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Background: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses., Patients and Methods: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone., Results: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS., Conclusions: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI., Competing Interests: Disclosure JAW is an inventor on a US patent application (PCT/US17/53.717); reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, MedImmune, and Bristol-Myers Squibb (BMS); serves as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline (GSK), BMS, Merck, Biothera Pharmaceuticals, and Micronoma. JAW holds stock options from Micronoma. JLM serves as a consultant for Merck and in advisory board for Bristol-Myers Squibb. GVL is a consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd., Pierre Fabre, Provectus, Qbiotics, Regeneron. LW is an advisory board consultant/advisor for Novartis, Merck Sharp and Dohme, and Bristol-Myers Squibb. All other authors have declared no conflicts of interest. Data Sharing The data that support the findings of this study are available from the corresponding author on reasonable request. Role of the Funder/Sponsor The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication., (Copyright © 2023 European Society for Medical Oncology. All rights reserved.)

Green tea or its constituents have long been touted as a health promoting substance including claims it may have cancer prevention properties. We previously reported the in vitro ability of one tea polyphenol, epigallocatechin gallate (EGCG), to induce apoptotic cell death in the leukemic B-cells from a majority of patients with chronic lymphocytic leukemia (CLL). After the publication of our findings many patients with CLL and other low grade lymphomas began using over-the-counter products containing tea polyphenols despite the absence of evidence to suggest clinical benefit, definition of possible toxicities, or information on optimal dose and schedule. We have become aware of four patients with low grade B-cell malignancies seen in our clinical practice at Mayo Clinic who began, on their own initiative, oral ingestion of EGCG containing products and subsequently appeared to have an objective clinical response. Three of these four patients met criteria for partial response (PR) by standard response criteria. Although spontaneous remission/regression is occasionally observed in individuals with low grade B-cell malignancies, such events are rare. Several patients presented here had documented steady clinical, laboratory, and/or radiographic evidence of progression immediately prior to initiation of over-the-counter green tea products and then developed objective responses shortly after self-initiating this therapy. Such anecdotes highlight the need for clinical trials of tea polyphenols to define the optimal dosing, schedule, toxicities, and clinical efficacy before widespread use can be recommended. An NCI sponsored phase I/II trial of de-caffeinated green tea extracts for patients with asymptomatic, early stage CLL opened at Mayo Clinic in August 2005.

The anti-fibrotic and cytokine modulatory properties of pirfenidone suggest its usefulness in the treatment of myelofibrosis with myeloid metaplasia (MMM). In a prospective study, 28 patients with MMM were treated with oral pirfenidone. Twelve patients completed 1 year of therapy; 13 were withdrawn because of disease progression and three because of drug intolerance. Only one patient experienced a clinically relevant benefit with respect to anaemia and splenomegaly. The overall lack of clinical benefit correlated with no significant improvement in the bone marrow morphological features of the disease. We conclude that pirfenidone has no significant clinical or biological activity in MMM.

Thrombosis resulting from intravenous immunoglobulin infusion is a relatively unknown complication. We describe a patient who developed deep venous thrombosis of her left arm shortly after intravenous immunoglobulin administration. In addition, we review the thrombotic incidences reported in the literature and the possible association with hepatic veno-occlusive disease after bone marrow transplantation. Measures that can potentially prevent this complication are discussed.

A Phase I study of rIL-2 and levamisole was performed to evaluate the activity, toxicity, and effect on immune parameters of this combination of agents in patients with advanced malignancy. Twelve patients with advanced cancer were included and begun on therapy with rIL-2, 1 x 10(6) U/m2 subcutaneously (SQ) daily for 5 days and levamisole beginning at 25 mg/m2 orally three times daily for 5 days. The dose of levamisole was increased to 50 mg/m2 thrice daily during this study. Immune parameter analysis included the percentages of lymphocyte subsets in peripheral blood, cellular cytotoxicity assays versus K562 and Daudi cells, and lymphocyte blastogenesis to the recall antigens tetanus toxoid and Candida albicans. The dose-limiting toxicities were pruritus, nausea, and facial edema. There were no indications of significant hematologic or hepatorenal toxicities. No patient fulfilled the traditional criteria for an objective response. In 8 of 9 patients with immune parameter data available there was an increase in cellular cytotoxicity and in the percentage of lymphocytes with the natural killer phenotype (CD3-, CD16/56+). This regimen can be given as an outpatient with acceptable toxicity. For Phase II investigations the doses of rIL-2, 1 x 10(6) U/m2 SQ daily x 5 days and levamisole, 50 mg/m2 three times daily x 5 days is recommended.

Peripheral blood mononuclear cells from 11 patients with untreated B-chronic lymphocytic leukemia (CLL) were exposed to sodium phenylacetate (NaPA) in culture to assess its ability to induce differentiation. We found no evidence of cellular differentiation or induction of tartrate resistant acid phosphatase activity, as seen when B-CLL cells were treated with phorbol ester. We observed a striking decrease in the viability of the B-CLL cells in a time and dose dependent fashion when exposed to NaPA. After six days of culture, control cells from the 11 patients studied had a median viability of 90%, whereas cells exposed to NaPA at 5 and 10 mM concentrations had median viabilities of 39 and 16%, respectively. The cells treated with NaPA developed prominent cytoplasmic vacuoles. NaPA binds and depletes glutamine which is an important amino acid for lymphocyte metabolism. Although the mechanism of the cytocidal effects demonstrated in this study are unknown, they may relate at least partially to glutamine deprivation.

Objective: To determine the incidence of leukemia in Olmsted County, Minnesota, for a recent 15-year period and to compare the data with reported rates for the previous 40 years., Design: We conducted a population study of leukemia diagnosed between 1975 and 1989 in residents of Olmsted County by review of medical records identified through diagnostic indexes, death certificates, autopsy files, and histologic preparations., Material and Methods: Diagnoses of leukemia were categorized into various subtypes, and age- and sex-specific incidence rates were calculated for leukemia as a whole and for each subtype. In addition, incidence rates were age- and sex-adjusted to the 1970 US white population for comparison with earlier published rates. Age and annual trends as well as sex differences were assessed with the generalized linear interactive model approach., Results: During 1975 through 1989, the mean annual incidence rate for leukemia was 12.3 per 100,000 population in Olmsted County. When adjusted for age and sex, the rate per 100,000 was 13.6, in comparison with a similarly adjusted rate of 11.8 for the previous decade (1965 through 1974). The rates for chronic myelogenous leukemia and acute lymphocytic leukemia remained stable throughout the entire study period; however, rates for acute myelogenous leukemia and chronic lymphocytic leukemia increased, most prominently in patients 50 years of age or older. This increased rate occurred in both males and females, but the incidence rates for both subtypes began increasing earlier for males than for females., Conclusion: Although we cannot rule out an actual increase in incidence rates for these types of leukemia in the elderly population, we believe that the increase in persons older than 50 years of age reflects social change in improved health care and its better utilization by elderly persons, as well as the ability to diagnose leukemia earlier than in the past.

Objective: To determine whether the stage at the time of diagnosis of chronic lymphocytic leukemia (CLL) had changed during a 55-year period., Design: We conducted a study of the cohort of residents of Olmsted County, Minnesota, who had been diagnosed as having CLL during the period from 1935 through 1989., Material and Methods: By analysis of medical records, patients with CLL were characterized by Rai stage, absolute lymphocyte count, age at diagnosis, need for therapy, and reported cause of death in nonsurvivors. Trends for these variables were analyzed by decade throughout the study period., Results: The overall annual incidence rate of CLL per 100,000 population in Olmsted County increased from 2.6 in the 1935 through 1944 period to 5.4 in the 1975 through 1984 period; however, the increasing rate was found only for those 50 years of age or older and was especially dramatic for those 75 years old or older. Analysis of Rai stage over time demonstrated an increase in the proportion of cases diagnosed as Rai stage 0. In addition, the median absolute lymphocyte count decreased, the median time to initiation of therapy increased, and the median age of patients with Rai stage 0 CLL at the time of diagnosis increased over time. Overall, 54% of patients had received therapy for CLL by the time of last follow-up. Among the nonsurvivors, CLL was documented as the underlying or a contributing cause of death in 69%., Conclusion: The overall increase in CLL was thought to be due to enhanced methods of early diagnosis and improved health care for the elderly population. Thus, artifact may best explain the observed trend, although we cannot exclude the possibility of an actual increase in incidence rates over time.

A small motile worm was found in the posterior pole of the eye of a patient, producing a decrease in visual acuity. The patient had signs of meningitis and had cerebrospinal fluid eosinophilia. His serum was positive for antibodies to Angiostrongylus cantonensis. Without surgical intervention, the patient recovered and his visual acuity returned to normal.