Hematologic malignancies: high-yield review

Acute leukemias — high-yield

• AML:
  • Cytogenetic risk: favorable (t(8;21), inv(16), t(15;17) APL, NPM1 mut with or without FLT3-ITD (favorable only without adverse-risk cytogenetics; with adverse cytogenetics it is adverse risk)), intermediate (normal cytogenetics, FLT3-ITD without NPM1), adverse (complex, monosomal, TP53, MECOM, etc.).
  • 7+3 induction: cytarabine + daunorubicin/idarubicin.
  • CPX-351 (Vyxeos): for therapy-related AML or AML-MRC. Improved OS in older.
  • Targeted: FLT3 (midostaurin, gilteritinib, quizartinib), IDH1 (ivosidenib, olutasidenib), IDH2 (enasidenib), CD33 (gemtuzumab), Hedgehog (glasdegib), BCL2 (venetoclax), menin (revumenib for R/R KMT2A-r or NPM1-mut; ziftomenib for R/R NPM1-mut).
  • Older / unfit: ven + aza (VIALE-A — mOS 14.7 vs 9.6 mo).
  • APL (acute promyelocytic leukemia): t(15;17) PML-RARA. ATRA + arsenic trioxide for low/int risk; add idarubicin for high (WBC >10K). Watch for differentiation syndrome (dex prophylaxis).
• ALL:
  • B-ALL: Ph+ → TKI (imatinib, dasatinib, ponatinib) + chemo. Blinatumomab for MRD+ or relapsed. CD22 (inotuzumab). CD19 CAR-T (tisa, brexu).
  • T-ALL/LBL: asparaginase-containing regimens; nelarabine for refractory.
  • Ph-like ALL: CRLF2/JAK2/ABL1 alterations; TKI candidate.
  • Obe-cel (Aucatzyl, FELIX NEJM 2024, FDA Nov 2024): fast-off CD19 CAR-T for R/R adult B-ALL; less CRS/ICANS — first CAR-T approved without REMS.
  • Blina 1L (E1910 NEJM 2024, FDA Jun 2024): adding 4 cycles blinatumomab to consolidation in MRD-neg Ph- B-ALL adults — 3-yr OS 85% vs 68% (HR 0.41). Standard for newly dx CD19+ Ph- B-ALL in CR.
  • Ponatinib 1L Ph+ ALL (PhALLCON, FDA Mar 2024): ponatinib + chemo — MRD-neg CR 30% vs 12% imatinib; preferred TKI in fit newly dx Ph+ ALL.

CML

• BCR-ABL t(9;22). Chronic, accelerated, blast phase (ICC 2022 retains accelerated phase; WHO 5th edition uses a biphasic model of chronic and blast phase).
• 1L TKI: imatinib, dasatinib, nilotinib, bosutinib, asciminib (STAMP inhibitor, ABL myristoyl pocket; 1L per ASC4FIRST, FDA Oct 2024).
• Resistance / T315I: ponatinib, asciminib.
• Treatment-free remission (TFR) after sustained DMR (MR4 or deeper) for ≥2 yrs (on TKI ≥3 yrs).

CLL / SLL

• Diagnosis: ≥5 × 10⁹/L clonal B lymphocytes for ≥3 months, clonality and phenotype (CD5+, CD23+, CD19+, CD20 dim, kappa/lambda restricted) confirmed by flow cytometry.
• Prognostic markers: IGHV mutated (favorable) vs unmutated; del 17p / TP53 (poor); del 11q (ATM); del 13q (favorable); CD38, ZAP-70.
• Indications to treat (iwCLL): symptomatic, progressive marrow-failure cytopenias, bulky/progressive disease, B symptoms; AIHA/ITP only when poorly responsive to corticosteroids/standard therapy.
• 1L: BTK-i (acalabrutinib, zanubrutinib > ibrutinib due to safety) OR ven + obinutuzumab × 12 cycles (CLL14 — fixed-duration). Fit + IGHV-mut + no del(17p)/TP53 → FCR (rare now); TP53-aberrant disease gets targeted therapy, not FCR.
• R/R: switch class (BTK-i ↔ BCL2-i). Pirtobrutinib (non-covalent BTK-i). CD19 CAR-T (lisocabtagene).
• Richter transformation: aggressive DLBCL transformation; treat as DLBCL ± clonally-related strategies.
• AMPLIFY (NEJM 2025, FDA Feb 2026): acalabrutinib + venetoclax (FDA-approved without obinutuzumab) fixed-duration all-oral 1L CLL/SLL (excl 17p/TP53) — superior to chemoimmunotherapy; first all-oral fixed-duration frontline CLL regimen approved by the FDA (ibrutinib + venetoclax approved earlier in Europe).
• Liso-cel (TRANSCEND CLL 004, FDA Mar 2024): first CAR-T approved for R/R CLL/SLL after at least 2 prior lines including a BTK inhibitor and a BCL2 inhibitor.

Lymphomas — quick reference

• Reed-Sternberg cells (CD15+, CD30+, CD20−).
• Subtypes: nodular sclerosis (most common), mixed cellularity, lymphocyte-rich, lymphocyte-depleted, NLPHL (CD20+, treat differently).
• Early-stage: ABVD × 2–4 + ISRT (RAPID, HD16, etc.). (S1826 applies to advanced stage III to IV cHL: nivolumab-AVD was superior to brentuximab-AVD; it did not test BV-AVD plus nivolumab and is not an early-stage regimen.)
• Advanced: S1826 — nivolumab + AVD × 6 (new SOC). Or escalated BEACOPP (Europe).
• Refractory/relapsed: pembrolizumab (KEYNOTE-204), brentuximab, salvage chemo + autoSCT.

• DLBCL: R-CHOP × 6 (POLARIX — pola-R-CHP improved PFS). High-risk: dose-adjusted EPOCH-R for double-hit. CAR-T (axi-cel ZUMA-7, liso-cel TRANSFORM 2L per high-risk).
• CNS prophylaxis for high IPI/CNS risk score (HIV+, testicular, kidney/adrenal, double-hit) — IT MTX or HD-MTX.
• Follicular lymphoma: watch and wait if asymptomatic; R-bendamustine, R-CHOP. Mosunetuzumab (CD20×CD3 bispecific antibody), tisagenlecleucel CAR-T, axi-cel.
• MCL: BTK-i, ven, lenalidomide. CAR-T (brexu) for relapsed.
• Marginal zone: MALT (H. pylori), splenic, nodal. Antibiotics for H. pylori-positive MALT.
• Burkitt: very aggressive, rapid TLS. R-CODOX-M / IVAC, DA-EPOCH-R.
• Primary CNS lymphoma: HD-MTX + rituximab → autoSCT or WBRT.
• PTCL: CHOEP. Brentuximab for ALK+ ALCL. Belinostat, pralatrexate for relapsed (romidepsin still used but its US PTCL indication was withdrawn 2021).
• Cutaneous T-cell lymphoma (mycosis fungoides, Sezary): skin-directed therapy → mogamulizumab, romidepsin, brentuximab.

Multiple myeloma

• Diagnosis (CRAB): hyperCa, renal, anemia, bone lesions. SLiM-CRAB adds: ≥60% clonal marrow plasma cells; involved:uninvolved serum FLC ratio ≥100 (involved FLC ≥100 mg/L); >1 focal MRI lesion, each ≥5 mm.
• Standard 1L (transplant-eligible): Dara-RVd induction → autoSCT → maintenance lenalidomide. (D-VRd per PERSEUS — quadruplet improved PFS).
• Standard 1L (transplant-ineligible): D-Rd, or quadruplet Isa-VRd (IMROZ) or D-VRd (CEPHEUS) in fit patients; DVRd-lite option.
• Maintenance: lenalidomide ± daratumumab.
• Relapsed / refractory: triplet/quad combinations. Carfilzomib, pomalidomide, isatuximab, selinexor, elotuzumab.
• Advanced / penta-refractory:
  • CAR-T (BCMA): ide-cel (KarMMa), cilta-cel (CARTITUDE-1, -4 — even earlier-line approval).
  • Bispecific (BCMA, GPRC5D): teclistamab, elranatamab, talquetamab, linvoseltamab.
  • Belantamab mafodotin: BCMA ADC (re-approved by FDA Oct 2025 as Bela-Vd per DREAMM-7).
  • IMROZ (Facon NEJM 2024, FDA Sep 2024): Isa-VRd for newly dx TIE MM — superior PFS vs VRd (5-yr PFS 63% vs 45%). Quad becomes new standard for TIE, parallel to PERSEUS for TE.
  • CEPHEUS (FDA Jan 2026): Dara-VRd for newly dx TIE / transplant-deferred MM — sustained MRD-neg superior. Expanded Dara-VRd from TE to TIE.
  • Belantamab RE-APPROVED (Oct 2025): Bela-Vd (DREAMM-7) for R/R MM after ≥2 prior lines incl. a PI and an IMiD; Bela-Pd (DREAMM-8) not FDA-approved. Ocular toxicity REMS.
  • Bone disease: bisphosphonate or denosumab. Spine MRI for cord compression.
  • Renal: avoid nephrotoxic chemo; dose-adjust lenalidomide.

Plasma cell disorders

• MGUS: monitor; ~1%/yr progression to MM.
• Smoldering MM: observe vs early intervention (lenalidomide ↓ progression). High-risk SMM: SC daratumumab monotherapy FDA-approved Nov 2025 (AQUILA, first approved SMM therapy).
• AL amyloidosis: light chain deposition. Dara + CyBorD (ANDROMEDA). Cardiac/renal involvement common.
• Waldenström macroglobulinemia (LPL): MYD88 L265P. BTK-i (ibrutinib, zanubrutinib).
• POEMS: polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes. Treat plasma cell clone.

High-yield heme pearls

• APL: ATRA + ATO; differentiation syndrome → dex.
• Ven + aza for older/unfit AML.
• CLL 1L: BTK-i or ven + obinutuzumab.
• S1826: nivo + AVD new SOC for advanced HL.
• POLARIX: pola-R-CHP for DLBCL (PFS, not OS).
• CAR-T 2L DLBCL (ZUMA-7, TRANSFORM): for high-risk relapse <12 mo.
• PERSEUS / D-VRd quadruplet for transplant-eligible MM.
• Cilta-cel CARTITUDE-4: earlier-line MM approval.
• Asciminib 1L CML (ASC4FIRST 2024).
• Universal MMR/MSI (already covered in genetics).