What are the treatment strategies and outcomes of the Gimema (Gruppo Italiano Malattie Ematologiche dell'Adulto) and Pethima trials for hematological malignancies?

GIMEMA and PETHEMA Trials: Key Findings and Treatment Strategies

Multiple Myeloma Trials

GIMEMA Phase III Trial (Bortezomib/Thalidomide/Dexamethasone)

The GIMEMA Italian Multiple Myeloma Network demonstrated that bortezomib/thalidomide/dexamethasone (VTD) as induction therapy before double autologous hematopoietic stem cell transplantation (HSCT) significantly improves long-term survival compared to thalidomide/dexamethasone alone. 1

Response Rates After Induction:

• VTD group achieved 31% CR/near CR (95% CI, 25.0-36.8) versus 11% with thalidomide/dexamethasone (95% CI, 7.3-15.4) 1
• Response rates remained significantly higher after first and second autologous HSCT and consolidation therapy 1
• Single-institution data confirmed 94% overall response rate with VTD, including VGPR rate ≥56% 1

Long-Term Survival Outcomes (10-Year Follow-Up):

• 10-year progression-free survival: 34% (VTD) versus 17% (thalidomide/dexamethasone) with HR 0.62 (95% CI 0.50-0.77; p<0.0001) 2
• 10-year overall survival: 60% (VTD) versus 46% (thalidomide/dexamethasone) with HR 0.68 (95% CI 0.51-0.90; p=0.0068) 2
• VTD was an independent predictor of improved progression-free survival (HR 0.60; p<0.0001) and overall survival (HR 0.68; p=0.010) 2

Toxicity Profile:

• Grade 3/4 peripheral neuropathy occurred more frequently in the bortezomib-containing regimen 1
• Second primary malignancies: 0.87 per 100 person-years (VTD) versus 1.41 (thalidomide/dexamethasone) 2

PETHEMA/GEM Phase III Trial Results

The Spanish Myeloma Group (PETHEMA/GEM) trial confirmed superior complete response rates with VTD, particularly in high-risk cytogenetics patients. 1

Response Rates:

• Overall CR rate: 35% (VTD) versus 14% (thalidomide/dexamethasone) (p=0.001) 1
• High-risk cytogenetics CR rate: 35% (VTD) versus 0% (thalidomide/dexamethasone) (p=0.002) 1
• Post-autologous HSCT CR rate: 46% (VTD) versus 24% (thalidomide/dexamethasone) 1

Clinical Implications:

• VTD is listed as Category 1 primary treatment option for transplant-eligible patients with newly diagnosed multiple myeloma 1
• Particularly useful in resource-constrained settings where thalidomide is more readily available and affordable 1
• No significant difference in overall survival was observed, requiring longer follow-up 1

Acute Promyelocytic Leukemia (APL) Trials

PETHEMA APL Studies

PETHEMA protocols using idarubicin and mitoxantrone without cytarabine achieved excellent outcomes in low-to-intermediate risk APL patients. 1

Key Findings on Cytarabine Use:

• Joint PETHEMA-European APL analysis showed significantly lower relapse incidence in patients <65 years with WBC <10×10⁹/L treated without cytarabine in PETHEMA LPA99 trial 1
• Trend favoring cytarabine administration observed in high-risk patients (WBC >10×10⁹/L) 1
• PETHEMA protocol used idarubicin (cumulative dose 80-100 mg/m²) and mitoxantrone (cumulative dose 50 mg/m²) 1

Assessment Timing Critical Point:

• No cases of resistant leukemia recorded among last 350 PETHEMA patients after implementing delayed response assessment strategy 1
• Premature assessment (18-33 days post-chemotherapy while pancytopenic) led to false primary resistance diagnoses 1
• Repeat bone marrow assessment after additional 2-3 weeks on ATRA recommended if CR uncertain 1

GIMEMA APL Trials (AIDA Protocol)

The GIMEMA AIDA-2000 trial demonstrated that risk-adapted consolidation with ATRA significantly improves outcomes in APL. 1, 3

AIDA-2000 Results:

• Complete remission rate: 94.4% (420/445 patients) 3
• 6-year overall survival: 87.4% versus 78.1% in previous AIDA-0493 trial (p=0.001) 3
• 6-year cumulative incidence of relapse: 10.7% versus 27.7% in AIDA-0493 (p<0.0001) 3

Risk-Adapted Strategy:

• Low/intermediate-risk patients: 3 anthracycline-based consolidation courses without cytarabine 3
• High-risk patients: significantly improved outcomes with cytarabine addition (CIR 9.3% vs 49.7% in AIDA-0493; p<0.0001) 3
• All patients received ATRA for 15 days during each consolidation cycle 3

ATRA Role in Consolidation:

• Historical comparisons by GIMEMA and PETHEMA showed statistically significant improvement when ATRA (45 mg/m²/day for adults; 25 mg/m²/day for children) given for 15 days with chemotherapy 1
• Contributes to reduction in relapse risk 1

Common Pitfalls and Clinical Considerations

Multiple Myeloma:

• Herpes prophylaxis mandatory for all patients receiving bortezomib-containing regimens 1
• Higher peripheral neuropathy rates with VTD require careful monitoring 1, 2
• Thalidomide availability varies by region; VTD particularly valuable in resource-limited settings 1

APL Management:

• Avoid premature response assessment before count recovery to prevent misdiagnosis of primary resistance 1
• Molecular assessment by RT-PCR immediately post-induction has no clinical relevance; delayed maturation may cause false positivity 1
• PCR analysis after consolidation completion is critical for determining individual relapse risk 1
• Cytarabine benefit depends on anthracycline type/dose and patient risk category 1, 3