Ruxolitinib combined with dexamethasone in newly diagnosed adult hemophagocytic lymphohistiocytosis patients in China [Phase 2 clinical trial]

Highlights: 

●      Chinese patients with lymphoma-associated hemophagocytic lymphohistiocytosis (HLH) had poorer outcomes than those with HLH that developed in the absence of underlying lymphoma.

●      The ruxolitinib plus dexamethasone (Ru-D) regimen was well tolerated, resulting in overall survival (OS) rates of 85.7%, 67.9%, and 53.6% at 2 months, 6 months, and 2 years, respectively, with an overall response rate (ORR) of 85.7%.

In this prospective phase 2 clinical trial, a total of 28 Chinese patients were enrolled, and the median follow-up time was 25.1 months (range, 0.87-34.0). The 2-month OS rate (the primary endpoint) was 85.7%. The 6-month and 2-year OS rates were 67.9% (19/28) and 53.6% (15/28), respectively. The median OS of lymphoma-associated HLH (LAHS) patients was 5.8 months, and most of these patients had natural killer/T-cell lymphoma. In contrast, the 2-year OS rate of non-LAHS patients was 75%. The ORR was 85.7% (24/28); 17.9% (5/28) of patients achieved a complete response during the Ru-D regimen. Overall, the Ru-D regimen was well tolerated in HLH patients.

A phase 3 randomized controlled study is warranted.

Impact of calreticulin mutations on treatment and survival outcomes in myelofibrosis during ruxolitinib therapy [Retrospective study]

Highlights:

●      Calreticulin (CALR) mutations are detected in around 20% of patients with primary and post-essential thrombocythemia myelofibrosis (MF).

●      Compared to type 2-like, type 1-like CALR mutations are associated with an improved survival in primary MF. 

●      Regardless of driver mutations, patients with splenomegaly and symptoms are generally treated with JAK2-inhibitors, most commonly ruxolitinib.

●      The current study provides real-world observations in CALR-mutated MF patients with splenomegaly and/or symptoms requiring therapy with JAK2 inhibitors.

This is the report of a sub-analysis of the “RUX-MF” study, comprising 135 CALR-mutated and 786 JAK2-mutated ruxolitinib-treated patients. Compared to JAK2-mutated patients, CALR-mutated patients started ruxolitinib with a more severe disease (higher peripheral blast counts, lower hemoglobin levels and worse marrow fibrosis) and after a longer median time from diagnosis (2.6 versus 0.7 years, p<0.001). At 6 months, spleen responses were numerically inferior in CALR-mutated patients, who also had significantly lower rates of symptom responses (56.1% versus 66.7%, p=0.04). The relatively low number of CALR-mutated patients with complete molecular information (e.g., type and variant allele frequency, high molecular risk mutations) prevented subgroup analyses that would add knowledge to this comparison.

Itacitinib for the Prevention of IEC Therapy–Associated CRS: Results From the Two-Part Phase 2 INCB 39110-211 Study

Highlights:

●      Prophylactic itacitinib (200 mg twice daily) was effective in preventing cytokine release syndrome (CRS) and immune effector cell (ICE)–associated neurotoxicity syndrome ICANS in patients undergoing CD19-directed IEC therapy.

●      Prophylactic itacitinib treatment for 30 days was well tolerated and did not appear to impact efficacy of CD19-directed IEC therapy.

This two-part, phase 2 study investigated safety and efficacy of itacitinib, a potent, highly selective Janus kinase 1 inhibitor with broad anti-inflammatory activity, for prevention of CRS and ICANS in patients receiving commercial CD19-directed IEC therapy. Patients in part 1 (n=63) received once daily itacitinib 200 mg 3 days before IEC therapy (axicabtagene ciloleucel [axi-cel], brexucabtagene autoleucel, or tisagenlecleucel) through Day 26, with guidelines for use of other CRS/ICANS interventions. In part 2 (double-blind), patients (n=48) were randomized to receive twice-daily (bid) itacitinib 200 mg or placebo 3 days before IEC therapy with axi-cel. Itacitinib 200 mg bid resulted in a significantly lower proportion of patients with grade ≥2 CRS by day 14 (primary endpoint) versus placebo (17.4% vs. 56.5%; P=0.003). The proportion of patients with grade ≥2 ICANS by Day 28 was lower than with placebo (8.7% vs. 21.7%). Itacitinib was well tolerated, with pyrexia the most common treatment emergent adverse event and itacitinib-related cytopenias manageable. Importantly, itacitinib did not impact IEC therapy efficacy.

Enterocolitis associated with glofitamab—First report and clinicopathological findings in three cases

Highlight:

Clinicians should consider this toxicity (immune-mediated enterocolitis) in glofitamab (CD3-CD20 bispecific antibody)-treated patients presenting with sustained diarrhoea or abdominal pain when infectious colitis has been comprehensively excluded.

This is a report of  three cases of enterocolitis occurring with glofitamab use at a single institution. Similarities between cases include onset post cycle 4–5, moderately elevated fecal calprotectin, abnormal bowel avidity on positron emission tomography scan (2/3), absence of CD20-positive B cells on gut histology and steroid responsiveness. There was variability in the area of gastrointestinal inflammation, severity of symptoms, histological findings and impact on subsequent therapy. The mechanism for this phenomenon is unknown. Possible explanations include B-regulatory cell depletion and T-cell recruitment to the gastrointestinal tract because of CD20 antigen density.

Waldenström Macroglobulinemia: 2025 Update on Diagnosis, Risk Stratification, and Management [Review]

Key points:

●      Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity.

●      The presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells (in contrast to the World Health Association cut-off point)  in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in most patients with IgM monoclonal gammopathy of uncertain significance. MYD88 is not required for the diagnosis.

●      Age, albumin, hemoglobin level, platelet count, β2 microglobulin, lactate dehydrogenase, and monoclonal IgM concentrations are characteristics that are predictive of outcomes.

●      Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to combination regimens. Recommended first-line therapy can be chemoimmunotherapy or a covalent Bruton tyrosine kinase inhibitor. The preferred Mayo Clinic induction is either rituximab and bendamustine (without rituximab maintenance) or zanubrutinib.

●      Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, pirtobrutinib, carfilzomib, lenalidomide, bendamustine, and venetoclax have all been shown to have activity in relapsed WM. Given WM's natural history, the reduction of therapy toxicity is an important part of treatment selection. Most patients succumb to causes unrelated to macroglobulinemia.