Dr Jurcic on the Evolution of Combination Therapies in the Management of Myelofibrosis

Joseph G. Jurcic, MD, professor, medicine, Columbia University Medical Center; director, Hematologic Malignancies Section, Division of Hematology/Oncology, Columbia University Herbert Irving Comprehensive Cancer Center, discusses the evolution of myelofibrosis treatment, emphasizing the potential of combination therapies in the management of this disease.

Jurcic mentions  that the BET inhibitor pelabresib (CPI-0610) stands out, generating significant improvement in spleen response in combination with ruxolitinib in the phase 3 MANIFEST-2 trial (NCT04603495). Likewise, navitoclax , a BCL-2 inhibitor with BCL-xL inhibitory properties, exhibited promising results in the phase 3 TRANSFORM-1 trial (NCT04472598), particularly in enhancing spleen response, according to Jurcic .

Looking forward, Jurcic suggests the benefits of exploring combinations between JAK inhibitors and other agents, such as LSD1 inhibitors, XPO1 inhibitors, and PIN1 inhibitors. 

 investigational LSD1 inhibitor bomedemstat (IMG-7289) elicited clinical activity and a tolerable safety profile as monotherapy in patients with advanced myelofibrosis, according to findings from a phase 2 study (NCT03136185) presented during the 

 is under investigation as monotherapy and in combination with the JAK inhibitor ruxolitinib (Jakafi) in patients with JAK inhibitor–naive myelofibrosis and moderate thrombocytopenia in the phase 2 XPORT-MF-044/SENTRY-2 (NCT05980806) and phase 3 XPORT-MF-034/SENTRY (NCT04562389) trials, respectively.

Clinical trials incorporating JAK inhibitor–based combinations aim to target multiple disease abnormalities, thereby potentially resulting in symptom alleviation, spleen improvement, cytokine reduction, and allelic burden reduction, Jurcic says. These outcomes may serve as crucial surrogate end points for evaluating long-term survival, Jurcic notes.

The pursuit of combination therapies signifies a paradigm shift in myelofibrosis management, emphasizing a multifaceted approach to addressing the complexity of theis disease, Jurcic emphasizes. By targeting various pathways implicated in the pathogenesis of myelofibrosis, oncologists aim to optimize treatment outcomes and improve patients' quality of life, Jurcic explains.

Jurcic's insights underscore the importance of ongoing research and clinical trials in elucidating optimal therapeutic strategies for myelofibrosis. As new agents and combinations emerge, the field is moving toward a more personalized and effective approach to managing this challenging-to-treat hematologic malignancy, Jurcic concludes.

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Joseph G. Jurcic, MD, discusses the evolution of combination therapies in the management of myelofibrosis.

Dr Jurcic on the Use of JAK Inhibitors in Myelofibrosis Management

Joseph G. Jurcic, MD, professor, of mMedicine at, Columbia University Medical Center; and dDirector, of the Hematologic Malignancies Section, of the Division of Hematology/Oncology, Columbia University Herbert Irving Comprehensive Cancer Center, discusses emphasizes the role of Janus kinase (JAK) inhibitors in the management of myelofibrosis, as well as as an essential consideration for oncologists navigating treatment pathways. Specifically, he commented on the nuanced selection criteria for variousof JAK inhibitors based on patient characteristics and disease progression.

JAK inhibitors are an integral part of management strategies in Jurcic advocated for the utilization ofruxolitinib as the primary therapeutic agent in patients presenting with myelofibrosis, Jurcic begins.He recommends ruxolitinib (Jakafi) for. This recommendation is particularly pertinent the treatment of patients for individuals with relatively preserved blood counts but who manifest distressing symptoms and substantial splenomegaly. Ruxolitinib's efficacy in alleviating symptoms and reducing spleen size underscores its status as the cornerstone of therapy in this patient population.

However, the landscape of myelofibrosis management extends beyond initial treatment choices, as patients who experiencedisease progressionandtreatment tolerability or intolerable toxicities duringinitial treatment will require necessitate alternative regimens, Jurcic continuesstrategies. Jurcic He notes that the selective oral JAK2 and FLT3 inhibitor fedratinib (Inrebic) has emerged as a viable option for patients who exhibit disease progression despite on prior ruxolitinib therapy. By targeting JAK2 and FLT3, fedratinib offers a therapeutic avenue for individuals experiencing refractory disease, enriching the armamentarium of oncologists managing myelofibrosis.

Moreover, the consideration ofadverse effects such as thrombocytopenia and anemia further complicates treatment decision-makings in myelofibrosis, Jurcic adds. The unique mechanism of action and potency of pacritinib (Vonjo) can be leveraged for Jurcic highlights the utility of procritinib in patients with significant thrombocytopenia, leveraging its potential to mitigate both thrombocytopenia and/or myelofibrosis-associated anemia in the second line, he explains. Additionally, the JAK1/JAK2 and ACVR1 inhibitor momelotinib (Ojjara) is a standard treatment for adult patients with intermediate or high-risk myelofibrosis with anemia after its 

 for this indication, Jurcic says. This nuanced approach underscores the importance of tailoring treatment strategies to address multifaceted disease manifestationstoxicity concerns, optimizing patient’ outcomes and quality of life.

Additionally, tThe management of myelofibrosis extends beyond symptom control, and curative therapy may be considered forl, younger with a subset of patients with favorable fitness andharboring higher-risk disease, Jurcic states necessitating consideration of curative modalities. Jurcic He notes that transplantation ias currently the sole only curative intervention in the myelofibrosis armamentarium, particularly in younger patients with favorable fitness profiles and elevated disease risk.. This assertion underscores the imperative of prognostic stratification and personalized treatment planning in myelofibrosis, integrating transplant as a potentially curative option in select patient cohorts.

Jurcic's insights underscore the Overall, understanding the multifaceted nature of myelofibrosis management and considering , emphasizing the nuanced whether patients would benefit most from symptom control, disease modification, or curative interventions can help inform JAK inhibitor selection and selection of JAK inhibitors based on individual patient characteristics and disease progression. By delineating treatment strategies that encompass symptom control, disease modification, and curative interventions, oncologists can optimize therapeutic outcomes and enhance patient-centric care in the management offer patients with myelofibrosis.

Joseph G. Jurcic, MD, discusses the use of JAK inhibitors in the management of myelofibrosis.

	Director, Hematologic Malignancies Section

	Attending Physician, New York-Presbyterian Hospital

	Member, Herbert Irving Comprehensive Cancer Center

Although standard induction therapy produces complete remissions in 50% to 70% of patients with acute myeloid leukemia (AML), long-term survival is seen in only 20% to 40% of patients. The prognosis for older patients is even worse, with a 5-year survival rate of 5% for patients older than 65 years.

 Therefore, new therapies are needed to improve survival and reduce therapy-related toxicity.

By targeting specific cell types, monoclonal antibodies (mAbs) offer the possibility of improved efficacy and decreased toxicity compared with conventional chemotherapy. The use of mAbs to deliver radiation selectively to tumor cells is an attractive strategy to increase their potency.

Early studies showed that β particle—emitting anti-CD33 constructs labeled with iodine-131 (

I) could eliminate large leukemic burdens but resulted in prolonged myelosuppression requiring hematopoietic cell transplantation (HCT).

I-labeled anti-CD45 mAbs3 as well as rhenium-188 (

 have subsequently been used to intensify conditioning before HCT.

The unique physical and radiobiological properties of α-particles may provide more efficient tumor cell killing with fewer nonspecific cytotoxic effects than β-emitters. Compared with β-particles, α-particles have a shorter range (50-80 μm vs 800-10,000 μm) and a higher linear energy transfer (LET) (100 keV/μm vs 0.2 keV/ μm). As few as one or two α-particles can kill a target cell. Clinical studies using α-particle emitters for AML have targeted CD33, a cell surface glycoprotein expressed on most myeloid leukemia cells, using the humanized mAb lintuzumab (

Initial trials were performed with the first-generation construct, bismuth-213 (

Bi is a radiometal that emits a single α-particle and has a half-life of 45.6 min. It is prepared using a generator that consists of its parent isotope actinium- 225 (

Ac) dispersed onto a cation exchange resin from which 

Bi-lintuzumab in advanced myeloid leukemia, doses up to 1 mCi/kg were administered safely, although myelosuppression and transient minor liver function abnormalities were seen. Nearly all the 

Bi-lintuzumab rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Despite avidity for free bismuth, the kidneys were not visualized, suggesting that no significant catabolism of the drug occurred. Bone marrow blasts were reduced in 14 of 18 patients, but no complete remissions were seen, likely due to large tumor burdens in heavily pretreated patients. Nevertheless, this study demonstrated proof of concept for systemic targeted α-particle immunotherapy in humans.

		Table 1. Clinical Trials Using Alpha-Particle Radiopharmaceuticals for AML

					14 patients with reductions in marrow blasts

					Untreated Untreated >60 y; Relapsed/refractory

					10 patients with reductions in marrow blasts; 3 with ≤5%

					4 patients with reductions in marrow blasts after cycle 1

		AML indicates acute myeloid leukemia; CR, complete remission; CRp, CR with incomplete platelet recovery; LDAC, low-dose cytarabine; PR, partial remission.

Subsequently, a phase I/II trial was undertaken to assess the effects of 

 Patients with both relapsed/refractory AML and older patients with poor-risk AML were included.

After receiving nonremittive doses of cytarabine, patients were treated with 213Bi-lintuzumab (0.5-1.25 mCi/kg). Prolonged myelosuppression was seen in two of four patients treated with 1.25 mCi/kg, and the maximum tolerated dose (MTD) was 1 mCi/kg. Clinical responses were observed in six of the 25 patients (24%) who received doses of ≥1 mCi/kg. All responders had poor-risk features, including age ≥70 years or secondary AML; however, none of the seven patients with primary refractory AML or multiply treated relapsed disease responded, indicating that effective cytoreduction was necessary to achieve remission after administration of 

The major obstacles to the widespread use of 

Bi are its short half-life and the requirement of an onsite 225Ac/213Bi generator. Therefore, a secondgeneration construct was developed by directly conjugating 

Ac has a 10-day half-life and emits four α-particles in its decay to stable isotopes.

			Unwilling to undergo intensive chemotherapy, presence of poor-risk prognostic factors, presence of significant comorbidities, or age ≥70 years

			Cytarabine 20 mg injected subcutaneously every 12 hours on days 1 to 10 of every cycle

			Lintuzumab-Ac 225 with starting dose level of 1.0 μCi/kg and 15 μg/kg unlabeled HuM195 divided into 2 equal fractionated doses (0.5 μCi/kg and 7.5 μg/kg + 0.5 μCi/kg and 7.5 μg/kg)

			Furosemide and spironolactone at various points in cycle

			Phase I seeks to find highest tolerable dose

			Phase II aims to evaluate disease control and safety

 NIH Registry. www.ClinicalTrials.gov. Identifier: NCT01756677.

In a phase I trial conducted in patients with relapsed or refractory AML, a single infusion of 

Ac-lintuzumab was administered at doses of 0.5-4 μCi/kg.

 Dose-limiting toxicities included prolonged myelosuppression in one patient treated at the highest dose level. No evidence of radiation nephritis was seen. Peripheral blasts were eliminated in 10 of 16 evaluable patients (63%). Bone marrow blast reductions were seen in 10 of 15 evaluable patients (67%) at 4 weeks, and three patients achieved marrow blasts of ≤5%.

Based on these findings, a multicenter, phase I/II trial is now under way to determine the MTD and efficacy of fractionated-dose 

Ac-lintuzumab (lintuzumab-Ac 225) in combination with low-dose cytarabine (LDAC) in patients ≥60 years with untreated AML (Table 2).

An earlier study showed that repetitive cycles of LDAC resulted in improved 12-month survival compared with hydroxyurea in this population, but produced remissions in only 18% of patients.

In the current study, patients receive LDAC twice daily for 10 days every 4 to 6 weeks.

Ac-lintuzumab are given approximately 1 week apart following completion of LDAC. Seven patients, all of whom had prior myelodysplastic syndrome, were treated with 0.5 or 1 μCi/kg/fraction to date. Bone marrow blast reductions (mean, 58%) were seen in four patients (57%) after cycle 1. Accrual continues to define the MTD, with planned dose levels up to 2 μCi/kg/fraction. Additional patients will be treated at the MTD in the phase II portion of this trial to determine response rate, progression-free survival, and overall survival.

Early studies of systemically administered targeted α-particle immunotherapy for AML have shown significant antitumor activity. The shorter range and higher energy of α-particles compared with β-particles potentially allow for more efficient and selective killing of individual tumor cells. Reductions in leukemic blasts were seen with both 

Ac-lintuzmab in phase I trials, but the use of 

Ac overcomes the logistical difficulties associated with short-lived radionuclides such as 

Ac-lintuzumab in combination with LDAC for older patients with untreated AML builds on the encouraging results seen with 

Bi-lintuzumab for cytoreduced leukemia. These studies provide the rationale for the further investigation of targeted α-particle therapy in patients with residual disease.

Joseph G. Jurcic, MD

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Dr Jurcic on the Evolution of Combination Therapies in the Management of Myelofibrosis

Dr Jurcic on the Use of JAK Inhibitors in Myelofibrosis Management

Alpha-Particle Radiopharmaceuticals Moving Forward as AML Therapy