Setting Of Chronic Lymphocytic Leukemia Research Articles

Allogeneic Transplant for CLL Richter's Transformation: Single Center Retrospective Analysis

Introduction: Richter transformation (RT) describes the emergence of an aggressive lymphoma in the setting of chronic lymphocytic leukemia (CLL). The prognosis is poor, with a median overall survival (OS) of 10 months. Treatment of RT is still challenging despite the availability of novel agents, and stem cell transplant (SCT) is commonly used as a consolidation strategy. Data on outcomes post-allogeneic-SCT for RT is limited. The OS on these reports' ranges from 41 to 75%. Methods: We conducted a retrospective study of patients diagnosed with RT at our center who underwent allogeneic SCT between 2005 and 2022. We evaluated predictors of outcome using Cox's proportional hazards regression analysis for overall and progression-free survival (PFS) and Fine and Grey regression for disease progression and non-relapse mortality (NRM). Results: 88 patients were identified, 85 had a diffuse large lymphoma histology and 3 Hodgkin's lymphoma. The median age was 61 years (range 25-74), and the majority (n=61, 69%) of patients were in complete response (CR, N=21) or partial response (PR, N=40) pre-SCT. Median follow-up among survivors was 74 months (range: 8-168); all outcomes are reported at 6 years. Overall, OS was 45% (95% CI: 34-56), and PFS 32% (95% CI: 22-43). The cumulative incidence of disease progression was 41% (95% CI: 31-53) and NRM 25% (95% CI: 17-36). In the univariate analysis, response prior to transplant was the most significant predictor of disease progression, OS, and PFS. Patients in CR/PR had a lower rate of disease progression (32% vs. 61%, HR: 0.2, 95% CI 0.2-0.6, p=0.002) and higher OS (59% vs 16%, HR: 0.3, 95% CI 0.2-0.5, p<0.001, Figure) and PFS (44% vs. 6%, HR: 0.2 (0.1-0.4), p<0.001) compared with those advanced (>CR2)or progressive disease. In addition, the presence of deletion 17p (del17p) or TP53 mutation was associated with a higher rate of disease progression (HR=3.1, 95% C 1.3 -7.3, p=0.01), but not with PFS or OS. The use of reduced intensity regimens resulted in favorable OS (HR=0.5, 95% CI 0.3-1.0, p=0.05) as compared to non-myeloablative conditioning. Age, HCT-CI score, donor type, donor-to-recipient gender, cell source, and graft-versus-host disease prophylaxis, or the presence of other cytogenetic abnormalities were not significantly associated with OS, PFS, disease progression, or NRM. There was also no advantage for any outcome when comparing individuals who achieved CR versus PR pre-SCT. The independent predictive value of CR/PR was confirmed in multivariate analysis for OS (HR=0.3, 95% CI 0.2-0.5, p<0.001) and disease progression (HR=0.4, 95% CI: 0.2-0.8, p=0.01), after adjusting for conditioning intensity for OS and deletion 17p (del17p) or TP53 mutation for disease progression. Discussion: In this single center series of patients treated with allogeneic SCT as consolidation for RT, disease status prior to SCT (CR/PR) emerged as a strong independent predictor of outcomes. The influence of tumor burden prior to SCT may be related to disease biology (e.g., patients not in CR/PR may have more aggressive RT) or may be related to decreased graft-versus-lymphoma effect. Based on our findings, we recommend that aggressive control of the disease with the goal of achieving a CR or PR should be attempted before allogeneic stem cell transplantation in patients with Richter transformation.

Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter's Transformation: An International Multicenter Retrospective Study

Background: Aggressive lymphoma, most commonly large B-cell lymphoma (LBCL), arising in the setting of chronic lymphocytic leukemia (CLL) is known as Richter's transformation (RT), and is associated with poor outcomes. CD19 CART has revolutionized the treatment (tx) of LBCL, with durable responses for patients (pts) with relapsed/refractory disease. Pts with RT have been excluded from most major CD19 CART trials. Therefore, there is limited data describing outcomes of pts with RT receiving CD19 CART Methods: We conducted an international multicenter retrospective study of pts with RT who received CD19 CART approved for hematologic malignancies at 9 academic centers. RT was defined as pts with LBCL with preceding or concurrently diagnosed CLL. We collected pt, disease, and tx characteristics. Progression-free survival (PFS) and overall survival (OS) were measured from date of CD19 CART infusion and estimated using the Kaplan-Meier method. Cox regression model was used to associate prognostic factors with PFS and OS. Response was assessed by Lugano criteria. Results: 62 pts were included. Median age at CD19 CART infusion was 65 (range: 27-80). Median prior lines of therapy for CLL or RT were both 2 (CLL range: 0-10, RT range: 0-7). 52 (84%) pts previously received a Bruton tyrosine kinase inhibitor (BTKi) or BCL2 inhibitor (BCL2i) for CLL or RT. Median Ki-67 on pathology sample was 80% (range: 40-100), median SUV on brightest lymph node (LN) on PET-CT was 15.0 (range: 3-50.6), median size of largest LN was 3.8cm (range: 0-16), and median LDH prior to CD19 CART was 244 (range: 96-2878, ULN range: 190-271). Median time from apheresis to CD19 CART infusion was 33 days (range: 24-100), and 52 (84%) pts received bridging therapy. 40 (65%), 14 (23%), 7 (11%), and 1 (2%) pts received axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), lisocabtagene maraleucel (liso-cel), and brexucabtagene autoleucel (brexu-cel), respectively. Overall response rate was 65%, with 29 (47%) and 11 (18%) pts attaining complete response (CR) and partial response (PR), respectively. After a median follow up of 24.1 months (mos) from CD19 CART infusion, the median PFS was 4.7 mos (95% CI: 2.3-6.9), and median OS was 8.5 mos (95% CI: 5.1-32.5) (Figure). Median duration of response was 14.5 mos (95% CI: 4.0-NR), with a median not reached (NR) (95% CI: 13.1-NR) for pts who achieved a CR, and a median of 2.3 mos (95% CI: 1.0-3.3) for pts who achieved a PR. Among 39 pts who died, 28 (72%) died due to progression of disease (PD), and 11 (28%) died for other reasons including 8 infections (4 COVID), 1 septic shock, 1 stroke, and 1 respiratory failure. The cumulative incidence of non-relapse mortality at 12 mos was 13% (95% CI: 6.2-23.4). 3 pts in a CR underwent allogeneic stem cell transplantation, 2 were alive at last known follow up (3.9 and 24.2 mos post-transplant), and 1 pt died from PD 21 mos post-transplant. 55 (89%) pts had CRS, with 9 (15%) grade ≥3 events. 43 (69%) pts had ICANS, with 23 (38%) grade ≥3 events. On univariable analysis, increasing Ki-67 and LDH were found to be associated with worse PFS and OS, and attaining a CR with CD19 CART was found to be associated with improved PFS and OS. On multivariable analysis, increasing Ki-67 and LDH, and greater number of prior lines of therapy for RT were independent prognostic variables for worse PFS and OS, and attaining a CR was associated with improved OS. All other variables, including type of CD19 CART product received, were not correlated with PFS or OS (Table). Conclusions: We report findings from the largest cohort of pts with RT who received CD19 CART. Of note, 84% of pts were exposed to either BTKi or BCL2i for the tx of CLL or RT. RT remains a disease of unmet need, as the median OS was 8.5 mos in this study. However, there is some progress made as historically the median OS for patients with RT previously treated with BTKi is 4 mos (Kittai et al AJH 2023). Given higher number of prior therapies is associated with worse OS, earlier use of CD19 CART in the RT disease course may be warranted. Our data support the use of CD19 CART for pts with RT, with durable disease control in a subset of pts, however there is clear room to improve and develop better therapies. Given observed high response rate to CD19 CART, along with most pts experiencing early relapse, allogeneic stem cell transplantation at response should be considered. Prospective clinical trials evaluating CD19 CART with novel agents for RT are currently ongoing.

Translated article] Adjusted indirect comparison of zanubrutinib and ibrutinib in first-line treatment of chronic lymphocytic leukemia

ObjectiveThe aim of this study was to perform an adjusted indirect treatment comparison, according to the cytogenetic profile, in terms of efficacy between different Bruton tyrosine kinase inhibitors used as first-line monotherapy for chronic lymphocytic leukemia. Safety outcomes considered of interest were also evaluated to establish whether these options can be considered equivalent therapeutic alternatives. MethodA literature search was conducted in Pubmed and Embase on November 10, 2022 for phase III clinical trials studying Bruton tyrosine kinase inhibitors in monotherapy in the first-line setting for chronic lymphocytic leukemia. Results were filtered according to whether the combination of bendamustine and rituximab was used as comparator and whether they had similar populations and follow-up times. Subgroup results were meta-analyzed according to mutational characteristics by classifying patients into high and low cytogenetic risk. An adjusted indirect comparison was developed using Bucher's method. Possible therapeutic equivalence was determined by applying the guide to equivalent therapeutic alternatives. ResultOf the 39 studies obtained in the review, 2 clinical trials were selected: 1 for zanubrutinib and 1 for ibrutinib. The remaining studies were not included because they did not meet the inclusion criteria. The results obtained in the adjusted indirect treatment comparison for both cytogenetic risk subgroups showed no statistically significant differences. The most relevant safety differences were atrial fibrillation, hypertension, and cardiovascular events in patients treated with ibrutinib and higher incidence of secondary cancers in patients treated with zanubrutinib. Applying the equivalent therapeutic alternatives guideline criteria, both treatments cannot be considered equivalent therapeutic alternatives. ConclusionsAssuming the uncertainty associated with the adjusted indirect comparison, zanubrutinib could be considered equivalent in efficacy to ibrutinib, however, the presence of differentiating safety features precludes assigning the 2 alternatives as equivalent therapeutic alternatives.

Long term outcomes in patients with anti-DPPX autoimmunity

DDPX antibody-associated encephalitis is characterized by cognitive dysfunction, neuropsychiatric symptoms, and CNS hyperexcitability, preceded by prodromal weight loss and diarrhea. Data regarding long-term outcomes is scarce. We retrospectively identified six anti-DPPX encephalitis patients across all three Mayo Clinic sites with inclusion criteria: 1) positive DPPX cell-based assay and mouse tissue-based immunofluorescence samples in both serum and CSF; 2) duration of follow up of at least 36 months from symptom onset to last follow up. Only one patient had a paraneoplastic process in the setting of chronic lymphocytic leukemia. At last follow up, all patients had resolution of GI symptoms. Residual cognitive impairment was seen in 4/6 (67%). Clinical stability was reached in 3/6 (50%) while on immunotherapy. Immunotherapy was discontinued in 2/6 (33%) and they remained stable without relapse at last follow up. One patient died of unclear etiology. Overall long-term outcomes are good in anti-DPPX encephalitis. Symptoms can improve on immunotherapy, but full resolution and return to premorbid baseline is unlikely.

Treatment of Richter Transformation of Chronic Lymphocytic Leukemia in the Modern Era.

Richter Transformation (RT) refers to the development of an aggressive lymphoma in the setting of chronic lymphocytic leukemia (CLL). While many variants of RT are recognized, diffuse large B-cell lymphoma (RT-DLBCL) is the most common (80%), followed by Hodgkin's lymphoma (RT-HL, 19%). Diagnosis is based upon histologic evaluation of clinically suspicious lymph nodes. Positron emission tomography (PET) may be used to select the node of interest for biopsy. Although clonality testing is not a prerequisite of RT diagnosis, it has significant implications for survival. Clonally related DLBCL carries the worst prognosis with a median overall survival (OS) of less than one year in the era of combination chemotherapies with or without anti-CD20 antibodies. Prognosis has improved with the use of stem cell transplant and newer agents such as targeted therapy and newer forms of immunotherapy. Consideration of a clinical trial is encouraged. This review describes our current understanding of RT and focuses on treatment of RT-DLBCL, including clinical trials in progress and new therapies in development. We also report an illustrative example of a patient with clonally related DLBCL who survived two years after diagnosis without the use of combination chemotherapy.

Utilizing Clinical Features of Progression to Predict Richter's Syndrome in Patients with CLL Progressing after Ibrutinib

Background:Aggressive lymphoma arising in the setting of chronic lymphocytic leukemia (CLL), known as Richter's syndrome (RS), is associated with poor outcomes with standard of care therapies. There is limited capacity for PET-CT to distinguish patients (pts) who develop RS after ibrutinib (Mato Haematologica 2019). Data on outcomes of pts with RS having previously received ibrutinib is limited. Here we sought to determine if clinical characteristics associated with iwCLL criteria for progression (Hallek Blood 2018) predict the risk of RS and overall survival (OS) in pts treated with ibrutinib.Methods:We conducted a retrospective analysis of pts with CLL treated with ibrutinib from 2010-2019 at The Ohio State University. We identified pts that progressed after ibrutinib and classified the progression by 2018 iwCLL criteria. We then identified who developed RS on or after progression. Risk of developing RS was assessed through Fine and Gray model treating death as the competing risk. OS was measured from time of progression and estimated using Cox model.Results:We analyzed 559 pts who had received ibrutinib for CLL, and identified 179 pts who progressed per iwCLL criteria. 94% of the pts who progressed were relapsed/refractory prior to ibrutinib. 116 pts progressed on ibrutinib, and the median time to progression from ibrutinib start was 40.8 months (mos) (range: 0.2-103.9). 63 pts progressed after stopping ibrutinib due to an adverse event or development of a resistance mutation, and the median time to progression from ibrutinib start for these pts was 28.5 mos (range: 0.7-92.9).Of the 179 pts who progressed, 54 developed RS. Of these 54 pts; 83% had enlarging lymphadenopathy, 9% had an enlarging liver or spleen, 17% had constitutional symptoms, 31% had increasing lymphocytosis, 15%, 15%, and 2% had worsening thrombocytopenia, anemia, or neutropenia respectively. No pts had worsening of CLL in the bone marrow (BM) and 2% had new appearance of other organ involvement. As lymphadenopathy and lymphocytosis were the most common clinical features identified we analyzed them jointly; 61% had lymphadenopathy without lymphocytosis, 9% had lymphocytosis without lymphadenopathy, 22% had both, and 7% had neither.Among pts with RS, median time from progression to RS was 0.4 mos (range: 0-49.3). Nine pts had biopsy confirmed RS on the date of progression. Median time from ibrutinib start to RS was 27.8 mos (range: 0.7-92.9). We performed a univariable analysis to determine whether clinical signs of relapse were associated with subsequent risk of RS, and found that presence of lymphadenopathy without lymphocytosis at progression was significantly associated with risk of RS (HR 3.58, 95% CI 1.44-8.88, p=0.006) (Table 1, Figure 1A).To determine if there was an association between clinical features of progression and OS we evaluated all 179 pts that progressed; 72% had enlarging lymphadenopathy, 10% had an enlarging liver or spleen, 15% had constitutional symptoms, 46% had increasing lymphocytosis, 15%, 17%, and 2% had worsening thrombocytopenia, anemia, or neutropenia respectively, only 2% had worsening of CLL in the BM, and 1% had new appearance of other organ involvement. When analyzed jointly; 45% had lymphadenopathy without lymphocytosis, 20% had lymphocytosis without lymphadenopathy, 26% had both, and 9% had neither.Median OS from progression was 24.4 mos (95% CI: 18.6-45.5), while median OS from RS diagnosis was 4.0 mos (95% CI: 2.1-7.1). Median OS from progression was 15.2 mos (95% CI: 7.8-24.6), and 49.9 mos (95% CI: 20.0-NR) for the lymphadenopathy without lymphocytosis and the lymphocytosis without lymphadenopathy groups respectively (Figure 1B). On univariable analysis lymphadenopathy without lymphocytosis was associated with a shorter OS (Table 1). These findings were maintained on multivariable analysis, with lymphadenopathy without lymphocytosis remaining an independent predictor of OS (HR 2.12, CI 1.17-3.87, p=0.01).Conclusions:Here we show that pts who have received prior ibrutinib for CLL who progress with lymphadenopathy have a higher likelihood of having RS than those pts who progress without lymphadenopathy. Furthermore, pts who progressed with lymphadenopathy without lymphocytosis have a shorter OS. Our data suggests that consideration should be given to perform a biopsy to rule out RS in any pts progressing with lymphadenopathy after receiving ibrutinib therapy for CLL. [Display omitted] DisclosuresKittai: Abbvie: Consultancy; Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy. Bhat: Beigene: Consultancy; Onclive: Honoraria; AstraZeneca: Consultancy; Aptitude Health: Honoraria. Bond: Kite/Gilead: Honoraria. Byrd: Pharmacyclics LLC: Research Funding; Acerta Pharma: Research Funding; Genentech, Inc.: Research Funding; Janssen Pharmaceuticals, Inc.: Research Funding. Rogers: Genentech: Consultancy, Research Funding; Janssen: Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Research Funding. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding.

Evaluation of the Incidence and Risk Factors Associated with Bleeding Events in Patients Receiving Acalabrutinib Therapy

Background:Acalabrutinib is a more selective, second generation covalent binding Bruton tyrosine kinase (BTK) inhibitor. It was designed with the intent to mitigate adverse events (AEs) associated with ibrutinib, such as bleeding and cardiovascular events. In the phase 3 trial that that led to acalabrutinib approval in the front line setting for chronic lymphocytic leukemia (CLL), 37% and 2% of patients who received acalabrutinib monotherapy experienced grade 1-2 or ≥3 bleeding events, respectively. Currently, there are no long term studies evaluating the incidence of bleeding events associated with acalabrutinib. Therefore, the purpose of this study was to assess the incidence of bleeding events, and risk factors associated with bleeding events for patients treated with acalabrutinib for hematologic malignancies.Methods:This was a single center retrospective study conducted at The Ohio State University. Patients were included if they were ≥18 years old, diagnosed with a hematologic malignancy, and initiated on acalabrutinib (monotherapy or combination therapy) between January 1, 2010 and August 31, 2019. The International Society on Thrombosis and Haemostasis (ISTH) bleeding scale (no bleed, clinically non-relevant bleed, and clinically relevant/major bleed) and Common Terminology Criteria for Adverse Events V5.0 (CTCAE) were used to evaluate the grade and class of bleed events. Descriptive statistics were used to summarize demographic information and bleed events; univariable analysis was used to assess risk factors.Results:We analyzed 289 patients who received acalabrutinib for a hematologic malignancy. The main source of acalabrutinib was from clinical trials (85%) and the median acalabrutinib exposure time for all patients was 40.8 months (range: 0-81.6 months). 89% of patients had CLL, 2% had mantle cell lymphoma, and 9% had other non-Hodgkin's lymphoma. Additionally, 18% of patients had a prior bleed history and 51% were continued on concomitant medications that increase bleeding (Table 1). There were a total of 241 (83%) patients who experienced at least one bleed event. Per ISTH categorization, 143 (59%) patients' most severe bleed event was clinically non-relevant and 98 (41%) patients' was clinically relevant/major; cutaneous bleeds were most common in both groups, 71% and 31%, respectively. Only 6% of patients had a major bleed, hence, clinically relevant and major bleeds were analyzed together for the purpose of this study.There were a total of 633 bleed events that occurred in this study population; 76% were clinically-non relevant and only 3% (n=17) were CTCAE grade ≥3. Acalabrutinib was not discontinued or held for any clinically non-relevant bleeds, was discontinued for six (1%) clinically relevant/major bleeds, and held for 44 (7%) clinically relevant/major bleeds. Clinically relevant /major bleeds also resulted in discontinuations of concomitant anticoagulation and antiplatelet therapy in only 4% (n=24) of cases. 1263 procedures were identified and the incidence of clinically non-relevant and clinically relevant/major bleeds related to surgeries/procedures was 1% (n=12) and 1.3% (n=16), respectively.10% of clinically non-relevant and 57% of clinically relevant/major bleeds led to hospitalizations, emergency room visits, or physician office visits; including two major CNS bleed events which resulted in death. The overall survival (OS) was not reached in the clinically non-relevant and clinically relevant/major bleed groups and was 14 months (95% CI 6-40) in the no bleed group (p=0.021). Univariate analysis showed that risk factors associated with a clinically relevant/major bleed included concomitant medications (OR 3.06, 95% CI 1.49-6.26) and prior bleed history (OR 4.40, 95% CI 1.45-13.40) (Table 3).Conclusions:Overall, our study had a long acalabrutinib exposure time and demonstrated a low incidence of grade ≥3 bleeds. There was also a low risk of bleeds related to procedures. The majority of bleeds were clinically non-relevant that did not result in significant treatment adjustments, hospitalizations, or death. This study identified prior bleed history and concomitant medications that increase bleeding as risk factors for bleeds and should be evaluated prior to starting acalabrutinib therapy. Our data supports acalabrutinib as a safe long-term treatment in regards to bleeds for patients with hematologic malignancies. [Display omitted] DisclosuresWiczer: BTG Specialty Pharmaceuticals: Consultancy. Bhat: Beigene: Consultancy; Aptitude Health: Honoraria; AstraZeneca: Consultancy; Onclive: Honoraria. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Rogers: Janssen Pharmaceuticals, Inc: Research Funding; Pharmacyclics LLC: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Innate Pharma: Consultancy; ovartis Pharmaceuticals Corporation: Research Funding; AbbVie Inc.: Consultancy, Research Funding. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Kittai: Bristol-Meyers Squibb: Consultancy; Janssen: Consultancy; Abbvie: Consultancy.

Hemophagocytic lymphohistiocytosis in a patient with Legionella infection and bone marrow monotypic plasma cells in the setting of chronic lymphocytic leukemia

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition in which the body makes too many activated immune cells (macrophages and lymphocytes) that phagocytose hematologic cells. HLH can be inherited or acquired. Acquired HLH has been associated with: infection, immunosuppressive medications, autoimmune diseases, certain cancers, and metabolic diseases. Here, we report the case of a 50 year old male with a history of chronic lymphocytic leukemia Rai Stage IV status post chemotherapy and a recent admission for Legionella pneumonia who presented with worsening fever despite levofloxacin treatment and marked hypercalcemia. A bone marrow biopsy showed 20–30% lambda‐restricted plasma cells. Additionally, hemophagocytosis was found in the bone marrow, which prompted the clinician to consider HLH in the diagnosis. After further testing, the patient met the criteria for HLH with an H‐score of 234 (98.4% probability of patient having HLH). Despite steroid treatment, the patient's condition deteriorated and the patient died 6 days after bone marrow biopsy.

Hodgkin lymphoma variant of Richter transformation: morphology, Epstein-Barr virus status, clonality, and survival analysis—with comparison to Hodgkin-like lesion

Hodgkin/Reed-Sternberg (HRS) cells in the setting of chronic lymphocytic leukemia (CLL) exist in 2 forms: type I with isolated HRS cells in a CLL background (Hodgkin-like lesion) and type II with typical classic Hodgkin lymphoma, a variant of Richter transformation (CHL-RT). The clinical significance of the 2 morphological patterns is unclear, and their biological features have not been compared. We retrospectively reviewed 77 cases: 26 of type I and 51 of type II CHL-RT; 3 cases progressed from type I to type II. We examined clinical features, Epstein-Barr virus (EBV) status, and clonal relatedness after microdissection. Median age for type I was 62 years versus 73 years for type II (P=.01); 27% (type I) versus 73% (type II) had a history of CLL. HRS cells were positive for EBV in 71% (55/77), similar in types I and II. Clonality analysis was performed in 33 cases (type I and type II combined): HRS cells were clonally related to the underlying CLL in 14 and unrelated in 19. ZAP-70 expression of the CLL cells but not EBV status or morphological pattern was correlated with clonal relatedness: all 14 clonally related cases were ZAP-70 negative, whereas 74% (14/19) of clonally unrelated cases were ZAP-70 positive. Overall median survival (types I and II) after diagnosis was 44 months. Advanced age was an adverse risk factor for survival, but not histologic pattern, type I versus type II. HRS-like cells in a background of CLL carries a similar clinical risk to that of CHL-RT and may progress to classic Hodgkin lymphoma in some cases.

The Eµ-Myc/TCL1 Transgenic Mouse As a New Aggressive B-Cell Malignancy Model Suitable for Preclinical Therapeutics Testing

Background: Aggressive B-cell lymphomas occurring in the setting of Chronic Lymphocytic Leukemia (CLL) as a large cell transformation are an important clinical problem, and improved mouse models to test novel and targeted therapeutics are needed. The Eµ-Myc mouse overexpresses c-Myc gene which is placed under control of the Myc promoter and lymphoid-specific IgH enhancer (Eµ), resulting in c-Myc overexpression and spontaneous B-cell lymphoma development. The Eµ-Myc mice have been used in drug development, however malignancy develops at variable ages and with differing genetics and response to therapeutic agents, making drug studies difficult. The Eµ-TCL1 transgenic mouse overexpresses the human TCL1 oncogene, under the control of the B-cell specific IgVH promoter and Eµ enhancer. Mice develop a spontaneous mature B-cell leukemia after a long latency period and represent a well-established model of human CLL. We crossed the Eµ-Myc and TCL1 mice to create a new model of aggressive B-cell lymphoma to test novel therapeutics that would be more homogeneous than the Eµ-Myc model.Methods: Eµ-Myc and TCL1 mice on C57BL/6 background strain were crossed and resulting genotypes were verified by PCR. All mice were kept in standard pathogen-free housing until death or removal from study. All mice born within a 24 month time period were followed for survival. At the time of death, spleen, lymph nodes, bone marrow, and liver were fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned at 4uM, and stained with hematoxylin and eosin for histologic evaluation. For engraftment studies, adoptive cell transfer was done by injecting fresh splenic white blood cells (1e7 cells, >75% CD5+/CD19+) into the tail vein of C57BL/6 wild type recipient mice. In the drug treatment experiments ibrutinib (~30mg/kg/day) was administered in drinking water and KPT-8602 (15mg/kg) by daily oral gavage. Survival was shown using Kaplan-Meier curves and survival curves compared statistically using a log-rank test.Results: The Eµ-Myc/TCL1 mice had significantly worse survival (median 45.5, range 29-74 days) compared to Eµ-Myc (median 118, range 42-520 days) or TCL1 (median 359.5, range 188-531 days) mice (p=<0.0001). Survival curves are show in Figure 1. Pathologic examination revealed aggressive B-cell histology similar to Burkitt lymphoma in both the Eµ-Myc mice and Eµ-Myc/TCL1 mice, whereas the TCL1 mice showed mature B-cell morphology. Infiltration of the bone marrow of Eµ-Myc and Eµ-Myc/TCL1 mice was extensive in comparison with TCL1 mice. In all three mouse genotypes the normal architecture in the spleen was effaced by neoplastic cells. Adoptive transfer of Eµ-Myc/TCL1 splenic lymphocytes produced similar pathologic findings to the Eµ-Myc/TCL1 transgenic mice with less severe splenic enlargement in the engrafted mice. Median survival of the engrafted mice was short (38 days). There was a differential response to targeted therapeutics between the groups. Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK) previously demonstrated to improve survival in TCL1 mice, had no survival advantage over vehicle treatment in either Eµ-Myc or Eµ-Myc/TCL1 mice (p=0.876 and P=0.83 respectively). KPT-8602, a second generation selective inhibitor of exportin 1 (XPO1) was tested in Eµ-Myc/TCL1 engrafted mice, and demonstrated a significant improvement in survival compared to vehicle alone (p=<0.0001). A first generation agent (selinexor) targeting XPO1 is currently in human clinical trials for aggressive lymphomas, including large cell transformation of CLL.Conclusions: Mice with both c-Myc and TCL1 transgenes develop an aggressive B-cell malignancy and have decreased survival compared to Eµ-Myc or TCL1 mice. The histology of the disease is similar to that of Eµ-Myc mice, but with shorter survival with less variability. The resulting mouse model has differential responses to targeted therapeutics, with a poor response to ibrutinib more similar to aggressive lymphoma than CLL. The malignant B cells can be adoptively transferred into immunocompetent mice for experimental drug treatment studies. These qualities make Eµ-Myc/TCL1 mice a useful tool to test new therapies for aggressive lymphoma where there is an unmet clinical need. Work is currently underway to further define the genetic characteristics of this mouse in comparison to human lymphoma sub-types and responsiveness to targeted agents. [Display omitted] DisclosuresByrd:Acerta Pharma BV: Research Funding.

Increased incidence of malignant melanoma and other rare cutaneous cancers in the setting of chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or non-Hodgkin lymphoma (NHL) are at increased risk for the development of skin malignancies. This study was conducted to estimate the incidences of rare skin malignancies in patients with CLL/SLL or NHL. Patients with a diagnosis of CLL/SLL or NHL recorded in the Surveillance, Epidemiology and End Results (SEER) database during 1992-2007 were identified. Diagnoses of specific skin malignancies were identified from SEER files. During 1992-2007, a total of 128,674 patients with first diagnoses of CLL/SLL or NHL were recorded in SEER; 4743 were excluded because follow-up data were unavailable. Among the remaining 123,931 patients, 28,964 had CLL/SLL and 94,967 had NHL. Standardized incidence ratios (SIRs) for invasive malignant melanoma, Merkel cell carcinoma, malignant fibrous histiocytoma, dermatofibrosarcoma protuberans, Kaposi's sarcoma, and sebaceous carcinoma were 2.3, 8.2, 3.6, 2.5, 2.9, and 1.4, respectively, in CLL/SLL patients and 1.6, 3.2, 1.5, 1.3, 17.6, and 0.8, respectively, in NHL patients. When invasive melanoma was stratified by patient age and sex, the highest SIR (17.8) was found in men aged 0-49 years with CLL (P<0.001). Patients with CLL/SLL or NHL have a higher risk for the subsequent development of rare skin cancers. Given the more aggressive nature of these malignancies in this setting, regular monitoring for the development and prompt treatment of cutaneous malignancy is prudent in patients with NHL and particularly in patients with CLL. Regular use of sun protection may decrease the morbidity associated with skin cancer in this immunosuppressed population.

Gastric Sarcoidosis in the Setting of Chronic Lymphocytic Leukemia

Gastric Sarcoidosis in the Setting of Chronic Lymphocytic Leukemia

Metastatic Renal Cell Carcinoma to the Parotid Gland in the Setting of Chronic Lymphocytic Leukemia

Renal cell carcinoma (RCC) is infamous for its unpredictable behavior and metastatic potential. We report a case of a patient with a complex history of multifocal renal cell carcinoma and chronic lymphocytic leukemia (CLL), who subsequently developed a parotid mass. Total parotidectomy revealed this mass to be an additional site of metastasis which had developed 19 years after his initial diagnosis of RCC.

Increased Metastasis of Malignant Fibrous Histiocytoma in Patients With Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma

OBJECTIVE To further understand the characteristics and behavior of malignant fibrous histiocytoma (MFH) in the clinical setting of chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS The patient database of MHF diagnosed at our institution from January 1, 1976, to December 31, 2008, was reviewed. For each MFH case with prior NHL or CLL, 3 matched controls from the same cohort without prior CLL or NHL were randomly selected. A retrospective chart review collected patient data, including sex; age; pathologic confirmation of MFH; tumor grade, size, and location; time since MFH diagnosis; history of chemotherapy or irradiation; treatment of MFH; recurrence; metastasis; and death. The Kaplan-Meier method was used to estimate overall survival, survival free of recurrence, and survival free of metastasis. Cox proportional hazards models were fit to evaluate associations between case status and outcomes. RESULTS Fifteen MFH cases with prior NHL or CLL were identified. Cases had frequent bone (n=7 [47%]) and cutaneous (n=5 [33%]) involvement. Five cases (33%) had previous irradiation, 6 (40%) had metastases, and 4 (27%) had recurrence. Overall survival and survival free of recurrence were not significantly different between the cases and controls (5-year overall survival, 49.9% and 58.7%; 12-month survival free of recurrence, 79.4% and 90.3%). However, cases were significantly more likely than controls to have metastasis (hazard ratio, 3.79; 95% confidence interval, 1.22-11.79; P=.02). In addition, survival free of metastasis at 12 months was 65.2% and 90.7%, respectively. CONCLUSION In the presence of CLL or NHL, MFH seems to behave more aggressively, suggested by the increased likelihood of metastases compared with controls without prior CLL or NHL. However, overall survival does not appear to be worse in cases of MFH and CLL or NHL than in MFH alone.

Merkel Cell Carcinoma in the Setting of Chronic Lymphocytic Leukemia

Merkel cell carcinoma (MCC) is a rare, aggressive, primary skin cancer that usually occurs in elderly white people on the sun-exposed areas of skin. Chronic lymphocytic leukemia (CLL) is a low-grade, clonal, B-cell, lymphoproliferative disorder that also usually affects older adults. CLL has been associated with multiple other secondary malignancies, especially skin cancer. To further understand the characteristics and behavior of MCC in the setting of concomitant CLL. We identified patients with diagnoses of both MCC and CLL who were seen at the Mayo Clinic (Rochester, MN) from January 1, 1976, to December 31, 2008, and retrospectively reviewed the charts of the identified patients. Seven patients received diagnoses of MCC and CLL. Five of these patients appeared to have higher rates of recurrence, metastasis, and mortality than patients with MCC but not CLL. MCC may behave more aggressively in the setting of concomitant CLL, but more studies are needed to definitively evaluate the characteristics and behavior of MCC in these patients.

Atypical Fibroxanthoma in the Setting of Chronic Lymphocytic Leukemia and Other Non-Hodgkin Lymphomas

Atypical fibroxanthoma (AFX) is a rare cutaneous malignancy of older adults. Little is known about the behavior of AFX in the setting of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). To further understand the development, characteristics, and behavior of AFX in the setting of concomitant CLL and other types of NHL. Study approval was obtained from the Mayo Clinic Institutional Review Board. The master diagnosis index was queried from January 1, 1980, through December 31, 2008, to identify patients with AFX and CLL or other types of NHL. A retrospective chart review was conducted. Ten patients were identified with AFX and NHL. These patients did not show a greater risk of recurrence, metastasis, or death than that found in previous case reports. Of these 10 patients, four had AFX and CLL. The outcomes of these patients were no different from those of patients with AFX and other types of lymphoma. AFX did not demonstrate aggressive features such as recurrence or metastasis in patients with concomitant CLL or other NHL. More studies are needed to definitively characterize the behavior of AFX in this patient population.

Malignant fibrous histiocytoma in the setting of chronic lymphocytic leukemia and non-Hodgkin lymphoma

Malignant fibrous histiocytoma in the setting of chronic lymphocytic leukemia and non-Hodgkin lymphoma

Primary cutaneous follicle center lymphoma in the setting of chronic lymphocytic leukemia

Primary cutaneous malignancies arising in association with chronic lymphocytic leukemia (CLL) are notable for their atypical clinical and histological presentation. We report a 69-year-old man with a 17-year history of CLL who presented for evaluation of a well-defined red to violaceous nodule with a central depressed scar on the left lower extremity. Microscopic examination of a punch biopsy revealed an infiltrate of predominantly small lymphocytes with scattered large, atypical epithelioid cells. Immunohistochemical stains revealed diffuse positive staining of the lesional cells with CD20+ and bcl-6+ and focal positive staining with bcl-2+ (negative CD10 and CD23), findings which, in conjunction with the histology, were most compatible with a diagnosis of primary cutaneous follicle center lymphoma (PCFCL). A review of the clinical charts revealed several prior biopsies with varied diagnoses. In light of the most recent biopsy findings, all previous biopsies were re-reviewed and interpreted as PCFCL arising in the setting of CLL. Features contributing to the diagnostic conundrum in this case included an atypical clinical and histological presentation, lack of pertinent clinical history and multiple presentations at different institutions.