Myelodysplastic Syndromes Treatment Protocols 

Myelodysplastic Syndromes Treatment Protocols 

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Treatment recommendations for myelodysplastic syndromes (MDS) are based on a patient’s  Revised International Prognostic Scoring System score in addition to evaluation of a patient’s performance status. Currently, only a few FDA-approved therapies for MDS are available, including hypomethylating agents such as azacitidine and decitabine, iron chelators such as deferasirox, and lenalidomide. [1] Special considerations and supportive care are also described below. [2]

See Myelodysplastic Syndromes: Classification, Features, Diagnosis, and Treatment Options, a Critical Images slideshow, to help identify, classify, work up, and treat these disorders.

These patients should receive supportive care. Selected patients who have not required transfusion and have modest, asymptomatic cytopenias may be observed initially.

Patients with symptomatic anemia; <2 units (U) of red blood cell (RBC) transfusion required per month; and 5q31 deletion, with or without other cytogenetic abnormalities:

Lenalidomide 10 mg PO daily, either continuous dosing or on days 1-21 every 28 d

If no response or intolerance, treat as for patients without del5q

low (≤500 mU/mL) serum erythropoietin levels:

Patients with symptomatic anemia; <2 units (U) of red blood cell (RBC) transfusion required per month; no del5q; ring sideroblasts <15%; and low (≤500 mU/mL) serum erythropoietin levels:

Epoetin alfa 40,000-60,000 U SC 1-3 times weekly, or

Darbepoetin alfa 150-300 µg SC weekly [3, 4]

Patients with symptomatic anemia; <2 units (U) of red blood cell (RBC) transfusion required per month; no del5q; ring sideroblasts ≥15%; and low (≤500 mU/mL) serum erythropoietin levels:

Epoetin alfa 40,000-60,000 U SC 1-3 times weekly, or

Darbepoetin alfa 150-300 µg SC weekly [3, 4]  plus

Filgrastim 300 µg SC 3 times weekly, doses adjusted to hemoglobin (Hb) level of 11-13 g/dL, and total white blood cell (WBC) count ≤10 × 109/L [5]

Patients with symptomatic anemia; <2 units (U) of red blood cell (RBC) transfusion required per month; no del5q, and serum erythropoietin levels >500 mU/mL:

Evaluate likelihood of response to immunosuppressive therapy

Patients who are < 60y and have ≤5% marrow blasts or those with hypocellular marrows, are human leukocyte antigen (HLA)–DR15 positive, paroxysmal nocturnal hemoglobinuria (PNH) clone positive, or have STAT-3 mutant cytotoxic T cell clonesare likely to respond to equine antithymocyte globulin (ATG) 40 mg/kg/day IV over 4-6h for 4d plus cyclosporine starting at 5-12 mg/kg/day IV beginning on day 14, dosed to maintain therapeutic levels of 200-400 ng/mL [6]

Patients without those characteristics are unlikely to respond to immunosuppressive therapy and should be considered for  azacitidine/decitabine or lenalidomide [6]

Recommended azacitidine dose is 75 mg/m2 SC or IV on days 1-7; every 28 d [7, 8, 9] or

Alternative azacitidine schedule, associated with similar response rates: 75 mg/m2 SC or IV on days 1-5, 8, and 9; every 28 d [10] or

R-IPSS high-risk or very-high-risk patients regardless of transfusion frequency or intermediate-risk patients with high transfusion needs (>2 U RBC per month):

Evaluate patients for candidacy for high-intensity therapy

Good candidates for high-intensity therapy include young patients with few or no comorbidities, good performance status, and adequate psychosocial support

Patients who are not good candidates for high-intensity therapy:

Azacitidine has been associated with improvements in transfusion dependence, quality of life (QOL), and overall survival (OS) in phase III trials

Azacitidine 75 mg/m2 SC or IV on days 1-7; every 28 d; this regimen has been associated with improvements in transfusion dependence, QOS, and OS in phase III trials [7, 8, 9] or

Alternative schedule of azacitidine, associated with similar response rates: 75 mg/m2 SC or IV on days 1-5, 8, and 9; every 28 d [10] or

Decitabine on FDA-approved schedule: 15 mg/m2 IV over 3 h every 8h (or 45 mg/m2/day) for 3 d; every 6 wk [11] or

Decitabine on outpatient schedule, now widely adopted: 20 mg/m2 IV over 1 h daily on days 1-5; every 28 d [11, 12, 13]

Patients who are good candidates for high-intensity therapy:

Acute myelogenous leukemia (AML)–type induction therapy, such as 7+3 (idarubicin 12 mg/m2 IV push on days 1-3 plus cytarabine 100-200 mg/m2/day continuous IV infusion on days 1-7) [14] or azacitidine or decitabine, as outlined above

Allogeneic stem cell transplantation consultation should also be recommended

Allogeneic stem cell transplantation may be performed as initial therapy or following cytoreduction with any of the other therapies for MDS

See the list below:

Allogeneic stem cell transplantation is the only potentially curative therapy for MDS

Appropriate patients should be referred early for consultation with a transplant specialist, before extensive transfusion support, infectious complications, or transformation to AML

Generally, early transplantation is advocated for young patients who are IPSS INT-2–risk and high-risk patients [15]

Consider referral for clinical trial participation at any stage of therapy

The regimens above have been tested in the frontline setting, and there is no standard of care at the inevitable time of frontline therapeutic failure

Clinical trial participation in this situation is highly recommended

When considering the choice of a particular therapeutic regimen, it is important to consider the time to best response; the duration of time to response is also critical in evaluating the success of therapies

Therapeutic regimens should generally not be changed in the absence of progression or toxicity unless an adequate trial of the current regimen has been undertaken

The median time to response for the therapies listed above is as follows:

ESAs with or without granulocyte-colony stimulating factor (G-CSF): 8-12wk [16, 12]

Lenalidomide: 4.6wk [17]

ATG + cyclosporine: 4mo [18]

Azacitidine or decitabine: 1.7 mo [13] to 3 mo [19]

7+3 induction therapy: 4-6wk

Infection prophylaxis

Indicated for patients with prolonged, severe neutropenia (< 0.5 × 109/L ≥ 7 d) due to either disease or therapy, who are at risk for opportunistic infections and febrile neutropenia

Infection prophylaxis during periods of neutropenia should be considered with a fluoroquinolone, [20] a second-generation azole antifungal, [21] and an antiherpetic agent [22]

Transfusion support

Management of transfusion iron overload

End-organ iron deposition may cause cardiac, hepatic, or endocrine dysfunction

Iron-chelating agents (deferoxamine, deferasirox) are available, but they have not been shown to decrease complications in MDS patients in prospective randomized trials. For this reason, many experts limit the use of these agents to patients likely to survive several years with transfusion dependence (eg, R-IPSS very-low-risk and low-risk patients).

Each iron-chelating agent has the following drawbacks: Deferoxamine is associated with inconvenient subcutaneous infusions, infusion-site reactions, and cataracts; deferasirox is an oral agent, but it is costly, requires monitoring of vision and renal and hepatic function, and is contraindicated in severe thrombocytopenia

Gotlib J. The hematologist: immunosuppression in myelodysplastic syndrome:where do we go from here? American Society of Hematology. [Full Text].

Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med. 2009. 361:1872-85.

Giraldo P, Nomdedeu B, Loscertales J, et al, and the Aranesp in Myelodysplastic Syndromes (ARM) Study Group. Darbepoetin alpha for the treatment of anemia in patients with myelodysplastic syndromes. Cancer. 2006. 107:2807-16.

Stasi R, Abruzzese E, Lanzetta G, Terzoli E, Amadori S. Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes. Ann Oncol. 2005. 16:1921-7.

Mannone L, Gardin C, Quarre MC, et al, and the Groupe Francais des Myelodysplasies. High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. Br J Haematol. 2006. 133:513-9.

[Guideline] NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes. National Comprehensive Cancer Network. Available at Version 1.2016; Accessed: November 12, 2015.

Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al, and the International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009. 10:223-32.

Kornblith AB, Herndon JE 2nd, Silverman LR, et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol. 2002. 20:2441-52.

Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002. 20:2429-40.

Lyons RM, Cosgriff TM, Modi SS, et al. Hematologic response to three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol. 2009. 27:1850-6.

Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006. 106:1794-803.

Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007. 109:52-7.

Steensma DP, Baer MR, Slack JL, et al. Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol. 2009. 27:3842-8.

Kantarjian H, Beran M, Cortes J, et al. Long-term follow-up results of the combination of topotecan and cytarabine and other intensive chemotherapy regimens in myelodysplastic syndrome. Cancer. 2006. 106:1099-109.

Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004. 104:579-85.

Park S, Grabar S, Kelaidi C, et al, and the GFM Group (Groupe Francophone des Myelodysplasies). Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood. 2008. 111:574-82.

List A, Dewald G, Bennett J, et al, and the Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006. 355:1456-65.

Sloand EM, Wu CO, Greenberg P, Young N, Barrett J. Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol. 2008. 26:2505-11.

Silverman LR, McKenzie DR, Peterson BL, et al, and the Cancer and Leukemia Group B. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006. 24:3895-903.

Gafter-Gvili A, Fraser A, Paul M, Leibovici L. Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Intern Med. 2005. 142(12 pt 1):979-95.

Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007. 356:348-59.

Glenny AM, Fernandez mauleffinch LM, Pavitt S, Walsh T. Interventions for the prevention and treatment of herpes simplex virus in patients being treated for cancer. Cochrane Database Syst Rev. 2009. 21:CD006706.

Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, et al, and the Scandinavian MDS Group. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol. 2003. 120:1037-46.

Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008. 111:86-93.

Saunthararajah Y, Nakamura R, Wesley R, Wang QJ, Barrett AJ. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood. 2003. 102:3025-7.

Passweg JR, Giagounidis AA, Simcock M, et al. Immunosuppressive therapy for patients with myelodysplastic syndrome: a prospective randomized multicenter phase III trial comparing antithymocyte globulin plus cyclosporine with best supportive care—SAKK 33/99. J Clin Oncol. 2011. 29:303-9.

Matthew C Foster, MD Assistant Professor, Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill School of Medicine

Disclosure: Received grant/research funds from Celgene, Inc for research support.

Jasmeet Anand, PharmD, RPh Adjunct Instructor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee

Christopher D Braden, DO is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Myelodysplastic Syndromes Treatment Protocols 

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