Does Hypergammaglobulinemia Predispose to Secondary Solid Tumors in Patients with Chronic Lymphocytic Leukemia?.

Abstract Background:Occurrence of second hematological malignancies in patients with chronic lymphocytic leukemia (CLL) is well known but development of secondary solid tumors has not been well documented. Isolated case reports indicate, CLL patients may have a predisposition to develop solid tumors. There is not enough literature available to support this hypothesis. We here intend to study the incidence of secondary solid tumors in CLL patients with regard to their treatment and immunoglobulin levels. Methods: We reviewed the medical records of 323 CLL patients over the last 20 years at Veteran Affairs Medical Center, Kansas City. Broadly the patients were divided into two groups; the group who received chemotherapy for CLL(74/323) versus the group who did not receive treatment (249/323) and their median immunoglobulin levels were also documented. Patients who developed secondary hematological malignancies were excluded from this study. Results: The overall incidence of solid tumors was found to be 14.8% (48/323). In the chemotherapy treated CLL, the incidence of solid tumors was 18%(14/74) as compared to 13.6% (34/249) in the non-therapeutic group(P value 0.12). The most common malignancies noted were gastro-intestinal malignancies, genitor-urinary tumors and skin cancers including melanomas. Interestingly CLL patients who developed secondary solid tumors had a higher median IgG levels (1010 g/L) when compared to those who did not develop secondary tumors (738 g/L, P value <0.003) Conclusion: Our study shows that there is a higher overall incidence of secondary solid tumors in patients with CLL when compared with incidence in the general population. There is no significant increase in the incidence of therapy related solid tumors in CLL patients. Upward drift in immunoglobulin levels should raise a suspicion for diagnosis of secondary solid tumors in patients with CLL. More studies are warranted to confirm this finding.

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Autoimmune Cytopenias in Patients with Chronic Lymphocytic Leukemia Treated with Cladribine

Blood ◽

10.1182/blood.v112.11.4179.4179 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4179-4179

Author(s):

Jerzy Z Blonski ◽

Tadeusz Robak ◽

Jacek Trelinski ◽

Krzysztof Chojnowski ◽

Krzysztof Warzocha ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Case Reports ◽

Lymphocytic Leukemia ◽

P Value ◽

Indirect Bilirubin ◽

Cytotoxic Treatment ◽

Trial Protocols ◽

Autoimmune Cytopenias ◽

Adult Leukemia ◽

Positive Direct

Abstract Autoimmune disorders like immune haemolytic anemia (AIHA) and immune thrombocytopenia (IT) represent the autoimmune haematological conditions most frequently associated with chronic lymphocytic leukemia (CLL). Recently there has been several case reports suggesting relation between occurrence of these disorders and treatment with purin analogues. The aim of this study was to compare the frequency and prognostic value of AIHA and IT in the group of CLL patients treated with chlorambucil or cladribine. Retrospective analysis of 777 patients treated in 1999–2004 years according to two randomized clinical trial protocols coordinated by Polish Adult Leukemia Group (PALG) was performed. In 104 patients chlorambucil and in 673 cladribine was applied according to NCIWG criteria. In the cladribine group 315 were given monotherapy, in 170 combination therapy with cyclophosphamide (CC) and in 188 with cyclophosphamide and mitoxantron (CMC) were used. The details of the treatment schedules were published previously. IT patients had to fulfill the following diagnostic criteria: rapid and severe fall of the platelet count, normal or augmented number of megakariocytes in bone marrow, no reaction to platelet transfusions, no palpable splenomegaly and no chemotherapy in the last 30 days. No patient had IT before enrolment to any cytotoxic treatment. Diagnosis of AIHA was based on haemoglobin <100 g/l and a positive direct antiglobulin test (DAT) for either immunoglobulin or the complement fragment C3d in the absence of bleeding. For patients with negative DAT the diagnosis was based additionally on the presence of at least two indicators of haemolysis (increased indirect bilirubin, increased reticulocyte count, increased LDH concentration, low haptoglobin concentration). The occurrence of studied events was estimated among end of first and beginning of second line treatment. The results of the study are shown in Table 1. In conclusion the application of cladribine either in monotherapy or in combination with cyclophosphamide or mitoxantron did not significantly increase the frequency of AIHA and/or IT in the studied population in comparison to chlorambucil. Although the remission rates (CR-complete and OR-overall) in patients with concomitant AIHA and IT treated with cladribine was lower than in patients without these complications no influence on and overall survival (OS) was observed. Table.1. Characteristic Cladribine Chlorambucil p value AIHA Yes No Yes No Total (%) 48 (7.1) 625 (92.9) 6 (5.8) 98 (94.2) 0.61 OR (%) 35 72.9 448 80.9 2 33.3 57 58.8 0.11 vs 0.22 CR (%) 10 20.8 194 35.0 0 0.0 12 12.4 0.008 vs 0.36 Death (%) 29 60.4 342 55.1 6 100.0 69 71.1 - OS (median. years) 4.226 3.247 4.843 2.614 0.16 vs 0.81 IT Yes No Yes No Total (%) 50 7.4 623 92.6 5 4.8 99 95.2 0.33 OR (%) 31 63.3 449 81.6 2 40.0 57 58.2 0.004 vs 0.42 CR (%) 5 10.2 196 35.6 1 20.0 11 11.2 0.0006 vs 0.55 Death (%) 36 72.0 335 54.1 5 100.0 70 71.4 - OS (median. years) 2.231 9.595 4.300 5.237 0.11 vs 0.23

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Chronic Lymphocytic Leukemia in Blood Relatives: Two Case Reports of Male Siblings

Clinical oncohematology ◽

10.21320/2500-2139-2021-14-1-69-72 ◽

2021 ◽

Vol 14 (1) ◽

pp. 69-72

Author(s):

Nadezhda Viktorovna Kurkina ◽

E.A. Repina

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Case Reports ◽

Lymphocytic Leukemia

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Chronic lymphocytic leukemia (CLL) terminating in multiple myeloma: report of two cases

Blood ◽

10.1182/blood.v52.3.532.532 ◽

1978 ◽

Vol 52 (3) ◽

pp. 532-536 ◽

Cited By ~ 14

Author(s):

RH Kough ◽

AZ Makary

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Chronic Lymphocytic Leukemia ◽

Plasma Cells ◽

Medical Center ◽

White Male ◽

Lymphocytic Leukemia ◽

Light Chains ◽

White Female ◽

Pathologic Fractures

Abstract Two cases of multiple myeloma (MM) developed late in the course of chronic lymphocytic leukemia (CLL). An 81-yr-old white female developed, after 6 yr of CLL, IgAk MM with sheets of plasma cells abutting sheets of lymphocytes in the bone marrow, multiple pathologic fractures, and 0.26 g/24 free k light chains in the urine. A 74-yr-old white male developed, after 16 yr of CLL, k light chain MM with 20% plasma cells in the bone marrow, multiple panthologic fractures, and 3.7 g/24 hr free k light chains in the urine. In both cases the CLL had responded well to intermittent low-dose chlorambucil therapy, but the MM failed to respond to cyclic melphalanprednisone therapy. A review of 105 cases of CLL seen at the Geisinger Medical Center failed to turn up any other cases of MM developing during the course of CLL. The suggestion that there is an increased prevalence of MM in CLL is an attractive one because both diseases are B cell neoplasms and because of the increased frequency of asymptomatic monoclonal gammopathies in CLL found by others.

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Trends in the risk of second primary malignancies among survivors of chronic lymphocytic leukemia

Blood Cancer Journal ◽

10.1038/s41408-019-0237-1 ◽

2019 ◽

Vol 9 (10) ◽

Cited By ~ 5

Author(s):

Vivek Kumar ◽

Sikander Ailawadhi ◽

Leyla Bojanini ◽

Aditya Mehta ◽

Suman Biswas ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Hematological Malignancies ◽

Lymphocytic Leukemia ◽

Second Primary ◽

Standardized Incidence Ratio ◽

Improved Outcomes ◽

History Of ◽

Second Primary Malignancies

Abstract With improving survivorship in chronic lymphocytic leukemia (CLL), the risk of second primary malignancies (SPMs) has not been systematically addressed. Differences in risk for SPMs among CLL survivors from the Surveillance, Epidemiology, and End Results (SEER) database (1973–2015) were compared to risk of individual malignancies expected in the general population. In ~270,000 person-year follow-up, 6487 new SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.2 (95% CI:1.17–1.23). The higher risk was for both solid (SIR 1.15; 95% CI:1.12–1.18) and hematological malignancies (SIR 1.61; 95% CI:1.5–1.73). The highest risk for SPMs was noted between 2 and 5 months after CLL diagnosis (SIR 1.57; 95% CI:1.41–1.74) and for CLL patients between 50- and 79-years-old. There was a significant increase in SPMs in years 2003–2015 (SIR 1.36; 95% CI:1.3–1.42) as compared to 1973–1982 (SIR 1.19; 95% CI:1.12–1.26). The risk of SPMs was higher in CLL patients who had received prior chemotherapy (SIR 1.38 95% CI:1.31–1.44) as compared to those untreated/treatment status unknown (SIR 1.16, 95% CI:1.13–1.19, p < 0.001). In a multivariate analysis, the hazard of developing SPMs was higher among men, post-chemotherapy, recent years of diagnosis, advanced age, and non-Whites. Active survivorship plans and long-term surveillance for SPMs is crucial for improved outcomes of patients with a history of CLL.

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Chronic Lymphocytic Leukemia Presenting as a Subcortical Watershed Infarct

Case Reports in Hematology ◽

10.1155/2019/2089359 ◽

2019 ◽

Vol 2019 ◽

pp. 1-5

Author(s):

Mridul Gupta ◽

Divita Singh ◽

Patrick Lee ◽

Sandhya Kadiyam

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Hemolytic Anemia ◽

Immune Thrombocytopenia ◽

Case Reports ◽

Pure Red Cell Aplasia ◽

Lymphocytic Leukemia ◽

Red Cell ◽

Cerebral Infarcts ◽

Autoimmune Cytopenia ◽

Watershed Infarcts

Internal watershed infarcts (WI) involve white matter between deep and superficial arterial systems of middle cerebral artery. These infarcts are considered to be either from low blood flow or microembolism. Anemia is an extremely rare cause of watershed infarcts. Very few cases of hemolytic anemia causing watershed cerebral infarcts have been reported. Chronic lymphocytic leukemia (CLL) is frequently complicated with secondary autoimmune cytopenia such as autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and pure red cell aplasia. AIHA is present in about 7–10% of patients with CLL. AIHA from CLL presenting as WI is an extremely rare phenomenon with no previously published case reports to the best of our knowledge.

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V H mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v100.4.1410.h81602001410_1410_1416 ◽

2002 ◽

Vol 100 (4) ◽

pp. 1410-1416 ◽

Cited By ~ 558

Author(s):

Alexander Kröber ◽

Till Seiler ◽

Axel Benner ◽

Lars Bullinger ◽

Elsbeth Brückle ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

Expression Level ◽

Chain Gene ◽

P Value ◽

Prognostic Impact ◽

Survival Times ◽

Mutation Status ◽

Cd38 Expression ◽

Genomic Aberrations

In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (VH) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed VH mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q−, +8q, 11q−, +12q, 13q−, t(14q), 17p−) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of VH mutation rate and CD38 expression level was tested by maximally selected log-rank statistics. A corrected P value (Pcor) for a cutoff level allowing the best separation of 2 subgroups with different survival probabilities was identified at 97% VH homology (95% confidence interval [CI], 96%-98% homology,Pcor <.001) and at 7% CD38 expression (95% CI, 20%-71% expression, Pcor = .02). In univariate analyses, unmutated VH genes and high CD38 expression levels predicted for shorter survival times. The overall incidence of genomic aberrations was similar in theVH unmutated and VHmutated subgroups. High-risk genomic aberrations such as 17p− and 11q− occurred almost exclusively in the VHunmutated subgroup, whereas favorable aberrations such as 13q− and 13q− as single abnormalities were overrepresented in theVH mutated subgroup. In multivariate analysis, unmutated VH, 17p deletion, 11q deletion, age, WBC, and LDH were identified as independent prognostic factors, indicating a complementary role of VH mutation status and genomic aberrations to predict outcome in CLL.

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Free Light Chains, Monoclonal Proteins, and Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v110.11.4697.4697 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4697-4697 ◽

Cited By ~ 3

Author(s):

Rosa Ruchlemer ◽

Constantine Reinus ◽

Esther Paz ◽

Ahuva Cohen ◽

Natalia Melnikov ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Light Chain ◽

Lymphocytic Leukemia ◽

Light Chains ◽

P Value ◽

Advanced Stage ◽

Free Light Chains ◽

Monoclonal Protein ◽

Low Levels ◽

Monoclonal Proteins

Abstract Monoclonal proteins(MPs) can frequently be detected in the serum/urine of chronic lymphocytic leukemia(CLL) patients. Serum free light chains(FLC) assays can detect MPs in the absence of M bands on immunofixation(IMF).An abnormal FLC ratio indicates excess of one light chain type suggesting clonality.We evaluated fresh serum/urine samples from 34 CLL patients at various stages of disease by quantitative nephelometric assay,IMF and FLC assay.Median age was 66 yrs(43–87),M:F 1.9:1 and median time from diagnosis 41.5 mos(5–288). 45% had advanced stage and 39% prior treatment with 1–7 therapies.Only 2 patients had mild renal failure.Serum immunoglobulins were normal/low in 94% of patients:IgG (171–1580 mg/l, median 803 mg/l), IgA(<25–310 mg/l, median 88 mg/l),IgM(<18–290 mg/l, median 38 mg/l), irrespective of the presence of a monoclonal protein. 71% of patients had evidence of abnormal immunoglobulin synthesis: by IMF alone (8),IMF and FLC(10) or FLC alone(8).Abnormal FLC ratios were more frequently associated with advanced stage disease and increased κ chains(see table 1). Abnormal FLC ratios(< 0.26 or >1.65) were measured in 18(53%) patients, 8 of whom did not have MPs by IMF. Two advanced stage patients had abnormal FLC ratios due to very low levels of a single light chain, most probably reflecting secondary hypogammaglobulinemia due to CLL and/or chemotherapy.Abnormal FLC ratios reverted to normal after 1 course of chemotherapy(FC+/−R) in 3 patients despite persistence of minimal residual disease(MRD).FLC were of the same type as expressed on the surface of CLL cells, with discrepancies observed in 5 patients.BM biopsy staining for light chains revealed IgAκ MGUS in addition to λ chain restricted CLL in one patient, but was noncontributory in the other 4. Conclusions: Neither IMF nor the FLC assay alone could detect all MPs. Normal FLC ratios do not exclude the presence of MPs. The FLC ratio should be interpreted with caution in CLL patients with advanced disease and hypogammaglobulinemia. Monoclonal bands and abnormal FLC ratios can be detected despite normal or low levels of serum immunoglobulins in CLL patients. The significance of these monoclonal gammopathies in CLL is not clear and warrants further study in a larger group of patients. Discrepancies between surface immunoglobulins and serum/urine MPs might suggest the presence of an additional condition:ex. MGUS. FLC may not be a sensitive measure of MRD. Normal FLC ratio Abnormal FLC ratio P value *median No. patients 16(47%) 18(53%) M:F 1.3:1 3.5:1 NS Age* 62.5 yrs(49–73) 68 yrs(43–87) NS Time from CLL diagnosis* 25.3 mos(0–282) 59 mos(0–210) NS Adv stage(Rai III/IV-Binet C) 25% 66.7% 0.018 Untreated 62% 50% NS CLL:κ:λ restriction 7:8(0.88:1) 11:6(1.8:1) NS Monoclonal protein 8(50%) 10(56%) NS Increased freeκ no. 8 15 0.043 Freeκ level* 19.6(4.5–200) 39.2(2.9–386) 0.0064 Increased freeλ no 4 3 NS Free λ level* 19.3(12.4–146) 15.4(0.1–517) NS Serum β 2m* 3.1(1.8–6.7) 4.3(2.2–10.2) NS Zap70≥20 86% 36% 0.002 CD38≥30 44% 44% NS 17pdel/11qdel 40% 44% NS

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Richter Transformation of Chronic Lymphocytic Leukemia: Incidence, Risk Factors and Outcome

Blood ◽

10.1182/blood.v112.11.3179.3179 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3179-3179 ◽

Cited By ~ 2

Author(s):

Sina Alipour ◽

Heather Leitch ◽

Linda M Vickars ◽

Lynda M Foltz ◽

Paul F Galbraith ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Lymphocyte Count ◽

Rare Complication ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Age At Diagnosis ◽

P Value ◽

Prior Therapy ◽

Electronic Database Search ◽

Baseline Characteristics

Abstract Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL). There is little information in the literature about its risk and outcome. In this study we assessed the incidence, presenting characteristics and outcomes of patients (pts) with CLL who developed RT. An electronic database search of pts with CLL who presented at St Paul’s Hospital between 1969 and 2007 was performed. Among 465 pts with CLL, 24 pts (5%) developed RT. Presenting features included B-symptoms (17%), lymph node enlargement (58%), progressive cytopenia (29%), hypercalcemia (4%), and spleno/hematomegaly (13%). The median age at diagnosis of CLL and RT were 64 y (range 33–80 y) and 67 y (range 48–81 y) respectively. The median time to transformation from CLL diagnosis was 61 months (range 1–257 m). Twenty one patients (88%) had been previously treated for CLL. Seventeen patients (71%) had received >1 prior therapy. The median lymphocyte count at diagnosis was 12 ×109/L (range 4–120 ×109/L). Six patients (25%) are still alive with a median follow up of 38 m (range: 3–66 m). The only predictive factor for better survival post-transformation on univariate analysis was age of less than 60 y at CLL diagnosis (p=0.01). Other factors such as CLL Rai stage, lymphocyte count at diagnosis were not predictive for survival. This group of patients was compared with randomly selected group of patients with CLL but did not have RT. The baseline characteristics of the groups are presented in the table. No significant differences were found between the two groups in terms of gender, age at diagnosis, Rai stage or median lymphocyte count at diagnosis. The 5 and 10 year OS for the RT group were 76% and 39% compared to 93% and 84% for the CLL group (p= 0.002), respectively. In summary, RT significantly shortens the survival of CLL patients. There were no obvious predictive factors for RT in CLL pts at diagnosis. Table: Baseline characteristics of Richter and CLL groups. Parameter Richter group (%) CLL group (%) P value Number 24 37 Sex: M/F (ratio) 16/8 (2:1) 22/15 (1.5:1) 0.052 Age at Diagnosis: Median (range) 64 (33–80) 60 (37–85) 0.6 Rai stage at diagnosis: 0, 1+2, 3+4 7, 16,1 (29, 67, 4) 23, 14, 0 (62, 38, 0) 0.3 Median lymphocyte count at diagnosis (range) 12 ×109/1 (4–120) 8 × 109/1 (5–394) 0.056 Fig: OS of pts with RT compared with CLL pts and no RT Fig:. OS of pts with RT compared with CLL pts and no RT

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Vegf and bFGF Single-Nucleotide Polymorphisms In Chronic Lymphocytic Leukemia: Impact On Susceptibility

Blood ◽

10.1182/blood.v122.21.5287.5287 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5287-5287

Author(s):

Sandra Ballester ◽

Begoña Pineda ◽

Eduardo Tormo ◽

Blanca Navarro ◽

Ariadna Perez ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Conflicts Of Interest ◽

Expression Patterns ◽

Lymphocytic Leukemia ◽

P Value ◽

Nucleotide Polymorphisms ◽

Exact Test ◽

Cd38 Expression ◽

Mutational Status ◽

The Individual

Abstract Background B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease with a highly variable clinical outcome. Recent studies have identified a number of different molecular prognostic markers (including mutational status of the IgVH gene, ZAP70 and CD38 expression) that allow to discriminate patients in prognostic subgroups. However, different expression patterns of angiogenic factors as VEGF, VEGFR1 and bFGF have been related with B-CLL susceptibility and treatment requirements. We have analyzed the polymorphisms: -710 C/T in VEGFR1, rs1109324, rs1547651, rs3025039 (936C/T) and rs833052 in VEGF and rs1449683 (223 C/T) in bFGF in order to determine the possible association with susceptibility in B-CLL. Methods Peripheral blood samples from 230 B-CLL patients and 476 healthy controls were genotyped using probes TaqMan SNP Genotyping Assays. Samples were providing from the Hospital Clinic of Valencia. Four SNPs in the VEGF gene, one SNP in the bFGF gene and one SNP in the VEGFR1 gene were evaluated. Statistical analysis was performed using SNPStats program (Catalan Institute of Oncology) and Fisher's exact test was applied to evaluate the significance. Results We have observed an increased frequency of the T allele in the rs1449683 SNP [OR 1.62 (95% CI: 0.98-2.66) p-value =0.063] and in the rs1547651 SNP [OR 0.72 (95% CI: 0.51-1.03), p-value=0.072] in our B-LLC patients when compared to control subjects. Moreover we observed that T allele carriers of rs3025039 (VEGF) have a significant protective effect concerning this disease [OR 0.59 (95% CI: 0.39-0.89) p-value=0.009]. Conclusion Our data indicate an increased frequency of the T allele in polymorphisms rs1449683 (bFGF) and rs1547651 (VEGF) in the group of patients, which possibly account for the individual susceptibility to develop B-CLL. On the other hand the data provided suggest that the T allele of VEGF rs3025039 is likely important genetic marker of susceptibility to B-CLL. Further studies regarding the role of pro-angiogenic markers in B-CLL would be beneficial to help elucidate pathogenic pathways in this disease. Disclosures: No relevant conflicts of interest to declare.

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