abt-199 and Tumor-Lysis-Syndrome

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Sulfonamides; Tumor Lysis Syndrome

The treatment landscape in relapsed/refractory chronic lymphocytic leukaemia (CLL) has rapidly evolved over the past five years, with one such emergent treatment being the BCL2 inhibitor, venetoclax. This oral treatment has demonstrated significant clinical advantages in indicated patients, but rapid tumour debulking can lead to a treatment-related risk of the acute condition known as tumour lysis syndrome (TLS). Here, I present real patient cases to show how I have used the recommended predose monitoring and prophylactic procedures to mitigate the risk of TLS. I also used the ramp-up dose escalation schedule of venetoclax therapy initiation to safely take patients through the treatment, successfully providing them with sustained clinical benefits.

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Sulfonamides; Tumor Lysis Syndrome

Tumour lysis syndrome is a complication of chemotherapy for haematological malignancies; in particular, aggressive leukaemias and lymphomas. For haematological malignancies, targeted therapies, such as small molecule inhibitors and monoclonal antibodies, have a high anti-tumour activity, are well tolerated, and have a low incidence of associated tumour lysis syndrome. The BCL-2 inhibitor venetoclax has a high anti-tumour activity in chronic lymphocytic leukaemia, achieving deep remissions by potently inducing apoptosis and increasing the risk for tumour lysis syndrome. In this Viewpoint, we discuss the pathophysiology, risk factors, monitoring, changes in laboratory parameters, and clinical manifestations of tumour lysis syndrome, and the prophylaxis and treatments available for this complication. Prophylaxis and treatment strategies have been implemented as standard of care in patients receiving venetoclax to minimise the risk of both laboratory and clinical manifestations of tumour lysis syndrome.

Topics: Acute Kidney Injury; Allopurinol; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arrhythmias, Cardiac; Bridged Bicyclo Compounds, Heterocyclic; Drug Synergism; Humans; Hyperphosphatemia; Hyperuricemia; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Neoplasm Proteins; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Renal Dialysis; Risk Factors; Severity of Illness Index; Sulfonamides; Tumor Lysis Syndrome; Urate Oxidase

Acute myeloid leukemia (AML) is associated with poor outcomes, especially in older patients in whom the disease is most common. B-cell lymphoma 2 (BCL-2) is an antiapoptotic protein involved in the survival and maintenance of AML, and it is overexpressed in the leukemia stem cell population. Venetoclax is an oral BCL-2 protein inhibitor recently approved by the United States Food and Drug Administration (FDA) for use in combination with a hypomethylating agent (HMA) (azacitidine or decitabine) or low-dose cytarabine for front-line treatment of AML in older patients or those unfit for induction chemotherapy. Given that its mechanism of action is unique, it is not surprising that this widely effective therapy presents unique challenges, including but not limited to the rapidity of responses, the rate and depth of cytopenias, and issues related to drug-drug interactions. With the recent FDA approval and increasingly widespread use, we aim here to summarize, based on evidence and experience, emerging management strategies for the combination of HMAs and venetoclax in the treatment of AML.

Topics: Antibiotic Prophylaxis; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease Management; DNA Methylation; Epigenesis, Genetic; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Mycoses; Sulfonamides; Treatment Outcome; Tumor Lysis Syndrome

Patients with chronic lymphocytic leukemia with the 17p deletion have a poor prognosis and treatment options are limited. Venetoclax, a novel B-cell lymphoma-2 inhibitor, has been approved for treatment-experienced chronic lymphocytic leukemia patients with the 17p deletion. A phase 1 dose-escalation study to 400 mg daily showed overall response rates across all doses of 79% with a complete response achieved in 20%. A phase 2 multicenter open-label study demonstrated overall response rate of 79.4% of patients (95% confidence interval 70.5-86.6) with median duration of follow-up of 12.1 months (IQR 10.1-14.2). Tumor lysis syndrome has been observed during initiation and titration. Assessing risk of tumor lysis syndrome prior to therapy initiation is essential to provide appropriate prophylactic medications. Neutropenia, potentially warranting dose reduction or discontinuation, has been observed. Venetoclax has demonstrated activity in other leukemias, multiple myeloma, and lymphomas. Venetoclax has shown response, and is well tolerated in patients with highly resistant chronic lymphocytic leukemia. It has the potential to be part of the treatment armamentarium for other malignancies.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Sulfonamides; Tumor Lysis Syndrome

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.. 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.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Disease Management; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Purines; Quinazolinones; Risk Factors; Sulfonamides; Tumor Burden; Tumor Lysis Syndrome

Venetoclax (Venclexta™) is a potent, selective, orally available, small-molecule B-cell lymphoma 2 inhibitor that achieves response rates of about 80% and has an acceptable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
.. The aim was to describe treatment management considerations when caring for patients using venetoclax.
.. A review was done of safety and management considerations based on current clinical practice and 240 patients with CLL who received venetoclax monotherapy on clinical trials from 2011-2016.
.. Common adverse events were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Because of rapid tumor reduction with venetoclax, nurses should be aware of the potential for tumor lysis syndrome (TLS) and the need to educate patients on steps to minimize risks, including gradual dose ramp-up, adequate hydration, and use of prophylactic antihyperuricemia agents. Following implementation of these risk-reducing measures, no clinical TLS events were reported in ongoing trials.

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Tumor Lysis Syndrome

Venetoclax, an orally bioavailable inhibitor of BCL-2, was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients with 17p deletion [del(17p)], who have received at least one prior therapy. Areas covered: We focus on the mechanism of action of venetoclax and on the clinical trial data that led to the approval of venetoclax for CLL patients. We also review the studies in which this drug has being explored in combination with other anti-CLL drugs. Expert opinion: Data from early clinical trials have shown that venetoclax, as a single agent, is highly effective for relapsed/refractory CLL patients, including those cases with high-risk features. Furthermore, venetoclax seems to be an appropriate option for patients who progress on B-cell receptor (BCR) pathway kinase inhibitors. Venetoclax is also safe, with the most common serious adverse events being neutropenia. The risk of tumor lysis syndrome (TLS) can be reduced by a slow dose ramp-up, careful monitoring, and adequate prophylaxis. Ongoing trials will further clarify the safety and efficacy of venetoclax in combination with other drugs in both relapsed/refractory and untreated CLL patients.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Sulfonamides; Tumor Lysis Syndrome

To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies.. A literature search was performed of PubMed and MEDLINE databases (2005 to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta.. Studies of pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of venetoclax in lymphoid malignancies were identified.. Recently, treatment of B-cell lymphoproliferative disorders has shifted from conventional cytotoxic chemotherapy to novel small-molecule inhibitors. The advent of recently Food and Drug Administration-approved oral agents ibrutinib and idelalisib has shifted the paradigm of chronic lymphocytic leukemia (CLL) treatment; however, complete remission is uncommon, and the outcome for patients progressing on these treatments remains poor. Attention has been focused on a novel target, the B-cell lymphoma-2 protein (BCL-2), which serves an essential role in regulation of apoptosis. Venetoclax has demonstrated efficacy in multiple subtypes of lymphoid malignancies, including patients with relapsed/refractory CLL harboring deletion 17p, with an overall response rate of nearly 80%. Venetoclax is generally well tolerated, with the significant adverse effect being tumor lysis syndrome, for which there are formal management recommendations.. Venetoclax has demonstrated promising results in relapsed/refractory lymphoid malignancies, with an acceptable adverse effect profile. As the role of BCL-2 inhibition in various malignancies becomes further elucidated, venetoclax may offer benefit to a myriad other patient populations.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Remission Induction; Sulfonamides; Treatment Outcome; Tumor Burden; Tumor Lysis Syndrome

In a Phase 3 international clinical trial (VIALE-C), venetoclax plus low-dose cytarabine improved the response rate and overall survival versus placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia who were ineligible for intensive chemotherapy. After the enrollment period of VIALE-C ended, we conducted an expanded access study to provide preapproval access to venetoclax in combination with low-dose cytarabine in Japan.. Previously, untreated patients with acute myeloid leukemia who were ineligible for intensive chemotherapy were enrolled according to the VIALE-C criteria. Patients received venetoclax (600 mg, Days 1-28, 4-day ramp-up in Cycle 1) in 28-day cycles and low-dose cytarabine (20 mg/m2, Days 1-10). All patients took tumor lysis syndrome prophylactic agents and hydration. Safety endpoints were assessed.. Fourteen patients were enrolled in this study. The median age was 77.5 years (range = 61-84), with 78.6% over 75 years old. The most common grade ≥ 3 treatment-emergent adverse event was neutropenia (57.1%). Febrile neutropenia was the most frequent serious adverse event (21.4%). One patient developed treatment-related acute kidney injury, leading to discontinuation of treatment. Two patients died because of cardiac failure and disease progression that were judged not related to study treatment. No patients developed tumor lysis syndrome.. The safety outcomes were similar to those in VIALE-C without new safety signals and were well managed with standard medical care. In clinical practice, more patients with severe background disease are expected, in comparison with in VIALE-C, suggesting that it is important to carefully manage and prevent adverse events.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Humans; Japan; Leukemia, Myeloid, Acute; Middle Aged; Tumor Lysis Syndrome

Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia.. In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax-rituximab group) or bendamustine plus rituximab for 6 months (bendamustine-rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine-rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival.. After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax-rituximab group (32 events of progression or death in 194 patients) than in the bendamustine-rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P<0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax-rituximab group versus 27.8% in the bendamustine-rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group, but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax-rituximab group was 3.1% (6 of 194 patients).. Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab. (Funded by Genentech and AbbVie; ClinicalTrials.gov number, NCT02005471 .).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Neutropenia; Recurrence; Rituximab; Sulfonamides; Tumor Lysis Syndrome; Young Adult

New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells.. We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.. The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.. Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Recurrence; Remission Induction; Sulfonamides; Tumor Lysis Syndrome

Venetoclax is utilized with low-dose cytarabine or a hypomethylating agent for the treatment of acute myeloid leukemia. Clinical trials report a risk of tumor lysis syndrome and the package insert recommends a venetoclax dose ramp-up at the initiation. The purpose of this study was to evaluate the risk of tumor lysis syndrome in a large population of patients with acute myeloid leukemia outside of a clinical trial and evaluate the incidence of hospital-acquired complications during inpatient ramp-up.. We performed a retrospective study of adult patients with acute myeloid leukemia receiving venetoclax with a hypomethylating agent or low-dose cytarabine. The primary outcome was the incidence of tumor lysis syndrome. Secondary outcomes included risk factors for tumor lysis syndrome, length of admission, and incidence of hospital-acquired complications.. One hundred thirteen patients were included. Although all patients were given some form of prophylaxis, the incidence of tumor lysis syndrome was 8.8%. All were laboratory tumor lysis syndrome; one with hyperuricemia, nine with hypocalcemia, and ten with hyperphosphatemia. Six patients received sevelamer. Tumor lysis syndrome was resolved in all cases. No clinical tumor lysis syndrome occurred. Hepatic dysfunction, tumor lysis syndrome high-risk stratification, higher baseline white blood cell count, and lactate dehydrogenase levels were more common in the tumor lysis syndrome group. Hospital-acquired complications reached 13% in those directly admitted for dose ramp-up.. Tumor lysis syndrome was uncommon and manifested as minor lab abnormalities. White blood cell count continues to be an indicator of risk for tumor lysis syndrome. Those who present with an elevated white blood cell or are otherwise at high risk for tumor lysis syndrome should be admitted for ramp-up. Otherwise, initiation and monitoring of venetoclax are feasible in the outpatient setting.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Humans; Leukemia, Myeloid, Acute; Retrospective Studies; Tumor Lysis Syndrome

Venetoclax is a treatment option in patients with acute myeloid leukemia (AML) in both the front-line and relapsed/refractory settings. Initiation of therapy has been previously restricted to the inpatient setting at some institutions due to a risk of tumor lysis syndrome (TLS) and limitations in medication access efficiency given the high cost of therapy.. We assessed the safety of initiating venetoclax in the outpatient setting through a single-arm, retrospective study of adult AML patients between April 1, 2019 and June 30, 2020.. Eighty-two patients started venetoclax during this time, with 47 (57%) patients initiated in the outpatient setting. Fifty-five percent of patients received venetoclax as first-line treatment for AML (n = 45) and 45% of patients received venetoclax for relapsed/refractory AML (n = 37). Successful initiation, defined as no hospitalizations secondary to TLS within seven days of therapy initiation, occurred in 98% of patients. The rate of TLS was 2.1% (n = 1) following venetoclax initiation. TLS symptoms were managed during hospitalization, requiring only one day of missed AML therapy. Median turnaround time for medication access was three days. Hospitalizations within seven days occurred in 17% of patients (n = 8), with the majority due to febrile neutropenia.. The results of our study provide further evidence for the safety and feasibility of initiating venetoclax in the outpatient setting with a pharmacist-led interdisciplinary protocol.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Outpatients; Retrospective Studies; Tumor Lysis Syndrome

To report the activity of venetoclax in patients with relapsed mantle cell lymphoma (MCL), we identified 81 patients treated with venetoclax monotherapy (n = 50, 62%) or in combination with a Bruton tyrosine kinase inhibitor (BTKi) (n = 16, 20%), an anti-CD20 monoclonal antibody (n = 11, 14%), or other active agents at 12 US academic medical centers. Patients had high-risk disease features including Ki67 >30% (61%), blastoid/pleomorphic histology (29%), complex karyotype (34%), and TP53 alterations (49%), and received a median of 3 prior treatments including BTKis in 91%. Venetoclax alone or in combination resulted in an overall response rate (ORR) of 40% and median progression-free (PFS) and overall survival (OS) of 3.7 and 12.5 months, respectively. The receipt of ≤3 prior treatments was associated with higher odds of response to venetoclax in a univariable analysis. In a multivariable analysis, having a high-risk Mantle Cell Lymphoma International Prognostic Index score before receiving venetoclax and disease relapse or progression within 24 months of diagnosis were associated with inferior OS whereas the use of venetoclax in combination was associated with superior OS. Although most patients (61%) had low risk for tumor lysis syndrome (TLS), 12.3% of patients developed TLS despite the implementation of several mitigation strategies. In conclusion, venetoclax resulted in good ORR but short PFS in patients with MCL who are at high risk, and may have a better role in earlier lines of treatment and/or in conation with other active agents. TLS remains an important risk in patients with MCL who initiate treatment with venetoclax.

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Tumor Lysis Syndrome

Venetoclax combined with a hypomethylating agent (HMA) has become the standard of care for elderly/unfit patients with newly diagnosed acute myeloid leukemia (AML). This study is aimed at characterizing the impact of an interdisciplinary team on the length of stay (LOS) of patients with newly diagnosed AML receiving venetoclax with an HMA.. This retrospective observational study included patients with AML who received HMA with venetoclax as an initial treatment between December 2015 and July 2021. The primary outcome was the median LOS during induction stratified by HMA. Secondary outcomes included barriers to hospital discharge, incidence of tumor lysis syndrome (TLS), response rates, and utilization of the institution's prescription assistance program (PAP).. Seventy-eight patients were included in our analysis: 51 received azacitidine/venetoclax, and 27 received decitabine/venetoclax. The median LOS from therapy initiation was eight days (range 7-38) for the azacitidine group and six days (range 5-26) for the decitabine group. The most common barriers to discharge were transfusion dependence (33 patients, 42.3%) and insurance coverage (12 patients, 15.4%). Twelve patients (15.3%) had tumor lysis syndrome during hospital admission, and 20 (25.6%) were readmitted during induction. Twenty-three patients (29.5%) required financial assistance for AML care, and a pharmacy-led PAP generated approximately $342,646 in cost savings.. The utilization of an interdisciplinary AML team to target early hospital discharge proved to be safe and effective and led to a reduction in costs for the health system. Future research may identify select patients who may be suitable for earlier discharge or outpatient induction.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Decitabine; Humans; Induction Chemotherapy; Leukemia, Myeloid, Acute; Patient Care Team; Patient Discharge; Treatment Outcome; Tumor Lysis Syndrome

This retrospective, observational study evaluated patterns of inpatient versus outpatient tumour lysis syndrome (TLS) monitoring during venetoclax ramp-up in 170 patients with chronic lymphocytic leukaemia. The primary outcome was clinical/biochemical TLS. Two clinical and four biochemical TLS occurred (4.1%). Five of the six events occurred in high-risk patients, four occurred at 20 mg dose and three at the 6-h time-point. Inpatient versus outpatient TLS rates within the high-risk subgroup were 15% and 8%. Risk category was the only predictor of TLS events in multivariate analysis. Outpatient escalation did not associate with clinically meaningful TLS events, suggesting outpatient escalation has manageable associated TLS risks, including in high-risk cohorts. These observations require confirmation in larger studies.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Retrospective Studies; Tumor Lysis Syndrome

Venetoclax is used to treat relapsed/refractory chronic lymphocytic leukemia (r/r CLL). Tumour lysis syndrome (TLS) is a serious toxicity associated with venetoclax, and real-world studies suggest that the incidence may be higher than in clinical trials. The purpose of this study is to describe the incidence of venetoclax toxicities in British Columbia (BC).. Retrospective review of electronic medical charts for patient characteristics and clinical outcomes of patients treated with venetoclax for r/r CLL in BC. Patients were classified according to their risk for developing TLS. The incidence of TLS was categorized based on laboratory metrics or clinical diagnosis. Other non-TLS toxicities were also collected.. Of 33 patients identified, 40%, 33%, and 27% were at low, intermediate, and high risk for TLS, respectively. Laboratory TLS occurred in 1/33 patients (3%), and no clinical TLS was reported. Grade 3 or 4 toxicities occurred in 19/33 patients (58%). Of these, neutropenia was the most common, occurring in 16 patients (84%) followed by thrombocytopenia, which occurred in 8 patients (42%).. The incidence of TLS in patients treated with venetoclax for r/r CLL in BC was lower than in other real-world studies. Findings may warrant further investigation to determine if the higher incidence of TLS in real-world reports may be mitigated through modifying TLS risk categorization and associated prophylactic measures. Neutropenia was the most common grade 3 or 4 venetoclax toxicity reported, and the incidence in BC is comparable to other centres.

Topics: Antineoplastic Agents; British Columbia; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Recurrence; Tumor Lysis Syndrome

Venetoclax is a BCL-2 inhibitor approved for treatment of adult patients with chronic lymphocytic leukemia (CLL). Due to significant risk of tumor lysis syndrome (TLS) upon treatment initiation, a 5-week dose ramp-up is recommended. University of North Carolina Medical Center (UNCMC) utilizes a novel interdisciplinary model of care involving clinical pharmacists (CPs) who oversee the 5-week ramp-up to minimize treatment-related adverse events. The aim of this study was to investigate the effects of a pharmacist-led venetoclax initiation protocol on patient outcomes. The primary objective was to determine the incidence of venetoclax-induced TLS during dose ramp-up in patients managed by a CP. In this cohort (

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Tumor Lysis Syndrome

A combination of azacitidine and venetoclax (AZA-VEN) has been approved for the treatment of adult treatment-naïve acute myeloid leukemia (AML) patients, ineligible for intensive chemotherapy. The protocol may also constitute an alternative for the treatment of patients with mixed phenotype acute leukemia (MPAL), for which no established treatment guidelines exist. It may be anticipated, that alike in AML or chronic lymphocytic leukemia, the treatment of MPAL may be complicated by the tumor lysis syndrome (TLS). No case of TLS in MPAL after VEN has been however reported so far. Here, we present a case of a patient with MPAL, who received AZA-VEN. The patient had a substantial bulk of disease with generalized lymphadenopathy and increased white blood cell count. Despite preventive measures, the patient developed the clinical TLS, which was successfully treated. Based on the current case and other published cases, the incidence of TLS after AZA-VEN was established at 17%.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Phenotype; Sulfonamides; Tumor Lysis Syndrome

Venetoclax (Ven) in combination with azacitidine or decitabine (hypomethylating agent; HMA) is the standard-of-care treatment for older (≥75 years) or intensive chemotherapy ineligible adults with newly diagnosed acute myeloid leukemia (AML). Tumor lysis syndrome (TLS) and infectious complications are two of the most concerning associated adverse events. We studied the real-world incidence and outcomes of these adverse events with HMA/Ven in AML patients. Our retrospective analysis included 106 patients (median age 70 years). Of these, 61 (58%) received HMA/Ven in frontline setting while 45 (42%) received in salvage setting. 19 (18%) met laboratory criteria for TLS, five (5%) developed clinical TLS (acute kidney injury). The median time to develop TLS was 2 days (range -2 to 4). During cycle 1, 29 patients (27%) were diagnosed with febrile neutropenia while 26 (25%) developed new infections. Median time to development of new infection was 10 days (1-25). Pneumonia was the most common infection (8%). Febrile neutropenia and/or new infection during cycle 1 was associated with poorer median overall survival compared to those without these complications (4.9 months vs 11.6 months; p = 0.03). In conclusion, incidence of TLS and infections was high in our cohort during initiation of HMA/Ven therapy. This data emphasizes the need for closer monitoring in these patients, especially during the first 7-10 days of treatment, which is often achieved in the inpatient setting.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Febrile Neutropenia; Humans; Leukemia, Myeloid, Acute; Retrospective Studies; Sulfonamides; Tumor Lysis Syndrome

The phase II CAPTIVATE study investigated first-line treatment with ibrutinib plus venetoclax for chronic lymphocytic leukemia in two cohorts: minimal residual disease (MRD)-guided randomized treatment discontinuation (MRD cohort) and fixed duration (FD cohort). We report tumor debulking and tumor lysis syndrome (TLS) risk category reduction with three cycles of single-agent ibrutinib lead-in before initiation of venetoclax using pooled data from the MRD and FD cohorts.. In both cohorts, patients initially received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day).. In the total population (N = 323), the following decreases from baseline to after ibrutinib lead-in were observed: percentage of patients with a lymph node diameter ≥5 cm decreased from 31% to 4%, with absolute lymphocyte count ≥25 × 109/L from 76% to 65%, with high tumor burden category for TLS risk from 23% to 2%, and with an indication for hospitalization (high TLS risk, or medium TLS risk and creatinine clearance <80 mL/minute) from 43% to 18%. Laboratory TLS per Howard criteria occurred in one patient; no clinical TLS was observed.. Three cycles of ibrutinib lead-in before venetoclax initiation provides effective tumor debulking, decreases the TLS risk category and reduces the need for hospitalization for intensive monitoring for TLS.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Creatinine; Cytoreduction Surgical Procedures; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Piperidines; Sulfonamides; Tumor Lysis Syndrome

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Decitabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Risk Factors; Sulfonamides; Tumor Lysis Syndrome

Topics: Allografts; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Decitabine; DNA Methylation; Drug Evaluation; Febrile Neutropenia; Germany; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Leukocyte Count; Myelodysplastic Syndromes; Recurrence; Retrospective Studies; Salvage Therapy; Sulfonamides; Thrombocytopenia; Transplantation Conditioning; Tumor Lysis Syndrome

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Decitabine; Female; Fluid Therapy; Humans; Hydroxyurea; Incidence; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Leukocytosis; Male; Middle Aged; Phosphate-Binding Proteins; Phosphorus; Proto-Oncogene Proteins c-bcl-2; Retrospective Studies; Sulfonamides; Tumor Lysis Syndrome; Urate Oxidase; Uric Acid

The BCL2 inhibitor venetoclax is transforming the management of patients with chronic lymphocytic leukemia (CLL), given its high efficacy in relapsed/refractory CLL as observed in both early-phase and randomized clinical trials. The present study aimed to determine whether venetoclax is effective and well tolerated in patients with CLL or Richter's syndrome (RS) in a real-world setting and to highlight factors impacting survival. Data from a venetoclax French compassionate use program were collected for 67 patients (60 with CLL and 7 with RS). Most patients presented adverse genetic features, such as TP53 disruption (74%) or complex karyotype (58%). Tumor lysis syndrome was observed in 14 (22%) patients, and 16 (24%) patients were hospitalized for grade III/IV infection. In the CLL cohort, ORR was 75 %, 1-year PFS was 61% (95% CI = 47-72%) and 1-year OS 70% (95% CI = 56-80%). No impact of TP53 disruption was noted while complex karyotype was identified as a predictor of both inferior PFS (HR = 3.46; 95% CI = 1-12; log-rank p = 0.03) and OS (HR = 3.2; 95% CI = 0.9-11.4, log-rank p = 0.047). Among the seven patients with RS, two achieved an objective response to venetoclax; however, the median OS was only 1.1 month. The well-balanced safety/efficacy profile of venetoclax is confirmed in this real-world setting. Complex karyotype should be evaluated as a predictive factor of survival for patients treated by venetoclax.

Topics: Abnormal Karyotype; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Compassionate Use Trials; Drug Evaluation; Female; France; Genes, p53; Hematopoietic Stem Cell Transplantation; Humans; Infections; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Progression-Free Survival; Retrospective Studies; Sulfonamides; Treatment Outcome; Tumor Lysis Syndrome

Venetoclax along with hypomethylating agents (HMAs) is the new standard therapy for older patients with acute myeloid leukemia (AML) not fit for intensive frontline induction chemotherapy. Venetoclax is associated with fatal episodes of tumor lysis syndrome (TLS) in chronic lymphocytic leukemia (CLL), and recommendations are for its initiation for CLL and AML in the inpatient setting with close monitoring. Herein, we evaluated the safety of outpatient venetoclax ramp up when given in addition to HMAs for the treatment of AML.. We conducted a retrospective review of patients diagnosed with AML at our institution from 12/1/2016 until 7/1/2020. We identified patients who received HMAs and venetoclax for AML, either as frontline or relapsed/refractory therapy. Records were reviewed for evidence of laboratory or clinical tumor lysis episodes in all patients.. Between 12/1/2016 and 7/1/2020 43, patients at our institution received venetoclax/HMA for the treatment of AML. Thirty-nine patients (91%) had venetoclax initiation and ramp up in the outpatient setting. One episode of laboratory TLS (2.5%) was identified. This patient required admission to the hospital for rasburicase and IV fluids with resolution of the laboratory effects without resultant clinical TLS. There were no episodes of clinical TLS in either group. Thirty-day mortality from venetoclax initiation was 0% in both groups.. Our experience with HMAs and venetoclax showed that outpatient ramp up of venetoclax is safe with a very low risk of laboratory TLS (2.5%) and no evidence of clinical TLS within our cohort.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Inpatients; Leukemia, Myeloid, Acute; Outpatients; Retrospective Studies; Sulfonamides; Tumor Lysis Syndrome

Topics: Aged; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Male; Sulfonamides; Tumor Lysis Syndrome

The risk of TLS in patients with relapsed CLL treated outside of clinical trials is not well described. Using the Mayo Clinic CLL Database, 48 patients treated with venetoclax for relapsed CLL in routine practice were identified; chart review determined baseline risk for TLS and laboratory abnormalities during venetoclax ramp-up. Overall, 6 (13%) patients developed laboratory TLS, 3 of whom demonstrated clinical TLS. The majority of patients who developed TLS were stratified as low or medium risk by the package insert. Of the 42 patients who did not meet Howard criteria for TLS, isolated hyperphosphatemia occurred in 19 patients (45%), hyperkalemia in 13 patients (31%), hyperuricemia in 2 patients (5%), and hypocalcemia in 1 patient (2%). In routine practice, the incidence of TLS appears higher than reported in clinical trials (3-6%). Half of patients who did not meet criteria for TLS developed clinically significant electrolyte abnormalities that required medical intervention.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Tumor Lysis Syndrome

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Child; Creatinine; Cytochrome P-450 Enzyme Inhibitors; Drug Administration Schedule; Drug Synergism; Female; Humans; Hyperuricemia; Leukemia, Myeloid, Acute; Male; Middle Aged; Retrospective Studies; Sulfonamides; Triazoles; Tumor Lysis Syndrome; Urate Oxidase; Uric Acid; Young Adult

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Patients; Sulfonamides; Tumor Lysis Syndrome

Recent developments in the management of chronic lymphocytic leukemia (CLL) have moved the standard of care away from chemoimmunotherapy to targeted agents such as oral kinase inhibitors or BCL-2 antagonists, alone or in combination with anti-CD20 antibodies. Two different treatment approaches have evolved: continuous, indefinite treatment and, more recently, fixed-duration combination treatment. With venetoclax-based treatment, there is a requirement to follow the established guidelines for close monitoring during initiation and ramp up, to reduce the risk of tumor lysis syndrome. The patient's risk should be assessed before the initiation of venetoclax. Appropriate management strategies should be used, including uricosuric agents, hydration, and routine laboratory monitoring, per guidelines. With early identification, immediate management, and dose adjustments, we suggest that tumor lysis syndrome and other toxicities, such as neutropenia and infections, with venetoclax-based treatment can be dealt with successfully.

Topics: Agammaglobulinaemia Tyrosine Kinase; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Kinase Inhibitors; Sulfonamides; Tumor Lysis Syndrome

Venetoclax is a highly effective agent in chronic lymphocytic leukemia and acute myeloid leukemia. Phase I/II clinical trials have shown it to be safe and effective in non-Hodgkin lymphoma (NHL). Adverse events were consistent with package labeling despite escalation to high doses. To the best of our knowledge, venetoclax use outside the setting of a clinical trial of NHL has not been reported.. We conducted a single-center, retrospective study of 34 adult patients who had been treated off-label with venetoclax-containing regimens from 2016 to 2018.. Of the 34 patients with NHL treated with venetoclax therapy, 13 had had high-grade B-cell lymphoma/diffuse large B-cell lymphoma, 10 mantle cell lymphoma, 5 transformed follicular lymphoma, 2 Richter transformation, 2 marginal zone lymphoma, 1 follicular lymphoma, and 1 post-transplant lymphoproliferative disorder. The patients had received a median of 4 previous therapies. The overall response rate was 26% (3% with a complete response and 35% with stable disease). The median venetoclax dose achieved was 400 mg. Of those receiving combination therapy, 18% had undergone radiation and 62% had received other systemic antineoplastic therapy. The median progression-free and overall survival for the cohort was 2 and 4.5 months, respectively. Adverse events occurred in 76% of the patients during venetoclax therapy. The adverse events included neutropenia, thrombocytopenia, tumor lysis syndrome, infection, neutropenic fever, diarrhea, and 1 opportunistic infection.. Venetoclax therapy in a real-world cohort offered modest benefits in heavily pretreated patients. Adverse events were observed at a greater incidence than in the clinical trials. A wide heterogeneity of venetoclax dose escalation, multiagent combinations, and timing of initiation were identified and require investigation in subsequent clinical trials.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Off-Label Use; Recurrence; Retreatment; Retrospective Studies; Sulfonamides; Treatment Outcome; Tumor Lysis Syndrome

Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.. This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.. These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Patient Safety; Practice Patterns, Physicians'; Proto-Oncogene Proteins c-bcl-2; Retrospective Studies; Sulfonamides; Treatment Outcome; Tumor Lysis Syndrome

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease Management; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Recurrence; Sulfonamides; Survival Analysis; Treatment Outcome; Tumor Lysis Syndrome

Early data on venetoclax-containing regimens for the treatment of chronic lymphocytic leukemia (CLL) show promising results with deep remissions, but are hampered by potential risk for tumor lysis syndrome (TLS). Whether optimal duration of venetoclax treatment can be guided by minimal residual disease (MRD) is currently unknown. To study whether TLS risk can be mitigated in an unfit population by introducing preinduction, and whether MRD-guided duration of venetoclax treatment is a feasible and efficacious approach, we performed the Dutch-Belgian Cooperative Trial Group for Hemato-oncology (HOVON) 139/GIVE trial. The study treatment consists of 4 treatment phases: preinduction (2 cycles obinutuzumab), induction I (6 cycles obinutuzumab and venetoclax), induction II (6 cycles venetoclax), and a randomization phase (group A: maintenance with 12 additional cycles of venetoclax irrespective of MRD; group B: MRD guided venetoclax maintenance with a maximum of 12 cycles). Here we report on a planned interim safety analysis as well as preliminary efficacy and MRD data of the first 30 patients enrolled. Downgrading of TLS risk after preinduction occurred in 25 patients: 3 from high to medium, 3 from high to low, and 19 from medium to low risk. No patient remained high risk. From these 30 patients, peripheral blood MRD data were obtained for 28 patients at the end of induction II (6 months after the last obinutuzumab dose), of whom 26 had undetectable MRD levels, and for 18 patients who reached the 3-month after-randomization point, of whom 16 had undetectable MRD levels. Obinutuzumab preinduction is tolerated well in these unfit patients and results in abrogating high TLS risk in all patients. Preliminary data indicate that efficacy is maintained with a high proportion of patients with undetectable MRD levels after combination treatment.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Remission Induction; Risk Factors; Sulfonamides; Tumor Lysis Syndrome

Venetoclax is a potent, selective inhibitor of BCL-2, a key regulator of the intrinsic pathway of apoptosis. In preclinical studies, venetoclax bound to BCL-2 with high affinity and rapidly induced apoptosis in chronic lymphocytic leukemia (CLL) cells. In early-phase clinical trials in CLL, venetoclax treatment led to tumor lysis syndrome in some patients with a large tumor burden, but this risk was subsequently mitigated by a revised study design that included lower initial dosing with intrapatient dose ramp up and close tumor lysis syndrome monitoring and prophylaxis. Other toxicities, such as neutropenia and gastrointestinal adverse events, were manageable. Venetoclax monotherapy resulted in durable and deep responses in patients with relapsed, refractory CLL, including for those with deletion 17p, leading to the approval of venetoclax by the US FDA for relapsed or refractory deletion 17p CLL, and recently to additional approvals in Europe and Canada. Trials also suggest that venetoclax induces deeper and more durable responses when used in combination with rituximab, and combination studies with other agents are ongoing. Phase III trials are also underway, and will provide data on the efficacy and safety of venetoclax in combination with monoclonal antibodies and targeted therapies in larger patient populations.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug-Related Side Effects and Adverse Reactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Proto-Oncogene Proteins c-bcl-2; Recurrence; Sulfonamides; Tumor Lysis Syndrome