Rhabdoid tumour predisposition syndrome (RTPS) is a rare syndrome caused by inheritance of a mutated INI1 gene for which only two multigeneration families have been reported. To further characterise the genotype and phenotype of RTPS, we present a third family in which at least three cousins developed an atypical teratoid/rhabdoid tumour (AT/RT) at a young age. Two of these patients showed unusual long survival, and one of these developed an intracranial meningioma and a myoepithelioma of the lip in adulthood. Mutation analysis of INI1 revealed a germline G4A mutation in the donor splice site of exon 4 (c.500 þ 1G4A) in the patients and in their unaffected fathers. This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsensemediated mRNA decay. Biallelic inactivation of INI1 in the tumours, except for the meningioma, was confirmed by absence of nuclear INI1-protein staining. The myoepithelioma of one of the patients carried an identical somatic rearrangement in the NF2 gene as the AT/RT, indicating that both tumours originated from a common precursor cell. In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma.
This Phase I study investigated the recommended Phase II dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple-relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL). Patients (≥1-<18 years) received three InO doses (Days 1, 8, 15) per course. Dose-escalation was based on dose-limiting toxicities (DLT) during Course 1 . Dose level 1 (DL1)=1.4 mg/m2 (0.6-0.4-0.4 mg/m2); DL2=1.8 mg/m2 (0.8-0.5-0.5 mg/m2). Secondary endpoints included safety, anti-leukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLT) were enrolled. In Course 1, first cohort, 1/6 (DL1) and 2/5 (DL2) patients experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, where 0/6 (DL1) and 1/6 (DL2) patients had a DLT. Twenty-three patients experienced Grade 3-4 adverse events; hepatic sinusoidal obstruction syndrome was reported in two patients after subsequent chemotherapy. Overall response rate after Course 1 was 80% [95% CI: 59-93%] (20/25 patients; DL1=75% [43-95%], DL2=85% [55-98%]); 84% [60-97%] of responders obtained minimal residual disease-negative CR; 12-month overall survival was 40% [95% CI: 25-66%]. Nine patients received hematopoietic stem cell transplant or chimeric-antigen receptor T-cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating anti-leukemic activity in heavily pre-treated children with CD22-positive R/R ALL. RP2D was established as 1.8 mg/m2/course, as in adults.
Ependymomas frequently display allelic loss of chromosome 22 in the absence of mutations in the known tumor-suppressor genes on chromosome 22, suggesting the role of an alternative predisposing gene or genes from this chromosome. In an effort to localize these genes, 37 ependymomas derived from 33 patients were analyzed for the presence of copy number changes by use of a high-resolution chromosome 22 genomic microarray. Eighteen ependymomas (49%) displayed an array-CGH profile consistent with monosomy of chromosome 22. However, in 10 of these tumors, the fluorescence ratios for 22q clones scored as deleted were different from those at the single gene copy level. This suggests either analysis of mixed populations of tumor and normal stromal cells or analysis of mixed tumor cell populations with different genetic profiles. Four ependymomas derived from two patients showed overlapping interstitial deletions of 2.2 Mb and approximately 510 kb. Further analyses revealed that these deletions were present in the constitutional DNA of these two patients as well as in some of their unaffected relatives. Detailed microsatellite analysis of these families refined the commonly deleted segment to a region of 320 kb between markers RH13801 and D22S419. Our results provide additional evidence for the involvement of genes on chromosome 22 in the development of ependymoma and suggest the presence of a low-penetrance ependymoma susceptibility locus at 22q11.
Objective We report on a patient who developed a meningioma more than two decades after removal at a young age of an atypical teratoid/rhabdoid tumour (AT/RT), which was due to a germline INI1 mutation, and radio-and chemotherapy. Materials and methods We present genetic evidence that the meningioma is not a recurrence or metastasis of the AT/ RT and not due to the INI1 mutation, but is a radiationinduced tumour. Conclusion This is the first case illustrating that improved survival of young patients with an AT/RT after aggressive treatment may be gained at the cost of an increased risk for the development of radiation-induced, non-INI1-related tumours.
Background: Inotuzumab ozogamicin (InO) was well tolerated and demonstrated anti-leukemia activity in heavily pre-treated pediatric patients (pts) with CD22-positive relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) in the Phase (Ph) I ITCC-059 study. With the established recommended phase 2 dose (RP2D) (1.8 mg/m2/course, as in adults) a consecutive Ph II study has been performed, sponsored by Erasmus MC and supported by Pfizer (NTR57360). Study design: Pts aged 1-18 years with R/R CD22+ BCP-ALL were included after informed consent was obtained. Key inclusion criteria included, M2/M3 marrow and adequate liver and kidney function. Overall response rate (ORR) was the primary endpoint, and included CR, CRp (ANC >500/µL but PLT ≤50.000/µL) and CRi (ANC ≤500/µL and/or PLT ≤50,000/µL). Secondary endpoints included safety, minimal residual disease (MRD) levels and durability of response. The study consisted of a single-stage design to test the null hypothesis (H0) ORR ≤30% and the alternative hypothesis of ORR >55%. With 25 pts, the study had 80% power to reject H0 at a significance level of 0.05. Central MRD analysis by flow cytometry was considered negative if <0.01%. Survival analysis used the Kaplan-Meier method. Results are based on a database snapshot on June 30, 2020. Results: 32 pts were enrolled (Jun 2019-Apr 2020), including 2 screen failures and 2 pts who did not start treatment due to rapidly progressive disease. The median age of the 28 treated pts was 7.5 years (range 1-17); 19 pts were male (68%); 6 (21.5%) were primary refractory, 16 (57%) had ≥2nd relapse and 6 (21.5%) had 1st relapse post-HSCT (median 2 prior regimens, range 2-7). 50% of the pts had received a previous HSCT, 3 (11%) CAR T-cell therapy and 7 (25%) blinatumomab. Median baseline WBC was 3.1 x109/L (range 0.7-132). At time of data snapshot, 48 courses of InO were administered (range 1-4 per pt); one pt was still receiving InO. Disease response was not assessed in 1 pt (discontinued early due to sinusoidal obstruction syndrome (SOS)), 27 pts were evaluable for efficacy analyses. Twenty-two pts achieved a response (ORR 81.5%; 95% CI 61.9%, 93.7%), all after the first cycle (CR n=14, CRp n=1, CRi n=7). Hence, the primary objective was achieved (P-value<0.0001). Overall 21/22 (95%) achieved MRD-negativity as best response (of whom 82% after course 1). When combining these results with pts treated at the RP2D in the Ph I study (n=13), 33/40 (82.5%) achieved a response (94% of whom achieved MRD-negativity). Of 9 primary refractory patients included in Ph I and II, 3 (33%) did not respond to InO. The median follow-up time was 7.3 months (mo). The EFS at 6 and 12 mo was 57.9% (95% CI: 40.3−83.3) and 24.8% (95% CI: 9.8−62.9); and OS at 6 and 12 mo was 61.6% (95% CI: 43.3−87.8) and 54.8% (95% CI: 35.9−83.6), respectively. The median EFS was reached at 6.34 mo (95% CI 2.53, NA). The cumulative incidence of non-response or relapse was 32% and 57% at 6 and 12 mo; 3 pts died in CR (2 due to HSCT complications, 1 due to neurological deterioration considered related to previous CNS leukemia and prolonged intrathecal treatment). Nine of 22 responding pts underwent HSCT (median 35 days after the last InO dose, range 20-72); 4 are still in CR. Three responders received consolidation with CAR T (52, 55 and 215 days after last Ino dose), all are still in CR. Four cases of VOD/SOS were reported. One case occurred during InO treatment (gr 3, resolved). Three of 9 transplanted pts (33%) developed post-HSCT SOS. None of these pts received prophylactic defibrotide. One pt, previously transplanted and treated with CAR T, received 1 course of InO prior to a second HSCT and developed SOS (gr 3), ongoing at the time of death due to multiorgan failure. The other 2 pts developed gr 2 SOS after 2 and 3 courses of InO before their first HSCT, both events resolved. All pts had at least 1 adverse event (AE) during the study and 19 pts reported at least 1 of gr 3-4 AE. The most common AE was fever. Detailed data will be presented at the meeting. Conclusion: InO was well tolerated in this Ph II study which confirmed remarkable activity in these heavily pretreated pts. The ORR was 81.5% with 95% MRD-negativity; 55% of pts remained alive after 1 year. Twelve pts proceeded to consolidation treatment (either HSCT or CAR T). In contrast with the Ph I cohort (where no pts developed SOS post 7 HSCTs), 3 cases of SOS were recorded here after 9 HSCTs. A Ph I cohort of this study combining InO with chemotherapy in R/R pediatric ALL is ongoing. Disclosures Brivio: Pfizer Inc.: Other: Erasmus MC received institutional funding for the study from Pfizer. Rossig:BMS: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Sleight:Pfizer Inc.: Current Employment. Reinhardt:Novartis: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees. von Stackelberg:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau. Zwaan:Servier, Sanofi, Daiichi Sankyo, Novartis, Janssen, Roche, Incyte, Pfizer, Celgene: Consultancy; Pfizer, Celgene, BMS: Research Funding; Jazz Pharmaceuticals: Other: Travel funding.
Background: Inotuzumab ozogamicin (InO) is an anti-CD22 antibody linked to calicheamicin, approved for relapsed/refractory (R/R) CD22+ B-cell precursor adult acute lymphoblastic leukemia (BCP-ALL) at starting dose of 1.8 mg/m2/course. A phase I study in pediatric patients (pts) is being performed and sponsored by Erasmus MC in collaboration with Pfizer, registered in the Dutch Trial Registry (NTR57360). Study design: Children aged 1-18 years with R/R CD22+ BCP-ALL (ALL) were included after IRB approval and informed consent was obtained. Key inclusion criteria consisted of M2/M3 marrow and adequate liver and kidney function. The study aimed to determine the recommended phase 2 dose (RP2D) of single agent InO; secondary objectives included safety, response and pharmacokinetics (PK). Dose escalation followed the Rolling-6 design, with dose-limiting toxicity (DLT) evaluation during course 1 and defined as delay in hematological (hem) recovery after D42 in responding pts and grade (gr) ≥3 non-hem toxicities >48 hours (or >7 days for liver tests). DL1 was 1.4 mg/m2 (0.6-0.4-0.4 mg/m2). Overall response rate (ORR) was defined as CR, CRp (ANC >0.5x10.9/l but PLT ≤50x10.9/l) and CRi (ANC ≤0.5x10.9/l and/or PLT ≤50,000/µL). Central minimal residual disease (MRD) analysis by flow cytometry and RQ-PCR was considered negative if <0.01% or <1x10-4. PK samples were measured with validated HPLC/MS/MS methods. In the first cohort, 2 patients at DL2 experienced a DLT per protocol definition, however these toxicities were considered non-dose limiting; both pts achieved CR. An IRB-approved amendment allowed repeating the DL1 and DL2 DLT assessment in a 2nd cohort. Survival analysis used the Kaplan-Meier method. Results are based on a database snapshot on June 22, 2019. Results: 25 pts were enrolled (Jan 2017-Apr 2019), median age 11 years (range 1.7-16.9); 3 (12%) were refractory, 15 (60%) ≥2nd relapsed ALL and 7 (28%) 1st relapse post-HSCT (median 2 prior treatment regimens, range 2-7). Eleven (44%) pts were previously transplanted; median baseline WBC 3.5 x109/L (range 0.2-8.6). In total, 46 courses of InO were administered (median 2/pt, range, 1-4). 23 of 25 treated pts were DLT-evaluable. In the first cohort, 1/6 and 2/5 pts at DL1 and DL2 experienced a DLT per protocol definition (transaminases elevation and no hem. recovery), but considered non-dose limiting. After the IRB-approved amendment, in the 2nd cohort, 0/6 and 1/6 pts in DL1 and DL2 had a DLT (no hem recovery). All 25 pts had at least 1 adverse event (AE) in Course 1 [24 gr 3-4]: 20 pts experienced ≥1 gr 3-4 hem AE, 15 pts a gr 3-4 non-hem AE (13 treatment-related, mainly febrile neutropenia/infections and lab abnormalities). Gr 3-4 transaminases elevation related to InO was seen in 3 pts (12%) and bilirubin in 2 (8%) in Course 1. 2 cases of VODs (gr 3-4) were reported after InO, both after follow-up chemotherapy (including HD-MTX) for R/R disease. None of these pts received any HSCT. After Course 1, 75% of pts responded at DL1 and 85% at DL2; ORR 80% (CR n=15, CRp n=1, CRi n=4). MRD was available in 19/20 responding pts: 15 (79%) reached MRD-negative CR as best response (6/9 at DL1 and 9/10 at DL2). Consolidation treatment with HSCT (n=6) or CAR-T cells (n=2) was given a median time of 61 days (range 23-125) after the last InO dose. None of these pts had been previously transplanted. The median follow-up for responding pts was 13.3 months (mos), median duration of response 8 mos (range 1.1-14.0). EFS was 66.7% (95% CI 47.9-93.0) and 33.4% (95% CI: 16.5 − 67.4), while the OS 63.3% (95% CI: 45.8−87.6) and 38.7% (95% CI: 21.3 - 70.4) at 6 and 12 mos, respectively. During follow-up, at relapse 13 pts had material available and sufficient ALL cells for reliable CD22 analysis: 2/13 showed CD22-negativity. After multiple doses, observed Ino medium maximum concentrations in DL1 (n=9) and DL2 (n=5) were 217 and 246 ng.hr/mL, comparable to the simulated adult concentration 234 ng.hr/mL at 1.8 mg/m2 dose. Conclusions: InO was well tolerated and showed remarkable activity in these heavily pretreated pts. The RP2D was established at 1.8 mg/m2/course (0.8-0.5-0.5 mg/m2), confirming the dose used in adults. Two cases of VOD were recorded after follow-up chemotherapy. The ORR was 80%; 79% of responding pts had MRD-negative CR, with 40% of pts being alive after 1 year of follow-up. A phase II single agent study in R/R pediatric ALL is ongoing and a Phase 1 of InO in combination with chemotherapy will start soon. Disclosures Díaz de Heredia: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rossig:Amgen, Celgene,EUSA Pharma, Genetech, Novartis, Roche: Other: advisory board; BMS, Pfizer, Roche: Other: speaker honoraria. van der Velden:Amgen: Honoraria, Research Funding; Jansen: Research Funding; BD Biosciences: Research Funding. van der Sluis:medac: Consultancy; jazz farmaceuticals: Consultancy. Chen:Pfizer Inc.: Employment. Sleight:Pfizer: Employment, Equity Ownership. Nysom:Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Teaching and lectures. Øra:Bayer: Membership on an entity's Board of Directors or advisory committees. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zwaan:Novartis: Consultancy; Janssen: Consultancy; Jazz pharmaceuticals: Other: Travel support; Daiichi Sankyo: Consultancy; Servier: Consultancy; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Roche: Consultancy; Incyte: Consultancy.
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