Acute lymphoblastic leukemia (ALL)

Epidemiology & Basics

• Incidence: bimodal, with peaks in childhood (2 to 5 yo, ~85% B-ALL) and adults >50. ~5,600 to 6,500 new cases/yr US.
• Pediatric outcomes: CR rates 97% to 99%, 5-yr EFS 80% to 87%, 5-yr OS 90% to 94% with modern protocols.
• Adolescents and young adults: CR up to 95%, 5-yr OS ~70% to 75% in AYA cohorts; older adults do substantially worse (5-yr OS often ~20% to 40%) (improved with pediatric-inspired regimens, MRD-guided therapy, immunotherapy, and allo-HSCT).
• ALL vs LBL: distinction is by percent bone marrow lymphoblasts. Marrow involvement ≥25% = ALL; <25% = lymphoblastic lymphoma (LBL). LBL is now treated by ALL principles rather than as NHL.
• Risk factors: prior chemo (5q-, -7, 11q23/KMT2A), Down syndrome (esp B-ALL, incidence 10 to 20x), NF1, Li-Fraumeni, ataxia-telangiectasia, Bloom syndrome, Klinefelter.

WHO Classification

• WHO 2022 / ICC 2022 framework:
  • B-ALL/lymphoblastic lymphoma defined by recurring genetic abnormalities: B-ALL w/ t(9;22) BCR::ABL1 (Ph+); KMT2A-rearranged; ETV6::RUNX1; hyperdiploid; hypodiploid; Ph-like (BCR::ABL1-like); iAMP21; TCF3::PBX1.
  • T-ALL/lymphoblastic lymphoma, including early T-cell precursor (ETP) variant.
  • Mixed-phenotype acute leukemia (MPAL): blast population(s) meeting criteria for myeloid (MPO, or monocytic differentiation by at least 2 monocytic markers) plus a defined lymphoid lineage (B or T by their specific criteria), in one population or as distinct populations. WHO 2022 entities: B/myeloid w/ BCR::ABL1, B/myeloid w/ KMT2A-r, B/myeloid NOS, T/myeloid NOS. Usually treated with ALL-type regimens.

Immunophenotype: What You Need to Know

• B-cell ALL (70% to 80% of adult ALL): almost always CD19+, cytoplasmic CD79a+, cytoplasmic CD22+ (so CD19 and CD22 are targetable). Most also express CD10, surface CD22, PAX5, and TdT. CD20 variable (~30% to 50% of adult B-ALL, targetable); CD34 positive in most precursor B-ALL.
• T-cell ALL (20% to 30% of adult ALL): usually TdT+, cytoplasmic CD3+, CD7+; CD1a, CD4, and CD8 vary by maturation stage (CD1a+ in cortical T-ALL). Lymphoblasts are TdT+ with variable CD1a, CD2, CD3, CD4, CD5, CD7, CD8; cytoplasmic CD3 and CD7 often positive.
• Early T-precursor ALL (ETP-ALL, 5% to 10% of adult ALL): CD7+ but CD8- and CD1a-, and always positive for at least one myeloid/stem-cell marker (CD34, CD117/KIT, HLA-DR, CD33, CD13). Adverse, treatment-resistant.
• Burkitt lymphoma/leukemia (mature): strong surface IgM with light-chain restriction (mature markers); strong CD20 (only ~30% in B-ALL), plus CD19, CD22, CD79a, PAX5, and often CD10, BCL6; Ki-67 near 100%. Defined by MYC translocation t(8;14) or t(2;8), t(8;22) with L3 morphology (basophilic, vacuolated lymphoblasts). Treat as Burkitt (R-CODOX-M/IVAC or DA-EPOCH-R).
• Ph+ ALL: L2 morphology, pre-B immunophenotype (CD19+, CD10+); usually TdT+ and CD25+ (CD25 characteristic of Ph+ ALL); CD34, CD10, and aberrant myeloid antigens (CD13/CD33) common; myeloid antigen expression also seen. About 70% of adults express the p190 and about 30% the p210 BCR-ABL1 transcript (p190 in ~90% of pediatric Ph+ ALL).

Diagnostic Workup

• Bone marrow: ≥25% lymphoblasts (ALL vs LBL cutoff; some protocols use ≥20%).
• Cytogenetics: conventional karyotype plus FISH (complementary): panel for Ph-like subset, t(9;22), 11q23 (KMT2A), MYC rearrangements, hypodiploid, hyperdiploid.
• Molecular: RT-PCR for BCR-ABL1; NGS increasingly important; RNA-seq to identify Ph-like fusions. IKZF1 deletion (worse prognosis).
• Flow, B-ALL: TdT+, CD19+, CD22+, CD79a+, CD10 variable; surface Ig neg in pre-B; mature B-ALL (Burkitt) = sIg+, CD20+, MYC-r.
• Flow, T-ALL: TdT+, cytoplasmic CD3+, CD7+, CD2/CD5/CD8 variable.
• CSF analysis: diagnostic LP at presentation; cytology plus flow. CNS-1 (no blasts), CNS-2 (<5 WBC w/ blasts), CNS-3 (≥5 WBC w/ blasts or cranial nerve palsy).
• TLS assessment: UA, LDH, K, P, Ca, Cr.

Prognostic Cytogenetics (Good vs Poor Risk)

• Ph t(9;22)+ increases with age (~50% of ALL >60 yo is Ph+). t(12;21) is chemo-sensitive, mainly in children. t(4;11)/KMT2A-rearranged is mainly in infants (<1 yr); also occurs in adults (KMT2A::AFF1).
• Classic good-risk features: hyperdiploidy and t(12;21) ETV6-RUNX1; newer favorable molecular subtypes include DUX4-rearranged and NUTM1-rearranged B-ALL. ETP-ALL, Ph+, Ph-like, hypodiploid (often TP53-mutated), KMT2A-r, and Ph- with CD20 expression are all poor.

• Consolidation implication: B-ALL in CR and MRD-negative after induction with one of these abnormalities should be considered for allo-HSCT as consolidation. If MRD-positive, give blinatumomab first to convert to MRD-negative, then proceed to allo-HSCT in CR1.
• Rituximab in CD20+ Ph-: improves EFS (GRAALL-2005/R, age 18 to 59: 2-yr EFS 65% vs 52%, HR 0.66; CR rate not changed) but minimal to no benefit in older patients.

Hypodiploidy

• Poor prognosis; seen in 1% to 2% of ALL.
• Near-haploid (24 to 31 chr): alterations targeting receptor tyrosine kinase and Ras signaling (71%) and IKZF3 (AIOLOS; 13%).
• Low-hypodiploid (32 to 39 chr): TP53 alterations (91.2%, often in non-tumor cells), IKZF2 (HELIOS; 53%), RB1 (41%). Document whether TP53 is germline (possible Li-Fraumeni).
• Both near-haploid and low-hypodiploid show Ras and PI3K pathway activation and sensitivity to PI3K inhibitors (investigational).

MRD-Guided Therapy (CRITICAL)

• MRD is important in every subset, age, and treatment timepoint; presence of MRD is the most decisive determinant of outcome.
• Threshold: at least 1 cancer cell in 10,000 normal cells (≥0.01%, i.e. sensitivity 10^-4) is commonly used. Use the first small-volume (up to 3 mL) marrow aspirate pull for MRD.
• Methods: ≥6-color flow MRD; RT-qPCR for fusion genes or BCR::ABL1; NGS-based clonoSEQ for clonal Ig-heavy-chain or TCR rearrangements (sensitivity to 10^-6). End-of-induction and end-of-consolidation timepoints.
• Early MRD eradication is the goal: 3-yr DFS 85% vs 56% for MRD-negative vs MRD-positive (HR 0.25, p=0.0006; Gokbuget Blood 2012, Stock Blood 2019).
• Blinatumomab for MRD+ B-ALL: BLAST trial achieved molecular CR; FDA approved 2018 for MRD ≥0.1% in CR1 or CR2. Converts MRD+ to MRD-negative before transplant or maintenance.
• Blina in newly diagnosed (E1910, Litzow MR et al, NEJM 2024): adding 4 cycles of blinatumomab to consolidation in MRD-negative Ph- B-ALL adults improved 3-yr OS (85% vs 68%, HR 0.41) and RFS (80% vs 64%). FDA approved June 14, 2024 for newly diagnosed CD19+ Ph- B-ALL in CR/CRi; standard of care.
• Blina in pediatric standard-risk B-ALL (COG AALL1731, Gupta S et al, NEJM 2025): adding 2 nonsequential cycles of blinatumomab to chemotherapy improved 3-yr DFS (96.0% vs 87.9%) in NCI standard-risk B-ALL with average or higher relapse risk; the June 2024 label covers patients ≥1 month.

Treatment: Ph+ ALL Induction

• Backbone: TKI is essential (outcomes transformed). Options combine TKI with chemo, immunotherapy, or steroids depending on fitness.

• Maintenance: add TKI to maintenance (optimal duration unknown, minimum 1 yr). POMP: monthly prednisone/vincristine (2 to 3 yrs), weekly MTX + daily 6-MP as tolerated.
• CR and MRD-negative: consolidate with blinatumomab + TKI, multiagent chemo + TKI, TKI alone, or allo-HCT in select candidates. In the TKI era it is unclear whether transplant is needed.
• CR but persistent/rising MRD+: blinatumomab plus or minus TKI, or multiagent chemo/steroids + TKI, or TKI alone, followed by allo-HSCT.

Ph+ Frontline Regimens: Key Trials

• Dasatinib + hyper-CVAD (S0805, Ravandi F et al, Blood Adv 2016;1:250-259): improved PFS and OS (many received allo-HSCT).
• Ponatinib + hyper-CVAD: improved long-term survival with or without transplant; 3-yr EFS ~70%.
• Dasatinib + blinatumomab (GIMEMA LAL2116 D-ALBA): chemotherapy-free induction (with IT chemo). 63 patients (median age 54.5 yr), newly diagnosed Ph+ ALL. OS 95.2% (95% CI 90.1 to 100), DFS 89.7% (82.3 to 97.9), molecular response 29% at day 85 (end of dasatinib/steroid induction), rising to ~60% after 2 blinatumomab cycles.
• Ponatinib frontline (PhALLCON, Jabbour E et al, JAMA 2024): ponatinib + chemo gave 34.4% MRD-negative CR vs 16.7% with imatinib at end of induction. FDA accelerated approval Mar 19, 2024 for newly diagnosed Ph+ ALL + chemo; first frontline Ph+ approval using MRD-negative CR as primary endpoint. Now preferred TKI in fit patients.
• Ponatinib + blinatumomab (chemo-free, MD Anderson; Jabbour Lancet Haematol 2023 / Short JCO 2024): 83% CMR by RT-PCR and 98% MRD negativity by NGS; 3-yr OS 91%, EFS 77% (n=60) without intensive chemo or routine allo-HSCT. Phase 2 and ongoing phase 3.
• TKI generation: 2nd (dasatinib, nilotinib) and 3rd (ponatinib) generation preferred (dasatinib has CNS penetration and faster MRD clearance; lower likelihood of emerging resistant clone, though clonal T315I more common). Durable remissions achievable with and without allo-HSCT.

Treatment: Ph- ALL Induction

• Mnemonic: CALGB 8811, GRAALL-2005, and MRC UKALLXII/ECOG2993 all have cyclophosphamide + steroid + vincristine + anthracycline + asparaginase. Hyper-CVAD has no asparaginase (has MTX); USC/MSKCC has no cyclophosphamide (has MTX); Linker 4-drug has no cyclophosphamide.
• POMP maintenance: monthly prednisone/vincristine (2 to 3 yrs), weekly MTX + daily 6-MP as tolerated. No maintenance for Burkitt regimens.
• Adult regimens use intensive myelosuppressive agents (daunorubicin, cytarabine, cyclophosphamide) with allo-SCT in CR1 for high-risk disease. Pediatric regimens use the BFM backbone: glucocorticoids, vincristine, asparaginase, early/frequent CNS prophylaxis, prolonged maintenance.

AYA: Pediatric-Inspired Regimens

• Historically AYAs (age 16 to 20) treated on adult CALGB protocols did worse than same-age patients on pediatric CCG protocols (7-yr OS ~46% vs ~67%; Stock Blood 2008). Using true pediatric regimens (NOPHO ALL2008, CALGB 10403) improved OS to 70% to 75%.

Relapsed/Refractory ALL

Ph+ R/R

BCR-ABL1 Mutation to TKI Selection

• Key resistance pearls: T315I is resistant to all earlier-generation TKIs; ponatinib is the established option in Ph+ ALL. Asciminib also inhibits T315I but is FDA-approved for T315I CML, not ALL (off-label/investigational in ALL). E255K/V (nilotinib resistance), F317L and V299L (dasatinib resistance; V299L also bosutinib) are other kinase-domain mutations to check at relapse.

Ph- R/R B-ALL

Targeted & Immune Therapies in B-ALL

• Blinatumomab (Blincyto): CD19xCD3 BiTE, continuous IV (28-day CIVI), step-up dose (9 then 28 mcg/day) in cycle 1 for R/R ALL to mitigate CRS; MRD-positive and consolidation indications use 28 mcg/day flat (no step-up). Dexamethasone premedication before the first dose of each cycle, before step doses, and on restarts.
  • 2014: R/R Ph- B-ALL (accelerated, single-arm MT103-211; converted to full approval 2017 based on TOWER).
  • Sept 2016: pediatric R/R Ph- B-ALL (accelerated).
  • 2017: R/R Ph+ B-ALL.
  • Mar 2018: MRD ≥0.1% in CR1 or CR2 (BLAST, Gokbuget Blood 2018).
  • June 14, 2024: newly diagnosed CD19+ Ph- B-ALL in CR/CRi consolidation (E1910).
• Inotuzumab ozogamicin (Besponsa): CD22 ADC with calicheamicin; internalized, binds DNA and induces double-strand breaks and apoptosis.
  • Aug 2017: R/R adult B-ALL (INO-VATE, Kantarjian NEJM 2016).
  • Mar 2024: pediatric ≥1 yo R/R CD22+ B-ALL.
• Tisagenlecleucel (Kymriah): CD19 CAR-T (4-1BB co-stim). Aug 2017: pediatric/young adult ≤25 yo R/R B-ALL (ELIANA, Maude NEJM 2018; CR 81%, EFS 50% at 12 mo).
• Brexucabtagene autoleucel (Tecartus): CD19 CAR-T (CD28 co-stim). Oct 2021: adult R/R B-ALL (ZUMA-3, Shah Lancet 2021; CR/CRi 71%).
• Obecabtagene autoleucel (Aucatzyl, obe-cel): CD19 CAR-T with fast-off-rate binder (less T-cell exhaustion). Nov 8, 2024: adult R/R B-ALL (FELIX, Roddie C et al, NEJM 2024; ORR 76%, CR 54%, CRi 21%; G≥3 CRS 3%, G≥3 ICANS 7%). First CAR-T approved without REMS.

Key R/R Trials

• Blinatumomab BLAST: patients in CR after chemo but MRD+, single-arm, endpoint MRD-negative status. Complete MRD-negative response 80% (82/103).
• TOWER (Kantarjian NEJM 2017;376:836-847): R/R Ph- pre-B-ALL, blinatumomab (n=271; step-up 9 mcg/day x7 days then 28 mcg/day) vs standard chemo (n=134). ORR 44% vs 25%; CR 34% vs 16%; MRD-negative 76% vs 48% of responders. Primary endpoint OS.
• Inotuzumab + mini-hyper-CVD (Kantarjian, Lancet Oncol 2018), a FRONTLINE trial in newly diagnosed Ph- older adults (age 60+): 52 patients, median age 68; 98% CR/CRp/CRi; MRD-negative CR within 3 cycles 96%; 2-yr PFS 59%; median PFS 35 mo. Toxicity: thrombocytopenia 81%, hepatic G3+ 33%, VOD 8% (from calicheamicin).
• INO-VATE (Kantarjian NEJM 2016;375:740-753): 326 patients, Ph- or Ph+ R/R B-cell precursor ALL, inotuzumab (n=164) vs investigator chemo (FLAG, HIDAC, or mitoxantrone/AraC; n=162). CR 35.8% vs 17.4% (CR/CRi 80.7% vs 29.4%); MRD-negative 89.7% vs 31.6% (responders 78.4% vs 28.1%); mDOR 4.6 vs 3.1 mo.
• Anti-CD19 CAR-T for B-ALL: manufacturing is the hardest part given aggressive disease. Tisagenlecleucel (age <26, refractory or ≥2 relapses) and brexucabtagene autoleucel (adults) with very high CR and MRD-negative rates.

Ph-like (BCR-ABL1-like) ALL

• Defined by a BCR::ABL1-like gene expression profile (not one karyotype); driven mainly by diverse kinase and cytokine-receptor rearrangements (plus some mutations). Many lesions are cryptic, but some are detectable by conventional cytogenetics. Recurrent gene fusions/mutations activate ABL1, ABL2, CRLF2 (60% of all Ph-like ALL), CSF1R, EPOR, JAK, PDGFRB, and mutations of FLT3, IL7R, SH2B3, JAK1/2/3. ABL-class, CSF1R, JAK2, PDGFRB fusions give cytokine-independent proliferation and phospho-STAT5 activation.
• Ph-like ALL is ~15% of children and ~1/3 of adults with ALL. Majority (60%) carry CRLF2 (a cytokine receptor activating JAK/STAT), which carries worse prognosis. More aggressive: adult 5-yr EFS only 20% to 25% vs ~50% for non-Ph-like.
• Treatment by lesion: ABL-class fusions (ABL1, ABL2, CSF1R, PDGFRB) → dasatinib; JAK/CRLF2/EPOR → ruxolitinib (investigational, in trials); ETV6-NTRK3 → TRK/crizotinib inhibition (investigational); CD19+/CD22+ → blinatumomab and inotuzumab.
• Identify by FISH or RNA sequencing; peaks in early adulthood. MRD-negative status going into transplant is key; if MRD-negativity is achieved, whether transplant is necessary is unclear.

T-ALL Specific

• ~20% of ALL; adults > children, incidence falls in older age. Often marked leukocytosis, CNS and mediastinal (thymic mass) involvement, and testicular involvement. CNS involvement is higher in T-cell than pre-B-cell ALL, so IT MTX or Ara-C prophylaxis is a must in both.
• T-ALL is a precursor lymphoid neoplasm, distinct from adult T-cell leukemia/lymphoma (HTLV-1-driven, mature T cells). Lymphoblasts are TdT+ with variable CD1a, CD2, CD3, CD4, CD5, CD7, CD8; cytoplasmic CD3 and CD7 often positive. Stages: pro-T, pre-T, cortical T, medullary T.
• Nelarabine: guanine nucleoside analog approved for R/R T-ALL (CR ~31%) after ≥2 regimens. Now incorporated into frontline (COG AALL0434) with improved DFS (5-yr 88.2% vs 82.1%; OS difference not significant) in children and young adults ≤30 yo, driven by fewer CNS relapses (1 vs 14). In frontline AALL0434 nelarabine did not add benefit for T-LBL, but nelarabine is FDA-approved for R/R T-ALL and T-LBL (after 2+ regimens) and is active in relapsed T-LBL. Major toxicity is neurotoxicity (peripheral neuropathy, somnolence, seizures), dose-limiting.
• ETP-ALL: high early chemoresistance and slow response, but modern response/MRD-adapted regimens abrogate the poor prognosis (adult 5-yr OS ~60%); transplant guided by MRD and risk, not ETP phenotype alone.
• R/R T-ALL: venetoclax (BCL2) with navitoclax (BCL-XL) plus low-dose chemo (CR ~60%, B and T); bortezomib with chemo (pediatric data). No established immune strategy yet; CD5 and CD7 CAR-T and anti-CD38 (daratumumab, CD38 BiTE) under investigation.
• T-cell LBL: 85% to 90% of lymphoblastic lymphomas; usually a mediastinal mass in males in late childhood. Same disease as T-ALL, differing by marrow burden (<25% marrow = T-LBL, ≥25% = T-ALL). Use pediatric-inspired induction, IT therapy, and POMP maintenance x 2 to 3 years.

Related Mature T-cell Entities (for contrast)

• Adult T-cell leukemia/lymphoma (HTLV-1): aggressive; osteolytic lesions with hypercalcemia, skin lesions, visceral involvement; flower cells (polylobated nuclei) on smear. Treatment: observation, antiviral, or skin-directed for favorable chronic and smoldering ATL; unfavorable chronic ATL is treated as aggressive ATL (systemic therapy); systemic therapy for acute; for large lymphoma burden, brentuximab vedotin + CHP (must be CD30+), dose-adjusted EPOCH or other lymphoma-directed chemo, with allo-HSCT in eligible patients (zidovudine + interferon is for leukemic subtypes, not lymphoma-type ATL).
• T-cell large granular lymphocyte leukemia (T-LGL): indolent, clonal CD3+ cytotoxic T cells (usually CD4-/CD8+), >6 months of LGL elevation; associated with rheumatoid arthritis, splenomegaly, anemia, neutropenia. Treat when cytopenias worsen with immunosuppression: cyclophosphamide, MTX, or cyclosporine; many can be observed.

Allo-HSCT in ALL

• Conditioning: TBI-containing regimens (TBI with etoposide or cyclophosphamide) are the standard for ALL; RIC also used. FORUM trial showed TBI/etoposide superior to chemo-based conditioning in pediatric ALL >4 yo.
• CR1: increasingly MRD-driven. If MRD-negative without high-risk genetics, generally no transplant in CR1 (combine cytogenetics and MRD; MRD-negativity alone is important, especially in CR1). High-risk groups to consider for allo-SCT in CR1: hypodiploid, KMT2A-rearranged, Ph-like, ETP-ALL. Pediatric regimens can give superior survival vs allo-SCT in CR1 (CALGB 10403 and DFCI AYA vs CIBMTR).
• GRAALL 2003/2005 (N=955): high-risk <56 yo in CR1 (N=522), SCT (283) vs no-SCT (239). By post-induction MRD1: good MRD responders (<10^-3) not clearly benefited by transplant; poor MRD responders (≥10^-3) benefited (RFS HR 0.40).
• Beyond CR1: allo-HSCT remains the destination. Immune-targeting approaches (blina, inotuzumab, CAR-T) give high CR and MRD-negative rates and serve as a bridge to transplant, but, except CD19 CAR-T (durable remissions in a subset of children and adults without subsequent allo-HSCT, e.g. ZUMA-3, FELIX), are generally a bridge to transplant; post-CAR-T transplant is individualized. Post-transplant relapse: DLI, blina, CAR-T, or 2nd transplant.

CNS Prophylaxis (REQUIRED in all ALL)

• CNS prophylaxis is required in all ALL, but the number and timing of intrathecal treatments are protocol-specific (hyper-CVAD gives a defined number during intensive courses, not routinely throughout POMP maintenance) (IT MTX, or AraC, or triple MTX+AraC+hydrocortisone). Systemic high-dose MTX/AraC also contributes.
• Many regimens no longer use cranial irradiation; CNS-3 at diagnosis or CNS relapse intensifies IT therapy plus or minus cranial radiation (24 Gy classic, less in modern protocols).

Drug Toxicities

• Toxicity increases with age and obesity.
• Asparaginase: thrombosis, pancreatitis, chemical hepatitis, anhedonia.
• Glucocorticoids: hyperglycemia, osteonecrosis.
• Vincristine: neuropathy, myopathy. Avoid concurrent potent azoles (posaconazole, voriconazole), which exacerbate peripheral neurotoxicity.
• Methotrexate: leucovorin rescue when high-dose; CNS toxicity, mucositis, chemical hepatitis, renal failure.
• 6-MP: transaminitis, myelosuppression (if profound, consider TPMT/NUDT15 polymorphism and dose-reduce). TPMT testing often required before thiopurines.
• Blinatumomab: CRS, neurotoxicity (ICANS-like); continuous IV infusion.
• Inotuzumab ozogamicin: hepatotoxicity, VOD/SOS (major risk if proceeding to allo-HSCT).
• CAR-T: CRS (tocilizumab, anti-IL-6R), neurotoxicity/ICANS (steroids first-line per ASTCT 2019), prolonged cytopenias, hypogammaglobulinemia. Obe-cel: less exhaustion, lower CRS/ICANS, no REMS.

Asparaginase: Toxicity Management & Formulations

• Hypersensitivity: rash, fevers, chills, flushing, rarely dyspnea/anaphylaxis; matters because inactivating antibodies reduce efficacy. Usually develops weeks to months into treatment. Switch to Erwinia formulation.
• Pancreatitis: permanently discontinue for grade 3 or 4; for grade 2 (enzyme/radiologic only), hold until normalized then resume.
• Non-CNS hemorrhage: for grade ≥2, hold until grade 1 then resume; consider coagulation factor replacement; do not hold for asymptomatic lab abnormalities.
• Non-CNS thromboembolism: for grade ≥2, hold and treat with antithrombotics; resume once stable/completed; check AT III if giving heparin.
• Intracranial hemorrhage: discontinue; consider factor replacement; MRA/MRV to exclude sinus venous thrombosis. For grade ≤3 with full resolution, consider resuming at lower dose/longer intervals; grade 4, permanently discontinue.
• Cerebral thrombosis/ischemia/stroke: discontinue; consider antithrombotics; same grade-based resumption as above.
• Hyperglycemia: insulin as needed; for grade ≥3, hold asparaginase and steroids until glucose controlled.
• Hypertriglyceridemia: treat; for grade 4, hold until normalized.
• Hepatotoxicity: direct bilirubin ≤3.0 mg/dL continue; 3.1 to 5.0 hold until <2.0 then resume; >5.0 discontinue or hold until <2.0 then resume with dose reduction. Grade 3 AST/ALT hold until grade 1; grade 4 hold until grade 1 (resume if within 1 week, otherwise discontinue or resume with close monitoring).

• On DFCI ALL Consortium protocols, patients receive a single SS-PEG dose during induction, then 15 doses every 2 weeks post-induction to maintain therapeutic serum asparaginase activity (≥0.1 IU/mL) for 30 consecutive weeks.

Hyper-CVAD/MA Dosing

• 8 alternating courses of Course A (cyclophosphamide, vincristine, doxorubicin, dexamethasone) and Course B (methotrexate, cytarabine), every 21 to 28 days (A-B-A-B-A-B-A-B), ~6 months total.

CNS Intrathecal Schedule (Hyper-CVAD)

Maintenance & Long-Term Follow-up

• 6-MP/MTX maintenance: dose to maintain ANC ~500 to 1500/µL. TPMT/NUDT15 testing (poor metabolizers risk severe myelosuppression with 6-MP).
• Asparaginase complications: pancreatitis (hold), thrombosis (esp CNS/sagittal sinus), bleeding (low fibrinogen); low antithrombin III promotes thrombosis, hepatotoxicity, hypersensitivity (switch to Erwinia formulation).
• Late effects: cardiomyopathy (anthracyclines), second cancers (alkylators, TBI), endocrine (TBI), neurocognitive (cranial XRT).
• New-patient checklist: full pathologic workup; ECHO/MUGA for cardiac function; fertility discussion; hydration and allopurinol (rasburicase per institution, guided by LDH/uric acid); antimicrobial prophylaxis (acyclovir; TMP-SMX for PJP).

Burkitt-type B-ALL / Burkitt Leukemia

• Defining: MYC translocations [t(8;14), t(2;8), t(8;22)] with mature B-cell phenotype (sIg+, CD20+, CD10+, TdT-, Ki-67 ~100%).
• Treatment: intensive short-duration regimens (DA-EPOCH-R, R-hyperCVAD, CODOX-M/IVAC + R); high cure rates; no maintenance phase; CNS prophylaxis essential.
• TLS risk: extreme; aggressive IVF for all, with risk-adapted urate-lowering: rasburicase for high-risk (check G6PD first, contraindicated in deficiency), allopurinol for lower-risk.
• HIV-associated: common; treat similarly with concurrent ART; outcomes near non-HIV with proper supportive care.

Summary Pearls

• MRD monitoring is critical for prognosis and treatment decisions (flow, PCR for clone-specific IgH/TCR/fusion rearrangements, NGS).
• Pediatric-inspired regimens improve survival in adults <50; nelarabine improves T-ALL DFS in children and young adults ≤30.
• TKIs have transformed Ph+ ALL, with movement toward chemo-sparing TKI + immunotherapy backbones.
• Less-intensive antibody-based regimens are improving outcomes in older adults (>50).
• Allo-HSCT in CR1 is guided by MRD response; blinatumomab can convert MRD+ patients before transplant.
• Menin inhibitors for KMT2A (MLL) 11q23-rearranged leukemias (block MLL-menin interaction, induce differentiation): revumenib FDA-approved Nov 15, 2024 for R/R acute leukemia (ALL or AML) with a KMT2A translocation, age ≥1 yr (AUGMENT-101). Watch for differentiation syndrome and QTc prolongation.