Denosumab for Treatment of Hypercalcemia of Malignancy in Patients with Solid Tumors or Hematological Malignancies Refractory to IV Bisphosphonates: A Single-Arm Multicenter Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2483-2483
Author(s):  
Mimi I Hu ◽  
Rasim Gucalp ◽  
Karl Insogna ◽  
Ilya Glezerman ◽  
Sophie Leboulleux ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Solid Tumors ◽  
Advanced Cancer ◽  
Serum Calcium ◽  
Interim Analysis ◽  
Hematological Malignancies ◽  
Human Monoclonal Antibody ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Hypercalcemia Of Malignancy

Abstract Abstract 2483 Introduction: Hypercalcemia of malignancy (HCM) is a serious complication in patients with advanced cancer, including those with hematological malignancies. HCM is thought to largely result from tumor-driven increases in bone resorption. IV bisphosphonates (BP) are used for treatment of HCM, but patients may relapse after treatment or become refractory to IV BP treatment. In animal models of HCM, inhibition of RANK ligand (RANKL), the key mediator of bone resorption, reversed established HCM more effectively than BP. Denosumab (Xgeva®) is a fully human monoclonal antibody against RANKL. We present data from a planned interim analysis of a single-arm study evaluating the effect of denosumab treatment in patients with HCM who have not responded to recent BP treatment. Methods: Patients eligible for enrollment in this trial are those with confirmed solid tumors or hematologic malignancies, recent IV BP treatment (7 to 30 days prior), and corrected serum calcium (CSC) levels of > 3.1 mmol/L (12.5 mg/dL). Patients with benign hyperparathyroidism, hyperthyroidism, adrenal insufficiency, or on dialysis are ineligible. Patients receive a single subcutaneous injection of denosumab (120 mg) on study days 1, 8, 15, 28, and every 4 weeks thereafter. Evaluable patients are those who received ≥ 1 dose of denosumab. The primary endpoint is the proportion of responding patients, defined as a CSC level ≤ 2.9 mmol/L (11.5 mg/dL) by day 10 of treatment. Secondary endpoints include complete response (CSC ≤ 2.7 mmol/L [10.8 mg/dL] by day 10 of treatment), response duration, and safety. The interim analysis was planned after at least 10 denosumab-treated patients received ≥ 2 doses of denosumab and provided a serum sample at study day 10 for measurement of CSC level. This trial is registered at clinicaltrials.gov (NCT00896454) and is sponsored by Amgen Inc. Enrollment is ongoing for this trial. Results: To date, 15 patients have enrolled and received ≥ 1 dose of denosumab. Five patients have advanced stages of hematological malignancies (multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma). The median baseline CSC level was 3.4 mmol/L (13.6 mg/dL). At day 10, 12 of the 15 patients (80%; 95% exact confidence interval [CI]: 51.9%, 95.7%) achieved a response, with a median decrease in CSC from baseline of 0.68 mmol/L (2.71 mg/dL). Among these 12 patients, the median duration of response was 28 days (95% CI: 7, not estimable) based on Kaplan-Meier estimates. A complete response was achieved by 10 of the15 patients (66.7%; 95% exact CI: 38.4%, 88.2%). Adverse events (AEs), serious AEs, and deaths were reported for 14, 12, and 8 patients, respectively, and were as expected in this population of patients with advanced cancer. Conclusions: Results from this interim analysis demonstrate that denosumab effectively lowers serum calcium in patients with HCM who did not or no longer respond to recent treatment with IV BP. These results suggest that denosumab may be an effective treatment for HCM in this challenging population. Disclosures: Hu: Amgen Inc.: Speaker. Off Label Use: Denosumab for treatment of hypercalcemia of malignancy. Gucalp:Eisai: Consultancy. Glezerman:Amgen Inc.: Research Funding. Ying:Amgen Inc.: Employment. Yeh:Amgen Inc.: Employment.

Influence of Chromosomal Aberrations on Response to First Line Therapy in B-Cell Chronic Lymphocytic Leukemia: Interim Analysis of PALG-CLL3 Randomized Study Comparing Cladribine Plus Cyclophosphamide vs Fludarabine Plus Cyclophosphamide.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2046-2046
Author(s):  
Tadeusz Robak ◽  
Jerzy Z. Blonski ◽  
Ewa Wawrzyniak ◽  
Aleksandra Palacz ◽  
Joanna Gora-Tybor ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Chromosomal Aberrations ◽  
Interim Analysis ◽  
Chromosomal Abnormalities ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Lower Probability ◽  
Trisomy 12 ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Impact of cytogenetic abnormalities on treatment with different purine nucleoside analogs in patients (pts) with B-cell chronic lymphocytic leukemia (B-CLL) is largely unknown. One of objectives of PALG-CLL3 trial, comparing cladribine plus cyclophosphamide (CC) with fludarabine plus cyclophosphamide (FC) in previously untreated progressive B-CLL, was to verify the response to treatment in subsets of pts characterized by common cytogenetic abberrations. Chromosomal abnormalities were assessed using fluorescence in situ hybridization (FISH) on interphase nuclei of lymphocytes on whole blood smears prior to the start of the study treatment. Pts were screened for trisomy 12, deletions (del) 11q, del 13q and del 17p using DNA probes: CEP12, LSI: ATM, D13S319 and p53 (Vysis), respectively. For the purpose of the present interim analysis complete cytogenetic results were available in 133 pts out of 423 pts included to the study. In this group the chromosomal aberrations were detected in 102 pts (77%) including single abnormalities observed in 69 pts (52%) and two or more aberrations in 33 pts (25%). Thirty-one pts (23%) exhibited a normal interphase FISH pattern. The most frequent single abnormality was del 13q found in 38 pts (29%), while del 17p, trisomy 12 and del 11q were identified in 14 pts (11%), 11 pts (8%), and 6 pts, (5%), respectively. The most frequently observed associations of chromosomal aberrations were: del 13q with del 11q (11 pts, 8%) and del 13q with del 17p (10 pts, 8%). Four pts (3%) revealed three chromosomal abnormalities including association of trisomy 12/del 11q/del 13q in two pts, trisomy 12/del 11q/del 17p in one pt and del 11q/del 13q/del 17p in one pt. Overall, treatment was completed and response assessed in 113 out of 133 pts with known FISH pattern. In this group of pts del 17p was the only chromosomal abnormality that correlated significantly with treatment outcome. Pts with del 17p (21, 19%) had lower probability to achieve a complete response (CR) (0.044). Interestingly, in independent analyses of both treatment arms, the negative impact of 17p was seen in pts treated with FC (p=0.002), but not in pts treated with CC (p=0.6). Moreover, comparing response rates between treatment arms we found that CC was superior to FC in terms of complete response in pts with del 17p (57% CR in CC v 14% CR in FC arm, p=0.04). In conclusion, chromosomal abnormalities can be detected in majority B-CLL pts requiring treatment. Our preliminary results suggest that CC combination may have some advantage in terms of CR achievement in B-CLL pts harboring del 17p.

Denosumab For The Treatment Of Hypercalcemia Of Malignancy Refractory To IV Bisphosphonates In Patients With Hematologic Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2536-2536
Author(s):  
Rasim Gucalp ◽  
Karl Insogna ◽  
Mimi Hu ◽  
Ilya Glezerman ◽  
Sophie Leboulleux ◽  
...  
Keyword(s):  
Treatment Response ◽  
Research Funding ◽  
Ad Hoc ◽  
Human Monoclonal Antibody ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Bisphosphonate Treatment ◽  
Study Visit ◽  
Hypercalcemia Of Malignancy ◽  
Equity Ownership

Abstract Background Hypercalcemia of malignancy (HCM) is a serious complication in patients with advanced cancer, including those with hematologic malignancies. HCM is commonly treated with intravenous (IV) bisphosphonates, but HCM may persist or relapse despite bisphosphonate therapy. Denosumab (XGEVA®) is a fully human monoclonal antibody that binds to RANK ligand (RANKL) to inhibit osteoclast-mediated bone resorption. Methods In this single-arm, open-label study, patients with solid tumors or hematologic malignancies who had HCM (corrected serum calcium [CSC] >12.5 mg/dL) despite IV bisphosphonate treatment ≥7 and ≤30 days before screening received subcutaneous denosumab 120 mg on days 1, 8, 15, and 29, then every 4 weeks thereafter. The primary endpoint was the proportion of patients who had a treatment response (defined as CSC ≤11.5 mg/dL) within 10 days of denosumab initiation. Key secondary endpoints included the proportion of patients with a treatment response at each study visit and the proportion of patients with a complete response (defined as CSC ≤10.8 mg/dL) by day 10 or at each study visit. This ad hoc analysis summarizes results for patients with hematologic malignancies. Results The study enrolled 33 patients, of whom 9 had hematologic malignancies (5 myeloma, 2 non-Hodgkin lymphoma, 2 chronic lymphocytic leukemia [CLL] with Richter's transformation). Key baseline characteristics are shown in the Table. By day 10, 21 of the 33 patients in the study (64%) had a treatment response. Also by day 10, all 9 patients (100%) with hematologic malignancies had a treatment response, and 5 of 9 (56%) had a complete response. Eight of the 9 hematologic malignancy patients (89%) had a complete response over the course of the study. The most frequently reported serious adverse events (SAEs) in the overall study population were worsening of hypercalcemia (n=5, 15%) and dyspnea (n=3, 9%). In patients with hematologic malignancies, disease progression was reported in 2 patients (22%), and worsening of hypercalcemia was reported in 1 patient (11%); all other SAEs occurred in only 1 patient each. Two patients, including 1 with CLL, had isolated episodes of CSC levels ≤8.0 mg/dL; none had CSC <7.0 mg/dL. No osteonecrosis of the jaw was reported. Conclusions In this ad hoc analysis from a study of patients with persistent or relapsed HCM despite recent IV bisphosphonate treatment, 100% of patients with hematologic malignancies responded to denosumab within 10 days. No unexpected safety findings were identified. Disclosures: Off Label Use: This abstract describes the use of denosumab for the treatment of hypercalcemia of malignancy, which is investigational and not an approved indication for denosumab. Hu:Amgen Inc.: Research Funding. Glezerman:Amgen Inc.: Research Funding. Misiorowski:Amgen Inc.: Research Funding. Zorsky:Galena Biopharma: Equity Ownership; RxI: Equity Ownership. Tosi:Novartis: Research Funding. Ying:Amgen Inc.: Employment. Braun:Amgen Inc.: Employment, Equity Ownership. Jain:Amgen Inc.: Employment.

Rituximab Maintenance Treatment After Combined Fludarabine, Cyclophosphamide and Rituximab In Previously Untreated Patients with Progressive B-Cell Chronic Lymphocytic Leukemia (CLL): Interim Analysis of An Ongoing Phase II Multicenter Trial On Behalf of the Spanish CLL Study Group (GELLC)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2448-2448
Author(s):  
Jose A Garcia-Marco ◽  
Javier Lopez-Jimenez ◽  
Secundino Ferrer ◽  
Pilar Giraldo ◽  
Eva González-Barca ◽  
...  
Keyword(s):  
Overall Survival ◽  
Interim Analysis ◽  
Residual Disease ◽  
Viral Myocarditis ◽  
Complete Response ◽  
Multicenter Trial ◽  
Lymphocytic Leukemia ◽  
Induction Treatment ◽  
Rituximab Maintenance ◽  
Trisomy 12

Abstract Abstract 2448 Introduction. Combination of Rituximab (R) with fludarabine (F) and cyclophosphamide (C) as first line treatment of B-CLL, results in a high complete response rate, improved progression free and overall survival compared with FC in randomised trials (Hallek et al, Blood 2009). However, more than 30% of patients relapse or show disease progression at 3–4 years after FR or FCR treatment (Byrd et al., Blood 2005; Keating et al., J Clin Oncol 2005). We report on the efficacy and safety results of an interim analysis after one year of Rituximab maintenance (Rm) following FCR in previously untreated CLL patients (pts). Methods and Patients. Between October 2007 and June 2009, a cohort of 84 physically fit pts with CD20 positive CLL received treatment with 6 cycles of FCR (R:375mg/m2 iv cycle-1 and 500mg/m2 iv, cycles 2–6; F:25mg/m2 iv, days 1–3; and C:250mg/m2 iv days 1–3; every 28 days). After 3 months of clinical response evaluation, pts achieving a response were treated with R: 375mg/m2 iv every 2 months for 3 years. Anti-infective prophylaxis included trimethoprim-sulfamethoxazole and acyclovir during treatment and until CD4 positive lymphocyte reached 0.3×109/L. Pts achieving a complete response (CR) and negative minimal residual disease (MRD) in peripheral blood (PB) and bone marrow (BM) after 4 courses of FCR, were allowed to stop FC and complete 2 courses of R and continue with Rm. The median age was 59.5 (range 37–70), 32% were females, 6% were Rai low risk, 69% intermediate risk and 25% high risk stage. IGHV status was unmutated in 64.4%, CD38 positive (>30%) in 47.6% and ZAP-70 positive (>20%) in 57.3% of pts. The incidence of genetic abnormalities by FISH for del 6q, del 11q (ATM), trisomy 12, del 13q and del 17p (p53) was 3.5%, 26.1%,15,4%, 50% and 4.7% respectively. MRD was evaluated by multicolor flow cytometry (sensitivity: 1 CLL cell positive in 10000 leukocytes). The primary end point was to evaluate the response rates and adverse events (AEs) profile of FCR and Rm treatments. Secondary endpoints included progression free and overall survival, correlation of response with MRD after FCR and Rm treatments. The mean number of FCR cycles was 5.3, and the complete treatment was administered in 80% of pts. Results. We present the results of a planned interim analysis after 1 year (6 cycles) of Rm following FCR as induction treatment. Of 90 pts screened from 29 centres, 84 were assigned (6 failed eligible criteria) to FCR and were evaluable for response. On an intent to treat analysis, overall response, CR, partial response (PR), non response and progression rates were 95.2%, 73.8%, 21.4%, 3.6% and 1.2% respectively. Of 79 pts evaluable for BM-MRD status, MRD-negative CR, MRD-positive CR, MRD-negative PR and MRD-positive PR rates were 57%, 21.5%, 7.6% and 13.9% respectively. The most common AEs after FCR were rituximab infusion (65.1%), myelotoxicity (33.7%) in 29 pts and infections (34%) with 1 serious AEs (SAEs)(1 exitus by viral myocarditis). In addition, there were 12 non hematological SAEs. Seventy five out of 84 pts continued with Rm treatment, 9 were withdrawn by progression (1), toxicity (5) and investigator decision (3). As of June 2010, 70 out 75 eligible pts had initiated Rm and 37 (49.3%) had completed 1 year of Rm (6 cycles) and were evaluable for response. Of them, 24 (64.8%) pts were in MRD-negative CR and only 1 pts converted to MRD-positive CR; 8 (21, 6%) pts were in MRD-positive CR and 3 converted to MRD-Negative CR, while 5 (13.5%) continued in MRD-positive CR with a sustained decreasing number of CLL cells in BM. Five pts were in MRD-positive PR and of them, 4 were in sustained PR with BM-MRD response and one pts presented clinical progression. In summary, 70.2% reached MRD-negative CR and 97.3% were in sustained response. The most common AEs after Rm were grade 3/4 neutropenia between cycles in 6 (16.7%) pts, infections in 15 (41.7%) pts and there were 2 (5.6%) SAEs (2 pneumonia) reported in this population. Conclusion: Based on these preliminary results, the addition of rituximab maintenance following FCR is feasible and effective in untreated CLL pts and increases the quality of clinical responses by obtaining a higher number of MRD-negative CR cases with an acceptable safety profile. Disclosures: Garcia-Marco: ROCHE: Consultancy, Honoraria, Research Funding. Off Label Use: Rituximab is not approved as maintenance therapy. Leon: ROCHE: Employment.

scholarly journals Ibrutinib Plus Fludarabine, Cyclophosphamide, and Rituximab As the Treatment for Chronic Lymphocytic Leukemia/ Small Lymphocytic Leukemia: A Single-Center Real World Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Huayuan Zhu ◽  
Hui Shen ◽  
Yilian Yang ◽  
Chong-Yang Ding ◽  
Yeqin Sha ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Interim Analysis ◽  
Response Rate ◽  
Risk Group ◽  
Complete Response ◽  
High Risk Group ◽  
Lymphocytic Leukemia ◽  
Occurrence Rate ◽  
Hematological Toxicity

Purpose: To evaluate the safety and efficacy of ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) as the treatment for chronic lymphocytic leukemia (CLL)/ small lymphocytic leukemia (SLL) patients, we conducted time-limited, minimal residual disease (MRD)-driven real world study in The First Affiliated Hospital of Nanjing Medical University Methods: We enrolled patients aged 18 to 65 years old with CLL/SLL who required treatment. Oral Ibrutinib was given continuously (420 mg/day) from day 0, and patients were administered intravenously rituximab (375mg/m2 in day 0 of cycle 1; 500mg/m2 in day 0 of cycle 2-3), fludarabine (25mg/m2, days 1-3) and cyclophosphamide (250mg/m2, days 1-3), every 28-day cycles. All the patients received 3 cycles of iFCR in the first stage. Interim analysis was done according to the 2018 iwCLL criteria and MRD was detected by flow cytometry. Patients who achieved complete response (CR) or partial response (PR) with low MRD level (L-MRD, 10-4-10-2) or undetectable MRD (uMRD) level (&lt;10-4) in peripheral blood (PB) were given 3 times of rituximab or the 4th cycle of iFCR, and then turned to ibrutinib maintenance. Patients who achieved PR with high MRD level (&gt;10-2) in PB or bone marrow (BM), or with diameter of residual lymph node larger than 3cm were administered another 3 cycles of iFCR (6 in all) and followed by ibrutinib maintenance. The primary endpoint was the proportion of patients who achieved uMRD in the PB after 3 cycles of iFCR. The secondary endpoint was overall response rate (ORR), complete response rate (CR) and the number of adverse events (AE). Results: Between May 2019 and June 2020, 29 CLL/SLL patients were enrolled in this cohort with 27 CLL and 2 SLL. 26 of patients were the previously untreated and 3 of patients were relapse or treated before. The median age of patients was 53 years old. Unmutated IGHV was detected in 14 (50.0%) of 29 patients, 4 patients had del(17p) and/or TP53 mutation (13.8%), 7 patients had del(11q) (24.1%), 7 had NOTCH1 mutation (24.1%) and 7 had MYD88 mutation (24.1%). 8 patients (30.8%) were classified as low-risk group according to CLL-IPI, with 9 in intermediate-risk group (34.6%), 5 in high-risk group (19.2%) and 4 in very-high risk group (15.4%). At data cutoff (1st July, 2020), the median follow-up and treatment time was seven months (1-13 months) with 23 patients had completed at least two cycles of iFCR. At interim analysis, the ORR was 100% with 8 patients achieved CR (34.8%), 3 achieved CRi (13.0%) and 12 achieved PR (52.2%). 57.1% (12/21) achieved uMRD in both PB and BM, among which 6 of them (28.6%) achieved CR/CRi and 6 achieved PR (28.6%). All four patients with TP53 abnormalities achieved PR and two of them (50.0%) achieved uMRD in both PB and BM. One of 6 patients with del(11q) achieved CR (16.7%) and five achieved PR (83.3%), with 2 achieved uMRD in both PB and BM (33.3%). Among 13 assessable patients with unmutated IGHV, four of them achieved CR (30.8%) and nine achieved PR (69.2%), with 5 achieved uMRD in both PB and BM (38.5%). 18 patients had turned to ibrutinib maintenance with 12 of them finished 4th cycle of iFCR or 3 additional cycles of rituximab and could be assessed further. 10 of the patients achieved CR/CRi (83.3%) and 2 achieved PR (16.7%), with 8 achieved uMRD in both PB and BM (66.7%). The most common hematological toxicity events were neutropenia and thrombocytopenia and the non-hematological toxicity events were nausea and vomiting. The occurrence rate of grade 3 to 4 neutropenia and agranulocytic fever were 51.9% (15/29) and 17.2% (5/29) respectively. The most common ibrutinib-related AE were purpura, rash and diarrhea. The occurrence rate of AE induced discontinued ibrutinib more than 7 days, discontinued ibrutinib fewer than 7 days and ibrutinib decrement were 20.7%(6/29), 17.2%(5/29) and 20.7%(6/29) respectively. Conclusion: MRD-driven Ibrutinib plus FCR could achieve high response rate with uMRD in yonger fit patients with CLL/SLL, with manageable toxicity. Ibrutinib plus FCR could be one of the most promising choice as a time-limited regimen in the new drug era. Disclosures No relevant conflicts of interest to declare.

Subcutaneous Alemtuzumab in Patients with Refractory/Relapsed B-Cell CLL after a Fludarabine-Based Regimen. An Interim Analysis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2843-2843
Author(s):  
R. Fernando Bezares ◽  
German Stemmelin ◽  
Daniel Argentieri ◽  
Emilio Lanari ◽  
Efrain Guy-Garay ◽  
...  
Keyword(s):  
B Cell ◽  
Interim Analysis ◽  
Residual Disease ◽  
Single Agent ◽  
Complete Response ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Prior Therapy ◽  
Barr Virus ◽  
Epstein Barr

Abstract Background: Alemtuzumab is the only single agent immunotherapy to demonstrate a survival benefit in patients with B-cell chronic lymphocytic leukemia (B-CLL), who have relapsed from or are refractory to Fludarabine therapy. The optimized schedule for alemtuzumab that achieves maximal efficacy with manageable toxicity is still being explored. Here, we report the second interim analysis of a new, less intensive schedule of alemtuzumab administered subcutaneously (SC) to patients with refractory/relapsed B-CLL. Methods: Alemtuzumab was dose escalated from 10 to 20 mg during the first week, 30 mg twice week during the second and third weeks, and 30 mg once weekly during Weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 34, and 40. Antiviral prophylaxis included TMP/SMX bid 3 times a week and acyclovir 200 mg three-times daily. Results: Of the 38 patients who were recruited to participate in the trial, 12 (31.6%)were refractory and 26 (68.4%) had relapsed from prior therapy. Patients had a median age of 66.5 years (range, 43–86 years), 30 were male (79%), 45%/53% had Binet stage B/C disease. The median number of prior therapies was 1 (range: 1–4). The median duration of therapy was 7 weeks (range, 2–24 weeks), with a median cumulative alemtuzumab dose of 457 mg (range, 120–1,080 mg). Among the 35 patients who were evaluable for response, the overall response rate was 88.6%: 45.8%complete response (CR), 2.9% unconfirmed CR, 42.8% partial response (PR). Four patients ( 11.5%) did not respond to therapy. Of the 9 patients with refractory disease, 1 achieved a CR, 6 a PR and 2 did not respond. Median follow up was 13 months and median overall survival was not achieved. Minimal residual disease (MRD) was measured by flow cytometry in 6 patients who achieved a CR: 4 patients had <0.5% of CD5/CD19+ cells, 1 patient had <5% of CLL cells, and 1 patient had <10% CLL cells. According to WHO toxicity criteria, over 38 evaluable patients, 4 (10,6%) experienced grade 3/4 infection; 2 patients had grade 2/3 granulocytopenia/thrombocytopenia; 1 patient had cytomegalovirus (CMV) reactivation without CMV disease; and 1 patient developed Epstein-Barr Virus with prolonged bone marrow hypoplasia. Conclusion: Results of this second interim analysis suggest that a less intense regimen of alemtuzumab is feasible, effective, and safe for patients with refractory/relapse B-CLL after fludarabine therapy.

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

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5343-5343
Author(s):  
Vijay Patel ◽  
Jaswinder Singh ◽  
Ashok Malani ◽  
Barry Skikne ◽  
Chao Haung ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Solid Tumors ◽  
Kansas City ◽  
Hematological Malignancies ◽  
Medical Center ◽  
Case Reports ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Secondary Tumors ◽  
Immunoglobulin Levels

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

Venothromboembolism (VTE) in Patients (pts) with Acute Lymphocytic Leukemia (ALL), Burkitt’s Leukemia/Lymphoma (BL) or Lymphoblastic Lymphoma (LL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4338-4338
Author(s):  
Khanh D. Vu ◽  
Julie C. Hubbard ◽  
E. Lin ◽  
Stefan H. Faderl ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Hematological Malignancies ◽  
Philadelphia Chromosome ◽  
Significant Proportion ◽  
Lymphocytic Leukemia ◽  
Cancer Center ◽  
High Dose ◽  
Cell Transplant ◽  
Acute Leukemias ◽  
History Of

Abstract It has been reported that cancer increases the risk of VTE 4-6-fold. The incidence of VTE in cancer pts has been estimated at 1 in 200 per year and has been well documented in solid tumors. Far less is known about the incidence of VTE in pts with hematological malignancies although a recent publication (Blom et al, JAMA293:715, 2005) suggested that pts with hematological malignancies such as lymphoma and multiple myeloma may be at a higher risk of developing VTE than pts with solid tumors. The incidence and risk of VTE has not been well studied in acute leukemias, a population in which prophylaxis is underutilized given the thrombocytopenia associated with intensive chemotherapy. To evaluate the incidence of VTE in pts with hematological malignancies further and to assess the need for VTE prophylaxis, we conducted a retrospective chart review of 299 pts with ALL, BL, or LL who were seen at M.D. Anderson Cancer Center Center from November 1999 to May 2005. Pts received a hyper-CVAD based regimen (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and high-dose cytarabine). The median observation period was 188 weeks (range 1–328 wks) and included post-consolidation chemotherapy, allogeneic stem cell transplant, and/or salvage chemotherapy. Among 298 evaluable pts, 52 (17%) had confirmed VTE by imaging studies. In 7 pts, VTE was the presenting sign of the malignancy. The median age of pts who developed VTE was significantly higher than of those who did not develop VTE, 48.5 yrs (range 19–75) vs. 42 yrs (range 15–83), respectively (p=0.04). With each year increase in age, the risk of having VTE increased approximately by 1.7% (p=0.059). ALL pts with Philadelphia chromosome (Ph) had a higher incidence of VTE than all other pts (p=0.02), and were 1.8 times more likely to have VTE than non-Ph ALL pts (p=0.007). Caucasian pts or those with history of prior VTE had a significantly higher incidence of VTE (p=0.03 and p=0.002, respectively). The risk was 2 fold higher for Caucasians and 12 fold higher for those with a prior history of VTE. At the time of VTE, platelet counts were below 50 x 109/L in 33%, 50–100 x 109/L in 10%, and greater than 100 x 109/L in 57%. VTE occurs in a significant proportion of pts with ALL, BL, and LL. Thrombocytopenia does not preclude the development of VTE. Older age, Ph positivity, race, and history of prior VTE were significantly associated with the development of VTE. Further analysis of other known risk factors such as the use of erythropoiesis-stimulating agents, hormonal therapy, and other comorbidities is underway to better refine the subpopulation at risk.

Denosumab for the treatment of bisphosphonate-refractory hypercalcemia of malignancy (HCM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20512-e20512
Author(s):  
Mimi I-Nan Hu ◽  
Ilya Glezerman ◽  
Sophie Leboulleux ◽  
Karl L. Insogna ◽  
Rasim A. Gucalp ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Serum Calcium ◽  
Complete Response ◽  
Osteonecrosis Of The Jaw ◽  
Open Label ◽  
Serious Adverse Events ◽  
Duration Of Response ◽  
New Treatment ◽  
Grade 3

e20512 Background: HCM, caused primarily by tumor-induced bone resorption, is treated with intravenous (IV) bisphosphonates (BisP), but patients (pts) can relapse or become refractory. Denosumab binds to RANK ligand (RANKL) to inhibit osteoclast-mediated bone resorption. Methods: In this single-arm, open-label, proof-of-concept study, pts with HCM (corrected serum calcium [CSC] >12.5 mg/dL [CTCAE grade ≥3]) despite IV BisP treatment ≥7 and ≤30 days before screening received subcutaneous denosumab 120 mg on days 1, 8, 15, and 28, then every 4 weeks. The primary endpoint was the proportion of pts with CSC ≤11.5 mg/dL (CTCAE grade ≤1) within 10 days of denosumab initiation. Results: The study enrolled33 pts (64% men; mean age 60 years; 76% with advanced solid tumors, 39% with bone metastases [BM]), with a median (25th, 75th percentile [Q1, Q3]) follow-up of 56 (18, 79) days. Median (Q1, Q3) baseline CSC was 13.7 (13.2, 14.2) mg/dL; 19 pts (58%) had HCM symptoms. Median (Q1, Q3) time from last BisP treatment to first dose was 17 (13, 22) days. At day 10, 21 pts (64%) reached CSC ≤11.5 mg/dL, including 54% of pts with BM and 70% without BM. Over the course of the study, 23 pts (70%) reached CSC ≤11.5 mg/dL, by a median (95% confidence interval [CI]) of 9 (5–19) days. A complete response (CSC ≤10.8 mg/dL, as defined by previous studies) occurred in 12 pts (36%) at day 10, and in 21 pts (64%) during the study, by a median (95% CI) of 23 (11–43) days. Among pts who reached CSC ≤11.5 mg/dL, the median (95% CI) duration of response was 104 (9–not estimable) days. The most frequently reported serious adverse events were worsening of HCM (5 pts, 15%) and dyspnea (3 pts, 9%). Two pts had isolated episodes of CSC levels ≤8.0 mg/dL (CTCAE grade 2); no pts had CSC <7.0 mg/dL (grade 3). No osteonecrosis of the jaw was reported. Conclusions: In this study of pts with HCM despite recent IV BisP treatment, denosumab effectively lowered serum calcium to grade ≤1 in 64% of pts within 10 days, and induced durable responses. These findings are particularly meaningful given that pts entered this study with grade ≥3 HCM within a median 17 days after receiving IV BisP. No unexpected safety findings were identified. Denosumab may offer a new treatment option for HCM in these pts. Clinical trial information: NCT00896454.

Randomized Comparison of Cladribine with Cyclophosphamide and Fludarabine with Cyclophosphamide in Previously Untreated Progressive and Symptomatic Chronic Lymphocytic Leukemia: The Interim Analysis of PALG CLL3 Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2121-2121 ◽  
Author(s):  
Tadeusz Robak ◽  
Jerzy Z. Blonski ◽  
Joanna Gora-Tybor ◽  
Jacek Najda ◽  
Beata Stella-Holowiecka ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Interim Analysis ◽  
Residual Disease ◽  
Complete Response ◽  
Similar Efficacy ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Grade 3 ◽  
Toxicity Criteria ◽  
Related Mortality

Abstract The efficacy and toxicity of cladribine (2-CdA) + cyclophsphamide (CY) - CC versus fludarabine (FA) + CY - FC were compared in previously untreated chronic lymphocytic leukemia (CLL) patients. The study was started in January 2004. Eligible patients were asigned to either 2-CdA 0,12mg/kg/d and CY 250mg/m2/d for 3 consecutive days or FA 25mg/m2/d and CY 250mg/m2/d also for 3 days. Courses were repeated at 28 days intervals or longer if myelosupression and/or infection developes for a maximum 6 courses. The response and toxicity criteria were those recommended by NCI SWG. Minimal residual disease (MRD) was evaluated by flow cytometry if complete response (CR) was achieved. As shown in the table, there were no significant differences in the rates of overall response (OR), CR, grade 3/4 thrombocytopenia, neutropenia and infections between the programmes. MRD negativity was obtained in 4 patients in CC arm and in 6 patients in FC arm (p=0.69). The death rate was similar in both groups, 2 (3.2%) and 6 (8.2%), respectively (p=0.19). The therapy related mortality was not observed. In conclusion, CC and FC programmes seem to have similar efficacy and toxicity in previously untreated CLL patients. The results of the interim analysis of PALG CLL3 trial justify continuation of this study. Treatment Pts enrolled Pts evaluated OR (%) CR (%) Thrombocytopenia Neutropenia Infections CC 96 63 57 (90.5) 20 (31.7) 8 (12.7) 15 (23.8) 26 (41.3) FC 100 73 62 (84.9) 25 (34.3) 6 (8.2) 17 (23.3) 20 (27.4) p value 0.24 0.45 0.27 0.53 0.06

scholarly journals CAR-NK Cells in the Treatment of Solid Tumors

2021 ◽  
Vol 22 (11) ◽  
pp. 5899
Author(s):  
Ewa Wrona ◽  
Maciej Borowiec ◽  
Piotr Potemski
Keyword(s):  
Nk Cells ◽  
Solid Tumors ◽  
Hematological Malignancies ◽  
Toxicity Profile ◽  
Multiple Sources ◽  
Eligibility Criteria ◽  
Hematological Neoplasms ◽  
Current State ◽  
Car T ◽  
The Cost

CAR-T (chimeric antigen receptor T) cells have emerged as a milestone in the treatment of patients with refractory B-cell neoplasms. However, despite having unprecedented efficacy against hematological malignancies, the treatment is far from flawless. Its greatest drawbacks arise from a challenging and expensive production process, strict patient eligibility criteria and serious toxicity profile. One possible solution, supported by robust research, is the replacement of T lymphocytes with NK cells for CAR expression. NK cells seem to be an attractive vehicle for CAR expression as they can be derived from multiple sources and safely infused regardless of donor–patient matching, which greatly reduces the cost of the treatment. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have activity against non-hematological neoplasms. Here, we present a thorough overview of the current state of knowledge regarding the use of CAR-NK cells in treating various solid tumors.

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