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Letters to the Editor
High rate of minimal residual disease responses in young and fit patients with IGHV mutated chronic lymphocytic leukemia treated with front-line fludarabine, cyclophosphamide, and intensified dose of ofatumumab (FCO2)
Since its first use at the MD Anderson Cancer Center, FCR (fludarabine, cyclophosphamide, rituximab) chemoimmunotherapy has been considered the gold standard for the front-line treatment of young and fit patients with chronic lymphocytic leukemia (CLL).1-3 Superior outcomes with this regimen have been observed in IGHV mutated (M-IGHV) compared to IGHV unmu- tated (UM-IGHV) patients.3-5 Responses with unde- tectable minimal residual disease (uMRD) have been associated with a significantly longer progression-free survival (PFS) and overall survival (OS). Ofatumumab, a fully human anti-CD20 monoclonal antibody, revealed in vitro higher complement-mediated activity compared to rituximab. The clinical efficacy of ofatumumab as a single agent or combined with chemotherapy has been demonstrated in relapsed/refractory (R/R) patients as well as in treatment naïve (TN) patients with CLL.6-8 In a meta-analysis that included six randomized trials, an improvement in the PFS, with no differences in the OS, was seen in the group of patients who received an ofatu- mumab-based treatment compared to the group of patients who received different regimens or who were only observed.9
In a study by Wierda et al.,10 50% of fit patients with CLL who received the front-line FC regimen combined with ofatumumab (FCO), given at a flat dose of 1000 mg, achieved a complete response (CR). Based on the efficacy of this regimen, the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) carried out a prospective, multicenter study (the LLC 0911 study) to evaluate the efficacy and safety of a front-line FCO regi- men that was intensified with an additional dose of 1,000 mg of ofatumumab (FCO2). The primary endpoint of this study was the rate of CR obtained with the FCO2 regi- men.
Between November 2013 and November 2015, 78 fit and young patients with CLL requiring front-line therapy according to the 2008 International Workshop CLL (iwCLL) criteria11 were enrolled in this study. Age ≤65 years, Cumulative Illness Rating Score (CIRS) score up to 6, creatinine clearance of at least 60 mL/min, Eastern Cooperative Oncology Group (ECOG) performance sta- tus 0-1, were required for inclusion in the study. A central screening included immunophenotype, fluorescence in situ hybridization, the assessment of the IGHV and TP53 mutation status.
Treatment consisted of six cycles of intravenous flu- darabine (25 mg/m2 daily) and cyclophosphamide (250 mg/m2 daily) given on the first three days of each 28-day cycle. Ofatumumab was administered intravenously on day 14 of cycle 1 at the dose of 300 mg and on day 21 at the dose of 1000 mg. During the subsequent five cycles (cycles 2-6), ofatumumab was given at the dose of 1,000 mg on days 1 and 14 of each course. An additional dose of 1,000 mg of ofatumumab was given on day 28 of cycle 6. To prevent infusion reactions with ofatumumab, a pre- medication consisting of paracetamol 1,000 mg, chlor- phenamine 10-20 mg, prednisolone 100 mg, or equiva- lent, was administered. All patients received Pneumocystis Carinii prophylaxis with co-trimoxazole and, as primary prophylaxis of granulocytopenia, pegfilgrastim on day 5 of each FCO2 course.
Table 1. Intention-to-treat response to the FCO2 regimen. N (%)
All patients
ORR
CR
PB and BM Flow-uMRD-CR1
PB and BM PCR-uMRD-CR2
78 (100)
72 (92.3)
60 (77)
36 of 78 (46.1)
17 of 78 (21.8)
12 (15.4)
6 (7.7)
PR
Failures
3
FCO2:front-line fludarabine,cyclophosphamide,and intensified dose of ofatumum- ab; N: number; ORR: overall response rate; CR: complete response; MRD: minimal residual disease; Flow-uMRD: undetectable minimal residual disease by flow- cytometry; PCR: polymerase chain reaction; PCR-uMRD: undetectable minimal residual disease by PCR. 1Peripheral blood (PB) and bone marrow (BM) Flow- uMRD in 36 of 60 (60%) patients with CR. 2PB and BM PCR-uMRD in 17 of 60 (28.3%) patients with CR. 3Failures: no response in five patients (stable disease, n=4; progressive disease, n=1) and unknown in 1.
Response was assessed according to the iwCLL criteria.11 In patients who achieved a CR, MRD was checked both in peripheral blood (PB) and bone marrow (BM) by a 6/4-color flow cytometry assay with a sensitiv- ity of at least 10-4.12 MRD was further assessed by allele- specific oligonucleotide polymerase chain reaction (PCR) in the PB and BM of patients with no evidence of MRD by flow cytometry. According to the MRD levels, CR was sub-classified as follows: (i) MRD-positive CR in the pres- ence of residual disease by flow cytometry in the PB and/or BM; (ii) CR with undetectable MRD by flow cytometry (Flow-uMRD-CR) in the absence of residual cytometric disease in both the PB and BM; (iii) CR with uMRD by flow cytometry and allele-specific oligonu- cleotide PCR (PCR-uMRD-CR) in the absence of MRD by flow cytometry and PCR in the PB and BM. In patients with a Flow-uMRD-CR or PCR-uMRD-CR, MRD was monitored during the follow-up every six months. The baseline clinical and biologic characteristics of patients and patient disposition are summarized in Online Supplementary Table S1 and Online Supplementary Figure S1. Median follow-up of patients was 31 months; median age 55 years (range: 36-65 years). A TP53 disruption, del17p and/or TP53 mutation, was detected in 11% of the cases, and 64% of patients were UM-IGHV.
Median number of administered cycles was six (range: 1-6). On an intention-to-treat (ITT) basis, 72 patients (92.3%) achieved a response with a CR in 60 (77%) (Table 1). The presence of TP53 disruption was the only significant and independent variable with an impact on the achievement of CR (P=0.014) (Online Supplementary Tables S2 and S3). A Flow-uMRD-CR was achieved in 36 of 78 (46.1%) patients and a PCR-uMRD-CR in 17 of 78 (21.8%) (Table 1). In multivariate analysis (MVA), Binet stage was the only factor with statistical significance on the achievement of a Flow-uMRD-CR (P=0.042) while the IGHV mutational status was the only significant fac- tor with an impact on the achievement of a PCR-uMRD- CR (Online Supplementary Table S3).
In the subset of patients without TP53 aberrations, a CR was recorded in 84.4% of the cases, a Flow-uMRD- CR in 50% and a PCR-uMRD-CR in 23.4%. When the analysis was further restricted to the M-IGHV patients without TP53 disruption, Flow-uMRD-CR and PCR- uMRD-CR rates were 68.2% and 45.4%, respectively, and significantly higher than those observed in UM- IGHV patients: 39% (P=0.036) and 12.2% (P=0.005), respectively (Online Supplementary Table S4). The IGHV
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