Concurrent Chronic Lymphocytic Leukemia Research Articles

Risks and outcomes of hospitalizations in patients with chronic lymphocytic leukemia admitted with immune thrombocytopenia: an analysis of the National Inpatient Sample Database.

Immune thrombocytopenia (ITP) is a known autoimmune complication of chronic lymphocytic leukemia (CLL). Currently, there is limited data regarding the risk CLL confers on hospitalization outcomes in patients admitted with ITP.The National Inpatient Sample (NIS) database was queried using the International Classification of Diseases (ICD) codes to identify hospitalizations for ITP and then subclassified the data into hospitalizations with and without CLL. A multivariate logistic regression was designed to account for patient characteristics and comorbidities. The primary outcome was all-cause mortality. Secondary outcomes included major bleeding, gastrointestinal bleeding, intracranial bleeding, and the need for platelet transfusions, intravenous immunoglobulin, and splenectomy. Among 662,171 cases of ITP between 2005 and 2019, 15,672 had concurrent CLL. CLL patients were significantly older and had more comorbidities compared to patients without CLL. Multivariate analysis revealed CLL patients with ITP had a risk of all-cause mortality (odds ratio: 1.28, 95% CI: 1.19-1.37; p < 0.01). CLL patients also had a higher risk of complications, second-line ITP treatments, blood transfusions, and bleeding, with the exception of intracranial hemorrhage. Our study suggests CLL is an independent risk factor for increased morbidity and mortality among hospitalized patients with ITP. Prospective studies are needed to determine if refractoriness to conventional treatments for ITP can account these results.

Characterizing the Development of Secondary Myelodysplastic Syndrome (MDS) with Antecedent or Concurrent Chronic Lymphocytic Leukemia (CLL) in the Era of Small Molecule Inhibitors for the Treatment of CLL

Introduction Secondary MDS (sMDS) is defined by MDS arising from another bone marrow disorder or related to previous therapy [chemotherapy (CT), radiation, or immunosuppression], and comprises about 10% of MDS cases. The rate of sMDS following CLL (including treatment-naïve CLL) has been reported as high as 3.5%. Developing in elderly populations, both CLL and MDS are associated with clonal hematopoiesis (CH), and chemoimmunotherapy (CIT) treatment for CLL likely contributes to the occurrence of MDS. There is little published data on the characteristics of patients (pts) who develop sMDS with antecedent/concurrent CLL, particularly in the era where kinase inhibitor therapy has displaced CIT. Therefore, we sought to characterize a cohort of CLL pts who develop sMDS in the era of modern treatments. Methods We performed a retrospective chart review at The Ohio State University between 01/01/2016 and 02/10/2021 of pts with a diagnosis of CLL who subsequently or concurrently were diagnosed with MDS. Clinical, next generation sequencing (NGS), and outcome data were collected. NGS test refers to a 50 gene hematologic neoplasm mutation panel. Overall survival (OS) was calculated from MDS diagnosis and estimated using Kaplan-Meier method. Results We identified 27 sMDS pts with antecedent/concurrent CLL. At CLL diagnosis, median age was 58 years (range 40-86). 5 pts (18.5%) had a TP53 mutation and/or del(17p) noted during their CLL disease course prior to sMDS diagnosis. Median number of therapies for CLL prior to sMDS was 1 (range 0-10), with 4 pts diagnosed with CLL at the same time as MDS. CLL treatments, as any line of therapy, included CT/CIT in 21 pts (77.8%) and ibrutinib in 10 pts (37.0%). Of the pts that received CLL therapy, only 1 pt did not receive CT/CIT. 5 pts (18.5%) were not treated for CLL. A median of 6.9 years (range 0-31.8) elapsed between the diagnosis of CLL and sMDS. At sMDS diagnosis median age was 70 years (range 50-86), 17 pts (65.4%) were MDS IPSS-R category high/very high. 5 pts transformed to AML after a median of 9.2 months (mos) from MDS diagnosis (range 4.1-21.3). After a median follow-up of 6.3 mos (range 0.8-109.2), the median OS from MDS diagnosis was 18.8 mos (95% CI, 10.2-not reached). (Table 1) In pts who received CT/CIT for CLL (n=21) and those who did not (n=6), a TP53 mutation developed following CLL or MDS diagnosis in 10 pts (47.6%) and 1 pt, respectively. All but 1 pt who developed TP53 mutations (n=11) received prior CT. 15 pts (71.4%) who received CT/CIT for CLL therapy had MDS with complex karyotype; this was seen in 2 pts who never received CT/CIT. Twenty-six (96.3%) pts had NGS testing. 5 pts (18.5%) had 1 or more tests completed for CLL prior to sMDS: 4 pts had TP53 mutations, 2 pts each had DNMT3A and SF3B1 mutations, and 1 pt each had an ASXL1, KMT2A, BTK, or PLCG2 mutation. Of these 5 pts, 1 pt had 5 NGS tests performed on serial B-cell selected samples (as opposed to total leukocytes): mutations included 2 TP53, 1 SF3B1 and 1 BTK mutation. 25 (92.6%) pts had 1 or more tests completed at or after sMDS diagnosis (all assessed total leukocytes): 8 pts (36.4%) had TP53, 6 pts (27.3%) had DNMT3A, 5 pts (22.7%) had RUNX1, and 3 pts (13.6%) each had ASXL1, SF3B1, and TET2 mutations. Finally, 4 pts (14.8%) had NGS testing done both pre and post sMDS diagnosis (all assessed total leukocytes). Two pts had the same mutation present pre and post sMDS diagnosis: 1 ASXL1, 1 DNMT3A. A third pt had 3 identical mutations pre and post sMDS diagnosis: 1 TP53 p.G244D, 1 TP53 p.N235_Y236del, and 1 SF3B1. (Table 2) Conclusions Here we have characterized a cohort of CLL pts who developed sMDS in the modern era, where small molecule inhibitors are commonly used for CLL, and NGS is widely available for both CLL and MDS. While the majority of pts with CLL received CT, 5 pts were treatment-naive, and 1 pt only received a BTK inhibitor and an anti-CD20 antibody. The OS of this cohort following MDS diagnosis is similar to historical data of pts with comparable IPSS-R scores, despite the fact that this is a sMDS population; this may be due to lead time bias as pts likely received frequent blood work for CLL. Prior to sMDS diagnosis, complex karyotype and TP53, SF3B1 and CH-associated mutations DNMT3A and ASXL1 were prevalent. TP53, SF3B1, and CH-associated mutations DNMT3A, ASXL1, and TET2 mutations were prevalent at the time of or following a sMDS diagnosis. Further investigation into the interplay between CLL and CH in MDS development in the modern therapy era is needed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Prevalence of Beta-Human Papilloma Virus in Patients with Concurrent Chronic Lymphocytic Leukemia and Non-Melanoma Skin Cancer

Introduction Patients with chronic lymphocytic leukemia (CLL) are at least twice as likely to develop a second malignancy as their age-matched peers, which is likely secondary chronic CLL-related immunosuppression (Royle 2011). Non-melanoma skin cancers (NMSC) are the most common type of second cancer and those with CLL are seven times more likely to have recurrent NMSC than those without CLL (Mehrany 2005). The etiology of NMSC is likely multifactorial, but we hypothesized that viral load of beta-subtype of human papillomavirus (B-HPV) is correlated with likelihood of NMSC in patients with CLL. Virtually all of the currently available commercial HPV testing targets alpha-subtypes of HPV, but B-HPV has recently been associated with NMSC's (Rollison 2021). The prevalence and viral load of B-HPV in patients with CLL has not been studied. Methods We collected blood samples from patients with CLL and non-CLL controls (patients with solid malignancies) through the ORIEN AVATAR program and performed whole exome sequencing. We used Kraken2 metagenomic software to identify co-purifying HPV DNA using a custom-built viral database composed of unique sequences from alpha and beta HPV reference genomes. Comparison of viral load between patients with and without CLL, and CLL patients with and without NMSC was performed by a 2 sample t-test. Statistic significance was set as p<0.05. Results We measured B-HPV viral loads in the peripheral blood of 333 CLL patients and 69 non-CLL control patients. We determined that the average B-HPV viral load in the peripheral blood of CLL patients was double the load in our non-CLL controls (2724.9 versus 1315.0 viral counts; p<0.001). When we classified the B-HPV subtypes, we found higher viral loads of the subtypes 8, 15, 110, 143, 150 in CLL patients than non-CLL controls (p<0.001 for all CLL vs control comparisons). B-HPV subtype 8 (B-HPV8) was the subtype with the highest viral load as determined by exact matches to our Kraken2 HPV database. We identified 29 CLL patients with known diagnosis of NMSC. In this population, the viral load of B-HPV8 was >6-fold higher than that found in the non-CLL control patients (1009.8 vs 149.6 viral sequences; p<0.001; 2-sample t-test). Conclusions These preliminary data support our hypothesis that B-HPV infection is associated with NMSC in CLL patients. At minimum, it may serve as a biomarker for level of immunosuppression, which predisposes to NMSC. We are currently enrolling a prospective clinical trial for CLL patients with recurrent NMSC (NCT04844528). We plan to sequence both the peripheral blood and the skin cancer samples from these patients to determine whether there is a correlation between B-HPV subtype and NMSC occurrence. We will also evaluate components of the immune system such as T-cell function in an attempt to quantify and correlate immune dysfunction in these patients.

Outcome of patients with concurrent chronic lymphocytic leukemia and Hodgkin lymphoma

Abstract Introduction/Objective Concurrent diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and Hodgkin lymphoma (HL) is rare. CLL/SLL can rarely advance into Hodgkin-variant of Richter transformation, or there can be a simultaneous presence of separate CLL/SLL and HL from different clonal origins. Due to its rarity, the epidemiological features and outcome of concurrent CLL and HL are not well-known. Here we have used the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database to identify concurrent CLL/SLL and HL cases and analyzed overall and disease-specific survival across various epidemiological factors. Methods/Case Report We identified all patients diagnosed with CLL/SLL and HL between the period of 1975 to 2017. Next, we identified the patients with a simultaneous CLL/SLL and HL diagnosis by matching the patient identification number. Overall survival and disease-specific survival were calculated using Kaplan-Meier curves and Cox proportional hazards models. Results (if a Case Study enter NA) We identified 166 cases with a concurrent diagnosis of CLL, and HL. 4 cases were excluded from analysis as the diagnosis of CLL and HL were not simultaneous. The age distribution of the patient showed a unimodal distribution, with most patients being diagnosed between the age of 50 and 79. 67% of patients were male, and 92% of patients were Caucasian. The majority of the CLL was diagnosed in bone marrow or lymph nodes, while almost all HL were diagnosed in lymph nodes. Both disease-specific and overall survival were worse for patients with the advanced age of diagnosis. Race or sex did not significantly affect patients’ survival. Conclusion Our comprehensive review of clinical and epidemiological features of concurrent CLL and HL cases shows that the age of diagnosis is the most significant factor in determining the survival of these patients.

Competing risks analysis of Merkel cell carcinoma with concurrent chronic lymphocytic leukemia and non-Hodgkin lymphoma.

Although hematogenous malignancy is a risk factor for poorer prognosis in Merkel cell carcinoma (MCC), current guidelines make no specific recommendations for surveillance. We aim to characterize MCC-specific mortality compared to other causes of death for patients with hematologic malignancy in MCC, which will guide workup and surveillance strategies. The Surveillance, Epidemiology, and End Results-18 registry was queried for MCC patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL). Of 8519 patients with MCC, 146 (1.7%) had CLL and 234 (2.8%) had NHL. Chronic lymphocytic leukemia patients had 5-year cumulative incidence of MCC-specific mortality of 38.4% versus 28.4% in patients without CLL/NHL. For both cohorts, oncologic risk was highest within the first three years of diagnosis with competing risks favored thereafter. On competing risk regression, a history of CLL trended toward statistical significance with poorer MCC-specific mortality (subdistribution hazard ratio: 1.33, 95% CI: 0.963-1.834, P=0.084), while NHL was not prognostic. Merkel cell carcinoma patients with CLL may benefit from more aggressive initial management. Surveillance for similar length in CLL patients with MCC may be appropriate; this co-morbidity did not affect the timeframe by which the risk of competing causes of death exceeded oncologic risks.

The Effect of Immune Checkpoint Inhibitors in Patients with Concomitant Advanced Melanoma and Chronic Lymphocytic Leukaemia

Immune checkpoint inhibitors (ICI's) have revolutionized the management of patients with advanced melanoma (AM). However, the data on the effectiveness of ICI's has been largely restricted to patients on clinical trials, thus excluding patients with second malignancies. Chronic Lymphocytic Leukemia (CLL) is the most prevalent adult leukemia and is associated immune dysregulation and a 3.8 fold increase in melanoma incidence. We report a multi-center, retrospective case-control study examining differences between patients who received checkpoint therapy in the context of the dual diagnoses of CLL and advanced melanoma (n = 20) compared to those with advanced melanoma alone (n = 154).Prognostic features for AM (including age, brain metastasis, visceral involvement, LDH and neutrophil count) were comparable between the two cohorts, however absolute lymphocyte count (ALC) was higher in CLL patients (p <0.0001) as anticipated. 3/20 of the CLL cohort experienced haematological autoimmune adverse events (AIHA, ITP, HLH), which necessitated cessation of ICI therapy; these events were not reported in the non-CLL cohort.There was not a significant difference between response rates to ICI's, 1-year survival or overall survival between CLL and non-CLL cohorts (Fig 1A). All recorded mortality (8/8) in the CLL cohort was attributable to AM progression or complications of ICI therapy rather than progressive CLL. The most significant predictor of survival in CLL cohort was prior exposure to fludarabine which showed a significantly shorter OS (median 2.3 vs 29.23 months, HR 7.406, p < 0.0001) than those who had not (Fig 1B).This cohort also offers a unique opportunity to observe the effects of ICI therapy on the progression of CLL. To our knowledge, this is the largest reported cohort of CLL patients treated with checkpoint inhibitors to date. The diagnosis of CLL pre-dated the diagnosis of AM in 18/20 cases. 5 cases had required prior treatment for CLL, while the remaining 15 cases were under observation alone. All 20 cases were Stage 0-1 according to the Rai classification at the time of melanoma diagnosis and no cases demonstrated a transformation to an aggressive subtype. 0/20 cases experienced a haematological response of their CLL while on ICI therapy and 6/20 cases progressed clinically either on the basis of tumour burden or absolute lymphocyte count within 12 months of ICI therapy (Fig 1C).This retrospective data demonstrates that ICI's have equivalent therapeutic efficacy in AM in patient with concurrent CLL This was unexpected as it was anticipated that the immune dysregulation associated with CLL would impair the ICI-mediated anti melanoma immunological response. The exception to this trend, was the poor efficacy of ICI's in patients with prior fludarabine exposure, presumably owing to the profound T cell depletion associated with this therapy. Additionally, ICI therapy alone appears ineffective in the management of CLL in keeping with recent phase II trial data. [Display omitted] DisclosuresGill:Janssen: Consultancy, Honoraria, Other: travel expenses.

Ibrutinib Could Suppress CA-125 in Ovarian Cancer: A Hypothesis

Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase, an enzyme central in B cell development. It is indicated as a therapy for certain hematological diseases such as chronic lymphocytic leukemia (CLL), but also exerts off-target effects on several receptors and kinases. In this paper, we hypothesize that ibrutinib may suppress the tumor marker CA-125 in ovarian cancer. The hypothesis is based on an observation of CA-125 normalization in a patient with low-grade serous ovarian cancer who received ibrutinib for concurrent CLL. We propose a mechanistic model explaining this possible drug effect as a foundation for further research.

An incidental finding of chronic lymphocytic leukaemia in a patient with pulmonary tuberculosis

In this case report, we described a 48-year-old human immunodeficiency virus-negative man with pulmonary tuberculosis (TB) who had an incidental finding of concurrent chronic lymphocytic leukaemia. We highlighted the importance of considering other differential diagnoses when patients present with TB or haematological malignancies. We also discussed the difficulties in diagnosis when both of these conditions co-exist and how this affected treatment and management.

CLL-229: Efficacy of Immune Checkpoint Inhibitors in Metastatic Melanoma (MM) Patients with Concurrent Chronic Lymphocytic Leukemia (CLL)

Context CLL patients have a high incidence of melanoma, and checkpoint inhibitors (CPI) are approved for treatment of patients with metastatic disease. However, patients with CLL are known to have a profoundly impaired immune system with various types of T-cell abnormalities, and the impact of these defects on response to (CPI) is not known. We sought to evaluate the response to treatment with CPI in patients with concomitant MM and CLL. Objective Primary objective included objective response rate (ORR) by RECIST1.1 criteria. Secondary outcomes included progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Setting Retrospective study of patients with concurrent CLL and MM treated with CPI therapies at MD Anderson Cancer Center between 1997 and 2020. Patients Twenty-four patients were included, with a median age of 64 years. Seventy-one percent were male, 67% had early-stage CLL, and 71% were untreated. Thirty-three percent had prior melanoma treatment; 83% of patients had stage IV, and 17% had stage III melanoma. Interventions Thirty-eight CPI therapies were administered to 24 patients: single-agent PD-1 inhibitors pembrolizumab or nivolumab (53%), CTLA-4 inhibitor ipilimumab (29%), and combination therapies (18%). Results The ORR was 25% after first-line CPI and 21% for subsequent treatments, with a DOR of 50 and 16 months, respectively. After a median follow-up of 37 months, 12 patients died, 9 due to melanoma progression. The OS and PFS were 26 and 6 months, respectively. Increased LDH was associated with lower OS, and high LDH, and intermediate/high-risk CLL with a lower PFS. There were no significant changes in absolute lymphocyte counts during CPI. 2 patients received CPI while on ibrutinib or ibrutinib+venetoclax therapy with ongoing CLL responses. Conclusions CPIs are an effective treatment option for patients with MM and concurrent CLL, with a portion of patients able to achieve durable responses. A lower ORR was observed after first-line CPI; however, the number of patients in this group is small, and 33% of them had received prior treatments. Further studies are needed to determine if concurrent treatment for CLL could improve the efficacy of treatment with CPIs by reducing some of the disease-related immunodysfunction.

Efficacy of immune checkpoint inhibitors for the treatment of metastatic melanoma (MM) in patients with concurrent chronic lymphocytic leukemia (CLL).

e22044 Background: Patients with CLL have immune impairment with abnormalities in T-cell subset composition and immune synapse formation. The impact of these defects on response to immune checkpoint inhibitors (CPI) is not known. Given the high incidence of melanoma in patients with CLL we sought to evaluate the response to CPI in patients with concomitant MM and CLL. Methods: Retrospective analysis of 24 patients (pts) with concurrent CLL and MM who received a total of 38 CPI therapies between July 1997 and July 2019. Primary objective was to determine objective response rate (ORR), defined as complete response (CR) or partial response (PR) by RECIST1.1. Secondary outcomes included event-free survival; overall survival (OS), and duration of response (DOR). Results: The median age at CLL and melanoma diagnosis was 62 and 63 years, respectively. 71% of patients were male. Most presented with early stage CLL at diagnosis (67%), 60% had mutated IGVH, and 47% had deletion of 13q by FISH. 71% remained on observation for their CLL. Median time from melanoma diagnosis to CPI initiation was 13.5 months. 83% had stage IV MM and 17% stage III MM at the time of therapy. 17% had increased LDH. The most common melanoma mutations were BRAF(35%), BRAFV600 (26%), TP53 (30%) and NRAS (26%). Median follow up was 37 months and the ORR was 24% (Table). Median DOR was 41 months and median OS is 26.4 months. Immune-mediated adverse events occurred in 42%, including 13% fever, 11% thrombotic events, 8% endocrine dysfunction. 13 pts are alive and 11 pts died (8 pts due to MM progression). There were no significant changes in absolute lymphocyte counts during CPI therapy. 2 pts received CPI while on ibrutinib or ibrutinib+venetoclax therapy with ongoing CLL responses. Conclusions: Our experience indicates that CPIs can be effective for the treatment of MM in patients with concurrent CLL, achieving durable responses. Immuno-mediated toxicities were frequently observed. A lower ORR was observed in first-line CPI in MM, however the numbers of pts are small. Further studies are needed to determine if initial or concurrent treatment for CLL could improve CPI outcomes and survival. Additional studies evaluating T cells function and tissue infiltration in these patients are ongoing. [Table: see text]

Turning the Heat up a Notch in Biclonal Lymphoproliferative Disorders

Biclonal lymphoid disorders (BLD) are a rare (1.4%) but distinct entity in which Chronic lymphocytic leukaemia (CLL) co-exists with a second lymphoproliferative disorder (LPD) and are poorly understood in terms of pathogenesis and clinical impact. The NOTCH1 pathway is involved in cell proliferation, cell cycle progression and is anti-apoptotic, with mutations of the regulatory PEST domain causing constitutive up-regulation of the pathway. NOTCH1 mutations occur early in CLL leukaemogenesis and are found in 10% of poor prognosis CLL at diagnosis as well as being associated with 50% of Richter's transformation (both Hodgkin's and non-Hodgkin's subtype). We hypothesised that NOTCH1 mutations may be implicated in BLD pathogenesis both because they occur early in leukaemogenesis when clonal divergence is possible and because of its association with Hodgkin's Richter's, which is biologically distinct from CLL.We identified 19 patients with BLD at initial presentation, confirmed by flow cytometry and/or molecular analysis of the Immunoglobulin heavy (IgH) and light (IgL) chain genes between 2008 and 2015. This cohort consisted of 14 males and 5 females with a mean age of 72 (range 47-90) years. BLD was defined as follows: (1) co-existence of cells with different immunophenotypes such as a CD5+/CD19+ and CD5-/CD10- population confirming the co-existence of 2 diagnoses, (2) demonstration of both kappa (κ) and lambda (λ) light chain restriction on a CD5+/CD19+ population and (3) CD5+/CD19+ population without demonstrable surface light chains but with >2 clonal gene rearrangements of their IgH and IgL loci. All 19 cases were tested for a c.7544-7545delCT resulting in truncation of the regulatory C-terminal PEST domain of the NOTCH1 gene by PCR.Eleven of 19 patients had CLL co-existing with a different LPD as follows: Mantle Cell Lymphoma (MCL) (2), Hairy Cell Leukaemia (HCL) (2) and Marginal Zone Lymphoma (7). Of this subgroup 5 of 11 cases (45%) had a NOTCH1 mutation. Four samples in our cohort displayed dual κ and λ light chain expression detected by flow cytometry and confirmed molecularly by identifying 2 clonally distinct populations of LPD and 3 samples (75%) had a NOTCH1 mutation. Four samples were identified with >90% CD5+/CD19+ expression but no monoclonality by flow cytometry, but with 2 distinct populations identified by IgH and IgL rearrangements and of this subgroup 2 (50%) had NOTCH1 mutations. Clinical data was available on 13/19 patients, of whom 11 patients had Binet A and 2 Binet B disease. No patient has required CLL-directed treatment, 2 patients have died of other causes and 11 remain under surveillance. Three of 9 patients with a second LPD have required treatment: both patients with HCL received cladribine for pancytopaenia and a patient with MCL was treated with Rituximab and Bendamustine.Overall, 10 of the 19 (52%) patients with BLD had a NOTCH1 mutation at diagnosis, which is higher than the 10% reported in CLL literature. The absence of any germinal centre cell derived lymphoma in the cohort of patients with additional LPD is intriguing and needs confirmation in other series. The prognostic implications of BLD and NOTCH1 mutations are not possible to assess in this small cohort, but accurate characterization of BLD aids therapeutic decision-making as in the case of concurrent CLL and HCL. Light chain restriction by flow cytometry in a mature B-cell population confirms monoclonality and suggests malignancy, however dual κ and λ expressing CLL may give a polyclonal pattern resulting in failure to make a CLL diagnosis; therefore awareness of this rare subtype of CLL is important.In summary we have added a further association between NOTCH1 mutations and CLL associated disorders which currently includes: poor prognosis CLL at diagnosis, Hodgkin's and non Hodgkin's Richter's transformation and most recently BLD. Increased sensitivity of NOTCH1 detection by next generation sequencing techniques may provide a further insight into the evolutionary origin and pathogenesis of BLD and further elucidate the enigmatic role of NOTCH1. DisclosuresCrotty:BMS, Takeda, Novartis, Janssen, Roche: Honoraria.

Chronic Lymphocytic Leukemia Involving the Breast Parenchyma, Mimicker of Invasive Breast Cancer: Differentiation on Breast MRI

Leukemic involvement of the breast is rare, particularly involvement by chronic lymphocytic leukemia (CLL). While concurrent invasive ductal carcinoma and CLL manifesting as a collision tumor in the breast is extremely rare, this association (CLL and carcinoma) has been described in other organs. We report here a case of a 58-year-old woman with concurrent invasive ductal carcinoma and CLL and describe the imaging features of CLL, particularly the differentiation on MRI.

Prior Treatment with Chemotherapy Is Associated with Poor Outcomes of High Risk Skin Cancers in Patients with Chronic Lymphocytic Leukemia

Abstract 3920The increased incidence of skin cancer in patients with chronic lymphocytic leukemia (CLL) has been well-documented; however, the outcomes for CLL patients with high risk skin cancers are not as well-characterized. Moreover, little is known about the association between outcomes of high risk skin cancers and CLL prognostic factors or exposure to prior chemotherapy.We identified 225 patients at our institutions over the last 20 years with concurrent CLL and skin cancer, and we retrospectively examined outcomes for the 139/225 (61.8%) who had high risk skin cancer as defined by a diagnosis of squamous cell carcinoma (SCC), melanoma, or Merkel cell carcinoma (MCC). Poor skin cancer outcome (defined by local recurrence, nodal metastasis, and disease specific death) was determined by review of patient medical records and verified by pathology reports. Associations between various risk factors and poor skin cancer outcomes were evaluated via chi-square statistics (STATA 12.0 College Station, TX).The study group included a representative CLL population, with 98/139 (70%) males and a median age at diagnosis of 65 years (range 35–84), with a median follow-up of 120 months (range 2–410). Over the course of the study, 76 CLL patients remained alive (55%), 16 patients died due to CLL (12%), and 42 patients died from other causes (30%), including 18 (13%) from skin cancer. Median age at time of skin cancer diagnosis was 72 years (range 44–98), and median follow-up time after skin cancer diagnosis was 41 months (range 2–182). Skin cancer diagnoses included SCC in 122 patients (81%), melanoma in 22 patients (13%), and MCC in 8 patients (6%). Sixty-three (45%) patients had more than one skin cancer diagnosed. In the 122 patients with SCC, there were a total of 353 tumors, 297 of which occurred in males (84%). Half of the SCCs were in the head and neck (n=175, 49.6%). Fifty-four SCCs (15%) were greater than 2 cm in diameter. Rates of nodal metastases and death due to SCC were 12% and 6%, respectively. In the 22 patients with melanoma, 14 occurred in men (63.6%), with the largest number of tumors again located on the head and neck (n=8, 36.4%). Breslow thickness was greater than 1 mm in 12 patients (54.5%). Local recurrence and nodal metastases each occurred in 5 patients (22.7%). The five patients (22.7%) who died due to melanoma were the same patients with nodal metastases. In the 8 patients with MCC, 5 patients (62.5%) were male, and there was no location predominance. Five tumors (62.5%) were greater than 2 cm at time of diagnosis, local recurrence occurred in 1 patient (12.5%), and 5 patients (62.5%) had nodal metastases, with 4 of these 5 dying from MCC. Interestingly, prior treatment with any CLL chemotherapy was significantly associated with poorer skin cancer outcome, with increased rates of local recurrence, metastatic disease, or death due to skin cancer (p=0.001). We also explored whether high risk CLL prognostic factors were associated with poorer skin cancer outcomes. Eleven out of 18 patients tested (61%) had unmutated IGHV, 9/69 patients tested (13%) had del(17p) or del(11q) cytogenetics, and 71 patients did not have prognostic marker data available. In this limited prognostic marker data set, neither unmutated IGHV, poor risk cytogenetics, nor advanced Rai stage was associated with skin-cancer specific outcomes.Overall, the majority of the skin cancers in our cohort occurred in males, and the most common site of disease was the head and neck, highlighting an area in need of especially close surveillance. Relative to the historical experience of high-risk skin cancer patients in the general population, we found skin cancers in our CLL population to be more aggressive. For example, 2 of the skin-cancer related deaths were in CLL patients with stage I melanoma, which is unusual in the general population. Additionally, rates of nodal metastases and death in our SCC group were 12% and 6%, respectively, compared to rates of 4% and 2% in most studies of SCC in the general population. Strikingly, the risk of death from skin cancer was equivalent to the risk of death from CLL. The poor skin cancer outcomes in patients in our study were driven by the group who had received prior chemotherapy. Outcomes were not influenced by high risk CLL prognostic markers, although this latter analysis was limited by incomplete data. Disclosures:No relevant conflicts of interest to declare.

Allogeneic stem cell transplantation for acute myeloid leukemia with del(7q) following untreated chronic lymphocytic leukemia

The development of hematologic malignancy in the presence of chronic lymphocytic leukemia (CLL) is rare. We present a case of acute myeloid leukemia (AML) with del(7q) occurring in a patient with a 4-year history of untreated CLL. Application of flow cytometry and immunohistochemistry allowed for characterization of two distinct coexisting malignant cell populations. After undergoing induction and consolidation chemotherapy, the patient achieved complete remission of AML with the persistence of CLL. Allogeneic transplantation was pursued given his unfavorable cytogenetics. Subsequent matched unrelated donor allogeneic stem cell transplantation resulted in full engraftment and complete remission, with no evidence of AML or CLL. Due to a scarcity of reported cases, insight into treatment and prognosis in cases of concurrent AML and CLL is limited. However, prognosis seems dependent on the chemosensitivity of AML. CLL did not have a detrimental effect on treatment or transplant outcome in our case. This is the first reported case of concomitant de novo AML and CLL to undergo allogeneic transplantation. The patient remained in complete hematologic and cytogenetic remission of both malignancies over a year after transplantation.

The Clinical Course of Head and Neck Cancer in Patients with Chronic Lymphocytic Leukemia

Abstract 4741 BACKGROUND.Patients with chronic lymphocytic leukemia (CLL) have an increased risk of developing second primary malignancies, including squamous cell cancers (SCC) of the Head and Neck (HNC). While cutaneous SCC have been shown to behave more aggressively in the setting of CLL, little information exists on the clinical course and outcome of SCC of the oral cavity and pharynx. METHODS.The Massachusetts General Hospital Tumor Registry was queried for all patients with ICD-O-3 codes corresponding to both CLL/SLL and HNC from January 1989 to July 2010, returning seventeen patients. The data collected included patient demographics, blood work and cytogenetics (when available) at the time of CLL diagnosis, primary HNC tumor histology and stage, and all pertinent treatment data, including types of treatment and clinical response. Survival was calculated using the Kaplan-Meier method. RESULTS.Seventeen patients had a diagnosis of both CLL and HNC. Of those, three were excluded from the study as treatment data was unavailable. The fourteen remaining included 12 males and 2 females. Eight patients had their CLL diagnosed first, and had a median interval to HNC diagnosis of 80 months (2-210 months; mean 89 months), four had their HNC diagnosed first and had a median interval to CLL of 1 month (1-100 months; mean 26 months), and two patients had concurrent diagnoses. The median age at diagnosis was 58.5 years (CLL) and 64 years (HNC). Nine patients (64%) were former or current smokers, all with at least a 20 pack year smoking history. Seven patients presented with Rai stage 0 CLL, three patients with Rai stage 1, one patient each with Rai stage 2 and 3, and two with unknown presentations. HNC tumor presentations included 3 T1 tumors, 3 T2 tumors, 3 T3 tumors, 2 T4 tumors, and 3 TX tumors. Three patients had HPV assessed in their tumor and all were positive.Out of the fourteen patients, nine (64%) received first-line chemotherapy for their CLL: 4 with chlorambucil, 1 with fludarabine/rituximab (FR), 1 with FR/lenalidomide, 1 with rituximab, and 1 each with cytoxan/vincristine and steroid monotherapy. Eight patients received second line therapy, three received third line therapy and one received 7 lines of therapy. Six patients (43%) received chemotherapy and radiation as their primary treatment for their Head and Neck tumor, three (21%) received surgery and radiation, three (21%) received only radiation, one received surgery, and one received radiation, chemotherapy, and surgery. One patient required hospitalization due to neutropenic fever during their radiation treatment, and one patient had a week of chemotherapy withheld due to leukopenia, but both were able to complete their full course of therapy. Three patients (21%) received chemotherapy for their CLL before any HNC treatment. These three patients were able to tolerate full HNC therapy without infectious complications or unanticipated cytopenias.First-line therapy for HNC had a median progression-free survival of 26.9 months (range 10.7 – 145.2 months; 95% CI, 12 to 42 months) and a median overall survival of 45.1 months (range 1 to 256.1 months; 95% CI, 9 to 81 months). The median overall survival from HNC for treated CLL patients was 22.6 months and for untreated 59.2 months (p= 0.596). Five patients died from their HNC (36%), two patients died from their CLL (14%), two patients died from unrelated causes, and five patients remain in remission. There were no significant differences in HNC presentation or survival between treated and untreated CLL. CONCLUSIONS.Prior or concurrent CLL therapy did not affect HNC treatment or induce any unexpected toxicities. Interestingly, seven out of fourteen patients (including 2 out of 3 HPV positive) were diagnosed with HNC within 6 months of CLL diagnosis, suggesting that the risk of secondary malignancies may be independent of the degree of immunosuppression attributable to progressive CLL or its therapy. This hypothesis should be explored in a larger population. Disclosures:No relevant conflicts of interest to declare.

Chronic lymphocytic leukemia mimicking recurrent carcinoma of the breast: Case report and review of the literature

Secondary localization of chronic lymphocytic leukemia (CLL) in breast is rare, while concurrent invasive ductal carcinoma and CLL manifesting as a collision tumor in breast is extremely rare. The observation of a CLL infiltration closely associated with a distinct breast neoplasm with the absence of any other localization for the leukemia is an indisputable argument for a relationship between the two diseases. The presence of both tumors is not simply due to chance. This association (CLL and carcinoma) has also been described in other organs. Hereafter, we report a second case of an 80 year-old woman in whom a leukemic infiltrate was confined to the region immediately surrounding poorly differentiated primary breast carcinoma, and we will discuss the association between CLL and carcinoma.

Characterization of a novel t(2;5;11) in a patient with concurrent AML and CLL: a case report and literature review

Acute myeloid leukemia (AML) that occurs concurrent with a diagnosis of chronic lymphocytic leukemia (CLL) is rare, but the number of cases recognized has recently dramatically increased as a result of the application of flow cytometry. This raises a series of questions regarding the clinical characterization of mixed leukemia, whether this diagnosis possesses unique cytogenetic abnormalities, and the possible association between AML and CLL cell clones. The current study attempts to answer these questions by evaluating an 80-year-old man with concurrent diagnoses of AML-M0 and CLL. Routine G-banded chromosome, array based comparative genomic hybridization, and fluorescence in situ hybridization analyses were used to characterize complex chromosomal rearrangements in the patient's bone marrow. Novel complex translocations involving chromosomes 2, 5, and 11, as well as submicroscopic deletions and duplications, were revealed. This case study reports a t(2;5;11) in either AML-M0 or in CLL by using array based comparative genomic hybridization and fluorescence in situ hybridization analyses to facilitate the diagnosis. The study also delineates the clinical characteristics and cytogenetic changes that occur with concurrent AML and CLL.

Concurrent chronic lymphocytic leukemia and prolymphocytic leukemia derived from two separate B‐cell clones

An 82-year-old man presented with leukocytosis and splenomegaly. His blood counts showed a white cell count of 134 × 109/l, hemoglobin 96 g/l, and platelet count 86 × 109/l. The blood film showed two distinct populations of lymphocytes, morphologically, 60% typical CLL cells and 40% large prolymphocytes (Image 1). Patient's spleen was palpable 14 cm below the left costal margin. There were mildly enlarged cervical and axillary lymph nodes up to 2 cm but no evidence of localized lymphoma. Blood film shows two populations of CLL and PLL cells. Flow cytometry analysis showed 90% B lymphocytes. Although all the B cells had lambda light chain restriction, they were heterogeneous for CD5 and CD23 expression, including the CD5+/CD23+ B cells typical of CLL phenotype, and the cells lacking CD5 and CD23 consistent with a PLL population. Clonality analysis was performed with use of multiplex PCR (polymerase chain reaction) assays for IgH rearrangement. With this assay, a clonal B-cell population gives rise to PCR product identical in size and independent clones can be distinguished by unique size of the PCR products. The patient's blood sample showed a pattern of two clones of B lymphocytes (Image 2), indicating the two independent clones of CLL and PLL cells. PCR clonality analysis is based on IgH gene rearrangement and two peaks of PCR products indicate two independent clones of B cells. The patient was treated initially with chlorambucil 2 mg daily with a poor response. His white cell count rose quickly to 240 × 109/l in 5 months. He required transfusion for worsening anemia. Further treatment with fludarabine and cyclophosphamide was tried and discontinued due to poor intolerance. This patient presented with a mixed population of CLL and PLL. The genetic relationship between CLL and PLL may be revealed by immunoglobulin isotypes or immunoglobulin gene rearrangements [1]. Similar to diffuse large B-cell lymphoma developing in CLL (Richter syndrome), B-cell PLL may arise from clonal progression of CLL or a second malignancy unrelated to CLL [1-3]. It is likely that this patient had an indolent and undiagnosed CLL, but the duration of CLL before the emerging PLL is unclear. Nonetheless, the finding of clonality analysis indicates PLL derived from an independent clone to that of CLL.

Predictive Value of the Pre-Operative CT Scan for Splenectomy in Patients with Primary, and Post Essential Thrombocythemia/Post Polycythemia Vera Myelofibrosis.

BACKGROUND: Splenectomy is performed for palliating symptoms in patients with primary myelofibrosis (PMF; as well as post essential thrombocythemia myelofibrosis/ post polycythemia myelofibrosis (Mesa et. al. Cancer 2006; 107(2):361–70). Pre-operative computed tomograms (CTs) of the spleen are frequently performed for estimating spleen size and anatomy, but sometimes raise concern over radiographic splenic masses. We performed a retrospective analysis of splenectomized PMF patients to determine the predictive value of CT in these patients.METHODS: Splenectomized patients, with confirmed PMF (and POST ET/PV MF), with an available pre-operative CT scan were included. Pre-operative CT scans were reviewed in a blinded fashion by a radiologist (B.B.), and histopathology was concurrently reviewed in a blinded fashion by a hematopathologist (C.Y.L.), with attention for radiographic evidence of splenic masses, splenic infarction and hemorrhage, evidence of extra-splenic masses. Additionally splenic volume was calculated by CT through an algorithm using maximal splenic length, width, and slice size (prorated ellipsoid where volume = (30+.58(XxYxZ)). Results from each review were compared and analyzed against clinical outcomes and documented splenic mass.RESULTS: Thirty-eight patients had concurrent CT and splenic pathology available underwent splenectomy for myelofibrosis (20 PMF; median age at diagnosis 64.6 years (range (46–79), 52% males). Splenic volume estimations by CT correlated well with splenic mass measurements. Splenic volume estimation by CT was 2365 CC (range 736–11355 CC), compared with a measured median splenic mass of 2000 mg (range 730–11750 mg) (bivariate analysis p<0.001). Splenic lesions were identified in a total of 33 patients (87%), 10 only by histopathology (30%), 3 only by CT (9%), and 20 by both (61%). Histopathologically 15 patients had localized hemorrhage, 13 had splenic infractions, and 8 had nodular foci of extramedullary hematopoiesis. Only 2 patients had evidence of an alternative malignancy (concurrent chronic lymphocytic leukemia (CLL, n =1) or systemic mast cell disease (n = 1). CT was very sensitive for detecting focal low density lesions (LDLs), which are roughly spherical regions of decreased contrast enhancement in the spleen, and detected the majority of macroscopic lesions. The presence of splenic infarctions histologically was associated with decreased post splenectomy survival (p=0.02; median 7.2 months vs. 15.0 months), however the sensitive (but not specific) presence of LDL lesions by CT did not have prognostic significance. The CT appearance of splenic hemorrhage was nonspecific, and since these areas of parenchymal hemorrhage were likely subacute/chronic, they could not be reliably distinguished from other LDLs.CONCLUSIONS: Pre-operative CT in patients whom undergo palliative splenectomy for myelofibrosis is a sensitive tool for determining the presence of small splenic lesions (hemorrhage, infarction and EMH). Additionally splenic volume estimation by CT, correlates well with measured splenic mass and may assist in operative planning. Splenic lesions in PMF (post ET/PV MF) by CT rarely represented an alternative malignant process, and should likely not be the sole indication for splenectomy. Splenic infarctions were associated with decreased survival after splenectomy, however CT is not always able to distinguish these lesions from EMH and hemorrhage.

Concurrent acute myeloid leukemia with inv(16)(p13.1q22) and chronic lymphocytic leukemia: Molecular evidence of two separate diseases

Acute myeloid leukemia (AML) occurring concurrently with or after untreated chronic lymphocytic leukemia (CLL) is rare. We report a case of a 59-year-old man who was evaluated for anemia, thrombocytopenia, and leukocytosis with circulating blasts. On the basis of the morphology and immunophenotyping results, a preliminary diagnosis of chronic myelomonocytic leukemia with concurrent CLL was considered. Subsequently, cytogenetic analysis of the leukemic blood specimen revealed inv(16)(p13.1q22) with secondary trisomy 22 in a sideline clone. Fluorescence in situ hybridization confirmed the CBFbeta rearrangement associated with inv(16) in myeloblasts and myelomonocytic cells, but not in CLL cells. Therefore, a final diagnosis of AML with inv(16) with concurrent CLL was made. After standard chemotherapy for AML, the patient achieved complete remission for both his AML and CLL. The unique aspects of this case include concomitant AML and CLL, which do not share clonality, complex cytogenetic abnormalities with trisomy 22 as a secondary abnormality associated with inv(16), and achievement of remission for both AML and CLL by AML chemotherapy regimen. This case also represents one of the rare instances where a diagnosis of AML can be established even when the blast percentage in the marrow and blood is less than 20%.