ASCT is no longer suitable for the majority of patients with DLBCL

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Most patients with diffuse large B-cell lymphoma do not derive significant benefit from treatment with autologous stem cell transplantation and better treatment options are currently available for this population.

Most patients with diffuse large B-cell lymphoma (DLBCL) do not experience significant benefit from treatment with autologous stem cell transplantation (ASCT) and better treatment options are currently available for this population, according to a presentation at the Pan Pacific Lymphoma Conference 2022.1

“ASCT is lousy therapy in the modern age,” said Jeremy S. Abramson, MD, MMSc. “There are select patients who are still suitable for ASCT, but that’s a tiny minority in the modern era.”

Abramson is the director of the Lymphoma Program and the Jon and Jo Ann Hagler Chair in Lymphoma at Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts.

Salvage treatment with high-dose chemotherapy plus ASCT for patients with DLBCL who have responded to their initial treatment often fails most patients, Abramson explained. About 75% of patients who relapse do so within a year of their first-line treatment, he noted, adding that about half of patients with relapsed/refractory DLBCL are not eligible for treatment with ASCT due to factors such as age or comorbidities.

Abramson cited data from the Phase 3 ORCHARRD trial (NCT01014208), which compared the efficacy of ofatumumab plus cisplatin, cytarabine, and dexamethasone (DHAP) followed by ASCT with that of rituximab (Rituxan) plus DHAP. followed by ASCT in patients with relapsed/refractory DLBCL . The 2-year progression-free survival (PFS) rates were 24% and 26%, respectively (HR, 1.12; 95% CI, 0.89-1.42; P = 0.33). Additionally, the 2-year event-free survival (EFS) rates were 18% and 16%, respectively HR, 1.10; 95% CI, 0.90-1.36; P = .35).2

In another study, the NCIC-CTG LY.12 Phase 3 trial (NCT00078949), researchers evaluated gemcitabine, dexamethasone, and cisplatin followed by ASCT versus DHAP in patients with relapsed/refractory aggressive lymphoma. Patients with B-cell lymphoma also received rituximab. No significant difference was noted in EFS at 4 years (HR, 0.99; 95% CI, 0.82-1.21; log-rank stratified P = 0.95), overall survival (OS; RR, 1.03; 95% CI, 0.83-1.28; P = 0.78) or PFS (HR, 0.99; 95% CI, 0.82-1.21; P = 0.95).3

“More Contemporary Essays [such as] ORCHARRD and the NCIC-CTG LY.12 study [have shown] lasting remissions in less than a quarter of patients. Abramson said. “It’s not good therapy.”

Abramson said CAR T-cell therapy is a superior choice for most patients with DLBCL. CAR T-cell agents have been shown to be particularly useful in treating patients with refractory or early relapsing primary disease, he said.

In the ZUMA-7 phase trial (NCT03391466), the CAR T-cell agent axicabtagene ciloleucel (axi-cel; Yescarta) was evaluated against the standard of care of chemoimmunotherapy followed by chemotherapy with high dose with ASCT in patients who have responded to chemoimmunotherapy. The trial included patients with relapsed/refractory large B-cell lymphoma who were relapsed or refractory within one year of their first-line treatment. Patients were randomized 1:1 to receive either axi-cel (n=180) or standard treatment (n=179).4

At a median follow-up of 24.9 months, the median EFS in the axi-cel arm was 8.3 months (95% CI, 4.5-15.8) versus 2.0 months (95 %, 1.6-2.8) in the standard care arm (HR, 0.40; 95% CI, 0.31-0.51; P

In terms of response, axi-cel was also superior to the standard of care. The overall response rate (ORR) was 83% versus 50%, respectively. Patients who received axi-cel also achieved a complete response (CR) rate of 65% compared to 32% in patients treated with standard therapy. Additionally, axi-cel was associated with improved quality of life as assessed by patient-reported outcomes.

The safety results were mostly similar between the 2 arms; all patients in both groups experienced an adverse event (AE) of any grade. Grade 3 or higher AEs occurred in 91% of patients and 83% of patients in the experimental and control groups, respectively. However, cytokine release syndrome (CRS) of any grade was present in 92% of patients in the axi-cel arm, and neurological AEs of any grade were more common in the axi-cel arm than in the standard treatment arm ( 60% versus 20%).

“With CAR T-cell [therapy] we expect some CRS and neurotoxicity; we see a lot of that with axi-cel,” Abramson said. “The majority of patients developed CRS, but only 6% were severe. Also, [most] patients developed neurological toxicity, [but it was] serious in only 20%. And these toxicities are almost entirely reversible.

Another trial of a CAR T-cell agent, the Phase 3 TRANSFORM trial (NCT03575351), examined the efficacy and safety of lisocabtagen maraleucel (liso-cel; Breyanzi) versus standard of care in patients with relapsed/refractory LBCL. Patients included in the trial had primary refractory disease or early relapse.5

At a median follow-up of 6.2 months (range, 4.4-11.5), the median EFS was 10.1 (95% CI, 6.1-NE) compared to 2.3 months ( 95% CI, 2.2-4.3) in the liso-cel (n=92) and standard care arms (n=92), respectively (HR, 0.35; 95% CI, 0, 23-0.53; P

Similar to the results of the ZUMA-7 trial, liso-cel also resulted in a higher ORR compared to standard of care (86% vs. 48%). Patients in the liso-cel arm also achieved a CRR of 66% versus 39% in the standard treatment arm. More than half of the standard-of-care arm (54%) crossed over to be treated with liso-cel and the patients’ quality of life reported results were again in favor of the CAR T-cell agent.

Treatment-emergent AEs (TEAEs) occurred in almost all patients in both arms (100% versus 99%). Grade 3 or higher TEAEs were slightly more common in the liso-cel arm (92%) than in the standard treatment arm (87%). CRS of any grade was present in 49% of patients who received liso-cel.

“As shown on ZUMA-7, not a single subset [of patients] preferred high-dose chemotherapy and ASCT to CAR T cells [therapy] in this lawsuit,” Abramson said. “This was an extremely well-tolerated and fully reversible therapy for patients who had a higher likelihood of cure with this treatment compared to standard of care.”

Some patients still benefit from ASCT

Despite compelling evidence against the use of ASCT, there is still a subset of patients with DLBCL for whom the treatment may be effective, argued Blood Transplant Program Director Craig S. Sauter, MD. and bone marrow at the Cleveland Clinic in Cleveland, Ohio.

“Value-based care has many facets, including not just endpoints [such as] EFS, PFS and OS, but the costs weigh on the limited resources in the space, the quality of life of the patients,” said Sauter. “Financial toxicity is a real problem. Access to resources is a real problem. It will be an ongoing conversation.

Sauter went on to explain that access to CAR T-cell therapy is limited in the United States and around the world. The profitability of second-line CAR T-cell agents is also unclear, Sauter noted. Axi-cel was found to have $80,000 per quality-adjusted life year over standard of care and CAR T-cell therapy in general had up to $2 million per year of life quality-adjusted to standard of care, he said.

Additionally, Sauter noted that ASCT has been shown to provide durable remissions in patients with DLBCL with a positive partial response (PR) to PET scan. According to data from the Center for International Blood and Marrow Transplant Research, the median PFS of patients with DLBCL who received ASCT was comparable in patients with and without early failure of chemoimmunotherapy (P = 0.22).6

Stauter also pointed out that the findings recently published in Blood showed that ASCT may in fact be superior to CAR T-cell therapy for patients with DLBCL who are in PR after salvage chemotherapy. The 2-year PFS rates favored ASCT (52%) over CAR T-cell therapy (42%; P = 0.06). Additionally, the 2-year OS rates were 69% and 47%, respectively (P = 0.007).seven

“There may be a signal of improved durability of ASCT,” Sauter said. “But [these are] very different groups [of patients] and registry-level data that should be taken with a grain of salt.

References

  1. Abramson JS, Sauter CS. Autologous transplantation for DLBCL. Presented at: 2022 Pan Pacific Lymphoma Conference: July 18-22, 2022; Koloa, Hawaii.
  2. van Imhoff GW, McMillan A, Matasar MJ, et al. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD study. J Clin Oncol. 2017;35(5):544-551. doi:10.1200/JCO.2016.69.0198
  3. Crump M, Kuruvilla J, Couban S, et al. Randomized Comparison of Gemcitabine, Dexamethasone, and Cisplatin Versus Dexamethasone, Cytarabine, and Cisplatin Chemotherapy Prior to Autologous Stem Cell Transplantation for Relapsed and Refractory Aggressive Lymphoma: NCIC-CTG LY.12. J Clin Oncol. 2014;32(31):3490-3496. doi:10.1200/JCO.2013.53.9593
  4. Locke FL, Miklos DB, Jacobson CA, et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as a second-line treatment for large B-cell lymphoma. N English J med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133
  5. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard treatment with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results of an interim analysis of a phase 3 open-label, randomized trial [published correction appears in Lancet. 2022;400(10347):160]. Lancet. 2022;399(10343):2294-2308.
  6. Shah NN, Ahn KW, Litovich C, et al. Is autologous transplantation in relapsed DLBCL patients achieving only PET+ PR appropriate in the era of CAR-T cells? Blood. 2021;137(20):2854-2855. doi:10.1182/blood.2021011979
  7. Shadman M, Pasquini M, Ahn KW, et al. Autologous transplant vs. chimeric antigen receptor T cell therapy for relapsed DLBCL in partial remission. Blood. 2022;139(9):1330-1339. doi:10.1182/blood.2021013289

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