Niblack, Joyce

Abstract Background: Current dogma for the management of patients with PV dictates controlling erythrocytosis (to goal hematocrit levels of <45% (males) or <42%(females)) to decrease risks of thrombohemorrhagic complications. Control is achieved by either phlebotomy (through induction of iatrogenic iron deficiency), and/or direct myelosuppression (through hydroxyurea, interferon-alpha, or anagrelide). Although phlebotomy is clinically considered a very benign therapy, we hypothesize that PV associated fatigue is exacerbated by iron deficiency induced fatigue (Qual Life Res2000;9:5(491–7)), and evaluated the impact of therapeutic control of erythrocytosis on PV patients. Methods: A detailed analysis of patients with PV whom responded to an international web based survey of MPD patients which registered responses regarding diagnosis, disease course, current medications, current blood counts, frequency of phlebotomy, constitutional symptoms, and fatigue (FACT-An and Brief Fatigue Inventory). Results: A total of 405 self reported PV patients (median age 56; 48% female) from a wide geographic international distribution responded. Individuals were a median of 4 years from their initial diagnosis of PV (range 0–36). Prior PV associated complications were reported as thrombotic (n=98; 24%), hemorrhagic (n=101; 25%), or both events (n=37; 9%). When these latter values were combined with age (i.e. >60 years) 61% of patients (n=246) would be considered high risk. Therapy for their PV was reported by 96% (n=388) patients, with 89% (361) having been phlebotomized, 72% (n = 291) received aspirin, 64% (n = 261) having received 1 or more myelosuppressive agent (hydroxyurea 53% (n = 216), anagrelide 22% (n = 88), interferon-alpha 16% (n = 63)). Amongst patients whom were phlebotomized over the past year (43%; n =174: median 4 units (range 1–18)), 53% (n = 92) received concurrent myelosuppressive therapy. Amongst patients whom originally, but no longer required phlebotomy 35% (n = 142), 94% (n = 134) were receiving myelosuppressive treatments. QOL assessments indicated fatigue as measured by both instruments is clearly increased across the PV respondents compared to published controls for those instruments (p<0.001). Additionally, although the burden of fatigue was not significantly higher in “high-risk” PV, fatigue levels were higher amongst those with prior thrombo-hemorrhagic events (p=0.03, or both types of events p<0.01). In regards to the impact of PV therapy upon fatigue, the burden of this symptom was not significantly diminished for those individuals on phlebotomy alone compared to those on cytoreductive therapy. Neither did fatigue levels correlate with the frequency or intensity of phlebotomy. Additionally, although fatigue burden was high (compared to controls) amongst patients on cytoreductive therapy, no agent had a clear advantage in alleviating (or disadvantage in exacerbating) fatigue. Conclusions: Fatigue amongst patients with PV is significantly increased compared to controls, and no therapeutic option seems to have a significant advantage with regards to fatigue. Given the multifactorial and subjective nature of fatigue it is impossible to separate the individual contributions of disease activity and therapy to the burden of fatigue in these patients. Hopefully, targeted therapy against the molecular origins of myeloproliferation in these patients will lead to better improvements in fatigue than current options offer.

Abstract Background: Debate continues as to the clinical relevance of subclassifying patients with the myeloproliferative disorder (MPD) MMM into the subgroups of agnogenic myeloid metaplasia (AMM), post-polycythemic myeloid metaplasia (PPMM), and post-thrombocythemic myeloid metaplasia (PTMM). We looked to validate previously described phenotypic variability amongst subtypes, and explore relevant and differences in constitutional symptoms. Methods: An detailed analysis of patients with MMM whom responded to an international web based survey of MPD patients which registered responses regarding diagnosis, disease course, complete blood counts, co-morbidities (Charlson Co-morbidity index), symptoms, and fatigue (Fact-An and Brief Fatigue Inventory (BFI)). Results: A total of 456 patients self described as MMM responded of which 32.3% had AMM (n = 148), 38.0% % had PPMM (n = 174), and 29.7% had PTMM (n = 136). Detailed breakdown of differences in demographics, clinical course, current laboratory studies, treatment history, and current symptoms are outlined in the table below. Phenotypic Variability Amongst 458 MMM Patients Category AMM (N=148; 32.3%) PPMM (N=174; 38.0%) PTMM (N=136; 29.7%) MMM Total (N=458) Δ between groups (p = ) Hb = Hemoglobin; SCT = Stem Cell Transplant Age (Median) 61 57 57 58 0.09 Sex (% Males) 60% 49% 30% 47% <0.01 Yrs from MPD Dx 5 6 8 6 <0.01 Labs/ Prior History Hb (g/dL) 11.0 13.7 11.6 12.1 <0.01 % with RBC Tx 43% 6% 11% 20% <0.01 Leukocytes (×10(9)/L) 8.0 7.6 7.2 7.7 0.64 Platelets (×10(9))/L) 200 352 396 321 <0.01 % with Splenomegaly 76% 49% 41% 54% <0.01 % with Prior Thrombosis 10% 22% 31% 21% <0.01 % with Prior Bleed 16% 20% 31% 22% 0.01 Treatment History for the MMM % with Prior Tx for MPD 64% 88% 77% 77% <0.01 % Medical Therapy 57% 70% 75% 67% <0.01 # Meds (Median (Range)) 1 (0–8) 2 (0–6) 2 (0–6) 2 (0–8) <0.01 % with Splenectomy 8% 5% 6% 6% 0.48 % with SCT 6% 1% 1% 3% <0.01 MMM Associated Constitutional Symptoms % with Fatigue 85% 81% 85% 84% 0.56 % with Bone Pain 51% 46% 44% 47% 0.51 % with Fevers 19% 17% 18% 18% 0.87 % with Pruritus 39% 69% 39% 50% <0.01 % with Night Sweats 55% 58% 53% 56% 0.67 % with Weight Loss 30% 15% 16% 20% <0.01 Overall the data suggests patients with AMM are more likely male, with greater burdens of anemia, splenomegaly, and weight loss. However they are less likely to have experienced thrombohemorrhagic complications and have received fewer MPD medications. In contrast PPMM patients (not unsurprisingly) have little trouble from anemia, but have the most pruritus. Patients with PTMM are most likely female, with the highest platelet counts, and the greatest likelihood of thrombohemorrhagic complications. Additionally, all three subgroups of MMM had significant fatigue compared to published controls for both fatigue instruments (P<0.0001) yet there was no difference between MMM subtypes for the severity of fatigue. Conclusions: A large unselected series of MMM patients supports that although constitutional symptoms are significant and similar amongst MMM subgroups, these patients have variable burdens of other MPD manifestations.

Abstract 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.

Abstract Background: Little objective data exists regarding the impact that myeloproliferative disorders (MPDs) (essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis with myeloid metaplasia (MMM)) have on quality of life. Methods: An Internet based survey of MPD patients regarding clinical course, co-morbidities (through the Charlson Co-Morbidity Index), fatigue (through two validated fatigue instruments (FACT-AN and Brief Fatigue Inventory (BFI)), and exercise tolerance (Godin Leisure-Time Questionnaire). Results: Patient Demographics: A total of 830 MPD patients (median age 56; 60.8% male) from a broad geographic distribution (77% USA: 50 states, 30 countries, 5 continents) responded to the survey. Self reported diagnoses were PV (N=272; 33%), ET (N=221; 27%), or MMM (N=329; 40%) for a median of 5 years (range (0–53). Clinical History: 708 patients (87%) had undergone treatment for their MPD (drugs 84.6%, phlebotomy 49.5%, other 16%). A history of thrombotic (n=195, 24%) or hemorrhagic events (N=214; 26%) were frequently reported. Blood tests (available in 597 a median 1.65 months prior to survey) showed 37% were anemic (7% transfusion dependent). Additionally, 347 (44%) had splenomegaly, painful in 21%. Symptoms: Frequent symptoms reported included fatigue (90%), pruritus (57%), night sweats (54%), bone pain (48%), undesired weight loss (15%), and/or fevers (15%). 41% felt restricted in their activities, and 89 (11%) were medically disabled secondary directly to their MPD. 82% of patients felt their fatigue was linked to their MPD. Additionally 69% curtail social activity because of fatigue, and 41% need some degree of assistance with activities of daily living. Charlson co-morbidity index demonstrated 722 (87%) had minimal co-morbidities strengthening the association between fatigue and their MPD. The burden of fatigue decreased from MMM to PV to ET respectively (p=0.0002). Results from both fatigue assessment tools (FACT-AN and BFI) were highly correlated. Fatigue (FACT-AN fatigue subscale) strongly correlated with multiple MPD disease features including: anemia, bone pain, constitutional symptoms, pruritus, splenic pain, hemorrhagic events (all p<0.0001) and thrombosis(p=0.01). Additionally, currently smoking (as opposed to being a prior smoker) was highly associated with increased fatigue (p<0.0001). Interestingly, even in “asymptomatic” patients (those without anemia, splenomegaly, or thrombohemorrhagic complications (n=187)) 73% (n=128; 40% PV, 32% ET, 27% MMM; p=N.S.) described moderate to severe MPD associated fatigue. Reported physical activity was diminished (Godin Leisure Score) between MPD patients and published norms, with 38% describing minimal to no exercise. Overall, 86% stated fatigue was the major obstacle to exercise. Conclusions: Fatigue is an extremely common problem in patients with MPDs despite current therapies, and a minimal burden of co-morbidities in the majority of patients. Fatigue is also common in patients lacking advanced MPD disease features, or thrombohemorrhagic complications. Clearly, direct attempts to improve fatigue (through pharmacologic and non-pharmacologic interventions) are necessary.

Abstract 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.

Abstract Abstract 2904 Poster Board II-880 Background: The myeloproliferative neoplasm (MPN) of essential thrombocythemia (ET) can cause a constellation of symptoms in afflicted patients either from direct consequence of vascular and circulatory events (i.e. thrombosis, hemorrhage, erythromelalgia), or more indirectly as a consequence of the myeloproliferation itself (fatigue, pruritus, constitutional symptoms). These latter symptoms, of significant importance to patients, are more challenging for physicians to interpret given they are self reported by patients and influenced by many factors including culture. We sought to identify the concordance of self reported fatigue, and impact on daily life in patients with ET between 2 large and independently administered studies performed in the USA and France, respectively. Methods: Two large, separate, trials of symptomatic burden were used for the analysis. The first an internet based trial originating from the USA of self reported symptoms across the spectrum of patients with MPNs (Mesa et. al. Cancer 2007), the data included in this analysis a previously unreported subset analysis on patients from the USA with ET. The second trial a multi-centre, prospective questionnaire based analysis including many aspects of the impact of ET upon patients in France including fatigue and daily life. Key areas of overlap between these 2 trials were analyzed to assess whether any substantive differences in the impact of ET on daily life or fatigue between these 2 patient groups. Results: PATIENTS: A total of 447 patients with ET were included in the analysis (222 from the French Series (median age 57.8 years (range 19-90), 225 from the USA Series (median age 53 years (range 16-82)). In the 2 series, respectively, 78%, and 77% received cytoreductive therapy, and 16%, and 22% had a history of a vascular event. FATIGUE AND IMPACT ON DAILY LIFE: Fatigue was a self reported problem across the majority respondents in this analysis 287/447 (64%) self reporting fatigue as a problem. The prevalence of fatigue did not vary significantly between the 2 countries (158/225 (70.2%) - USA, - 129/222 (58%) – France). In contrast, in the French study where parallel questionnaires were completed by the patients and their hematologists, the doctor considered fatigue as a significant symptom in only 17% of patients. Additionally the majority of respondents felt the ET was the reason, at least partially, for their fatigue (316/447; 71%) again with no significant difference amongst the regions (69% USA, 73% France). Self reported metrics such as decreased libido (25% USA, 24% France) demonstrated remarkable similarity across cultural and geographic differences. Finally when asked directly whether ET negatively impacted their daily life, 46% of US patients responded in the affirmative (ranging from modest to severe impact). In France), the patients reported impact of ET on their: professional life (37%), hobbies (24%) and mood (74%). Conclusions: The symptomatic impact of a diagnosis of ET upon afflicted patients is significant, present in a majority of patients, and surprisingly consistent across 2 different cultural and geographic regions. The deep difference between patient's and doctors' consideration of fatigue as a meaningful symptom underlines the need for objective symptom assessment tools in MPN. (The French portion of this study was sponsored by Shire, Inc.) Disclosures: No relevant conflicts of interest to declare.