To improve patient quality of life and reduce health care costs, many conditions formerly thought to require inpatient care are now treated in the outpatient setting. Outpatient induction chemotherapy for acute myeloid leukemia (AML) may confer similar benefits. This possibility prompted a pilot study to explore the safety and feasibility of intensive outpatient initial or salvage induction chemotherapy administration for adults with AML and high-risk myelodysplastic syndrome (MDS). Patients with no significant organ dysfunction and a treatment-related mortality (TRM) score corresponding to a day 28 mortality rate of <5% to 10% were eligible for study. Patients were treated as outpatients with daily evaluation by providers and only admitted to the hospital if mandated by complications. Twenty patients were consented, and 17 were treated. Eight patients received initial induction chemotherapy and 9 received salvage induction chemotherapy. Fourteen patients completed induction chemotherapy administration in the outpatient setting (82.4%; exact 95% confidence interval [CI], 55.8-95.3). Three patients were admitted during the course of chemotherapy administration, 2 for neutropenic fever and 1 for grade 3 mucositis. No patients died within 14 days of the initiation of induction chemotherapy (exact 95% CI, 0-22.9). Results of this pilot study suggest it is feasible to complete outpatient induction chemotherapy in select patients with AML and high-risk MDS. A team including nurses, social workers, medical providers, and pharmacists was key to the successful implementation of outpatient induction.
Background: The treatment of multiple myeloma (MM) is optimized by use of combination regimens consisting of agents with different mechanisms of action. Panobinostat is a pan-inhibitor of histone deacetylases types I,II, and IV. Panobinostat, bortezomib, dexamethasone was shown to be an effective regimen (San Miguel et al Lancet Hematol 2016; Richardson et al Blood 2016), leading to the FDA approval of panobinostat for patients with relapsed/refractory MM. Carfilzomib is a proteasome inhibitor that was FDA approved in relapsed/refractory MM with the advantage of minimal neuropathy. Panobinostat and carfilzomib has also been shown to be a highly active regimen in relapsed/refractory MM with an overall response rate of up to 75% (Berdeja et al, Haematologica, 2015). With the heterogeneity of MM, individual patients exhibit wide variability in responses to drug combinations. A test that could predict patient responses to specific agents might enable clinicians to optimize therapy for patients, improving outcomes. We developed an in vitro high throughput drug sensitivity assay with formal synergy testing to predict response. In this ongoing trial, Panobinostat with Carfilzomib and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Correlation with In Vitro Chemosensitivity Testing (NCT03256045), we will correlate individual patient in vitro sensitivity assay results with individual clinical response to the same triple drug regimen. Study Design and Methods: This study's objective is to directly demonstrate the utility of a high throughput drug sensitivity assay in determining biomarkers (e.g. individual IC50s, AUCs and/or synergy scores) to accurately predict response to combination therapy that was given prospectively to all enrolled patients. We are enrolling patients with relapsed/refractory MM by IMWG criteria with measurable disease defined by the detection of a quantifiable monoclonal protein in the urine or serum or an abnormal serum free light chain ratio. Additionally, patients must have adequate blood counts and organ function. Patients who have had prior autologous or allogeneic transplants or CAR-T cell therapy are eligible. The regimen consists of panobinostat 20 mg orally on days 1,3,5,15,17,19; carfilzomib 20 mg/m2/dose IV on days 1,2 of cycle 1, then dose escalation up to 45 mg/m2/dose days 8,9,15,16 and all days for subsequent cycles; and dexamethasone 20 mg orally on days of carfilzomib. Dose reductions of all three drugs are permitted per patient tolerance to allow continuation on study treatment. Up to 12 cycles of treatment are permitted. Patients are monitored by serial electrocardiograms and assessments of cardiac function. Safety parameters including adverse events are recorded. CD138+ plasma cells are procured from the patient bone marrow (aspiration and biopsy) and blood (when present) by magnetic bead separation. Cells are then added to 384-well plates and incubated overnight before the drugs are added. Cells are exposed to 8 concentrations (spanning 4 logs) of panobinostat, carfilzomib, or dexamethasone as singlet, doublet and triplet combinations for 72 hours. Cell viability is determined using CellTiter-Glo and IC50 and AUC values are are calculated by fitting data using least squares method to the standard four-parameter logistic model. Curve fitting is performed using IDBS XLFit software. The combination index is calculated by the method described by Chou and Talalay, Trends Pharmacol Sci 1983;4:450-4. Concentrations of Drug1 and Drug2 (that is, panobinostat and dexamethasone or panobinostat and carfilzomib) alone or in combinations are determined that give rise to 90% growth inhibition. At 90% Growth Inhibition, the Combination Index or CI = ([D1] in the combination / [D1] alone) + ([D2] in the combination / [D2] alone). All patients are treated with panobinostat, carfilzomib, and dexamethasone and evaluated for response using the IMWG response criteria. At the completion of enrollment at 35 patients, we plan to correlate the in vitro testing data with in vivo clinical response to determine appropriate biomarkers. This will be done by correlating the IC50s and AUCs for the individual drugs for responders vs. non-responders (including degree of response VGPR vs PR vs SD), as well as correlations of the synergy scores for each of the pairs of drugs in the responders vs. non-responders. Enrollment was initiated in April 2018. Disclosures Becker: Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; The France Foundation: Honoraria. Libby:Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy; Akcea: Consultancy; Alnylam: Consultancy. Cowan:Juno: Research Funding; Abbvie: Research Funding; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; Cellectar: Consultancy; Celgene: Consultancy, Research Funding. Hammer:Glycomimetics: Consultancy.
7007 Background: Outcomes for adults with R/R B-ALL remain poor, with existing options limited by efficacy and safety. InO has been combined with low-intensity chemotherapy, the benefit of which is unclear. DA-EPOCH is safe and active as frontline therapy in adults with ALL, so we combined this with InO in adults with R/R B-ALL (NCT03991884). Aims: The primary objective was to estimate the maximum tolerated dose (MTD) of InO when added to DA-EPOCH. Methods: Eligible patients (pts) were adults with R/R CD22+ B-ALL with ≥5% blood or marrow (BM) blasts or ≥1 site of measurable extramedullary disease (EMD); other eligibility criteria included ECOG ≤2 and no history of sinusoidal obstructive syndrome (SOS) or chronic liver disease. DA-EPOCH was given on days (d) 1-5 with GCSF. After cycle 1, dose adjustments to EPOCH were made based on hematologic nadirs from the prior cycle. Three dose levels (DL) of InO were studied, with InO given on d 8 + 15 as follows (respectively): 0.3 + 0.3 mg/m2 (DL1); 0.6 + 0.3 mg/m2 (DL2); and 0.6 + 0.6 mg/m2 (DL3). Up to 4 28-d cycles were given. The MTD was the highest DL of InO that yielded ≤33% rate of dose limiting toxicity (DLT), defined as grade 4+ non-heme treatment-related adverse events (TRAEs), any SOS regardless of timing, unable to complete 1 cycle due to TRAE, and treatment delays > 3 weeks. After the first 5 pts received DL1, a Bayesian Optimal Interval Design was used. Target accrual was 24 pts. BM and EMD response was assessed by NCCN criteria, with measurable residual disease (MRD) evaluated by multiparameter flow cytometry (MFC) and clonoSEQ. Results: 24 pts were screened: all were enrolled and evaluable for DLT and response. Median age was 46 (range: 28-76) years; median prior lines of therapy was 3 (range: 1-16); 13 pts (54%) had previously received allograft (HCT). 5 pts were enrolled at DL1, 8 pts at DL2, and 11 pts at DL3. There were 4 total DLTs: 1 at DL1 (grade 4 sepsis) and 3 at DL3 (grade 4 hyponatremia; delay for pancytopenia; grade 5 SOS after post-study HCT). DL3 was thus determined to be the MTD. No deaths occurred on study. Three pts (12%) had Grade 3 AST/ALT elevation; the SOS rate was 4%. Other grade 3+ non-heme TRAEs seen in >1 pt included infections (6 pts; 9 events), neutropenic fever (7; 8), and oral mucositis (3; 4). In the pts with ≥5% blood/BM blasts (n=20), the CR/CRi rate was 85%. By MFC, 70% achieved MRD- (45% after 1 cycle); using clonoSEQ, 33% were MRD-. Of the 6 pts with EMD, 83% responded (4 CR; 1 PR). The per-protocol and intent-to-treat (ITT) overall response rate was 83%. With median follow-up of 12 months (m), the median overall and relapse-free survival were 19 m and 12 m. Nine (38%) pts received post-study HCT. Conclusions: The addition of InO to DA-EPOCH in adults with heavily-pretreated R/R B-ALL is safe, with ITT response rates among the highest reported to date. Many pts proceeded to HCT. Further investigation of this combination is warranted. Clinical trial information: NCT03991884 .
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