No abstract

SummaryThe primary objective of this study was to investigate factors associated with fatigue severity in newly diagnosed patients with higher-risk myelodysplastic syndromes (MDS). The secondary objectives were to assess symptom prevalence and to examine the relationships between fatigue, quality of life (QoL) and overall symptom burden in these patients. The analyses were conducted in 280 higher-risk MDS patients. Pre-treatment patient-reported fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Female gender (P = 0Á018), poor performance status (i.e., ECOG of 2-4) (P < 0Á001) and lower levels of haemoglobin (Hb) (P = 0Á026) were independently associated with higher fatigue severity. The three most prevalent symptoms were as follows: fatigue (92%), dyspnoea (63%) and pain (55%). Patients with higher levels of fatigue also had greater overall symptom burdens. The mean global QoL scores of patients with the highest versus those with the lowest levels of fatigue were 29Á2 [standard deviation (SD), 18Á3] and 69Á0 (SD, 18Á8), respectively and this difference was four times the magnitude of a clinically meaningful difference. Patient-reported fatigue severity revealed the effects of disease burden on overall QoL more accurately than did degree of anaemia. Special attention should be given to the female patients in the management of fatigue.

Comorbidities significantly affect the prognosis and outcomes of patients with hematological malignancies. We have previously reported the impact of comorbidities on the International Prognostic Scoring System (IPSS) score. The aim of this study was to determine whether comorbidities continued to have a significant impact when patients were reclassified according to the Revised-IPSS (IPSS-R). The medical records of 600 consecutive myelodysplastic syndrome patients who presented to MD Anderson Cancer Center between January 2002 and June 2004 were reviewed. The Adult Comorbidity Evaluation-27 (ACE-27) was used to assess the severity of comorbid conditions. Four hundred and two (67%) patients were male. Median age at presentation was 66.6 years (17–94). Mean duration of follow-up was 54 months (1–100). Five hundred and two (84%) patients died, and 54 (9%) patients underwent stem cell transplantation. Overall median survival was 16.8 months (1–100). Median survival by IPSS-R was 47, 34, 21, 16, and 6 months for patients in very low, low, intermediate, high, and very high-risk groups, respectively (P < 0.001). The ACE-27 comorbidity score significantly impacted the median survival of patients in the intermediate (P < 0.001), high (P = 0.045), and very high (P = 0.004) IPSS-R groups; but did not significantly impact the median survival in the low (P = 0.11) and very low (P = 0.49) IPSS-R groups. The ACE-27 comorbidity score significantly impacted the median survival of patients ≤65 years (P < 0.001) but did not significantly impact those >65 years (P = 0.18). Assessment of comorbidity may enhance the prognostic ability of the IPSS-R. Am. J. Hematol. 89:509-516, 2014.

Background Comorbidities have been shown to play an important role in prognostic assessment of several hematologic conditions; however, the role of comorbidities in primary myelofibrosis has not been studied. The aim of our study was to evaluate the prevalence and impact of comorbidities in patients with primary myelofibrosis (PMF) using the Adult Comorbidity Evaluation-27 (ACE-27). Methods In this retrospective observational cohort study, we evaluated 349 consecutive patients with a confirmed diagnosis of PMF who presented to our institution from 2000 to 2008. We evaluated the frequency and severity of comorbidities in these patients and assessed their impact on survival in a bivariable model that included the ACE-27 and Dynamic International Prognostic Scoring System (DIPSS) scores as covariates. Results Sixty-four percent of patients had at least one comorbid condition, and diseases of the cardiovascular system (63%) were most common. Comorbidities had a significant negative impact on survival (P < 0.001). Patients with severe comorbidities had twice the risk of death as those with no comorbidities. When stratified by demographic and clinical characteristics, comorbidities were significantly associated with worse survival in patients younger than 65 years (P < 0.001) and those with performance status < 1 (P < 0.001). In a multivariable model that included the ACE-27 and Dynamic-International Prognostic Scoring System scores, comorbidities retained a significant association with shorter survival (P ≤ 0.001). Conclusions Assessment of comorbid conditions in patients with PMF, particularly those who are younger and with good performance status, has important implications for overall prognosis and treatment planning.

Immunotherapy (IT) and targeted therapy (TT) are both effective against melanoma, but their combination is frequently toxic. Here, we investigated whether the sequence of IT (anti–PD-1)→ TT (ceritinib–trametinib or dabrafenib–trametinib) was associated with improved antitumor responses in mouse models of BRAF- and NRAS-mutant melanoma. Mice with NRAS-mutant (SW1) or BRAF-mutant (SM1) mouse melanomas were treated with either IT, TT, or the sequence of IT→TT. Tumor volumes were measured, and samples from the NRAS-mutant melanomas were collected for immune-cell analysis, single-cell RNA sequencing (scRNA-seq), and reverse phase protein analysis (RPPA). scRNA-seq demonstrated that the IT→TT sequence modulated the immune environment, leading to increased infiltration of T cells, monocytes, dendritic cells and natural killer cells, and decreased numbers of tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells. Durable responses to the IT→TT sequence were dependent on T-cell activity, with depletion of CD8+, but not CD4+, T cells abrogating the therapeutic response. An analysis of transcriptional heterogeneity in the melanoma compartment showed the sequence of IT→TT enriched for a population of melanoma cells with increased expression of MHC class I and melanoma antigens. RPPA analysis demonstrated that the sustained immune response induced by IT→TT suppressed tumor-intrinsic signaling pathways required for therapeutic escape. These studies establish that upfront IT improves the responses to TT in BRAF- and NRAS-mutant melanoma models.