Is autologous stem cell transplant (ASCT) more effective than CAR (Chimeric Antigen Receptor) T-cell therapy for a patient with relapsed or refractory high-risk T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL)?

CAR-T Cell Therapy is Superior to Autologous Stem Cell Transplant for Relapsed/Refractory THRLBCL

For patients with relapsed or refractory T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), CAR-T cell therapy should be the preferred second-line treatment over autologous stem cell transplantation (ASCT), based on the most recent high-quality evidence demonstrating superior outcomes in high-risk relapsed DLBCL and specific data showing excellent results in THRLBCL with ASCT. However, the decision requires understanding that THRLBCL actually performs better than standard DLBCL with ASCT, creating a nuanced clinical scenario.

The Evidence Hierarchy

CAR-T as Second-Line Standard for High-Risk Disease

• Lisocabtagene maraleucel (liso-cel) and axicabtagene ciloleucel (axi-cel) are now approved as second-line therapies for high-risk relapsed/refractory DLBCL based on the TRANSFORM and ZUMA-7 trials, which demonstrated superior outcomes compared to standard salvage chemotherapy followed by ASCT 1.

• These trials specifically enrolled patients with primary refractory disease or early relapse (within 12 months), which represents the highest-risk population 1.

• For fit patients with high-risk relapsed/refractory disease, either axi-cel or liso-cel should be used as second-line therapy 1.

• Standard DLBCL patients treated with axicabtagene ciloleucel achieve 2-year overall survival of 51% and 2-year progression-free survival of 39%, with an overall response rate of 82% (54% complete response) 2.

THRLBCL-Specific ASCT Data Shows Surprisingly Good Outcomes

• THRLBCL demonstrates significantly superior outcomes with ASCT compared to standard DLBCL: 2-year PFS of 78% versus 59% (p<0.001) and 2-year OS of 81% versus 74% (p=0.02) 3.

• The relapse incidence at 2 years is dramatically lower in THRLBCL: 16% versus 35% for DLBCL (p<0.001) 3.

• On multivariate analysis, THRLBCL maintained favorable relapse risk (HR 0.46) and PFS (HR 0.58) compared to DLBCL 3.

• These results prove auto-HCT as an effective treatment option for salvage-sensitive relapsed/refractory THRLBCL 3.

The Clinical Algorithm

Step 1: Assess Disease Sensitivity and Patient Fitness

• Only proceed with either CAR-T or ASCT if the disease is chemosensitive to salvage therapy 4.

• Patients with chemoresistant disease should not proceed to auto-HCT as they have predictably poor outcomes 4.

• Assess whether the patient is medically fit for intensive therapy (both ZUMA-7 and TRANSFORM required fitness for ASCT) 1.

Step 2: Choose Between CAR-T and ASCT

For primary refractory or early relapse (<12 months):

• CAR-T therapy (liso-cel or axi-cel) is preferred as second-line treatment 1.
• This recommendation is based on Level 1 evidence from randomized trials showing superiority over the ASCT pathway 1.

For late relapse (>12 months) with chemosensitive disease:

• ASCT remains a highly effective option for THRLBCL specifically, given the 78% 2-year PFS and 81% 2-year OS 3.
• The survival curves plateau at 12-24 months, suggesting curative potential 4.
• Consider ASCT particularly if CAR-T is not immediately available or if there are logistical barriers.

For transplant-ineligible patients:

• Liso-cel is a reasonable treatment option based on the PILOT trial 1.

Step 3: Salvage Chemotherapy Selection

• Preferred combination regimens include DHAP, ICE, ESHAP plus platinum, GDP, GemOx, or DHAX 5.
• R-ICE demonstrated a 60% CR/PR rate in relapsed/refractory disease 5.
• The goal is achieving metabolic complete response (negative PET) before proceeding to either CAR-T or ASCT 5.

Critical Pitfalls to Avoid

Do Not Proceed with ASCT in Chemoresistant Disease

• Patients with chemoresistant disease have significantly inferior outcomes and should not undergo auto-HCT 4.
• Historical data shows 0% OS in patients relapsing post-ASCT without subsequent salvage therapy versus 39% with additional treatment lines 6.

Do Not Delay CAR-T in Primary Refractory Disease

• Research demonstrates that patients with primary refractory DLBCL do not benefit from ASCT 1.
• For primary refractory disease, proceed directly to CAR-T rather than attempting ASCT 1.

Do Not Ignore the THRLBCL-Specific Data

• While CAR-T is superior for high-risk DLBCL generally, THRLBCL shows exceptional outcomes with ASCT (78% 2-year PFS) that exceed standard DLBCL CAR-T outcomes (39% 2-year PFS) 3, 2.
• This creates a scenario where late-relapsing, chemosensitive THRLBCL may do equally well or better with ASCT.

Nuanced Considerations

The Timing Paradox

• 81% of relapses after ASCT occur within the first year, with significantly worse outcomes (19% OS) compared to later relapses (40% OS) 6.
• This suggests that early relapse post-ASCT represents biologically aggressive disease that would have benefited from upfront CAR-T.

Performance Status Matters

• Performance status before CAR-T infusion is a significant prognostic factor, with poor performance status more than doubling mortality risk 2.
• Patients with THRLBCL in the ASCT cohort had better performance status, which may partially explain superior outcomes 3.

The Evolving Landscape

• With bispecific T-cell-engaging antibodies emerging, the treatment landscape may be further upended 1.
• Clinical trial participation should be considered for all patients with relapsed/refractory disease 5.