Stem Cell Transplant Yields Enduring Disease Control in TP53-Mutated MCL

"We recommend that all patients with newly diagnosed MCL be tested for TP53 mutations, and that such patients should either receive targeted frontline agents—if accessible—or switch to these at the earliest evidence of inadequate response," according to lead study author Thomas E. Lew.

The use of allogeneic stem cell transplantation (alloSCT) may be curative in patients with mantle cell lymphoma (MCL), including those with diseases harboring TP53 mutations, according to findings from a study published in Leukemia & Lymphoma.

Investigators reported estimated 10-year progression-free survival (PFS) and overall survival (OS) rates of 48% (95% CI, 30%-64%) and 56% (95% CI, 36%-72%), respectively, in the study’s overall cohort (n = 36) after a median follow-up of 10.8 years. The 4-year estimates of PFS and OS in a cohort of patients with TP53-mutated disease (n = 13) were 51% (95% CI, 21%-75%) and 59% (95% CI, 28%-81%), respectively, after a median follow-up of 4.2 years. Investigators reported comparable long-term disease control in patients with or without PET- or CT-confirmed complete remissions (CRs) before undergoing alloSCT (HR, 0.9; 95% CI, 0.3-3.1; P = .927).

“We hope that clinicians will consider autologous SCT [alloSCT] in first CR for patients with this high-risk subset of MCL,” lead study author Thomas E. Lew stated in a written comment to CancerNetwork^®. “Outcomes after conventional chemoimmunotherapy and [autoSCT] are very poor, and the majority of patients will [have] disease progression or death within 1 year. Especially when the path to CAR T cells is uncertain or non-existent, these data suggest that [alloSCT] should be strongly considered in patients with adequate fitness.”

Lew is part of the Department of Clinical Haematology at Royal Melbourne Hospital and Peter MacCallum Cancer Centre in Melbourne, Australia.

Among 13 patients with relapsed disease after undergoing alloSCT, the median OS from disease progression was 2.1 years (95% CI, 0.3-not estimable [NE]). Investigators observed 3 instances of durable survival in patients with relapsed disease within 2 years following transplantation, which included one who received local radiotherapy and interferon. Additionally, another patient with TP53-mutated disease experienced a CR when treated with ibrutinib (Imbruvica) plus 4 donor lymphocyte infusions. The third patient received a regimen consisting of nivolumab (Opdivo), ibrutinib, and pirtobrutinib (Jaypirca).

Investigators reported 2 events of late relapsed disease that were managed with salvage chemotherapy and second transplants. One patient who had relapsed disease at 5 years after initial transplantation experienced remission for 31 months followed by disease progression and death at 5 years after a second alloSCT. A second patient with relapsed disease at 15 years was treated with platinum-based chemotherapy and underwent autoSCT; they were alive at 12 months following relapse. Investigators noted a statistically significant relationship between the site of relapse and OS following progression, although these samples were limited in size (P = .003).

Lew also discussed how the study data may inform treatment decision-making concerning patients with MCL, including those with TP53 mutation-positive disease.

“We recommend that all patients with newly diagnosed MCL be tested for TP53 mutations, and that such patients should either receive targeted frontline agents—if accessible—or switch to these at the earliest evidence of inadequate response,” Lew wrote. “Due to the considerable logistical preparation required, when [alloSCT] is considered a possible consolidative strategy, we recommend referral to a transplant physician and initiation of work up during induction.”

Investigators assessed 36 patients with MCL who were treated with alloSCT between July 2000 and February 2023.

The median patient age was 52.5 years (range, 33-71). Additionally, 61% of patients were treated with alloSCT during first response, and 39% received a transplant following relapse. Overall, 75% of patients received cytarabine-containing induction regimens, 81% of whom were treated with reduced intensity conditioning.

Of those with TP53-mutated disease, 92% received initial treatment with intensive chemoimmunotherapy, and 1 patient received venetoclax (Venclexta) plus ibrutinib in the first-line setting. Investigators reported that 69% of patients in this group received a Bruton tyrosine kinase (BTK) inhibitor with or without venetoclax before undergoing alloSCT.

According to Lew, the next steps for research may involve conducting prospective studies evaluating treatment options outside of chemoimmunotherapy in this patient population. These studies may make use of BTK inhibitors with or without venetoclax or “[incorporate] bispecific antibodies into frontline regimens.”

Lew also wrote about the need to further assess the extent to which patients with responsive disease should receive consolidation therapy.

“Current data suggest that the standard approaches utilizing autologous stem cell transplantation in first response are not likely to improve disease control, and probably only add cumulative toxicity that may complicate salvage therapies,” Lew stated.

“At the Peter MacCallum Cancer Centre, we are not routinely proceeding with [autoSCT] in this scenario. However, whether it is better to proceed to [alloSCT] in first response or pursue CAR T-cell therapy at relapse is likely to remain controversial for some time.”

Lew concluded by discussing how there is a “considerable need” for additional data on outcomes for patients with TP53-mutated disease, stating that most available datasets were small and often collected information on multiple forms of TP53 dysfunction without specifically highlighting the highest-risk TP53-mutated subsets.

Reference

Lew TE, Scheffer Cliff ER, Dickinson M, et al. Allogeneic stem cell transplantation achieves long-term remissions in mantle cell lymphoma, including in TP53-mutated disease. Leuk & Lymp. Published online August 2, 2023. doi:10.1080/10428194.2023.2241095