Tumor lysis syndrome: an uncommon complication of fludarabine therapy of chronic lymphocytic leukemia.

1998 ◽  
Vol 16 (7) ◽  
pp. 2313-2320 ◽  
Author(s):  
B D Cheson ◽  
J N Frame ◽  
D Vena ◽  
N Quashu ◽  
J M Sorensen
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Duration ◽  
Tumor Lysis Syndrome ◽  
Laboratory Data ◽  
Lymphocytic Leukemia ◽  
Phase Ii Trials ◽  
Tumor Lysis ◽  
Laboratory Features

PURPOSE To quantify the incidence and severity of tumor lysis syndrome (TLS) as a consequence of fludarabine therapy in patients with advanced chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS A retrospective review and questionnaire follow-up of clinical and laboratory data were performed on patients with intermediate or high-risk CLL on the National Cancer Institute Group C protocol or special exception mechanisms, or phase II trials of fludarabine, for whom adverse drug reports of TLS were available. Fludarabine was administered at a dose of 20 to 40 mg/m2 per day for 5 days at monthly intervals. RESULTS Among the 6,137 patients, TLS was suspected in 26 (0.42%), with clinical and laboratory features consistent with TLS present in 20 (0.33%). Prophylaxis against TLS had been administered to 60% of these patients. Clinical or laboratory features were similar to patients who did not develop TLS. Of the patients with TLS, 90% had high-risk CLL, 60 months of prior disease duration, with a median pretreatment WBC of 109 x 10(9)/L, two prior regimens, lymphadenopathy in 89%, splenomegaly and/or hepatomegaly in 90%. TLS developed on approximately day 7 and lasted a median of 9.5 days. Dialysis was required in 30% during the TLS episode; 20% of patients died during cycle one of fludarabine therapy with renal failure, and another 20% died of infection or congestive heart failure. Six patients were retreated with fludarabine without recurrent TLS. CONCLUSION TLS after fludarabine therapy is extremely uncommon, but may be associated with significant morbidity and mortality.

Early Ofatumumab Treatment For High-Risk, Treatment-Naive Patients With Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5307-5307
Author(s):  
Nitin Jain ◽  
Michael J. Keating ◽  
Alessandra Ferrajoli ◽  
Marina Konopleva ◽  
Deborah A. Thomas ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Delay Time ◽  
Early Stage ◽  
Lymphocytic Leukemia ◽  
Early Stage Disease ◽  
Tumor Lysis ◽  
Ighv Gene ◽  
Grade 3

Background Ofatumumab is a human IgG1-kappa monoclonal antibody that binds to CD20 on normal B cells and on B chronic lymphocytic leukemia cells, resulting in B cell lysis. Ofatumumab has single-agent activity in patients (pts) with refractory CLL (Wierda, JCO 2010). Pts with CLL who have early stage disease (Rai 0-II) but have high-risk prognostic markers such as deletion 17p or deletion 11q have an increased risk of disease progression. Currently, these pts are offered watch-and-wait approach. The objective of this Phase II study is to evaluate the efficacy of ofatumumab in treating these pts with the goal to delay time to first chemoimmunotherapy treatment. Methods Pts with CLL/SLL were eligible provided they had high-risk for progression based on the presence of at least one of the following features: Rai stage II, serum beta-2 microglobulin (β2M) ≥3 mg/L, absolute lymphocyte count ≥25,000/µL, unmutated (≤2%) IGHV gene or mutated IGHV3-21, ZAP70 positive, CD38 positive (≥ 30%), or 11q or 17p deletion by FISH. Pts having a 2008 IWCLL/NCI-WG indication for CLL treatment were not eligible. Pts with Rai stage III-IV CLL were not eligible. Ofatumumab 300 mg dose 1, then 1000 mg weekly for 7 additional weeks (8 doses) was administered. Response assessment, including bone marrow evaluation, was done at least 2 months after last dose of ofatumumab and pts were followed for progression-free survival and time to first chemoimmunotherapy. Results Twenty-five pts (9 women, 16 men) were enrolled so far. The median age was 59 yrs (range, 40-81). The baseline characteristics are listed in the Table. Fifty percent of pts had unmutated IGHV gene. Thirty-four percent of pts had high-risk cytogenetic by FISH analysis. The median follow-up on the study is 4.7 months (range, 0.5-26). Grade 3-4 adverse events included infusion reaction in 6 pts. Autoimmune hepatitis with grade 4 ALT, grade 4 AST, and grade 4 alkaline phosphatase elevations was seen in 1 pt. Other grade 3-4 toxicities included rash (1 pt), shingles (1 pt), and tumor lysis (1 pt). Tumor lysis was seen in the pt with the WBC count of 207 K/µL. Eighteen pts (7 too early) are evaluable for response. Responses are as follows: 6 CR, 3 nPR, 3 PR, and 6 with stable disease. Three pts have progressed at 18.8, 14.1 and 3.2 months after starting the study treatment; 2 pts had unmutated IGHV gene (FISH negative) and one pt had trisomy 12 (IGHV mutation status unknown). None of the pts with deletion 17p or deletion 11q have progressed. All pts are alive at this time. The median overall follow up time is 7.6 months (range, 1-28). Conclusions Ofatumumab is well tolerated in pts with early stage CLL and may delay time to first chemoimmunotherapy. Disclosures: Ferrajoli: GlaxoSmithKline: Research Funding.

Tumor Lysis Syndrome/Tumor Flare Reaction in Lenalidomide-Treated Chronic Lymphocytic Leukemia

2007 ◽  
Vol 25 (31) ◽  
pp. 5047-5047 ◽  
Author(s):  
Laure A. Moutouh-de Parseval ◽  
Lilia Weiss ◽  
Robert J. DeLap ◽  
Robert D. Knight ◽  
Jerome B. Zeldis
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Tumor Lysis ◽  
Flare Reaction

Frontline Combined Chemoimmunotherapy with Fludarabine, Cyclophosphamide, Alemtuzumab and Rituximab (CFAR) in High-Risk Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 208-208 ◽  
Author(s):  
Sameer A Parikh ◽  
Michael Keating ◽  
Susan O'Brien ◽  
Alessandra Ferrajoli ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Frontline Therapy ◽  
Grade 3 ◽  
Tract Infections ◽  
Cmv Reactivation

Abstract Abstract 208 Background: Combined chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has excellent clinical activity as frontline therapy for patients (pts) with chronic lymphocytic leukemia (CLL). In a subset of pts who exhibited high-risk features, such as serum beta-2 microglobulin (B2M) ≥4 mg/L; the complete remission (CR) was lower and time to progression (TTP) and overall survival (OS) were shorter; therefore characterizing these pts as high-risk. Alemtuzumab (A) has activity as a single-agent and in combination with F in pts with relapsed/refractory CLL. To improve the CR and OS for pts with high-risk CLL, we added A to the FCR regimen (CFAR) as frontline therapy in a Phase II clinical trial. Methods: All pts who met NCI-WG criteria to initiate therapy, were < 70 years and had a B2M ≥4 mg/L were eligible for the study. Frontline CFAR consisted of C-200 mg/m2 D3-5, F-20mg/m2 D3-5, A-30mg IV D1,3,5, and R-375–500 mg/m2 D2. Courses were repeated every 28 days for a total of 6 courses. All pts received pegylated filgrastim 6mg SC with each course of therapy. All pts received allopurinol for tumor lysis prophylaxis. Antibiotic prophylaxis with TMP/SMX DS and valacyclovir or valganciclovir was also given to all pts. CMV antigenemia was monitored before each course. Results: A total of 60 pts were enrolled from July 2005 through August 2008 (Table). One pt was lost to follow-up. The median age was 59 yrs (range 42–69) and 44 (75%) were male. Median B2M was 5.1 mg/L (4–11.6); HGB was 11.5gm/dL (5.5–15.1); PLT was 139 k/μL(41–446); WBC was 100k/μL (5–665); ALC was 92k/μL (4–619); and 30 pts (51%) were Rai stage III-IV. The median number of courses administered was 4 (2–6); reasons for not completing 6 courses included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and pt. choice (2). CR was achieved in 70%, nPR in 3%, PR in 18%, and 7% pts did not respond, leading to an ORR of 92% (Table). There was no significant correlation between CR or OR with Rai Stage, IgVH mutation status, FISH status, ZAP70 and CD38 expression. After a median follow-up of 24 months (3–49), 19(32%) pts have progressive disease. Patients with 17p deletion and unmutated IgVH had significantly shorter TTP as shown in the >Table. Eleven (19%) pts have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 transformed into AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. In a historic cohort of high-risk pts treated with FCR, grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 10% courses; and major and minor infections were seen in 15% and 23% pts respectively, all comparable to that seen with frontline CFAR. A-associated infusion reactions occurred in 42 (71%) pts. CMV reactivation occurred in 7 (12%) pts, all of whom were on valacyclovir prophylaxis. There was 1 death due to CMV pneumonia; all other episodes of CMV reactivation were promptly treated with valaganciclovir leading to resolution of fever and/or antigenemia. The median OS for all pts has not been reached (49+mo) and the median TTP is 38 months. Conclusion: CFAR is an active frontline regimen in high-risk pts with CLL. Although CR rates in pts with other high-risk features such as 17p deletion and unmutated IgVH were >50%, TTP was significantly shorter for these pts than for pts without these features. With current follow-up, OS, TTP, infectious complications and grade 3/4 hematologic toxicity are comparable to historic high-risk pts treated with FCR. Disclosures: Keating: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Genentech: Consultancy, Honoraria; Genzyme: Research Funding.

Fever after anti-programmed cell death-1 treatment to predict the response in advanced hepatocellular carcinoma.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 90-90 ◽  
Author(s):  
San-Chi Chen
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Partial Response ◽  
Tumor Lysis Syndrome ◽  
Laboratory Data ◽  
Complete Response ◽  
Advanced Hepatocellular Carcinoma ◽  
Sorafenib Treatment ◽  
Tumor Lysis

90 Background: Anti-programmed cell death (PD)-1, an immune checkpoint inhibitor, has been recently approved for the treatment of patients with HCC following prior sorafenib. However, a reliable predictor of treatment response has not been established. Patients who experienced immune-related adverse events (irAEs) of any grade yielded a significantly higher response rate than did those did not experience irAEs. Methods: Three cases of advanced HCC with or without previous sorafenib treatment, underwent anti-PD-1 treatment (pembrolizumab, 2 mg/kg, at 3-week interval) with or without combination of sorafenib (400mg daily). Results: Case 1 Fever (38.3°C) developed 2 days after anti-PD-1 treatment. The fever persisted for 2 months and gradually subsided (Figure 2B). Follow-up computed tomography (CT) revealed persistent tumor shrinkage and complete response at the latest time of examination (Figure 1B); the treatment is ongoing. Case 2 Spiking fever developed after each time of anti-PD-1 treatment. Follow-up CT revealed a remarkable decrease in the tumor size (3 cm), resulting in a partial response (Figure 1D); the treatment is ongoing. Case 3 Twelve days after the treatment, the patient complained of fever and general weakness. Laboratory data revealed tumor lysis syndrome and disseminated intravascular coagulopathy (DIC). HBV, hepatitis B virus; HCV, hepatitis C virus; BCLC, Barcelona Clinic Liver Cancer; AFP, alpha-fetoprotein; TACE, transarterial chemoembolization; CR, complete response; PR, partial response. Conclusions: Fever may be an early predictor of response to anti-PD-1 treatment. The degree of fever seemed to be correlated with tumor burden. High fever may suggest cytokine storm and possible tumor lysis syndrome. Early detection is necessary for the immediate prescription of steroids and management of tumor lysis.[Table: see text]

Change in tumor lysis syndrome risk after lead-in treatment in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax for chronic lymphocytic leukemia.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 7528-7528
Author(s):  
Kerry Anne Rogers ◽  
Ying Huang ◽  
Amy S. Ruppert ◽  
Todd Civils ◽  
Subhashish Das ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Tumor Lysis ◽  
Phase 1B

Flavopiridol Administered as a Pharmacologically-Derived Schedule Demonstrates Marked Clinical Activity in Refractory, Genetically High Risk, Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 341-341 ◽  
Author(s):  
John C. Byrd ◽  
Thomas S. Lin ◽  
James T. Dalton ◽  
Di Wu ◽  
Beth Fischer ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Opportunistic Infections ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Calf Serum ◽  
Potassium Phosphate ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Tumor Lysis

Abstract Flavopiridol is a broad cyclin dependent kinase inhibitor that induces p53/IL4 independent apoptosis in CLL cells. Despite potent pre-clinical activity, phase I/II studies of both a 24 and 72-hour continuous IV (CI) schedule demonstrated no activity in CLL or other cancers. Discordant binding of flavopiridol to human plasma proteins as compared to fetal calf serum prompted us to perform pharmacokinetic modeling from the Aventis-sponsored CI studies. This suggested optimal dosing would be a 30-minute IV bolus followed by 4-hour infusion. We report a mature phase I dose escalation study of flavopiridol with this schedule. We enrolled 23 pts (median age 61, range 44–84, 8 female) previously treated for CLL (median prior therapies 3, range 2–13) . At study entry, 21 pts had no response to their last therapy, 9 had intermediate risk disease, and 14 were stage III/IV. Pts received 50% of the flavopiridol dose IV over 30 minutes, the remaining 50% followed over 4 hours. This was repeated weekly 4 times on a 6-week cycle. Six pts in cohort 1 received 60 mg/m2/dose with 1 dose limiting toxicity (DLT, neutropenic fever) and 3 pts in cohort 2 received 80 mg/m2/dose. The maximally tolerated dose was exceeded in cohort 2. Acute tumor lysis syndrome (TLS) following the first flavopiridol dose was the DLT. One pt developed TLS that was controlled with aggressive medical management. The 2nd pt with TLS died with hyperkalemia before dialysis could be initiated, and on autopsy had extensive apoptosis/necrosis of diffuse intra-abdominal lymphadenopathy. No additional pts were treated at this dose, but a 3rd pt previously without TLS at the 80 mg/m2/dose developed TLS on day 1,cycle 2 at the 60 mg/m2 dose. An inpatient management plan to prevent further life-threatening TLS was initiated. We enrolled 14 additional pts. Several pts developed transient tumor lysis upon initial treatment, with increased serum potassium, phosphate, and LDH, but only 1 pt required temporary dialysis. Other manageable toxicities observed included neutropenia, anemia, thrombocytopenia, fatigue, nausea, diarrhea, and anorexia. Twenty-two patients have been followed long enough for NCI 96 response assessment. Nine pts achieved a PR (41%); 7 pts remain in remission (3–11+ months), and 2 pts relapsed at 7 and 12 months, respectively. Of the 9 responding pts, 8 were fludarabine refractory or intolerant, 8 had bulky LN (> 5cm), and 8 had del(11q) [n=6] or del(17p) [n=3] abnormalities. Additionally, opportunistic infections have not been noted to date. Eight of 9 responding pts with enlarged LN had a 50% reduction with the 1st treatment, compared to 2 of 10 who did not ultimately achieve a PR. The AUC of flavopiridol did not increase proportionally with dose, but pharmacologic data support our hypothesis that the clinical activity and toxicity of flavopiridol may be directly related to the Cmax, AUC, and Css. In summary, single agent flavopiridol given with this novel, pharmacologically modeled schedule has significant clinical activity in pts with fludarabine-refractory, genetically high-risk CLL. Further study of flavopiridol in CLL and other B-cell diseases using this pharmacokinetically modeled schedule is warranted.

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