Overview of Myelofibrosis and Risk Stratification

Posted on by

Abdulraheem Yacoub, MD

Myelofibrosis, as a myeloproliferative neoplasm, is defined and characterized by JAK-STAT activation. Myeloproliferative neoplasms—particularly myelofibrosis—are dependent on JAK-STAT activation in the pathogenesis and clinical features, including proliferation, constitutional symptoms, and risk of transformation to higher-risk myeloid neoplasms. JAK-STAT activation can be the result of an acquired somatic JAK2 mutation, an acquired MPL mutation, an acquired CALR [calreticulin] mutation, or other unknown mutations that continue to be discovered as we go on.

[Regardless of] the driver mutation, it will result in the downstream STAT activation and uncontrolled proliferation and constitutional symptoms. Although the common pathway of pathogenesis is the same in the majority of patients with myelofibrosis, patients present with different clinical vignettes or subtypes. Classically, we’ve recognized the proliferative vs the cytopenic myelofibrosis, especially as the treatment pathways have diverged for these clinical subtypes. Cytopenic myelofibrosis has recently been recognized, particularly in patients who present with a uniquely low white blood cell count, severe-to-moderate thrombocytopenia, and severe-to-moderate anemia, including transfusion requirements.

Most patients who are cytopenic meet many of those cytopenic features, and this relates to the pathogens of these diseases. Because those patients are often primary vs secondary myelofibrosis, they’re often JAK2 mutated or triple negative. And they often have higher-risk karyotype, higher-risk mutations, and generally worse prognosis and high-risk transformation. Cytopenic myelofibrosis has been recognized because it carries a worse clinical presentation, more restrictions to the standard therapies for myelofibrosis, and worse prognosis in general. We’re fortunate that we have dedicated therapeutic options available commercially for those patients. That’s why we try to recognize them early, so we can address their diseases differently and more effectively.

Because many oncologists are very familiar with the staging of cancers, we often [give] a solid tumor a stage so we can describe it to patients, prescribe therapy, and provide prognosis for patients. In myelofibrosis, we use a calculator for risk assessment to define the prognostic risk for those patients, which serves the same purposes. One is for providing prognostic information for our patients. A second is for choosing the appropriate therapy. And third is also for clinical trial enrollment, to better define inclusion and exclusion criteria for those studies.

Prognostic models have evolved over time, from simple clinical prognostic models to more sophisticated, integrated models that include clinical, cytogenetic, and molecular data. We often use multiple prognostic calculators in each patient to serve different purposes. For example, our patient has an advanced age, which by all prognostic models adds a relatively negative prognostic value to these patients. She has circulating blasts. On the other hand, she’s not anemic or thrombocytopenic, which is favorable. She has symptoms that seem to be adverse in all prognostic models. She has a favorable cytogenic and molecular profile. By integrating all these variables, she has an intermediate-2 prognostic risk on the clinical features and an intermediate risk on the molecular-inspired prognostic scores. These prognostic scores provide a relative estimate of life expectancy of under 5 years on a clinical prognostic model without therapy. Of course, with modern therapy, patients do much better than they did in historical reports.

This creates a different therapeutic approach to these patients. Patients with relatively higher-risk disease, such as this patient, will advance into a more immediate intervention path. They should be advancing into earlier evaluation for curative-intent therapy. This will put heightened clinical attention on immediate intervention rather than a watch-and-wait approach, where you would implement that in patients with relatively lower-risk disease. This is an integrated and very essential step in every new case of myelofibrosis as we make that diagnosis and provide staging and prognostic value for our patients. In addition, these are dynamic scores, meaning that as patients live longer with their disease, they can potentially be reassessed for their prognosis. At different time intervals, they probably will transform, or advance into a high-risk category. Then we have to adapt to their new score and treat them differently. This is a dynamic tool that we need to apply every time the patient has a disease event or worsening of their clinical features.

Read more

MorphoSys Completes Enrollment of Phase 3 MANIFEST-2 Study of Pelabresib in Myelofibrosis with Topline Results Expected by End of 2023

Posted on by

MorphoSys Completes Enrollment of Phase 3 MANIFEST-2 Study of Pelabresib in Myelofibrosis with Topline Results Expected by End of 2023

Enrollment of Phase 3 frontMIND study of tafasitamab in first-line diffuse large B-cell lymphoma is also complete

MorphoSys AG (FSE: MOR; NASDAQ: MOR) announced today that enrollment is complete for MANIFEST-2, the ongoing Phase 3 study exploring the efficacy and safety of pelabresib, an investigational BET inhibitor, in combination with ruxolitinib versus ruxolitinib alone in patients with myelofibrosis who have not previously been treated with a JAK inhibitor (JAK inhibitor-naïve). The topline data are now expected by the end of 2023, earlier than previously anticipated.

Myelofibrosis – which belongs to a group of diseases called myeloproliferative disorders – is a difficult-to-treat form of blood cancer with limited treatment options. JAK inhibitors are a current standard of care treatment for myelofibrosis, which focus on relieving symptoms of the disease rather than treating its cause. But, with this treatment strategy, only about half of patients attain adequate disease control, and durability of response is often limited. Clinical data suggest synergistic effects between BET inhibition and JAK inhibition in myelofibrosis, supporting the potential of this combination therapy.

“With so many patients left behind by current treatment options for myelofibrosis, there is a critical need for regimens that elevate the standard of care for patients suffering from this debilitating disease,” said Tim Demuth, M.D., Ph.D., Chief Research and Development Officer, MorphoSys. “Now that MANIFEST-2 has completed enrollment earlier than anticipated, we look forward to the coming insights into the therapeutic potential of pelabresib in combination with ruxolitinib for JAK inhibitor-naïve patients with myelofibrosis. MANIFEST-2 is the latest milestone in our efforts to improve outcomes for blood cancer patients and is a testament to our continued commitment to the myelofibrosis community.”

MANIFEST-2 is a global, multicenter, double-blind, Phase 3 study of more than 400 patients who were naïve to JAK inhibitors. Patients were randomized 1:1 to pelabresib in combination with ruxolitinib or placebo plus ruxolitinib. The primary endpoint of the trial is the proportion of patients who achieve a 35% or greater reduction in spleen volume at week 24 (known as SVR35). Reduction in spleen size is an important clinical endpoint in myelofibrosis because spleen enlargement reflects disease activity and can cause significant pain and discomfort.

The key secondary endpoint is the proportion of patients achieving a 50% or greater improvement in total symptom score, as measured by the Myelofibrosis Symptom Assessment Form v4.0, at week 24. Patients with myelofibrosis experience a severely diminished quality of life due to symptoms such as severe fatigue, fever and weight loss. The Myelofibrosis Symptom Assessment Form is a validated self-assessment tool designed specifically for myelofibrosis patients that can track changes in these symptoms.

The MANIFEST-2 trial is supported by findings from the Phase 2 MANIFEST trial of pelabresib in combination with ruxolitinib in patients with myelofibrosis, including those who were JAK inhibitor-naïve. Updated results from MANIFEST presented at the American Society of Hematology 2022 Annual Meeting and Exposition suggest that pelabresib in combination with ruxolitinib provided prolonged improvement in both spleen size and symptom severity at and beyond 24 weeks.

Enrollment of the Phase 3 frontMIND study is also complete, with more than 880 patients enrolled in the trial. frontMIND is a global, multicenter, randomized, double-blind, placebo-controlled trial exploring tafasitamab, marketed in the U.S. as Monjuvi® and outside the U.S. by Incyte as Minjuvi®, plus lenalidomide in addition to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) versus R-CHOP alone as a first-line treatment for high-intermediate and high-risk patients with diffuse large B-cell lymphoma. The topline data from this study are expected in the second half of 2025.
About Pelabresib

Pelabresib (CPI-0610) is an investigational selective small molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet been evaluated or approved by any regulatory authorities.

About Myelofibrosis

Myelofibrosis – one of a group of diseases called myeloproliferative disorders – is a difficult-to-treat form of blood cancer that’s characterized by bone marrow fibrosis (a buildup of scar tissue in the bone marrow), spleen enlargement and anemia (low red blood cell counts) often requiring periodic blood transfusions. Patients with myelofibrosis can also suffer from a range of physical symptoms, including severe fatigue, night sweats, itching, increased bleeding and significant pain caused by their enlarged spleen. For many living with myelofibrosis, the combination of symptoms often severely impacts their quality of life. At diagnosis, several factors, such as age, genetics and bloodwork, help determine a patient’s long-term prognosis. About 90% of newly diagnosed patients have intermediate- to high-risk disease, which has a worse prognosis and a higher likelihood of disease-associated symptoms. Today, myelofibrosis treatments revolve around the use of medications called JAK inhibitors, which focus on relieving symptoms of myelofibrosis rather than treating its cause. But with this strategy, only about 50% of patients achieve adequate symptom control, and, unfortunately, that relief fades with time for many. Patients suffering from myelofibrosis are in critical need of treatment options that not only address their symptoms but also change the overall course of their disease.

About MANIFEST-2

MANIFEST-2 (NCT04603495) is a global, double-blind, randomized Phase 3 clinical trial with pelabresib in combination with ruxolitinib versus placebo plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis. The primary endpoint of the study is a 35% or greater reduction in spleen volume (SVR35) from baseline at 24 weeks. The key secondary endpoint of the study is a 50% or greater improvement in total symptom score (TSS50) from baseline at 24 weeks. Constellation Pharmaceuticals, Inc., a MorphoSys company, is the MANIFEST-2 trial sponsor.

About MANIFEST

MANIFEST (NCT02158858) is an open-label Phase 2 clinical trial of pelabresib in patients with myelofibrosis. The MANIFEST trial is evaluating pelabresib in combination with ruxolitinib in JAK-inhibitor-naïve myelofibrosis patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. The trial is also evaluating pelabresib either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1) or as add-on therapy in combination with ruxolitinib in patients with a suboptimal response to ruxolitinib or myelofibrosis progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on transfusion-dependent (TD) status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment. Constellation Pharmaceuticals, Inc., a MorphoSys company, is the MANIFEST trial sponsor.

About Monjuvi® (tafasitamab-cxix)

Tafasitamab is a humanized Fc-modified CD19 targeting immunotherapy. In 2010, MorphoSys licensed exclusive worldwide rights to develop and commercialize tafasitamab from Xencor, Inc. Tafasitamab incorporates an XmAb® engineered Fc domain, which mediates B-cell lysis through apoptosis and immune effector mechanism including Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP).

In the United States, Monjuvi® (tafasitamab-cxix) is approved by the U.S. Food and Drug Administration in combination with lenalidomide for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT). This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

In Europe, Minjuvi® (tafasitamab) received conditional marketing authorization in combination with lenalidomide, followed by Minjuvi monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT).

Tafasitamab is being clinically investigated as a therapeutic option in B-cell malignancies in several ongoing combination trials.

Monjuvi® and Minjuvi® are registered trademarks of MorphoSys AG. Tafasitamab is co-marketed by Incyte and MorphoSys under the brand name Monjuvi® in the U.S., and marketed by Incyte under the brand name Minjuvi® in Europe and Canada.

XmAb® is a registered trademark of Xencor, Inc.

Important Safety Information

What are the possible side effects of MONJUVI?
MONJUVI may cause serious side effects, including:

– Infusion reactions. Your healthcare provider will monitor you for infusion reactions during your infusion of MONJUVI. Tell your healthcare provider right away if you get fever, chills, rash, flushing, headache, or shortness of breath during an infusion of MONJUVI.

– Low blood cell counts (platelets, red blood cells, and white blood cells). Low blood cell counts are common with MONJUVI, but can also be serious or severe. Your healthcare provider will monitor your blood counts during treatment with MONJUVI. Tell your healthcare provider right away if you get a fever of 100.4 F (38 C) or above, or any bruising or bleeding.

– Infections. Serious infections, including infections that can cause death, have happened in people during treatments with MONJUVI and after the last dose. Tell your healthcare provider right away if you get a fever of 100.4 F (38 C) or above, or develop any signs and symptoms of an infection.

The most common side effects of MONJUVI include:

– Feeling tired or weak

– Diarrhea

– Cough

– Fever

– Swelling of lower legs or hands

– Respiratory tract infection

– Decreased appetite

These are not all the possible side effects of MONJUVI.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Before you receive MONJUVI, tell your healthcare provider about all your medical conditions, including if you:

– Have an active infection or have had one recently.

– Are pregnant or plan to become pregnant. MONJUVI may harm your unborn baby. You should not become pregnant during treatment with MONJUVI. Do not receive treatment with MONJUVI in combination with lenalidomide if you are pregnant because lenalidomide can cause birth defects and death of your unborn baby.

– You should use an effective method of birth control (contraception) during treatment and for at least 3 months after your final dose of MONJUVI.

– Tell your healthcare provider right away if you become pregnant or think that you may be pregnant during treatment with MONJUVI.

– Are breastfeeding or plan to breastfeed. It is not known if MONJUVI passes into your breastmilk. Do not breastfeed during treatment for at least 3 months after your last dose of MONJUVI.

You should also read the lenalidomide Medication Guide for important information about pregnancy, contraception, and blood and sperm donation.

Tell your healthcare provider about all the medications you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to MORPHOSYS US INC. at (844) 667-1992.

Please see the full Prescribing Information for MONJUVI, including Patient Information, for additional Important Safety Information.

About Diffuse Large B-cell Lymphoma (DLBCL)

DLBCL is the most common type of non-Hodgkin lymphoma in adults worldwide, characterized by rapidly growing masses of malignant B-cells in the lymph nodes, spleen, liver, bone marrow or other organs. It is an aggressive disease with about 40% of patients not responding to initial therapy or relapsing thereafter, leading to a high medical need for new, effective therapies, especially for patients who are not eligible for an autologous stem cell transplant in this setting.

About frontMIND

The frontMIND (NCT04824092) trial is a randomized, double-blind, placebo-controlled, global Phase 3 clinical study in previously untreated high-intermediate and high-risk DLBCL patients that is conducted in partnership with the German Lymphoma Association (GLA), the Italian Lymphoma study group and the US Oncology Network. The study enrolled more than 880 DLBCL patients to receive either tafasitamab plus lenalidomide in addition to rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or R-CHOP alone. The primary endpoint is investigator-assessed progression-free survival, according to Lugano 2014 criteria, and key secondary endpoints include event-free survival by investigator, overall survival, metabolic complete response rate by a Blinded Independent Review Committee, and overall response rate.

About MorphoSys

At MorphoSys, we are driven by our mission: More life for people with cancer. As a global commercial-stage biopharmaceutical company, we develop and deliver innovative medicines to patients, aspiring to redefine how cancer is treated. MorphoSys is headquartered in Planegg, Germany, and has its U.S. operations anchored in Boston, Massachusetts. To learn more, visit us at www.morphosys.com and follow us on Twitter and LinkedIn.

Forward Looking Statements

This communication contains certain forward-looking statements concerning the MorphoSys group of companies. The forward-looking statements contained herein represent the judgment of MorphoSys as of the date of this release and involve known and unknown risks and uncertainties, which might cause the actual results, financial condition and liquidity, performance or achievements of MorphoSys, or industry results, to be materially different from any historic or future results, financial conditions and liquidity, performance or achievements expressed or implied by such forward-looking statements. In addition, even if MorphoSys’ results, performance, financial condition and liquidity, and the development of the industry in which it operates are consistent with such forward-looking statements, they may not be predictive of results or developments in future periods. Among the factors that may result in differences are that MorphoSys’ expectations may be incorrect, the inherent uncertainties associated with competitive developments, clinical trial and product development activities and regulatory approval requirements, MorphoSys’ reliance on collaborations with third parties, estimating the commercial potential of its development programs and other risks indicated in the risk factors included in MorphoSys’ Annual Report on Form 20-F and other filings with the U.S. Securities and Exchange Commission. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements. These forward-looking statements speak only as of the date of publication of this document. MorphoSys expressly disclaims any obligation to update any such forward-looking statements in this document to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statement is based or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements, unless specifically required by law or regulation.

Read more

Clonal architecture evolution in Myeloproliferative Neoplasms: from a driver mutation to a complex heterogeneous mutational and phenotypic landscape

Posted on by
  • Nabih Maslah, Lina Benajiba, Stephane Giraudier, Jean-Jacques Kiladjian & Bruno Cassinat

Leukemia (2023)

Abstract

Myeloproliferative neoplasms are characterized by the acquisition at the hematopoietic stem cell level of driver mutations targeting the JAK/STAT pathway. In addition, they also often exhibit additional mutations targeting various pathways such as intracellular signalling, epigenetics, mRNA splicing or transcription. The natural history of myeloproliferative neoplasms is usually marked by a chronic phase of variable duration depending on the disease subtype, which can be followed by an accelerated phase or transformation towards more aggressive diseases such as myelofibrosis or acute leukemia. Besides, recent studies revealed important new information about the rates and mechanisms of sequential acquisition and selection of mutations in hematopoietic cells of myeloproliferative neoplasms. Better understanding of these events has been made possible in large part with the help of novel techniques that are now available to precisely decipher at the single cell level both the clonal architecture and the mutation-induced cell modifications. In this review, we will summarize the most recent knowledge about the mechanisms leading to clonal selection, how clonal architecture complexity can explain disease heterogeneity, and the impact of clonal evolution on clinical evolution.

Introduction

BCR::ABL1-negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). In these chronic hematological malignancies, the main short-term risk is the occurrence of thrombosis but a subset of patients may also evolve into secondary myelofibrosis, myelodysplastic syndrome or acute myeloid leukemia in the long run. However, the risk of long term evolution is heterogeneous between MPN subtypes: recent retrospective studies suggest that a high proportion of PV patients (up to 75% in 13 years) may experience progression to secondary myelofibrosis or AML [1], while in ET only a minority of patients experience clonal evolution and deterioration of MPN. The clinical course of MPNs is therefore characterized by a hitherto not fully understood nor accurately predicted inter-patient heterogeneity.

In the recent years, disease heterogeneity has been mainly linked to the diversity of genetic lesions found in patients’ hematopoietic stem cells (HSC). Indeed, MPNs represent a model of sequential acquisition of genetic abnormalities over time, allowing the study of the influence of environmental and intrinsic factors on tumor shape. Numerous studies have shown that precise genetic characterization of the disease can help to evaluate its prognosis [2] as the number and type of mutations are the main criteria considered to predict the outcome of patients. Indeed, recent prognostic scoring systems include the mutational pattern [3,4,5]. Dissecting the prognostic impact of diverse molecular markers allows a better understanding of the heterogeneity of tumor cells and demonstrates its predominant role in MPN evolution. Furthermore, implementation of new sequencing techniques at the single-cell level allows more precise characterization of complex molecular patterns associated with disease heterogeneity. Despite an improved understanding of the clonal architecture of MPNs over the past years, the mechanisms leading to clonal selection once the mutations are acquired remain poorly understood. In several types of cancers, a clear role of the microenvironment has been demonstrated in the selection of mutations. Specific clones harboring particular mutations may be selected due to inter-clone competition for nutrients or to the presence of an inflammatory environment. The drugs received during the chronic phase of the disease can also participate in clonal selection, which may be of particular importance in MPN patients who often require lifelong treatments. The aims of this review are to recapitulate the current knowledge of the different molecular lesions acquired in MPNs, highlight their impact on disease evolution and discuss the processes influencing their selection and expansion over time.

Read more

Rusfertide Improves Responses, Meets Primary End Point of REVIVE Trial in Polycythemia Vera

Posted on by

Caroline Seymour

Treatment with rusfertide led to a higher response rate of 69.2% vs 18.5% with placebo in patients with polycythemia vera, meeting the primary end point of the phase 2 REVIVE trial.

Treatment with rusfertide (PTG-300), a subcutaneous injectable hepcidin mimetic, led to a higher response rate of 69.2% vs 18.5% with placebo in patients with polycythemia vera (PV), meeting the primary end point of the phase 2 REVIVE trial (NCT04057040; P = .0003).1

Responders included those who completed 12 weeks of double-blind treatment while maintaining hematocrit control without meeting criteria for phlebotomy or undergoing phlebotomy.

“Participants in our studies who required frequent phlebotomy, with or without cytoreductives, have now been treated with rusfertide for more than two years, remaining largely phlebotomy free,” Arturo Molina, MD, MS, chief medical officer of Protagonist, said in a press release. “Data from the REVIVE study suggest that rusfertide treatment results in a highly statistically significant reduction in the need for therapeutic phlebotomy in phlebotomy-dependent patients, leading to rapid, sustained, and durable control of hematocrit levels below 45%. Part 2 of REVIVE, the randomized withdrawal study, yielded no new safety findings while confirming previously reported efficacy and safety findings observed in the open-label portion of REVIVE [part 1].”

“These randomized withdrawal data from the REVIVE study indicate a dramatic difference in the experience of the treatment group versus the placebo group,” Ronald Hoffman, MD, the Albert A. and Vera G. List Professor of Medicine (Hematology and Oncology), director of the Myeloproliferative Research Program at the Icahn School of Medicine at Mount Sinai, and principal investigator of the study, said. “With robust and strongly positive results observed across a diverse set of patients, we now have further confirmation of rusfertide’s potential to serve as an important future treatment option for patients with PV.”

Patients with PV who have hematocrit levels above 45% are at a greater risk of thrombosis. Standard therapy for these patients includes therapeutic phlebotomy alone or in combination with cytoreductive agents. However, current therapies are not effective in reducing hematocrit levels below 45% and are not all well tolerated. Rusfertide is a hepcidin mimetic being developed as a non-cytoreductive option to maintain hematocrit levels below 45% in patients with PV.2

The phase 2 study enrolled patients with excessive erythrocytosis despite therapeutic phlebotomy (3 or more in the 6 months prior to enrolling) with or without cytoreductive therapy with a hematocrit level below 45% at study entry.

Eligible participants were first treated in a 28-week, open-label, dose-titration and efficacy evaluation phase (part 1).1 Patients administered rusfertide in doses ranging from 10 mg to 120 mg weekly. Doses were adjusted each month to maintain hematocrit levels below 45%.2

Afterward, patients (n = 53) were randomly assigned 1:1 to rusfertide or placebo for another 12 weeks as part of the double-blind, placebo-controlled phase (part 2). Patients in this cohort had frequent phlebotomy requirements. Notably, 92.3% (n = 24/26) of patients in this cohort treated with rusfertide remained free from phlebotomy (P = .0003).

Additionally, the change from moderate or severe Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF) symptom scores at baseline was statistically significant in fatigue, problems with concentration, inactivity, and itching during the 28-week, open-label portion of part 1 of the study.

A comparison of symptom assessments in part 2 was not made because most patients administered placebo had discontinued treatment prior to the 12-week MPN-SAF symptom assessment.

“All study subjects who participated in the REVIVE clinical trial had been previously unsuccessful in controlling their hematocrit using standard-of-care therapies alone,” Andrew Kuykendall, MD, Department of Malignant Hematology, Moffit Cancer Center, added. “These new data from REVIVE provide important insights into the role that rusfertide can potentially have within a future PV treatment paradigm, supporting patients and their physicians in achieving the treatment goal of hematocrit below 45%, in step with current National Comprehensive Cancer Network Clinical Practice Guidelines.”

Regarding safety, the agent was well tolerated, and no new adverse effects (AEs) were reported since the safety analysis was presented at the 2022 ASH Annual Meeting and Exposition. The most common AEs were localized injection site reactions.

Rusfertide is also under study in the ongoing, phase 3 VERIFY trial (NCT05210790) vs placebo in patients with PV maintaining hematocrit control and in improving symptoms of disease.3

“The new randomized withdrawal data confirm our previous efficacy and safety findings of rusfertide in PV and support our strong conviction that rusfertide can be a potentially transformational therapeutic option for polycythemia vera,” Dinesh V. Patel, PhD, president and chief executive officer of Protagonist, said. “With the completion of the REVIVE study, the company’s topmost priority continues to be execution of the 250-patient global, pivotal, phase 3 VERIFY study in PV. The Protagonist team continues to work with full dedication alongside investigators, site staff and other partners with the shared aim of bringing this important potential therapy to PV patients.”

References

  1. Protagonist Therapeutics announces highly statistically significant results from the randomized withdrawal portion of the REVIVE study of rusfertide in polycythemia vera. News release. Protagonist Therapeutics. March 15, 2023. Accessed April 3, 2023. https://www.yahoo.com/lifestyle/protagonist-therapeutics-announces-highly-statistically-113000427.html
  2. Hoffman R, Ginzburg Y, Kremyanskaya M, et al. Rusfertide (PTG-300) treatment in phlebotomy-dependent polycythemia vera patients. J Clin Oncol. 2022;40(suppl 16):7003. doi:10.1200/JCO.2022.40.16_suppl.7003
  3. A phase 3 study of rusfertide in patients with polycythemia vera (VERIFY). ClinicalTrials.gov. Updated March 28, 2023. Accessed April 3, 2023. https://clinicaltrials.gov/ct2/show/NCT05210790

Read more

Secreted Mutant Calreticulins Act as Cytokines in Myeloproliferative Neoplasms

Posted on by

March 29, 2023

Lauren Dembeck, PhD

Mutant calreticulin (CALR) resulting from a frameshift mutation becomes a “rogue cytokine,” pathologically activating the thrombopoietin receptor (TpoR), driving proliferation of hematopoietic cells in patients with myeloproliferative neoplasms (MPNs), according to research published in Blood. The findings suggest the level of circulating mutant CALR proteins could potentially be used as a biomarker for risk stratification of CALR-mutated MPNs.

The researchers used a combination of molecular and cell-based assays as well as microscopy studies to evaluate whether secreted mutant CALRs act in a paracrine or autocrine manner to activate the TpoR of adjacent cells and whether this “rogue cytokine” effect is relevant to MPN pathogenesis.

Using 159 plasma samples from patients with MPN, the researchers discovered that mutant CALR proteins are secreted. They detected soluble mutant CALR in 106 of 111 (95%) patients at levels up to 160 ng/mL in patient plasma, with a mean level of 25.64 ng/mL.

In cases where mutational CALR burden and clinical diagnosis data were available (n=57), the team demonstrated that plasma levels of soluble mutant CALR were directly correlated with the allele burdens in the patients’ blood (r2=0.43; P <.0001).

To study the functional relevance of extracellular mutant CALR, the researchers immunoprecipitated the plasma from 5 patients with MPN and 5 control participants without MPN and analyzed the precipitating proteins using mass spectrometry. They found that plasma mutant CALR is found in complex with soluble transferrin receptor 1 (sTFR1), and that this carrier protein complex increases mutant CALR half-life.

They went on to demonstrate that recombinant mutant CALR proteins are able to bind and activate the TpoR in cell lines and primary megakaryocytic progenitors from patients with mutated CALR in which they drive thrombopoietin-independent colony formation.

Using an assay able to assess protein interactions in cultured cells (HEK293), the researchers demonstrated that mutant CALR proteins produced in 1 cell specifically interact with the TpoR on different target cell. Compared with cells that only carry TpoR, they found that cells carrying both TpoR and mutant CALR are hypersensitive to exogenous mutant CALR and respond to levels of mutant CALR that are similar to those found in patient plasma.

To test the cytokine effect of CALR, the team treated primary cells from patients with MPN carrying CALR mutations or JAK2 V617F or from healthy control participants with mutant or wildtype CALR. They demonstrated that the secreted mutant CALR induces a significant increase in megakaryocyte colony formation for patients with CALR mutations but not for patients with JAK2 V617F or healthy control participants.

“To our knowledge, this work is the first to demonstrate that circulating mutant CALR proteins can exert a rogue cytokine activity on cells that express the TpoR,” the authors wrote in their report. “Our finding that mutant CALR proteins act as rogue cytokines could open new perspectives for treating patients with CALR-mutated MPNs.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Pecquet C, Papadopoulos N, Balligand T, et al. Secreted mutant calreticulins as rogue cytokines in myeloproliferative neoplasms. Blood. 2023;141(8):917-929. doi:10.1182/blood.2022016846

Discussing the Ever-Changing MPN Treatment Landscape

Posted on by

Andrew Kuykendall, MD

Andrew Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, discusses some of the most recent approvals seen in the myeloproliferative neoplasm (MPN) space.

Ruxolitinib (Jakafi) was the first JAK1/2 inhibitor to receive FDA approval for the treatment of MPNs. Others, including fedratinib (Inrebic) and pacritinib (Vonjo), have since gained FDA approval, and are showing benefit for this patient population.

Transcription:

0:08 | With ropeginterferon, for a long time, we’ve been using interferon formulations within polycythemia vera and essential thrombocythemia, maybe to a lesser extent within myelofibrosis. This is going back to the 90s. We know that it’s effective, it can help control counts, and we have seen in small numbers of patients that it may be able to decrease the JAK2 allele burden and potentially could correlate with delayed disease progression and potential disease modification. That’s something that has been exciting to patients.

0:42 | Historically, interferon has been challenged by toxicity, especially the short acting forms. As we got pegylated interferon, we had longer acting, better tolerated, and lower doses, and patients stayed on for a longer period of time, did better, could appreciate some of those durable responses that you get when you’re on long term therapy. With ropeginterferon, we’ve now got an approved agent as opposed to using something off-label. It’s given less frequently, so every 2 weeks, and we have seen good long-term data with more robust datasets that have shown the ability to decrease allele fractions and JAK2 mutations. What that’s brought to the table is something not completely new, because we’ve been using interferons, but something that has stronger data to support it. It’s something that we can use as an approved on-label medication for many patients. I think it’s gotten patients very excited about potentially having something that can alter the natural history of disease.

1:40 | Pacritinib on the other hand is something that was approved for an unmet need. It’s an accelerated approval for patients with thrombocytopenia with less than 50,000 platelets, and for those patients, we don’t have many great options. We have ruxolitinib and fedratinib that are approved, but typically, they’ve been given in patients with over 50,000 platelets. We have struggled to treat these patients with lower platelet counts. Pacritinib has great data in the PERSIST-1 trial and PERSIST-2 trials [NCT01773187; NCT02055781], and in the ongoing PACIFICA study [NCT03165734]. It shows that it can be safely leveraged in these patients with lower platelet counts. We were happy to get the accelerated approval because now, we have an option for those patients, and we’re not having to do things off-label or give modified doses. Now, we have something we can fully dose and bring an effective treatment for these patients that have an unmet need.

Read more

Hydroxyurea Does Not Appear to Increase Second Malignancy Risk in Myeloproliferative Neoplasms

Posted on by

March 28, 2023

Jonathan Goodman, MPhil

Patients with myeloproliferative neoplasms (MPNs) treated with hydroxyurea do not appear to have a higher risk of secondary malignancies (SMs), according to research published in Blood Advances.

Classical Philadelphia chromosome-negative MPNs, which include polycythemia vera (PV), essential thrombocythemia (ET), and primary/secondary myelofibrosis (MF), are linked with an annual risk of transformation into acute myeloid leukemia (AML) of up to 20%.

Previous research has suggested, furthermore, that the use of hydroxyurea — a myelosuppressive agent used as a cytoreductive therapy in the MPN setting — may increase the risk of SMs through interference with DNA synthesis.

For this population-based study, researchers evaluated data from patients with MPNs including PV, ET, and MF to determine whether a link exists between hydroxyurea and SM development, whether hematologic or solid.

Overall, data from 4023 patients with an MPN were included, of whom 2683 had received hydroxyurea. The most common diagnosis was ET (49.1%), while 42% of patients had PV and 8.9% of patients had MF. The median age in the cohort was 77 years, 61.3% of patients were female sex, and 24% of patients had had a previous cancer. All data were obtained from the Surveillance, Epidemiology, and End Results Medicare-linked database.

The median follow-up was 3.25 years. At this point, 489 patients in the overall cohort had developed an SM, which included solid (346 cases), lymphoid (73 cases), and myeloid (70 cases) malignancies.

Analysis showed that, among those treated with hydroxyurea, the cumulative incidence of SM was 19.88%, compared with 22.31% not treated with hydroxyurea (P <.01 on a Gray’s test). No differences, furthermore, were noted in the incidence of solid or specific hematologic SMs (P =.3) between the 2 groups.

“[Hydroxyurea] use in older patients with MPN was not associated with an increased incidence of SM overall or AML…specifically, supporting [hydroxyurea] as the preferred cytoreductive option for this patient population,” the authors wrote in their report. “However, a longer follow-up may be necessary to confirm these findings.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Wang R, Shallis RM, Stempel JM, et al. Second malignancies among older patients with classical myeloproliferative neoplasms treated with hydroxyurea. Blood Adv. 2023;7(5):734-743. doi:10.1182/bloodadvances.2022008259

Read more

Immunosuppressive Therapies, Comorbidities Heighten COVID-19 Risk in People With MPNs

Posted on by

Jared Kaltwasser

Older age was also a risk factor for hospitalization and death in patients with myeloproliferative neoplasms (MPN) who contract COVID-19, the investigators found.

People with myeloproliferative neoplasms (MPN) who contract COVID-19 have particularly poor outcomes, according to a new study, especially if they have a history of taking immunotherapies or are older than 70 years of age.

The report, published in Therapeutic Advances in Hematology, suggests better strategies are needed to help protect this patient group if they are exposed to viruses such as SARS-CoV-2.

Corresponding author Jon Salmanton-García, of the University of Cologne, and colleagues, noted that people with Philadelphia-negative MPN face a higher risk of infections generally, but they said factors such as medications and comorbidities can affect a patient’s level of risk.

Previous research has suggested that people with MPN face 3 times the risk of infection compared to the general population, and the investigators said that data point alone suggests patients with MPN could be more likely to experience severe cases of COVID-19.

In the new study, Salmanton-García and colleagues wanted to better understand how a patient’s previous therapies and other clinical characteristics might affect their disease course when they were diagnosed with COVID-19. To find out, they turned to an international cooperative registry, dubbed EPICOVIDEHA, which was launched in February 2020 by a working group of the European Hematology Association.

The team identified a total of 398 patients with MPN who were diagnosed with COVID-19 since the start of the database. Those patients had a median age of 69 years, and they were followed for a median follow-up period of 76 days.

The largest proportion of the cohort was diagnosed with myelofibrosis (MF; 46%), while 28.4% had essential thrombocythemia (ET), and 25.6% of patients had a diagnosis of polycythemia vera (PV).

In terms of medication history, 37.2% of patients had most recently received hydroxyurea as therapy for their cancer, and 27.9% had most recently taken Janus kinase (JAK) inhibitors. Other types of therapies reported by patients included immunomodulating agents and steroids.

A majority of patients in the cohort eventually required hospitalization for their COVID-19 (54%). Of those hospitalized, one quarter were admitted to the intensive care unit, and 29 patients required mechanical ventilation, the investigators said.

Patients with exposure to immunosuppressive therapies prior to COVID-19 onset had a higher risk of hospitalization (odds ratio [OR], 2.186; 95% CI, 1.357-3.519), as did people who were over the age of 70 years (OR, 2.636; 95% CI, 1.683-4.129).

Nearly one-quarter (22.4%) of the cohort died during the follow-up period. Again, older age and exposure to immunosuppressive therapies increased the risk to patients, as did previous comorbidities.

Turning toward potential strategies to improve outcomes for these patients, Salmanton-García and colleagues noted that COVID-19 vaccines have helped to reduce the risk of severe disease, but they said the risks remain high in patients with blood cancers.

The authors said they believe their study to be the first to find that previous exposure to immunosuppressive agents are an independent risk factor for hospitalization and death in patients with COVID-19.

“Specific preventative strategies need, thus, to be tailored for these individuals at risk, including application of potentially protective preventative antibody cocktails as well as meaningful tapering strategies for MPN patients pretreated with JAK inhibitors,” they wrote.

The authors said more data will be needed to more fully understand the interplay of certain therapies, MPNs, and COVID-19 risk, including data on how vaccination might affect risk.

In the meantime, they said clinicians should carefully consider these factors when making therapeutic decisions related to patients with MPNs.

Reference

Marchetti M, Salmanton-García J, El-Ashwah S, et al. Outcomes of SARS-CoV-2 infection in Ph-neg chronic myeloproliferative neoplasms: results from the EPICOVIDEHA registry. Ther Adv Hematol. Published online March 11, 2023. doi:10.1177/20406207231154706

Read more

Abbas Assesses the Use of Allogenic Transplant In MPNs

Posted on by

Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Jonathan Abbas, MD, discussed with his fellow clinicians the use of allogeneic hematopoietic stem cell transplant in patients with myeloproliferative neoplasms and how ruxolitinib fits into their care.

CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of mild fatigue, moderate night sweats and abdominal pain/fullness lasting 4 months; she also reported increased bruising and unexplained weight loss​. Her spleen was palpable 8 cm below the left costal margin. Genetic testing showed she was negative for a JAK2 V617F or CALR mutation. Her karyotype was 46XX​ and a bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis.

A blood smear revealed leukoerythroblastosis and she was diagnosed with primary myelofibrosis​ with a DIPSS (Dynamic International Prognostic Scoring System) risk score of intermediate-2 and also had an intermediate MIPSS70 risk score.

DISCUSSION QUESTIONS

  • In your experience with myelofibrosis, which symptoms/presentations have the most negative impact on patients’ quality of life?​
  • What are the treatment goals for a patient like this? ​

In your practice:​

  • What is the trigger to initiate therapy for a patient with myelofibrosis?​
  • What is the timing to start JAK (Janus kinase) inhibitor therapy, and how do you choose?​
  • How does the nature and burden of symptoms influence your decision to initiate JAK inhibitor therapy? ​
  • How important is it to initiate therapy early?​

JONATHAN ABBAS, MD: Is this a patient where from day 1 you’re talking about an allogeneic [hematopoietic stem cell] transplant [HSCT] referral? Is this a patient that a transplanter would want to see early in the disease course or is this something that you might want to hold off on a HSCT consult until something isn’t behaving as well as it could?

JEREMY PANTIN, MD: The [patient is] approaching the age limit where things are going to start getting [difficult] and not somebody that we’ll take straight to allogeneic HSCT transplant, but you probably want to consider therapy to reduce that spleen size. If the patient appears to not have comorbidities and may be a good candidate for HSCT, the intermediate-2 or greater risk will certainly allow them to move forward, in terms of the favorable risk-to-benefit ration, if everything is aligned.

MICHAEL T. BYRNE, MD: I think we used to argue about this, not argue [necessarily], but these were the hard patients because nobody knows what to do with them. She’s the right age for transplant, but also, transplant is not without risk. Quality of life is probably worse after an allogeneic HSCT than it could be without, so I don’t know. I think you plug her in then you see what her donor search looks like, and regardless of whether she goes to treatment, I think this is somebody that you probably treat if for no other reason than to try and improve her quality of life.

OLALEKAN O. OLUWOLE, MBBS, MD: I completely agree with what my colleague just said. We have several targeted therapies in this area, and we can just find 1 to give them to control their symptoms.1 If that fails, there will be another. There are many in development, so for those who are not keen on getting transplanted, there is a viable pathway to just keep treating them. Now for the patient who says, “I want to see what the odds are,” like what [Dr. Bryne] said, find out if they have a donor, talk about the risk-benefit, and go for it.

ABBAS: From my HSCT days, I would totally agree with you. I think this is a patient I would want to see early, to explain that you might not need me now, but you might need me one day. You’ve potentially got years left of transplant eligibility, and we don’t have a crystal ball about how your response to treatment is going to be and where this disease is going.

Then just to be the devil’s advocate for the case, this is a lucky one where we had intermediate risk with 1% blasts. If this [patient] had 6% or 7% of 8% blasts and we were now nudging closer to high risk, that might sway all of us to maybe think initially therapy might be more of a bridge to HSCT, because there might be a little bit less stable disease.

[This] is a symptomatic patient. Is there anybody out there who would watch and wait with this patient regardless of whether they are seeing the allogeneic HSCT team or not? Or does everyone feel this patient warrants some therapy?

RYAN CARR, MD: Yes, based on her symptoms, if you tried to watch and wait, so [the patient] might end up seeing somebody else.

ABBAS: I agree with you. She will certainly be finding another group in town if you said, “You have [myelofibrosis], but it’s not that big a deal. Let’s just see you back in 3 months.” I think it’s unanimous this is a [patient] who’s not a watch-and-wait case. They are out there, but this is not her.

CASE UPDATE

Additional lab values showed the following counts:

  1. Red blood cells: 3.40 × 1012/L
  2. Hemoglobin: 13.2 g/dL
  3. Hematocrit: 36%
  4. Mean corpuscular volume: 94 fL
  5. White blood cells: 23.0 × 109/L
  6. Platelets: 450 × 109/L
  7. Peripheral blood blasts: 1%

DISCUSSION QUESTIONS

  • How do you use platelet count?
  • What if a patient had thrombocytopenia at baseline? ​
  • How does age/frailty factor in?

ABBAS: [If there is] thrombocytopenia at baseline, I guess we have 2 options for this. One would be; are we comfortable still sticking with ruxolitinib [Jakafi], which we all agree on [in a patient case like this], but dose modifying potentially for thrombocytopenia or would just any thrombocytopenia necessarily make us think about another agent, if anybody wants to weigh in on it?

BRYNE: I think a thrombocytopenia of 140 × 109/L is different than thrombocytopenia of 30 × 109/L. That’s quite a difference [between the level where a patient should receive] ruxolitinib vs pacritinib [Vonjo].

ABBAS: Yes, I would agree with you. Without the specific measurements, it’s hard to say. Just also remember you certainly can, and we’ve been doing for years is dose decreasing the ruxolitinib with a lot of benefit.2 Unless you’re in that extreme situation like down below 50 × 109/L platelet count, I still think there’s a window to go with the tried and true [method here].

How about frailty? How about if this woman, let’s say she was extremely frail and it wasn’t necessarily a disease-related frailty, just other comorbidities? Would that sway us? Do we feel that JAK inhibitors are particularly tough on patients? Would this factor in at all if she were 78 years old or if she was 88 years old?

JACK ERTER, MD: No. I think this drug is, all things considered, quite on target and easy to take for most patients. I would certainly have no hesitation to give an 88-year-old a trial at a dose-modified start of ruxolitinib.

References

1. Li B, Rampal RK, Xiao Z. Targeted therapies for myeloproliferative neoplasms. Biomark Res. 2019 Jul 16;7:15. doi: 10.1186/s40364-019-0166-y

2. Mesa RA, Cortes J. Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. J Hematol Oncol. 2013 Oct 22;6:79. doi: 10.1186/1756-8722-6-79

Read more

Patient Outcomes in the Myeloproliferative Neoplasm Treatment Landscape

Posted on by

Prithviraj Bose, MD
Prithviraj Bose: The outcomes for patients with PV and ET overall are good. So, these are, of course, the indolent ones among the classic myeloproliferative neoplasms. And so when you compare to myelofibrosis, for example, the outcomes are much better. And for that reason, we’re not transplanting anybody with ET and PV, for example, because their median survival is fairly long. At least compared to myelofibrosis. So, in ET, we generally think that the median survival is not different from an age and gender matched population. In PV, it’s been reported to be between 14 and 19 years. And PV definitely is a worse disease than ET. That’s well known. Both of them can, of course, progress to myelofibrosis and rates have been published at 10 years, at 15 years, you definitely have a reasonable chance around 10% in PV, although there are ranges, of course, across different studies of progression to myelofibrosis and smaller risk, thankfully, of transformation to AML. So, generally, these are diseases that people live with for many years. And obviously, because of that, day to day symptoms become an issue. It’s not just about controlling the counts and preventing blood clots, which continues to be goal number one. But I think there’s a lot of other things that we need to pay attention to. In fact, there have been studies like the MPN landmark study, which have shown that there is some discordance between patients’ priorities and physicians’ priorities. So, for example, patients are very keen to modify their underlying biology to sort of stop or halt or slow this inexorable disease progression that may otherwise occur. So that is more important to them sometimes than preventing a blood clot. That’s not to say that a blood clot couldn’t be bad. It could be a stroke or a heart attack, but in patients with these chronic diseases, it’s really important to them to try and do something to the root cause, so to speak, and its natural course. So this is where I think the increasing interest in getting this allele burden of JAK2 down, regardless whether that’s with an interferon or with ruxolitinib, is gaining ground. And the hope is that that would translate to improved myelofibrosis-free survival, improved overall survival, and increased leukemia-free survival, all of that. Now, symptoms is another whole different and important domain. Symptoms, many studies have shown that MPN patients, PV, ET, MF, all of them, MF usually more symptomatic than PV, but PV more symptomatic than ET, have a wide range of symptoms. And they can be debilitating, disabling sometimes, or at least bad enough that they impair quality of life, work productivity, etc. There’s been many surveys of patients that have shown these. And so certainly, this is important to elicit from patients. As I said earlier, using that MPN SAFTSS form is very helpful, because it allows you to objectify it and follow it over time. And we do have drugs, for example, ruxolitinib that comes to mind first, as a drug that addresses symptoms really more effectively than any other drug right now with PV. And so, it certainly draws attention to the fact that we need to be cognizant of symptoms and always elicit those and see how well we’re doing with that aspect, beyond the more traditional aspects of treating patients with PV.