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IACH NEWS OF THE WEEK

November 10, 2025
Prepared by Dr Edwin Uriel Suárez

Ropeginterferon alfa-2b in hydroxyurea-intolerant or hydroxyurea-refractory essential thrombocythaemia (SURPASS ET): a multicentre, open-label, randomised, active-controlled, phase 3 study

Highlights:

●      The initial therapy for high-risk essential thrombocythaemia (ET) is usually hydroxyurea, but about a third of patients develop intolerance or resistance. A standard second-line agent has been anagrelide.

●      Ropeginterferon alfa-2b (Ropeg), a new-generation interferon-based therapy, is approved for polycythaemia vera based on evidence of durable haematological responses, with evidence of molecular responses.

●      The SURPASS-ET trial (ClinicalTrials.gov, NCT04285086) is the first randomised, phase 3 study to compare Ropeg with anagrelide in high-risk patients with ET with leukocytosis who are resistant or intolerant to hydroxyurea.

●      The findings of this trial suggest that Ropeg has superior efficacy and safety over anagrelide and could be considered as a second-line treatment option for patients with ET and leukocytosis.

 

Patients were randomly assigned (1:1) to Ropeg (n=91) or anagrelide (n=83). Ropeg was subcutaneously dosed every 2 weeks, initially at 250 μg, then titrated to 350 μg at week 2, and to 500 μg from week 4 onward. Oral anagrelide was started beginning at 0·5 mg four times daily or 1 mg twice daily, titrated as tolerated.The primary endpoint was the rate of response at months 9 and 12, as per modified European LeukemiaNet (ELN) criteria. The median follow-up was 12.5 months (IQR 11.5–12-9). 167 (96%) of 174 participants were Asian and seven (4%) were white. The trial met its primary endpoint, with 39 (43%) of 91 participants in the Ropeg group showing durable modified ELN criteria responses at months 9 and 12, compared with five (6%) of 83 participants in the anagrelide group. This difference (36.5%, 95% confidence interval 25.4–47.7) was staistically significant (p=0.0001). Grade 3 or worse treatment-emergent adverse events (AEs) occurred in 27 (34%) of 80 patients in the anagrelide group and 21 (23%) of 91 patients in the Ropeg group. In the latter group, the most common grade 3 or worse AEs were infections and infestations, occurring in eight (9%) of 91 patients, compared with five (6%) of 80 patients in the anagrelide group. In the latter group, the most frequent grade 3 or worse AEs were nervous system disorders, occurring in six (8%) of 80 patients, compared with one (1%) of 91 patients with Ropeg. There were no treatment-related deaths in either study group.
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· Low (0.1% to ≤ 1%) or Very Low (0.06% to < 0.1%) JAK2V617F Allele Burden in Routine Testing: Clinical Correlates and Clonal Trajectory [Retrospective study / Correspondence]

Highlights:

●      Both the International Consensus Classification (ICC)  and the WHO classification systems include JAK2 mutation information in their diagnostic criteria for myeloproliferative neoplasms (MPN); however, neither defines a diagnostic variant allele frequency (VAF) cutoff level.

●      With increasing sensitivity of current molecular assays for measuring JAK2V617F allele burden, there is a need for evidence to help determine the clinical relevance of a low (0.1% to ≤ 1%) or very low (< 0.1%) JAK2V617F allele burden.

●      JAK2V617F VAF of ≤ 1%, by itself, can neither rule out nor rule in a diagnosis of MPN or other myeloid neoplasm and should be interpreted in conjunction with other clinical or morphological data. By contrast, as opposed to patients with very low (VAF< 0.1%) JAK2V617F allele burden, the mutation was more likely to endure on repeat testing in patients with low VAF (VAF≥ 0.1% to ≤ 1%), where clonal expansion was also more likely to occur.

●      These findings support the concept of JAK2 clonal hematopoiesis of indeterminate potential (CHIP) but suggest a lower VAF (possibly 0.1%) threshold for its diagnosis.

●      The association of clinically overt MPN with sometimes very low JAK2V617F allele burden highlights knowledge gaps in the molecular pathogenesis of the disease and the need to consider broader gene panel mutation screening in such cases.

 

140 (16%) patients withJAK2V617F VAF ≤ 1% were identified, against a background of 886 adult patients (age > 18 years) with quantitatively detectable JAK2 mutation. Among these, bone marrow examination was performed and available for central review in 91 patients (the study population). The latter were further stratified into two groups: Group A (low) with JAK2V617F VAF ≥ 0.1% to ≤ 1% (n = 52) and Group B (very low) with JAK2V617F VAF ≥ 0.06% (i.e., lowest assay detection limit) to < 0.1% (n = 39). The two groups were similar in terms of age and sex distribution and presenting symptoms. Laboratory and clinical features at the time of JAK2 mutation screening were similar between the two groups, including serum erythropoietin level, palpable splenomegaly, and thrombosis history.  At the time of initial detection of JAK2V617F, clinically or morphologically overt MPN was documented in 23 (44%) patients from

Group A and only 8 (20%) from Group B (p=0.02).  JAK2V617F clonal expansion to > 1% VAF was more likely to be seen in Group A versus Group B patients (32% over a median of 2 years versus 0%; p=0.046). 
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Decitabine-cedazuridine in patients with MDS and TP53 mutations [Prospective and retrospective cohorts / Letter to editor]

Highlights:

●      Hypomethylating agents (HMA) are the only therapy that has resulted in improved survival in patients with higher-risk myelodisplastic syndromes (MDS).

●      In 2020, the Food and Drug Administration approved decitabine-cedazuridine (DEC-C), an oral combination, for the treatment of MDS based on the results of the ASCERTAIN trial.  

●      The activity of DEC-C in patients with TP53 mutation (TP53mut) MDS is not well defined (the International Consensus Criteria and the WHO have provided diverging definitions of the TP53mut state).

●      Significant variability in survival outcomes has been reported among patients with TP53mut due to TP53 state inference using variant allele frequency cutoffs and lack of clinical copy-neutral loss of heterozygosity testing.

●      This study showed better overall survival (OS) of oral DEC-C than parenteral HMA in TP53mut MDS.

 

The authors describe the response dynamics and survival of patients with TP53mut MDS treated with DEC-C in phase 2/3 clinical trials. They also performed propensity score matching to compare outcomes of patients treated with DEC-C compared to parenteral HMA. Of 180 patients, 73 (40.5%) had TP53mut. The median follow-up time was 21.5 (IQR 10.4 – 28.8) months. Fifty (27.7%) patients were TP53single-hit, and 23 (12.7%) were TP53multi-hit. The results suggest that the TP53 state does not impact response rate, but TP53multi-hit results in earlier relapse. The authors then evaluated an institutional cohort of 102 patients with TP53mut MDS and matched them to the 73 patients with TP53mut MDS treated in the DEC-C trials. These patients were treated with either azacitidine for 5-7 days (47.1%) or decitabine for 5 days (52.9%). Propensity matching balanced 47 from each group. In the matched cohort, the OS was 13.1 months (95% confidence interval [CI]: 8.4 - 21.3) for DEC-C, and 8.0 months (95% CI: 5.2 - 13.0) for parenteral single-agent HMA therapy (log-rank p=0.047).
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The Michigan Appropriateness Guide for Intravenous Catheters in Adult Patients With Cancer (MAGIC-ONC): Results From a Multispecialty Panel Using the RAND/UCLA Appropriateness Method

MAGIC-ONC is a robust framework to guide vascular access decision making for patients with cancer. The use of MAGIC-ONC can help to maximize benefit and

mitigate harm by treating VAD selection and care as a modifiable risk for patients with cancer.

 

Key points: See Figure 2 in paper.

●      Among patients with acute leukemias or aggressive lymphomas, the panel rated the insertion of double-lumen peripherally inserted central catheters (PICCs) or double-lumen tunneled central venous catheters (CVCs) as appropriate for delivery of chemotherapy across all variations of intensity, urgency, infusate type (vesicant, irritant), and phase (induction, consolidation, maintenance) of treatment. Although ports may be safer in terms of longer-term complications, they were rated as inappropriate for patients requiring urgent therapy (See Figure 5 in paper).

○      In addition, all single-lumen devices were rated as inappropriate in this setting as concurrent infusions of intravenous fluids, antimicrobial agents, and blood products are often required with intensive induction treatment regimens (See Figure 4 in paper). 

●      For patients with indolent lymphomas or plasma cell dyscrasias, the panelists rated the placement of double-lumen PICCs or double-lumen tunneled CVCs as appropriate across all scenarios incorporating intensity, urgency, or type (for example, vesicant or irritant) of treatment (See Figure 6 in paper). Ports were rated as appropriate for nonurgent vesicant or irritant therapies (such as R-CHOP for lymphoma).

○      Peripheral intravenous catheters (PIVs) were rated as neutral when nonvesicant and nonirritant therapies are prescribed for treatment of these conditions (for example, rituximab or obinutuzumab, bendamustine for indolent lymphomas, or cyclophosphamide as part of myeloma regimens).

●      Many patients with myelodisplastic syndromes or myeloproliferative neoplasms require low-intensity chemotherapeutic regimens, but they may also require long-term infusion of blood products. With this in mind, the panelists rated the insertion of PICCs and tunneled CVCs as appropriate for these cancers. Ports were rated as appropriate specifically for infusion of vesicant or irritant therapies.                   

●      For patients requiring urgent chemotherapy for mediastinal masses but lacking feasible insertion sites in the chest or upper arm, the panelists rated the placement of either nontunneled or tunneled femoral CVCs as appropriate.

○      The panelists expressed preference for tunneled over nontunneled femoral CVCs, with the exit site positioned distal to the inguinal crease, citing reduced risk for infection due to avoidance of direct catheter insertion into the inguinal region.

●      For apheresis only, catheters with 2 lumens were rated as appropriate for this indication; the panelists rated the insertion of a double-lumen, large-bore, nontunneled CVC as appropriate for short-term apheresis regardless of the indication (for example, autologous stem cell collection, chimeric antigen receptor (CAR) T-cell collection, and apheresis for hyperleukocytosis or hyperviscosity syndrome).

○      For autologous stem cell collection and leukapheresis for CAR T-cell therapy, which are typically 1-time procedures performed weeks before transplant or CAR T-cell infusion, insertion of 2 PIVs was also rated as appropriate (See Figure 9 in paper). 
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