Anagrelide in Essential Thrombocythemia (ET): Results from 150 patients over 25 years by the 'Ph1‐negative Myeloproliferative Neoplasms Latium Group'

Background and aims: Anagrelide is a drug effective in reducing platelet counts in essential thrombocythemia (ET) and Ph1‐negative myeloproliferative neoplasms. The aim of this study was to evaluate the real‐life use of anagrelide in patients with ET followed over 25 years at the Haematological Institutes belonging to "Ph1‐negative Myeloproliferative Neoplasms Latium Group." Patients and methods: Eligibility criteria were diagnosis of ET and treatment with anagrelide. Data were collected through an ad hoc case report form. Results: One hundred and fifty patients received anagrelide for a median time of 7.4 years (0.1‐23.2). Anagrelide was administered as first‐line therapy in 34.7% of patients, as second‐line in 52% and as third‐line in 13.3%: 85.4% responded to therapy. Sixty‐eight/136 evaluable patients reported side effects: palpitations, peripheral vasodilation, anaemia, diarrhoea and gastric distress. Fourteen thrombotic (arterial 10, venous 4) and 51 bleeding events (minor 48, major 3) occurred. Sixteen/150 (10.6%) patients developed secondary myelofibrosis and 3/150 (2%) an acute myeloid leukaemia. Conclusions: In our experience, anagrelide is an effective drug in reducing platelet levels in a high percentage of patients with ET. It is especially addressed to younger people. A careful assessment of the thrombotic risk and monitoring of cardiac function, at diagnosis and during follow‐up, is mandatory.

Keywords: adverse events; anagrelide; essential thrombocythemia; haemorrhage; thrombosis

Essential thrombocythemia (ET) is a Ph1/BCR‐ABL‐negative myeloproliferative neoplasm (Ph1neg‐MPN), with an incidence of 0.01‐2.61/100 000.1 Diagnosis should be made according to the World Health Organization (WHO) criteria and recent modifications2‐5 in order to distinguish true ET from both early primary myelofibrosis (PMF) and "masked" polycythaemia vera (mPV),6 because of differences in prognosis and evolution. Main challenges for the management of this disease are the occurrence of arterial and venous thromboses, vasomotor disturbances, haemorrhagic events, either at diagnosis or during the follow‐up, as well as evolution towards myelofibrosis (MF) and myelodysplastic syndrome/acute leukaemia (MDS/AL).7‐11

While three or four decades ago, almost all patients with diagnosis of ET started treatment immediately after diagnosis, in more recent years, therapeutic approach has been influenced by the risk factors assessment at diagnosis.11‐19 An International Prognostic Score for ET, IPSET, was recently proposed to predict survival in patients with WHO‐defined ET at diagnosis.20 A new prognostic scoring system for thrombosis (IPSET‐thrombosis), taking also into account cardiovascular (CV) risk factors and JAK2V617F (JAK2) mutation, was subsequently developed, revised and validated.21‐23 Since the eighties, hydroxycarbamide has become the drug of choice for the treatment of thrombocytosis and erythrocytosis in ET and PV.17,24‐28 However, other drugs appeared later for ET treatment, such as recombinant interferon‐α (rIFN‐α)29‐32 and anagrelide.17,26,33‐43 Anagrelide hydrochloride is an oral imidazo‐quinazoline compound that is effective in reducing elevated platelet counts in ET and related Ph1 neg‐MPN, by selective inhibition of megakaryocyte maturation in the postmitotic phase. It has been used since 1985 and in 1997 it was approved by FDA for the treatment of ET and of thrombocytosis in Ph1 neg‐MPN. In November 2004, it was licensed by EMA as a platelet‐reducing agent in high‐risk ET patients, intolerant or resistant to other treatments.17,26,33‐43 Some practice guidelines were published concerning therapeutic approach of ET. In 2004, the Italian guidelines17 recommended anagrelide as first‐line therapy for high‐risk patients aged less than 40 years and for those between 40 and 60 without history of thrombosis. Then, the UK guidelines44 recommended hydroxycarbamide plus aspirin as first‐line therapy for high‐risk patients and anagrelide plus aspirin as a reasonable second‐line approach. Recommendations from the European Leukaemia Net published in 2011 and updated in 2018 stated that in high‐risk ET patients anagrelide should be just considered as a second‐line treatment.45,46

The purpose of the present study was to evaluate the real‐life use of anagrelide during the last 25 years in patients with ET followed in the Haematological Institutes of Italian Latium region belonging to the "Ph1 neg‐MPN Latium Group" ("Latium Group").

This is an observational, retrospective, multicentric study that was approved by our IRB (study code: TE ANA 2013, reference number 3054/13‐02‐2014) and by IRB of all participating centres. Primary aim was to describe how anagrelide has been used in the last 25 years for the therapeutic approach of patients with ET at each participating centre. Secondary aims were to evaluate the adherence to the Italian guidelines, published in 2004,17 regarding the prescription of anagrelide in ET; to describe the patients' population; to evaluate the efficacy of anagrelide in reducing platelet count; and to record the occurrence of adverse events and side effects. Complete response (CR) to anagrelide was defined as a decrease of platelet count to less than 400 × 109/L; partial response (PR) as a platelet count of 400‐600 × 109/L. Side effects were monitored during treatment. Patients were evaluated for those drug‐related side effects reported by the Anagrelide study group.33 All adverse events were recorded.

Patients were screened between January and October 2015 in 12 Haematology Institutes of the "Latium Group." Eligibility criteria were diagnosis of ET according to PVSG47 or WHO criteria2‐5 and treatment with anagrelide. An ad hoc case report form (CRF) was sent to all participating centres to collect the patients' data.

Patients' characteristics were summarised by means of cross tabulations for categorical variables or by means of quantiles for continuous variables. In univariate analysis, non‐parametric tests were performed for comparisons between groups (Chi‐squared and Fisher's exact test in case of categorical variables or response rate, Mann‐Whitney and Kruskal‐Wallis test in case of continuous variables). Time to treatment discontinuation was calculated by means of cumulative incidence method, considering inefficacy, adverse events, side effects, death, pregnancy and other causes as competing risks, starting from the date of anagrelide start. Time to evolution to MF or to AL and to occurrence of secondary neoplasia was calculated by means of cumulative incidence method, considering these 3 events as competing risks, starting from the date of diagnosis.

One hundred fifty adult patients (F 101, M 49), who received a diagnosis of ET between January 1981 and January 2012 and treated with anagrelide, are the subjects of this study. They represented 16% of 938 patients with ET who needed treatment, diagnosed and followed in 12 Haematology Institutes of the "Latium Group" in the same time period.

Median age at diagnosis was 42.7 years (20.9‐87.7). Out of 150 patients, the diagnosis was performed in 83 (56%) according to PVSG criteria47 and in 65 to WHO criteria (44%)2‐5; in 2 patients, the datum was unknown. All patients underwent bone marrow biopsy at diagnosis. Patients' characteristics are summarised in Table 1. They started anagrelide between July 1989 and January 2014:56/150 (37.3%) before and 94/150 (62.7%) after the licence of the drug by EMA. At anagrelide start, median patients' age was 45.9 (22.7‐87.8), median platelet number 797x109/L (186‐2390). Spleen enlargement was present in 41/138 evaluable subjects (29.7%); 117/149 evaluable patients (78.5%) were taking anti‐platelet therapy.

1 TablePatient characteristics

1 Abbreviations: Hb, haemoglobin; Plts, platelets; WBC, white blood cells.

• 2 a JAK2 mutation absent;
• 3 b JAK2 and CALR mutations absent.

Anagrelide was prescribed as first‐line therapy in 52 patients (34.7%), as second‐line in 78 (52%) and as third‐line in 20 (13.3%), respectively. The reasons for the choice of anagrelide as first‐line therapy were platelet count >1000 × 109/L in 39 patients aged <60 years (75%); previous thrombotic events in 5 aged <60 (9.6%); platelet count between 800 and 1000 × 109/L in 5 patients aged <60 (9.6%), who had been included in a pre‐registration study (years 1989‐1996); microvascular symptoms resistant to anti‐platelet therapy in 1 patient aged <60 (1.9%); and refusal of hydroxycarbamide in 2 patients aged >60 (3.9%). Previous thrombotic events were arterial thromboses in 4 cases and venous thrombosis in another one. In 78 patients, the reasons for starting anagrelide as second‐line therapy, after the switch from a previous drug, were intolerance to first‐line treatment in 45 (57.7%), inefficacy in 23 (29.5%) and age < 60 years in 10 (12.8%). In 20 patients, the reasons for using anagrelide as third‐line therapy were inefficacy in 9 (45%), intolerance to second‐line treatment in 6 (30%) and age < 60 years in 5 (25%). In Table 2, the drugs administered before the switch are reported: hydroxycarbamide had been previously given in most cases [69/98 (70.4%)]. In Table 3, the relation between patients' age and therapy lines is described. Overall, 112/150 of treated patients (74.7%) were aged less than 60 years: of these, 50 received anagrelide as first‐line therapy, 45 as second‐line and 17 as third‐line, respectively. Fifty‐six/150 patients (37.3%) received anagrelide before the publication of the Italian Guidelines in 200417 and 94/150 (62.7%) subsequently. In particular, before 2004, anagrelide was given as first‐line therapy in 30/56 (53.6%) patients and in 26/56 (46.4%) as second‐ or third‐line, respectively; after 2004, it was administered as front‐line therapy in 22/94 (23.4%) and as second‐ or third‐line in 72/94 (76.6%), respectively. This difference resulted statistically significant (P.0002).

2 TableDrugs used before switching to anagrelide

3 TableAge at anagrelide start

The patients received anagrelide for a median time of 7.4 years (0.1‐23.2). Overall, 123/144 evaluable patients (85.4%) responded to anagrelide: 55 (38.2%) achieved a CR and 68 (47.2%) a PR. Twenty‐one (14.6%) did not obtain any response. During follow‐up, among 117 evaluable responding patients, response was maintained for more than 50% of the treatment period by 45 (38.5%) with a platelet count <400 × 109/L (RC) and by 67 (57.3%) with a platelet count ranging between 400 × 109/L and 600 × 109/L (RP). Five patients (4.3%) lost the response. Median follow‐up of responding patients was 12.7 years (range 3.1‐33.7). In responding patients, median daily anagrelide dose at response and during follow‐up was 1.5 mg in both cases (0.5‐5 and 0.35‐3.5 mg, respectively). Median follow‐up from the diagnosis to the last available control was 12.5 years (0.6‐33.7).

During treatment, 136/150 patients were evaluable for the occurrence of one or more side effects possibly related to anagrelide. Sixty‐eight/136 (50%) patients did not show any side effect, while in the other 68 the following side effects were recorded: palpitations in 55 cases, peripheral vasodilation in 12, anaemia in 10, diarrhoea in 5 and gastric distress in 5. Anaemia was defined as haemoglobin level <120 g/L and at least a decrease of 100 g/L from the baseline haemoglobin level since anagrelide start, with the exclusion of other causes of anaemia. In Table 4, characteristics of patients, who developed anaemia, are described. In 6/10 patients, anaemia occurred within 1 year since anagrelide start. Median anagrelide daily dose at the event was 1.75 mg (1‐2.5). The patient number 7 had been previously treated with hydroxycarbamide; 8/10 patients reduced the daily dose and then 3/8 discontinued anagrelide. Patient number 3 showed a subsequent evolution towards MF.

4 TableAnaemia occurrence

• 4 Abbreviation: Hb, haemoglobin.
• 5 a Patients 3, 5 and 10, firstly reduced anagrelide dose, then stopped therapy;
• 6 b previous treatment with hydroxyurea.

In 14/148 (9.5%) evaluable patients, 14 thrombotic events occurred during anagrelide therapy: arterial 10 (6.8%) (acute myocardial infarction 8, cerebral arterial thrombosis 2, [major events 10]) and venous 4 (2.7%) (deep vein thromboses 2, superficial venous thromboses 2 [major events 2]). Characteristics of these patients are reported in Table 5. Anagrelide was being administered as first‐line therapy in 3, as second‐line in 10 and as third‐line in one. At thrombotic event, median anagrelide daily dose was 1.5 mg (0.7‐2.25), median platelet number 437 × 109/L (207‐1080), median white blood cells count 8 × 109/L (3‐29) and median haemoglobin level 122 g/L (108‐130). Five/14 patients discontinued anagrelide after thrombosis. We analysed the IPSET‐thrombosis21 and the revised IPSET thrombosis22 in 12 evaluable patients: the results are showed in Table 5. Five were at low risk (0‐1), 3 at intermediate (2) and 4 at high risk (≥3).21 Moreover, applying the revised thrombotic risk stratification scheme,22 which identifies four categories (very low, low, intermediate and high risk), the patients were categorised as follows: 3 very low risk, 4 low, 3 intermediate and 2 high risk (Table 5). In 51/143 (35.7%) evaluable patients, 51 bleeding events occurred: minor 48 (33.6%) and major 3 (2.1%). These latter were haematuria (1) and gastrointestinal haemorrhages (2). At the event, median platelet count was 493 × 109/L (213‐792), median white blood cells count 9.14 × 109/L (5.6‐32.9) and median haemoglobin level 125 g/L (9.1‐14.6). Median anagrelide daily dose at bleeding event was 1.9 mg (1‐3.5). No patient discontinued anagrelide permanently, while ongoing anti‐platelet therapy was suspended at the time of the event.

5 TableThrombotic events and patients' characteristics

7 Abbreviations: AMI, acute myocardial infarction; DVT, deep venous thrombosis; HR, high risk; IR, intermediate risk; LR, low risk; na, not available; SVT, superficial vein thrombosis; VLR, very low risk.

Sixteen/150 (10.6%) patients developed a secondary MF at a median age of 55.6 years (35.6‐77.7): diagnosis of ET had been performed according to PVSG and WHO criteria in 8 and in 7 patients, respectively, while in 1 patient the datum was not reported. Median time from diagnosis and from anagrelide start was 9.1 years (5.3‐18) and 5.7 years (1.7‐13.8), respectively. Seven patients were JAK2‐positive, 7 JAK2‐negative, and one of these latter showed CALR mutation. Two patients were not screened for mutations. Median platelet count at the event was 836 × 109/L (231‐1536). Two patients were receiving anagrelide as first‐line therapy, 9 as second‐line and 5 as third‐line, respectively. In these latter 14 patients, hydroxycarbamide, pipobroman and rIFN‐α had been given before anagrelide start. The two patients treated with anagrelide as first‐line therapy were diagnosed with secondary MF when they were 35.7 and 42.5 years old, respectively; MF occurred at 6.0 and 7.2 years from diagnosis and at 5.9 and 6.4 from anagrelide start. Overall, 9/16 (56.3%) patients discontinued the drug permanently. Three/150 (2%) patients developed an acute myeloid leukaemia at a median age of 70.5 years (64.8‐76.1). Median time from diagnosis and from anagrelide start was 11.2 (10.3‐25.6) and 2.9 years (0.9‐4.6), respectively. They suspended anagrelide at AL occurrence. These 3 patients were taking anagrelide as second‐line therapy and had been previously treated with hydroxycarbamide. In 12/150 (8%), a secondary malignancy, other than MDS/AL, occurred at a median age of 53.9 years (40.8‐78.2). Median time from diagnosis and from anagrelide start was 8.4 (0.6‐23.6) and 3.1 years (0.9‐19.1), respectively. Three patients were receiving anagrelide as first‐line therapy, 5 as second‐line and 4 as third‐line. In these latter 9 patients, hydroxycarbamide, pipobroman and rIFN‐α had been used before anagrelide start. Secondary neoplasms were non‐Hodgkin lymphoma 2, colon carcinoma 1, breast cancer 2, thyroid carcinoma 4, prostate cancer 2 and unspecified type 1. Five/12 patients had discontinued anagrelide before the occurrence of malignancy. One patient suspended the drug at malignancy diagnosis, and two discontinued for inefficacy; afterwards, four remained on anagrelide treatment.

Seven pregnancies occurred in 6 women during anagrelide treatment. Median patients' age at diagnosis was 27.6 years (22.4‐32.8) and at pregnancy start 35.2 (26.5‐40.8), respectively. They had been taking anagrelide for a median period of 5.2 years (1.1‐12.9). The outcome of the 7 pregnancies was as follows: 3 voluntary abortions, 1 first trimester spontaneous abortion and 3 at term deliveries with the birth of normal babies. In the case of spontaneous or voluntary abortions, anagrelide was not discontinued. In the 3 cases of successful pregnancies, anagrelide was suspended at the 4th, 8th and 9th weeks, respectively, before switching to rIFN‐α treatment.

Overall, 12/150 patients (8%) died, at a median age of 78.2 years (56.2‐92.0) and at a median time from diagnosis and from anagrelide start of 10.3 (4.3‐23.5) and 4.7 years (1.4‐23), respectively. In 6/12 patients, the causes of death are known: acute myeloid leukaemia 3, pneumonia in secondary MF 1, acute renal failure 1 and bowel obstruction 1.

In this paper, we describe the "Latium Group's" experience regarding treatment with anagrelide in 150 patients with ET, who started therapy between July 1989 and January 2014. Before EMA licence in 2004, the treatment with anagrelide was allowed in the frame of clinical trials only or for compassionate use: in fact, most of our patients (62.7%) started the drug from 2004 onwards. It is relevant that median patients' age at diagnosis and at anagrelide start was 42.7 and 45.9 years, respectively, which may be considered a young age (Table 1). The occurrence of thrombo‐haemorrhagic complications and vasomotor disturbances is the main challenge in the management of ET and, in the late follow‐up, evolution towards MF and AL may strongly affect morbidity and mortality.7,9‐11 Cytoreductive therapy in ET is aimed at reducing morbidity and mortality related to thrombotic and haemorrhagic events, but the risks and benefits of each therapeutic agent should be evaluated according to patients' characteristics: age, platelet levels, ET‐related symptoms, past and present major events. Therefore, a balance between the reduction of thrombo‐haemorrhagic risk and the hazard of MDS/AL, MF evolution or secondary neoplasia occurrence should be pursued in the choice of the best therapeutic approach. Anagrelide, due to its intrinsic characteristics, was initially considered a non‐leukaemogenic drug and, accordingly, a very promising tool for the treatment of ET. However, in 2005, the randomised "PT‐1 study" from Harrison et al26 stated that hydroxycarbamide plus low‐dose aspirin had to be considered superior to anagrelide plus low‐dose aspirin in high‐risk ET patients, because of a lower incidence of arterial thrombosis, bleeding events and MF evolution. Thus, a warning arose regarding the use of anagrelide in high‐risk patients and, at the same time, there was the doubt that this drug was not effective enough to prevent arterial thrombosis or bleeding. Although these results were not confirmed by a subsequent randomised clinical trial, including previously untreated ET patients diagnosed according to WHO criteria,41 nevertheless the conclusions of "PT‐1 study" influenced greatly the therapeutic approach of ET. In 2004, the Italian guidelines recommended anagrelide as front‐line treatment for high‐risk ET patients aged less than 40 years or between 40 and 60 without previous thrombosis.17 The UK guidelines44 and the recommendations of the European Leukaemia Net45,46 considered anagrelide only as a second‐line treatment. Therefore, we believe that the above‐mentioned guidelines and the EMA's indication have influenced the prescription modality of anagrelide. In our study, indeed, anagrelide was used as first‐line therapy only in 52/150 patients, but 96.1% of them were under 60 years, and 53.8% under 40 (Table 3). Ninety‐eight patients received anagrelide as second‐ or third‐line therapy after a switch from another drug (Table 3). Interestingly, hydroxycarbamide, alone or given sequentially with other drugs, had been previously administered in over 70% of cases (Table 2). The reasons for the switch were mostly intolerance and inefficacy; however, in 15.3% of patients the switch was justified by an age under 60. Therefore, anagrelide was considered by the clinicians a useful therapeutic tool after intolerance or inefficacy of other medications. We want to emphasise that young age was a relevant driver in the choice of anagrelide, because in the whole population 75% of patients were under 60 years and 36% under 40 (Table 3). Moreover, we noted that before 2004, 30/56 patients (53.6%) had received anagrelide as first‐line therapy in comparison with only 22/94 (23.4%) treated after 2004. On the contrary, from 2004 onwards, most patients, 72/94 (76.6%), received anagrelide as second‐ or third‐line approach versus only 26/56 (46.4%) treated before 2004: this difference was statistically significant (P 0.0002). Regarding our data concerning the preferential use of anagrelide in young people, we noted that similar results have been reported in the recent publication of the large observational "EXELS" study, in which, indeed, median age (55.5 years) of patients receiving anagrelide alone was lower in comparison with that of the groups treated with other cytoreductive drugs (70.0 years) or with anagrelide plus cytoreductive therapy (59.0 years).43 We underline that in our study median follow‐up from diagnosis to the last available control was quite long (12.5 years) and that the median duration of treatment was considerable (7.4 years). More than 85% of treated patients achieved a response and about 96% of the evaluable responding patients maintained the response for more than 50% of the treatment period. So, we recorded a high response rate and a good persistent response, while the percentage of unresponsive (14.6%) and relapsed patients (4.3%) did not reach 20%. These results are consistent with those reported by the literature.26,33‐43 Moreover, in responding patients, median daily dose of anagrelide at response and during follow‐up was rather low (1.5 mg). As regards to side effects, mild/moderate anaemia occurred in 7.3% of the evaluable patients and in 6/10 cases within 1 year from therapy start (Table 4): therefore, it did not appear to be a late event. On the contrary, in many publications occurrence of anaemia was recorded as a late event, in a rate of 2%‐50%.33,35,37,38,40 We believe that the anaemia must be carefully evaluated, because it could be a symptom of an evolution towards MF or a sign of an underlying pathological condition. During follow‐up, in 9.5% of the evaluable patients 14 thromboses occurred. Median age at the event was about 60 years and most patients (11/14) were receiving anagrelide as second‐ or third‐line therapy, but only one had experienced a previous thrombosis. Major arterial and major venous events were 8.1% that is a rate comparable to that reported by the "PT‐1" (6.7%) and the "ANAHYDRET" (7.4%) studies. In our cases, we confirmed the different incidence rate between major venous and major arterial events, although the reason of this remains unknown.26,41 It is noteworthy that cerebral arterial thromboses occurred in the two patients identified as high risk with both the IPSET thrombosis21 and the revised IPSET thrombosis22 (Table 5). The most frequent thrombotic event was myocardial infarction (8/14) that occurred in 4 patients rather early (≤1 year) from anagrelide start: at diagnosis 7/8 were aged <60 years and only in 2 CV risk factors were present, but at the event only one of these had just exceeded 60 years (Table 5). In view of these considerations, we highlight that the inotropic effect of anagrelide should be considered and that a careful monitoring of cardiac function at the beginning and during follow‐up must be performed. Major bleeding events occurred only in 3 of the evaluable patients (2.1%), but in no case platelet levels exceeded 1000 × 109/L, while median anagrelide daily dose was rather high (1.9 mg). This rate is lower than those reported in the "PT‐1" and in the "ANAHYDRET" studies, in which bleeding rate was 5.4% and 4.1%, respectively.26,41 Moreover, the "EXELS" study underlined a higher incidence of haemorrhagic events in patients treated with anagrelide versus other "cytoreductive therapy groups": the authors emphasised the need of a cautious use of anti‐platelet drugs in combination with anagrelide.43 During follow‐up, 16 patients (10.6%, median age 55.6 years) showed a progression towards MF. Interestingly, only 2 patients were receiving anagrelide as first‐line therapy, while the other 14 had been previously treated with other drugs. Only 3 patients (2%) developed an acute myeloid leukaemia at a median time from diagnosis of 11.2 years. Their median age was rather old (70.5 years) and they were taking anagrelide as a second‐line therapy, after a previous treatment with hydroxycarbamide. This finding seems to confirm a low leukaemic evolution rate in patients affected by ET, even in the late follow‐up8,10 and the absence of leukaemogenic potential of anagrelide.48 Twelve patients (8%, median age 53.9 years) developed a secondary malignancy, other than MDS/AL. Only 3 patients were receiving anagrelide as first‐line therapy. There is a debate about the influence of cytoreductive therapy on the occurrence of a second neoplasm in Ph1neg‐MPN. A recent publication has demonstrated that different cytoreductive treatments do not have a statistically significant influence on secondary malignancy development.49 Regarding the 7 pregnancies occurred during anagrelide treatment, in the 3 cases that resulted in successful deliveries of healthy babies, anagrelide was discontinued and treatment with rIFN‐α was started and carried on. This outcome is noteworthy, because very few similar cases have been described in the literature.50

In summary, anagrelide seems to be an effective drug in reducing platelet levels in patients with ET in a high percentage of cases. In real‐life medical practice, it appears to be particularly suitable for younger people. Side effects are not irrelevant, but not always such as to induce the drug withdrawal. A careful assessment of thrombotic risk and monitoring of cardiac function should be performed in all patients, including young people, at diagnosis and during follow‐up.