Cancer Treatment Today » Myelodysplastic

Is Myelodysplastic syndrome a cancer? – pro

M Levin, MD — Sun, 13 Jan 2013 03:21:54 +0000

Whether a condition is a cancer or not in a contractual context can be analyzed using some widely accepted definitions of the word “cancer”. Myelodysplastic syndrome is a name given to variety on conditions characterized by defects in inter-cellular communications, deficient hematopoietic cell production and genetic changes that increase the risk of developing of acute leukemia. It used to be called “preleukemia”. World Health Organizations defines cancer as: “Cancer is a generic term for a large group of diseases that can affect any part of the body. Other terms used are malignant tumours and neoplasms. One defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs. This process is referred to as metastasis. Metastases are the major cause of death from cancer.”

National Cancer Institue defiens “cancer” as, “Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems.”

Merriam-Webster says: “can·cer

noun \ˈkan(t)-sər\

Definition of CANCER

: a malignant tumor of potentially unlimited growth that expands locally by invasion and systemically by metastasis

: an abnormal state marked by a cancer “

Because myelodysplastic syndrome is a precancerous state that does not possess the features of tissue invasion and metastatic spread, it should not be called cancer.

WHO definition: http://www.who.int/cancer/en/

NCI definition: http://www.cancer.gov/cancertopics/cancerlibrary/what-is-cancer

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

Promacta for AML or MDS – pro

M Levin, MD — Fri, 05 Oct 2012 02:32:34 +0000

Thrombocytopenia is a frequent symptom in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Eltrombopag is a small molecule thrombopoietin receptor agonist that might be a new option to treat thrombocytopenia in these diseases, provided that it can be shown does not stimulate malignant hematopoiesis. Unfortunately, there is no significant literature to support Promacta in the setting of ongoing treatment for AML or in MDS. Currenlty PROMACTA is not indicated for the treatment of thrombocytopenia due to causes of thrombocytopenia (eg, myelodysplasia or chemotherapy) other than chronic ITP. Several studies showed that Eltrombopag was capable of increasing megakaryocytic differentiation and formation of normal megakaryocytic colonies in patients with AML and MDS but the clinical significance of this observation remains unclear. Promacta is currenlty in a study: Eltrombopag in Myelodysplastic Syndrome (MDS) Patients With Thrombocytopenia, NCT01286038.

Will B, Kawahara M, Luciano JP, Bruns I, Parekh S, Erickson-Miller CL, Aivado MA, Verma A, Steidl U.
Effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. Blood. 2009 Oct 29;114(18):3899-908

S. Wroblewski, W. Shi, P. Mudd Jr., M. Aivado;Eltrombopag in thrombocytopenic patients with advanced myelodysplastic syndromes (MDS) or secondary acute myeloid leukemia after MDS: A phase I/II study.J Clin Oncol 28:15s, 2010 (suppl; abstr TPS184)

For Lay version see here

Allogeneic stem cells for Myelodysplasia (MDS) – pro

admin — Sat, 01 Sep 2012 20:18:15 +0000

Lay Summary: Allogeneic stem cell transplantation is standard of care for younger patients with MDS.

Allogeneic stem cell transplantation is standard of care for younger patients with MDS. Age 60 is considered appropriate for it. The guidelines recommend that all patients < 65 years should be assessed for fitness/eligibility for allogeneic SCT as soon as possible after diagnosis, as SCT outcome is improved if performed early. If eligible and a sibling donor is available, it is recommended that patients < 50 years are offered ablative allogeneic SCT (evidence grade B, level IIb) and patients > 50 < 65 years are considered for non-ablative allogeneic SCT, within clinical trials where available (evidence grade C, level IV). The kind of transplant had not been defined, but the filed has moved toward older ages for both of these types of transplant.

Until the mid 1990s few patients over 55 years were offered allogeneic HSCT63 due to higher NRM in older patients. As only about 25% of MDS patients are younger than 60 years, efforts have focused on reducing the elevated risk of NRM associated with older age by modifying conditioning regimens (as discussed above), supportive care and complication management. Recent successfully transplanted cohorts included patients with median ages of 55–60 years, with some patients older than 70 years.

Patients with no sibling donor, but with an unrelated donor should also be considered for ablative unrelated-donor SCT. Case series and retrospective analyses demonstrate similar disease-free and overall survival rates with myeloablative and non-myeloablative/reduced-intensity conditioning regimens. Two-, three-, and four-year overall survival rates are 33% versus 35%, 39% versus 33%, and 36% versus 27%, respectively, for individuals undergoing allogeneic HSCT with myeloablative or non-myeloablative/reduced-intensity therapy
NCCN 2015 on p.MD S-11 footnotes the high dose therapy recommendation with “Hematopoietic stem cell transplant (HSCT): Allogeneic-matched sibling including standard and reduced-intensity preparative approaches or MUD”.

Laport GG, Sandmaier BM, Storer BE, Scott BL, Stuart MJ, Lange T, Maris MB, Agura ED, Chauncey TR, Wong RM, Forman SJ, Petersen FB, Wade JC, Epner E, Bruno B, Bethge WA, Curtin PT, Maloney DG, Blume KG, Storb RF. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biol Blood Marrow Transplant. 2008 Feb;14(2):246-55

nccn, myelodysplatic, 2019

L. Muffly, M.C. Pasquini, M. Martens, R. Brazauskas, X. Zhu, K. Adekola, et al.Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States Blood, 130 (2017), pp. 1156-1164

Luca Malcovati et al,Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013 Oct 24; 122(17): 2943–2964.

Majhail, Navneet S. et al.Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation
Biology of Blood and Marrow Transplantation , Volume 21 , Issue 11 , 1863 – 1869

Teresa Field and Claudio Anasetti. Role and Timing of Hematopoietic Cell Transplantation for Myelodysplastic Syndrome Medit J Hemat Infect Dis 2010, 2(2)
Matthias Bartenstein and H. Joachim Deeg, Hematopoietic Stem Cell Transplantation for MDS. Hematol Oncol Clin North Am. 2010 Apr; 24(2): 407–422.

Vidaza, Dacogen for Myelodysplasia – pro

admin — Sat, 01 Sep 2012 20:17:12 +0000

Lay Summary: I review some of the new drugs for myelodysplastic syndromes.

The main options available to MDS patients in the past were blood transfusions, antibiotics to prevent infection and blood cell growth factors, drugs designed to jumpstart blood cell production. Today, almost all patients still receive blood transfusions, but transfusions don’t provide long-term relief and repeated red blood cell transfusions often leave patients with iron-rich blood, a serious condition if left uncorrected. (Last year’s approval of Exjade® [deferasirox], the first oral drug designed to reduce iron overload, now makes the consequences of transfusion therapy less intrusive by replacing traditional infusion-based pump therapy.)

Donor stem cell transplant—currently the only curative treatment for MDS—may not be realistic for this older population.

Both Vidaza (5 azacytidine) and Dacogen (decitabine) are DNA methyltransferase inhibitors (DMTI) approved by the FDA for use in all French- American British (FAB) categories for MDS. In its pivotal trial, Vidaza was reported to produce a 60% response rate (RR) (7%CR, 16%PR 37% hematological improvement). Vidaza prolonged median time to progression (TTP) to MDS/acute myeloid leukemia (AML) from 12 months to 21 months (p=0.07). The response rates for Dacogen were 30% (9% CR, 8% PR, 13% HI). Median TTP was prolonged from 7.8 months to 12.1 months compared to supportive care (p=0.1). Higher response rates have been reported in a single institution trial using lower doses of Dacogen.

Silverman L, Demakos E, Peterson B, et L. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J. Clin. Oncol 2002; 10: 2241-2252.

Saba H, Rosenfeld C, Issa JP, et al. First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome. American Society of Hematology Meeting. San Diego, Calif. 2004. Abstract #64.

Kantarjian H, O’Brien S, Giles F, et al.Decitabine Low-Dose Schedule (100 mg/m2/Course) in Myelodysplastic Syndrome (MDS). Comparison of 3 Different Dose Schedules.American Society of Hematology Meeting. Atlanta, Georgia. 2005. Abstract #2522.

Revlimid for Myelodysplastic syndrome (MDS) – pro

admin — Sat, 01 Sep 2012 20:14:27 +0000

Lenalidomide, an oral immunomodulatory agent, has received approval in the USA from the Food and Drug Administration (FDA) for the management of myelodysplastic syndromes (MDS) classified by the International Prognostic Scoring System (IPSS) as low risk or intermediate-1 risk and with a deletion 5q (del(5q)) cytogenetic abnormality. Although some patients with del(5q) have a relatively good prognosis, all del(5q) patients will become transfusion-dependent at some point during the course of their disease. The results of two clinical trials in more than 160 patients with MDS have demonstrated clear therapeutic benefits of lenalidomide, with >60% of patients achieving independence from transfusion during therapy, irrespective of age, prior therapy, sex, or disease-risk assessment. The recommendations are for this subset of MDS pateints; in other subgroups responses are around 15-20%. Guidelines do not require a prior attempt to treatment with erytropoietin to use Revlimid, but they do require an assessment and treatmetn based on its results.

Revlimid is very teratogenic and has been associated with increased risk of deep vein thrombosis and pulmonary embolism. Patients should receive education on the symptoms associated with these conditions, and seek medical help immediately if symptoms appear. It is unknown if prophylactic anticoagulant therapy is effective in reducing this risk; any such treatment course should be administered under the close supervision of a medical professional.

Giagounidis AA, Germing U, Strupp C, Hildebrandt B, Heinsch M, Aul C. Prognosis of patients with del(5q) MDS and complex karyotype and the possible role of lenalidomide in this patient subgroupAnnals of Hematology 2005 Sep;84(9):569-71. Epub 2005 May 13.

Dredge K, Horsfall R, Robinson SP, Zhang LH, Lu L, Tang Y, Shirley MA, Muller G, Schafer P, Stirling D, Dalgleish AG, Bartlett JB. Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro Microvascular Research 2005 Jan;69(1-2):56-63

List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes New England Journal of Medicine2005 Feb 10;352(6):549-57

NCCN , MDS-9 2015

Notes: Calculate IPSS score here: http://www.qxmd.com/calculate-online/calculate

Thalidomide for Myelodysplasia (MDS) – pro

admin — Sat, 01 Sep 2012 20:09:40 +0000

Thalidomide exerts in vitro heterogeneous biological effects on hematopoiesis which have supported its possible use in treating myelodysplastic syndromes (MDS). Some recent clinical trials have confirmed that thalidomide may improve anemia and, less frequently, other cytopenias, in a proportion of younger patients with low-risk MDS (11–56%, on intention-to-treat analysis). Of interest, erythroid responses may be achieved also in transfusion-dependent subjects with high serum levels of endogenous erythropoietin, a subset of MDS patients with little chance of responding to recombinant erythropoietin, alone or in combination with G-CSF.

Although the FDA currenlty apporvies thalidomide only for the 5q- deletion, there are many trials confirming effectiveness, albeit lesser effectiveness, in patients with MDS who do not have this deletion. NCCN mentions thalidomide and notes that it has greater effectiveness in the cases with 5q- deletion.Thus, it is recognized as a reasonably effective treatment for MDS, even without the 5q- diletion and there are more than 2 phase II trials that support it.

Raza A, Meyer P, Dutt D, et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with

ment of patients with myelodysplastic syndromes. Leukemia 2002;16:1-6. Musto P. Thalidomide therapy for myelodysplastic syndromes: current

status and future perspectives.

Leuk Res

. 2004;28:325-332.

Musto P, Falcone A, Sanpaolo G, et al. Thalidomide abolishes transfusion-

dependence in selected patients with myelodysplastic syndromes.

Haematologica

. 2002;87:884-886.
P . Musto Thalidomide therapy for myelodysplastic syndromes: current status and future perspectives . Leukemia Research , Volume 28 , Issue 4 , Pages 325 – 332, 2004

http://www.moffittcancercenter.com/CCJRoot/v11s6/pdf/07.pdf

nccn.org, myelodysplastic

myelodysplastic syndromes.Blood . 2001;98:958-965.

ATG for MDS – pro

admin — Sat, 01 Sep 2012 20:07:48 +0000

Myelodysplastic syndromes (MDS) are clonal hematologic stem cell disorders characterized by ineffective and dysplastic hematopoiesis leading to progressive anemia, leukopenia, and thrombocytopenia. Low risk disease can usually be treated with supportive measures and a variety of drugs, some of which have been found ineffective for this patient. Antithymocyte globulin (ATG) has been successfully used to treat pancytopenia resulting from severe aplastic anemia. There may be some overlap between low risk MDS and aplastic anemia, in which ATG is a mainstay of treatment, and there has been interest in the use of ATG for MDS. Some studies especially in in hypoplastic refractory anemias with diploid cytogenetics have been reported. However, such conclusions about being able to select subgroups based on genetics are not securely based, having been made on the basis of case reports, series and small prospective studies; no comparative prospective studies have been conducted. I found one guideline that in the presence of a hypocellular maarow, PNH clone adn HLA-DR 15 recommends, “consider a short course of immunosupression with ATG + or minus cyclosporin” (Alberta Cancer Board guideline at http://www.cancerboard.ab.ca/NR/rdonlyres/AFC31B7D-C008-4884-883D-A466F158330B/0/LYHE_004_myelodysplastic_summary.pdf). NCCN, which a more prestigious guidelines, recommends ATG for patients with low risk MDS and high erytropoietin level with transfusion dependence. It does not include cytogenetic criteria.

http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf, p.8

S Yazji et al, Antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndromes Leukemia (2003) 17, 2101–2106.

Molldrem JJ, Jiang YZ, Stetler-Stevenson M, Mavroudis D, Hensel N, Barrett AJ. Haematological response of patients with myelodysplastic syndrome to antithymocyte globulin is associated with a loss of lymphocyte-mediated inhibition of CFU-GM and alterations in T-cell receptor Vbeta profiles. Br J Haematol 1998; 102: 1314–1322. |

Thalidomide and Revlimid for myelofibrosis – pro

admin — Sat, 01 Sep 2012 20:05:50 +0000

Myelofibrosis characterized by splenomegaly and bone marrow dysfunction leading ultimately to acute leukemia. Except for allogeneic and autologous stem cell transplantation, treatment is unsatisfactory. Non-transplant treatment modalities have not improved the average 3-5 year survival associated with this disease. The usual palliative treatments include erythropoietin, androgens, hydroxyurea, and splenectomy. Myelofibrosis ( also called agnogenic myeloid metaplasia ) is a myeloproliferative disorder in which the bone marrow is initially over-active but then develops fibrosis.

There are a number of studies suggesting that thalidomide and revlimid with or without prednisone can ameliorate cytopenias of myelofibrosis with or withotu myelod metaplasia, although the latter group do not respond as well. There is supporting phase II evidence. A Phase II study evaluated Revlimid ( Lenalidomide ) in previously treated patients with myelofibrosis, a rare blood disorder that can be fatal if untreated. It was reported at the 47th American Society of Hematology ( ASH ) Meeting in Atlanta.The patients with a median age of 65 ( range, 42 to 83 ) received Lenalidomide at 10 mg/day orally ( 5 mg daily for patients with a platelet count less than 100,000 at the start of the study ). Thirty-two patients were evaluable for response or toxicity. Responses were observed in nineteen patients ( 46% ), including complete response ( CR ) achieved in three patients defined by normalization of Hgb and WBC, respectively.Partial response ( PR ) was achieved in five patients as a result of improvement in platelets and Hgb, +/- spleen, and hematologic improvement was observed in eleven patients based on improvement in platelets, spleen, WBC and BM blasts. Five of thirteen transfusion-dependent patients became transfusion independent.The median time to response was six weeks ( range, 1 to 22 ). Responses were sustained for a median of thirty-one weeks ( range, 1 to 40 weeks ).

Revlimid is not listed by DrugDex for this indication but Thaldomid is. At this point, Revlimid is not FDA approved or guideline recommended for myelofibrosis but there are several supporting studies and in 2009 several additional supporting articles have appeared, which I reference.

Ayalew Tefferi, Jorge Cortes, Srdan Verstovsek, Ruben A. Mesa, Deborah Thomas, Terra L. Lasho, William J. Hogan, Mark R. Litzow, Jacob B. Allred, Dan Jones, Catriona Byrne, Jerome B. Zeldis, Rhett P. Ketterling, Rebecca F. McClure, Francis Giles, and Hagop M. Kantarjian Lenalidomide therapy in myelofibrosis with myeloid metaplasia Blood 108: 1158-1164;

Tefferi, Ayalew Pathogenesis of Myelofibrosis With Myeloid Metaplasia J Clin Oncol 2005 23: 8520-8530

A. Quintas-Cardama, H. M. Kantarjian, T. Manshouri, D. Thomas, J. Cortes, F. Ravandi, G. Garcia-Manero, A. Ferrajoli, C. Bueso-Ramos, and S. Verstovsek Lenalidomide Plus Prednisone Results in Durable Clinical, Histopathologic, and Molecular Responses in Patients With Myelofibrosis J. Clin. Oncol., October 1, 2009; 27(28): 4760 – 4766.
R. Vaidya, S. Siragusa, J. Huang, S. M. Schwager, C. A. Hanson, K. Hussein, A. Pardanani, and A. Tefferi
Mature Survival Data for 176 Patients Younger Than 60 Years With Primary Myelofibrosis Diagnosed Between 1976 and 2005: Evidence for Survival Gains in Recent Years Mayo Clin. Proc., December 1, 2009; 84(12): 1114 – 1119.
A. Tefferi, S. Verstovsek, G. Barosi, F. Passamonti, G. J. Roboz, H. Gisslinger, R. L. Paquette, F. Cervantes, C. E. Rivera, H. J. Deeg, et al. Pomalidomide Is Active in the Treatment of Anemia Associated With Myelofibrosis
J. Clin. Oncol., September 20, 2009; 27(27): 4563 – 4569.

Cytogenetics in Myelodysplasia – pro

admin — Sat, 01 Sep 2012 20:04:41 +0000

The biologic and clinical relevance of cytogenetic analysis in myelodysplastic syndromes (MDS) is well established and karyotype has been identified by the International Prognostic Scoring System (IPSS) as one of the three variables for the definition of prognosis in MDS. The German–Austrian MDS Study Group presented cytogenetic findings in 2,072 patients with MDS, which serve as a basis for the characterization of the cytogenetic subgroups. The availability of new therapeutic options for low- and high-risk MDS targeted against distinct entities characterized by specific chromosome abnormalities, like 5q-deletions, monosomy 7, and complex abnormalities underlines the important role of cytogenetics for the clinical management of MDS. In fact, it is not possible to properly manage MDS withotu obtaining cytogenetics.
Occhipinti E, Correa H, Yu L, Craver R. Comparison of two new classifications for pediatric myelodysplastic and myeloproliferative disorders. Pediatr Blood Cancer. Mar 2005;44(3):240-4.

Galili N, Cerny J, Raza A.Current treatment options: impact of cytogenetics on the course of myelodysplasia.Curr Treat Options Oncol. 2007 Apr;8(2):117-28.

nccn.org, myelodysplastic