B-cell Chronic Lymphocytic Leukemia in Chronic Immune Thrombocytopenic Purpura: a Case Report

A patient suffering from chronic immune thrombocytopenia developing B-cell chronic lymphocytic leukemia seventeen years later, is reported. The possible mechanisms of association between the two disorders are discussed.     

Antigen Receptor Function in Chronic Lymphocytic Leukemia B Cells

Functional studies revealed that two groups of B chronic lymphocytic leukemia (B-CLL) can be distinguished based on their capacity to mount a proliferative response following B-cell antigen receptor (BCR) cross-linking. The molecular basis for the functional distinction between these B-CLL groups most probably resides within or proximal to the BCR since non-responsive B-CLL, in marked contrast to responsive B-CLL, do not respond to BCR ligation with tyrosine phosphorylation of cellular substrates and increases in the free intracellular [Ca⁺⁺]. Detailed biochemical analysis showed overall structural identity between responsive and non-responsive B-CLL with respect to both transmembrane and intracellular associates of the BCR complex. However expression levels of the protein tyrosine kinase syk, which is a key enzyme for the early signalling through the BCR, were found to be markedly lower in non-proliferating B-CLL. Here, we will review current functional and biochemical data on responding and non-responding B-CLL and discuss the relevance of these findings for disease progression and our insight into the immunobiology of B-CLL.     

Mitoxantrone in the Treatment of Chronic Lymphocytic Leukemia

During the last few years it has been shown that intensive or continuing chemotherapy of patients with advanced chronic lymphocytic leukemia prolongs survival. In the search for new effective drugs with tolerable toxicity, mitoxantrone was evaluated in this phase 2 study. Seven of 11 previously untreated patients achieved complete or partial remission after single agent treatment with mitoxantrone, and 5 of 16 previously treated patients had the same degree of response. Only minor toxicity was observed. Therefore, it appears likely that mitoxantrone is as effective as chlorambucil, and it would seem justified to evaluate mitoxantrone in future combination chemotherapy regimens in patients with advanced chronic lymphocytic leukemia.     

Clinical Response to Busramustine (KM-2210) in Chronic Lymphocytic Leukemia: A Pilot Evaluation of Estrogen Receptor in Relation to Its Therapeutic Effect

Busramustine (KM-2210), the benzoate of a 17ß-estradiol-chlorambucilconjugate,$$$ was administered to 11 patients with chronic lymphocyticleukemia (CLL) which included eight cases of B-cell CLL andthree cases of T-cell CLL. Four patients had received priorchemotherapy. Busramustine was given orally at an initial dailydose of 50–100 mg continuously, and the dose was modifiedaccording to hematological improvement. Two cases of B-cellCLL achieved clinical complete responses, six cases includingtwo of T-cell CLL and four of B-cell CLL achieved partial responsesand one case of B-cell CLL achieved improvement. The partialand complete response rate was 72.7%. Four patients showed estrogenreceptor activity of CLL cells ranging from 3.5 to 57.5 fmol/mgcytosol protein, but there seemed to be no correlation betweenthe estrogen receptor activity of the CLL cells and the therapeuticeffects of busramustine. Toxic effects included diarrhea (2/11)and estrogen-related symptoms including breast pain (4/11),genital bleeding (2/5), gynecomastia (2/6) and loss of libido(2/6). The findings of this preliminary study suggest that busramustineis effective in the treatment of CLL, irrespective of the presenceof the estrogen receptor.     

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

Introduction

Chronic 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.

Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia with Novel Targeted Agents

Tumor lysis syndrome (TLS) is an uncommon but potentially life‐threatening complication associated with the treatment of some cancers. If left untreated, TLS may result in acute renal failure, cardiac dysrhythmia, neurologic complications, seizures, or death. Tumor lysis syndrome is most commonly observed in patients with hematologic malignancies with a high proliferation rate undergoing treatment with very effective therapies. In chronic lymphocytic leukemia (CLL), historically, TLS has been observed less often, owing to a low proliferation rate and slow response to chemotherapy. New targeted therapies have recently been approved in the treatment of CLL, including the oral kinase inhibitors, idelalisib and ibrutinib, and the B‐cell lymphoma‐2 protein inhibitor, venetoclax. Several others are also under development, and combination strategies of these agents are being explored. This review examines the diagnosis, prevention, and management of TLS and summarizes the TLS experience in CLL clinical trials with newer targeted agents. Overall, the risk of TLS is small, but the consequences may be fatal; therefore, patients should be monitored carefully. Therapies capable of eliciting rapid response and combination regimens are increasingly being evaluated for treatment of CLL, which may pose a higher risk of TLS. For optimal management, patients at risk for TLS require prophylaxis and close monitoring with appropriate tests and appropriate management to correct laboratory abnormalities, which allows for safe and effective disease control.

Implications for Practice

Tumor lysis syndrome (TLS) is a potentially fatal condition observed with hematologic malignancies, caused by release of cellular components in the bloodstream from rapidly dying tumor cells. The frequency and severity of TLS is partly dependent upon the biology of the disease and type of therapy administered. Novel targeted agents highly effective at inducing rapid cell death in chronic lymphocytic leukemia (CLL) may pose a risk for TLS in patients with tumors characterized by rapid growth, high tumor burden, and/or high sensitivity to treatment. In this review, prevention strategies and management of patients with CLL who develop TLS are described.     

Pulmonary Involvement as the Major Manifestation of Chronic Lymphocytic Leukemia

Respiratory symptoms and abnormal findings on chest X-ray are frequently noted in patients with chronic lympllocytic leukemia (CLL). However, most of these represent pulmonary infections or mediastinal lymphadenopathy, and leukemic involvement of the lung is seldom diagnosed during life. In this report we describe three patients with non-progressive, responsive CLL who developed biopsy proven pulmonary infiltration with CLL. In one case, pulmonary involvement was the sole manifestation of recurrent disease and a second case had little disease elsewhere with minimal CLL in the blood at the time pulmonary involvement appeared. In all three cases, transbronchial biopsy and bronchoalveolar lavage performed during fibreoptic bronchoscopy provided adequate tissue for diagnosis. We conclude that CLL may involve the lung even in the presence of a low peripheral white blood cell count with responsive disease elsewhere, and can readily be diagnosed by transbronchial biopsy and bronchoalveolar lavage.     

Alterations of the Retinoblastoma a Susceptibility Gene in Chronic Lymphocytic Leukemia

Research in recent years has shown that malignant transformation is a genetic multistep process. This holds true not only for in-vitro model systems, but has also been elegantly shown in-vivo, as in colorectal cancer. Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in Western countries and occurs mainly in elderly patients, suggesting that in this form of leukemia, cumulative molecular lesions may be necessary for transformation. However, the molecular background is unknown in most cases. Cytogenetic aberrations may be used as markers for genes, involved in the process of malignant transformation. In CLL, the most frequently observed structural cytogenetic lesion is a deletion/translocation involving the long arm of chromosome 13, a region where the retinoblastoma susceptibility gene (Rb-gene) has been mapped (13q14). Many groups have studied the question as to whether alterations of the Rb-gene play a causal role in the pathogenesis of CLL., This review deals with recent data indicating that i) the Rb-gene may be altered in a minority of CLL cases, and ii) there may be another gene localized on chromosome 13q14 that may be important in the molecular biology of CLL.     

Survival and Clinical Aspects for Patients with Chronic Lymphocytic Leukemia in Kermanshah,Iran

Chronic lymphocytic leukemia (CLL)is the most common leukemia in adults in Western countries but is relatively rare in Asia. Immune hemolytic anemia, Evan’s syndrome, lymphadenopathy, organomegaly and B symptoms are the main complaints of patients in CLL. The present retrospective analysis evaluated a group of 109 patients with CLL over a 9-year period, studying correlations between sex, age and overall survival. The patients were hospitalized in the Clinic of Hematology and Oncology, Kermanshah, Iran, between 2006 and 2014. Data analysis for sex and age was performed using IBM SPSS19 and overall survival was plotted by Kaplan- Meier plot, Log-rank test in Graph Pad prism 5 Software for five-year periods. The mean age of diagnosis for CLL patients was 60.73 years, 59.6% male. Survival rate patients was 64% and mean overall survival was 38.5 months. In the Rai system, fourteen patients (12.8%) had stage ΙΙΙ and twenty eight patients (25.7%) had stage IV. Most frequent clinical features in patients with CLL were lymphadenopathy (38.7%) and organomegaly (34%), respectively. There is not relationship between sex and age in patients but overall survival rate in females was higher than in males. In Asian countries, CLL is more in male and in age above 60 years. Complaints about lymphadenopathy and virus infection are prevalent.     

The Complement System in Chronic Lymphocytic Leukemia: A Possible Role in Autoimmune Manifestations

We describe the complement system of three CLL patients who developed autoimmune complications in the course of their disease. The complement profile was pathological in both CLL patients with active autoimmune diseases, while it showed no deficiency in the patient with quiescent autoimmunity. The complement profile could be an early marker for development of autoimmunity in CLL patients.     

Chlorambucil in Chronic Lymphocytic Leukemia: Mechanism of Action

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries but the clinical presentation and rate of disease progression are highly variable. When treatment is required the most commonly used therapy is the nitrogen mustard alkylating agent, chlorambucil (CLB), with or without prednisone. Although CLB has been used in the treatment of CLL for forty years the exact mechanism of action of this agent in CLL is still unclear. Studies in proliferating model tumor systems have demonstrated that CLB can bind to a variety of cellular structures such as membranes, RNA, proteins and DNA; however, DNA crosslinking appears to be most important for antitumor activity in these systems. In addition, a number of different mechanisms can contribute to CLB resistance in these tumor models including increased drug metabolism, DNA repair and CLB detoxification resulting from elevated levels of glutathione (GSH) and glutathione S-transferase (GST) activity. However, unlike tumor models in vitro, CLL cells are generally not proliferating and studies in CLL cells have raised questions about the hypothesis that DNA crosslinking is the major mechanism of antitumor action for CLB in this disease. CLB induces apoptosis in CLL cells and this appears to correlate with the clinical effects of this agent. Thus, alkylation of cellular targets other than DNA, which can also induce apoptosis, may contribute to the activity of CLB. Alterations in genes such as p53, mdm-2, bcl-2 and bax which control entry into apoptosis may cause drug resistance. Loss of wild-type p53 by mutation or deletion occurs in 10 to 15% of CLL patients and appears to correlate strongly with poor clinical response to CLB. The induction of apoptosis by CLB is paralleled by an increase in P53 and Mdm-2 but this increase is not observed in patients with p53 mutations indicating that with high drug concentrations CLB can produce cell death through P53 independent pathways. The level of Mdm-2 mRNA in the CLL cells is not a useful predictor of drug sensitivity. In addition, although Bax and Bcl-2 are important regulators of apoptosis and the levels of these proteins are elevated in CLL cells compared with normal B cells, the levels of Bax and Bcl-2, ortheBax:Bcl-2 ratio, are not important determinants of drug sensitivity in this leukemia. Finally, whereas CLB and nucleoside analogs may produce cell death in CLL by a P53 dependent pathway other agents, such as dexamethasone or vincristine, may act through P53-independent pathways.     

Ibrutinib-associated Arthralgias/Myalgias in Patients With Chronic Lymphocytic Leukemia: Incidence and Impact on Clinical Outcomes

IntroductionThe Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has transformed the treatment of chronic lymphocytic leukemia (CLL), leading to unprecedented improvements in progression-free and overall survival for all patients, including those with poor prognostic features. The side effect profile of ibrutinib is unique compared with chemoimmunotherapy and includes atrial fibrillation, increased bleeding risk, and arthralgias/myalgias. Although common, arthralgias/myalgias and their management are poorly described.Patients and MethodsWe identified 214 patients with CLL treated with ibrutinib (as a single agent or in combination) from 2011 to 2018 at the University of Pennsylvania.ResultsIn this cohort, 36% (76/214) of patients developed arthralgias/myalgias during follow-up with a median onset of 34.5 months. Most (79%) events were grade 1 or 2. Risk factors for developing arthralgias/myalgias included younger age at start of ibrutinib, female gender, and ibrutinib use as first treatment. Twenty-eight percent of patients with grade 1 or 2 toxicity continued ibrutinib and had resolution of symptoms. Dose holds were frequently used to manage this toxicity, and this strategy was more successful than dose reduction. Sixty-two percent of patients with grade 3 toxicity ultimately discontinued ibrutinib. Supportive care measures such as discontinuing statins or use of non-steroidal anti-inflammatory drugs, acetaminophen, or corticosteroids were not used frequently enough in this cohort to evaluate their efficacy.ConclusionsAdditional studies to determine the mechanism of ibrutinib-related arthralgias/myalgias are needed to develop optimal management strategies.     

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia

On November 5, 2020, a marketing authorization valid through the European Union (EU) was issued for acalabrutinib monotherapy or acalabrutinib in combination with obinutuzumab (AcalaObi) in adult patients with treatment‐naïve (TN) chronic lymphocytic leukemia (CLL) and also for acalabrutinib monotherapy in adult patients with relapsed or refractory (RR) CLL. Acalabrutinib inhibits the Bruton tyrosine kinase, which plays a significant role in the proliferation and survival of the disease. Acalabrutinib was evaluated in two phase III multicenter randomized trials. The first trial (ACE‐CL‐007) randomly allocated acalabrutinib versus AcalaObi versus chlorambucil plus obinutuzumab (ChlObi) to elderly/unfit patients with TN CLL. The progression‐free survival (PFS), as assessed by an independent review committee, was superior for both the AcalaObi (hazard ratio [HR], 0.1; 95% confidence interval [CI], 0.06–0.17) and acalabrutinib (HR, 0.2; 95% CI, 0.13–0.3) arms compared with the ChlObi arm. The second trial (ACE‐CL‐309) randomly allocated acalabrutinib versus rituximab plus idelalisib or bendamustine to adult patients with RR CLL. Also in this trial, the PFS was significantly longer in the acalabrutinib arm (HR, 0.31; 95% CI, 0.20–0.49). Adverse events for patients receiving acalabrutinib varied across trials, but the most frequent were generally headache, diarrhea, neutropenia, nausea, and infections. The scientific review concluded that the benefit‐risk ratio of acalabrutinib was positive for both indications. This article summarizes the scientific review of the application leading to regulatory approval in the EU.Implications for PracticeAcalabrutinib was approved in the European Union for the treatment of adult patients with chronic lymphocytic leukemia who have not received treatment before and for those who have received therapy but whose disease did not respond or relapsed afterward. Acalabrutinib resulted in a clinically meaningful and significant lengthening of the time from treatment initiation to further disease relapse or patient''s death compared with standard therapy. The overall safety profile was considered acceptable, and the benefit‐risk ratio was determined to be positive.     

Autoimmune Hemolytic Anemia in Chronic Lymphocytic Leukemia Patients Treated with Fludarabine

Autoimmune hemolytic anemia (AHA) is a frequent complication of chronic lymphocytic leukemia (CLL). Although the pathogenesis of AHA is still unknown, an imbalance of normal residual T cells is believed to play a central role. Since fludarabine is reported to affect primarily T lymphocytes, we conducted a retrospective study to evaluate the incidence and outcome of AHA in 112 CLL patients treated with fludarabine alone. Eight patients had AHA before therapy; only one achieved remission of both CLL and AHA after fludarabine alone. In the other seven patients, we observed no effect or even a worsening of AHA, although the CLL was responding to fludarabine. Five patients developed AHA from 1 to 19 months after fludarabine therapy while the CLL was responding. One additional patient developed pure red cell aplasia (PRCA) 3 months after starting therapy. Most patients in both groups responded to steroids or other immunosuppressive therapy. The study showed that in these patients, AHA evolved independently of CLL and was not affected by fludarabine.     

Sudden Onset Deafness as a Presenting Manifestation of Chronic Lymphocytic Leukemia

An unusual patient with typical Rai Stage 2 (Binet Stage A) chronic lymphocytic leukaemia (CLL), who presented with sudden onset deafness as the initial manifestation of disease is reported. This sensorineural hearing loss improved dramatically after the administration of chemotherapy. This unique observation was also associated with reduction of the circulating B-CLL cells and with the achievement of a partial response, lasting for almost three years. Recently there was another episode of sudden deafness, associated with a rising leukocyte count, and disease activity followed once again by recovery after chemotherapy. Audiograms were recorded showing positive findings on presentation and recovery after therapy. This very rare manifestation of CLL was presumed to be due to infiltration of the cochlear duct or the 8th cranial nerve although all imaging techniques were negative, because of the rapid relief and recovery achieved after specific chemotherapy. The importance of early diagnosis and therapy is stressed in the light of the rapid clinical recovery observed here.     

Two Distinct Clinical Patterns of Ibrutinib-to-Venetoclax Transition in Relapsed Chronic Lymphocytic Leukemia Patients

Patients with chronic lymphocytic leukemia (CLL) relapsing on ibrutinib are often treated with the Bcl-2 inhibitor venetoclax. However, the transition from one agent to another poses some clinical challenges due to disease flares sometimes occurring right after ibrutinib interruption. Here, we describe three clinical vignettes highlighting two distinct patterns of ibrutinib-to-venetoclax transition. While patients following the favorable pattern transited to venetoclax without experiencing disease flare, the one patient who took the unfavorable path showed rapid disease rebound, with large-cell transformation occurring one week after ibrutinib interruption. A high burden of BTK and PLCG2 mutations was found only in patients with the favorable transition pattern, suggesting that removing BTK inhibition might be particularly harmful if CLL cells are progressing through mechanisms external to the BTK axis.