An Update on Current and Emergent Therapies for Essential Thrombocytosis

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Daniel H. Foley, MD
Kristen Pettit, MD

The therapeutic landscape for myeloproliferative neoplasms is shifting toward a goal of meaningful disease modification.

Our understanding of pathophysiology driving Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) has evolved considerably over the past decade. As a result, the therapeutic landscape is shifting toward a goal of meaningful disease modification. For patients with essential thrombocytosis (ET), the immediate goals remain thrombosis risk reduction and symptom control, but newer therapies on the horizon are likely to change our treatment paradigms considerably for this disease.

How do you approach a new patient with ET?
When it comes to the treatment of patients with ET, the main goal of current approved therapy is to mitigate the risk of thrombotic events, as the treatments have minimal impact on disease progression. The choice of treatment is determined by an individual’s specific risk factors for these events. The International Prognostic Score for Thrombosis in ET revised score is used to stratify patients into 4 risk groups: very low risk, low risk, intermediate risk, and high risk. For the majority of low-risk patients, low-dose aspirin is recommended, as it aids in preventing clotting, but patients classified as intermediate or high risk are generally advised to undergo cytoreductive therapy.

What are the standard options for cytoreductive therapy?

The selection of the most suitable cytoreductive agent depends on factors such as the patient’s comorbidities, tolerability of the treatment, future family planning, and individual preferences. Hydroxyurea (HU) and pegylated interferon alfa (peg-IFN) are the primary options for frontline cytoreductive treatment. In the phase 3 study MPD-RC 112 [NCT01259856], which included patients with both ET and polycythemia vera (PV), HU and peg-IFN demonstrated comparable rates of complete response and thrombotic events after 12 months.1 However, over time peg-IFN has shown improved molecular responses in both ET and PV.1-4 Although the clinical implications of these molecular responses aren’t yet entirely clear, these findings are quite exciting to see in this disease that has been so difficult to target. A longer-acting interferon (ropeginterferon alfa-2b-njft; Besremi) is currently in evaluation for patients with ET and has been approved in the United States for patients with PV. In cases where initial treatment approaches do not yield satisfactory results, anagrelide is another option, though its use is often limited by toxicities (eg, headaches, dizziness, palpitations, and fluid retention).

What is on the horizon for treatment of ET?

As we delve deeper into understanding the biologic drivers of ET, promising new therapeutic directions are emerging, including JAK inhibitors, epigenetic agents, and mutation-specific biologic/immunologic therapies.Ruxolitinib (Jakafi), a JAK1/2 inhibitor already widely used for other MPNs, continues to be evaluated in ET. In a randomized study, MAJIC [NCT05057494], ruxolitinib was compared with best available therapy (BAT) for patients with ET who had resistance or intolerance to HU. Both treatments showed similar rates of hematologic response, thrombosis, and hemorrhage. However, ruxolitinib outperformed BAT in improving disease-related symptoms.5 Another ongoing trial called Ruxo-BEAT [NCT02577926] is further exploring the use of ruxolitinib in ET.

When it comes to epigenetic regulators, BET inhibitors and LSD1 inhibitors are emerging as potential therapeutic targets. Both BET inhibitors and LSD1 inhibitors have shown the ability to reduce cytokine production via different mechanisms and impair self-renewal of malignant hematopoietic stem cells, so they may have more significant disease-modifying activity compared with other agents.6,7 The BET inhibitor pelabresib (CPI-0610) is currently being evaluated for ET as well as myelofibrosis. The LSD1 inhibitor bomedemstat is also being studied for both ET and MF, and preliminary reports from the ET study show encouraging ability to control platelets and improve symptoms for many patients.8

Biologic and immunologic approaches are emerging as promising strategies as well. Recently, at the American Society of Hematology annual meeting in 2022, preclinical data were presented on a monoclonal antibody that targets mutant CALR, a key diver for approximately 25% of patients with ET.9 This antibody showed impressive potency in selectively targeting mutant CALR-driven oncogenic mechanisms. There are also other antibody-based therapies showing significant efficacy in preclinical studies, and these strategies are now moving toward the development phases.10 Furthermore, the discovery of T-cell responses against mutant CALR has sparked the development of vaccine-based treatment strategies.11,12 

What are your final thoughts regarding the future of ET?

The development of more targeted agents with the potential to meaningfully disrupt the mechanisms driving MPNs provides a lot of optimism for the future in these diseases. As these therapies move toward “prime time,” we will need to reassess our treatment goals for our patients. Hopefully we will be able to raise the bar for response from simply hematologic control and thrombosis prevention toward the more lofty aims of lengthening survival, improving quality of life, and lowering risk of disease progression.

REFERENCES:

1. Mascarenhas J, Kosiorek HE, Prchal JT, et al. A randomized phase 3 trial of interferon-alpha vs hydroxyurea in polycythemia vera and essential thrombocythemia. Blood. 2022;139(19):2931-2941. doi:10.1182/blood.2021012743

2. Masarova L, Patel KP, Newberry KJ, et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017;4(4):e165-e175. doi:10.1016/S2352-3026(17)30030-3

3.Quintás-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood. 2013;122(6):893-901. doi:10.1182/blood-2012-07-442012

4.Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065-3072. doi:10.1182/blood-2008-03-143537

5.Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017;130(17):1889-1897. doi:10.1182/blood-2017-05-785790

6.Kleppe M, Koche R, Zou L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(1):29-43.e27. doi:10.1016/j.ccell.2017.11.009

7.Jutzi JS, Kleppe M, Dias J, et al. LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease clone. Hemasphere. 2018;2(3):e54. doi:10.1097/HS9.0000000000000054

8.Gill H, Palandri F, Ross DM, et al. A phase 2 study of the LSD1 inhibitor bomedemstat (IMG-7289) for the treatment of essential thrombocythemia (ET). Blood. 2022;140(suppl 1):1784-1787. doi:10.1182/blood-2021-148210

9.Reis E, Buonpane R, Celik H, et al. Discovery of INCA033989, a monoclonal antibody that selectively antagonizes mutant calreticulin oncogenic function in myeloproliferative neoplasms (MPNs). Blood. 2022;140(suppl 1):14-15. doi:10.1182/blood-2022-159435

10.Tvorogov D, Thompson-Peach CAL, Foßelteder J, et al. Targeting human CALR-mutated MPN progenitors with a neoepitope-directed monoclonal antibody. EMBO Rep. 2022;23(4):e52904. doi:10.15252/embr.202152904

11.Holmström MO, Martinenaite E, Ahmad SM, et al. The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy. Leukemia. 2018;32(2):429-437. doi:10.1038/leu.2017.214

12.Holmström MO, Riley CH, Svane IM, Hasselbalch HC, Andersen MH. The CALR exon 9 mutations are shared neoantigens in patients with CALR mutant chronic myeloproliferative neoplasms. Leukemia. 2016;30(12):2413-2416. doi:10.1038/leu.2016.233

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Current Approaches to Diagnose and Treat Primary Myelofibrosis

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Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Rami Komrokji, MD, discussed elements to diagnosing myelofibrosis and how to approach risk stratification before treatment.

KOMROKJI: MF could be either primary de novo or coming from secondary from essential thrombocythemia [ET] or polycythemia vera [PT]. [Concerning] the major criteria listed [by the World Health Organization (WHO)], I always bring up the 2 points that not every fibrosis in the bone marrow is myelofibrosis.1 You can see it in lymphomas, hairy cell leukemia, connective tissue disease, etc, and you don’t need fibrosis in the early stages of myelofibrosis to make the diagnosis. The classical megakaryocytic atypia is enough and in the prefibrotic MF, that’s enough to diagnose the disease.

Prefibrotic MF is a relatively new entity that we talk about. Many patients in practice are labeled as ET, and sometimes it’s hard to tease those [differences] out. But those are the patients who we would think have ET, and in 3 to 4 years, they have overt MF. Usually, it will it take a decade to get there, but if a patient had ET and then in 3 or 4 years was in [overt] MF, those probably were patients with prefibrotic MF. There are few clues…most of the time, those patients will have high LDH [lactate dehydrogenase], on the bone marrow there will be more hypercellular granulocytic hyperplasia. There is more clustering of the megakaryocytes.

Currently, we manage them almost the same, but those are the patients who will transform earlier, at higher risk of leukemia. Maybe in the future, those are the patients we will target with some more interventions to try to prevent the overt MF.

The presence of a clonal marker excludes other diseases. [However], myelodysplastic syndrome [MDS] with fibrosis is sometimes hard to distinguish. Fibrosis can be seen in MDS; it’s typically associated with bad outcomes and the new WHO classification with the blast increase has MDS with fibrosis [as a] category on its own. In the clinical phenotype, they typically don’t have the hepatosplenomegaly as much as constitutional symptoms. They’re cytopenic, more like MDS. If a good pathologist sees myeloid or erythroid dysplasia, that will favor MDS with fibrosis. The megakaryocytes are tricky because you always see megakaryocytic atypia in MPNs [myeloproliferative neoplasms], and it depends on how experienced the hematopathologist is. If they are mistakenly calling them dysplasia, that could be deceiving. There are some minor criteria: the anemia, leukocytosis, splenomegaly, LDH, and leukoerythroblastosis.

What is the role of risk stratification when treating patients with MF?

Once we establish the diagnosis, we want to risk stratify the patients and there are many models in MF, 3 or 4 clinical and 2 molecular. I like the MIPSS70 [MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis] most because it’s comprehensive and it was designed to look at the question of transplant or not in younger patients not counting the age as a factor.2 Anemia, transfusion dependency, thrombocytopenia, and leukocytosis… [lead to poor prognosis]. Circulating blasts, unfavorable karyotype, [etc], all of those are weighed in these models. Molecular models…account for bad mutations like ASXL1, SRFS2, or absence of calreticulin. But at the end, we are putting the patients into a spectrum of a low-risk disease, where the survival spans many years, to a high-risk disease where the survival is less than 2 years.

Why is it important to use prognostic models for MF?

The disease risk value in practice is deciding on transplant. If somebody is not eligible for stem cell transplant [SCT], you may argue that those models are not that important. Somebody who’s very low risk will rarely be symptomatic, because if they have any symptoms, they probably move up to intermediate-1 risk.

If somebody’s survival estimate is 2 to 3 years, or an intermediate-2 or higher risk by any of those models, we think of the SCT earlier on in the course of the disease [to consider if they are] eligible for transplant by functional status and comorbidities, not necessarily by age. The second thing is [having] enough disease risk to justify the SCT. In patients who have higher risk, the timing of the transplant is probably early on. In patients with lower risk, even if they are eligible for SCT, the optimal timing is probably to try to delay the SCT. It’s always a hard decision because you don’t want to go too early [because of] upfront transplant-related mortality. But you also never want to go into an MPN accelerated phase or acute myelocytic leukemia from MPN because those diseases have terrible outcomes.

What recommendations are there for treatment of higher-risk myelofibrosis?

Once we label the patients intermediate or higher risk, we are assessing the symptoms and deciding on treatment. We rarely see patients who just [have] transfusion-dependent anemia. Those patients are probably not the classical candidates for JAK2 inhibitors, at least the classical ruxolitinib [Jakafi] or fedratinib [Inrebic].

[For] most patients…you’re treating either constitutional symptoms or splenomegaly. For those patients, JAK2 inhibitors are reasonable. The National Comprehensive Cancer Network guidelines split that choice of JAK2 inhibitor based on the platelet count.3 If it’s below 50 × 109/L, pacritinib [Vonjo] is the choice; if it’s above 50 × 109/L, [the choice is] ruxolitinib or fedratinib. Most [physicians] are more used to ruxolitinib, [it has] more data…but fedratinib is a reasonable option as well. Sometimes I think even a platelet cutoff of 100 × 109/L would be reasonable to consider pacritinib; the platelet cutoff of 50 × 109/L was for the truly unmet need and accelerated approval of pacritinib.

If patients are candidates for SCT, many times we do start the JAK2 inhibitors before the SCT because the SCT will still take 3 to 4 months to happen. If patients have a big spleen [and] poor performance from the disease, shrinking the spleen and getting them ready for SCT is reasonable.

The 3 available JAK2 inhibitors, ruxolitnib, fedratinib, and pacritinib…have different targets. Ruxolitinib targets JAK1/JAK2, [and has] potent JAK1 [activity]. Pacritinib has different targets; it doesn’t have any JAK1 activity. It has some ACVR1 [activity] so some anemia response can be explained through that [and] other inflammatory pathways like IRAK1. Fedratinib also has some FLT3 activity and some JAK1 activity. Momelotinib has JAK1 and ACVR1 activity.

The choices are based on the cytopenia profile. Fedratinib most of the time is positioned as second line after ruxolitinib in patients that are still proliferative. Ruxolitinib is the first line in patients that are proliferative, not cytopenic. Pacritinib is for thrombocytopenia and when we have approval for momelotinib, hopefully that will be for the anemia phenotype.

References:

1. Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8(2):15. doi:10.1038/s41408-018-0054-y

2. Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis. J Clin Oncol. 2018;36(4):310-318. doi:10.1200/JCO.2017.76.4886

3. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 2.2023. Accessed September 7, 2023. https://tinyurl.com/yw9ka77m

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Health Outcomes in Hematologic Malignancies Impacted By Insurance, Marital, and Economic Status

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Hayley Virgil

Findings from a systematic review of several observational studies reveal that increasing disparities in survival outcomes within hematologic malignancies can be primarily attributed to 5 social determinants of health: lack of access to health insurance, treatment at a non-academic facility, low income or education level, and unmarried status.

Key takeaways from the review were presented at the 2023 Society of Hematologic Oncology (SOHO) Annual Meeting. The analysis examined survival outcomes in several subgroups of patients with hematologic cancers and compared them with the overall population. Investigators were able to conclude that although survival was improving overall, disparities were only growing.

Results showed that insurance status was significantly associated with survival in the multivariate analysis (76%), subgroup analysis (12%), and unadjusted analysis (3%), and not significant in a small portion (9%). Findings were similar regarding facility type (56%, 17%, 6%, and 22%, respectively). Distance traveled did show some significant association in multivariate (18%) and subgroup analyses (27%), but was primarily found to not be significant (55%). The association of both provider expertise and marital status proved significant in the multivariate analysis (100% each).

When assessing the impact of economic stability and education on outcomes, income had a significant association in the multivariate analysis (63%), as well as in a subgroup (4%) and unadjusted analyses (8%). Similar findings were reported with regard to high school education (44%; 6%; 17%; and 33%, respectively). Employment and nineth grade education were not significantly associated with survival (100%). Poverty was insignificant in the multivariate analysis (26%), and a subgroup (26%), vs not significant in 50% of patients.

“When we compare those [survival] curves with the overall population of the United States, we can see that those improvements have not reached everybody,” Marisol Miranda-Galvis, DDS, MS, PhD, research project manager at Georgia Cancer Center, said during a presentation on the analysis. “There are obvious reasons that could explain those differences, but our interest is to identify what those actions are that clinicians could implement in clinical practice, regardless of limitations, that could help to close that gap.”

Investigators defined social determinants of health (SDH) as a “set of non-biologic factors that shape the environment of daily life that influence health outcomes.” Such factors include education access and quality, health care access and quality, social and community context, economic stability, and neighborhood/built environment. The goal of the analysis was two-fold: identify the SDH that have been assessed with regard to their impact on outcomes and determine which SDH were linked with worse treatment-related outcomes.

To be included in the systematic review, several criteria were required during the literature search:

  • Patients must have had a hematologic cancer,
  • Any SDH,
  • No comparisons,
  • Any treatment survival measures,
  • Observational studies held in the United States.

The review included a total of 24,353 patients (range, 95-132,402). The most common study setting was national (63.4%), and the most common data source was the National Cancer Database (41.5%). Several types of hematologic malignancies were included in the review, including Hodgkin lymphoma, non-Hodgkin lymphoma, and Burkitt lymphoma (34.1%); multiple myeloma and polymyositis (31.7%); acute myeloid leukemia, acute lymphocytic leukemia, and myelodysplastic syndrome (29.3%); and chronic myeloid leukemia and chronic lymphocytic leukemia (4.9%).

In a population of 57 patients, the outcomes evaluated in the included studies were overall survival (73.2%), early mortality (10.7%), cancer-specific survival (8.9%), progression-free survival (3.6%), and disease-free survival and treatment-related mortality (1.8% each).

SDH that were evaluated were health care access (53.0%), including insurance status (47.1%) and facility type (28.5%); economic stability (25.0%), including income (81.8%) and poverty (12.1%); education access (14.4%), including high school education (94.7%); and social context (7%), including marital status (100%).

When looking specifically at health care access (n = 70) and social context (n = 10), Miranda-Galvis shared several key takeaways.

“In terms of health care access, this domain was evaluating insurance status; those with Medicaid, Medicare, and who were uninsured had lower survival rates compared with those with private or military health coverage,” she said. “In terms of facility type where the patients were treated, those who didn’t receive treatment at an academic institution or research institution presented with a [worse] mortality compared with those who received treatment at community, comprehensive, or integrated cancer centers.”

Several economic stability (n = 33) and education (n = 19) factors were also associated with a survival disadvantage, including having a lower income and education level. The impact of poverty rate appeared inconclusive, while no significant correlations were observed from unemployment rate, and ninth grade education level.

Reference

Miranda-Galvis M, Tjioe K, Balas A, Cortes J. Cancer disparities in survival of patients with hematologic malignancies in the context of social determinants of health: a systematic review. Presented at: 2023 Society of Hematologic Oncology (SOHO) Annual Meeting; September 6-9, 2023; Houston, TX. Abstract MDS-044.

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Socio-Racial Factors May Impact Primary Myelofibrosis Outcomes

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Russ Conroy

Mohammad Bakri Hammami, MD, highlights a need to address socio-racial disparities among Black and non-Black patients with primary myelofibrosis to ensure that everyone receives high-quality treatment.

Investigators retrospectively reviewed socio-racial characteristics as potential determinants of survival in patients with primary myelofibrosis and compared the dataset with single-center outcomes of patients treated at Montefiore Medical Center.

Investigators identified that certain socio-racial factors, including race, sex, and age, may potentially affect survival outcomes in patients with primary myelofibrosis, according to data from a retrospective review that were presented at the 2023 Society of Hematologic Oncology (SOHO) Annual Meeting.

Data collected from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2020 highlighted a median overall survival (OS) of 47 months in the overall population with primary myelofibrosis. Additionally, investigators reported an estimated OS rate of 69% at 2 years and 41% at 5 years.

According to presenting author Mohammad Bakri Hammami, MD, an internal medicine resident at Albert Einstein College of Medicine and Jacobi Medical Center, patient age significantly correlated with OS (HR, 1.042; 95% CI, 1.038-1.046; P <.001) in the SEER cohort. Additionally, investigators observed statistically significant worse OS outcomes in male patients compared with their female counterparts (HR, 1.399; 95% CI, 1.277-1.533; P <.001), as well as in Black patients compared with non-Black patients (HR, 1.202; 95% CI, 1.016-1.422; P <.032).

Hammami noted that patients pulled from the SEER database who were diagnosed with primary myelofibrosis after 2011 experienced significantly better survival with respect to cause-specific and all-cause mortality (P = .001). Being married was also a protective factor against all-cause mortality (P = .001).

In a cohort of patients with primary myelofibrosis treated at Montefiore Medical Center, the 2-year and 5-year OS rates, respectively, were 92% and 63%. The most common treatment modalities administered to Black and non-Black patients in the Montefiore cohort, respectively, included ruxolitinib (Jakafi; 50.0% and 43.9%), hydroxyurea (20.0% and 19.5%), and fedratinib (Inrebic; 10.0% and 0.0%). Additionally, 10.0% of Black patients and 14.6% of non-Black patients were treated as part of a clinical trial. Overall, Hammami stated that there were “no real differences” in the rates of treatment modalities between Black and non-Black patients treated at Montefiore.

In an analysis of genetic mutations in patients receiving treatment at Montefiore, Black and non-Black patients, respectively, typically had JAK2 (70% and 78%), CALR (20% and 16%), and ASXL1 (40% and 5%) mutations. According to Hammami, there was a generally similar distribution of genetic mutations in patients regardless of race, which was consistent with prior reports.

“There is a real role for social factors in terms of survival, especially when it comes to Black and non-Black patients,” Hammami said. “There is a need to focus on addressing these factors when we want to provide high-quality care to these patients.”

Investigators retrospectively reviewed socio-racial characteristics as potential determinants of survival in patients with primary myelofibrosis and compared the dataset with single-center outcomes of patients treated at Montefiore Medical Center. Patients with no histological confirmation of disease or active follow up were not included in the analysis. Additionally, investigators assessed medical records from patients treated at Montefiore Medical Center from 2007 to 2023.

Across the 17 SEER registries, investigators assessed data from 5403 patients. The overall population consisted of patients who were White (82.0%), Black (8.4%), and Asian or from the Pacific Islands (7.7%).

Among non-Black and Black patients included in the SEER cohort, respectively, the mean age was 69 years and 64 years (P <.001); most patients were male (60.7% vs 52.1%; P <.001). Additionally, the majority of non-Black patients were married (57.4%), whereas most Black patients were unmarried (63.4%; P <.001). Hammami also highlighted that 55.0% of non-Black patients had an annual income of over $70,000, while 59.6% of Black patients earned less than $70,000 per year.

The Montefiore cohort consisted of 51 patients, including 43 who were censored and 8 who died due to cancer. Additionally, 57% of patients were male, and 49% were married. The median patient age in this cohort was 66 years. The Montefiore population consisted of patients who were White (35%), Black (20%), Asian (10%), or another or unknown race (35%).

Reference

Hammami MB, Yang J, Thakur R, et al. Examining racial disparities in the incidence and survival of myelofibrosis: insights from SEER database and an institutional cohort (2000-2020). Presented at: 2023 Society of Hematologic Oncology (SOHO). Annual Meeting; September 6-9, 2023; Houston, TX. Abstract MPN-470.

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Prognostic Model Could Help Predict Survival Outcomes for Patients With Myelofibrosis Undergoing AlloHCT

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Megan Hollasch

A predictive system developed using data from United States and European stem cell transplant registries was prognostic of survival in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation.

A predictive system developed using data from United States and European stem cell transplant registries was prognostic of survival in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation (alloHCT), according to data from a retrospective study published in Blood Advances.

United States patients with myelofibrosis who underwent allogeneic hematopoietic cell transplantation from an HLA-matched related/unrelated donor or unrelated HLA-mismatched donor and had data available from the Center for International Blood and Marrow Transplant Research (CIBMTR) from 2000 to 2016 were included in the study (n = 623). Then, investigators assigned a weighted score using these factors to a cohort of patients who received a transplant in Europe (European Bone Marrow Transplant [EBMT] cohort; n = 623).

Study authors created the prognostic scoring system after a Cox multivariable model was used to identify factors prognostic of mortality. An age of more than 50 years (HR, 1.39; 95% CI, 0.98-1.96) and an HLA-matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with an increased risk of death and were each assigned 1 point. Hemoglobin levels less than 100 g/L at the time of transplantation (HR, 1.63; 95% CI, 1.2-2.19) and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25-2.52) were also found to be related to an increased risk of death, and these were each worth 2 points. Patients with 1 to 2 points were deemed to have a low score, 3 to 4 points was an intermediate score, and 5 points was a high score.

At 3 years, the overall survival (OS) rate for the CIBMTR cohort was 69% (95% CI, 61%-76%) for patients with a low score, 51% (95% CI, 46%-56.4%) for those with an intermediate score, and 34% (95% CI, 21%-49%) for those with a high score (P < .001). Using the low-risk group as reference, the intermediate-risk group had a HR of 1.64 (95% CI, 1.23-2.18), and the high-risk group had an HR of 2.65 (95% CI, 1.70-4.14; overall P = .0002).

“Increasing score was predictive of increased transplant-related mortality [TRM; P = .0017] but not of relapse [P = .12],” lead study author Roni Tamari, MD, and colleagues wrote. Tamari is an assistant attending physician and bone marrow transplant specialist at Memorial Sloan Kettering Cancer Center in New York, New York.

Additionally, the 3-category system was predictive for disease-free survival (DFS) in the intermediate-risk group (HR, 1.44; 95% CI, 1.14-1.81) and high-risk group (HR, 1.83; 95% CI, 1.24-2.71; overall P = .0015). It was also predictive for TRM in the intermediate-risk group (HR, 1.63; 95% CI, 1.10-2.44) and high-risk group (HR, 3.09 (95% CI, 1.75-5.48; overall P = .0017).

In the EBMT cohort, the 3-category system was prognostic of OS (P = .0011), DFS (P = .0007), and TRM (P = .0021), but it was not predictive of relapse (P = .1673).

The study included data from patients at least 40 years of age with myelofibrosis who underwent alloHCT. Patients were excluded if they underwent syngeneic umbilical cord blood or mismatched related-donor transplantation, had graft-versus-host disease (GVHD) prophylaxis by ex vivo T-cell depletion or CD34-positive selection procedure, or unknown GVHD prophylaxis. Additionally, those with donor data, diagnosis date, or complete 100-day follow-up data missing were excluded.

Patients in the CIBMTR and EBMT cohorts had a median age of 54 years (range, 40-75) and 52 years (range, 40-74) at diagnosis, respectively, and were mostly males (63% and 68%). Before alloHCT, Karnofsky performance status scores were between 90 and 100 in 60% and 50% of patients, respectively. At diagnosis, patients in the CIBMTR and EBMT cohorts had myelofibrosis (87% and 80%), polycythemia vera (5% and 8%), essential thrombocythemia (8% and 8%), and polycythemia vera/essential thrombocythemia (0% and 3%). Spleen status was normal (21% and 13%), splenomegaly (72% and 49%), or splenectomy (4% and 14%), and patients had received 0 (24% and 37%), 1 (41% and 20%), 2 (17% vand3%), or at least 3 (16% and 3%) prior lines of pretreatments. JAK2 mutations were present in 32% and 34% of patients, respectively, and the rates of patients who received ruxolitinib (Jakafi) were 28% and 14%, respectively.

Patients in the CIBMTR cohort had a Dynamic International Prognostic Scoring System score before alloHCT of low (12%), intermediate-1 (45%) intermediate-2 (38%), or high (2%). Cytogenetics were either normal (40%), other (18%), unfavorable (18%), or not tested (5%).

The median time from diagnosis was 18 months (range, 2-294) and 26 months (range, 2-268) in the CIBMTR and EBMT cohorts, respectively. Donors included an HLA-identical sibling (35% and 75%), well-matched unrelated donor (52% and 17%), and partially matched unrelated donor (13% and 8%). Sex matches of donor and recipient were male to male (41% and 41%), male to female (22% and 27%), female to male (22% and 17%), and female to female (15% and 15%), respectively. Additionally, patients received a graft from peripheral blood (89% and 90%), did not receive total body irradiation (84% and 85%), and received myeloablative (46% and 29%), reduced intensity (47% vs 71%), or nonmyeloablative (6% vs 0%) conditioning regimens.

At diagnosis, patients in the CIBMTR and EBMT cohorts had blast in peripheral blood of greater than 1% (14% and 17%), a hemoglobin level of greater than 100 g/L (35% and 34%), a white blood cell count greater than 25 × 109 /L (9% and 8%), a platelet count of 50 × 109 /L to 100 × 109 /L (13% and 14%), and constitutional symptoms (29% and 28%), respectively.

Before alloHCT, patients in the CIBMTR and EBMT cohorts had blast in peripheral blood of greater than 1% (30% and 32%), a hemoglobin level of greater than 100 g/L (71% and 66%), a white blood cell count greater than 25 × 109 /L (13% and 15%), a platelet count of 50 × 109 /L to 100 × 109 /L (21% and 17%), and constitutional symptoms (17% and 29%), respectively.

In the CIMBTR cohort, the 1-, 3-, and 5-year OS rates were 65.7% (95% CI, 61.9%-69.4%), 54.6% (95% CI, 50.4%-58.7%), and 49.9% (95% CI, 45.5%-54.3%), respectively. TRM rates at 1, 3, and 5 years were 20.6% (95% CI, 17.4%-23.9%), 24.7% (95% CI, 21.3%-28.3%), and 27.1% (95% CI, 23.5%-31.0%), respectively.

Additionally, the 1-, 3-, and 5-year DFS rates were 39.7% (95% CI, 35.7%-43.7%), 31.1% (95% CI, 27.3%-34.9%), and 26.5% (95% CI, 22.7%-30.5%), respectively. The relapse rates at 1, 3, and 5 years were 39.7% (95% CI, 35.8- 43.6), 44.2% (95% CI, 40.2-48.3), and 46.3% (95% CI, 42.2- 50.5), respectively.

In the EBMT cohort, the 1-, 3-, and 5-year OS rates were 68.6% (95% CI, 64.9%-72.2%), 55.0% (95% CI, 51.0%-58.9%), and 51.2% (95% CI, 47.1-55.2), respectively. The 3-year TRM rate was 27.9% (95% CI, 24.4%-31.6%), and the 3-year relapse rate was 24.3% (95% CI, 20.9%-27.8%).

Study authors noted that a limitation of the study was that it included patients treated over a long time period, and between 2000 to 2016, changes and advances were made in the field of stem cell transplantation.

“The proposed system was prognostic of survival in 2 large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with myelofibrosis about the transplantation outcomes,” study authors concluded.

Reference

Tamari R, McLornan DP, Ahn KW, et al. A simple prognostic system in patients with myelofibrosis undergoing allogeneic stem cell transplantation: a CIBMTR/EBMT analysis. Blood Adv. 2023;7(15):3993-4002. doi:10.1182/bloodadvances.2023009886

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An Update on Current and Emergent Therapies for Essential Thrombocytosis

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Daniel H. Foley, MD
Kristen Pettit, MD

The therapeutic landscape for myeloproliferative neoplasms is shifting toward a goal of meaningful disease modification.

Our understanding of pathophysiology driving Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) has evolved considerably over the past decade. As a result, the therapeutic landscape is shifting toward a goal of meaningful disease modification. For patients with essential thrombocytosis (ET), the immediate goals remain thrombosis risk reduction and symptom control, but newer therapies on the horizon are likely to change our treatment paradigms considerably for this disease.

How do you approach a new patient with ET?
When it comes to the treatment of patients with ET, the main goal of current approved therapy is to mitigate the risk of thrombotic events, as the treatments have minimal impact on disease progression. The choice of treatment is determined by an individual’s specific risk factors for these events. The International Prognostic Score for Thrombosis in ET revised score is used to stratify patients into 4 risk groups: very low risk, low risk, intermediate risk, and high risk. For the majority of low-risk patients, low-dose aspirin is recommended, as it aids in preventing clotting, but patients classified as intermediate or high risk are generally advised to undergo cytoreductive therapy.

What are the standard options for cytoreductive therapy?

The selection of the most suitable cytoreductive agent depends on factors such as the patient’s comorbidities, tolerability of the treatment, future family planning, and individual preferences. Hydroxyurea (HU) and pegylated interferon alfa (peg-IFN) are the primary options for frontline cytoreductive treatment. In the phase 3 study MPD-RC 112 [NCT01259856], which included patients with both ET and polycythemia vera (PV), HU and peg-IFN demonstrated comparable rates of complete response and thrombotic events after 12 months.1 However, over time peg-IFN has shown improved molecular responses in both ET and PV.1-4 Although the clinical implications of these molecular responses aren’t yet entirely clear, these findings are quite exciting to see in this disease that has been so difficult to target. A longer-acting interferon (ropeginterferon alfa-2b-njft; Besremi) is currently in evaluation for patients with ET and has been approved in the United States for patients with PV. In cases where initial treatment approaches do not yield satisfactory results, anagrelide is another option, though its use is often limited by toxicities (eg, headaches, dizziness, palpitations, and fluid retention).

What is on the horizon for treatment of ET?

As we delve deeper into understanding the biologic drivers of ET, promising new therapeutic directions are emerging, including JAK inhibitors, epigenetic agents, and mutation-specific biologic/immunologic therapies.Ruxolitinib (Jakafi), a JAK1/2 inhibitor already widely used for other MPNs, continues to be evaluated in ET. In a randomized study, MAJIC [NCT05057494], ruxolitinib was compared with best available therapy (BAT) for patients with ET who had resistance or intolerance to HU. Both treatments showed similar rates of hematologic response, thrombosis, and hemorrhage. However, ruxolitinib outperformed BAT in improving disease-related symptoms.5 Another ongoing trial called Ruxo-BEAT [NCT02577926] is further exploring the use of ruxolitinib in ET.

When it comes to epigenetic regulators, BET inhibitors and LSD1 inhibitors are emerging as potential therapeutic targets. Both BET inhibitors and LSD1 inhibitors have shown the ability to reduce cytokine production via different mechanisms and impair self-renewal of malignant hematopoietic stem cells, so they may have more significant disease-modifying activity compared with other agents.6,7 The BET inhibitor pelabresib (CPI-0610) is currently being evaluated for ET as well as myelofibrosis. The LSD1 inhibitor bomedemstat is also being studied for both ET and MF, and preliminary reports from the ET study show encouraging ability to control platelets and improve symptoms for many patients.8

Biologic and immunologic approaches are emerging as promising strategies as well. Recently, at the American Society of Hematology annual meeting in 2022, preclinical data were presented on a monoclonal antibody that targets mutant CALR, a key diver for approximately 25% of patients with ET.9 This antibody showed impressive potency in selectively targeting mutant CALR-driven oncogenic mechanisms. There are also other antibody-based therapies showing significant efficacy in preclinical studies, and these strategies are now moving toward the development phases.10 Furthermore, the discovery of T-cell responses against mutant CALR has sparked the development of vaccine-based treatment strategies.11,12 

What are your final thoughts regarding the future of ET?

The development of more targeted agents with the potential to meaningfully disrupt the mechanisms driving MPNs provides a lot of optimism for the future in these diseases. As these therapies move toward “prime time,” we will need to reassess our treatment goals for our patients. Hopefully we will be able to raise the bar for response from simply hematologic control and thrombosis prevention toward the more lofty aims of lengthening survival, improving quality of life, and lowering risk of disease progression.

REFERENCES:

1. Mascarenhas J, Kosiorek HE, Prchal JT, et al. A randomized phase 3 trial of interferon-alpha vs hydroxyurea in polycythemia vera and essential thrombocythemia. Blood. 2022;139(19):2931-2941. doi:10.1182/blood.2021012743

2. Masarova L, Patel KP, Newberry KJ, et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017;4(4):e165-e175. doi:10.1016/S2352-3026(17)30030-3

3.Quintás-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood. 2013;122(6):893-901. doi:10.1182/blood-2012-07-442012

4.Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065-3072. doi:10.1182/blood-2008-03-143537

5.Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017;130(17):1889-1897. doi:10.1182/blood-2017-05-785790

6.Kleppe M, Koche R, Zou L, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33(1):29-43.e27. doi:10.1016/j.ccell.2017.11.009

7.Jutzi JS, Kleppe M, Dias J, et al. LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease clone. Hemasphere. 2018;2(3):e54. doi:10.1097/HS9.0000000000000054

8.Gill H, Palandri F, Ross DM, et al. A phase 2 study of the LSD1 inhibitor bomedemstat (IMG-7289) for the treatment of essential thrombocythemia (ET). Blood. 2022;140(suppl 1):1784-1787. doi:10.1182/blood-2021-148210

9.Reis E, Buonpane R, Celik H, et al. Discovery of INCA033989, a monoclonal antibody that selectively antagonizes mutant calreticulin oncogenic function in myeloproliferative neoplasms (MPNs). Blood. 2022;140(suppl 1):14-15. doi:10.1182/blood-2022-159435

10.Tvorogov D, Thompson-Peach CAL, Foßelteder J, et al. Targeting human CALR-mutated MPN progenitors with a neoepitope-directed monoclonal antibody. EMBO Rep. 2022;23(4):e52904. doi:10.15252/embr.202152904

11.Holmström MO, Martinenaite E, Ahmad SM, et al. The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy. Leukemia. 2018;32(2):429-437. doi:10.1038/leu.2017.214

12.Holmström MO, Riley CH, Svane IM, Hasselbalch HC, Andersen MH. The CALR exon 9 mutations are shared neoantigens in patients with CALR mutant chronic myeloproliferative neoplasms. Leukemia. 2016;30(12):2413-2416. doi:10.1038/leu.2016.233

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Understanding Different Types of Blood Cancers and Diagnostic Procedures

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September 3, 2023

Jaishankar Chigurula

Blood cancers encompass a diverse range of types, each with its own set of symptoms and characteristics. Early detection and appropriate diagnostic procedures are crucial for effective treatment and management of these conditions. By recognizing the common symptoms and undergoing comprehensive testing, individuals can increase their chances of early intervention and improved outcomes.

Leukaemia

Leukaemia is a blood cancer that originates in the bone marrow and affects white blood cells, compromising the body’s immune response. Common subtypes include Acute Myeloid Leukaemia (AML) and Acute Lymphoblastic Leukaemia (ALL).

Lymphoma

Lymphomas are blood cancers that target the lymphatic system and involve abnormal lymphocyte growth. Examples of lymphomas include Hodgkin lymphoma and non-Hodgkin lymphoma. These cancers can lead to the enlargement of lymph nodes and other organs.

Multiple Myeloma

Multiple Myeloma is a blood cancer that affects plasma cells, which are crucial for immune function. The overproduction of abnormal plasma cells can damage bones and other organs.

There are also related blood diseases that can progress to Acute Leukaemia:

Myelodysplastic Syndromes (MDS)

MDS is characterized by faulty bone marrow function, resulting in insufficient production of healthy blood cells. In some cases, MDS can progress to acute leukaemia.

Myeloproliferative Neoplasms (MPN)

MPNs are a group of diseases where the bone marrow produces too many specific blood cells. Examples include polycythemia vera, essential thrombocythemia, and myelofibrosis.

Recognizing the symptoms of blood cancers is essential for early detection. While the symptoms can vary depending on the specific type and stage of the cancer, there are common indicators to be aware of. Comprehensive blood tests can reveal abnormal cell counts, types, and characteristics, providing crucial insights into potential blood cancer presence. Bone marrow tests involve the extraction of samples for analysis, aiding in identifying specific cancer types and assessing disease progression.

Specialized testing techniques, such as Flowcytometry immunophenotyping, Cytogenetics, Immunohistochemistry, and Molecular techniques like PCR, Sequencing, and NGS, are used to aid in diagnosis, lineage determination, prognosis, and monitoring of blood cancers. Imaging tests such as CT scans, PET scans, and X-rays help visualize the extent of cancer spread and the involvement of lymph nodes and other organs.

A thorough physical examination can also help identify visible symptoms, such as enlarged lymph nodes, that might indicate blood cancer. In some cases, surgical removal of lymph nodes may be necessary for accurate staging and prognosis determination.

Early detection and prompt diagnosis of blood cancers can significantly improve treatment outcomes. If you experience any concerning symptoms or have a family history of blood cancers, it is important to consult with a healthcare professional for appropriate testing and evaluation.

 

Renin Angiotensin Inhibitors Reduce Thrombotic Adverse Effects in Chronic Myeloproliferative Neoplasms

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Kyle Doherty

Patients with essential thrombocythemia and polycythemia vera who also had arterial hypertension experienced a higher cumulative incidence of thrombotic adverse effects compared with those without hypertension and fewer thrombotic complications following treatment with renin angiotensin system inhibitors.

Patients with essential thrombocythemia and polycythemia vera (PV) who also had arterial hypertension experienced a higher cumulative incidence of thrombotic adverse effects (AEs) compared with those without hypertension and fewer thrombotic complications following treatment with renin‑angiotensin system (RAS) inhibitors, according to findings from a retrospective study published in Annals of Hematology.

In the overall cohort of patients with myeloproliferative neoplasms (MPNs; n = 404), treatment with RAS inhibitors conferred a protective effect from thrombotic AEs (HR, 0.46; 95% CI, 0.21-0.98; P = .04), including those with a thrombotic high-risk score (n = 272; HR, 0.49; 95% CI, 0.24-1.01; P = .04). Moreover, patients with essential thrombocythemia and a thrombotic high-risk score experienced an especially defined benefit following treatment with RAS inhibitors (HR, 0.27; 95% CI, 0.07-1.01; P = .03).

“The main goal of managing MPNs is to prevent thrombotic incidents,” study authors wrote. “The results indicated that patients [with MPNs] had a significantly higher risk [4.9-fold] of arterial thrombosis than the healthy controls. We found a protective association between the use of RAS inhibitors and the reduction in thrombotic AEs in our cohort of patients [with MPNs].”

To conduct their study, investigators collected data from patients diagnosed with PV or essential thrombocythemia by WHO 2016 classification who were treated at the Hematology Unit of the Businco Hospital in Cagliari, Italy, from November 2000 through August 2021. Patients with PV were stratified by low risk of developing thrombosis (age < 60 years and no history of thrombosis) and high risk of developing thrombosis (age ≥ 60 years or a history of thrombosis). Patients with essential thrombocythemia were stratified by International Prognostic Score for Essential Thrombocythemia score, cardiovascular risk factors, age over 60 years, thrombosis history, and the presence of a JAK2 V617F mutation. Study authors also collected clinical data at the time of diagnosis, including constitutional symptom, performance status, hemoglobin, white blood cell counts, and the presence of somatic driver gene mutations among other data.

Patients had PV (n = 133) or essential thrombocythemia (n = 271). The median age at diagnosis was 63 years (range, 17-98) and the median follow-up was 5.5 years (range, 0-24) in the overall population. Most patients had comorbidities at diagnosis (70%) and a high thrombotic risk score (67.3%). Cardiovascular AEs experienced before (66.3%) MPN diagnosis included ischemic heart disease (7.7%), peripheral arterial disease (3.5%), cerebrovascular event (6.9%), atrial fibrillation (6.2%), deep vein thrombosis (4.7%), and other (4.2%); after diagnosis, thrombotic AEs (15.0%) that occurred were ischemic heart disease (3.5%), peripheral arterial disease (2.9%), cerebrovascular event (3.7%), and deep vein thrombosis (4.4%).

Most patients also had a positive mutational status (89.3%), including mutations in JAK2 V617F (78.5%), calreticulin (8.9%), and MPL (1.5%); 48.2% of patients also had essential thrombocythemia JAK2 V617F positivity. The therapies received for MPNs were low-dose aspirin (72.3%), phlebotomy (30.0%), cytoreduction therapy (62.9%), and IFN-2a (0.2%).

Median values were 10.5 × 103 /μL (range, 1.0-96.1) for leukocytes, 15.0 g/dL (range, 7.0–15.0) for hemoglobin, and 696 × 103/μL (range, 87–2320) for platelets. Median hematocrit was 48% (range, 29.0%-77.0%).

Investigators noted that “there was a significant difference in the JAK2 V617F mutation status within the group of patients [with essential thrombocythemia] with hypertension (27% vs 21.2%, P = .01).”

Most patients in the study had hypertension (53.7%) and in this subgroup, patients had PV (n = 78/217) and essential thrombocythemia (n = 139/217). Those with positive mutational status (n = 197/217) had JAK2 V617F (n = 182/217), calreticulin (n = 12/217), MPL (n = 3/217), and essential thrombocythemia– positive JAK2 V617F (n = 109/217) mutations. Median values were 10.9 × 103/μL (range, 1.09-19.2) for leukocytes, 15.2 g/dL (range, 10.4-21.0) for hemoglobin, and 720 × 103/μL (139–1170) for platelets. Median hematocrit was 47.6% (range, 33.1%-69.0%).

The majority of patients with hypertension had cardiovascular AEs before being diagnosed with an MPN (n = 216/217) including ischemic heart disease (n = 20/217), peripheral arterial disease (n = 7/217), cerebrovascular event (n = 19/217), atrial fibrillation (n = 15/217), deep vein thrombosis (n = 11/217), and other (n = 9/217); after diagnosis, 39 patients experienced thrombotic AEs; these included ischemic heart disease (n = 10/217), peripheral arterial disease (n = 6/217), cerebrovascular event (n = 12/217), and deep vein thrombosis (n = 11/217).

Additionally, patients with hypertension underwent prior hypertension therapy with a RAS inhibitor (n = 147/217) including angiotensin receptors blockers (n = 87/217), angiotensin-converting enzyme inhibitors (n = 59/217), and inhibitors without association (n = 116/217). Calcium antagonists were given to 52 patients and other agents including thiazide diuretics, beta-blockers, and doxazosin were given to 101 patients. Patients with hypertension also received treatment with low-dose aspirin (148/217), phlebotomy (70/217), cytoreduction therapy (159/217) and IFN-2a (1/217) as therapy for their MPN.

Additional findings showed that the cumulative incidence of thrombotic AEs over 15 years was significantly higher among patients with hypertension (66.8% ± 10.3%) compared with those without (38.5% ± 8.4%; HR, 1.83; 95% CI, 1.08-3.1). Findings from a multivariate analysis also revealed that hypertension (HR, 1.8; 95% CI, 0.983-3.550; P = .05) and PV diagnosis (HR, 3.5; 95% CI, 1.928-6.451; P < .001) were both associated with an increased risk of developing thrombotic AEs. Considering only patients with MPNs and hypertension, diagnosis of PV displayed a predictive role in developing thrombotic AEs (HR, 4.4; 95% CI, 1.92-10.09; P < .01).

“In conclusion, to improve the treatment of patients with MPNs, it is crucial to pay close attention to their cardiovascular risk factors, as these factors play a significant role in the complications of the disease. A more targeted approach could provide more effective and personalized care for patients with MPNs. Although the study’s retrospective nature poses limitations, the robust connections between the RAS system and hematological disorders make it crucial to conduct a more comprehensive analysis of the effects of RAS inhibitors on MPNs,” investigators wrote in summary.

Reference

Mulas O, Mola B, Costa A, et al. Renin-angiotensin inhibitors reduce thrombotic complications in essential thrombocythemia and polycythemia vera patients with arterial hypertension. Ann Hematol. Published online August 21, 2023. doi:10.1007/s00277-023-05417-w

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Momelotinib Could Represent Pivotal New Treatment Option in Myelofibrosis

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Ryan Scott
Aaron T. Gerds, MD, PhD, expands on the potential role of momelotinib in the treatment of patients with myelofibrosis who present with anemia, details the data from MOMENTUM, and explains what FDA approval of momelotinib could mean for the treatment of this patient population.

The benefits in symptom burden, spleen size, and transfusion dependence demonstrated by treatment momelotinib in patients with myelofibrosis represent a potential key advance for this treatment paradigm, according to Aaron T. Gerds, MD, PhD.

A new drug application (NDA) seeking the approval of momelotinib as a potential therapeutic option in patients with myelofibrosis is currently under review by the FDA, and the review period was extended to a target action date of September 16, 2023.1

The NDA is supported by data from the phase 3 MOMENTUM trial (NCT04173494), which evaluated the agent in patients with symptomatic and anemic myelofibrosis who received a prior JAK inhibitor. Data showed that 25% of patients treated with momelotinib (n = 130) experienced a reduction in tumor symptom score of at least 50% at week 24 compared with 9% of patients treated with danazol (n = 65; proportion difference, 16%; 95% CI, 6%-26%; P = .0095).2

Additionally, 39% of patients in the momelotinib arm achieved a spleen volume reduction of at least 25% from baseline to week 24 vs 6% in the danazol arm (P < .0001); moreover, 22% and 3% of patients, respectively, experienced a reduction of 35% or more (P = .0011). At week 24, the rates of transfusion independence were 30% (95% CI, 22%-39%) for momelotinib and 20% (95% CI, 11%-32%) for danazol (noninferiority difference, 14%; 95% CI, 2%-25%; 1-sided P = .0016).

“The potential approval of momelotinib is incredibly important for patients. Having additional agents to treat myelofibrosis would be welcomed. As little as a couple of years ago, we only had 1 approved therapy to treat myelofibrosis,” Gerds said in an interview with OncLive®. Gerds is an assistant professor in the Department of Medicine, a member of the Developmental Therapeutics Program, and medical director of the Case Comprehensive Cancer Center in Cleveland, Ohio.

In the interview, Gerds expanded on the potential role of momelotinib in the treatment of patients with myelofibrosis who present with anemia, detailed the data from MOMENTUM, and explained what FDA approval of momelotinib could mean for the treatment of this patient population. Gerds also serves as an associate professor of Medicine in the Department of Hematology and Medical Oncology at the Cleveland Clinic Taussig Cancer Institute.

OncLive: How could the potential approval of momelotinib affect current and future practice patterns for patients with myelofibrosis?

Gerds: The [potential] approval of momelotinib could be another pivotal moment in the care of patients with myelofibrosis. I would argue that the first pivotal moment was the discovery of recurrent JAK2 mutations, followed several years later by the approval of ruxolitinib [Jakafi], the first JAK inhibitor.

Momelotinib provides an extra opportunity for patients, specifically patients who have anemia along with enlarged spleens and significant symptom burden. This drug promises to try to hit all 3 of those key elements of care in patients with myelofibrosis with a single pill.

What unmet needs exist for patients with myelofibrosis and anemia?

Anemia itself in these patients is a key unmet need. Roughly 40% of patients will be anemic at the time of diagnosis. It is common diagnostic and prognostic criteria that is used to predict who may have aggressive disease. Anemia will also develop in patients within the first year after diagnosis, and at some point, every patient will develop anemia as the [bone] marrow begins to fail. Therefore, anemia is something that is incredibly common and difficult to treat.

We can give red blood cell transfusions to combat anemia, but that comes with adverse effects, such as iron overload, transfusion reactions, and the development of alloantibodies. Moreover, blood is a valuable and somewhat scarce resource. The Red Cross is constantly trying to get us to donate more blood because it is a scarce commodity, and it is also expensive to do red blood cell transfusions. In general, it’s one of the biggest costs in delivering health care for patients with hematologic malignancies. For all these reasons, treating anemia is incredibly important.

Treatments for anemia are somewhat limited. I mentioned transfusions already, and there are also erythropoiesis stimulating agents [ESAs] that can be given. Another drug, luspatercept-aamt [Reblozyl], is already approved to treat anemia in patients with myelodysplastic syndrome and beta thalassemia. It is used off-label to treat anemia in patients with myelofibrosis. danazol is also commonly used.

We already have these 3 agents; however, none of them are perfect or work 100% of the time, and there are still many patients who suffer from anemia who have [myelofibrosis]. Any new agent that is coming along that can potentially treat anemia in a different mechanism of action is always welcome.

What is the mechanism of action of momelotinib, and what prompted this agent’s examination in patients with myelofibrosis?

Momelotinib, in terms of treating anemia, works very differently than ESAs, luspatercept, and danazol. It works by inhibiting ACVR1, also known as ALK2, which is a regulator of hepcidin. Hepcidin is a key piece in what we think about in hematology in iron regulation and red blood cell production. It is a hot topic in myeloproliferative neoplasms right now, and it has been in the world of hematology for some time.

Hepcidin is a master iron regulator that helps regulate the shuttling of iron out of the iron stores, making it available for the body to use, for example, to make red blood cells. In patients with myelofibrosis, they have anemia or an inflammatory block, meaning that hepcidin levels are very high and can shut a lot of those iron stores. By lowering the levels of hepcidin by blocking ACVR1, we can restore effective erythropoiesis by dropping that anemia or inflammatory block. That component of a patient’s anemia can be reversed, potentially by this medication.

What were some of the key efficacy data from MOMENTUM?

The MOMENTUM study pitted momelotinib vs danazol, looking at a couple of key end points. The first was symptom burden reduction, and we also looked at spleen volume reduction—traditional end points for measuring response with JAK inhibitors in patients with myelofibrosis. Another key end point was transfusion independence, and that was the proportion of patients who were transfusion independent at weeks 24 and 48.

We saw that momelotinib outperformed danazol in terms of spleen volume reduction, as well as symptom burden reduction. Momelotinib was also statistically not inferior—this was a non-inferiority analysis—for transfusion independence at week 24 compared with danazol.

What does the safety profile look like for momelotinib in this population?

With respect to safety, one of the early concerns during the development of momelotinib was an increased risk of peripheral neuropathy. This was seen in some earlier studies. However, in subsequent investigations, such as the SIMPLIFY trials [NCT01969838; NCT02101268] and the MOMENTUM study, we did not see excess neuropathy in patients treated on momelotinib compared with best available therapy or danazol, respectively. The rates of peripheral neuropathy were similar in the 2 groups. That was a key take-home point in terms of safety data from the MOMENTUM study.

Certainly, some patients did develop cytopenias while on momelotinib, as well as danazol. There weren’t excess gastrointestinal toxicities, as we see with some of the other JAK inhibitors. There was no signal toward increased risk of non-melanoma skin cancers or bile reactivations. However, we certainly watch for those things whenever we’re treating a patient with a JAK inhibitor.

If it is approved, where do you see momelotinib fitting into the current treatment paradigm for this population?

With the potential approval of momelotinib, we will see what the uptake looks like in everyday practice. That will be a big part of what happens with this medication: how organically it is picked up by different oncologists and hematologists out there in the community. Clearly, it has efficacy in patients with anemia, so it would be right at home in the treatment of a patient who has myelofibrosis who needs spleen volume reduction and symptom control, and has anemia.

If we look closely at the MOMENTUM inclusion criteria, those patients did have prior exposure to a JAK inhibitor for at least one month, and they all had hemoglobin [levels] less than 10g/dL; that is where this drug tends to shine. However, the amount of JAK inhibition given to those patients prior to going on MOMENTUM was limited. We also do have up-front data in patients previously untreated [with a JAK inhibitor] from the SIMPLIFY trials. You could say that if a patient with myelofibrosis and is borderline anemic, they could also benefit from momelotinib, not just in the second line, but potentially in the frontline setting as well.

References

  1. Verstovsek S, Gerds AT, Vannuchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0
  2. GSK announces extension of FDA review period of momelotinib. News release. GlaxoSmithKline. June 16, 2023. Accessed August 31, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-announces-extension-of-fda-review-period-for-momelotinib/

Mind-Body Therapies for Anxiety, Depression a Critical Part of Comprehensive Cancer Care

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August 30, 2023

The recent publication of a guideline recommending mindfulness-based interventions highlight how important it is as a tactic to address symptoms of anxiety and depression in patients with cancer.

Mind-body therapies have been shown — and are recommended in guidelines — to decrease symptoms of anxiety and depression in patients with cancer who may be at any part of the care continuum, an expert said.

With this whole-person system of care, patients can use techniques including mindfulness-based stress reduction, cognitive therapy, meditation and others to address depression and anxiety symptoms. Now that mindfulness-based interventions are now recommended in a guideline prepared by the Society for Integrative Oncology (SIO) and American Society of Clinical Oncology (ASCO) as a way to treat anxiety and depression during cancer treatment, this may allow more cancer centers to offer this as part of their multidisciplinary care.

CURE® spoke with Linda E. Carlson, Enbridge Research Chair in Psychosocial Oncology and professor in the department of oncology at Cumming School of Medicine at the University of Calgary in Canada, to learn more about the ASCO/SIO guideline that she and an expert committee prepared, why they are important for patients and how patients with cancer can advocate for themselves to obtain care related to integrative oncology.

CURE®: Why are these guidelines so important?

Carlson: We know that patients suffer high levels of anxiety and depression, quite commonly around the time of diagnosis, but also going forward through transitions in care, the end of care, trying to get back into regular life. And so anxiety and depression symptoms can haunt people for a very long time.

At the same time, there’s no really good pharmacological treatments, … and many people prefer to go non-pharmacological, more natural routes.

The integrative therapies, the mind-body therapies that are in this guideline are proven. You can see through the evidence they help decrease symptoms of anxiety and depression. And so they’re non-pharmacological alternatives for patients to help cope with these difficult symptoms.

What exactly is integrative oncology?

The definition of integrative oncology … is this idea that it’s incorporating a whole-person system of care that incorporates conventional treatments, as well as complementary therapies where appropriate to help manage symptoms throughout the continuum, from prevention through lifestyle interventions, things like exercise and nutrition, right through treatment with modalities like the mind-body therapies, natural health products, and into survivorship and even end of life.

The idea is that it’s consistent with the person’s beliefs and values. It takes these complementary therapies that have an evidence base to them, applies them throughout the whole cancer journey to improve treatment tolerance and symptom reduction.

Is integrative oncology meant for all patients regardless of disease, stage and other factors?

Absolutely. The evidence base is a bit lacking for some of the rarer forms of cancer. A lot of the research has been done on women with breast cancer. So there’s definitely some holes in the evidence that have limited the kinds of recommendations that could go into the guideline, because the guideline’s based on very strict criteria, randomized-controlled trials, etc. There have been many studies done with more diverse groups of patients, but not enough to get some of those things in the guideline.

Another side note is that just because a complementary therapy may not be included in the guideline, it doesn’t mean that it isn’t helpful or it doesn’t work. It just means there hasn’t been enough research to date. So for example, things like energy therapies or massage may still have potential, but just didn’t make it into the guideline because there hasn’t been the research done yet.

The strongest recommendation was given to mindfulness-based interventions like stress reduction, meditation and mindful movement. Can you go into more detail about what those are?

We use mindfulness-based interventions as an umbrella term to talk about, usually adaptations that stem from the mindfulness-based stress reduction program that was developed by Jon Kabat-Zinn back in the 1970s.

Mindfulness-based stress reduction has been around for about 40 years, but there’s many different takes on it, different adaptations. So there’s some that are specific for people with cancer, like mindfulness-based cancer recovery, or mindfulness-based stress reduction for breast cancer, there’s mindfulness-based cognitive therapy. But what these all have in common is they’re usually group programs, they usually meet once a week over a period of six to eight weeks.

And people are taught mindfulness meditation techniques. So usually, they practice at home for 20 minutes a day or so of meditation on the breath, on the body. And mindfulness is really this idea of bringing awareness into the present moment, non-judgmentally with kindness, self-compassion with openness. And so the meditation is training people on how to do that in a systematic way. Because often our minds are trained to be out of the present moment. We’re either reliving the past and saying, “Why me? If only this or that.” We have regrets, we get depressed or we’re worrying about the future. The mind’s going off to what if this? What if that? How am I going to cope, all the terrible things that could happen, the pressures. And so, we worry and get anxious.

Depression, regret, worry, anxiety, it’s all caused by the past and future focus. But mindfulness training is more about living in the moment. It’s easy to say, it’s a simple idea, but it’s not easy to do. So the mindfulness based intervention trains people in that capacity to be in the present moment, through sitting meditation, body scan, different kinds of awareness practices, everyday mindfulness.

Usually, they have the form of mindfulness meditation practice. And they also have mindful movement, or yoga, incorporated in them. And that is around bringing awareness into the body, learning to identify when there’s stress or tension, identifying our triggers of stress, we even get into the stories we tell ourselves and the interpretations we make and how that elevates stress. There are many components to a mindfulness-based intervention. But we do know that the studies, many of them have consistently shown that they really help people cope with anxiety and depression.

There has always been some thought that any form of mindfulness would be beneficial for patients with cancer. But why was it so important to put these into a formalized guideline?

The way the medical system works is that the guidelines drive treatment decisions, and they drive insurance reimbursement. So while many people have experienced these therapies and know they’re helpful, until we have it formalized with a recommendation from a trusted body like ASCO, like SIO, that’s the first step in really making it standard of care. In fact, it makes it almost compulsory that for cancer centers to be credited as comprehensive cancer centers, they need to include these types of therapies.

The recommendations around mindfulness-based interventions, the language is “should;” people with cancer should have access, not “may,” which is the less strong language. But they should be part of comprehensive cancer care because we know they’re helpful, and they’re less harmful than other pharmacological approaches and more useful, they’re more effective.

There’s no reason why we shouldn’t take advantage of these relatively low-cost interventions with very few side effects, little harm and make those available to everybody. Everybody who’s suffering from anxiety and depression can benefit. So this is a really important institutional step in moving more towards that idea of having them really part of standard of care.

If a patient thinks that this would be a good fit for their care, how should they bring it up to their cancer team?

I would advise patients to get a copy of those guidelines and put them on the desk the next time they go to see the oncologist and say, “How come we don’t have these programs at our cancer center? Why do I have to go to the community and seek this out and pay out of my pocket? Why isn’t this covered by my insurance?” I think we need the patients to stand up and advocate. And they can use (this guideline) as a tool, a very strong tool to help them do that.

This transcription has been edited for clarity and conciseness.

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