Autologous HSCT Shows Sustained Long-Term Benefit in MCL, But Role May Be Rechallenged By Novel Approaches

Autologous hematopoietic stem-cell transplantation (HSCT) maintained its long-term efficacy over interferon alfa in patients with mantle cell lymphoma (MCL), confirming its place as the standard frontline treatment in this population, according to a post-hoc analysis of a phase 3 trial published in The Lancet Haematology. However, the approach must be rechallenged in light of the targeted options that have since become available in the paradigm.

Data from an exploratory intention-to-treat analysis showed that the median progression-free survival (PFS) for those who underwent HSCT was 3.3 years (95% CI, 2.5-4.3) vs 1.5 years (95% CI, 1.2-2.0) for those who received interferon alfa maintenance (adjusted hazard ratio [aHR], 0.50; 95% CI, 0.36-0.69; P < .0001). Moreover, the median overall survival (OS) was 7.5 years (95% CI, 5.7-12.0) in the HSCT group compared with 4.8 years (95% CI, 4.0-6.6) in the interferon alfa group (aHR, 0.66; 95% CI, 0.46-0.95; P = .019).

Moreover, for patients who received induction therapy without rituximab (Rituxan), the aHR for PFS in the HSCT group vs interferon alfa group was 0.40 (95% CI, 0.26-0.61; P < .0001), compared with 0.72 (95% CI, 0.42-1.24; P = .087) in patients who did receive rituximab. The aHR for OS in the HSCT group vs interferon alfa group was 0.52 (95% CI, 0.33-0.82; P = .016) without rituximab and 1.05 (95% CI, 0.55-1.99; P = .680) for patients who received rituximab.

“Whether an autologous HSCT should be generally recommended despite the available additional therapeutic options cannot be appropriately addressed with this trial alone,” lead author Anna-Katharina Zoellner, MD, of Ludwig-Maximilians-University Hospital of Munich-Grosshadern, Munich, Germany, and colleagues, wrote. “However, the absence of any significant benefit of autologous HSCT for patients after rituximab-containing induction underlines the need to further explore the value of autologous HSCT in comparison with the most effective regimens available.”

Data from several studies done over the past 2 decades have demonstrated that HSCT results in high response and PFS rates. As such, this approach serves as the current standard of care for younger, fit patients with MCL in advanced stages.

This study, which was initiated in 1996 by the European Mantle Cell Lymphoma Network, was one of the first to establish the role of this modality. This was also the first to have an open-label, multicenter, randomized, phase 3 trial design that was conducted to specifically analyze the safety and efficacy of HSCT vs interferon alfa maintenance therapy following a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)–like induction therapy, without or with rituximab (R-CHOP), in patients with advanced-stage MCL who were younger than 65 years of age.

Primary results from the trial showed that although autologous HSCT significantly prolonged PFS over vs maintenance interferon alfa, the OS benefit with the former was not found to be statistically significant at a median follow-up of 25 months. In the 15 years since the primary publication of the study, treatment for this patient population has evolved substantially, with use of rituximab in induction therapy, as well as high-dose chemotherapy regimens, and targeted treatments.

For the current report, investigators sought to examine the long-term results from the trial, including OS, in patients with primary advanced-stage MCL treated with high-dose radiochemotherapy and autologous HSCT, or interferon alfa maintenance in remission following chemotherapy without or with rituximab. Additionally, the study authors assessed whether the efficacy of HSCT was modified by the addition of rituximab to frontline induction in this setting.

A total of 292 patients were registered to the European Mantle Cell Lymphoma Network trial. These patients were between the ages of 18 years and 65 years and had previously untreated advanced stage III and IV MCL. Those with a poor performance status, defined as an ECOG performance status of higher than 2, or who had severe cardiac, pulmonary, hepatic, or renal impairment, were excluded from the research.

Patients were randomized 1:1, prior to induction, to receive either myeloablative radiochemotherapy followed by autologous HSCT (n = 134) or interferon alfa maintenance afterinduction therapy was completed (n = 135).

Induction therapy consisted of 4 cycles of CHOP for those who experienced a complete remission (CR) following 4 cycles, or 6 cycles for all others; CHOP-like regimens; or a combination of IV rituximab at a dose of 375 mg/m2 on day 0 or 1 of each cycle plus CHOP. Those who were given CHOP received intravenous (IV) cyclophosphamide at a dose of 750 mg/m2 on day 1, IV doxorubicin at a dose of 50 mg/m2 on day 1, IV vincristine a dose of 1.4 mg/m2 on day 2, and oral prednisone at a dose of 100 mg/m2 on days 1 through 5; this was repeated every 21 days.

Per protocol, further treatment for patients who did not have a partial remission (PR) after 6 cycles of induction therapy was up to the discretion of the treating physician.

Additionally, patients randomized to the HSCT arm received intensified stem-cell mobilization chemotherapy. Myeloablative therapy was given within 2 months of mobilization and consisted of a total body irradiation and a high-dose cyclophosphamide regimen. The previously harvested peripheral blood stem cells were then reinfused on day 0 and granulocyte colony-stimulating factor was started on day 1.

Those randomized to the interferon alfa arm received 2 additional cycles of conventional chemotherapy to balance the mobilization scheme. Subcutaneous interferon alfa was thereafter given at a starting dose of 6 × 106 IU 3 times weekly until disease progression. The dose was adapted based on toxicity.

Patients were the followed until disease progression, through assessment history, physical examinations, ultrasound examinations of the abdomen, and a complete laboratory investigation every 3 months. Chest radiography was performed every 6 months, and survival follow-up until death was planned.

The primary outcome of the post-hoc analysis was PFS from the end of induction until disease progression or death among those who achieved a remission. The secondary outcome was OS from end of induction to death.

Participants included in the analysis had a median age of 55 years (range, 47-60), and the majority were male (78%), had stage IV disease (82%), and an ECOG performance status of 1 (53%). Moreover, 73% of patients had a low-risk disease, 29% had elevated serum lactate dehydrogenase concentration, and 40% had B symptoms present.

Regarding induction treatment, 51% received CHOP, 39% received CHOP with rituximab, and 10% received a CHOP-like chemotherapy regimen. By the end of induction, 29% achieved a CR and 71% experienced a PR.

Of the 114 patients with MCL enrolled to the interferon arm and the 118 patients enrolled to the HSCT arm, 81 and 93 patients, respectively, experienced remissions following induction treatment.

Results from an exploratory analysis of secondary malignancies revealed no clear effect of autologous HSCT vs maintenance interferon alfa on the risk of secondary myelodysplastic syndrome or leukemia (HR, 1.6; 95% CI, 0.31-8.3; P = .58).

Moreover, data from an exploratory subgroup analysis, showed that patients who achieved a CR after induction therapy experienced a median PFS of 3.9 years (95% CI, 3.0-7.5) in the HSCT group vs 1.9 years (95% CI, 1.06-3.00) in the interferon alfa group (P = .0003); those who achieved a PR had a median PFS of 2.5 years (95% CI, 2.3-4.3) and 1.4 years (95% CI, 1.1-2.0), respectively (P = .0026).

Patients who achieved a CR following induction therapy reported a median OS of 9.7 years (95% CI, 6.7–not reached [NR]) in the HSCT group vs 6.5 years (95% CI, 4.0-18.5) in the interferon alfa group (P = .15); those who achieved a PR had a median OS of 6.3 years (95% CI, 5.1-12.0) and 4.6 years (95% CI, 3.7-7.4), respectively (P = .10).

Patients who received an induction regimen without rituximab experienced a significantly increased PFS and OS following HSCT compared with interferon alfa maintenance therapy, according to findings from further exploratory subgroup analyses.

Specifically, the median PFS was 3.1 years (95% CI, 2.5-4.3) in the HSCT group vs 1.2 years (95% CI, 1.0-1.9) in the interferon alfa group (P < .0001). The Cox regression analysis adjusted for MIPI score showed an aHR of 0.40 (95% CI, 0.26-0.61). Moreover, the median OS was 6.7 years (95% CI, 5.4-12.9) and 4.3 years (95% CI, 3.6-6.6), respectively (P = .016). The aHR was 0.52 (95% CI, 0.33-0.82).

For those treated with a rituximab-containing induction regimen, the median PFS survival was 3.4 years (95% CI, 2.4-6.8) in the HSCT group vs 1.7 years (95% CI, 1.4-5.9) n the interferon alfa group (P = .087). The aHR was 0.72 (95% CI, 0.42-1.24). Additionally, the median OS was 9.6 years (95% CI, 5.5-12.2) and 5.5 years (95% CI, 4.6–NR), respectively (P = .68). The Cox regression analysis adjusted to MIPI score gave an adjusted HR of 1.05 (95% CI, 0.55-1.99).

“On the basis of these mature data, the significantly improved PFS after autologous HSCT is independent of remission status after induction therapy, with OS showing the same trend,” study authors concluded. “Therefore, these data from the first randomized phase 3 trial of the European Mantle Cell Lymphoma Network underline the relevance of post-induction autologous HSCT in the context of a CHOP-like induction therapy.”

However, the treatment of the disease has changed since the start of this trial. As such, data from ongoing efforts like the phase 3 TRIANGLE trial (NCT02858258) could serve to challenge the future role of autologous HSCT in young patients with MCL.

Reference

1. Zoellner A-K, Unterhalt M, Stilgenbauer S, et al. Long-term survival of patients with mantle cell lymphoma after autologous haematopoietic stem-cell transplantation in first remission: a post-hoc analysis of an open-label, multicentre, randomised, phase 3 trial. Lancet Haemat. 2021;8(9):e648-e657. doi:10.1016/S2352-3026(21)00195-2