GemCloBu: A New Conditioning Regimen for Aggressive Lymphomas

Jeremy Ramdial, MD

Myeloablative conditioning regimens for allogeneic stem cell transplants (alloSCT) in aggressive lymphomas can present significant toxicities while still lacking cytoreductive power. Investigators including Jeremy Ramdial, MD, explored the use of a new conditioning regimen to fill these gaps.

A phase 1/2 study (NCT01701986) explored the combination of gemcitabine, clofarabine, and busulfan (GemCloBu) before alloSCT in patients with relapsed aggressive lymphomas. The combination was chosen due to its synergistic effect on damaging lymphoma cells and inhibiting DNA repair mechanisms. Escalating doses of gemcitabine were tested, with the maximum tolerated dose identified as 975 mg/m²/day.

Sixty-four patients with different types of aggressive lymphomas, including B-cell non-Hodgkin lymphoma (B-NHL), T-cell non-Hodgkin lymphoma (T-NHL), and Hodgkin lymphoma (HL) were included in the study. Most patients (66%) had active disease at the time of alloSCT, while 42% had received an earlier autologous SCT which failed.

The regimen was effective in eliminating malignant cells, with high complete response (CR) rates. In B-NHL, the overall response rate (ORR) was 78.5% with a 71% CR rate. The ORR and CR were both 93% in the T-NHL arm, while the ORR and CR rates were both 67% in the HL arm.

The regimen was well-tolerated with manageable adverse effects, including mucositis and temporary liver enzyme abnormalities. The myeloablative regimen prepared patients for alloSCT, leading to engraftment within a median of 10 days

While the findings were promising, investigators identified that relapse remained a challenge, with 20 patients experiencing disease recurrence after treatment. Graft-vs-host disease (GVHD), a potential complication of alloSCT, occurred in 37% of patients. Further, long-term survival requires further investigation in larger studies.

“We know that these B[-cell] lymphomas behave more aggressively, and because of that, we want to approach them with a more myeloablative regimen. But we will also want it to be highly potent and safe, and that can be found in GemCoBu,” Ramdial, assistant professor at MD Anderson Cancer Center, said in an interview with Targeted Oncology^TM.

In the interview, Ramdial discussed the study, which was presented at the 2024 Transplantation and Cellular Therapy Tandem Meetings, as well as its findings and implications for community oncologists.

Lymphomas: © immimagery - stock.adobe.com

Targeted Oncology: What was the rationale for the study you presented?

Ramdial: Current myeloablative conditioning regimens for aggressive lymphomas for allogeneic stem cell transplant seem to be too toxic. The reduced intensity conditioning regimens that are available now do not provide enough adequate cytoreduction to allow for graft-vs-lymphoma effect. We decided to look into a strategy of ours called sequence-dependent synergy, where we combine a nucleoside analog to be given before an alkylating agent, and we then decided to optimize that by doing 2 nucleoside analogs, which is gemcitabine and clofarabine to be given before the alkylating agent busulfan. We then tested this in preclinical studies, and that led to the development of our phase 1/2 clinical trial of GemCloBu.

What are some of the unmet needs in this space?

As previously mentioned, myeloablative conditioning regimens were a bit too toxic, and the reduced intensity conditioning regimen didn't provide enough cytoreduction. We know nowadays, especially [in] patients who are post [chimeric antigen receptor (CAR) T-cell therapy] or things like that, they may have more of an aggressive behaving lymphoma. They will require a more potent and active conditioning regimen that is also safe.

What were the goals of the study?

The biggest goals were [first] to show that the combination of treatment resulted in adequate cytoreduction and was highly active and the second being safety and manageable self-limited toxicities.

Can you summarize your findings?

In our phase 1/2 clinical trial, we wanted to demonstrate first, [in] the phase 1 portion, the maximum tolerated dose of gemcitabine. We landed on our dose level 3, which was 975 mg/m² gemcitabine, and 37 patients were treated in this phase. We then moved on to phase 2 where we wanted to look into overall response rate, non-relapse mortality, [and] graft-vs-host disease rate.

We were able to show that in the 2 tumor types—B[-cell] non-Hodgkin lymphoma, T[-cell] non-Hodgkin lymphoma, and Hodgkin lymphoma, an overall response rate of approximately 80%. The day 100 non-relapse mortality was 7%. At 1 year, it was 18%. For grade 3 to 4 acute GVHD, it was 18%, and for chronic GVHD, about 1/3 of the patient population experienced chronic GVHD ranging in severity.

From these findings, what would be your key takeaways for the community oncologist?

In the current landscape of treatment for lymphoma, we know that with the success of CAR [T-cell therapies], bispecific [antibodies], immunotherapies, if you happen to run across a patient that is relapse after these treatments, or refractory to this therapy, or even having less than a [partial response] to second salvage therapy, they may benefit from a myeloablative conditioning regimen and allogeneic stem cell transplant. We know that these B[-cell] lymphomas behave more aggressively, and because of that, we want to approach them with a more myeloablative regimen. We will also want it to be highly potent and safe, and that can be found in GemCoBu.

REFERENCE:

Ramdial J, Valdez B, Lin R, et al. Gemcitabine (Gem)/clofarabine (Clo)/busulfan (Bu) (GemCloBu): a new myeloablative conditioning regimen with reduced toxicity and high activity for allogeneic stem-cell transplant (alloSCT) for aggressive lymphomas. Presented at: 2024 Transplantation & Cellular Therapy Meetings; San Antonio, Texas; February 21-24, 2024. Abstract 63.