Recent publications have documented an increased prevalence of cutaneous T‐cell lymphoma (CTCL) in patients undergoing tumor necrosis factor alpha (TNF‐α) inhibitor therapy. Herein, we present an ...uncommon manifestation of mycosis fungoides (MF) with unique pathological findings after the initiation of adalimumab therapy for the treatment of psoriasis. One year after starting treatment, the patient noticed a slowly growing, eroded plaque on the left cheek, the biopsy of which demonstrated mixed granulomatous and adnexotropic lymphocytic infiltrate with features characteristics of MF. In the following months, the patient developed pink‐ and violet‐colored scaly plaques on the right posterior upper arm and right medial upper arm. Biopsy of these plaques also revealed findings compatible with MF. T‐cell receptor (TCR) clonality studies by PCR revealed identical T‐cell clones in the samples obtained from the cheek, right posterior upper arm, and right medial upper arm. TCR clonality studies of a long‐standing psoriatic plaque on the right thigh failed to reveal similar T‐cell clones. Blurring of histopathologic presentation by TNF‐α inhibitors could greatly complicate the identification of MF subtypes. Providers treating patients with TNF‐α inhibitors must be aware of the risk of cutaneous lymphoma development and the potential deviations from their expected presentations. In patients without an initial biopsy, the possibility of pre‐existing CTCL with psoriasiform presentation should be considered.
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is primarily a disease of older adults and is occasionally an incidental finding on skin biopsies accompanying epithelial neoplasms ...and insect bite reactions. In rare instances, however, it produces leukemic infiltrates showing clinical and histopathologic overlap with primary cutaneous B‐cell lymphomas including primary cutaneous marginal zone lymphoma (PCMZL). Even less frequently, such findings serve as the initial disease manifestation. We present an exceptional case of a 61‐year‐old man with no past medical history whose clinical and histopathologic findings raised consideration for PCMZL with abnormal B‐cells colonizing germinal center follicles; however, faint CD5 and CD23 co‐expression raised the differential diagnosis of CLL/SLL. In light of an ambiguous clinical presentation with widely distributed papules and plaques, peripheral blood flow cytometry was also performed, revealing high count of CLL‐type monoclonal B lymphocytosis. Subsequent workup revealed bone marrow involvement and mesenteric lymphadenopathy, supporting the diagnosis of SLL. Follicular colonization by SLL has not been previously reported. Our case underscores the importance of subtle immunophenotypic clues and correlations with clinical and radiologic findings in the workup of B‐cell lymphomas presenting in the skin.
Thrombotic thrombocytopenic purpura (TTP) is a rare but frequently fatal complication of SLE. It occurs in the context of both active and inactive lupus and carries a worse overall prognosis than ...idiopathic acquired TTP. Recent advances in the knowledge and treatment of TTP do not seem to have brought similar improvements in the management and outcome of TTP in SLE. The illumination of the role of the von Willebrand factor multimer protease, ADAMTS13 in idiopathic TTP continues to enhance our comprehension of the pathogenesis of the disease and has contributed to improvements in diagnosis and management. We explore the overlap of TTP and SLE, and discuss the current understanding of the involvement of ADAMTS13 and its implications for patients with this uncommon form of microangiopathic haemolytic anaemia.
Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We ...aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.
This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.
The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated
, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.
These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.
Denileukin diftitox (Ontak(®)) is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL), a rare lymphoproliferative disorder of the skin. Denileukin ...diftitox was the first fusion protein toxin approved for the treatment of a human disease. This fusion protein toxin combines the IL2 protein with diphtheria toxin, and targets the CD25 subunit of the IL2 receptor, resulting in the unique delivery of a cytocidal agent to CD-25 bearing T-cells. Historically, immunotherapy targeting malignant T-cells including monoclonal antibodies has been largely ineffective as cytocidal agents compared to immunotherapy directed against B-cells such as rituximab. This review will summarize the development of denileukin diftitox, its proposed mechanism of action, the pivotal clinical trials that led to its FDA approval, the improvements in quality of life, and the common toxicities experienced during the treatment of patients with CTCL. CTCL is often a chronic progressive lymphoma requiring the sequential use of treatments such as retinoids, traditional chemotherapy, or biological response modifiers. The incorporation of the immunotoxin denileukin diftitox into the sequential or combinatorial treatment of CTCL will also be addressed.
Introduction Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Sézary syndrome (SS) is a rare, aggressive and advanced type of CTCL. It has a unique biology, with high ...expression of KIR3DL2, a killer immunoglobulin-like receptor, reported in more than 85% of patients. SS is characterized by erythroderma, significant blood involvement with malignant SS cells, and lymphadenopathy. These patients suffer from debilitating itching and recurrent skin infections, often affecting quality of life (QoL). SS is distinguished by its poor prognosis, as the median survival of patients is approximately 5 years. Lacutamab is a first-in-class monoclonal antibody designed to specifically deplete KIR3DL2-expressing cells via antibody-dependent cell-cytotoxicity and phagocytosis. Methods TELLOMAK is an international, open-label, Phase 2 trial with multiple cohorts (NCT03902184). We report here results from Cohort 1, designed to evaluate safety and efficacy of single agent lacutamab in patients with relapsed/refractory (R/R) SS after at least 2 prior systemic therapies including mogamulizumab. Patients had blood stage B2 (≥1000 circulating Sézary cells/mm 3) at screening based on central evaluation by flow cytometry. Patients with evidence of large cell transformation were excluded. Lacutamab 750 mg is administered as an intravenous infusion weekly × 5 weeks (w), every 2 w × 10, then every 4 w until progression or unacceptable toxicity. Primary endpoint was Objective Response Rate (ORR) by global response score based on the evaluation of 4 compartments: skin, blood, lymph nodes and viscera according to International Consensus criteria (Olsen 2011). Secondary endpoints included but not limited to additional efficacy endpoints, safety, QoL assessments. Results At the data cut-off of May 1, 2023, 56 SS patients were enrolled treated and evaluated in Cohort 1. Median age was 69 years (range: 42-86), the median prior lines of systemic therapies was 6.0 (range: 2-15), 60.7 % (n=34) had stage IVA1, 32.1 % (n=18) had stage IVA2 and 7.1% (n=4) had stage IVB disease at baseline, all patients (100%) had blood involvement (B2), 67.9% (n=38) had confluence of erythema covering ≥ 80% body surface area (T4), 35.7% (n=20) had lymph node lymphoma involvement (N3). Median follow-up was 14.4 months (95% CI 9.0-18.4). In the ITT population (n=56), Global confirmed ORR was 37.5% (n=21; 95% CI 26.0-50.6) including 2 CRs, with a median time to response of 2.8 months (range 1-9; Figure 1). Confirmed ORR in skin was 46.4% (n=26; 95% CI 34.0-59.3) including 5 CRs. Confirmed ORR in blood was 48.2% (n=27; 95% CI 35.7-61.0) including 15 CRs. Clinical Benefit Rate (CBR, defined as CR+PR+SD) was 87.5 % (n=49; 95% CI 76.4-93.8). Median PFS was 8.0 months (95% CI 4.7-21.2). Grade ≥ 3 Treatment-related (TR) Treatment-Emergent Adverse events (TEAEs) were observed in 10/56 (17.9%) pts, Serious TR TEAEs were observed in 4/56 (7.1%) and 3/56 (5.4%) pts discontinued study drug due to TR TEAE. Data from additional key endpoints will be presented. Conclusion In this SS cohort from the TELLOMAK study, our data confirm that lacutamab monotherapy shows promising clinical activity in a R/R population previously treated with 2 or more prior systemic therapies including mogamulizumab, and an overall favourable safety profile. Continued evaluation of this new targeted treatment option for patients with SS is warranted.
Background: Patients withacute myeloid leukemia (AML) are at increased risk for both hemorrhage and thrombosis, including in the central nervous system. There is limited data on the incidence, ...clinical association and mortality associated with cerebrovascular accident (CVA) in hospitalized patients with active AML. The aim of this study is to evaluate the epidemiology and mortality of hospitalized patients with AML who suffered concurrent stroke from a large national database.
Methods: Using the 2012 National Inpatient Sample (NIS), admissions with an International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes for AML without remission and AML in relapse (205.00 and 205.02, respectively) were extracted, and correlated with age, gender, length of stay and mortality. All CVA (ICD-9-CM 434.91) data were extracted as well for comparison of mortality, length of stay (LOS).
Results: Of the 7,296,968 unweighted admissions in the 2012 NIS, 9384 involved AML patients who had not yet achieved remission, and 1600 involved relapsed AML (Prevalence of 0.12% and 0.021% respectively). Of the combined group of admitted patients with active AML (N=10,984), 65 patients (0.59%) had a concomitant CVA (either hemorrhagic or ischemic, of whom 56 (0.51%) had active disease and 9 (0.08%) had relapsed disease). Compared to all other active AML patients, those who developed stroke were older (Mean age 66 y/o vs 58 y/o P=0.003), had longer LOS (20 days vs 12 days P= 0.53), were predominantly female (55% vs 45%; p=0.078) and had significantly higher inpatient mortality rates (36.9% vs 10.5%; OR 3.5; 95%CI 2.2, 5.5; P<0.0001). AML patients with CVA had significantly higher inpatient mortality then all admitted patients with stroke (36.9% vs 6.7%; OR 5.5; 95%CI 3.5, 8.8; P<0.0001). Multivariate logistic regression attempting to find significant clinical associations in AML patients who develop stroke, after controlling for confounding variables, found that acute renal failure with tubular necrosis(OR 4.47; 95%CI 1.8, 11.2; P=0.0013), hypernatremia (OR 3.85; 95%CI 1.6, 9.1; P=0.002), urinary tract infection (OR 3.28; CI95% 1.8, 6.1; P=0.0002) and secondary thrombocytopenia (OR 2.92; 95%CI 1.5, 5.7; P=0.0018) were all significantly predictive, as were mechanical ventilation >96 hours (OR 4.92; CI95% 1.02, 23.6; P=0.047) and continuous positive airway pressure ventilation (OR 3.03; CI95% 1.11, 8.26; P=0.031). Disseminated intravascular coagulation (DIC) and leukocytosis were more prevalent in AML patients with CVA compare to all AML patients, but the difference did not reach statistical significance.
Conclusions: CVA in patients with active AML was strongly associated with older age and higher mortality, and appeared to be a relatively rare event, occurring in only 0.59% of patients. There was no statistically significant difference in LOS or gender distribution between those who developed CVA and those who did not amont active AML patients. As compared to all CVA patients, active AML patients with CVA had 5-fold higher risk of mortality. Significant acute renal failure, hypernatremia and thrombocytopenia appear to portend a higher risk of stroke in patients with active AML. It is unclear if UTI, and the need for mechanical ventilation is a predictor of stroke, as much as they may be a ramification of it. While more common in AML patients with CVA vs AML patients without CVA, we did not find DIC or hyperleukocytosis to be significantly predictive.
No relevant conflicts of interest to declare.
Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol ...3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression‐free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48‐96), with a median of 2 prior lines of therapy (range, 1‐7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1–not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki–intolerant CLL population can result in durable well-tolerated responses.
•Umbralisib is safe and effective in this BTKi- and PI3Ki-intolerant CLL population.
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