To study clonal evolution in chronic myeloid leukemia (CML), we searched for BCR-ABL-independent gene mutations in both Philadelphia chromosome (Ph)-negative and Ph-positive clones in 29 chronic-phase CML patients by targeted deep sequencing of 25 genes frequently mutated in myeloid disorders. Ph-negative clones were analyzed in 14 patients who developed clonal cytogenetic abnormalities in Ph-negative cells during treatment with tyrosine kinase inhibitors (TKI). Mutations were detected in 6/14 patients (43%) affecting the genes DNMT3A, EZH2, RUNX1, TET2, TP53, U2AF1 and ZRSR2. In two patients, the mutations were also found in corresponding Ph-positive diagnostic samples. To further investigate Ph-positive clones, 15 randomly selected CML patients at diagnosis were analyzed. Somatic mutations additional to BCR-ABL were found in 5/15 patients (33%) affecting ASXL1, DNMT3A, RUNX1 and TET2. Analysis of individual hematopoietic colonies at diagnosis revealed that most mutations were part of the Ph-positive clone. In contrast, deep sequencing of subsequent samples during TKI treatment revealed one DNMT3A mutation in Ph-negative cells that was also present in Ph-positive cells at diagnosis, implying that the mutation preceded the BCR-ABL rearrangement. In summary, BCR-ABL-independent gene mutations were frequently found in Ph-negative and Ph-positive clones of CML patients and may be considered as important cofactors in the clonal evolution of CML.

It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86pDC (n=12). This suggested that low CD86pDC might be predictive of TFR. Indeed, in a prospective analysis of 122 patients discontinuing their TKI within the EURO-SKI trial, the one-year relapse-free survival (RFS) was 30.1% (95% CI 15.6-47.9) for patients with >95 CD86pDC per 10 lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with <95 CD86pDC (hazard ratio (HR) 3.4, 95%CI: 1.9-6.0; P<0.0001). Moreover, only patients with <95 CD86pDC derived a significant benefit from longer (>8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86pDC counts significantly correlated with leukemia-specific CD8 Tcell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86pDC counts have a higher risk of relapse after TKI discontinuation.

Background:We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinib’s price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness (“imatinib-first”) would be cost-effective compared with the current standard of care: “physicians’ choice” of initiating treatment with any one of the three TKIs.Methods:We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physician’s choice from a US commercial payer perspective, assuming 3% annual discounting ($US 2013). The models’ clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truven’s MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of $100 000/QALY. A panel of European LeukemiaNet experts oversaw the study’s conduct.Results:Both strategies met the threshold. Imatinib-first ($277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of $88 343 over five years to payers compared with physician’s choice ($365 744, 3.97 QALYs). The imatinib-first incremental cost-effectiveness ratio was approximately $883 730/QALY. The results were robust to multiple sensitivity analyses.Conclusion:When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP.

To examine the impact of comorbidity on overall survival (OS) in a population‐based study of patients with head and neck cancer who were treated between 2009 and 2011. Data of 1094 patients with primary head and neck carcinomas without distant metastasis from the Thuringian cancer registries were evaluated concerning the influence of patient's characteristics and comorbidity on OS. Data on comorbidity prior to head and neck cancer diagnosis was adapted to the Charlson Comorbidity (CCI), age‐adjusted CCI (ACCI), head and neck CCI (HNCCI), simplified comorbidity score (SCS), and to the Adult Comorbidity Evaluation–27 (ACE‐27). Most patients were male (80%; median age: 60 years; 50% stage IV tumors). Smoking, alcohol abuse, and anemia were registered for 38%, 33%, and 23% of the patients, respectively. Predominant therapy was surgery + radiochemotherapy (30%), surgery (29%), and surgery + radiotherapy (21%). Mean CCI, ACCI, HNCCI, SCS and ACE‐27 were 1.0 ± 1.5, 2.6 ± 2.1, 0.6 ± 0.8, 4.4 ± 4.2, and 0.9 ± 0.9, respectively. Median follow‐up was 25.7 months. Multivariable analyses showed that higher age, higher UICC stage, no therapy, including surgery or radiotherapy, alcohol abuse, and anemia, higher comorbidity were independent risk factors for worse OS (all P < 0.05). According to the discriminatory power analysis none of the five comorbidity scores was superior to the other scores to prognosticate OS. This population‐based study showed that comorbidity is frequent in German patients with head and neck cancer and is an important risk factor for poor OS. Comorbidity should be routinely assessed and taken into account in prospective clinical trials.

A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2-12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24-9.3). After a median of 2.8 years (range, 0.7-5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.