Highlights: 

-        Preliminary reports suggest interim positron emission tomography (PET) could drive treatment duration in limited-stage diffuse large B-cell lymphoma (DLBCL).

-        A risk-adapted approach using early PET after two cycles of R-CHOP was beneficial, minimizing toxicity without compromising efficacy in patients treated in first-line therapy for low-risk DLBCL.

LNH2009-1B study is a two-arm, open-label, multicenter, prospective, randomized phase III noninferiority trial, evaluating treatment de-escalation based on PET after two cycles of R-CHOP in previously untreated DLBCL patients aged 18-80 years, with aaIPI (age-adjusted International Prognostic Index) = 0. A total of 650 patients were enrolled. In the experimental PET-adapted arm (n=319), patients with a negative PET after two cycles received four cycles in total of R-CHOP, whereas those with a positive PET after two cycles received a total of six cycles. In the standard arm (n=331), treatment was six cycles regardless of PET results after two cycles. No radiotherapy was planned.

In the PET-adapted arm, 77.7% of patients had a negative PET scan after two cycles and received a total of four cycles of R-CHOP. The 3-year progression-free survival (primary endpoint) in PET-adapted and standard arms were 92.0% [95% confidence interval (CI) 88.3% to 94.5%] and 89.2% (95% CI 85.3% to 92.2%), respectively (P=0.070). The noninferiority of the experimental PET-adapted arm was demonstrated (hazard ratio 0.72, 95% CI 0.47-1.12, P<0.0001). Patients in the PET-adapted arm had fewer adverse events of grades ≥3 (54.7% versus 62.7%, P=0.046) and serious adverse events (9.5% versus 14.2%, P=0.039).

Addition of autologous stem-cell transplantation to an ibrutinib-containing first-line treatment in patients aged 18–65 years with mantle cell lymphoma (TRIANGLE): 4·5-year follow-up of a three-arm, randomised, open-label, phase 3 superiority trial of the European MCL Network (Update clinical trial). 

Highlights:

-        Adding ibrutinib to standard, first-line immunochemotherapy improves failure-free survival (FFS; primary endpoint) in adult patients aged 18–65 years with mantle cell lymphoma (MCL), according to the first results from the TRIANGLE trial (NCT02858258).

-        With a median follow-up of more than 4 years, the TRIANGLE trial showed improvements not only in FFS but also in overall survival (secondary endpoint) when adding ibrutinib to first-line R-CHOP, alternating with R-DHAP.

-        The addition of ASCT to ibrutinib-containing, first-line treatment did not show superior efficacy and was associated with more frequent, severe side-effects.

-        Induction treatment with ibrutinib and R-CHOP plus R-DHAP (or R-DHAOx), followed by 2 years of maintenance treatment with ibrutinib, should be considered as a new standard of care for younger patients with MCL.

Between 2016 and 2020, 870 patients aged 18–65 years with untreated, stage II–IV MCL  and suitable for autologous stem cell transplant (ASCT) were randomly assigned (1:1:1) to control group A (n=288) or experimental groups A + I (n=292) or I (n=290). Treatment in group A consisted of six alternating, 21-day cycles of R-CHOP and R-DHAP or R-DHAOx, followed by ASCT. In group A + I, oral ibrutinib was added on days 1–19 of R-CHOP cycles and as 2-year maintenance after ASCT. In group I, ibrutinib was given the same way, but ASCT was omitted. Rituximab maintenance was allowed in all treatment groups according to national guidelines. After median follow-up of 54.9 months (95% confidence interval [CI] 54.4–56.0), group A + I did not show superiority over group I, with 4-year FFS of 82% (95% CI 78–87) vs 81% (76–86; hazard ratio 0.86 [one-sided 98.33% CI 0.00–1.27]; one-sided p=0.21). 

Ruxolitinib for ciltacabtagene autoleucel–associated refractory diarrhea (Case series). 

Highlights:

-        Intractable diarrhea is a recently described severe complication following B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma with reported mortality rates of 36% to 50%.

-        Ruxolitinib (Janus kinase inhibitor) mitigated severe intractable diarrhea following ciltacabtagene-autoleucel (cilta-cel).

-        Diarrhea is driven by apparent CAR) T-cell activity in the gut, with potential clonal evolution into CAR T-cell–associated indolent T-cell lymphoproliferative disease of the gastrointestinal tract (ITLPD-GT).

Here, the authors report a series of 5 patients who presented with severe diarrhea after cilta-cel treatment. They hypothesized that ruxolitinib might be an effective therapy based on its success in graft-versus-host disease after allogeneic bone marrow transplant and other immune-driven diarrhea syndromes. Three patients received ruxolitinib, all of whom experienced rapid clinical improvement. Among the 2 patients with matched pretreatment and posttreatment biopsies, both showed signs of histopathologic response, including 1 with CAR T-cell– associated ITLPD-GT.

Fertility preservation in 2026: current landscape in Europe and the United States for children and adolescents undergoing hematopoietic stem cell transplantation—recommendations on behalf of the Westhafen Intercontinental Group

Key points:

Risk of infertility after allogeneic hematopoietic stem cell transplantation (HSCT):

●      Myeloablative regimens with total body irradiation (TBI) and/or alkylating agents are highly gonadotoxic.

○      Women: spectrum ranging from diminished ovarian reserve to premature ovarian insufficiency (POI); reported incidence of POI 44–100% following HSCT in childhood, depending on gonadotoxicity of conditioning and demographic diversity .

○      Men: azoospermia in >85–90% with myeloablative therapy; Leydig cell function is usually preserved with chemotherapy alone, but is affected by TBI.

○      Risk stratification tools:

■      Cyclophosphamide equivalent dose; useful but has limitations in predicting gonadal function.

■      Busulfan is among the most gonadotoxic; treosulfan may be more “gonadal-sparing” (emerging data).

■      TBI: age-dependent thresholds for risk of developing POI: 20.3 Gy in infants, 18.4 Gy at the age of 10 years, and 16.5 Gy at the age of 20; even lower doses reduce future fertility.

Fertility preservation (FP) techniques by pubertal stage and sex: See Figure 1 and Figure 2 in original paper.

●      Prepubertal:

○      Females: ovarian tissue cryopreservation (OTC; laparoscopic removal of ovarian tissue, which is subsequently dissected and cryopreserved) is the only current clinical FP option; it can restore endocrine/exocrine function upon reimplantation; outcome data on live births in adolescents/adults are limited if the tissue was obtained before puberty.

○      Males: testicular tissue cryopreservation (surgical biopsy of testicular tissue, which is then cryopreserved).

●      Post-pubertal patients:

○      Females: cryopreservation of oocytes (standard; requires 2–3 weeks), embryos (if sperm is available), and OTC when urgent, or stimulation is not possible. Gonadotropin-releasing hormone agonists should not replace established FP methods.

○      Males: cryopreservation of semen prior-to-treatment; consider multiple samples. If there are no sperm in the ejaculate, it may still be possible to retrieve sperm directly from the testes by testicular sperm extraction.

●      Timing and implementation considerations (See Table 3 in original paper):

○      Early counseling, ideally at diagnosis; identify “windows” between treatment cycles, during remission, or just before conditioning.

○      Reassess FP throughout treatment and after HSCT; consider secondary FP if residual function is present or if the patient undergoes pubertal maturation following prior FP.

●      Reproductive safety and outcomes:

○      Congenital malformations: there is no significant increase in the children of survivors treated prior-to-conception; assisted reproductive technology carries slightly higher risks than spontaneous conception, but oocyte vitrification does not show a significant increase.

○      Risk of reintroduction of malignant cells upon reimplantation of gonadal tissue: of particular concern in leukemias; collect tissue during complete remission, and assess minimal residual disease.

○      Uterine dysfunction following TBI/busulfan: reduced uterine volume and increased risk of miscarriage, preterm birth, intrauterine growth restriction, and postpartum hemorrhage; requires specialized obstetric counseling and follow-up.