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Purpose: Gilteritinib is a type 1 FLT3 inhibitor active as monotherapy for relapsed or refractory FLT3 -mutated AML. We investigated the safety, tolerability, and efficacy of gilteritinib incorporated into intensive induction and consolidation chemotherapy, and as maintenance therapy for adult patients with newly diagnosed, non-favorable-risk AML., Methods: In this phase IB study (2215-CL-0103; ClinicalTrials.gov identifier: NCT02236013), 103 participants were screened and 80 were allocated to treatment. The study was divided into four parts: dose escalation, dose expansion, investigation of alternate anthracycline and gilteritinib schedule, and continuous gilteritinib during consolidation., Results: After dose escalation, 120 mg gilteritinib once daily was chosen for further study. There were 58 participants evaluable for response at this dose, 36 of whom harbored FLT3 mutations. For participants with FLT3 -mutated AML, the composite complete response (CRc) rate was 89% (83% were conventional complete responses), all achieved after a single induction cycle. The median overall survival time was 46.1 months. Gilteritinib was well-tolerated in this context although the median time to count recovery during induction was approximately 40 days. Longer time-to-count recovery was associated with higher trough levels of gilteritinib, which, in turn, were associated with azole use. The recommended regimen is gilteritinib at a dose of 120 mg once daily from days 4 to 17 or 8 to 21 of a 7 + 3 induction with either idarubicin or daunorubicin and from day 1 continuously with high-dose cytarabine consolidation. Maintenance therapy with gilteritinib was well-tolerated., Conclusion: These results demonstrated the safety and tolerability of gilteritinib incorporated into an induction and consolidation chemotherapy regimen, and as single-agent maintenance therapy for patients with newly diagnosed FLT3 -mutant AML. The data herein provide an important framework for the design of randomized trials comparing gilteritinib with other FLT3 inhibitors.

Treatment results for patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive chemotherapy are disappointing. This multicenter, open-label, phase 3 trial randomized (2:1) untreated adults with FLT3mut+ AML ineligible for intensive induction chemotherapy to receive gilteritinib (120 mg/d orally) and azacitidine (GIL + AZA) or azacitidine (AZA) alone. The primary end point was overall survival (OS). At the interim analysis (August 26, 2020), a total of 123 patients were randomized to treatment (GIL + AZA, n = 74; AZA, n = 49). Subsequent AML therapy, including FLT3 inhibitors, was received by 20.3% (GIL + AZA) and 44.9% (AZA) of patients. Median OS was 9.82 (GIL + AZA) and 8.87 (AZA) months (hazard ratio, 0.916; 95% CI, 0.529-1.585; P = .753). The study was closed based on the protocol-specified boundary for futility. Median event-free survival was 0.03 month in both arms. Event-free survival defined by using composite complete remission (CRc) was 4.53 months for GIL + AZA and 0.03 month for AZA (hazard ratio, 0.686; 95% CI, 0.433-1.087; P = .156). CRc rates were 58.1% (GIL + AZA) and 26.5% (AZA) (difference, 31.4%; 95% CI, 13.1-49.7; P < .001). Adverse event (AE) rates were similar for GIL + AZA (100%) and AZA (95.7%); grade ≥3 AEs were 95.9% and 89.4%, respectively. Common AEs with GIL + AZA included pyrexia (47.9%) and diarrhea (38.4%). Gilteritinib steady-state trough concentrations did not differ between GIL + AZA and gilteritinib. GIL + AZA resulted in significantly higher CRc rates, although similar OS compared with AZA. Results support the safety/tolerability and clinical activity of upfront therapy with GIL + AZA in older/unfit patients with FLT3mut+ AML. This trial was registered at www.clinicaltrials.gov as #NCT02752035., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

A chemotherapy roadmap is a summary of the chemotherapy plan for a pediatric oncology patient. Chemotherapy roadmaps exist as paper documents for most, if not all, pediatric oncology programs. Paper chemotherapy roadmaps are associated with risks that can negatively affect the safety of the chemotherapy process. This institution explored the feasibility of converting paper chemotherapy roadmaps into an electronic form. The pediatric information systems team developed an innovative computer application that can generate electronic chemotherapy roadmaps, and the pediatric oncology program established a novel workflow that can operationalize them. Electronic chemotherapy roadmaps have been produced for 36 treatment protocols, and 369 electronic chemotherapy roadmaps have been used for 352 pediatric oncology patients. They have functioned as designed and have not had any unintended effects. In the 5 years after their implementation, the average proportion of patient safety events involving paper or electronic chemotherapy roadmaps decreased by 78.7%. This report is the first to demonstrate the feasibility of creating and implementing electronic chemotherapy roadmaps. Continued expansion of the current library will be necessary to formally test the hypothesis that electronic chemotherapy roadmaps can decrease the risks associated with their paper counterparts and increase the safety of the chemotherapy process.

Therapy-related myeloid neoplasm (t-MN) is a subtype of acute myeloid leukemia with adverse cytogenetics and poor overall prognosis despite intensive induction chemotherapy and allogeneic hematopoietic cell transplantation (allo-HCT). It is increasingly recognized as a late complication of chronic immunosuppression in patients who have received solid organ transplantation. In this paper, we describe a case of t-MN following orthotopic cardiac transplantation and its treatment with allo-HCT. We discuss molecular and biological challenges and considerations in double solid organ and bone marrow transplantation and review similar cases at our institution. Our experience suggests general feasibility and safety of allo-HCT in patients who have received solid organ transplantation.

We conducted a 45 patient prospective study of reduced-intensity conditioning (RIC) and transplantation of unrelated umbilical cord blood (UCB) and CD34(+) stem cells from a haploidentical family member. Median age was 50 years; weight was 80 kg. Fifty-eight percent had active disease. Neutrophil engraftment occurred at 11 days (interquartile range [IQR], 9-15) and platelet engraftment at 19 days (IQR, 15-33). In the majority of patients, early haploidentical engraftment was replaced by durable engraftment of UCB by 100 days, with regular persistence of minor host and/or haplo-hematopoiesis. Percentage of haplochimerism at day 100 correlated with the haplo-CD34 dose (P = .003). Cumulative incidence of acute GVHD (aGVHD) was 25% and chronic GVHD (cGVHD) was 5%. Actuarial survival at 1 year was 55%, progression-free survival (PFS) was 42%, nonrelapse mortality (NRM) was 28%, and relapse was 30%. RIC and haplo-cord transplantation results in fast engraftment of neutrophils and platelets, low incidences of aGVHD and cGVHD, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay, and promising long-term outcomes. UCB cell dose had no impact on time to hematopoietic recovery. Therefore, UCB selection can prioritize matching, and better matched donors can be identified rapidly for most patients. This study is registered at http://clinicaltrials.gov as NCI clinical trial no. NCT00943800.

Few clinical protocols have focused on patients with therapy-related myeloid neoplasms (t-MN). Therefore, we enrolled 32 patients with previously untreated t-MN on a clinical trial testing the effectiveness of a unified induction regimen of high-dose cytarabine and mitoxantrone. The complete remission (CR) rate was 66% (95% CI 47-81%) and the partial remission (PR) rate was 16% (95% CI 5-33%), for an overall response rate of 82%. Day 30 treatment mortality was 9% (3/32), and the most serious induction toxicity was cardiac dysfunction. Among the patients with CR, 13 (62%) received consolidation therapy using an allogeneic hematopoietic cell transplant (HCT), four (21%) received an autologous HCT, and three (16%) received further chemotherapy. We observed long-term disease-free survival in patients who received all three types of consolidation therapy. The remission induction of high-dose cytarabine and mitoxantrone for t-MN is a well-tolerated efficacious combination, which allows aggressive consolidation and long-term disease-free survival.

We tested the independent prognostic impact of 2 commonly used biomarkers, C-reactive protein (CRP) and interleukin (IL)-6, on the outcomes of allogeneic hematopoietic cell transplantation (HCT). Consecutive patients who underwent a uniform reduced-intensity conditioning (RIC) regimen of fludarabine (Flu), melphalan (Mel), and alemtuzumab were evaluated retrospectively. Cryopreserved serum samples drawn before the RIC were available to measure CRP levels in 81 patients and IL-6 levels in 79 patients. Patients with CRP levels above the median of 18.5 mg/L had significantly more grade 3-4 hepatic toxicity (P=.01), longer HCT hospital stay (P=.005), more acute graft-versus-host disease (aGVHD) (P=.003), greater nonrelapse mortality (NRM) (P=.01), and inferior overall survival (OS; P=.02). Higher baseline CRP showed no significant correlation with grade 3-4 infectious toxicity (P=.09). In contrast to CRP, pre-HCT IL-6 levels above the median of 78.3 pg/mL did not confer a statistically significant increased risk of toxicity or mortality. An elevated HCT comorbidity index (HCT-CI) did not predict for any measure of HCT morbidity. After adjustment for disease status, comorbidity, performance status, and age, elevated CRP concentration remained predictive of NRM. These data require confirmation in non-T cell-depleted conditioning regimens. If validated, they suggest that preconditioning CRP holds promise for enhancing estimates of transplantation tolerance.

The hormone 1alpha,25-dihydroxyvitamin D (1alpha,25(OH)(2)D) inhibits growth and induces differentiation of prostate cells. The enzyme responsible for 1alpha,25(OH)(2)D synthesis, 25-hydroxyvitamin D (25(OH)D)-1alpha-hydroxylase (1alpha-OHase), has been demonstrated in human prostate cells. We compared the levels of 1alpha-OHase activity in prostate cancer cell lines, LNCaP, DU145 and PC-3 and in primary cultures of normal, cancerous and benign prostatic hyperplasia (BPH) prostate cells. We observed a marked decrease in 1alpha-OHase activity in prostate cancer cells, including an undetectable level of activity in LNCaP cells. Transient or stable transfection of 1alpha-OHase cDNA into LNCaP cells increased 1alpha-OHase activity from undetectable to 4.95pmole/mg+/-0.69pmole/mg and 5.8pmole/mg+/-0.7pmole/mg protein per hour, respectively. In response to 25(OH)D, the prohormone of 1alpha,25(OH)(2)D, the transfected LNCaP cells showed a significant inhibition of 3H-thymidine incorporation (37%+/-6% and 56%+/-4% at 10(-8)M for transiently and stably transfected cells, respectively). These findings support an important autocrine role for 1alpha,25(OH)(2)D in the prostate and suggest that the re-introduction of the 1alpha-OHase gene to prostate cancer cells, in conjunction with the systemic administration of 25(OH)D, constitutes an endocrine form of gene therapy that may be less toxic than the systemic administration of 1alpha,25(OH)(2)D.

Protein kinase CK2 (casein kinase II) is a heterotetrameric enzyme implicated in many essential regulatory pathways in cells. We have determined the sequence of the murine CK2 alpha' cDNA that encodes a 350-amino-acid protein that would have 99 and 98% homology with the human and chicken proteins, respectively, and is also highly homologous to murine CK2 alpha. To clarify the sequence of the 5' end of the cDNA and to elucidate the structure and regulation of the gene, we obtained a bacterial artificial chromosome clone that contains the 35-kb CK2 alpha' gene. The gene consists of 12 small exons; the 5' end, including the first exon and intron, is extremely GC rich and contains a CpG island. The putative promoter contains potential binding sites for a variety of transcriptional factors but appears to lack CCAAT- or TATA-like elements. A polymorphic dinucleotide repeat in the fifth intron allowed us to map the CK2 alpha' gene to murine Chromosome 8.

To investigate the possible interaction of a beta adrenergic blocking agent and marihuana, six healthy experienced marihuana smokers received the two drugs separately and in combination. Propranolol (120 mg per os) reduced resting HR and BP; there were no changes in performance on tasks designed to test psychomotor speed, attention, memory and learning. Marihuana (10 mg delta9-THC), administered in smoke, induced the typical subjective state ("high") with marked increases in HR, BP and conjunctival injection; it impaired performance on a learning test without significantly affecting attention. Pre-treatment with propranolol blocked effectively the cardiovascular effects of marihuana; it prevented the learning impairment and, to a lesser degree, the characteristic subjective experience.

A video microscope system has been constructed and tested that incorporates computer-controlled video cameras for high-resolution and low-light microscopy. The low-light camera system involves a dual microchannel plate-image intensifier capable of photon gain as high as 500 000 and a gated silicone-intensified target vidicon to achieve usable photon sensitivity with a noise equivalent signal of only 2 photons (500 nm) per pixel per second. We have compared the limitations and capabilities of this camera system with those of a high-resolution video camera and conventional photomicroscopy. Uses of the low-light camera coupled to a computer system include image acquisition of weak-light images from self-luminous specimens, fluorescence microscopy with weak exciting light, kinetic resolution of calcium-mediated events as monitored by the calcium-sensitive bioluminescence of aequorin, and spatially resolved spectroscopic measurements. Flexible use of this system in these various applications is possible because it allows operation with illumination intensities over a dynamic range of 100 000:1.

Earthworm bioluminescence (species Diplocardia longa) is a sensitive tool for determination of peroxide titers in biological systems, with linearity of the standard curve for hydrogen peroxide extending from 10 nmol/L in the assay to greater than 1 mmol/L, and with sensitivity to 2 pmol of peroxide per assay. This assay's insensitivity to extraneous protein, turbidity, and solutes that are not redox active makes it particularly useful for automated or crude sample analysis and for analysis of oxidases and their substrates in coupled reactions. Examples of this latter application we discuss are analyses of glucose and putrescine oxidases and their substrates. In each case linear standard curves are obtained, covering several decades of concentration. The coupled reactions also allow in situ detection of oxidases in electrophoresis gels. We also describe a small, portable photometer system and an on-line computer-controlled instrument system that has facilitated development of these assays and will also allow automatic scanning of bioluminescence in gels. The data-collection and decision-making algorithms of this system are simple and easily adaptable for use in an inexpensive computer-based photometer system.

The hypothesis of visceral learning has opened a new avenue in the search for a pathway between psychosocial stimuli and physiological changes. To apply this approach to asthma required a technique for the measurement of the airways' patency, which could be interfaced with the strategy of visceral learning. The method of forced oscillations was shown to correlate highly with whole body plethysmography. The rapid output of the instrument was used on line to control a visual reinforcement signal. Forty-six mild asthmatics, blind to the effect sought in order to minimize the role of suggestion, were tested in a series of evolving experiments. In the first series, two groups of subjects (N=15,13) were able, with this sensory feedback, to decrease (p less than 0.01) their total respiratory resistance; subsequently a smaller group of subjects (N=5), who received reinforcement signals unrelated to the state of their airways, showed no such change. Similar results were obtained in the second series of tests; in A-B-B-A order, the subjects (N=13) received either contingent or noncontingent reinforcement; furthermore, the reinforcement was available only if their lung volume was within the range observed during baseline.