News of the Week

Highlights:

• Anitocabtagene autoleucel (anito-cel), a B-cell maturation antigen (BCMA)–directed autologous chimeric antigen receptor (CAR) T-cell therapy with a synthetic D-domain binder (ddBCMA).
• Anito-cel therapy led to a high incidence of response among patients with heavily pretreated relapsed or refractory multiple myeloma (RRMM). Cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome (ICANS) of grade 3 or higher were rare.

In a phase 1 study (ClinicalTrials.gov number, NCT04155749), the authors evaluated the safety and efficacy of anito-cel (dose level 1, 100×10⁶ CAR+ T cells; dose level 2,300×10⁶ CAR+ T cells) in patients with RRMM who had received three or more lines of therapy previously or had triple-class refractory disease. Primary end points were adverse events (AEs) during the treatment period and establishment of the recommended phase 2 dose. Of 40 patients enrolled, 38 received anito-cel. All 38 patients had an AE during the treatment period, and 37 patients (97%) had an AE of grade 3 or higher (neutropenia 84%). Among patients who received the recommended phase 2 dose (100×10⁶ CAR+ T cells), 94% had cytokine release syndrome of grade 1 or 2, with no events of grade 3 or higher. A total of 16% of the patients had an immune effector cell–associated neurotoxicity syndrome (ICANS) of grade 1 or 2, and 1 patient (3%) had a grade 3 event. No non-ICANS or delayed neurotoxic effects occurred. At a median follow-up of 38.1 months, all 38 patients (100%) had had a response, with 79% having a complete response. The 24-month progression-free survival (PFS) was 57%; the median PFS was 30.2 months. The 36-month overall survival was 65%.

Highlights:

• In myeloma, >45% of patients have vertebral fractures at the time of myeloma diagnosis. However, the risk of myeloma in individuals with incidentally detected vertebral fractures is unknown.
• The absolute 5-year risk of myeloma was quite modest in individuals with incidentally detected vertebral fractures on computed tomography (CT) scans, indicating that it is likely of limited or no benefit to evaluate individuals with incidentally detected vertebral fractures for underlying myeloma, unless there are symptoms or other clinical findings raising suspicion of myeloma.

9059 CT-scanned individuals aged 40–94 years from the Copenhagen General Population Study (a contemporary Danish general population cohort study enrolling >120,000 individuals as of April 2019) were studied. Low-dose CT scans, including abdominal images, were performed for a randomly selected subgroup of participants a median of 3 months after their study enrollment visit.  Among the 9059 individuals, 1571 (17.3%) had any vertebral fracture on the CT scan, and of these, 873 (9.6%) had a grade 1 fracture, and 698 (7.7%) had a grade 2 or 3 fracture.  Median follow-up was 5.5 years after the baseline CT scan. The age-standardized incidence of myeloma during follow-up was 4.6 per 100,000 person-years (95% confidence interval [CI]:2.0-7.2), similar to the age-standardized incidence of 4.4 per 100,000 person-years in the entire Danish population as reported by the NORDCAN cancer statistics database (year:2021).

Relative risk of myeloma was increased in individuals with any vertebral fracture (multivariable adjusted hazard ratio:3.73; 95% CI:1.24-11.21) when compared to individuals without vertebral fractures, and more pronounced for individuals with grade 2–3 vertebral fractures (4.99; 95% CI:1.43-17.44). When studying absolute risk irrespective of age, absolute 5-year risks of myeloma were 0.07% for women with no vertebral fracture, 0.17% for women with grade 1 fractures, and 0.43% for women with grade 2-3 fractures. Risk estimates were more pronounced for men, with 5-year risks of 0.10% for men with no vertebral fracture, 0.24% for men with grade 1 fractures, and 0.63% for men with grade 2-3 fractures. Individuals with any vertebral fracture were not at increased risk of lymphoma (1.00; 95% CI:0.54-1.88) or myeloid hematologic malignancies (1.05; 0.46-2.40). Likewise, risk of any non-hematologic cancer was not increased in individuals with any vertebral fracture (0.98; 0.80-1.22), and we did not find convincingly increased risk for any of the 23 non-hematologic cancer subtypes investigated.

In four representative cases, the authors describe how we currently use measurable residual disease (MRD) testing for adult patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (allo-HCT).

Key points: See BOX 1 in original paper.

• Allo-HCT is long established as the only curative option for many patients with AML.
• Recent evidence demonstrates that MRD testing, known to help stratify patients with AML in remission based on their risk for post-HCT relapse and mortality, can provide opportunities for patient-specific allo-HCT personalization.
• This includes patient selection for transplantation, guiding conditioning regimen intensity, surveillance for early identification of relapse during post-transplant remission, and, in some cases, selecting patients predicted to benefit from post-transplant maintenance or pre-emptive therapy.
• Transplant works. A positive MRD result before allo-HCT is a reason to optimize the approach, not to abandon the transplant. There is no guarantee that “MRD erasing” efforts will be successful, and the associated delay may convert a transplant-eligible patient to ineligible by allowing time for relapse, infection, or other toxicity harm. Allo-HCT may be the next best therapy for low-level refractory disease. Not everyone who enters allo-HCT with detectable MRD suffers relapse.
• MRD testing is not a crystal ball. A negative MRD test result does not exclude relapse. We are testing MRD in a small sample from the patient, not the entire patient. MRD test results should be used to modify relapse risk estimates, not be treated like a full accounting of the leukemia left to treat. Treatment discontinuation to below current standard of care on the basis of a negative MRD test should be conducted in the context of a clinical trial.
• Not all somatic mutations detected at initial AML diagnosis are good MRD targets. Isolated detection of persistent mutations in DNMT3A, TET2, or ASXL1 in remission may be clonal hematopoiesis, not residual leukemia. Detection of IDH1 mutation pre-HCT has also not been associated with increased post-HCT risk in multiple cohorts.
• There is no validated “safe” FLT3-ITD MRD threshold. Even very low-level detection (down to 1×10⁻⁶) peri-transplant confers measurable relapse risk. Measure using high-sensitivity next-generation sequencing-MRD testing before and after transplant for patients with FLT3-ITD AML to identify those with greatest likelihood of benefit from post-transplant gilteritinib maintenance.
• You can do things. Detection of AML MRD does not have to represent inevitable fate. There is growing evidence that pre-, peri-, and post-transplant interventions including conditioning intensification and post-transplant therapy can significantly mitigate risk by delaying or pre-empting relapse. Clinical trial enrollment is recommended.
• TP53 mutation is different. In TP53 mutation AML, clearance of detectable TP53 mutation after initial treatment has not been shown to predict improved survival for those in remission; do not be falsely reassured. Consider post-HCT intervention (accelerated immunosuppression taper, hypomethylated maintenance, donor lymphocyte infusions, or trial enrollment) regardless of pre-computed tomography MRD test status.

Highlights:

• In relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL), responses to the CD22 antibody-drug conjugate inotuzumab ozogamicin (INO) are frequent but short-lived.
• Venetoclax (VEN)+INO is safe and effective for R/R B-ALL/LBL, producing frequent and durable measurable residual disease (MRD)-negative remissions.

Based on preclinical evidence of synergy, the authors conducted a phase 1 trial (ClinicalTrials.gov number, NCT05016947) of the BCL-2 inhibitor VEN plus standard-dose INO for adults with R/R CD22+ ALL/LBL. Twenty-three patients enrolled (15 ALL, 8 LBL). The recommended dose was VEN 400 mg/day for 21 days per cycle. No dose-limiting toxicities or early mortality occurred. Patients received a median of 2 cycles (range 1-5). The most common grade 3 adverse events were thrombocytopenia (43.5%) and neutropenia (39.1%). Four patients (17.4%) developed sinusoidal obstructive syndrome. Of 22 evaluable patients, 21 (95.5%) achieved complete remission, including 19 after one cycle. MRD cleared in 16/18 (88.9%) by flow cytometry (<10^-4) and 14/19 (73.7%) by next-generation sequencing (<10^-6). Fourteen (63.6%) patients proceeded to hematopoietic stem cell transplantation. With a median follow-up of 25.3 months (95% CI 19.0-32.4), two-year disease-free (DFS) and overall survival (OS) were 48% (95% CI 24-72%); median DFS was 22.1 months (95% CI 10.4-NA), and median OS was not reached. MRD-positivity was associated with lower baseline BCL-2 dependence.

Key points:

• Because T-cell neoplasms often present with nonspecific findings, T-cell clonality assessment is performed across many clinical scenarios, including the workup of cytopenias, lymphocytosis, eosinophilia, and suspected lymphoma.
• Sensitive assays, including flow cytometric staining of the T-cell receptor (TCR) constant region and molecular-based TCR clonality testing, have enhanced our ability to detect T-cell neoplasms, but these techniques frequently identify T-cell clones in patients without suspicion of T-cell malignancy.
• These incidentally detected clones, sometimes called T-cell clones of uncertain significance, do not clearly have universal potential for progression to overt T-cell neoplasia.
• These clones, commonly generated by infection or homeostatic proliferation, generally have no malignant or premalignant potential.
• Their detection can prompt unnecessary diagnostic procedures, generate unwarranted patient anxiety, and even lead to inappropriate therapeutic interventions.
• Appropriate diagnosis of these entities requires careful synthesis of immunophenotypic features, clone size, and clinical context.
• Substantial work, particularly longitudinal studies incorporating molecular studies and clinical outcomes, is needed to define evidence-based thresholds that reliably separate benign clonality from early T-cell neoplasia.
• See Figure 2 (Algorithm for approaching peripheral blood T-cell clonality in patients without established diagnosis of T-cell neoplasm) in original paper.

The authors propose a practical framework for risk stratification of unexpected T-cell clones in peripheral blood that minimizes the risk of unnecessary intervention while maintaining vigilance for true T-cell malignancy.