Analysis of Intent and Reason for Oncologic Therapy Administration in Cancer Patients Admitted to the Intensive Care Unit

Purpose To investigate the intent of, and reason for, administration of oncologic therapies in the intensive care unit (ICU). Methods Single center, retrospective, cohort study of patients with cancer who received oncologic therapies at a tertiary cancer center ICU between April 1, 2019 and March 31, 2020. Oncologic therapies included traditional cytotoxic chemotherapy, targeted therapy, immunotherapy, hormonal or biologic therapy directed at a malignancy and were characterized as initiation (initial administration) or continuation (part of an ongoing regimen). Results 84 unique patients (6.8% of total ICU admissions) received oncologic therapies in the ICU; 43 (51%) had hematologic malignancies and 41 (49%) had solid tumors. The intent of oncologic therapy was palliative in 63% and curative in 27%. Twenty-two (26%) patients received initiation and 62 (74%) received continuation oncologic therapies. The intent of oncologic therapy was significantly different by regimen type (initiation vs. continuation, p = <0.0001). Initiation therapy was more commonly prescribed with curative intent and continuation therapy was more commonly administered with palliative intent (p = <0.0001). Oncologic therapies were given in the ICU mainly for an oncologic emergency (56%) and because the patients happened to be in the ICU for a non-oncologic critical illness when their oncologic therapy was due (34.5%). Conclusion Our study provides intensivists with a better understanding of the context and intent of oncologic therapies and why these therapies are administered in the ICU.

Organization of immunobiological therapy for severe bronchial asthma in the Sverdlovsk region

Background: Biologicals use in severe asthma (SA) is associated with problem of targeted therapy (TT) availability. Ensuring availability of biologicals can be resolved within the territorial compulsory medical insurance program (TCMIP) in day-stay or round-the-clock hospital. Aims: development and implementation of program for introduction of immunobiological therapy (IBT) for SA in Sverdlovsk Region (SR). Materials and methods: Program for introduction of IBT for SA was developed in SR in 2018 to provide patients with expensive biologicals within the TCMIP. Program includes: SA prevalence study in SR; practitioners training in differential diagnosis of SA; organization of affordable therapy for patients with SA; register of SA patients сreation and maintenance; patients selection and management of patients with SA in accordance with federal clinical guidelines. Results: Atopic phenotype in SA was detected in 5%, eosinophilic - in 2.3% of all analyzed cases of asthma (n=216). Practitioners of SR were trained in differential diagnosis of SA. The orders of the Ministry of Health of SR were issued, regulating the procedure for referring patients with SA to IBT, a list of municipal medical organizations providing IBT in a day-stay or round-the-clock hospital; approved regional register form of SA patients requiring biologicals use; ungrouping of clinical and statistical groups of day-stay hospital was carried out depending on INN and dose of biologicals; patients with SA are selected for TT and included in the regional register. Initiating of TT in round-the-clock hospital and continuation therapy in day-stay hospital provides a significant savings in compulsory medical insurance funds. Conclusions: introduction of IBT for SA in SR is carried out within framework of developed program. Principle of decentralization brings highly specialized types of medical care closer to patients and makes it possible to provide routine medical care in allergology-immunology profile in context of restrictions caused by COVID-19 pandemic.

Naturalistic outcomes of continuation right unilateral ultrabrief ECT in major depression: a retrospective chart review

Objective: Continuation treatment of major depression following an acute course of electroconvulsive treatment (ECT) may be often required to prevent relapse. Data on continuation phase of right unilateral ultrabrief ECT are sparse and there are doubts if it is inherently capable of relapse prevention. Methods: All consecutive adult patients with major depression who received the first ‘run’ of continuation phase of right unilateral ultrabrief ECT over a 10-year period were routinely followed up. ECT frequency varied from weekly to up to once every 4 weeks for a maximum period of 6 months. The data were extracted from a retrospective chart review. Results: 20 out of 22 patients persisted with ultrabrief pulses (0.3 ms) with two needing 0.5 ms pulse widths. The median duration of continuation treatment was 51 days (range: 14–460). At the end of 1 month ( n = 17), treatment gap in days mean (SD): 10.18 (7.08), widening to mean (SD): 20.11 (16.85) at 4 months ( n = 9). Stimulus dose increased throughout the continuation phase: p = 0.026. In 16 out of 22 patients, more than 70% of the visits were charted as being ‘in remission’. Conclusion: As most patients receiving ultrabrief ECT remained well, this study suggests that ultrabrief ECT can be used effectively in continuation therapy.

Blinatumomab consolidation and maintenance therapy in adults with relapsed/refractory B-precursor acute lymphoblastic leukemia

In a phase 3 clinical study of heavily pretreated adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL), overall survival (OS) following blinatumomab, a BiTE (bispecific T-cell engager) immunooncology therapy, was significantly improved vs chemotherapy following induction (cycles 1 to 2). Here we report the efficacy and safety of those who received additional cycles of blinatumomab. Blinatumomab was administered as a continuous IV infusion for 4 weeks in a 6-week cycle. Patients who achieved a bone marrow response (≤5% blasts) or complete remission (full, partial, or incomplete hematological recovery) during induction could receive additional cycles of blinatumomab. OS and relapse-free survival (RFS) for consolidation (cycles 3 to 5) vs no consolidation, and maintenance (cycles ≥6) vs no maintenance were analyzed using Simon-Makuch and Mantel-Byar odds ratios. Of 267 patients who received blinatumomab induction, 86 (32%) entered consolidation and 36 (13%) entered maintenance. Evidence of longer OS was demonstrated among the maintenance group compared with no-maintenance (median OS [95% confidence interval, CI]: not reached for maintenance vs 15.5 months for no maintenance). Median RFS (months; 95% CI) was numerically longer among maintenance group (14.5; 7.1 to 21.9) compared with no-maintenance (9.8; 8.5 to 11.1). A lower incidence of adverse events was seen during maintenance (72.2%) compared with induction (97.2%) and consolidation (86.1%). Adults with R/R ALL who achieved remission following blinatumomab induction had longer survival on continuation therapy than those who discontinued blinatumomab early, supporting the use of blinatumomab as long-term therapy. No new safety signals were reported. This trial was registered at www.clinicaltrials.gov as #NCT02013167.

A Phase 1/2 Study of Quizartinib (Q) in Combination with Re-Induction Chemotherapy and As Single-Agent Continuation Therapy in Pediatric and Young Adult Patients with Relapsed/Refractory (R/R) FLT3-ITD Acute Myeloid Leukemia (AML)

Background Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations occur in 10%-15% of pediatric/adolescent patients with AML and are associated with treatment resistance, risk of relapse, and poor survival. Nearly 50% of children with newly diagnosed FLT3-ITD AML fail treatment or relapse as their first event (Levis, et al, Intl J Hematol 2005; Gilliland, Blood 2002). Therefore, targeting FLT3-ITD may improve clinical responses or prevent relapse in younger patients with FLT3-ITD mutations. No FLT3 inhibitors are approved for use in children. Q is an oral, highly potent and selective, type II FLT3 inhibitor. In the phase 3 QuANTUM-R trial, Q monotherapy prolonged overall survival vs salvage chemotherapy in adult patients with R/R FLT3-ITD AML (Cortes, et al, Lancet Oncol 2019). In another study, Q combined with chemotherapy in pediatric patients (age ≤ 21 years) with R/R AML or acute lymphoblastic leukemia, regardless of FLT3-ITD status, resulted in a marked reduction in bone marrow blasts for patients with FLT3-ITD vs other patients (Cooper, et al, Clin Cancer Res 2016). Thus, there is a strong rationale to investigate Q for treatment of R/R FLT3-ITD AML in pediatric/adolescent patients. Study Design and Methods This open-label, multicenter, single-arm, phase 1/2 study (NCT03793478) consists of dose-escalation and -expansion phases. Patients will be stratified into 2 age groups: 1 to < 12 months (younger age group) and 1 to ≤ 21 years (older age group). Key inclusion criteria are diagnosis of FLT3-ITD AML, first relapse or refractory to first-line high-dose chemotherapy with adequate organ function. Patients who received prior therapy with other FLT3 inhibitors or prior stem cell transplant (SCT) are eligible. Key exclusion criteria include acute promyelocytic leukemia or juvenile myelomonocytic leukemia, significant cardiovascular disease (including QTc > 450 ms), active systemic infections, liver disease, or HIV infection. Phases 1 and 2 include ≤ 2 reinduction cycles, optional consolidation therapy, and continuation therapy for those having a partial response (PR) or remission. Reinduction therapy will consist of fludarabine and cytarabine (FLA; 30 mg/m2/day and 2000 mg/m2/day, respectively) followed by Q in 28-day cycles. Patients will be treated with intrathecal (IT) triple chemotherapy prophylaxis before reinduction cycles 1 and 2 and after cycle 2. Additional IT triple chemotherapy prophylaxis may be given at investigator discretion for patients with CNS2 disease. Patients achieving at least a PR after reinduction may receive optional consolidation chemotherapy as a bridge to allogeneic hematopoietic SCT (HSCT). Optional consolidation regimens are high-intensity chemotherapy (cytarabine 500 mg/m2/day + etoposide 100 mg/m2/day) followed by Q, or low-intensity consolidation with either Q monotherapy or cytarabine (75 mg/m2/day). Patients who achieve at least a PR after reinduction or continue to be in remission after HSCT may receive continuation therapy with Q monotherapy (for up to twelve 28-day cycles). In phase 1, the starting dose of Q for the reinduction cycle for patients 1 to ≤ 21 years will be 40 mg/m2 once daily with body surface area (BSA) < 1.5 m2 or 60 mg once daily for patients with BSA ≥ 1.5 m2. The starting dose of Q for younger patients in phase 1 will be determined from the recommended phase 2 dose (RP2D) from the older age group and pharmacokinetic (PK) modeling. Up to 9 patients per dose level will be enrolled in the older age group, and younger patients will be enrolled using a rolling 6 design. Patients in phase 2 will receive the RP2D for their respective age group. The planned sample size is 41-65 patients to meet the target of 41 response-evaluable patients at the RP2D. QTc based dose modifications will be instituted for Q. The primary endpoints are safety, composite complete remission rate (CRc; defined as complete remission + complete remission with incomplete recovery), and PK parameters. Secondary endpoints include duration of responses, relapse rates, overall survival, and event-free survival at 1, 2, and 3 years, number of patients proceeding to HSCT, pharmacodynamics, gene mutations in bone marrow blasts, minimal residual disease, and FLT3 allelic ratio. This study is recruiting and being conducted in collaboration with the Children's Oncology Group in North America and the Innovative Therapies for Children with Cancer Consortium in Europe. Disclosures Zwaan: Servier: Consultancy; Pfizer: Research Funding; BMS: Research Funding; Janssen: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Jazz Pharmaceuticals: Other: Travel support; Incyte: Consultancy; Novartis: Consultancy. Mires:Daiichi Sankyo: Employment. Vigliotti:Daiichi Sankyo, Inc.: Employment. Xie:Daiichi Sankyo, Inc.: Employment. Downs:Daiichi Sankyo, Inc.: Employment. DeCillis:Pyramid: Consultancy; Codiak: Consultancy; Eleven: Consultancy; Arvinas: Consultancy; Exelixis: Consultancy; Novartis: Consultancy; Genocea: Consultancy; Daiichi Sankyo, Inc.: Consultancy; CytomX: Consultancy.

1023. Isavuconazonium Use at an Academic Transplant Center

Background Isavuconazonium is an appealing anti-fungal due to its broad spectrum of activity, predictable pharmacokinetics, oral bioavailability, and lack of QTc prolongation, but real-world experience with it is limited. At our academic medical center, isavuconazonium is restricted to the infectious diseases (ID) service for treatment of invasive fungal infections, including endemic mycoses due to high prevalence, and is recommended for patients intolerant of first-line agents. The purpose of this study was to describe isavuconazonium use at our institution and assess adherence to its formulary guidelines. Methods Inpatients with an order for isavuconazonium between June 2016 and November 2018 were analyzed via retrospective chart review. Prescribing team, indication, and rationale for use were evaluated. Results There were 97 inpatient encounters with an isavuconazonium order among 57 patients. Of those, 30 were solid-organ transplants and 9 had bone marrow transplants. Indications for isavuconazonium were: histoplasmosis 25%, high-risk fungal prophylaxis 21%, invasive aspergillosis 9%, candidiasis 2%, and other 44% (Table 1). Preceding anti-fungal therapy included: voriconazole 49%, posaconazole 12%, fluconazole 9%, micafungin 7%, amphotericin B 5%, itraconazole 4%, and none 35%. The rationale for the use of isavuconazonium is described in Table 2. ID consultation occurred in 79% of patients. Those without a consult had an indication of prophylaxis or were continuation of therapy started outpatient or at an outside hospital (OSH). Conclusion Histoplasmosis was the most common infection treated with isavuconazonium, despite limited data for that indication. Further investigation of the clinical course for these patients is warranted. Reasons for use most commonly centered on concern for QTc prolongation, clinical failure, and drug interactions. Over one-third of patients received no anti-fungal therapy prior to initiation. Adherence to required ID consultation was high. Patients on isavuconazonium for prophylaxis or as continuation therapy without a consult may still benefit from ID review to assess the appropriateness of therapy. Disclosures All authors: No reported disclosures.

An algorithmic approach to deriving line of therapy in a real-world data set for non-small cell lung cancer (NSCLC).

e18099 Background: Real World Data (RWD) is being used for outcomes research and regulatory submissions. A key variable needed to understand treatment outcomes is Line of Therapy (LoT). However, LoT is generally not captured in RWD sources such as electronic health records (EHR) or claims data, and is typically derived using manual abstraction. To determine whether an automated approach to LoT derivation is possible, we created an algorithm and applied it to patients (pts) in the Syapse Learning Health Network. Methods: We selected confirmed NSCLC pts from 4 health systems in the RWD set, verifying diagnosis using ICD-9/10/O3 topography and morphology codes. We analyzed the EHR-derived medication list using a regimen-independent algorithm that classified antineoplastic drugs (AD), as defined by ATC L01, into LoT. Within each LoT, we compared the top 80% of AD prescribed (by volume of pts) to the LoT as indicated on each drug’s FDA label. We then used descriptive statistical summaries to outline the alignment between automated algorithmic results and indicated usage within that LoT. Results: In a set of 10,842 NSCLC pts, a total of 106 unique AD were prescribed in the first line as identified by our algorithm, and 13 drugs were prescribed as first line for 80% of the pts. Of those, 9 (69%) of those are indicated for first line, 3 are not indicated for NSCLC, and 1 is indicated for a subsequent NSCLC line, per FDA labels. 82 unique AD were prescribed in the second line as identified by our algorithm, and 15 drugs were prescribed as second line for 80% of the pts. Of those, 11 (73%) are indicated for treatment/continuation therapy for recurrent, advanced or metastatic disease, 3 are not indicated for NSCLC, and 1 is indicated for first line NSCLC per FDA labels. 36 unique AD were prescribed in subsequent line as identified by our algorithm, and 18 drugs were prescribed as subsequent line for 80% of the pts. Of those, 12 (67%) are indicated for treatment of recurrent, advanced or metastatic disease or subsequent systemic therapy, 5 are not indicated for NSCLC and 1 is indicated for first line per FDA labels. Conclusions: An automated algorithmic approach for deriving lines of therapy may be a viable solution to scalably calculate LoT in RWD sets. A deeper analysis using statistical sensitivity and specificity assessment of such algorithms is needed to validate the potential of an algorithmic approach.

Development of a Novel Next-Generation Sequencing (NGS)-Based Assay for Measurable Residual Disease (MRD) in FLT3-ITD AML and Its Potential Clinical Application in Patients Treated with Chemotherapy Plus FLT3 Inhibitors

The presence of MRD in patients with acute myeloid leukemia (AML) who are in morphologic remission has been shown to be a powerful predictor of eventual relapse. FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) confer a negative prognostic impact by increasing the risk of relapse. However, the ability to detect these mutations in remission bone marrow specimens is hampered by the limited sensitivity of conventional polymerase chain reaction (PCR)-based assays, which detect approximately only 1 of every 100 (1%) mutant cells. To address this problem, we have developed a novel NGS-based MRD assay for the detection of FLT3-ITD mutations. Using isolated genomic DNA from bone marrow aspirates or whole-blood samples, PCR primers flanking exons 14 and 15 of the FLT3 gene were designed and highly diverse NGS libraries were generated. These libraries were then sequenced by Illumina's sequencing-by-synthesis method. The bioinformatics approach we used identifies unique FLT3-ITD mutations of varying length along with wild type sequences and calculates a mutant allelic frequency. The assay was validated using clinical samples to assess accuracy and reproducibility. DNA samples from selected mutant cell lines representing different FLT3-ITD lengths were spiked into normal DNA to evaluate assay sensitivity and linearity. The assay was linear (R2 = 0.958) down to FLT3-ITD allele frequency levels of 0.035% but was capable of detecting FLT3-ITD mutations at a level as low as 0.003%. We next validated the assay using clinical samples from patients with FLT3-ITD AML. The negative prognostic impact of FLT3-ITD mutations can be mitigated in part when an FLT3 inhibitor is administered in combination with induction chemotherapy, as demonstrated in CALGB10603/RATIFY (N Engl J Med. 2017;377:454). It was reported in this study that patients treated with an FLT3 inhibitor combined with chemotherapy followed by allogeneic transplant in first remission had better overall survival than their counterparts in the control arm. One hypothesis for this outcome is that the FLT3-inhibitor-treated patients had a lower leukemic burden prior to transplant. As a pilot test of this concept, we used our MRD assay on a series of bone marrow aspirate samples collected from 10 patients with newly diagnosed FLT3-ITD AML. The patients were selected to be as uniform as possible. All patients had intermediate-risk karyotype, a detectable FLT3-ITD mutation by conventional PCR, and mutated NPM1. All patients received cytarabine-based intensive induction and achieved morphologic first remission with a single course of chemotherapy. Finally, all patients underwent allogeneic transplant in first remission. The sample analyzed for MRD was the first collected after remission induction, 5-8 weeks after the start of therapy. The investigators performing the MRD assay were blinded to the clinical data. Four patients received chemotherapy alone, while 6 were treated with chemotherapy (7+3) plus an FLT3 inhibitor. In all patients' remission samples, the MRD assay identified the FLT3-ITD mutation that precisely matched the one observed in the original diagnostic specimen. This demonstrates the sensitivity of the assay (all samples had a detectable mutation), and the unique length of each patient's mutation confers a degree of specificity not achievable with MRD detection methods that focus on other AML-associated mutations. Supporting our hypothesis was the observation that patients treated with FLT3 inhibitors had MRD levels lower than those in patients treated with chemotherapy alone (Figure). Our results help establish the role of NGS-based MRD assays for the clinical management of FLT3-ITD AML. This assay could be used to define the depth of remission, identify persistent disease, and help guide decision making in the use of FLT3 inhibitors as continuation therapy. This study provides validation of the clinical utility of our MRD assay, which will be used to analyze the remission samples from patients in the ongoing phase 3, randomized, double-blind, placebo-controlled QuANTUM-First clinical trial, in which patients with newly diagnosed FLT3-ITD AML are randomized to receive either the highly potent and selective FLT3 inhibitor quizartinib or placebo in combination with chemotherapy, followed by single-agent quizartinib as continuation therapy. Disclosures Shi: Novartis: Employment, Equity Ownership; Daiichi Sankyo: Other: Provide clinical trial testing services. Chang:Daiichi Sankyo: Employment. Laing:Novartis: Employment; Daiichi Sankyo: Other: Provide clinical trial testing services. Berisha:Daiichi Sankyo: Employment. Adams:Johns Hopkins University: Employment. Ding:Navigate BP: Employment; Daiichi Sankyo: Other: Provide clinical trial testing services. Nakamaru:Daiichi Sankyo: Employment. Lameh:Navigate BioPharma Inc,: Employment; Daiichi Sankyo: Other: Provide clinical trial testing services. Pollner:Navigate BioPharma Inc.: Employment. Kobayashi:Daiichi Sankyo: Employment.