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Introduction: Lymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC regimen, including dose and frequency. Methods: We retrospectively reviewed consecutive patients at a single institution that received LDC prior to treatment with the CD19 directed CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel. Patients treated at our center received fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 for 3 consecutive days prior to May 2019. After this timepoint patients routinely received fludarabine 40 mg/m² and cyclophosphamide 500 mg/m² for 2 consecutive days. Clinical data from each cohort were obtained from the electronic medical record and compared for differences in CAR T-cell efficacy and toxicity. Results: From June 2018 to August 2023, LDC was given to 92 patients prior to CD19 directed CAR T-cell therapy for relapsed non-Hodgkin's lymphoma. Twenty-eight patients received a 3-day regimen, and 64 patients received a 2-day regimen. In the total cohort, 75% of patients received axicabtagene ciloleucel and 25% received tisagenlecleucel. The overall response rates in both the 2-day regimen group and the 3-day regimen group were similar (69% vs 75%, p= 0.21) as were the complete response rates (50% vs 54%, p=0.82). There were no significant differences between the 2-day and 3-day regimens for grade 2-4 cytokine release syndrome (55% vs 50%, p=0.82), grade 2-4 immune effector cell associated-neurotoxicity syndrome (42% vs 29%, p=0.25), or time to resolution of neutropenia or thrombocytopenia. The rate of prolonged platelet recovery lasting greater than 60 days was higher with the 3-day regimen (9% vs 27%, p=0.026). Discussion: As the number of patients eligible for CAR T-cell therapy continues to increase, optimizing each component of therapy is necessary. We show that a 2-day regimen of LDC with fludarabine and cyclophosphamide is feasible without significant impact on CAR T-cell efficacy or toxicity. Prospective studies are necessary to further determine the most effective LDC regimen. [ABSTRACT FROM AUTHOR]

Objectives: Acute graft versus host disease (aGVHD) is a common complication of allogeneic hematopoietic cell transplant (HCT) and is associated with morbidity and mortality. Identifying those at risk for developing aGVHD is crucial for early intervention. The current study assessed whether scores on a brief cognitive screening measure could identify those that develop aGVHD by 100 days post-HCT. Methods: Participants were 37 patients undergoing allogeneic HCT, assessed prior to transplant, and at 30- and 100-days post-HCT. Of those completing all evaluations, patients were divided into those who did (n = 14) and did not (n = 16) develop aGVHD by day 100 post-HCT. At 100 days post-transplant, groups did not differ on relevant demographic factors, disease, conditioning regimen, relatedness of donor, stem cell source, steroid use, total body irradiation use, human leukocyte antigens (HLA) match, or frequency of infection. Results: At 100 days post-HCT, those with aGVHD performed significantly worse on a working memory measure than those without aGvHD. The presence of aGVHD at day 100 increased significantly with every one standard deviation decrease in working memory from baseline to 30 days post-HCT (odds ratio = 3.08; 95% CI: 1.00–9.36). These findings were observed despite a small sample size and statistically controlling for multiple analyses. Conclusions: While this study is exploratory in nature, and has a small sample size, findings suggest that early detection of working memory declines could coincide with, or signal the development of, aGVHD. Potential etiologies are discussed. Implementing early cognitive screening within the first 30 days post-HCT may be useful in identifying patients at risk for aGVHD. [ABSTRACT FROM AUTHOR]

The article focuses on allogeneic haematopoietic cell transplantation for extranodal natural killer and T-cell lymphoma and association with Epstein–Barr virus (EBV). It mentions treatment with cyclophosphamide, doxorubicin and prednisolone like therapies alone generally does not provide durable remissions and reduced-intensity (RIC) or myeloablative conditioning (MAC). It also mentions relapse remains a major cause of treatment-failure.

Background: Race/ethnicity remains an important barrier in clinical care. The authors investigated differences in the receipt of autologous hematopoietic cell transplantation (AHCT) among patients with multiple myeloma (MM) and outcomes based on race/ethnicity in the United States.Methods: The Center for International Blood and Marrow Transplant Research database was used to identify 28,450 patients who underwent AHCT for MM from 2008 through 2014. By using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results 18 registries, the incidence of MM was calculated, and a stem cell transplantation utilization rate (STUR) was derived. Post-AHCT outcomes were analyzed among patients ages 18 to 75 years who underwent melphalan-conditioned peripheral cell grafts (N = 24,102).Results: The STUR increased across all groups from 2008 to 2014. The increase was substantially lower among Hispanics (range, 8.6%-16.9%) and non-Hispanic blacks (range, 12.2%-20.5%) compared with non-Hispanic whites (range, 22.6%-37.8%). There were 18,046 non-Hispanic whites, 4123 non-Hispanic blacks, and 1933 Hispanic patients. The Hispanic group was younger (P < .001). Fewer patients older than 60 years underwent transplantation among Hispanics (39%) and non-Hispanic blacks (42%) compared with non-Hispanic whites (56%). A Karnofsky score <90% and a hematopoietic cell transplantation comorbidity index score >3 were more common in non-Hispanic blacks compared with Hispanic and non-Hispanic whites (P < .001). More Hispanics (57%) versus non-Hispanic blacks (54%) and non-Hispanic whites (52%; P < .001) had stage III disease. More Hispanics (48%) versus non-Hispanic blacks (45%) and non-Hispanic whites (44%) had a very good partial response or better before transplantation (P = .005). Race/ethnicity did not impact post-AHCT outcomes.Conclusions: Although the STUR increased, it remained low and was significantly lower among Hispanics followed by non-Hispanic blacks compared with non-Hispanic whites. Race/ethnicity did not impact transplantation outcomes. Efforts to increase the rates of transplantation for eligible patients who have MM, with an emphasis on groups that underuse transplantation, are warranted. Cancer 2017;123:3141-9. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

The optimal intensity of conditioning for allogeneic hematopoietic stem cell transplantation (HCT) in acute myeloid leukemia (AML) remains undefined. Traditionally, myeloablative conditioning regimens improve disease control, but at the risk of greater nonrelapse mortality. Because fludarabine with myeloablative doses of intravenous busulfan using pharmacokinetic monitoring has excellent tolerability, we reasoned that this regimen would limit relapse without substantially elevating toxicity when compared to reduced intensity conditioning. We retrospectively analyzed 148 consecutive AML patients in remission receiving T cell replete HCT conditioned with fludarabine and intravenous busulfan at doses defined as reduced (6.4 mg/kg; FluBu2, n = 63) or myeloablative (12.8 mg/kg; FluBu4, n = 85). Early and late nonrelapse mortality (NRM) was similar among FluBu4 and FluBu2 recipients, respectively (day + 100: 4 vs 0 %; 5 years: 19 vs 22 %; p = 0.54). NRM did not differ between FluBu4 and FluBu2 in patients >50 years of age (24 vs 22 %, p = 0.75). Relapse was lower in recipients of FluBu4 (5 years: 30 vs 49 %; p = 0.04), especially in patients with poor risk cytogenetics (22 vs 59 %; p = 0.02) and those >50 years of age (28 vs 51 %; p = 0.02). Overall survival favored FluBu4 recipients at 5 years (53 vs 34 %, p = 0.02), a finding confirmed in multivariate analysis (HR: 0.57; 95 % CI: 0.34-0.95; p = 0.03). These data suggest that myeloablative FluBu4 may provide equivalent NRM, reduced relapse, and improved survival compared to FluBu2, emphasizing the importance of busulfan dose in conditioning for AML. [ABSTRACT FROM AUTHOR]

Objectives: To describe a rare case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) with morphologic and immunophenotypic evidence of bone marrow involvement. Methods: Biopsy specimens of skin and subcutis and bone marrow were examined using H&E-stained sections. Immunohistochemical studies for CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, CD56, and granzyme B were reviewed. In addition, T-cell receptor gene rearrangement studies were performed. Results: A bone marrow core biopsy demonstrated several lymphohistiocytic aggregates containing atypical, cytotoxic T cells that rimmed adipocytes and were associated with karyorrhexis. These T cells were morphologically and immunophenotypically identical to a concurrent SPTCL, expressing CD2, CD3, CD7, CD8, and granzyme B but with diminished CD5 expression. Conclusions: SPTCL may rarely involve the bone marrow. Bone marrow infiltrates show a similar morphologic and immunophenotypic appearance to those in the subcutaneous fibroadipose tissue, including rimming of adipocytes by neoplastic lymphocytes. [ABSTRACT FROM AUTHOR]

A letter to the editor on long-term safety and efficacy of cyclosporin A therapy for T-cell large granular lymphocyte leukemia is presented.

We sought to determine the effects of the immunosuppressants, cyclosporin A (CsA), tacrolimus and sirolimus, on drug transport by the ATP-binding cassette proteins, P-glycoprotein (Pgp; ABCB1), multidrug resistance protein-1 (MRP-1; ABCC1) and breast cancer resistance protein (BCRP; ABCG2), and the major vault protein lung resistance protein (LRP). Cellular content of mitoxantrone, a Pgp, MRP-1 and BCRP substrate, was measured by flow cytometry in cells overexpressing these proteins following incubation with and without CsA, tacrolimus or sirolimus. Interaction of BCRP with these compounds was studied by photolabeling and ATPase assays. Nuclear–cytoplasmic distribution of doxorubicin was studied by confocal microscopy in cells overexpressing LRP. CsA increased cellular drug uptake in cells overexpressing Pgp, MRP-1 or BCRP and nuclear drug uptake in cells overexpressing LRP at the clinically achievable concentration of 2.5 μM. Tacrolimus enhanced cellular drug uptake at 1 μM, but not at 0.08 μM, its clinically achievable concentration, and did not enhance nuclear drug uptake. Sirolimus enhanced cellular drug uptake in cells overexpressing Pgp, MRP-1 and BCRP with optimal effects at 2.5 μM, but was effective at its clinically achievable concentration of 0.25 μM if cells were pre-incubated for at least 30 min before drug exposure, and also enhanced nuclear drug uptake at 0.25 μM. BCRP modulation by all three immunosuppressive agents was associated with competitive binding to the drug transport sites. CsA, tacrolimus and sirolimus modulate drug transport by Pgp, MRP-1 and BCRP and CsA and sirolimus modulate drug transport by LRP at concentrations that differ from immunosuppressive concentrations and maximum tolerated concentrations. [ABSTRACT FROM AUTHOR]

Purpose: We sought to determine the effects of the immunosuppressants, cyclosporin A (CsA), tacrolimus and sirolimus, on drug transport by the ATP-binding cassette proteins, P-glycoprotein (Pgp; ABCB1), multidrug resistance protein-1 (MRP-1; ABCC1) and breast cancer resistance protein (BCRP; ABCG2), and the major vault protein lung resistance protein (LRP).Methods: Cellular content of mitoxantrone, a Pgp, MRP-1 and BCRP substrate, was measured by flow cytometry in cells overexpressing these proteins following incubation with and without CsA, tacrolimus or sirolimus. Interaction of BCRP with these compounds was studied by photolabeling and ATPase assays. Nuclear-cytoplasmic distribution of doxorubicin was studied by confocal microscopy in cells overexpressing LRP.Results: CsA increased cellular drug uptake in cells overexpressing Pgp, MRP-1 or BCRP and nuclear drug uptake in cells overexpressing LRP at the clinically achievable concentration of 2.5 microM. Tacrolimus enhanced cellular drug uptake at 1 microM, but not at 0.08 microM, its clinically achievable concentration, and did not enhance nuclear drug uptake. Sirolimus enhanced cellular drug uptake in cells overexpressing Pgp, MRP-1 and BCRP with optimal effects at 2.5 microM, but was effective at its clinically achievable concentration of 0.25 microM if cells were pre-incubated for at least 30 min before drug exposure, and also enhanced nuclear drug uptake at 0.25 microM. BCRP modulation by all three immunosuppressive agents was associated with competitive binding to the drug transport sites.Conclusions: CsA, tacrolimus and sirolimus modulate drug transport by Pgp, MRP-1 and BCRP and CsA and sirolimus modulate drug transport by LRP at concentrations that differ from immunosuppressive concentrations and maximum tolerated concentrations. [ABSTRACT FROM AUTHOR]

AbstractBackground and Aims: Primary hepatocellular carcinoma (HCC) is common in Thailand and its prognosis is extremely poor. Hepatic resection and liver transplantation are modes of curative therapy and various therapies have been developed to treat inoperable HCC. This study was performed to determine the outcome of therapy and to identify prognostic factors for survival among Thai patients with HCC. Methods: Three hundred and sixty-eight patients with tissue-proven or serodiagnosed HCC were studied. Differences in laboratory investigations, patient survival, treatment outcomes and prognostic factors were analysed. The Kaplan–Meier method and the log-rank test were used to calculate and compare survival of patients receiving different therapies. Results: Of the 368 patients 317 were males (86.1%, M: F ratio 6.2: 1). The median age of all patients was 52 years range (2–85 years). Fifty-nine patients were specifically treated and 209 were conservatively treated. Among those tested, 70% had hepatitis B virus-related HCC. The overall median survival (range) after diagnosis and that of the treated and untreated patients were 5.6 (0–92.1), 9.0 (0–92.1) and 2.3 (0–25.9) months, respectively. More than 50% of the Okuda I patients survived beyond 30 months. The Okuda II and III patients had a median survival (range) of 5.7 (0.1–75.2) and 1.6 (0.1–25.9) months, respectively. Those patients treated by surgery, transcatheter oil chemoembolization and systemic chemotherapy had a better survival rate than did the conservatively managed patients. Surgery was found to be a better treatment than systemic chemotherapy. However, no differences between other pairs of treatment groups were identified. Subgroup analysis of the Okuda II group patients revealed the same results. Independent predictors of death were multiple lesions, advanced Okuda stage and treatment modality. Conclusion: Despite various kinds of therapy, the treatment outcomes for Thai HCC patients remain poor and largely depend on the disease extent and treatment received. Most Thai HCC patients are at an advanced stage at diagnosis. Thai patients who received disease-specific treatment other than intra-arterial chemotherapy had a better survival rate than did supportive treatment patients. [ABSTRACT FROM AUTHOR]

The author comments on research appearing within this issue of the journal concerning the frequency of B-cell dyscraisias in patients with T-cell large granular lymphocyte (T-LGL) leukemia. The diagnostic criteria of the study "Chronic B-cell dyscrasias are an important clinical feature of T-LGL leukemia," is assessed. The hypothesis that clonal T cell expansion is stimulated by aberrant B cells in the case of T-LGL leukemia associated with B-cell dyscraisias is examined.