Real-world evidence of obinutuzumab and venetoclax in previously treated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

Venetoclax-obinutuzumab (Ven-O) is frequently administered off-label in relapsed/refractory (r/r) CLL/SLL where venetoclax-rituximab is the approved regimen. We conducted this retrospective, real-world study to evaluate Ven-O in r/r CLL/SLL. Between 7/2019 and 6/2022, 40 patients with r/r CLL/SLL on Ven-O were included. The median age was 72, 28.2% had TP53 mutation and/or 17p deletion, median number of prior therapies was 1 (range, 1-6), and 55% had prior BTK inhibitor exposure. The overall response rate was 90% (complete response [CR] or CR with incomplete marrow recovery in 27.5% and partial response in 62.5%) of patients, and the 2-year progression-free survival was 81.2% (95% CI, 69.5-94.8). Therapy was well tolerated. No laboratory or clinical TLS occurred with venetoclax (Howard criteria). One (3%) patient experienced laboratory TLS with obinutuzumab initiation. In summary, this retrospective cohort study demonstrated that Ven-O achieves frequent, durable responses and can be safely administered in r/r CLL/SLL.

Japanese phase Ib study of the oral PI3K-δ and -γ inhibitor duvelisib in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

This phase Ib, open-label, single-arm, multicenter study assessed the efficacy and safety of duvelisib, an oral dual inhibitor of phosphatidylinositol 3-kinase-δ and -γ, in Japanese patients with relapsed or refractory (r/r) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Duvelisib was administered orally at 25 mg twice a day (BID) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) and all responses were assessed by an independent review committee. Nine CLL patients and 1 SLL patient were enrolled. ORR was 80% (95% confidence interval 44.4, 97.5) for all 10 patients. All 6 patients previously treated with a Bruton's tyrosine kinase (BTK) or BCL2 inhibitor achieved a partial response. The most common adverse events were neutropenia (50%), diarrhea (40%), anemia, hypokalemia, constipation and rash (30% each). The most common grade ≥ 3 adverse events were neutropenia (50%), anemia (30%) and thrombocytopenia (20%). Duvelisib 25 mg BID showed favorable efficacy and a manageable safety profile in selected Japanese patients with r/r CLL/SLL, including patients previously treated with BTK or BCL2 inhibitors (Clinical trial registration: jRCTs2080224791).

Real-World Comparison of First-Line Treatment Adherence Between Single-Agent Ibrutinib and Acalabrutinib in Patients with Chronic Lymphocytic Leukemia.

Purpose: Increased dosing frequency adversely affects treatment adherence and outcomes in chronic diseases; however, such data related to treatment adherence is lacking in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This study compared adherence between patients treated with ibrutinib (once-daily) versus acalabrutinib (twice-daily) as first-line (1L) therapy for CLL/SLL. Patients and Methods: Specialty pharmacy electronic medical records were used to identify adults with CLL/SLL initiating 1L ibrutinib or acalabrutinib between 01/01/2018 and 11/30/2020. Adherence was measured by the proportion of days covered (PDC) and medication possession ratio (MPR) and was compared between cohorts using odds ratios (ORs) obtained from logistic regression models adjusted for baseline characteristics. Results: Between 01/01/2018 and 11/30/2020, 1374 and 140 patients initiated ibrutinib and acalabrutinib, respectively. Based on PDC/MPR ≥80%, patients treated with once-daily ibrutinib were more likely to be adherent than those treated with twice-daily acalabrutinib (OR ranges: PDC: 1.04-1.76; MPR: 1.03-1.58). At 6 months, patients on ibrutinib had a 58-76% higher likelihood of staying adherent compared to patients on acalabrutinib (PDC: 75.9% for ibrutinib vs 63.6% for acalabrutinib, OR: 1.76, P=0.008; MPR: 76.8% vs 66.9%, OR: 1.58, P=0.036) with a similar trend noted for the entire line of treatment (LOT) (PDC: 53.0% vs 41.4%, OR: 1.53, P=0.021; MPR: 58.7% vs 47.1%, OR: 1.50, P=0.027). Conclusion: In this real-world analysis, CLL/SLL patients initiating 1L once-daily ibrutinib had >50% higher treatment adherence than those initiating twice-daily acalabrutinib during their LOT. Given the importance of sustained adherence for disease control in CLL/SLL, dosing frequency may be an important consideration for patients and physicians.

SOHO State of the Art Updates and Next Questions: Updates on BTK Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.

Over the last decade, targeted inhibition of Bruton's tyrosine kinase (BTK) has led to a paradigm shift in the way chronic lymphocytic leukemia (CLL) is managed. BTK inhibitors (BTKi) are broadly classified as covalent BTKI and noncovalent BTKi (cBTKi and ncBTK) Ibrutinib, as the first approved cBTKi, vastly improved outcomes for patients with CLL over prior chemoimmunotherapy regimens. However, long-term use is limited by both intolerance and resistance. The second generation of more selective BTKi were developed to improve tolerability. While these agents have led to an improved safety profile in comparison to Ibrutinib (both acalabrutinib and zanubrutinib), and improved efficacy (zanubrutinib), intolerance occasionally occurs, and resistance remains a challenge. The third generation of BTKi, which noncovalently or reversibly inhibits BTK, has shown promising results in early phase trials and are being evaluated in the phase 3 setting. These drugs could be an effective treatment option in patients with either resistance and intolerance to cBTKi. The most recent development in therapeutic agents targeting BTK is the development of BTK degraders. By removing BTK, as opposed to inhibiting it, these drugs could remain efficacious irrespective of BTK resistance mutations, however clinical data are limited at this time. This review summarizes the evolution and ongoing development of newer BTKi and BTK degraders in the management of CLL, with a focus of future directions in this field, including how emerging clinical data could inform therapeutic sequencing in CLL management.

Indirect comparisons of efficacy of zanubrutinib versus orelabrutinib in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma or relapsed or refractory mantle cell lymphoma.

We conducted two indirect comparisons to estimate the efficacy of zanubrutinib versus orelabrutinib in Chinese patients with relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or R/R mantle cell lymphoma (MCL). An unanchored matching-adjusted indirect comparison (MAIC) was performed in R/R CLL/SLL patients. Individual patient data from zanubrutinib trial (BGB-3111-205) were adjusted to match the aggregated data from the orelabrutinib trial (ICP-CL-00103). A naïve comparison was performed in R/R MCL for the different response assessment methodology and efficacy analysis set between the zanubrutinib (BGB-3111-206) and orelabrutinib (ICP-CL-00102) trials. Efficacy outcomes included ORR and PFS. In R/R CLL/SLL patients, after matching, IRC-assessed ORR was comparable (86.6% vs. 92.5%; risk difference, -5.9% [95% CI: -15.8%-3.8%]); IRC-assessed PFS was similar with a favorable trend in zanubrutinib over orelabrutinib (HR, 0.74 [95% CI: 0.37-1.47]) and the 18-month PFS rate was numerically higher in zanubrutinib (82.9% vs. 78.7%). In R/R MCL patients, naïve comparison showed investigator-assessed ORR was similar (83.7% vs. 87.9%; risk difference, -4.2% [95% CI: -14.8%-6.0%]), and CR rate was significantly higher in zanubrutinib over orelabrutinib (77.9% vs. 42.9%; risk difference, 35.0% [95% CI: 14.5%, 53.7%]). Investigator-assessed PFS was similar with a favorable trend (HR, 0.77 [95% CI: 0.45-1.32]) in zanubrutinib over orelabrutinib and the 12-month PFS rate was numerically higher in zanubrutinib (77.5% vs. 70.8%). MAIC result showed zanubrutinib demonstrated favorable PFS over orelabrutinib for R/R CLL/SLL patients. The naïve comparison showed zanubrutinib had favorable PFS and higher CR rate than orelabrutinib for R/R MCL patients.

MYD88-Mutated Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma as a Distinctive Molecular Subgroup Is Associated with Atypical Immunophenotypes in Chinese Patients.

Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) is a heterogeneous disease in Western and Chinese populations, and it is still not well characterized in Chinese patients. Based on a large cohort of newly diagnosed CLL/SLL patients from China, we investigated immunophenotypes, genetic abnormalities, and their correlations. Eighty-four percent of the CLL/SLL patients showed typical immunophenotypes with scores of 4 or 5 points in the Royal Marsden Hospital (RMH) scoring system (classic group), and the remaining 16% of patients were atypical with scores lower than 4 points (atypical group). Trisomy 12 and variants of TP53, NOTCH1, SF3B1, ATM, and MYD88 were the most recurrent genetic aberrations. Additionally, unsupervised genomic analysis based on molecular genetics revealed distinctive characteristics of MYD88 variants in CLL/SLL. By overlapping different correlation grouping analysis from genetics to immunophenotypes, the results showed MYD88 variants to be highly related to atypical CLL/SLL immunophenotypes. Furthermore, compared with mantle cell lymphoma (MCL), the genetic landscape showed potential value in clinical differential diagnosis of atypical CLL/SLL and MCL patients. These results reveal immunophenotypic and genetic features, and may provide insights into the tumorigenesis and clinical management of Chinese CLL/SLL patients.

Immune evasion phenotype is common in Richter transformation diffuse large B-cell lymphoma variant.

Immune checkpoint inhibitors (PD-1 inhibitors) have shown clinical activity in Richter transformation-diffuse large B-cell lymphoma variant (RT-DLBCL), thus providing for a novel therapeutic approach. The study group consists of 64 patients with RT-DLBCL. Expression of PD-1, PD-L1, CD30, and microsatellite instability (MSI) status (hMLH1, hMSH2, hMSH6, PMS1) was assessed using immunohistochemistry. EBV-encoded RNA (EBER) was evaluated using colorimetric in situ hybridization. PD-1 and PD-L1 expression levels were categorized on the basis of tumor cell expression as follows: negative (< 5%), positive to low-positive (5-50%), or high-positive (> 50%). An "immune evasion phenotype" (IEP) was defined as RT-DLBCL cases having high-positive expression of PD-1 and/or PD-L1 on tumor cells. The level of PD1-positive tumor-infiltrating lymphocytes (TILs) was estimated as a fraction of total lymphocytes and categorized as negative/low vs. brisk (> 20%). 28/64 (43.7%) patients were characterized as IEP+ RT-DLBCL. A brisk level of PD1+ TILs was significantly more common in IEP1+ compared with IEP- tumors (17/28, 60.7% vs. 5/34, 14.7%; p = 0.001). In addition, CD30 expression was significantly more common in IEP+ compared with IEP- RT-DLBCL (6/20, 30% vs. 1/27, 3.7%; p = 0.0320). Two (2/36; 5.5%) cases were positive for EBER, both IEP+. There was no significant difference between the two groups in terms of age, sex, or time to transformation. Assessment of mismatch repair proteins demonstrated absence of microsatellite instability (MSI) in all cases (18/18; 100%). Notably, patients with brisk PD1+ TILs had a significantly better OS compared to those with a negative/low infiltrate (p = 0.0285).

How Have Targeted Agents Changed the Treatment Landscape for Elderly Patients with CLL?

PURPOSE OF REVIEW: Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy in elderly patients. At the time of diagnosis, most patients have comorbid medical conditions. Although patients have other competing medical issues, the majority of patients will die from CLL or CLL-related complications. This review will discuss treatment in elderly patients with CLL. RECENT FINDINGS: Recent work has focused on understanding the role comorbid medical conditions play in the management of CLL in elderly patients, including the use of geriatric assessment, Charlson comorbidity index, cumulative illness rating scale, and most recently, the CLL-comorbidity index. The treatment landscape for CLL has shifted from chemoimmunotherapy to the use of targeted agents. Several clinical trials in elderly patients have demonstrated improvement in progression-free survival (PFS) with ibrutinib + / - obinutuzumab, acalabrutinib + / - obinutuzumab, zanubrutinib, venetoclax-obinutuzumab, idelalisib, and duvelisib. The adverse event profile and potential for drug-drug interactions in the treatment of CLL in elderly patients have not been described, and further studies are needed to determine optimal treatment. Treatment of elderly patients with CLL should be made on a case-by-case basis based on a patient's fitness, comorbid medical conditions, and concomitant medications. The use of targeted agents has improved outcomes in this patient population, but further studies are needed to determine the best practice.

Minimal/Measurable Disease Analysis in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma by Flow Cytometry.

CLL/SLL is the most common leukemia in the western world. The disease is indolent; however, most patients require treatment at some point of the disease course. Outside of allogeneic transplants, the treatment is rarely curative but often controls CLL/SLL manifestations for many years. Several lines of therapy may be used sequentially to prolong clinical remission. Because of the prolonged disease course, CLL/SLL monitoring represents a sizable portion of the workload in a typical flow cytometry laboratory involved in the diagnosis and monitoring of hematopoietic neoplasms. Minimal/measurable disease monitoring of CLL/SLL has emerged as a key component in treatment monitoring and sequencing. In the face of effective therapies, clinical laboratories are tasked with monitoring ever smaller proportions of MRD with high precision and accuracy. With the recent addition of surface antigen-targeting biologics such as antibodies and CAR-T cells, the task has become more complex due to the unavailability of commonly analyzed antigens for flow cytometric analysis. This article details a flow cytometric test developed at Memorial Sloan Kettering Cancer Center that has proven to consistently achieve high sensitivity (<0.01% of nucleated cells) in the bone marrow and peripheral blood, even when CD19 is lost or unavailable for analysis. Moreover, the test helps distinguish between CLL and other CD5-positive B cell neoplasms. The Basic Protocol provides a detailed operational procedure for processing, staining, and cytometric acquisition of samples. The Support Protocol provides typical steps and caveats for MRD data analysis in CLL/SLL and in distinguishing CLL/SLL from other B cell neoplasms and normal CD5-positive B cells. © 2022 Wiley Periodicals LLC. Basic Protocol: Processing, staining, and cytometric analysis of bone marrow or peripheral blood cells for MRD analysis of CLL/SLL Support Protocol: Analysis and interpretation of CLL MRD assay.

Real-World Persistence and Time to Next Treatment With Ibrutinib in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Including Patients at High Risk for Atrial Fibrillation or Stroke.

BACKGROUND: Atrial fibrillation (AF) is a recognized adverse consequence associated with all Bruton's tyrosine kinase inhibitors used to treat chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL); however, real-world time to discontinuation (TTD) and time to next treatment (TTNT) of CLL/SLL patients with a high baseline AF/stroke risk remain unknown. MATERIALS AND METHODS: Patients with CLL/SLL from a nationwide electronic health record-derived database (February 12, 2013-January 31, 2021) initiating first-line (1L) or second or later-line (2L+) treatment with ibrutinib or other regimens on or after February 12, 2014 (index date) were analyzed. Kaplan-Meier survival analysis was used to assess TTD and TTNT among all patients, patients with high AF risk (CHARGE-AF risk score ≥10.0%), and patients at high risk of stroke (CHA2DS2-VASc risk score ≥3 [females] or ≥2 [males]). RESULTS: In 1L/2L+, 2190/1851 patients received ibrutinib and 4388/4135, were treated with other regimens. Median TTD for ibrutinib was similar regardless of AF/stroke-related risk (1L: all patients, 15.7 months; high AF risk, 11.7 months; high stroke risk, 13.7 months; similar results in 2L+). Median TTNT was significantly longer for ibrutinib vs. other regimens (1L: not reached vs. 45.9 months; 2L+: not reached vs. 23.6 months; both P < .05), including among those with high AF/stroke risk. TTNT was similar between all patients and high-risk cohorts in 1L and 2L+ (all P > .05). CONCLUSION: This study highlights that elevated baseline AF/stroke-related risk does not adversely impact TTD and TTNT outcomes associated with ibrutinib use. Additionally, TTNT was significantly longer for patients treated with ibrutinib vs. other regimens.

Zanubrutinib Monotherapy for Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pooled Analysis of Three Studies.

INTRODUCTION: Zanubrutinib is a highly selective irreversible inhibitor of Bruton tyrosine kinase which has shown significant activity in lymphoid malignancies in early phase studies. We report here the long-term follow-up outcomes of zanubrutinib in various lines of therapy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). METHODS: This post hoc analysis pooled patients with treatment-naïve (TN) or relapsed/refractory (R/R) CLL/SLL receiving zanubrutinib monotherapy from three phase 1/2 studies (BGB-3111-1002, BGB-3111-AU-003, BGB-3111-205). RESULTS: A total of 211 patients with CLL/SLL (TN 19, R/R 192) were included. After weighting (TN 19, R/R 24), the overall response rate (ORR) was 95.4% and significantly higher in the TN group than in the R/R group (100 vs. 91.0%, p < 0.0001). ORR was also significantly higher in the TN group than in the one prior line of therapy group (100 vs. 98.9%, p < 0.0001). Among those with R/R disease, the ORR was 97.8% in patients with one prior line of therapy (n = 79) and 90.7% in those with > 1 prior lines of therapy (n = 85; p = 0.080). The median follow-up times were 50.1, 35.7, and 45.9 months for TN, R/R and all cohorts, respectively. Progression-free survival and overall survival were significantly longer in the TN group and only one prior line of therapy group compared with the > 1 prior lines of therapy group (all p < 0.05) and were similar in the TN group compared with the one prior line therapy group. Efficacy was similar regardless of the presence of genomic aberrations. Most frequent grade ≥ 3 adverse events were infections (41.7%), neutropenia (34.1%), and thrombocytopenia (9.4%). Atrial fibrillation occurred in only 1.9% of patients. CONCLUSIONS: With extended follow-up, zanubrutinib yielded long-term benefits and demonstrated a favorable safety profile for patients with TN or RR CLL/SLL. Earlier utilization of zanubrutinib was associated with better outcomes. TRIAL REGISTRATION: Clinical Trials.gov identifiers, NCT03189524, NCT02343120 (retrospectively registered), and NCT03206918 (retrospectively registered).

Immunohistochemistry for LEF1 and SOX11 adds diagnostic specificity in small B-cell lymphomas.

Lymphocyte enhancer-binding factor 1 (LEF1) and SRY-Box 11 (SOX11) are highly sensitive and specific for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL) including the cyclin D1-negative subtype, respectively. We assessed the utility of these markers in a large cohort of small B-cell lymphomas (SBCLs) on varied sample types. Immunohistochemistry (IHC) was performed for LEF1 and SOX11 on 354 SBCLs (129 CLL/SLLs, 33 MCLs, 142 marginal zone lymphomas [MZLs]-nodal MZL [NMZL]: 40, extranodal MZL [ENMZL]: 28, splenic MZL [SMZL]: 74 cases-and 50 lymphoplasmacytic lymphomas [LPLs]/Waldenstrom macroglobulinemias [WMs]). Ninety-eight percent of CLL/SLLs were LEF1 positive. SOX11 showed good sensitivity (82%) and excellent specificity for MCL (99%), with only 2 of 142 MZLs (both SMZLs) showing SOX11 expression. The low sensitivity for SOX11 was on account of inclusion of 4 non-nodal cases. All 50 LPL/WMs were negative for both LEF1 and SOX11. The expression of SOX11 and LEF1 was not always mutually exclusive, as 2 confirmed MCLs expressed both markers. LEF1 and SOX11 have excellent utility as diagnostic markers especially for atypical CD5-positive SBCLs.

Clinical utility of chromosomal microarray in establishing clonality and high risk features in patients with Richter transformation.

Richter transformation (RT) refers to the development of an aggressive lymphoma in patients with pre-existing chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). It carries a poor prognosis secondary to poor response to therapy or rapid disease relapse. Currently there are no randomized trials to guide treatment. Therapeutic decisions are often influenced by the presence or absence of a clonal relationship between the underlying CLL/SLL and the new lymphoma given the poor prognosis of patients with clonally related RT. Chromosomal microarray analysis (CMA) can help to establish clonality while also detecting genomic complexity and clinically relevant genetic variants such as loss of CDKN2A and/or TP53. As a result, CMA has potential prognostic and therapeutic implications. For this study, CMA results from patients with Richter transformation were evaluated in paired CLL/SLL and transformed lymphoma samples. CMA revealed that 86% of patients had common aberrations in the two samples indicating evidence of common clonality. CMA was also useful in detecting aberrations associated with a poor prognosis in 71% of patients with RT. This study highlights the potential clinical utility of CMA to investigate the clonal relationship between CLL/SLL and RT, provide prognostic information, and possibly guide therapeutic decision making for patients with Richter transformation.

Mantle cell lymphoma with chronic lymphocytic leukemia-like features: a diagnostic mimic and pitfall.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by t(11;14) (q13;q32) and cyclin D1 overexpression in >95% of cases. Classic MCL cases are composed of a monotonous population of small- to medium-sized lymphocytes with irregular nuclear contours that are positive for cyclin D1 and SOX11 and negative for CD23 and CD200. By contrast, occasional MCL cases express CD23 and CD200 but lack SOX11 and morphologically and immunophenotypically resemble chronic lymphocytic leukemia (CLL), termed as CLL-like MCL in this study. These neoplasms pose a diagnostic challenge and are easy to be diagnosed as CLL in daily practice. We studied 14 cases of CLL-like MCL to define their clinicopathologic features and compared them with 33 traditional CLL cases. There were 8 men and 6 women with a median age of 62 years (range, 44-80). Compared with CLL, patients with CLL-like MCL have lower levels of peripheral blood and bone marrow involvement and more frequently had mutated IGHV. Immunophenotypically, CLL-like MCL often showed moderate to bright expression of B-cell antigens and surface immunoglobulin light chain, dim and partial expression of CD23 and CD200, infrequent CD43 positivity, and lack of LEF1. The overall survival of patients with CLL-like MCL was similar to that of CLL patients. In conclusion, CD23+, CD200+, and SOX11-negative MCL closely resemble CLL, both clinically and pathologically, including a similar indolent clinical course. They may pose a diagnostic challenge. However, patients with CLL-like MCL also have distinctive immunophenotypic features that are useful to distinguish these neoplasms from CLL.

Artificial intelligence strategy integrating morphologic and architectural biomarkers provides robust diagnostic accuracy for disease progression in chronic lymphocytic leukemia.

Artificial intelligence-based tools designed to assist in the diagnosis of lymphoid neoplasms remain limited. The development of such tools can add value as a diagnostic aid in the evaluation of tissue samples involved by lymphoma. A common diagnostic question is the determination of chronic lymphocytic leukemia (CLL) progression to accelerated CLL (aCLL) or transformation to diffuse large B-cell lymphoma (Richter transformation; RT) in patients who develop progressive disease. The morphologic assessment of CLL, aCLL, and RT can be diagnostically challenging. Using established diagnostic criteria of CLL progression/transformation, we designed four artificial intelligence-constructed biomarkers based on cytologic (nuclear size and nuclear intensity) and architectural (cellular density and cell to nearest-neighbor distance) features. We analyzed the predictive value of implementing these biomarkers individually and then in an iterative sequential manner to distinguish tissue samples with CLL, aCLL, and RT. Our model, based on these four morphologic biomarker attributes, achieved a robust analytic accuracy. This study suggests that biomarkers identified using artificial intelligence-based tools can be used to assist in the diagnostic evaluation of tissue samples from patients with CLL who develop aggressive disease features. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Complete eradication of chronic lymphocytic leukemia with unusual skin involvement of high mitotic index after time-limited venetoclax/obinutuzumab treatment.

The novel time-limited combinations with the bcl-2 inhibitor venetoclax can induce deep responses even in CLL cases with unusual and biologically aggressive presentations, like the skin masses of our patient.

Concurrent Adjacent Merkel Cell Carcinoma and Chronic Lymphocytic Leukemia without Simultaneous Merkel Cell Polyomavirus Detection: A Case Series.

BACKGROUND: The association between Merkel cell carcinoma (MCC) and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) is well established in the literature. A majority of MCCs are known to be associated with Merkel cell carcinoma polyomavirus (MCPyV), which is postulated to be a possible causative agent linking these two entities. We aim to identify the presence of MCPyV in patients with concurrent adjacent MCC and CLL/SLL. METHODS: Archived pathology materials of three cutaneous or surgical excisions with concurrent MCC and CLL/SLL were reviewed. Additional 12-µm sections from paraffin-embedded tissue of these resections were matched with original hematoxylin and eosin-stained slides and used to extract foci from each tumor separately. DNA was extracted from these tissues, and polymerase chain reaction (PCR), utilizing a primer set within a highly conserved "small T" viral DNA region, was done to detect MCPyV. RESULTS: Out of 140 cases of cutaneous or surgical excisions with MCC identified in our electronic medical records (EMR), three had coexisting neighboring CLL/SLL in the same resection specimen. In one case out of three, MCPyV was detected in MCC but not in CLL/SLL. The remaining two cases showed no detection of MCPyV in either MCC or CLL/SLL. CONCLUSION: MCPyV was not concurrently associated with adjacent MCC and CLL/SLL, indicating that it is not driving simultaneous tumorigenesis, at least in a subset of these cases.

The pathological features of leukemic cells infiltrating the renal interstitium in chronic lymphocytic leukemia/small lymphocytic lymphoma from a large single Chinese center.

BACKGROUND: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is rare in Asians, and patients with CLL/SLL seldomly undergo kidney biopsy. The histopathological features and clinical relevance of tubulointerstitial injury in CLL/SLL have not been extensively characterized. Hence, we attempted to describe the clinical characteristics, renal pathology and clinical outcome of a well-characterized population of CLL/SLL patients with CLL cell infiltration in the renal interstitium from a large single center in China. METHODS: Between January 1st, 2010 and September 31st, 2020, 31946renal biopsies were performed at Peking University First Hospital, and 10 CLL/SLL patients with CLL cell infiltration in the renal interstitium were included. Complete clinical data were collected from these 10 patients, and renal specimens were examined by routine light microscopy, immunofluorescence and electron microscopy. RESULTS: The extent of the infiltrating CLL cells in patients with CLL/SLL varied among different patients and ranged from 10 to 90% of kidney parenchyma. Six (60%) of 10 patients presented with an extent of infiltrating CLL cells ≥50%. Interestingly, we found that three patients (3/10, 30%) expressed monoclonal immunoglobulins in the infiltrating CLL cells, and special cytoplasmic crystalline structures were found in two of the three patients by electron microscopy for the first time. Severe renal insufficiency (Scr ≥200 µmol/L) was associated with ≥50% interstitial infiltration of CLL cells in the renal interstitium. CONCLUSIONS: The current study confirmed that CLL cells infiltrating the renal interstitium can directly secrete monoclonal immunoglobulins, indicating that the interstitial infiltrating CLL cells possibly cause renal injury directly by secreting monoclonal immunoglobulins in situ. This finding may prove a new clue to elucidate the pathogenetic mechanism of renal injury involved with CLL/SLL.

An unusual presentation of chronic lymphocytic leukemia/small lymphocytic lymphoma on mammography: Case report.

Although rare, breast CLL/SLL should be considered in the differential diagnosis of a breast mass. A high index of suspicion is needed to differentiate this neoplasm from more common breast carcinomas like solid variant of invasive lobular carcinoma.

Deep Learning for the Classification of Non-Hodgkin Lymphoma on Histopathological Images.

The diagnosis and the subtyping of non-Hodgkin lymphoma (NHL) are challenging and require expert knowledge, great experience, thorough morphological analysis, and often additional expensive immunohistological and molecular methods. As these requirements are not always available, supplemental methods supporting morphological-based decision making and potentially entity subtyping are required. Deep learning methods have been shown to classify histopathological images with high accuracy, but data on NHL subtyping are limited. After annotation of histopathological whole-slide images and image patch extraction, we trained and optimized an EfficientNet convolutional neuronal network algorithm on 84,139 image patches from 629 patients and evaluated its potential to classify tumor-free reference lymph nodes, nodal small lymphocytic lymphoma/chronic lymphocytic leukemia, and nodal diffuse large B-cell lymphoma. The optimized algorithm achieved an accuracy of 95.56% on an independent test set including 16,960 image patches from 125 patients after the application of quality controls. Automatic classification of NHL is possible with high accuracy using deep learning on histopathological images and routine diagnostic applications should be pursued.