Risk of transformation to aggressive B-cell lymphoma in patients with primary refractory FL

Patients with primary refractory follicular lymphoma (FL) are known to have an unfavorable prognosis, with a very different clinical course compared with patients with FL, including exhibiting a higher risk of histological transformation (HT) to an aggressive lymphoma. The definition and time of onset of HT are highly variable, and there is no evidence regarding the most effective treatment for this population. Although the transformation of FL to an aggressive disease is rare, HT modifies the indolent evolution of FL, leading to considerably shortened overall survival. Therefore, study of the biological characteristics and clinical events in this population is required in order to predict patients that are most likely to undergo HT. The Lymphoma Hub has previously reported the Aristotle study, demonstrating that the risk of HT as a first event had been significantly reduced with the use of rituximab.

Here we present the findings from a secondary analysis of the Aristotle study¹ exploring the risk of HT in patients with primary refractory FL, recently published by Alonso-Álvarez et al.² in the European Journal of Cancer.

Study design

This was a retrospective analysis of the cohort of patients with newly diagnosed FL from the Aristotle study. Eligible patients from the Aristotle cohort were newly diagnosed with FL (Grade 1, 2, or 3a) between 1997 and 2013 across 11 European centers, had biopsy proven HT, received active treatment, and had an evaluable response at the end of induction therapy. Patients were grouped into four categories based on response to frontline therapy:

• Patients achieving complete response (CR), defined as disappearance of all evidence of disease at the end of induction therapy
• Patients achieving partial response (PR), defined as regression of measurable disease and no new sites
• Patients with stable disease (SD)
• Patients with primary refractory disease

The primary endpoints included the cumulative incidence of HT and survival after relapse (SAR), measured from diagnosis of refractory disease or relapse till either death from any cause or last clinical contact. Time to HT was considered from the date of FL diagnosis to the date of HT. Response assessment was performed using computed tomography at each local site.

Results

Baseline characteristics

A total of 6,339 of the 6,970 patients from the Aristotle study cohort were included (Figure 1). The baseline characteristics are shown in Table 1.

CR, complete response; FL, follicular lymphoma; PR, partial response; SD, stable disease.
*Adapted from Alonso-Álvarez, et al.²

Table 1. Baseline characteristics by treatment response*

CR, complete response; FLIPI, Follicular Lymphoma International Prognostic Index; PR, partial response; PREF, primary refractory; SD, stable disease. *Adapted from Alonso-Álvarez, et al.2
Characteristics, % unless otherwise stated	CR	PR/SD	PREF
Age >60 years	39	45	47
Sex, female	53	49	48
Histology
Grade 1–2	66	66	58
Grade 3	16	12	11
FLIPI
0–1	34	22	15
2	33	33	22
3–5	32	46	63
Rituximab-containing regimens at frontline	79	74	56

5-year cumulative incidence of histological transformation and survival after relapse

Regarding the 5-year cumulative incidence of HT:

• In patients with primary refractory FL, the 5-year cumulative incidence of HT was 34% (Table 2).
• In patients with PR + SD, the 5-year cumulative incidence of HT was 7%.
• In patients who achieved CR, the 5-year cumulative incidence of HT was 4%.
• The rate of cumulative incidence had a hazard ratio (HR) of 11 (95% confidence interval [CI], 9–15) vs 6 (95% CI, 5–8) in patients achieving CR and PR/SD, respectively.

Regarding the 5-year SAR:

• In the primary refractory group, the 5-year SAR was 33% (Table 2).
• In the groups of patients with PR and SD after initial therapy who subsequently relapsed, the 5-year SAR rates were 57% and 51%, respectively.
• In the group of patients with initial CR who eventually relapsed, the 5-year SAR was 63%.

Median survival after relapse

• In patients with primary refractory disease, the median SAR was 1.1 years.
  • The median SAR was 0.6 years in patients with primary refractory disease who developed HT, compared with 1.8 years in those who did not have HT (HR, 1.7; p = 0.001).
• In the groups of patients with PR and SD after initial therapy who subsequently relapsed, the median SAR was 6.3 years and 5.2 years, respectively.
• In the group of patients with initial CR who eventually relapsed, the median SAR was 10.4 years. The HR for patients with primary refractory disease was 3.4 compared with patients achieving CR, and 2.2 and 1.4 in patients achieving PR and SD, respectively (p < 0.001).

Table 2. 5-year cumulative incidence of HT and SAR*

CI, confidence interval; CR, complete response; HT, histological transformation; PR, partial response; PREF, primary refractory; SAR, survival after relapse; SD, stable disease. *Adapted from Alonso-Álvarez, et al.2 †n = 73. ‡n = 216.
Outcomes	CR, % (95% CI)	PR/SD, % (95% CI)	PREF, % (95% CI)	p value
5-year cumulative incidence	4 (3–4)	7 (6–9)	34 (27–43)	<0.001
5-year SAR	63 (66–72)	57 (54–61)/51 (43–58)	33 (28–39)	<0.001
PREF who developed HT†	—	—	21 (12–31)	<0.001
PREF who did not develop HT‡	—	—	38 (31–44)	<0.001

Conclusion

This retrospective subgroup analysis of patients from the Aristotle study demonstrated that patients with primary refractory FL have an unfavorable prognosis, including very poor survival with a high risk of HT. Although the study was limited by the small sample size of patients with primary refractory disease and its retrospective nature (as well as incomplete data), this was the largest study in this population reported to date. Further research is needed to understand the clinical and biological parameters in patients with primary refractory FL to detect and/or predict histological transformation.