BACKGROUND: Mycosis fungoides (MF) and leukemic Sézary syndrome (SS) are the most common cutaneous T cell lymphomas (CTCL), but their etiology remains unknown. After patients were observed with hydrochlorothiazide (HCTZ)-associated CTCL, HCTZ was examined as a putative chronic antigen in a cohort of prospectively staged patients. METHODS: Demographic and drug exposure data was examined from 1443 confirmed MF and SS patients. Hypertensive CTCL patients were divided into HCTZ users or nonusers for statistical analysis by chi-square and t tests. Causality in a case series was rated by the Naranjo Adverse Drug Reaction Probability Scale. RESULTS: A total of 815 of 1443 MF and SS patients (56.5%) were hypertensive; 205 (25.2%) were taking HCTZ at initial staging. Comparing stage of patients who were using or not using HCTZ, the most significant difference was between stage I and stage IV (odds ratio of 0.45; 95% confidence interval of 0.25-0.78, P ¼ .003), demonstrating reduced likelihood of being stage IV in patients who were on HCTZ. Seventy-seven percent of the MF patients on HCTZ were stage I. A total of 125 patients of 196 (63.8%) started HCTZ prior to developing CTCL lesions, and 35 of 121 (28.0%) started within 1 year of first skin rash. Thirty-six of 125 patients (28.8%) experienced complete or partial remissions after discontinuing HCTZ. A monoclonal T cell receptor rearrangement was detected more frequently in the hypertensive stage I patients not taking HCTZ as compared with those who were (55.3% vs 69.1%, P ¼ .032). Three patients were rechallenged and developed MF lesions that resolved or improved with discontinuation. CONCLUSIONS: HCTZ is commonly prescribed and may be a putative antigen in a small subset of early MF patients. Careful drug histories and a trial off medication are warranted. Cancer 2013;119:825-31.
9105 Background: The aurora kinase and mTOR pathways are implicated in resistance to EGFR inhibitor osimertinib. Here, we investigated the safety and efficacy of the aurora kinase inhibitor alisertib and the mTOR inhibitor sapanisertib in combination with osimertinib. Methods: This is a phase 1b study with dose finding and expansion portions (NCT04479306). The dose finding portion used a Bayesian optimal interval (BOIN) design to assess two arms: osimertinib 80 mg daily in combination with alisertib 20 mg, 30 mg, and 40 mg daily day 1-21 of 28-day cycle (osi-ali arm) and osimertinib 80 mg daily in combination with sapanisertib 2 mg and 3 mg daily (osi-sapa arm). Dose limiting toxicities (DLTs) were predefined in the protocol. Patients with EGFR (L858R/exon 19 deletion) mutant NSCLC whose disease have progressed on osi and up to one additional line of systemic therapy were assigned, at investigator discretion, to either study arm. Tumor biopsy was mandatory at study entry and optional upon progression. Results: As of February 1, 2022, 40 patients are enrolled (20 in each arm). One DLT was observed in each arm: grade 3 nausea in ali-osi arm and grade 3 AST elevation in osi-sapa arm. Grade 3 treatment emergent adverse events (TEAEs) occurred in 10% of each arm, and no grade 4 TEAEs were observed. The most common TEAEs in osi-ali arm was leucopenia (45%) and anemia (35%) while in osi-sapa arm, hyperglycemia (45%) and stomatitis (40%). In osi-ali arm (n = 20), median progression free survival (mPFS) was 1.9 months while objective response rate (ORR) and disease control rate (DCR) were 5% (95% CI: 0.1 ̃ 24.9%) and 40% (95% CI: 19.1 ̃ 63.9%), respectively. In osi-sapa arm (n = 16, evaluated for response to date), mPFS was 4.6 months while ORR and DCR were 12.5% (95% CI: 1.6 ̃ 38.3%) and 68.7% (95% CI: 35.7 ̃ 82.7%), respectively. Conclusions: Osimertinib with alisertib or sapanisertib is well tolerated in osimertinib-resistant, EGFR mutant NSCLC. The sapanisertib combination, but not the alisertib combination, demonstrates antitumor activity suggesting that mTOR inhibition warrants further exploration in this population. Biomarker analysis is ongoing to identify the molecular determinants of response and resistance to sapasertib. Clinical trial information: NCT04479306.
3907 After treatment with purine analog-based combination chemoimmunotherapy, 40% to 60% of patients with CLL have residual disease. As the extent of the residual disease often correlates with time to progression, eradication of residual disease may improve the duration of remission. Although alemtuzumab has been used as consolidation therapy with improvement of responses in 56% of the patients (pts) (Montillo et al, 2006), its use as been limited by concerns of immunosuppression. Lenalidomide is an oral agent with activity in pts with CLL. Lenalidomide's easy oral administration and its immunomodulatory properties make it an interesting agent to be evaluated as consolidation therapy. We, therefore, designed a phase II study to evaluate the efficacy and toxicity of lenalidomide for treatment of residual disease after chemotherapy. Pts with stable PR (at two time assessments at least 3 months apart), nodular PR (nPR), or CR with evidence of disease on immunophenotyping were eligible. Pts were required to enroll between 3 and 9 months after completion of combination chemotherapy. Pts received lenalidomide 10mg daily for 12 months (the first 12 pts in this trial received lenalidomide for 3 months, and the study was then amended to allow up to 12 months of therapy). Early discontinuation of treatment was allowed if pts achieved negativity for minimal residual disease (MRD) before 12 months. Responses were evaluated at 4 months and 12 months according to 1996 NCI-WG criteria. Bone marrow biopsy and BM immunophenotyping by multicolor flow cytometry (MFC) with quantification of residual disease were performed at the time of response assessment. The MFC assay used has a sensitivity of 0.02% (20 aberrant cells/100,000 total cells analyzed). Twenty-six pts have been enrolled in this study, and 21 are evaluable for response. Three pts discontinued treatment within the first 28 days (after 2, 7, and 21 days of therapy) and 2 pts are too early for response assessment. The median age is 62 years (range, 41–76), median number of prior treatment was 2 (range, 1–12). Six pts entered the study in CR, 8 pts had nPR and 12 pts were in PR. The outcome of lenalidomide consolidation and duration of therapy are summarized in the table.Pt #Latest chemotherapyResponse at start of lenalidomideDuration of therapyResponse at end of lenalidomide1FCRCR2 daysNot evaluable2OFARCR49 daysProgression3FCRCR21 daysNot evaluable4R-hyperCVADCR12 monthsCR, MRD +5FCRCR5 monthsCR, MRD +6FBRCR10 days +Too early7FCMRnPR3 monthsCR, MRD +8FCRnPR3 monthsnPR9R-CHOPnPR3 monthsCR, MRD −10CFARnPR3 monthsCR, MRD −11R-hyperCVADnPR12 monthsnPR12FCRnPR3 monthsnPR13FCR bevacizumabnPR12 monthsnPR14FCR bevacizumabnPR4 monthsnPR15OFARPR3 monthsCR, MRD −16CFARPR3 monthsPR17PCRPR3 monthsPR18FCRPR3 monthsnPR19FCRPR3 monthsPR20FCRPR6 monthsnPR21FCR bevacizumabPR9 months +CR, MRD +22FCRPR9 months +PR23FCRPR8 months +PR24FCRPR7 daysNot evaluable25FCR bevacizumabPR7 months +PR26FCRPR3 months +Too early For the 6 pts in CR at study initiation: 2 pts had no changes in MRD status, 1 pt had disease progression, 2 pts are not evaluable due to early discontinuation and 1 pt has not had enough time on study. For the 8 pts with an nPR: 3 improved response to CR (2 of them MRD negative) and 5 pts had stable nPR. For the 12 pts with a PR: 2 pts improved to a CR (1 of them MRD negative), 2 pts to a nPR, 5 pts remained in PR, 1 pt is not evaluable due to early discontinuation and 1 pt has not had enough time on study. At a median follow up of 23 months, the median time to progression has not been reached in the 7 pts that improved their response as a result of th, and 5 pts remain in remission between 18 and 35 months after therapy. The most common lenalidomide-related adverse event was myelosuppression: grade 3–4 neutropenia (8 pts, 31%) and grade 3–4 thrombocytopenia (2 pts, 8%). Infections occurred in 5 patients: 3 pneumonia (1 RSV, 1 Pseudomonas and 1 unknown pathogen), 1 vaginal Herpes, 1 sinusitis. One patient experienced a grade 4 PE. Other common grade 1–2 toxicities considered lenalidomide-related were fatigue (8 pts, 31%), rash (8 pts, 31%), constipation (4 pts, 15%), diarrhea (4 pts, 15%), cough (3 pts, 8%) and body aches (3 pts, 8%). Based on our early experience, lenalidomide consolidation after chemotherapy can further improve responses in 27% of patients with CLL. Elimination of MRD was seen in 12% of patients treated. Enrollment to this study is ongoing. Disclosures: Keating: Celgene: Consultancy. O'Brien:Celgene: Consultancy. Ferrajoli:Celgene: Research Funding.
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