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Letters to the Editor
AB
C
P=0.0003
P=0.102
Figure 1. Progression-free survival (PFS) by the response to treatment.
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P=0.0189
CR: complete response; MRD: minimal residual disease; PCR: poly- merase chain reaction; MRD pos: positive MRD; Flow-uMRD: unde- tectable MRD by flow cytometry; PCR-uMRD: undetectable MRD by PCR; UM-IGHV: unmutated IGHV; M-IGHV: mutated IGHV. (A) PFS by CR. 24- month PFS, CR versus no CR; 94.7% versus 66.7% (hazard ratio [HR]: 0.139; 95% confidence interval [CI]: 89.1-100 versus 48.1-92.4); P=0.0003. (B) PFS in CR patients by MRD. 32-month PFS, Flow-uMRD-CR versus Flow-MRD pos CR, 95.5% versus 69% (95%CI: 87.1-100 vs. 43.1- 100]: P=0.042; Flow-uMRD-CR vs. PCR-uMRD-CR, 90% versus 100% (95%CI: 73.2-100 vs. 100-100); P=0.27. (C) PFS in CR patients by MRD and IGHV mutational status. 32-month PFS, UM-IGHV patients with Flow- MRD pos CR versus M-IGHV patients with Flow-MRD pos CR, 67% versus 78.8% (HR 0.729; 95%CI: 0.15-3.4); UM-IGHV patients with Flow-MRD pos CR versus UM-IGHV patients with Flow-uMRD-CR, 67% versus 91% (HR 0.166; 95%CI: 0.02-1.34); M-IGHV patients with Flow-MRD pos CR vs. M-IGHV patients with Flow-uMRD-CR, 78.6% versus 100% (HR: 0.145; 95%CI: 0.01-1.16); P=0.0189.
mutational status was the only factor with a significant and independent impact on the achievement of both a Flow-uMRD-CR and a PCR-uMRD-CR in patients with- out TP53 disruption (Online Supplementary Table S3).
The 36-month PFS was 76.4% (Online Supplementary Figure S2A). The only variable with a significant and inde- pendent impact on PFS was the presence of a TP53 dis- ruption (Online Supplementary Tables 3 and 5; P=0.002). After excluding patients with TP53 disruption, none of the baseline factors revealed an impact on PFS (Online Supplementary Table S6). A significantly higher PFS was observed in patients who achieved a CR (P=0.0003). Moreover, a significantly higher PFS was seen in patients who achieved a CR with Flow-uMRD (P=0.042) (Figure 1A and B). All M-IGHV patients and 91% of UM-IGHV patients with a Flow-uMRD-CR were progression-free at 32 months (Figure 1C). All 17 patients (11 M-IGHV and 6 UM-IGHV) who achieved a PCR-uMRD-CR were pro- jected as progression-free at 32 months. After a median time of 40 months (range: 28-56 months) from the initial response, residual disease was still absent in 11 of 13 patients at the last re-assessment of MRD by PCR. The
36-month OS was 94.7% (Online Supplementary Figure S2B). A significantly inferior survival probability was observed in patients with TP53 disruption (P<0.001) and ≥5cm enlarged nodes (P=0.0015) (Figure 2). However, in MVA TP53 disruption emerged as the only significant factor with an impact on OS (Online Supplementary Tables S3 and S7 and Online Supplementary Figure S3A). Patients who achieved a CR with Flow-uMRD showed a signifi- cantly superior survival than those with residual disease (P=0.055) (Figure 2). All CR patients with Flow-uMRD (19 patients) or PCR-uMRD (17 patients) were still alive at 32 months.
Adverse events recorded during treatment are listed in Online Supplementary Table S8. No unexpected toxicities were observed. Despite the prophylactic use of growth factors, grade ≥3 granulocytopenia leading to fludarabine and cyclophosphamide dose reduction was observed in 33 patients (42.3%). However, a severe infection was experienced by 21 (27%) patients. Taken together, the results of this study show that the FC regimen combined with a double dose of ofatumumab was associated with a high rate of CR and Flow-uMRD-CR in young and fit
haematologica | 2020; 105(11)