Abstract
The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) is a validated quality of life (QoL) instrument. In our Swedish cohort of 114 patients the symptomatic burden was found to ...be severe, with fatigue reported in 88% of the patients and reduced QoL in the majority of patients. Patients with primary myelofibrosis had the highest scores, low QoL, for most MPN-SAF items, compared to patients with polycythemia vera and essential thrombocythemia. Higher age showed significant associations with the BFI (Brief Fatigue Inventory) score, early satiety, concentration problems, dizziness, insomnia, cough and weight loss. Blood values, disease duration and myelosuppressive treatment did not significantly associate with any of the MPN-SAF items, with the exception of higher hemoglobin, which correlated with sad mood. Male patients with MPN scored significantly higher as regards sexual problems and weight loss compared to female patients. Overall, the MPN-SAF was found to be a valid instrument for assessing symptomatic burden among this population.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Myeloproliferative neoplasms (MPN) are most common in old people (>60 years) and are rarely identified in children and young adults where information about complication rates and long-term data are ...lacking. To improve our knowledge, we retrospectively collected cases of young patients diagnosed with MPN before 25 years of age and analysed data of their disease to date, including vascular events and disease evolution.
Data were collected in 29 hospital centres from 12 countries. Between 1971 and 2018, 335 young patients were diagnosed for an MPN before the age of 25. They were mostly females (n=246; 73.4%) with a median age of 20.3 years at diagnosis (2.5 months-25 years). Essential thrombocythemia was diagnosed in 234 patients (69.8%), polycythemia vera in 60 (17.9%) and myelofibrosis or unclassified MPN in 41 (12.3%).
Most of the diagnoses were made following a coincidental blood count analysis (n=75; 51%) some based on symptoms (n=57; 38.8%) or thrombotic events (n=15; 10.2%). In terms of complications before or at diagnosis, 31 (9.3%) patients experienced thrombosis, mostly venous (75%) and 13 (3.9%) had hemorrhage. At diagnosis, the median leukocyte count was 9x109/l (range: 3-22.8), median hemoglobin count 140 g/l (65-220) and median platelet count 900x109/l (99-3290). To assess the diagnosis, 158 patients (47.2%) had had bone marrow aspirates and 214 (63.9%) a bone marrow biopsy. Mutational status was available in 319 (90%) cases: 194 (60.8%) were JAK2V617F positive, 48 (15%) had a calreticulin mutation, 76 (23.8%) were triple-negative and 1 patient had MPL mutation.
The median follow-up of the cohort was 7.7 years (0-46.8) with 134 patients (40%) having follow-up for more than 10 years. 81 female patients (32.9%) experienced pregnancies. During this period, 295 patients (88%) received at least one drug for their MPN: 254 patients (77.2%) received antithrombotic drug and 222 patients (66.5%) a cytoreductive drug. As first line of treatment, hydroxycarbamide was given to 111 patients (50%) whereas anagrelide was given to 56 patients (25.2%) and interferon to 50 (22.5%).
During the follow-up, 97 patients (29%) experienced at least one complication. In terms of cardiovascular events, 38 (11.3%) patients experienced thromboses with 50 events in total (recurrences in 12 cases), including 33 venous events (66%) of which 15 were localized in the splanchnic territory (45.5%). Hemorrhagic events were recorded in 34 cases (10.1%). During the follow-up, 39 patients (11.6%) have evolved: 11 from ET to PV (28.2%), 26 into MF (66.7%) and 2 into AML (5.1%). All evolutions were exclusive: one event per patient. At the time of the analysis, 66 patients (19.7%) were declared as lost of follow up and 4 were dead (1.2%).
This is the largest cohort of patients aged below 25 years at the time of diagnosis demonstrates that despite their youth most of them (88%) received drug(s) for the management of their MPN. There was a high incidence of complications (29%), with vascular events and disease evolution occurring at equal frequency although death was uncommon (1.2%). Rates of events were disease evolution: 1.51/100pts/y; thromboses: 1.47 and hemorrhages: 1.32. No specific national or international guidance exists for MPN patients of this age; but our data suggest that these are not benign conditions and patients need to be carefully followed and treated.
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Kiladjian:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Giraudier:Novartis: Research Funding. Griesshammer:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria.
Conventional interferon-alpha (IFN) is an effective treatment for patients with myeloproliferative disorders. However, many patients discontinue therapy because of side effects.
In this 24-month, ...Phase II feasibility study of pegylated interferon alpha-2b (PEG-IFN) treatment, a starting dose of 0.5 microg/kg per week was received by 21 patients with polycythemia vera (PV) and 21 patients with essential thrombocythemia (ET). The treatment objective, a complete platelet response (CR), was a platelet count<400x10(9)/L in symptomatic patients and <600 in asymptomatic patients. Neutrophil polycythemia rubra vera-1 (PRV-1) messenger RNA expression was analyzed prior to and during therapy. Quality of life (QoL) was investigated by using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire.
At 6 months, 29 of 42 patients (69%) had achieved a CR after a median of 83 days. The CR rate was not related to diagnosis, gender, or previous therapy. Nineteen patients completed the planned 2-year treatment in CR. No thromboembolic or bleeding complications were observed. Phlebotomy requirements were reduced in the majority of patients with PV. Five of 14 patients (36%) who initially were positive for PRV-1 achieved normalized PRV-1 expression under PEG-IFN treatment. Side effects were the cause of therapy failure in 16 of 23 patients. However, only 8 of 19 patients reported any side effects at 2 years. The QLQ-C30 revealed clinically significant impairments in several aspects of QoL at 6 months; however, at 2 years, QoL measurements were not different from baseline.
PEG-IFN effectively reduced platelet counts in 29 of 42 patients, but only 19 patients maintained a CR at 2 years. The reversal of PRV-1 positivity noted in a subset of patients suggested that PEG-IFN may have an effect on the malignant clone. PEG-IFN is a valuable therapeutic alternative for patients who tolerate its initial side effects.
Abstract
Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 ...countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year pt/y), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age < 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN.
Background
In myeloproliferative neoplasms (MPN), Interferon-α (IFN-α) has been shown effective in inducing hematologic and molecular responses and in reducing vascular events. In clinical practice ...its use is mainly limited by intolerance due to side effects.
Aim
We sought to evaluate the tolerability of IFN-α therapy, the thromboembolic incidence and the causes of termination of therapy in a cohort of MPN, treated outside of clinical trials.
Methods
One hundred patients (M/F 41/59, median age 48 years, range 15-73) with a diagnosis of polycythemia vera (PV, n=47), essential thrombocythemia (ET, n=43) and myelofibrosis (MF, n=10) according to the WHO 2008 criteria, on current or previous treatment with IFN-α (IFN-α-2b, Peg-IFN-α-2b, Peg-IFN-α-2a) were included. The patients, diagnosed 1987-2012, were recruited from 9 centers in Sweden and Norway, and retrospectively analyzed. Hematologic response in PV and ET was assessed according to ELN criteria from 2009. Response to treatment in MF was defined as platelets ² 400x109 /L, white blood counts ² 10x109/L and transfusion independency.
Results
IFN-α treatment characteristics are displayed in Table 1. The median treatment duration for IFN-α was 34 months. Treatment prior to IFN-α had been received by 44 pts including hydroxyurea (n=34), anagrelide (n=19), busulphan (n=2), radioactive phosphorus (n=1), 10 pts having received more than one cytoreductive agent. Complete hematologic response (CR) was observed in 58 pts (PV=28/47, ET=30/43) and partial hematologic response (PR) in 15 pts (PV=2, ET=13). In MF, hematologic response was noted in 8 out of 10 patients. IFN-α related adverse events (AE) were recorded in 76 pts (76/100, 76%) with similar rates between genders (M 30/41, 73%, F 45/59, 76%). AE were generally of low grade. Twenty pts experienced multiple (³ 3) side effects (M/F 6/14), females reporting a total of 96 AE compared to 53 in males. Hematologic toxicity was low with 4 pts presenting with anemia, 4 with leukopenia and 3 with thrombocytopenia. Most common non-hematologic toxicities were fatigue in 30 pts (M/F 11/19), myalgia in 28 (M/F 11/17) and depression in 21 (M/F 4/17), followed by liver function test elevation (n=9), headache (n=9), alopecia (n=8) and skin reaction (n=7). In two pts with autoimmune co-morbidities (rheumatoid arthritis, psoriasis), flare-up of symptoms related to autoimmune activity were seen, leading to discontinuation of therapy. Only one vascular event occurred in a 64 year old woman with PV, in CR since 92 months, who developed a myocardial infarction after 94 months of IFN-α-2b treatment. A total of 43 pts (M 16/41, 39%, F 27/59, 46%) discontinued therapy, of whom 34 (M 13/41, 32%, F 21/59, 36%) due to side effects. The most common cause of discontinuation of therapy due to side effects was depression (15/21), followed by fatigue (12/30) and myalgia (9/28). Nineteen (19/34, 58%) of the pts who discontinued therapy due to side effects were in CR. Discontinuation due to other reasons than side effects were lack of efficacy/progression of disease (n=5), co-morbidities (n=2), CR including molecular response (n=2) and pregnancy (n=1). Out of the 53 pts with ET and MF, 25 were JAK2V617F mutated and 14 had a CALR-mutation. No significant differences between these two groups were seen regarding side effects or discontinuation rate. Out of the 57 pts remaining on IFN-α, 19 still received IFN-α-2b (19/35, 54%), 7 PegIFN-α-2b (7/12, 58%) and 31 PegIFN-α-2a (31/53, 58%).
Conclusion
In this retrospective cohort study, the treatment discontinuation rate due to side effects was higher than in previous reports. This may be explained by the relatively long median duration of treatment in this cohort, reflecting a poor tolerance of low-grade toxicity over time. Depression was frequent and the most common reported side effect when therapy was discontinued. Gender difference, with females reporting a higher incidence of depression and a larger total burden of AE, was noted. The frequency of thromboembolic events was very low in this IFN-α treated cohort.
Table 1IFN-α treatment characteristics.Type of InterferonPatiens (n)Dose per week–median (range)Treatment time-medianIFN α-2b359 MIE (1,2-20)58PegIFN α-2b1240 μg (30-80)46PegIFN α-2a5390 μg (30-135)15
No relevant conflicts of interest to declare.
Abstract 5055
To retrospectively assess hematological response rates, and other clinical and molecular variables, in MPN patients treated with pegylated interferon α-2a (Pegasys®, Roche Ltd). ...Responses were graded according to criteria published by the European Leukemia Net for PV and ET (Barosi G et al Blood 2009;113:4829), with the exception that mesurement of spleen size using ultrasound was not routinely performed, and the European Myelofibrosis Network for PMF (Barosi G et al Blood 2005;106:2849), respectively.
The 23 patient cohort consisted of 13 PV, 5 ET, 3 PMF and 2 post-ET/PV MF pts. Thirteen pts were JAK2V617F+, 6 were JAK2V617F wt, and in 4 pts JAK2 status is unknown. Median age was 50 years (range 26–69), 13 were female and 10 male. Median time from MPN diagnosis to start of pegylated interferon α-2a (Peg-IFN) therapy was 67 months (range 0–204). Six pts had a previous thrombotic event (TIA=2, portal vein thrombosis=2, DVT lower extremity=2), and 2 pts had a previous major hemorrhage (gynecological=1, gastrointestinal=1). Eleven pts had previously received therapy with anagrelide (n=8), hydroxyurea (n=4), interferon α-2b (n=1), busulfan (n=1) or P32 (n=1), while 12 pts had not received bone marrow suppressive therapy. All PV and ET pts were on aspirin. Phlebotomies were performed in PV with the aim of keeping the hematocrit < 0.45. Peg-IFN was given at a dose of 90 μg/week in 16 pts, 135μg/week in 6, and 180μg/week in 1.
The overall hematological response rate (CR+PR) was 18/21 (86 %), 14 pts achieving CR and 4 PR. Two pts are too early to evaluate at the time of astract submission. One PV and 1 PMF patient were non-responders. Resonse rates were similar in PV vs ET, female vs male pts, and previously treated vs previously untreated pts. Median time of follow-up on Peg-IFN therapy is 16 months (3+ - 49+). Thirteen pts are still on therapy, 9 in CR, 2 in PR, and 2 too early to evaluate. These 13 pts have very limited or no side effects. Therapy has also been stopped according to plan after long hematological CR with molecular response in 2 pts. Therapy has been discontinued in 8 pts, in five (22 %) due to side effects (depression n=3, joint pain n=3, hair loss n=2, pruritus n=1), non-response in 2 pts, and PMF progression in 1. Serial JAK2V617F measurements are available at time of abstract submission in 4 pts, 1 achieved molecular CR, 2 PR whereas 1 patient treated for 5 months had no molecular response. Three of 4 mildly anemic MF pts normalized their hemoglobin (HgB 113 → 137, 106 → 123, and 110 → 125 respectively). In one PMF patent a clear reduction of marrow fibrosis was noted, whereas it progressed in another. No thromboembolic or bleeding complications were observed during PEG-IFN therapy. Longer follow-up, as well as additional molecular and morphological studies will be presented.
Pegylated interferon α-2a induced a higher hematological response rate with improved tolerability, compared to our previous experience with Peg-IFN α-2b (Samuelsson et al Cancer 2006;106:2397), although the current number of patients is limited. However, the two previous publications that describes Peg-IFN α-2a therapy in larger MPN patients cohorts have observed results similar to ours (Kiladjian JJ et al Blood. 2008;112:3065, Quintás-Cardama A et al J Clin Oncol. 2009;27:5418). Molecular responses noted in a subset of patients further highlights the effect of Peg-IFN α-2a on the malignant clone in MPN:s. Peg-IFN α-2a is a valuable therapeutic alternative in patients who tolerate initial side effects, and will soon be compared to hydroxyurea in a randomized trial in high-risk PV and ET pts performed by the MPD research consortium.
Samuelsson:Roche Sweden: Advisory board on use of recombinant erytropoetin. Off Label Use: Alpha-interferon does not have a label for use in myeloproliferative neoplasms. Merup:Roche Sweden: Received honoraria for lectures on rituximab use in lymphoma.
Early erythroblasts from patients with refractory anemia (RA) and RA with ringed sideroblasts (RARS) show constitutive mitochondrial release of cytochrome c. Moreover, mature erythroblasts in RARS, ...but not in RA, display aberrant accumulation of mitochondrial ferritin (MtF). We analyzed cytochrome c release, MtF expression, and gene expression during erythroid differentiation in bone marrow cells from myelodysplastic syndrome (MDS) patients and healthy controls. Whereas none or few cultured erythroid cells from healthy individuals and RA patients expressed MtF, those from RARS patients showed MtF expression at an early stage, when cells were CD34+ and without morphologic signs of erythroid differentiation. The proportion of RARS erythroblasts that were MtF+ increased further upon in vitro maturation. Moreover, a significant overexpression of mRNA encoding cytochrome c, and proapoptotic Bid and Bax, was seen in freshly isolated cells from MDS patients. Genes involved in erythroid differentiation were also dysregulated in MDS cells. Importantly, GATA-1 expression increased during normal erythroid maturation, but remained low in MDS cultures, indicating a block of erythroid maturation at the transcriptional level. In conclusion, aberrant MtF expression in RARS erythroblasts occurs at a very early stage of erythroid differentiation and is paralleled by an up-regulation of genes involved in this process.
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