Is Inotuzumab ozogamicin (Inotuzumab ozogamicin) a suitable treatment option for a patient with a history of Hodgkin lymphoma who now has acute lymphoblastic leukemia (ALL)?

Inotuzumab Ozogamicin in ALL with Prior Hodgkin Lymphoma History

Inotuzumab ozogamicin is a suitable and FDA-approved treatment option for relapsed/refractory CD22-positive B-cell precursor ALL, regardless of prior Hodgkin lymphoma history, though heightened vigilance for hepatic sinusoidal obstruction syndrome (SOS) is essential. 1

Mechanism and Indication

Inotuzumab ozogamicin (InO) is a CD22-directed antibody-drug conjugate that binds to CD22 (expressed on >90% of B-cell blasts in nearly all B-cell ALL patients) and delivers the cytotoxic agent calicheamicin intracellularly, inducing DNA strand cleavage and apoptosis. 2 It received full FDA approval in August 2017 for adults with relapsed or refractory B-cell precursor ALL. 2

Efficacy Data Supporting Use

Relapsed/Refractory Setting

• In the pivotal INO-VATE phase 3 trial (n=326), InO demonstrated superior outcomes compared to standard chemotherapy:

  • CR/CRi rate: 80.7% vs 29.4% (P<.001) 2
  • MRD-negative rate: 78.4% vs 28.1% (P<.001) 2
  • Median OS: 13.9 vs 9.9 months (P=.005) 2
  • 2-year OS: 22.8% vs 10.0% 3

• Responses were consistent across subgroups, including those with high marrow burden and Ph-positive disease. 2

• InO served as an effective bridge to HSCT: 39.6% of InO patients proceeded directly to HSCT after achieving CR/CRi versus 10.5% with standard chemotherapy (P<.0001). 3

Frontline Setting for Older Adults

• In a phase II study of older adults (median age 68 years) with newly diagnosed Ph-negative ALL, InO combined with mini-hyper-CVD showed:
  • 2-year progression-free survival: 59% (95% CI: 43-72%) 2
  • SOS occurred in 8% of patients 2

Critical Safety Considerations

Sinusoidal Obstruction Syndrome (SOS)

The most significant toxicity is hepatic SOS/veno-occlusive disease, particularly post-HSCT:

• In INO-VATE, SOS occurred in 14.0% of InO patients vs 2.1% with chemotherapy. 3
• In pediatric patients, 52% who underwent HSCT following InO developed SOS (11 of 21 patients). 2
• Risk factors include dual alkylator-based transplant conditioning regimens. 2

To minimize SOS risk: 1

• Avoid dual alkylator conditioning regimens pre-HSCT
• Consider reduced-intensity conditioning
• Monitor liver function tests closely
• Limit InO to maximum 2 cycles before HSCT when possible

Infectious Complications

When used as monotherapy, InO has a favorable infectious profile compared to combination therapy: 2

• Phase 3 data showed lower rates with InO vs standard therapy:

  • Febrile neutropenia: 11.6% vs 18.9% 2
  • Sepsis: 2.4% vs 7% 2
  • Septic shock: 1.8% vs 2.1% 2

• However, when combined with chemotherapy (mini-hyper-CVD), infection rates increase to 67-73%. 2

ECIL recommendations for antimicrobial management: 2

• No specific antimicrobial prophylaxis required (A-IIr)
• No specific recommendations for use during active infection or fever
• Exercise caution when combining with QT-prolonging agents (levofloxacin, posaconazole) (A-IIr)

QT Interval Prolongation

QT interval prolongation has been observed with InO; concomitant use with other QT-prolonging medications (including certain antimicrobials like levofloxacin and posaconazole) requires careful monitoring. 2

Dosing Considerations

Standard FDA-approved dosing: 1

• Cycle 1: 1.8 mg/m² per cycle (0.8 mg/m² on Day 1,0.5 mg/m² on Days 8 and 15)
• Subsequent cycles: 1.5 mg/m² per cycle (0.5 mg/m² on Days 1,8, and 15)

Lower starting dose option for patients at higher SOS risk:

• A recent phase 4 study demonstrated that starting at 1.2 mg/m²/cycle showed consistent efficacy (CR/CRi rate 71.9%) with potentially acceptable SOS rates (25.8% post-HSCT) in high-risk patients. 4

Specific Considerations for Prior Hodgkin Lymphoma

There is no evidence that prior Hodgkin lymphoma treatment contraindicates InO use, as:

• InO targets CD22, which is specific to B-cell lineage malignancies 2
• The mechanism of action is independent of prior chemotherapy exposure 5
• However, patients with prior anthracycline or alkylator exposure may have increased baseline hepatic risk, warranting closer SOS monitoring 3

Treatment Algorithm

For a patient with prior Hodgkin lymphoma now presenting with relapsed/refractory B-cell ALL:

1. Confirm CD22 positivity (expressed in >90% of B-cell ALL cases) 2

2. Assess hepatic function and SOS risk factors:

   • Prior liver disease or hepatotoxic therapy
   • Baseline bilirubin and transaminases
   • Consider lower starting dose (1.2 mg/m²) if multiple risk factors present 4

3. Evaluate HSCT candidacy:

   • If HSCT planned, limit InO to ≤2 cycles pre-transplant 3
   • Avoid dual alkylator conditioning regimens 2
   • Consider reduced-intensity conditioning 1

4. Monitor for QT prolongation:

   • Baseline and serial ECGs
   • Avoid concomitant QT-prolonging agents when possible 2

5. Assess MRD status after treatment:

   • MRD negativity strongly predicts improved OS 3
   • Consider proceeding to HSCT if MRD-negative CR/CRi achieved 3

Common Pitfalls to Avoid

• Do not use dual alkylator-based conditioning regimens (e.g., busulfan/cyclophosphamide) pre-HSCT after InO exposure 2
• Do not exceed 2 cycles of InO before proceeding to HSCT if transplant is planned 3
• Do not overlook baseline hepatic assessment before initiating therapy 1
• Do not combine with multiple QT-prolonging antimicrobials without ECG monitoring 2