ALBERT

Description: Medical requirements for the future Crew Exploration Vehicle (CEV), Lunar Surface Access Module (LSAM), advanced Extravehicular Activity (EVA) suits and Lunar habitat are currently being developed. Crews returning to the lunar surface will construct the lunar habitat and conduct scientific research. Inherent in aggressive surface activities is the potential risk of injury to crewmembers. Physiological responses and the operational environment for short forays during the Apollo lunar missions were studied and documented. Little is known about the operational environment in which crews will live and work and the hardware will be used for long-duration lunar surface operations. Additional information is needed regarding productivity and the events that affect crew function such as a compressed timeline. The Space Medicine Division at the NASA Johnson Space Center (JSC) requested a study in December 2005 to identify Apollo mission issues relevant to medical operations that had impact to crew health and/or performance. The operationally oriented goals of this project were to develop or modify medical requirements for new exploration vehicles and habitats, create a centralized database for future access, and share relevant Apollo information with the multiple entities at NASA and abroad participating in the exploration effort.

Description: Key Points The authors developed a novel method for isolating tumor membrane antigens. LCP1 is functionally relevant to leukemia chemokine induced migration.

Description: Key Points Cytoreduction with obinutuzumab and ibrutinib followed by the addition of venetoclax has acceptable safety with no tumor lysis syndrome. This combination has preliminary activity including complete remissions with undetectable residual disease in relapsed or refractory CLL.

Description: BACKGROUND Development of targeted therapies for CLL including the anti-CD20 monoclonal antibody obinutuzumab (OBIN), Bruton's tyrosine kinase inhibitor ibrutinib (IBR), and Bcl-2 inhibitor venetoclax (VEN) have demonstrated significant clinical activity in CLL. As they have high response rates as single agents, largely non-overlapping toxicities, and distinct and potentially synergistic mechanisms of action, we designed and initiated a triplet regimen with OBIN, IBR, and VEN for a fixed duration of treatment. The goal of the regimen is to achieve deep remissions and facilitate treatment discontinuation. The previously reported phase 1b cohort on this study established VEN 400 mg daily as the recommended dose for use with the label doses of OBIN and IRB in this combination. To determine response rates, eradication of minimal residual disease (MRD), and progression-free survival (PFS) in relapsed/refractory (RR) and treatment-naïve (TN) CLL with this regimen, two separate cohorts were accrued to a phase 2 trial. METHODS Patients with RR or TN CLL requiring therapy were eligible. Patients were required to have ECOG PS ≤1 and preserved end-organ function, including normal serum creatinine or creatinine clearance ≥50 mL/min/m2. RR patients had to have ≥1 prior CLL therapy. Treatment was given at the doses and schedule established in the preceding phase 1b study (Jones ASH 2016) for 14 cycles (C) of 28 days with OBIN, IBR, and VEN started sequentially over the first 3 cycles. Risk for tumor lysis syndrome (TLS) with VEN was assessed according to US prescribing information with monitoring instituted according to risk. Adverse events (AEs) were assessed and graded using the NCI CTCAE v4.03 except hematologic AEs which were graded according to the IWCLL 2008 guidelines. Response was determined according to IWCLL 2008 criteria after C8 (mid-therapy) and 2 months after completing C14 (EOT). MRD was measured in the bone marrow and peripheral blood by standard 10-color flow cytometry at these time points. The primary endpoint was MRD negative complete response at EOT. For each cohort, 25 patients provided at least 90% power to detect an increase in MRD negative complete response rate from 10% to 30% using a single stage design and constraining type I error rate to 10%. Herein, toxicity and mid-therapy responses are presented. RESULTS The study enrolled a total of 50 patients with 25 RR and 25 TN in separate cohorts. Baseline characteristics are in Table 1. The adverse event (AE) profile was similar to the phase 1b study and consistent with the known toxicities of the included individual agents. Frequent treatment-related AEs are found in Table 2. Hematologic toxicity was most frequent with the majority of patients experiencing thrombocytopenia (80%) and/or neutropenia (76%). The most frequent non-hematologic toxicities were hypertension (70%), infusion related reactions (66%), bruising (52%), myalgia (50%), and nausea (50%). Grade 3-4 toxicities were largely hematologic with 56% experiencing grade 3-4 neutropenia and 34% grade 3-4 thrombocytopenia. The only frequently occurring non-hematologic grade 3-4 toxicity was hypertension (32%). The median follow-up for the study was 18.0 months (range 0-24.8) for the RR cohort and 20.6 months (range 7.4-23.9) for the TN cohort. At mid-therapy assessment 23/25 of the RR patients remained on study and all had achieved a response. Three patients achieved CR, 3 a CR with incomplete marrow recovery, and 17 a partial remission. The ORR in RR patients at mid-therapy was 92% (95% CI: 74-99%). Twenty-three (92%) RR patients tested for mid-therapy MRD, with 16 (70%) MRD negative in both the blood and marrow. Two patients had MRD in the blood only, 2 in the marrow only, and 3 in both the blood and the marrow. Mid-therapy responses for the TN cohort have previously been reported (Rogers ASH 2017). To date in 21 (84%) TN patients completed treatment through C14 and 23 (92%) RR remain on study with 21 completing treatment. No patients in either cohort had progressive disease. There was one death from neutropenia and colitis in a TN patient. CONCLUSIONS OBIN, IBR, and VEN in combination have a tolerable safety profile in both RR and TN CLL patients with the majority of toxicities being hematologic. This regimen has a high mid-therapy response rate (92%) in RR patients with early MRD negative responses. EOT responses in TN and RR patients will be presented at the meeting. Disclosures Maddocks: Teva: Honoraria; AstraZeneca: Honoraria; Pharmacyclics/Janssen: Honoraria; Novartis: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; BMS: Research Funding. Jones:Celgene: Employment, Equity Ownership.

Description: Abstract 2472 Background: As a result of the previously demonstrated efficacy of the cyclin dependent kinase inhibitor, flavopiridol, and the immunomodulatory agent, lenalidomide, in heavily pre-treated patients (pts) with bulky adenopathy and adverse cytogenetics, we conducted a phase I trial to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of combined therapy. Both agents are active in pts with relapsed/refractory cytogenetically high risk CLL, utilize different novel mechanisms of action, and do not deplete T-cells, leading to the potential development of a well tolerated regimen for pts with del (17p13.1) and del (11q22.3) with greater efficacy and less infectious toxicity than observed with currently accepted fludarabine or alemtuzumab combinations. Methods: Pts with histologically confirmed CLL relapsed after at least 1 prior therapy with a WBC ≤ 150,000/mm3, ANC ≥ 1000/mm3, platelets ≥ 30,000/mm3, and creatinine ≤ 1.5 mg/dL were enrolled. Treatment consisted of flavopiridol alone (30 mg/m2 bolus + 50 mg/m2 4-hour continuous IV infusion (CIVI)) days 1, 8, and 15 of cycle 1 to decrease the pre-treatment disease burden and minimize the potential risks of simultaneous tumor flare and tumor lysis syndrome (TLS) with concurrent lenalidomide and flavopiridol. Starting in cycle 2, flavopiridol 30 mg/m2 bolus + 30 mg/m2 4-hour CIVI days 3, 10, and 17 was combined with lenalidomide 2.5, 5.0, 7.5, 10, 15, or 25 mg days 1–21 every 28 days. All pts received 20 mg of dexamethasone 30 minutes prior to flavopiridol dosing and 4 mg of dexamethasone 24 hours after flavopiridol to minimize cytokine release symptoms. Results: Twenty-one pts (12 males) with a median age of 59 (range 42–71) previously treated with a median of 4 prior therapies (range 1–10) were enrolled. All pts received prior fludarabine, 9 pts were fludarabine refractory, no pts previously received flavopiridol, and 1 pt was previously treated with lenalidomide. Pts had Rai stage I/II (n=6) or IV (n=15) disease and 13 pts had bulky adenopathy ≥ 5 cm. Thirteen pts had del (17p13.1) and 8 pts had del (11q22.3). Seventeen pts completed two or more cycles of therapy (median 3, range 2–8), receiving 2.5 mg (n=6), 5.0 mg (n=7), and 7.5 mg (n=4) of lenalidomide. Four pts completed only one cycle of therapy and were removed prior to receiving lenalidomide due to progressive disease (n=2), TLS requiring dialysis (n=1), and grade 4 thrombocytopenia (n=1). DLT consisting of grade 3–4 transaminitis persisting 〉 7 days occurred in 2 pts treated with 2.5 mg (n=1) and 5.0 mg of lenalidomide (n=1), respectively. Grade 3–4 toxicities consisted of neutropenia (86%), diarrhea (62%), transaminitis reversible in ≤ 7 days (57%), anemia (38%), thrombocytopenia (38%), hyperglycemia (38%), infection without neutropenia (24%, cellulitis in 1 pt, pneumonia in 3 pts, and catheter-associated in 1 pt), febrile neutropenia (14%, unknown source in 2 pts and pneumonia in 1 pt), TLS not requiring dialysis (14%), and fatigue (14%). Grade 1 tumor flare occurred in 1 pt and did not require additional steroids or cessation of lenalidomide. In 15 evaluable pts who completed 1 or more cycles of combined lenalidomide and flavopiridol, partial responses were observed in 7 pts, including 4 pts with del (17p13.1), 3 pts with del (11q22.3), 5 fludarabine-refractory pts, 3 pts with bulky lymphadenopathy ≥ 5 cm, and 1 pt previously treated with lenalidomide. Conclusions: Combined flavopiridol and lenalidomide is well tolerated, with activity in pts with previously treated, cytogenetically high-risk CLL. The MTD has not been reached and dose escalation continues. This trial is supported by NCI R21 CA133875, NCI K23 CA109004, NCI U01 CA076576, LLS SCOR 7080-06, and the D. Warren Brown Foundation. Disclosures: Blum: Celgene: Research Funding. Off Label Use: The efficacy of the cyclin dependent kinase inhibitor, flavopiridol, and the immunomodulatory agent, lenalidomide, are under investigation in CLL.

Description: Abstract 3113 Background: Pre-transplantation FDG-PET/CT (PET/CT) has been associated with progression-free survival (PFS) and overall survival (OS) in patients (pts) with relapsed Hodgkin's and diffuse large B-cell lymphoma (Spaepan, Blood.102 :53-59, 2003). However, no data exist regarding the role of PET/CT pre-transplant in pts with mantle cell lymphoma (MCL). We performed a retrospective analysis of pts with MCL and available pre-transplant PET/CT to evaluate the association of pre-transplant PET/CT findings with PFS and OS. Methods: PET/CT was reviewed by a single radiologist according to International Harmonization Committee (IHC) criteria with mediastinal blood pool as the referenced background activity and also utilizing liver blood pool. Bone marrow (BM) uptake was not utilized in the PET/CT response assessment. Associations between PET/CT positivity and clinical characteristics were performed using Fisher's Exact and Wilcoxon rank sum tests. PFS curves were constructed from date of transplant until date of relapse or death by the Kaplan-Meier method and evaluated by the log-rank test. Univariable proportional hazards models described the relationship between clinical variables and PFS. Results: Twenty-nine pts with PET/CT prior to autologous stem cell transplant were included. Median age was 60 (range 37–73), and 86% were male. Median MIPI was 5.9 (range 4.9–7.0), with 36%, 40%, and 24% of pts classified as low (〈 5.7), intermediate (5.7–6.2), or high risk (〉 6.2), respectively. At diagnosis, 93% of pts had BM involvement, 56% had splenomegaly, and 27% had bulky adenopathy ≥ 5cm. Sixty-nine percent of pts were induced with RCHOP and methotrexate (RCHOP+M, Damon, JCO 27 :6101–6108); other therapies included RCHOP (n=4), RHyperCVAD (n=2), bortezomib (n=2), and REPOCH (n=1). Sixty-six percent, 21%, and 14% of pts received 2, 3–5, or 6 induction cycles prior to transplant, respectively. Conditioning regimens were BEAM (59%) and BEC (41%) and 90% of pts underwent transplant in first remission. Median time to transplant from diagnosis was 5.4 months (range 3.4–82). With a median follow up of 18 months (range 0.7–43), estimated median PFS is 42 months (95% CI 15–45). There have been 7 relapses (4 RCHOP, 1 RCHOP+M, 1 bortezomib, 1 REPOCH) and 5 deaths (disease progression, n=3, and pneumonia, n=2). Seventeen pts (59%) had a negative PET/CT prior to transplant, with identical results using mediastinal or liver blood pool. In 19, 6, and 4 pts respectively receiving 2, 3–5, and 6 cycles of induction therapy, 58%, 50%, and 75% were PET/CT negative prior to transplant. PET/CT positive pts received RCHOP+M (n=10), RCHOP (n=1), and bortezomib (n=1), Compared to PET/CT negative pts, PET/CT positive pts were younger (median age 55 v. 62, p=0.04) with lower MIPI (p=0.05). There was no significant association of bulky adenopathy (p=0.09), induction with RCHOP+M (p=0.23), or number of induction cycles (p=0.87) with PET/CT findings. 5 pts had a positive pre-transplant BM biopsy, of which 2 were BM negative by PET/CT. BM positivity on pre-transplant PET/CT was observed in 14 pts with only 3 also positive by BM biopsy. Median PFS was 45 months (95% CI 13–45) for PET/CT negative pts and 33 months (95% CI 3–33) in PET/CT positive pts (Figure 1; p=0.03). At this time, 4 of 17 PET/CT negative pts have progressed or died compared to 5 of 12 PET/CT positive pts. Of the 5 deaths experienced thus far, 4 have occurred in PET/CT positive pts. Presence of bulky adenopathy ≥ 5cm was also associated with a worse PFS (p=0.01), but MIPI (p=0.31) and age (p=0.61) were not. Conclusions: PET/CT associates with PFS after autologous stem cell transplantation in MCL (p=0.03). However, additional follow-up is needed to see if this association between PET/CT positivity and early relapse in MCL persists. In addition, as the majority of pts had 2 cycles of induction therapy with RCHOP+M, the impact of treatment regimen and number of cycles is difficult to assess in this series. Interestingly, neither age nor MIPI were associated with PFS from transplant, perhaps indicating that clinical characteristics at diagnosis are less important in pts that achieve a complete response by IHC criteria prior to transplant. Prospective investigation with centrally reviewed PET/CT scans compared with standard CT is required to determine the predictive role of pre-transplant PET/CT in MCL. Disclosures: No relevant conflicts of interest to declare.

Description: Key Points The expression level of ROR1 on CLL cells varies between patients. High-level CLL-cell expression of ROR1 associates with more aggressive disease.