POMP (Proteasome Maturation Protein)

The findings of this study highlight the importance of incorporating ordinal information in microbiome studies and provide robust statistical tools for advancing microbial biomarker discovery in complex disease contexts.

Many guidelines were of poor quality, providing few decision-making tools for practical use. Conversely, those of good quality had established a management strategy addressing the current problems associated with the emergence of antibiotic-resistant strains.

Little progress has been seen, where nelarabine is the only approved drug (overall response rate of 50%; associated hematologic/neurological toxicities)...Patient is currently 32 months post-transplant, continuing maintenance therapy, remains in CR.Patient 2: ETP-ALL (mutant NOTCH1/EZH2), received induction with hyperCVAD with persistent MRD (TCR-rearrangements), received re-induction with augmented-BFM/venetoclax, had undetectable TCR-rearrangements, received a haploidentical-HSCT (fludarabine/TBI-8Gy conditioning)...Last bone marrow evaluation showed CR but detectable TCR MRD, received two DLI doses complicated with liver GVHD responsive to systemic corticosteroids.Patient 4: Near-ETP ALL (normal karyotype-ASXL1/NOTCH1/TET2 mutations), received asparaginase-based treatment (GRAALL regimen), achieved CR with negative MRD, then completed two consolidation cycles, early-intensification followed by a matched-related allo-HSCT (clofarabine/TBI-8Gy conditioning)... Encouraging results presenting a foundation for further studies that could assess the efficacy of HMAs combined with BCL2 inhibitors not only in the post-transplant setting but also for high-risk T-ALL patients.

Odd cycles of mini-HCVD consisted of cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracyclines. Even cycles consisted of cytarabine (0.5 g/m2 given every 12 h on days 2 and 3) and methotrexate (250 mg/m2 on day 1). During the first 4 courses, pts received rituximab when CD20 expression was ≥20%, and intrathecal chemotherapy...Pts received maintenance therapy with POMP, consisting of 1 year of monthly prednisone 50 mg/d for 5 days and vincristine at 2 mg every month, along with 3 years of 6-mercaptopurine 50 mg twice daily and weekly oral methotrexate 10 mg/m2...These adjustments reduced the rate of VOD and improved survival. Long-term survival was similar regardless of subsequent ASCT.

Pts received 8 cycles of HCVAD (cycles 1,3, 5, 7) alternating with high dose ara-C and methotrexate (MTX) (cycles 2, 4, 6, 8) at approximately 3-week intervals. At a median follow-up of 50 months (1-174), 84 patients (66%) are alive with a 5-year PFS and OS of 60% and 61% (Figure 1) and 79 pts (62%) remain in CR.Conclusion : The addition of NEL/PEG cycles to the HCVAD regimen is feasible. The addition of VEN to each cycle is associated with significant myelosuppression.

Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) for up to 8 cycles...Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles...Despite the reduced intensity of this regimen, a substantial proportion of pts >70 years of age died in remission. Ongoing efforts are evaluated for INO and blinatumomab without chemotherapy for these pts.

Patients (pts) between the ages of 30 and 70 with newly diagnosed BCR::ABL1 negative B-lineage ALL were enrolled and initially received 2.5 months of combination induction chemo utilizing a BFM-like regimen adapted from the E2993/UKALLXII clinical trial with extended remission induction, addition of pegaspargase for patients <55 years of age and addition of rituximab for CD20 positive patients (figure 1)... The addition of blin to consolidation chemo resulted in a significantly better overall survival in pts with newly diagnosed B-lineage ALL who were MRD negative after intensification chemo. No significant safety concerns were noted. The addition of blin to consolidation chem in adult pts aged 30-70 years represents a new standard of care for BCR::ABL1 negative ALL pts.

Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2)...Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C and to 2 cycles of blinatumomab consolidation (4 total cycles with INO)... The addition of INO to hyper-CVAD with sequential blinatumomab is safe and highly effective as frontline treatment of Ph-negative B-cell ALL. This study shows the feasibility of incorporating both INO and blinatumomab into the frontline treatment of pts with B-cell ALL. Outcomes of the pts treated in the INO cohort are particularly promising.

Pts with Ph+ disease received dasatinib or imatinib (TKI), and rituximab was added for CD20+ disease at physician discretion. In our cohorts, more pts given DA-EPOCH had high risk features. DA-EPOCH and HyperCVAD yielded similar outcomes for Ph+ ALL while OS and EFS favored HyperCVAD for Ph- ALL. However, HyperCVAD caused significantly more life-threatening toxicity and reliance on transfusions.

After a prephase including 5 days (D) of dexamethasone (DEX) 10mg per D and intrathecal (IT) methotrexate (MTX), the induction regimen was delivered in 2 parts. Induction part I (Ind1) consisted of one triple IT, vincristine (VCR) 2 mg (1 mg over 70 years of age) D1 D8 D15 D22 and DEX 20 mg D1D2 D8D9 D15D16 D22D23 combined with 3 injections of INO (0.8 mg/m² D1, 0.5 mg/m² D8 and D15)...Ind2 consisted of DEX 20mg D1D8, cyclophosphamide (CY) 300 mg/m² D1 to D3, one triple IT D2 and 2 injections of INO (0.5 mg/m² D1 and D8). Patients in CR/CRp were programmed to receive 6 blocks of consolidation (Ara-C 1.5g/m²/12h adapted to renal clearance D1D2 and DEX 10mg/12h D1D2, cycles 1 and 4; MTX 1.5 g/m² over 24h D1, VCR 1 or 2 mg D1, one triple IT D2 and 6-mercaptopurin (6-MP) D1 to D7, cycles 2 and 5; CY 500 mg/m² D1D2, VP16 75 mg/m² D1D2, one triple IT D2 and MTX 25 mg/m² D1, cycles 3 and 6) followed by a POMP maintenance (VCR, 6-MP, MTX, DEX) during 18 months...Cancer 2019). An updated analysis will be provided at ASH meeting.