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Background: Myelofibrosis (MF) is recognized for its debilitating constitutional symptoms, splenomegaly, profound cytopenias and inflammatory state. Current MPN PROs (MF-SAF, MPN-SAF and MPN-10) have proven sensitive for symptom detection. Formal FDA qualification requires that these tools integrate a comprehensive literature search of previously reported symptoms as well as complete physician cognitive debriefing. Aims: In this investigation, we aimed to complete these required steps to ascertain the most prevalent and pertinent MPN symptoms for PRO inclusion. Methods: Literature Search: An initial review of the published literature was performed using OVID Medline®. The Medical Subject Headings (MeSH) terms included 'primary myelofibrosis' or 'MF', 'Myeloid metaplasia' and 'agnogenic myeloid metaplasia' which were meshed with 'symptom' or 'signs and symptoms' and limited from 1980 to 2011. Articles that were not original research or in the English language were excluded. Articles were then individually reviewed for content with further exclusion of case reports where search terms occurred concurrently with other medical conditions, articles presenting in-vitro data and articles with a primary focus on pharmacotherapy that utilized the MPN-SAF, MPN-SAF TSS or MF-SAF. Articles were then evaluated for all symptoms and recorded by the number of publications they were reported in. Cognitive Debriefing: International MPN specialists were contacted via email to complete the Physician Cognitive Debriefing Evaluation via a REDCAP® survey. Implied consent was provided through survey completion and demographic data was recorded. Responders were asked a series of questions on each symptom acquired through the literature search, along with three free-standing questions on MF PRO development. Thirteen responders were also contacted to complete an in-person interview and respond to eight questions on MF-PRO development. Descriptive statistics were used for data analysis. Results: The OVID Medline search yielded 166 articles for MF which were then individually reviewed. A total of 30 symptoms were extracted from the literature and recorded for incorporation into the REDCAP survey. The survey was distributed to 48 MPN specialists and 17 (35.4%) agreed to participate. Most responders were Caucasian (94.1%) and male (76.5%) with >5 years experience (94.1%) as physicians. Providers saw between 1-5 (58.8%), 6-10 (23.5%) or >10 (11.8) MF patients per week and most held primary practices in Europe (70.6%). Survey responses to symptom questions are provided in Figure 1. During in-person interviews, some providers felt that a different list of symptoms should be provided to patients with: early vs late MF (61.5%), primary vs secondary MF (7.7%) and clinical trial settings vs office environments (23.1%). Most providers felt that 'inactivity' (100%), 'fever' (92.3%) and 'weight loss' (92.3%) were signs as opposed to symptoms of the disease, though should still be included in the PRO (92.3% for each). Most providers believed that the ideal survey length should be between 10-20 questions. Two providers believed that 'health economics' and 'activities of daily living' should be integrated into a final PRO. Summary/Conclusions: Results of the literature search and Physician Cognitive Debriefing support that the MPN-SAF currently addresses the most frequent and symptomatic MF symptoms, with the exception of four items (dyspnea, easy bruising, arthralgias, nausea). Addition Patient Cognitive Debriefing is required to ensure that the final PRO is comprehensive of the most important symptoms to patients. (Figuer Presented).

Secondary myelodysplastic syndrome (MDS) and acute leukemia (AL) are well-known complications of antineoplastic therapy. The incidence of these serious complications after autologous hematopoietic transplantation ranges from 1.1% to 24%. Prior chemotherapy is its most likely cause, but other variables related to these long-term complications are seriously discussed. There is evidence that priming of progenitor cells isolated from peripheral blood with chemotherapy is also related to a higher risk of secondary MDS/AL. Whether progenitor cells isolated from bone marrow or peripheral blood after mobilization only with cytokines are related to higher risk is a controversial issue. In this paper, we analyze the incidence and variables related to these complications in a series of 99 patients diagnosed with lymphoma or multiple myeloma who underwent autologous transplantation using hematopoietic progenitors isolated from peripheral blood mobilized with granulocyte colony-stimulating factor (G-CSF). The probability of MDS/AL in patients alive 5 years after transplant in our series is 8.58%, similar to that reported in other series using bone marrow grafts. The total dose of cyclophosphamide ( p=0.099), the number of chemotherapy cycles ( p=0.04) received before transplant, and the total dose of mononuclear cells infused at the time of transplant were the only variables associated with secondary MDS/AL. Autologous transplantation with progenitor cells isolated from peripheral blood after mobilization with cytokines has probability and risk factors for secondary MDS/AL development similar to bone marrow grafts when compared with other published series.

Background. Symptom burden in MPNs is severe and a risk factor for mortality in some disease subtypes (Blood 2010;115(9):1703-8). A recent trial comparing JAK2 treatment to best available therapy revealed that patients receiving conventional MPN therapies experienced no difference or worsening of symptoms (Blood 2011;118(21):a6501). No studies have evaluated the specific associations of conventional therapies on individual MPN symptoms using a validated patient-reported measure of symptom burden. Aims. We aimed to assess associations between conventional therapies on specific MPN symptoms using the MPN-SAF TSS (Blood 2011;118(21):a3839). Methods. Patient demographics, symptom burden and disease traits including therapies were collected from MPN patients and physicians at a single time point during therapy. MPN-SAF TSS included "worst"fatigue from the BFI and MPN-SAF items of concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss and fever. MPN-SAF TSS was calculated as the total 10-item score, reported in a range of 0 to 100 for patients completing at least 6 of the 10 items. Results. Demographics: 1433 MPN patients were prospectively enrolled, including 594 essential thrombocythemia(ET), 538 polycythemia vera(PV) and 293 myelofibrosis(MF) patients from 11 countries. Of these, 1408 patients completed at least 6 of the 10 required items. Patients were 54% female with a median age of 63.Therapies: Common therapies included hydroxyurea/hydroxycarbamide(47.7%), salicylates(43.8%), interferon/pegylated- interferon(9.4%), and phlebotomies(5.3%) with 12.6% receiving no therapy. MPN-SAF TSS variations were observed between patients receiving and not receiving each therapy, although only one reached statistical significance (Table 1). Overall Treatment Effects: When comparing the overall effects of current therapy, worst fatigue was significantly more severe among PV patients undergoing treatment as compared to patients not receiving treatment (4.5(n=497) vs. 3.4(n=30), p=0.03). Among MF patients, abdominal comfort was significantly worse among patients not receiving therapy (3.3(n=57) vs. 2.3(n=230),p=0.02) .Aspirin: ET patients receiving aspirin reported significantly less weight loss than patients not receiving salicylates (0.62(n=298) vs. 0.98(n=283),p=0.03). Additionally, aspirin among ET patients reduced pruritus (1.5(n=296) vs. 2.0(n=284),p=0.02). PV patients receiving aspirin reported more concentration difficulties than patients on a non-aspirin regimen (3.0(n=254) vs. 2.4(n=264),p=0.01). MF patients receiving aspirin reported decreased bone pain (1.5(n=58) vs. 2.4(n=228),p=0.04) and abdominal discomfort (1.9(n=58) vs. 2.7(n=229),p=0.04). Hydroxyurea/hydroxycarbamide: PV patients receiving hydroxyurea/hydroxycarbamide reported decreased itching than patients not on this therapy, although this effect was of borderline significance (2.5(n=272) vs. 3.0(n=255),p=0.05). Phlebotomies: PV patients being given phlebotomies had significantly decreased problems with concentration compared to non-phlebotomized patients (1.9(n=71) vs. 2.8(n=447),p=0.02). Interferon/pegylatedinterferon: PV patients receiving interferon therapy reported increased early satiety (3.1(n=69) vs. 2.4(n=257),p=0.04), fever (0.7(n=67) vs. 0.3(n=455), p=0.02), and MPN-SAF TSS (25.5(n=69) vs. 21.2(n=460),p=0.04) than noninterferon- receiving counterparts. Conclusions. Few significant effects in overall symptom burden were observed in patients undergoing traditional MPN therapies. Though some effects reached nominal statistical significance, a portion may be spurious given the large number of tests performed. Further studies are needed to determine whether treatments impart additional symptom burden or if patients with specific symptom characteristics are selected to receive a particular treatment. Prospective serial assessment of conventional therapy impact is ongoing as part of a new clinical trial.

Patients previously diagnosed with invasive aspergillosis (IA) have been considered to be at risk for relapse of mycosis during subsequent hematopoietic transplant. Even with prophylactic measures, reactivation of the infection occurs in 29% of patients undergoing bone marrow transplantation (BMT). A period of neutropenia is one of the variables considered to be a risk factor for reactivation. Peripheral blood stem cell transplant (PBSCT) results in a shorter neutropenia period leading to a lower risk of fungal infection. A retrospective data analysis performed on patients undergoing autologous PBSCT for hematological malignancies in our unit showed that nine patients were diagnosed before transplantation with IA. All patients received only medical treatment during their primary infection. Medical prophylaxis was administered in seven of these patients, and two underwent transplantation without prophylaxis. All patients developed severe neutropenia after a myeloablative regimen. All but one had neutropenic fever, although the fever was controlled and no fungal complications occurred. All patients in this series achieved complete hematological engraftment without delay in granulocyte recovery (mean: 8.78 vs 9.76; p=0.58). No significant differences were observed in toxicities with regards to transplantation between patients previously diagnosed with IA and their controls. Recurrence of IA related to transplantation was avoided since no relapse of IA was demonstrated. This series of nine patients with a previous history of IA shows that medical treatment, secondary prophylaxis, and peripheral blood as a source of stem cells could be effective measures to avoid reactivation of previous aspergillosis during hematopoietic transplantation, although prospective randomized trials should still be performed to confirm these findings in a wider setting.