → often favor venetoclax–obinutuzumab, after reviewing individual risks. 🫘 Renal impairment + bulky disease → increased tumor lysis syndrome risk with venetoclax. 🏥 Assess hydration, laboratory access and admission capacity. 💊 BTKi lead-in can reduce disease burden, but does not replace venetoclax ramp-up and TLS precautions. (pmc.ncbi.nlm.nih.gov⁠, fda.gov⁠) 5️⃣ Ask what matters to the patient 🤝 💊 All-oral treatment or acceptable IV infusions? ⏳ Continuous disease control or a planned treatment-free interval? 🚗 Ability to attend frequent initial visits? 💰 Drug access, affordability and long-term adherence? 🎯 Aim for durable control, preserved quality of life and meaningful time off therapy when feasible. “Functional cure” remains an aspiration—not a promise. 6️⃣ Read the slides critically 🔎 🧪 Pirtobrutinib: promising frontline trial data do not equal frontline FDA approval. Its verified FDA indication is R/R CLL/SLL after a covalent BTKi. (fda.gov⁠) 🧬 MRD-guided ibrutinib–venetoclax: supported by FLAIR, but its stopping rules should not be transferred automatically to other regimens. (pubmed.ncbi.nlm.nih.gov⁠) ➕ Adding obinutuzumab to acalabrutinib–venetoclax: the slide suggests consideration in selected younger patients with unmutated IGHV; this is not a universal requirement. 📊 Never rank regimens using cross-trial PFS percentages alone—populations, exclusions and follow-up differ. 📚 Mayo lySMART 2026⁠ • LRF consensus⁠ • FLAIR⁠ #CLL #Hematology #PrecisionMedicine #MedEd #KFSHRC

🧬 R/R LARGE B-CELL LYMPHOMA: CAR-T & BISPECIFIC ANTIBODIES 🧵 1️⃣ 🏆 ZUMA-7: second-line axi-cel improves survival 👥 Primary refractory LBCL or relapse ≤12 months after first-line therapy. ⚖️ Axi-cel versus salvage chemotherapy → autologous SCT in responders. 📆 Median follow-up: 47.2 months ✅ 4-year OS: 54.6% vs 46.0% 📉 HR 0.726 → 27.4% lower hazard of death 📊 Absolute OS difference: 8.6 percentage points. (ascopubs.org⁠, nejm.org⁠) 💡 Supports second-line axi-cel in this population; the trial did not directly randomize second-line versus third-line CAR-T. 2️⃣ 📈 Real-world axi-cel: durable benefit, ongoing survivorship needs 👥 275 infused patients after ≥2 prior lines. At 5 years: 🟢 OS: 40% 🔵 PFS: 29% 🟣 Lymphoma-specific survival: 53% ⚠️ Correction to the slide: 53% represents lymphoma-specific survival—not disease-free survival. 🦠 Nonrelapse mortality: 16.2%, with infections and subsequent malignancies important contributors. ➡️ Long-term outcomes support curative potential in a subset, alongside continued infection prevention and surveillance. (pmc.ncbi.nlm.nih.gov⁠, scholarship.miami.edu⁠, mdanderson.elsevierpure.com⁠) 3️⃣ 🎯 Glofitamab: activity after CAR-T failure Pivotal phase II study: 👥 155 enrolled; 154 received study treatment. ✅ ORR: approximately 52% 🎯 Best CR rate: 39% 🧬 Prior CAR-T subgroup: 52 patients; CR 35% 📆 12-month PFS: 37% ⏳ Among complete responders, 78% remained in CR at 12 months. ⚠️ “39% CR at 12 months” mixes two different endpoints: best CR rate and duration of CR. (pubmed.ncbi.nlm.nih.gov⁠, gene.com⁠) 4️⃣ 💉 Bispecific schedules are drug-specific 🔹 Glofitamab: IV, obinutuzumab pretreatment, step-up dosing, fixed course of 12 cycles—approximately 8 months. 🔹 Epcoritamab monotherapy for DLBCL: SC, step-up dosing, continued until progression or unacceptable toxicity. ⚠️ “Repeated infusions for up to one year” is not a class-wide rule. 🔥 Key risks include CRS, infections, cytopenias and possible ICANS. (pubmed.ncbi.nlm.nih.gov⁠, dailymed.nlm.nih.gov⁠) 5️⃣ 🌍 Approval wording matters I Glofitamab monotherapy has an established indication after ≥2 prior systemic therapies in specified LBCL populations. 🇪🇺 Glofitamab–GemOx is also authorized for R/R DLBCL NOS in adults ineligible for autologous SCT. ⚠️ ASCT-ineligible and CAR-T-ineligible are different populations. Specify the drug, combination, jurisdiction and exact indication. (fda.gov⁠, ema.europa.eu⁠) 🧠 Memory anchors: “ZUMA-7 → second-line survival.” “Glofitamab → 12 cycles; CR about 4 in 10.” “Real-world axi-cel → 40 OS / 29 PFS / 53 lymphoma-specific.” 📚 ZUMA-7 OS⁠ • Real-world 5-year axi-cel⁠ • Glofitamab pivotal study⁠ • EMA indication⁠ #DLBCL #Lymphoma #CART #BispecificAntibodies #Hematology #KFSHRC

🫁 PMBCL: the LYSA 2025 PET-adapted algorithm 💡 Interpret the Deauville score alongside the change in uptake—PET positivity alone does not prove treatment failure. 1️⃣ Induction: 4 cycles 💊 R-CHOP14 every 2 weeks OR DA-EPOCH-R every 3 weeks OR R-ACVBP every 2 weeks. 2️⃣ PET after cycle 4: assess response 🟢 DS1–3, OR DS4–5 with >70% reduction in SUVmax from baseline ➡️ Continue planned consolidation: • 2 additional R-CHOP14 or DA-EPOCH-R cycles. • Protocol-specific consolidation after R-ACVBP. 🔴 DS4–5 with ≤70% SUVmax reduction ➡️ Consider biopsy. ✅ Negative → continue chemotherapy. ❌ Lymphoma confirmed → salvage therapy. ❓ Inconclusive/unfeasible → prompt multidisciplinary decision. 3️⃣ End-of-treatment PET 🟢 DS1–3 ➡️ Follow-up; no routine mediastinal RT. 🟠 DS4 ➡️ Consider observation with serial imaging. ➡️ Repeat PET or diffusion-weighted MRI may help clarify residual uptake. 🔴 DS5: distinguish the response pattern! 📉 Partial metabolic response ➡️ Consider biopsy. • Positive → salvage therapy. • Negative/inconclusive/unfeasible → consider serial PET, diffusion-weighted MRI or consolidation RT. 📈 Progressive disease or no metabolic response ➡️ Consider biopsy and proceed toward salvage treatment. 🧠 CNS prophylaxis is selective: LYSA suggests considering 2 HD-MTX doses for CNS-IPI 4–6, particularly with renal/adrenal involvement—not routinely for every PMBCL patient. 🎯 Key nuance: LYSA separates DS5 with improving disease from DS5 with progression/no response. 📚 Adapted from the displayed LYSA algorithm: Renaud et al. Eur J Cancer, 2025. 🔗 Original guidelines #PMBCL #Lymphoma #PETCT #LYSA #Hematology #KFSHRC

🧬 CAR-T toxicities: beyond CRS & ICANS Highlights from Prof. Martin Hutchings’ slides at the 8th International Lymphoma Conference 👇 1️⃣ ⏳ Toxicity evolves over time 🔴 Early: first 30 days • CRS, ICANS & lymphodepletion-related toxicity • Bacterial infections predominate; viral & fungal infections also occur 🟠 Intermediate: D+30–90 • Persistent cytopenias & hypogammaglobulinemia • Viral & opportunistic infections • Neurological/neuropsychiatric complications 🔵 Late: >D+90 • Ongoing immune dysfunction & infections • Persistent or recurrent cytopenias • Rare immune-mediated events • Subsequent malignancies requiring long-term surveillance 2️⃣ 🦠 Infection risk starts BEFORE CAR-T 🩸 Disease-related marrow involvement → reduced hematopoietic reserve 💊 Prior chemotherapy → cytopenias & mucosal injury 🎯 Anti-CD20 therapy → prolonged B-cell depletion 🧪 Bendamustine & other lymphotoxic treatments → impaired cellular immunity 💉 Corticosteroids → broad immunosuppression ➡️ CAR-T adds to an already compromised immune system. 3️⃣ 🛡️ Why does CAR-T increase infection risk? 🎯 CD19-directed therapy depletes normal B cells: an on-target, off-tumor effect 📉 Hypogammaglobulinemia → impaired antibody protection 🩸 Prolonged neutropenia → bacterial/fungal vulnerability 🧬 Delayed T-cell recovery → impaired antiviral & opportunistic pathogen control 🔥 Severe inflammation and treatment of CRS/ICANS can further increase susceptibility ⚠️ The degree and duration of immune dysfunction vary between patients and CAR-T products. 4️⃣ 🚨 CRS and infection can coexist 🌡️ Fever after CAR-T should trigger assessment for infection, even when CRS is suspected. 💉 Corticosteroids and tocilizumab may blunt inflammatory signs. 🦠 Improvement after CRS treatment does not exclude an accompanying infection. 5️⃣ 📆 The timeline is a guide—not an expiry date Mold infections and Pneumocystis pneumonia do not follow rigid calendar boundaries. Risk depends on: 🩸 Depth/duration of cytopenias 🧬 Immune recovery 💊 Ongoing immunosuppression 🛡️ Prophylaxis exposure 6️⃣ 🔎 Long-term care matters Follow blood counts, immunoglobulins, infections and neurological symptoms. Individualize antimicrobial prophylaxis, immunoglobulin replacement and revaccination as immune recovery evolves. (ashpublications.org⁠) 🙏 Credit: Prof. Martin Hutchings for the educational slides. 📚 Further reading: ASTCT infection prevention guidance⁠ | ASH: Late complications and long-term care⁠ #CART #CellularTherapy #Lymphoma #Hematology #InfectiousDiseases #Survivorship #KFSHRC