Cancer Treatment Today » Platelet Disorders

Paroxysmal Nocturnal Hemoblobinuria(PNH) and Myelodysplastic syndromes: Treatment Approach – pro

M Levin, MD — Wed, 14 Nov 2012 15:35:33 +0000

It is rare to have MDS and PNH coexist as two full blown disorders but PNH clones can be present in MDS and PNH can resemble some features of MDS. Among acquired stem cell disorders, pathological links between myelodysplastic syndromes (MDS) and aplastic anaemia (AA), and paroxysmal nocturnal haemoglobinuria (PNH) and AA, have been often described, whereas the relationship between MDS and PNH is not entirely clear. Many reports identified small PNH clones in other stem cell failure syndromes, such as aplastic anemia or low-risk myelodysplastic syndrome have at least biochemical evidence of hemolysis, but typically the PNH clone is small (< 10%) so that hemolysis does not contribute significantly to the underlying anemia. Using high-sensitivity flow cytometry, approximately 60% of patients with aplastic anemia and 20% of patients with low-risk MDS have been found to have a detectable population of GPI-AP–deficient erythrocytes and granulocytes. In these cases, the focus of treatment is on the BM failure component of the disease. Intravascular hemolysis is the dominant feature of classic PNH, and this process is blocked by the complement inhibitor eculizumab(Soliris). When intravascular hemolysis is the predominant feature, treatment should be directed to the PNH component. The large majority of patients with PNH/AA and PNH/MDS have relatively small PNH clones (< 10%) and require no specific PNH therapy; in these cases, treatment should focus on the underlying BM failure syndrome(Parker et al).

Iwanaga M, Furukawa K, Amenomori T, Mori H, Nakamura H, Fuchigami K, Kamihira S, Nakakuma H, Tomonaga M. Paroxysmal nocturnal haemoglobinuria clones in patients with myelodysplastic syndromes.Br J Haematol. 1998 Jul;102(2):465-74.

Wang SA, Pozdnyakova O, Jorgensen JL, Medeiros LJ, Stachurski D, Anderson M, Raza A, Woda BA. Detection of paroxysmal nocturnal hemoglobinuria clones in patients with myelodysplastic syndromes and related bone marrow diseases, with emphasis on diagnostic pitfalls and caveats. Haematologica. 2009 Jan; 94(1):29-37.

Young NS. Paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes: clonal expansion of PIG-A-mutant hematopoietic cells in bone marrow failure.Haematologica. 2009 Jan;94(1):3-7.

Charles J. Parker, Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy ASH Education Book December 10, 2011 vol. 2011 no. 1 21-29
Fahri Sahin et al, Pesg PNH diagnosis, follow-up and treatment guidelines. Am J Blood Res. 2016; 6(2): 19–27.

For Lay version see here

JAK2 for diagnosis – pro

admin — Sat, 01 Sep 2012 20:24:59 +0000

Lay Summary: JAK2 testing can now be performed for a diagnosis of a myeloproliferative disorder. This is now an acceptable approach to diagnosing myeloproliferative disorders.

In early 2005, several groups of investigators reported a somatic acquired point mutation in the JAK2 (Janus kinase 2) protein in the blood and bone marrow of patients with BCR/ABL-negative chronic myeloproliferative disorders. JAK2 is a tyrosine kinase which plays an important role in normal hematopoietic growth factor signaling, and the mutation results in activation of the kinase and deregulated intracellular signaling with cell proliferation that is independent of normal growth factor control.

Using sensitive assays, the JAK2 mutation can be detected in approximately 90-95% of cases of polycythemia vera, 50-70% of patients with essential thrombocythemia, and 40-50% of cases of idiopathic myelofibrosis. The mutation has also been described in rare cases of myelodysplastic syndromes, acute myeloid leukemia, systemic mastocytosis and hypereosinophilic syndrome. It is specific for diagnosis of a clonal myeloid lineage proliferative disorder. The mutation has not been described in BCR/ABL-positive chronic myeloid leukemia, any acute or chronic lymphoid disorders, any healthy persons, or any patient with secondary polycythemia or a reactive blood count elevation. The JAK2 test promises to be very useful in distinguishing between clonal myeloproliferative disorders and reactive cellular proliferations.

Mary F. McMullin, John T. Reilly, Peter Campbell, David Bareford, Anthony R. Green, Claire N. Harrison, Eibhlin Conneally, on behalf of the National Cancer Research Institute, Myeloproliferative Disorder Subgroup, Kate Ryan, on behalf of the British Committee for Standards in Haematology (2007) Amendment to the guideline for diagnosis and investigation of polycythaemia/erythrocytosis
British Journal of Haematology 138 (6), 821–822.

James, C., Ugo, V., Le Couedic, J.P., Staerk, J., Delhommeau, F., Lacout, C., Garcon, L., Raslova, H., Berger, R., Bennaceur-Griscelli, A., Villeval, J.L., Constantinescu, S.N., Casadevall, N. & Vainchenker, W. (2005) A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature, 434, 1144–1148.

McMullin, M.F., Bareford, D., Campbell, P., Green, A.R., Harrison, C., Hunt, B., Oscier, D., Polkey, M.I., Reilly, J.T., Rosenthal, E., Ryan, K., Pearson, T.C. & Wilkins, B., General Haematology Task Force of the British Committee for Standards in Haematology. (2005) Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. British Journal of Haematology, 130, 174–195.

Prithviraj Bose and Srdan Verstovsek, AK2 inhibitors for myeloproliferative neoplasms: what is next?
Blood 2017 130:115-125;

Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;129(6):667-679.

Intravenous gammaglobulin for ITP – pro

M Levin, MD — Thu, 30 Aug 2012 18:05:01 +0000

Lay Summary: IVIG is standard for ITP but represents a “holding action” rather than a cure.

IVIG is approved by the FDA for use in the treatment of the following diseases: Kawasaki disease, dermato/polymyositis, idiopathic thrombocytopenic purpura (ITP), Guillain-Barre syndrome, polyneuropathy, some viral diseases, and some forms of immune deficiency. The place of IVIG in the treatment of ITP is not well clarified. It does not modify the disease as do steroids and splenectomy, but only gains a temporary rise in platelet counts, until definitive therapy can be planned or accomplished. In addition, a number of alternatives exist, including: Anti-RhoD, vincristine, Rituximab, danazol, high dose pulse steroids and even chemotherapy. IVIG is accordingly best used as a temporary measure, to prepare the patient for spenectomy or while discussions of other treatments take place. It is also occasionally used to wait and see if a spontaneous remission of the ITP occurrs; however, this use is less supported by the literature.
Based on the literature, CMS advises the following:IVIG is indicated for chronic ITP only when all of the following conditions are met:

Prior treatment with corticosteroids and splenectomy;
Duration of illness less than 6 months;
Age of 10 years or older;
No concurrent illness/disease explaining thrombocytopenia; and
Platelet counts persistently at or below 20,000/ml.

The Australian guideline sets the plt. level at 30K and adds preoperative use and use in preagnant women as well as for severe bleeding and other indications.

Anderson D, Ali K, Blanchette V, et al. Guidelines on the use of intravenous immune globulin for hematologic conditions. Transfus Med Rev. 2007;21(2 Suppl 1):S9-56.

George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, Blanchette VS, Bussel JB, Cines DB, Kelton JG, Lichtin AE, McMillan R, Okerbloom JA, Regan DH, Warrier I: Idiopathic thrombocytopenic purpura: A practice guideline developed by explicit methods for the American Society of Hematology. Blood 88:3, 1996

Download 2011 ITP Pocket Guide[1]

Cines DB, Blanchette VS: Immune thrombocytopenic purpura. N Engl J Med 2002 Mar 28; 346(13): 995-1008

Kahn MJ, McCrae KR: Splenectomy in Immune Thrombocytopenic Purpura: Recent Controversies and Long-term Outcomes. Curr Hematol Rep 2004 Sep; 3(5): 317-23

McMillan R, Durette C: Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004 Aug 15; 104(4): 956-60

Australian Guideline(2007)

http://www.nba.gov.au/ivig/pdf/criteria-qrg.pdf

Alan H. Lazarus^{* Mechanism of action of IVIG in ITP}2002 Blackwell Science Ltd Vox Sanguinis Volume 83, Issue Supplement s1, pages 53–55, August 2002

Cindy Neunert et al, The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. April 21, 2011; Blood: 117 (16)