Severe GI Toxicities Remain a Significant Source of Clinical Meaningful Morbidity Especially in Older Patients Receiving Autologous Transplant for Lymphoma

Introduction:

High-dose chemotherapy and autologous hematopoietic cell transplant (HDT-AHCT) is considered a standard-of-care (SOC) consolidation therapy for patients with aggressive systemic non-Hodgkin (NHL) and Hodgkin lymphomas (HL). This therapy is associated with improved survival in relapsed/refractory NHL and HL as well as in first complete remission in mantle cell lymphoma. The most widely used HDT regimen consists of carmustine, etoposide, cytarabine and melphalan (BEAM). Although potentially curative, significant morbidities occur with HDT, especially in older patients. Aside from the expected severe hematologic toxicities, the most common clinically meaningful morbidities include signs and symptoms related to severe alimentary tract mucositis such as CTCAE Grade ≥ 3 nausea/vomiting, diarrhea and oral mucositis and febrile neutropenia (FN). The majority of FN, other infectious complications and sepsis are thought to occur due to translocation of the normal gut flora into the peripheral circulation in the presence of oral/GI mucositis. In the present study, we retrospectively analyzed patients undergoing HDT-AHCT for lymphoma in a contemporary cohort from 2 academic transplant centers, focusing on rates of oral/GI severe regimen related toxicity (SRRT) and febrile neutropenia.

Methods:

We conducted a retrospective analysis of 143 consecutive adult patients from 2 transplant centers undergoing HDT-AHCT as SOC consolidation for a diagnosis of NHL or HL between 2018 and 2020. The protocol was approved by the IRB at both institutions. Standard prophylactic and supportive care were provided as per institutional guidelines for HDT-AHCT. Toxicities were graded by CTCAE v5 criteria. SRRT was defined as oral/GI grade 3 or higher (G≥3) including adverse events related to alimentary tract mucositis. Partial response (PR) and complete response (CR) were defined by Lugano criteria. Statistics presented are descriptive only with no multiplicity adjustments.

Results:

143 patients were included in the analysis, 99% (n=141) of whom received BEAM for the HDT regimen, while 1% (n=2) received BeEAM (bendamustine in place of carmustine) (Table 1). 71% had NHL, while 29% had HL. Median prior lines of therapy were 2 (range, 1-4). Median CD34+ cell count was 4.3 x10 ⁶ cells/kg (range, 1.9-19.6).

Oral/GI SRRT occurred in 45% (n=65) of patients, with the most common G≥3 GI toxicities being diarrhea (26%), nausea / vomiting (20%), and oral mucositis (10%) (Table 2). Importantly, rates of SRRT were higher among patients ≥65 (63% vs 41%, p=0.031). The predominant differences were higher rates of G≥3 diarrhea (44% vs 21%, p=0.011), nausea (28% vs 18%, p=0.214) and oral mucositis (16% vs 8%, p=0.215).

Considering only oral/GI SRRT of oral mucositis, nausea / vomiting, diarrhea (SSRT4), the overall rate of SRRT4 was 41%, with 56% and 37% occurring in patients ≥65 yo and <65 yo respectively.

Rates of SRRT were similar regardless of gender, disease, number of prior lines of therapy or best response at the time of HDT-AHCT (Table 3).

Interestingly, rates of FN were also numerically higher among older adults (75% vs 64%, p=0.247). Consistent with the notion that GI toxicity predisposes to bacterial translocation from the gut, patients with SRRT had numerically higher rates of FN compared to those without (74% vs 60%, p=0.088). Time to engraftment and length of hospital stay did not appear to vary by age group (Table 4).

Conclusion:

We identify severe GI toxicities including alimentary mucositis as a significant source of morbidity in patients receiving HDT-AHCT for lymphoma. Older age increases risk with 63% of the elderly experiencing ≥G3 GI toxicities and 72% experiencing FN. New therapies that have the potential to revive the alimentary tract repair mechanism will not only have impact on reducing severe oral/GI toxicities but will also enhance innate immunity by preventing translocation of bacteria into the bloodstream from the GI tract, as indicated by the association between SRRT and FN in our cohort of patients.

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