May 8, 2026
Prepared by Dr Edwin Uriel Suárez

Highlights:

●      Clonal hematopoiesis (CH) is a feature of severe aplastic anemia (SAA), but its clinical significance is debated.

●      Among patients with SAA treated with immunosuppression plus eltrombopag (IST-EPAG), early and late patterns of clonal evolution to myeloid cancer were observed: Chromosome 7 abnormalities occurred within 1 year, whereas later events (4–5 years) involved stepwise mutation acquisition in preexisting ASXL1- or U2AF1-mutated clones.

In total, 204 SAA patients treated with IST-EPAG were evaluated from disease onset to median follow-up of 5.5 years. CH (defined as the presence of somatic mutations at a variant allele frequency of 0.1% or greater) was observed in 128 of 204 (63%) patients before treatment and in 131 of 180 (73%) after therapy. Patients mostly had CH in PIGA (N=53, 26%), DNMT3A (N=42, 21%), BCOR (N=35, 17%), and ASXL1 (N=25, 12%). There appeared to be two distinct patterns of malignant clonal evolution. Early evolutions, within 1 year from treatment, were primarily chromosome 7 aberrations and occurred in 11 (5%) patients. In another eight (4%) patients, late evolutions, 4–5 years after therapy, were initiated by early selection of ASXL1-mutated or U2AF1-mutated clones. Evolution to paroxysmal nocturnal hemoglobinuria, observed in 10 of 204 patients (5%), was associated with expansion of PIGA clones usually present before treatment. 

Highlights:

●      A Phase 3 randomized trial (The RACE trial; NCT02099747) compared immunosuppressive therapy (horse anti-thymocyte globulin-cyclosporine) with or without eltrombopag in untreated patients with aplastic anemia (AA) and showed that addition of eltrombopag increased the rate, rapidity, and durability of hematological response, without increasing transformation to myeloid malignancies.

●      In this secondary sub-analysis, clonal hematopoiesis (CH) was frequent in patients with AA and its prevalence appeared to be higher at posttherapy timepoints than at diagnosis. CH in AA may reflect the survival and expansion of selected residual hematopoietic stem/progenitor cells associated with immune - mediated damage.

The authors systematically evaluated CH dynamics from patient samples from the Race trial. Samples were collected from patients at baseline (n=170) and 6 (n=150) and 24 months (n=103); 85 patients’ samples were tested at all three timepoints. Somatic mutations were present in 30% of patients at baseline, 55.3% at 6 months and 79.6% at 24 months, with a mean number of mutations per patient of 0.4, 1.2, and 2.5, at baseline, 6 and 24 months, respectively. 

Highlights:

●      Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for myelodysplastic syndromes (MDS) and optimising patients for transplant is critical to achieving the best outcomes.

●      Hypomethylating agents (HMAs), particularly azacitidine, are used as a bridging strategy with the aim of achieving disease control and limiting leukemic transformation.

●      The role of pre-transplant azacitidine in higher-risk transplant-eligible MDS has remained uncertain and recent studies comparing azacitidine to upfront transplant have not demonstrated a clear survival benefit.

●      This study suggests the absence of a survival benefit of pre-transplant azacitidine in higher-blast subgroups, even when complete remission (CR) is achieved; and the association between azacitidine and poorer outcomes was not fully explained by enrichment for adverse-risk disease.

This study included 289 adults who underwent allo-HSCT for MDS between 2013 and 2020. The median age at transplant was 58 years (range 19–75). WHO 2016 MDS subtypes were distributed across the cohort, with MDS with excess blasts-2 the most common (93/289, 32%). Most patients (197/289, 68%) had Revised International Prognostic Scoring System (IPSS-R) scores of Intermediate or higher. Overall, 140 patients (48%) received pre-transplant azacitidine, including 107 of 197 (54%) patients with higher-risk disease (IPSS-R ≥ Intermediate). Median overall survival (OS) was 7.0 years (0.02–11.2) and median relapse-free survival was 6.8 years (0.2–11.2). Pre-transplant azacitidine was associated with inferior OS in the overall cohort (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.04–2.08) and remained associated with poorer survival in higher-risk patients. Among 93 azacitidine-treated patients with available response data, CR was achieved in 29 (31%). Achieving CR was associated with improved OS compared with non-responders (HR 0.47, 95% CI 0.24–0.97). However, patients who achieved CR did not show a significant survival advantage compared with patients who never received azacitidine (HR 0.99, 95% CI 0.49–2.00). Number of azacitidine cycles (median=5, range 1-35) did not modify survival and responders did not require additional cycles to achieve benefit. Pre-transplant azacitidine was associated with poorer survival in MDS without excess blasts. Remarkably, further stratification by CR did not demonstrate a survival advantage in patients with excess blasts who achieved CR. 

Highlights: 

Circulating tumor DNA (ctDNA) is a noninvasive method for detecting measurable residual disease (MRD). ctDNA-MRD provided prognostic value beyond  positron emission tomography, supporting its role as a complementary biomarker for treatment response and relapse prediction.

The authors report correlative ctDNA analyses from TRANSFORM (NCT03575351) evaluating lisocabtagene maraleucel (liso-cel) versus standard of care (salvage immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation [ASCT]) in second-line large B-cell lymphoma. ctDNA association with efficacy was investigated at predefined time points (random assignment, day 43, day 64, and day 126 [3 months after liso-cel, approximately 2 months after ASCT]) for 136 patients using ultrasensitive PhasED-Seq. ctDNA clearance (MRD^neg) predicted longer event-free survival (EFS) at all time points in both arms, with significantly more liso-cel–treated patients achieving MRD neg. Liso-cel demonstrated superior outcomes versus ASCT, including longer EFS, progression-free survival, and duration of response among patients in complete response (CR) and MRD^neg. ctDNA re-emergence in patients with CR after ASCT confirmed its potential in predicting relapse. 

This paper presents an expert opinion on the use of diagnostic modalities and treatment options, including chemotherapy, radiation therapy, and immunotherapy, for acute leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloproliferative neoplasms, aplastic anemia, and multiple myeloma during pregnancy. 

This expert opinion is an initiative of the International Network on Cancer Infertility and Pregnancy (INCIP).

Key points:

●      The article emphasizes that clinical decision-making is largely based on expert opinion, given the absence of prospective trials and the exclusion of pregnant patients from most studies.

●      A central principle is that maternal prognosis should not be compromised by pregnancy. Standard-of-care therapies should be delivered whenever feasible, as undertreatment or delay may adversely affect both maternal and fetal outcomes.

●      Imaging strategies for diagnosis and staging are tailored to balance maternal risk and diagnostic needs with fetal safety, with a primary focus to keep fetal exposure to ionizing radiation and gadolinium-based contrast agents (GBCAs) as low as reasonably achievable.

○      For complete staging of hematologic malignancy, ionizing radiation–based modalities, including computed tomography (CT) and fluorodeoxyglucose positron emission tomography-CT (FDG-PET-CT), are not recommended as primary imaging modality during pregnancy.

○      Whole-body magnetic resonance imaging with diffusion weighted sequence (WB-DWI/MRI) represents a noninvasive imaging alternative for staging as it is a nonionizing radiation imaging modality and obviates the use of GBCAs by the functional DWI-sequence, enabling the detection of disease sites without underlying anatomical disruption and functional response assessment in hematologic malignancies.

■      WB-DWI/MRI has shown higher per patient sensitivity for detecting bone disease in multiple myeloma and has similar impact on treatment decisions as PET-CT.

■      In lymphoma, WB-DWI/MRI has a concordance of 99.4% with PET-CT for detecting nodal and extranodal involvement, while staging with both modalities has shown similar impact on progression-free survival and patient management.

■      WB-DWI/MRI also enables reliable interim and post-treatment response evaluation with reported agreement of 99.2% with PET-CT for predicting outcome.

●      Treatment must be individualized based on: Disease type and aggressiveness, gestational age, maternal preferences. Gestational age is the key determinant of treatment strategy (See Figure 1 in original paper).

○      First trimester: High teratogenic risk; systemic therapy is avoided when possible.

○      Second and third trimesters: Several conventional therapies (e.g., selected chemotherapies) can be administered with relatively acceptable fetal safety.

●      Because of the toxic effects of chemotherapy on the maternal bone marrow, and consequently also on the fetal bone marrow, it is important to consider a specific window of time between the last chemotherapy administration and delivery to minimize the risk of maternal infections and bone marrow depletion in the child during and after birth. 

○      In most cases, this will result in a planned and coordinated delivery, which will allow for the timely resumption of further chemotherapy postpartum, if indicated.

○      Granulocyte colony-stimulating factor is classified as US FDA category C in pregnancy, necessitating careful consideration before use.

●      Radiation therapy should only be used in exceptional cases in the first trimester. The risks are lower and the threshold higher in the second and third trimesters. However, there remains a risk for potential intelligence quotient decrease with radiation exposure up to 25 weeks of gestation.

○      Preference should be given to reducing the delivered radiation by exploiting all means of treatment optimization for the fetus in close collaboration with appropriate medical radiotherapy experts, considering both the individual clinical case and availability of equipment and procedures for delivery and image guidance.

●      Management varies widely across hematologic malignancies:

○      Acute leukemias: Require urgent treatment irrespective of pregnancy. See Table 1, 2 and 3 in original paper.

○      Lymphomas: May allow limited treatment delay or modification in selected cases. See Figure 2 and 3 in original paper.

○      Chronic disorders: Often permit more conservative strategies.

●      The article stresses that no universal algorithm exists, and care must be disease-driven.

●      While conventional treatments have growing safety data in later trimesters, evidence for novel agents remains sparse, requiring careful risk–benefit assessment.

●      Close fetal monitoring and planned delivery in specialized centers are recommended. Coordination of treatment cycles and timing of delivery is essential to minimize maternal and neonatal complications.

●      Given the ethical and clinical complexity, shared decision-making and detailed counseling are critical. Discussions should include maternal prognosis, fetal risks, and therapeutic uncertainties.