Akriti G. Jain, MD, is a hematologist and medical oncologist at the Cleveland Clinic in Ohio.

Akriti G. Jain, MD, detailed the current unmet needs in polycythemia vera and myelofibrosis, including how to define disease modification.

Dr Jain on Persisting Gaps in Defining Disease Modification in Polycythemia Vera and Myelofibrosis

“Right now, the only cure we have for any stem cell or myeloid disorder is a stem cell transplant. Is it possible for us to cure these or modify the natural history of these diseases without a stem cell transplant? That's a big unmet need.”

Akriti G. Jain, MD, a hematologist and medical oncologist at the Cleveland Clinic, detailed the unmet needs that remain in the myeloproliferative neoplasms landscape, particularly regarding JAK inhibition in patients with polycythemia vera and myelofibrosis.

A significant unmet need in polycythemia vera and myelofibrosis is determining what is considered disease modification, which is often a point of discussion at most conferences, Jain began. More research is needed to identify whether disease modification depends on driving the 

, based on the present mutations, she explained. Specifically, in polycythemia vera, common mutations include 

 exon 12 to 15 mutations, she noted. Conversely, in myelofibrosis, frequently observed mutations comprise 

, she added. Therefore, it has not been established whether disease modification means driving the allele burden down, the reversal of fibrosis, or the decrease in cytokine or inflammatory hormone levels, she emphasized.

Furthermore, more work needs to be done until combination therapies can help bridge the gap in polycythemia vera and myelofibrosis, Jain continued. The only potential cure for stem cell or myeloid disorders remains a stem cell transplant, she noted. However, another significant need is whether it’s possible to cure or alter the diseases without requiring a stem cell transplant, along with getting patients safely to transplant, she stated. Additionally, essential questions to be addressed include how much spleen shrinkage is needed, and whether patients should continue receiving a JAK inhibitor is necessary after receiving a stem cell transplant.

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Akriti G. Jain, MD, discusses factors that affect treatment sequencing with JAK inhibitors for the treatment of patients with myelofibrosis.

Dr Jain on Considerations for Sequencing JAK Inhibitors in Myelofibrosis

“The sequencing of JAK inhibitors doesn't have a lot of clinical trial [data]; therefore, we do not have a lot of clinical trials to help us figure out how to sequence JAK inhibitors. We usually pick one based on the presentation of whether anemia is a problem or [if] thrombocytopenia is a problem, [along with other factors].”

Akriti G. Jain, MD, a hematologist and medical oncologist at the Cleveland Clinic, discussed sequencing strategies with JAK inhibitors and novel combination therapies for the treatment of patients with myelofibrosis.

Sequencing strategies are still not officially established in myelofibrosis, with a lack of prospective clinical trial data to help guide these decisions, Jain began. When sequencing in clinical practice, treatment selection is often based on the presentation of whether problems arise regarding anemia or thrombocytopenia, or based on a patient’s blood counts, she explained. Typically, when a patient has good blood counts, the first option is the JAK inhibitor ruxolitinib (Jakafi), she added. However, she noted that dose modifications may be necessary based on cytopenias and adverse effects. Having a window of between 12 to 24 weeks to achieve a response is optimal, which reflects end points often used in clinical trials, she asserted. Nevertheless, if a response has not been achieved by 12 weeks, then moving onto the next treatment is key, she stated. Following the first treatment, observing problems regarding anemia and thrombocytopenia remains essential, she said.

Within the myelofibrosis space, 3 other JAK inhibitors have also been approved by the FDA. In 2019, 

 (Inrebic) for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis after polycythemia vera or essential thrombocythemia. In 2022, the 

 (Vonjo) for the treatment of adult patients with intermediate or high-risk primary or secondary myelofibrosis with a platelet count less than 50 x 10

 for the treatment of patients with intermediate or high-risk myelofibrosis, including primary or secondary myelofibrosis with anemia.

Akriti G. Jain, MD, details the treatment decision-making of JAK inhibitors for the treatment of patients with myelofibrosis.

Dr Jain on Treatment Decision-Making With JAK Inhibitors in Myelofibrosis

“Out of the 4 JAK inhibitors we have FDA-approved, the harder part is choosing a JAK inhibitor for [a patient] who has cytopenias. Even before that, the question is: does everyone with myelofibrosis need a JAK inhibitor? Not necessarily.”

Akriti G. Jain, MD, a hematologist and medical oncologist at the Cleveland Clinic, detailed the approach to JAK inhibitor selection for the treatment of patients with myelofibrosis in clinical practice.

Based on the 4 JAK inhibitors that have been FDA-approved for the treatment of patients with myelofibrosis, a challenge when selecting treatment is when a patient presents with cytopenias, Jain began. She emphasized that a significant question also arises: do all patients with myelofibrosis require a JAK inhibitor? If a patient has lower-risk disease per risk stratification using the Molecular International Prognostic Scoring System 2.0 and they do not have an enlarged spleen or heavy symptom burden, they may not require a JAK inhibitor and could undergo observation, she explained.

If a patient has intermediate- to high-risk disease with an enlarged spleen or the presence of symptoms, there are factors to consider when selecting a JAK inhibitor, according to Jain. If the patient’s counts look good, then selecting ruxolitinib (Jakafi) first would be the option, based on its efficacy regarding both spleen and symptom responses. If the patient has anemia, especially if they are transfusion dependent, then ruxolitinib may not be the ideal initial option, as ruxolitinib could cause anemia during therapy, she asserted. Of note, reducing the dose of ruxolitinib may not be ideal, namely because receiving less of the dose means less of a benefit, she explained. In cases where patients present with anemia, selecting momelotinib (Ojaara) could be a feasible option, notably because of its ACVR1 inhibition to provide anemia benefit.

Nevertheless, in the phase 3 SIMPLIFY-1 (NCT01969838), which compared momelotinib with ruxolitinib as frontline therapy, data revealed that momelotinib was noninferior for spleen response of spleen volume reduction by 25% or more at week 24, Jain continued. Still, ruxolitinib demonstrated better symptom control compared with momelotinib. Treatment selection depends on every patient; therefore, if their symptoms, spleen volume, or anemia are major burdens, respectively, treatment could differ, she concluded.

Akriti G. Jain, MD, discusses the role of ruxolitinib for the treatment with polycythemia vera and myelofibrosis.

Dr Jain on the Role of Ruxolitinib in Polycythemia Vera and Myelofibrosis

“For polycythemia vera, the only JAK inhibitor that is approved right now is ruxolitinib, and it is approved for second-line therapy. This is for patients who are hydroxyurea-intolerant or hydroxyurea-resistant—there is a potential benefit with ruxolitinib.”

Akriti G. Jain, MD, a hematologist and medical oncologist at the Cleveland Clinic, discussed the role of ruxolitinib (Jakafi) for the treatment of patients with polycythemia vera and myelofibrosis.

 for the treatment of patients with polycythemia vera who are resistant or intolerant to hydroxyurea. Ruxolitinib continues to stand as the only FDA-approved JAK inhibitor for the treatment of patients with polycythemia vera, with the agent indicated in the second-line setting, Jain began. She noted that this patient population could derive potential benefit from ruxolitinib, especially with a reduction of 

 allele burden, which could potentially be disease modifying.

 in November 2011 for the treatment of patients with myelofibrosis. Although JAK inhibitors have demonstrated their importance regarding symptom control and spleen volume control in myelofibrosis, disease modification is more difficult to confirm, Jain added. There have not been many observations of fibrosis reversals, which is being evaluated in combination trials to further identify room for improvement in the work of JAK inhibitors to potentially be disease modifying, she asserted. So far, within the myelofibrosis treatment paradigm, ruxolitinib has been the only JAK inhibitor that has demonstrated survival benefit, although fibrosis benefit and disease modification remain an unmet need, according to Jain.

The myelofibrosis treatment paradigm has seen a significant shift within the past decade, considering the addition of 3 JAK inhibitors. In 2019, 

 (Inrebic) for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis after polycythemia vera or essential thrombocythemia. Moreover, in 2022, the 

/L. Most recently, in 2023, momelotinib (Ojjaara) received the 

Dr Jain on the VERONA Study in Higher-Risk MDS

Akriti Jain, MD, Department of Hematology and Medical Oncology, Cleveland Clinic, discusses the phase 1b VERONA study (NCT02942290) of venetoclax (Venclexta) with azacitidine (Vidaza) to assess change in complete remission (CR) and overall survival (OS) in patients with treatment-naive higher-risk myelodysplastic syndromes (MDS).

The high-risk MDS patient population is currently the focus of much anticipation surrounding the VERONA trial, which is evaluating the combination of venetoclax and azacitidine, Jain begins. Updated results from the phase 1b study were presented at the 

. In this investigation, 107 patients with high-risk MDS were enrolled, and the outcomes demonstrated a notable modified overall response rate of 80.4% (95% CI, 71.6%-87.4%), she reports. Among patients who responded to treatment, 50.5% (95% CI, 40.6%-60.3%) achieved marrow complete remission (CR), and within this subgroup, 37.0% (95% CI, 24.3%-51.3%) also experienced hematological improvement—a promising finding indicating potential disease control and symptom relief, Jain says. Jain added that 29.9% (95% CI, 21.4%-39.5%) of patients achieved CR, reflecting a significant treatment response.

The median OS observed in this study was 26.0 months (95% CI, 18.1-51.5), with a CR duration reaching 16.6 months (95% CI, 10.0-not reached). These results underscore the potential of combining venetoclax with azacitidine in the high-risk MDS setting to achieve meaningful clinical responses and extend survival outcomes, she explains.

This area of research holds significant promise for patients with high-risk MDS, especially in facilitating successful transplantation or improving long-term outcomes by prolonging OS and response duration, Jain continues. The data from the VERONA trial are eagerly awaited within the medical community as they hold the potential to further enhance the understanding of treatment approaches for patients with MDS, she notes.

The integration of combination treatment approaches represents a promising strategy in the pursuit of more effective and personalized therapies for high-risk MDS, according to Jain. The results from ongoing clinical trials, including the VERONA study, will be instrumental in guiding clinical practice for patients with MDS, Jain concludes.

Akriti Jain, MD, discusses the phase 1b VERONA study of venetoclax plus azacitidine in higher-risk myelodysplastic syndromes.

Dr Jain on Unmet Needs in the Treatment of Low- and High-Risk MDS

Akriti Jain, MD, Department of Hematology and Medical Oncology, Cleveland Clinic, discusses unmet needs in patients with low- and high-risk myelodysplastic syndromes (MDS).

When addressing unmet needs in patients with MDS, it's essential to differentiate between patients classified as having low-risk and high-risk disease, Jain begins. In the realm of low-risk MDS, several drugs are currently available or in development that hold promise for improving patient outcomes, Jain says. Among these, erythropoiesis-stimulating agents, luspatercept-aamt (Reblozyl), and azacitidine (Vidaza) stand out as notable options, she reports. Additionally, the emergence of innovative drugs, such as imetelstat, that are pending regulatory approval in this therapeutic setting presents exciting prospects, Jain emphasizes. Further exploration into promising therapeutic candidates, such as KER-050, which was highlighted at the 

, and monoclonal antibodies, offers potential avenues for enhancing treatment efficacy and quality of life (QOL) for low-risk patients, Jain explains. These treatment opportunities underscore the ongoing efforts to address cytopenias and overall patient well-being in this subgroup, she adds.

Conversely, for patients classified as having high-risk MDS who are deemed transplant candidates, the primary objective is to facilitate their transition to transplantation and strive for optimal responses in the frontline setting, Jain continues. Here, the combination of azacitidine and venetoclax (Venclexta) emerges as a pivotal therapeutic approach, representing a significant area of clinical innovation and investigation, according to Jain. However, for patients who are not deemed suitable candidates for transplantation, the focus shifts toward mitigating cytopenias and improving overall response rates, she elucidates. Novel combination therapies offer a compelling avenue for augmenting treatment efficacy in this patient cohort, Jain says. By exploring innovative therapeutic approaches, oncologists aim to treat patients’ existing cytopenias and enhance patient outcomes by minimizing treatment-related complications and maximizing therapeutic benefits, Jain expands.

In essence, the pursuit of improved treatment strategies for patients with MDS encompasses a multifaceted approach tailored to the distinct needs of both low-risk and high-risk subgroups, she says. By leveraging a diverse array of therapeutic agents and novel combinations, oncologists endeavor to optimize treatment outcomes, alleviate cytopenias, and enhance overall QOL for patients with this complex hematological disorder, Jain concludes.

Akriti Jain, MD, discusses unmet needs in patients with low- and high-risk myelodysplastic syndromes.

Dr Jain on the Long-Term Investigation of Luspatercept in Anemic MDS

Akriti Jain, MD, Department of Hematology and Medical Oncology, Cleveland Clinic, discusses updated data from the phase 3 MEDALIST trial (NCT02631070) evaluating luspatercept-aamt (Reblozyl) for the treatment of anemia following progression on an erythropoiesis stimulating agent (ESA) in adult patients with very low– to intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (MDS-RS) or myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).

The MEDALIST trial stands as a pivotal study that led to the FDA approval of luspatercept

 for the treatment of patients with MDS-RS or MDS/MPN-RS-T, which came as a breakthrough for patients who have experienced ESA progression or intolerance, Jain begins. Recently, updated results from the trial, extending until a data cutoff of January 2nd, 2023, were disclosed during the 

. Notably, the data revealed a significant improvement in red blood cell (RBC) transfusion independence lasting at least 8 weeks, with rates climbing from what has been previously reported she notes, saying that this enhancement underscores the therapeutic efficacy of luspatercept in addressing transfusion dependency in patients with MDS.

Another noteworthy aspect of the updated findings was the prolonged duration of response observed among patients who achieved transfusion independence, Jain expands. This sustained benefit highlights the enduring impact of luspatercept therapy in managing RBC transfusion needs over an extended period, according to Jain. Furthermore, regarding safety outcomes, fatigue is an important consideration in the management of MDS. Despite achieving RBC transfusion independence, many patients continue to experience fatigue, Jain elucidates.

The discourse on fatigue in patients with MDS at the 2023 ASH Annual Meeting seamlessly segued into an intriguing avenue of exploration involving a TGF- β inhibitor, she continues. Promising reports indicate that this inhibitor holds potential in alleviating fatigue, Jain says. Anticipation is high for further insights and clinical data on the efficacy of TGF-βinhibitors, with hopes that upcoming conferences will shed more light on this promising therapeutic avenue, Jain concludes.

Akriti Jain, MD, discusses updated data from the phase 3 MEDALIST trial evaluating luspatercept for the treatment of anemic myelodysplastic syndromes.

Akriti Jain, MD, discusses the outcomes of the phase 3 COMMANDS trial in transfusion-dependent lower-risk myelodysplastic syndromes.

Dr Jain on Results From the COMMANDS Trial in Lower-Risk MDS

Akriti Jain, MD, Department of Hematology and Medical Oncology, Cleveland Clinic, discusses results from the phase 3 COMMANDS trial (NCT03682536) in patients with transfusion-dependent lower-risk myelodysplastic syndromes (MDS), according to a presentation at the 2023 ASH Annual Meeting.

The COMMANDS study evaluated the use of luspatercept-aamt (Reblozyl) in low-risk patients with MDS. This study examined the efficacy and safety of luspatercept compared with epoetin alfa in patients with transfusion-dependent, low-risk MDS who had not been previously treated with an erythropoiesis-stimulating agent (ESA), Jain explains. Findings from this study were also recently published in the 

phase 3 trial also supported the regulatory approval of luspatercept

 in the United States for the management of anemia in ESA-naive low-risk MDS patients, Jain expands. The approval of this agent provides patients with an option that may enhance transfusion independence and overall responses among, she says. The primary end point of the study was sustained red blood cell (RBC) transfusion independence for more than 12 weeks, coupled with a simultaneous increase in hemoglobin levels by 1.5 grams per deciliter, Jain explains.

The results demonstrated a significant improvement in RBC transfusion independence compared with ESA in the intention-to-treat population, she continues. The luspatercept arm exhibited a robust and statistically significant response rate of 60.4%, surpassing the 34.8% response rate in the alternative arm (

 < 0.0001), Jain explains. These findings have sparked considerable interest in luspatercept within MDS, as they mark an advancement in the understanding and management of MDS-related anemia in patients with ESA-naive, low-risk disease, Jain concludes. 

Overall, findings from the COMMANDS trial are consistent with data from the prior interim analysis, affirming that the duration of red blood cell transfusion independence and the erythroid responses achieved with luspatercept are superior to those achieved with epoetin

Akriti G. Jain, MD

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