B-cell prolymphocytic leukemia (B-PLL) is a very rare lymphoid neoplasm accounting for less than 0.5% of lowgrade mature B-cell lymphomas.1-3 B-PLL is a poor-prognosis disease with a historical median overall survival (OS) of 3 years.3 B symptoms, marked lymphocytosis, cytopenia and massive splenomegaly are hallmarks of B-PLL patients at diagnosis.1-3 A minority of patients present with an indolent phase, not requiring immediate therapy. The characterization of B-PLL genetic landscape has led to the identification of recurrent abnormalities including complex karyotype (CK), MYC translocations/gains (MYC aberration), 17p deletion (del17p) and TP53 mutations (TP53 abnormalities [TP53abn]).1,4-6 Due to the rarity of the disease, the absence of international guidelines and randomized clinical trial data, most therapeutic approaches used chemoimmunotherapy (CIT) or are executed according to chronic lymphocytic leukemia (CLL) guidelines. A watch and wait strategy is proposed to asymptomatic B-PLL patients while, for symptomatic B-PLL, rituximab-based CIT, alemtuzumab and more recently BCR inhibitors (BCRi) have been used for frontline therapy. Recent case reports and small series have indeed described the efficacy of Bruton tyrosine ki nase inhibitor (BTKi)7-10 and phosphoinositide 3-kinase inhibitor (P13Ki),11 notably in frontline and relapse TP53abn B-PLL population. Allogeneic stem cell transplantation (allo-SCT) is still considered as the only curative therapy for eligible and responsive B-PLL patients. Our group has recently shown in a retrospective cohort of 34 patients with rigorous diagnostic criteria for B-PLL that three distinct cytogenetic risk groups could be identified: low (no MYC aberration), intermediate (MYC aberration but no del17p), and high-risk (MYC aberration and del17p), with profound impact on OS5.
Despite these advances, several questions remain unanswered in B-PLL. Factors associated with initial asymptomatic disease and those predicting time to first treatment (TFT) are still unknown as the impact of CIT or BCRi in different genetic subgroups. Based on our previous biological work,5 we describe here the clinical outcomes and associated prognostic factors of initially asymptomatic or symptomatic diseases, and the impact of different therapies in an extended and homogenously defined cohort of 41 de novo B-PLL patients. We conducted a retrospective analysis of French adult patients with a diagnosis of de novo B-PLL, according to the 2016 World Health Organization classification criteria1 after thorough exclusion of potential differential diagnoses as described previously.5 While the 2022 World Health Organization classification included it in “splenic B-cell lymphoma/leukemia with prominent nucleoli”12 that also includes “hairy cell leukemia variant” (HCL-v), B-PLL is still recognized as a specific entity by the International Consensus Classification of mature lymphoid neoplasms.13 Forty-one patients diagnosed between 1992 and 2020 in 17 French centers were included after the reviewing of blood smears by three independent expert cytologists. In addition to the 2016 classification criteria (i.e., prolymphocytes accounting for at least 55% of the lymphoid cells in peripheral blood), inclusion cytological criteria included round nucleus and prominent central nucleolus while presence of hybrid features overlapping HCL, such as hairy projections was a strict exclusion criterion. Although we cannot exclude that some cases previously defined as HCL-v may be present in our cohort, it should be noted that only one case harbored usage of the IGHV4-34 gene family (n=1/25) and no MAP2K1 mutation was observed in the 20 cases explored by next-generation sequencing. Patients with a history of another B-cell malignancy (CLL or marginal zone lymphoma [MZL]) were excluded and diagnosis of MCL was ruled out according to karyotype and fluorescence in situ hybridization (FISH) assays looking for CCND1 rearrangements or translocations involving CCND2 or CCND3. Cytogenetic and molecular analyses for detection of MYC aberration and TP53abn were performed as described previously.5 All cases were analyzed for del17p by FISH and 23 of 41 had DNA available for evaluation of TP53 mutations by molecular analyses. CK and high CK (HCK) were defined by the presence of ≥3 and ≥5 chromosomal abnormalities respectively. The study was performed in accordance with the Declaration of Helsinki and was approved by the local Investigational Review Board (CPP Ile-de-France VI, Paris, France, 05/21/2014). The primary endpoints were overall survival (OS) defined as time from diagnosis to death from any cause or last follow-up, and progression-free survival (PFS) defined as time from first treatment initiation to progression, death, or last follow-up. TFT was defined as time from diagnosis to first therapy in asymptomatic B-PLL. Response to therapy was evaluated using modified criteria from those of iwCLL.9,14 Baseline characteristics are described as median and range for continuous variables and frequency and percentage for categorical variables. Comparisons between categorical variables were performed by χ2 or Fisher’s exact test, as appropriate. Comparisons between continuous variables were performed by Wilcoxon-Mann-Whitney non-parametric test. Median follow-up was calculated using the reverse Kaplan-Meier method. Survival curves were calculated by using the Kaplan-Meier method, and the log-rank test was used for comparisons between groups. Univariate analyses were performed using the Cox proportional hazards model. All tests of statistical significance were two-sided, and a P value <0.05 was considered statistically significant. All statistical analyses were performed using the R statistical package (version 4.1.0, R Core Team, 2021) and the RStudio software (versions 1.2.5033).
The main characteristics of the whole cohort at diagnosis are detailed in Table 1 and correspond to those previously reported in the literature.3 Median age at B-PLL diagnosis was 72 years old (range, 46-88 years) and most patients were male (25/41, 61%). Splenomegaly was present in 62% of patients (24/39) while lymphadenopathy (11/39, 28%) and extranodal disease (4/32, 12%) were rarer. The distribution of cytogenetic abnormalities was as follows: MYC aberrations (30/41, 73%), CK (28/41, 68%), high CK (HCK, 19/41, 46%) and del17p (16/40, 40%). TP53abn (mutation or del17p) was detected in 18 0f 31 patients (58%). Del17p was significantly associated with lymphocytosis, CK, HCK and TP53 mutations, while MYC aberration was enriched in patients lacking del17p (Online Supplementary Table S1). Median follow-up for the whole cohort was 102 months (range, 0.2-171 months). B-PLL was symptomatic at diagnosis in 22 of 39 (56%) patients. Main differences observed between asymptomatic and symptomatic B-PLL patients are summarized in Table 2. As expected, the proportion of patients with cytopenia and/or tumoral disease was higher in the symptomatic B-PLL subgroup. Interestingly, significantly more symptomatic B-PLL patients harbored both MYC aberrations and del17p (7/22, 32%) than asymptomatic B-PLL patients (0/16, 0%; P=0.04). Among the 17 asymptomatic B-PLL patients, 13 (76%) progressed with a median TFT of 46.9 months. Of note, the four patients who did not progress harbored either MYC aberration (n=3) or del17p (n=1) but no HCK (0/4 compared to 8/13 asymptomatic B-PLL who progressed; P=0.08). During follow-up, 34 of 41 (83%) B-PLL patients required therapy. The median number of therapeutic lines was two (range, 1-4). Frontline therapies consisted of chemotherapy (CT) (9/34, 26%), CIT (15/34, 44%), BTKi (5/34, 15%), alemtuzumab (3/34, 9%) and rituximab monotherapy (1/34, 3%). Only two patients received allo-SCT. Overall- response rates (ORR) for frontline CT (78%), CIT (60%), BTKi (100%) and alemtuzumab (100%) were not significantly different (P=0.3) (Online Supplementary Figure S1). In the whole cohort, median PFS of patients receiving frontline therapy was 30 months and median OS was 67 months (Figure 1A, B). Twenty-six of 41 patients (63%) have died due to B-PLL progression (38%), therapy-related toxicity (23%), other causes (27%) and of unknown origin (12%). Main clinical and biological factors associated with PFS and OS in univariate analyses are summarized in Table 1. Median OS was significantly longer in asymptomatic B-PLL compared to symptomatic B-PLL (126 vs. 54 months; P=0.003; Online Supplementary Figure S2A). The presence of del17p pejoratively influenced both PFS (median 8 vs. 45 months; P=0.004) and OS (median 34 vs. 126 months; P=0.02) (Figure 1C, D) while low platelet count (hazard ratio [HR]=0.99, 95% confidence interval [CI]: 0.98-0.99) and extranodal disease (HR=5.71, 95% CI: 1.34-24.4) were associated with shorter OS (Table 1). The poorest median OS and PFS were observed in MYC aberration / del17p patients (20 and 6 months, respectively) (Table 1; Online Supplementary Figure S2B, C) while patients with either MYC aberration (101 and 58 months, respectively) or del17p (78 and 9 months, respectively) harbored comparable intermediate prognosis inferior to those without any of these abnormalities (145 and 36 months, respectively). The presence of TP53 mutation was highly correlated to the presence of del17p (Online Supplementary Table S1). Although the presence of TP53 mutation did not significantly affect OS (HR=2.41, 95% CI: 0.76-7.65; P=0.14) or PFS (HR=1.72, 95% CI: 0.52-5.72; P=0.38), the statistical analysis is limited by the reduced number of patients with available TP53 mutation status. The specific prognostic impact of TP53 mutation was not possible due to the very few cases (n=2) of TP53 mutation without del17p.
We eventually interrogated the impact of different frontline therapies on outcomes (Online Supplementary Figure S2D, E). The type of frontline therapies did not significantly modify PFS or OS but was not randomly distributed among genetic subgroups as patients that received BTKi all harbored del17p. Looking specifically in the del17p subgroup, patients receiving BTKi (n=5) displayed better outcomes compared to those receiving CT/CIT (n=7) (respective median PFS and OS of 24 and 101 vs. 3 and 15 months; P=0.03 and P=0.2) (Figure 1E, F). Although definitive conclusions are limited by its retrospective nature, the small numbers of patients in specific subgroups and lack of available DNA for TP53 mutation analysis in all samples, our study of the largest B-PLL cohort to date provides meaningful insights in this very rare disease. We identified that asymptomatic B-PLL represents around 40% of patients at diagnosis, do not harbor both MYC aberration and del17p, and displays a significant better OS. We highlight the pejorative impact of del17p and confirm that the subgroup presenting with both MYC aberration and del17p has the worst outcome with a median OS shorter than 2 years. Finally, albeit on a small number of patients, we confirm the efficacy of frontline BTKi in del17p B-PLL.7,8,9
- Received September 26, 2022
- Accepted December 14, 2022
No conflicts of interest to disclose.
CA, EC, VL, FNK and DRW designed the study; CA, LP, EC, VL, FNK and DRW analyzed data; CA, LP and DRW wrote the manuscript; CA, LP, EC, LB, KM, CS, JFL, JS, AD, ASM, EM, PF, CT, AB, DG, LMF, SI, SS, IRW, VE, CL, LS, VL, FNK and DRW recruited patients. All authors critically reviewed and approved the manuscript.
The data that support the findings of this study are available on request from the corresponding author.
We thank Mohamad Sabbah for his assistance in data collection.
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