If you have trouble reading this newsletter, view the web version here

   

IACH NEWS OF THE WEEK

October 20, 2025
Prepared by Dr Edwin Uriel Suárez

Genomic landscape of IgM-MGUS and patients with stable or progressive asymptomatic Waldenström macroglobulinemia [Retrospective study]

Highlights:

●      Immunoglobulin M (IgM)-Monoclonal gammopathy of undetermined significance (IgM-MGUS) and asymptomatic Waldenström (aWM) are precursor conditions of symptomatic Waldenström macroglobulinemia (sWM) with an annual 1.5-12% risk of progression.

●      Although clinical prognostic models exist for risk stratification, it remains challenging to distinguish asymptomatic patients who will eventually progress from those who will not. Hence, the characterization of genomic features that shape disease progression could potentially improve risk stratification.

●      IgM-MGUS patients display two genetically distinct entities with "benign" and "aWM" like genomic features.

 

Bagratuni et al. performed whole-exome sequencing on 232 samples from 139 patients, including 9 patients with sequential samples. They observed an increasing mutation burden through the stages of disease evolution. Genes such as CD79B, ARID1A, and CREBBP were more often mutated in the aWM progressed (aWMpr) compared to the non-progressor aWM group (aWMst), while MYD88 L265 variant allele frequency was significantly higher in aWMpr compared to aWMst patients. In addition, IgM-MGUS patients with MYD88 Wild Type genotype showed a distinct genomic profile compared to the MYD88 MUT patients. Furthermore, the presence of more aneuploidies showed a significant association with a higher risk of progression to the symptomatic disease. 
Click for the full article

Ruxolitinib Versus Best Available Therapy in Patients With Steroid-Refractory Acute Graft-Versus-Host Disease: Final Analysis From the Randomized Phase III REACH2 Trial [Clinical trial update / post hoc analysis]

Highlights:

●      Approximately 30%-50% of patients develop acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (Allo-HCT),

●      Up to 50% of patients become steroid-refractory (SR).

●      REACH2 is a phase III study of ruxolitinib versus best available therapy (BAT) in patients age ≥12 years with SR-aGVHD after Allo-HCT.

●      In this analysis, ruxolitinib provided efficacy advantages over BAT in patients with SR-aGVHD over 24 months.

 

Cumulative median (range) duration of response was 167 (22-677) days with ruxolitinib and 106 (10-526) days with BAT. Median overall survival and event-free survival were 10.7 and 8.3 months with ruxolitinib, compared with 5.8 and 4.2 months, respectively, with BAT. Median failure-free survival was significantly longer with ruxolitinib than with BAT (4.86 vs. 1.02 months, P <0.001). Similar numbers of non-relapse mortality events were observed with ruxolitinib and BAT (72 vs. 71), and malignancy relapse/progression events remained low across both groups. Numerically higher chronic GVHD rates were noted with ruxolitinib than with BAT from 12 months; however, 95% confidence intervals overlapped. Safety observations were consistent with the primary analysis results. 
Click for the full article

Central nervous system myeloma: Pathogenesis, diagnostic challenges, and practical management strategies [Review]

Key points:

●      Central nervous system (CNS) involvement in multiple myeloma (MM) is a rare but devastating complication, associated with poor prognosis, that occurs in approximately 1% of MM patients.

●      It accounts for approximately 20% of all EMD relapses, typically occurring 2-3 years after the initial MM diagnosis, and it is observed in a small percentage of MM cases at the time of diagnosis.

●      If any MM patient has unexplained neurological symptoms (e.g., headache, diplopia, limb weakness, paresis, dizziness and nausea, confusion, facial palsy, dysphagia, seizures, and dysarthria) at any stage of the disease, perform:

○      Advanced imaging (magnetic resonance imaging of the whole neuroaxis: leptomeningeal enhancement or thickening, dural enhancement, intraparenchymal lesions, intraspinal lesions, nodular meningeal tumors).

○      Cerebrospinal fluid (CSF) examination (lumbar puncture for cytology, biochemistry, lactate dehydrogenase, next generation flow cytometry for clonal plasma cells, free light chain).

■      High suspicion of CNS-MM (if imaging findings are ambiguous and CSF is negative, histopathological confirmation through tissue biopsy may be required to establish a definitive diagnosis).

●      Treatment options:

○      Clinical trial (preferred if available).

○      Potentially active (case reports: anti-B‐cell maturation antigen bispecific antibodies or chimeric antigen receptor T-cells).

○      Novel agents and combinations (immunomodulatory agents, proteosome inhibitors, selinexor, anti-CD38 monoclonal antibodies).

○      Systemic chemotherapy (drugs crossing blood-brain barrier [BBB]: cytarabine, methotrexate, and thiotepa have been reported as useful for the treatment of CNS‐MM because of their ability to cross the BBB, however, they display low therapeutic potential, as they have minimal activity on MM cells), corticosteroids (benefit when used in isolation), and autologous stem cell transplantation. 

○      Intrathechal chemotherapy (particularly in patients with leptomeningeal involvement)

○      Radiation therapy (craniospinal radiotherapy has a particularly critical role in cases of spinal cord compression or devastating symptoms resulting from brain or cranial nerve compression).

●      Close monitoring of CSF clearance is essential to guide therapy.
Click for the full article

Emerging therapeutic strategies for mature T-cell and natural killer-cell lymphomas [Review]

In this Series paper, Tse et al. discuss the limitations of the conventional treatment options and the use of these novel approaches for mature T-cell and natural killer-cell lymphomas.

 

Key points:

●      Mature T-cell and natural killer-cell neoplasms are a heterogenous group of uncommon lymphomas (See Panel 1 in original paper). Conventional therapy with mainly cytotoxic chemotherapy for this subgroup is suboptimal, and the treatment outcome is unsatisfactory.

●      Given the heterogeneity of this group of lymphomas, a ‘one size fits all’ approach is unlikely to be effective.

●      Monoclonal antibodies or antibody–drug conjugates (targeting T-cell lymphoma surface antigens) have been approved, including brentuximab vedotin which binds to CD30 receptors, is internalized by the cell, and then releases its cytotoxic payload (monomethyl auristatin E), for the treatment of CD30-positive nodal and cutaneous T-cell lymphoma, and mogamulizumab (targeting the C-C chemokine receptor type 4), for mycosis fungoides and adult T-cell leukaemia/lymphoma.

●      Immune checkpoint blockade (nivolumab) and epigenetic therapy (chidamide, valemetostat) have also shown promise in the management of mycosis fungoides and extranodal natural killer-/T-cell lymphoma.

●      The successful introduction of novel and effective treatment, including bispecific T-cell engagers and chimeric antigen receptor (CAR) T-cells for B-cell lymphomas, has not yet been replicated for mature T-cell and natural killer-cell lymphomas. 
Click for the full article

Does everyone with newly-diagnosed, untreated acute myeloid leukaemia need remission-induction chemotherapy before advancing to a transplant? [Perspective]

Most people with high- and many with intermediate-risk, newly diagnosed, untreated acute myeloid leukaemia (AML) who are eligible for intensive treatment receive induction and postremission chemotherapy before advancing to an allogeneic haematopoietic cell transplant (HCT).  This strategy is based on 3 assumptions:

(1) Achieving a histological complete remission (CR) pretransplant decreases risk of posttransplant leukaemia relapse.

(2) A person in histological CR is better able to survive the rigors of HCT compared with that person with active leukaemia.

(3) Time is needed to identify an appropriate donor and/or secure funding.

 

The need for pretransplant chemotherapy in someone advancing to HCT is rarely questioned. Yet, data convincingly supporting this assumption are lacking.

 

The phase-3 ASAP study is the only randomized controlled trial in AML comparing the impact of pretransplant chemotherapy with advancing immediately to HCT, albeit in a setting other than newly-diagnosed, untreated AML.

 

Superiority of sequential conditioning in reducing cumulative incidence of relapse is also unclear even when compared with standard reduced-intensity regimens. Arguably, success of HCTs may particularly rely on a so-called graft-versus-leukaemia effect in the context of advanced leukaemia. E. Rodríguez-Arbolí and R. P. Gale consider sequential conditioning jargon: chemotherapy given immediately pretransplant is part of pretransplant conditioning. 
Click for the full article

IACH Webinars

Stay tuned for the upcoming IACH webinars
Click here

For questions please contact:
info@clinical-hematology.org

If you prefer not to receive future email communications from us, please unsubscribe here

This newsletter was sent using ITnewsletter