Even when immune memory cells form in the lung after influenza infection, insufficient dietary iron leaves them less able to mount a strong antiviral response, revealing how nutrition can shape long-term immune protection
Study:

Even when immune memory cells form in the lung after influenza infection, insufficient dietary iron leaves them less able to mount a strong antiviral response, revealing how nutrition can shape long-term immune protection
Study:

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The addition of azacitidine (Vidaza) and ventoclax (Venclexta) to tagraxofusp (Elzonris) was feasible in patients with first-line or relapsed/refractory blastic plasmacytoid dendritic cell neoplasm (BPDCN), and may increase both complete response (CR) rates and the number of patients proceeding the transplant compared with tagraxofusp alone, according to results from a phase 2 trial (NCT03113643) presented during the
In previously untreated patients (n = 16), at a median follow-up of 16.7 months (95% CI, 8.6-26.6), the composite CR rate was 88%, comprising best responses of CR (50%), CR with incomplete hematologic recovery (CRi; 38%) and clinical CR (0%). The overall response rate (ORR) was 94%, including 1 partial response (PR; 6%). The median duration of response (DOR) was not reached (NR). No patients achieved stable disease (SD) or experienced disease progression (PD), and 1 patient was not evaluable due to early death.
For patients with relapsed/refractory disease (n = 11), the composite CR rate was 64%; this included CR, CRi and CRc rates of 9%, 36% and 18%, respectively. The ORR was comprised entirely of CRs. SD was achieved by 27% of patients and 9% experienced PD. The median DOR was 7.2 months (95% CI, 5.5-36.4%). Of note, all but one patient in this cohort had disease relapse or death; the remaining patient had a median follow-up of 42.4 months.
Notably, 63% and 55% of patients in the first-line and relapsed/refractory groups, respectively, proceeded directly to allogeneic stem cell transplant (SCT), including 10 of the 11 patients age 75 or older in the first-line cohort.
Regarding safety, investigators reported that the toxicity profile of the tagraxofusp, azacitidine, and venetoclax triplet was as expected and consistent with prior studies of this regimen in patients with acute myeloid leukemia (AML).
Moreover, the rate of capillary leak syndrome (CLS) was equivalent or lower with the triplet than with single-agent tagraxofusp, according to historical data. Overall, the CLS rate with the triplet was 14.8%; respective rates of grade 2 and 3 CLS were 11.1% and 3.7%, and no grade 4 or 5 CLS events occurred. All CLS events occurred in cycle 1 and were manageable with albumin and diuresis.
“There is a high rate of known prior and concomitant hematologic malignancies in these patients with BPDCN,” lead study author Andrew A. Lane, MD, PhD, stated in an oral presentation of the data. “The addition of agents like azacitidine and venetoclax [to tagraxofusp] is attractive because it can have activity in those diseases that may not be as high with tagraxofusp alone. [Therefore,] we think [that this triplet] is an effective new treatment option for patients with BPDCN.”
Lane serves as a physician and director of the Blastic Plasmacytoid Dendritic Cell Neoplasm Center at Dana-Farber Cancer Center, and is an associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts.
“We previously found in the laboratory that tagraxofusp resistance in AML and BPCDN is mediated by DNA methylation and silencing of diphthamide genes, which are necessary for the cytotoxicity of diphtheria toxin, and that tagraxofusp resistance can be reversed with azacitidine treatment,” Lane explained. “We’ve also shown that BPDCN is highly dependent on BCL2 and sensitive to venetoclax.”
Lane also noted clinical data from a phase 1b study (NCT03113643), which evaluated the safety of tagraxofusp plus azacitidine with or without venetoclax in AML. Results showed that 69% of patients with first-line AML who received the triplet (n = 26) achieved a best response of CR, 19% achieved a CRi, and 12% achieved a morphologic leukemia-free state. The median time to best response among these 18 patients was 55 days. Furthermore, there was no indication of increased toxicity with tagraxofusp with azacitidine with or without venetoclax in combination, and adverse effects (AEs) related to tagraxofusp were also as expected.
This phase 2 study enrolled patients 18 years of age or older with previously untreated or relapsed/refractory BPDCN onto separate cohorts. Patients were required to have albumin levels of 3.2 g/L or greater, alanine aminotransferse (ALT)/aspartate aminotransferase (AST) levels below 2.5 x the upper limit of normal (ULN), bilirubin levels below 1.5 x ULN, and creatinine levels below 1.5 x ULN; an ECOG performance status of 2 or lower; and normal cardiac ejection fractions. Screening lumbar puncture was required. Patients with asymptomatic central nervous system disease were permitted to enroll and receive intrathecal (IT) chemotherapy, and IT prophylaxis was both permitted and encouraged for all.
Eligible patients received 12 µg/kg of tagraxofusp on days 4 through 6, 75 mg/m2 of azacitidine on days 1 through 7, and 400 mg of venetoclax on days 1 through 21 for a 28-day cycle. Venetoclax ramp-up occurred on days 1 through 3 of cycle 1. Notably, patients were hospitalized in cycle 1 until the completion of tagraxofusp administration to monitor for CLS. Outpatient treatment was allowed starting at cycle 2 and beyond.
The study’s primary end point was safety, and key secondary end points included response rate, estimated progression-free survival (PFS) and overall survival (OS). Response evaluation in marrow, skin, and the extramedullary space was also conducted.
In the overall patient population (n = 27), the median age was 70 years (range, 21-81). Most patients were male (93%), White (93%), had non-Hispanic ethnicity (78%), and an ECOG performance status of 1 (63%). “Skin only” disease occurred in 30% of patients. Overall, 37% of patients had a prior or concomitant hematologic malignancy, including chronic myelomonocytic leukemia (n = 4), myelodysplastic syndrome (n = 4), or a myeloproliferative neoplasm (n = 3). Mutations in TET2 (37%), ASXL1 (26%), RNA splicing factor (19%), NRAS/KRAS/FLT3 (15%), and TP53 (7%) were observed.
For patients with relapsed/refractory disease, prior therapies included tagraxofusp (64%), pivekimab sunirine (IMGN632; 36%), venetoclax (27%, 2 with a hypomethlyating agent), and SCT (36%).
Patients with previously untreated BPDCN received a median of 2.5 cycles (range, 1-4) of treatment. In the relapsed/refractory group, the median number of cycles was 2 (range, 1-5).
For patients with previously untreated BPDCN, the median OS, PFS, and DOR were all NR. The 2-year PFS and OS rates were 65% (95% CI, 40%-91%) and 53% (95% CI, 30%-80%), respectively. In the relapsed/refractory group, the median OS was 8.4 months (95% CI, 4.8-21.7) and the median PFS was 6.3 months (95% CI, 2.2-11.2). The median DOR was 7.2 months (95% CI, 5.5-36.4).
In the overall patient population, the most common grade 3 or higher treatment-related AEs were thrombocytopenia (63%), decreased white blood cell count (59%), neutropenia (48%), anemia (19%), and hypoxia (11%). Other AEs included increased ALT levels, increased AST levels, atrial fibrillation, febrile neutropenia, hyperglycemia, hypophosphatemia, multi-organ failure, sinus tachycardia, and syncope (4% each).
No cases of veno-occlussive disease were reported. In the overall patient population, the all-cause mortality rates at 30- and 60-days were 3.7% and 7.4%, respectively. One patient with first-line BPDCN died in cycle 1 due to multi-organ failure, and 1 patient with relapsed/refractory disease died after cycle 1 due to disease progression. The median time from the start of cycle 1 to cycle 2 was 33 days.
Disclosures: Lane received consultancy fees from ProteinQure, IDRx, Cimeio, Qiagen, Jnana Therapeutics, Stemline, and AbbVie. He also holds stock options in Stelexis BioSciences and Stemline.


Sitting in Idan Weiss’ drafts folder is an email to his agent. He declares he’s going to quit acting.
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