Acute Lymphoblastic Leukemia (ALL)

Background:

• Second most common acute leukemia in adults

• 75% of cases are B-cell lineage, 25% are T-cell lineage

• Diagnosis requires ≥20% bone marrow lymphoblasts

Work up:

• CBC with diff, CMP, LFT

• DIC panel

• TLS panel

• Hepatitis B/C and HIV serologies

• BMBx: Cytogenetics, Molecular analyses

  • To identify if philadelphia chromosome/ philadelphia-like chromosome is present

    • Philadelphia-like chromosome:

      • Lacks the BCR-ABL1 gene

      • Associated with poor prognosis

      • Consider use of TKIs and early transplantation

• Peripheral blood smear:

  • May be substituted for BMBx if there is significant circulating disease (≥1000 lymphoblasts), especially when BMBx is not feasible

Risk assessment:

• Favorable risk:

  • High hyperdiploidy (51–65 chromosomes)

    • Especially with simultaneous trisomies of chromosomes 4, 10, and 17

  • ETV6-RUNX1 fusion

• Poor risk:

  • Hypodiploidy (cells with <44 chromosomes)

  • TP53 mutation

  • KMT2A (MLL) rearrangements, especially t(4;11)

  • IgH rearrangement

  • HLF rearrangement

  • ZNF384 rearrangement

  • MEF2D rearrangement

  • MYC rearrangement

  • PAX5-altered

  • Complex karyotype (5 or more chromosomal abnormalities)

  • Philadelphia-like chromosome (JAK-STAT, ABL class)

  • Intrachromosomal amplification of chromosome 21

  • IKZF1 alterations

Treatment:

• ALL therapy is divided into:

  • Induction:

    • Initial phase of multiagent chemo to rapidly reduce tumor burden by eradicating leukemic blasts from the BM and achieving CR.

  • Consolidation:

    • Post-induction phase of multiagent chemo to eliminate residual leukemic cells and further reduce the risk of relapse.

  • Maintenance

• All patients need CNS prophylaxis

  • Intrathecal chemo ± systemic high-dose MTX or cytarabine

• Philadelphia chromosome positive B-cell ALL:

  • TKI + chemo (e.g. HyperCVAD)

  • TKI + blinatumomab 

    • Blinatumomab: Bispecific T-cell engager (CD19 × CD3)

  • TKI + steroid or vincristine/dexamethasone

    • If elderly or frail patient

  • If CR after induction: check MRD status:

    • MRD+

      • Blinatumomab +/- TKI

      • Inotuzumab ozogamicin +/- TKI

        • Inotuzumab ozogamicin: Anti-CD22 ADC

        • Increases risk of veno-occlusive disease/liver toxicity

      • TKI

      • TKI + chemo

      • allo-HSCT followed by TKI

    • MRD-

      • Blinatumomab + TKI

      • TKI

      • TKI + chemo

      • allo-HSCT

  • If no CR: Treat as relapsed/refractory disease:

    • ABL domain testing

      • TKI +/- chemo

      • TKI +/- steroid

      • Blinatumomab +/- TKI

      • Inotuzumab ozogamicin +/- TKI

      • CAR-T cell therapy

• Philadelphia chromosome negative B-cell ALL:

  • Adolescent/Young Adult (AYA): 

    • Pediatric-inspired protocols:

      • CALGB 10403:

        • Daunorubicin, pegaspargase, prednisone, vincristine

      • DFCI Protocol 00-01:

        • Doxorubicin, high-dose methotrexate, pegaspargase, prednisone, vincristine

  • Adult <65 and no significant comorbidities: 

    • Multi-agent chemo:

      • ECOG 1910:

        • Cyclophosphamide, cytarabine, daunorubicin, dexamethasone, mercaptopurine, pegaspargase, vincristine

        • + rituximab for CD20+ disease and CD20 expression ≥20%

      • HyperCVAD:

        • Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin (Adriamycin), Dexamethasone

        • Alternating with high-dose methotrexate and cytarabine

        • + rituximab for CD20+ disease and CD20 expression ≥20%

  • Adult >65 or with significant comorbidities:

    • Multi-agent chemo (less intense chemo: e.g. POMP)

      • POMP: Prednisone, Vincristine (Oncovin), Methotrexate, 6-Mercaptopurine

    • Palliative steroid

    • Inotuzumab ozogamicin

  • If CR after induction: check MRD status:

    • MRD+

      • Blinatumomab → allo-HSCT

      • Inotuzumab ozogamicin → allo-HSCT

    • MRD-

      • Blinatumomab +/- alternating with chemo

      • allo-HSCT if high risk features

  • If no CR: Treat as relapsed/refractory disease:

    • Blinatumomab

    • Inotuzumab ozogamicin

    • Revumenib (if KMT2A rearranged)

    • Multiagent chemo

    • CAR-T cell therapy

• T-cell ALL:

  • Typically present with leukocytosis, mediastinal, CNS involvement 

  • Adolescent/Young Adult (AYA) and Adult <65 and no significant comorbidities:

    • Pediatric-inspired protocols:

      • CALGB 10403

      • DFCI Protocol 00-01

  • Adult >65 or with significant comorbidities:

    • Multi-agent chemo (less intense chemo: e.g. POMP)

    • Palliative steroid

  • If CR after induction: check MRD status:

    • MRD+ (or high risk features)

      • Allo-HSCT

      • Continue multi-agent chemo (POMP maintenance)

    • MRD-

      • Continue multi-agent chemo (POMP maintenance)

      • Consider allo-HSCT

  • If no CR: Treat as relapsed/refractory disease:

    • Nelarabine → allo-HSCT

    • Revumenib (if KMT2A rearranged) → allo-HSCT

    • Multiagent chemo → allo-HSCT