Category Archives: Blood Cancer

TP53 mutations and Their Impact on Survival in Patients with Myeloproliferative Neoplasms

Posted on by

November 28, 2023

Benjamin Rolles, MD; Cilomar Martins De Oliveira Filho, MD; Julia Keating, MS; Marlise Luskin. MD, MSCE; Daniel DeAngelo; Coleman Lindsley, MD, PhD; Annette Kim, MD, PhD; Jessica Hem; Chulwoo Kim; Lachelle Week, MD, PhD; Mohammad Wazir; Joan How, MD; Anne Marneth, PhD; Yiwen Liu; Martin Aryee, PhD; Harrison Tsai, MD, PhD; Maximilian Stahl, MD; Ann Mullaly, MD

Introduction: TP53 mutations in patients with myeloproliferative neoplasms (MPN) are associated with poor prognosis, including progression to blast phase MPN. However, low variant allele fraction (VAF) TP53 mutations have been reported to remain stable over years in chronic phase MPN. A major unmet clinical need in MPN is the ability to discriminate patients with TP53-mutant MPN who are at high-risk of secondary AML (sAML) and warrant immediate intervention from those who are at lower risk of sAML in whom active surveillance can be employed. Therefore, we sought to identify parameters associated with leukemic transformation and overall survival in the context of MPN with genetic aberrations in TP53.

Materials and Methods: We retrospectively analyzed a cohort of 947 MPN patients from the Dana-Farber Cancer Institute Hematologic Malignancies Data Repository (HMDR) with at least one clinical next-generation sequencing (NGS) panel performed. Patient characteristics such as age at MPN diagnosis, gender, MPN subtype and driver mutations were recorded. Furthermore, information about the course of disease was extracted including occurrence of sAML and overall survival (Figure 1). We also analyzed type and number of additional mutations as well as cytogenetics. With respect to TP53-specific parameters, we evaluated the number of TP53 mutations, TP53 VAF, loss of heterozygosity (LOH) at the TP53 locus, phenotypic annotations of TP53 (i.e. PHANTM score) and 17p deletion. We defined “multi-hit” TP53 as the presence of two or more TP53 mutations, TP53 VAF higher than 50%, TP53 mutation plus 17p deletionor TP53 mutation and documented LOH.

Results: A total of 947 patients were analyzed, of which 40 harbored at least one detectable TP53 mutation. A total of 13 patients were found to have a multi-hit TP53 mutations defined by > 50% VAF in 6 patients, two or more TP53 mutations in 5 patients and TP53 mutation + 17p deletion in 5 patients. The MPN diagnosis at time of TP53 mutation detection was post ET/PV myelofibrosis (secondary MF) (n=23, 58%), primary myelofibrosis (MF) (n=7, 18%), pre-fibrotic MF (n=2, 5%), essential thrombocythemia (ET) (n=6, 15%) and polycythemia vera (PV) (n=2, 5%). Two patients with ET and one patient with PV did not have a concurrent in-house bone marrow biopsy performed at the time the TP53 mutation was detected. Two patients with ET developed sAML within 12 months of TP53 mutation detection, without prior mention of fibrosis. Age at first MPN diagnosis was not significantly different between patients with or without TP53 mutation. The average time from initial MPN diagnosis to detection of the first TP53 mutation was 9 years (range: 0-33 years). The most common MPN driver mutation among patients with TP53 mutations was JAK2 (75%), followed by CALR (13%)and MPL (5%). Out of all TP53-mutated patients, 8% showed a triple negative status. The most frequent additional mutations among patients with TP53 mutations were TET2 (25%), U2AF1 (15%), ASXL1 (13%), and DNMT3A (10%). There was no significant difference between single-hit and multi-hit TP53 status regarding MPN subtype, driver mutations and co-mutations (Table 1). Seven patients (single-hit: 15%, multi-hit: 23%) with a TP53 mutation developed sAML during the course of their disease, compared with only 3% of all patients without a TP53 mutation and 50% (single-hit: 41%, multi-hit: 69%) were deceased at the time of the last follow-up compared to 18% of all patients without a TP53 mutation.

We focused on overall survival from the initial MPN diagnosis and considered whether patients developed bone marrow fibrosis during their disease course (Figure 1). Survival did not differ significantly between single-hit TP53 and patients with multi-hit TP53 (p=0.2), but survival did differ significantly between multi-hit TP53 patients and TP53 wildtype patients with MF/prefibrotic MF/Secondary MF (p=0.02) as well as compared to all MPN patients without a TP53 mutation (p<0.001). Survival was not significantly different between single-hit TP53 and TP53 wildtype MF/prefibrotic MF/Secondary MF patients (p=0.4).

Conclusions: In a large cohort of 947 molecularly characterized MPN patients, 4% of the cohort developed a TP53 mutation during their course of disease. 18% of all TP53-mutant patients developed sAML with an adverse effect on overall survival for patients with multi-hit but not single-hit TP53 mutations.

Read more

Defining and Treating Classic Cases of Myeloproliferative Neoplasms

Posted on by

Targeted Oncology Staff

In the first article of a 2-part series, Pankit Vachhani, MD, discusses what makes classical cases of myeloproliferative neoplasms unique and how ruxolitinib impacts their reduction of spleen volume.

CASE

  • A 68-year-old woman presented to her physician with symptoms of mild fatigue.
  • Her spleen was palpable 6-7 cm below the left costal margin​.
  • Medical History: No known comorbidities
  • Next-generation sequence testing: JAK2 V617F mutation​
  • Karyotype: 46XX​
  • Bone marrow biopsy: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis​
  • Blood smear: leukoerythroblastosis​
  • Diagnosis: Primary myelofibrosis​
  • Dynamic International Prognostic Scoring System: intermediate-1​
  • Mutation-enhanced International Prognostic Score System 70: intermediate risk
  • The patient was not interested in transplant​.
  • A decision was made to initiate ruxolitinib (Jakafi).

Targeted Oncology: What makes myeloproliferative neoplasms (MPNs) unique among blood cancers?

PANKIT VACHHANI, MD: Every time I have a patient with chronic myeloid neoplasms, meaning a myeloid neoplasm that’s not an acute leukemia, I like to think of it under the framework of World Health Organization 2022 classification schemes….1 It’s important because there are a few different subcategories of chronic myeloid neoplasms, one of which is MPNs. This [disease] used to be called myeloproliferative disorders, but around 2008 the name was formally changed to neoplasms…putting it into perspective, the fact that it is a blood cancer.1

When looking at the category of MPNs, there are many of these…including the classic chronic myeloid leukemia, Philadelphia chromosome–positive MPN, and [more]. These also include polycythemia vera [PV], essential thrombocythemia [ET], myelofibrosis, pre-fibrotic and overt myelofibrosis, chronic neutrophilic leukemia, eosinophilic leukemia, and the MPN unclassifiable. Now, when we think of MPNs, the 3 classical Philadelphia chromosome–negative MPNs [specifically], include PV, ET, and myelofibrosis, which are the most common of the MPNs.

How do MPNs present in patients?

What connects all these MPNs is that they present somewhat similarly. They present with high white blood counts, or high blood counts in general, and they present [in patients] with symptoms, an enlarged spleen, for example. But if you’ve looked just at PV, ET, and myelofibrosis, what you will see is that there is a Janus Kinase [JAK]-STAT signaling pathway that is over activated.2

If you want to take a step back and think about it, we all know that there are cells and cells have receptors, receptors need lichens to be active, and one such receptor would be the erythropoietin [EPO] receptor. You need the EPO ligand to bind to the EPO receptor, and then the JAK would get activated and they would make the STATs activated and the activated STATs would go inside the nucleus and lead to transcription of different proteins.

What mutations are there in this disease?

The JAK-STAT pathway is involved in transmitting the signal from outside of the cell to inside of the nucleus, therefore making the changes.2 What happens in PV, ET, and myelofibrosis is that this pathway is hyperactive; it doesn’t even need a signal frequently to be over activated. In the case of PV, for example, most of the cases have a classic JAK2 V617F mutation, then a very small fraction [of the patients without this mutation have] either the JAK2 exon 12 mutation, or some very unusual [and rare] mutations….3 The same JAK2 V617F [mutation can] also be found in ET and myelofibrosis. In fact, that JAK2 mutation constitutes about 60% of myelofibrosis and ET cases.3

If you look at the [patients with] myelofibrosis, what happens to those remaining 40% of patients who don’t have the JAK2 mutation? They have a CALR mutation or committal mutation, with CALR being the more common of those 2.3 About 10% of patients don’t have a mutation in either of these 3 driver gene mutations and that’s when we call it triple-negative myelofibrosis. Largely speaking, you are not going to find more than 1 of these mutations in the same case, so they’re more or less mutually exclusive. What’s common, however, between all 3 [disease types] is that the all 3 leads to this JAK-STAT pathway being over activated.2 So that’s the commonality that connects MPNs.

What were the spleen reduction outcomes in the COMFORT-I study (NCT00952289)?

Data from COMFORT-1 showed that the 35% spleen volume reduction [SVR], which was a primary end point at 24 weeks, was met in about 42% of patients [given ruxolitinib] vs less than 1% of patients on placebo [P < .001].4 The SVR results were comparable with COMFORT-II [NCT00934544] with 28% of patients on jak[having a SVR compared with no one on the best available therapy].5

So, there was a massive difference [in these results] with ruxolitinib and the comparator…. If you look at the change in spleen response for individual patients…most patients who got ruxolitinib in COMFORT-I had a spleen volume that decreased. On the other hand, the patients who got placebo had an increase of spleen volume, and there were very similar data from the COMFORT-II study [showing SVR in individuals who got ruxolitinib].4,5 Further, these results support ruxolitinib across the different subgroups, be that male vs female, primary or secondary myelofibrosis, or patients positive for the JAK2 mutation.

References

1. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1

2. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-90. doi:10.1056/NEJMoa1311347

3. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391-2405. doi:10.1056/NEJMoa1312542

4. 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

5. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-98. doi:10.1056/NEJMoa1110556

Read more

CHA2DS2-VASC Predicted Thrombotic Risk in Patients With MPNs and Atrial Fibrillation

Posted on by

November 16, 2023

Andrea S. Blevins Primeau, PhD, MBA

Although CHA2DS2-VASC does not account for myeloproliferative neoplasms (MPNs), it accurately predicted thrombotic risk in this patient population with atrial fibrillation (AF). However, HAS-BLED did not predict bleeding risk, according to the results of a retrospective study.

“Further investigation is needed to refine risk scores in MPN,” the authors wrote in their report. The study, which was published in the Journal of Thrombosis and Thrombolysis, analyzed data from 1617 patients with and 24,185 matched patients without MPNs from the National Readmission Database. All patients had AF. The primary outcomes were in-hospital or 30-day readmission for bleeding or thrombosis.

Characteristics were balanced between the cohorts. Overall, 29% of patients were on long-term anticoagulation, 25% were on long-term antiplatelet therapy. Comorbidities were common, with 76% of patients with hypertension, 42% with congestive heart failure, 35% with anemia, 33% with coronary artery disease, 24% with chronic lung disease, and 22% with diabetes.

However, patients with MPN were not at an increased risk of bleeding, with 2.60% experiencing a bleed compared with 2.98% of patients without MPNs (OR, 0.87; 95% CI, 0.63-1.19). Risk of bleeding was not accurately predicted by HAS-BLED, with a c-statistic of 0.55 (95% CI, 0.46-0.64) among patients with MPNs. For patients without MPN, the HAS-BLED was moderately predictive (c-statistic, 0.56; 95% CI, 0.54-0.58).

Patients with MPN were more likely to experience bleeding if their MPN type was essential thrombocythemia (P =.009), if they had anemia (P <.001), peripheral vascular disease (P =.024), or chronic kidney disease (P =.047). However, after multivariate analysis only ET remained independently associated with bleeding (adjusted OR, 3.08; 95% CI, 1.04-9.16).

Any hospital readmission within 30 days occurred among 18.6% of patients with MPN compared with 11.9% of patients without MPNs (P <.001). Within 90 days, 26.4% and 20.4% of patients with and without MPNs had a hospital readmission (P <.001).

Cardiovascular (CV)-related hospital readmission, which included arterial thrombosis, heart failure, and arrythmia, was also more common among patients with MPNs, occurring among 6.2% compared with 5.0% without MPN within 30 days (P =.046). However, there was no significant difference in CV readmission rates during the 90-day period.

Reference
Leiva O, How J, Grevet J, et al. In-hospital and readmission outcomes of patients with myeloproliferative neoplasms and atrial fibrillation: insights from the National Readmissions Database. J Thromb Thrombolysis. Published online October 15, 2023. doi: 10.1007/s11239-023-02900-z

Read more

Allogeneic HCT Provides OS Benefit Independent of TP53 Allelic Status in MDS

Posted on by

November 18, 2023

By Kyle Doherty

Patients with myelodysplastic syndrome (MDS) harboring a TP53 mutation experienced a survival benefit with allogeneic hematopoietic cell transplantation (HCT) compared with non-HCT treatment regardless of TP53 allelic status, according to findings from an analysis of the phase 2 Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1102 study (NCT02016781) published in the Journal of Clinical Oncology.1

Findings from a univariate analysis showed that, irrespective of treatment strategy, patients with a TP53 mutation (n = 87) experienced a 3-year overall survival (OS) rate of 21% (standard error [SE] ± 5%) compared with 52% (SE ± 4%) among patients who were TP53 wild-type (n = 222; HR, 2.55; 95% CI, 1.86-3.50; P < .001). Additionally, the 3-year OS rate among patients with a single TP53 mutation (n = 39) was comparable with that of patients with a TP53 multi-hit mutation (n = 48), at 22% (SE ± 8%) vs 20% (SE ± 6%), respectively (HR, 1.29; 95% CI, 0.79-2.11; P = .31).

When HCT was used as a time-dependent covariate, patients with a TP53 mutation who received HCT (n = 48) experienced a 3-year OS rate of 23% (SE ± 7%) vs 11% (SE ± 7%) in patients who were treated with non-HCT therapy (n = 32; HR, 1.76; 95% CI, 1.02-3.06; P = .04). Moreover, the 3-year OS rate among patients with very high-risk MDS per the Molecular International Prognostic Scoring System per molecular International Prostate Symptom Score (IPSS-M) without a TP53 mutation who received HCT (n = 22) was significantly improved compared with those with the same risk profile and mutational status who received non-HCT therapy (n = 8), at 68% (SE ± 10%) vs 0% (SE ± 12%), respectively (P = .001).

“The absence of a non-HCT control group in [other] retrospective analyses has called into question whether the long-term survival observed in these studies was reasonably attributable to the transplantation intervention,” investigators wrote. “In this study, we directly addressed this question and now conclude definitively that reduced intensity transplantation mediates long-term survival for patients with TP53-mutated MDS compared with non-HCT treatment. Moreover, we show that the benefit of HCT over non-HCT treatment was independent of TP53 allelic state and not restricted to specific subgroups of TP53-mutated MDS.”

Previously published findings from the primary analysis of BMT CTN 1102 showed that patients who received reduced intensity conditioning HCT (n = 260) achieved a 3-year OS rate of 47.9% (95% CI, 41.3%-54.1%) compared with 26.6% (95% CI, 18.4%-35.6%) among those who were treated with non-HCT therapy or best supportive care (n = 124), for an absolute difference of 21.3% (95% CI, 10.2%-31.8%; P = .0001). The 3-year leukemia-free survival rates were 35.8% (95% CI, 29.8%-41.8%) vs 20.6% (95% CI, 13.3%-29.1%), respectively (absolute difference, 15.2%; 95% CI, 13.3%-29.1%; P = .003).2

BMT CTN 1102 was a multicenter prospective trial that evaluated the efficacy of reduced intensity conditioning HCT (donor arm) vs that of hypomethylating therapy or best supportive care (no donor arm) in patients with IPSS intermediate-2 or high-risk de novo MDS who were 50 to 75 years old. To perform their genetic analysis of BMT CTN 1102, study authors performed targeted DNA sequencing on frozen whole blood samples collected at the time of enrollment, which were available for 229 patients in the donor arm and 80 patients in the no donor arm. Baseline patient characteristics did not differ significantly between those in the donor and no donor arms.1

Patients included in the genetic analysis (n = 309) had a median age of 66.9 years (range, 50.1-75.3), with most patients being over 65 years old (61.8%). Most patients were female (62.1%), had IPSS intermediate-2 disease (66.7%), and complex karyotype (65.0%). At baseline, the median hemoglobin was 9.3 g/dL (range, 8.1-10.7) and the median platelet count was 70 x 109/L (range, 34-132).

In addition to a univariate analysis, investigators constructed 2 multivariable models adjusted for age at enrollment, performance status, IPSS risk status, MDS disease duration, and clinical and genetic variables. One model was based on random assignment on the basis of donor availability and the other compared HCT vs non-HCT treatment with HCT representing a time-dependent covariate.

Additional findings from the univariate analysis showed that, outside of TP53 mutations, the presence of KMT2Apartial tandem duplications was associated with a decrease in 3-year OS rate compared with those who did not have these duplications (HR, 2.21; 95% CI, 1.22-3.99; P = .009). However, patients with a germline DDX41 mutation (HR, 0.39; 95% CI, 0.17-0.87; P = .022) and somatic mutations in STAG2 (HR, 0.57; 95% CI, 0.34-0.96; P = .034) displayed superior OS compared with those who did not have these mutations.

Results from the donor vs no donor analysis revealed that patients in the donor arm experienced an OS improvement compared with those assigned to the no donor arm (HR, 1.60; 95% CI, 1.10-2.32; P = .013). Among patients with a TP53 mutation, assignment to the donor arm did not significantly improve OS compared with the no donor arm (HR, 1.76; 95% CI, 0.95-3.26; P = .073).

In the model that compared HCT with non-HCT treatment, patients who received HCT (n = 197) experienced a significantly lower risk of death compared with those treated with non-HCT therapies (n = 78; HR, 2.31; 95% CI, 1.53-3.49; P < .001). Findings from this model showed that patients with a TP53 mutation had a much greater risk of dying if they did not receive HCT vs those who did (HR, 3.89; 95% CI, 1.87-8.12; P < .001), which study authors noted could signify that, “…HCT might improve long-term survival in patients with mutated TP53, independent of other risk factors.” Investigators also found molecular clearance of TP53 mutation before HCT not to be predictive of long-term survival.

“Together, these data indicate that no patient with TP53-mutated MDS should be excluded from consideration for HCT a priori on the basis of TP53 status alone. Despite the relative benefit of HCT over non-HCT treatment, however, the absolute survival benefit remains modest, meriting value-based discussions between physicians and patients on the appropriateness of transplantation,” study authors concluded.

Reference

  1. Versluis J, Saber W, Tsai HK, et al. Allogeneic hematopoietic cell transplantation improves outcome in myelodysplastic syndrome across high-risk genetic subgroups: genetic analysis of the blood and marrow transplant clinical trials network 1102 study. J Clin Oncol. 2023;41(28):4497-4510. doi:10.1200/JCO.23.00866
  2. Nakamura R, Saber W, Martens MJ, et al. Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50-75 years of age with advanced myelodysplastic syndrome. J Clin Oncol. 2021;39(30):3328-3339. doi:10.1200/JCO.20.03380

Read more

MPN Linked to Lower Death and Cardiac Arrest, Higher Bleeding in Patients Hospitalized With AMI

Posted on by

Among patients hospitalized with acute myocardial infarction (AMI), those with myeloproliferative neoplasms (MPN) have an increased risk of in-hospital bleeding but a decreased risk of in-hospital death or cardiac arrest compared with patients without MPNs. This is according to a study published in JACC: CardioOncology.

“MPN poses a clinical conundrum. They are a heterogenous group of clonal hematopoietic neoplasms that portend a prognosis measured in years in some cases,” said Orly Leiva, MD, of the New York University Grossman School of Medicine. “The association between MPN and thrombosis has been well described. However, outcomes among patients with MPN who have had AMI have not been well studied.

“There are no current guidelines on specific treatment of AMI among patients with MPN. As such, current treatment of patients with MPN, including revascularization strategy and choice and duration of antithrombotic therapies, is usually made per current guidelines of the general population and on an individual basis based on the patient’s perceived thrombotic and bleeding risks,” Dr. Leiva said. “Our study aimed to shed some light on describing the characteristics of patients with MPN admitted for AMI and outcomes compared to the general population and to encourage further study that may lead to a more refined and personalized approach to the management of AMI among patients with MPN.”

Between January 2006 and December 2018, 1,644,304 patients (mean age = 67.2 years; 61.1% male) admitted for AMI were identified using the National Inpatient Sample, which captures around 20% of hospitalizations in the U.S. Among the 5,374 patients (0.3%) with MPN, 48.8% had polycythemia vera (PV), 47.8% had essential thrombocythemia (ET), and 5.8% had primary myelofibrosis (MF). The procedures captured included left heart catheterization, percutaneous coronary intervention (PCI), mechanical circulatory support (MCS), and coronary artery bypass grafting (CABG). The researchers compared the in-hospital outcomes between patients with and without MPN. The primary outcome was in-hospital death or cardiac arrest, and the secondary outcome was major bleeding.

Baseline patient characteristics were adequately balanced between patients with and without MPN after propensity score weighting. Compared with patients without MPN, those with MPN had a lower risk of in-hospital death or cardiac arrest (odds ratio [OR] = 0.83; 95% CI 0.82-0.84) but a higher risk of major bleeding (OR=1.29; 95% CI 1.28-1.30). Patients without MPN had a decreasing temporal rate of in-hospital death or cardiac arrest and bleeding (ptrend<0.001 for both). However, patients with MPN had an increasing temporal rate of in-hospital death or cardiac arrest (ptrend<0.001) and a stable rate of major bleeding (ptrend=0.48). This was despite a similar reduction in ST-segment elevation myocardial infarction (STEMI) presentations between patients with and without MPN over time (ptrend for both < 0.001). The risk factors associated with an increased likelihood of death, cardiac arrest, or bleeding included peripheral vascular disease, anemia, STEMI presentation, and an ET and primary MF MPN phenotype.

Invasive management (left heart catheterization, PCI, or CABG) was lower, although not significantly so, in patients with MPN than in those without (68.8% vs. 71.6%; SMD = 0.06). Patients with MPN were less likely than those without MPN to undergo PCI (38.3% vs. 43.2%; standardized mean difference [SMD] = 0.10) but not CABG (8.9% vs. 8.8%; SMD = 0.002). For patients with and without MPN, use of MCS (5.5% vs. 5.0%; SMD = 0.018) and prevalence of cardiogenic shock (3.6% vs. 3.9%; SMD = 0.02) were similar.

“Our study suggested no increase in in-hospital mortality among patients with MPN compared with the general population. However, patients with MPN had increased rates of bleeding events, including gastrointestinal and procedure-related bleeding,” said Dr. Leiva. “Additionally, patients with MPN were less likely to be treated with PCI.”

Limitations to the study include its retrospective design. Further, the data in the National Inpatient Sample are abstracted from billing codes, which are prone to errors. Data on the treatment of MPN, blood counts, disease duration, and genetic testing (JAK2 mutation) are not reported and may affect cardiovascular outcomes.

“My hope is that our study spurs further research on the management of AMI among patients with MPN and other cancers to better understand bleeding and thrombotic risk and to develop therapeutic paradigms that better balance these competing risks,” Dr. Leiva said.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Leiva O, Xia Y, Siddiqui E, et al. Outcomes of patients with myeloproliferative neoplasms admitted with myocardial infarction: insights from National Inpatient Sample. JACC CardioOncol. 2023;5(4):457-468.

Read more

GSK and Queer Eye’s Thom Filicia Partner on Blood Cancer Awareness Initiative

Posted on by

• GSK launches Mapping Myelofibrosis to help chart course for those affected by the disease.
• Myelofibrosis is a complex blood cancer that impacts nearly 25,000 people in the U.S.

Download (PDF, 155.2KB) 

Issued: Philadelphia, PA

GSK plc (LSE/NYSE: GSK) has partnered with former Queer Eye star and interior designer Thom Filicia to launch Mapping Myelofibrosis, a new health education initiative aiming to help those impacted by myelofibrosis (MF) better navigate the disease. This year marks the 10-year anniversary of Filicia donating bone marrow to his brother, who was diagnosed with MF a few months prior to the transplant. Filicia now looks to use his voice to help raise awareness of this blood cancer, which can be difficult to diagnose and manage.1

MF impacts nearly 25,000 people in the U.S. and is part of a larger group of blood cancers that affect the bone marrow, called myeloproliferative neoplasms (MPNs).2,3 Each person experiences MF differently, presenting significant challenges in identifying symptoms and mapping out treatment paths.1

“After my brother’s diagnosis, we didn’t understand the magnitude of what he was up against,” said Filicia. “The reality of MF presents unique challenges for each individual, and as my brother overcame this disease, I realized the need to ensure more accessible information and resources. This experience led me to team up with GSK on Mapping Myelofibrosis to continue raising awareness of this complex blood cancer.”

Mapping Myelofibrosis includes the launch of a website featuring educational resources about MF, community stories, and messages from Filicia. In developing the initiative, GSK sought input from the MF community through collaborations with organizations including the MPN Research Foundation (MPNRF) and MPN Advocacy & Education International (MPN A&E).

Faris El Refaie, Head of Oncology, US of GSK said: “At GSK, we are committed to advancing the standard of care in oncology and supporting communities impacted by hematologic cancers. Recognizing an unmet need in myelofibrosis, we developed Mapping Myelofibrosis to cultivate awareness and provide a platform to foster support and education.”

Kapila Viges, CEO of MPN Research Foundation said: “This initiative by GSK represents a meaningful step forward in ensuring those living with MF and their families have access to tailored resources to help guide them through the complexities of this disease. Hearing Filicia tell his story reinforces the importance of enhancing our understanding of MF, and all MPNs.”

Ann Brazeau, CEO and Founder of MPN A&E said: “Ensuring that patients with MF and their loved ones feel seen and heard while navigating a rare disease is so important. Educational resources like GSK’s Mapping Myelofibrosis initiative are critical for patients and their families when it comes to making informed decisions around their care.”

In early stages, approximately one third of individuals with MF will not exhibit symptoms.1 However, key signs and symptoms of the disease may include, but are not limited to low blood counts (anemia), low platelet counts (thrombocytopenia) or enlarged spleen (splenomegaly).1 For those who have not been diagnosed, early detection of the disease may be beneficial. For those who have been diagnosed, understanding your symptoms is key to making informed decisions regarding treatment and care with your healthcare providers.1

Explore MappingMF.com to find resources and learn more.

About Mapping Myelofibrosis
GSK created Mapping Myelofibrosis to increase awareness of myelofibrosis, seeking to connect the community with educational tools, resources and stories to help navigate all aspects of the disease.

Explore MappingMF.com to find resources and learn more about myelofibrosis. You can also follow the initiative on Facebook.

About myelofibrosis (MF)
Myelofibrosis is a complex blood cancer affecting approximately 25,000 people in the U.S.2 MF is part of a larger group of blood cancers that affect the blood and bone marrow, known as myeloproliferative neoplasms, or MPNs.3 In people with MF, blood cells may not be produced in a typical way, causing inflammation and scarring of the bone marrow, which is called fibrosis.3 The signs and symptoms of MF may include severe low blood counts or anemia, enlarged spleen (splenomegaly), low blood platelets (thrombocytopenia), and other symptoms.1

GSK in oncology
GSK is focused on maximizing patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, tumor cell targeting therapies and synthetic lethality. Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilizing modalities such as small molecules, antibodies and antibody-drug conjugates, either alone or in combination.

About GSK
GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com.

References:
1. Cleveland Clinic. Myelofibrosis. Available at: https://my.clevelandclinic.org/health/diseases/15672-myelofibrosis. Accessed October 2023
2. Data on file. Sierra Oncology. 2021.
3. MPN Research Foundation. Primary Myelofibrosis (PMF). Available at: http://www.mpnresearchfoundation.org/primary-myelofibrosis-pmf/.Accessed October 2023.

Read more

Dr Tremblay on the Identification and Prevalence of MDS/MPN Overlap Syndromes

Posted on by

Douglas A. Tremblay, MD

Douglas A. Tremblay, MD, assistant professor, medicine, Icahn School of Medicine at Mount Sinai, discusses the prevalence of myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes and the evolving treatment paradigm for these diseases, which he discussed in a presentation at the 41st Annual CFS®.

MDS/MPN overlap syndromes include a cluster of 4 related diseases: chronic myelomonocytic leukemia (CMML); atypical chronic myeloid leukemia; MDS/MPN with ring sideroblasts and thrombocytosis; and unclassifiable MDS/MPN, Tremblay says. These diseases are often difficult to manage because they share many characteristics that are indicative of both myeloproliferative diseases and MDS, Tremblay notes. Although these conditions are considered rare, they are likely more prevalent than initially hypothesized because of the overlapping nature of MPNs and MDS, Tremblay explains. However, treatment decisions for patients with these overlap syndromes are typically influenced by insights garnered from the MDS and MPN treatment paradigms, Tremblay emphasizes. In the future, the management of these overlap syndromes may become more specialized, Tremblay says. Tailored therapies are emerging, particularly in the CMML field, where JAK inhibitors have gained prominence, Tremblay explains.

Treatment decisions for patients with MDS/MPN overlap syndromes are largely based on the main issue patients experience, such as cytopenias, splenomegaly, or constitutional syndromes, Tremblay notes. Overall, patients with high-risk disease should be referred to autologous stem cell transplant because it is the only curative therapy for these syndromes, Tremblay says. Conversely, many of the treatment strategies for patients who are ineligible for transplant, such as hypomethylating agents (HMAs), are borrowed from the MDS/MPN treatment paradigms, Tremblay explains. However, HMAs have displayed limited efficacy in this population, Tremblay emphasizes. For instance, the phase 3 DACOTA trial (NCT02214407) showed no difference in event-free survival (EFS) or overall survival (OS) with decitabine vs hydroxyurea in patients with a myeloproliferative subtype of CMML.

Efforts to find effective therapies for patients with MDS/MPN overlap syndromes beyond HMAs have spurred research with JAK inhibitors in patients with CMML, according to Tremblay. The JAK-STAT signaling pathway is hypersensitive in CMML cells, and preclinical studies have shown the efficacy of halting that pathway, Tremblay says. Furthermore, a phase 1/2 trial (NCT03722407) showed the advantages of using ruxolitinib (Rituxan) to improve spleen and symptom responses in patients with CMML. Further research is investigating JAK inhibitors in combination with HMAs in patients with CMML and other MDS/MPN overlap syndromes, Tremblay concludes.

Read more

Characteristics, Primary Treatment, And Survival of MDS/MPN with Neutrophilia: A Population-Based Study

Posted on by

Saskia Klein (UMCG, Netherlands) Gerwin Huls (University Medical Center Groningen, Netherlands), Otto Visser (IKNL, Netherlands) Hanneke Kluin-Nelemans (University Medical Center Groningen, University og Groningen, Netherlands) Avinash Dinmohamed (Erasmus MC AND Amsterdam UMC, Netherlands)

Abstract
MDS/ MPN with neutrophilia, until recently called atypical chronic myeloid leukemia (aCML), being part of the myelodysplastic/myeloproliferative neoplasms is a very rare disease with poor prognosis. Although emerging data reveal its cytogenetic and molecular profile, integrated survival and treatment data remain scarce. We analyzed a cohort of 347 adult patients diagnosed with MDS/
MPN with neutrophilia, registered in the Netherlands Cancer Registry between 2001 and 2019. Our demographic baseline data align with other cohorts. We observed cytogenetic aberrations exclusively in patients aged >65 years, with trisomy 8 being the most common abnormality. We identified 16 distinct molecular mutations, with some patients (16/101) harboring up to 3 different mutations; ASXL1 being the most frequent one (22%). In a multivariable Cox regression analysis, only age, hemoglobin level and allogeneic hematopoietic stem cell transplant (alloHSCT) were associated with overall survival (>65 years of age HR 1.85, P=0.001 and alloHSCT HR 0.51, P=0.039). As no other treatment modality, seemed to impact survival and might cause toxicity, we propose that all patients eligible for alloHSCT should whenever possible receive an allogeneic transplant. It is imperative that we strive to improve outcomes for patients not eligible for alloHSCT. Tackling this challenge requires international collaborative efforts to conduct prospective intervention studies.

Read more

MPN Subtypes May Predict Risk of Thromboembolic Events

Posted on by

November 8, 2023

Johnathan Goodman, MPHiL

Patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs) are at an increased risk of arterial and venous thromboembolic (ATE and VTE, respectively) complications, according to research published in Hamostaseologie. Patients with polycythemia vera (PV), furthermore, appeared to be at a particularly high risk for these events.
BCR-ABL-negative MPNs, which include PV, essential thrombocythemia (ET), and myelofibrosis (MF), are each associated with an increased risk of VTE and ATE. These events, moreover, are linked with an increased risk of both morbidity and mortality.

Previous research has suggested that JAK2 mutations are linked with an increased risk of thromboembolic events, while CALR mutations in the MF setting may reduce this risk. Detailed data in these populations are lacking, necessitating further study for risk stratification.

Overall, in the enrolled cohort, 39.1% of patients were male, the median age at MPN diagnosis was 50.7 years, and 31.7%, 34.1%, and 31.1% of patients had ET, PV, and MF, respectively; 3% of patients had an unclassified MPN. Genetic analysis showed that 69.8% of patients had a JAK2 mutation, while 14.4% of patients had a CALR mutation.

The median follow-up was 6.6 years, during which 180 first thromboembolic events were noted; 105 and 75 events were VTEs and ATEs, respectively. The incidence rate for first ATE or VTE was 2.43% per patient/year; the overall probability of a vascular event was 36.2%.

The most commonly noted VTE subtype was deep vein thrombosis (incidence rate, 0.59% per patient/year); the most common ATE subtype was stroke (incidence rate, 0.32% per patient/year).

Analysis showed that PV was linked with a higher risk of ATE or VTE (hazard ratio [HR], 1.66; 95% CI, 1.206-2.286). Compared with JAK2 mutations, CALR mutations were linked with a lower risk of these events (HR, 0.346; 95% CI, 0.172-0.699).

“While patients diagnosed with PV or generally JAK2 mutated MPN patients had a significantly increased risk of thromboembolic complications compared with the other MPN subtypes, this risk was significantly reduced in CALR-mutated patients,” the authors wrote in their report.

Reference

Wille K, Deventer E, Sadjadian P, et al. Arterial and venous thromboembolic complications in 832 patients with BCR-ABL-negative myeloproliferative neoplasms. Hamostaseologie. Published online October 9, 2023. doi:10.1055/a-2159-8767

Read more

Exploring Promising New Treatments for Myeloproliferative Neoplasms

Posted on by

By Catlin Nalley

With ongoing advancements, the therapeutic landscape for myeloproliferative neoplasms continues to evolve. Naveen Pemmaraju, MD, Associate Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, discussed where the field currently stands during his presentation, “Promising New Drugs for MPN Therapy,” at the International Congress on Myeloproliferative Neoplasms, held November 2-3, 2023, in New York.

When it comes to myeloproliferative neoplasms, “we have entered into a new golden era of research and potential that we have never seen before,” he noted. “Our field has been previously dominated by the first breakthrough—JAK inhibitor monotherapy—which was fantastic for our patients. However, as much of a revolution as this era was, by and large, it did not lead to cures of the disease. The only curative therapy as we close 2023 remains allogeneic stem cell transplant.”

In recent years, the field has seen breakthroughs with novel agents beyond the JAK/STAT pathway, according to Pemmaraju, who also highlighted the growing exploration of combination therapies in this patient population. “This is an important time in the MPN field,” he emphasized. “All of this is coming together, hopefully for the immediate good of our patients and then also establishing a new scientific era in myeloproliferative neoplasms,” he stated.

Main Takeaways

While discussing his presentation—and the MPN field as a whole—with Oncology Times, Pemmaraju highlighted a research study that explored life after ruxolitinib in myelofibrosis patients (Cancer 2020; doi: 10.1002/cncr.32664). Interestingly, he noted that the trial found that 40.8 percent of patients had stopped ruxolitinib at 3 years. Reasons for discontinuation included lack or loss of a spleen response, ruxolitinib-related adverse events, progression to blast phase, ruxolitinib-unrelated adverse events, and allogeneic transplantation during response.

The data also showed that the median survival after ruxolitinib was 13.2 months and the use of investigational agents was in fact associated with improved outcomes versus conventional agents, according to Pemmaraju, who noted this underscores the importance of ongoing investigation and advances.

In terms of combination treatments, Pemmaraju highlighted many different approaches, such as navitoclax, a BCL-XL/BCL-2 inhibitor. The potential of this agent has been explored in several studies, including the Phase II REFINE study (J Clin Oncol 2022; doi: 10.1200/JCO.21.02188). Data showed the addition of navitoclax to ruxolitinib among patients with persistent or progressive myelofibrosis led to durable spleen volume reduction, improved total symptom score, and hemoglobin response, reported Pemmaraju, an investigator on the trial.

Two phase III trials are currently underway to further explore the combination of navitoclax and ruxolitinib. The TRANSFORM-1 study is a frontline, upfront JAK inhibitor-naive study of ruxolitinib plus navitoclax versus ruxolitinib plus placebo. The other Phase III study, TRANSFORM-2, is looking at the efficacy and safety of this combination beyond the frontline setting.

Pemmaraju also highlighted several new novel agents that could have an impact on how we approach the treatment of MPNs. This includes but is not limited to agents that target the MDM2 pathway, telomerase inhibition, and cell cycle.

Additionally, he discussed another avenue targeting anemia in myelofibrosis. For instance, momelotinib was recently approved in September 2023 for intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post-polycythemia vera and post-essential thrombocythemia), in adults with anemia. Luspatercept is another example. This agent recently gained FDA approval for the treatment of anemia in myelodysplastic syndrome and is currently being studied in patients with myelofibrosis.

As the field evolves and advancements continue, Pemmaraju emphasized what is most important—the patient. “Everything we do is for our patients and every stakeholder has an important role to play,” he said. “Let’s continue to have awesome discoveries in the lab. Let’s pledge together to try to translate those quickly with all of our stakeholders who can help bring these findings to the clinic.

“And then, let’s make a pledge together to disseminate those findings accurately, faithfully, and rapidly through all platforms, not just academic literature, so that everyone can see these data in real time, debate, discuss, and have a say,” Pemmaraju concluded.

Read more