# JAK2 V617F polycythemia vera and essential thrombocythemia: dynamic clinical features associated with long-term outcomes

Léa Sureau, Caroline Buors, Jean-Christophe Ianotto, François Constant

Boyer, Aline Tanguy-Schmidt, Lydia Roy, Emilie Cayssials, Laura Cailly, Jean-Claude Chomel, Aurelie Chauveau, et al.

► To cite this version:

Léa Sureau, Caroline Buors, Jean-Christophe Ianotto, François Constant Boyer, Aline Tanguy-Schmidt, et al. JAK2 V617F polycythemia vera and essential thrombocythemia: dynamic clinical features associated with long-term outcomes. Blood Cancer Journal, 2022, 12 (4), pp.56. 10.1038/s41408-022-00646-0. hal-03665167

HAL Id: hal-03665167

https://hal.science/hal-03665167

Submitted on 11 May 2022

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
**CORRESPONDENCE**

**OPEN**

# JAK2 V617F polycythemia vera and essential thrombocythemia: dynamic clinical features associated with long-term outcomes

© The Author(s) 2022

<figure><img src="image_2.png" /></figure>

Check for updates

*Blood Cancer Journal* (2022)12:56; https://doi.org/10.1038/s41408-022-00646-0

**Dear Editor,**

Myeloproliferative neoplasms (MPN) are acquired clonal hema-topoietic stem cell disorders characterized by abnormal prolifera-tion leading to accumulation of mature blood cells. They comprise polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). A somatic JAK2V617F mutation is found in almost all cases of PV and ~60% of ET and PMF resulting in the constitutive activation of JAK-STAT pathway. PV and ET are the most indolent MPN with a median survival over 10 and 15 years, respectively [1]. Nevertheless, overall survival is reduced by two major complications: an increased risk of both thrombosis and hemorrhage and, in the long-term, a risk of evolution to myelofibrosis (MF) or accelerated phase (myelodysplastic syn-drome (MDS) or acute myeloid leukemia (AML)). Prognostic classifications in ET and PV are based on characteristics at diagnosis: age, leukocyte count, history of thrombosis, and the presence of JAK2V617F [2–4]. However, no dynamic prognostic systems have been proposed for these chronic diseases followed for decades.

In the present work, we aimed to evaluate the prognostic relevance of defining an early clinical worsening at 3 years of follow-up in a cohort of JAK2V617F-mutated ET or PV patients. For this purpose, we analyzed data from the prospective JAKSUIVI study that was conducted from 2007 to 2013 in six French University Hospitals. In this study, 191 JAK2V617F-positive PV or ET patients were enrolled at the time of diagnosis and the worsening status was defined after 3 years of follow-up by at least one of the following criteria: (i) leukocytosis >12 G/L or presence of immature granulocytes >2% or erythroblasts >1%; (ii) anemia (hemoglobin <12 g/dL in a woman or <13 g/dL in man) not related to treatment toxicity; (iii) thrombocytopenia (platelet count <150 G/L) not related to treatment toxicity; (iv) onset of splenomegaly or progression of pre-existing splenomegaly; (v) thrombocytosis despite cytoreductive therapy. The working hypothesis of JAKSUIVI study was to test at 3 years of follow-up, a possible association between JAK2V617F allele burden evolution and clinical worsening (Supplemental Table S1). Herein, we report the long-term prognostic impact of this worsening criterion with a median cohort follow-up of 10 years (Fig. 1A).

After 3 years of follow-up, 58/191 (30.4%) patients met worsening criteria (W+) with a similar proportion between PV and ET (Table 1). For 48/58 (82.8%) of these patients, only one criterion for W+ definition was present, the most common being persistent thrombocytosis despite hydroxyurea therapy present in 40 patients (18 PV and 22 ET patients) (Fig. 1B). The main reasons for the 51 deaths observed in the cohort were: other neoplasms (13.7%), thrombosis (9.8%), cardiac failure (9.8%), secondary AML

(9.8%), infection (5.9%). These data were missing for 37.3% of patients. Kaplan-Meier analysis showed that W+ status was predictive of decreased overall survival with significance in PV patients (p = 0.0042, Fig. 1C). The univariable analysis also revealed that age at diagnosis (*P* < 0.001) and leukocyte count (*P* = 0.042) but not gender, history of thrombosis, or JAK2V617F allele burden were associated with reduced overall survival in PV (Supplemental Table S2). As suspected, the proportional hazard assumption of death events was not valid among the groups W+ and W-. Thus, we performed landmark analyses that highlighted different profiles (Fig. 1D). Indeed, the worsening status was able to distinguish events occurring during the 5 years following the worsening evaluation but not after (Fig. 1D). Finally, applying a multivariable Cox model with a manual backward variable selection, which minimizes the Akaike criteria, we confirmed that both worsening status (HR: 3.4; *P* = 0.001) and age at diagnosis (HR: 4.9; *P* = 0.003 for age >60 years, Fig. 1E) were associated with reduced overall survival in PV patients. Furthermore, the W+ status significantly predicted overall survival independently of the prognostic classification proposed by Tefferi et al. [2]. (HR: 2.9; *P* = 0.004 for worsening status and HR:4.7; *P* = 0.002 for high risk vs low risk; Supplemental Fig. S1).

Although the worsening status did not significantly affect overall survival in ET patients, we found a higher risk of death after 5 years post evaluation applying the same landmark analysis than in the PV group (*P* = 0.071, Supplemental Fig. S2). In multivariable analysis, age at diagnosis and a history of thrombosis were significant predictive factors of reduced survival (Supplemental Fig. S3).

We then studied the impact of worsening at 3 years on hematological transformation into either MDS, MF, or AML with the same methodology. In ET patients, a W+ status was predictive of an increased risk of hematological transformation 5 years or more after worsening (*P* = 0.00028, Supplemental Figs. S4, and S5 for PV). Finally, we found no significant association between the worsening criteria and thrombotic events in either ET (*P* = 0.52) or PV patients (*P* = 0.82).

To date, prognostic evaluation of PV and ET is assessed at diagnosis based on age, blood counts, and history of thrombosis [5]. In the present work, we propose an early and easy-to-identify worsening criterion evaluated at 3 years of follow-up, associated with reduced survival in PV, independently of other classical prognosis markers. To validate this finding, we applied the worsening criteria at 3 years to an independent multicentric cohort of 147 PV patients (from FIMBANK network, details in Supplemental data) and found similar results as patients with a W + status at 3 years displayed a higher risk of death during the first 5 years (Fig. 1F, *p* = 0.0029), but not afterward (*P* = 0.41, data not shown). Therefore, in PV patients, both initial and validation cohorts, the worsening status was associated with a higher risk of death during the first 5 years post-assessment (i.e., 3–8 years after diagnosis), but not in a longer-term. It is possible that repeating the worsening evaluation during follow-up may improve the

Received: 7 February 2022 Revised: 8 March 2022 Accepted: 9 March 2022

Published online: 08 April 2022
A. Design of the study

<figure><img src="image_3.png" /></figure>

* Overall survival

* Hematological evolution

* Thrombosis

B. Criteria of worsening at 3-years

<figure><img src="image_4.png" /></figure>

C. Overall survival according to diagnosis and 3-years worsening

<figure><img src="image_5.png" /></figure>

D. Overall survival in PV with landmark analysis

<figure><img src="image_6.png" /></figure>

E. Multivariate analysis for overall survival in PV

<figure><img src="image_7.png" /></figure>

F. Validation of the worsening criteria in an external cohort

<figure><img src="image_8.png" /></figure>

**Fig. 1** **Worsening at 3 years and long-term prognosis.** A Flow-chart representing the design of the JAKSUIVI study. B Distribution of items for the worsening criteria at 3 years of follow-up. C Kaplan-Meier curve represents overall survival according to the diagnosis (ET: essential thrombocythemia, PV: polycythemia vera) and the worsening status (W+: worsened at 3 years, W-: not worsened). Starting time t0 was the 3 years (3 y) follow-up (FU). D Kaplan-Meier curves for the landmark analysis of overall survival in PV patients. The top plot represented the follow-up of the five first years after the 3-year evaluation and the bottom plot represented the follow-up from 5 to 7 years after the 3-year evaluation with a t0 at 5 years. E Forest plot representing the results of multivariate Cox analysis for overall survival in PV. F Kaplan-Meier curve represents overall survival according to the worsening status in the validation cohort.
<table><caption>**Table 1.** Characteristics of the whole cohort.</caption><thead><tr><th></th><th>Global cohort</th><th>PV</th><th>ET</th></tr></thead><tbody><tr><td>Participants (n)</td><td>191</td><td>97</td><td>94</td></tr><tr><td>Age at diagnosis (y)</td><td>65 [23; 90]</td><td>64 [24; 90]</td><td>65 [23; 85]</td></tr><tr><td>Gender (M/F)</td><td>96 (50.26%)/95 (49.74%) R: 1.01</td><td>56 (57.73%)/41 (42.27%) R: 1.37</td><td>40 (42.55%)/54 (57.45%) R: 0.74</td></tr><tr><td>At diagnosis</td><td></td><td></td><td></td></tr><tr><td>Biological data at diagnosis (median [IQR])</td><td></td><td></td><td></td></tr><tr><td>Hemoglobin (g/dL)</td><td>15.6 [11.2;25]</td><td>17.8 [12.2;25]</td><td>14.6 [11.2;17.7]</td></tr><tr><td>Hematocrit (%)</td><td>46.9 [33.5;72.8]</td><td>53.6 [40.8;72.8]</td><td>43.7 [33.5;52.7]</td></tr><tr><td>Platelets (G/L)</td><td>618 [135;1378]</td><td>514 [135;1262]</td><td>698 [392;1378]</td></tr><tr><td>Leukocytes (G/L)</td><td>9.8 [4.4;21.3]</td><td>10.7 [5.5;21.3]</td><td>8.95 [4.4;18]</td></tr><tr><td>Neutrophils (G/L)</td><td>6.9 [1.15;18.5]</td><td>8 [1.15;18.5]</td><td>6.2 [2.8;15.35]</td></tr><tr><td>JAK2V617F allele burden (%)</td><td>24.24 [1.26; 94.96]</td><td>39.81 [1.26; 94.96]</td><td>15.3 [1.66; 68.36]</td></tr><tr><td>At 3 y FU</td><td></td><td></td><td></td></tr><tr><td>Biological data at 3 y FU (median [IQR])</td><td></td><td></td><td></td></tr><tr><td>Hemoglobin (g/dL)</td><td>13.9 [8.9; 17.9]</td><td>14.1 [8.9; 17.9]</td><td>13.7 [10.8; 17.3]</td></tr><tr><td>Hematocrit (%)</td><td>41.7 [29.8; 55.1]</td><td>42.8 [29.8; 55.1]</td><td>40.85 [32.2; 52.8]</td></tr><tr><td>Platelets (G/L)</td><td>350 [98; 1110]</td><td>287 [98; 712]</td><td>386.5 [149; 1110]</td></tr><tr><td>Leucocytes (G/L)</td><td>6.2 [2.2; 38.2]</td><td>6.2 [2.6; 38.2]</td><td>6.5 [2.2; 18.5]</td></tr><tr><td>Neutrophils (G/L)</td><td>4.3 [1.08; 16]</td><td>4.2 [1.08; 16]</td><td>4.45 [1.3; 15.8]</td></tr><tr><td>JAK2V617F allele burden (%)</td><td>15.02 [0; 91.37]</td><td>24.37 [0.12; 91.37]</td><td>10.075 [0; 80.25]</td></tr><tr><td>Absolute change in allele burden</td><td>-5.1 [-81; +36.98]</td><td>-9.82 [-81; +36.98]</td><td>-2.125 [-31.7; +25.1]</td></tr><tr><td>Relative change in allele burden</td><td>-21.088 [-100; +578.659]</td><td>-33.56 [-99.255; +578.659]</td><td>-16.2 [-100; +233.65]</td></tr><tr><td>Decreased allele burden (absolute ≥-10% or relative ≥-50%)</td><td>77 (40.3%)</td><td>50 (51.5%)</td><td>27 (28.7%)</td></tr><tr><td>Recorded events at inclusion (n, %)</td><td></td><td></td><td></td></tr><tr><td>Splenomegaly (clinical or volume >12 with ultrasound)</td><td>52 (27.2%)</td><td>36 (37.1%)</td><td>16 (17%)</td></tr><tr><td>Thrombosis history</td><td>64 (33.5%)</td><td>30 (30.9%)</td><td>34 (36.2%)</td></tr><tr><td>Hemorrhage history</td><td>16 (8.4%)</td><td>8 (8.3%)</td><td>8 (8.5%)</td></tr><tr><td>Worsening status at 3 y FU (n, %)</td><td>58 (30.4%)</td><td>31 (32%)</td><td>27 (28.7%)</td></tr><tr><td>1 event</td><td>48 (82.8%)</td><td>27 (87.1%)</td><td>21 (77.8%)</td></tr><tr><td>2 events</td><td>8 (13.8%)</td><td>4 (12.9%)</td><td>4 (14.8%)</td></tr><tr><td>3 events</td><td>2 (3.4%)</td><td>0 (0%)</td><td>2 (7.4%)</td></tr><tr><td>Long-term follow-up</td><td></td><td></td><td></td></tr><tr><td>Follow-up time in years (median [IQR]))</td><td>10.6 [3; 14.6]</td><td>10.5 [3; 14.1]</td><td>10.6 [3.3; 14.6]</td></tr><tr><td>Thrombosis</td><td>35 (18.3%)</td><td>19 (19.6%)</td><td>16 (17.0%)</td></tr><tr><td>Transformation</td><td>24 (12.6%)</td><td>12 (12.4%)</td><td>12 (12.8%)</td></tr><tr><td>Including secondary MF</td><td>14 (7.3%)</td><td>6 (6.2%)</td><td>8 (8.5%)</td></tr><tr><td>Including secondary LAM</td><td>10 (5.2%)</td><td>6 (6.2%)</td><td>4 (4.3%)</td></tr><tr><td>Including secondary MDS</td><td>2 (1%)</td><td>1 (1%)</td><td>1 (1.1%)</td></tr><tr><td>Deaths</td><td>51 (26.7%)</td><td>31 (32%)</td><td>20 (21.3%)</td></tr></tbody></table>

FU follow-up.

prognostic assessment of late events in PV. In contrast, for ET patients, we observed that the W+ status at 3 years was associated with events occurring only after 8 years of follow-up, with a significant difference for hematological transformation and a trend for overall survival. These results may be explained by the different prognostic course of ET compared with PV, with a late excess of mortality during follow-up and a lower rate of short-term fibrotic or leukemic evolution [1, 6–8].

Additional mutations can be found in MPN, some of which are associated with a significantly altered outcome [9]. This has been mostly studied in PMF, which presents with a more complex

molecular landscape with some mutations recently incorporated into a prognostic scoring system [10]. In PV and ET, a prognostic score has also been recently published based on the identification of adverse mutations in *SRSF2* for PV and in *SRSF2*, *SF3B1*, *U2AF1*, and *TP53* in ET [11]. However, *SRSF2* mutations occurred in only 1–3% of PV patients [9, 12], thus limiting the number of patients benefitting from this prognostic assessment. At the last ASH meeting, the potential prognostic impact of repeated molecular evaluations in PV and ET using next-generation sequencing (NGS) has been reported [13]. Emerging mutations, which were detected in 29% of patients with a median interval between NGS evaluation
of 1.6 years, were associated with reduced overall survival. This suggests that a dynamic scoring system can also include additional mutations. This should be investigated in future prospective studies to determine in which patients and how often such evaluation should be performed.

To conclude, we propose a simple and easy-to-use worsening criterion allowing identification of patients at high risk at 3 years of follow-up. These results pave the way for a new dynamic prognostic system in PV that will need validation for any follow-up time. Indeed, the re-evaluation of prognosis during the follow-up is crucial in such chronic diseases, as it could influence patient management and therapy.

## REPORTING SUMMARY

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Léa Sureau ID 1,2,3, Caroline Buors 3,4, Jean-Christophe lanotto ID 3,5, Françoise Boyer 3,6, Aline Tanguy-Schmidt 2,3,6, Lydia Roy 7, Emilie Cayssials 3,8, Laura Cailly 8, Jean-Claude Chomel 3,9, Aurélie Chauveau 10, Corentin Orvain 2,3,6, Olivier Mansier 11, Dana Ranta 12, Margot Robles 13, Emmanuel Gyan 3,14, Olivier Hérault ID 3,15, Stanislas Nimubona 3,16, Tony Marchand 3,16,17, Eric Lippert ID 3,4, Jérémie Riou ID 18,19,20, Valérie Ugo ID 1,2,3,20 and Damien Luque Paz ID 1,2,3,20

¹CHU Angers, Laboratoire d'Hématologie, Angers, France. ²Univ Angers, Nantes Université, CHU Angers, InserN, CNRS, CRCI2NA, F-49000 Angers, France. ³Fédération Hospitalo-Universitaire "Grand Ouest Against Leukemia" (FHU GOAL), Angers, France. ⁴CHU Brest, Laboratoire d'Hématologie, Brest, France. ⁵CHU Brest, Service d'Hématologie Clinique, Brest, France. ⁶CHU Angers, Service des Maladies du Sang, Angers, France. ⁷Hôpital Universitaire Henri Mondor, Service Hématologie Clinique, APHP & UPEC, UFR de Santé, Créteil, France. ⁸CHU Poitiers, Service d'Oncologie Hématologique et Thérapie Cellulaire, Poitiers, France. ⁹CHU Poitiers, Service de Cancérologie Biologique, Poitiers, France. ¹⁰CH de Cornouaille, Laboratoire d'Hématologie, Quimper, France. ¹¹CHU de Bordeaux, Laboratoire d'Hématologie et Université de Bordeaux, Inserm U1034, Bordeaux, France. ¹²CHU Nancy, Hématologie Clinique, Nancy, France. ¹³CH Périgueux, Hématologie Clinique, Périgueux, France. ¹⁴CHU Tours, Service d'Hématologie et Thérapie Cellulaire, CNRS EMR 7001 LNOX, université de Tours EA7501, Tours, France. ¹⁵CHU Tours, Service d'Hématologie Biologique, CNRS EMR 7001 LNOX, université de Tours EA7501, Tours, France. ¹⁶CHU Rennes, Service d'Hématologie Clinique, Rennes, France. ¹⁷INSERM U1236, Faculté de Médecine, Université Rennes 1, Rennes, France. ¹⁸CHU Angers, Département de Biostatistiques et de Méthodologie, DRCI, Angers, France. ¹⁹Univ Angers, CHU Angers, Inserm, CNRS, MINT, SFR ICAT, Angers, France. ²⁰These authors contributed equally: Valérie Ugo, Damien Luque Paz. email: valerie.ugo@chu-angers.fr; damien.luquepaz@chu-angers.fr

## REFERENCES

1. Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;124:2507-13.

2. Tefferi A, Rumi E, Finazzi G, Gisslinger H, Vannucchi AM, Rodeghiero F, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27:1874-81.

3. Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120:5128-33.

4. Barbui T, Vannucchi AM, Buxhofer-Ausch V, Stefano VD, Betti S, Rambaldi A, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J. 2015;5:e369.

5. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95:1599-613.

6. Cerquozzi S, Tefferi A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J. 2015;5:e366.

7. Alvarez-Larrán A, Senín A, Fernández-Rodríguez C, Pereira A, Arellano-Rodrigo E, Gómez M, et al. Impact of genotype on leukaemic transformation in polycythemia vera and essential thrombocythaemia. Br J Haematol. 2017;175:764-71.

8. Posthuma TSM, Visser O, te Boekhorst PAW, Dinmohamed AG. Late excess mortality in essential thrombocythemia: a population-based study in the Netherlands, 2001-2018. Leukemia. 2022;36:275-8.

9. Lundberg P, Karow A, Nienhold R, Looser R, Hao-Shen H, Nissen I, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood. 2014;123:2220-8.

10. Guglielmelli P, Lasho TL, Rotunno G, Mudireddy M, Mannarelli C, Nicolosi M, et al. MIPSS70: mutation-enhanced international prognostic score system for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2018;36:310-8.

11. Tefferi A, Guglielmelli P, Lasho TL, Coltro G, Finke CM, Loscocco GG, et al. Mutation-enhanced international prognostic systems for essential thrombocythaemia and polycythemia vera. Br J Haematol. 2020;189:291-302.

12. Grinfeld J, Nangalia J, Baxter EJ, Wedge DC, Angelopoulos N, Cantrill R, et al. Classification and personalized prognosis in myeloproliferative neoplasms. N. Engl J Med. 2018;379:1416-30.

13. Zhao L-P, Cazaux M, Maslah N, Daltro De Oliveira R, Verger E, Soret-Dulphy J, et al. Myeloproliferative neoplasms (MPN) clonal evolution landscape and its impact on patients' prognosis. Blood. 2021;138:317-317.

## ACKNOWLEDGEMENTS

This work was supported in part by grants from the 'Canceropole Grand Ouest', the 'Ligue contre le Cancer Grand Ouest', and the French National Institute of Cancer (FIMBANK, INCa BCB 2013). The authors would like to thank François Girodon (CHU Dijon), Jean-Jacques Kiladjian (APHP St Louis), Charles Bescond (CH Cholet), Kamel Laribi (CH Le Mans), Guillaume Denis (CH Rochefort), Fiorenza Barraco (APHL Lyon) and Laure Stalnikiewicz (CH Lens) for including patients in FIMBANK, and the France Intergroup of Myeloproliferative neoplasms (FIM) for helpful discussions. The FIM and the LNOX team are members of the OPALE Carnot Institute. The authors thank the Brest Biological Resources Center BB-0033-00037 ("CRB Santé du CHRU de Brest") for providing high-quality annotated samples.

## AUTHOR CONTRIBUTIONS

J.C.I. and V.U. conceived and design the JAKSUIVI study and D.L.P. actualized the follow-up. C.B., E.C., J.C.C., A.C., V.U., and D.L.P. performed the experiments, analyzed, and interpreted the data; J.C.I., F.B., A.T.S., L.R., E.C., L.C., J.C.C., C.O., O.M., D.R., M.R., E.G., O.H., T.M., S.N., and E.L. cared for the patients and provide clinical and biological data; L.S., J.R., and D.L.P. performed the statistical analysis. L.S., V.U., and D.L.P. wrote the manuscript, and C.B., J.C.I., C.O., E.L., and J.R. revised it critically.

## CONFLICT OF INTEREST

The authors declare no competing interests.

## ADDITIONAL INFORMATION

**Supplementary information** The online version contains supplementary material available at https://doi.org/10.1038/s41408-022-00646-0.

**Correspondence** and requests for materials should be addressed to Valérie Ugo or Damien Luque Paz.

**Reprints and permission information** is available at http://www.nature.com/ reprints

**Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
<figure><img src="image_9.png" /></figure>

**Open Access** This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

© The Author(s) 2022