Expression of the Immune Checkpoint Regulators LAG-3 and TIM-3 in Classical Hodgkin Lymphoma.

INTRODUCTION: The role of the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis is well established in classical Hodgkin lymphoma (HL), where PD-1 blockade demonstrated spectacular efficacy in relapsed/refractory disease. However, little is known about the frequency and cellular distribution of other immune checkpoints in HL samples. PATIENTS AND METHODS: Using immunohistochemistry, we investigated, along with PD-L1 and PD-1, the expression of lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) in 57 biopsy samples of patients with classical HL. RESULTS: Hodgkin and Reed/Sternberg (HRS) cells were strongly positive for PD-L1 in nearly all cases. HRS cells were TIM-3 positive in 36% of samples, whereas LAG-3 was rarely expressed (5.2%). In the microenvironment, PD-1, LAG-3, and TIM-3 were expressed by ≥ 5% of cells in 65%, 98%, and 96% of cases, respectively. T-cell rosettes surrounding HRS cells consisted of CD4+ FoxP3- helper T cells expressing both PD-1 and LAG-3, with a variable expression of TIM-3. CONCLUSION: This study demonstrates for the first time that LAG-3 and TIM-3 are nearly always expressed in the microenvironment of classical HL. This may constitute the basis for targeting LAG-3 or TIM-3 in combination with anti-PD-1 antibodies in the treatment of relapsed/refractory HL.

Ibrutinib-Induced Neutrophilic Dermatosis.

We report the case of a 64-year-old woman treated with ibrutinib for a chronic lymphocytic leukemia with 17p deletion, who developed several erythematous, painful, and papulo-nodular skin lesions in the limbs, neck, and face. The skin biopsy was consistent with the diagnosis of neutrophilic dermatosis. Rechallenge with ibrutinib at full dose was followed by the recurrence of the same skin lesions, strongly suggesting a direct relationship.

Novel targeted therapeutics for mantle cell lymphoma--what's on the horizon?

Major advances have significantly improved the outcome of mantle cell lymphoma (MCL). Incorporation of rituximab to CHOP regimen, the adoption of high dose cytarabine with frontline autologous stem cell transplantation in young patients, maintenance rituximab or bortezomib based chemotherapy in elderly patients, improved the disease outcome. Bortezomib, lenalidomide, temsirolimus and ibrutinib have proven their efficacy and are approved for the use in refractory or relapsed MCL patients. Several other molecules are currently being evaluated such as cyclin dependent kinase 4/6 (CDK4/6), phosphoinositide 3-kinase (PI3K), B cell lymphoma-2 (BCL2) and Poly ADP-ribose polymerase (PARP) inhibitors. Unfortunately, we don't have specific biomarkers that could reveal which of the underlying pathways or genetic alterations are mostly involved in each individual case of MCL. Efforts should be done in this field aiming to an optimal personalized therapy.

Assessment of Molecular Markers in AML Patients: A Hospital-Based Study in Lebanon.

BACKGROUND: In the past, research has been focused on elucidating the molecular genetics and epigenetic basis of acute myelogenous leukemia (AML). This has led to the change in the classification and management of AML patients. Because no molecular studies regarding AML characterization in Lebanese patients had yet been reported, we decided to determine in our institution the prevalence of the recurrent genetic rearrangements t(8;21), inv(16), t(15;17) and Fms-like (Suzanne McDonough feline sarcoma) tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) mutations. MATERIALS AND METHODS: Fusion gene transcripts from chromosome aberrations were analyzed according to standardized reverse transcription polymerase chain reactions after the report of BIOMED-1 concerted action: investigation of minimal residual disease in acute leukemia. FLT3 and NPM1 mutations were screened using home-brew methodologies. RESULTS: We reviewed 144 bone marrow samples from AML patients referred to Saint George Hospital for molecular and cytogenetic studies from September 2006 to July 2014. The male to female patient ratio was 1.34 to 1. We detected the inv(16) in 6 patients [4.2%] (type A, 5 [83%]; type D, 1 [17%]), t(8;21) in 7 patients [4.9%] (e5e2), and t(15;17) in 36 patients [25.0%] (24 [67%] breakpoint cluster region 1 (bcr1), 12 [33%] bcr3). Other chromosomal abnormalities (trisomy 8, complex karyotype, t(6;9),…) were found in 44 patients [31.4%] and 51 [35.5%] cases showed normal karyotype. Among the normal karyotypes, 6 patients [11.8%] were FLT3-positive (4 [67%] internal tandem duplication [ITD], 2 [33%] D835V), 8 [15.7%] had type A NPM1 mutation and 8 [15.7%] type A NPM1 and FLT3/ITD concomitantly. CONCLUSION: Our results, except for the prevalence of acute promyelocytic leukemia, are concordant with those reported in the literature with approximately 35% of the patients cytogenetically normal. Testing patients with normal karyotype for other molecular markers such as CCAAT/enhancer-binding protein alpha mutations, isocitrate dehydrogenase 1/2 mutations, and mixed lineage leukemia rearrangements could therefore provide additional prognostic, predictive, and therapeutic values for AML patients.