Francoise Boyer

Myeloproliferative Neoplasm (MPN) Symptom Assessment Form Total Symptom Score: Prospective International Assessment of an Abbreviated Symptom Burden Scoring System Among Patients With MPNs

PURPOSE Myeloproliferative neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy. PATIENTS AND METHODS The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. RESULTS MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P<.001), with a mean of 18.7 (SD, 15.3), 21.8 (SD, 16.3), and 25.3 (SD, 17.2) for patients with essential thrombocythemia, polycythemia vera, and myelofibrosis, respectively. The MPN-SAF TSS strongly correlated with overall quality of life (QOL; r=0.59; P<.001) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) functional scales (all P<.001 and absolute r≥0.50 except social functioning r=0.48). No significant trends were present when comparing therapy subgroups. The MPN-SAF TSS had excellent internal consistency (Cronbachs α=.83). Factor analysis identified a single underlying construct, indicating that the MPN-SAF TSS is an appropriate, unified scoring method. CONCLUSION The MPN-SAF TSS is a concise, valid, and accurate assessment of MPN symptom burden with demonstrated clinical utility in the largest prospective MPN symptom study to date. This new prospective scoring method may be used to assess MPN symptom burden in both clinical practice and trial settings.

PEG-IFN-α-2a therapy in patients with myelofibrosis

and a ratio of 0Æ0177% at quantitative RT-PCR. As regard to B-CLL, the peripheral blood flow-cytometric analysis revealed that the percentage of clonal lymphocytes had dropped from 80% to 8% (absolute count: from 8Æ33 to 0Æ33 · 10/l), while FISH analysis showed trisomy 12 in 7% of the 300 nuclei examined. No peripheral lymphadenopathies were detected by physical examination. Abdominal ultrasound showed the reduction of splenomegaly (13 cm diameter) and the complete disappearance of the retroperitoneal lymphadenopathies. Our clinical observation, carried out on a rare case of B-CLL associated with CML, follows the few previously reported experiences on the successful use of dasatinib in B-CLL (Pitini et al, 2009). Although in vitro dasatinib appeared to be effective mainly in cases of unmutated B-CLL (Veldurthy et al, 2008) at concentrations difficult to attain in vivo (Amrein et al, 2008), our experience suggests that it can be active also in a IGHVmutated ZAP-70 negative case, at the usual dose. Obviously, the effectiveness of dasatinib in the treatment of patients affected by B-CLL needs to be exploited in prospective studies.

Symptomatic Profiles of Patients With Polycythemia Vera: Implications of Inadequately Controlled Disease

PURPOSE Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. PATIENTS AND METHODS Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). RESULTS The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). CONCLUSION The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present.

Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group.

The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients’ characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients’ characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest that gender contributes to the heterogeneity of myeloproliferative neoplasms by influencing phenotypic profiles and symptom expression.

Clinical and biological characterization of MPN patients harboring two driver mutations, a French intergroup of myeloproliferative neoplasms (FIM) study

To the Editor: Mutations in “driver” genes (JAK2, MPL, or CALR) are found in the vast majority of Philadelphia-negative myeloproliferative neoplasms (MPN): JAK2V617F or exon 12 mutations in polycythemia vera (PV), JAK2V617F, CALR exon 9, or MPL exon 10 mutations in essential thrombocythemia (ET) or primary myelofibrosis (PMF). In the latter, phenotypic presentation and evolutive course vary according to the mutation, eg, higher platelet counts in CALR mutated ET patients and higher hemoglobin, white blood cell counts and higher risk of thrombosis in JAK2-mutated ET. Driver mutations were initially described as mutually exclusive, but can co-exist in rare “doubly mutated” (DM) patients. We have previously shown that double mutations were more frequently encountered in patients with low (<5%) JAK2V617F allelic burdens. However, due to the limited reports of DM patients, it is unclear how co-occurrence of driver mutations affects the presentation or evolution of MPN. In order to confirm DM frequency in a multicentric fashion, two additional cohorts of JAK2-mutated MPN were screened for CALR mutations: 134 JAK2V617F-mutated ET from the University Hospital of Cr eteil (France) and a cohort of 31 MPN with a low JAK2V617F allele burden (<2%) from the University Hospital of Nantes (France). Five of 49 patients with a JAK2V617F allele burden <5% also had a CALR mutation (10.2%), similar to our previous findings (14.3%) versus none of the 119 patients with JAK2V617F>5%. This confirms the relatively high frequency of DM in patients with low JAK2V617F burden. In addition, clinical and biological data were gathered on 21 DM patients discovered fortuitously in 4 other French centers. Overall, 47 cases of DM patients (Supporting Information Figure 1) were analyzed, of which 28 harbored a JAK2V617F allele burden equal to or below 1% (60%) while only 2 (5%) had a JAK2V617F allele burden above 5%. Among the 47 DM patients, 40 were diagnosed with ET, 5 with PMF, 1 with PV, and 1 with MDS/MPN-RS-T. Thirty-two patients (68%) presented with JAK2V617F and CALR mutations, 11 (23%) with JAK2V617F and MPL mutations, 2 with CALR and MPL mutations, 1 PV patient had JAK2V617F and JAK2 exon 12 mutations, and 1 patient had an association of two different CALR mutations. In order to know whether a double mutation impacts the clinical presentation or the evolutive course, the 40 DM patients with ET were compared to a control cohort comprising 577 “classical” ET patients from OBENE cohort, NCT02897297. Patients’ characteristics were compared using Fisher exact test for categorical variables as well as Mann and Whitney and Kruskal–Wallis (followed by Dunn tests for multiples comparisons) tests for continuous variables. For multiple tests, P-values were adjusted with Hochberg’s method. Survival estimates were obtained with the Kaplan–Meier method, and statistical analyses were performed with Log-rank test and Cox model. DM-ET patients were more often males (M/F sex ratio 1.4 [23/17] vs. 0.68 [233/344], P 5 .045) and significantly older than control ET patients (median: 72 vs. 61 years old, P< .001), especially compared to JAK2-singly mutated (SM) (63 years old, P 5 .006), CALR-SM (59 years old, P< .001) or triple-negative (56 years old, P< .001) ET patients. For clinical comparisons, the 37 DM-ET patients with a JAK2V617F mutation (29 with JAK2-CALR and 8 with JAK2-MPL) were compared to ageand sex-matched ET patients (Supporting Information Table 1): each CALR-JAK2V617F DM patient was matched with 3 JAK2V617F and 2 CALR; MPL-JAK2V617F DM with 3 JAK2V617F and 1 MPL-SM ET patients. At diagnosis, DM-ET and CALR or MPL-SM matched control patients had similar hemoglobin and platelet counts, but lower hemoglobin and higher platelet counts than JAK2-SM controls (Figure 1A,B). Leukocyte counts of JAK2-CALR DM-ET patients were intermediate between those of CALR and JAK2-mutated controls, without statistically significant difference (Figure 1C). Splenomegaly at diagnosis was observed in 17% (4/24) of JAK2-CALR DM-ET patients and none of the 6 JAK2-MPL DM-ET for whom this data was available. These frequencies were not significantly different from those observed in respective JAK2, CALR, or MPL SM control groups (Supporting Information Table 1). A history of thrombosis before or at diagnosis was found in 3/16 (19%) of JAK2-CALR DM-ET, which is equivalent to the proportion observed in CALR mutated controls (21%), but lower than that in JAK2 mutated controls (41%), without reaching statistical significance (P5 .27). The JAK2V617F allele burden was much lower in DM-ET patients than in matched controls (median 1% vs. 26%, P< .001, Supporting Information Figure 2A). The relatively frequent discovery of low JAK2V617F burdens in DM patients might be explained by a preexisting clonal hematopoiesis of indeterminate potential (CHIP), followed by the acquisition of a second oncogenic event (CALR or MPL mutation) leading to the MPN phenotype. This would be supported by

Sequential analysis of 18 genes in polycythemia vera and essential thrombocythemia reveals an association between mutational status and clinical outcome

Philadelphia‐negative classical myeloproliferative neoplasms (MPN) are clonal diseases characterized by driver mutations of JAK2, MPL, or CALR. Additional mutations may occur in epigenetic regulators, signaling, or splicing genes that may be useful in the prognostic assessment of MPN patients. In primary myelofibrosis, molecular‐based prognostic scoring systems have been recently proposed, but few data are available to date for polycythemia vera (PV) and essential thrombocythemia (ET). In this study, we used a next generation sequencing‐based 18‐gene panel in 50 JAK2V617F positive PV and JAK2V617F positive ET patients from an institutional cohort investigated at diagnosis and at 3‐year follow‐up (3y). Disease progression at 3y was defined by a composite criterion. Patients (28 PV and 22 ET) were included according to their clinical status, with or without disease progression. At diagnosis, we found 28 additional mutations in 21 of the 50 patients. Patients with disease progression were more likely to have at least one additional mutation. There was no difference between PV and ET. All patients with two or more additional mutations exhibited disease progression at 3y. No novel mutations appeared at 3y. The allele burden increase by at least one mutation at 3y was more frequent in patients with disease progression. Our data suggest that screening for additional mutations in PV and ET could identify patients at a higher risk of disease progression.

Symptom burden profile in myelofibrosis patients with thrombocytopenia: Lessons and unmet needs

Myelofibrosis is a myeloproliferative neoplasm associated with progressive cytopenias and high symptom burden. MF patients with thrombocytopenia have poor prognosis but the presence of thrombocytopenia frequently precludes the use of JAK2 inhibitors. In this study, we assessed quality of life and symptom burden in 418 MF patients with (n=89) and without (n=329) thrombocytopenia using prospective data from the MPN-QOL study group database, including the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and Total Symptom Score (MPN10). Thrombocytopenia, defined as platelet count <100×109/L (moderate 51-100×109/L; severe ≤50×109/L), was associated with anemia (76% vs. 45%, p<0.001), leukopenia (29% vs. 11%, p<0.001), and need for red blood cell transfusion (35% vs. 19%, p=0.002). Thrombocytopenic patients had more fatigue, early satiety, inactivity, dizziness, sad mood, cough, night sweats, itching, fever, and weight loss; total symptom scores were also higher (33 vs. 24, p<0.001). Patients with severe thrombocytopenia were more likely to have anemia (86% vs. 67%, p=0.04), leukopenia (40% vs. 20%, p=0.04), and transfusion requirements (51% vs. 20%, p=0.002) but few differences in symptoms when compared to patients with moderate thrombocytopenia. These results suggest that MF patients with thrombocytopenia experience greater symptomatic burden than MF patients without thrombocytopenia and may benefit from additional therapies.