Publications by authors named "Aurore Perrot"

56 Publications

Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, MAIA.

Blood 2021 Jul 21. Epub 2021 Jul 21.

Dana-Farber Cancer Institute, Boston, Massachusetts, United States.

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible newly diagnosed multiple myeloma (TIE NDMM) using data from four phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD-negativity rates and reduced the risk of disease progression or death by approximately half versus standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response (CR) or better with MRD-negative status, and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10‒5 threshold). Patient-level data were pooled from all four studies, and for patients with TIE NDMM plus patients with RRMM who received ≤2 prior lines of therapy (≤2PL). PFS was evaluated by response and MRD status. Median follow-up (months) was: POLLUX, 54.8; CASTOR, 50.2; ALCYONE, 40.1; and MAIA, 36.4. Patients who achieved ≥CR and MRD negativity had improved PFS versus those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.ClinicalTrials.gov: NCT02076009/NCT02136134/NCT02195479/NCT02252172.
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http://dx.doi.org/10.1182/blood.2021011101DOI Listing
July 2021

Subgroup analysis of ICARIA-MM study in relapsed/refractory multiple myeloma patients with high-risk cytogenetics.

Br J Haematol 2021 Jul 25;194(1):120-131. Epub 2021 May 25.

Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Treatment benefit in multiple myeloma (MM) patients with high-risk cytogenetics remains suboptimal. The phase 3 ICARIA-MM trial (NCT02990338) showed that isatuximab plus pomalidomide-dexamethasone prolongs median progression-free survival (mPFS) in patients with relapsed/refractory MM (RRMM). This subgroup analysis of ICARIA-MM compared the benefit of isatuximab in high-risk [defined by the presence of del(17p), t(4;14) or t(14;16)] versus standard-risk patients. The efficacy of isatuximab in patients with gain(1q21) abnormality was also assessed in a retrospective subgroup analysis. In ICARIA-MM, 307 patients received isatuximab-pomalidomide-dexamethasone (n = 154) or pomalidomide-dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28-day cycle, and every other week thereafter. Standard pomalidomide-dexamethasone doses were given. Isatuximab-pomalidomide-dexamethasone improved mPFS (7·5 vs 3·7 months; HR, 0·66; 95% CI, 0·33-1·28) and overall response rate (ORR, 50·0% vs 16·7%) in high-risk patients. In patients with isolated gain(1q21), isatuximab addition improved mPFS (11·2 vs 4·6 months; HR, 0·50; 95% CI, 0·28-0·88) and ORR (53·6% vs 27·6%). More grade ≥3 adverse events occurred in high-risk patients receiving isatuximab (95·7%) versus the control group (67·6%); however, isatuximab did not increase events leading to discontinuation or treatment-related mortality. Isatuximab-pomalidomide-dexamethasone provides a consistent benefit over pomalidomide-dexamethasone treatment in RRMM patients regardless of cytogenetic risk.
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http://dx.doi.org/10.1111/bjh.17499DOI Listing
July 2021

Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenström macroglobulinemia.

Blood Adv 2021 05;5(9):2438-2446

Hematology Department, Sorbonne Université, Hôpital Pitié Salpêtrière APHP, Paris, France; and.

We present the results of a phase 2 study evaluating the combination of obinutuzumab + idelalisib in relapsed/refractory (R/R) Waldenström macroglobulinemia (WM). The goal was to determine the safety and efficacy of a fixed-duration chemotherapy-free treatment. During the induction phase, patients received idelalisib + obinutuzumab for 6 cycles, followed by a maintenance phase with idelalisib alone for ≤2 years. Forty-eight patients with R/R WM were treated with the induction combination, and 27 patients participated in the maintenance phase. The best responses, reached after a median of 6.5 months (interquartile range, 3.4-7.1; range, 2.6-22.1 months), were very good partial response in 5 patients, partial response in 27 patients, and minor response in 3 patients, leading to overall response rate and major response rate estimates of 71.4% (95% confidence interval [CI], 56.7-83.4) and 65.3% (95% CI, 50.4-78.3), respectively. With a median follow-up of 25.9 months, median progression-free survival was 25.4 months (95% CI, 15.7-29.0). Univariate analysis focusing on molecular screening found no significant impact of CXCR4 genotypes on responses and survivals but a deleterious impact of TP53 mutations on survival. Although there was no grade 5 toxicity, 26 patients were removed from the study because of side effects; the most frequent were neutropenia (9.4%), diarrhea (8.6%), and liver toxicity (9.3%). The combination of idelalisib + obinutuzumab is effective in R/R WM. Nonetheless, the apparent lack of impact of genotype on outcome could give new meaning to targeting of the phosphatidylinositol 3-kinase pathway in WM. This trial was registered at www.clinicaltrials.gov as #NCT02962401.
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http://dx.doi.org/10.1182/bloodadvances.2020003895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114554PMC
May 2021

Multiple Myeloma: Heterogeneous in Every Way.

Cancers (Basel) 2021 Mar 13;13(6). Epub 2021 Mar 13.

Centre de Recherche en Cancérologie de Toulouse, Institut National de la Santé et de la Recherche, Médicale U1037, 31059 Toulouse, France.

Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of tumor plasma cells (PCs) in the bone marrow (BM). Despite considerable advances in terms of treatment, patients' prognosis is still very heterogeneous. Cytogenetics and minimal residual disease both have a major impact on prognosis. However, they do not explain all the heterogeneity seen in the outcomes. Their limitations are the result of the emergence of minor subclones missed at diagnosis, detected by sensible methods such as single-cell analysis, but also the non-exploration in the routine practice of the spatial heterogeneity between different clones according to the focal lesions. Moreover, biochemical parameters and cytogenetics do not reflect the whole complexity of MM. Gene expression is influenced by a tight collaboration between cytogenetic events and epigenetic regulation. The microenvironment also has an important impact on the development and the progression of the disease. Some of these determinants have been described as independent prognostic factors and could be used to more accurately predict patient prognosis and response to treatment.
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http://dx.doi.org/10.3390/cancers13061285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998947PMC
March 2021

Multiple myeloma with hungry plasma cells.

Br J Haematol 2021 May 12;193(3):443. Epub 2021 Feb 12.

Haematology Laboratory, Cancer University Institute of Toulouse - Oncopole, Toulouse, France.

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http://dx.doi.org/10.1111/bjh.17299DOI Listing
May 2021

Health-Related Quality of Life in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: Findings From the Phase III MAIA Trial.

J Clin Oncol 2021 Jan 16;39(3):227-237. Epub 2020 Dec 16.

Department of Oncology, Hematology, BMT with Department of Pneumology, University Medical Center Hamburg, Hamburg, Germany.

Purpose: To evaluate the effects of daratumumab, lenalidomide, and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) on patient-reported outcomes (PROs) in the phase III MAIA study.

Patients And Methods: PROs were assessed on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item and the EuroQol 5-dimensional descriptive system at baseline and every 3 months during treatment. By mixed-effects model, changes from baseline are presented as least squares means with 95% CIs.

Results: A total of 737 transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma were randomly assigned to D-Rd (n = 368) or Rd (n = 369). Compliance with PRO assessments was high at baseline (> 90%) through month 12 (> 78%) for both groups. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item global health status scores improved from baseline in both groups and were consistently greater with D-Rd at all time points. A global health status benefit was achieved with D-Rd, regardless of age (< 75 and ≥ 75 years), baseline Eastern Cooperative Oncology Group (ECOG) performance status score, or depth of response. D-Rd treatment resulted in significantly greater reduction in pain scores as early as cycle 3 ( = .0007 Rd); the magnitude of change was sustained through cycle 12. Reductions in pain with D-Rd were clinically meaningful in patients regardless of age, ECOG status, or depth of response. Similarly, PRO improvements were observed with D-Rd and Rd on the EuroQol 5-dimensional descriptive system visual analog scale score.

Conclusion: D-Rd compared with Rd was associated with faster and sustained clinically meaningful improvements in PROs, including pain, in transplant-ineligible patients with newly diagnosed multiple myeloma regardless of age, baseline ECOG status, or depth of treatment response.
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http://dx.doi.org/10.1200/JCO.20.01370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078427PMC
January 2021

Vaccination during the First Diagnosis of Multiple Myeloma: A Cohort Study of the French National Health Insurance Database.

Vaccines (Basel) 2020 Dec 2;8(4). Epub 2020 Dec 2.

Service de Pharmacologie Médicale et Clinique, CHU de Toulouse, 31000 Toulouse, France.

Purpose: Infections are frequent and often result in serious complications in patients with multiple myeloma (MM). Prophylactic vaccination is recommended for influenza virus, , and . The aims of this study were to measure the vaccination rates within 24 months after the diagnosis of multiple myeloma and to identify factors associated with vaccine use.

Methods: MM patients were selected through the French national health insurance database from 1 January 2010 to 31 December 2015. Patients with a previous history of MM were excluded.

Results: Vaccination rates against influenza, and among 22,831 newly diagnosed MM patients were, respectively, 28.5%, 10.3%, and 1.4%. Only 0.7% received all three vaccines. Factors associated with vaccination were young age, male gender, an absence of comorbidity, a history of higher medication and vaccine consumption, Herpes simplex virus (HSV), Varicella zoster virus (VZV), and the use of pneumocystis prophylaxis.

Conclusion: The low rates of vaccination indicate the need to improve physician and MM patient adherence and education regarding vaccination.
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http://dx.doi.org/10.3390/vaccines8040722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712872PMC
December 2020

Risk and Response-Adapted Treatment in Multiple Myeloma.

Cancers (Basel) 2020 Nov 24;12(12). Epub 2020 Nov 24.

Centre de Recherche en Cancérologie de Toulouse, Institut National de la Santé et de la Recherche Médicale U1037, 31059 Toulouse, France.

Myeloma therapeutic strategies have been adapted to patients' age and comorbidities for a long time. However, although cytogenetics and clinical presentations (plasmablastic cytology; extramedullary disease) are major prognostic factors, until recently, all patients received the same treatment whatever their initial risk. No strong evidence allows us to use a personalized treatment according to one cytogenetic abnormality in newly diagnosed myeloma. Retrospective studies showed a benefit of a double autologous transplant in high-risk cytogenetics according to the International Myeloma Working Group definition (t(4;14), t(14;16) or del(17p)). Moreover, this definition has to be updated since other independent abnormalities, namely gain 1q, del(1p32), and trisomies 5 or 21, as well as TP53 mutations, are also prognostic. Another very strong predictive tool is the response to treatment assessed by the evaluation of minimal residual disease (MRD). We are convinced that the time has come to use it to adapt the strategy to a dynamic risk. Many trials are ongoing to answer many questions: when and how should we adapt the therapy, its intensity and duration. Nevertheless, we also have to take into account the clinical outcome for one patient, especially adverse events affecting his or her quality of life and his or her preferences for continuous/fixed duration treatment.
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http://dx.doi.org/10.3390/cancers12123497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760158PMC
November 2020

Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy (PLEIADES): an open-label Phase II study.

Br J Haematol 2021 03 30;192(5):869-878. Epub 2020 Jul 30.

Hematology Department, University Hospital Hôtel-Dieu, Nantes, France.

Daratumumab is a CD38-targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard-of-care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D-VRd) for transplant-eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D-VMP) for transplant-ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D-Rd) for relapsed/refractory MM. In total, 199 patients were treated (D-VRd, n = 67; D-VMP, n = 67; D-Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21-day induction cycles for D-VRd was 71·6% [90% confidence interval (CI) 61·2-80·6%], and the overall response rates (ORRs) for D-VMP and D-Rd were 88·1% (90% CI 79·5-93·9%) and 90·8% (90% CI 82·6-95·9%). With longer median follow-up for D-VMP and D-Rd (14·3 and 14·7 months respectively), responses deepened (ORR: 89·6%, 93·8%; ≥VGPR: 77·6%, 78·5%), and minimal residual disease-negativity (10 ) rates were 16·4% and 15·4%. Infusion-related reactions across all cohorts were infrequent (≤9·0%) and mild. The median DARA SC administration time was 5 min. DARA SC with standard-of-care regimens demonstrated comparable clinical activity to DARA IV-containing regimens, with low infusion-related reaction rates and reduced administration time.
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http://dx.doi.org/10.1111/bjh.16980DOI Listing
March 2021

Standardization of F-FDG-PET/CT According to Deauville Criteria for Metabolic Complete Response Definition in Newly Diagnosed Multiple Myeloma.

J Clin Oncol 2021 01 5;39(2):116-125. Epub 2020 Nov 5.

Nuclear Medicine Department, Nantes University Hospital, CRCINA INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France.

Purpose: F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is currently the standard technique to define minimal residual disease (MRD) status outside the bone marrow (BM) in patients with multiple myeloma (MM). This study aimed to define criteria for PET complete metabolic response after therapy, jointly analyzing a subgroup of newly diagnosed transplantation-eligible patients with MM enrolled in two independent European randomized phase III trials (IFM/DFCI2009 and EMN02/HO95).

Patients And Methods: Two hundred twenty-eight patients were observed for a median of 62.9 months. By study design, PET/CT scans were performed at baseline and before starting maintenance (premaintenance [PM]). The five-point Deauville scale (DS) was applied to describe BM (BM score [BMS]) and focal lesion (FL; FL score [FS]) uptake and tested a posteriori in uni- and multivariable analyses for their impact on clinical outcomes.

Results: At baseline, 78% of patients had FLs (11% extramedullary), 80% with an FS ≥ 4. All patients had BM diffuse uptake (35.5% with BMS ≥ 4). At PM, 31% of patients had visually detectable FLs (2% extramedullary), 24% and 67.7% of them with an FS of 3 and ≥ 4, respectively. At PM, 98% of patients retained residual BM diffuse uptake, which was significantly lower than at baseline (mainly between BMS 2 and 3, BMS was ≥ 4 in only 8.7% of patients). By both uni- and multivariable analysis, FS and BMS < 4 were associated with prolonged progression-free survival (PFS) and overall survival (OS) at PM (OS: hazard ratio [HR], 0.6 and 0.47, respectively; PFS: HR, 0.36 and 0.24, respectively).

Conclusion: FL and BM FDG uptake lower than the liver background after therapy was an independent predictor for improved PFS and OS and can be proposed as the standardized criterion of PET complete metabolic response, confirming the value of the DS for patients with MM.
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http://dx.doi.org/10.1200/JCO.20.00386DOI Listing
January 2021

del(17p) without TP53 mutation confers a poor prognosis in intensively treated newly diagnosed patients with multiple myeloma.

Blood 2021 03;137(9):1192-1195

Unit for Genomics in Myeloma, Institut Universitaire du Cancer de Toulouse-Oncopole, University Hospital, Toulouse, France.

Despite tremendous improvements in the outcome of patients with multiple myeloma in the past decade, high-risk patients have not benefited from the approval of novel drugs. The most important prognostic factor is the loss of parts of the short arm of chromosome 17, known as deletion 17p (del(17p)). A recent publication (on a small number of patients) suggested that these patients are at very high-risk only if del(17p) is associated with TP53 mutations, the so-called "double-hit" population. To validate this finding, we designed a much larger study on 121 patients presenting del(17p) in > 55% of their plasma cells, and homogeneously treated by an intensive approach. For these 121 patients, we performed deep next generation sequencing targeted on TP53. The outcome was then compared with a large control population (2505 patients lacking del(17p)). Our results confirmed that the "double hit" situation is the worst (median survival = 36 months), but that del(17p) alone also confers a poor outcome compared with the control cohort (median survival = 52.8 months vs 152.2 months, respectively). In conclusion, our study clearly confirms the extremely poor outcome of patients displaying "double hit," but also that del(17p) alone is still a very high-risk feature, confirming its value as a prognostic indicator for poor outcome.
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http://dx.doi.org/10.1182/blood.2020008346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933766PMC
March 2021

A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis.

Blood 2020 04;135(18):1531-1540

Centre de Référence pour l'Amylose AL et autres Maladies de Dépôts d'Immunoglobulines Monoclonales and.

Daratumumab is a human monoclonal antibody targeting CD38, an antigen uniformly expressed by plasma cells in multiple myeloma and light-chain amyloidosis (AL). We report the results of a prospective multicenter phase 2 study of daratumumab monotherapy in AL (NCT02816476). Forty previously treated AL patients with a difference between involved and uninvolved free light chains (dFLC) >50 mg/L were included in 15 centers between September of 2016 and April of 2018. Patients received 6 28-day cycles of IV daratumumab, every week for cycles 1 and 2 and every 2 weeks for cycles 3 through 6. Median age was 69 years (range, 45-83). Twenty-six patients had ≥2 organs involved, with heart in 24 and kidney in 26. Median time from diagnosis to enrollment was 23 months (interquartile range, 4-122), with a median of 3 prior therapies (range, 1-5). At data cutoff (September of 2019), all patients discontinued therapy; 33 received the planned 6 cycles. Overall, 22 patients had hematological response, and 19 patients (47.5%) achieved very good partial response (dFLC <40 mg/L) or better. Median time to hematological response was 1 week. Patients with no response after 4 doses were unlikely to respond further. Renal and cardiac responses occurred in 8 and 7 patients, respectively. Daratumumab was well tolerated, with no unexpected adverse events. With a median follow-up of 26 months, the 2-year overall survival rate was 74% (95% confidence interval, 62-81). Daratumumab monotherapy is associated with deep and rapid hematological responses in previously treated AL patients, with a good safety profile. Further studies of daratumumab in combination regimens are warranted.
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http://dx.doi.org/10.1182/blood.2019004369DOI Listing
April 2020

Health-related quality of life results from the IFM 2009 trial: treatment with lenalidomide, bortezomib, and dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma.

Leuk Lymphoma 2020 06 22;61(6):1323-1333. Epub 2020 Feb 22.

Institut Universitaire du Cancer de Toulouse-Oncopole and University Hospital, Toulouse, France.

The Intergroupe Francophone du Myelome 2009 trial (NCT01191060) assessed health-related quality of life (HRQoL) in patients with newly diagnosed multiple myeloma (NDMM) receiving lenalidomide/bortezomib/dexamethasone (RVd) induction therapy followed by consolidation therapy with either autologous stem cell transplantation (ASCT) plus RVd (RVd-ASCT) or RVd-alone; both groups then received lenalidomide maintenance therapy for 1 year. Global HRQoL, physical functioning, and role functioning scores significantly improved for both cohorts from baseline to the end of consolidation and were sustained during maintenance and follow-up, with clinically meaningful changes (RVd-alone:  = .0002; RVd-ASCT:  < .001). Similarly, both groups showed clinically meaningful improvements from baseline in fatigue, pain, and disease symptom scores. Side effects of treatment scores remained stable. In the RVd-ASCT group, there was transient worsening in HRQoL immediately after ASCT. These findings suggest that the clinical improvements observed with RVd-based treatment are accompanied by overall improvements in HRQoL for patients with NDMM.
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http://dx.doi.org/10.1080/10428194.2020.1719091DOI Listing
June 2020

Lenalidomide maintenance for diffuse large B-cell lymphoma patients responding to R-CHOP: quality of life, dosing, and safety results from the randomised controlled REMARC study.

Br J Haematol 2020 04 8;189(1):84-96. Epub 2019 Nov 8.

Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute, Salzburg, Austria.

Lenalidomide maintenance therapy prolonged progression-free survival (PFS) versus placebo in elderly patients with diffuse large B-cell lymphoma (DLBCL) responding to induction chemotherapy in the phase 3 REMARC study. This subpopulation analysis assessed the impact of lenalidomide maintenance and treatment-emergent adverse events (TEAEs) on health-related quality of life (HRQOL). Global health status (GHS), and physical functioning and fatigue subscales were evaluated in patients who completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-C30 v3.0. The impact of TEAEs classified post hoc as subjective (patients can feel) or observable (only measurable by physicians) on dose reductions and discontinuations was assessed. Among 457 patients (lenalidomide, n = 229; placebo, n = 228), mean (standard deviation) GHS was similar between treatment arms [68·2 (20·7) Versus 72·0 (17·8)] at randomisation and remained similar during maintenance. Patients receiving lenalidomide experienced no meaningful changes in GHS, physical functioning, or fatigue. Observable TEAEs were more common (81·1% Versus 66·3%) and more likely to lead to dose reductions, than subjective TEAEs in both arms. PFS was superior in the lenalidomide arm regardless of dose reduction. Lenalidomide maintenance prolonged PFS and did not negatively impact HRQOL in patients with DLBCL despite TEAEs being more common, when compared with placebo.
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http://dx.doi.org/10.1111/bjh.16300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154674PMC
April 2020

Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma.

N Engl J Med 2019 08;381(8):727-738

From the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai (A.C., S.P., S.J.), and New York University Langone Medical Center (D.K.) - both in New York; the Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.T.V.); the School of Medicine, National and Kapodistrian University of Athens, Athens (M.G., M. Dimopoulos); the Winship Cancer Institute, Emory University, Atlanta (A.K.N., S.L.); Massachusetts General Hospital Cancer Center (A.J.Y.), Tufts Medical Center (R.L.C.), and the Dana-Farber Cancer Institute (P.G.R.), Boston, and Karyopharm Therapeutics, Newton (M.G.K., S.S., L.L., S. Tang, C.P., J.-R.S.-M., M.C., H.C., Y.L., J.S.) - all in Massachusetts; Johns Hopkins University, Baltimore (C.A.H.); the University of Nantes, Nantes (P.M.), Hôpital Necker (L.F.), Hôpital Saint-Antoine (M.M.), and La Pitié-Salpêtrière Hospital (S.C.), Paris, University Hospital, Lille (T.F.), Centre Hospitalier Lyon Sud, Pierre-Benite (L.K.), and Centre Hospitalo-Universitaire Vandoeuvre-lès-Nancy, Nancy (A.P.) - all in France; the Mayo Clinic, Rochester, MN (D.D.); the University of Michigan, Ann Arbor (C.C.); the Mayo Clinic of Arizona, Phoenix (A.K.S.); Hackensack University Medical Center, Hackensack, NJ (J.R.); Washington University School of Medicine, St. Louis (R.V.); Lineberger Comprehensive Cancer Center at University of North Carolina-Chapel Hill, Chapel Hill (S. Tuchman); the University of Heidelberg, Heidelberg (M.S.R.), University Medical Center Hamburg-Eppendorf, Hamburg (K.C.W.), the University of Tübingen, Tübingen (K.C.W.), University Hospital Würzburg, Würzburg (M.S.), the University of Freiburg, Freiburg (M.E.), and Gemeinschaftspraxis Hämatologie-Onkologie, Dresden (T.I.) - all in Germany; the University of Leuven, Leuven (M. Delforge), Institut Jules Bordet, Université Libre de Bruxelles, Brussels (N.M.), University Hospital Ghent, Ghent (P.V.), and Centre Hospitalier Universitaire Université Catholique de Louvain Namur, Yvoir (C.D.) - all in Belgium; Vanderbilt University Medical Center, Nashville (R.F.C.); Sylvester Cancer Center, University of Miami, Miami (J.E.H.); the University of Alabama at Birmingham, Birmingham (L.J.C.); Yale School of Medicine, New Haven, CT (T.L.P.); Baylor University Medical Center, Dallas (M.L.); the David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (G.S.); and University Hospital Krems, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria (K.P.).

Background: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options.

Methods: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point.

Results: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients.

Conclusions: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).
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http://dx.doi.org/10.1056/NEJMoa1903455DOI Listing
August 2019

Daratumumab and dexamethasone is safe and effective for triple refractory myeloma patients: final results of the IFM 2014-04 (Etoile du Nord) trial.

Br J Haematol 2019 11 19;187(3):319-327. Epub 2019 Jun 19.

Department of Haematology, Hôpital Claude Huriez, Lille University Hospital, Lille, France.

Single agent daratumumab has shown clinical activity in relapsed, refractory multiple myeloma (RRMM). The Intergroupe Francophone du Myélome 2014-04 trial was designed to further investigate daratumumab in combination with dexamethasone in triple RRMM patients. Patients received daratumumab infusions in combination with weekly dexamethasone until disease progression or unacceptable toxicity. Fifty-seven patients were included in the trial and evaluable for response. The overall response rate and the clinical benefit rate were 33% (n = 19) and 48% (n = 27), respectively. Five (8·8%) patients achieved a very good partial response or better. The median time to response was 4 weeks. For responding patients, the median progression-free survival was 6·6 months, compared to 3·7 months (3·0-5·5) for those with a minimal or stable disease. The median overall survival (OS) for all patients was 16·7 months (11·2-24·0). For responding patients, the median OS was 23·23 months, whereas that of patients with progressive disease was 2·97 months. The incidence of infusion-related reactions was 37%; all cases were manageable and did not lead to dose reduction or permanent treatment discontinuation. These data demonstrate that treatment with daratumumab and dexamethasone results in a meaningful long-term benefit with an acceptable safety profile for patients with triple RRMM.
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http://dx.doi.org/10.1111/bjh.16059DOI Listing
November 2019

Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study.

Lancet 2019 07 3;394(10192):29-38. Epub 2019 Jun 3.

Department of Hematology, University Medical Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

Background: Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma.

Methods: In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383.

Findings: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21-2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33-0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23-0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%).

Interpretation: D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma.

Funding: The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.
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http://dx.doi.org/10.1016/S0140-6736(19)31240-1DOI Listing
July 2019

Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma.

N Engl J Med 2019 05;380(22):2104-2115

From University of Lille, Centre Hospitalier Universitaire (CHU) Lille, Service des Maladies du Sang, Lille (T.F.), Hematology Department, University Hospital Hôtel-Dieu, Nantes (P.M.), Department of Hematology, Hospital Haut Leveque, University Hospital, Pessac (C.H.), Hematology Department, University Hospital, Vandoeuvre lès Nancy (A.P.), Service d'Hématologie, CHU de Toulouse-Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse (M.A.), Department of Hematology, Vendée Hospital, La Roche sur Yon (M.T.), CHU de Caen, Caen (M.M.), Department of Clinical Hematology, Assistance Publique-Hôpitaux de Paris, Necker Hospital, Paris (L.F.), and Department of Hematology, CHU la Miletrie and INSERM CIC 1402, Poitiers (X.L.) - all in France; the Department of Hematology, Mayo Clinic Rochester, Rochester, MN (S.K.); Vejle Hospital and University of Southern Denmark, Vejle (T.P.); Department of Lymphoma-Myeloma, University of Texas M.D. Anderson Cancer Center, Houston (R.Z.O.); University of Calgary, Arnie Charbonneau Cancer Research Institute, Calgary, AB (N.B.), and the Division of Medical Oncology, University of Alberta, Edmonton (C.P.V.) - both in Canada; Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, United Kingdom (S.B.); Karolinska Institute, Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, Stockholm (H.N.); University of Melbourne, St. Vincent's Hospital, Melbourne, VIC, Australia (H.Q.); University Hospital Heidelberg and National Center of Tumor Diseases (NCT), Heidelberg (H.G.), and the Department of Oncology, Hematology and Bone Marrow Transplantation, Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg (K.W.) - both in Germany; Department of Medicine-Haematology, National University of Ireland, Galway (M.O.); Florida Cancer Specialists and Research Institute, St. Petersburg (J.R.M.); the Department of Hematology-Oncology, Massachusetts General Hospital, Boston (N.R.); Genmab US, Princeton (T.A.), and Janssen Research and Development, Raritan (J.W., R.K.) - both in New Jersey; Janssen Research and Development, Spring House, PA (C.C., C.M.U., M.Q.); Janssen Research and Development, Beerse, Belgium (R.V.R.); and Levine Cancer Institute-Atrium Health, Charlotte, NC (S.Z.U.).

Background: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population.

Methods: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival.

Results: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 10 white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).

Conclusions: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).
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http://dx.doi.org/10.1056/NEJMoa1817249DOI Listing
May 2019

Development and Validation of a Cytogenetic Prognostic Index Predicting Survival in Multiple Myeloma.

J Clin Oncol 2019 07 15;37(19):1657-1665. Epub 2019 May 15.

25 Institut Universitaire du Cancer de Toulouse-Oncopole and Centre de Recherches en Cancérologie de Toulouse Institut National de la Santé et de la Recherche Médicale, Toulouse, France.

Purpose: The wide heterogeneity in multiple myeloma (MM) outcome is driven mainly by cytogenetic abnormalities. The current definition of high-risk profile is restrictive and oversimplified. To adapt MM treatment to risk, we need to better define a cytogenetic risk classification. To address this issue, we simultaneously examined the prognostic impact of del(17p); t(4;14); del(1p32); 1q21 gain; and trisomies 3, 5, and 21 in a cohort of newly diagnosed patients with MM.

Methods: Data were obtained from 1,635 patients enrolled in four trials implemented by the Intergroupe Francophone du Myélome. The oldest collection of data were used for model development and internal validation. For external validation, one of the two independent data sets was used to assess the performance of the model in patients treated with more current regimens. Six cytogenetic abnormalities were identified as clinically relevant, and a prognostic index (PI) that was based on the parameter estimates of the multivariable Cox model was computed for all patients.

Results: In all data sets, a higher PI was consistently associated with a poor survival outcome. Dependent on the validation cohorts used, hazard ratios for patients in the high-risk category for death were between six and 15 times higher than those of patients in the low-risk category. Among patients with t(4;14) or del(17p), we observed a worse survival in those classified in the high-risk category than in those in the intermediate-risk category. The PI showed good performance for discriminating between patients who died and those who survived (Harrell's concordance index greater than 70%).

Conclusion: The cytogenetic PI improves the classification of newly diagnosed patients with MM in the high-risk group compared with current classifications. These findings may facilitate the development of risk-adapted treatment strategies.
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http://dx.doi.org/10.1200/JCO.18.00776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804890PMC
July 2019

Variable BCL2/BCL2L1 ratio in multiple myeloma with t(11;14).

Blood 2018 12 14;132(26):2778-2780. Epub 2018 Nov 14.

Unit for Genomics in Myeloma, Institut Universitaire du Cancer-Oncopole, Toulouse, France.

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http://dx.doi.org/10.1182/blood-2018-09-876433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307986PMC
December 2018

Efficacy of bendamustine and rituximab in splenic marginal zone lymphoma: results from the phase II BRISMA/IELSG36 study.

Br J Haematol 2018 12 8;183(5):755-765. Epub 2018 Nov 8.

Department of Diagnostic, Clinical, and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

Splenectomy in addition to immunotherapy with rituximab can provide quick and sometimes durable disease control in patients with splenic marginal zone lymphoma (SMZL). However, systemic chemotherapy is ultimately required in many cases. The BRISMA (Bendamustine-rituximab as first-line treatment of splenic marginal zone lymphoma)/IELSG (International Extranodal Lymphoma Study Group)36 trial is an open-label, single arm phase II study designed by the IELSG in cooperation with the Fondazione Italiana Linfomi and the lymphoma Study Association according to Simon's two-stage method. The primary endpoint was complete response rate. Fifty-six patients with SMZL diagnosis confirmed on central revision were treated with bendamustine (90 mg/m  days 1, 2) and rituximab (375 mg/m  day 1) every 28 days for six cycles (B-R). The overall response and CR rates were 91% and 73%, respectively. Duration of response, progression-free survival and overall survival at 3 years were 93% (95% confidence interval [CI] 81-98), 90% (95% CI 77-96) and 96% (95% CI 84-98), respectively. Toxicity was mostly haematological. Neutropenia grade ≥3 was recorded in 43% of patients; infections and febrile neutropenia in 5·4% and 3·6%. Overall, 14 patients (25%) experienced serious adverse events. Five patients (9%) went off-study because of toxicity and one patient died from infection. In conclusion, B-R resulted in a very effective first-line regimen for SMZL. Based on the results achieved in the BRISMA trial, B-R should be considered when a chemotherapy combination with rituximab is deemed necessary for symptomatic SMZL patients.
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http://dx.doi.org/10.1111/bjh.15641DOI Listing
December 2018

Pomalidomide, cyclophosphamide, and dexamethasone for relapsed multiple myeloma.

Blood 2018 12 3;132(24):2555-2563. Epub 2018 Oct 3.

Centre Hospitalier Universitaire, Limoges, France.

It is important to have an effective therapy for patients with multiple myeloma (MM) at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage. This multicenter, phase 2 trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in patients with MM in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). All patients had received RVD as induction and consolidation therapy, plus lenalidomide maintenance for 1 year (arm A). Half had also received an ASCT after induction (arm B). At MM relapse, all patients received 4 oral cycles of pomalidomide 4 mg (days 1-21), cyclophosphamide 300 mg (days 1, 8, 15, and 22), and dexamethasone 40 mg (days 1-4 and days 15-18 of a 28-day cycle; PCD). Responding patients in arm A underwent ASCT and received 2 additional cycles of PCD, whereas those in arm B received 5 cycles of PCD. All patients received pomalidomide-dexamethasone maintenance until disease progression. Primary end point was partial remission or better after the initial 4 cycles of PCD. Responses were obtained in 82/97 (85%) patients evaluated: complete remission (n = 1; 1%), very good partial remission (n = 32; 33%), and partial remission (n = 49; 51%). Three patients (3%) had stable disease, and 6 (6%) had disease progression (6 response failures). Forty-five (94%) of the 48 patients in arm A underwent planned ASCT. PCD was effective therapy after first relapse with RVD. After 4 cycles, the rate of partial remission or better was 85%, and 94% of planned ASCTs were performed. Toxicity was mostly hematologic and manageable. This trial was registered at www.clinicaltrials.gov as #NCT02244125.
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http://dx.doi.org/10.1182/blood-2018-07-863829DOI Listing
December 2018

Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma.

Blood 2018 12 24;132(23):2456-2464. Epub 2018 Sep 24.

Adaptive Biotechnologies, Seattle, WA.

The introduction of novel agents has led to major improvements in clinical outcomes for patients with multiple myeloma. To shorten evaluation times for new treatments, health agencies are currently examining minimal residual disease (MRD) as a surrogate end point in clinical trials. We assessed the prognostic value of MRD, measured during maintenance therapy by next-generation sequencing (NGS). MRD negativity was defined as the absence of tumor plasma cell within 1 000 000 bone marrow cells (<10). Data were analyzed from a recent clinical trial that evaluated the role of transplantation in newly diagnosed myeloma patients treated with lenalidomide, bortezomib, and dexamethasone (RVD). MRD negativity was achieved at least once during maintenance in 127 patients (25%). At the start of maintenance therapy, MRD was a strong prognostic factor for both progression-free survival (adjusted hazard ratio, 0.22; 95% confidence interval, 0.15-0.34; < .001) and overall survival (adjusted hazard ratio, 0.24; 95% confidence interval, 0.11-0.54; = .001). Patients who were MRD negative had a higher probability of prolonged progression-free survival than patients with detectable residual disease, regardless of treatment group (RVD vs transplant), cytogenetic risk profile, or International Staging System disease stage at diagnosis. These results were similar after completion of maintenance therapy. Our findings confirm the value of MRD status, as determined by NGS, as a prognostic biomarker in multiple myeloma, and suggest that this approach could be used to adapt treatment strategies in future clinical trials.
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http://dx.doi.org/10.1182/blood-2018-06-858613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284215PMC
December 2018

Risk Stratification and Targets in Multiple Myeloma: From Genomics to the Bedside.

Am Soc Clin Oncol Educ Book 2018 May;38:675-680

From the Hematology Department, University Hospital, Nancy, France; Myeloma Genomics Laboratory, University Hospital, Toulouse, France; and Myeloma Genomics Laboratory, University Hospital, Toulouse, France.

In the past 15 years, significant improvements in overall survival have been observed in multiple myeloma (MM), mainly due to the availability of novel drugs with variable mechanisms of action. However, these improvements do not benefit all patients, and some of them, defined as high risk, still display short survival. The most important risk factors are the genetic abnormalities present in the malignant plasma cells. The most important high-risk features are the del(17p), the del(1p32), the t(4;14), and 1q gains. Assessing these markers is mandatory at diagnosis and at least at first relapse, since it has been clearly shown that the lenalidomide-dexamethasone combination is not efficient in these high-risk patients. In contrast, a triplet combination adding a proteasome inhibitor or a monoclonal antibody to the lenalidomide-dexamethasone backbone clearly improves the survival. Another way to improve the outcome would be to specifically target genetic abnormalities with specific inhibitors. The sequencing of more than 1,000 MM exomes revealed again a huge heterogeneity. The most frequent mutations involve the KRAS and NRAS genes (20%-25% each). However, to date, no good RAS-inhibitors are clinically available, preventing targeted therapy. The only drugable target is the V600E BRAF mutation. Unfortunately, this specific mutation is present in only 3% of the patients. Finally, it has been recently reported a specific efficiency of the BCL2-inhibitor venetoclax in patients with the t(11;14) translocation, which is found in 20% of the patients.
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http://dx.doi.org/10.1200/EDBK_200879DOI Listing
May 2018
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