Skip to Content
Rush-Copley Medical Group
Home > Health & Fitness > Healthwise > Myelodysplastic/ Myeloproliferative Neoplasms Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal myeloid disorders that possess both dysplastic and proliferative features but are not properly classified as either myelodysplastic syndromes (MDS) or chronic myeloproliferative disorders (CMPD). This category is composed of three major myeloid disorders: chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), and atypical chronic myeloid leukemia (aCML). Myeloid disease that shows features of both MDS and CMPD but does not meet the criteria for any of the three major MDS/MPN entities is designated as myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-UC).
The French-American-British classification scheme for myeloid disorders did not contain this overlap category, which made the classification of CMML particularly difficult.[2,3] Recognizing the special diagnostic challenge that these diseases represent, a group of pathologists and clinicians sponsored by the World Health Organization (WHO) created the MDS/MPN category to provide a less restrictive view of myeloid disorders, which in some instances clearly overlap. The WHO group proposed that the new MDS/MPN category would allow for more focused clinical and laboratory investigations of myeloid proliferation, abnormal proliferation, and dysplasia.[1,4]
The etiology of MDS/ MPN is not known. The incidence of MDS/MPN varies widely, ranging from approximately 3 per 100,000 individuals older than 60 years annually for CMML to as few as 0.13 per 100,000 children from birth to 14 years annually for JMML. Reliable data concerning the incidence of aCML, a recently defined entity, are not available. The incidence of MDS/MPN-UC is unknown.
The pathophysiology of MDS/MPN involves abnormalities in the regulation of myeloid pathways for cellular proliferation, maturation, and survival. Clinical symptoms are caused by complications resulting from the following:
Patients with MDS/MPN do not have a Philadelphia chromosome or BCR/ABL fusion gene. No specific genetic defects have been identified for any of these entities, though abnormalities in regulation of the ras pathway of signaling proteins appears to be a common finding in CMML, aCML, and JMML and may have some role in the abnormal myeloid proliferation associated with these diseases. In general, treatment of these diseases is tailored to the manifestations, myeloproliferative or myelodysplastic, that predominate in the individual patient.
Note: Chronic myelomonocytic leukemia (CMML) was classified as a myelodysplastic syndrome (MDS) under the French-American-British scheme. The World Health Organization classification removed CMML from MDS, placing it in the new category Myelodysplastic/ Myeloproliferative Neoplasms (MDS/MPN).
CMML is a clonal disorder of a bone marrow stem cell. Monocytosis is a major defining feature. CMML exhibits heterogenous clinical, hematological, and morphologic features, varying from predominantly myelodysplastic to predominantly myeloproliferative.
CMML is characterized pathologically by the following:[3,4]
Clinical features of CMML include the following:[3,4]
The median age at diagnosis of CMML is 65 to 75 years with a male predominance of 1.5 to 3.1.[3,4] Because CMML is grouped with chronic myeloid leukemia in some epidemiologic surveys and with MDS in others, no reliable incidence data are available for CMML. Although the specific etiology of CMML is unknown, exposure to occupational and environmental carcinogens, ionizing radiation, and cytotoxic agents has been associated in some cases.
Morphologically, the disease is characterized by a persistent peripheral blood monocytosis (always >1 × 109 /L) that may exceed 80 × 109 /L with monocytes typically accounting for more than 10% of the white blood cells.[3,4] Monocytes, though typically mature with an unremarkable morphology, can exhibit abnormal granulation, unusual nuclear lobation, or finely dispersed nuclear chromatin. Fewer than 20% blasts are seen in the blood or bone marrow. Neutrophilia occurs in nearly 50% of patients with neutrophil precursors (e.g., promyelocytes and myelocytes) accounting for more than 10% of the white blood cells. Mild normocytic anemia is common. (Refer to the PDQ summary on Fatigue for more information on anemia.) Moderate thrombocytopenia is often present. Bone marrow findings include the following:[3,4,8,9]
Hepatosplenomegaly may be present.[3,4] Autoimmune phenomena, including pyoderma gangrenosum, vasculitis, and idiopathic thrombocytopenia have been observed in CMML. Care should be taken to identify cases of CMML with eosinophilia, a subtype of CMML, because of its association with severe tissue damage secondary to eosinophil degranulation. In CMML with eosinophilia, all criteria for CMML are present, and the eosinophil count in the peripheral blood is more than 1.5 × 109.
Although clonal cytogenetic abnormalities are found in 20% to 40% of patients with CMML, none is specific.[3,11,12] Point mutations of ras genes may occur in as many as 40% of patients with CMML.[3,12] The median survival time for CMML is 12 to 24 months.[12,13,14] Prognostic factors associated with shorter survival include the following:[12,14]
Progression to acute leukemia occurs in approximately 15% to 20% of cases.[12,14]
Treatment Overview for Myelodysplastic/ Myeloproliferative Neoplasms
Various chemotherapy regimens for CMML have been used with only modest success. In a study evaluating single-agent therapy with topotecan, a topoisomerase I inhibitor, 25 patients with CMML were treated with topotecan at doses that induce bone marrow aplasia (2.0 mg/m2 /day by continuous infusion for 5 days). Complete hematologic remissions were induced in 28% of patients. Toxic effects were significant, and the median duration of remission was 8 months.[Level of evidence: 3iiiDiv] In a follow-up study, topotecan was used in combination with cytarabine, a pyrimidine-analog antimetabolite. This combination regimen induced complete remission in 44% of patients with CMML; median duration of complete response was 50 weeks, and patients required monthly maintenance therapy.[Level of evidence: 3iiiDiv]
Treatment with hydroxyurea is an option. In a randomized clinical trial, 105 patients with advanced CMML were enrolled to compare treatment with hydroxyurea versus treatment with etoposide. Doses were scheduled to escalate to hydroxyurea 4 g/d and etoposide 600 mg/week in the absence of response and finally to adjust to maintain white blood cells between 5 × 109 /L and 10 × 109 /L. Median actuarial survival was 20 months in the hydroxyurea arm versus 9 months in the etoposide arm (P < .001). Main factors associated with poor survival were allocation to the etoposide arm, unfavorable karyotype (i.e., monosomy 7 or complex abnormalities), and anemia.[Level of evidence: 1iiA]
The nucleoside 5-azacitidine is an inhibitor of DNA methyltransferase that has been approved for the treatment of MDS, largely based on a Cancer and Leukemia Group B randomized trial. This trial, in which patients were randomized to supportive care versus 5-azacitidine (75 mg/m2 /day subcutaneously for 7 days every 28 days), included 10 patients with CMML.[Level of evidence: 1iiDii]
Bone marrow transplantation (BMT) or stem cell transplantation appears to be the only current treatment that alters the natural history of CMML. In a review of 118 young MDS patients (median age 24, age range 0.3–53 years) who received allogeneic BMT from matched unrelated donors, the actuarial probability of survival at 2 years for the 12 patients with CMML was 10%. Transplant-related mortality was influenced by the age of the patient (i.e., <18 years, 40%; 18–35 years, 61%; >35 years, 81%). This study included patients who received transplants as early as 1986, which may have influenced the patient survival data.[Level of evidence: 3iiiA] In a recent review of 50 allogeneic transplantations for CMML (i.e., median age 44, age range 19–61 years) from related (n = 43) or unrelated (n = 7) donors, the 5-year-estimated overall survival was 21%. The 5-year estimated probability of relapse was 49%. The data showed a trend for a lower relapse probability of acute graft versus host disease grade II through grade IV and for a higher relapse rate in patients with T cell-depleted grafts, suggesting a graft-versus-CMML effect. This latter series represents the largest cohort of patients with adult CMML and allogeneic stem cell transplantation to date.[Level of evidence: 3iiiA]
A case report suggests that targeted therapy with imatinib mesylate may be effective in a subset of patients with CMML related to PDGFβR fusion oncogenes.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with chronic myelomonocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Note: Juvenile myelomonocytic leukemia (JMML) was classified as a myelodysplastic syndrome (MDS) under the French-American-British scheme. The World Health Organization classification removed JMML from MDS, placing it in the new category Myelodysplastic/ Myeloproliferative Neoplasms (MDS/MPN).[1,2,3]
JMML (also known as juvenile chronic myelomonocytic leukemia) is a rare hematopoietic malignancy of childhood accounting for 2% of all childhood leukemias. A number of clinical and laboratory features distinguish JMML from adult-type chronic myeloid leukemia, a disease noted only occasionally in children. In children presenting with clinical features suggestive of JMML, a definitive diagnosis requires the following:[5,6,7]
Major criteria (all three required)
Minor criteria (two or more required)
The clinical features of JMML at the time of initial presentation may include the following:[5,6,7,8,9]
The clinical and laboratory features of JMML can closely mimic a variety of infectious diseases, including the following:
Laboratory testing can distinguish whether JMML or infectious diseases have affected the clinical and hematologic findings.[5,6,10,11,12]
JMML typically presents in young children (median age approximately 1 year) and occurs more commonly in boys (male to female ratio approximately 2.5:1). The cause for JMML is not known.[6,7] Children with neurofibromatosis type 1 (NF1) are at increased risk for developing JMML, and up to 14% of cases of JMML occur in children with NF1.[9,13]
Morphologically, the peripheral blood picture in this disease shows leukocytosis, anemia, and frequently, thrombocytopenia.[6,7,8,9,14,15] The median reported white blood cell count varies from 25 × 109 /L to 35 × 109 /L. In 5% to 10% of children with JMML, however, it is greater than 100 × 109 /L. The leukocytosis is comprised of neutrophils, promyelocytes, myelocytes, and monocytes. Blasts, including promonocytes, usually account for less than 5% of the white blood cells and always for less than 20%. Nucleated red blood cells are seen frequently. Thrombocytopenia is typical and may be severe.[6,7,8,9,14,15] Bone marrow findings include the following:[6,7,9,14,15]
A distinctive characteristic of JMML leukemia cells is their spontaneous proliferation in vitro without the addition of exogenous stimuli, an ability that results from the leukemia cells being hypersensitive to GM-CSF.[16,17] No Philadelphia chromosome or BCR/ABL fusion gene exists. Although cytogenetic abnormalities, including monosomy 7, occur in 30% to 40% of patients, none is specific for JMML.[6,15,18] In JMML associated with NF1, loss of the normal NF1 allele is common, and loss of heterozygosity for NF1 has been observed in some patients with JMML who lack the NF1 phenotype. This genetic alteration results in a loss of neurofibromin, a protein that is involved in the regulation of the ras family of oncogenes. Point mutations in ras have been reported to occur in the leukemic cells of 20% of patients with JMML.[6,19]
The median survival times for JMML vary from approximately 10 months to more than 4 years, depending partly on the type of therapy chosen.[8,9,20] Prognosis is related to age at the time of diagnosis. The prognosis is better in children younger than 1 year at the time of diagnosis. Children older than 2 years at the time of diagnosis have a much worse prognosis.[6,8] A low platelet count and a high Hb F level have been associated with a worse prognosis.[9,14] Approximately 10% to 20% of cases may evolve to acute leukemia.[8,9]
No consistently effective therapy is available for JMML. Historically, more than 90% of patients have died despite the use of chemotherapy. Patients appeared to follow three distinct clinical courses:
A recent retrospective review described 60 children with JMML treated with chemotherapy (nonintensive and intensive) and/or bone marrow transplantation (BMT) using sibling or unrelated human leukocyte antigen (HLA)-matched donor marrow or autologous marrow. The median survival was 4.4 years.[Level of evidence: 3iiiA]
BMT seems to offer the best chance of cure for JMML.[4,9,20,21,22,23] A summary of the outcome of 91 patients with JMML treated with BMT in 16 different reports is as follows: 38 patients (41%) were still alive at the time of reporting, including 30 of the 60 (50%) patients who received grafts from HLA-matched or 1-antigen mismatched familial donors, 2 of 12 (17%) with mismatched donors, and 6 of 19 (32%) with matched unrelated donors.
In a retrospective study investigating the role of BMT for chronic myelomonocytic leukemia (CMML), 43 children with CMML and given BMT were evaluated. In 25 cases, the donor was a HLA-identical or a one-antigen-disparate relative, in four cases a mismatched family donor, and in 14 cases a matched unrelated donor. Conditioning regimens consisted of total-body radiation therapy and chemotherapy in 22 patients, whereas busulfan with other cytotoxic drugs were used in the remaining patients. Six of 43 patients (14%), five of whom received transplants from alternative donors, failed to engraft. Probabilities of transplant-related mortality for children transplanted from HLA-identical/one-antigen-disparate relatives or from matched unrelated donors/mismatched relatives were 9% and 46%, respectively. The probability of relapse for the entire group was 58%; the 5-year event-free survival (EFS) rate was 31%. The authors of this study concluded that children with CMML and an HLA-compatible relative should be transplanted as early as possible.[Level of evidence: 3iiiDii]
In a more recent retrospective review from Japan, the records of 27 children with JMML who underwent allogeneic hematopoietic stem cell transplantation (SCT) were examined to determine the role of different variables that potentially influence outcome. The source of grafts was HLA-identical siblings in 12 cases, HLA-matched unrelated individuals in 10 cases, and HLA-mismatched donors in five cases. Total-body radiation therapy was used in 18 cases. At 4 years after SCT, EFS and overall survival (OS) were 54.2% (+/- 11.2% standard error [SE]) and 57.9% (+/- 11.0% [SE]), respectively. Six patients died of relapse and three died of complications. Patients with abnormal karyotypes showed a significantly lower OS than those with normal karyotypes (P < .001). Patients younger than 1 year showed a significantly higher OS than those older than 1 year. Other variables studied were not associated with OS. A multivariate analysis of these factors indicated that the abnormal karyotype was the only significant risk factor for lower OS.[Level of evidence: 3iiiA] Five of 10 patients with JMML responded to the oral administration of 13-cis retinoic acid (i.e., two complete responses, three partial responses); median duration of response was 37 months. Treatment with retinoic acid was associated with a decrease in spontaneous colony formation and in GM-CSF hypersensitivity.
Molecular-targeting therapies currently under evaluation include the use of farnesyltransferase inhibitors that prevent ras protein maturation, which may result in increased tumor cell apoptosis and inhibition of tumor cell growth.[17,26]
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with juvenile myelomonocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Atypical chronic myelogenous leukemia (aCML) is a leukemic disorder that exhibits both myelodysplastic and myeloproliferative features at the time of diagnosis.
Atypical CML is characterized pathologically by the following:
Clinical features of aCML include the following:[1,2,3,4]
Although cytogenetic abnormalities are found in as many as 80% of the patients with aCML, none is specific.[1,2,3,5] No Philadelphia chromosome or BCR/ABL fusion gene exists.
The exact incidence of aCML is unknown. The median age at the time of diagnosis of this rare leukemic disorder has been reported to be in the seventh or eighth decade of life.[1,2,3]
Morphologically, aCML is characterized by myelodysplasia associated with bone marrow and peripheral blood patterns similar to chronic myelogenous leukemia, but cytogenetically it lacks a Philadelphia chromosome or BCR/ABL fusion gene. The white blood cell count in the peripheral blood is variable. Median values range from 35 × 109 /L to 96 × 109 /L, and some patients may have white blood cell counts greater than 300 × 109 /L.[1,2,3,5] Blasts in the peripheral blood typically account for less than 5% of the white blood cells. Immature neutrophils usually total 10% to 20% or more. The percentage of monocytes is rarely more than 10%. Minimal basophilia may be present.[1,2,3,5] Nuclear abnormalities, such as acquired Pelger-Huët anomaly, may be seen in the neutrophils. Moderate anemia (often showing changes indicative of dyserythropoiesis) and thrombocytopenia are common.[1,2,3,4] Bone marrow findings include the following: [1,2,3,5]
The median survival times for aCML are reported to be less than 20 months, and thrombocytopenia and marked anemia are poor prognostic factors.[1,2] Atypical CML evolves to acute leukemia in approximately 25% to 40% of patients.[1,3] In the remainder, fatal complications include resistant leukocytosis, anemia, thrombocytopenia, hepatosplenomegaly, cerebral bleeding associated with thrombocytopenia, and infection.[3,4]
The optimal treatment of aCML is uncertain because of the rare incidence of this chronic leukemic disorder. Treatment with hydroxyurea may lead to short-lived partial remissions of 2- to 4-months' duration. Atypical CML, appears to respond poorly to treatment with interferon-alpha.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with atypical chronic myeloid leukemia, BCR-ABL1 negative. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable (MDS/ MPN-UC) (also known as mixed myeloproliferative/ myelodysplastic syndrome, unclassifiable and overlap syndrome, unclassifiable) shows features of both myeloproliferative disease and myelodysplastic disease but does not meet the criteria for any of the other MDS/MPN entities.
Diagnostic criteria for MDS/MPN-UC can be either:
Clinical characteristics of MDS/MPN-UC include the following:
The incidence and etiology of MDS/MPN-UC are unknown.
Laboratory features typically include anemia and dimorphic erythrocytes on the peripheral blood smear. Thrombocytosis (platelet count >600 × 109 /L) or leukocytosis (white blood cell count >13 × 109 /L) are present. Neutrophils may exhibit dysplastic features, and giant or hypogranular platelets may be present. Blasts make up less than 20% of the white blood cells and of the nucleated cells of the bone marrow. The bone marrow is hypercellular and may exhibit proliferation in any or all of the myeloid lineages. Dysplastic features are present in at least one cell line.
No cytogenetic or molecular findings are available that are specific for MDS/MPN-UC. In one small series, six of nine patients (those with ringed sideroblasts associated with marked thrombocytosis [RARS-T]) showed a JAK2 V617F mutation causing constitutive activation of the JAK2 tyrosine kinase (a mutation also commonly observed in patients with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis). Because of its rare occurrence, the prognosis and predictive factors are unknown.
Adult patients with MDS/MPN associated with platelet-derived growth factor receptor gene rearrangements are candidates for imatinib mesylate at standard dosages. Because of its rare occurrence, the literature only minimally addresses other treatment options for MDS/MPN-UC. Supportive care involves treating cytopenias and infection as necessary.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with myelodysplastic/myeloproliferative neoplasm, unclassifiable. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of myelodysplastic/ myeloproliferative neoplasms. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Myelodysplastic/ Myeloproliferative Neoplasms Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Myelodysplastic/ Myeloproliferative Neoplasms Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/mds-mpd/HealthProfessional. Accessed <MM/DD/YYYY>.
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.
More information about contacting us or receiving help with the Cancer.gov Web site can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the Web site's Contact Form.
For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.
The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.
Write to us
For more information from the NCI, please write to this address:
Search the NCI Web site
The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.
There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).
Last Revised: 2012-06-29
How this information was developed to help you make better health decisions.
Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.
Retrieving newsletters from the Web service...
Sorry, the newsletter Web service is unavailable at this time.
You have signed up for the selected newsletters.
© Copyright 2014 Rush-Copley Medical Center • 2000 Ogden Avenue; Aurora, IL 60504
Main: 630-978-6200 • Physician Referral & Information: 630-978-6700 or 866-4COPLEY (866-426-7539)