Background: IKZF1 encodes IKAROS, a transcription factor and key regulator of lymphocyte differentiation. IKZF1 deletions (D IKZF1 ) are commonly detected in B‐ALL and their prognostic relevance differs between reports. Aims: We aimed to determine impact of D IKZF1 on event free survival (EFS) of patients with precursor B‐ALL aged 23–65 years recruited to UKALL14 (ISRCTN 66541317) between December 2010 and July 2018 when the trial closed to recruitment. Methods: From 655 recruits with B‐ALL, all available diagnostic DNA samples were screened by PCR (n = 497), MLPA P335 SALSA kit (n = 437) or by both (n = 419). A multiplex endpoint PCR, designed to make detection rapid and straightforward covered 4 deletions‐ the dominant negative (DN) D4–7 or the loss of function (LOF) Δ2–7, Δ4‐8, and Δ2‐8, with primer sites located close to the putative breakpoints. All PCR‐detected deletions were confirmed by Sanger sequencing. Results: In the cohort screened for both PCR and MLPA, 88/419 were not congruous. Fifty‐eight of 88 (66%) of these were explicably positive by MLPA only, due to the placement of PCR primers. Fifteen of 88 (17%) were detected by PCR but not MLPA, likely explained by the greater sensitivity of PCR. These cases are being investigated for D IKZF1 in a sub/minor clone. In order to resolve the remaining 15 disparate cases, we are in the process of mapping the breakpoint sites. By PCR, as expected, D4–7 was the most commonly detected deletion (n = 61, 12.3%) followed by D2‐7 (n = 27, 5.4%), D4–8 (n = 20, 4%) with D2‐8 being the rarest (n = 6, 1.2%). Overall, there was no significant impact of PCR‐detected D IKZF1 on EFS (see figure). In a multivariable Cox model, D IKZF1 significantly interacted with both age and Philadelphia chromosome (Ph) status, with no detrimental effect seen in Ph+ cases and any negative impact confined to Ph‐ cases which increased with increasing age. The change in effect with increasing age for the four groups ( ΔIKZF1 /wild type IKZF1 and Ph‐/Ph+) is shown in the figure, wherein no adverse effect is seen for ΔIKZF1 compared to wild type IKZF1 for Ph+ patients at any age, but an increased risk for ΔIKZF1 in Ph‐ ALL as age increases can be seen. Consistent with the technical approach, MLPA detected a wider range of deletions than PCR:‐ D1‐2 (n = 9, 1.8%), D1‐3 (n = 3, 0.6%), D1‐7 (n = 5, 1%), D1‐8 (n = 36, 7.2%), D2‐3 (n = 4 0.8%,) D2‐7 (n = 32, 6.4%), D2‐8 (n = 15, 3%), D4‐7 (n = 49, 9.9%), D4‐8 (n = 19, 3.8%), D6‐8 (n = 1, 0.2%). As with PCR‐detected lesions, there was no impact of MLPA‐detected D IKZF1 on EFS in univariable analysis. In multivariable analysis, the differing effect with age was less evident and did not reach significance, though the same interaction with Ph status was observed. We did not detect any differential impacts by analysing PCR or MLPA‐detected DN or LOF deletions separately. Summary/Conclusion: Both PCR and MLPA have limitations for routine detection of D IKZF1 in clinical trials. However, in this final report on the prognostic relevance of DIKZF1 on the UKALL14 trial, D IKZF1 did not have a strong impact on EFS. image
PURPOSE The aim of the randomized trial, UKALL2003, was to adjust treatment intensity on the basis of minimal residual disease (MRD) stratification for children and young adults with acute lymphoblastic leukemia. We analyzed the 10-year randomized outcomes and the time for patients to be considered cured (ClinicalTrials.gov identifier: NCT00222612 ). METHODS A total of 3,113 patients were analyzed including 1,054 patients who underwent random assignment (521 MRD low-risk and 533 MRD high-risk patients). Time to cure was defined as the point at which the chance of relapse was < 1%. The median follow-up time was 10.98 (interquartile range, 9.19-13.02) years, and survival rates are quoted at 10 years. RESULTS In the low-risk group, the event-free survival was 91.7% (95% CI, 87.4 to 94.6) with one course of delayed intensification versus 93.7% (95% CI, 89.9 to 96.1) with two delayed intensifications (adjusted hazard ratio, 0.73; 95% CI, 0.38 to 1.40; P = .3). In the high-risk group, the event-free survival was 82.1% (95% CI, 76.9 to 86.2) with standard therapy versus 87.1% (95% CI, 82.4 to 90.6) with augmented therapy (adjusted hazard ratio, 0.68; 95% CI, 0.44 to 1.06; P = .09). Cytogenetic high-risk patients treated on augmented therapy had a lower relapse risk (22.1%; 95% CI, 15.1 to 31.6) versus standard therapy (52.4%; 95% CI, 28.9 to 80.1; P = .016). The initial risk of relapse differed significantly by sex, age, MRD, and genetics, but the risk of relapse for all subgroups quickly coalesced at around 6 years after diagnosis. CONCLUSION Long-term outcomes of the UKALL2003 trial confirm that low-risk patients can safely de-escalate therapy, while intensified therapy benefits patients with high-risk cytogenetics. Regardless of prognosis, the time to cure is similar across risk groups. This will facilitate communication to patients and families who pose the question “When am I/is my child cured?”
BackgroundAdverse 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.MethodsWe 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.FindingsBetween 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).InterpretationReduced 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.FundingMedical Research Foundation and Cancer Research UK.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
