Myelofibrosis Management

Management

Treatment Response Monitoring

MPN-SAF TSS is used as a monitoring tool for treatment response
Symptom response requires a reduction of ≥50% in the MPN-SAF TSS
A <50% reduction is clinically significant and justifies continued used of Ruxolitinib
Change in symptom status may be a sign of disease progression and should prompt evaluation of treatment efficacy and/or disease status
- Assessment of treatment response involves performing CBC to assess normalization of blood counts, monitoring symptom status using MPN-SAF TSS and monitoring spleen size by imaging or palpation
Monitoring response (anemia response, spleen response and symptom response) is recommended every 3-6 months during the course of therapy
- Continuation of Ruxolitinib or Fedratinib is recommended for patients with <50% symptom response upon the discretion of the physician
- Ruxolitinib should be discontinued if without response or improvement of symptoms after 6 months
Bone marrow aspirate and biopsy should be performed when increased symptoms or signs of progression are present
Molecular testing with multigene NGS panel may be performed in patients with higher-risk MF to assess for high-molecular risk mutations which is associated with disease progression
- ASXL1, TET2, TP53, SRSF2, IDH1 and IDH2 gene mutations and other chromosomal abnormalities (in chromosome 1q and 9p) are associated with transformation to AML
Disease progression of MF to accelerated phase (MF-AP) is characterized by the presence of <50 x 10⁹/L platelets, chromosome 17 abnormalities and ≥10% (10-19%) blasts in bone marrow or peripheral blood
Disease progression of MF in blast phase (MF-BP) is synonymous to AML and is characterized by the presence of ≥20% myeloid blasts in peripheral blood or bone marrow

2013 IWG-MRT and ELN Response Criteria for MF

Response Categories	Required Criteria (response should last ≥12 weeks)
Complete response	Bone marrow: • Age-adjusted normocellularity • <5% blasts • ≤grade 1 MF *and* Peripheral blood: • Hemoglobin ≥10 g/dL and <ULN • Neutrophil count ≥1 x 10⁹/L and <ULN • Platelet count ≥100 x 10⁹/L and <ULN • <2% immature myeloid cells	Clinical: • Resolution of disease symptoms • Liver and spleen not palpable • No evidence of extramedullary hematopoiesis
Partial response	Peripheral blood: • Hemoglobin ≥10 g/dL and <ULN • Neutrophil count ≥1 x 10⁹/L and <ULN • Platelet count ≥100 x 10⁹/L and <ULN • <2% immature myeloid cells or Bone marrow: • Age-adjusted normocellularity • <5% blasts • ≤grade 1 MF and Peripheral blood: • Hemoglobin ≥8.5 but <10 g/dL and <ULN • Neutrophil count ≥1 x 10⁹/L and <ULN • Platelet count ≥50 but <100 x 10⁹/L and <ULN • <2% immature myeloid cells	Clinical: • Resolution of disease symptoms • Liver and spleen not palpable • No evidence of extramedullary hematopoiesis
Progressive disease	• Appearance of a new splenomegaly, palpable at least 5 cm below the left costal margin (LCM) or • ≥100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-10 cm or • 50% increase in palpable distance, below LCM, for baseline splenomegaly of >10 cm or • Leukemic transformation confirmed by a bone marrow blast count ≥20% or • Peripheral blood blast content ≥20% associated with an absolute blast count of ≥1 x 10⁹/L that lasts for ≥2 weeks
Clinical improvement (CI)	Achievement of anemia, spleen, or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia
Relapse	• Not meeting the criteria for at least CI after achieving complete response, partial response or CI or • Loss of anemia response persisting for ≥1 month or • Loss of spleen response persisting for ≥1 month
Anemia response	• Transfusion-independent patients: Hemoglobin level increase of ≥2 g/dL • Transfusion-dependent patients: Conversion to transfusion-independent
Spleen response	• Baseline splenomegaly palpable at 5-10 cm below LCM becomes non-palpable or • Baseline splenomegaly palpable >10 cm below LCM, decreases by ≥50% • Baseline splenomegaly palpable <5 cm below LCM, not eligible for spleen response • Spleen response required confirmation by MRI or CT showing ≥35% spleen volume reduction
Symptom response	≥50% reduction in the MPN-SAF TSS
Stable disease	Belonging to none of the above listed response categories
References: Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013 Aug;122(8):1395-1398; National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: myelofibrosis. Version 2.2022.

Recommendations for the Assessment of Treatment-induced Cytogenetic and Molecular Changes
Cytogenetic remission	Cytogenic response evaluation should include ≥10 metaphases and confirmed using repeat testing within 6 months Complete remission: Clearance of a pre-existing abnormality Partial remission: ≥50% reduction in abnormal metaphases (for patients with ≥10 abnormal metaphases at baseline)
Molecular remission	Peripheral blood analysis should be included in the evaluation of molecular response and confirmed using repeat testing within 6 months Complete remission: Clearance of a pre-existing abnormality Partial remission: ≥50% decrease in allele burden (for patients with ≥20% mutant allele burden at baseline)
Cytogenetic/molecular remission	Re-emergence of a pre-existing cytogenetic or molecular abnormality that is confirmed by repeat testing
References: Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013 Aug;122(8):1395-1398; National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: myelofibrosis. Version 2.2022.

Management of MF-Associated Anemia

Anemia is a negative prognostic risk factor for patient’s survival
Coexisting causes of anemia (hemolysis, bleeding, and iron, vitamin B12 and folate deficiency) should be ruled out and treated before other treatment options are considered
Transfusion of leuko-reduced RBC is recommended for symptomatic anemia
Ruxolitinib or Fedratinib may be continued to reduce splenomegaly and improve other disease-related symptoms
Enrollment in clinical trials should be considered for all patients with MF-associated anemia and is the preferred option for patients with serum EPO ≥500 mU/mL
Treatment options are based on EPO level

Serum EPO <500 mU/mL

Erythropoiesis-stimulating Agents (ESAs)

Eg Darbepoetin alfa, Epoetin alfa
Recommended for treatment of anemia and should be continued in patients with anemia response
Not effective for transfusion-dependent anemia
Patients with loss of response or no response should be tried with androgens or immunomodulating agents

Serum EPO ≥500 mU/mL

Continuation of present treatment is recommended in patients with treatment response
Patients without response or with loss of response should be treated with agents, either Danazol or immunomodulating agents, not previously used

Androgens

Eg Danazol, Fluoxymesterone, Methandrostenolone, Nandrolone, Oxymetholone, Testosterone enanthate
Danazol is a synthetic attenuated androgen and is the androgen of choice to improve hemoglobin concentration in patients with MF and transfusion-dependent anemia
- Has been shown to decrease spleen size and improve platelet counts
- May be an option in patients with EPO ≥500 mU/mL
  - Treatment option for patients with EPO <500 mU/mL and treated with ESAs and have not achieved treatment response or with loss of response
- Monitoring of LFTs and screening for prostate cancer in men is recommended for patients with Danazol treatment

Immunomodulatory Agents

Eg Lenalidomide, Thalidomide
Lenalidomide with or without Prednisone or Thalidomide with or without Prednisone may be treatment options for patients with EPO ≥500 mU/mL
- Patients with del(5q) mutation have better response rates with Lenalidomide
- Treatment option for patients with EPO <500 mU/mL and treated with ESAs but have not achieved treatment response or with loss of response

Luspatercept

A recombinant fusion protein that functions as an erythroid maturation agent
Treatment option, preferrably within a clinical trial, for patients with EPO ≥500 mU/mL who failed an ESA and require ≥2 RBC units over an 8-week period

Management of Disease Progression

Treatment options are based on transplant eligibility
Workup includes bone marrow aspirate and biopsy with reticulin and trichome stain, bone marrow cytogenetics if bone marrow is inaspirable, flow cytometry and molecular testing for AML-associated mutations
Continuation of Ruxolitinib or Fedratinib to the start of conditioning therapy is recommended to reduce splenomegaly and improve other disease-related symptoms

Transplant-eligible Patients

Reduction of blast counts or disease control may be achieved with hypomethylating agents (Azacitidine or Decitabine) or with intensive AML-type induction chemotherapy followed by allogeneic HSCT
Enrollment in clinical trials may be another option

Transplant-ineligible Patients

Treatment with hypomethylating agents or low-intensity AML-type induction chemotherapy or enrollment in clinical trials are recommended

Optimizing metastatic hormone-sensitive prostate cancer treatment in advanced prostate cancer

Assoc Prof. Darren Poon, Assoc Prof. Edmund Chiong, 14 Jan 2021

Metastatic hormone-sensitive prostate cancer (mHSPC) refers to the condition whereby patients have metastatic prostate cancer and no prior hormonal therapy or androgen deprivation therapy (ADT). Typically, patients with mHSPC have been treated with ADT alone, following which, the overwhelming majority develop castration resistance over time and head towards eventual mortality. In recent years, the publication of various landmark trials has prompted dramatic changes in the mHSPC treatment landscape, and had favourably impacted overall survival (OS) in these patients. At a recent webinar, A/Prof Darren Poon, Honorary Consultant in Clinical Oncology, Hong Kong Sanatorium & Hospital, and Honorary Clinical Associate Professor, Department of Clinical Oncology, The Chinese University of Hong Kong, reviewed treatment options in mHSPC, while A/Prof Edmund Chiong, Head and Senior Consultant, Department of Urology, National University Hospital, Singapore, presented a case which was discussed by an esteemed panel of experts. This webinar was jointly organized by the Singapore Society of Oncology and the Singapore Urological Association, and supported by Astellas.

Product Highlight - Lanzotred

13 Sep 2023

Enzalutamide 40 mg softcap

Carfilzomib-based triplet regimen a potential upfront treatment for high-risk MM

Pearl Toh, 22 Oct 2020

The combination therapy comprising carfilzomib, cyclophosphamide and dexamethasone (KCd) is effective, with a tolerable safety profile, in an Asian cohort with high-risk multiple myeloma (MM) — thus providing a more economical alternative as a potential upfront regimen in resource-limited settings, according to leading experts during a myeloma education webinar.