SUN-518 Graves’ Disease Newly Diagnosed in the Setting of Hypokalemic Periodic Paralysis in an HIV+ Patient

Relevance: A rare yet distinct cause of sudden onset paralysis is severe hypokalemia associated with thyrotoxicosis. This is thought to be associated with mutations in genes encoding cellular potassium channels. We report a case of acute onset paralysis with profound hypokalemia and a new diagnosis of Graves’ thyrotoxicosis in a previously asymptomatic African American, HIV+ man on highly active antiretroviral therapy (HAART) for over 8 years. Clinical case: A 49-year-old man with hypertension and HIV presented with acute paralysis of his bilateral upper and lower extremities. His initial potassium was 1.8 mEq/L (3.5-5.0). Prior to sudden onset loss of motor strength, he denied any preceding palpitations, tremor, anxiety, diaphoresis, hyper-defecation, weight loss, heat or cold intolerance, neck pain, increase in neck girth or difficulty swallowing, proptosis or other ocular symptoms. He has no family history of thyroid disease. He had an enlarged palpable thyroid without nodules and no audible bruit. There was no periorbital edema or proptosis, and no signs of dermopathy. A thyroid ultrasound showed a hyperemic and diffusely enlarged thyroid gland without nodules. Labs included a TSH of 0.007 mCU/mL (0.43-3.8), Free T4 2.1 ng/dL (0.71-1.85), Total T3 229.6 ng/dL (58-194), and thyrotropin receptor antibody 2.6 IU/L (0-1.75). The CD4+ count was 146 in 2010 with a slow gradual rise to 673 in 2019, and HIV viral load was undetectable. There were no offending medications or supplements identified. With aggressive potassium repletion, the serum potassium improved to 4.6 mEq/L and he regained normal strength within several hours. He was started on Methimazole 10mg daily and propranolol 10mg TID. At one month, the thyroid function tests normalized. Methimazole 10mg daily was continued and propranolol was tapered off. He remains euthyroid. Genetic testing is pending. Conclusions: Graves’ disease is the most common thyroid disease triggered by immune reconstitution in HIV + individuals on HAART. The incidence of thyroid disease in HIV patients on HAART is higher in women and Africans with a 1.5-2 fold increase compared with the general population [Muller et. al, Eur Thyroid J 2019;8:173-185]. Despite a higher incidence of hyperthyroidism in women, over 95% of cases of hypokalemic periodic paralysis have been reported in men, with a 10-fold higher incidence among Asians compared to Westerners. There has been one prior case report of Thyrotoxic Periodic Paralysis in an HIV + patient and this was in a Polynesian male (Brown JD et al. Hawaii Med J 2007). To our knowledge, this is the first case report of an African American HIV+ patient with this disorder. An association with mutations in the Kir2.6 gene (encodes a potassium channel, is expressed in skeletal muscle, and is transcriptionally regulated by thyroid hormone) has been proposed [Ryan et. al, Cell 2010 January 8; 140(1):88-98].

An Phase 2 Study of Lenalidomide in Combination with Oral Dexamethasone in Previously Untreated, Symptomatic Patients with Chronic Lymphocytic Leukemia (CLL)

Introduction: Although lenalidomide, as an immunomodulatory agent, has anti-tumor activity in CLL, its use in this disease is complicated by tumor lysis (TLS) and tumor flare (TF), especially when used frontline. From our experience using low-dose lenalidomide (10mg daily), TLS can be prevented but TF remains frequent and few CRs are achieved (Chen et al. 2010). The current trial tests the combination of lenalidomide and dexamethasone, aiming to enhance anti-tumor activity through synergy and mitigation of toxicities such as TF, enabling escalation to higher doses of lenalidomide. We hypothesized that higher doses of lenalidomide with dexamethasone, given over a finite 18 cycles, may achieve deeper and more durable responses, without requiring long term continuous treatment. Final analysis of 31 patients is presented. Methods: Eligible patients had treatment-naïve, symptomatic CLL. The starting dose for lenalidomide was 5mg daily continuously, with 5mg escalations every 28 days to a maximum of 25 mg, and dexamethasone 12 mg daily orally days 1-7, 14, 21 of each 28 day cycle, both to a maximum of 18 cycles. Supportive measures: allopurinol for TLS prophylaxis, DVT prophylaxis with ASA, sulfatrim for pneumocystis prophylaxis. Results: Demographics: 31 pts were enrolled: median age 59 yrs (range 40-84), male 21 pts (68%), Rai stage III-IV 18 pts (58%), median peripheral lymphocytes 185 x109/L (range 9.3-509), β2M 4.1 mg/L (range 1.7-10.9); normal <3.2), bulky nodes 3 pts (10%), organomegaly 16 pts (52%). High risk features included: del17p/del11q on FISH in 6 pts (19%), ZAP70+ in 17 of 27 pts tested (63%) and unmutated IgVH in 16 of 26 pts tested (62%). All 31 pts received at least 1 cycle and were evaluable for toxicity and response. Hematologic toxicity: 19pts (61%) developed Gr 3-4 neutropenia during at least 1 cycle; 6 pts (19%) developed febrile neutropenia. Nine pts (29%) developed Gr 3-4 thrombocytopenia, without bleeding. Gr 3-4 neutropenia occurred in 14% and Gr 3-4 thrombocytopenia in 5% of the 431 cycles administered to all patients. Nonhematologic toxicity: Most common toxicities (all grades) included: non-desquamating rash (64%), diarrhea (61%), insomnia (55%), fatigue (52%), and edema (51%). Infections (all grades) were frequent (25 pts; 80%) but Grade 3-4 infections developed in only 4 pts (13%), including pneumonia (3 pts), and bacteremia (1 pt). Other common grade 3-4 toxicities included rash (3 pts), tumor flare (3 pts), abdominal pain (2 pts), and fatigue (2 pts). In contrast to the high rate of TF from our previous single-agent lenalidomide trial (88%), TF was considerably less common (9 pts; 29%). No TLS was noted. Dose modifications/study withdrawals: The median number of cycles received was 18 (range 1-18), with 58% completing protocol treatment. A median daily dose of 20mg (range 2.5-25mg) was reached. Dose reductions of lenalidomide were required in 14 pts (45%), most due to cytopenias. Reasons for early study discontinuation: toxicity (5 pts), patient withdrawal (5 pts), progressive disease (1 pt), and unrelated death (1 pt). Efficacy: All 31 pts achieved stable disease (SD) or better on study. Overall response rate was 74%: 21 PR (68%), 8 SD (26%), 2 CR (6%). Responses were reached at a median of 3.7 mos (range 0.8-13.7), though best response was not achieved until median 5 mos (range 0.8-25). At a median follow-up of 26 mos, 9 pts have progressed, only one during the treatment period. Duration of response was prolonged with greater depth of response: CR 28.6 mos, PR 17.9 mos, SD 4.6 mos. Median PFS was 27.8 months (95%CI: 22.1%-NA). The median OS has not been reached. Correlatives: Cereblon (CRBN) is a direct target of lenalidomide with expression required for anti-tumor activity. CRBN protein was detected by Western blot analysis in CD19-selected cells from screening blood samples of all 28 pts evaluated. Expression of CRBN substrates IKZF1 (Ikaros) and IKZF3 (Aiolos) pre and post-treatment and correlation with response and PFS are under evaluation and will be reported. Conclusion: Final results from this phase 2 study suggests that lenalidomide plus dexamethasone has significant activity in previously untreated CLL, is generally well-tolerated, and dramatically reduces the incidence of TF symptoms. This approach facilitates dose escalation beyond the 10mg daily dose used in our previous single agent study and achieves durable responses, without continuing therapy until progression. Disclosures Chen: Lundbeck: Honoraria; Janssen: Honoraria; Roche: Honoraria; Sanofi: Research Funding; Celgene: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria. Off Label Use: Lenalidomide is not currently approved for use in CLL.. Trudel:BMS: Honoraria; Merck: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Honoraria, Speakers Bureau; GSK: Honoraria, Research Funding; Celgene: Consultancy, Equity Ownership, Honoraria, Speakers Bureau.

A Randomized Controlled Trial comparing the efficacy of low-dose amitriptyline, amitriptyline with pindolol and surrogate placebo in the treatment of chronic tension-type facial pain

Background: Patients often present to otolaryngologists with chronic facial pain, presumed to be of sinus origin despite normal nasal endoscopy and sinus CT. This pain has increasingly been recognized as being of neurological origin with one of the commonest underlying causes being mid-facial segmental tension-type pain (MFP) which is a version of tension-type headache affecting the midface. Primary outcome measures: 1. To determine whether low-dose amitriptyline reduces pain scores compared to surrogate placebo in patients with chronic MFP. 2. To determine whether the addition of pindolol, a beta blocker with serotonin receptor blocking properties hastens onset of action or improves efficacy of amitriptyline. Secondary outcome measure: to determine whether amitriptyline or amitriptyline with pindolol significantly reduces analgesic consumption. Methodology: Sixty two patients were randomized to three treatment groups (a) amitriptyline 10mg daily (b) amitriptyline 10mg daily with pindolol 5mg twice daily and (c) loratadine 10mg daily. Daily pain scores using a facial pain diary were recorded over eight weeks. Results: At 8 weeks, pain frequency and intensity were significantly reduced in patients treated with amitriptyline and in those receiving amitriptyline with pindolol compared to surrogate placebo. Patients on the combination therapy showed significantly improved clinical outcome and significantly reduced analgesic intake compared to those on amitriptyline alone. Conclusion: Low dose amitriptyline is effective in the management of MFP and is enhanced by the addition of pindolol.

A Phase II Study of Lenalidomide in Previously Untreated, Symptomatic Chronic Lymphocytic Leukemia (CLL).

Introduction: Lenalidomide is an immunomodulatory compound known to downregulate VEGF and TNFa; stimulate production of inhibitory cytokines such as IL-2; and modulate activity of T cells and natural killer cells. These effects form the basis for investigation of lenalidomide in CLL. Promising results from 2 studies in relapsed/refractory CLL have been reported (Chanan-Khan et al J Clin Oncol 2006; Ferrajoli et al ASH 2006). To date, there are no reports using lenalidomide in previously untreated CLL. We present preliminary data on 12 patients (pts) enrolled in an ongoing phase II study of single-agent lenalidomide in previously untreated, symptomatic CLL. Methods: Eligible pts must have histologically confirmed CLL; no prior therapy (excluding steroids alone for autoimmune cytopenias); and symptomatic disease (any of symptomatic adenopathy/organomegaly, cytopenias, constitutional symptoms, lymphocyte doubling count <12 mos). Starting dose for lenalidomide: 10mg daily with weekly 5mg dose escalations to the target dose of 25mg daily × 21 days every 28 day cycle. Prophylactic allopurinol and ASA are mandated. Steroids are allowed for management of tumor flare symptoms but routine prophylaxis is not used. Results: In October 2006, accrual was initiated. Two pts were enrolled at the starting dose of 10mg daily. Pt 1 reached the target dose of 25 mg with a lymphocyte reduction from 152 to 25 but at 6 weeks developed acute tumor lysis with renal failure and was removed from study. Pt 2 developed grade 4 neutropenia on cycle 1 day 21 leading to a septic death. The study was halted and the protocol was revised with reduced starting and target doses (2.5mg and 10mg, days 1–21), slower dose escalations (2.5mg cycle 1, 5mg cycle 2, 10mg cycle 3 and thereon), and extension of allopurinol tumor lysis prophylaxis to minimum 3 cycles. Upon study reactivation in March 2007, 10 pts have been accrued. Median age 61(range 33–71), 5 pts with Rai stage III–IV, baseline median Hb 109g/L (range 80–158), platelets 180×109/L (range 43–233), lymphocytes 70×109/L (range 3.4–190), β2microglobulin 214 nmol/L (range 139–498; normal <170). Eight pts have received at least 1 cycle and are evaluable for toxicity. Hematologic toxicity: 5/8 pts developed Gr 3–4 neutropenia, leading to dose reductions in 3 pts and hospitalization for febrile neutropenia in 1 pt. Gr 4 thrombocytopenia developed at the 10mg dose in 1 pt. Nonhematologic toxicity: Gr 1–2 fatigue(5), tumor flare(4), non-desquamating rash(3), and infections(3) are most common. Tumor flare (painful, enlarged nodes often associated with nasal congestion/scalp pruritis) can occur with each dose escalation but is responsive to short course prednisone. No further episodes of tumor lysis have been noted. Responses: Dramatic lymphocyte reductions at as early as 1 week are seen, with 6 of 8 pts (75%) achieving a partial response (PR), all by end of cycle 2 (using ≤5mg doses). Phosphoproteomic and microarray studies from blood samples at baseline and during treatment will be presented. Conclusion: Preliminary data from this ongoing phase II study suggests that lenalidomide has significant activity in previously untreated CLL patients. Toxicities such as tumor lysis, tumor flare and myelosuppression are common and mandate a more conservative dosing regimen than previously used in relapsed/refractory CLL or myeloma. Responses seen at low doses (≤5mg daily) are encouraging.