Dose-Adjusted EPOCH Plus Inotuzumab Ozogamicin in Adults With Relapsed or Refractory B-Cell ALL: A Phase 1 Dose-Escalation Trial.

Importance: Options for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (B-ALL) are limited, and new approaches are needed. Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL. Objective: To assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL. Design, Setting, and Participants: This single-center, single-arm, nonrandomized, phase 1 dose-escalation trial included adults with relapsed or refractory CD22+ B-ALL and was conducted between September 2019 and November 2022. At least 5% blood or marrow blasts or measurable extramedullary disease (EMD) was required for enrollment. Interventions: DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design. Main Outcomes and Measures: The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%. Secondary objectives included response rates, survival estimates, and descriptions of toxic effects. Results: A total of 24 participants were screened and enrolled (median age, 46 [range, 28-76] years; 15 [62%] male). The median number of lines of prior therapy was 3 (range, 1-12). Three of 11 participants (27%) treated at the highest dose level (InO, 0.6 mg/m2, on day 8 and day 15) experienced dose-limiting toxicity, making this the maximum tolerated dose. No deaths occurred during the study, and only 1 patient (4%; 95% CI, 0.1%-21%) developed sinusoidal obstructive syndrome after poststudy allograft. The morphologic complete response rate was 84% (95% CI, 60%-97%), 88% (95% CI, 62%-98%) of which was measurable residual disease negative by flow cytometry. Five of 6 participants with EMD experienced treatment response. The overall response rate was 83% (95% CI, 63%-95%). Median overall survival, duration of response, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively. Conclusions: In this study, adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. Many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. Further investigation of this combination is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03991884.

Intensive Reinduction Chemotherapy Followed by Early Allogeneic Hematopoietic Cell Transplantation for Relapsed/Refractory High-Grade Myeloid Neoplasms.

Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplantation (HCT) the sole therapy likely to result in cure. We conducted the present study to determine the feasibility of early HCT-within 60 days of beginning reinduction chemotherapy-to see whether getting patients to HCT in an expeditious manner would expand the number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults age 18 to 75 years with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis who were eligible for a reduced-intensity HCT. Subjects received reinduction chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/ melphalan). We enrolled 30 subjects, all of whom received CLAG-M reinduction, although only 9 underwent HCT within 60 days (<15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range, 42 to 60 days). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplantation of 83 days (range, 53 to 367 days). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit the real-world uptake of such early-to-transplantation protocols.

How I prevent and treat central nervous system disease in adults with acute lymphoblastic leukemia.

The central nervous system (CNS) is the most important site of extramedullary disease in adults with acute lymphoblastic leukemia (ALL). Although CNS disease is identified only in a minority of patients at the time of diagnosis, subsequent CNS relapses (either isolated or concurrent with other sites) occur in some patients even after the delivery of prophylactic therapy targeted to the CNS. Historically, prophylaxis against CNS disease has included intrathecal (IT) chemotherapy and radiotherapy (RT), although the latter is being used with decreasing frequency. Treatment of a CNS relapse usually involves intensive systemic therapy and cranial or craniospinal RT along with IT therapy and consideration of allogeneic hematopoietic cell transplant. However, short- and long-term toxicities can make these interventions prohibitively risky, particularly for older adults. As new antibody-based immunotherapy agents have been approved for relapsed/refractory B-cell ALL, their use specifically for patients with CNS disease is an area of keen interest not only because of the potential for efficacy but also concerns of unique toxicity to the CNS. In this review, we discuss data-driven approaches for these common and challenging clinical scenarios as well as highlight how recent findings potentially support the use of novel immunotherapeutic strategies for CNS disease.

New drug approvals in acute myeloid leukemia: an unprecedented paradigm shift.

We are witnessing an unprecedented paradigm shift in the treatment of acute myeloid leukemia (AML). For nearly 4 decades-since the introduction of cytarabine- and anthracycline-based induction chemotherapy in the 1970s-treatment options for patients with AML have remained limited, and outcomes remain poor for the majority of patients, particularly the elderly. Over the past 10 to 15 years, we have better elucidated the genetic and molecular basis of AML, which has led to our current understanding of disease heterogeneity. We now appreciate that numerous distinct disease subtypes exist, each with their own disease characteristics and risk profile. In keeping with this improved understanding, we have seen the introduction of numerous new agents that are mechanistically targeted against a specific mutation, a deranged cellular pathway, and/or a specific AML disease subset. Within the last 3 years alone, the US Food and Drug Administration has approved 8 new targeted agents for the treatment of AML. With their introduction comes a new sense of optimism, along with questions about how to best use these agents. In this article, we discuss the recently approved agents in AML, the rationale behind their development and the trials that served as the basis for their approval, and the implications of their introduction into the treatment armamentarium.

Getting to the Heart of the Matter: A 20-Year-Old Man With Fever, Rash, and Chest Pain.

Infection with Helicobacter cinaedi can encompass a wide spectrum of clinical manifestations, including fever, rash, endocarditis, osteomyelitis, and meningitis. The present case demonstrates the ability of H cinaedi to masquerade as acute rheumatic fever and represents the first reported case of cardiac tamponade caused by H cinaedi.

H/ACA small RNA dysfunctions in disease reveal key roles for noncoding RNA modifications in hematopoietic stem cell differentiation.

Noncoding RNAs control critical cellular processes, although their contribution to disease remains largely unexplored. Dyskerin associates with hundreds of H/ACA small RNAs to generate a multitude of functionally distinct ribonucleoproteins (RNPs). The DKC1 gene, encoding dyskerin, is mutated in the multisystem disorder X-linked dyskeratosis congenita (X-DC). A central question is whether DKC1 mutations affect the stability of H/ACA RNPs, including those modifying ribosomal RNA (rRNA). We carried out comprehensive profiling of dyskerin-associated H/ACA RNPs, revealing remarkable heterogeneity in the expression and function of subsets of H/ACA small RNAs in X-DC patient cells. Using a mass spectrometry approach, we uncovered single-nucleotide perturbations in dyskerin-guided rRNA modifications, providing functional readouts of small RNA dysfunction in X-DC. In addition, we identified that, strikingly, the catalytic activity of dyskerin is required for accurate hematopoietic stem cell differentiation. Altogether, these findings reveal that small noncoding RNA dysfunctions may contribute to the pleiotropic manifestation of human disease.

rRNA pseudouridylation defects affect ribosomal ligand binding and translational fidelity from yeast to human cells.

How pseudouridylation (Ψ), the most common and evolutionarily conserved modification of rRNA, regulates ribosome activity is poorly understood. Medically, Ψ is important because the rRNA Ψ synthase, DKC1, is mutated in X-linked dyskeratosis congenita (X-DC) and Hoyeraal-Hreidarsson (HH) syndrome. Here, we characterize ribosomes isolated from a yeast strain in which Cbf5p, the yeast homolog of DKC1, is catalytically impaired through a D95A mutation (cbf5-D95A). Ribosomes from cbf5-D95A cells display decreased affinities for tRNA binding to the A and P sites as well as the cricket paralysis virus internal ribosome entry site (IRES), which interacts with both the P and the E sites of the ribosome. This biochemical impairment in ribosome activity manifests as decreased translational fidelity and IRES-dependent translational initiation, which are also evident in mouse and human cells deficient for DKC1 activity. These findings uncover specific roles for Ψ modification in ribosome-ligand interactions that are conserved in yeast, mouse, and humans.

Deregulation of oncogene-induced senescence and p53 translational control in X-linked dyskeratosis congenita.

Defects in ribosome biogenesis and function are present in a growing list of human syndromes associated with cancer susceptibility. One example is X-linked dyskeratosis congenita (X-DC) in which the DKC1 gene, encoding for an enzyme that modifies ribosomal RNA, is found to be mutated. How ribosome dysfunction leads to cancer remains poorly understood. A critical cellular response that counteracts cellular transformation is oncogene-induced senescence (OIS). Here, we show that during OIS, a switch between cap- and internal ribosome entry site (IRES)-dependent translation occurs. During this switch, an IRES element positioned in the 5'untranslated region of p53 is engaged and facilitates p53 translation. We further show that in DKC1(m) cells, p53 IRES-dependent translation is impaired during OIS ex vivo and on DNA damage in vivo. This defect in p53 translation perturbs the cellular response that counteracts oncogenic insult. We extend these findings to X-DC human patient cells in which similar impairments in p53 IRES-dependent translation are observed. Importantly, re-introduction of wild-type DKC1 restores p53 expression in these cells. These results provide insight into the basis for cancer susceptibility in human syndromes associated with ribosome dysfunction.