Jurnal Internasional Nilai prognostik MRD pada pasien CLL dengan komorbiditas yang menerima chlorambucil plus obinutuzumab atau rituximab

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Jurnal Internasional Nilai prognostik MRD pada pasien CLL dengan komorbiditas yang menerima chlorambucil plus obinutuzumab atau rituximab


Most patients with chronic lymphocytic leukemia (CLL) are elderly (70% older than 65 years of age 1 ) and not feasible, often with 1 or more comorbidities, so making them not eligible for intensive chemoimmunotherapy regimens such as rituximab plus fludarabine and cyclophosphamide. 2 An important experiment CLL11 ( NCT01010061] establishes obinutuzumab (GA101 19459104g anti-gabntibodimonoclonal CD20 with increased narcototoxicity depending on the antibodies and increased direct killer killer 3 5 Clb) as a new standard of care for previously CLL patients not treated with comorbidity. 6 7 In CLL11, G-Clb showed a greater effect on development-free survival (PFS) and overall survival (OS) vs. rituximab plus chlorambucil (R-Clb) and vs Clb only . 8 10

PFS is the standard primary end point in the CLL trial phase 3; However, because progress in treatment options continues to grow, longer follow-up periods (up to 5 years) are required to reach this end point, and short-term endpoints are being sought. The measurement of minimal residual disease (MRD) has been identified as a potential surrogate marker for PFS (and possibly OS), 11 12 and can provide prior information about the effectiveness of new treatments. strategy in CLL trials. Previous studies have shown that post induction MRD levels can independently predict PFS 13 19 16 ; However, most data has been generated in young physically healthy patients.

The aim of the current analysis is to investigate prospectively the relative effects of treatment with G-Clb vs. R-Clb on the MRD level and to explore the prognostic value of the assessment MRD in patients with previously untreated CLL and comorbidity is listed in the CLL11 study. CLL11 is an open-label, randomized, 3-arm, phase 3 study that evaluates the efficacy and safety of G-Clb and R-Clb vs Clb only (stage 1) and G-Clb vs R-Clb (stage 2), in patients with Previous untreated CLL and comorbidity (Figure 1 additions, available on the Blood website [1945]. 8 9 Only patients from stage 2 (data cutoff), October 2017) are considered here. CLL11 was carried out in accordance with the Declaration of Helsinki and was approved by the institutional review board or independent ethics committee of each institution.

Patients who fulfilled previously untreated conditions CD20 + CLL (diagnosed according to International Workshop on CLL criteria ), 17 Cumulative Rating Scale score (CIRS)> 6 which shows reduced comorbid burden, and / or kidney function (creatinine clearance 30-69 mL / minute). Patients were randomly assigned 1: 2: 2 to receive six cycles of 28 days Clb only, G-Clb, or R-Clb (see Additional data for the dosage regimen). Further details about research design and eligibility criteria have been published elsewhere. 8 9

MRD was analyzed prospectively in peripheral blood (PB) and bone marrow in 2 central laboratories in Kiel, Germany, and Rotterdam, Netherlands (stage 2 analysis). PB samples are taken at a time point that is repeated before, during, and up to 12 months after treatment. MRD values ​​are obtained through polymerase chain reactions (see Additional data for full details). Only PB samples taken at the end of treatment (EOT) were considered in this report (additional analysis described in Additional data).

Patients were grouped into 1 of the 3 MRD categories: positive MRD (≥1% or ≥10) −2 [≥100 CLL cells per 10,000 leukocytes]); Intermediate MRD (−2 and ≥10 −4 [1-99 CLL cells per 10 000 leukocytes]); or undetectable MRD (−4,90940] 14 [1945900] Patients were included in the population that could be evaluated for MRD if they had a MRD sample that could be measured in PB and / or bone marrow in EOT (in 56 to 190 days from the last day care) Patients who did not have an MRD sample were available on EOT but with progressive disease or death within this period were considered positive MRD on EOT. Statistical analysis was presented in Additional data.

In total, 781 patients were registered; 663 (G-Clb , n = 333; R-Clb, n = 330) completed stage 2. Of these patients, 474 (71.4%) had PB samples that could be evaluated at EOT. Median follow-up was 65.6 months (range, 4, 6-85.1 months.) The average age was 73 years (range, 39-90 years), with 61.5% patients (n = 297) aged> 70 years (Table 1 additional).

In the NT at EOT, 90 patients (19.0%) were categorized as undetectable MRD, 132 (27.8%) as intermediaries for MRD, and 252 (53.2%) as positive MRD (including 15 patients [3.2%] with progressive disease; 12 patients [2.5%] died). The response of the MRD was significantly related to PFS ( Figure 1A ); patients with undetectable MRD had a median PFS of 56.4 months compared with 23.9 months for patients categorized as intermediate MRD (intermediate MRD vs. MRD undetectable: hazard ratio [HR] 2.65; 95% confidence interval [CI] 1 , 91-3.69; ] P PP = .125; MRD positive vs. MRD undetectable: HR, 2.24; 95% CI, 1.49-3.37; P <.001 gambar="" tambahan="" wp_automatic_readability="72.515529358422">

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Figure 1.

PFS according to the MRD and care group categories. (A) PFS according to the MRD category on EOT in PB; (B) PFS according to the MRD category on EOT in PB plus treatment groups.

MRD is not detected in PB on EOT significantly more general in patients en who received G-Clb vs those who received R-Clb (35.8%) vs 3.3%, respectively; P <.001 tabel="" tambahan="" untuk="" pasien="" yang="" dikategorikan="" sebagai="" mrd="" tidak="" terdeteksi="" pfs="" secara="" numerik="" lebih="" lama="" pada="" mereka="" diobati="" dengan="" g-clb="" bulan="" n="82)" dibandingkan="" r-clb="" meskipun="" perbedaan="" ini="" signifikan="" statistik=""> P = .120 [log-rank test]; Figure 1B ). These observed differences may suggest preferential PB cleansing in the G-Clb group; however, the number of patients in the R-Clb group is too low to allow decisive conclusions to be taken. The median PFS was comparable for patients between intermediate MRDs in the arm, and no difference between treatments was observed for MRD-positive patients (1945-1961) Figure 1B .

The following MRD response categories were used as variables in multivariable analysis: MRD positive, which includes all patients with detectable levels of MRD (i.e., all previously categorized as positive MRD or currently MRD), and MRD undetectable. After a multivariable analysis, positive MRD was identified as an independent prognostic factor for PFS in PB on EOT (HR, 3.94; 95% CI, 2.75-5.64; P. 19459030) P 10 U / L and presence genetic risk factors ( Table 1 ) The positivity of MRD in PB on EOT was also identified as an independent prognostic factor for OS (HR, 1.98; 95% CI, 1.26-3.12; P

Table 1.

Multivariable analysis of the effects of prognostic factors on PFS in combination with the MRD category in PB on EOT

Now there is increasing evidence to support the use of MRD as a replacement endpoint for long-term results in testing 18 19 Although most of this evidence comes from studies conducted in young patients, healthy patients, 14 20 our data shows that MRD maintains significance prognostic in a patient population that is generally older, less fit, and n treated with a less intense treatment regimen. In addition to MRD and treatment groups, several other risk factors are prognostic for PFS and / or OS, including Binet stage C, CIRS score, serum thymidine kinase, and genetic risk factors, as also seen previously. 21 [19659058][1945 23

In conclusion, this analysis shows that MRD status is independently associated with PFS and OS in CLL patients with comorbidity and has the potential to act as a replacement. marker for results in clinical trials. In addition, it has confirmed the advantages of G-Clb rather than R-Clb; G-Clb allows more patients to reach undetectable levels of MRD.


The authors thank patients and their families and acknowledge laboratory scientists and technicians in the German CLL Group for assessment of MRD samples and analysis statistics and the Roche CLL11 study team.

This study was supported by F. Hoffmann-La Roche Ltd. Helen Cathro from Gardiner-Caldwell Communications (Macclesfield, UK) provides medical writing support (under the direction of AWL) and is funded by F. Hoffmann-La Roche Ltd.


Contributions: KH, MK, MR, and SS contribute to research design and data acquisition, analysis, and interpretation; J.B., G.F.-R., M.T., and S.R. contribute to the analysis and interpretation of data; MISS. and S.P. contribute to data acquisition and interpretation; V.G., K.F., and K.T. contribute to research design and data interpretation; A.W.L., S.B., and U.J.M.M. contribute to data acquisition, analysis and interpretation; M.B. contribute to data analysis; M.H. and J.J.M.v.D. contribute to the interpretation of data; and all authors helped write the script and agreed to the final version for publication.

Disclosure of conflict of interest: A.W.L. received research funding from Roche and was a member of the advisory board for AbbVie. V.G. receive consultation fees from Roche; is a member of the advisory board for Roche, Janssen, Gilead Sciences, and AbbVie; and receive honorariums from Roche, Janssen and Gilead Sciences. K.F. receive a travel grant from Roche. MISS. receive consulting fees, research funds, and honorarium from and are members of the advisory board for Roche, Janssen, Gilead Sciences, and AbbVie. M.T. receive consulting fees and honoraria from Roche, Celgene, Janssen, AbbVie, Bristol-Myers Squibb, Takeda, and Gilead Sciences and research funding from Roche and Celgene. U.J.M.M. received an honorarium from and was a member of the advisory board for Roche. S.S receives consulting fees, speaker honorarium, research funding, and travel support from and is a member of the advisory board for AbbVie, Celgene, Roche / Genentech, Science Gilead, GlaxoSmithKline, Janssen, and Novartis. S.B. received research funding from Roche, Celgene, Janssen, and AbbVie; is a member of the advisory board for Roche; and receive honorariums from Roche, Abbie, Novartis and Janssen. M.B. receive consultation fees from PRMA, research funds from Amgen, and honorariums from Pfizer and Amgen and are members of the advisory board for Incyte and Amgen. M.K. received research funding from Roche. J.J.M.v.D. received research funding from Roche, Amgen, and BD Biosciences. M.H. receive an honorarium and research fund from and are members of the advisory board for AbbVie, Amgen, Celgene, Roche, Sciences Gilead, Janssen, and Mundipharma. M.R. receive research funding from and are members of the advisory board for Roche. K.T, G.F.-R., and K.H. employed by F. Hoffmann-La Roche Ltd. The remaining authors state no competing financial interests.

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