Combined Fludarabine, Cyclophosphamide, and Alemtuzumab (FCC), an Active Regimen for Treated Patients with Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3133-3133 ◽  
Author(s):  
Marco Montillo ◽  
Sara Miqueleiz ◽  
Alessandra Tedeschi ◽  
Francesca Ricci ◽  
Eleonora Vismara ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Synergistic Activity ◽  
Color Flow ◽  
Grade Iii

Abstract Fludarabine (F) in combination with cyclophosphamide (C) showed a relevant advantage over single-agent F in pts with relapsed CLL. Although minimal residual disease (MRD) remains detectable in many pts achieving CR, the combination of F and C seems to reduce MRD more efficiently. Still, pts in CR eventually relapse and require treatment, demonstrating the need for improved treatments able to further reduce or eliminate MRD and induce “better quality” and thus more durable responses. Alemtuzumab (CAM), anti-CD52 monoclonal antibody, acts synergistically with F in vitro and appears to have synergistic activity in vivo. Additionally, CAM is highly effective at clearing disease from bone marrow, the usual site of residual disease following purine analogue-based treatment. Therefore, we designed a phase II study to determine feasibility and efficacy, overall response rate (ORR)-duration of response-ability at clearing MRD, of a 4-weekly combination regimen consisting of F, C, and CAM (FCC). The study population is represented by pts with B-CLL with relapsed or refractory disease after at least one line of treatment. Subcutaneous route of administration of CAM has been adopted in this trial. MRD was measured by 4-color flow cytometry in the bone marrow. The FCC regimen consisted of F 40 mg/m2/d os (d 1–3), C 250 mg/m2/d os (d 1–3) and CAM 10 mg sc (d 1–3). This combination was repeated on d 29 for up to 6 cycles. The dose of CAM was increased after the first cohort of 10 treated pts from 10 mg to 20 mg sc. Currently, 25 pts have been enrolled in this trial. Median age was 57 years (range 42–79), 15/25 (60%) were male, 23/25 (92%) were in Binet stage B or C, median number of prior treatment regimens was 2 (range 1–4). In six (24%) pts 17p deletion was detected. IgVH unmutated was observed in 17 (68%) pts. At the moment of writing 19 pts are eligible for evaluation of toxicity and response. The ORR was 79%, with 7 (37%) pts achieving CR, 7 (37%) pts a PR, 1 (5%) pt a PRn. Three pts had SD, while 1 showed progression of the disease. MRD negativity was achieved in the bone marrow of 4/15 (27%) pts. Grade III-IV neutropenia episodes were observed in 43% of the administered courses while grade III-IV thrombocytopenia episodes were detected only in 8% of cycles. Four major infections were recorded: two sustained by Mycobacterium tuberculosis (1 cutis, 1 lung), one by Nocardia (lung) and one by E. coli (sepsis). The patient with pneumonia due to M. tuberculosis died because of respiratory failure. CMV reactivation occurred in 6 pts: no CMV disease was recorded. After a median follow up of 10 m (range 1–22) 73% of responding pts did not progressed. In conclusion, results from the interim analysis of this new, 4-weekly dosing FCC regimen suggest that combination therapy with F, C and CAM is feasible, safe, and effective in treating pts with relapsed and refractory CLL, even in those patients with inherent poor prognostic factors and who had received.

Fludarabine, Cyclophosphamide, and Alemtuzumab (FCC) In Relapsed/Refractory Patients with B-Cell Chronic Lymphocytic Leukemia (CLL): Final Report of the Italian Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1384-1384
Author(s):  
Marco Montillo ◽  
Alessandra Tedeschi ◽  
Francesca Ricci ◽  
Alfonso Zaccaria ◽  
Monica Crugnola ◽  
...  
Keyword(s):  
Research Funding ◽  
Residual Disease ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Final Report ◽  
Combination Regimen ◽  
Hbv Reactivation ◽  
Synergistic Activity ◽  
Color Flow ◽  
Grade Iii

Abstract Abstract 1384 Introduction: Purine Analogues in combination with cyclophosphamide (C) have a relevant advantage over monotherapy approach in patients(pts) with CLL. However, pts in complete remission (CR) eventually relapse and require treatment, demonstrating the need for improved treatments able to induce “better quality” and thus more durable responses. Monoclonal antibody alemtuzumab (CAM), directed towards CD52 antigen expressed on the surface of CLL cells has been proven to be the most effective antibody in CLL treatment. As previously reported by Elter et al. (JCO 23:7024-7031.2005) CAM appears to have synergistic activity with fludarabine (F) in vivo in relapsed and refractory CLL. Therefore, we designed a phase II study to determine the efficacy and safety of a 4-weekly combination regimen consisting of F, C, and CAM in CLL with relapsed or refractory disease after at least 1 line of treatment. Methods: The FCC regimen consisted of oral F 40 mg/m2/day and oral C 250 mg/m2/day immediately followed by sc CAM 10 mg/day (Days 1–3). A-2 day escalation of CAM was administered prior to the first cycle. This combination was repeated on Day 29 for up to 6 cycles. According to the safety profile of the schedule described above the dose of CAM was increased after the first cohort of 10 treated patients from 10 mg to 20 mg. Minimal residual disease (MRD) was measured by 4-color flow cytometry. Anti-infective prophylaxis included acyclovir 400 mg twice daily and trimethoprim sulfamethoxazole (TMP + SMX) 1000 mg given every other day from treatment initiation until 6 months after treatment end. CMV antigen in blood was tested in 7–days interval. Results: Recruitment was stopped when the planned number of 43 patients have been enrolled in the trial. The median age of the patients was 60 years (range, 39–77), 26/43 (60%) were male, 42/43 (98%) had Binet stage B and C disease, and the median number of prior treatment regimens was 2 (range, 1–4); 32/43 (74%) of patients were relapsed while 11/43(26%) were refractory to prior therapy. Pretreatment included F in 93% of patients (F+C 35%) and monoclonal antibodies (MoAb) in 39.5% of patients (Rituximab 28%, CAM 19%; both MoAb 7%). More than a half of pts presented with deleted 11q or 17p with 28% of pts showing 17p as the sole aberration. Unmutated IgVH was detected in 23/34 (68%) pts while 17/43 (52%) were tested positive for ZAP70. Median number of given cycles was 4. Myelosuppression of all grades was the most commonly occurring adverse events. Grade III-IV neutropenia episodes were observed in 66% of the administered courses while grade III-IV thrombocytopenia episodes were detected only in 8.0 % of cycles. Symptomatic CMV reactivation occurred in 8 cases, no CMV disease was recorded. Twelve major infections occurred, including hepatitis B virus (HBV) reactivation (1 patient), pneumonia (8 episodes), and sepsis (3 episodes). Two major late infections were also observed: 1 tuberculosis and 1 aspergillosis. There were 8 deaths among 29 responding patients due to disease progression (5 patients), Richter's syndrome (2 patients), and one major late infection (tuberculosis). Progressive disease was the cause of death in 11 cases among 14 non-responding patients. An overall response rate (ORR) of 67% (29/43) was recorded with 13 pts (30%) achieving CR (MRD- in 6 pts) and 16 PR (37%). Higher ORR (p=0.003) was observed in pts not previously treated with MoAb. After a median follow up of 16.7 months (range, 1–49.5 mo) patients receiving FCC had a median PFS of 24.4 months. Finalized data of all patients will be presented. Conclusion: Results from the final analysis of this new, 4-weekly dosing FCC regimen suggest that combination therapy with F, C and CAM is effective. Poor prognostic factors were strongly represented in these patients, including 68% unmutated IgVH and 54% deleted 17p or 11q. Although there were a number of major infections, most were manageable. Disclosures: Montillo: Bayer: Research Funding, Speakers Bureau; Genzyme: Research Funding, Speakers Bureau.

Results of the Fludarabine and Cyclophosphamide Combination Regimen in Chronic Lymphocytic Leukemia

2001 ◽  
Vol 19 (5) ◽  
pp. 1414-1420 ◽  
Author(s):  
Susan M. O’Brien ◽  
Hagop M. Kantarjian ◽  
Jorge Cortes ◽  
Miloslav Beran ◽  
Charles A. Koller ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Alkylating Agents ◽  
Single Agent ◽  
Unknown Origin ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Synergistic Activity

PURPOSE: To assess the efficacy of combination therapy with fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia (CLL) based on data suggesting in vitro synergistic activity of the two agents. PATIENTS AND METHODS: A total of 128 patients with CLL were treated with fludarabine 30 mg/m2 intravenously daily for 3 days and cyclophosphamide at either 500 mg/m2 daily for 3 days (n = 11), 350 mg/m2/d for 3 days (n = 26), or 300 mg/m2 daily for 3 days (n = 91). The cyclophosphamide dose was decreased because of myelosuppression in the early part of the study. Patients were divided into four groups based on the expectation for response to single-agent fludarabine, including previously untreated patients, patients previously treated with alkylating agents, patients successfully treated with alkylating agents and fludarabine but relapsing, and patients refractory to fludarabine with or without alkylating agents. RESULTS: Fludarabine and cyclophosphamide produced ≥ 80% response rates in all patients not refractory to fludarabine at the start of therapy as well as a 38% response rate in patients who were refractory to fludarabine. The complete remission (CR) rate was 35% in previously untreated patients, which was not significantly different from the CR rate in historical control patients treated with single-agent fludarabine. However, residual disease assessed by flow cytometry occurred in only 8% of previously untreated patients achieving CR, and median time to progression has not been reached after a median follow-up of 41 months. The main complication of therapy was related to myelosuppression and infection. Neutropenia to less than 500 × 109/L was noted in 48% of patients who received cyclophosphamide 300 mg/m2. Pneumonia or sepsis occurred in 25% of patients, and fever of unknown origin occurred in another 25%. Pneumonia or sepsis were significantly more frequent in patients who were refractory to fludarabine at the start of combination chemotherapy. CONCLUSION: Fludarabine and cyclophosphamide seem to have a significant advantage over single-agent fludarabine in the salvage setting. Although the CR rate was not increased in previously untreated patients, residual disease detected by flow cytometry was rare and remission durations seemed to be prolonged in this subset. Myelosuppression and infection remain the most significant complications of therapy in CLL.

Combination of Fludarabine (FAMP) Cyclophosphamide (CTX) and Alemtuzumab for Patients with Relapsed Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5036-5036
Author(s):  
Alessandra Tedeschi ◽  
Marco Montillo ◽  
Sara Miqueleiz ◽  
Michela Draisci ◽  
Francesca Ricci ◽  
...  
Keyword(s):  
Opportunistic Infections ◽  
Residual Disease ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
High Rate ◽  
Hematologic Toxicity ◽  
Combination Regimen ◽  
Synergistic Activity ◽  
Color Flow ◽  
Short Period

Abstract Previous studies have shown that FAMP in combination with CTX seems to have a significant advantage over single-agent FAMP in patients with relapsed CLL who had previously received alkylators or alkylators plus fludarabine, but are still fludarabine-sensitive. Despite the improved response rates, patients who achieve CR eventually relapse and require alternate therapies. The high rate of relapse in CLL affirms the need for improved treatments, which reduce or eliminate residual disease (MRD) to induce “better quality,” more durable responses. The monoclonal antibody alemtuzumab (Campath®), which is directed towards the CD52 antigen expressed on the surface of B-CLL cells, acts synergistically with fludarabine in vitro and appears to have synergistic activity in vivo. Alemtuzumab is one of a few single agents that has demonstrated the ability to eliminate minimal residual disease in CLL. Therefore, we designed a phase II study to determine the efficacy and safety of a 4-week combination regimen consisting of FAMP, CTX, and alemtuzumab (FCC) in relapsed patients with CLL. Objectives of this study also included the evaluation of the overall response rate (ORR), duration of response (DR), and the presence of MRD following treatment with FCC. Patients received FCC after a short period of alemtuzumab dose escalation, from 1 mg to 3 mg to 10 mg on consecutive days. The FCC regimen consisted of FAMP 40 mg/m2/day PO (Days 1–3), CTX 250 mg/m2/day PO (Days 1–3), followed by alemtuzumab 10 mg SC (Days 1–3). This combination was repeated on Day 29 for up to 6 cycles. MRD was measured by 4-color flow cytometry and consensus primer PCR. Nine patients (7 male and 2 female), have been enrolled in this trial. The median age of patients was 60.3 years (range, 43–78 years); 2 patients (22%) were in Binet stage C, 3 patients were in stage A and 4 patients were in stage B. Median number of prior treatment regimens was 2 (range, 1–3). Currently, 3 patients completed treatment, and 2 patients received 3 courses while the remaining 4 patients completed the first course. Among the 3 patients who completed treatment, 1 achieved a complete response (CR) and 2 patients a partial response (PR). MRD negativity was achieved in the peripheral blood in 1 patient. No CMV reactivation has been observed. No opportunistic infections have been recorded. Hematologic toxicity was manageable: 2 patients required G-CSF support. No nonhematologic toxicity was documented. This preliminary data on safety and efficacy of this regimen are encouraging and warrant further study.

FluCam—a New, 4-Weekly Combination of Fludarabine and Alemtuzumab for Patients with Relapsed Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2517-2517 ◽  
Author(s):  
Thomas Elter ◽  
P. Bochmann ◽  
H. Schulz ◽  
M. Reiser ◽  
S. Trelle ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Single Agent ◽  
Response Rates ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Combination Regimen ◽  
Color Flow ◽  
Short Period ◽  
Cmv Reactivation

Abstract Purine analogs, particularly fludarabine (Fludara®), have a major impact on the management of chronic lymphocytic leukemia (CLL), having achieved overall response rates (ORR) of 60%–80% as a single agent in previously untreated patients. Despite these high response rates as compared with other agents, patients continue to have detectable minimal residual disease (MRD) and will eventually relapse. It has become clear that even with the most highly active combination regimens, chemotherapy alone cannot cure CLL. Monoclonal antibodies such as alemtuzumab (Campath®) that have been developed against antigens expressed on the surface of B-CLL cells act synergistically with fludarabine in vitro and also appear to have synergistic properties in vivo. We, therefore, evaluated the safety and efficacy of a new, 4-weekly combination regimen consisting of fludarabine and the anti-CD52 monoclonal antibody alemtuzumab (FluCam) for patients with CLL in a phase II study. Objectives of this study were to evaluate the feasibility, ORR, duration of response (DR), and the presence of MRD following treatment with FluCam. Patients received FluCam therapy after a short period of alemtuzumab dose escalation, with doses rising from 3 mg to 10 mg to 30 mg on consecutive days. The FluCam regimen consisted of fludarabine 30 mg/m2/day IV over 15–30 min (Days 1–3) immediately followed by alemtuzumab 30 mg IV over 2 h (Days 1–3). This combination was repeated on Day 29 for up to 6 cycles. MRD was measured by 4-color flow cytometry. Currently, 34 patients are eligible for evaluation out of a total of 37 patients included in this study. The median age of the patients was 61.0 years (range, 38–80), 26/34 (76%) were male, 26/34 (76%) had Binet stage C disease, and the median number of prior treatment regimens was 2 (range, 1–8). The ORR was 85%, with 10 (29%) patients achieving a complete response (CR) and 19 (56%) patients a partial response (PR). One (3%) patient had stable disease (SD), while 4 (12%) others had progression of their disease (PD). MRD negativity was achieved in the peripheral blood for 15/34 (44%) patients. CMV reactivation occurred in 2 patients: 1 patient had CMV confirmed by PCR and died due to E. coli sepsis, and 1 patient had subclinical CMV reactivation that was successfully treated with IV ganciclovir. Two patients with refractory disease developed fungal pneumonia. Notably, 7 patients had active autoimmune hemolytic anemia (AIHA) and/or autoimmune thrombocytopenia (AITP) when entering the trial and were successfully treated with FluCam. Moreover, 9 other patients with transfusion-dependent thrombocytopenia and/or anemia due to bone marrow infiltration prior to therapy were successfully treated with FluCam. In conclusion, results from the interim analysis of this new, 4-weekly dosing regimen of FluCam suggest that combination therapy with fludarabine and alemtuzumab is feasible, safe, and effective in treating patients with relapsed and refractory CLL, even in those patients with inherent poor prognostic factors, those who had received multiple prior therapies, or those who were refractory to fludarabine or alemtuzumab monotherapy. Based on these promising results, a prospective, randomized, phase III trial has been initiated comparing FluCam to fludarabine alone in patients with relapsed CLL.

scholarly journals MicroRNA dysregulation to identify therapeutic target combinations for chronic lymphocytic leukemia

2017 ◽  
Vol 114 (40) ◽  
pp. 10731-10736 ◽  
Author(s):  
Laura Z. Rassenti ◽  
Veronica Balatti ◽  
Emanuela M. Ghia ◽  
Alexey Palamarchuk ◽  
Luisa Tomasello ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Single Agent ◽  
Leukemia Cell ◽  
Surface Protein ◽  
Lymphocytic Leukemia ◽  
Synergistic Activity ◽  
High Level Expression ◽  
High Level

Loss of miR-15/16 is the most common genetic lesion in chronic lymphocytic leukemia (CLL), promoting overexpression of BCL2, which factors in leukemia pathogenesis. Indeed, an inhibitor of Bcl2, venetoclcax, is highly active in the treatment of patients with CLL. However, single-agent venetoclcax fails to eradicate minimal residual disease in most patients. Accordingly, we were interested in other genes that may be regulated by miR-15/16, which may target other drivers in CLL. We found that miR-15/16 targets ROR1, which encodes an onco-embryonic surface protein expressed on the CLL cells of over 90% of patients, but not on virtually all normal postpartum tissues. CLL with high-level expression of ROR1 also have high-level expression of Bcl2, but low-to-negligible miR-15/16. Moreover, CLL cases with high-level ROR1 have deletion(s) at the chromosomal location of the genes encoding miR-15/16 (13q14) more frequently than cases with low-to-negligible ROR1, implying that deletion of miR-15/16 may promote overexpression of ROR1, in addition to BCL2. ROR1 is a receptor for Wnt5a, which can promote leukemia-cell proliferation and survival, and can be targeted by cirmtuzumab, a humanized anti-ROR1 mAb. We find that this mAb can enhance the in vitro cytotoxic activity of venetoclcax for CLL cells with high-level expression of ROR1, indicating that combining these agents, which target ROR1 and Bcl2, may have additive, if not synergistic, activity in patients with this disease.

A phase I trial of intraperitoneal recombinant gamma-interferon in advanced ovarian carcinoma.

1988 ◽  
Vol 6 (4) ◽  
pp. 689-695 ◽  
Author(s):  
R D'Acquisto ◽  
M Markman ◽  
T Hakes ◽  
S Rubin ◽  
W Hoskins ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Peritoneal Cavity ◽  
Residual Disease ◽  
Single Agent ◽  
Laboratory Data ◽  
Malignant Cell ◽  
Biological Agents ◽  
Gamma Interferon

The interferons are a class of biological agents that have demonstrated antineoplastic activity in a variety of tumors both in vitro and in vivo. Previous reports have suggested that interferons can be safely administered by the intraperitoneal (IP) route with a pharmacokinetic advantage for peritoneal cavity exposure compared with the systemic circulation and with objective antitumor activity being demonstrated. On the basis of these reports and laboratory data suggesting activity for recombinant gamma-interferon (r-GIFN) against several malignant cell lines, we treated 27 refractory ovarian carcinoma patients, including six with very-small-volume residual disease, with this agent delivered by the IP route. While r-GIFN was found to be remarkably well tolerated, with a 150- to 200-fold pharmacokinetic advantage for peak levels achieved in the peritoneal cavity compared with the plasma, no objective responses were observed. Despite the lack of demonstrated activity for single-agent IP-administered r-GIFN in this clinical setting, there remains considerable interest in this agent when delivered by the IP route because of in vitro data suggesting concentration-dependent synergy between r-GIFN and other biological agents.

Pharmacokinetics and Response to Treatment Using a Combination of Fludarabine and Alemtuzumab (FluCam) in Patients with Relapsed/Refractory CLL.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4991-4991
Author(s):  
T. Elter ◽  
J. Kilp ◽  
T. Piironen ◽  
P. Borchmann ◽  
H. Schulz ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Plasma Levels ◽  
Residual Disease ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Response Rates ◽  
Response To Treatment ◽  
Synergistic Activity ◽  
Refractory Disease

Abstract Combination chemoimmunotherapy regimens have shown substantial efficacy in the treatment of lymphoproliferative disorders, particularly in comparison to the efficacy of single-agent therapies. Fludarabine has become an established treatment regimen in CLL, and although overall response rates (ORR) in previously untreated patients range between 60% to 80%, patients who are refractory to fludarabine have poor outcomes. Alemtuzumab, the anti-CD52 monoclonal antibody, is the most effective single-agent therapy in CLL, and is capable of inducing minimal residual disease (MRD)-negative responses even among patients with fludarabine-refractory disease. Our previous clinical experience with the combination of alemtuzumab and fludarabine (FluCam) resulted in 83% ORR in 36 patients with relapsed/refractory CLL, with 30% achieving a complete response (CR; Elter et al J Clin Oncol2005;23:7024–7031). In addition, among 12 patients with fludarabine-refractory disease, 8 achieved responses (4 CRs), and median time-to-progression (TTP) for all patients was 13 months. In order to optimize the dose and schedule of the FluCam combination, we performed pharmacokinetic (PK) analysis of the previously reported 6-cycle regimen. PK data were collected for a 14-patient cohort that participated in the phase 2 FluCam trial. Median patient age was 60 years (range, 49–73), 9 patients had Binet C disease (5 were Binet B), and patients received a mean 2.5 prior therapies. Alemtuzumab 30 mg (after initial dose escalation) and fludarabine 30 mg/m2 were administered on days 1–3 of a 28-day cycle for up to 6 cycles. PK parameters were measured from samples collected before each subsequent cycle, and at days 1, 4, 7, 14, 21, 28, and 42, for a total of 158 patient samples, of which 120 were tested. Plasma concentration of alemtuzumab increased steadily from day 1 to day 4 of therapy to a median Cmax 1.55 mg/mL, but decreased to a median 0.145 mg/mL by 7 days after initiation of treatment. By day 21 of therapy, alemtuzumab plasma concentration decreased to undetectable levels. Because efficacy of alemtuzumab has been shown to correlate with serum levels of this antibody, significant improvement in progression free survival (PFS) may require a elevated plasma levels of alemtuzumab for the duration of the treatment cycle. Therefore, the significant responses seen in this trial can be attributed to documented synergistic activity between alemtuzumab and fludarabine, which has been demonstrated both in vitro and in vivo. Despite low CD4 counts through the duration of therapy, favorable safety results seen in the trial could be attributed to opportunity for hematologic recovery between treatment cycles. Detailed PK analysis is currently being completed and will be presented at the conference. Conclusions: Treatment with the FluCam immunotherapy combination yielded positive results among patients with fludarabine resistant/refractory CLL, a difficult-to-treat population. As shown previously, response rates correlate with higher alemtuzumab plasma concentrations. Therefore, longer PFS durations may require longer, more sustained alemtuzumab plasma levels, which may be achieved with either consolidation or maintenance.

Final Results of Lower Dose Fludarabine (F) and Cyclophosphamide (C), and High Dose Rituximab (R), (FCR-Lite) for Patients with Untreated Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2037-2037
Author(s):  
Ahmad A. Tarhini ◽  
S. Land ◽  
L. Pietragallo ◽  
A. Laman ◽  
M. Sulecki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Response Rate ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Color Flow ◽  
Major Toxicity ◽  
Grade 3 ◽  
Age Range

Abstract Introduction Standard FCR therapy in untreated CLL patients (F-25 mg/m2 d1–3 q 4wk; C-250 mg/m2 d 1–3 q 4wk; R-500 mg/m2 d1 q 4wk for 6 cycles) was reported to have complete remissions (CR) of 70% and overall responses (OR) of 95% (J Clin Oncol2005;23:4079). The major toxicity was grade 3/4 neutropenia during 52% of treatment courses. One approach to decrease neutropenia without compromising efficacy could be by reducing the doses of F and C and increasing the dose of R. Methods We conducted a phase II study for previously untreated advanced CLL patients treated with FCR-Lite (F-20mg/m2 d1–3 q 4 wk; C-150 mg/m2 d1–3 q 4 wk; R-500mg/m2 d1 and d14 q 4wks; maintenance R-500 mg/m2 ×1 q 3 months until progression). A Simon two-stage design was used where 15 patients were accrued in the first stage and because of acceptable toxicity and response rate in stage I an additional 35 patients were treated. The primary endpoint was response rate. Results A total of 50 patients were entered into this study and 42 are currently evaluable. There were 29 male and 13 female patients with an age range of 36–85 years (median 58) treated with a total of 236 courses of FCR-Lite. All 42 patients were evaluable for toxicity. Grade 3/4 neutropenia occurred during 29 (12%) courses with two episodes of neutropenic fever. One patient had cellulitis, another had pneumonia (not neutropenic). Grade 3/4 thrombocytopenia occurred during 7 (3%) courses and grade III/IV anemia during 6 (2.5%) courses. Among the 40 evaluable patients for response, the CR rate was 85%, PR rate was 15% with an OR rate of 100%. All of the CR patients were tested by flow cytometry and had <1% CD5+/CD19+ cells in their bone marrow after therapy. One patient with potential CR was excluded due to the absence of follow up bone marrow biopsy. Minimal residual disease (MRD) was tested by four color flow cytometry (sensitivity 0.01%) in 8 patients with CR (Genzyme Genetics Corp.). Seven had no evidence of MRD at 7, 8, 8, 14, 22, 25 and 30 months respectively, post CR, and one patient had 0.03% and 0.06% when tested at 12 and 18 months post CR respectively. Conclusions Our results in 42 patients suggest FCR-Lite is highly effective with considerably less grade 3/4 neutropenia than standard FCR. Complete responders had no detectable CD5+/CD19+ cells in their bone marrow following FCR-Lite. MRD testing is currently underway for all patients.

SGX70393 Inhibits Bcr-AblT315I In Vitro and In Vivo and Completely Suppresses Resistance When Combined with Nilotinib or Dasatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 535-535 ◽  
Author(s):  
Thomas O’Hare ◽  
Christopher A. Eide ◽  
Jeffrey W. Tyner ◽  
Amie S. Corbin ◽  
Matthew J. Wong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Resistance Profile ◽  
Murine Bone Marrow ◽  
Abl Kinase ◽  
A Cell

Abstract Overview: Bcr-AblT315I is detected in the majority of CML patients who relapse after dasatinib- or nilotinib-based second-line Bcr-Abl kinase inhibitor therapy. SGX70393, an azapyridine-based Abl kinase inhibitor, is effective against Bcr-Abl and Bcr-AblT315I at low nanomolar concentrations in vitro and in cell lines. Here, we comprehensively profiled SGX70393 against native and mutant Bcr-Abl in vitro and in vivo. We also used a cell-based mutagenesis screen to evaluate the resistance profile of SGX70393 alone and in combination with imatinib, nilotinib, or dasatinib. Methods: We assessed colony formation in the presence of SGX70393 by murine bone marrow infected with retroviruses for expression of Bcr-Abl, Bcr-AblT315I, or a variety of other mutants. Toxicity was tested in clonogenic assays of normal bone marrow. SGX70393 effects on cellular tyrosine phosphorylation were measured by immunoblot and FACS in primary Bcr-AblT315I cells isolated from patients with CML or Ph+ B-ALL. In vivo activity was evaluated in a xenograft model using Ba/F3 cells expressing Bcr-AblT315I. Lastly, the resistance profile of SGX70393 was evaluated alone and in dual combinations with imatinib, nilotinib, or dasatinib in a cell-based mutagenesis assay. Results: Colony formation by murine bone marrow cells expressing Bcr-AblT315I (IC50: 180 nM) was reduced by SGX70393 in a dose dependent manner, while no toxicity was observed in colony forming assays of normal human or murine mononuclear cells at concentrations up to 2 μM. Ex vivo exposure of human Bcr-AblT315I mononuclear cells to SGX70393 decreased CrkL phosphorylation, while imatinib, nilotinib, or dasatinib had no effect. SGX70393 inhibited Bcr-AblT315I-driven tumor growth in mice and this was correlated with reduced levels of pCrkL in tumor tissue, while imatinib was ineffective. A cell-based mutagenesis screen revealed a profile of resistant clones confined to four p-loop residues and position 317. SGX70393 in combination with imatinib contracted the spectrum of resistant mutations relative to either single agent, though outgrowth could not be completely suppressed. Combining SGX70393 with low concentrations of nilotinib or dasatinib narrowed the resistance profile still further (residues 248 and 255 for nilotinib; 317 for dasatinib) and, with clinically achievable doses of either second drug, completely abrogated emergence of resistant subclones. Conclusions: SGX70393, a potent inhibitor of Bcr-AblT315I, exhibits a resistance profile centered around the p-loop and residue 317 of Bcr-Abl. Remarkably, in combination with nilotinib or dasatinib, outgrowth of resistant clones is completely suppressed. Single-agent therapy with an effective T315I inhibitor may provide a viable option for patients who relapse with Bcr-AblT315I. However, as a broader spectrum of mutations accounts for imatinib resistance, patients with acquired dasatinib or nilotinib resistance may continue to harbor residual mutant clones other than T315I. Thus, the full clinical potential of SGX70393 may be realized in combinations with a second Abl kinase inhibitor. Our findings provide the first demonstration that Abl kinase inhibitor combinations that include a T315I-targeted component such as SGX70393 have the potential to pre-empt Bcr-Abl-dependent resistance.

The Novel Aurora Kinase Inhibitor ENMD-2076 Has Potent Single Agent Activity against Multiple Myeloma (MM) in Vitro and in Vivo, and Shows Synergistic Activity in Combination with Lenalidomide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3660-3660 ◽  
Author(s):  
Xiaojing Wang ◽  
Anthony L. Sinn ◽  
Attaya Suvannasankha ◽  
Colin D. Crean ◽  
Li Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Caspase 3 ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Synergistic Activity ◽  
Significant Activity ◽  
Aurora A Kinase ◽  
Free Base

Abstract ENMD-2076 is a novel, orally-active molecule that has been shown to have significant activity against Aurora A kinase as well as multiple receptor tyrosine kinases (RTK). We investigated the single agent activity of ENMD-2076 against MM cells in vitro and in vivo, and in combination with lenalidomide. ENMD-2076 free base showed significant cytotoxicity against MM cells with a mean LC50 of 3.84±0.86 μM at 48 hours in vitro. Cytotoxicity was associated with cleavage of caspase 3, 8, 9 and PARP, and loss of mitochondrial membrane potential as early as 6 hours. ENMD-2076 free base inhibited c-kit, FGFR-1, 3 and VEGFR1 and subsequently inhibition of downstream targets phosphorylated (p)-BAD, p-Foxo1a and p-GSK-3β was observed at 6 hours. NOD/SCID mice implanted with H929 human plasmacytoma xenografts and treated for 30 days with 50, 100, 200mg/kg/d ENMD-2076 showed a dose-dependent inhibition of tumor growth (Figure 1), with minimal toxicity as assessed by the stable weight of treated animals. Immunohistochemical staining of tumors from sacrificed animals showed significant reduction in Ki67 at all dose levels of treatment compared to control tumors. An increase in cleaved caspase-3 was observed on Western blot from the lysates of H929 tumors obtained from treated animals. ENMD-2076 free base also showed synergistic cytotoxic activity when combined with lenalidomide against H929, MM1.R and MM1.S cells as assessed by MTT assay and Annexin-V/PI staining. Using the Chou-Talalay method, the combination indices (CI) were < 1 for all three cell lines across a range of concentrations of ENMD-2076 free base (0.25–1.0 μM) plus lenalidomide (2.5–10 μM) indicating synergistic activity (CI=0.362 H929; CI=0.315 MM1.R; CI=0.415 MM1.S). Our results provide rationale for the investigation of ENMD-2076 alone and in combination with lenalidomide in patients with multiple myeloma. Figure Figure

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