Letter to the editor

Concurrent chronic myeloid leukemia and CALR-mutated myeloproliferative neoplasm

Stephen E. Langabeer1[*]

1Cancer Molecular Diagnostics, St. James's Hospital, Dublin, Ireland

EXCLI J 2020;19:Doc86

 

Dear Editor,

After the JAK2 V617F mutation, insertion and/or deletion (indel) mutations of CALR exon 9 are the second most common driver mutations in the myeloproliferative neoplasms (MPN) of essential thrombocythemia and primary myelofibrosis and their detection is considered a major diagnostic criterion for these malignancies. It is becoming increasingly apparent that MPNs harboring CALR mutations (along with the mutations of JAK2 V617F and MPL exon 10) may occur in patients with BCR-ABL1-positive chronic myeloid leukemia (CML) as evidenced by a wave of recently reported cases. The CALR-positive MPN and CML may appear concurrently with composite morphology or sequentially with either malignancy revealed as a consequence of specific treatment for one of the malignancies (Table 1(Tab. 1); References in Table 1: Balducci et al., 2019[1]; Blouet et al., 2018[2]; Boddu et al., 2018[3]; Bonzheim et al., 2015[4]; Cabagnols et al., 2015[5]; da Costa et al., 2019[6]; De Roeck et al., 2018[7]; Diamond et al., 2016[8]; Dogliotti et al., 2017[9]; Gilles et al., 2015[10]; Guidotti et al., 2020[11]; Jeromin et al., 2017[12]; Kandarpa et al., 2017[13]; Klairmont et al., 2018[14]; Lewandowski et al, 2018[15]; Loghavi et al., 2015[16]; Nomani et al., 2016[18]; Pagoni et al., 2014[19]; Seghatoleslami et al, 2016[20]; Xia et al., 2019[21]). Review of patients shows that the presenting malignancy was unknown in one case, CML in 11/24 (46 %) and CALR-mutated MPN in the remaining 12/24 (50 %) cases. Evidence exists for molecular abnormalities occurring within a single clone and in distinct clonal populations.

While co-existence of CML and another MPN has clinical relevance with respect to selection and timing of tyrosine kinase inhibitor therapy, there is currently insufficient follow-up data to ascertain overall survival of such cases. There is limited value in assessing the JAK2 V617F mutation in all newly presenting CML cases (McCarron et al., 2012[17]): screening for the less frequent CALR and MPL mutations in all likelihood would show a similar redundancy. Given the low incidence but increasing awareness of co-existing CML and MPN, testing for the relevant rearrangement should therefore be implemented when there is clinical, hematological or morphological evidence.

Conflict of interest

The author declares no conflicts of interest.

 

References

1. Balducci A, Sanekli S, Hugues P, Soubeyrand M, Borie C, Fund X, et al. Co-occurrence of BCR-ABL1 rearrangement and CALR mutation in a single leukemic stem cell: evidence that BCR-ABL1 oncogenic addiction prevails over CALR signalling. Leuk Lymphoma. 2019. doi: 10.1080/10428191.2019.1658101. [Epub ahead of print].
2. Blouet A, Rousselet M-C, Le Bris Y, Ribourtout B, Bouvier A, Cottin L, et al. Imatinib treatment of chronic myeloid leukemia reveals a pre-existing CALR-mutated essential thrombocythemia. Hema-Sphere. 2018;2:e29.
3. Boddu P, Chihara D, Masarova L, Pemmaraju N, Patel KP, Verstovsek S. The co-occurrence of driver mutations in chronic myeloproliferative neoplasms. Ann Hematol. 2018;97:2071-80.
4. Bonzheim I, Mankel B, Klapthor P, Schmidt J, Hinrichsen T, Wachter O, et al. CALR-mutated essential thrombocythemia evolving to chronic myeloid leukemia with coexistent CALR mutation and BCR-ABL translocation. Blood. 2015;125:2309-11.
5. Cabagnols X, Cayuela JM, Vainchenker W. A CALR mutation preceding BCR-ABL1 in an atypical myeloproliferative neoplasm. N Engl J Med. 2015;372:688-90.
6. da Costa VEF, de Oliveira RD, Traina F, Chahud F, Palma LC, de Figueiredo-Pontes LL. Co-occurrence of BCR-ABL1-positive chronic myeloid leukaemia and CALR-mutated essential thrombocythaemia. Brit J Haematol. 2019. doi: 10.1111/bjh.16274. [Epub ahead of print]
7. De Roeck L, Michaux L, Debackere K, Lierman E, Vandenberghe P, Devos T. Coexisting driver mutations in MPN: clinical and molecular characteristics of a series of 11 patients. Hematology. 2018;23:785-92.
8. Diamond JM, de Almeida AM, Belo HJ, da Costa MP, Cabeçadas JM, Abecasis MM. CALR-mutated primary myelofibrosis evolving to chronic myeloid leukemia with both CALR mutation and BCR-ABL1 fusion gene. Ann Hematol. 2016;95:2101-4.
9. Dogliotti I, Fava C, Serra A, Gottardi E, Daraio F, Carnuccio F, et al. CALR-positive myeloproliferative disorder in a patient with Ph-positive chronic myeloid leukemia in durable treatment-free remission: a case report. Stem Cell Investig. 2017;4:57.
10. Gilles S, Baughn L, Courville E, Sachs Z, Nelson A. CALR mutation thrombocytosis following imatinib treatment for BCR-ABL1+ chronic myelogenous leukemia: a case of concomitant genetic alterations in an overlap myeloproliferative neoplasm. Am J Clin Path. 2015;143:A049.
11. Guidotti F, Gardellini A, Feltri M, Zancanella M, Sacca V, Alberio F, et al. Concurrent chronic myeloid leukemia and CALR-mutated chronic myeloproliferative neoplasm. Blood Cells Mol Dis. 2020;81:102395.
12. Jeromin S, Meggendorfer M, Fasan A, Haferlach C, Kern W, Haferlach T. Frequency of concurrent BCR-ABL1, JAK2, CALR and MPL mutations in a cohort of 5,545 cases with suspected MPN by a deep sequencing approach. Haematologica. 2017;102(Suppl 1):538.
13. Kandarpa M, Wu YM, Robinson D, Burke PW, Chinnaiyan AM, Talpaz M. Clinical characteristics and whole exome/transcriptome sequencing of coexisting chronic myeloid leukemia and myelofibrosis. Am J Hematol. 2017;92:555-61.
14. Klairmont MM, Cheng J, Schwartzberg L, Ho HH, Gradowski JF. Chronic myeloid leukemia, BCR-ABL1-positive with CALR and MPL mutations. Int J Lab Hematol. 2018;40:e41-2.
15. Lewandowski K, Gniot M, Wojtaszewska M, Kandula Z, Becht R, Paczkowska E, et al. Coexistence of JAK2 or CALR mutation is a rare but clinically important event in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Int J Lab Hematol. 2018;40:366-71.
16. Loghavi S, Pemmaraju N, Kanagal-Shamanna R, Mehritra M, Medeiros LJ, Luthra R, et al. Insights from response to tyrosine kinase inhibitor therapy in a rare myeloproliferative neoplasm with CALR mutation and BCR-ABL1. Blood. 2015;125:3360-3.
17. McCarron SL, Haslam K, Crampe M, Langabeer SE. The incidence of co-existing BCR-ABL1 and JAK2 V617F rearrangements: implications for molecular diagnostics. Lab Hematol. 2012;18:20-1.
18. Nomani L, Bodo J, Zhao X, Durkin L, Loghavi S, His ED. CAL2 immunohistochemical staining identifies CALR mutations in myeloproliferative neoplasms. Am J Clin Path. 2016;146:431-8.
19. Pagoni M, Garofalaki M, Tziotziou I, Nikolou E, Karakatsanis S, Tsonis I, et al. Concurrent or sequential BCR-ABL translocation and CALR gene or JAK2 V617F mutation. Blood. 2014;124:1844.
20. Seghatoleslami M, Ketabchi N, Ordo A, Asl JM, Golchin N, Saki N. Coexistence of p190 BCR/ABL transcript and CALR 52-bp deletion in chronic myeloid leukemia blast crisis: a case report. Mediterr J Hematol Infect Dis. 2016;8:e2016002.
21. Xia D, Hsi ED, Cin PD, Hasserjian RP. Composite chronic myeloid leukemia and essential thrombocythemia with BCR-ABL1 fusion and CALR mutation. Am J Hematol. 2019;94:504-5.
 
 
 

Table 1: Clinical presentation order of cases of co-existing BCR-ABL1-positive chronic myeloid leukemia (CML) and CALR-positive myeloproliferative neoplasm (MPN). ET: essential thrombocythemia; PMF: primary myelofibrosis; MF: myelofibrosis; UNK: unknown

[*] Corresponding Author:

Stephen E. Langabeer, Cancer Molecular Diagnostics, St. James’s Hospital, Dublin, Ireland; Phone: +353-1-4162413, Fax: +353-1-4103513, eMail: slangabeer@stjames.ie