Common Lymphoproliferative Disorder Research Articles

A Real-World Evidence Study of the Temporal Evolution in Treatment Patterns and Outcomes for Chronic Lymphocytic Leukemia

CONCLUSIONS Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in North America. Treatment of CLL is currently indicated only for patients with disease-related symptoms or organ compromise, such as cytopenias, with no evidence of survival benefit for the treatment of asymptomatic patients. Patients with CLL are not cured with conventional therapy and typically require repeated treatments over their lifetime. Median overall survival (OS) is difficult to estimate given recent advances in therapy options but is dependent upon disease features, patient characteristics, and treatment choice. Since the recent introduction of targeted therapy for CLL, there has been limited Canadian data on the evolution of management approaches in a real-world setting. Data are needed to improve the current understanding of the treatment landscape of CLL. This retrospective observational cohort study used real-world, population-level data to describe the baseline characteristics, treatment patterns, clinical outcomes, and healthcare resource use of individuals diagnosed with CLL in Alberta, Canada. The study cohort included all individuals in Alberta over 18 diagnosed with CLL between 2010-2020 and who subsequently initiated systemic therapy. Data were collected through electronic health records and administrative databases. OS was defined as the date of diagnosis to death from any cause or last known contact with the health care system. A total of 890 individuals diagnosed with CLL between 2010-2020 who initiated first-line (1L) systemic therapy were included in the analyses. The mean age at initiation of 1L therapy was 69 years, and 68% were male. Among individuals who initiated 1L therapy in 2020+, the primary form of 1L systemic therapy was ibrutinib monotherapy (IBR) (29%), followed by bendamustine plus rituximab (BR) (21%). A considerable number of individuals did not initiate subsequent lines of therapy, with a drop of approximately 40-45% between each successive line. The treatment landscape changed over time, particularly with respect to decreased use of 1L fludarabine, cyclophosphamide, and rituximab (FCR; 40% in 2010-2013 vs. 9% in 2020+) and increased use of 1L IBR (6% in 2014-2017 vs. 29% in 2020+). Individuals treated at an academic centre were more likely to receive 1L IBR than those treated at a community centre. The median duration of 1L therapy was considerably longer for patients treated with targeted therapy (IBR: 9.8 months) compared to chemoimmunotherapy (BR: 5.6 months, FCR: 5.6 months). The majority of individuals did not initiate therapy immediately after diagnosis, with a median time from diagnosis to initiation of 1L therapy of 24 months (recognizing that the population described includes only those who initiated 1L therapy such that time to first therapy would be much longer for the entire CLL population). The time to next line of therapy (from the start of each line to the start of the subsequent line) was 17 months from 1L to second-line (2L), 14 months from 2L to third-line (3L), and 12 months from 3L to fourth-line. Median OS from initiation of 1L was 104 months, 2L was 70 months, and 3L was 64 months. On average, individuals had 39 healthcare encounters within the first year of initiating 1L systemic therapy, with an average of one hospitalization, six ambulatory care encounters, 25 non-cancer practitioner encounters, and seven cancer physician visits. The mean number of healthcare encounters within the first year of front-line therapy tended to decrease over time, which may be attributable to the changing treatment landscape. These findings highlight the rapid changes in CLL therapy that have occurred over the last decade. Our results demonstrate the significantly smaller cohorts of real-world patients receiving 2L or later therapies compared to 1L and highlight declining survival with subsequent lines of therapy, and a decreasing trend of healthcare resource use over time.

Pathologic Characteristics of Patients in the Kamuzu Central Hospital Lymphoma Study (2013-2019)

PURPOSE We evaluated the concordance of lymphoproliferative disorder (LPD) diagnoses made initially at Kamuzu Central Hospital (KCH) with a limited immunohistochemistry panel and telepathology consultation with University of North Carolina (UNC) at Chapel Hill and second review at UNC with an extensive immunohistochemistry panel available. METHODS The prospective KCH Lymphoma Study in Lilongwe has been enrolling patients with LPDs since 2013. Diagnoses are made by pathologists in Malawi and supported by US pathologists and Malawian clinicians at weekly telepathology conferences. Diagnostic tissue blocks are sent quarterly to UNC for secondary review and further confirmatory studies. Concordance of diagnosis from primary to secondary review was scored as: exact match (level 1), differences in granularity of the diagnosis (level 2), a change in classification but not in treatment (level 3), and a change to the diagnosis that would have altered the treatment course (Major Discordance). Cases with insufficient tissue for review at UNC were excluded from concordance evaluation. RESULTS Three hundred eighty-eight adult patients were enrolled (June 2013-May 2019). Three hundred twenty-seven tissue blocks were sent to UNC for review and 292 LPDs diagnostic samples had sufficient quality for concordance review. The five most common LPDs were diffuse large B-cell lymphoma (n = 143, 49%), Burkitt lymphoma (9%, n = 25, 8%), classical Hodgkin lymphoma (8%, n = 23), Multicentric Castleman disease (8%, n = 23), and low grade non-Hodgkin lymphoma (6%, n = 17). Level 1, 2 and 3 concordance represented 175 (60%), 49 (17%) and 50 (17%) cases, respectively, and a Major Discordance was identified in 18 cases (6%). CONCLUSION With a limited, selected immunohistochemistry panel and telepathology consultation, 94% of cases were accurately classified in real-time, leading to appropriate therapy. The evaluation of concordance provides a measure of quality assurance of the telepathology program, confidence in diagnoses for involvement in interventional trials, and useful data for understanding the epidemiology of LPDs in Malawi.

Chronic lymphocytic leukaemia trends and features at a tertiary hospital in South Africa (2011–2016)

Background: Chronic lymphocytic leukaemia (CLL) is a common lymphoproliferative disorder in developed countries. However, this condition is rare in Africa and there is a paucity of information on CLL, specifically on the continent.Aim: This study described, retrospectively, the frequency, demographics and laboratory features of CLL cases diagnosed from 2011 to 2016.Setting: Department of Pathology, National Health Laboratory Service, Tygerberg Academic Hospital, Cape Town.Methods: A retrospective analysis was performed for all CLL diagnoses made between 01 January 2011 and 31 December 2016.Results: Eighty CLL cases were diagnosed between 2011 and 2016. Men and women presented with the disease equally (48.8% vs. 51.2%, p 0.05). The mean age at diagnosis was 66.79 years (range of 37–95 years) and the modal age range (36.3%) was 60–69 years. Men presented with the disease at a significantly younger age than women (mean = 64 years vs. mean = 69.5 years, p 0.05). There were three (3.75%) human immunodeficiency virus (HIV)-positive patients (age range 43–50 years). Chromosome 13q14 deletion was found in 6 out of 19 patients (31.6%). Trisomy 12 and deletion 11q22 were found in 5 out of 21 (24%) and 7 out of 21 (33.3%) patients, respectively. Deletions 13q34 and 17p were negative for 6 and 20 patients, respectively.Conclusion: Chronic lymphocytic leukaemia at our facility presented equally in men and women. Men presented with the disease at a younger age than women. Additionally, our findings suggested that HIV is uncommon amongst CLL patients tested for HIV.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Presenting as Chronic Diarrhea; An Unusual Presentation of a Common Lymphoproliferative Disorder

Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the United States. It has a variable presentation with most patients having asymptomatic lymphocytosis. Many other patients present with lymphadenopathy or enlargement of other organs of the reticuloendothelial system. However, CLL can present with extramedullary involvement. Most commonly, this is in the form of skin or central nervous system involvement, though rarely it can present with gastrointestinal involvement. Here, we present the case of a 70-year-old Caucasian male who presented with chronic diarrhea for over 4 months. After failing conservative treatment, a colonoscopy was performed which showed diffuse mucosal nodularities with a biopsy revealing CLL. The patient was treated successfully with chemotherapy and his diarrhea improved. This is a differential to keep in mind in patients with chronic diarrhea, once the more common causes have been ruled out.

S1675 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Presenting as Chronic Diarrhea: An Unusual Presentation of a Common Lymphoproliferative Disorder

INTRODUCTION: B-cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. It has a variable presentation with most patients having asymptomatic lymphocytosis. CLL can present with extramedullary involvement. Most commonly this is in the form of skin or central nervous system involvement, though rarely it can present with gastrointestinal involvement. CASE DESCRIPTION/METHODS: We are highlighting a case of a 70-year-old male who presented with complaints of diarrhea for the last 4 months. He was having 4–5 bowel movement a day ranging from semi-solid to watery stools. He denied any history of fevers, abdominal pain, vomiting, weight loss, night sweats, skin rashes, travel history, or exposure to anyone with similar symptoms. On physical examination, his abdomen was soft, non-tender, and without apparent hepatomegaly or splenomegaly. The rest of the system examinations were unremarkable. The initial laboratory evaluation was unremarkable. After failing conservative treatment, a colonoscopy was performed which showed diffuse mucosal nodularities (Image 1 and 2). Histopathology of the biopsied tissue revealed multiple aggregates for small mature lymphocytes in the submucosa (Image 3). Immunohistochemical staining revealed a diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma. CT scan revealed extensive bilateral axillary, hilar, abdominal, and pelvic lymphadenopathy. He subsequently underwent bone marrow biopsy histopathology and flow cytometric immunophenotyping which were consistent with CLL. Oncology started him on chemotherapy and he went into remission from his CLL. On 3- and 6-month follow-ups, the patient was asymptomatic. DISCUSSION: A review of the literature revealed a total of n = 4 prior reported cases where the initial presentation of CLL/SLL was diarrhea. In the existing case reports with similar presentation a mean age of presentation was n = 74 years, ages ranging from 65 to 81 years. They had fecal urgency, abdominal pain, and weight loss as associated symptoms. Only one patient had history of CLL for which he had undergone treatment and was thought to be in remission. Imaging with CT with contrast in all cases revealed abdominal and pelvic lymphadenopathy. Histopathology of the colonic biopsy in all cases revealed lymphocytic infiltration. This patient was treated successfully with chemotherapy and his diarrhea improved. This is a differential to keep in mind in patients with chronic diarrhea, once the more common causes have been ruled out.Figure 1.: Image 1: Colonoscopy showing submucosal nodularity.Figure 2.: Image 2: Colonoscopy showing submucosal nodularity.Figure 3.: Image 3: Hematoxylin and eosin stain showing lymphoid aggregate with normal colon mucosa.

PB1913 CIRS SCORE AS A RELIABLE COMORBIDITY EVALUATION TOOL MAY INFLUENCE THERAPEUTIC DECISIONS IN ELDERLY CLL PATIENTS

Background:Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the elderly population and many of these patients have multiple comorbidities, which might limit the eligibility for upfront chemoimmunotherapy options. The Cumulative Illness Rating Scale (CIRS) score seems to be a reliable tool for assessment of the burden of comorbidity in elderly cancer patients. It may identify fit and unfit CLL patients and influence the therapeutic decision‐making process.Aims:The primary objective of our study was to assess the CIRS score status in CLL patients in real clinical practice. The secondary objective was to analyze which treatment option was used in each patient's group, classified according to CIRS.Methods:In our prospective, single‐center study we focused on CLL patients that visited the University clinic for hematology in Skopje between March 20th 2017 and January 22nd 2019. Comorbidity was assessed by the CIRS‐G score in all patients included in our study (n = 56) prior to reaching a multidisciplinary treatment decision.Results:In our series, 56 CLL patients; 30 (53.6%) males and 26 (46.4%) females, were included. Median age was 69 (± 9.4) years (range 38‐85). Comorbidities were identified in 80.4% of the study population, with an average CIRS score of 3.9 (range 0‐13). Only 19.6% of the patients were comorbidity free. There was a positive correlation between the CIRS score and the age (rs = 0.2276, p = 0.04). Two thirds, or 67.9% of the patients had a CIRS score <6, 21.4% had CIRS score between 6 and12 and CIRS score was >12 in only 8.9% of patients. The three most common comorbidities were related to affections of the vascular system (41.1%), endocrine‐metabolic disorders (32.1%), and respiratory system disorders (17.9%). Only 16.1% of the patients had only 1 affected organ or system, other than hematological issues, while 64% of the patients had ≥2 affected systems. In 33.9% of the study patient cohort, the watch and wait approach was the standard of care; 66.1% of patients were eligible for treatment as follows: chemotherapy (chlorambucil, fludarabine + cyclophosphamide, bendamustine) only (30.4%), rituximab‐based therapy (33.9%) and 1.8% of patients, due to the high comorbidity burden, received only supportive care. There was a stable trend of correspondence between the CIRS score assessment and the treatment option prescribed (rs = 0.7188, p < 0.000001). Despite their eligibility for novel therapies (e.g. obinutuzumab, ibrutinib, idelalisib etc.) none of the patients received them due to their local unavailability.Summary/Conclusion:Our study shows that comorbidity is a very common feature in CLL patients and that it is increasing with age. Despite the fact that 8 out of 10 patients had at least one affected organ/system, the general comorbidity burden was low. CIRS is helpful in identifying the best treatment combination for the patients, that will enhance achieving long‐term control of CLL, maintaining an optimal quality of life level.

Chronic lymphocytic leukemia: An Indian experience.

e19007 Background: Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the West accounting for about 30% of leukemias, whereas in Indian subcontinent it accounts for 3-5% of all leukemias. We aimed to evaluate biological and molecular prognostic parameters as well as therapeutic considerations in CLL patients in India. Methods: We retrospectively analyzed 510 patients with CLL, who presented at our institute over a period of 18 years. Results: The median age of CLL patients at presentation was 60 years (range: 28 - 92 years) with male: female ratio = 3:1. The median total leukocyte count was 45X109/L . As per clinical Rai stage distribution 55 (10.08%) patients were in Stage 0, 92 (18%) in stage I, 174 (34%) in stage II, 92 (18%) in stage III and 97 (19%) were in stage IV. ZAP-70 was positive ( > 20%) in 206 (57% , n = 361) , CD 38( > 30%) in 107 (29% , n = 363), and CD49d was positive ( > 30%) in 63 (50.3%, n = 127) cases. Beta-2 microglobulin (B2M) was elevated (≥3.5 mg/L) in 243 patients (70%, n = 347). One hundred and fifty six cases (57%, n = 273) were IGHV mutated and Del (17p) by FISH was observed in 18 cases (12%, n = 150). A total of 331 (64.9 %) patients required treatment wherein 155 patients (46.8%) received Chlorambucil-based, 110 ( 33.2%) received BR, 42 (12.6%) received Fludarabine based ( FC-7,FCR-35) and 41 patients received others regimen. Overall response rate seen with Chlorambucil, BR and Fludarabine based regimen was 67% ( CR-3.2%), 90% ( CR-45%) & 88% ( CR-44%) respectively. Median event free survival (EFS) and overall survival (OS) and was 3.5 years and 5.5 years respectively, with median follow up period of 3.9 years. Clinical stage (Rai III/IV), elevated B2 M, IGHV-unmutated had statistically significant adverse impact on OS and EFS. Fludarabine based chemotherapy appeared toxic as half of patients developed febrile neutropenia and various infections whereas in BR , cutaneous side effects were more common(p = 0.001) . In early stage CLL, median time to first treatment was 22 months and; IGHV-unmutated, elevated B2M and CD38 positivity were significantly associated with shorter treatment free survival. Conclusions: This is the largest series of CLL reported from Asia. Clinical Rai Stage III/IV, unmutated IGHV and elevated B2M have statistically significant adverse impact on survival of patients with CLL. BR was better tolerated than fludarabine based regimen with similar responses and events.

Pathologic Findings in Bronchopulmonary Leukemic Infiltrates in Patients With Chronic Lymphocytic Leukemia

IntroductionChronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder worldwide. Although thoracic complications are frequent in CLL, only limited data exists regarding these complications. Pleural, parenchymal, and airway disease may occur owing to CLL itself, treatment-related adverse events, typical or opportunistic infections, or from preexisting comorbidities. The etiology of parenchymal infiltrates is often attributed to pneumonia and can be difficult to properly identify without a diagnostic procedure. Patients and MethodsWe conducted a retrospective chart review of patients admitted from 2000 through 2016 with a diagnosis of CLL and abnormal radiography that underwent a bronchoscopy with biopsy, surgical lung biopsy, or transthoracic biopsies for nonresolving infiltrates after a course of antibiotics. We described the incidence of bronchopulmonary leukemic infiltrates (BPLI), describe other diagnosis achieved by the biopsy, and also describe the pathologic findings associated with BPLI in these patients. ResultsThere were 111 procedures performed on 98 patients that yielded a diagnosis in 82 patients. In 16 patients, no histologic or pathologic diagnosis was identified after the biopsy. BPLI was diagnosed in 32 (39%) cases. In 27 (85%) of 32 cases, the biopsies returned with only BPLI owing to CLL (without inflammation), whereas 5 (15%) of 32 cases showed concomitant acute or chronic inflammation. ConclusionDirect infiltration by leukemic cells may cause pulmonary symptoms and signs indistinguishable from infection. Biopsy is necessary to establish a definitive diagnosis, and physicians caring for these patients, including pathologists, should be aware of the clinicopathologic picture of BPLI to render an informative diagnosis.

Identification of new phosphorylation sites of CD23 in B-cells of patients with chronic lymphocytic leukemia

B-cell chronic lymphocytic leukemia (B-CLL) is the most common lymphoproliferative disorder in adults. Patients with B-CLL strongly express the CD23 – C type of lectin (low affinity IgE receptor, Fc epsilon RII), which is linked to B cell activation and proliferation. Phosphorylation in lymphocytes is tightly associated with regulation of protein activities, functional regulation and cell signaling, and may thus affect initiation and/or progression of the disease. Here we report changes in the phosphorylation of CD23 on threonine (pThr314) and two serine residues (pSer254, pSer265) in B lymphocytes of B-CLL patients, using a flow cytometry approach. The majority of tested patients with active forms of B-CLL presented a notable overexpression of CD23 along with pThr314, pSer254, and pSer265 CD23 phosphorylation positivity. Moreover, we have experimentally stimulated the CD23 phosphorylations in a subset of peripheral blood lymphocytes of healthy controls by phorbol-12-myristate-13-acetate treatment. This affects the activation of competent phosphorylation mediating kinases, resulting in the enhanced phosphorylation pattern. Together, these data confirm that CD23 protein is phosphorylated in B cells of B-CLL patients, report the identification of new CD23 phosphorylation sites, and suggest a possible role(s) of such phosphorylations in the activation of CD23 during the process of lymphocytic activation in B-CLL.

Thoracic Complications in Chronic LymphocyticLeukemia.

Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder worldwide. Although thoracic complications are frequent in CLL, only limited data exist regarding the etiologies of these complications. A retrospective chart review was performed on all patients admitted to a tertiary care, CLL referral center, with CLL and a respiratory complaint from 2001 through 2013, to categorize pulmonary complaints and diagnoses. There were 277 patients with CLL admitted on 409 occasions with respiratory complaints. The median age was 73 years, with a male to female ratio of 2:1. The majority of patients had a high-risk Rai classification and had received prior treatment. Common presenting symptoms included dyspnea, cough, and sputum production. The most common diagnoses were pneumonia (62.8%), with an identified organism in 44.7%, pleural effusions (31.8%), lung cancer (6.9%), and leukemic infiltrates (5.9%). Invasive procedures were performed 138 times: 70 bronchoscopies, 24 surgical lung biopsies, 10 computed tomography-guided lung biopsies, and 34 thoracenteses. In-hospital mortality was 24.9%. In a multivariable analysis, an elevated blood urea nitrogen level and creatinine, thrombocytopenia, and a presenting symptom of dyspnea correlated significantly with in-hospital mortality. Thoracic manifestations in CLL are common among hospitalized patients. Although infectious pneumonia remains most common, unusual or opportunistic infections may be increasing, and direct lung damage owing to CLL itself or to newer biologic agents are being diagnosed with lung tissue sampling. Recognition of these complications will allow earlier diagnosis, which may change management including removal of offending biologic agents or augmentation of treatment for CLL when infiltrative leukemic cells are present.

Linfoma cutáneo tarsal en gato – estudio de caso

El linfoma representa la enfermedad linfoproliferativa más frecuente en gatos. Sin embargo, el linfoma cutáneo es una rara forma de linfoma extranodal. Recientemente, el linfoma cutáneo se reportó localizado en el tarso. Tanto clínica como histopatologicamente, esta forma difiere de la forma cutánea típica, y se denominó linfoma tarsal felino. Este estudio describe el caso de un gato, doméstico de pelo largo, 13 años de edad con una masa subcutánea, de 30 días de evolución en la región tarsal del miembro pélvico derecho. La histopatologia reveló neoplasia de células redondas, sugestiva de linfoma de células grandes. La inmunohistoquímica confirmó el diagnóstico de linfoma imunoblástico de células B. El tratamiento realizado fue lomustina y prednisolona con tiempo de sobrevida de 2,1 meses. La agresividad de este linfoma, refuerza la necesidad de estudios para entender su curso y mejorar protocolos terapéuticos que incrementen tanto la sobrevida como la calidad de vida para estos pacientes.

Issues in diagnosis of small B cell lymphoid neoplasms involving the bone marrow and peripheral blood. Report on the Bone Marrow Workshop of the XVIIth meeting of the European Association for Haematopathology and the Society for Hematopathology.

Small B cell lymphoid neoplasms are the most common lymphoproliferative disorders involving peripheral blood (PB) and bone marrow (BM). The Bone Marrow Workshop (BMW) organized by the European Bone Marrow Working Group (EBMWG) of the European Association for Haematopathology (EAHP) during the XVIIth EAHP Meeting in Istanbul, October 2014, was dedicated to discussion of cases illustrating how the recent advances in immunophenotyping, molecular techniques and cytogenetics provide better understanding and classification of these entities. Submitted cases were grouped into following categories: (i) cases illustrating diagnostic difficulties in chronic lymphocytic leukaemia (CLL); (ii) cases of BM manifestations of small B cell lymphoid neoplasms other than CLL; (iii) transformation of small B cell lymphoid neoplasms in the BM; and (iv) multiclonality and composite lymphomas in the BM. This report summarizes presented cases and conclusions of the BMW and provides practical recommendations for classification of the BM manifestations of small B cell lymphoid neoplasms based on the current state of knowledge.

Myeloablative Allogeneic Stem Cell Transplantation in CLL: A Single Centre Retrospective Study

Introduction:Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the Western world. Despite recent advances in therapy, CLL remains incurable with conventional chemo-immunotherapy. Allogeneic hematopoietic stem cell transplantation (alloSCT) remains the only curative option in CLL. AlloSCT relies on graft-versus-leukemia effect and can achieve the possibility of long-term disease control even in poor prognosis CLL such as chemotherapy refractory or high-risk cytogenetics. Unfortunately, alloSCT is associated with significant morbidity and mortality risks from regimen related toxicity, graft-versus-host disease (GVHD) and infectious complications. In order to reduce the rates of non-relapse mortality (NRM), reduced intensity conditioning regimens have been routinely adopted in most centers. While these newer regimens have shown lower NRM, they result in higher relapse rates compared to traditional myeloablative (MA) regimens. This retrospective analysis describes the outcomes of using contemporary MA conditioning in a consecutive series of patients transplanted for high-risk CLL including patients with relapsed/refractory disease or 17p deletion.Patients & Methods:We retrospectively reviewed CLL patients who underwent alloSCT between February 2000 to July 2012 at a single center using a uniform myeloablative conditioning regimen comprising Fludarabine 250mg/m2, PK targeted Busulfan 12.8mg/kg IV, and Thymoglobulin 4.5mg/kg (FLUBUPATG) with cyclosporine and methotrexate GVHD prophylaxis. Major eligibility criteria were relapsed CLL or del(17p) CLL in adults (18-70yrs) with an available HLA-compatible donor. Cox regression models were used to evaluate the impact of variables on outcomes including OS, PFS, and NRM. Cumulative incidence function (CIF) was used to estimate relapse. Statistical analysis was conducted using SAS (SAS Institute, Cary, NC) version 9.3 software. A p-value <0.05 was used for all statistical significance. Responses were defined according to the iwCLL criteria.Results:Sixty-one patients (46 males, 15 females) with a median age of 53 years (range, 38-65 years) including 21% ≥ 60 years were analyzed. The median time from diagnosis to alloSCT was 48 months (range, 3-236 months). Fifty-six percent of patients were treated with ≥ 2 regimens prior to alloSCT and 74% were fludarabine-refractory. Forty-three percent were considered chemosensitive prior to alloSCT and 5 (8%) were transplanted due to Richter's transformation. Twenty percent had poor-risk cytogenetics including del17p (n=6) and del11q (n=7). Sixty-nine percent were fully HLA matched including a total of 33 (54%) matched related donors and 9 (15%) matched unrelated donors. A total of 19 (31%) patients had a mismatched donor, including 6 (10%) with 2 mismatches. A complete remission (CR) was achieved in 62%, while 16% had partial remission (PR). Twelve (20%) patients relapsed after achieving CR/PR. The 5-year cumulative incidence of relapse was 26%. Fifty-two percent of patients remain alive at a median follow-up of 83 months. The estimated 5-year overall survival (OS) and progression free survival (PFS) were 61% and 47%, respectively. Twenty-nine patients died, 12 from CLL and 17 NRM. The 2-year NRM was 24%. Although 74% of patients had acute GVHD, only 10% had grade III or IV GVHD. Extensive chronic GVHD developed in 49% of patients, of whom 85% required second-line therapy. Only 6 patients (10%) remain on chronic cGVHD treatment and 6 deaths were caused by GVHD. Based upon multivariate analysis, extensive chronic GVHD was associated with improved OS (HR 0.289, [95% CI, 0.136-0.614, p=0.001]) and PFS (HR 0.136, [95% CI, 0.060-0.305, p=0.001]). A mismatched donor was associated with worse OS (HR 2.347, [95% CI, 1.078-5.109, p=0.03]) and the use of a female donor resulted in worse PFS (HR 2.738, [95% CI, 1.290-5.811, p=0.009]).Conclusions:This study illustrates that myeloablative alloSCT in high-risk CLL patients is both feasible and relatively well tolerated, resulting in excellent survival outcomes with comparable NRM to popular reduced intensity regimens. The positive impact of cGVHD confirms a graft versus leukemia effect with this MA regimen. These favorable PFS and OS rates support the value of allogeneic transplantation in the treatment of CLL. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Chronic Lymphocytic Leukemia with Bi-Nucleated Lymphocytes

Introduction: B-cell chronic lymphocytic leukemia is one of the common lymphoproliferative disorders in the adult patient population. It is very uncommon to find bi-nucleated lymphocytes as a morphological feature in this disorder. Our patient was diagnosed with CLL and was found to have bi-nucleated lymphocytes in the peripheral smear. The mechanism behind this type of morphological feature of lymphocytes is unknown in CLL, and whether it has prognostic value on disease outcome is undetermined.Case Description: 62 y/o man was referred to hematology oncology after diagnosis of small cell lymphocytic leukemia was made s/p a right inguinal lymph node biopsy. His CBC revealed a wbc count of 14,000, Rbc count of 4,360, Absolute lymphocyte count of 11,500 and Platelet count of 125,000. The patient did not have any B-symptoms. On physical exam, a pertinent finding was palpable right axillary adenopathy. The CT of abdomen /pelvic to evaluate these findings. This revealed extensive axillary, abdominal/pelvic lymphadenopathy, hepatosplenomegaly and cardio phrenic lymphadenopathy.The patient had a biopsy of the right inguinal lymph node as well as bone marrow biopsy. Biopsy results showed small lymphocytic cells, some of which show occasional large nucleoli were consistent with small lymphocytic lymphoma/chronic lymphocytic leukemia, and morphologic characteristics of the lymphocytes showed bi-nucleated lymphocytes in peripheral blood smear (figure A). Flow cytometric analysis confirmed a lymphocytic population with lambda light chain restriction, expressing CD5, CD19, CD20, and CD23 consistent with chronic lymphocytic leukemia/small lymphocytic lymphoma. Bone marrow biopsy showed a hypercellular marrow with 75 % cellularity mainly composed of mature lymphocytes with scattered macrophages and eosinophils, Flow cytometric analysis (Clarient FI11-041053) of the bone marrow is interpreted as chronic lymphocytic leukemia/small cell lymphoma with the abnormal B cells representing 56% of the viable white cells. FISH study showed deletion of the ATM gene (11q22-23), D13S319 (13q14) and TP53 (p53) were observed in 29%, 71% and 35.5% of the cells analyzed, respectively. A subset of cells with the 13q deletion (20.5% of the total cells) showed homozygous deletion of D13S319 (13q14). ATM deletion is associated with progressive disease and poor prognosis in cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).He did not have any other previous history of malignancy or hematologic disorder.Discussion:B-cell chronic lymphocytic leukemia is one of the common lymphoproliferative disorders in the adult patient population. To make a diagnosis requires absolute lymphocyte count >4x10 9 and lymphoid cell morphology. In CLL, leukemic cells are small and mature appearing lymphocytes, which have regular nuclear and cytoplasmic outlines and scant weakly basophilic cytoplasm. Surface markers that define a CLL cell are proteins such as antibody light chains (kappa or lambda) and CD proteins (CD5, CD19, CD20, and CD23). In our patient absolute lymphocyte count was 11.5x109 and lymphocytic population showed surface marker lambda light chain and CD proteins CD5, CD19, CD20 and CD23 which was consistent with CLL/SLL on inguinal lymph node biopsy, but morphology of lymphocytes was small and mature bi-nucleated lymphocytes, which is very uncommon. Although bi-nucleated lymphocytes are described in a disorder "Polyclonal chronic B-cell lymphocytosis with bi-nucleated lymphocytes". Detection of an extra chromosome for the long arm of chromosome 3 +i(3)(q10) has been considered a specific marker of Polyclonal B-cell lymphocytosis with binucleated lymphocytes (PPBL),which was not present in our case. One case study by Amouroux et al, included four patients with B-cell CLL who were found to have bi-nucleated lymphocytes. Disease course was stable in one patient, one patient had an indolent course and only one required treatment due to rapid doubling time of lymphocytes. Our patient initiated chemotherapy with Rituxan and Fludara, as he had progressive disease with hepatosplenomegaly, lymph nodes and bone marrow involvement.Conclusion:Bi -nucleated lymphocytes in B-cell CLL are very rare. Explanations as to the etiology of this morphological feature in B-cell CLL is unknown. There is no sufficient evidence that bi-nucleated lymphocytes in CLL has any impact on disease progression. DisclosuresNo relevant conflicts of interest to declare.

Novel Therapies for Chronic Lymphocytic Leukemia: A Canadian Perspective.

Chronic lymphocytic leukemia (CLL) is the most common adult lymphoproliferative disorder in Western countries. The current standard of care for CLL is chemoimmunotherapy, typically with fludarabine, cyclophosphamide, and rituximab (FCR). However, most patients with CLL are elderly with comorbidities and are unable to tolerate FCR. In order to choose the best treatment for each individual patient, physicians must balance efficacy with toxicity. In addition, most currently available treatments are ineffective in CLL patients with loss of TP53. Two groups of novel therapeutic agents-anti-CD20 monoclonal antibodies and small molecule inhibitors-are attempting to address these issues, and 5 of these agents have progressed to phase 3 trials: obinutuzumab, idelalisib, ibrutinib, venetoclax (ABT-199), and duvelisib (IPI-145). We present the current evidence for these novel agents in the treatment of CLL, along with the perspectives of 4 Canadian oncology experts.

Obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia: overview and perspective.

Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the Western world and predominantly affects older people. Until recently, most studies in CLL focused on younger patients in whom intensive therapy with the addition of rituximab to fludarabine and cyclophosphamide was shown to improve survival. Obinutuzumab is a novel type II anti-CD20 monoclonal antibody (mAb) that recently demonstrated an overall survival advantage when combined with chemotherapy in previously untreated older patients with CLL and comorbidities. Obinutuzumab was superior to rituximab in this same study in terms of response rates and progression-free survival. Several preclinical and early phase clinical studies also support the efficacy of obinutuzumab. The most frequent adverse event noted with obinutuzumab is infusion-related reactions, which occur more frequently than with rituximab and are typically restricted to the first cycle of therapy. Based on these results, obinutuzumab should be considered the gold standard mAb for combination with chemotherapy in previously untreated patients with CLL and comorbidities. The marked efficacy of obinutuzumab with a weak chemotherapy backbone implies significant potency of this mAb, making it the ideal partner for combination studies with other agents in CLL.

Heterozygous Alterations ofTNFRSF13B/TACIin Tonsillar Hypertrophy and Sarcoidosis

TNFRSF13B/TACI defects have been associated with CVID pathogenesis and/or phenotype, especially the development of benign lymphoproliferation and autoimmunity. Our purpose was to investigate the role of TNFRSF13B/TACI defects in the pathogenesis of two common lymphoproliferative disorders, namely, sarcoidosis and tonsillar hypertrophy (TH). 105 patients (71 with sarcoidosis and 34 with TH, including 19 without infectious causative and 15 due to Haemophilus influenzae) were analyzed for TNFRSF13B/TACI defects. Two out of 19 TH patients without infectious cause (10.5%) and 2 patients with sarcoidosis (2.8%) displayed rare TNFRSF13B/TACI defects (I87N, L69TfsX12, E36L, and R202H, resp.). Both mutations identified in TH patients have been assessed as deleterious for protein function, while the patient with the R202H mutation and sarcoidosis exhibited also sIgG4D. Our study further supports the notion that TNFRSF13B/TACI defects alone do not result in CVID but may be also found frequently in distinct clinical phenotypes, including benign lymphoproliferation and IgG subclass deficiencies.

Assessment of 285 cases of chronic lymphocytic leukemia seen at single large tertiary center in Northern India

Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the West accounting for about 30% of leukemias, but about 2–4% in India. There is no large series reported from India, and hence we decided to undertake this study. We assessed the clinicohematological profiles and treatment outcomes in 285 patients seen over 11 years at our center (median age 59 years, 209 males). Sixty-three patients (22%) were asymptomatic and diagnosed incidentally. The median total leukocyte count at presentation was 50 × 109/L. Rai stage distribution was: stage 0, 10%; stage I, 16%; stage II, 33%; stage III, 20%; and stage IV, 21%. Fifty percent of patients required treatment at presentation. Ninety-six patients received chlorambucil-based (overall response rate [ORR] 69%, complete remission [CR] 3%) and 27 patients received fludarabine-based (ORR 89%, CR 44%) chemotherapy. With a median follow-up of 2.9 years, the median overall survival (OS) and event-free survival (EFS) were 5.1 and 4.6 years, respectively. Fludarabine was more toxic, as half of the patients developed febrile neutropenia and various infections. The majority of patients presented with advanced stage disease. Fludarabine was less commonly used as first-line therapy. Advanced clinical stage (Rai III and IV) was associated with poor OS (hazard ratio [HR] 2.46, 95% confidence interval [CI] 1.19–5.11, p = 0.001) and EFS.

Two smalls in one: Coincident small cell carcinoma and small lymphocytic lymphoma in a lymph node diagnosed by fine-needle aspiration biopsy

Background:B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) is one of the most common lymphoproliferative disorders in western countries. Patients with SLL / CLL are at increased risk of site-specific secondary cancers. We present a unique case of a 71-year-old male, with a history of SLL / CLL, who presented with pulmonary symptoms and a mediastinal mass. Fine needle aspiration (FNA) of the mediastinal lymph node revealed synchronous SLL / CLL and small cell carcinoma (SCC).Materials and Methods:The patient underwent a computed tomography (CT) scan of the chest and endobronchial ultrasound-guided transbronchial fine needle aspiration of the mediastinal lymph node (4R). The sample was submitted for cytopathology, immunohistochemical stains, and flow cytometry evaluation.Results:Fine needle aspiration of the mediastinal lymph node revealed neoplastic cells, in clusters and singly, with cytological features suggestive of small cell carcinoma. The immunohistochemistry results confirmed this diagnosis. Small-to-medium, mature-appearing lymphocytes were also present in the background. Flow cytometry analysis revealed that these lymphocytes possessed an immunophenotype consistent with CLL / SLL.Conclusions:This case illustrates the importance of a pathologist's awareness of the possibility of concurrent lymphoma and metastatic carcinoma in a lymph node. When evaluating lymph nodes, pathologists must strive to identify both foreign cells and subtle lymphoid changes. As demonstrated by our case, ancillary techniques (such as immunohistochemistry and flow cytometry) can be critical to making a complete and accurate diagnosis. The diagnosis of small cell carcinoma in the enlarged lymph node, primarily harboring CLL / SLL, is of critical importance for decision-making and treatment purposes, in addition to having a significant adverse impact on the overall survival.

Unanswered Questions in HIV Hematology

Hematological abnormalities are common manifestations of HIV infection that are regularly encountered in the clinical setting. Although initially recognized with the first descriptions of HIV infection over 30 years ago, our understanding of the epidemiology, natural history, and treatment of these blood disorders continues to evolve. Aggressive lymphomas such as diffuse large B-cell lymphoma and primary CNS lymphoma have decreased since the introduction of combination antiretroviral therapy (cART), though these and other HIV-associated malignancies continue to a have a major impact on the morbidity and mortality of persons with HIV. Other blood disorders frequently associated with HIV include cytopenias, particularly anemia and thrombocytopenia. In this special issue, studies investigating hematologic diseases associated with HIV infection are discussed. The diagnosis, treatment, and prognosis of Hodgkin lymphoma (HL) in the era of cART are reviewed by Jacobson and Abramson. Unlike non-Hodgkin lymphomas (NHL), the incidence of HL in HIV-infected patients has not decreased in the cART era. However, the introduction of cART has allowed the delivery of full doses of chemotherapy with significantly improved outcomes. Despite these advances, patients with HIV-associated HL remain at risk of treatment-related toxicity, and interactions between antiretroviral and chemotherapeutic agents necessitate careful attention to supportive care. Two papers focus on HIV-associated Burkitt lymphoma (BL). Though the outcome of HIV-NHL has improved substantially in the cART era, the outcome of HIV-BL with standard chemotherapy remains poor. J. A. Rodrigo et al. describe the combined experience in four Canadian centers treating patients with HIV-BL with the CODOX-M/IVAC regimen with or without rituximab in the modern era. In this study, intensive chemotherapy with CODOX-M/IVAC ± R yielded acceptable toxicity and favorable survival rates. A. M. Petrich et al. review the larger picture in the treatment of HIV-BL in the paper entitled “paradigms and controversies in the treatment of HIV-related Burkitt lymphoma.” In this paper, available data on the treatment of patients with HIV-BL with current BL-directed chemotherapy regimens are discussed in detail, including Hyper-CVAD, dose-adjusted EPOCH, the PETHEMA regimen, and CODOX-M/IVAC. Areas of uncertainty in the treatment of these patients include the addition of rituximab to chemotherapy regimens, the optimal approach to patients with relapsed or refractory BL and the role of stem cell transplantation, the appropriate approach to older patients and patients with central nervous system involvement, and the role of antiretroviral therapy and supportive care. An intriguing and pressing challenge in the management of patients with both malignant and nonmalignant hematologic disorders in HIV infection is the optimal approach to be taken in the developing world. This topic is addressed by M. Ulrickson et al. in the paper “Epidemiology, diagnosis, and treatment of HIV-associated NHL in resource-limited settings.” The epidemiology of NHL in Africa is compared to that of the US, and discrepancies in survival highlighted by cancer registries are discussed. Challenges in managing patients with NHL in resource-limited settings include diagnostic challenges due to limited access to a full battery of immunohistochemical tests and limited molecular testing. Treatment challenges include limited access to antiretroviral regimens, prophylactic agents, IV infusion centers, and a higher incidence of major infectious complications including tuberculosis and hepatitis B. Response assessments are further limited by a lack of ready access to cross-sectional imaging in some regions. Despite these challenges, progress has been made in developing tolerable and effective treatment regimens appropriate to these circumstances, and these important advances are reviewed. A common nonmalignant complication of HIV infection is immune thrombocytopenia (ITP). The characteristics of HIV-associated ITP were documented prior to the cART era, and the optimal treatment beyond cART is unknown. For this reason, K. L. S. Ambler et al. present a retrospective cohort study reviewing individuals with severe HIV-associated ITP diagnosed in the cART era. Their series is the largest such report of severe HIV-ITP in the post-cART era. The major finding from this study was that, although the various treatments were well tolerated and most patients achieved a safe platelet count, nearly all patients (87%) required retreatment for recurrence of severe ITP. This highlights that new approaches to the treatment of ITP in this population are needed. The intent of this special issue was to initiate interest in and further inquiry into the many hematologic complications faced by persons living with HIV. In addition to the topics discussed in this issue, areas for future exploration include the approach to management of patients with less common lymphoproliferative disorders such as indolent NHL, paraproteinemias, and Castleman disease, as well as non-malignant causes of cytopenias and their management. Heather A. Leitch Jeremy S. Abramson Matthew C. Cheung Lisa K. Hicks