Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms

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Jing Guo, Klaudia Walter, Pedro M. Quiros, Muxin Gu, E. Joanna Baxter, John Danesh, Emanuele Di Angelantonio, David Roberts, Paola Guglielmelli, Claire N. Harrison, Anna L. Godfrey, Anthony R. Green, George S. Vassiliou, Dragana Vuckovic, Jyoti Nangalia & Nicole Soranzo

Nature Genetics (2024)

Abstract

Myeloproliferative neoplasms (MPNs) are chronic cancers characterized by overproduction of mature blood cells. Their causative somatic mutations, for example, JAK2V617F, are common in the population, yet only a minority of carriers develop MPN. Here we show that the inherited polygenic loci that underlie common hematological traits influence JAK2V617F clonal expansion. We identify polygenic risk scores (PGSs) for monocyte count and plateletcrit as new risk factors for JAK2V617F positivity. PGSs for several hematological traits influenced the risk of different MPN subtypes, with low PGSs for two platelet traits also showing protective effects in JAK2V617F carriers, making them two to three times less likely to have essential thrombocythemia than carriers with high PGSs. We observed that extreme hematological PGSs may contribute to an MPN diagnosis in the absence of somatic driver mutations. Our study showcases how polygenic backgrounds underlying common hematological traits influence both clonal selection on somatic mutations and the subsequent phenotype of cancer.

Main

Myeloproliferative neoplasms (MPNs) are rare chronic hematological cancers characterized by the overproduction of mature blood cells leading to elevated blood cell parameters. They are typically driven by somatically mutated JAK2-mediated, calreticulin (CALR)-mediated or MPL-mediated clonal expansion1. JAK2 mutations are found in both polycythemia vera (PV) and essential thrombocythemia (ET), which are distinct but overlapping MPNs characterized by increased numbers of red blood cells and platelets, respectively. Mutant JAK2 is commonly detectable in 0.1–3% of the healthy population as clonal hematopoiesis (CH)2,3,4,5,6,7, with the vast majority of carriers not meeting or going on to develop disease-defining characteristics of MPN. Little is understood about why only a minority of individuals with mutated JAK2 develop more severe hematological manifestations of MPN and the factors that influence blood count heterogeneity in MPNs.

The 46/1 haplotype near JAK2 is a known germline risk factor for MPNs in the population8. Genome-wide association studies (GWAS) have identified additional disease-associated germline risk loci, estimating the liability-scale heritability of MPNs based on common single-nucleotide polymorphisms (SNPs) to be ~6.5% (refs. 9,10,11). However, these germline risk loci insufficiently explain the phenotypic heterogeneity observed within MPNs and in JAK2-mutated healthy carriers.

Blood cell traits vary widely in the healthy population. The genetic architecture underlying these traits is highly polygenic, with more than 11,000 independently associated genetic variants discovered so far12,13,14. These genome-wide associated variants, when combined in polygenic scores (PGSs), explain a large proportion of phenotypic variance among healthy individuals (from 2.5% for basophil count to 27.3% for mean platelet volume) and are associated with multiple common diseases and rare hematological disorders14. We hypothesized that a genetic burden of germline variants associated with extreme hematological traits could influence phenotypic heterogeneity in association with mutated JAK2, by influencing the clonal dynamics of mutant JAK2 and/or modifying its downstream consequences. In this study, we integrate information on somatic driver mutations, germline genetic variants associated with MPNs, and CH and hematological trait PGSs to study how inherited polygenic variation underlying blood cell traits influences clonal selection on mutated JAK2 and MPN disease phenotypes (Supplementary Fig. 1).

Results

Inherited polygenic contribution to JAK2 V617F positivity

One in 30 healthy individuals reportedly harbors JAK2V617F in their blood, as determined using sensitive assays6. The majority of such individuals have low levels of JAK2V617F and do not meet clinical criteria for MPN due to the absence of elevated blood cell parameters. We wished to understand whether inherited polygenic loci that underlie blood cell traits influence the strength of clonal selection on JAK2V617F.

We studied the germline characteristics of individuals in UK Biobank (UKBB) with and without JAK2V617F. From 162,534 genetically unrelated individuals of European ancestry within the UKBB whole-exome sequencing cohort (‘200k UKBB-WES cohort’; Methods), we identified 540 individuals with one or more mutant reads for JAK2V617F (0.3%, median variant allele frequency (VAF) = 0.056, range = 0.019–1; Supplementary Fig. 2; ‘UKBB-JAK2V617F cohort’). The lower rate of JAK2V617F in the UKBB-WES cohort compared to other population studies6,7 could be explained by its low sequencing coverage (21.5× depth), as also reported previously15 (Supplementary Fig. 3). As expected, there was some overlap among individuals with JAK2V617F and those with a diagnosis of MPN. Of the 423 individuals labeled with a diagnosis of MPN (156 with ET, 161 with PV and 106 with myelofibrosis (MF)), 72 were positive for JAK2V617F (Supplementary Table 1).

We built PGSs for 29 blood cell traits covering a wide range of hematopoietic parameters (Supplementary Table 2). Blood cell trait-specific PGSs were then weighted (by effect size) by the sum of all common (minor allele frequency (MAF) > 0.01) variants that were independently associated with a blood cell trait at genome-wide significance (P < 5 × 10−8) in UKBB (Methods)14. To assess the association between hematological PGSs and small (VAF < 0.1, n = 397) or large (VAF ≥ 0.1, n = 143) JAK2V617F clones, we used multinomial logistic regression including PGSs for each hematological trait (units of s.d.), together with previously reported germline sites associated with MPN9 and CH16 (PGSMPN and PGSCH) as covariates. To account for the recognized predisposition risk for MPN driven by the JAK2 46/1 haplotype8, we computed two PGSMPN scores, separating rs1327494 (tagging the JAK2 46/1 haplotype; PGSMPN–46/1) from nontagging JAK2 variants (PGSMPN-other). We found a negative association between the PGSs for both mean reticulocyte volume (PGSMRV) and immature reticulocyte fraction (PGSIRF) and small JAK2V617F clones (P = 6.2 × 10−4 and 0.0018, false discovery rate (FDR) < 0.05; Supplementary Table 3). We also found significant positive associations with small JAK2V617F clones for the PGSs of plateletcrit (PGSPCT) and monocyte count (PGSMONO) (P = 9.5 × 10−4 and 0.0036, FDR < 0.05). Germline predisposition to high MONO and PCT values was also positively associated with large JAK2V617F clones at modest significance (P = 0.033 and 0.0022, FDR-adjusted P = 0.31 and 0.064; Fig. 1a). Repeating the analysis above excluding MPN cases still demonstrated a significant association between PGSPCT or PGSMONO and small JAK2V617F clones (P < 0.013, Bonferroni corrected; Supplementary Table 4), suggesting that the inherited effects on JAK2V617F were not driven by the subset of MPN cases. These associations were independent of the known germline risk loci associated with MPN and CH (Supplementary Table 3). Validating these associations in the full UKBB-WES dataset (n = 799 and 326 for small and large clones, respectively, and n = 338,919 for controls), we again replicated the associations between PGSPCT and small JAK2V617F clones and between PGSMONO and large JAK2V617F clones at FDR < 0.05 (PCT: odds ratio (OR) = 1.15 (change in odds per increase of 1 s.d. in PGS), 95% confidence interval (CI) = 1.07–1.24, P = 1.4 × 10−4; MONO: OR = 1.20, 95% CI = 1.07–1.34, P = 0.0014; Supplementary Table 5).

Data are presented as ORs (solid dots) with 95% CIs (error bars). a, PGSs with significant associations with small clone size of JAK2V617F (FDR < 0.05) compared to the CH and MPN PGSs (Supplementary Table 3). OR was defined as the change in odds per increase of 1 s.d. in PGS. b, Causal effects estimated by four MR methods for the exposure traits whose PGSs were found to have significant predisposition risk for JAK2V617F positivity (Supplementary Table 7). OR was defined as the change in odds per increase of 1 s.d. in exposure. The MR results shown were based on GWAS summary statistics for JAK2V617F positivity in the full UKBB (Supplementary Fig. 4). Results based on the main discovery set (200k UKBB-WES cohort) are shown in Supplementary Table 6. The MR result for MRV was not available due to a lack of corresponding GWAS summary data in INTERVAL.

To understand the causal relationship among these associations, we undertook Mendelian randomization (MR) analyses with GWAS estimates for the exposure (blood traits) and the outcome (JAK2V617F positivity; Supplementary Fig. 4) obtained from two independent sources. We used genetic instruments for hematological traits identified from UKBB, with effect size estimates from INTERVAL17 (n = 30,305), an external independent cohort. MRV was excluded due to a lack of data in INTERVAL. Both PCT and MONO showed significant causality on the presence of a JAK2V617F clone based on inverse variance-weighted (IVW)18 MR and demonstrated consistent effect estimates using two other MR methods (simple median and weighted median), suggesting that higher MONO and higher PCT values cause a detectable JAK2V617F clone (Supplementary Table 6).

Extending this analysis to the full UKBB-WES cohort (JAK2V617F, n = 1,125; controls, n = 338,919) validated these causal associations with greater estimation accuracy (PCT: ORIVW = 1.52, 95% CI = 1.29–1.78, P = 3.0 × 10−7; MONO: ORIVW = 1.3, 95% CI = 1.15–1.49, P = 4.6 × 10−5; Fig. 1b and Supplementary Table 7). The IVW method of MR (Methods) assumes that the germline loci that drive MONO and PCT have no direct causal effect on driving a JAK2V617F clone (that is, there are no direct causal effects of the genetic instruments on the outcome). We found no evidence of pleiotropy using the MR-Egger19 test; the estimated intercept was not significantly different from zero with P = 0.84 and P = 0.90 for PCT and MONO, respectively. The causal relationship was also significant for PCT and MONO (P < 0.05; Supplementary Table 7 and Supplementary Fig. 5). Additionally, the estimates were not biased by any potential pleiotropic outlier variants and were highly consistent with outlier-corrected causal estimates (Supplementary Table 7 and Methods). Lastly, to ensure the results were not confounded by the possibility that the genetic loci used as instruments for MR directly promoted the outcome (that is, JAK2V617F positivity), we repeated the analysis excluding genetic instruments associated with JAK2V617F positivity (Passociation < 10−6), as well as those that correlated with JAK2V617F variants (that is, those variants and JAK2V617F variants are in linkage disequilibrium (LD) r2 > 0.01) or were in proximity to JAK2V617F variants (in the 10-Mb region centered on each variant), and found no major changes (Supplementary Table 8). Importantly, any reverse causal effect we detected for MONO and PCT was subtle and with pleiotropic effects (PEgger > 0.05 and PEgger-intercept < 0.05; Supplementary Table 9 and Supplementary Fig. 6).

Overall, the association results combined with MR suggest that higher PCT and MONO are causal for the presence of a JAK2V617F clone. This would also explain why individuals with germline predisposition to high PCT and MONO are also more likely to harbor a JAK2V617F clone. Given that acquisition of somatic mutations in blood is largely stochastic in healthy populations20, our data suggest that genetically predicted PCT and MONO influence clonal selection on nascent JAK2V617F cells to promote mutation acquisition.

Germline contribution to blood cell count variation in MPNs

Having shown that polygenic germline loci can predispose to JAK2 clone positivity through their influence on blood cell trait levels, we next studied the contribution of these inherited sites to clinical phenotypes of MPN. We first considered the four blood cell traits that are used to define MPN subcategories clinically21 as follows: hemoglobin concentration (HGB) (g dl–1 divided by 10), hematocrit (HCT) (%), platelet count (PLT) (×109 divided by 1,000) and white blood cell count (WBC) (×109 divided by 100). We used SNP arrays to measure genome-wide polymorphism in an MPN cohort of 761 patients (PV, n = 112; ET, n = 581; MF, n = 68), in whom diagnostic blood cell counts were available and mutation status for a panel of cancer-associated genes (Fig. 2a) had previously been characterized22.

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GB2064 Displays Preliminary Efficacy, Tolerability in Myelofibrosis

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January 16, 2024

Kyle Doherty

The potential first-in-class, oral, lysyl oxidase-like 2 (LOXL2) inhibitor GB2064 displayed efficacy with a generally acceptable tolerability profile in the treatment of patients with myelofibrosis, according to topline findings from the phase 2a MYLOX-1 trial (NCT04679870).1

Among evaluable patients with myelofibrosis who were treated with GB2064 monotherapy for a minimum of 6 months (n = 10), 6 experienced a reduction in collagen fibrosis of the bone marrow of at least 1 grade. All patients who achieved this reduction in bone marrow fibrosis displayed stable hematological parameters, including hemoglobin, white blood cell count, and platelet count. This indicates the agent’s potential impact on disease progression and disease-modifying capabilities. At 6 months of treatment, 1 patient experienced a reduction in spleen volume of at least 35%, 2 reduced their Total Symptom Score (TSS) by over 50%, and another patient experienced an anemia response.

“It is exciting and encouraging to see that the data from the MYLOX-1 trial affirms the safety and effectiveness of LOXL-2 inhibition in the challenging landscape of myelofibrosis,” Claire Harrison, MD, FRCP, FRCPath, chair of the Safety Review Committee for the MYLOX-1 trial, a professor of myeloproliferative neoplasms, and the clinical director of Guy’s and St Thomas’ NHS Foundation Trust in London, England, said in a press release. “I am especially intrigued by the unique observed improvements in bone marrow collagen fibrosis, showcasing the targeted impact on a crucial aspect of this relentless disease.”

MYLOX-1 was an open-label, single-arm study that enrolled adult patients with primary or secondary myelofibrosis who were ineligible, refractory, or intolerant to treatment with a JAK inhibitor. Patients had intermediate-2 or high-risk disease by the Dynamic International Prognostic Scoring System-plus, or low-risk disease with symptomatic splenomegaly. Eligible patients were also required to have an ECOG performance status of 2 or less, not be receiving JAK inhibitor therapy, display required baseline laboratory counts, and have a documented history of transfusion records in the preceding 12 weeks to day 1 of study treatment.2

All patients on the study treatment received 1000 mg of oral GB2064 twice daily for 9 months. Patients underwent bone marrow biopsies at the beginning of the trial and again at 3, 6 and 9 months. The primary end point was the safety and tolerability of GB2064; key secondary end points included evaluating hematological parameters and the direct anti-fibrotic activity of GB2064 by blocking LOXL2 in an indication that allows for repeated tissue biopsies.1,2

The study dosed a total of 18 patients with myelofibrosis. Most patients (61%) had previously received the JAK inhibitor ruxolitinib (Jakafi); 8 of these patients were refractory to JAK inhibitor therapy and 3 were intolerant.1

Additional assessment of bone marrow biopsies in MYLOX-1 revealed that GB2064 penetrated the bone marrow and could exert its anti-fibrotic effect directly in the disease compartment. Additionally, the agent displayed systemic target engagement by binding to LOXL2 in plasma. Four patients who experienced clinical benefit with GB2046, as determined by the treating physician, have entered the extension phase of MYLOX-1. Notably, 1 of these patients has received treatment for over 30 months.

GB2064 displayed a tolerable safety profile, with 8 of the 18 dosed patients completing treatment in the core phase of MYLOX-1. The remaining 10 patients discontinued treatment due to adverse effects or progressive disease. The most common any-grade treatment-related adverse effects were manageable with standard therapy and gastrointestinal in nature. The lone treatment-related serious adverse effect was a case of fall, which was determined to be possibly related to GB2064 treatment.

“We believe that the topline results from the MYLOX-1 trial reaffirm the anti-fibrotic activity observed in the intermediate assessment of the trial announced in September 2022,” Hans T. Schambye, MD, PhD, the president and chief executive officer of Galecto, said in the press release. “We are very excited with the proof of principle achieved with GB2064, showcasing its strong anti-fibrotic impact in a very challenging patient population. The encouraging topline results from the MYLOX-1 trial reinforce our confidence in GB2064’s potential as a transformative therapy for various cancers and a range of fibrotic diseases, but we will not make any decisions relating to funding additional trials with GB2064 until we complete our previously announced strategic alternative process.”

In September 2023, Galecto announced that it completed a review of its business and would conduct a comprehensive exploration of strategic alternatives focused on maximizing shareholder value. Galecto did not set a timetable for completion of the evaluation and said it did not intend to disclose further developments or guidance on the status of its programs unless it determined that further disclosure is appropriate or necessary.3

References

  1. Topline results from MYLOX-1 trial demonstrate reduction in fibrosis of the bone marrow in patients with myelofibrosis. News release. Galecto, Inc. December 21, 2023. Accessed January 16, 2024. https://www.biospace.com/article/releases/topline-results-from-mylox-1-trial-demonstrate-reduction-in-fibrosis-of-the-bone-marrow-in-patients-with-myelofibrosis/
  2. A study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of oral GB2064 in participants with myelofibrosis. ClinicalTrials.gov. Updated May 6, 2023. Accessed January 16, 2024. https://clinicaltrials.gov/study/NCT04679870
  3. Galecto announces plans to explore strategic alternatives. News release. Galecto, Inc. September 26, 2023. Accessed January 16, 2024. https://ir.galecto.com/news-releases/news-release-details/galecto-announces-plans-explore-strategic-alternatives

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INCA-033989 by Incyte for Myelofibrosis: Likelihood of Approval

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January 12, 2024

INCA-033989 is under clinical development by Incyte and currently in Phase I for Myelofibrosis. According to GlobalData, Phase I drugs for Myelofibrosis have an 86% phase transition success rate (PTSR) indication benchmark for progressing into Phase II. GlobalData’s report assesses how INCA-033989’s drug-specific PTSR and Likelihood of Approval (LoA) scores compare to the indication benchmarks.

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

INCA-033989 overview

INCA-033989 is under development for the treatment of myelofibrosis (MF), essential thrombocythemia (ET). The drug candidate is a monoclonal antibody which acts by targeting calreticulin (CALR).

It was also under development for post-essential thrombocythemia myelofibrosis (Post-ET MF) and primary myelofibrosis (PMF).

Incyte overview

Incyte is a biopharmaceutical company, which discovers, develops and commercializes proprietary cancer therapeutics. The company’s lead product, Jakafi (ruxolitinib) is marketed in the US for the treatment of patients with high-risk myelofibrosis; and polycythemia vera who are intolerant to hydroxyurea. The company distributes Jakafi through a network of specialty pharmacy providers and wholesalers. In collaboration with Incyte, Novartis International Pharmaceutical Ltd (Novartis) develops and commercializes ruxolitinib outside the US for hematologic and cancer indications under the name Jakavi. The company’s pipeline portfolio encompasses drugs for the treatment of lung cancer, graft versus host disease, b-cell malignancies, solid tumors, non-small cell lung cancer, glioblastoma, liver cancer, and advanced malignancies. Incyte is headquartered in Wilmington, Delaware, the US.

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Transfusion Independence With Momelotinib Impacts OS in Myelofibrosis

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Targeted Oncology Staff

DISCUSSION QUESTION

  • How do the most recent data on Janus kinase (JAK) inhibitors support/change your approach to treating patients?​

DRAUPADI TALREJA, MD: I’m all for momelotinib [Ojjaara]. I was never for ruxolitinib [Jakafi] but there was nothing else available, so I used it.

HARIS ALI, MD: Would you use momelotinib in the majority of your patients or just on certain patients with moderate or severe anemia?

TALREJA: I will use it for them because it reduces the spleen anyway; all [JAK inhibitors] reduce the spleen beautifully. Because it does not cause anemia and can make them transfusion independent, if they have symptoms, a big spleen, and anemia, I have many reasons to use momelotinib. So I’m going to go there, and I’m going to [use less] ruxolitinib.

ALI: Maybe the once-daily dose might be helpful as well.

ARATI CHAND, MD: Was the SIMPLIFY-1 study [NCT01969838] powered for superiority or noninferiority?

ALI: It was powered for noninferiority for [spleen volume reduction] and symptoms, and superiority for the transfusion independence.1

CHAND: What about the adverse event [AE] profile?

ALI: Ruxolitinib has a bit more thrombocytopenia and anemia, and momelotinib has some more gastrointestinal [AEs] and nausea. Otherwise, they were quite comparable.1

CHAND: It looks less toxic compared with ruxolitinib. I would probably change and start using more momelotinib now that is available. Earlier, we didn’t have anything except ruxolitinib and fedratinib [Inrebic]. Pacritinib had such a restricted indication that you could only use it for those patients with very thrombocytopenic myelofibrosis. I think I would definitely start my new patients on momelotinib.

ALI: Would that be regardless of the hemoglobin and platelet count?

CHAND: I think so. It looks like it’s better tolerated. Patients are different, so there may be patients who don’t tolerate this. But in that case, it would make sense to switch and see if they tolerate ruxolitinib better. Efficacy is one thing, but tolerance is also important, especially for treatments that have to be given over prolonged periods of time.

GEORGE HAJJAR, MD: The dosing is also an issue. Adjusting the dose of ruxolitinib is very frequent, depending on the platelet count and hemoglobin level. It’d be interesting to know how many patients got the full dosing of ruxolitinib in that trial vs momelotinib.

ALI: The correct dosing is also important, but it usually goes by the package insert, like 20 mg [twice daily ruxolitinib] for patients with greater than 200 × 109/L platelets, or [15 mg twice daily for patients with between 100 × 109/L and 200 × 109/L platelets].2

HAJJAR: Dose adjustments are always frequent. If we see platelet count drop, we have to tell the patient to decrease the dose, which will be a pain.

ALI: [In the COMFORT-I trial (NCT00952289)], although anemia was a big factor, discontinuation of ruxolitinib because of anemia was in less than 1% of the patients.3 Regardless, patients felt better with the improvement in the symptoms and the spleen symptoms. For whatever reason, that was not the one of the common reasons for discontinuation. I think one of the most common was thrombocytopenia; it wasn’t anemia.

One thing with momelotinib is that it has a lot of drug interactions with OATP1B1/B3 inhibitors, including with statins and different drugs.4 It’s something to watch out for, because hepatic dysfunction was another reason for the hold and [we need to] look at it further. Drug interactions may be the one thing to look out for in a patient, as most of the patients over 65 will be on 5 or 6 different medication for different comorbidities.

CHAND: Was that interaction only for 1 statin or for all statins? Because [many patients] are on a statin now.

ALI: That’s right, so dose reduction might be needed for the statins. There’s a whole drug list with OATP1B1/B3 inhibitors, so you just have to watch for that, but it has more than 1 statin listed there.

DISCUSSION QUESTION

  • How do the overall survival (OS) data influence your choice of therapy?​

ALI: We looked into an OS advantage with ruxolitinib.5 We don’t have too much survival data with [momelotinib] but we do have with the transfusion independence vs non-independence.6 How does that affect your therapy?

TALREJA: I think OS [could be] better with momelotinib. With ruxolitinib, the only good thing is they feel good. It’s their quality of life that helps them live longer. I don’t think ruxolitinib does anything to the bone marrow to reduce the myelofibrosis, so I think momelotinib is a much better drug.

ALI: Would everyone say the same thing about momelotinib for OS compared with other JAK inhibitors including ruxolitinib?

CHAND: I don’t know if you can say that momelotinib has superior OS [based on the trials], but it is basically dependent on transfusion burden. Regardless of what medication you are on, if you’re transfusion dependent, your survival is poor, and if you’re transfusion independent, you’re going to do better in the long run.

ALI: You’re right. Anemia is a big [factor]; if we’ll look at the HR…among all the other risk factors like age or low platelet count, anemia is the biggest factor and transfusion dependence [is based on] patients who are more anemic, so there is definitely poorer survival in those patients.

SWARNA CHANDURI, MD: Is this because this drug works on the hepcidin as an inhibitor? Is that the reason why this is better tolerated and [leads to] less dependence on the transfusions?

ALI: Yes, [inhibiting] the hepcidin pathway, and further reduction to ACVR1 leads to [transfusion independence].7

CHANDURI: If this drug has the additional quality of [ruxolitinib] and improving it, then it is a better drug than ruxolitinib. But the main thing is that is why patients with anemia do better.

References:

1. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A Phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-3850. doi:10.1200/JCO.2017.73.4418

2. Jakafi. Prescribing information. Incyte; 2021. Accessed December 18, 2023. https://tinyurl.com/3t6dd8jj

3. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557

4. Ojjaara. Prescribing information. GlaxoSmithKline; 2023. Accessed December 18, 2023. https://tinyurl.com/4wc5dmet

5. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156. doi:10.1186/s13045-017-0527-7

6. Mesa R, Harrison C, Oh ST, et al. Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. Leukemia. 2022;36(9):2261-2268. doi:10.1038/s41375-022-01637-7

7. Oh ST, Talpaz M, Gerds AT, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 2020;4(18):4282-4291. doi:10.1182/bloodadvances.2020002662

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Tamoxifen Reduces Allele Burden of Patients With Myeloproliferative Neoplasms

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Vicki Moore, PhD

In a clinical trial evaluating the use of tamoxifen in patients with stable myeloproliferative neoplasms (MPNs), 3 patients showed a 50% or greater reduction in mutant allele burden at 24 weeks. This and other results from the study appeared to support further investigation of this agent in this population, but with consideration of possible thrombotic risk. Study results were reported in the journal Nature Communications.

The study’s primary endpoint was a ≥50% reduction in the mutant allele burden in peripheral blood at 24 weeks, with trial success involving at least 3 patients having met this outcome. Several secondary and exploratory outcomes were also evaluated.

These results warrant further investigation of tamoxifen as potential therapeutic for MPN in larger studies, after careful consideration of the risk of thrombosis.

There were 38 patients recruited into the study, with 32 patients completing 24 weeks of treatment. In the total population of 38 patients, 36.8% had essential thrombocythemia, 28.9% had polycythemia vera, 15.8% had primary myelofibrosis, 13.2% had post-polycythemia vera myelofibrosis, and 5.3% had post-essential thrombocythemia myelofibrosis. The overall population had a mean age of 66.3 years (range, 50.0-87.0 years).

There were 3 patients who reached the primary outcome of a ≥50% reduction in mutant allele burden at 24 weeks. Therefore, this study was considered a success in terms of its primary outcome. An additional 5 patients met a secondary outcome of achieving a ≥25% reduction in mutant allele burden, of whom 3 patients had JAK2V617F mutations.

The study investigators additionally performed analyses using hematopoietic stem/progenitor cells that revealed distinctive molecular signatures in responders and nonresponders at baseline. In responders, increased expression of genes associated with JAK-STAT signaling and oxidative phosphorylation appeared to become downregulated in the presence of tamoxifen.

References: Fang Z, Corbizi Fattori G, McKerrell T, et al. Tamoxifen for the treatment of myeloproliferative neoplasms: a phase II clinical trial and exploratory analysis. Nat Commun. 2023;14(1):7725. doi:10.1038/s41467-023-43175-5

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Stumbling Through PV

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“Even if you stumble, you are still moving forward.” This is my go-to quote when life’s difficulties arise. Hearing the words, you’ve got cancer
multiple times will make you feel like you are stumbling through life. The question is how do you stop the feeling of stumbling through a
cancer diagnosis?

In November 2017, I came back from a 200-mile bike ride and felt a little more fatigued and weak than usual. My platelets were in the high 700 range. Docs initially thought this was from inflammation from my bike ride. After a number of blood tests and a bone marrow biopsy, I was initially diagnosed with Essential Thrombocytosis. My diagnosis changed two years ago to Polycythemia Vera. In retrospect, I truly believe I was having symptoms long before my diagnosis. Learning how to manage your symptoms takes a lot of trial and error and patience. Being open to making a little change in your daily routine here and there to manage some of your symptoms is really helpful. When you try something different, write down the change and try that change for a week or so. If the change works for you, move forward. If not, try to find another little tweak of change to help you with your symptoms.

Some of my most challenging symptoms initially were itchy skin, fatigue, and gut issues. Some tweaks to my daily routine such as increased hydration, tweaking of my diet, taking lukewarm & quick showers, and being active most days, have really helped me. Additionally, my current medications and an occasional phlebotomy have really helped manage most of my symptoms. On a day when your symptoms are challenging, just give yourself some grace and relax. Remember as we age, not every little symptom we experience is related to our MPNs.
Finally, a cancer journey is never easy and can feel like you are stumbling through life. When you stumble, you have to learn how to get back up and move on which can be challenging. For me, my attitude about my PV diagnosis now is, that this is just a little stumble on life’s road. That helps me move forward and focus on living every day in this journey called life.

JBI-802 initial Phase I data suggests therapeutic potential in sensitizing immunotherapy resistant tumors and in Myeloproliferative Neoplasms with thrombocytosis

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BEDMINSTER, N.J., Jan. 8, 2024 /PRNewswire/ — Jubilant Therapeutics Inc., a clinical-stage biotechnology company pioneering the development of a first-in-class CoREST (Co-repressor of Repressor Element-1 Silencing Transcription) inhibitor JBI-802 with the dual activity on LSD1 and HDAC6, today announced preliminary safety, pharmacokinetic and initial efficacy results of the Phase I trial in advanced cancer patients. Furthermore, the study results provide a human proof of principle for expanding the development of JBI-802 in Essential Thrombocythemia (ET) and related Myeloproliferative Neoplasms (MPN/MDS) with thrombocytosis.

The data from first 11 patients with advanced cancer revealed a dose-proportional increase in exposure across cohorts and a strong correlation between the exposure and the on-target effects of platelet decrease, indicating that pharmacological relevant level of LSD1 inhibition have been achieved. At the same time, platelet decrease is the only adverse event above grade 1 observed in these patients, which differentiates JBI-802 from LSD1-only inhibitors. Specifically, no AEs (Adverse Events) of anemia has been observed, which is potentially due to the positive benefit of inhibition of HDAC6 in erythrocytes. Also, there are no reports of Dysgeusia, an adverse event that has been observed with LSD1-only inhibitors.

Among the 11 patients, two were NSCLC (Non-small Cell Lung Cancer) patients, both had progressed on doublet immunotherapy, nivolumab+ipilimumab as first line treatment and both showed anti-tumor activity. Both the patients were treated at lower dose level (10mg) where no relevant decrease of platelets is seen, suggesting that in patients with sensitive tumors this dose can be pharmacologically active with a desirable safety profile.

Both NSCLC patients had failed first line treatment with doublet immunotherapy, nivoluman/ipilumab prior to enrolling in the JBI-802 study. The first patient had a STK11 mutation, known to decrease the effectiveness of immunotherapy, present in around 10% of NSCLC patients (higher frequency in lung adenocarcinoma). JBI-802 showed a confirmed partial response in this IO-refractory NSCLC patient with a 39% decrease in the target lung tumor mass. The tumor shrinkage outcome was accompanied by a complete resolution of pancoast syndrome (lung lesion affecting the nerves of brachial plexus). The response appears to be durable after nine cycles and the patient remains on JBI-802 therapy.

The second patient had both lung lesion and liver metastasis, which are known to confer resistance to immunotherapy and lead to poor prognosis. Treatment with JBI-802 resulted in over 50% shrinkage of the patient’s liver metastasis and a complete resolution of related portal hypertension, edema and improvement of quality of life.

Dr. Alexander Starodub, The Christ Hospital – Cincinnati, treating physician for the above patients commented, “The anti-tumor activity seen in these two NSCLC patients is remarkable given the poor prognosis based on their genetic and metastatic pattern. The 10 mg dose of JBI-802 was well-tolerated without any clinically significant adverse effects and the initial clinical data suggest a good therapeutic index for JBI-802.”

Preclinical studies showed a synergistic anti-tumor effect by combining immunotherapy and JBI-802 in xenograft models. In addition, the CoREST inhibition was reported to sensitize immunotherapy resistant tumors, especially those with STK11 mutations. Taken together, the preliminary efficacy data from the JBI-802 Phase I study suggest the opportunity that a combination between immunotherapy and JBI-802 could bring a new therapy option to such patient populations with limited treatment options.

In addition, the on-target dose/exposure-proportional decrease in platelet constitute a proof-of-principle that JBI-802 can be an active compound in hematological malignancies like Essential Thrombocythemia (ET) and other MPN/ MDS characterized by thrombocytosis. A follow up Phase I/II study in MPN/ET and MPN/MDS with thrombocytosis is being planned in the first quarter of this year to investigate JBI-802 as potential novel treatment option.

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SRSF2 Mutation in JAK2V617F-Associated MPNs Reduces Polycythemia, Impairs Hematopoietic Progenitor Activity

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Ryner Lai

SFSR2 mutation reduces polycythemia and impairs the activity of hematopoietic stem/progenitor cells in JAK2V617F-associated myeloproliferative neoplasms (MPNs), according to a study published in Blood Cancer Journal. 

Prior research has shown that JAK2V617F is one of the most common somatic mutations associated with MPNs; in turn, SFSR2 mutations are commonly associated with JAK2V617F, especially in myelofibrosis. Nevertheless, the consequences of SRSF2 mutation in JAK2V617F-associated MPNs have yet to be clearly elucidated in existing medical literature.

Researchers conducted a study on Cre-induced SRSF2P95H/+JAK2V617F/+ knock-in mice. The research team induced Mx1Cre expression by injecting mice models with 3 doses of polyinosine-polycytosine (pl-pC) at a dose of 300 μg at 4 weeks after birth. This allowed the researchers to identify the impact of SRSF2 mutation on blood parameters and the bone marrow 24 weeks after pl-pC administration (or 28 weeks after birth).

Additional mutations or genetic abnormalities are required in association with SRSF2P95H and JAK2V617F mutations in the development of full-blown myelofibrosis.

The research team discovered that concurrent SRSF2P95H and JAK2V617F mutations resulted in a reduction in the polycythemia phenotype; mice with concurrent mutations demonstrated a significant reduction in erythrocytes, leukocytes, platelets, neutrophils, and hematocrit parameters compared to mice that only had the JAK2V617F mutation. In addition, mice with concurrent SRSF2P95H and JAK2V617F mutations had higher mean corpuscular volume (MCV) volumes compared to JAK2V617F/+ mice.

Although Jak2V617F/+ mice demonstrated significant splenomegaly, the investigators found that SRSF2P95H/+JAK2V617F/+ mice exhibited reduced spleen size. In addition, whereas JAK2V617F/+ mice exhibited bone marrow hypercellularity alongside significant increases in erythroid precursors and megakaryocyte clusters, SRSF2P95H/+JAK2V617F/+ mice exhibited normal bone marrow cellularity.

The research team found absent/mild bone marrow fibrosis at 24 weeks in both mice groups. They also reported that SRSF2P95H mutation reduced the competitiveness of hematopoietic stem/progenitor cells; in addition, mice with this mutation had reduced transforming growth factor (TGF)-β levels and increased expressions of S100A8 and S100A9 compared to mice without this mutation; overexpression of S100A8 and S100A9 in turn led to erythroid differentiation defects and myelodysplastic syndrome pathogenesis.

“In conclusion, we demonstrate that SRSF2P95H mutant reduces development of bone marrow fibrosis in JAK2V617F-induced MPNs,” the authors of the study wrote in their report. “Additional mutations or genetic abnormalities are required in association with SRSF2P95H and JAK2V617F mutations in the development of full-blown myelofibrosis.”

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Merck Announces Phase 3 Trial Initiations for Four Investigational Candidates From its Promising Hematology and Oncology Pipeline

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January 5, 2024 6:45 am ET

Global Phase 3 studies started for bomedemstat (LSD1 inhibitor), nemtabrutinib (BTK inhibitor), MK-2870 (anti-TROP2 ADC) and MK-5684 (CYP11A1 inhibitor)

Comprehensive clinical development programs being initiated for each investigational candidate

Demonstrates company’s commitment to research across novel mechanisms of action in hematologic neoplasms/malignancies, as well as lung, endometrial and prostate cancers

RAHWAY, N.J.–(BUSINESS WIRE)– Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the initiation of pivotal Phase 3 trials for four of its investigational candidates from its diverse pipeline in hematologic malignancies and solid tumors. Global Phase 3 studies have been initiated and are actively enrolling for the following investigational candidates:

  • Bomedemstat, an investigational orally available lysine-specific demethylase 1 (LSD1) inhibitor, being evaluated for the treatment of certain patients with essential thrombocythemia (ET);
  • Nemtabrutinib, an investigational oral, reversible, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, being evaluated for the treatment of certain patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL);
  • MK-2870, an investigational trophoblast cell-surface antigen 2 (TROP2)-directed antibody drug conjugate (ADC) being developed in collaboration with Kelun-Biotech, which is being evaluated for certain patients with non-small cell lung cancer (NSCLC) and certain patients with previously treated endometrial carcinoma;
  • and MK-5684, an investigational CYP11A1 inhibitor being developed in collaboration with Orion, which is being evaluated for the treatment of certain patients with metastatic castration-resistant prostate cancer (mCRPC).

“These Phase 3 trial initiations for four of our investigational candidates represent a critical step forward in our efforts to advance potential treatment options for people with solid tumors and hematologic neoplasms and malignancies,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “We have a proud legacy of turning breakthrough science into medicines that save and improve lives around the world, and we are dedicated to continuing research to expand our broad portfolio of oncology therapeutics to continue to address unmet needs in cancer care.”

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Patients With MPNs Face a Heighted Risk for Thrombotic, Cardiovascular Events

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Alex Biese
Patients with myeloproliferative neoplasms (MPNs) — a group of blood cancers that causes the bone marrow to overproduce red or white blood cells or platelets (including polycythemia vera, essential thrombocythemia and myelofibrosis) — face a height risk for thrombotic and cardiovascular events.

But Kim Noonan, DNP, ANP-BC, AOCN, FAAN, Nursing and Patient Care Services Chief Nurse Practitioner at the Dana-Farber Cancer Institute in Boston, said there are things nurses can do to help manage that risk, such as inquiring about patients’ history of blood clots and encouraging patients to not be sedentary, as well as watching for symptoms such as elevated heart rate and shortness of breath.

“I am always thinking about thrombosis first, and then I can relax if I have maybe another explanation for their shortness of breath,” Noonan said. “But we’re always working it up, we really do due diligence to not miss some kind of thrombotic event that’s going on.”

Noonan spoke with Oncology Nursing News about awareness of the potential for thrombotic and cardiovascular events, risk factors to be mindful of and everyday actions patients can take to lower their risk.

Transcript:

Noonan: NCCN, the National Comprehensive Cancer Network, really has done a lot of work in identifying this for multiple myeloma patients, and they actually have come up with guidelines as to who really needs to be on anticoagulant therapy and who does not, and they’ve identified factors that we need to consider. And so, I think it’s getting a lot of press, it’s getting a lot of attention, certainly in the myeloma world. But I think it deserves a little bit more attention, I hate to say it, but maybe in solid tumor worlds as well.

One of the things that I didn’t mention was that, I think I said people that are dehydrated are at risk, but also people that have been on like airplane rides, people that have been in long car rides, too, are really at risk. So those are other risk factors that I think I failed to mention.

Oncology Nursing News: Would working a sedentary job, such as a desk job, also potentially be a risk factor as well?

Noonan: That’s a huge risk factor, as well, to the point of, we say to people, if you’re not getting up and walking around, maybe we should consider putting you on anticoagulation therapy right up front as opposed to just using an aspirin.

Oncology Nursing News: What are some simple things, such as getting up and walking around, that folks can do in their everyday lives to lower their risk?

Noonan: Yeah, that’s a really good question. We really want people to stay hydrated. We want them to get up and walk around. We want them to be aware of what the symptoms are, they can be doing everything right and still develop a clot because of the medication that they’re on.

But I think also, education is essential, that you are on a medication that can increase your chances of developing a clot or thrombosis, and just be aware of what the symptoms are.

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