Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial.

BACKGROUND: Adverse effects on reproductive function are a key concern in young women treated with chemotherapy for advanced Hodgkin's lymphoma. We aimed to identify risk factors for the extent of ovarian damage in women with Hodgkin's lymphoma treated with different chemotherapy regimens to inform accurate advice on options for fertility preservation. METHODS: We recruited female participants from the randomised phase 3 RATHL trial, aged 18-45 years, based on availability of participants at recruiting sites in the UK. The RATHL trial key inclusion criteria were histologically confirmed classic Hodgkin's lymphoma, stage IIB-IV or IIA with adverse features (bulky disease or more than two sites of involvement), no previous treatments, and a performance status of 0-3. As part of RATHL, participants were treated with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or AVD followed by an interim PET-CT scan. Participants who had negative interim scans (PET score of 1 to 3 according to the Lugano classification) were randomly assigned (1:1) by use of minimisation, stratified by interim PET score and study centre, to continue ABVD or AVD for four more cycles. Participants with positive scans (PET score of 4 or 5) were escalated to treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP-14 or escalated BEACOPP) for four cycles. For the protocol-driven prospective cohort substudy, ovarian function was assessed before treatment, during chemotherapy, and then annually for 3 years by use of serum antimüllerian hormone and follicle-stimulating hormone measurements. The RATHL study is registered with ClinicalTrials.gov, number NCT00678327. FINDINGS: Between Dec 13, 2010, and Dec 19, 2012, 67 eligible participants were recruited for this prospective cohort study; 57 had received ABVD or AVD (ABVD-AVD group) and ten BEACOPP-14 or escalated BEACOPP (BEACOPP group). Follow-up was fixed at 3 years. Antimüllerian hormone concentrations decreased during both chemotherapy regimens. At 1 year after chemotherapy, antimüllerian hormone concentrations recovered to a median of 10·5 pmol/L (IQR 4·3-17·3) in the ABVD-AVD group, but little recovery was seen after BEACOPP (median 0·11 pmol/L [0·07-0·20]). Age also affected the extent of ovarian function recovery, with antimüllerian hormone recovery in participants aged 35 years or older in the ABVD-AVD group to 37% (SD 10) of their before treatment concentrations, compared with full recovery to 127% (SD 12) in those younger than 35 years (p<0·0001). Follicle-stimulating hormone recovery to less than 25 IU/L occurred for 95% of women younger than 35 years in the ABVD-AVD group by 2 years and was also dependent on age (hazard ratio 0·49, 95% CI 0·37-0·65; p<0·0001). INTERPRETATION: Reduced recovery of ovarian function observed in women older than 35 years treated with ABVD or AVD compared with younger women indicates that treatment could reduce their reproductive lifespan and supports discussion of fertility preservation before treatment. Women treated with BEACOPP should be informed of its potential high gonadotoxicity. These findings warrant further investigation in large, prospective studies with fertility and reproductive lifespan as outcomes. FUNDING: Medical Research Foundation and Cancer Research UK.

Posttransplant immune-mediated hemolysis.

BACKGROUND: Immune-mediated hemolysis is a well-recognized complication of transplantation, but few reports have drawn together the different mechanisms that could be involved. STUDY DESIGN AND METHODS: The clinical and laboratory records of three patients are used to illustrate different types and complexities of posttransplant immune-mediated RBC destruction. RESULTS: Patient 1 received bone marrow from an HLA-matched, unrelated donor. At 7 months after transplant, his Hb level fell to 50 g per L. The serum contained warm autoantibodies, and the DAT was strongly positive for IgG, IgM, and C3d; an eluate yielded IgG and IgM autoantibodies. Autoimmune hemolytic anemia was diagnosed. Patient 2, blood group A, experienced severe hemolysis 14 days after receiving a lung from a group O donor. The DAT was positive for IgG. Serum and RBC eluate contained anti-A produced by immunocompetent B cells in the transplanted lung-this was the passenger lymphocyte syndrome. Patient 3 experienced posttransplant hemolysis caused by two different immune mechanisms. Originally group A, D- with anti-C, -D, -E, she received a peripheral blood progenitor cell (PBPC) transplant from her HLA-identical group A, D+ son. Six months later, chimerism was evident; the remaining recipient marrow was still producing antibodies that destroyed D+ RBCs made by the transplant. Later, autoimmune hemolytic anemia also developed; the DAT became positive for IgG, and warm autoantibodies were eluted from D- RBCs. CONCLUSION: An understanding of the causes and circumstances under which posttransplant immune hemolysis arises is required for proper management. As more patients become long-term survivors of unrelated bone marrow and/or PBPC transplants, chimerism and complex serologic problems will become more common.