Hematology Media Center (HMC)💡

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🧬 Trisomy 21 (Down Syndrome) in Hematology – High-Yield Pearls 🧬 🧬 Genetics: ➕ Extra copy of chromosome 21 → gene dosage effect (RUNX1, ERG, DYRK1A) → leukemogenesis 👶 Neonatal hallmark: 🔥 Transient Abnormal Myelopoiesis (TAM) 📊 Incidence ~10% of DS neonates 🧪 Blasts in blood + GATA1 mutation (pathognomonic) ⏳ Spontaneous resolution in most within 3 months ⚠️ TAM complications: 💥 Hepatic fibrosis / cholestasis 💥 High WBC → hyperviscosity 💥 Risk early death ~10–20% 👉 Treat only if severe → low-dose cytarabine 🔁 Progression risk: ⚡ ~20–30% TAM → Myeloid Leukemia of Down Syndrome (ML-DS) within 4 years 🩸 ML-DS (AMKL subtype): 📌 Peak age <5 years 🧪 Megakaryoblastic phenotype (CD41, CD61) 🧬 Always GATA1 mutation 💊 Excellent chemo sensitivity → reduced-intensity regimens 📊 Prognosis ML-DS: 📈 Survival >80–90% (better than non-DS AML) ⚠️ BUT ↑ treatment toxicity (infection, mucositis) 🧠 ALL in Down syndrome: 📉 Worse outcomes vs non-DS ALL ⚠️ Higher toxicity (methotrexate, asparaginase) 🧬 CRLF2 rearrangements, JAK mutations common ⚠️ Treatment challenges: 💊 ↑ chemo toxicity → need dose adjustment 🫀 Cardiac + pulmonary comorbidities 🧫 High infection risk 🧪 Screening recommendation: 👶 All DS neonates → CBC + peripheral smear (rule out TAM) 📌 Key diagnostic pearl: 👉 DS + blasts in neonate = assume TAM until proven otherwise 📌 Key molecular axis: 👉 Trisomy 21 + GATA1 mutation = TAM / ML-DS pathway ⸻ 🧠 MCQ: Most characteristic mutation in Down syndrome–associated AML? A) NPM1 B) FLT3 C) GATA1 D) IDH2 ✅ Answer: C ⸻ 🎭 OSCE Scenario: Neonate with DS + leukocytosis + blasts 👉 Explain: “This is often a transient leukemia-like condition (TAM) that may resolve, but needs close monitoring due to risk of progression.” ⸻ #Hematology #AML #DownSyndrome #Pediatrics #Leukemia #KFSHRC

Chimeric antigen receptor T cells for autoimmune diseases, in particular immune thrombocytopenia @BrJHaem onlinelibrary.wiley.com/doi/10.1111/bj…

🧬 CTCL (Cutaneous T-Cell Lymphoma) — Diagnosis Framework 🔬 Morphology (Skin Biopsy) 🧠 Epidermotropism (hallmark) → atypical lymphocytes migrating into epidermis 🧠 Pautrier microabscesses → clusters of atypical T-cells in epidermis (specific but not always present) 🧠 Atypical lymphocytes → cerebriform nuclei (Sezary cells) 🧠 Band-like infiltrate in superficial dermis 🧠 Minimal spongiosis (helps distinguish from eczema) 🧠 Folliculotropism (variant MF) → infiltrate around hair follicles 🧠 Syringotropism possible 🧠 Dermal fibrosis in advanced stages ⸻ 🧪 Immunohistochemistry (IHC) 🧬 CD3+ (pan T-cell marker) 🧬 CD4+ predominance (CD4:CD8 ↑ >4–6 suspicious) 🧬 Loss of T-cell markers:  ❗ CD7 loss (most sensitive)  ❗ CD26 loss (important in Sezary)  ❗ CD5 ↓ (less common) 🧬 CD8 variants exist (rare) 🧬 CD30+ → suggests transformation (large cell transformation) 🧬 Ki-67 ↑ → aggressive disease 🧬 PD-1 / ICOS → follicular helper phenotype (subset) ⸻ 🧫 Flow Cytometry (Blood — Sezary Syndrome) 🩸 CD3+ CD4+ T-cell expansion 🩸 CD4/CD8 ratio >10 highly suggestive 🩸 Loss of CD7 and/or CD26 (key diagnostic clue) 🩸 Aberrant T-cell phenotype (dim CD3, abnormal markers) 🩸 Absolute Sezary count ≥1000/µL (diagnostic threshold) ⸻ 🧬 Molecular Studies 🧬 TCR gene rearrangement (PCR/NGS):  ✔ Clonality supports CTCL (not diagnostic alone)  ✔ Same clone in skin + blood → strong evidence 🧬 Common mutations:  🔹 PLCG1  🔹 STAT3 / STAT5B  🔹 DNMT3A  🔹 TET2  🔹 RHOA (less common vs PTCL) 🧬 Copy number alterations:  🔺 Gains: 8q, 17q  🔻 Loss: 10q, 17p (TP53) ⸻ 🧠 Diagnostic Pitfalls ⚠️ Early MF mimics eczema/dermatitis → clinicopath correlation essential ⚠️ Sparse infiltrate ≠ exclude CTCL ⚠️ Clonality alone ≠ lymphoma (can be reactive) ⸻ 🧾 Diagnostic Integration (ISCL/EORTC approach) ✅ Clinical (patch/plaque progression) ✅ Histology (epidermotropism + atypia) ✅ Immunophenotype (loss markers) ✅ Molecular clonality ⸻ 🎯 Practical Take-Home ✔ CD7/CD26 loss + CD4 predominance = strongest immunophenotypic clue ✔ Epidermotropism without spongiosis = key morphologic discriminator ✔ Always correlate with clinical evolution ⸻ ❓MCQ A patient with suspected CTCL has CD3+, CD4+, CD7 loss, and TCR clonality. What is the MOST supportive feature for diagnosis? A) TCR clonality alone B) CD4 positivity C) Loss of CD7 D) Presence of inflammation ✅ Answer: C) Loss of CD7 (most sensitive immunophenotypic abnormality) ⸻ 🩺 OSCE Scenario 📌 Patient with chronic “eczema” not responding to steroids → Skin biopsy: epidermotropism, CD4+, CD7 loss → Blood: CD4/CD8 = 12 👉 Next step: ✔ Peripheral blood flow + Sezary count ✔ TCR clonality (skin + blood) ✔ Stage as MF vs Sezary syndrome

Review: From Time-Limited Therapy to Treatment-Free Observation: The Evolving Role of MRD in CLL Management onlinelibrary.wiley.com/doi/full/10.11…

12/ Big picture takeaways ✅ Proof-of-concept: CAR-T can induce deep MRD(-) in SMM ⚠️ But: • Not practice-changing yet • Needs randomized trials + long-term data Bottom Line: I will not feel comfortable to treat HRSMM with Cilta-Cel!!! Even on a clinical trial #ICE_T #MedEd #medtwitter #USMIRC @US_HMC @MedwatchKate @oncodaily @Larvol @USMIRCNEWS #mmsm #MYELOMA

11/ ⚠️ No QoL data • Hospitalization • Toxicity burden • Long-term function 👉 Critical in asymptomatic population #ICE_T #MedEd #medtwitter #USMIRC @US_HMC @MedwatchKate @oncodaily @Larvol @USMIRCNEWS #mmsm #MYELOMA

10/ ⚠️ Neurotoxicity concerns • Novel NINTs (movement disorders) • Some persistent 🧠 In asymptomatic patients → BIG issue 👉 Tolerance threshold is much lower vs RRMM #ICE_T #MedEd #medtwitter #USMIRC @US_HMC @MedwatchKate @oncodaily @Larvol @USMIRCNEWS #mmsm #MYELOMA

9/ ⚠️ Overtreatment risk SMM ≠ always destined to progress 💥 Treating all HR-SMM with CAR-T = • Cost • Toxicity • Resource burden 👉 Risk-benefit balance unclear #ICE_T #MedEd #medtwitter #USMIRC @US_HMC @MedwatchKate @oncodaily @Larvol @USMIRCNEWS #mmsm #MYELOMA

Outcomes of relapsed or refractory acute myeloid leukemia after menin inhibition failure ashpublications.org/bloodadvances/… #leusm

LR-MDS + thrombocytopenia treated with VLD decitabine + rhTPO (n=20): 🩸 HI-P: 63% (rapid, ~1 mo) 🧪 Any hematologic response: 74% 🔁 PLT Tx independence: 57% 🩸 RBC independence: 86% ⚠️ AEs: neutropenia, infections 📉 No progression on treatment; later progression in 2 pts

💊 Chemo in Hematology → Alopecia Risk (High-Yield Exam Pearls) 💇‍♂️⬇️ 🔥 Mechanism Hair follicles = rapidly dividing → highly sensitive to cytotoxic agents → anagen effluvium (rapid hair loss within 1–3 weeks) ⸻ 💥 HIGH RISK (Almost universal alopecia) 💣 Anthracyclines → Doxorubicin, Daunorubicin, Idarubicin 💣 Alkylators (high dose) → Cyclophosphamide, Ifosfamide, Busulfan 💣 Taxanes → Paclitaxel, Docetaxel 💣 Topoisomerase inhibitors → Etoposide (VP-16) 👉 Classic regimens: 👉 CHOP (Cyclophosphamide + Doxorubicin) → 🎯 alopecia common 👉 AML induction (7+3) → 💯 expected hair loss ⸻ ⚠️ MODERATE RISK (Variable alopecia) ⚡ Antimetabolites → Cytarabine (Ara-C), Methotrexate ⚡ Platinum agents → Cisplatin, Carboplatin ⚡ Bendamustine → partial thinning ⸻ 🟡 LOW / MINIMAL RISK 🟢 Vinca alkaloids → Vincristine, Vinblastine (less hair loss vs others) 🟢 Bleomycin → minimal alopecia 🟢 Hydroxyurea → mild thinning only ⸻ 🧬 Targeted / Novel Agents (Important distinction) ✨ Venetoclax (Venclexta) → ❌ no significant alopecia ✨ Imatinib (Gleevec) / TKIs → rare hair thinning ✨ Rituximab (Rituxan) → ❌ no alopecia ✨ CAR-T → ❌ no direct hair loss (conditioning chemo is culprit) ⸻ ⏱️ Timeline 🕐 Starts: 1–3 weeks after chemo 📉 Peak: 1–2 months 🔄 Regrowth: 1–3 months post chemo (may change texture/color) ⸻ 🛡️ Prevention / Mitigation ❄️ Scalp cooling → ↓ follicular exposure (limited in heme protocols) 💊 Minoxidil → may speed regrowth (not prevention) 📢 Counseling = essential before induction ⸻ 🎯 Exam Pearl 👉 Alopecia = marker of high cytotoxic intensity (anthracycline + alkylator combo) 👉 Absence of hair loss ≠ ineffective therapy (e.g., targeted agents) ⸻ #Hematology #Oncology #ChemoToxicity #AML #Lymphoma #BMT #KFSHRC

8/ ⏳ Short follow-up (15 months) • SMM is a long disease course ❗ Key unanswered: • Are we curing disease? • Or just delaying progression? 👉 Durability remains UNKNOWN #ICE_T #MedEd #medtwitter #USMIRC @US_HMC @MedwatchKate @oncodaily @Larvol @USMIRCNEWS #mmsm #MYELOMA

Infections after bispecific antibodies in B-cell lymphomas ashpublications.org/bloodadvances/… #lymsm

Outcomes of Allogeneic Hematopoietic Cell Transplantation for Hypoplastic Myelodysplastic Syndrome: A Latin American Multicenter Analysis @ASTCT_Journal astctjournal.org/article/S2666-…

Critiques/Limitations 6/ ⚠️ Small sample size (n=20) • No statistical power • Rare toxicities likely missed 👉 Signals ≠ definitive conclusions 7/ ⚠️ Single-arm, no comparator • No randomized control • Cannot compare vs: – Dara – KRd-based early intervention 👉 Magnitude of benefit unclear #ICE_T #MedEd #medtwitter #USMIRC @US_HMC @MedwatchKate @oncodaily @Larvol @USMIRCNEWS #mmsm #MYELOMA

🧬 Prophylactic Steroids in CAR-T — What do guidelines & trials say? ⸻ 🚫 Not standard for all patients ➡️ American Society for Transplantation and Cellular Therapy & National Comprehensive Cancer Network ❌ Do NOT recommend routine prophylactic steroids ➡️ Concern: ↓ CAR-T expansion & efficacy (theoretical, not consistently proven) ⸻ 🟡 When considered (selected high-risk patients) ➡️ High tumor burden 🔥 ➡️ High inflammatory markers (CRP/ferritin) ➡️ Prior severe CRS risk factors ➡️ Bridging failure / bulky disease ⸻ 💊 Evidence-based regimens (center protocols / trials) 👉 Axi-cel (ZUMA-1 cohort 4) ➡️ Early steroid strategy ↓ CRS/ICANS Dexamethasone 10 mg PO/IV daily Start Day 0–2 (around infusion) Short course (3 days) ⸻ 👉 Alternative early-use approach ➡️ Not pure prophylaxis (more “very early preemptive”) Dexamethasone 10 mg IV q6–12h Triggered by persistent fever or early CRS signs ⸻ ⚖️ What is the real benefit? ✅ ↓ Grade ≥3 CRS ✅ ↓ ICANS incidence ❗ No clear compromise in response rates in modern data ⸻ ⚠️ Key risks 🦠 Infection ↑ 🧬 Potential ↓ CAR-T persistence (theoretical) 📉 Masking CRS severity ⸻ 🎯 Very high-yield distinction ➡️ True prophylactic steroids = BEFORE symptoms (rare use) ➡️ Most practice = early preemptive steroids, not pure prophylaxis ⸻ 🔥 Current practical approach (expert level) 🟢 Low-risk → ❌ no steroids 🟡 Intermediate/high-risk → consider early steroids (center protocol) 🔴 Established CRS/ICANS → steroids per grading ⸻ 🎓 MCQ Routine prophylactic steroids in CAR-T: A) Standard of care B) Always recommended C) Not routinely recommended ✅ D) Mandatory with axi-cel ⸻ 🩺 OSCE Q: “Do you give steroids prophylactically for CAR-T?” ✔️ “Not routinely per ASTCT/NCCN; considered only in high-risk pts or trial-based approaches like ZUMA-1 cohort 4 using short-course dexamethasone.” ⸻ 📚 Key Evidence ZUMA-1 Cohort 4 (axi-cel early steroid strategy) ashpublications.org/blood/article/… ASTCT/NCCN CAR-T toxicity guidance

#Hematology Real-world safety and effectiveness of zanubrutinib vs ibrutinib in #CLL: the CLL-ZANU2024 Italian cohort #lymsm #RWE ashpublications.org/bloodadvances/…

POD24 is a novel determinant of prognosis in patients with Waldenström macroglobulinemia ashpublications.org/bloodadvances/… #VWD

5/ 🧠 Neurotoxicity signal (important!) • Associated with ↑ CAR-T expansion & ALC • Some persistent grade 1 symptoms ⚠️ Raises concern for: • Parkinsonian features • Long-term neurologic risk 👉 Mechanism still unclear #ICE_T #MedEd #medtwitter #USMIRC @US_HMC @MedwatchKate @oncodaily @Larvol @USMIRCNEWS #mmsm #MYELOMA