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The study evaluated the diagnostic value and cost-effectiveness of next-generation sequencing (NGS)-based testing versus various combinations of single-gene tests (SGTs) for selection of first-line treatment for patients with advanced/metastatic non-squamous non-small-cell lung cancer in the United States. A dynamic decision analysis model was developed comparing NGS versus SGT from a payer perspective. Inputs were obtained from published sources and included diagnostic performance, biomarker-positive disease rates, biomarker-directed recommendations for treatment, and survival outcomes. Costs were reported in 2020 US dollars. In the base case, NGS improved the detection of actionable biomarkers by 74.4%, increased the proportion of patients receiving biomarker-driven therapy by 11.9%, and decreased the proportion of patients with biomarker-positive disease receiving non-biomarker-driven first-line treatment by 40.5%. The incremental cost-effectiveness ratio per life-year gained of NGS testing versus SGT was $7224 (excluding post-diagnostic costs); the incremental cost-effectiveness ratio for NGS-directed therapy was $148,786 versus SGT-directed therapy. Sensitivity analyses confirmed the robustness of these findings; survival outcomes and targeted therapy costs had the greatest impact on results. Testing strategies with NGS are more comprehensive in the detection of actionable biomarkers and can improve the proportion of patients receiving biomarker-driven therapies. NGS testing may provide a cost-effective strategy for advanced/metastatic non-squamous non-small-cell lung cancer; however, the value of NGS-directed therapy varies by the willingness-to-pay threshold of the decision-maker.

Purpose Results of a study in which population-based body weight and body surface area (BSA) data were used for vial size optimization to reduce drug waste associated with administration of the i.v. anticancer agent olaratumab are reported. Methods A retrospective observational study was conducted to determine weight and BSA distributions in a large sample of U.S. oncology patients using data from a large electronic medical record database. Body weight and BSA values at the time of initial systemic anticancer therapy were used to compute olaratumab dose requirements in a cohort of patients with soft tissue sarcoma; those data were analyzed to derive estimates of drug waste likely to result from the use of various proposed olaratumab vial sizes in combination with an existing 500-mg size. Weight and BSA distributions were calculated for additional cohorts of patients with 7 other cancer types. Results Median weight values in men ( n = 1,179) and women ( n = 1,078) with soft tissue sarcoma were 82.55 kg (interquartile range [IQR], 72.58–95.53 kg) and 68.69 kg (IQR, 58.51–84.28 kg), respectively. Modeling of olaratumab dosing scenarios indicated that use of the 500-mg vial only would result in estimated average drug waste of 234 mg per patient per administration; analysis of various potential vial size combinations showed that waste could be reduced by 87.6% with the addition of a 190-mg vial size. Conclusion Analysis of real-world patient weight and BSA data allowed olaratumab vial size optimization to enable maximal dosing flexibility with minimal drug waste.

Breast cancer patients receiving curative chemotherapy often experience pain, nausea/vomiting, and anxiety. These symptoms are treated with opioids and benzodiazepines (1,2). In 2016, the American ...

The CXCR4 receptor (Chemokine C-X-C motif receptor 4) is highly expressed in different hematological malignancies including chronic lymphocytic leukemia (CLL). The CXCR4 ligand (CXCL12) stimulates CXCR4 promoting cell survival and proliferation, and may contribute to the tropism of leukemia cells towards lymphoid tissues. Therefore, strategies targeting CXCR4 may constitute an effective therapeutic approach for CLL. To address that question, we studied the effect of Ulocuplumab (BMS-936564), a fully human IgG4 anti-CXCR4 antibody, using a stroma – CLL cells co-culture model. We found that Ulocuplumab (BMS-936564) inhibited CXCL12 mediated CXCR4 activation-migration of CLL cells at nanomolar concentrations. This effect was comparable to AMD3100 (Plerixafor - Mozobil), a small molecule CXCR4 inhibitor. However, Ulocuplumab (BMS-936564) but not AMD3100 induced apoptosis in CLL at nanomolar concentrations in the presence or absence of stromal cell support. This pro-apoptotic effect was independent of CLL high-risk prognostic markers, was associated with production of reactive oxygen species and did not require caspase activation. Overall, these findings are evidence that Ulocuplumab (BMS-936564) has biological activity in CLL, highlight the relevance of the CXCR4-CXCL12 pathway as a therapeutic target in CLL, and provide biological rationale for ongoing clinical trials in CLL and other hematological malignancies.

Allergic transfusion reactions (ATRs) are a common complication of blood transfusions. Advances in transfusion medicine have significantly decreased the incidence of ATRs; however, ATRs continue to be burdensome for patients and problematic for providers who regularly order packed red blood cells and platelet transfusions. To further decrease the frequency of ATRs, routine premedication with diphenhydramine is common practice and is part of "transfusion culture" in a majority of institutions. In this article, we review the history, practice, and literature of transfusion premedication, specifically antihistamines given the adverse-effect profile. We discuss the rationale and original academic studies, which have supported the use of premedication for transfusions for decades. However, despite the common use of premedication to prevent ATRs, recent literature has not conclusively validated its use. In addition, the existing premedication that is routinely prescribed often causes a number of adverse effects. These findings have motivated the Moores Cancer Center (University of California, San Diego) to change its current transfusion premedication practices, particularly with regard to ATRs and first-generation antihistamines. We outline the preliminary development of an evidence-based and patient-specific approach to transfusion premedication, including the challenges and steps taken to revise inpatient premedication protocols. We plan to expand this protocol to the outpatient setting at a later date. Future efforts require a prospective validation of our presented transfusion premedication guidelines.

Background The cost of cancer care is increasing, and tools are needed to understand the economic impact of new drugs on the hospital pharmacy budget. Objective To develop an interactive budget impact model (BIM) through a collaborative effort of industry, academia, and modeling experts to evaluate the use of a new agent in non-small cell lung cancer (NSCLC); this BIM included an institutional module specific to the needs of practices that purchase medications for use in institutional settings. Methods Treatment regimens, doses, duration of therapy, toxicity, and cost data are from published sources. All input data may be modified to match the local population. Outputs include cost of care, reimbursement, and margin overall and by treatment regimen. Results The base case assumes 20 NSCLC patients progressing after initial therapy (3 receiving ramucirumab+docetaxel, 2 bevacizumab+erlotinib, 3 docetaxel, 6 erlotinib, and 6 pemetrexed), wholesale acquisition cost (WAC) purchase price, and reimbursement at WAC+4.3%. The model estimated the total cost and reimbursement for the institutional oncology pharmacy to be $699,413 and $729,487, respectively, resulting in a margin of $30,075 (difference due to rounding) for the year for regimens utilized in the treatment of NSCLC in the post-progression setting. Results will vary depending on the input data. Conclusions There is an increasing need for institutional pharmacies to plan ahead and anticipate the impact of new drugs on their oncology budgets. This interactive Excel-based institutional BIM may provide evidence-based support for pharmacy decision making.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults in the Western world. This leukemia is not curable and resistance to therapy is promoted by factors present in the tumor microenvironment including the chemokine CXCL12 (SDF-1), which interacts with its receptor CXCR4 and is thought to promote cancer cell survival. Here we explored the therapeutic potential of blocking CXCL12-CXCR4 interactions using PF-06747143, a humanized IgG1 antibody specific for CXCR4, which is expressed at high levels by CLL cells. Using primary leukemia cells from CLL patients, we found that PF-06747143 inhibited CXCL12-induced cell migration and blocked cytoskeletal changes via F-actin polymerization similar to AMD-3100 (Mozobil, a small molecule inhibitor of CXCR4). In addition, PF-06747143 induced apoptosis on CLL cells cultured alone or in the presence of human bone marrow-derived stromal cells (stroma-NK-tert). The pro-apoptotic activity of PF-06747143 was independent of high-risk prognostic factors including IGHV mutation status, ZAP-70 expression or TP53 mutation / 17p-deletion. Interestingly, AMD-3100, which binds and inhibits signaling through CXCR4, did not induce cell death in CLL or any of the cell lines tested. PF-06747143 did not induce apoptosis on normal B and T cells, and the ability of this anti-CXCR4 antibody to induce cell death on CLL cells appeared to be dependent on the crosslinking of CXCR4. This was supported by the fact that a Fab only fragment derived from PF-06747143 did not induce apoptosis despite of its high binding affinity for CXCR4. We observed that PF-06747143 induced complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in CLL cells. However, this antibody did not induce caspase activation but rather its cell death activity appeared to be dependent on the production of reactive oxygen species (ROS) in leukemia cells. This effect was similar to that observed with other ROS dependent antibodies such as obinutuzumab (Gazyva). ROS induction was observed with PF-06747143, but not its Fab derived fragment and preceded apoptosis suggesting that this is critical component of its mechanism of action. We evaluated synergism of PF-06747143 with other CLL therapeutic agents and observed that this antibody synergized with fludarabine, bendamustine, ibrutinib and rituximab in the majority of CLL patient samples tested. In summary, our studies showed that PF-06747143, a CXCR4 IgG1 antibody is a potent inhibitor of the CXCR4-CXCL12 pathway and induces cell death primarily in CLL cells but not in normal lymphocytes. The cytotoxic effect of PF-06747143 was similar in CLL cells cultured alone or with stromal cells, suggesting that this antibody has the potential to overcome the protective effect of the tumor microenvironment. We also showed that PF-06747143 induced programmed cell death on CLL cells was dependent on ROS production and that this antibody synergized with agents currently used for the treatment of CLL patients. Overall, these findings highlight the biological relevance of the CXCR4-CXCL12 pathway in CLL, and provide rationale for clinical evaluation of PF-06747143 in CLL and other cancers. Disclosures Choi: Gilead: Consultancy, Other: Advisory Board, Speakers Bureau; AbbVie: Consultancy, Other: Advisory Board, Research Funding. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor.

Chronic lymphocytic leukemia (CLL) is not curable and ultimately patients (pts) relapse and require additional treatment. In addition, most of CLL pts are older than 65 years old or are unfit to receive chemotherapy. Because of these reasons there is a need for the development of novel therapeutic strategies. Obinutuzumab, a third-generation anti-CD20 mAb, in combination with chlorambucil is currently approved by the FDA for previously untreated pts. Studies have demonstrated that most of the clinical benefit of this regimen is derived from obinutuzumab rather than chlorambucil, and also that obinutuzumab has superior clinical activity than rituximab. Because of these and our previous clinical studies that have shown synergism between HDMP and anti-CD20 antibodies, we initiated an open label phase Ib/II clinical study of obinutuzumab with HDMP for therapy of pts with CLL. The study is divided in two cohorts of 20 pts each, front-line (FL) and relapsed / refractory (RR) CLL. Pts receive HDMP 1g/m2 on Day 1-3 of cycles 1-4 (28 days / cycle) and obinutuzumab administered based on FDA dosing recommendations for 6 cycles. All pts received prophylactic medications (trimethoprim/sulfamethoxazole, acyclovir, fluconazole and allopurinol). 85% of target accrual has been completed (RR cohort=19 pts; FL cohort=15 pts). Here we present a preliminary analysis of safety /tolerability of this regimen. The median age in the RR cohort was 68 years +/- 7.8 and 62 years +/- 7.3 in the FL cohort. 84% and 87% of the pts in the RR and FL cohorts had a CIRS > 6, respectively. The median baseline absolute lymphocyte count was 32.9 +/- 32.6 x103/mm3 for pts in the RR cohort and 49.3 +/- 98.1 x103/mm3 for pts in the FL cohort. Pts showed the following cytogenetic abnormalities: del(17p) in 32% RR vs. 0% FL, del(13q) in 63% RR vs.67% FL, del(11q) in 21% RR vs. 33% FL, and trisomy 12 in 16% RR vs. 20% FL. All 34 pts were assessed for adverse events (AEs). Most AEs were grade 1-2 (RR=88%; FL=92%) without development of dose-limiting toxicities (DLTs). One pt in the RR cohort developed asymptomatic metformin-associated lactic acidosis that required overnight inpatient observation without therapy discontinuation. Grade 1-2 obinutuzumab-infusion-related reactions (IRR) were observed in 42% and 87% of pts in the RR and FL cohort, respectively. We did not observe grade 3-4 IRR. Only one patient has required therapy discontinuation due to asymptomatic GI bleeding that required blood transfusion and resolved spontaneously. We observed neutropenia (RR: all grades: 63%, grade 3-4: 26%; FL: all grades: 53%, grade 3-4: 33%), thrombocytopenia (RR: all grades: 68%, grade 3-4: 37%; FL: all grades: 80%, grade 3-4: 40%) and anemia (RR: all grades: 58%; FL: all grades: 53%). There were no cases of febrile neutropenia. Three pts (16%) in the RR cohort developed community-acquired pneumonia, requiring outpatient treatment with oral antibiotics but not study treatment discontinuation. The most frequent non-hematological AEs were transaminitis, hyperglycemia, and electrolyte alterations (grade 1-2). All 34 pts have had favorable clinical and hematological responses. Six pts (4 pts in the RR cohort and 2 pts in the FL cohort) were evaluable for response assessment by iwCLL criteria. The four pts in the RR cohort achieved a PR. In the FL cohort, 1 pt achieved a CR MRDneg ( Overall, obinutuzumab with HDMP has been well tolerated with no evidence of DLTs. The profile of AEs appears favorable compared to those noted with obinutuzumab in combination with chlorambucil, particularly in terms of grade 3-4 IRR (0% vs 20%) or rate of therapy discontinuation (3% vs 7%). Enrollment continues and updated information will be presented during the meeting. Disclosures Choi: AbbVie: Consultancy, Other: Advisory Board, Research Funding; Gilead: Consultancy, Other: Advisory Board, Speakers Bureau. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor.

Sleep disruption is a common complaint in breast cancer patients receiving chemotherapy. We describe the sleep aid prescribing practices of oncologists treating women receiving adjuvant or neoadjuvant chemotherapy for breast cancer at a single institution.Subjects with early-stage breast cancer who received four cycles of neoadjuvant or adjuvant Adriamycin® and cyclophosphamide (AC) at the University of California, San Diego over a 2-year period were evaluated by retrospective chart review. Clinical data pertinent to sleep disorders and electronic prescriptions for sleep aids were collected using the electronic medical record.Of the 124 breast cancer subjects, 52.4% discussed sleep with their provider. Whereas 13.7% of subjects reported prior sleep aid use, 32.3% were prescribed sleep aids during chemotherapy, most commonly lorazepam (31.4%) and zolpidem (29.4%). Women prescribed sleep aids during chemotherapy were significantly more likely to discuss sleep with their provider, more likely to have been taking sleep aids previously, and more likely to be taking psychiatric medications.Sleep disturbances during AC chemotherapy for early-stage breast cancer are common and are frequently treated with sleep aid medications. We show that women with prior sleep aid use and concurrent psychiatric medication use were more likely to need sleep aids during chemotherapy, suggesting these are high-risk populations that could be targeted for intervention prospectively.

Abstract 2866 Despite advances in the treatment of patients with chronic lymphocytic leukemia (CLL), the disease still remains incurable and eradication of minimal residual disease (MRD) being one of the most challenging goals of treatment. Alemtuzumab (Campath-H1™) has been shown to effectivily eradicate MRD from the bone marrow and induce long-term remissions, however its use is limited to patients without bulky disease. Futhermore, combination of alemtuzumab with chemotherapy has resulted in serious adverse events. In this study, we evaluate the toxicity and efficacy of alemtuzumab as consolidation therapy for CLL patients following induction with high-dose methylprednisolone in combination with rituximab (HDMP-R). Twenty-one patients with evidence of residual disease after treatment with HDMP-R received additional treatment with alemtuzumab. This antibody was administered three times a week for a total of 8 weeks. Patients received antibiotic prophylaxis with trimethoprim-sulfamethoxazole 160/800 mg twice a day × 3 per week, fluconazole 100 mg / day and valganciclovir 900 mg / day. The median age was 60 years (range, 49–73), with Rai stage III-IV in 81% of the patients. Twelve patients (57%) had evidence of unmutated IgVH gene and thirteen (62%) had high level of ZAP-70 expression. Cytogenetic and FISH analysis showed eight patients with deleletion 13q, three patients with trisomy 12, one patient with deletion 11q, five patients with no chromosomal abnomalities and in six patients data was not available. The median number of previous treatments was 1.3 (range, 0–5) and the median time from the end of HDMP-R treatment to initiation of alemtuzumab was 5 months (range, 1–14). After HDMP-R, nine patients (43%) achieved CR and twelve (57%) were in PR; all of them had evidence of residual disease in the bone marrow by 4-color flow cytometry analysis. Eight additional patients achieved CR after consolidation with alemtuzumab for a total of 17 patients (81%) in CR at the end of the study. We found no evidence of MRD (MRDneg) in 12 of those patients (57% of the total and 71% of CR patients). Of the remaining patients, one had PR and three patients had progressive disease for an overall response rate of 86%. The median progression-free survival (PFS) was 63 months (range, 6–84) for all patients. The median PFS in CR MRDneg patients has not been reached at a median follow-up of 46 months (range, 18–84), with 8/12 patients that have not progressed after a time at risk of 3.8 years. CR MRDpos patients have a median PFS of 48 months (range, 6–48). The treatment was well tolerated and there were no deaths attributed to therapy. Adverse events were classified following the NCI common terminology criteria for adverse events (CTCAE) Version 4.0. Two patients (9.5%) developed infections. The first event occurred during the administration of alemtuzumab and required hospitalization of the patient for management of pneumonia galactomannan positive suspicious for invasive aspergillosis (Grade 3), the second event was in a patient with aspegillus sp. infection of the skin that occurred four months after completion of alemtuzumab (Grade 2). Both patients recovered completely. We observed no CMV or other opportunistic infections. Three patients (14%) developed cytopenias; two patients with (Grade 4) thrombocytopenia and three patients with (Grade 4) neutropenia. In conclusion, alemtuzumab consolidation for residual disease after treatment with HDMP-R was well tolerated and effective in patients with CLL. We observed a near two-fold increase in the number of patients that achieved CR and the majority of these (71%) had no evidence of MRD. Moreover, patients with CR MRDneg have an exceptionally long PFS. The low rate of infection and lack of treatment related mortality compares very favorably with previous studies using alemtuzumab consolidation after chemotherapy treatment in which toxicities including treatment related death were found to be prohibitive. These encouraging results provide the rationale for additional studies using this combination therapy. Disclosures: James: Celgene: Research Funding.

Treatment options for relapsed / refractory or heavily pretreated patients with chronic lymphocytic leukemia (CLL) are limited, and these patients typically have a poor prognosis. We conducted a study to evaluate the combination of High-dose methylprednisolone (HDMP) with ofatumumab (HDMP-O) in patients who were not considered eligible to receive chemotherapy due to the presence of comorbidities, poor performance status, severe cytopenias and / or refractory status to fludarabine or alemtuzumab. Patients received HDMP 1 g/m IV daily 3 every 28 days for three consecutive cycles, and ofatumumab 300 mg (dose 1) followed by 11 doses of 2,000 mg over a 6 month period, along with prophylactic antimicrobial therapy (trimethoprim-sulfamethoxazole 160/800 mg twice a day 3 per week, fluconazole 100 mg/day and valganciclovir 900 mg/day). Eight patients were evaluated; all of them were males with progressive and symptomatic CLL. Median age was 69 years (range 49–78 years). The mean number of prior treatment regimens was 3.75, including four patients that had previously received HDMP and rituximab and two patients that underwent matched unrelated donor stem cell transplantation. All patients had been previously treated with rituximab, 75% of the patients were refractory to fludarabine and / or aletuzumab, and 88% had high-risk disease based on the presence of unfavorable cytogenetics (17p-, 11q-), unmutated IgVH status, or ZAP-70 expression. Bulky disease and splenomegaly were present in 62.5% of patients. All patients completed the planned therapy with no major side effects or toxicities. There was no evidence of myelosupression, and even patients with pancytopenia improved their peripheral blood counts. Response assessment based on the IW-CLL 2008 criteria showed an overall response rate of 50% (4 partial responses), 25% of patients had stable disease and the remainder showed progressive disease. The median time to progression in responders was 7 months. Overall survival 6 months after treatment was 65%. This study suggests that the combination of HDMP and Ofatumumab is a safe and effective salvage regimen for high-risk CLL patients who otherwise would not be candidates for additional treatment. 5.57 Pattern of Use and Effectiveness of RituximabBased Therapy in CLL/SLL in the Province of Manitoba, Prior to its Approval as First-Line Treatment for CLL Kimi Guilbert, Bernie Lozar, Baptist Joseph, Patricia Burns, Venetia Bourrier, Pamela Skrabek, Sri Navaratnam, James Johnston, Rajat Kumar University of Manitoba and CancerCare Manitoba, Departments of Hematology & Medical Oncology, Provincial Oncology Drug Program, and Epidemiology and Cancer Registry, Winnipeg, Canada

Abstract 4638 High-dose methylprednisolone (HDMP) and the fully human monoclonal anti-CD 20 Ofatumumab each can produce partial responses in CLL, even though complete remissions are not often observed following treatment with either agent alone. Previously we have reported that the combination of Rituximab and HDMP is an effective non-myelosuppressive treatment combination for previously untreated CLL patients as well as in patients that are fludarabine refractory. We report here our single institution experience of treatment using the combination of HDMP and Ofatumumab in CLL patients that were not considered to be good candidates for chemotherapy treatment due to comorbidities, poor performance status, profound cytopenias or because refractory status to fludarabine and/or alemtuzumab. Eight patients with progressive, symptomatic CLL were treated with HDMP 1 g/m2 IV daily × 3 every 28 days for three consecutive cycles, and ofatumumab administered based on package insert instructions (300 mg dose # 1 followed by 11 doses of 2,000 mg over a 6 month period) along with prophylactic antimicrobial therapy. The main objectives were to determine the safety, toxicity and clinical efficacy of this regimen. All of the patients were males with a median age of 69 years (range 49–78). The median of prior treatments was 4.5 including 4 patients that have received previously HDMP and rituximab and two patients that underwent matched unrelated donor stem cell transplant. All patients have been previously treated with rituximab, 75% of the patients failed or were intolerant to fludarabine and/or aletuzumab and 88% had high-risk disease by the modified Rai classification. Most of the patients had bulky disease with median lymph node product of 42 cms2 and median splenomegaly of 6. 5 cm (range 0–17) below the left costal margin. The median lymphocyte count was 28,000 cells/mm3. 75% of the patients had high-risk prognostic markers including unfavorable cytogenetics, unmutated IgVH region genes or high expression levels of ZAP-70. All patients completed the planned therapy with no major side effects or toxicities. There was no evidence of marrow suppression and even patients with pancytopenia improved their peripheral blood counts with this salvage regimen. During treatment patients experience significant decrease in peripheral white blood cell counts, increase in hemoglobin, elevation of platelets and a dramatic reduction in lymphadenopathy and splenomegaly. Response assessment based on the IW-CLL 2008 criteria showed that the overall response rate was 50% (4 partial remissions), 25% of patients had stable disease and the remainder showed progressive disease. Overall, these data suggest that the combination of HDMP and Ofatumumab is a safe and effective salvage regimen for high-risk CLL patients that otherwise were not candidates for additional treatment. The response rates observed for the combination of HDMP and Ofatumumab in this group of patients appear to be favorable with the majority of patients achieving a response to therapy or experiencing disease stabilization. Moreover, HDMP and Ofatumumab treatment was not associated with bone marrow suppression, which is a major limiting factor for treatment administration, making this regimen a potential valid alternative for high-risk CLL patients. Additional clinical studies of this combination are warranted. Disclosures: No relevant conflicts of interest to declare.