Point-Counterpoint
Autologous Hematopoietic Cell Transplantation: An Option for Some Patients With Diffuse Large B-cell Lymphoma After Early Failure of Firstline Therapy

Autologous hematopoietic cell transplantation (AHCT) remains a curative-intent option for some patients with diffuse large B-cell lymphoma (DLBCL) after early failure of firstline therapy.

For decades, the goal for transplant-eligible patients with relapsed or refractory (R/R) DLBCL has been high-dose therapy with AHCT. The randomized PARMA trial initially demonstrated AHCT as curative in a subset of patients, also noting effects superior to those observed with second-line conventional chemotherapy alone.¹  The primary drawback of this approach, however, has been that only patients with chemosensitivity to second-line chemotherapy stand to benefit from AHCT. Historically, only around 50% of patients will demonstrate such chemosensitivity. Further, some patients are not AHCT candidates due to advanced age, frailty, or comorbidity.

As such, AHCT has not been considered a viable solution for at least half of patients with R/R DLBCL for many years, particularly those over age 75, those with serious comorbidities, and the approximately 50% who are refractory to second-line chemotherapy. However, among those who demonstrate chemosensitivity and proceed to transplant, 40 to 50% will achieve long-term remission.¹  Even in the rituximab era and for those with failure of firstline therapy within one year, long-term remission rates of 40 to 50% can be expected among those who proceed to AHCT.^2-5 

CD19 chimeric antigen receptor T-cell (CAR-T) therapy has been a game-changing addition to the therapeutic arsenal against R/R DLBCL. In 2022, three randomized prospective trials were published comparing AHCT with CD19 CAR-T in patients with R/R DLBCL who experienced either failure of primary induction or relapse within one year.^6-8  Of these trials, two showed a benefit in favor of CD19 CAR-T,^6,7  leading to second-line approval of axicaptagene ciloleucel and lisocaptagene maraleucel for this subgroup of patients. However, considering the definition of “event” used in these studies, one can argue that the control (AHCT) arm really had no chance in terms of event-free survival. Patients in the control arm received both second-line chemotherapy and AHCT; therefore, 50% of patients assigned to the control arm were expected to experience an event since, at most, 50% of patients are expected to exhibit at least a partial response to second-line therapy. Illustrating this, only 32 to 46% of patients actually underwent transplant in the AHCT arms, in contrast to the 95 to 98% who received CAR-T in the CAR-T arms.^6-8  Among the subset of patients who made it to AHCT, the outcomes were nearly comparable to those observed in the CAR-T arm, with approximately 50% remaining event-free at one year.

Recent data from the Center for International Blood and Marrow Transplant Research (CIBMTR) also suggest that, for patients with chemosensitive disease, outcomes are comparable between those who undergo AHCT and those who undergo CAR-T.⁹  Moreover, for patients with progressive disease after AHCT, CAR-T remains an excellent option.^6,7  On the other hand, we do not have much data to address whether AHCT is a viable option after failure of CAR-T. Therefore, skipping AHCT and going straight to CAR-T may result in some patients missing out on a chance at cure with AHCT.

As great as it is to have new options, with new options come new choices. How do we choose between AHCT and CAR-T for patients with R/R DLBCL who experience treatment failure within one year? For some patients, the choice is easy. For example, outcomes for AHCT are known to be poor in patients with primary progressive disease on R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone) or those with MYC gene rearrangement.¹⁰  Such patients are better served with CAR-T. In addition, CAR-T may be an option in the subset of patients who are not candidates for AHCT due to age or frailty. For the remainder, a trial of second-line chemotherapy is very reasonable to determine whether AHCT represents an additional curative-intent option.

Dr. Fenske has reported speaker and consultant activity for Kite/Gilead and MorphoSys and consultant activity for ADCT.