New Risk Score Assists in Predicting Myeloid Neoplasms in Individuals With Clonal Hematopoiesis

Posted on May 30, 2023May 30, 2023 by mpn_admin

May 25, 2023

Vicki Moore, PhD

Researchers developed a clonal hematopoiesis risk score (CHRS) for patients with clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), and they evaluated its capacity to predict myeloid neoplasm (MN) risk in a recent study. Results were presented in the journal NEJM Evidence.

The study investigators obtained data from 438,890 individuals without MN who participated in the UK Biobank. Data on genetic mutations, laboratory values, and MN outcomes from 193,743 individuals were included in a subset used for derivation of the prognostic model, with the remaining 245,147 individuals included in a validation cohort. The primary study outcome was incident MN occurring after month 6 of study enrollment.

A total of 11,337 individuals in the derivation cohort were identified as meeting criteria for having either CHIP (10,479 individuals) or CCUS (858 individuals). The median follow-up duration was 11.7 years. In this cohort, there were 269 incident MN events reported, reflecting a rate of 2.37% in this population.

Several factors appeared associated with MN risk. These included high-risk mutations, single DNMT3A mutations, having 2 or more mutations, an age of 65 or more years, the presence of CCUS rather than CHIP, a mean corpuscular volume 100 fL or more, a red cell distribution width of 15% or more, and a variant allele fraction of 0.2 or more for any clonal hematopoiesis variant. Most of these features were linked to greater MN risk.

DNMT3A mutations were associated with a greater MN risk in individuals with CHIP/CCUS than in people without CHIP/CCUS. However, among individuals with CHIP/CCUS, DNMT3A mutations were associated with a lower risk of MN in comparison with other genotypes.

Using CHRS values developed with the prognostic model, the researchers categorized individuals with CHIP/CCUS into 3 risk groups. A low-risk group included 10,018 (88.4%) individuals, while an intermediate-risk group included 1196 (10.5%), and a high-risk group included 123 (1.1%).

In these groups, the 10-year cumulative incidence of MN was 0.669 ⁺ 0.0827% for the low-risk group, 7.83 ⁺ 0.807% for the intermediate-risk group, and 52.2 ⁺ 4.96% for the high-risk group. Ten-year survival rates were 93.7 ⁺ 0.243%, 84.0 ⁺ 1.06%, and 51.2 ⁺ 4.51%, respectively. In comparison, individuals without CHIP/CCUS in this study had a 10-year survival rate of 95.8 ⁺ 0.0471%.

“The CHRS robustly defines three distinct CHIP/CCUS risk groups and shows the low absolute risk of progression to overt MN in the vast majority of CHIP and CCUS,” the study investigators wrote in their report. They also concluded the CHRS may have a role in identifying individuals with CHIP/CCUS who may require greater surveillance and intervention.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Feasibility Phase

Posted on May 30, 2023May 30, 2023 by mpn_admin

Laura F. Mendez Luque,^1,² Julio Avelar-Barragan,³ Hellen Nguyen,¹ Jenny Nguyen,¹ Eli M. Soyfer,¹ Jiarui Liu,¹ Jane H. Chen,¹ Nitya Mehrotra,¹ Heidi E. Kosiorek,⁴ Amylou Dueck,⁴ Alexander Himstead,¹ Elena Heide,¹ Melinda Lem,¹ Kenza El Alaoui,¹ Eduard Mas Marin,¹ Robyn M. Scherber,⁵ Ruben A. Mesa,⁶ Katrine L. Whiteson,³ Andrew Odegaard,¹ and Angela G. Fleischman¹

Abstract

Purpose:

Chronic inflammation is integral to Myeloproliferative Neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among MPN patients.

Experimental Design:

We randomly assigned participants to either a Mediterranean diet or standard US Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four time points during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome.

Results:

The Mediterranean diet was as easy to follow for MPN patients as the standard USDA diet. Over 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any time point. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention.

Conclusions:

With dietician counseling and written education MPN patients can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially even be incorporated into the management of other chronic clonal hematologic conditions.

BET Inhibition Highlights Exploration of Novel Targeted Approaches in Myelofibrosis

Posted on May 30, 2023May 30, 2023 by mpn_admin

May 26, 2023

Ryan Scott

Andrew T. Kuykendall, MD, expands on the rationale for exploring BET inhibition in the treatment of patients with myelofibrosis, details the implications of data from the MANIFEST trial, and discusses other potential targets for novel therapies for myelofibrosis.

Although JAK inhibitors have been a standard of care for patients with myelofibrosis, the exploration of other targeted therapies such as BET inhibitors could lead to new agents and combinations to address symptoms for these patients, according to Andrew T. Kuykendall, MD, who added that disease modification remains a goal in the development of novel treatment approaches.

In the phase 2 MANIFEST trial (NCT02158858), 68% (95% CI, 57%-78%) of patients with JAK inhibitor–naïve myelofibrosis (n = 84) experienced a reduction in spleen volume of at least 35% (SVR35) at week 24 when treated with the combination of the BET inhibitor pelabresib (CPI-0610) and ruxolitinib (Jakafi). Additionally, 20% of patients with myelofibrosis who had previously experienced a suboptimal response to ruxolitinib (n = 81) experienced SVR35 at week 24.¹

Pelabresib plus ruxolitinib is being compared with ruxolitinib plus placebo in the phase 3 MANIFEST-2 trial (NCT04603495) in patients with JAK inhibitor–naïve myelofibrosis, and topline findings are anticipated by the end of 2023.²

“We need to do more [for patients with myelofibrosis] than what we’re currently doing. We see the limitations with single-agent JAK inhibition when we start to look at long-term data. It’s very effective and can change the lives of patients, but it seems to have a shelf life.” Kuykendall explained.

In an interview with OncLive^®, Kuykendall expanded on the rationale for exploring BET inhibition in the treatment of patients with myelofibrosis, detailed the implications of data from MANIFEST, and discussed other potential targets for novel therapies for myelofibrosis. Kuykendall is assistant member of the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

OncLive: What makes BET inhibition a potentially valuable approach in myelofibrosis?

Kuykendall: BET inhibition has been looked at for a long time in many different circumstances, and it is an intriguing pathway specifically within the hematology space. One of the things that BET inhibition does is target the NF-κB inflammatory pathway and signaling pathway.

Recently, the focus in myelofibrosis and myeloproliferative neoplasms [MPNs] has been on the JAK-STAT pathway, which is the hallmark of the disease. All these driver mutations lead to JAK-STAT upregulation. However, this is an inflammatory disease, and it’s not just driven by 1 pathway. This isn’t a one-lane road that goes from one place to another. There are a lot of different pathways that are activated, and if you shut down that [road], [the disease is] going to find other roads around it, especially with the molecularly complex diseases and myelofibrosis, as opposed to essential thrombocythemia and polycythemia vera.

Patients come off JAK inhibitors, often by 3 years. They develop cytopenias and have symptoms that aren’t necessarily responsive to the JAK inhibitors, and they continue to have fatigue. With JAK inhibitors, we’re not seeing complete responses or partial responses. We are seeing very good but symptomatic improvement. The idea is that we may need to target multiple pathways of inflammation to be able to suppress the advantage this malignant clone has. We have great basic science that shows that the combination of BET inhibition and JAK inhibition is synergistic, or at least additive, from the clinical side of things to suppress this clone.

What has been the impact of the MANIFEST trial?

In the MANIFEST trial, we saw that when you treat with a BET inhibitor, it gives this additional level of benefit in terms of spleen volume control, symptom control, and maybe even anemia control. NF-κB may be more important in the cytopenia pathways.

There are emerging data when we look at some of the translational studies being done on the MANIFEST study that [suggest] maybe we are having some impact at the level of the bone marrow microenvironment, and maybe we are seeing some changes with these malignant megakaryocytes that seem to be the driving force behind this disease.

We need long-term data, and we need changes over time. The idea is that we’re bringing something additional to the table that not only can improve symptomatic responses, but maybe can lead to disease modification. We are suppressing enough of those inflammatory pathways that promote continued progression of these diseases, and we may be tipping the scales back in our favor.

Are there any targets beyond BET that have garnered further attention?

There are other targets that are certainly intriguing. The most intriguing one right now, other than BET, is the BCL-2/BCL-XL pathway. BCL-2 inhibitors with venetoclax [Venclexta] have gained a lot of traction in many different diseases, recently getting into the myeloid space with myelodysplastic syndromes and acute myeloid leukemia. However, maybe BCL-2 itself isn’t the key target in MPNs. It seems like BCL-XL might be more of the key target, [and that] is where navitoclax [(ABT-263) is directed]. [Navitoclax] is an older drug that wasn’t as effective or had some toxicity concerns in other diseases, and it is now being re-leveraged in [myelofibrosis] with good impact.

In the phase 2 [REFINE] study [NCT03222609], we saw that adding navitoclax to ruxolitinib was able to recapture spleen responses [with 27% of patients achieving a SVR35 at week 24 (n = 9/34)], which is not a small number.3 This [combination] has some mechanistic rationale and some clinical data to support it. [Navitoclax] is probably the most exciting targeted agent, besides what’s going on with BET inhibition.

We are looking at how to best target the NF-κB pathway. There are a lot of NF-κB inhibitors out there, and there is some interest right now in selinexor [Xpovio] as an XPO1 inhibitor. Selinexor certainly has gotten great responses in early phase studies. [Although] this [has been] in a small number of patients, it is exciting.

There are other targets and other pathways that we’re trying to figure out how to leverage. Myelofibrosis is an inflammatory disease, and that inflammation leads to continued disease progression and evolution of the disease. If we can figure out the most optimal way—which is probably not a one-size-fits-all situation—to stop that inflammation and suppress disease progression, there is potential for combination strategies.

What are your thoughts on combining agents up-front vs sequencing them?

Regarding the idea of combination strategies up-front vs add-ons, this is something that we’re not too sure about. If you can make the case that combination does not allow the disease to progress, then let’s leverage these [combinations] early on. However, you have to build that rationale.

On the contrary, if we’re just giving an extra level of symptomatic benefit and that’s what we’re shooting for, then start with a ruxolitinib- or JAK inhibitor–based therapy. If that works well and the patient feels well, continue with just that. If that doesn’t work effectively, if it is suboptimal, or you think [a patient] could do better, then add the other agent on and see what you can capture.

The idea for combination therapy is a push for disease modification. We hem and haw about what that actually means, but if we do think the disease is driven by multiple pathways of inflammation, then we need to hit it hard early with a combination strategy. However, to have that translate into clinical practice, you need good data to support that [disease modification is occurring].

Although many of these agents are still in early development, could targeted approaches potentially displace the role of stem cell transplant down the road?

It’s tough because none of these [agents] look like they’re curative at this point. If we can get meaningful, more durable, longer responses, then [targeted agents] could potentially replace transplant for a subset of patients. Right now, a lot of patients are diagnosed [at] older [ages], and with our limited treatment options, we’re considering transplant in a lot [of patients]. The equation is different if we can get sustained responses.

[For example, if you have] a 74-year-old patient with high-risk disease who you do not think is going to do well with the single-agent ruxolitinib approach and who is motivated for transplant, that changes the equation for that patient. Maybe with a combination or the potential to add something later on as ruxolitinib or the JAK inhibitor stops having as marked of an effect, that patient may decide to change course and pursue a different option and get good quality-of-life.

We know that transplant, while potentially curative, is not 100% [effective]. Even in patients who do get cured, it doesn’t mean that they have no toxicity from the transplant process. Often, patients come out on the other side a different person. While [targeted agents] won’t replace transplant, they could certainly obviate the need for transplant in a subset of patients.

What has exploration of different targeted approaches meant for the treatment landscape in myelofibrosis?

There are a lot of different agents at play, and there’s a ton of optimism. The overarching message is that we’re taking what we’re learning from the basic scientists and the translational scientists, and we’re putting that into rationally designed treatment options, we’re bringing that to patients, and we’re hopefully going to get new drug approvals.

We need to continue to understand that this is not going to be a one-size-fits-all approach. Navitoclax, pelabresib, selinexor, and any of these additional agents that go into late-stage development are not going to be great for every single [patient with] myelofibrosis. Right now, they’re being tested broadly in myelofibrosis. However, we need to work in the academic side to try to figure out which patients these [agents] benefit. Instead of giving [a treatment] broadly and getting a 30% response rate, let’s enrich the population with who’s likely to benefit, figure out how to get the right population, and get a 70% response rate.

There are toxicities to these additional agents. Especially when you treat with 2 agents over 1, you’re going to have multiple toxicities. Understanding who’s unlikely to benefit vs who’s likely to benefit can make a huge difference for patients clinically.

We do have to have some humility in this as well. We always reference the COMFORT studies [of ruxolitinib] and the JAKARTA studies of fedratinib [Inrebic] as far as our response rates and symptoms. However, I don’t believe that’s going to be how it plays out in phase 3 trials. We’re better now at patient selection, and patients who go on trials are typically more favorable than they were when we didn’t have any agents. We were putting anyone onto the COMFORT studies. [With improved patient selection], the response rates for the [control] arm [in future phase 3 trials] may be higher than we think, and that may present a challenge for getting some of these new agents approved because it is a higher bar to reach if you have to show significant improvement over a higher response [in the control arm].

These are exciting times. We’re going to get readouts of some of these big trials over the course of the next [couple] years. Hopefully, we have some new agents to leverage, but once we get the approvals, that is when we must do the real work and try to figure out how best to use these in practice.

References

Mascarenhas J, Kremyanskaya M, Patriarca A, et al. BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in patients with myelofibrosis – JAK inhibitor-naïve or with suboptimal response to ruxolitinib – preliminary data from the MANIFEST study. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S198.
MorphoSys completes enrollment of phase 3 MANIFEST-2 study of pelabresib in myelofibrosis with topline results expected by end of 2023. News release. MorphoSys AG. April 4, 2023. Accessed May 23, 2023. https://www.morphosys.com/en/news/
Harrison CN, Garcia JS, Somervaille TCP, et al. Addition of navitoclax to ongoing ruxolitinib therapy for patients with myelofibrosis with progression or suboptimal response: phase II safety and efficacy. J Clin Oncol. 2022;40(15):1671-1680. doi:10.1200/JCO.21.02188

Besremi Designated as Preferred Treatment for Polycythemia Vera

Posted on May 30, 2023May 30, 2023 by mpn_admin

Published on: May 26, 2023

Alex Biese

Two years after receiving FDA approval, Besremi is a preferred treatment option in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology.

Besremi (ropeginterferon alfa-2b-njft) — a treatment for adults with the myeloproliferative neoplasm polycythemia vera (PV) — is now a preferred therapeutic option for patients with both high- and low-risk PV, regardless of their treatment history, according to the updated National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, according to a news release from drug developer, PharmaEssentia USA.

The U.S. Food and Drug Administration (FDA) approved Besremi in 2021, and last year the NCCN Guidelines were revised to include it as a recommended treatment for adults with PV, a type of blood cancer where the bone marrow makes too many red blood cells.

“Importantly, the NCCN Guidelines update includes moving Besremi to preferred status, reinforcing to treating physicians and patients that with its broad utility, Besremi is recommended for proactively treating PV,” Dr. John Mascarenhas, professor of medicine, hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York, said in the news release.

Besremi, as of the May 19 NCCN Guidelines update, is considered both a preferred treatment and a category 2A therapy, meaning “there is uniform NCCN consensus that the intervention is appropriate,” according to the PharmaEssentia announcement. It is currently intended to be administered every two weeks, or every four weeks after at least a year of hematological stability.

“This recent update to treatment guidelines by NCCN represents the community’s recognition of the value of Besremi as a therapeutic option for all adults with PV, regardless of their treatment history,” said Dr. Raymond Urbanski, head of clinical development and medical affairs for PharmaEssenta, in the press release. “Given its deep, durable control over the disease beyond the symptoms, we’re continuing to study Besremi in PV, as well as other myeloproliferative neoplasms (MPNs) and hematologic malignancies.”

The first patient was recently dosed in a 24-week phase 3B clinical trial evaluating an accelerated dose of Besremi — starting at 250 mcg then increasing to 350 mcg at week two, with a goal of 500 mcg at week four, as opposed to the currently approved dosing of 50 or 100 mcg. The study is expected to be completed in December 2025.

What is Optimal Donor Type for Patients With Cancer in Need of SCT?

Posted on May 22, 2023May 22, 2023 by mpn_admin

May 19, 2023

Jordyn Sava

In an interview with Targeted Oncology, Salman Fazal, MD, discussed differences between older matched sibling donors vs younger unrelated donors in stem cell transplants and donor preferences at his institution for patients with cancer.

While younger matched donors and older matched sibling donors provide similar outcomes, matched sibling donors are the optimal donor type for patients with cancer in need of a stem cell transplant, according to Salman Fazal, MD.

According to previous research, 3 to 5-year survival rates and outcomes between these donors are similar. However, a study published in Blood revealed that the average 3-year overall survival for patients with a matched sibling donor was 46% while it was 43% for unrelated donors. Having a matched sibling donor also lowered the risk of acute graft-versus-host-disease (GVHD).

“[A]t this point in time, even if we have a matched sibling, probably even above the age of 50, we would prefer using that matched sibling over a younger matched unrelated donor,” Fazal, director of the cell transplantation program in the division of hematology & cellular therapy at the Allegheny Health Network, told Targeted Oncology^TM.

In the interview, Fazal discussed the differences between older matched sibling donors vs younger unrelated donors in stem cell transplants and donor preferences at his institution for patients with cancer.

Targeted Oncology: What is the difference between younger, matched, unrelated donors and donor matched sibling donors? According to research, which achieves the better results?

Fazal: For each patient, we sometimes do not have the option of choosing between matched sibling [donor] vs an unrelated donor. So, if we have a match on an unrelated donor, we take that match from the unrelated donor for allogeneic stem cell transplant. However, in a situation where we have the options between an older matched sibling vs a younger matched unrelated donor the clinical study that was published in Blood, roughly about 8 to 10 years ago, looked at this comparison.

[They] found that using a matched sibling has resulted in a better outcome in terms of lowering the risk of acute and chronic graft versus host disease, and other complications related to transplant. So, at this point in time, even if we have a matched sibling, probably even above the age of 50, we would prefer using that matched sibling over a younger matched unrelated donor.

Can you discuss what kind of disease-free survival we’re seeing with young matched unrelated donors?

It is very relevant in terms of disease-free survival. It depends upon the type of disease the patient has, whether we’re dealing with acute leukemia or myelodysplastic syndrome, and we’re also dependent upon their status of the disease moving into the transplantation. In general, for different types of acute leukemia, depending upon the intensity of the conditioning, the disease-free survival rates vary between 50% to 70%, depending upon the status of the disease and the intensity of the conditioning chemotherapy. We do try to improve the disease-free survival with maintenance therapies which are used in conjunction with reducing the immunosuppression following the stem cell transplant to improve the disease-free survival.

Can you talk about acute and chronic GVHD occurring and younger match unrelated donor transplant?

Over the last few years, there has been a lot of interest in terms of using different modalities to lower the risk of acute and chronic graft-versus-host disease. I always feel that we would be performing more allogeneic stem cell transplantation for different diseases if there was no significant risk of acute or chronic graft-versus-host disease. In general, the matched donors prefer per cell transplantation, there have been different modalities or methods have been used to lower the risk of acute and chronic graft-versus-host disease. Historically, we have used strategies, which include calcineurin inhibitors and methotrexate to lower the risk of graft-versus-host disease.

More recently, there was a study which compared tacrolimus and methotrexate with post-transplant cyclophosphamide to further lower the risk of graft-versus-host disease. We found that using post-transplant cyclophosphamide, even in matched related donors, led to lowering the risk of acute and chronic graft-versus-host disease. However, that study did not have the comparator arm with antithymocyte globulin, which is 1 of the other modalities that has been used to lower the risk of acute and chronic graft-versus-host disease. But as we all know, post-transplant cyclophosphamide came into the scene with the haploidentical transplantation, and now it is making its way in other types of transplantation, including measuring later donor transplantation. It has shown that it is an effective strategy in terms of both acute and chronic efforts. However, we do still see significant risk of both acute and chronic, although I believe that chronic graft-versus-host disease remains a challenge in terms of allogeneic stem cell transplantation.

What is the donor preference in your institution and what studies support that choice?

It all depends upon each individual patient, which options we have at our institution, and we do always consider matched siblings and over a matched unrelated donor. However, unfortunately, because of health conditions and other exceptions, matches are not sometimes available in those circumstances. We do prefer using a match on a later donor for transplantation. However, in situations where we do not have a match and later donor, then we are posed with the question whether we choose a mismatched, unrelated donor vs a haploidentical transplantation?

Currently, that trial is ongoing in terms of trying to figure out which is a better strategy in that type of situation. Is a mismatched unrelated donor transplantation a better option than a haploidentical transplantation? At this time, at our institution, because of the reliability of haploidentical transplantation and immediate availability of the donor, we do usually prefer to proceed with the haploidentical transplantation.

I think clinical trials have to show that if using a haploidentical transplantation is associated with better outcomes as compared with mismatched unrelated donors, I think the use of post-transplant cyclophosphamide in haploidentical transplantation has now made its way of using post-transplant cyclophosphamide following mismatched unrelated donor transplantation as well. I think in that context, the outcomes probably could be similar between the 2 strategies. However, because of the reliability of availability of the donor with the haploidentical transplant and with the unrelated donor, we always are concerned about the possibility of a situation where an unrelated donor is unavailable. In that situation, the patient may be left with delay in transplantation. We like to proceed with haploidentical transplantation because of its reliability of availability. I think that is also stems from the time when we were doing transplantation during the COVID pandemic because during the COVID pandemic, it was much more practical to use a haploidentical transplant donor where we don’t have to cryopreserve the cells and use the the or the fresh stem cells from the haploidentical donor.

Can you discuss haploidentical donors and their overall survival and relapse-free survival data?

In general, with haploidentical transplantation, there is overall improvement in the outcomes. However, we still prefer to do unrelated donor vs haploidentical transplantation. There are certain institutions across the country that do prefer haploidentical transplant over unrelated donors. However, now, at least at our institution, we prefer to do match unrelated donor transplantation. In terms of the outcomes of the haploidentical transplantation, it is dependent on different diseases. In terms of acute leukemia, depending upon the intensity of conditioning, chemotherapy, and the status of the disease, the outcomes vary. Again, in terms of acute leukemia, as I mentioned earlier, the disease-free survival rates vary between 50% to 70%. Outcomes with chronic graft-versus-host disease vary somewhere between 30% to 50%. Up to 50% can develop graft-versus-host disease, however, the majority of these graft-versus-host diseases are mild to moderate.

How would you advise other doctors on deciding on which donor to select in deciding when to do a transplant?

In terms of the other dissenters, I would prefer that we continue to use the match unrelated donor. However, I think, for mismatch vs the haploidentical transplant, we certainly have to look at the data. I do like the idea that the haploidentical has the bigger liability. So, I think in those situations, taking a haploidentical donor is preferable over a mismatched unrelated donor.

In terms of the difference for transplantation, we hope that the transplant physician is involved with the care of the patient from the beginning. There are situations in acute leukemia, where the choice of initial therapy impacts the post-transplant outcome. There are situations even with the availability of immunotherapy where use of certain agents can increase the risk of graft-versus-host disease and such complications after transplantation. I think incorporating the transplant physician in terms of choice of initial therapy, and then getting them to the transplant physician in a timely fashion is important.

Data that was presented in terms of comparing post-transplant cyclophosphamide vs tacrolimus and methotrexate confirmed that post-transplant cyclophosphamide does improve the outcomes following the transplantation. I think using these during this phase 2 clinical trials are a way to improve patient outcomes following the transplantation.

MAJIC-PV Trial Confirms Clinical Benefit of Ruxolitinib in Polycythemia Vera

Posted on May 22, 2023May 22, 2023 by mpn_admin

May 19, 2023

Ashling Wahner

Treatment with ruxolitinib generated superior responses vs treatment with best available therapy in patients with hydroxycarbamide-intolerant or -resistant polycythemia vera, according to findings from the phase 2 MAJIC-PV trial.

Treatment with ruxolitinib (Jakafi) generated superior responses vs treatment with best available therapy (BAT) in patients with hydroxycarbamide-intolerant or -resistant polycythemia vera (PV), according to findings from the phase 2 MAJIC-PV trial (ISRCTN61925716).¹

At a median follow-up of 4.8 years and a data cutoff of April 2022, 43% (n = 40) of evaluable patients who received ruxolitinib achieved a complete response (CR) vs 26% (n = 23) of those who received BAT (odds ratio, 2.12; 90% CI, 1.25-3.60; P = .02).

Previously, the phase 3b RESPONSE-2 trial (NCT02038036), which evaluated ruxolitinib vs BAT in patients with inadequately controlled PV without splenomegaly, showed that 22% of patients in the ruxolitinib arm achieved durable hematocrit control by week 260. Additionally, during the 5-year follow-up period, the median hematocrit level in the ruxolitinib arm remained below 45%. Patients in the BAT arm could cross over to the ruxolitinib arm after week 28 and up to week 80 if BAT was ineffective or not tolerated.²

“In MAJIC-PV, there was no preplanned crossover to ruxolitinib, and patients were followed for 60 months, which enabled important novel clinical and biological outcome data to be assessed,” lead study author, Claire N. Harrison, DM, FRCP, of Guy’s and St Thomas’ NHS Foundation Trust in London, United Kingdom (UK), and coauthors, wrote in a paper of the data that was published in the Journal of Clinical Oncology.¹

Between August 2012 and August 2016, MAJIC-PV recruited 190 patients who were resistant or intolerant to hydroxycarbamide and randomized 180 of these patients to receive either ruxolitinib (n = 93) or BAT (n = 87). This trial was conducted at 38 sites in the UK and included patients at least 18 years of age with high-risk PV that was intolerant or resistant to hydroxycarbamide. Patients in the ruxolitinib arm received the agent at a starting dose of 10 mg twice daily or 5 mg twice daily for those with baseline platelet counts of 100 x 109/L to 200 x 109/L.

Patients in the BAT arm were permitted to change BAT therapies. Although crossover from the BAT arm to the ruxolitinib arm was not allowed, 10 patients in the BAT arm received ruxolitinib as BAT.

Patients were assessed twice weekly for 3 months, then 6 times a week until 12 months, then 4 times a month thereafter. Patients in the ruxolitinib arm could continue treatment beyond 1 year if they achieved a CR or partial response (PR) at 12 months.

The primary outcome for this trial was CR within 1 year per European LeukemiaNet criteria, which included hematocrit levels below 45% without venesection for 3 months, platelet counts of 400 x 109/L or fewer, white blood cell counts of 10 x 109/L or fewer, and normal spleen size. The key secondary outcomes were PR rates, duration of response, safety, histologic and molecular responses, quality of life, progression-free survival (PFS), overall survival (OS), and event-free survival (EFS).

In the overall study population, the median age was 66 years, and 58% (n = 105) of patients were male. In total, 30% (n = 54), 44% (n = 80), and 26% (n = 46) of patients were resistant to, intolerant to, or both resistant and intolerant to hydroxycarbamide.

The median duration of treatment was 1568 days in the ruxolitinib arm and 1220 days in the BAT arm. The mean ruxolitinib dose was 10 mg twice daily, and dose intensity increased over time. Patients in the BAT arm most frequently received hydroxycarbamide (32%), interferon (15%), and hydroxycarbamide plus interferon (12%).

Additionally, patients in the ruxolitinib arm achieved a superior CR duration compared with those in the BAT arm (HR, 0.38; 95% CI, 0.24-0.61; P < .001).

In total, 54% (n = 50) and 67% (n = 58) of patients in the ruxolitinib and BAT arms, respectively, achieved a best response of PR. Of these patients, 45 and 50 in the ruxolitinib and BAT arms, respectively, had hematocrit levels under 0.45 and had been venesection free for 3 months at the time of their first PR. The overall response rates were 97% and 93% in the ruxolitinib and BAT arms, respectively.

Regarding hematological responses, the patients in the ruxolitinib arm required 83 total venesections vs 307 total venesections in the BAT arm, and 29% (n = 27) and 52% (n = 45) of patients in the ruxolitinib and BAT arms, respectively, had at least 1 venesection. Of the 47 paired samples, 29 from the ruxolitinib arm and 18 from the BAT arm, that were available for 1-year histologic response, the investigators observed no CRs.

Additional results demonstrated that ruxolitinib treatment significantly improved thromboembolic EFS but not hemorrhage-free EFS (HR, 0.56; 95% CI, 0.32-1.00; P = .05). When controlled for sex and treatment, time to first thrombotic event within the first 3 years on the trial was associated with the average number of yearly venesections (sub-distribution HR, 1.20; 95% CI, 1.08-1.33; P < .001).

A multivariable logistic regression model, fitted to include treatment arm, sex, baseline hemoglobin, number or prior therapies, thrombosis history, hydroxycarbamide resistance or intolerance, and splenomegaly generated an odds ratio of 2.03 (90% CI, 1.09-3.78; P = .06).

The ruxolitinib arm also trended toward improved PFS, with a 3-year PFS rate of 84% (95% CI, 74%-90%) vs 75% (95% CI, 63%-83%) in the BAT arm.

The 3-year OS rates were 88% (95% CI, 79%-93%) and 87% (95% CI, 77%-93%) in the ruxolitinib and BAT arms, respectively.

A superior EFS was observed in patients who achieved a CR within 1 year (HR, 0.41; 95% CI, 0.21-0.78; P = .01) and in those who received ruxolitinib (HR, 0.58; 95% CI, 0.35-0.94; P = .03).

At baseline, the median JAK2 V617F variant allele fraction (VAF) was 64% in the ruxolitinib arm and 58% in the BAT arm. The investigators performed JAK2 V617F longitudinal quantification in 127 eligible patients, 70 from the ruxolitinib arm and 57 from the BAT arm. At 12 months, 32% (n = 20/63) and 30% (n = 15/50) of these patients in the ruxolitinib and BAT arms, respectively, had over a 25% VAF reduction, and 14% (n = 9/63) and 18% (n = 9/50) of these patients in the ruxolitinib and BAT arms, respectively, had over a 50% VAF reduction. At median follow-ups of 48 months and 36 months, 56% (n = 39/70) and 25% (n = 14/57) of evaluable patients in the ruxolitinib and BAT arms, respectively, achieved over a 50% VAF reduction (P < .001).

Overall, the median time to molecular response was 36 months in the ruxolitinib arm and not reached in the BAT arm. Molecular response at 12 months was associated with improved outcomes, as 24% of responders experienced events at 12 months vs 43% of nonresponders (P = .005). In the overall population and the ruxolitinib arm, but not the BAT arm, molecular responses at the last sample tested were associated with improved PFS (overall, P = .001; ruxolitinib arm, P = .001), EFS (P = .001; P = .006), and OS (P = .01; P = .04).

In the overall population, 59% (n = 98/167) of patients had a single driver mutation. The presence of additional mutations was associated with age (P = .04), and the most common additional driver mutations were TET2 and ASXL1. Patients with additional driver mutations had impaired EFS (treatment-, age-, and sex-adjusted HR, 1.92; 95% CI, 1.16-3.19; n = 167; P = .01). ASLX1 mutations were predictive for adverse EFS outcomes (n = 167; HR, 3.02; 95% CI, 1.47-6.17; P = .003) after adjusting for age, sex, and TET2 mutations. Additionally, at 12 months, in 14 patients, 8 of whom had JAK2 V617F molecular response data, ASXL1 mutations were overrepresented in JAK2 V617F molecular nonresponders (n = 8).

In total, 147 patients, 76 from the ruxolitinib arm and 71 from the BAT arm completed at least a baseline symptom assessment, and 39 total patients completed the 60-month symptom assessment. Baseline symptom scores were similar between the 2 arms, with the exception of weight loss per the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), which was 1.7 (standard deviation, 2.8) in the ruxolitinib arm and 0.7 (standard deviation, 1.7) in the BAT arm (P = .02). The mean total symptom score (TSS) was 52 months in the ruxolitinib arm. Additionally, patients in the BAT arm experienced worsened symptom burden that improved to baseline at 56 months.

A total of 115 patients had MPN-SAF TSS scores at baseline and at least 1 other time point. Of these patients, 61% (n = 36/59) and 30% (n = 17/56) of those in the ruxolitinib and BAT arms, respectively, had at least a 50% TSS reduction at 1 or more time points (P = .001). Statistically significant symptom reduction at more than 5 time points favoring ruxolitinib occurred for fatigue, night sweats, early satiety, itching, weight loss, and bone pain.

The most common adverse effects were gastrointestinal disorders, infections, and vascular disorders. In total, 27 and 12 grade 3/4 infection events, including respiratory infections, genitourinary infections, and cutaneous herpes zoster, occurred in the ruxolitinib and BAT arms, respectively. No infection-related deaths or atypical infections occurred. Additionally, squamous cell skin cancer occurred in 11 patients, all of whom received ruxolitinib treatment.

“Overall, MAJIC-PV confirms evidence that ruxolitinib is associated with improved treatment efficacy, for hematologic control and symptom responses, and significantly extends currently available data demonstrating novel benefits for ruxolitinib improving thrombosis-free survival and EFS in high-risk hydroxycarbamide-intolerant or -resistant PV,” the study authors concluded.

References

Harrison CN, Nangalia J, Boucher R, et al. Ruxolitinib versus best available therapy for polycythemia vera intolerant or resistant to hydroxycarbamide in a randomized trial. J Clin Oncol. Published online May 1, 2023. doi:10.1200/JCO.22.01935
Passamonti F, Palandri F, Saydam G, et al. Ruxolitinib versus best available therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study. Lancet Haematol. 2022;9(7):e480-e492. doi:10.1016/S2352-3026(22)00102-8

Dr Mascarenhas on Ongoing Research in Myelofibrosis

Posted on May 22, 2023May 22, 2023 by mpn_admin

May 18, 2023

John Mascarenhas, MD

John Mascarenhas, MD, professor of medicine, the Icahn School of Medicine, Mount Sinai, director, the Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, Mount Sinai, discusses ongoing trials and research in myelofibrosis.

Among the clinical trials currently investigating novel approaches for patients with myelofibrosis, data are emerging from studies evaluating non–JAK inhibitor approaches. For example, selinexor (Xpovio), which is approved for the treatment of select patients with multiple myeloma and other B-cell malignancies, was investigated in combination with ruxolitinib (Jakafi) in patients with myelofibrosis in a phase 1 trial (NCT04562389).

Data presented at the 2022 ASH Annual Meeting showed that patients treated with the combination experienced significantly reduced spleen volume, an improved total symptom score (TSS), and hemoglobin stabilization. Data also demonstrated that the doublet produced a manageable toxicity profile. Although more data are needed, the exploration of selinexor in the treatment of patients with myelofibrosis will be interesting to follow, Mascarenhas says.

Additionally, data have been presented on the use of navtemadlin (KRT-232), an MDM2 inhibitor, as a single-agent, and it is also being explored in combination with ruxolitinib and in combination with the BTK inhibitor TL-895. The phase 3 BOREAS trial (NCT03662126) is evaluating single-agent navtemadlin vs best available therapy in the second-line setting for patients with myelofibrosis who are relapsed/refractory to a JAK inhibitor.

Moreover, several agents are currently under exploration in combination with ruxolitinib as up-front or salvage therapy, such as parsaclisib, navitoclax (ABT-263), and pelabresib (CPI-0610), Mascarenhas says.

Accrual is ongoing for the phase 3 IMpactMF trial (NCT04576156), which is evaluating imetelstat vs best available therapy for patients with myelofibrosis who did not respond to a JAK inhibitor, Mascarenhas concludes.

Essential Thrombocythemia in Adolescents and Young Adults: Clinical Aspects, Treatment Options and Unmet Medical Needs

Posted on May 22, 2023May 22, 2023 by mpn_admin

Alessandra Iurlo MD,PhD, Cristina Bucelli MD, & Daniele Cattaneo MD

Current Treatment Options in Oncology (2023)

Opinion statement

Current treatment of essential thrombocythemia (ET) should primarily prevent thrombo-hemorrhagic events, without increasing the rate of fibrotic progression or leukemic evolution, and secondarily control microvascular symptoms. Unlike other classic BCR::ABL1-negative myeloproliferative neoplasms, ET is frequently diagnosed in adolescents and young adults (AYA), defined as individuals aged 15 to 39 years, in up to 20% of patients. However, since the current risk stratification of this disease is based on models, including that of ELN, IPSET-Thrombosis and its revised version, mainly applied to an older patients’ population, international guidelines are needed that specifically consider how to evaluate the prognosis of AYAs with ET. Furthermore, although ET is the most frequent MPN among AYA subjects, there is a lack of specific recommendations on how to treat it in this subgroup of patients, as management decisions are typically extrapolated from those for the elderly. Accordingly, since AYAs with ET represent a unique disease subset defined by attenuated genetic risk, more indolent phenotype, and longer survival than their older counterparts, treatment selection requires special attention to specific issues such as the risk of fibrotic/leukemic transformation, carcinogenicity, and fertility. This review article will provide a comprehensive overview of the diagnosis, prognostic stratification, and possible therapeutic approaches for AYA patients with ET, including antiplatelets/anticoagulants and cytoreductive agents, with a focus on pregnancy management in real-life clinical practice.

Study of significance of bone marrow microvessel density in myeloproliferative neoplasms in correlation with CD34 blasts, mast cell count and fibrosis

Posted on May 22, 2023May 22, 2023 by mpn_admin

Kesiya Thomas, Ranitha Rao, et al.

16 May 2023

Abstract

Background: Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell diseases characterised by myeloid cell growth from one or more lineages. Angiogenesis, in contrast to other subtypes, plays a substantial role in the pathophysiology of primary myelofibrosis (PMF). Research expressing the correlation of microvessel density (MVD), blasts, fibrosis and mast cell count in MPN cases are rarely conducted. We aimed to study the significance of MVD in correlation with CD34 blasts, mast cells and fibrosis in bone marrow biopsies of MPN patients.
Methods: The current research was a cross sectional study conducted on 66 cases diagnosed as MPN during a six-year period. This comprised of 32 chronic myeloid leukemia (CML), 31 PMF and three essential thrombocythemia (ET) cases. Routine staining along with reticulin stain to look for fibrosis and immunohistochemistry (IHC) using CD34 and mast cell tryptase (MCT) were performed.
Results: We found increased MVD in PMF, when compared to CML and ET (p = 0.042). Further, mean MVD was observed to be increased with high blast counts (p = 0.036). On follow up, raised mean MVD was seen in those cases with relapse/deceased as compared to disease-free patients, which was highly significant (p = 0.000).
Conclusions: Increased MVD score was mostly associated with PMF subtype among all the MPNs. Further, higher MVD was observed to be associated with increased blast count and poor prognosis. With angiogenesis playing a critical role in disease outcome, we now have drugs to regulate angiogenesis that are supported by contemporary research. However, further studies with larger cohorts to establish the theranostic role of MVD in MPNs is recommended.

Global Myeloproliferative Disorders Drugs Market to Reach $12.9 Billion by 2030

Posted on May 18, 2023May 18, 2023 by mpn_admin

ReportLinker

Wed, May 17, 2023 at 10:51 AM EDT

The global economy is at a critical crossroads with a number of interlocking challenges and crises running in parallel. The uncertainty around how Russia`s war on Ukraine will play out this year and the war`s role in creating global instability means that the trouble on the inflation front is not over yet.

New York, May 17, 2023 (GLOBE NEWSWIRE) — Reportlinker.com announces the release of the report “Global Myeloproliferative Disorders Drugs Industry” – https://www.reportlinker.com/p06032290/?utm_source=GNW
Food and fuel inflation will remain a persistent economic problem. Higher retail inflation will impact consumer confidence and spending. As governments combat inflation by raising interest rates, new job creation will slowdown and impact economic activity and growth. Lower capital expenditure is in the offing as companies go slow on investments, held back by inflation worries and weaker demand. With slower growth and high inflation, developed markets seem primed to enter into a recession. Fears of new COVID outbreaks and China’s already uncertain post-pandemic path poses a real risk of the world experiencing more acute supply chain pain and manufacturing disruptions this year. Volatile financial markets, growing trade tensions, stricter regulatory environment and pressure to mainstream climate change into economic decisions will compound the complexity of challenges faced. Year 2023 is expected to be tough year for most markets, investors and consumers. Nevertheless, there is always opportunity for businesses and their leaders who can chart a path forward with resilience and adaptability.

Global Myeloproliferative Disorders Drugs Market to Reach $12.9 Billion by 2030

In the changed post COVID-19 business landscape, the global market for Myeloproliferative Disorders Drugs estimated at US$9.3 Billion in the year 2022, is projected to reach a revised size of US$12.9 Billion by 2030, growing at aCAGR of 4.2% over the period 2022-2030. Ph+ Chronic myelogenous leukemia (CML), one of the segments analyzed in the report, is projected to record 3.5% CAGR and reach US$9.2 Billion by the end of the analysis period. Taking into account the ongoing post pandemic recovery, growth in the Ph- Myeloproliferative Neoplasms (MPNs) segment is readjusted to a revised 6.1% CAGR for the next 8-year period.

The U.S. Market is Estimated at $2.5 Billion, While China is Forecast to Grow at 7.3% CAGR

The Myeloproliferative Disorders Drugs market in the U.S. is estimated at US$2.5 Billion in the year 2022. China, the world`s second largest economy, is forecast to reach a projected market size of US$2.7 Billion by the year 2030 trailing a CAGR of 7.3% over the analysis period 2022 to 2030. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at 1.9% and 3% respectively over the 2022-2030 period. Within Europe, Germany is forecast to grow at approximately 2.8% CAGR.