The Effect of Diagnostic Wait Time on the Survival of Patients with Diffuse Large B-Cell Lymphoma Differs Depending on International Prognostic Index
Authors: Lee Shin , Eiju Negoro , Tetsuji Morishita , Fujita Kei , Yamauchi Hideaki , Oiwa Kana , Ueda Takanori , Yamauchi Takahiro 
Published: November 2019

Background
Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL featured by rapid progression. Given its rapid progression, prompt diagnosis and treatment are essential for achieving long-term survival in DLBCL. In solid cancers, it is known that prolonging diagnostic wait time (DWT), interval from diagnosis to initiation of treatment, could result in stage progression and a worse survival. In DLBCL patients, a prolonged DWT is also expected to be associated with a worse survival, however, little is known about this issue. The purpose of this investigation was to verify the impact of DWT on survival in DLBCL patients using a Cox hazards model with restricted cubic spline (RCS) because this model was more suitable to reflect real-world clinical practice than the linear model. It has been reported a possible association between the International Prognostic Index (IPI) and prognosis, hence the Cox hazards model with RCS was used to examine the differential effects of IPI on survival in association with DWT.
Methods
We conducted a single center, retrospective study of all consecutive patients seen from 2007 to 2017 at our Hospital. The inclusion criteria were newly diagnosed de novo DLBCL, aged 18 years and older, and treated with standard therapies. We define the standard regimens as R-CHOP [rituximab (RTX), cyclophosphamide (CPA), adriamycin, vincristine (VCR), and prednisolone (PSL)] and R-THP-COP (RTX, CPA, tetrahydropyranyl adriamycin, VCR, and PSL). The primary outcome was overall survival (OS). Exclusion criteria were central nerve system involvement, transformed DLBCL, and receiving non-standard therapies. Furthermore, the subgroup analysis according to IPI was performed.
Results
Among 179 patients, the median age was 72 (27 - 91) years, the median DWT was 39.5 (0 - 223) days and 53.9% patients had IPI ≥3, the median follow-up time was 29.2 (0.03 - 137.6) months, and 59 (31.3%) patients died during the follow-up period. A multivariate Cox proportional hazards model for OS showed DWT was not associated with worse OS in the entire study population. However, the Cox hazards model with RCS in the all study population revealed that there was nearly U-shaped association between DWT and OS. The Cox hazards model with RCS for each group depending on IPI score (0-5) showed the effect between DWT and OS differed by IPI. The mortality risk increased proportionally as DWT was prolonged in three groups with IPI 3 to 5, but rather negative correlations were seen between in three groups with IPI 0 to 2. Opposite tendencies between IPI ≥3 and <3 groups cancelled each other and resulted in ineffectiveness of DWT for OS of entire DLBCL population.
Discussion
These results demonstrated that the impact of DWT on OS differed depending on the IPI, while DWT did not affect OS of the entire DLBCL patients. DWT steadily increased the risk of mortality in IPI ≥3 group. On the other hand, in IPI <3 group, there was a certain patient population with a high mortality risk despite immediate diagnosis probably because of more aggressive clinical features such as testis or ovary involvement, retroperitoneal involvement, bone marrow involvement, and spleen involvement. At present, DLBCL is considered to be not a single disease entity, but rather a clinically heterogeneous disease not only in terms of genetics but also aggressiveness of progression and prognosis. The patient who already had IPI >3 at the initial visit should be expedited the diagnosis if there was suspicious of DLBCL, because DWT is a critical predictor determining prognosis in such patients. Moreover, in suspected DLBCL cases, computed tomography, positron emission tomography contributing to identify the IPI, and bone marrow biopsy might be needed immediately when the definitive IPI is uncertain at the initial visit.
Conclusions
In conclusion, DWT did not associate with survival of entire DLBCL patients who treated with standard therapies, but the impact of DWT on survival differed depending on IPI. Especially in patients with IPI ≥3 at the diagnosis, steadily increased mortality risk was observed.

Disclosures
Yamauchi: Astellas, AbbVie: Consultancy; Pfizer, Chugai, Teijin, Solasia: Research Funding.