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.

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.

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

View Full Size

View Full Size

View Full Size

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.^16–18 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 MDS^17,19 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).

View Full Size

View Full Size

Mutations in the IDH1 or IDH2 genes occur in approximately 4% to 12% of patients with MDS.^20–22 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).

View Full Size

View Full Size

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 XPC^delTG, ERCC6L2, and LIG-4.^31–36

View Full Size

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.

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.