New Criteria and Novel Agents May Help Spur MDS Advances

Publication
Article
Oncology Live®Vol. 17/No. 12
Volume Vol-17-No-
Issue 12

Although knowledge about the underlying biology of myelodysplastic syndromes has expanded rapidly in recent years, translating those findings into advances in the diagnosis and management of patients remains a significant challenge.

Mikkael A. Sekeres, MD, MS

Although knowledge about the underlying biology of myelodysplastic syndromes (MDS) has expanded rapidly in recent years, translating those findings into advances in the diagnosis and management of patients remains a significant challenge. Key research is focused on the development of drugs for lower-risk patients and second-line therapies for high-risk individuals.

That was the picture that emerged from a panel of experts who discussed key issues in MDS during a recent OncLive Peer Exchange® roundtable entitled “Myelodysplastic Syndromes: Translating Genetics to Clinical Practice.”

“We’re in a remarkable time in the study of MDS where our understanding of the biology is skyrocketing, and we can only hope that the therapies we have available to treat our patients are going to catch up soon,” said Mikkael A. Sekeres, MD, MS, who served as moderator for the discussion.

Ellen K. Ritchie, MD

Defining and Diagnosing MDS

Panelist Ellen K. Ritchie, MD, believes that an increased interest in aging is coinciding with efforts to develop strategies for MDS. “We’re finding that there are mutations that occur as people age that may have dovetailed into the development of disease,” she said. “There is a potential that we could interfere in the early phase of patients who are developing MDS. I think that this is a really exciting avenue of study and we really look forward to seeing what happens in the next few years.”MDS represent a heterogeneous spectrum of hematopoietic disorders, with allogeneic stem cell transplantation being the only curative option currently available, Sekeres noted. Most patients have an acquired somatic gene mutation in the clone, with the hallmark of the clone being ineffective hematopoiesis, said Rami S. Komrokji, MD. Yet, this is not to minimize the role of the microenvironment, he said. “In addition to the clone of the acquired somatic mutations, we have immune response, we have an inflammation going in the microenvironment that definitely contributes probably early on in the disease and to the myelosuppression observed,” Komrokji said.

Rami S. Komrokji, MD

Komrokji also acknowledged that “in a subset of patients we cannot identify clonal events,” either because of limitations of current technology or because these patients might not truly have MDS.

Indeed, panel member Jamile M. Shammo, MD, objected to labeling all cases of MDS as a malignancy. “I tend to think that perhaps on one end of the spectrum, there’s certainly clones and malignancies and propensity for AML [acute myeloid leukemia] development, but on the other side is merely manifestation of bone marrow failure without necessarily having any clones,” Shammo said.

The conundrum extends to how physicians discuss MDS with their patients. Ritchie believes it is important to talk about the spectrum of the disease and not “label it with the big C, necessarily,” because of the detrimental impact that such a characterization can have on the patient’s quality of life. Yet, as Komrokji said, a cancer diagnosis may help patients secure insurance coverage. Further, Sekeres said that the patient who thinks the illness is just a mild blood disorder may be resistant to tolerating the challenges accompanying chemotherapy, thus endangering long-term survival.

The World Health Organization (WHO) is in the process of revising its classification system for MDS, which is currently based on clinical features, peripheral blood and bone marrow findings, and cytogenetic analysis.1 Shammo said the new version may be more streamlined so that it is easier to classify patients and study MDS prospectively. However, Komrokji does not expect the revised WHO system to integrate acquired somatic mutations into the diagnostic criteria.

Changes in Risk Stratification

For diagnosis, a bone marrow biopsy with aspirate and a good core is needed, Ritchie said. Aspirate is sent off for cytogenetic analysis and for next-generation sequencing. She said the biopsy can be “a huge hurdle” for patients because they had thought they had nothing more than “a little anemia” or “a little thrombocytopenia.” And, if biopsy findings are ambiguous and next-generation sequencing identifies mutations or an isolated cytogenetic abnormality, it is “very hard on patients” when, months later, another biopsy is needed, Ritchie said.Another area of MDS management undergoing change is risk stratification. The revised International Prognostic Scoring System (IPSS-R) classifies patients within five risk categories: very low, low, intermediate, high, and very high.2 The IPSS-R places greater weight on the depth of the cytopenia than did the earlier version of this tool, while the IPSS-R continues to encompass such factors as percentage of blasts and cytogenetics.

Jamile M. Shammo, MD,

FASCP, FACP

The IPSS-R includes discussion of several rare conditions with favorable prognoses. Notably, even among patients with lower-risk disease, around 25% of patients “will unfortunately die from the disease or its complications within 2 years,” Komrokji said. This mortality may involve disease-related complications rather than AML transformation. Perhaps 30% to 35% of patients with MDS will die from infection or bleeding, Shammo pointed out. “That is why it is so important for us not just to work on controlling progression to leukemia, but also to deal with the consequences of bone marrow failure,” she said.

As for molecular abnormalities, “we are at the beginning of really understanding the implications of these molecular mutations,” Ritchie said. Many elderly people possess some of the same mutations seen in patients with MDS yet they are healthy and disease free, she noted.

Current Management of MDS

In general, the more mutations patients harbor, the worse their outcome is likely to be, said Sekeres. He said an SF3B1 mutation indicates a good risk but other mutations suggest either neutral or bad risks, with TP53 aberrations suggesting an “obvious bad risk.”Since no therapy has been shown to prolong survival for lower-risk patients, quality of life becomes the focus, Sekeres said.

Shammo’s first goal for patients dependent upon transfusion is achieving transfusion independence. For patients with symptomatic anemia, this means improving hemoglobin levels. For patients without severe anemia, watchful waiting may be reasonable. For patients with neutropenia or thrombocytopenia without symptoms, infection, or bleeding, watchful waiting with periodic monitoring of blood counts may be appropriate.

When she first meets a patient with MDS, Ritchie initiates a long discussion to learn the patient’s expectations around functional status. “Being transfusion- dependent is really a full-time job for a lot of patients,” she said, adding that it is a burden and “a spoiler of quality of life.” And, although achieving transfusion independence is a very important goal, some older patients cannot tolerate low hemoglobin levels, perhaps because of cardiovascular disease.

The panel largely agreed that transfusions should be individualized: that for the patient with platelets <10,000/mm3 and hemoglobin <7 g/dL or 8 g/dL, a transfusion may be desirable; the patient who is asymptomatic with a hemoglobin of 8 g/dL may not need a transfusion; and the patient with severe heart failure may require transfusions to be able to function. The patient who is anemic with an EPO level <500 mU/mL may respond to EPO-stimulating agents, Komrokji said. A growth factor like granulocyte colony-stimulating factor can be added but that may double the erythroid response.

For lower-risk patients, currently available options include immunosuppressive therapy, lenalidomide, and hypomethylating agents. Patients younger than 60 years probably have the highest likelihood of response.

Lenalidomide is the standard of care in the presence of deletion 5q (del[5q]). For patients without del(5q), several studies show approximately 25% to 30% percent responses in achieving transfusion independence with lenalidomide, Komrokji said.

His single-institution experience with lenalidomide suggests sequencing might be important. With patients who are purely anemic, he will use lenalidomide before he administers a hypomethylating agent. In contrast, responses to the DNA methyltransferase inhibitor 5-azacitidine were the same whether it was used as first-line or second-line therapy, he said.

The immunosuppressive agent antithymocyte globulin (ATG) was discussed by Sekeres, who participated in a phase II US study3 that enrolled patients with refractory cytopenia with multilineage dysplasia—not textbook patients with hypocellular bone marrow and not patients enrolled based on HLA-DR status&mdash;and achieved a response rate of 32%.

“The classic teaching about looking for a hypocellular marrow does not necessarily hold with ATG,” he said. Patients may have “an autoimmune destruction of the bone marrow contributing to their MDS picture.”

Especially with lower-risk patients, Ritchie tries to avoid “going to a hypomethylating agent for as long as possible, because once a patient fails a hypomethylating agent we really don’t have a good solution for them.”

The goals of therapy in high-risk MDS are controlling disease, delaying leukemia evolution, and avoiding transfusions and infections, Shammo said. Monitoring without therapy is not appropriate here. For high-risk patients, she typically selects 5-azacitidine (75 mg/m2; 7 days) followed by decitabine (20 mg/m2; 5 days).

Novel Approaches

When should transplantation be considered? For patients with lower-risk disease, as transplant-related mortality is approximately 20% and as chances of 2-year mortality approach zero, immediate transplantation is not appropriate, Komrokji said. For higher-risk patients, there is a 40% to 50% mortality rate in 2 years, so transplantation can be justified even though the curative rates are lower than they are with patients at lower risk levels. Komrokji always discusses treatment goals with patients. Ritchie noted that many patients lack sufficient support for the 2 or 3 years required for an elderly patient to regain pretransplant functional levels.The TGFβ pathway, which is activated or overexpressed in MDS and is implicated in myelosuppression, is emerging as a promising target for new therapies for patients with lower-risk disease. Luspatercept (ACE-536), a modified activin receptor type IIB fusion protein that traps TGFβ family ligands, is being evaluated in the phase III MEDALIST trial (NCT02631070) among patients with low- , very low- , and intermediate-risk MDS.

In phase II study results, 68% of high transfusion burden patients (13 of 19 patients) achieved a reduction of ≥4 units RBC over 8 weeks and 69% of low transfusion burden patients (9 of 13) reached a hemoglobin increase ≥1.5 g/dL for ≥8 weeks.4

Sotatercept (ACE-011), an activin receptor antagonist that modulates TGFβ signaling, stimulated erythropoiesis in nearly half of patients with MDS and nonproliferative chronic myelomonocytic leukemia following failure on erythropoiesis- stimulating agents, according to interim phase II study results that Komrokji presented at the 2015 International MDS Symposium.5

Among the 54 evaluable patients, a majority of those with low transplant burdens achieved sustained increases in hemoglobin levels while 40% of those with high burdens experienced erythroid hematological improvement (hemoglobin increase of ≥1.5 g/dL).5

Shammo said the development of second-line therapies for patients with MDS, particularly those with high-risk disease, is an important area of research. She noted that rigosertib, a small molecule that inhibits cell signaling in the RAS pathway, has entered phase III testing in the ASPIRE trial (NCT02562443).

The trial will evaluate rigosertib plus best supportive care versus treatment of physician’s choice from standard-ofcare options among patients with MDS who have failed treatment with azacitidine or decitabine.

References

  1. Foster MC. Myelodysplastic syndromes staging. Medscape website. emedicine.medscape.com/article/2007806-overview. Updated December 31, 2015. Accessed June 1, 2016.
  2. Revised International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes risk assessment calculator. MDS Foundation website. www.mdsfoundation.org/calculator/advanced/. Accessed June 1, 2016.
  3. Komrokji RS, Mailloux AW, Chen DT, et al. A phase II multicenter rabbit anti-thymocyte globulin trial in patients with myelodysplastic syndromes identifying a novel model for response prediction. Haematologica. 2014;99(7):1176-1183.
  4. Giagounidis A, Platzbecker U, Germing U, et al. Luspatercept treatment leads to long term increases in hemoglobin and reductions in transfusion burden in patients with low or intermediate-1 risk myelodysplastic syndromes (MDS): preliminary results from the phase 2 PACE-MDS Extension Study. Blood. 2015;126(13):92.
  5. Komrokji R, Garcia-Manero G, Ades L, et al. A phase 2, dose-finding study of sotatercept (ACE-011) in patients with lower-risk myelodysplastic syndromes (MDS) or non-proliferative chronic myelomonocytic leukemia (CMML) and anemia requiring transfusion. Leukemia Research. 2015;39:1s(suppl; abstr 16).
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