Chemotherapy For Chronic Lymphocytic Leukemia Research Articles

Not All Lymphocytosis Is Chronic Lymphocytic Leukemia (CLL): A Retrospective Review of Patients Referred to an Academic Hematology Oncology Center for CLL

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults, especially in elderly patients. Most patients with CLL are asymptomatic at presentation and have routine blood work that prompts further investigation. In patients with CLL, their complete blood cell count with differential typically demonstrates lymphocytosis due to the increased number of malignant B-lymphocytes. Although lymphocytosis can be suggestive of CLL, diagnostic workup can sometimes reveal an alternative diagnosis. Here we describe a retrospective review of 36 patients referred to our hematology oncology clinic for the suspected diagnosis of CLL. Out of the 36 patients referred for CLL, 8 patients (22%) had diagnostic workup confirming an alternative diagnosis including non-Hodgkin lymphoma (NHL) (5 patients), hairy cell leukemia (1 patient), and monoclonal B-cell lymphocytosis (2 patients). Only 28/36 (78%) of total patients had flow cytometry confirming the diagnosis of CLL. Out of the 36 total patients, 34 patients had lab work revealing lymphocytosis (absolute lymphocyte count greater or equal to 5.0 10 3/mL) prompting referral. At presentation, total patients (34/36) with lymphocytosis had an absolute lymphocyte count range of 5-593.0 (10 3/mL), median of 17.6 (10 3/mL), and average of 50.8 (10 3/mL). 27/34 (79%) of patients with lymphocytosis were diagnosed with CLL, while 7/34 (21%) of patients with lymphocytosis initially suggestive of CLL were diagnosed with alternative diagnoses (follicular lymphoma (1), marginal zone lymphoma (2), mantle lymphoma (1), hairy cell leukemia (1), and monoclonal B-cell lymphocytosis (2)). The patients with lymphocytosis not diagnosed with CLL (7/34 patients) had an absolute lymphocyte count range of 5-105.6 (10 3/mL), median of 18.27 (10 3/mL), and average of 45.2 (10 3/mL). Their average age at presentation was 63 years old (range of 53-80). Most common symptoms at presentation were asymptomatic (3), B-symptoms plus lymphadenopathy (2), lymphadenopathy (1), and gastrointestinal symptoms (1). The asymptomatic patients were monoclonal B-cell lymphocytosis (2) and mantle lymphoma (1). Hairy cell leukemia, marginal zone lymphoma, and follicular lymphoma had significantly elevated absolute lymphocyte count (86.8, 105.6, 89.45 (10 3/mL) respectively) and associated anemia. Only one patient referred for CLL was diagnosed with follicular lymphoma had anemia and thrombocytopenia without lymphocytosis. The patients with lymphocytosis confirmed to have CLL (27/34 patients) had an absolute lymphocyte count range of 5-593 (10 3/mL), median of 17.6 (10 3/mL), and average of 50.8 (10 3/mL). Their average age at presentation was 70 years old (range 54-93). Most common symptoms at presentation were asymptomatic (16), B-symptoms plus lymphadenopathy (5), lymphadenopathy only (2), B-symptoms only (2), and neck/back pain (2). 59% of patients were asymptomatic with abnormal lab work including lymphocytosis only (14), anemia (1), and abnormal M-spike on serum protein electrophoresis (1). We wish to emphasize the role of flow cytometry and its value in confirming diagnosis of CLL. Even if clinical suspicion for CLL is high, it is important to not solely rely on complete blood cell count and peripheral lymphocyte count. NHL, hairy cell leukemia, and monoclonal B-cell lymphocytosis can have similar lab work and initial presenting symptoms to patients with CLL. A few patients in this review were receiving chemotherapy for CLL initially and were later found to have a different diagnosis. It is important to keep clinical suspicion high for alternative diagnoses for lymphocytosis to guide appropriate management.

368: ANGIOEDEMA PREVENTING EXTUBATION IN A CASE OF ACQUIRED C-1 ESTERASE DEFICIENCY

Introduction: Acquired C1 esterase deficiency is a rare, life-threatening phenomenon that has been reported in association with lymphoproliferative and autoimmune disorders. Diagnosis is made based on the clinical presentation of angioedema and low C1 and C1q esterase inhibitor activity in a patient without a previous hereditary diagnosis. Treatment is aimed at addressing the underlying condition and plasma-derived C1 esterase inhibitor (C1-INH) concentrate, but clinical response can vary. Description: 75 year-old female with a past medical history of chronic lymphocytic leukemia (CLL) presented with spontaneous mouth and neck swelling unrelieved by antihistamines. Epinephrine and Solumedrol were administered, however the neck swelling worsened and the patient was intubated for airway protection. CT imaging of the neck revealed extensive subcutaneous neck edema. Attempts at extubation were limited by the patient’s persistent angioedema which was visualized by bronchoscopy. Glucocorticoids were ineffective as the patient had a reported allergy to Prednisone, therefore were further avoided. C1 esterase inhibitor (C1-INH) function was initially low at 7mg/dL, and repeat remained low at 10mg/dL with a C4 of .7mg/dL. C1q later returned low at < 1.2Eq/mL. The patient did not improve after treatment with plasma-derived C1-INH (Berinert). She eventually required tracheostomy placement, but had difficulty with subsequent downsizing due to persistent laryngeal edema with limited therapeutic options. Eventually, after 4 weeks, the patient was successfully decannulated. Discussion: There are no definitive guidelines for treatment of acquired C1 esterase deficiency, however therapies often follow the same course for hereditary forms including plasma-derived C1-INH. Often, these patients may not respond or require increased doses. If Berinert is ineffective, some immunologists and allergists have seen favorable outcomes and recommend treatment with the kallikrein inhibitor, ecallantide and the bradykinin B2 antagonist icatibant. To date, therapies targeted at prevention of angioedema in acquired cases have not been as successful as in hereditary forms, therefore, treatment is directed at the underlying condition, such as immunotherapy or chemotherapy for CLL.

Validation of a Mathematical Model Describing the Dynamics of Chemotherapy for Chronic Lymphocytic Leukemia In Vivo.

In recent years, mathematical models have developed into an important tool for cancer research, combining quantitative analysis and natural processes. We have focused on Chronic Lymphocytic Leukemia (CLL), since it is one of the most common adult leukemias, which remains incurable. As the first step toward the mathematical prediction of in vivo drug efficacy, we first found that logistic growth best described the proliferation of fluorescently labeled murine A20 leukemic cells injected in immunocompetent Balb/c mice. Then, we tested the cytotoxic efficacy of Ibrutinib (Ibr) and Cytarabine (Cyt) in A20-bearing mice. The results afforded calculation of the killing rate of the A20 cells as a function of therapy. The experimental data were compared with the simulation model to validate the latter’s applicability. On the basis of these results, we developed a new ordinary differential equations (ODEs) model and provided its sensitivity and stability analysis. There was excellent accordance between numerical simulations of the model and results from in vivo experiments. We found that simulations of our model could predict that the combination of Cyt and Ibr would lead to approximately 95% killing of A20 cells. In its current format, the model can be used as a tool for mathematical prediction of in vivo drug efficacy, and could form the basis of software for prediction of personalized chemotherapy.

Beware clonal haematopoiesis following chronic lymphocytic leukaemia treatment

Clonal myeloid haematopoiesis co-existing with chronic lymphocytic leukaemia (CLL) is not rare and is associated with high risks for development of therapy-related myeloid neoplasms (t-MNs) after cytotoxic chemotherapy. This has serious implications for the use of these therapies in newly diagnosed CLL patients. Therapy-related myeloid neoplasms are devastating conditions. Their development following cytotoxic chemotherapy for various neoplasms often ultimately leads to treatment-refractory acute myeloid leukaemia and is usually lethal for afflicted patients. These neoplasms often develop following exposure to alkylating agents or anthracyclines,1 but they have been reported following single-agent fludarabine.2 T-MNs typically present after prior cytotoxic therapy given in an adjuvant context or for relatively indolent neoplasms, and thus their development is particularly distressing for many otherwise cancer-free or cancer-controlled patients. Effective long-term control of t-MNs is difficult to achieve, and at present always requires allogeneic haematopoietic transplant. The paper by Voso et al.3 regarding clonal haematopoiesis of indeterminant potential (CHIP) as a risk factor for t-MNs following chemotherapy for CLL is thus timely and worthy of attention from all physicians who manage CLL. CHIP has (unsurprisingly) been associated with increased risks of t-MN. The current report is, however, the first reported study of t-MN following therapy for CLL. It is worth noting that this experience is based upon 15 patients who were selected only for the availability of pretreatment genomic material. Amongst the relevant 13 patients whose t-MN followed the use of cytotoxic therapy, a prior mutation consistent with myeloid CHIP was present in 10, or 77%. Mutations compatible with CHIP were found in 34 of 285 cases of CLL not developing t-MN. The authors thus appropriately conclude that CHIP seems to be a significant risk factor for the development of t-MN following cytotoxic therapy for CLL. This work presents a detailed description of the mutations found in prechemotherapy haematopoietic material. The authors are conservative in terms of attributing these mutations to the CLL or the myeloid elements found in the available pretreatment cells. They correctly observe that mutations of TP53 and SF3B1 could in principle arise either from clonal CLL cells or from a myeloid CHIP clone, and thus cannot be firmly identified as having driven the development of the t-MN. Data found in their table S4, however, show that in two patients (#6 and #8), mutations in TP53 (two cases) and in SF3B1 (one case), were identical in pretreatment samples of CLL containing cells and in the t-MN material. The same mutated sequences were found in these two paired samples in both cases and for both genes. Thus, although we cannot be completely certain, it seems very likely that in fact the pretreatment mutation was found in myeloid cells that were subsequently transformed in response to the exposure to cytotoxic agents, leading to the t-MN. These findings have important implications for the management of CLL and other neoplasms. First, CHIP is reasonably common in patients who are candidates to receive cytotoxic agents. Pre-existing CHIP clearly poses very significant risks for the development of t-MN and most of these secondary neoplasms will prove to be lethal for affected patients. Thus, particularly in older patients with higher risks of CHIP, it seems reasonable to consider screening patients for myeloid clonal states prior to offering cytotoxic therapy for management. Notably, there are now alternative systemic therapies available for CLL (and many other neoplasms) which do not involve cytotoxic therapy and thus should not pose the same risk of potential secondary neoplasm. Another and potentially provocative conclusion is that mutations of TP53 or SF3B1 found in pretreatment blood or other tissues from CLL patients may not necessarily represent changes in the CLL clone but may be situated in associated myeloid cells. This issue in it itself may affect decisions concerning CLL management, as TP53 mutations are associated with poor prognosis and as this finding in a CLL patient may potentially increase the desire for aggressive therapy. Finally, in such patients the use of cytotoxic chemotherapy in disease management might have disastrous downstream consequences, leading to a lethal t-MN. The development of effective systemic targeted therapies for CLL not employing cytotoxic or mutagenic agents has revolutionized the therapy of CLL. The application of these agents has already greatly reduced the use of potentially leukaemogenic therapies. Recently, however, it has been asserted that “In fit patients with immunoglobulin heavy chain mutation, it is still acceptable to use the chemotherapy regimen with fludarabine, cyclophosphamide, and rituximab (FCR) and, in those who [are] not fit or are not IgVH-mutated, bendamustine-rituximab regimen”.4 Given the availability of effective non-cytotoxic agents for management of essentially all CLL patients, haematologists and oncologists managing this group of highly treatable but fragile patients should take pause, and note the findings described by Voso et al.

Immunoglobulin substitution in patients with secondary antibody deficiency in chronic lymphocytic leukemia and multiple myeloma: a representative analysis of guideline adherence and infections

IntroductionIn secondary immunodeficiency, immunoglobulin replacement therapy (IgRT) is recommended by guidelines (GL) for patients with IgG level < 4 g/l and more than 3 infections or a severe infection. IgRT may be appropriate if IgG level < 4 g/l and/or 1–3 less severe infections (≤ grade 2).MethodsThis was a retrospective sample analysis representative for practices and hospitals in Germany. The treatments and infection data were collected from patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). GL adherence (GLAD) was analyzed.ResultsData from 1086 patients (CLL 490, MM 596) were collected from 86 centers. Of all patients, 34.8% developed IgG deficiency during therapy (CLL 35.5%; MM 34.2%). IgRT was given in 23.5% of CLL and 14.4% of MM patients. GLAD in hypogammaglobulinemia and indication to IgRT was 23.3% of 86 CLL and 22.1% of 77 MM patients. Without GLAD, the hazard ratio (HR) for any infection was 4.49 (95% CI 3.72–5.42; p < 0.001) and for severe infections (grade ≥ 3) 10.64 (95% CI 7.54–15.00; p < 0.001). Significant independent risk factors for infections were a higher Charlson Comorbidity Index, IgG deficiency, and 3rd + line treatment, as well as therapy with BTK inhibitors or chemotherapy in CLL. Multivariable analysis showed a significantly lower risk of severe infections after start of IgRT with a HR of 0.47 (95% CI 0.28–0.77; p = 0.003).ConclusionsGuideline adherence correlated with fewer and less severe infections but was low in patients with indication to IgRT. Risk factors for infection can be identified. Risk of severe infections was significantly lower in patients with IgRT.

Activity of Limited-Schedule Bendamustine and Methylprednisolone in Chronic Lymphocytic Leukemia

Bendamustine was approved by the United States Food and Drug Administration in 2008 for the treatment of Chronic Lymphocytic Leukemia (CLL). Corticosteroids have been administered in regimens with chemotherapy for CLL for more than 40 years. Despite this, the combination of Bendamustine and Methylprednisolone has not been explored in CLL. We describe our experience with Bendamustine 100 mg/m2 and Methylprednisolone 125 mg IV on days 1 and 2 and Peg-filgastrim 6 mg subcutaneously on day 3 every 28 days for 3-4 cycles in 12 patients with CLL. Cycles have been limited to attempt to prevent cumulative marrow toxicity due to Bendamustine. Patient characteristics: 7 males/5 females, median age-58, Binet stage B (8), C (2), A (2); ZAP70/CD38+ (5), Trisomy 12 (3), 13q- (2), normal cytogenetics (2); median ECOG status 1, no prior therapy in 8. Median number of cycles received = 3 (two received 4 cycles). Most common toxicities: nausea/emesis (5), fever/flu-like symptoms (4), arthralgia/myalgia (4). There have been no treatment-related deaths. One patient was briefly hospitalized for pneumonia. Complete responses have been seen in 6 patients (median duration = 50.7 months; range: 12.1+ to 87.3 months). Partial responses have been seen in 4 patients (median duration = 17.3+ months; range: 3.3 to 26.9+ months). The combination of Bendamustine and Methylprednisolone given in a limited schedule is well-tolerated and is active in CLL. DisclosuresNo relevant conflicts of interest to declare.

Invasive aspergillosis and endocarditis

IntroductionAspergillusfumigatus can cause a systemic infection called invasive aspergillosis causing pulmonary and extra-pulmonary damage. Aspergillus endocarditis (AE) is a relatively rare disease but can be life-threatening. Case reportsWe report here on five cases of endocarditis due to invasive aspergillosis: a 58-year-old man receiving immunosuppressive medication following a kidney graft, a 58-year-old man undergoing chemotherapy for chronic lymphocytic leukaemia, a 55-year-old man receiving corticosteroids for IgA vasculitis, a 52-year-old HIV-infected woman under no specific treatment and a 17-year-old boy under immunosuppressive therapy for auto-immune chronic neutropenia. DiscussionAspergillus accounts for 25–30% of fungal endocarditis and 0.25% to 8.5% of all cases of infectious endocarditis. Aspergillus endocarditis results from invasion of the lung arterioles by hyphae and blood dissemination. It is associated with a very high mortality rate (42–68%). Diagnosing Aspergillus endocarditis is mainly problematic because blood cultures are almost always negative, and fever may be absent. Immunosuppression, haematological malignancies, recent cardiothoracic surgery, negative blood cultures with endocarditis and/or systemic or pulmonary emboli are predictors of AE. In the setting of endocarditis, some clinical characteristics may raise early suspicions of aspergillosis rather than a non-fungal agent: no fever, vegetations affecting the mitral valve, non-valve or aortotomy sites, aortic abscess or pseudo-aneurysm. The identification of invasive aspergillosis is based on a chest CT scan, microscopy/culture or other serological and molecular tests. The treatment of Aspergillus endocarditis requires triazole antifungal drugs, and frequently additional surgical debridement. ConclusionAspergillus endocarditis is rare but is associated with a very high mortality rate. Knowledge of its predictive factors and key clinical features can help to differentiate aspergillosis from non-fungal endocarditis and may enable improved survival rates.

Central Nervous System Involvement is Associated with Ibrutinib-Induced Severe Hyperleukocytosis and Controlled by the Combination of Intrathecal Chemotherapy in Chronic Lymphocytic Leukemia: A Case Report

Central nervous system involvement (CNSi) is a rare complication of chronic lymphocytic leukemia (CLL) with a very poor prognosis. Its diagnosis, predictive factors, and standard treatment remain elusive. Ibrutinib, an oral inhibitor of Bruton’s tyrosine kinase, has been approved to treat CLL, yet little is known of its effect on the occurrence and management of CNSi. Here, we report, for the first time, an elderly CLL patient with secondary CNSi following ibrutinib-induced severe hyperleukocytosis, characterized by subcutaneous lesions and unmutated IgHV gene. Ibrutinib combined with intrathecal chemotherapy induced a prompt and durable remission of CNSi. This case indicates that severe hyperleukocytosis caused by ibrutinib is associated with the emergence of CNSi, and a combined treatment with intrathecal chemotherapy is effective and safe in the treatment of CLL patient with CNSi.

The Broad Spectrum of TP53 Variants in CLL: NGS Analysis of 573 Pathogenic TP53 Variants

The Broad Spectrum of TP53 Variants in CLL: NGS Analysis of 573 Pathogenic TP53 Variants

Developmental DNA Methylation Subtype Predicts Progression to Treatment and Survival in High-Count Monoclonal B Lymphocytosis

Developmental DNA Methylation Subtype Predicts Progression to Treatment and Survival in High-Count Monoclonal B Lymphocytosis

Ibrutinib and Rituximab Provides Superior Clinical Outcome Compared to FCR in Younger Patients with Chronic Lymphocytic Leukemia (CLL): Extended Follow-up from the E1912 Trial

Shanafelt: Pharmacyclics: Research Funding; Patent: Patents & Royalties: US14/292,075 on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia; Polyphenon E International: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Glaxo-SmithKline: Research Funding; Hospira: Research Funding; Cephalon: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; Acerta: Research Funding; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Verastem: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; Kite: Research Funding. Barrientos:AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding. Coutre:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Gilead: Research Funding; BeiGene: Other: Travel, Accommodations, Expenses & Data Safety Monitoring Committee; Genentech: Consultancy. Barr:Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; Gilead: Consultancy; Verastem: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Celgene: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Astra Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Cashen:Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy. Erba:Amgen: Consultancy; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; Astellas Pharma: Consultancy; Astellas Pharma: Consultancy; Amgen: Consultancy; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Pfizer: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding. Stone:Arog Pharmaceuticals: Consultancy, Honoraria, Research Funding; Otsuka-Astex Pharmaceuticals: Consultancy; Fujifilm: Consultancy; AstraZeneca: Consultancy; Celator Pharmaceuticals: Consultancy; Abbvie: Consultancy, Research Funding; Ono Pharmaceutical-Theradex Oncology: Consultancy; Cornerstone Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Other: Fees for serving on a data and safety monitoring board ; Orsenix: Consultancy; MacroGenics: Consultancy; Jazz Pharmaceuticals: Consultancy; Agios: Consultancy, Research Funding; Stemline Therapeutics: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Fees for serving on a steering committee, and fees for serving on a data and safety monitoring board; Novartis: Consultancy, Research Funding; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees; Argenx: Other: Fees for serving on a data and safety monitoring board ; Roche: Consultancy. Tallman:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Obinutuzumab plus fludarabine and cyclophosphamide in previously untreated, fit patients with chronic lymphocytic leukemia: a subgroup analysis of the GREEN study

GREEN (NCT01905943) is a nonrandomized, open-label, single-arm, phase 3b study investigating the safety and efficacy of obinutuzumab alone or in combination with chemotherapy in chronic lymphocytic leukemia (CLL). We report the preplanned subgroup analysis of 140 previously untreated, fit CLL patients who received obinutuzumab plus fludarabine and cyclophosphamide (G-FC). The primary endpoint was safety and tolerability. Efficacy was the secondary endpoint. Obinutuzumab 1000 mg was administered intravenously on Day (D)1 (dose split D1‒2), D8 and D15 of Cycle (C)1, and D1 of C2–6 (28-day cycles). Standard intravenous/oral doses of fludarabine and cyclophosphamide were administered on D1–3 of C1–6. Overall, 87.1% of patients experienced grade ≥ 3 adverse events (AEs), including neutropenia (67.1%) and thrombocytopenia (17.1%). Serious AEs were experienced by 42.1% of patients. Rates of grade ≥ 3 infusion-related reactions and infections were 19.3% and 15.7%, respectively. Overall response rate was observed in 90.0%, with 46.4% of patients achieving complete response (CR; including CR with incomplete marrow recovery). Minimal residual disease negativity rates were 64.3% in peripheral blood and 35.7% in bone marrow (intent-to-treat analysis). After a median observation time of 25.6 months, 2 year progression-free survival was 91%. Frontline G-FC represents a promising treatment option for fit patients with CLL.

Refining chemotherapy for chronic lymphocytic leukaemia with targeted drugs

The triple combination regimen of fludarabine, cyclophosphamide, and rituximab (FCR) has been a cornerstone of frontline treatment of young fit patients with chronic lymphocytic leukaemia.1 It produces long-term remissions, including complete remissions with undetectable minimal residual disease.2,3 However, this treatment also leads to high-grade toxicity, including longlasting neutropenia with the risk of late-onset infection and secondary malignancies. Furthermore, patients with unmutated IGHV have only limited benefit from this aggressive treatment, which results in only a few years of progression-free survival in this subgroup.

PB1876 GENETIC MARKERS OF THE PRIMARY AND SECOND TUMORS RISK DEVELOPMENT IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA

Background:Malignant tumors in patients with chronic lymphocytic leukemia (CLL) occur with equal frequency in both previously untreated patients and those receiving high‐dose therapy. This is due not only to the presence of CLL‐associated, but with drug‐induced immunodeficiency, and, probably, with modifications in the immune response genes.Aims:Identify the relationship of the several immune response genes mutational status with the development of primary and second tumors in patients with CLL.Methods:Surveyed 202 patients in the beginning of CLL at the age of 32 to 87 years (median‐63 years), 112 men (55.4%), 90 women (44.6%). Genotyping of 20 polymorphic regions of the 14 immune response genes (TLR2, TLR3, TLR4, TLR6, TLR9, IL1β, IL2, IL4, IL6, IL10, IL17A, CD14, TNFα, FCGR2A) in genomic DNA obtained from peripheral blood leukocytes was carried out by the PCR‐ASP. Intergenic interactions analysis was performed using the MDR program version 3.0.2, http://www.mybiosoftware.com/mdr‐2‐0‐multifactor‐dimensionality‐reduction.html.Results:Patients were divided into 3 groups. The first group consisted of 6 patients who had other malignancies before onset CLL. The appearance of CLL was preceded in 2 cases by the breast cancer and one: cancer of the testicle, ovary, skin and fungal mycosis from 36 to 252 months (median‐135.5 months). The second ‐ consisted of 190 CLL patients with no previous or second malignant tumors history. The third included 6 patients, who developed the second solid tumors in CLL remission after FCR treatment. Within 13‐94 months (median‐53.5 months) from the onset of CLL, they had skin cancer in 2 cases, colon cancer in 2 patients, melanoma and breast cancer in one case. In all selected groups, age and gender differences were not found. All possible combinations of the key immune response genes polymorphic variants were analyzed. It was found that the first group of patients is characterized by 2 statistically significant models: single‐ FCGR2A (A519C) (p = 0.0001) and two‐locus TLR4 (G896A)/FCGR2A (A519C) (p &lt; 0.0001). Patients who had a second tumors after onset CLL also distinguished two models: single‐locus with the participation of the IL17A gene (G197A), p = 0.00006 and three‐locus model TLR6 (C745T)/TLR9 (A2848G)/IL1β (T511C) (p &lt; 0.0001). It is very likely that the triggering factor for the second malignant tumors occurrence in these patients was high‐dose chemotherapy of CLL, which aggravated the existing CLL‐mediated immunodeficiency. As a result of the intergenic interactions evaluation, it was noted that in patients with a previous CLL cancer history, the risk factors for the development of primary tumors were 3 combined genotypes: FCGR2A‐519AA/TLR4‐896GG; FCGR2A‐519AA/TLR9‐2848AA/TLR4‐896GG; FCGR2A‐519AA/TLR9‐2848AG/TLR4‐896AG. For patients with CLL and second tumors detected in remission of leukemia, the most prognostically important were the combinations of genotypes: IL1β‐511CC/TLR9‐2848AA/TLR6‐745TT; IL1β‐511CC/TLR9‐2848AG/TLR6‐745TT; IL1β‐511TT/TLR9‐2848AG/TLR6‐745TT.Summary/Conclusion:Studies have confirmed the involvement of immune mechanisms in the carcinogenesis. Analysis of the polymorphic status genes FCGR2A, TLR6, TLR9 (A2848G), IL1β (T511C), IL17A, which are involved in the development and progression of various human tumors, will allow to select among patients with CLL a group with an increased risk of the development of previous and second malignant neoplasms.

Is it a Drug or a Bug? A Case of Chemotherapy and Immune Modulators Complicating the Diagnosis of Ehrlichiosis

Ehrlichiosis is caused primarily by Ehrlichia chaffeensis and Ehrlichia ewingii.1,2 These obligate intracellular gram-negative cocco-bacilli are transmitted by arthropod vectors. They reside in vertebrate reservoirs and undergo a tick-mammal-tick cycle during which humans are dead-end hosts. The life cycle of E. chaffeensis is perpetuated predominantly via the A. americanum (Lone star) tick.1,2 During human infection, E. chaffeensis preferentially targets monocytes. Men are affected more often than women. Individuals between the ages of 65 and 69 had the highest incidence rate (IR) between 2008 and 2012.1,3 During this period, Oklahoma and Missouri had the highest IR at 30.9 and 26.3 per million, respectively.3 Patients with hematologic malignancies undergoing chemotherapy can have similar symptoms to those found in ehrlichiosis without being infected. However, in the appropriate setting, tick-borne illness should be considered. We present a case of severe illness and prolonged fevers due to ehrlichiosis in a patient who received chemotherapy for chronic lymphocytic leukemia (CLL).

CYP2B6 polymorphism and lipoprotein lipase expression in chronic lymphocytic leukemia: impact on the outcome of fludarabine–cyclophosphamide regimen

Background Chronic lymphocytic leukemia (CLL) is the most common type of leukemia and has a highly variable clinical course. Cyclophosphamide (CPA)-containing regimens are the standard of care for patients lacking the 17p deletion. CYP2B6 is a polymorphic cytochrome P450 isoform that converts CPA to its active form. Lipoprotein lipase (LPL) catalyzes the hydrolysis of triacylglycerol. Remarkably, a growing body of data emphasizes its role in the biology of different tumors. Objectives This study aimed to study CYP2B6 polymorphism and LPL expression in fludarabine cyclophosphamide (FC)-treated CLL patients lacking 17p deletion. Methods 46 treatment-naive CLL patients negative for 17p deletion and indicated to receive chemotherapy were enrolled. CYP2B6 genotyping and lipoprotein lipase mRNA expression were assayed by Realtime PCR. FC-protocol was given then treatment-related toxicities, response, and event free survival were traced. Results CYP2B6*6 allele was associated with lower rates of treatment-related anemia and hospital admission. The response to FC was affected only by CYP2B6 polymorphism. The event-free survival of responders was significantly higher in patients having low LPL expression. Conclusion CYP2B6*6 infers lower CPA efficacy with lower treatment-induced side effects and increased risk of nonresponding to FC chemotherapy in CLL. LPL expression is a predictor of outcome in CLL, indicating poor survival.

Novel agents in the Canadian therapeutic landscape of chronic lymphocytic leukemia

In this brief commentary, we discuss oral novel agents within in the armementarium of therapeutic options for Canadian patients with chronic lymphocytic leukemia (CLL). Previously limited to chemotherapy, the Canadian patient with relapsed or refractory CLL has the option of treatment with B-cell receptor inhibitors ibrutinib or idelalisib (combined with rituximab), both individually showing superiority to anti-CD20 monoclonal antibody comparators regardless of high-risk deletion 17p (del(17p)) status in phase 3 clinical trials. BCL2-inhibitor venetoclax shows impressive efficacy for previously-treated patients with del(17p), but though approved, it is not yet funded. For treatment-naïve patients, ibrutinib has proven superior to chemotherapy for those over 65 with comorbidities, but its role remains to be seen for the young and/or fit. Whereas oral novel agents are generally well-tolerated, some side effects, such as infection, hemorrhage, cardiac arrhythmias and tumour lysis syndrome, can be severe, therefore expert clinical vigilance is essential. Regarding sequencing of these agents, most patients failing ibrutinib or idelalisib do respond to venetoclax. While future studies using combinations of novel agents may eventually obviate the use of chemotherapy for CLL, regimens that can be stopped when minimal residual disease is achieved, such as venetoclax, are particularly relevant for our publicly-funded health care system. For Canadian CLL patients, the availability of oral novel agents has greatly expanded treatment options and is improving outcomes.

Obinutuzumab plus bendamustine in previously untreated patients with CLL: a subgroup analysis of the GREEN study

GREEN (NCT01905943) is a non-randomized, open-label phase IIIb study investigating obinutuzumab alone or plus chemotherapy in chronic lymphocytic leukemia (CLL). We report a preplanned subgroup analysis of 158 previously untreated CLL patients receiving obinutuzumab–bendamustine (G-B). Patients received six 28-day cycles (C) of G-B: obinutuzumab day (D)1/D2 of C1 (25 mg D1/975 mg D2), 1000 mg D8 and D15 of C1, and D1 of C2–6; and bendamustine 70/90 mg/m2 D1 and D2 of C1–6. The primary endpoint was safety/tolerability. Grade ≥3 adverse events (AEs) occurred in 82.3% of patients, including neutropenia (49.4%), thrombocytopenia (12.0%) and febrile neutropenia (10.8%). Serious AEs included neutropenia (12.7%), febrile neutropenia (9.5%) and pneumonia (7.6%). Rates of grade ≥3 infections and infusion-related reactions were 20.3% and 17.1%, respectively. Due to tumor lysis syndrome (TLS; 8.2%), including two associated fatalities (one in another study cohort), additional risk-minimization measures were implemented. Overall response rate was 81.0%. After 32.8 months’ median observation time, 2-year progression-free survival was 81.8%. Minimal residual disease was undetectable in 59.5% (94/158) and 27.8% (44/158) of patients for blood and bone marrow, respectively. Frontline G-B appears to have manageable toxicity with clinical activity in CLL. Careful TLS risk assessment, pretreatment and monitoring is required.

Chromosomal abnormalities in bone marrow cells in relapse of chronic lymphocytic leukemia

The genetic mechanism of resistance to chemotherapy in chronic lymphocytic leukemia (CLL) is yet to be established. We aimed to determine molecular cytogenetic irregularities in chromosomes of bone marrow cells (BM) in relapse of CLL. For this, a study was carried out with 63 patients including 25 women and 38 men, aged from 36 to 73 years (average age was 57 years). Cytogenetic data showed that karyotypes, according to the clone structure, were represented into 10 groups: normal; normal/near tetraploid; abnormal/normal; abnormal/near tetraploid/normal; clonal evolution; clonal evolution/normal; clonal evolution/near tetraploid/normal; independent clones; independent/normal; independent/near tetraploid/normal clones. Various structural rearrangements were detected in chromosomes such as translocations, deletions, insertions and duplications. However, deletions in chromosomes were found to be dominant in 63.8% cases involving the band positions of especially 17p12, 13q12–q14, 11q14 and 11q23. The complexity was shown by the presence of one to four abnormalities in one karyotype using i-FISH methodology. Conventional cytogenetic and molecular cytogenetic analyses may indicate that chromosome rearrangements are multilevel process in formation of resistant karyotypes either through the loss of (1) tumour suppressor genes in the areas with bands 13q14, 13q34 and 17p13.1 (2) and/or the loss of regulation of ATM gene expression in the band position 11q22.3. The results obtained using both methods have demonstrated the presence of a heterogeneous cell population with a diverse degree of resistance to chemotherapy in CLL.

Adenovirus Hepatitis

Adenoviruses are common pathogens that usually cause self-limited infections. However, in the immunocompromised host they can cause severe infections involving multiple organs including the liver. A search of the pathology database at Stanford University Medical Center (1995 to 2016) identified 12 cases of adenovirus hepatitis including biopsy and autopsy specimens. There were 8 pediatric patients, 7 of which had received orthotropic liver transplants and 1 of which was receiving chemotherapy for lymphoblastic leukemia. There were 4 adult patients, of which 1 was actively receiving chemotherapy for chronic lymphocytic leukemia and 2 had undergone hematopoietic stem cell transplantation for hematologic malignancies. One patient had lymphoplasmacytic lymphoma and had received chemotherapy over a year prior but was not receiving therapy at the time he contracted adenovirus hepatitis. In all cases, histologic sections showed nonzonal coagulative hepatocyte necrosis and characteristic intranuclear inclusions. Hepatocyte necrosis ranged from spotty to massive. The majority of cases (7/12; 58%) had no associated inflammation. If present, inflammation was focal and lymphohistiocytic. In 1 case, findings were focal within the liver, requiring an image-guided biopsy. This patient underwent a simultaneous nontargeted liver biopsy that lacked histologic evidence of adenovirus. Among the pediatric patients, 63% (5/8) died secondary to organ failure, while there was 100% (4/4) mortality in the adult population.