The COP Regimen is not a Feasible Treatment for Advanced, Refractory Chronic Lymphocytic Leukemia

The COP regimen has been widely used as a second-line treatment for advanced chronic lymphocytic leukemia (CLL). In this retrospective analysis of COP therapy 24 patients with CLL were included. All but two patients had previously been treated with alkylating agents and had become refractory to the therapy. The overall response rate to COP was 25%. Three patients had CR (12.5%), three PR (12.5%), five SD (21%), four PD (17%), and nine patients died (37.5%) during the COP treatments. The cause of death was neutropenic sepsis in all cases. The median duration of responses was 18 months. The median survival of all patients was 9.5 months. The survival of responders was 24.5 and of non-responders only 5.5 months. The COP regimen seems to have low efficacy in the treatment of refractory CLL and the toxicity of this regimen in the late disease phase appears to be unacceptable.     

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.     

CD38 Expression Correlates with Adverse Biological Features and Predicts Poor Clinical Outcome in B-Cell Chronic Lymphocytic Leukemia

CD38 identifies a surface molecule with multi-functional activity. Its prognostic importance in B-cell chronic lymphocytic leukemia (B-CLL) is currently under investigation in view of the fact that two different groups have recently indicated that CD38 expression could be an independent prognostic marker in B-CLL.

We analyzed the clinico-biological features of 61 immunologically typical (CD5+CD23+) B-CLL patients stratified according to the CD38 expression. Twenty-two (36%) patients expressed CD38 in more than 30% of CD19-positive cells and were considered as CD38-positive B-CLL. Atypical morphology (p 0.02), peripheral blood lymphocytosis (p 0.01) and diffuse histopathologic bone marrow pattern (p 0.003) were findings found to be closely associated with CD38 expression. On the other hand, A and B Binet stages (p 0.02) and interstitial bone marrow involvement (p 0.005) were more represented in the CD38-negative B-CLL group. Trisomy 12 was detected more frequently in the CD38-positive B-CLL group, while 13q14 deletions mainly occurred in CD38-negative group (p 0.005). Finally, median survival of CD38-positive B-CLL patients was 90 months, while it was not reached at 180 months in CD38-negative patients.

Taken together, our data strongly suggest that the evaluation of CD38 expression may identify two groups patients with B-CLL greatly differing in their clinico-biological features.     

Survival of Young Patients with Chronic Lymphocytic Leukemia Failing Fludarabine Therapy: A Basis for the Use of Myeloablative Therapies

We examined the survival of 91 young patients (≤ 55 years) with chronic lymphocytic leukemia from the time of failure of fludarabine therapy, in an attempt to identify those with a poor outcome who may benefit from investigative dose-intensive therapies. The median survival of patients unresponsive to fludarabine (n = 42) was 48 weeks, and only 11% responded to subsequent therapies. The median survival of patients relapsing following a fludarabine-induced remission (n = 49) was 87 weeks, and 83% of those who had received fludarabine as their first therapy (n = 14) responded to further fludarabine-containing therapies, with 60% alive at four years. Only 7% of those relapsing patients who had received fludarabine as salvage therapy (n = 35) responded to subsequent therapies (median survival 72 weeks). The poor outlook for these patients justifies the consideration of innovative dose-intensive therapies, such as bone: marrow transplantation, with their attendant risk of toxicity.     

CD5 Negative IGM Rheumatoid Factor B Cells in B-Chronic Lymphocytic Leukemia and Benign Mixed Cryoglobulinemia

IgM-RF B cell precursors are abnormally overrepresentated in “well differentiated” lymphoid monoclonal proliferations while data on less mature lymphoid malignancies are still awaited. This nevertheless suggests that RF activity plays a role in the transforming process perhaps by inducing constant stimulation of the precursor B cells. Despite the preferential use of similar VH and VL genes with little or no somatic hypermutations in both malignant B-cell CLL and nonmalignant mixed cryoglobulinemia, these proliferations do differ in CD5 membrane expression and in their clinical evolution. One possibility could be that CD5 glycoprotein is lost during maturation of the lymphocyte into a secreting cell as suggested by data on Waldenstrom's disease and the LES-CLL and by in vitro studies. Alternatively, CD5 expression could play an additional direct role in malignant transformation as suggested by recent data on the CD5 receptor ligand. Further data on the proliferating cells in both situations as well as on the genetic control of CD5 expression in B cells and its physiology should shed additional light on the mechanisms of B-cell malignancy.     

Intratumoral Production of IL-6 in B Cell Chronic Lymphocytic Leukemia and B Lymphomas

Interleukin-6 is a major B lymphocyte growth factor, and may play a role in the proliferation of malignant B lymphocytes. In order to provide arguments supporting such a role, the intratumoral production of IL-6 was studied by in situ hybridization and immunohistochemistry in 53 neoplastic tissues from B cell chronic lymphocytic leukemia or B lymphomas. IL-6-producing cells were detected in all samples but 5. However, the number of IL-6 producing cells was variable amongst the different cases. Increased density of IL-6-producing cells was highly dependent on the presence of malignant immunoblasts within the neoplastic clone. IL-6 was produced in a paracrine way, macrophages and endothelial cells being the main producers of the cytokine while malignant immunoblasts expressed the IL-6 receptor. Taken together, these results suggest that IL-6 may indeed act as a growth factor for malignant cells in some B lymphoproliferations and that this paracrine loop could be the target of new therapeutic approaches.     

Proliferating Cell Nuclear Antigen (PCNA) Expression in Chronic Lymphocytic Leukemia (CLL)

Chronic Lymphocytic Leukemia (CLL) is usually an indolent disorder which in some patients assumes an aggressive clinical course. In order to assess at presentation the prognosis of a given patient, several staging systems and prognostic variables have been proposed including the expression of the Proliferating Cell Nuclear Antigen (PCNA). PCNA is a 36 kd nuclear protein, the regulation of which is cell cycle-dependent. In CLL, PCNA levels correlate with cell proliferation, clinical stage and the lymphocyte doubling time (LDT). Furthermore, preliminary data suggests that PCNA expression may also predict response to Fludarabine-based chemotherapy. Since PCNA is a cofactor for Delta DNA polymerase, PCNA overexpression in CLL may also reflect the intrinsic DNA repair activity of the leukemic cells and thus their resistance to chemotherapy. Further studies aiming at modulation of PCNA expression in CLL cells may clarify this issue and may offer a future new therapeutic strategy with which to treat this disorder.     

Cladribine in the Treatment of Chronic Lymphocytic Leukemia

Cladribine (2-chlorodeoxyadenosine, 2-CdA) is a nucleoside analog with substituted halogen atom at position 2 in its purine ring that makes it resistant to deamination by adenosine deaminase (ADA). 2-CdA is the drug of choice in the treatment of hairy cell leukemia, but it is also highly active in other low grade lymphoid malignancies including chronic lymphocytic leukemia (CLL). The results of the studies presented so far have shown that 2-CdA gives similar complete response (CR) rate and overall response (OR) rate to fludarabine but the influence of both agents on survival times of the patients with CLL is still uncertain. CR rate induced with 2-CdA is significantly higher than in the patients treated with conventional chemotherapy. In refractory or relapsed patients 2-CdA induces 31 to 68% of overall responses including CR in 4 to 31%. In previously untreated patients overall remission rates of about 56-82% have been achieved with 2-CdA alone. When 2-CdA was used as primary therapy the CR rate was also significantly higher and ranged from 10% to 47%. Patients who received 2-CdA as their initial therapy and experienced a response lasting at least a year may be successfully treated subsequently with the same agent. A second response has been achieved in 35 to 100% patients treated with this agent for the second time. Despite the fact that 2-CdA gives higher CR and OR rates than conventional chemotherapy, it has not been established whether it has any influence on survival time. However, cross resistance between 2-CdA and FAMP in CLL patients is evident in the majority of studies. Bone marrow suppression with anemia neutropenia and thrombocytopenia are the dose limiting factors for 2-CdA use. These side effects are pronounced in heavily pretreated patients and after multiple courses of therapy. Treatment with this agent also leads to the decrease of the CD4+/CD8+ ratio for an extensive period of time exceeding 12, even up to 24 months. In consequence, infections including opportunistic type, are frequently observed. We suggest, that in patients with CLL, 2-CdA should be used as second line treatment rather than the first line therapy until the final results of ongoing randomized clinical trials are available.     

Effect of Lenalidomide Maintenance in Chronic Lymphocytic Leukemia: A Meta-Analysis and Trial-Sequential Analysis

Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disease in adults. Despite durable responses and sustained remission rates to frontline therapy, CLL is still incurable within standard therapy and eventually relapses. Maintenance therapies aim to achieve deep remission. However, the efficacy and safety of lenalidomide maintenance are still debated. Randomized controlled trials published before March 2022 were retrieved from databases. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Trial sequential analysis examined analytical power in primary outcomes. Secondary outcomes were Grade 3–4 neutropenia, treatment discontinuation (TD), serious adverse events (SAE), and fatal adverse events (FAE). Hazard (HR) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Four articles (733 patients) met the selection criteria. Lenalidomide maintenance was associated with a statistically significant effect in prolonging PFS (HR, 0.43; 95% CI, 0.28–0.68; I² = 57%) and higher proportion of SAE (OR 4.64; 95% CI 2.96–7.26; I² = 0%) and exhibited no difference in OS (HR, 0.62; 95% CI, 0.29–1.30; I² = 52%) observation/placebo. It showed no significant difference compared with observation/placebo regarding Grade 3–4 neutropenia (OR 2.30; 95% CI 0.84–6.28; I² = 81%), TD (OR 0.76; 95% CI 0.29–1.99; I² = 84%), and FAE (OR 0.86; 95% CI 0.28–2.63; I² = 0%). Lenalidomide maintenance can prolong PFS in CLL. Further studies should verify its effect on OS.     

Molecular Analysis of Rearranged VH Genes during B Cell Chronic Lymphocytic Leukemia: Intraclonal Stability is Frequent but not Constant

Several genetic mechanisms have been shown to diversify the expressed antibody repertoire of commited B lymphocytes. These include V gene replacement, ongoing gene rearrangement and somatic hypermutation. These mechanisms may be operational at discrete points in the B cell differentiation pathway and generate idiotype diversity in various malignant B cell tumors. In particular, V region mutations have been established as a major mechanism of tumor escape from anti-idiotype immunotherapy in some lymphoma. On the other hand, previous studies on a few selected cases have shown that this mutation process does not affect the B cell clone during chronic lymphocytic leukemia. However, to what extent this intraclonal stability is a general phenomenon during B cell CLL is not clear. Therefore, we randomly selected 6 patients suffering from classical B cell CLL (sIgM (+), CD5 (+), CD19 (+)) at different stages of the disease and analysed the intraclonal variability of the expressed variable region of the heavy chain (VH). After PCR amplification of the cDNA corresponding to the rearranged VDJ regions, the products were cloned and sequenced. In five cases, multiple clone analysis did not show any intraclonal variability whatever the stage of the disease. Furthermore, in a single case, this intraclonal stability was confirmed during a three year period of time when the disease progressed. The sixth case behaved differently since we found multiple nucleotide substitutions, apparently accumulating as the malignant clone expanded. Besides the theoretical difficulties that these changes can induce during immunotherapy, two findings merit further discussion: 1) the distribution of the ongoing mutations affecting the VH region was not suggestive of an antigen driven selection, 2) this intraclonal variability was specific for the VH region, since the VL region showed no intraclonal variation.     

Marrow Histomorphology and Clinical Staging of Chronic Lymphocytic Leukemia-A Rare Disease in India: Experience with 26 Cases

Chronic Lymphocytic Leukemia is a relatively uncommon hemopoietic malignancy in the Indian subcontinent. We have made an attempt to correlate the morphology of the marrow with staging and clinical course of the disease in 26 cases. Four out of 6 cases in Stage A showed a nodular/interstitial marrow pattern, while 18 out of 20 cases of stage B and C demonstrated a mixed/diffuse involvement of marrow. Cases showing a nodular/interstitial pattern had a relatively benign clinical course even without chemotherapy, while patients with diffuse/mixed marrow pattern required chemotherapy. Trephine histological pattern was found to be a good prognosticator and was useful in segregating cases requiring chemotherapy from those which do not.     

Clinical Significance of bcr-abl Gene Rearrangement Detected by the Polymerase Chain Reaction After Allogeneic Bone Marrow Transplantation in Chronic Myelogenous Leukemia

Although serial detection of bcr-abl positive cells by PCR appears able to identify distinct patient groups with different risks of relapse following BMT, there remain many unanswered questions regarding the clinical utility and biological significance of PCR detectable cells in this disease. Many of the studies summarized have conflicting results and the influence of various clinical parameters which are known to affect the risk of relapse post-BMT has not yet been consistently associated with the ability to detect bcr-abl positive cells by PCR. These clinical parameters include GVHD, T-cell depletion and intensity of immunosuppression following BMT. Prospective studies with larger patient numbers will be necessary to define the impact of these factors in PCR status and relapse. The answers to all these questions will increase our understanding of the biology of chronic myelogenous leukemia and help provide more effective therapies for the future.     

Residual Cancer Lymphocytes in Patients With Chronic Lymphocytic Leukemia After Therapy Show Increased Expression of Surface Antigen CD52 Detected Using Quantitative Fluorescence Cytometry

BackgroundRituximab and alemtuzumab, mAbs used in recent years to treat CLL, are directed against antigens CD20 and CD52. CD20 is not highly expressed by CLL tumor cells, and rituximab does not have significant effectiveness in CLL unless combined with chemotherapy. Alemtuzumab targets CD52, which is much more highly expressed, and is currently the most effective agent used alone for CLL. Variability in expression of both antigens among these patients might be related to different individual therapeutic responses to mAb therapy.Patients and MethodsA total 95 patients diagnosed with CLL and/or SLL were divided into 4 groups: (1) untreated; (2) in complete or partial remission; (3) disease in progression; and (4) diagnosed with SLL. Flow cytometry of peripheral blood cells included gating of the CD5⁺CD19⁺ tumor population, within which mean fluorescence intensity of fluorescein isothiocyanate (FITC) conjugated with anti-CD20 or anti-CD52 antibody was measured. The resulting expression of the 2 antigens was deduced from the calibration curve using Quantum FITC particles.ResultsExpression of CD20 showed no significant differences among the 4 groups of patients. However, significantly greater expression of surface antigen CD52 was recorded in patient group 2 in complete or partial remission (P < .001).ConclusionThe residual population of CLL cells after therapy is characterized by increased surface detection of CD52. Although the exact cause of this phenomenon is unknown, our results provide a basis to consider the potential for CLL consolidation therapy using alemtuzumab.     

Serum β2-Microglobulin and Serum Thymidine Kinase are Independent Predictors of Progression-Free Survival in Chronic Lymphocytic Leukemia and Immunocytoma

Chronic lymphocytic leukemia (CLL) and immunocytoma (IC) are remarkably heterogeneous with regard to their clinical course. The current staging systems can distinguish prognostic subgroups, but do not seem to predict the risk of disease progression of an individual patient with sufficient accuracy. Given the increase of treatment options for CLL and IC, additional parameters are needed to decide which patients may benefit from early or intensified treatment. It has been shown that two biochemical markers, serum β₂microglobulin (s-β₂) and serum thymidine kinase (s-TK), might identify CLL and IC patients at high risk of disease progression. Therefore, the prognostic value of these two serum parameters was compared with a panel of several established prognostic factors in a prospective clinical trial. 113 patients with CLL and 41 patients with IC (mean age ± SD 63.9 ± 10.7 years) were included. The following parameters were determined: histopathological diagnosis (IC vs. CLL), age, sex, performance status (Karnofsky index), B symptoms, peripheral blood lymphocyte count, platelet count, blood hemoglobin, serum lactate dehydrogenase (s-LDH), S-β₂M, s-TK, serum creatinine, number of lymph node areas involved, prior therapy, and the time from diagnosis to inclusion in the study. Univariate analyses showed that nine parameters (Karnofsky index, peripheral blood lymphocytosis, platelet count, blood hemoglobin, lymph node areas involved, pretreatment, s-LDH, s-β₂M, and s-TK) significantly predicted progression-free survival. In a Cox regression model, only four of these parameters provided independent prognostic information on progression-free survival: 1. S-β₂M, 2. Karnofsky index, 3. platelet count, and 4. s-TK. The results show that s-β₂M and s-TK independently predict progression-free survival in patients with CLL and IC, and suggest that these prognostic factors may allow an improved prediction of progression-free survival, particularly in early disease stages.     

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.     

Neuropilin-1某因在髓细胞白血病和正常人骨髓基质细胞中的表达(英文)

目的了解 neuropilin-1(NP-1)基因在髓细胞白血病(AML 和 CML)患者及正常人骨髓基质细胞中的表达情况。方法收集12例 AML、14例 CML 和20例正常对照骨髓标本,分离单个核细胞。进行体外长期培养,收集贴壁细胞(骨髓基质细胞)。利用逆转录-聚合酶链反应分别检测3组骨髓基质细胞中 NP-1基因的表达。结果成功建立了 AML、CML 和正常人骨髓基质细胞培养方法,NP-1基因在 AML、CML 骨髓基质细胞中的表达率分别为47.1%和50%,明显低于正常对照(85%)。结论 NP-1基因可表达于部分 AML、CML 和大部分正常人的骨髓基质细胞中,其在髓细胞白血病患者骨髓基质细胞中的低表达,可能与其调节造血功能异常有关。     

Neuropilin-1基因在髓细胞白血病和正常人骨髓基质细胞中的表达

目的了解neuropilin-1(NP-1)基因在髓细胞白血病(AML和CML)患者及正常人骨髓基质细胞中的表达情况。方法收集12例AML、14例CML和20例正常对照骨髓标本,分离单个核细胞。进行体外长期培养,收集贴壁细胞(骨髓基质细胞)。利用逆转录-聚合酶链反应分别检测3组骨髓基质细胞中NP-1基因的表达。结果成功建立了AML、CML和正常人骨髓基质细胞培养方法,NP-1基因在AML、CML骨髓基质细胞中的表达率分别为47.1%和50%,明显低于正常对照(85%)。结论NP-1基因可表达于部分AML、CML和大部分正常人的骨髓基质细胞中,其在髓细胞白血病患者骨髓基质细胞中的低表达, 可能与其调节造血功能异常有关。     

Autologous Bone Marrow Transplantation in Acute Lymphoblastic Leukemia following In Vitro Treatment with Monoclonal Antibodies and with Complement: Analyses for Two Cases of Failure

Two children with acute lymphoblastic leukemia (ALL) receivedautologous bone marrow transplantation (BMT) using remissionbone marrow treated in vitro with the monoclonal antibodies,CD24 (BA-1), CD9 (BA-2) and CD 10 (BA-3), and with rabbit complement. In one child with second remission ALL, hematopoietic recoveryafter BMT was prompt but, 81 days after BMT, isolated centralnervous system (CNS) relapse occurred. Bone marrow relapse developedthree months later, and she died 11 months after BMT. In patientswith CNS leukemia prior to BMT, as in the present case, moreintensive pretransplant CNS treatment and/or a conditioningregimen may reduce the risk of relapse. In the other patient, with primary refractory ALL in first remission,marrow reconstitution was slower. The patient developed interstitialpneumonitis with pleural effusion, and died 54 days after BMT.No infectious causes could be detected by culture or from serologicalstudies of the pleural effusion. The rationale for applying autologous BMT to children with secondremission ALL and first remission refractory ALL is discussed.