Introduction
Traditional chemotherapy dosing is based on body surface area (BSA) using standard formulas, which can pose challenges in dosing patients at body weight extremes. Studies suggest that ...chemotherapy dosing according to actual body weight does not increase toxicity in obese patients and current guidelines recommend full weight-based dosing of chemotherapy regardless of body mass index (BMI). However, the dosing of anthracyclines in obese patients can be challenging given limitations in maximum cumulative dosage, particularly in those at very extreme BMI. In this case, we highlight the difficulties of dosing anthracycline-based induction chemotherapy in a patient with newly diagnosed acute myeloid leukemia (AML) and BMI >90 kg/m2.
Case report
A 40-year-old female with morbid obesity is diagnosed with AML (nucleophosmin 1 (NPMI) and isocitrate dehydrogenase-2 mutated, FMS-like tyrosine kinase 3-Internal tandem duplication negative).
Management and Outcome
The patient was initiated on induction therapy with 7 + 3 with dose capping of BSA at 2.75 m2 (cytarabine 200 mg/m2 continuous infusion over 24 h for 7 days, plus daunorubicin 60 mg/m2 slow intravenous push for 3 days), followed by two cycles of high-dose cytarabine consolidation therapy using actual BSA. The patient achieved morphologic complete remission; however, measurable residual disease testing for NPM1 remained positive after induction therapy.
Discussion
This case suggests that dose capping of anthracyclines in the treatment of newly diagnosed AML may be an effective and safe treatment alternative in those with extreme BMI elevations beyond what has been studied in the literature. Given the increasing incidence of morbid obesity, further studies are needed to confirm appropriate dosing of anthracycline-based regimens at upper BMI extremes (>60 kg/m2).
Options for treatment of incurable cancer remain scarce and are largely focused on limited therapeutic mechanisms. A new approach specific to advanced cancers is needed to identify new and effective ...treatments. Morbidity in advanced cancer is driven by functional decline and a number of systemic conditions, including cachexia and fatigue. This review will focus on these clinical concepts, describe our current understanding of their underlying biology, and then propose how future therapeutic strategies, including pharmaceuticals, exercise, and rehabilitation, could target these mechanisms as an alternative route to addressing incurable cancer.
Related donor haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplantation cyclophosphamide (PT-Cy) is increasingly used in patients lacking HLA-matched sibling donors ...(MSD). We compared outcomes after Haplo-HCT using PT-Cy with MSD-HCT in patients with lymphoma, using the Center for International Blood and Marrow Transplant Research registry.
We evaluated 987 adult patients undergoing either Haplo-HCT (n = 180) or MSD-HCT (n = 807) following reduced-intensity conditioning regimens. The haploidentical group received graft-versus-host disease (GVHD) prophylaxis with PT-Cy with or without a calcineurin inhibitor and mycophenolate. The MSD group received calcineurin inhibitor-based GVHD prophylaxis.
Median follow-up of survivors was 3 years. The 28-day neutrophil recovery was similar in the two groups (95% v 97%; P = .31). The 28-day platelet recovery was delayed in the haploidentical group compared with the MSD group (63% v 91%; P = .001). Cumulative incidence of grade II to IV acute GVHD at day 100 was similar between the two groups (27% v 25%; P = .84). Cumulative incidence of chronic GVHD at 1 year was significantly lower after Haplo-HCT (12% v 45%; P < .001), and this benefit was confirmed on multivariate analysis (relative risk, 0.21; 95% CI, 0.14 to 0.31; P < .001). For Haplo-HCT v MSD-HCT, 3-year rates of nonrelapse mortality (15% v 13%; P = .41), relapse/progression (37% v 40%; P = .51), progression-free survival (48% v 48%; P = .96), and overall survival (61% v 62%; P = .82) were similar. Multivariate analysis showed no significant difference between Haplo-HCT and MSD-HCT in terms of nonrelapse mortality (P = .06), progression/relapse (P = .10), progression-free survival (P = .83), and overall survival (P = .34).
Haplo-HCT with PT-Cy provides survival outcomes comparable to MSD-HCT, with a significantly lower risk of chronic GVHD.
Mantle cell lymphoma (MCL) is a rare mature B-cell non-Hodgkin lymphoma (B-NHL) with historically poor outcomes. Virtually all patients will eventually experience refractory or relapsed (R/R) ...disease, with a virulent course of resistance and serial relapses, making treatment challenging. The available therapies for R/R MCL are not curative with conventional therapy, their goal being to palliate and prolong survival. A variety of agents approved for R/R MCL, including Bruton's tyrosine kinase inhibitors (BTKi), changed the treatment landscape of R/R MCL. In the pre-BTKi era, the median progression-free survival (PFS) in R/R disease was 4-9 months. With the introduction of ibrutinib, the median PFS improved to 13-14.6 months. Despite these impressive results, the duration of response is limited, and resistance to BTKi inevitably develops in a subset of patients. Outcomes after progression on BTKi are extremely poor, with a median overall survival (OS) of 6 to 10 months. Certain therapies, such as chimeric antigen receptor (CAR) T cells, have shown promising results after BTKi failure. The preferred combination and sequencing of therapies beyond BTKi remain unestablished and are currently being investigated. In this review, we describe the current evidence for the available treatment of R/R MCL after progression on BTKi.
Patients with double-hit lymphoma (DHL), which is characterized by rearrangements of MYC and either BCL2 or BCL6, face poor prognoses. We conducted a retrospective multicenter study of the impact of ...baseline clinical factors, induction therapy, and stem cell transplant (SCT) on the outcomes of 311 patients with previously untreated DHL. At median follow-up of 23 months, the median progression-free survival (PFS) and overall survival (OS) rates among all patients were 10.9 and 21.9 months, respectively. Forty percent of patients remain disease-free and 49% remain alive at 2 years. Intensive induction was associated with improved PFS, but not OS, and SCT was not associated with improved OS among patients achieving first complete remission (P = .14). By multivariate analysis, advanced stage, central nervous system involvement, leukocytosis, and LDH >3 times the upper limit of normal were associated with higher risk of death. Correcting for these, intensive induction was associated with improved OS. We developed a novel risk score for DHL, which divides patients into high-, intermediate-, and low-risk groups. In conclusion, a subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed.
•A subset of DHL patients may be cured, and some patients may benefit from intensive induction.•Further investigations into the roles of SCT and novel agents are needed.
Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma with historically poor long-term survival compared with other B-cell malignancies. Treatment strategies for this disease are variable and ...dependent on symptoms and patient fitness. Despite recent advances, MCL remains incurable and patients with high-risk disease have particularly poor outcomes. This review focuses on recent developments that enhance our understanding of the biology of MCL and new treatment approaches that have led to substantial improvements in clinical outcomes. We will outline induction immuno-chemotherapy and maintenance strategies in transplant-eligible patients. In addition, effective strategies for patients unfit for intensive induction will be discussed, with a particular focus on novel molecular therapies with activity in MCL. Lastly, a number of ongoing clinical trials will be presented; the data from these trials are anticipated to redefine standards of care in the near future.
We investigated a recent (January 1999 to December 2009) cohort of 95 elderly Hodgkin lymphoma subjects. At diagnosis, median age was 67 years (range, 60-89 years), whereas 61% had significant ...comorbidity, 26% were unfit, 17% had a geriatric syndrome, and 13% had loss of activities of daily living. Overall response rate to therapy was 85%, whereas incidence of bleomycin lung toxicity was 32% (with associated mortality rate, 25%). With 66-month median follow-up, 2-year and 5-year overall survival were 73% and 58%, respectively (advanced-stage, 63% and 46%, respectively). Most International Prognostic Score factors were not prognostic on univariate analyses, whereas Cox multivariate regression identified 2 risk factors associated with inferior overall survival: (1) age more than 70 years (2.24; 95% CI, 1.16-4.33, P = .02) and (2) loss of activities of daily living (2.71; 95% CI, 1.07-6.84, P = .04). Furthermore, a novel survival model based on number of these risk factors (0, 1, or 2) showed differential 2-year OS of 83%, 70%, and 13%, respectively (P < .0001) and 5-year OS of 73%, 51%, and 0%, respectively (P < .0001).
Opinion Statement
It has become clear that there is immense biological heterogeneity in diffuse large B cell lymphoma (DLBCL). Developing technology has allowed better characterization of patient ...subsets at a molecular level, allowing for a link of phenotype and clinical outcomes to oncogenic mechanisms and biologic signatures. Cell of origin and double hit status are able to identify aggressive subsets, with molecular profiling allowing for a clearer understanding of biologic pathways that contribute to cellular resistance to conventional treatment in these subsets. Although the standard treatment for DLBCL remains R-CHOP or R-CHOP-like therapy at present, rational drug targets have been established with novel classes of drugs under investigation. In germinal center (GC) DLBCL, mechanisms of therapeutic interest include anti-apoptosis mediated by BCL-2, PI3K/AKT/mTOR, and EZH2, whereas drug interventions are directed at BCR, NF-κB, and/or JAK-STAT pathways in activated B cell (ABC) DLBCL. There is also evidence for cooperation of various oncogenic pathways in these subsets. As such, we are arguably on the verge of shifting to a more tailored approach using single and combinatorial strategies—this, however, relies on prioritizing the exploration of biomarkers for patient selection for validating novel treatment strategies.
Innovations in immuno-oncology for lymphomas have outpaced therapeutic developments in any other cancer histology. In the 1990s, rituximab, a CD20 monoclonal antibody, drastically changed treatment ...paradigms for B-cell non-Hodgkin lymphomas (B-NHLs). In parallel, the concept that T cells could be genetically reprogrammed and regulated to address tumor cell evasion was developed. Twenty years later, this concept has materialized-3 customized engineered CD19 chimeric antigen receptor T-cell (CART) constructs have been embraced as third-line therapies and beyond for aggressive B-NHL. Responses with CARTs are durable in 30% to 40% of patients, with consistent results in older patients, primary refractory disease, high-grade B-cell lymphoma, and patients with concurrent secondary central nervous system disease, all features historically associated with poorer outcomes. Challenges associated with the administration of CARTs include cumbersome and time-consuming manufacturing processes, toxicities, and cost, not to mention a substantial risk of relapse. Fortunately, as our understanding of how to manipulate the immune system to achieve full antitumor potential has grown, so has the rapid development of off-the-shelf immunotherapies, with CD20/CD3 bispecific antibodies standing out above all others. These agents have shown promising activity in aggressive B-NHL and have the potential to circumvent some of the challenges encountered with customized engineered products. However, toxicities remain substantial, dosing schedules intensive, and experience limited with these agents. Novel customized and off-the-shelf therapeutics as well as rational combinations of these agents are underway. Ultimately, growing experience with both customized engineered and off-the-shelf immunotherapies will provide guidance on optimal methods of delivery and sequencing.
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