What is the preferred treatment regimen between decitabine (hypomethylating agent)-pembrolizumab (programmed death receptor-1 inhibitor) and caelyx (pegylated liposomal doxorubicin)-vinorelbine-gemcitabine-pembrolizumab for refractory stage IIE classical Hodgkin lymphoma?

Treatment Selection for Refractory Stage IIE Classical Hodgkin Lymphoma

Direct Recommendation

For refractory stage IIE classical Hodgkin lymphoma, pembrolizumab combined with gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD/Caelyx-vinorelbine-gemcitabine-pembrolizumab) is superior to decitabine-pembrolizumab, as it achieves 95% complete response rates and successfully bridges 95% of patients to HDT/ASCR, which is the definitive curative treatment for refractory disease. 1

Evidence-Based Rationale

Pembro-GVD (Caelyx-Vinorelbine-Gemcitabine-Pembrolizumab) Performance

The pembro-GVD regimen demonstrates exceptional efficacy in the exact clinical scenario of refractory classical Hodgkin lymphoma:

• Complete response rate of 95% (36/38 evaluable patients) after 2-4 cycles, with an overall response rate of 100% 1
• 95% of patients successfully proceeded to HDT/ASCR (36/39 enrolled), which is the gold standard curative treatment for refractory disease per NCCN guidelines 2
• All 36 transplanted patients remained in remission at median follow-up of 13.5 months post-transplant 1
• The regimen was specifically tested in high-risk patients: 41% had primary refractory disease and 38% relapsed within 1 year of frontline treatment 1

Toxicity Profile Favors Pembro-GVD

The safety profile strongly supports pembro-GVD over intensive chemotherapy:

• Predominantly grade 1-2 toxicities, with minimal grade 3 events (transaminitis n=4, neutropenia n=4, mucositis n=2) 1
• GVD-based regimens without pembrolizumab already demonstrated favorable toxicity (grade 3/4 neutropenia 34.3%, thrombocytopenia 5.7%) 3
• Gemcitabine-containing regimens generally have favorable toxicity profiles with overall response rates exceeding 70% in relapsed/refractory disease 4

Decitabine-Pembrolizumab Lacks Supporting Evidence

Critical limitation: There is no published evidence supporting decitabine-pembrolizumab for classical Hodgkin lymphoma in the provided guidelines or research.

• Decitabine (a hypomethylating agent) is not mentioned in NCCN guidelines for refractory classical Hodgkin lymphoma 2
• NCCN-recommended second-line regimens include DHAP, ICE, IGEV, GVD, and GCD—but not decitabine-based combinations 2, 5
• The LYSA guidelines similarly recommend DHAP, GDP, ICE, and IVOx as salvage regimens, with no mention of decitabine 2

Alignment with Guideline-Directed Care

The treatment strategy must prioritize achieving chemosensitivity to enable HDT/ASCR:

• HDT/ASCR is the best treatment option for refractory classical Hodgkin lymphoma per NCCN guidelines 2
• Patients achieving complete response or partial response to second-line therapy before HDT/ASCR have significantly improved outcomes (60-62% event-free survival vs 19-23% in resistant disease) 5
• The goal of salvage therapy is achieving PET-negativity (Deauville ≤3) to proceed to HDT/ASCR 2, 5

Clinical Algorithm for Stage IIE Refractory Disease

1. Confirm refractory disease with biopsy before initiating salvage therapy 2

2. Initiate pembro-GVD for 2-4 cycles:

   • Pembrolizumab 200 mg IV day 1
   • Gemcitabine 1,000 mg/m² IV days 1 and 8
   • Vinorelbine 20 mg/m² IV days 1 and 8
   • Liposomal doxorubicin (Caelyx) 15 mg/m² days 1 and 8
   • 21-day cycles 1

3. Assess response with PET after 2 cycles:

   • If Deauville ≤3: proceed to HDT/ASCR 1
   • If Deauville 4-5: complete 4 cycles total, then reassess 1

4. Proceed to HDT/ASCR once PET-negative status achieved 2, 1

5. Consider brentuximab vedotin maintenance for 1 year post-HDT/ASCR if high-risk features present (primary refractory disease, remission <1 year, extranodal involvement, PET-positive at transplant, B symptoms, or >1 salvage regimen) 2

Important Caveats

• Avoid more than two lines of salvage chemotherapy before transplant to prevent selection of highly chemoresistant clones 5
• For stage IIE disease previously untreated with radiation, involved-site radiotherapy should be strongly considered for sites not previously irradiated, either as part of salvage or post-HDT/ASCR 2
• If pembro-GVD fails, alternative NCCN-recommended regimens include DHAP, ESHAP, ICE, IGEV, or BeGEV 2, 5
• Brentuximab vedotin can be incorporated if not previously used 2, 5