Phase Ib study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with advanced or metastatic solid tumors.

BACKGROUND: We conducted a phase I, multicenter, open-label, dose-finding, and expansion study to determine the safety and preliminary efficacy of eprenetapopt (APR-246) combined with pembrolizumab in patients with advanced/metastatic solid tumors (ClinicalTrials.gov NCT04383938). PATIENTS AND METHODS: For dose-finding, requirements were non-central nervous system primary solid tumor, intolerant to/progressed after ≥1 line of treatment, and eligible for pembrolizumab; for expansion: (i) gastric/gastroesophageal junction tumor, intolerant to/progressed after first-line treatment, and no prior anti-programmed cell death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy; (ii) bladder/urothelial tumor, intolerant to/progressed after first-line cisplatin-based chemotherapy, and no prior anti-PD-1/PD-L1 therapy; (iii) non-small-cell lung cancer (NSCLC) with previous anti-PD-1/PD-L1 therapy. Patients received eprenetapopt 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle. Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and recommended phase II dose (RP2D) of eprenetapopt. RESULTS: Forty patients were enrolled (median age 66 years; range 27-85) and 37 received eprenetapopt plus pembrolizumab. No DLTs were reported and the RP2D for eprenetapopt in combination was 4.5 g/day IV on days 1-4. The most common eprenetapopt-related AEs were dizziness (35.1%), nausea (32.4%), and vomiting (29.7%). AEs leading to eprenetapopt discontinuation occurred in 2/37 patients (5.4%). In efficacy-assessable patients (n = 29), one achieved complete response (urothelial cancer), two achieved partial responses (NSCLC, urothelial cancer), and six patients had stable disease. CONCLUSIONS: The eprenetapopt plus pembrolizumab combination was well tolerated with an acceptable safety profile and showed clinical activity in patients with solid tumors.

Economic burden in non-Hodgkin lymphoma survivors: The French Lymphoma Study Association SIMONAL cross-sectional study.

BACKGROUND: No study has focused on the economic burden in non-Hodgkin lymphoma (NHL) survivors, even though this knowledge is essential. This study reports on health care resource use and associated health care costs as well as related factors in a series of 1671 French long-term NHL survivors. METHODS: Health care costs were measured from the payer perspective. Only direct medical costs (medical consultations, outpatient treatments, hospitalizations, and medical transport) in the past 12 months were included (reference year 2015). Multiple linear regression was used to search for explanatory factors of health care costs. RESULTS: In total, 1100 survivors (66%) reported having used at least 1 health care resource, and 867 (52%) reported having used at least 1 outpatient treatment. After the authors accounted for missing data, the mean health care cost was estimated at €702 ± €2221. Hospitalizations and outpatient treatments were the main cost drivers. Sensitivity analyses confirmed the robustness of the results. For the 1100 survivors who reported using at least 1 health care resource, the mean health care cost was €1067 ± €2268. Several factors demonstrated statistically significant relationships with health care costs. For instance, cardiovascular disorders increased costs by 66% ± 16%. In contrast, rituximab or autologous stem cell transplantation as initial therapy had no effect on health care costs. CONCLUSIONS: The consideration of economic constraints in health care is now a reality. This retrospective study reports on a better understanding of health care resource use and associated health care costs as well as related factors. It may help health care professionals in their ongoing efforts to design person-centered health care pathways.

Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial.

Background: Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy. Patients and methods: In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS). Results: Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%-49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18-37) and median overall survival was 22.1 months (95% CI 17.1-27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%-71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%-36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths. Conclusions: Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%. Clinical trial name and number: KEYNOTE-001 (ClinicalTrials.gov, NCT01295827).

Influence of factor VIII level and its inhibitor titer on the therapeutic response to corticosteroids alone in the management of acquired hemophilia: A retrospective single-center study.

The treatment of acquired hemophilia (AH) involves discussing whether corticosteroids should be administered alone or combined with immunosuppressant drugs, which increase the risk of infection especially in elderly patients and/or those with autoimmunity or neoplastic diseases, who represent the target population of the disease. Prognostic factors highlighting adequate responses to corticosteroids alone must be identified for satisfactory clinical response and lower infectious risk.We aimed to evaluating the efficacy of corticosteroids alone in the management of AH depending on factor VIII (FVIII, ≥ or <1 IU/dL) levels and/or inhibitor (INH, ≤ or >20 Bethesda units per milliliter [BU/mL]) titer.We conducted a retrospective single-center study including 24 patients treated for AH with corticosteroids alone.Time to achieve partial remission (PR: absence of hemorrhage and FVIII levels >50 IU/dL) was significantly shorter in the FVIII ≥ 1 IU/dL group than in the FVIII < 1 IU/dL group (20 [10-55] vs 39 [20-207] days, P = 0.044) and in the INH ≤ 20 BU/mL and FVIII ≥ 1 IU/dL group than in the FVIII < 1 IU/dL and/or INH > 20 BU/mL group (15 [11-35] vs 41 [20-207] days, P = 0.003). In both subgroups, time to achieve complete remission (CR: negative INH and corticosteroids below 10 mg/d) was also significantly shorter than that observed in the opposite subgroups. INH titer, considered alone, did not affect the length of time to onset of PR or CR. CR and PR rates did not differ significantly depending on these variables.Our study suggests that in AH, patients with FVIII levels ≥1 IU/dL considered alone or combined with INH titer ≤20 BU/mL could be treated by corticosteroids alone, given that this subgroup of patients displayed faster therapeutic responses to this strategy.

Therapy-related acute promyelocytic leukemia following etoposide-based chemotherapy in non-seminomatous germ cell tumor.

Therapy related AML (t- AML) accounts for 10-20% of all cases of AML. Cytotoxic agents implicated are alkylating agents, topoisomerase II inhibitors and rarely anti metabolites and anti tubulin agents. A growing incidence of therapy related acute promyelocytic leukemia (t-APL) has been reported over the last few decades in malignant and non malignant conditions. To the best of our knowledge this is the first t-APL case report to be reported in NSGCT post etoposide based therapy.

PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature T lymphocytes.

Productive interaction of a T lymphocyte with an antigen-presenting cell results in the clustering of the T-cell antigen receptor (TCR) and the recruitment of a large signalling complex to the site of cell-cell contact. Subsequent signal transduction resulting in cytokine gene expression requires the activation of one or more of the multiple isoenzymes of serine/threonine-specific protein kinase C (PKC). Among the several PKC isoenzymes expressed in T cells, PKC-theta is unique in being rapidly recruited to the site of TCR clustering. Here we show that PKC-theta is essential for TCR-mediated T-cell activation, but is dispensable during TCR-dependent thymocyte development. TCR-initiated NF-kappaB activation was absent from PKC-theta(-/-) mature T lymphocytes, but was intact in thymocytes. Activation of NF-kappaB by tumour-necrosis factor alpha and interleukin-1 was unaffected in the mutant mice. Although studies in T-cell lines had suggested that PKC-theta regulates activation of the JNK signalling pathway, induction of JNK was normal in T cells from mutant mice. These results indicate that PKC-theta functions in a unique pathway that links the TCR signalling complex to the activation of NF-kappaB in mature T lymphocytes.

The reverse transcriptase component of the Tetrahymena telomerase ribonucleoprotein complex.

Telomerase is a eukaryotic reverse transcriptase that adds simple sequence repeats to chromosome ends by copying a template sequence within the RNA component of the enzyme. We describe here the identification of a Tetrahymena telomerase protein with reverse transcriptase motifs, p133. This subunit is associated with the previously identified Tetrahymena telomerase RNA and the telomerase proteins p80 and p95 in immunoprecipitation assays. Therefore, all four known Tetrahymena telomerase components are present in a single complex. Expressed in rabbit reticulocyte lysate, recombinant p133 and telomerase RNA alone catalyze a reverse transcriptase activity with some similarities to and some differences from native Tetrahymena telomerase. These experiments suggest a complexity of telomerase structure and function.

Interaction of recombinant Tetrahymena telomerase proteins p80 and p95 with telomerase RNA and telomeric DNA substrates.

Telomerase is a specialized reverse transcriptase that catalyzes telomeric repeat addition at the ends of existing telomeres or fragmented chromosomes. Two telomerase proteins from Tetrahymena thermophila, p80 and p95, were identified on the basis of their association with telomerase activity and telomerase RNA. Here we have produced recombinant versions of these proteins to characterize their functions in the ribonucleoprotein. Our findings indicate that the two proteins can form a complex whose association is independent of RNA. Each protein interacts directly with telomerase RNA, but the p80/p95 complex binds RNA with an affinity substantially greater than either protein alone. We have also characterized the DNA binding properties of p95 and show that it interacts with telomeric substrate DNAs with a specificity characteristic of the functionally defined Tetrahymena telomerase substrate anchor site. Together, these findings suggest a model in which protein-nucleic acid interactions separable from the active site contribute to positioning the template and primer, rather than exclusively the direct nucleic acid-active site interaction typical of other polymerases.

E1 recognition sequences in the bovine papillomavirus type 1 origin of DNA replication: interaction between half sites of the inverted repeats.

The E1 protein encoded by bovine papillomavirus type 1 (BPV-1) is required for viral DNA replication, and it binds site specifically to an A/T-rich palindromic sequence within the viral origin of replication. The protein is targeted to this site through cooperative interactions and binding with the virus-encoded E2 protein. To explore the nature of the E1 binding site, we inserted a series of homologous DNA linkers at the center of dyad symmetry within the E1 recognition palindrome. The effects of these modifications indicated that the E1 recognition palindrome can be separated into functional half sites. The series of insertions manifest a phasing relationship with respect to the wild-type BPV-1 genome in that greater biological activity was measured when full integral turns of the DNA helix separated the palindrome than when the separations were half-turns. This phasing pattern of activity was observed to occur in a variety of biological phenotypes, including transformation efficiency, stable plasmid copy number in cell lines established from pooled foci, and transient replication of full-length viral genomes. For replication reporter constructs where E1 and E2 are supplied in trans by the respective expression vectors, distance between the half sites seems to play a major role, yet the phasing relationships are measurable. DNase I protection studies showed that E1 bound very poorly to the construct containing a 5-bp linker, and binding was close to the wild-type level for the 10-bp insertion, consistent with a requirement for a phasing function between half sites with a modulus of 10 bp. Binding to the 15- and 20-bp insertion mutants was weak, but only for the 20-bp insertions was protection over both halves of the palindrome measurable. As it had been previously reported that the 18-bp palindrome contains sufficient nucleotide sequence information for E1 binding, we speculate that a minimal E1 recognition motif is presented in each half site. A comparison between this sequence and that of an upstream region that also binds E1 (the E2RE1 region) revealed a common pentanucleotide motif of APyAAPy. Mutants with substitutions of the ATAAT elements within E2RE1 failed to bind E1 protein. We present models for how repeats of the pentanucleotide sequence may coordinate E1 binding at the dyad symmetry axis of the origin and compare the DNA sequence organization of BPV-1 with those of the simian virus 40 and polyomaviruses at their origins of DNA replication.

Granisetron in the prevention of irradiation-induced emesis.

A double-blind double-dummy, comparative study was carried out in 30 patients receiving highly emetogenic fast dose rate, single fraction total body irradiation prior to bone marrow transplantation. Patients were randomised into one of two groups, receiving either granisetron, a specific 5-HT3 antagonist or a combination of metoclopramide, dexamethasone phosphate and lorazepam to assess the comparative efficacy of the two regimens in the control of irradiation-induced nausea and vomiting. After 24 h eight patient (53%) treated with granisetron showed a complete response compared with two patients (13%) in the comparator group. The control of vomiting by granisetron, over both 24 h and 7-day periods (P = 0.001 and P = 0.004), was significantly better than that seen with the comparator and required significantly fewer rescue doses. The safety profiles in the two groups appeared similar, with the exception that granisetron produced less drowsiness than the comparator.

Incidence of cataracts after single fraction total body irradiation: the role of steroids and graft versus host disease.

Eighty-eight patients who received single fraction total body irradiation (sfTBI) as part of their conditioning for allogeneic BMT have been evaluated for the risk of cataract formation. Thirty-eight (43%) have developed cataracts; 11 required surgery. With 9.5-13.6 years follow-up (median 10.7 years), all 12 recipients of unmanipulated marrow allografts have developed cataracts; the actuarial risk of needing surgery was 32 (+/- 18%, 95% confidence intervals (CI)). Ten of these 12 required high-dose steroids (prednisolone > 1 mg/kg/day) for the treatment of GVHD. Seventy-six patients received T cell-depleted allografts; 14 of 76 required post-transplant immunosuppression with high-dose steroids. With 1-9.4 years follow-up (median 5 years), the actuarial risk of cataract formation in T cell-depleted allograft recipients is 72% (+/- 52% CI), the actuarial risk for needing surgery is 20% (+/- 9% CI). Recipients of sfTBI and non-T cell-depleted allografts had a significantly greater risk of developing cataracts (p = 0.003, long rank test) and of needing surgery (p < 0.05, log rank test) than patients receiving T cell-depleted BM. Cataracts occurred more frequently in patients requiring post-transplant immunosuppression with steroids (relative risk 2.12, p < 0.01 log rank test).

Progress in the diagnosis and management of aspergillosis in bone marrow transplantation: 13 years' experience.

Over 13 years, we have seen 16 cases of proven invasive aspergillosis in 446 bone marrow transplant recipients, an incidence of 3.6%. The incidence of infection is low in patients with uncomplicated allogeneic or autologous bone-marrow transplants (< 2% and 0, respectively). Of the 16 episodes following transplantation, 10 occurred in patients with late transplant complications who were no longer in protective isolation. In patients who had focal pulmonary lesions (as diagnosed by computed tomographic scanning), culture of bronchoalveolar lavage (BAL) fluid was not an effective diagnostic procedure. In diffuse pulmonary disease due to Aspergillus, culture of BAL fluid had a sensitivity of 100%. Aspergillus species were isolated from an additional six patients who had no evidence of invasive aspergillosis. Graft rejection was a significant predisposing factor for the development of invasive aspergillosis (P < .001, log-rank test), and in our hospital, these patients now receive intravenous amphotericin B as prophylaxis. None of the six patients whose chest roentgenograms showed abnormalities before transplantation and who underwent surgical resection as part of the treatment for invasive aspergillosis developed recurrent infection.

Immunotherapy with interleukin 2 after ABMT in AML.

Myeloablative chemo (+/- radio) therapy and rescue with ABMT has been used as final consolidation therapy in 18 patients with AML in first remission. In seven (6 autologous, 1 syngeneic) marrow reinfusion was followed by iv IL-2. One patient, who commenced IL-2 4 days after BMT, died from pulmonary oedema due to the capillary leak syndrome. Thereafter, treatment with IL-2 was delayed until the platelet count reached 30 x 10(9)/l. All patients developed reversible hypotension (treated with infusion of colloid), but treatment was otherwise well tolerated. With 21-58 months (median 32 months) from the time of ABMT there has been one relapse (actuarial risk 17%, 95% confidence intervals (CI) 3-31%). The disease-free survival is 71% (95% CI 38-100%). Eleven patients with comparable remission induction and consolidation therapy, and an identical interval between diagnosis and ABMT (5-11 months, median 6 months) received an autograft without immunotherapy. With 24-45 months (median 29 months) follow-up the actuarial disease-free survival is 36% (95% CI 8-64%), the actuarial relapse risk is 54% (95% CI 18-90%). We conclude that immunotherapy given after ABMT to patients with AML in first remission when the platelet count exceeds 30 x 10(9)/l is safe and may induce an immunological environment which results in the elimination of residual leukaemia.

Failure of purged autologous bone marrow transplantation in high risk acute lymphoblastic leukaemia in first complete remission.

Patients in first remission of acute lymphoblastic leukaemia (ALL) considered to be at high risk of relapse were offered autologous bone marrow transplantation (ABMT) using purged marrow as a therapeutic alternative to cranial irradiation and maintenance chemotherapy. Twenty-seven bone marrows taken in remission, were purged using monoclonal antibodies (anti CD7 for T lineage and anti CD10 and/or anti CD19 for B lineage leukaemias) plus rabbit complement. Retrospective analysis of 19 purged marrows by immunophenotyping or immunoglobulin gene rearrangement studies demonstrated no evidence of disease. Engraftment was seen in 26 of the patients. No correlation was found between the numbers of infused nucleated cells or colony forming units-granulocyte-macrophage (CFU-GM) and subsequent engraftment kinetics. The actuarial disease-free survival (DFS) is 32% at 7 years (median follow-up 3.4 years). There were two transplant related deaths (actuarial risk 8%); the main cause of treatment failure has been disease recurrence with an overall actuarial risk of 67%; 76% for T-ALL (five of nine), 62% for common ALL (five of 10), two of five pre B and none of three patients with B-ALL. In these 27 high risk patients in vitro purging of remission marrow as part of ABMT appears not to improve patient outcome, although confirmation of this would require a randomized trial.

Granisetron, a selective 5-HT3 receptor antagonist, for the prevention of radiation induced emesis during total body irradiation.

The antiemetic efficacy of granisetron was tested in an open trial in patients undergoing highly emetogenic treatment by single fraction total body irradiation. Thirty-two consecutive patients were entered. Results were both patient- and observer-rated. Following a single intravenous dose of granisetron 18 patients (56.3%) experienced total protection and a further 13 (40.6%) had major antiemetic protection with four of these patients experiencing nausea only. One patient experienced an anaphylactic reaction on infusion of monoclonal antibody-treated donor marrow 5 h after administration of the trial drug and vomited on multiple occasions. The reaction was associated with hypotension. A further patient experienced transient hypotension secondary to septicaemia 8 h after receiving granisetron. Three patients required a second dose. Headache was the most frequent side-effect occurring in three patients, but in to of these patients the test drug was not thought to be implicated. In conclusion granisetron is a highly effective agent in controlling radiation induced emesis with a favourable toxicity profile.

Prostatic carcinoma metastatic to bone: sensitivity and specificity of prostate-specific antigen and prostatic acid phosphatase in decalcified material.

Decalcified bone marrow biopsies containing metastatic tumor from 36 patients were stained for prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) using the avidin biotin complex (ABC) immunoperoxidase technique. Of these patients, 22 had known prostate primaries, ten had known nonprostatic, and four female patients had unknown primaries. Prostate-specific antigen was identified in 86% (19/22) of the metastatic prostatic carcinomas. Prostatic acid phosphatase was present in only 36% (8/22). None of the patients with nonprostatic primaries or unknown primaries showed positive staining for either antigen (0/14). This study indicates that immunoperoxidase staining for PSA is very sensitive and specific in the diagnosis of metastatic prostate carcinoma, while PAP was less sensitive using decalcified bone marrow specimens. We believe that immunostaining with PSA should be of great value in diagnosis of prostatic carcinoma metastatic to the bone.