Improved Outcomes of Myeloma Cast Nephropathy in Newly Diagnosed Multiple Myeloma With Modern Anti-Myeloma Therapies [Retrospective study]

Highlights:

*  Myeloma cast nephropathy (MCN) is a driver of renal failure in newly diagnosed multiple myeloma (NDMM) and has been historically associated with increased early mortality.

*  This study reports that outcomes of patients with newly diagnosed MCN have substantially improved in the modern era, with about three-fourths of patients achieving renal response with bortezomib and daratumumab-based frontline therapies without plasma exchange.

The authors reviewed 274 consecutive NDMM patients from 2017 to 2023 at an academic center and identified 46 patients (16.8%) with MCN.  Control patients were defined as those with NDMM without MCN at presentation. MCN was defined as one of the following: (1) evidence of light-chain casts on histopathologic examination of renal biopsy; (2) evidence of renal impairment combined with significant proteinuria and accompanied by an involved free light chain titer of at least 50 mg/dL. Among the MCN patients, 96% had received bortezomib and 67% an anti-CD38+ monoclonal antibody as part of frontline therapy.  The time to initiation of anti-myeloma therapy was significantly shorter in MCN versus controls (6 vs. 16 days, p<0.001). The renal overall response rate was 76.1% (35/46), and the renal complete response rate was 32.6% (15/46) at 6 months. Overall survival at 6 months did not differ between MCN (100%) and controls (98.2%).

In summary, the authors report excellent 6-month renal recovery without early mortality in MCN patients with modern anti-myeloma therapies.

Methylation sequencing enhances the interpretation of clonal hematopoiesis dynamics [Basic research: Letter to the Editor]

Highlights:

* Clonal hematopoiesis of indeterminate potential (CHIP) occurs when hematopoietic stem cells acquire a preleukemic driver mutation and produce blood cells that constitute a variant allele fraction (VAF) of ≥0.02 in peripheral blood.

*  CHIP has a high prevalence (~10% of people aged >60 years) and confers an increased risk of hematologic malignancy, cardiovascular disease, and all-cause mortality.

*  Current clinical practice relies on monitoring clone size through serial measurements of VAF using DNA sequencing. However, because the proportion of cells carrying CHIP mutations varies across cell types, fluctuations of cell-type proportions in response to other factors may confound clonal trajectory interpretation based solely on VAF.

*  In this study, the authors developed a DNA methylation sequencing assay to improve monitoring of clonal hematopoiesis. By inferring cell-type proportions, this method enhances the interpretation of clonal trajectories compared with interpretation based on VAF only.

*  This assay is cost-effective, and therefore feasible for implementation in clinical practice.

This cohort study comprised 91 samples from 34 patients previously assessed for CHIP. They observed that 24 patients carried a CHIP mutation with VAF ≥0.02 at one or more time points. The authors showed that predictions of clonal behavior are driver gene-specific, with distinct equations governing predicted changes in VAF for TET2-mutant, DNMT3A-mutant, and other gene-mutant CHIP. Estimated VAF changes for TET2-mutant CHIP relied heavily on increased monocyte proportions, whereas estimates of DNMT3A-clonal behavior relied on decreasing monocytes.

Role of azathioprine in the management of ITP in the TPO-RA era: a single-center retrospective study

Highlights:

*  Access to modern therapeutics for immune thrombocytopenia (ITP), such as thrombopoietin-receptor agonists (TPO-RAs), remains challenging, limiting clinicians’ options.

*  Azathioprine remains a viable and safe treatment in relapsed/ refractory ITP in the TPO-RA era.

*  Azathioprine offers clinicians a comparable drug response irrespective of prior TPO-RA exposure or splenectomy.

The authors identified 92 patients with ITP who received azathioprine at a specialized care center in Ontario, Canada, between 2009 and 2022. Mean age was 55.6 years, 53 were female (57.6%), and 64 of the patients had primary ITP. The overall response rate was 47.8% (44/92), and 77.3% (34/ 44) of those responses lasted at least 6 months. The median time to first response was 6 weeks. Fourteen patients (31.8%) relapsed, with a median duration of response of 10 weeks. Most patients (73.9%) had side effects, with nausea/vomiting, infections, and blood cell count problems being the most common.

Vodobatinib for patients with Philadelphia chromosome-positive chronic myeloid leukemia resistant or intolerant to multiple lines of previous therapy: an open-label, multicentre, phase 1/2 trial [Clinical trial]

Highlights:

*  This study reports the safety, antileukemic activity, and pharmacokinetics of oral vodobatinib, a novel selective BCR::ABL1 tyrosine kinase inhibitor (TKI), in patients with Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia (CML) who previously received at least three TKIs, including ponatinib and asciminib.

*  Pooled analysis of the phase 1 and 2 studies showed clinically meaningful antileukemic activity of vodobatinib and a tolerable safety profile.

This open-label, multicentre, phase 1/2 trial (ClinicalTrials.gov, NCT02629692 [active]) included patients aged ≥18 years with Ph-positive CML or acute lymphoblastic leukemia (eligible only for the phase 1 study), and an Eastern Cooperative Oncology Group performance status of ≤2.  Phase 1 included patients who previously received at least three TKIs or had no other available treatment options. Phase 2 required patients to have treatment resistance or intolerance (or both) with loss of response to at least 3 TKIs and previous ponatinib use.

Of 115 CML patients, 78 were enrolled (phase 1=58; phase 2=20) and received at least one vodobatinib dose (safety and efficacy analysis set). Patients self-administered oral vodobatinib (12–240 mg) once per day for each 28-day treatment cycle and for up to 60 months (ie, 65 cycles).  At data cutoff, a major cytogenetic response was observed in 44 (70%) of 63 patients with chronic-phase CML, of which 12 (75%) of 16 patients in the phase 2 study had a major cytogenetic response.  The phase 2 study was statistically underpowered and warrants further investigation in a phase 3, randomised controlled trial and in an earlier treatment setting of the disease.

Long-term outcomes of tyrosine kinase inhibitors in chronic myeloid leukemia [Review Series]

In this volume of Blood, an article reviews the work of many key investigators, highlighting the long-term outcomes of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) over the past 25 years.  These outcomes show that the impact of TKIs on CML is sustained, as shown by 13 studies with 5- to 14-year-follow-up and numerous shorter-term studies of newly diagnosed chronic-phase CML. Twenty-five years of imatinib treatment confirm its beneficial effect on survival and possible cure of CML.

Other key points: 

*  Combinations of imatinib (IM) with interferon and low-dose cytarabine of high-dose IM do not improve survival compared to IM 400 mg/day.

*  Second-generation TKIs (2GTKIs) induce responses faster than IM and recognize IM- resistance mutations, but do not improve survival compared with IM.

*  Adverse drug-related reactions limit the general use of 2GTKIs

*  A new prognostic score (EUTOS: European Treatment and Outcome Study-long term survival score) accounts for the fact that the majority of CML patients die of other causes.

*  Non-CML determinants of survival have been identified (smoking, healthcare settings, comorbidities).

*  Despite merits of 2GTKIs, IM remains the preferred treatment option for CML because of its efficacy and superior safety.