Page 137 - Haematologica May 2022

Prephase therapy in older patients with DLBCL
ative chemoimmunotherapy.4,5 Moreover, if not adequate- ly addressed, these non-oncologic geriatric issues may exacerbate treatment-related toxicities, trigger functional decline, and adversely impact subsequent therapies such as hematopoietic cell transplantation and cellular thera- py.4-6 Therefore, it is essential that older patients with newly diagnosed DLBCL receive adequate assessment and management of their aging-related issues.
Biologically, inferior outcomes in older non-Hodgkin lymphoma (NHL) patients may result from preexisting geriatric deficits, the lymphoma itself, or treatment-relat- ed toxicities. Induction chemoimmunotherapy may wors- en health status when it results in toxicities or improve it by controlling disease related impairments. The German Non-Hodgkin Lymphoma Study Group (DSHNHL) found that after the initiation of the NHL-B2 trial, toxic mortality was most common in the first and second cycle of thera- py.7 They subsequently pioneered a strategy of “prephase” therapy with prednisone 100 mg daily for 5-7 days with or without vincristine 1 mg single dose prior to the initiation of full dose combination chemotherapy. This was incor- porated into the latter part of the NHL-B2 trial, RICOVER- 60 trial, and the LYSA group LNH097B trial with fewer toxic deaths reported.7-9 The mechanism of this effect has not been examined in detail, although it is thought that prephase therapy improves functional status and physio- logic reserve by reducing tumor burden. However, although vincristine is delivered by a simple 10-minute intravenous push, it is among the more toxic agents with significant risks of neuropathy and constipation resulting in its frequent dose reduction or omission.10
Geriatric assessment (GA) is increasingly incorporated into the care of older cancer patients to help guide treat- ment decision-making, predict toxicities, and manage non-oncologic geriatric issues. Multidimensional GA iden- tifies otherwise unrecognized health problems among unselected older patients beyond traditional Karnofsky performance scale (KPS) and includes function status, comorbidity, mobility, cognition, nutrition, and psychoso- cial status.11,12 A largely self-administered GA instrument, the Cancer Aging Research Group (CARG) chemotherapy toxicity risk score incorporates 11 variables to predict high-grade, chemotherapy-related toxicities for older solid tumor patients.13,14 Several GA domains have been exam- ined in small cohort studies of lymphoma patients, yet it remains unclear how they could be integrated into and improve outcomes in the context of curative intent chemoimmunotherapy.15
It has been long postulated that the mechanism under- lying phenotypic and functional aging is related to pertur- bations in several biochemical and cellular pathways.16 One of them is cellular senescence, a state of stable growth arrest once cells are subjected to significant stress and have accumulated enough DNA damage.17 Senescence cells create a highly dynamic and persistent program of senescence-associated secretory phenotype (SASP), consisting of abundant secretion of proinflamma- tory proteins into the tissue microenvironment that mod- ulates cancer immune surveillance and therapeutic response.18 Identification of important SASP components may generate novel targets to restore immune therapy responsiveness and enhance treatment outcomes.19 In this prospective pilot study, we examine the feasibility and safety of a novel prephase treatment with rituximab/pred- nisone for older, vulnerable patients with newly diag-
nosed DLBCL and its impact on meaningful toxicity out- comes, CARG-based GA measures, and the SASP-related, proinflammatory cytokine milieu.
Methods
Trial design and schema
We conducted a pilot study of rituximab/prednisone prephase treatment for older patients with newly diagnosed DLBCL prior to curative intent, anthracycline-based chemoimmunotherapy within our larger prospective observational study (Figure 1). Patients were eligible if they were aged 70 years or older, or were 60-70 years old with KPS <80. The protocol was approved by the Institutional Review Board at the Memorial Sloan Kettering Cancer Center and conducted according to the Declaration of Helsinki. All patients received a single dose of rit- uximab 375 mg/m2 given between 3 and 10 days and oral pred- nisone for at least 5 days during the 14 days prior to the first cycle. The preferred prednisone dose was 100 mg daily for 7 days with minimal allowable dose of 50 mg daily for 5 days.
Geriatric assessment
CARG-based GA was performed at baseline, following prephase treatment and before the first cycle, and prior to each subsequent cycle as previously described.13,14 The CARG chemotherapy risk calculator provided both a risk score (range, 0-19) and a corresponding absolute chemotherapy-toxicity risk percentage. The clinician portion of the GA included baseline patient and disease characteristics, clinician-rated KPS, memory screening test short Blessed Orientation-Memory-Concentration (BOMC),20 Timed Up and Go (TUG), and Mini-Nutrition Assessment (MNA).21
Outcome and toxicities assessment
The primary outcome was the composite of toxicity or severe toxicity events (TE). TE was defined as any of the following: i) hospitalization during or within 30 days following chemothera- py; ii) dose delay or reduction to a dose intensity ≤80% of the planned dose intensity; iii) discontinuation of chemotherapy due to toxicity. Severe TE (STE) was defined as the occurrence of either i) or iii) above. Secondary toxicity endpoints were: i) grade 3 or higher non-hematologic toxicity; ii) grade 4 or higher hema- tologic toxicity. Toxicity was graded according to CTCAE v4.0.3.
Proinflammatory cytokine analysis
Immunoassays of the levels of proinflammatory cytokines were batch performed in duplicate on singly thawed plasma samples on a commercial multiplex cytokine panel including IL- 6, IL-1b, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12, TNF-a, and IFN-g (Miso Discovery Laboratory). These cytokines were chosen given commercial availabilities on multiplex plates and technical expertise at our institution.
Statistical analyses
In order to compare pre- and posttreatment GA scales and cytokine (CK) levels, one-sided pairwise Wilcoxon tests were used. CK levels were log-transformed before analyses. Associations between baseline GA, ΔGA, baseline CK, ΔCK and toxicities were assessed with one-sided Wilcoxon rank sum tests. Associations between baseline GA, ΔGA, baseline CK, ΔCK and stage were assessed with two-sided Wilcoxon rank sum tests. Associations between toxicities and stage were assessed with Fishers’ Exact test. Correlations between baseline
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