Dr Sallman on the Significance of the FDA Approval of Luspatercept for Lower-Risk MDS

David Sallman, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses the clinical implications of 

the 2023 FDA approval of luspatercept-aamt (Reblozyl)

 for the first-line treatment of anemia in patients with very low– to intermediate-risk myelodysplastic syndrome (MDS). Notably, the agent was approved for those without prior erythropoiesis-stimulating agent (ESA) use who may require regular red blood cell (RBC) transfusions.

The regulatory approval of luspatercept was supported by findings from the phase 3 COMMANDS trial (NCT03682536). Treatment with luspatercept demonstrated superior rates of concurrent RBC transfusion independence (RBC-TI) and hemoglobin (Hb) increase vs treatment with epoetin alfa, irrespective of ring sideroblast status. As such, 58.5% (n = 86) of patients who were treated with luspatercept achieved the primary end point of RBC-TI of at least 12 weeks with a mean Hb increase of at least 1.5 g/dL within the first 24 weeks vs 31.2% (n = 48) of those given epoetin alfa (

Sallman says that in patients with MDS with ring sideroblasts, luspatercept is the most effective frontline therapy. In COMMANDS, the overall response rate with luspatercept was high, particularly in patients who were transfusion-dependent, he explains. For optimal treatment decisions, it is essential to perform a bone marrow biopsy and conduct molecular testing for the 

 mutation, Sallman notes. This ensures accurate diagnosis, as ring sideroblasts may be missed during staining, according to Sallman. Despite luspatercept’s proven efficacy in this population, its widespread adoption has not yet occurred in the broader medical community, though this agent should be more universally accepted as the optimal therapy for MDS with 

However, the use of luspatercept in non–ring sideroblast cases is controversial, Sallman continues. Although outcomes with luspatercept vs epoetin alfa were not inferior in these patients, the agent’s superiority was not dramatic, he states. Erythropoietin levels are also a key consideration, as patients with levels greater than 200 U/L tend to respond less well to ESAs than those with lower levels, he emphasizes. This strengthens the case for the use of luspatercept in this group, he notes. Although opinions may differ on whether luspatercept should be applied universally in MDS, it has undeniably revolutionized the treatment of frontline patients with MDS harboring 

mutations, with most of these patients achieving a favorable response with the agent, Sallman concludes.

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David Sallman, MD, discusses the clinical implications of the 2023 FDA approval of luspatercept for patients with very low– to intermediate-risk MDS.

Dr Sallman on the Significance of the FDA Approval of Frontline Luspatercept for Lower-Risk MDS

Dr Sallman on the Rationale For Investigating Fedratinib in MDS/MPN Overlap Syndromes

David A. Sallman, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses the rationale for conducting a phase 2, multi-institutional, investigator-initiated clinical trial (NCT05177211) on the use of fedratinib (Inrebic) in patients with myelodysplastic syndromes (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes and chronic neutrophilic leukemia.

This investigator-initiated trial was primarily motivated by the challenging treatment paradigm for patients with MDS/MPN overlap syndromes, Sallman begins. The unique characteristics of this patient population contribute to the exclusion of these patients from most MDS and MPN trials, he states. Despite the heterogeneity within this patient population, patients often have similar symptoms, Sallman note. These patients also often experience symptomatic splenomegaly and significant symptom burdens akin to those associated with MPNs, Sallman explains.

The central objective of the trial was to assess the potential applicability of JAK inhibitors, which have transformed the treatment paradigm for primary myelofibrosis, to patients with MDS/MPN overlap syndromes, he expands. Given the limited therapeutic options available for these patients, the trial explored the off-label use of the FDA-approved dose of fedratinib in this population, Sallman elucidates. Eligible patients were those with symptomatic splenomegaly, quantified through imaging, or those with substantial symptom burdens assessed through baseline and sequential symptom scores, he says.

The study incorporated standard methodologies, including serial lab counts, imaging of the spleen, sequential assessment of symptomatic question scores, and bone marrow biopsies, to gauge efficacy, Sallman continues. Presented as an oral presentation at the 

, the trial demonstrated that patients with MDS/MPN overlap syndromes who received fedratinib experienced response rates comparable with those of patients with symptomatic primary myelofibrosis, according to Sallman. Notably, patients exhibited both symptom and spleen responses, and these responses have proven to be durable thus far, he says. These findings indicate the potential effectiveness of using JAK inhibitors, specifically fedratinib, to address the therapeutic challenges faced by patients with MDS/MPN overlap syndromes, Sallman concludes.

David A. Sallman, MD, discusses the rationale for conducting a phase 2, multi-institutional, investigator-initiated clinical trial on the use of fedratinib in patients with myelodysplastic syndromes/myeloproliferative neoplasm overlap syndromes and chronic neutrophilic leukemia.

David Sallman, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses the background of the menin inhibitor, KO-539, in acute myeloid leukemia (AML).

Menin plays a critical pathway for several subgroups of patients with AML, specifically in patients with MLL rearrangements and 

 mutations, Sallman says. KO-539 is one of several menin inhibitors under exploration for these subsets of patients with AML. KO-539 features a unique pharmacokinetic profile that permits for dosing once per day, and current pharmacokinetic data have not revealed any interactions with other medications used in this patient population, Sallman explains.

In December 2021, the phase 1b KOMET-001 trial (NCT04067336) was placed on a partial clinical hold by the FDA due to a patient death from a serious adverse effect (AE) that was potentially associated with differentiation syndrome. The partial clinical hold was lifted in January 2022. Differentiation syndrome a known AE related to differentiating agents in the treatment of patients with AML, and while differentiation syndrome is a class effect, the current data are too small to know if the risk of this AE is higher or lower with the use of KO-539 in this patient population when compared to other agents, Sallman concludes.

David Sallman, MD, discusses the background of the menin inhibitor, KO-539, in acute myeloid leukemia.


Dr. Sallman on the Novel Menin Inhibitor KO-539 in AML

David Sallman, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses the examination of magrolimab in acute myeloid leukemia (AML).

One clinical trial investigating magrolimab is the phase 3 ENHANCE-2 trial (NCT04778397) in patients with 

-mutant AML. This patient population has been historically associated with poor outcomes, whether they were treated with venetoclax (Venclexta) plus a hypomethylating agent, or intensive chemotherapy, Sallman says. The 3 arms of the trial are investigating magrolimab plus azacytidine, vs physician's choice of venetoclax plus azacitidine or intensive 7+3 chemotherapy, Sallman explains.

Notably, the primary end point of overall survival will focus on the magrolimab plus azacytidine and venetoclax plus azacytidine arms, Sallman says. Patients with 

-mutated AML have not gained any significant benefit from venetoclax-based regimens, and ENHANCE-2 will aim to establish a new treatment backbone for this population, Sallman adds.

The phase 3 ENHANCE-3 trial (NCT05079230) is evaluating magrolimab plus venetoclax and azacytidine, vs placebo plus venetoclax and azacytidine, in elderly patients with AML and younger patients with AML and comorbidities, Sallman continues. The goal for ENHANCE-3 will be to establish a new standard-of-care therapy for this target population, which would also include a proportion of patients with TP53-mutated AML, Sallman concludes.

David Sallman, MD, discusses the examination of magrolimab in acute myeloid leukemia.

Dr. Sallman on the Examination of Magrolimab in AML

David Sallman, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses the role of uproleselan (GMI-1271) when utilized in acute myeloid leukemia (AML).

Uproleselan is a novel and specific inhibitor of E-selectin, which is vascular-adhesion molecule expressed on the vascular endothelium, Sallman says. In patients with AML, E-selectin can assist leukocytes in sticking to the vessel wall, sheltering the leukemic stem cells from chemotherapy and other agents in the bone-marrow microenvironment, Sallman explains. These cells typically do not divide, which is critical, since intensive chemotherapy targets cells that undergo active cell cycles, Sallman continues.

There are other potential bone-marrow microenvironment markers that may be targeted, though research with E-selectin is the farthest along, Sallman says. Moreover, additional research has demonstrated that E-selectin may help support and nurture leukemic stem cells, Sallman explains. 

Overall, the goal is to utilize uproleselan in conjunction with intensive chemotherapy to target these specific leukemic stem cells that are a major driver of relapse, Sallman concludes.

David Sallman, MD, discusses the role of uproleselan (GMI-1271) when utilized in acute myeloid leukemia.


Dr. Sallman on the Role of Uproleselan in Targeting E-Selectin in AML

David Sallman, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses responses achieved in a first-in-human dose escalation/dose expansion phase 1/1b clinical trial (NCT03927261) of an UltraCAR-T agent, PRGN-3006, in patients with acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome with hypomethylating agent failure.

A cohort of 6 patients who received lymphodepletion with fludarabine 30 mg/m2 and cyclophosphamide at 500 mg/m2 on days -5 to -3 and PRGN-3006 experienced encouraging responses with the agent, according to Sallman. Specifically, 3 patients achieved a response to treatment based on European LeukemiaNet criteria, Sallman says.

One patient subsequently underwent a successful allogeneic stem cell transplant (ASCT) and experienced a complete response (CR) with hematologic recovery for over 1 year, Sallman explains. Another patient with extramedullary AML achieved a partial response at day 28, Sallman adds. This patient may be the first with myeloid sarcoma to receive treatment with a novel CAR T-cell therapy, according to Sallman. A third patient, who experienced a post-ASCT relapse, achieved a CR with incomplete hematological recovery; this response also persisted for approximately 3 months, Sallman says.

These are early data with PRGN-3006, but they are intriguing and more information on this approach is anticipated, Sallman concludes.

David Sallman, MD, discusses responses achieved a first-in-human dose escalation/dose expansion phase 1/1b clinical trial of an UltraCAR-T agent, PRGN-3006, in patients with acute myeloid leukemia and higher-risk myelodysplastic syndrome with hypomethylating agent failure.

Dr. Sallman on the Responses to PRGN-3006 in Select AML and Higher-Risk MDS

David Sallman, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses the efficacy of pevonedistat plus azacitidine in higher-risk myelodysplastic syndrome (HR-MDS).

Findings from the randomized, proof-of-concept phase 2 study (NCT02610777) demonstrated a clinically meaningful improvement in overall survival and event-free survival with the combination of pevonedistat plus azacitidine vs azacitidine alone in patients with HR-MDS/chronic myelomonocytic leukemia or low-blast acute myeloid leukemia, Sallman says. 

The overall response rate (ORR) was 70.9% with pevonedistat/azacitidine vs 60.4% with azacitidine alone in the overall patient population. The ORR was 79.3% vs 56.7%, respectively, for patients with HR-MDS. The median duration of response was 34.6 months compared with 13.1 months, respectively, in patients with HR-MDS, Sallman concludes.

David Sallman, MD, discusses the efficacy of pevonedistat plus azacitidine in higher-risk myelodysplastic syndrome. 



Dr. Sallman on the Efficacy of Pevonedistat Plus Azacitidine in Higher-Risk MDS 

David Sallman, MD, an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center, discusses unmet needs in the treatment of patients with higher-risk myelodysplastic syndromes (MDS).

Real-world data show that this patient population has a median overall survival (OS) of 17 months to 18 months, according to Sallman. Additionally, half of patients are not experiencing any response to treatment, Sallman says. Moreover, one of the biggest challenges is that once treatment with a hypomethylating agent has failed, patients typically have a median OS of approximately 6 months, Sallman explains. 

Currently, no approved, or near approved, agents are available in the second-line setting, and targetable mutations are not utilized for this patient population, Sallman notes. Due to the average survival being less than 2 years, less than half of patients having responses to treatment, and the lack of salvage options outside of allogeneic stem cell transplant, a significant unmet need exists in terms of optimizing frontline therapy for this population, Sallman concludes.

David Sallman, MD, discusses unmet needs in the treatment of patients with higher-risk myelodysplastic syndromes. 


Dr. Sallman on Unmet Treatment Needs in Higher-Risk MDS

David Sallman, MD, assistant member, Moffitt Cancer Center, discusses the combination of APR-246 and azacitidine as a treatment for patients with 

-mutant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

In a phase Ib/II study, investigators evaluated the safety, preliminary activity, and minimal residual disease (MRD) status of APR-246 in combination with azacitidine in patients with 

-mutant MDS or AML. APR-246 is a novel agent that is classified as a p53 reactivator, according to Sallman. This agent is able to bind the mutant protein and restores a more wild-type confirmation. Sallman says that the patients focused on in this study have had poor molecular outcomes to treatments thus far, emphasizing the need for more novel therapies.

In this intial report, 9 of 12 patients were evaluable. This combination was well tolerated, and responses were achieved in all patients. Sallman reports that there was a 100% overall response rate, with 8 of 9 patients achieving a complete remission.

David Sallman, MD, assistant member, Moffitt Cancer Center, discusses the combination of APR-246 and azacitidine as a treatment for patients with TP53-mutant myelodysplastic syndrome and acute myeloid leukemia.

David Sallman, MD

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