News of the Week

Here is a summary of the initial study and first-line treatment. For information on treatment in cases of refractory disease or relapse, see the original publication.

Key points:

• Follicular lymphoma (FL) diagnosis should be based on an excision biopsy when feasible. Large core biopsies are an alternative for difficult anatomical sites. Expert hematopathology review is strongly recommended. See Table 1 in original paper.
• Reporting histological grades is optional, except for FL Grade 3B.
• Mutational profiling currently has no role in routine clinical practice.
• Histological transformation must be ruled out.
• The Lugano update of the Ann‐Arbor staging system should be used for initial staging. See Table 3 in original paper.
• FLIPI/FLIPI2/PRIMA‐PI and FLIPI24 risk scores may be used for prognostic assessment. See Table 2 in original paper.
• A complete blood count, routine blood chemistry including Ig levels, lactate dehydrogenase, beta-2-microglobulin, creatinine, uric acid, HIV, hepatitis B virus (HBV), and HCV virology are required.
• Positron emission tomography (PET)-computed tomography (CT) is more sensitive than CT for staging. In PET‐CT staged patients, bone marrow biopsy is recommended to confirm stage I/II disease but may be omitted in patients with stage III–IV disease.
• PET‐CT with Deauville scoring is recommended for response assessment at the end of systemic therapy.
• At retreatment, early disease progression is the most important prognostic factor.
• In localized stage (LS), 24‐30 Gy involved site radiation therapy (ISRT) ± rituximab (R) is the preferred In selected cases, active surveillance (III, C) or 2 × 2 Gy ISRT (II, C) or R monotherapy might be considered (III, B). See Figure 1 in original paper.
  • Duodenal‐type FL is usually a localized disease most often managed with observation or alternatively radiotherapy or R monotherapy if symptomatic (IV, B).
• Stage I–II patients should receive systemic therapy akin to advanced stage (AS) FL if there is high‐tumor burden or adverse clinical prognostic features, or if bulky Stage II disease is unsuitable for ISRT (IV, B). See Table 4 in original paper.
• In patients with AS FL without treatment criteria (low-tumor burden), active surveillance is recommended until treatment criteria are met (I, A). R monotherapy is an alternative selection (I, B).
• Induction treatment in advanced FL who meet treatment criteria (high‐tumor burden) is generally immunochemotherapy with R or obinutuzumab (O) (I, A). O is superior in terms of progression-free survival (PFS) in high‐risk FLIPI patients but more toxic.
• The anti‐CD20 monoclonal antibody (MoAb) should be combined with CHOP, CVP, or bendamustine (I, A).
• R monotherapy is an alternative non‐toxic option, if PFS prolongation is not the top priority (II, B).
• R2 (R + lenalidomide [Revlimid]) is an alternative first‐line option, where available (II, B).
• In patients with FL who respond (complete or partial response) to immunochemotherapy, maintenance treatment with the same anti‐CD20 MoAb used in induction is recommended to prolong PFS, balancing the potential benefits and risks in individual patients (I, B).

The panel agreed on 10 recommendations regarding prognostic testing, indications for interferon and JAK inhibitor therapy, management of myelofibrosis (MF)-associated anemia, timing of transplantation, anti-platelet therapy, and iron chelation

Key points:

• In all patients with MF, the American Society of Hematology (ASH) guideline panel suggests extended molecular genetic testing compared to limited testing for myeloproliferative neoplasm driver mutations.
• In patients with prefibrotic MF and no indication for cytoreduction, the ASH guideline panel suggests against routine use of pegylated interferons.
• In JAK-inhibitor naïve patients with higher risk (Dynamic International Prognostic Scoring System [DIPSS]/plus /intermediate-2/high, Mutation-Enhanced International Prognostic Score System [MIPSS] 70/+v2.0 high/very high) overt MF (primary and post-essential thrombocythemia/polycythemia vera [ET/PV] MF) without symptomatic splenomegaly and/or disease-related symptoms, the ASH guideline panel suggests against the initiation of JAK inhibitors.
• In JAK inhibitor naïve patients with lower risk (DIPSS]/plus low/intermediate-1, MIPSS70/+v2.0 very low/low/intermediate) overt MF (ET/PV MF) with symptomatic splenomegaly and/or disease-related symptoms, the ASH guideline panel suggests the use of JAK inhibitors.
• In patients who are JAK inhibitor naïve, with MF (primary, post-ET/PV) whose primary indication for treatment is disease-related anemia, the ASH guideline panel suggests either JAK inhibitor therapy (momelotinib or pacritinib) or non-JAK inhibitor anemia-directed therapies.
  • Pacritinib can be considered in patients with concurrent anemia and thrombocytopenia.
• In patients with MF who experience JAK inhibitor-associated anemia that prevents the use of an optimal dose of first-line JAK inhibitor for symptoms and spleen control, the ASH guideline panel suggests switching to momelotinib or pacritinib.
• In MF patients who experience JAK inhibitor-associated anemia but maintain adequate symptoms and spleen control on the current dose of first-line JAK inhibitor, the ASH guideline panel suggests implementing anemia optimization strategies.
• In patients with higher-risk MF (DIPSS/plus intermediate-2/high, MIPSS70/+v2.0 high/very high) receiving JAK inhibitor therapy, and responding to therapy, the ASH guideline panel suggests early referral for allogeneic hematopoietic cell transplantation consultation compared to delayed referral after failure of response to JAK inhibitor therapy.
• In JAK inhibitor–naïve patients planned for transplantation the ASH guideline panel suggests against the routine use of pre-transplant JAK inhibitors, except for those patients with marked splenomegaly or disease-related symptoms.
• In patients with JAK2 V617F-positive MF, the ASH guideline panel suggests primary prevention with low-dose aspirin over no aspirin. In all other MF patients, the ASH guideline panel suggests a shared decision-making process that incorporates MF subtype, thrombotic risk factors (e.g., age >60 years, cardiovascular risk factors) and bleeding risk factors (e.g., extreme thrombocytosis, acquired von Willebrand disease, thrombocytopenia, prior bleeding history).
• In patients with overt MF and transfusional iron overload, the ASH guideline panel suggests against routine iron chelation therapy.

Carriers of hemophilia and women and girls with hemophilia remain underdiagnosed despite increasing recognition that they may experience clinically significant bleeding, reduced clotting factor levels, and important reproductive and psychosocial challenges.

Key points:

• Hemophilia carriers and women and girls with hemophilia remain substantially underdiagnosed despite increasing recognition of their bleeding risk.
• Diagnosis should integrate pedigree analysis, bleeding assessment, coagulation testing, molecular genetics and genetic counselling rather than relying solely on clotting factor levels.
• Record reviews and updating of pedigrees should be done every 2 years or during every visit when follow-up is less frequent.
• Normal FVIII or FIX levels do not exclude carrier status or a clinically significant bleeding phenotype.
• Women with FVIII or FIX levels below 40 IU/dL should be registered, classified and managed as having hemophilia according to current international recommendations.
• Multidisciplinary, family-centered care and education are essential to optimize bleeding management, reproductive counselling and lifelong follow-up.
• Pragmatic strategies based on genetic risk assessment, education and preventive measures are particularly important where laboratory and genetic testing are unavailable.
• Improving equity in diagnosis and access to comprehensive hemophilia care for women and girls should remain a global priority.

Highlights:

• Treatment failure affects one-third of patients with aggressive large B-cell lymphoma (LBCL).
• Circulating tumor DNA (ctDNA) monitoring using an ultrasensitive technique provides a dynamic molecular tool to guide clinical decision-making during therapy and follow-up in patients with LBCL, with a negative predictive value (NPV) >90%.

The authors evaluated the added clinical value of longitudinal monitoring of circulating tumor DNA (ctDNA) in plasma by targeted duplex sequencing during therapy and follow-up in high-risk LBCL patients (n=119, aged 18-64 years) treated in a Nordic phase II trial. Early clearance of ctDNA after the first two immunochemotherapy cycles provided a rapid pharmacodynamic measure of treatment efficacy with excellent NPV (91%) for progression. Later clearance after four cycles improved prognostication, and elevated interim ctDNA levels among those with a measurable residual disease (MRD)-predicted refractory disease. At the end of therapy, MRD was a strong independent predictor of outcome, with two-year progression-free survival rates varying greatly (hazard ratio=18.7; 94.3% vs 18.2%, MRD-negative and -positive, respectively). Moreover, end-of-therapy ctDNA analysis resolved most false radiological response assessments and revealed poor targeting of post-therapy interventions to MRD-positive cases. On surveillance, ctDNA was detectable at least 3 months before systemic clinical relapse (median 6 months), while the patients with isolated central nervous system relapses had the shortest plasma ctDNA lead times.