Chronic lymphocytic leukemia (CLL) is associated with physical dysfunction and low overall fitness that predicts poor survival following commencement of treatment. However, it remains unknown whether higher fitness in CLL patients provides anti-oncogenic effects. We identified ten fit (CLL-FIT) and ten less fit (CLL-UNFIT) treatment-naive CLL patients from 144 CLL patients who completed a set of physical fitness and performance tests. Patient plasma was used to determine its effects on in vitro 5-day growth/viability of three B-cell cell lines (OSU-CLL, Daudi and Farage). Plasma exosomal miRNA profiles, circulating lipids, lipoproteins, inflammation levels, and immune cell phenotypes were also assessed. CLL-FIT was associated with fewer viable OSU-CLL cells at Day 1 (p=0.003), Day 4 (p=0.001) and Day 5 (p=0.009). No differences between groups were observed for Daudi and Farage cells. Of 455 distinct exosomal miRNAs identified, 32 miRNAs were significantly different between groups. Of these, 14 miRNAs had [≤]-1 or [≥]1 log2 fold differences. CLL-FIT patients had 5 exosomal miRNAs with lower expression and 9 miRNAs with higher expression. CLL-FIT patients had higher HDL cholesterol, lower inflammation, and lower levels of triglyceride components (all p<0.05). CLL-FIT patients had lower frequencies of low-differentiated NKG2+/CD158a/bneg (p=0.015 and p=0.014) and higher frequencies of NKG2Aneg/CD158b+ mature NK-cells (p=0.047). Absolute numbers of lymphocytes including CD19+/CD5+ CLL-cells were similar between groups (p=0.359). Higher physical fitness in CLL patients is associated with altered CLL-like cell line growth in vitro, and with altered circulating and cellular factors indicative of better immune functions and tumor control.

Background:Fludarabine, cyclophosphamide, rituximab (FCR) can provide prolonged disease free survival for young, fit chronic lymphocytic leukemia (CLL) patients with mutated IGHV; however, patients with unmutated IGHV rarely have durable response. The oral Bruton Tyrosine Kinase inhibitor, ibrutinib, is highly effective for patients irrespective of IGHV mutation status, but requires continuous therapy. We hypothesized that a time‐limited regimen of ibrutinib plus FCR (iFCR) would have curative potential for a broad population of young, fit CLL patients.Aims:The primary objective was to determine the rate of complete remission (CR) with undetectable bone marrow minimal residual disease (BM‐uMRD) two months after completing iFCR combination therapy. Secondary objectives were to assess clinical response rates, progression‐free and overall survival, rates of best response and BM‐uMRD, safety/tolerability, ibrutinib pharmacokinetics (PK), and association of established CLL prognostic factors with clinical response.Methods:We performed a multicenter, open‐label, non‐randomized, phase 2 investigator sponsored trial of iFCR, and enrolled CLL patients age ≤65 years without restriction by IGHV mutation status, all of whom met iwCLL criteria for initial treatment. Ibrutinib 420 mg daily was given for 7 days, followed by combination ibrutinib with FCR for up to 6 cycles. Responders continued on ibrutinib maintenance, and patients with BM‐uMRD after 2 years of maintenance discontinued therapy. Response was assessed by 2008 iwCLL criteria, and toxicity was assessed by CTCAE v4.03 and iwCLL criteria. This trial is registered with ClinicalTrials.gov (NCT02251548).Results:Between October, 2014, and April, 2018, 85 patients were enrolled at 9 US sites. The median age was 55 years (range 38–65). IGHV was unmutated in 46/79 patients (58.2%). Deletion of 17p and TP53 mutation were present in 4/83 (4.8%) and 3/81 (3.7%) patients, respectively; 2 of these patients had both. The median number of FCR cycles completed was 6 (range 1–6). The median AUC of ibrutinib in combination with FCR was 337.2 (IQR 198.6–553.9), and the median Cmax was 97.3 (IQR 65.1–168.8). These PK parameters are similar to ibrutinib monotherapy in prior studies, and did not appear to be altered by FCR. The rate of CR‐BM‐uMRD 2 months post‐FCR was 33% (28/85 patients, 95% CI: 0.25–1.0)), with a best rate at any point on trial that increased to 41% (35/85), and a best rate of CR/CRi irrespective of MRD status of 66%. The best rate of BM‐uMRD irrespective of IW‐CLL response status was 84% (71/85), and did not differ by IGHV mutation status (Figure 1). With a median follow‐up of 16.5 months (range 3.1–48.9), one patient progressed and one died due to a presumed cardiac event. The most common treatment‐emergent grade 3/4 adverse events were hematologic, including neutropenia 35%, thrombocytopenia 32%, and anemia 11%. Eight patients (9%) experienced grade ≥3 febrile neutropenia. No cases of Richter's Syndrome have been observed.Summary/Conclusion:The rate of BM‐uMRD induced by iFCR is, to our knowledge, the highest ever reported for a regimen treating a population of CLL patients unrestricted by prognostic marker status. The safety profile of iFCR was generally favorable, with typical toxicities of ibrutinib and FCR observed, and no additional toxicities discernable with the combination. These data establish iFCR as a highly effective novel‐agent‐containing time‐limited combination for initial therapy for young, fit CLL patients.image

Background:Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods:We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results:A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions:In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.