A 46-year-old man with no significant medical history presented to haematology with symptoms of fatigue, dyspnoea on exertion and weight loss. Physical examination revealed a lesion on the right shin and splenomegaly. Labs were significant for leucocytosis with immature components, thrombocytosis and 3% peripheral blasts on smear. A bone marrow biopsy confirmed a diagnosis of myelofibrosis (MF). Dynamic International Prognosis Scoring system was 2. He was started on ruxolitnib, with decitabine added subsequently prior to definitive therapy with an allogenic haematopoietic stem cell transplant. His course with decitabine was complicated with febrile neutropaenia with multiple tender erythematous plaques unresponsive to antibacterial and antifungal coverage. A skin biopsy showed neutrophilic dermatitis, consistent with a diagnosis of Sweet’s syndrome (SS) and empirical treatment with glucocorticoids was initiated resulting in resolution of symptoms. This report reviews the literature for cases of SS in the setting of MF.

Introduction: The effect of tyrosine kinase inhibitors (TKIs) on cognition in patients with chronic myeloid leukemia in chronic phase (CML-CP) is not well understood. Memory impairments have been reported in limited studies in CML patients on dasatinib and in gastrointestinal stromal tumor patients on imatinib, but additional research is needed. At our institution, we have observed that CML-CP patients spontaneously report new cognitive dysfunction (CD) while on TKIs. We sought to determine the prevalence of CD in CML-CP patients on TKIs, the TKIs associated with cognitive changes, and the management and outcomes of CML-CP patients with CD at our institution. Methods: We performed a single-center, retrospective cohort study of active CML-CP patients in our Hematology clinic seen between January 2017 and December 2019. Patients were identified by ICD-10 codes and chart notes were reviewed for treatment course. Patients met criteria for CD if they reported new difficulties with cognition while on TKI treatment (as documented in the subjective or review of systems) and had no prior history of cognitive impairment. Descriptive statistics, Chi-square tests, and two-tailed t-tests were used to summarize the data. Results: We identified 216 CML-CP patients who were actively or previously treated with a TKI, with 29 patients (13.4%) reporting CD while taking a TKI. The median age for patients with CD was 51 years (range 23-73), compared to a median age of 56 years (range 20-91) in those without CD (P=0.114); there were no significant differences in sex (P=0.984) or in median time since diagnosis (P=0.167) (Table 1). The 29 patients generated 36 reports of CD, as 7 patients (24.1%) reported 2 types of cognitive changes while on TKI. The types of CD were documented as "mental fog" (n=19/36, 52.8%), memory problems (n=7/36, 19.4%), decreased mental acuity (n=6/36, 16.7%), problems with concentration (n=2/36, 5.6%), word-finding difficulties (n=1/36, 2.8%), and impaired creativity (n=1/36, 2.8%) (Figure 1). Of the 29 patients who reported CD, 5 experienced it on 2 different agents, leading to 34 individual reports of CD. Among the 216 patients with CML-CP treated with TKIs, many used more than 1 agent: 31 used bosutinib, 183 dasatinib, 132 nilotinib, and 10 ponatinib. The percentage of CD reported in patients treated with each TKI was as follows: bosutinib 12.9% (n=4/31), dasatinib 11.5% (n=21/183), imatinib 5.3% (n=7/132), nilotinib 4.1% (n=2/49), and ponatinib 0% (n=0/10) (Table 2). For management, 20.7% (n=6/29) underwent successful prescribed discontinuation, 27.6% (n=8/29) attempted discontinuation but resumed TKI after loss of MMR, 24.1% (n=7/29) underwent TKI dose reductions, 20.7% (n=6/29) changed TKIs, and 6.9% (n=2) had no change in management. In the 6 patients who successfully discontinued TKI, all but 1 (83.3%) reported complete resolution of their CD while off of TKI. For those who attempted discontinuation but had loss of MMR, 6 of 8 (75%) had documented improvement of CD off of treatment; after restarting TKI, CD returned in 5 patients (83.3%). Of the remaining patients who underwent TKI dose reductions (n=7), 1 patient had documented improvement of CD, 2 had no change, and 4 had unspecified outcomes. Of the patients who changed TKIs (n=6), 1 patient had documented improvement of CD, 4 had no change, and 1 had unspecified outcomes. In the 2 with no change in management, outcomes were not specified. Conclusion: Cognitive dysfunction in CML-CP patients was reported with all first- and second-generation TKIs; the analysis of ponatinib was limited by small numbers. Bosutinib had the highest proportion of CD in our cohort, an association that has not been previously reported. Our analysis supports that TKI-associated CD is reversible since it resolved in 78.6% (n=11/14) patients when off of TKI during discontinuation. While 13.4% of our CML-CP patients had CD, due to spontaneous reporting and subtle presentation of cognitive impairment, the true prevalence of CD in CML-CP patients on TKIs is likely substantially higher. Future studies should involve prospective data collection of objective cognitive testing and patient reported outcomes in CML-CP patients for further evaluation of TKI-associated cognitive dysfunction. Disclosures Schoenbeck: American Society of Hematology: Research Funding. Smith:Sanofi: Honoraria; FujiFilm: Other: Research support, Research Funding; Revolution Medicines: Other: Research Support, Research Funding; Astellas Pharma: Honoraria, Other: Research Support, Research Funding; Daiichi Sanyko: Consultancy, Honoraria; Abbvie: Other: Research Support, Research Funding. Shah:Bristol-Myers Squibb: Research Funding.

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Introduction:Tyrosine kinase inhibitor (TKI) intolerance is commonly encountered in patients with chronic myeloid leukemia in chronic phase (CML-CP). Clinical trials define non-hematologic TKI intolerance as grade 3-4 toxicities, but lower grade toxicities may also impair patients' quality of life and lead to changes in medical management. We sought to compare TKI-intolerant and -tolerant CML-CP patients and their clinical outcomes, including molecular responses, rates of progression, survival, and utilization of allogeneic stem cell transplant (alloSCT). Methods:We performed a single-center, retrospective cohort study of active CML-CP patients in our Hematology clinic between January 2017 and December 2019. We defined TKI intolerance as any grade non-hematologic toxicity that led to a change in TKI management, such as dose reduction or change of TKI. We also reviewed CML-CP patients who underwent alloSCT in the TKI era (2002-2019). AlloSCT patients were identified for chart review by ICD-10 codes and query of the institution's transplant database. Descriptive statistics, Chi-Square tests, and two-tailed t-tests were used to summarize the data. Results:We identified 216 CML-CP patients (Table 1), and 161 (74.5%) met criteria for non-hematologic TKI intolerance. The median age was 59 years-old in TKI-intolerant patients and 49 in tolerant patients (P=0.011). Most patients experienced TKI-intolerance from symptoms (93.2%, n=150); symptoms included fatigue (n=77, 59.2%), arthralgias (n=36, 27.7%), nausea (n=29, 22.3%), headache (n=16, 12.3%), and edema (n=15, 11.5%). The remaining patients were TKI-intolerant based on abnormal laboratory findings such as transaminitis or hyperglycemia (6.8%, n=11/161). Of the 161 TKI-intolerant patients at last follow-up, 130 (80.7%) remained on TKI, 19 (11.8%) were on prescribed discontinuation, 6 (3.72%) were non-adherent, 5 (3.1%) were off TKI for non-CML medical problems, and 1 (0.6%) was on omacetaxine. Dose reductions occurred in the majority who remained on TKIs (n=103/130, 79.2%) and prior to TKI discontinuation (n=13/19, 68.4%). Most TKI-intolerant patients (n=122/161, 75.8%) switched TKIs, with a median of 2 agents used (range 1-5). Of 55 TKI-tolerant patients, 46 (83.6%) were on TKI, 8 (14.5%) were on discontinuation, and 1 (1.8%) was non-adherent. Only 19.6% (n=9/46) patients were dose-reduced, and they rarely changed TKIs (median of 1 agent used). MR4.5 was achieved in 49% (n=79/161) of TKI-intolerant and 41.8% (n=23/55) of TKI-tolerant patients. Only 1 patient in each group progressed to accelerated phase. TKI-intolerant and -tolerant patients had similar times since diagnosis (with a median follow up of 81.7 months and 79.7 months, respectively). Five of 161 (3.1%) TKI-intolerant patients died, all from causes unrelated to CML and TKI therapy. None of the TKI-tolerant patients died during the abstraction period. Twenty CML-CP patients underwent alloSCT from year 2002-2019; 10 (50%) were transplanted for TKI intolerance without other transplant indications (Tables 2 and 3). Three of those 10 patients also had hematologic intolerance. Four (40%) TKI-intolerant patients resumed TKI post-transplant: 3 for disease relapse, 1 for sclerotic GVHD. Seven (70%) developed GVHD, with most cases being chronic (n=6), extensive (n=6), and severe/moderate (n=6). While 80% of patients achieved MR4.5 post-transplant (n=8/10), 30% (n=3/10) experienced transplant-related mortality (TRM) with a mean post-transplant survival of 38.5 months; the remaining 7 patients were alive at a median follow-up of 37.1 months. Conclusion: CML-CP patients with non-hematologic TKI-intolerance achieved similar clinical outcomes as TKI-tolerant patients despite dose reductions and/or switching TKIs. The use of alloSCT was rare in our practice, and CML-CP patients transplanted for TKI intolerance commonly resumed TKI post-alloSCT and frequently developed extensive GVHD. In light of the high survival rate achieved with medical management in CML-CP patients with non-hematologic TKI-intolerance, including no disease- or treatment-related deaths, this analysis does not support the use of alloSCT for patients with non-hematologic TKI-intolerance. Disclosures Schoenbeck: American Society of Hematology:Research Funding.Olin:Astellas:Other: Site PI;Genentech:Consultancy;Daiichi Sankyo:Other: Site PI;Amgen:Consultancy;Genentech:Other: Site PI;Pfizer:Other: Site PI.Logan:Amphivena:Research Funding;Autolus:Research Funding;Jazz:Research Funding;Kadmon:Research Funding;Kite:Research Funding;Pharmacyclics:Research Funding;Abbvie:Consultancy;Amgen:Consultancy;Novartis:Consultancy.Smith:Revolution Medicines:Other: Research Support, Research Funding;Abbvie:Other: Research Support, Research Funding;FujiFilm:Other: Research support, Research Funding;Daiichi Sanyko:Consultancy, Honoraria;Astellas Pharma:Honoraria, Other: Research Support, Research Funding;Sanofi:Honoraria.Shah:Bristol-Myers Squibb:Research Funding.

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