Blood and Lymphatic Cancer-Targets and Therapy最新文献

The therapeutic landscape of multiple myeloma (MM) has benefited from an emergence of novel therapies over the last decade. By inducing T-cell kill of target cancer cells, chimeric antigen receptor (CAR) T-cell therapies have improved outcomes of patients with hematologic malignancies. B-cell maturation antigen (BCMA) is the current target antigen of choice for most CAR T-cell products under investigation for MM. However, their shortcomings deal with logistical and clinical challenges, including limited availability, manufacturing times, and toxicities. This article provides an overview of recently developed and investigational CAR T-cell therapies for MM, highlighting current evidence and challenges.

Waldenström's Macroglobulinemia (WM) is a clonal B-lymphocyte neoplasm characterized by the presence of IgM monoclonal protein and ≥10% bone marrow involvement with lymphoplasmacytic cells. Several mature B-cell and plasma cell disorders can potentially produce monoclonal IgM immunoglobulin and hence, careful consideration of the differential diagnosis is vital. Clinico-pathological features, immunophenotype, and MYD88 mutation status help distinguish WM from other plasma cell and lymphoproliferative disorders. Treatment is only indicated in patients symptomatic from adenopathy or organomegaly, neuropathy, hyper viscosity, cryoglobulinemia, cold agglutinin disease, cytopenia's or amyloidosis. Alkylators (cyclophosphamide, bendamustine) in combination with anti-CD20 antibodies and novel targeted agents including Bruton tyrosine kinase (BTK) inhibitors like ibrutinib are the mainstay of frontline treatment in symptomatic WM.

Richter transformation (RT) is defined as the transformation of chronic lymphocytic leukemia (CLL) to a high-grade B cell lymphoma. It usually carries a dismal prognosis and represents an unmet need for novel therapeutic interventions. We report a case of an 80-year-old male who developed double-hit (DH) RT with translocations of MYC and BCL6 after 5 years of watchful waiting for standard-risk CLL. He was treated with induction therapy consisting of 4 cycles of anthracycline-based chemoimmunotherapy (CIT) and 2 cycles of platinum-based CIT with intrathecal methotrexate for CNS prophylaxis followed by continuous maintenance therapy with ibrutinib. He achieved complete remission after the induction therapy. At the time of writing, four and a half years after the diagnosis with DH-RT, he remains in complete remission without evidence of RT or CLL. The novel therapeutic approach used in successful treatment of this patient should be further explored.

Advanced follicular lymphoma (FL) often relapses after front-line chemoimmunotherapy, and many patients will eventually require subsequent therapy. In 2021, two new therapies were granted approval by the Food and Drug Administration (FDA), including the PI3Kδ inhibitor umbralisib and the chimeric antigen receptor-T-cell therapy (CAR-T) axicabtagene ciloleucel. Herein, we present the latest advances in the management of FL, discussing the recently approved therapies in the relapsed and refractory (R/R) setting and various new therapeutic modalities that have the potential to change the treatment landscape and natural history of R/R FL.

The isocitrate dehydrogenase enzyme, catalyzing isocitrate conversion to α-ketoglutarate (αKG) in both the cell cytoplasm and mitochondria, contributes to the production of dihydronicotinamide-adenine dinucleotide phosphate (NADPH) as a reductive potential in various cellular processes. IDH1 gene mutations are revealed in up to 20% of the patients with acute myeloid leukemia (AML). A mutant IDH enzyme, existing in the cell cytoplasm and possessing neomorphic activity, converts αKG into oncometabolite R-2-hydroxyglutarate (R-2-HG) that accumulates in high amounts in the cell and inhibits αKG-dependent enzymes, including epigenetic regulators. The resultant alteration in gene expression and blockade of differentiation ultimately lead to leukemia development. Myeloid differentiation capacity can be restored by obstruction of the mutant enzyme, inducing substantial reduction in R-2-HG levels. Ivosidenib, a potent selective inhibitor of mutant IDH1, is a differentiating agent shown to be clinically effective in newly diagnosed AML (ND-AML) and relapsed/refractory (R/R) AML harboring this mutation. The drug is approved by the Food and Drug Administration (FDA) as a single-agent treatment for R/R AML. Significance of mutated IDH1 targeting and a potential role of ivosidenib in AML management, when used either as a single agent or as part of combination therapies, will be reviewed herein.

Acute lymphoblastic leukemia (ALL) is a heterogenous hematological malignancy representing 25% of all cancers in children less than 15 years of age. Significant improvements in survival and cure rates have been made over the past four decades in pediatric ALL treatment. Asparaginases, derived from Escherichia coli and Erwinia chrysanthemi, have become a critical component of ALL therapy since the 1960s. Asparaginases cause depletion of serum asparagine, leading to deprivation of this critical amino acid for protein synthesis, and hence limit survival of lymphoblasts. Pegaspargase, a conjugate of monomethoxypolyethylene glycol (mPEG) and L-asparaginase, has become an integral component of pediatric upfront and relapsed ALL protocols due to its longer half-life and improved immunogenicity profile compared to native asparaginase preparations. Over the past two decades great strides have been made in outcomes for pediatric ALL due to risk stratification, incorporation of multiagent chemotherapy protocols, and central nervous system prophylaxis with pegaspargase having played an important role in this success. However, adolescents and young adults (AYA) with ALL when treated on contemporaneous trials using adult ALL regimens, continue to have poor outcomes. There is increasing realization of adapting pediatric trial regimens for treating AYAs, especially those incorporating higher intensity of chemotherapeutic agents with pegaspargase being one such agent. Dose or treatment-limiting toxicity is observed in 25-30% of patients, most notable being hypersensitivity reactions. Other toxicities include asparaginase-associated pancreatitis, thrombosis, liver dysfunction, osteonecrosis, and dyslipidemia. Discontinuation or subtherapeutic levels of asparaginase are associated with inferior disease-free survival leading to higher risk of relapse, and in cases of relapse, a higher risk for remission failure. This article provides an overview of available evidence for use of pegaspargase in pediatric acute lymphoblastic leukemia.

Although much progress has been made in the treatment of multiple myeloma, the majority of patients fail to be cured and require numerous lines of therapy. Inhibitors of the BCL2 family represent an exciting new class of drugs with a novel mechanism of action that are likely to have activity as single agents and in combination with existing myeloma therapies. The BCL2 proteins are oncogenes that promote cell survival and are frequently upregulated in multiple myeloma, making them attractive targets. Venetoclax, a BCL2 specific inhibitor, is furthest along in development and has shown promising results in a subset of myeloma characterized by the t(11;14) translocation. Combining venetoclax with proteasome inhibitors and monoclonal antibodies has improved responses in a broader group of patients, but has come at the expense of a toxicity safety signal that requires additional follow-up. MCL1 inhibitors are likely to be effective in a broader range of patients and are currently in early clinical trials. This review will cover much of what is known about the biology of these drugs, biomarkers that predict response, mechanisms of resistance, and unanswered questions as they pertain to multiple myeloma.

Introduction: Obesity is a worldwide problem that is related to cardiac disease, thrombosis and cancer. However, little is known about the impact of obesity on the outcomes of adult acute lymphoblastic leukemia (ALL) patients.

Methods: We retrospectively evaluated a cohort of 154 newly diagnosed adult ALL patients between 1994 and 2011 at Mayo Clinic (Rochester). According to the World Health Organization (WHO) international BMI classification, patients were stratified as underweight, normal weight, overweight, and obese. For some analyses, patients were also stratified according to a two-sided non-obese or obese classification.

Results: The median follow-up time was 8.37 years. Obese patients were more likely to be women (p=0.024) and ≥60 years old (p=0.003). Five-year mortality rates were higher in obese patients than non-obese [HR 95% CI: 1.60 (1.03-2.50) p=0.035]. This was also the case in subgroup analysis among T-cell patients although the number of patients was small [HR 95% CI: 5.42 (1.84-15.98) p<0.001]. There was no difference in mortality among the B-cell patients. After adjusting for baseline variables, the difference in mortality remained in several models. There was no difference in EFS or cumulative incidence of relapse rates between obese and non-obese patients among the overall population.

Discussion: In conclusion, our study suggests that adult ALL patients with obesity have lower survival rates, especially in T-cell ALL.

Although adults with B-cell acute lymphoblastic leukemia (B-ALL) achieve high complete remission (CR) rates following treatment with intensive multi-agent chemotherapy regimens, up to two-thirds of these patients eventually relapse. Unfortunately, adults with relapsed or refractory (R/R) B-ALL have a poor prognosis, with variable responses to salvage chemotherapy regimens and allogeneic stem cell transplant. As such, the need to develop effective and well-tolerated treatments for this patient population has been of paramount importance over the past decade. In this regard, treatment options for R/R B-ALL patients have expanded considerably over a relatively short period of time, with the approvals of blinatumomab, inotuzumab ozogamicin and tisagenlecleucel occurring within only the past six years. Blinatumomab, a CD19 x CD3 bispecific T-cell engager (BiTE) was the first of these immune therapies to receive approval, and for many patients, is used as first-line salvage therapy. A number of large clinical trials have demonstrated improved progression-free survival and overall survival for R/R B-ALL patients receiving blinatumomab as compared to those receiving conventional salvage chemotherapy. In addition to being approved for both Philadelphia chromosome-negative and Philadelphia chromosome-positive R/R B-ALL, blinatumomab is also the only ALL therapy that carries approval for the treatment of measurable residual disease (MRD). Although blinatumomab has changed the therapeutic landscape for adults with R/R B-ALL, a number of important clinical considerations and questions remain, including the potential role of blinatumomab in the frontline setting, mechanisms of resistance, optimal goal MRD level, the role of transplant following MRD clearance, the optimal place for blinatumomab in the context of other recently approved immune-mediated therapies, and real world outcomes for patients treated outside the context of clinical trials. These issues are the focus of ongoing studies, which will hopefully inform future clinical practice regarding the utility of blinatumomab in the treatment of B-ALL patients.

Introduction: Recent randomized trials have demonstrated the efficacy of ibrutinib-based therapy in the treatment of patients with CLL. In Alliance A041202, a higher than expected number of unexplained deaths were reported with front-line ibrutinib in a patient population aged at least 65 years compared to ECOG 1912, which included patients up to 70 years of age.

Methods: Therefore, we conducted a retrospective analysis to investigate whether ibrutinib was associated with a greater mortality in older patients outside of a clinical trial setting. This multicenter analysis was performed by investigators at 20 academic and community practices.

Results: Amongst the 391 patients included, there was no correlation between age and response rate, PFS, or OS. However, there was a trend to higher rate of deaths in patients >65-years-old (8.7% vs 3.8%, p=0.097), with an increased number of early deaths (13 vs 4, p=0.3).

Conclusion: These data suggest greater intolerance, and possibly mortality, with ibrutinib in an older population. Patients should be educated regarding the potential complications related to ibrutinib and symptoms of concern to report.