The aborted trial of semagacestat has led some to invoke unanticipated effects of γ‐secretase inhibition on formation of amyloid β. However, the many substrates for γ‐secretases and the varied biological effects of each of the resultant cleavage products make ascribing causality much more complex than that. Ann Neurol 2011

Quality of life (QoL) in patients with myelofibrosis (MF) is severely compromised by severe constitutional symptoms (i.e. fatigue, night sweats, fever, weight loss), pruritus, and symptoms from frequently massive hepatosplenomegaly. Given that no current instrument of patient reported outcomes (PRO) exists that covers the unique spectrum of symptomatology seen in MF patients, we sought to develop a new PRO instrument for MF patients for use in therapeutic clinical trials. Utilizing data from an international internet based survey of 458 patients with MF we created a 20 item instrument (MFSAF: Myelofibrosis Symptom Assessment Form) which measures the symptoms reported by >10% of MF patients, and includes a measure of QoL. We subsequently validated the MFSAF in a prospective trial of MF patients involving patient and provider feedback, as well as comparison to other validated instruments used in cancer patients. The MFSAF results were highly correlated with other instruments, judged comprehensive and understandable by patients, and should be considered for evaluation of MF symptoms in therapeutic trials.

Background: Scant data exists regarding the burden of fatigue and constitutional symptoms in patients with myeloproliferative disorders (MPDs) (essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis with myeloid metaplasia (MMM)). Methods: An Internet based survey of MPD patients regarding clinical course, blood counts, constitutional symptoms, and fatigue (FACT-AN and Brief Fatigue Inventory (BFI)). Results: Patient Demographics: A total of 1179 MPD patients (median age 56; 41.4% male) internationally (76% USA: 50 states, 30 countries, 6 continents) responded to the survey. Self reported diagnoses were PV (35%), ET (26%), or MMM (39%). Clinical History: 1025 patients (87%) had undergone MPD therapy (drugs 70.5%, phlebotomy 44.1%, other 16%). Thrombosis (n=261, 22%), hemorrhage (N=272; 23%), and splenomegaly (N=478 (43%) were frequently reported. Blood tests (available in 917) showed 39% were anemic, 7% transfusion dependent. Symptoms: Fatigue, pruritus, night sweats and bone pain were present across the majority of MPD patients (see table). Additionally it was observed that these symptoms appeared with nearly equal frequency in PV as in MMM patients. However MMM patients displayed more advanced features (fevers, night sweats and weight loss). MPD Associated Constitutional Symptoms in 1179 Patients SYMPTOM PV (N=405) ET (N=304) MMM (N=456) MISSING (N=14) TOTAL (N=1179) P VALUE Fatigue 344 (84.9%) 220 (72.4%) 381 (83.6%) 7 945 (81.1%) <0.0001 Pruritus 265 (65.4%) 120 (39.5%) 228 (50.0%) 3 613 (52.6%) <0.0001 Night Sweats 199 (49.1%) 123 (40.5%) 254 (55.7%) 4 576 (49.4%) 0.0002 Bone Pain 174 (43.0%) 125 (41.1%) 214 (46.9%) 4 513 (44%) 0.2480 Fevers 53 (13.1%) 26 (8.6%) 81 (17.8%) 2 160 (13.7%) 0.0013 Weight Loss 39 (9.6%) 22 (7.2%) 93 (20.4%) 0 154 (13.2%) <0.0001 Spleen Pain 17 (4.2%) 27 (8.9%) 30 (6.6%) 4 74 (6.3%) <0.0001 Fatigue (82% MPD linked) was significantly increased across all MPD subtypes compared to published controls for both the BFI (P<0.0001) and Fact-An (P<0.0001). Additionally 69% curtail social activity because of fatigue, 35% need assistance with activities of daily living, and 11% reported MPD associated medical disability. Fatigue strongly correlated with multiple MPD disease features including: anemia, bone pain, constitutional symptoms, pruritus, splenic pain, smoking, thrombosis, and hemorrhagic events (all p<0.0001). Interestingly, even in “asymptomatic” MPD patients (those without anemia, splenomegaly, or thrombohemorrhagic complications) (n=279)) 24% (41% PV, 31% ET, 28% MMM) described significant fatigue worse than published controls. Conclusions: Fatigue and other constitutional symptoms are a significant burden to MPD patients, despite current therapies employed. Additionally fatigue is also a significant problem even in MPD patients lacking other advanced disease features. Clearly, direct attempts to improve fatigue (through pharmacologic and non-pharmacologic interventions) are necessary.

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Background: Myelofibrosis (MF) shortens survival but also compromises quality of life from disease associated splenomegaly and constitutional symptoms (fatigue, weight loss, night sweats, and bone pain). No current validated instrument of patient reported outcomes (PRO) captures the spectrum of MF associated symptoms. In an era of rapid development and testing of therapeutic agents which may impact the natural history and symptoms associated with MF (such as JAK2 inhibitors) a uniform and validated instrument for capturing the presence, severity (and potentially improvement) of MF symptoms is needed. We sought to develop and validate such an instrument, the myelofibrosis symptom assessment form (MFSAF). Methods: Based upon the results in our MF QOL survey (Cancer2007;109(1):68–76), we developed the MFSAF to assess fatigue (via the brief fatigue inventory (BFI-Cancer1999;85:1186)), additional symptoms were independently assessed for presence and severity on a scale from 0 (absent) to 10 (worst possible) for splenomegaly associated symptoms (early satiety, pain, inactivity, cough) night sweats, itching, bone pain, fever, unintentional weight loss as well as an estimate of overall quality of life. Additionally, patients provided feedback on the quality and nature of the MFSAF, and also completed for comparison validated instruments including the Memorial Symptom Assessment Scale (MSAS), the Insomnia Severity Index (ISI), and the Brief Pain Index. Physician input was included including their assessment of patient’s fatigue, spleen symptoms, and quality of life (blinded to patient’s responses) as well as clinical history, lab and exam findings. Results: MFSAF Results 34 MPD patients were enrolled (24 MF, 10 in the comparison group (4 polycythemia vera (PV), 6 essential thrombocythemia (ET)). the MFSAF was rated by patients as easy to understand (median score 1, range 0–6), and “addressed most of my symptoms” (median score 1, range 0–6) both on a scale of 0 (as good as possible to 10 as bad as possible). When asked if a symptom was not addressed (open ended response) no single symptom was named more than once. As we have previously reported fatigue was common with BFI scores (median 3.6 (0–10) for MF and 2.5 (range 0.2–3.8) for the ET/PV group (increasing BFI score associated with worsening fatigue) worse than median score of published “healthy” controls 2.2. Additional MF associated symptoms were captured well by the MFSAF with splenic, constitutional symptoms, and QOL (median 3 (range 0–7) MF, median 2 (0–3) ET/PV) documented easily and worse than ET/PV controls. Physicians estimation of QOL was excellent (median 3 (0–8) for MF, median 2 (0–4) for ET/PV). MFSAF Comparison to other Instruments: The MSAS demonstrated more adverse values for MF (than ET/PV) in the PSYCH (psychologic stress; mean-1.27 (STD DEV 0.80), PHYS (physical symptoms; mean 0.90 (STD DEV 0.53)), GDI (Global Distress Index mean-1.29 (STD DEV 0.77)) and a total MSAS symptom score (mean 0.85 (std dev (0.49)) comparable with advanced renal disease (PSYCH 0.99, PHYS 0.99, GDI 1.27, and MSAS of 0.81; J of Pall Med2007;10(6):1266), as well as advanced lung disease, AIDS, and various advanced malignancies. Individual, previously validated MSAS questions were all highly correlated (all p<0.01) with MFSAF (in italic) counterparts including lack of energy (fatigue), cough (same), pain (both abdominal pain and bone pain), sweats (night sweats), itching (same), and weight loss (same). Further validation of pain measurements in the MFSAF came from comparison to the BPI where both individually the presence, and intensity of pain (both abdominal and bone) were highly correlated (all p<0.01). Insomnia, not yet included in the MFSAF, was present in 68% and 63% of patients (MSAS and ISI, respectively). Additionally, problems with sexual interest, or activity, was noted in 35% of patients to the MSAS. Conclusions: Currently available instruments of PRO and symptoms are lengthy, and individually incomplete for assessing the presence and severity of the diverse nature of symptoms associated with MF. The proposed MFSAF, was comprehensive and well understood by patients and the results for the individual symptoms assessed were highly correlated with previously validated instruments for other conditions as well as with physicians perceptions of fatigue and QOL. The MFSAF, with the addition of questions regarding insomnia and sexuality, should be utilized in all trials of therapeutic agents in MF patients in which symptomatic improvements are an endpoint.