The impacts of zanubrutinib on immune cells in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

Ibrutinib, a first‐generation Bruton's tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second‐generation selective BTK inhibitor, has similar effects as ibrutinib remains to be determined. Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests. The expression intensity of programmed death‐1 (PD‐1) on total CD4⁺ (P < .01), total CD8⁺ (P < .01), and T helper cells (P < .05) and cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4) on total CD4⁺ (P = .010) and regulatory T cells (P < .05) reduced after treatment. There were significant differences in expression intensity of CD19 (P < .01), C‐X‐C chemokine receptor type 5 (CXCR5) (P < .01), and CD49d (P < .05) on B cells before and after treatment. Downregulation of PD‐1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. Programmed death‐ligand 1 expression downregulated, especially in the female, CLL, normal spleen, normal β2‐macroglobulin (β2‐MG) and abnormal lactate dehydrogenase (LDH) subgroups, and CTLA‐4 expression on CD4+ T cells tended to decrease in the male, old, CLL, splenomegaly, abnormal β2‐MG, normal LDH, IGHV‐mutated and wild‐type tumor protein 53 subgroups after zanubrutinib treatment. These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through downregulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors.     

含氟达拉滨的联合化疗方案治疗慢性淋巴细胞白血病／小淋巴细胞性淋巴瘤

目的：评价以氟达拉滨为主的化疗方案治疗慢性淋巴细胞白血病／小淋巴细胞淋巴瘤（CLI／SLL）的疗效和不良反应。方法：采用氟达拉滨为主的化疗方案，FC方案：氟达拉滨＋环磷酰胺；FMD方案：氟达拉滨＋米托蒽醌＋地塞米松；FMC方案：氟达拉滨＋米托蒽醌＋环磷酰胺，共治疗18例CLL／SLL患者，其中初发9例，复发、难治9例。结果：18例患者平均完成4．2个周期，完全缓解（CR）率61．1％，部分缓解（PR）率22．2％，总的有效（OR）率83．3％。初发组CR率66．7％。PR率33．3％，OR率100％；复发、难治组CR率55．6％，PR率11．1％，OR率66．7％，两组CR、OR率无显著性差异（P〉0．05）。FC方案和FMD方案治疗组CR、OR率无显著性差异（P〉0．05）。主要不良反应为骨髓抑制和免疫功能抑制，27．8％的患者出现Ⅲ～Ⅳ级粒细胞减少，22．2％的患者出现Ⅲ～Ⅳ级血小板减少。5例患者出现感染、发热，其中1例死亡。其它毒性包括恶心、呕吐，轻度肝肾功能损害，自身免疫性溶血性贫血。中位随访时间24月（1～40月），2年生存率88．9％，2年PFS率81．8％。初发组2年生存率100％，2年PFS率100％；难治组2年生存率83．3％，2年PFS率66．7％，两组无显著性差异（P〉0．05）。结论：氟达拉滨为主的联合化疗方案对CIL／SLL疗效好，同时患者对其耐受性亦较佳。     

Fluorescence in situ hybridization detection of cytogenetic abnormalities in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma

Routine cytogenetic analysis of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) frequently fails to identify an abnormal clone due to the low rate of spontaneous mitoses and poor response to mitogen stimulation. Recent studies utilizing interphase fluorescence in situ hybridization (FISH) suggest that prognostically significant chromosomal abnormalities occur more frequently in B-CLL/SLL than has been previously recognized. The purpose of this study was to compare the chromosomal abnormalities detected by karyotyping and FISH in cases of B-CLL/SLL, and to correlate these with clinical features and survival. Seventy-two cases were studied for chromosome 3, 12 or 18 aneuploidy, and for rearrangements involving 11q13, 11q23, 13q14, 14q32 and 17p13. The median age of the patients was 54 years (range, 30 - 87 years). Clinical staging of B-CLL patients showed that 70% of the patients were Rai stage 0, 1, or 2, and 30% stage 3 or 4. Karyotyping identified chromosomal abnormalities in 31% of the cases, whereas FISH studies were abnormal in 72% of cases including 64% of the cases with normal karyotypes. The most common abnormalities were deletion 13q14 (46%), trisomy 12 (21%), and 14q32 rearrangements (21%). At diagnosis, patients with trisomy 12 were more likely to have a high LDH (P = 0.04), but no other significant differences in the clinical or laboratory features, Rai stage, or survival were found among patients with normal cytogenetics vs. those with chromosomal abnormalities. Univariate analysis showed that B-symptoms (P = 0.044), anemia (P = 0.0006), absolute lymphocytosis ≥ 30,000/mm³ (P = 0.029), and Rai stage 3 or 4 (P = 0.0038) at initial presentation were associated with an increased risk of death, but only Rai stage 3 or 4 (P = 0.0038) was significant in multivariate analysis. Interphase FISH studies improve the cytogenetic diagnosis when performed in conjunction with karyotyping in B-CLL/SLL, but the prognostic relevance of various abnormalities could not be confirmed in this study.     

High incidence of relapse after autologous stem-cell transplantation for B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma

Background: High-dose therapy followed by autologous stem-cell transplantation (autoSCT) induces complete remissions in the majority of patients with advanced B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma (B-CLL). However, the long-term utility of this therapy for B-CLL is unknown.Patients and methods: Sixteen previously treated patients with B-CLL were transplanted using autologous blood (n = 13) or bone marrow (n = 3). The median age of the patients was 49 years (range 44–60 years), and the median number of prior chemotherapy regimens was two. Patients were eligible for transplantation if they had chemosensitive disease and no morphologic evidence of malignant cells in the graft. Preparative regimens included cyclophosphamide and total-body-irradiation, with or without cytarabine, or BEAC.Results: All patients engrafted and achieved a complete remission posttransplant. Ten patients were alive at a median of 41 months (range 22–125 months), and five were disease-free. Eight patients have relapsed and six have died (three from progressive malignancy). The projected three-year overall survival, failure-free survival and relapse rates were 68%, 37%, and 56%, respectively.Conclusions: AutoSCT for advanced B-CLL is associated with a high relapse rate. Whether this therapy can prolong life or produce cures is uncertain.     

The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation

BACKGROUND:

Patients with recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) often have chemotherapy‐resistant disease, resulting in poor prognosis. The aim of this study was to learn if inhibition of the mammalian target of rapamycin (mTOR) would produce tumor responses.

METHODS:

This was a phase 2 study of oral single‐agent everolimus (10 mg/day) for recurrent/refractory indolent lymphoid malignancies including CLL.

RESULTS:

Four of 22 patients with CLL (18%; 95% confidence interval, 5%‐40%) achieved a partial remission to therapy. An unanticipated finding in this study was an increase in absolute lymphocyte count (ALC) associated with a decrease in lymphadenopathy in 8 (36%) patients. ALC increased a median of 4.8‐fold (range, 1.9‐ to 25.1‐fold), and the clinically measurable lymphadenopathy decreased a median of 75.5% (range, 38%‐93%) compared with baseline measurements.

CONCLUSIONS:

Everolimus has modest antitumor activity against CLL and can mobilize malignant cells from nodal masses into the peripheral circulation in a subset of CLL patients. Because CLL cells in lymphatic tissue and bone marrow can be more resistant to therapy than circulating CLL cells, the ability of everolimus to mobilize CLL cells into the circulation could be used in combination therapeutic regimens. Cancer 2010. © 2010 American Cancer Society.     

An open-label expanded-access trial of bendamustine in patients with rituximab-refractory indolent non-Hodgkin lymphoma or previously untreated chronic lymphocytic leukemia: BEND-ACT

Background

Bendamustine is a bifunctional alkylating agent with unique properties that distinguish it from other agents in its class. Bendamustine is used as monotherapy or in combination with other agents to treat patients with non-Hodgkin lymphoma (nhl) and chronic lymphocytic leukemia (cll).

Methods

The prospective interventional open-label bend-act trial evaluated bendamustine in patients with rituximab-refractory indolent nhl (inhl) and previously untreated cll. Study objectives were to assess the safety and tolerability of bendamustine monotherapy and to provide patients with access to bendamustine before Health Canada approval. The study aimed to enrol up to 100 patients. All patients with inhl received an intravenous dose of bendamustine 120 mg/m² over 60 minutes on days 1 and 2 for up to eight 21- or 28-day treatment cycles. All patients with cll received an intravenous dose of bendamustine 100 mg/m² over 30 minutes on days 1 and 2 for up to six 28-day treatment cycles.

Results

Of 90 patients treated on study (16 with cll and 74 with inhl), 35 completed the study (4 with cll and 31 with inhl). The most common treatment-emergent adverse events (teaes) were nausea (70%), fatigue (57%), vomiting (40%), and diarrhea (33%)—mostly grades 1 and 2. Ondansetron was the most common supportive medication used in the patients (63.5% of those with inhl and 68.8% of those with cll). Neutropenia (32%), anemia (23%), and thrombocytopenia (21%) were the most frequent hematologic teaes, with neutropenia being the most common grade 3 or 4 teae leading to dose modification. Dose delays occurred in 28 patients (31.3%) because of grade 3 or 4 teaes, with a higher incidence of dose delays being observed in inhl patients on the 21-day treatment cycle than in those on the 28-day treatment cycle (50.0% vs. 24.1%). During the study, 33 patients (36.7%) experienced at least 1 serious adverse event, and 4 deaths were reported (all in patients with inhl).

Conclusions

The type and frequency of the teaes reported accorded with observations in earlier clinical trials and post-marketing experiences, thus confirming the acceptable and manageable safety profile of bendamustine.     

Merkel cell polyomavirus (MCPyV) in chronic lymphocytic leukemia/small lymphocytic lymphoma

Merkel cell polyomavirus (MCPyV) is a novel polyomavirus that shows a strong association with Merkel cell carcinoma (MCC). Recent studies have demonstrated MCPyV in some cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), a malignancy with a similar demographic as MCC. We tested for the presence of MCPyV by PCR and immunohistochemistry in 18 cases of CLL/SLL. Very low-level MCPyV DNA was detected in 33% of CLL/SLL cases by real-time PCR, but only one case demonstrated immunohistochemical positivity for MCPyV. MCPyV was not identified in 17 cases of follicular lymphoma, suggesting either that MCPyV is involved in CLL/SLL pathogenesis or that the immunodeficiency state of CLL/SLL induces low-level MCPyV reactivation.     

Hematologist/oncologist disease-specific expertise and survival: lessons from chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)

BACKGROUND:

The impact of physicians' disease‐specific expertise on patient outcome is unknown. Although previous studies suggest a survival advantage for cancer patients cared for at high‐volume centers, these observations may simply reflect referral bias or better access to advanced technologies, clinical trials, and multidisciplinary support at large centers.

METHODS:

We evaluated time to first treatment (TTFT) and overall survival (OS) of patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) at a single academic center based on whether they were cared for by a hematologist/oncologist who subspecializes in CLL (CLL hematologist) or a hematologist/oncologist with expertise in other areas (non‐CLL hematologist).

RESULTS:

Among 1309 newly diagnosed patients with CLL cared for between 1999 and 2009, 773(59%) were cared for by CLL hematologists and 536 were cared for by non‐CLL hematologists. Among early‐stage patients (Rai 0‐I), median TTFT (9.2 vs 6.1 years; P < .001) and OS (10.5 years vs 8.8 years; P < .001) were longer for patients cared for by CLL hematologists. For all patients, OS was superior for patients cared for by CLL hematologists (10.5 years vs 8.4 years; P = .001). Physician's disease‐specific expertise remained an independent predictor of OS after adjusting for age, sex, stage, and lymphocyte count at diagnosis. Patients seen by a CLL hematologist were also more likely to participate in clinical trials (48% vs 16%; P < .001).

CONCLUSIONS:

Physician disease‐specific expertise appears to influence outcome in patients with CLL. To the greatest extent possible, patients should be cared for by a hematologist/oncologist expert in the care of their specific malignancy. When not possible, practice guidelines developed by disease‐specific experts should be followed. Cancer 2012. © 2011 American Cancer Society.     

Combination therapy with fludarabine and rituximab followed by alemtuzumab in the first-line treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase 2 trial of the Minnie Pearl Cancer Research Network

BACKGROUND: The purpose of the current study was to evaluate the efficacy and toxicity of the combination of fludarabine and rituximab, followed by alemtuzumab, as first-line treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). METHODS: In a nonrandomized phase 2 trial, 41 patients who had previously untreated CLL or SLL and required treatment received 4 cycles of the fludarabine and rituximab combination followed 5 weeks later by 4 weeks (12 doses) of intravenous alemtuzumab therapy. The response to treatment was evaluated after completion of treatment with fludarabine and rituximab, and again after the completion of alemtuzumab consolidation. RESULTS: Initial treatment with the combination of fludarabine and rituximab was well tolerated, and produced a 71% overall response rate (13% complete response). Thirty-four patients began treatment with intravenous alemtuzumab, but this drug was relatively poorly tolerated when given at a short interval after fludarabine and rituximab, and only 20 patients (49% of total) were able to complete the prescribed course. Five patients had an improvement in their response with alemtuzumab; the final complete response rate was 21%. The median progression-free survival for the entire group was 42 months. Toxicity with alemtuzumab included infusion-related toxicity, myelosuppression, and opportunistic infections. CONCLUSIONS: The intravenous schedule of alemtuzumab employed in the trial was relatively poorly tolerated in this community-based trial. The relatively low complete response rates after treatment with the combination of fludarabine and rituximab and after the completion of treatment suggest that these abbreviated courses may compromise efficacy. The generalized use of alemtuzumab as consolidation therapy cannot yet be recommended for community practice. However, optimization of the route of administration, duration of treatment, and interval after completion of induction therapy may improve efficacy, and further investigation is ongoing.     

A Canadian perspective on bendamustine for the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma

Despite the success of standard treatments in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), patients are often unable to tolerate aggressive regimens, and they require effective alternatives. Bendamustine is a bifunctional alkylator with unique properties that significantly distinguish it from other agents in its class. In untreated CLL, bendamustine has demonstrated rates of response and progression-free survival (PFS) that are superior to those with chlorambucil, with an acceptable toxicity profile. In the relapsed setting, combination treatment with bendamustine-rituximab (BR) has demonstrated promising activity in high-risk patients such as those refractory to fludarabine or alkylating agents. In untreated patients with indolent NHL and mantle cell lymphoma, BR has demonstrated a PFS significantly longer than that achieved with R-CHOP (rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone), with significantly reduced toxicity. In the relapsed setting, br has demonstrated rates of response and PFS superior to those with fludarabine-rituximab, with comparable toxicity. In the United States and Europe, bendamustine has been approved for the treatment of CLL and indolent NHL; its approval in Canada is pending and eagerly awaited. Once available, bendamustine will benefit many Canadian patients with NHL and CLL.     

The ultrastructural study of non-Hodgkin’s lymphoma cell,chronic lymphocytic and hairy cell leukemia

Non-Hodgkin’s lymphoma cell leukemia (NHLCL), chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HLC) are the diseases very similar to each other. The differential diagnosis is very difficult, especially when there are small lymphoid cells in peripheral blood and bone marrow under light microscope. We have observed 34 cases with electron microscope. The studies were correlated with clinical manifestation, cytology, pathology and immunologic histochemistry. Ultrastructural features strongly indicated the difference in three various diseases, although all the immunologic markers showed B-cell type. It is concluded that electron microscopic examination is of a definite significance in the diagnosis and successful treatment.     

Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin's lymphoma and chronic lymphocytic leukemia

: Indolent non-Hodgkin’s lymphoma (INHL) and chronic lymphocytic leukemia (CLL) are highly sensitive to radiotherapy (RT). Previous retrospective studies have shown high response rates after local palliative RT of 4 Gy in 2 fractions, which prompted this prospective Phase II trial of the palliative effect of this regimen in patients with disseminated INHL or CLL.

: Twenty-two patients (11 men, 11 women, median age 62 years, range 30–89) with disseminated INHL (n = 15) or CLL (n = 7) were treated with local low-dose RT, 2 Gy × 2 within 3 days, with the aim of achieving palliation from localized lymphoma masses. The patients were treated to a total of 31 different sites. Seventeen patients had previously been treated with chemotherapy. The median observation time after the start of RT was 8 months (range 3–26).

: All patients and all irradiated sites were assessable for response. Of the 22 patients, 18 responded to the treatment, corresponding to an overall response rate (RR) of 82%; 12 patients (55%) achieved a complete response (CR), 5 patients (22%) a partial response (PR), and 1 patient had a CR at three sites and a PR at one site. Of the 31 irradiated sites, 27 responded to treatment, corresponding to an overall RR of 87%; in 20 sites (65%) a CR was achieved and in 7 sites (22%) a PR. Patients with disseminated INHL had an overall RR of 87% (74% CR, 13% PR); patients with CLL had an overall RR of 71% (29% CR, 42% PR). The median duration of response was estimated at 22 months. None of the patients had significant side effects from the treatment.

: Low-dose RT (4 Gy in 2 fractions) is a highly effective palliative treatment of localized lymphoma masses in patients with disseminated INHL and CLL. The treatment has minimal side effects.     

Veterans with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have a markedly increased rate of second malignancy, which is the most common cause of death

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have an increased incidence of high-grade lymphoid malignancy. The risk of non-lymphoid second malignancy in this population is not well-defined to date. To test the hypothesis that patients with CLL/SLL have an increased risk of second malignancy, we studied the rate of second malignancy in 132 CLL/SLL patients and compared it to the rate of malignancy (excluding non-melanomatous skin cancer) in the Central Arkansas Veterans Healthcare System population of approximately 38,000 veterans over a period of 11.5 years. The rate of second malignancy, diagnosed concomitantly or after CLL/SLL, and the age-adjusted rate of malignancy calculated from tumor registry reports and demographic data, were used to calculate a Standardized Morbidity Ratio (SMR) with 95% confidence interval (CI). Twenty-one (16%) of the CLL/SLL patients had second malignancies (19 non-lymphoid, 1 Richter's transformation and 1 Hodgkin's disease), which were fatal in 15 (71%) patients. The SMR for the CLL/SLL population was 2.97 (95% CI 1.84 - 4.55) for second malignancy and 2.69 (95% CI 1.62 - 4.21) for non-lymphoid second malignancy. This study of a well-defined CLL/SLL population shows a significantly increased risk of second malignancy, which was the primary cause of death for 9% of all CLL/SLL patients (34% of all patient deaths).     

Age at diagnosis and the utility of prognostic testing in patients with chronic lymphocytic leukemia

BACKGROUND:

A study was undertaken to analyze the survival of chronic lymphocytic leukemia (CLL) patients relative to age‐matched individuals in the general population and determine the age‐stratified utility of prognostic testing.

METHODS:

All 2487 patients diagnosed with CLL between January 1995 and June 2008 and cared for in the Mayo Clinic Division of Hematology were categorized by age at diagnosis and evaluated for differences in clinical characteristics, time to first treatment, and overall survival (OS).

RESULTS:

Among Rai stage 0 patients, survival was shorter than the age‐matched general population for patients aged <55 years (P < .001), 55 to 64 years (P < .001), and 65 to 74 years (P < .001), but not those aged ≥75 years at diagnosis (P = not significant). CD38, IGHV mutation, and ZAP‐70 each predicted time to first treatment independent of stage for all age groups (all P < .04), but had less value for predicting OS, particularly as age increased. IGHV and fluorescent in situ hybridization (FISH) predicted OS independent of stage for patients aged <55 years (P ≤ .001), 55 to 64 years (P ≤ .004), and 65 to 74 years (P ≤ .001), but not those aged ≥75 years. CD38 and ZAP‐70 each predicted OS independent of stage for only 2 of 4 age categories. Among Rai 0 patients aged <75 years, survival was shorter than the age‐matched population only for IGHV unmutated (P < .001) patients or those with unfavorable FISH (P < .001).

CONCLUSIONS:

Survival of CLL patients aged <75 years is shorter than the age‐matched general population regardless of disease stage. Among patients aged <75 years, the simple combinations of stage and IGHV or stage and FISH identifies those with excess risk of death relative to the age‐matched population. Although useful for predicting time to first treatment independent of stage for patients of all ages, prognostic testing had little utility for predicting OS independent of stage among patients aged ≥75 years. Cancer 2010. © 2010 American Cancer Society.     

Management of adverse events associated with idelalisib treatment in chronic lymphocytic leukemia and follicular lymphoma: A multidisciplinary position paper

The introduction of new therapeutic agents in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), including the new kinase inhibitor idelalisib, has changed the therapeutic landscape of these diseases. However, the use of idelalisib is associated with a peculiar profile of side effects, which require an optimization of the current approach to prophylaxis and supportive treatment. Moving from the recognition that the abovementioned issue represents an unmet need in CLL and FL, a multidisciplinary panel of experts was convened to produce a consensus document aiming to provide practical recommendations for the management of the side effects during idelalisib therapy for CLL and FL. The present publication represents a consensus document from a series of meetings held during 2017. The Panel generated clinical key questions using the criterion of clinical relevance through a Delphi process and explored 4 domains, ie, diarrhea/colitis, transaminitis, pneumonitis, and infectious complications. Using the consensus method, the Panel was able to shape recommendations which may assist hematologist to minimize adverse events and guarantee adherence to treatment in patients with CLL and FL candidate to receive idelalisib.     

Enzymatic differences between chronic lymphocytic leukemia and prolymphocytic leukemia

Chronic lymphocytic leukemia and prolymphocytic leukemia of the B-cell immunophenotype are closely related disorders, but differ in their cytomorphologic and clinical features. In an attempt to differentiate further between these two forms of leukemia, we measured adenosine deaminase and purine nucleoside phosphorylase activities by using a linked-enzyme spectrophotometric assay on peripheral-blood leukemic cells from seven patients with chronic lymphocytic leukemia, three patients with prolymphocytic leukemia, and one patient with prolymphocytoid transformation of chronic lymphocytic leukemia. By using discriminant analysis, we were able to distinguish the two groups only on the basis of purine nucleoside phosphorylase activity (F1,9; p less than 0.001). The purine nucleoside phosphorylase activity in leukemic cells with prolymphocytic cytomorphology was significantly elevated (mean = 58.6 nM/min/mg protein) compared to the activity in leukemic cells with lymphocytic cytomorphology (mean = 25.6 nM/min/mg protein). There was only one patient with chronic lymphocytic leukemia who was assigned to the prolymphocytic leukemia group on the basis of her purine nucleoside phosphorylase activity. Our study suggests that purine nucleoside phosphorylase activity in leukemic cells may be useful in the distinction of prolymphocytic leukemia from chronic lymphocytic leukemia, and that it may be an enzymatic marker for the early detection of prolymphocytoid transformation of chronic lymphocytic leukemia.     

Hybrid form of hairy cell leukemia and chronic lymphocytic leukemia

We report a case with mixed features of hairy cell leukemia (HCL) and chronic lymphocytic leukemia (CLL), which may represent a hybrid form of these two entities. Hairy projections were demonstrated on leukemic cells in the peripheral blood. Surface marker studies of blood and spleen specimens by flow cytometry and immunohistochemistry showed immunophenotype characteristic of HCL, namely, monoclonal IgG-kappa, positive reactions to CD 11c, CD 19, CD 20, Cd 22, and HLA-DR, but negative reactions to CD 3, CD 5, CD 7 and CD 10. The only atypical finding was the absence of CD 25. Immunogenotyping showed rearrangement of heavy-chain and kappa light chain genes. Leukemic cells were also positive for tartrate-resistant acid phosphatase (TRAP). A pseudosinus pattern was demonstrated in the spleen. However, the leukemic cells in the spleen showed atypical cytologic features. Clinically, the patient had generalized lymphadenopathy, high leukocyte counts, Coombs' negative hemolysis, hypoimmunoglobulinemia and IgG-kappa monoclonal gammopathy, features more consistent with CLL than HCL. Although only CD 11c, CD 22, CD 25 and TRAP are characteristic for HLC and CD 5, characteristic for CLL, a panel of eight markers is recommended for the differential diagnosis of HCL, CLL and other low-grade B-cell neoplasms, which may share some common features, making a clear-cut diagnosis difficult.     

Decreased sensitivity of 17p-deleted chronic lymphocytic leukemia cells to a small molecule BCL-2 antagonist ABT-737

BACKGROUND:

Despite the high complete response rates achieved with fludarabine‐based regimens, relapse is inevitable in chronic lymphocytic leukemia (CLL). Relapsed patients often acquire deletions of the short arm of chromosome 17 (del[17p]), which are closely associated with tumor protein 53 (TP53) mutations. Wild‐type p53 up‐regulates and activates B‐cell CLL/lymphoma 2 (BCL‐2)‐associated X protein (BAX), and it down‐regulates and inactivates BCL‐2. The small‐molecule BCL‐2 inhibitor ABT‐737 induces apoptosis in a BAX‐dependent and BCL‐2 homologous antagonist‐killer (BAK)‐dependent manner. The role of p53 in sensitivity of CLL cells to BCL‐2 inhibition has not been extensively investigated.

METHODS:

The authors investigated the association of del(17p) with ABT‐737 sensitivity in CLL cells from 50 patients. Stable p53 and BAX knockdown cells were used for mechanistic studies.

RESULTS:

CLL cells with del(17p) were less sensitive to ABT‐737‐induced BAX activation and apoptosis than CLL cells without del(17p) (39% ± 7.3% vs 63.7% ± 2.9% [specific annexin V induction]; P < .01). A positive correlation between the degrees of apoptosis induced by ABT‐737 and by the p53‐activating binding protein homolog murine double minute (MDM2) antagonist nutlin‐3a (correlation coefficient [r] = 0.75; P < .0001) was observed. CLL cells with del(17p) expressed lower levels of BAX than those without del(17p) (0.67 ± 0.12 vs 1.27 ± 0.10 in relative protein expression levels; P < .01). Knockdown of p53 or BAX in leukemia cells resulted in decreased apoptosis induced by ABT‐737.

CONCLUSIONS:

The current data indicated that p53 dysfunction may lead to decreased apoptosis induction by ABT‐737. Cancer 2012;. © 2011 American Cancer Society.     

慢性淋巴细胞白血病伴中枢神经系统浸润1例并文献复习

    目的   探讨慢性淋巴细胞白血病（chronic lymphocytic leukemia,CLL）伴中枢神经系统（central nervous system,CNS）浸润的发病率、诊治方法及预后。    方法   报道1例以头晕、复视、肢体无力为首发表现的CLL患者诊治经过并结合文献复习。    结果   尸解研究显示CLL浸润CNS的发生率为8%~71%,而患者生前出现有症状CNS浸润的发生率较低约1%,发生原因与临床分期、年龄、性别及疾病变异无明确相关性,临床表现不特异,诊断主要依靠脑脊液细胞形态学结合流式细胞分析,鞘内化疗及放疗可使多数患者CNS症状及脑脊液改善,未治疗的患者均迅速恶化死亡。    结论   CLL有症状的CNS浸润较少见,一旦发生预后差,及时诊断和积极治疗是获得长期缓解的关键。