NCCN Guidelines® Insights: Myelodysplastic Syndromes, Version 3.2022

Featured Updates to the NCCN Guidelines

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  • 1 Stanford Cancer Institute;
  • | 2 Dana-Farber/Brigham and Women’s Cancer Center;
  • | 3 Mayo Clinic Cancer Center;
  • | 4 University of Rochester;
  • | 5 The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute;
  • | 6 Massachusetts General Hospital Cancer Center;
  • | 7 UCLA Jonsson Comprehensive Cancer Center;
  • | 8 City of Hope National Medical Center;
  • | 9 Duke Cancer Institute;
  • | 10 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • | 11 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 12 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 13 University of Michigan Rogel Cancer Center;
  • | 14 UCSF Helen Diller Family Comprehensive Cancer Center;
  • | 15 The University of Texas MD Anderson Cancer Center;
  • | 16 Roswell Park Comprehensive Cancer Center;
  • | 17 Vanderbilt-Ingram Cancer Center;
  • | 18 UC Davis Comprehensive Cancer Center;
  • | 19 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 20 Fred & Pamela Buffett Cancer Center;
  • | 21 UC San Diego Moores Cancer Center;
  • | 22 Abramson Cancer Center at the University of Pennsylvania;
  • | 23 University of Colorado Cancer Center;
  • | 24 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 25 O'Neal Comprehensive Cancer Center at UAB;
  • | 26 Moffitt Cancer Center;
  • | 27 Yale Cancer Center/Smilow Cancer Hospital;
  • | 28 Huntsman Cancer Institute at the University of Utah;
  • | 29 St. Jude Children's Research Hospital/The University of Tennessee Health Science Center;
  • | 30 Fox Chase Cancer Center;
  • | 31 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; and
  • | 32 National Comprehensive Cancer Network.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-22-002-H01-P

Physician Assistants: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until February 10, 2023. PAs should only claim credit commensurate with the extent of their participation.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/91068; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.

Release date: February 10, 2022; Expiration date: February 10, 2023

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to the NCCN Guidelines for Myelodysplastic Syndromes

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Myelodysplastic Syndromes

Disclosure of Relevant Financial Relationships

None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

Individuals Who Provided Content Development and/or Authorship Assistance:

The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.

Aref Al-Kali, MD, Panel Member

H. Joachim Deeg, MD, Panel Member

Vishnu V. Reddy, MD, Panel Member

Rory Shallis, MD, Panel Member

Elizabeth Hollinger, BSN, RN, Guidelines Layout Specialist

Dorothy A. Shead, MS, Senior Director, Patient Information Operations

Cindy Hochstetler, PhD, Oncology Scientist/Medical Writer

The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.

Peter L. Greenberg, MD, Panel Chair, consulting fees from Novartis Pharmaceuticals Corporation.

Richard M. Stone, MD, Panel Vice Chair, scientific advisor for AbbVie Inc., Argos Therapeutics, Boston Scientific Corporation, CTI BioPharm Corp., Genentech, Inc., Janssen Pharmaceutica Products, LP, Jazz Pharmaceuticals Inc., Novartis Pharmaceuticals Corporation, and Syros Pharmaceuticals.

To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.

This activity is supported by educational grants from AstraZeneca; BeiGene; Exact Sciences; Gilead Sciences, Inc.; GlaxoSmithKline; Lantheus Medical Imaging Inc.; Novartis; Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Astellas. This activity is supported by an education grant from Astellas and Seagen Inc. This activity is supported by a medical education grant from Karyopharm® Therapeutics. This activity is supported through an Independent Medical Education grant from Merck & Co., Inc.

Overview

Myelodysplastic syndromes (MDS) encompass a group of myeloid clonal hemopathies with a relatively heterogenous spectrum of presentation. Diagnosis and disease stratification are based on multiple factors, which may include clinical data, morphology of peripheral blood and bone marrow, fluorescence in situ hybridization, cytogenetics, flow cytometry, and next-generation sequencing myeloid mutation studies. The major clinical problems resulting from these disorders are morbidities caused by cytopenias and the potential for MDS to evolve into acute myeloid leukemia (AML). In addition, there are complications that may arise from chronic transfusions, treatment toxicity, and in some cases, secondary phenomena such as systemic inflammatory conditions.1 The incidence rate of MDS is approximately 4.5 per 100,000 people per year in the general population.2 MDS is rare among children, adolescents, and young adults. Accounting for 1.6% of patients diagnosed with MDS, individuals aged <40 years have an incidence of 0.1 per 100,000 people per year. However, this incidence increases to 26.9 per 100,000 for those between age 70 and 79 years, and to 55.4 per 100,000 for those aged ≥80 years.2 Management of MDS is complicated by the generally advanced age of patients (median age, 77 years),3 the nonhematologic comorbidities commonly seen in this cohort, and the relative inability of older patients to tolerate certain intensive forms of therapy. Upon disease progression to AML, these patients experience lower response rates to standard therapy compared with patients with de novo AML.4

The MDS panel has proposed stratifying patients with clinically significant cytopenia(s) into 2 major risk groups: (1) patients with lower-risk MDS (ie, international prognostic scoring system [IPSS] low, intermediate-1 [int-1]; revised IPSS [IPSS-R] very low, low, intermediate; WHO prognostic scoring system [WPSS] very low, low, intermediate); and (2) patients with higher-risk MDS (ie, IPSS int-2, high; IPSS-R intermediate, high, very high; WPSS high, very high). Patients with IPSS-R intermediate risk may be managed as lower risk if their score is ≤3.5 versus higher risk if their score is >3.5.5 In addition, factors such as patient age, performance status, and presence of comorbidities have a major influence on the patient's ability to tolerate certain intensive treatments, and play a major role in selecting the optimal management strategy.

Management of Lower-Risk MDS

During the annual meeting to update the NCCN Guidelines for MDS in 2022, the panel revisited the recommendation for oral decitabine and cedazuridine, which was previously included as a footnote, and agreed to add this recommendation directly in the algorithm (see MDS-3 and MDS-5, page 108 and above, respectively). As the clinical study documenting bioequivalence for this combination enrolled patients with IPSS int-1 and above, the panel decided to specify the prognostic risk category in a footnote: “Oral decitabine and cedazuridine could be a substitution for intravenous decitabine in patients with IPSS int-1 and above” (see MDS-3 and MDS-5A, pages 108 and 110, respectively).6

Furthermore, the panel discussed the addition of eltrombopag to immunosuppressive therapy (IST) for patients with lower-risk MDS, and voted to modify a footnote (see MDS-3, page 108). In the setting of clinically relevant thrombocytopenia or neutropenia, IST is recommended as an option that is useful in certain circumstances for select patients (generally those aged ≤60 years and with ≤5% marrow blasts, or those with hypocellular marrows, paroxysmal nocturnal hemoglobinuria [PNH] clone positivity, or STAT-3–mutant cytotoxic T-cell clones). IST includes equine ATG, with or without cyclosporin A, and with or without eltrombopag. A phase I/II trial examined the combination of IST with eltrombopag, a thrombopoietin (TPO) agonist also known as a TPO mimetic, in patients with aplastic anemia (not MDS).7 Three cohorts were used that differed by the schedule for the start of treatment and the duration of treatment. The most common grade ≥3 adverse event attributed to eltrombopag was an abnormality in a liver test (18%), specifically transaminase elevation and/or hyperbilirubinemia. The complete hematologic response and overall response rate (ORR) for the combined cohorts at 6 months, when compared with a historical cohort of 102 patients who were treated with IST, were 39% (95% CI, 29%–49%) versus 10% and 87% (95% CI, 80%–94%) versus 66%, respectively. The rate of clonal evolution was not increased in patients who received eltrombopag compared with a historical cohort at the 2-year time point. A phase II trial with patients with aplastic anemia reported an ORR of 76% in those receiving the combination treatment compared with 71% in those treated with IST only.8 The complete remission rate, median time to response, and survival rate at 2 years were similar in both groups. Concerns for potential proliferation of leukemic blasts in response to exogenous TPO have been raised in earlier in vitro studies, particularly for high-risk MDS.9,10 Results from ongoing clinical trials with TPO mimetics will help elucidate the risks for leukemic transformations in patients with MDS. It should be noted that eltrombopag is not currently approved for use in patients with MDS. The panel voted to add eltrombopag as a treatment option in combination with ATG, with or without cyclosporin A, for patients with symptomatic anemia with no del(5q), with or without other cytogenetic abnormalities, with ring sideroblasts <15% (or ring sideroblasts <5% with an SF3B1 mutation), serum erythropoietin >500 mU/mL, and good probability to respond to IST (see MDS-5 and MDS-5A, page 109 and above, respectively). Eltrombopag combinations are category 2B recommendations.

Following a panel vote, eltrombopag was added as a treatment option for patients with lower-risk MDS with certain cytopenias (see MDS-3, page 108). The panel updated a footnote to include that eltrombopag alone could be considered for severe thrombocytopenia. A phase II study enrolled patients with low-risk or IPSS int-1 risk MDS with severe thrombocytopenia who were randomized 2:1 to receive eltrombopag or placebo.11 At the time of the interim analysis, in the intention-to-treat population, 47% of patients receiving eltrombopag demonstrated a platelet response, as opposed to 3% of patients in the placebo group (P<.0001; odds ratio, 27.1 [95% CI, 3.5–211.9; P=.0017]), and 46% of patients in the eltrombopag arm had grade 3/4 adverse events compared with 16% in the placebo group (P=.0053). Fewer bleeding events were reported in the eltrombopag arm compared with the placebo arm (14% vs 42%, respectively; P=.0025). Results from another phase II trial determined that eltrombopag monotherapy in patients with lower-risk MDS with cytopenia, including anemia, thrombocytopenia, or neutropenia, led to a 44% rate of hematologic response at 16 to 20 weeks.12 A few patients acquired chromosomal abnormalities. A study by Fan et al13 found that 50% of patients with moderate aplastic anemia or unilineage cytopenias (platelet count <30 × 109/L or dependence on platelet transfusions or hemoglobin count <8.5 g/dL or dependence on RBC transfusions) treated with eltrombopag achieved a clinically meaningful response at 16 to 20 weeks. Of 34 patients, 2 acquired cytogenetic abnormalities.

The panel received an external request to consider the inclusion of luspatercept-aamt as a treatment option for patients with anemia and lower-risk MDS without ring sideroblasts. After a thorough discussion, the panel did not recommend luspatercept-aamt for such patients because the data are only available in abstract format14 and the drug is not FDA-approved for this indication. The panel updated a footnote to highlight the emerging data on luspatercept-aamt for this group of patients and recommends such patients enroll in a clinical trial for the use of this agent (see MDS-5A, opposite page).

The panel members also discussed imetelstat, a telomerase inhibitor. Given that it is not FDA-approved, a decision was made to include information about imetelstat in the discussion section rather than in the algorithm. In a phase II trial comprising 57 patients with lower-risk MDS that had relapsed or was refractory to erythropoiesis-stimulating agents (ESAs) and who were RBC transfusion–dependent, treatment with imetelstat resulted in 37% and 23% rates of RBC transfusion independence (TI) at 8 and 24 weeks, respectively.15 At the same time points, RBC-TI rates of 42% and 29%, respectively, were observed in a subgroup of 38 patients without del(5q) and who were not previously treated with a hypomethylating agent (HMA) or lenalidomide. The median duration for TI was 65 weeks for the overall group compared with 86 weeks in the subgroup. Hematologic improvement, in terms of erythroid response per the International Working Group 2006 response criteria, was achieved in 65% of patients in the overall group and 68% of patients in the subgroup. Overall, the most common grade ≥3 hematologic adverse events were neutropenia (60%), thrombocytopenia (54%), and anemia (19%). At 5%, the most common grade ≥3 nonhematologic adverse events were back pain, increased alanine aminotransferase, increased aspartate aminotransferase, and bronchitis.

Management of Higher-Risk MDS

The panel included the combination of oral decitabine and cedazuridine directly in the algorithm for patients with higher-risk MDS and noted that the combined oral formulation could be a substitution for intravenous decitabine in patients with IPSS int-1 and above (see MDS-6 and MDS-6A, above and page 112, respectively).6 The panel also discussed recommendations for the management of higher-risk MDS and debated the merits of emerging therapies, such as the combination of venetoclax and HMAs, and noted that published phase III data for this combination are not available. There are also limited data for the use of targeted drugs such as IDH inhibitors for patients with MDS. As overexpression of the B-cell lymphoma 2 (BCL-2) protein has been linked to disease progression in MDS, studies are ongoing to investigate the efficacy and safety of venetoclax, a BCL-2 inhibitor, in patients with MDS either first-line or refractory or resistant to HMAs.1618 Preliminary results from a phase Ib study investigating the combination of venetoclax and azacitidine (AzaC) for 14 days in a 28-day cycle in up-front higher-risk MDS (IPSS int-2 or high) resulted in an ORR, median overall survival (OS), median progression-free survival, and median duration of response of 77%, not reached (95% CI, 16.2 months–not estimable), 17.5 months (14.5 months–not estimable), and 14.8 months (95% CI, 12.9 months–not estimable), respectively.17 The most frequent grade ≥3 adverse events were neutropenia (51%), febrile neutropenia (46%), and thrombocytopenia (30%). In a study exploring venetoclax as a salvage agent alone or in combination, preliminary results showed an ORR of 7% with venetoclax alone compared with 50% with venetoclax/AzaC.18 The panel updated a footnote to mention that emerging data have shown the efficacy of venetoclax in combination with HMAs or targeted IDH1/2 inhibitors for cytoreduction in patients with high-risk MDS17,19 refractory to HMAs (see MDS-6A, above). When used as cytoreduction for MDS in combination with an HMA, venetoclax has been effectively given for 14 days in monthly courses.17 Repeating the bone marrow evaluation after 1 to 2 cycles is important to clarify the recovery of hematopoiesis and potential requirement for further therapy.17 Clinical trials are preferred (eg, ClinicalTrials.com identifier: NCT04401748).

Mutations in the IDH1 or IDH2 genes occur in approximately 4% to 12% of patients with MDS.2022 Ongoing clinical trials are investigating the efficacy of targeted IDH1/2 inhibitors in patients with MDS (NCT03503409, NCT03471260, and NCT03744390). A phase I trial evaluating the efficacy and safety of ivosidenib in patients with AML or MDS with an IDH1 mutation19 found that of 12 patients with MDS, 11 had an overall response, 5 of whom achieved complete remission. A phase I/II trial evaluating the efficacy and safety of enasidenib, an inhibitor of the mutant IDH2 protein, found a 53% ORR (95% CI, 28%–77%), a median OS of 16.9 months (95% CI, 1.5–32.3 months), and a median duration of response of 9.2 months (95% CI, 1.0 month–not reached) in patients with MDS with an IDH2 mutation.23 Hyperbilirubinemia (35%), pneumonia (29%), and thrombocytopenia (24%) were the most frequent grade 3/4 treatment-emergent adverse occurrences. A phase II study in patients with higher-risk IDH2-mutated MDS/chronic myelomonocytic leukemia or low-blast AML determined an ORR, complete remission rate, and hematologic improvement rate of 84%, 24%, and 8%, respectively, in patients with no prior HMA treatment, compared with 43%, 24%, and 10%, respectively, in patients with disease that progressed or was refractory to HMA treatment.24 Frequent treatment-related grade 3/4 adverse occurrences reported in the combination arm included neutropenia (64%), thrombocytopenia (28%), and anemia (8%), as opposed to 10%, 0%, and 5%, respectively, in the monotherapy arm.

HMAs are listed as treatment options for patients with higher-risk MDS who are not eligible for transplant or as a bridge to transplant. In 2021, the panel completed the stratification of systemic therapy recommendations for patients with higher-risk MDS (see MDS-6, page 111). AzaC is listed as “preferred,” while decitabine and the combination of oral decitabine and cedazuridine are listed as “other recommended regimens,” both for nontransplant candidates as well as for individuals with MDS that relapsed after allogeneic hematopoietic cell transplant or did not respond. Clinical trial is also an option for these patients. Although the response rates for AzaC and decitabine are similar, survival benefit from one phase III randomized trial has been reported for AzaC25 and not for decitabine.

The panel also discussed the recent data regarding allogeneic hematopoietic cell transplant (HCT) versus continued HMA therapy for treating patients with higher-risk MDS, indicating a survival advantage for patients who underwent transplantation.26 These data have since been published.27 At 3 years, an intention-to-treat analysis revealed that the adjusted OS rate in patients aged 50 to 75 years was 47.9% (95% CI, 41.3%–54.1%) and 26.6% (95% CI, 18.4%–35.6%; P=.0001) for those in the donor arm (expected to undergo reduced-intensity conditioning HCT, n=260) and the no-donor arm (expected to receive HMA therapy or best supportive care, n=124), respectively. In addition, at the same time point, the leukemia-free survival rate was 35.8% (95% CI, 29.8%–41.8%) versus 20.6% (95% CI, 13.3%–29.1%; P=.003), respectively. Subgroup analyses showed no differences in outcomes by age ≤65 versus >65 years. Another study examined retrospectively the outcomes of patients with high-risk MDS or secondary AML who underwent transplantation without prior cytoreductive therapy (n=67) compared with those who received cytoreductive therapy in the form of induction chemotherapy (n=64) or HMAs (n=34) prior to transplantation.28 Patients had a blast count of ≥5% in the bone marrow. Reduced-intensity conditioning was applied before stem cell infusion in 68% of patients. Compared with the other groups, a higher percentage of patients in the HMA group (85%) were treated with a reduced-intensity conditioning regimen, which is likely due to the difference in age. Multivariate analyses revealed that the type of pretransplant treatment did not impact OS, relapse-free survival (RFS), and nonrelapse mortality. However, cytogenetics, reduced-intensity conditioning, and use of an unrelated donor were found to be predictors of negative outcomes. At 5 years, there was no difference in OS (61%, 50%, and 45%, respectively; P=.116) and RFS (38%, 41%, and 38%, respectively; P=.926) between the 3 groups. OS (P=.971) and RFS (P=.883) were similar in patients with blasts <10% or ≥10% in the bone marrow who underwent transplantation without prior cytoreductive therapy.

Based on the positive results of the donor versus no-donor analysis,26,27 a footnote was amended to clarify that early referral to transplant is recommended to allow moving to transplant efficiently (see MDS-6A, page 112). Pretransplant debulking therapy to reduce marrow blasts to <5% blasts with the goal of reducing posttransplant relapse is recommended, although the optimum strategy has not been determined. Reducing the disease burden pretransplant is particularly important in patients who will receive a reduced-intensity conditioning regimen.29 At some centers, failure to achieve <5% blasts with cytoreduction did not preclude from proceeding to transplant, as these patients appeared to derive survival benefit from transplant.27,28

An argument in favor of pretransplant cytoreduction was provided by Festuccia et al,29 who showed that the presence of minimal identifiable disease (MID) prior to transplantation in patients with MDS or AML arising from MDS impacted prognosis following transplantation. Among patients who were MID-positive by cytogenetics, irrespective of positivity by flow cytometry, the overall mortality risk was higher in those who underwent low-intensity conditioning compared with those who underwent high-intensity conditioning. However, in patients with an MID-negative status, as determined by both cytogenetics and flow cytometry, the risk of mortality with low- and high-intensity conditioning regimens was similar. It is important to note that this study did not specifically examine outcomes in patients who proceeded to transplant without cytoreductive therapy. Among patients with an MID-positive status, as assessed by both cytogenetics and flow cytometry, the risk of relapse was higher in those who underwent low-intensity conditioning, as opposed to those who underwent high-intensity conditioning. As the MID classification can help identify patient subgroups that may have better outcomes with high- or low-intensity conditioning, the authors propose considering the presence of MID to help determine the intensity of the conditioning regimen for patients being considered for transplant.

Supportive Care

Supportive care is an important aspect of MDS management, which entails observation, clinical monitoring, psychosocial support, and quality-of-life (QoL) assessment. In the 2022 update, the panel included some new recommendations for the pretransplant and posttransplant settings (see MDS-7 and MDS-8, page 113 and opposite page, respectively). Prior to transplant, transplant patients should receive support. Transfusion products should be irradiated with 25 Gy or per institution standard. Patients with ≥5% marrow blasts who are candidates for reduced-intensity conditioning are encouraged to receive “debulking” therapy with an HMA or induction chemotherapy. Transplantation should be carried out as long as patients are experiencing response and should not be delayed until the response is lost. Posttransplantation, patients should receive antibiotic prophylaxis at least as long as they are on immunosuppressive therapy. Detailed recommendations are provided in the guidelines generated by the American Society of Transplantation and Cellular Therapy30 and the NCCN Guidelines for Hematopoietic Cell Transplantation (available at NCCN.org).

Genetic Familial High-Risk Assessment: Hereditary Myeloid Malignancy Predisposition Syndromes

Molecular and genetic screening for hereditary hematologic malignancy predisposition is recommended in a subset of patients, particularly those aged <50 years. Diseases, syndromes, and mutations that may potentially be associated include GATA2 deficiency syndrome, Shwachman-Diamond syndrome, short telomere syndromes, DDX41 mutations (usually present at older ages), and others (see “Genetic/Familial High-Risk Assessment: Hereditary Myeloid Malignancy Predisposition Syndromes” and “Gene Mutations Associated with Hereditary Myeloid Malignancies” in the full algorithm at NCCN.org). This year, a subcommittee of the NCCN MDS Panel worked on updating recommendations for genetic familial high-risk assessment of hereditary myeloid malignancy predisposition syndromes. The subcommittee members discussed the new proposed content and panel members reviewed the content during the panel review process. The guidelines include information about pretest counseling prior to ordering testing, appropriate DNA source for germline genetic testing, consideration of the appropriate genetic testing methodologies and other diagnostic testing, and postcounseling performed when the test results are disclosed. In this update, limitations of the proposed approach were added to the recommendations, as well as recommendations about which patients should undergo surveillance, namely individuals who fulfill the clinical diagnostic criteria for a myeloid neoplasm with a germline predisposition (even if the pathogenic variant is undetermined), as well as individuals with a deleterious or likely deleterious genetic variant associated with a germline predisposition, regardless of clinical presentation (see MDS-D 4 of 5, page 115). In the evaluation for suspected hereditary myeloid malignancy predisposition syndromes, the panel included individuals with aberrations of chromosome 7 and age <50 years among individuals for whom testing is recommended, and also updated allogeneic sibling donor to allogeneic related donor in this setting. The panel also included information about some newly added germline gene mutations that are associated with hereditary myeloid malignancies, more specifically XPCdelTG, ERCC6L2, and LIG-4.3136

Conclusions

The NCCN Guidelines for MDS are based on extensive evaluation of the reviewed risk-based data and indicate current approaches for managing patients with MDS. These NCCN Guidelines Insights highlight some of the updated recommendations, preference stratification, and emerging data on novel agents. Treatment options vary based on the risk category and clinical characteristics. Ongoing clinical trials are underway to investigate new therapeutic avenues, and the results of these trials may help inform the panel’s recommendations.

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    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Zeidan AM, Pollyea DA, Garcia JS, et al. A phase 1b study evaluating the safety and efficacy of venetoclax as monotherapy or in combination with azacitidine for the treatment of relapsed/refractory myelodysplastic syndrome [abstract]. Blood 2019;134(Suppl):Abstract 565.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 2018;378:23862398.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Thol F, Weissinger EM, Krauter J, et al. IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica 2010;95:16681674.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Kosmider O, Gelsi-Boyer V, Slama L, et al. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 2010;24:10941096.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Patnaik MM, Hanson CA, Hodnefield JM, et al. Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic study of 277 patients. Leukemia 2012;26:101105.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Stein EM, Fathi AT, DiNardo CD, et al. Enasidenib in patients with mutant IDH2 myelodysplastic syndromes: a phase 1 subgroup analysis of the multicentre, AG221-C-001 trial. Lancet Haematol 2020; 7:e309319.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Venugopal S, Dinardo CD, Takahashi K, et al. Phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes (MDS) [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 7010.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. 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;10:223232.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Nakamura R, Saber W, Martens MJ, et al. A multi-center biologic assignment trial comparing reduced intensity allogeneic hematopoietic cell transplantation to hypomethylating therapy or best supportive care in patients aged 50-75 with advanced myelodysplastic syndrome: Blood and Marrow Transplant Clinical Trials Network study 1102 [abstract]. Blood 2020;136(Suppl):1921.

    • Search Google Scholar
    • Export Citation
  • 27.

    Nakamura R, Saber W, Martens MJ, et al. Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50-75 years of age with advanced myelodysplastic syndrome. J Clin Oncol 2021;39:33283339.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Schroeder T, Wegener N, Lauseker M, et al. Comparison between upfront transplantation and different pretransplant cytoreductive treatment approaches in patients with high-risk myelodysplastic syndrome and secondary acute myelogenous leukemia. Biol Blood Marrow Transplant 2019;25:15501559.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Festuccia M, Deeg HJ, Gooley TA, et al. Minimal identifiable disease and the role of conditioning intensity in hematopoietic cell transplantation for myelodysplastic syndrome and acute myelogenous leukemia evolving from myelodysplastic syndrome. Biol Blood Marrow Transplant 2016;22:12271233.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2015;21:18631869.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Sarasin A, Quentin S, Droin N, et al. Familial predisposition to TP53/complex karyotype MDS and leukemia in DNA repair-deficient xeroderma pigmentosum. Blood 2019;133:27182724.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Oetjen KA, Levoska MA, Tamura D, et al. Predisposition to hematologic malignancies in patients with xeroderma pigmentosum. Haematologica 2020;105:e144146.

  • 33.

    Tummala H, Kirwan M, Walne AJ, et al. ERCC6L2 mutations link a distinct bone-marrow-failure syndrome to DNA repair and mitochondrial function. Am J Hum Genet 2014;94:246256.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Tummala H, Dokal AD, Walne A, et al. Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants. Proc Natl Acad Sci USA 2018;115:77777782.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Douglas SPM, Siipola P, Kovanen PE, et al. ERCC6L2 defines a novel entity within inherited acute myeloid leukemia. Blood 2019;133:27242728.

  • 36.

    Chistiakov DA, Voronova NV, Chistiakov AP. Ligase IV syndrome. Eur J Med Genet 2009;52:373378.

NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.

The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2022.

All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

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    Garcia JS, Wei AH, Borate U, et al. Safety, efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: a phase 1b study [abstract]. Blood 2020;136(Suppl):5557.

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    Zeidan AM, Pollyea DA, Garcia JS, et al. A phase 1b study evaluating the safety and efficacy of venetoclax as monotherapy or in combination with azacitidine for the treatment of relapsed/refractory myelodysplastic syndrome [abstract]. Blood 2019;134(Suppl):Abstract 565.

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    • Search Google Scholar
    • Export Citation
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    DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 2018;378:23862398.

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    • Search Google Scholar
    • Export Citation
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    Thol F, Weissinger EM, Krauter J, et al. IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica 2010;95:16681674.

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    • PubMed
    • Search Google Scholar
    • Export Citation
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    Kosmider O, Gelsi-Boyer V, Slama L, et al. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 2010;24:10941096.

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    • PubMed
    • Search Google Scholar
    • Export Citation
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    Patnaik MM, Hanson CA, Hodnefield JM, et al. Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic study of 277 patients. Leukemia 2012;26:101105.

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    • Search Google Scholar
    • Export Citation
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    Stein EM, Fathi AT, DiNardo CD, et al. Enasidenib in patients with mutant IDH2 myelodysplastic syndromes: a phase 1 subgroup analysis of the multicentre, AG221-C-001 trial. Lancet Haematol 2020; 7:e309319.

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  • 24.

    Venugopal S, Dinardo CD, Takahashi K, et al. Phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes (MDS) [abstract]. J Clin Oncol 2021;39(Suppl):Abstract 7010.

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    • Search Google Scholar
    • Export Citation
  • 25.

    Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. 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;10:223232.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Nakamura R, Saber W, Martens MJ, et al. A multi-center biologic assignment trial comparing reduced intensity allogeneic hematopoietic cell transplantation to hypomethylating therapy or best supportive care in patients aged 50-75 with advanced myelodysplastic syndrome: Blood and Marrow Transplant Clinical Trials Network study 1102 [abstract]. Blood 2020;136(Suppl):1921.

    • Search Google Scholar
    • Export Citation
  • 27.

    Nakamura R, Saber W, Martens MJ, et al. Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50-75 years of age with advanced myelodysplastic syndrome. J Clin Oncol 2021;39:33283339.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Schroeder T, Wegener N, Lauseker M, et al. Comparison between upfront transplantation and different pretransplant cytoreductive treatment approaches in patients with high-risk myelodysplastic syndrome and secondary acute myelogenous leukemia. Biol Blood Marrow Transplant 2019;25:15501559.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Festuccia M, Deeg HJ, Gooley TA, et al. Minimal identifiable disease and the role of conditioning intensity in hematopoietic cell transplantation for myelodysplastic syndrome and acute myelogenous leukemia evolving from myelodysplastic syndrome. Biol Blood Marrow Transplant 2016;22:12271233.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2015;21:18631869.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Sarasin A, Quentin S, Droin N, et al. Familial predisposition to TP53/complex karyotype MDS and leukemia in DNA repair-deficient xeroderma pigmentosum. Blood 2019;133:27182724.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Oetjen KA, Levoska MA, Tamura D, et al. Predisposition to hematologic malignancies in patients with xeroderma pigmentosum. Haematologica 2020;105:e144146.

  • 33.

    Tummala H, Kirwan M, Walne AJ, et al. ERCC6L2 mutations link a distinct bone-marrow-failure syndrome to DNA repair and mitochondrial function. Am J Hum Genet 2014;94:246256.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Tummala H, Dokal AD, Walne A, et al. Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants. Proc Natl Acad Sci USA 2018;115:77777782.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Douglas SPM, Siipola P, Kovanen PE, et al. ERCC6L2 defines a novel entity within inherited acute myeloid leukemia. Blood 2019;133:27242728.

  • 36.

    Chistiakov DA, Voronova NV, Chistiakov AP. Ligase IV syndrome. Eur J Med Genet 2009;52:373378.

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