Abbreviated Regimen with 4 Cycles of Fludarabine, Cyclophosphamide and Rituximab (FCR) in Physically Fit Patients with Chronic Lymphocytic Leukemia Who Achieve Early Complete Remission with Undetectable Minimal Residual Disease: Safety and Efficacy Follow-up Results of a Single Center Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1739-1739 ◽  
Author(s):  
Carolina Pavlovsky ◽  
Isolda Fernandez ◽  
Miguel A Pavlovsky ◽  
Adriana Galeano ◽  
Federico Sackmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Secondary Neoplasms ◽  
Safety And Efficacy ◽  
Grade 3 ◽  
Minimal Residual

Abstract Introduction: Chemoimmunotherapy with 6 cycles of fludarabine, cyclophosphamide and rituximab (FCR) is considered standard therapy for physically fit patients with chronic lymphocytic leukemia (CLL). Due to treatment toxicity, some patients are unable to undergo standard 6 cycles of FCR. We evaluated safety and efficacy of abbreviating FCR treatment to 4 cycles in a cohort of 35 untreated physically fit CLL patients who achieved CR with negative minimal residual disease (MRD). Patients and methods: Within 150 physically fit CLL patients treated with FCR on 1st line at our Center, from April 2003 to November 2014, a subgroup of 35 patients interrupted treatment after achieving negative MRD at the end of the 4th cycle. Median age at start of treatment was 62.8 years (34-81). Binet A/B: 24pts and C: 11. CD38 expression was positive (>7% off cells) in 57.1% and negative in 9% of the pts. A bone marrow biopsy was performed at start of treatment and 1 month post 4th cycle. Response was assessed in peripheral blood (PB) or bone marrow (BM). Negative MRD was defined as < 10-4. We used NCI criteria for response modified for the evaluation of MRD by flow cytometry. Progression was defined according to the NCI recommendations. Overall survival (OS) was defined as the time of initiation of therapy until death or last follow-up and progression free survival (PFS) as the time to progression. Data analysis included frequency and contingency tables, survival curves were plotted by the Kaplan Meier method. Treatment schedule: Fludarabine 25 mg/m2 IV day 1-3, cyclophosphamide 250 mg/m2 IV day 1-3, rituximab 375 mg/m2 IV day 3 cycle 1 and day 1 cycles 2-4, in all cycles every 28 days. Results: All 35 patients had negative MRD in PB after one month post 4th cycle. In addition, 28 had bone marrow evaluation showing CR with negative MRD in all of them. No splenomegaly nor hepatomegaly, enlarged lymphadenopathies nor lymphocytosis was observed in all the patients with negative MRD. After a median follow-up of 57 months (7 -141), median PFS was 65.8 months, not being yet reached the median of OS. PFS and OS at 72 months was 46% and 68% respectively. A total of 10 pts ( 3.5%) died: 7 on progressive disease, 3 on secondary neoplasms. Patients who progressed before 24 months had a median of survival of 22 months; median not reached on the group who progressed after 24 months (p=0.0001). Neutropenia grade 3-4 and infectious events were observed in 25.7% and 9.1% during all cycles respectively. Grade 3-4 neutropenia showed to increase over time (Cycle 1: 24%, Cycle 4: 39%). There was no treatment related death. Conclusion: With a long median follow-up, abbreviating treatment to 4 courses of FCR in patients who obtained negative MRD showed durable remissions with high PFS and OS at 72 months, minimizing treatment related toxicity. Sixty five percent of the patients who progressed after 24 months are still alive. Large randomized trials will be necessary to confirm our data. Disclosures Pavlovsky: Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Pavlovsky:Novartis: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

Eradication of Minimal Residual Disease Using Alemtuzumab Consolidation After High-Dose Methyl-Prednisolone Plus Rituximab (HDMP-R) Is Safe, Effective and Induces Long Term Remission in Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2866-2866
Author(s):  
Januario E. Castro ◽  
Lina M. Ariza-Serrano ◽  
Juan S. Barajas-Gamboa ◽  
Julio A. Diaz-Perez ◽  
Danelle F. James ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Bulky Disease ◽  
Minimal Residual

Abstract Abstract 2866 Despite advances in the treatment of patients with chronic lymphocytic leukemia (CLL), the disease still remains incurable and eradication of minimal residual disease (MRD) being one of the most challenging goals of treatment. Alemtuzumab (Campath-H1™) has been shown to effectivily eradicate MRD from the bone marrow and induce long-term remissions, however its use is limited to patients without bulky disease. Futhermore, combination of alemtuzumab with chemotherapy has resulted in serious adverse events. In this study, we evaluate the toxicity and efficacy of alemtuzumab as consolidation therapy for CLL patients following induction with high-dose methylprednisolone in combination with rituximab (HDMP-R). Twenty-one patients with evidence of residual disease after treatment with HDMP-R received additional treatment with alemtuzumab. This antibody was administered three times a week for a total of 8 weeks. Patients received antibiotic prophylaxis with trimethoprim-sulfamethoxazole 160/800 mg twice a day × 3 per week, fluconazole 100 mg / day and valganciclovir 900 mg / day. The median age was 60 years (range, 49–73), with Rai stage III-IV in 81% of the patients. Twelve patients (57%) had evidence of unmutated IgVH gene and thirteen (62%) had high level of ZAP-70 expression. Cytogenetic and FISH analysis showed eight patients with deleletion 13q, three patients with trisomy 12, one patient with deletion 11q, five patients with no chromosomal abnomalities and in six patients data was not available. The median number of previous treatments was 1.3 (range, 0–5) and the median time from the end of HDMP-R treatment to initiation of alemtuzumab was 5 months (range, 1–14). After HDMP-R, nine patients (43%) achieved CR and twelve (57%) were in PR; all of them had evidence of residual disease in the bone marrow by 4-color flow cytometry analysis. Eight additional patients achieved CR after consolidation with alemtuzumab for a total of 17 patients (81%) in CR at the end of the study. We found no evidence of MRD (MRDneg) in 12 of those patients (57% of the total and 71% of CR patients). Of the remaining patients, one had PR and three patients had progressive disease for an overall response rate of 86%. The median progression-free survival (PFS) was 63 months (range, 6–84) for all patients. The median PFS in CR MRDneg patients has not been reached at a median follow-up of 46 months (range, 18–84), with 8/12 patients that have not progressed after a time at risk of 3.8 years. CR MRDpos patients have a median PFS of 48 months (range, 6–48). The treatment was well tolerated and there were no deaths attributed to therapy. Adverse events were classified following the NCI common terminology criteria for adverse events (CTCAE) Version 4.0. Two patients (9.5%) developed infections. The first event occurred during the administration of alemtuzumab and required hospitalization of the patient for management of pneumonia galactomannan positive suspicious for invasive aspergillosis (Grade 3), the second event was in a patient with aspegillus sp. infection of the skin that occurred four months after completion of alemtuzumab (Grade 2). Both patients recovered completely. We observed no CMV or other opportunistic infections. Three patients (14%) developed cytopenias; two patients with (Grade 4) thrombocytopenia and three patients with (Grade 4) neutropenia. In conclusion, alemtuzumab consolidation for residual disease after treatment with HDMP-R was well tolerated and effective in patients with CLL. We observed a near two-fold increase in the number of patients that achieved CR and the majority of these (71%) had no evidence of MRD. Moreover, patients with CR MRDneg have an exceptionally long PFS. The low rate of infection and lack of treatment related mortality compares very favorably with previous studies using alemtuzumab consolidation after chemotherapy treatment in which toxicities including treatment related death were found to be prohibitive. These encouraging results provide the rationale for additional studies using this combination therapy. Disclosures: James: Celgene: Research Funding.

Safety and Efficacy Of Abbreviated Induction With Only 4 Cycles Of Fludarabine (F), Cyclophosphamide (C) and Rituximab (R) In Physically Fit Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Early Complete Remission (CR) With Undetectable Minimal Residual Disease (MDR)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2886-2886
Author(s):  
Carolina Pavlovsky ◽  
Astrid Pavlovsky ◽  
Isolda Fernandez ◽  
Adriana Galeano ◽  
Francisco Lastiri ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Clinical Stage ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Blue Laser ◽  
Minimal Residual

Abstract Background Chemoimmunotherapy with 6 cycles of FCR is considered standard therapy for physically fit patients (pts) with Chronic Lymphocytic Leukemia (CLL). Many pts are unable to complete planned treatment, due to treatment related complications. Levels of minimal residual disease (MRD) have been shown to correlate with PFS in previously untreated patients with CLL (CLL8, Boettcher S et al. Leukemia, 2009). Achieving a negative MRD is therefore a mayor endpoint in treatment. Patients and methods From 4/2003, 39 physically fit pts with CLL who had IWCLL-NCI criteria for initiating treatment started therapy with FCR in our institution. Eleven pts had previously received chlorambucil/prednisone and 28 were not previously treated. Median age at start of therapy was 63 years (34-80), Binet´s clinical stage were A/B: 22 pts (56%) and C: 17 (44%). The CD38 expression was positive (>7% of cells) in 23 (59%) and negative in16 (41%) of the pts. After 4 courses of FCR response was assessed in peripheral blood (PB) or bone marrow (BM) using three colour flow Cytometry. Negative MRD was defined as < 0,1% of light chain restricted CD5+CD19+ B cells in PB and BM as assesed collecting 100000 CD19 cells in a three colour cytometer (FacsScalibur- blue laser ). All these patients stopped therapy after evaluation due to early CR with eradication of MRD. Results All patients had negative MRD in peripheral blood, 35 were also evaluated in bone marrow, 29 showed CR and 6 nodular partial remission (NPR). Neutropenia and infectious events grade 3-4 were observed in 24% and 7% of all the courses respectively. No pts died of toxicity. After a median follow-up of 81 months (4.6-120), progression free survival (PFS) and overall survival (OS) at 72 months was 51% and 75% respectively. Five pts died of progressive disease and 3 of a secondary neoplasm. Conclusion Stopping therapy in patients who achieve negative MRD after 4 cycles of FCR is safe and induces durable remission with a PFS and OS of 51% and 75% at 72 months exposing them to less chemotherapy. Large randomized trials are necessary to confirm this data. Disclosures: Pavlovsky: Novartis: Speakers Bureau; BMS: Speakers Bureau.

scholarly journals Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL

Blood ◽  
2014 ◽  
Vol 123 (24) ◽  
pp. 3727-3732 ◽  
Author(s):  
Paolo Strati ◽  
Michael J. Keating ◽  
Susan M. O'Brien ◽  
Jan Burger ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Early Treatment ◽  
Residual Disease ◽  
Treatment Discontinuation ◽  
Lymphocytic Leukemia ◽  
Prompt Treatment ◽  
Key Points ◽  
Minimal Residual

Key Points MRD eradication is a desirable end point in chronic lymphocytic leukemia. Early MRD eradication may prompt treatment discontinuation.

Bone Marrow May Be More Informative Than Peripheral Blood To Evaluate Minimal Residual Disease During 1st and 2nd Year Follow Up After First-Line Fludarabine, Cyclophosphamide, and Rituximab For Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1621-1621
Author(s):  
Paolo Strati ◽  
Michael J. Keating ◽  
Susan O'Brien ◽  
Jan A. Burger ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Response Assessment ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Final Response ◽  
Minimal Residual

Abstract Background Minimal Residual Disease (MRD) status at end of first-line chemoimmunotherapy is an independent prognostic factor for patients (pts) with chronic lymphocytic leukemia (CLL). In the CLL8 trial of the German CLL Study Group, peripheral blood (PB) was monitored for MRD during follow up. Because the microenvironment is important for CLL cell growth and survival and typically it is the last site to eliminate residual disease with chemoimmunotherapy, bone marrow (BM) might be a more reliable site to monitor MRD. Methods Two-hundred thirty-seven pts with CLL and an indication for therapy (IWCLL-WG 2008) received first-line fludarabine, cyclophosphamide, and rituximab (FCR) on protocol between 09/2008 and 09/2012. MRD was prospectively assessed in BM and/or PB by flow cytometry using the highly sensitive international standardized approach, 2 months after the last course of treatment (final response assessment) and every 3-6 months thereafter. Kaplan-Meier estimates were compared using the log-rank test. Results Sixty-one percent of pts were male, 21% were >65 years old, 40% had Rai stage III-IV, 41% had beta2-microglobulin (B2M) ≥4 mg/L, 61% had unmutated IGHV, and 21% had FISH analysis positive for deletion 11q and 7% for deletion 17p. Seventy-five percent of pts received ≥3 total courses of FCR. The complete remission (CR) and overall response (OR) rates were 65 and 97%, respectively. BM MRD negativity was achieved in 59% of pts at final response assessment. For monitoring, BM MRD was assessed in 121 pts during the 1st year and in 30 pts during the 2nd year after completion of treatment with FCR; all samples were serial. PB MRD was assessed in 106 pts during the 1st year and in 57 during the 2nd year of follow up; again all samples were serial. BM MRD negativity was observed in 63 (52%) pts during the 1st year of follow up and in 15 (50%) pts during the 2nd year. PB MRD negativity was observed at the same staging times in 81 (76%) and 29 (51%) pts, respectively. Concurrent BM and PB samples were taken during the 1st year in 51 pts, and in 6 pts during the 2nd year of follow up. We evaluated the association between MRD negativity during the 1st and 2nd year of follow-up and progression-free survival (PFS). BM MRD positive status was associated with shorter PFS when assessed during both the 1st and 2nd year of follow up (p<0.001 and p=0.001, respectively; Figure). In contrast, PB MRD positive status did not correlate with PFS for either time (p=0.15 and p=0.79, respectively; Figure). Conclusions After first-line FCR for pts with CLL, positive BM MRD may identify pts at higher risk for progression. Based on this finding, BM may be preferred to assess MRD status and pts with positive BM MRD could be considered for maintenance or consolidation strategies. Additional studies confirming these findings are warranted. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study

2019 ◽  
Vol 37 (4) ◽  
pp. 269-277 ◽  
Author(s):  
Arnon P. Kater ◽  
John F. Seymour ◽  
Peter Hillmen ◽  
Barbara Eichhorst ◽  
Anton W. Langerak ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Fixed Duration ◽  
Low Level ◽  
High Level ◽  
Minimal Residual

Purpose The MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes. Methods Patients were randomly assigned to 2 years of venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status—at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter—were secondary end points. Results Of 194 patients, 174 (90%) completed the venetoclax-rituximab phase and 130 (67%) completed 2 years of venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who received venetoclax-rituximab achieved a higher rate of PB undetectable MRD (uMRD; less than 10−4) at EOCT (62% v 13%) with superiority sustained through month 24 (end of therapy). Overall, uMRD status at EOCT predicted longer PFS. Among those with detectable MRD, low-level MRD (10−4 to less than 10−2) predicted improved PFS compared with high-level MRD (10−2 or greater). At a median of 9.9 months (range, 1.4 to 22.5 months) after completing fixed-duration venetoclax-rituximab, overall only 12% (16 of 130) of patients developed disease progression (11 high-level MRD, three low-level MRD). At the end of therapy, 70% and 98% of patients with uMRD remained in uMRD and without disease progression, respectively. Conclusion With all patients having finished treatment, continued benefit was observed for venetoclax-rituximab compared with bendamustine-rituximab. uMRD rates were durable and predicted longer PFS, which establishes the impact of PB MRD on the benefit of fixed-duration, venetoclax-containing treatment. Low conversion to detectable MRD and sustained PFS after completion of 2 years of venetoclax-rituximab demonstrate the feasibility of this regimen.

Eradication of Minimal Residual Disease with Alemtuzumab in Chronic Lymphocytic Leukemia Is Associated with Prolonged Survival and Is an Appropriate Theraputic Endpoint for Relapsed CLL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3114-3114 ◽  
Author(s):  
Hazem A. Sayala ◽  
Paul Moreton ◽  
Ben Kennedy ◽  
Guy Lucas ◽  
Michael Leach ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Median Survival ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
End Point ◽  
Long Term Follow Up ◽  
Minimal Residual

Abstract Eradication of minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL) is emerging as a desirable therapeutic end point predicting for better outcome. The monoclonal antibody alemtuzumab (Mabcampath) is approved for patients with fludarabine refractory CLL. We previously published 91 patients with relapsed CLL (74 men and 17 women, median age 58 years [range, 32 to 75 years]; 44 fludarabine-refractory) who received a median of 9 weeks (range 1 to 16) of alemtuzumab, 30mg 3x a week after dose escalation, between 1996 and 2003. 84 patients had i.v. alemtuzumab and 7 received it subcutaneously. Responses to alemtuzumab according to NCI-WG criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 (19%) and no response (NR) in 42 (46%). Detectable CLL to a level of less than one CLL cell in 10,000 leucocytes, assessed by four-color MRD flow cytometry, was eradicated from the blood and marrow in 18 patients (20%). 8 of these 18 patients were fludarabine refractory. We report here the results of long term follow up of this cohort of patients after a median follow up of 77 months (range 5 to 123 months). Median survival was significantly longer in patients achieving MRD negative responses compared with those with detectable CLL at the end of therapy. The median survival for all 18 MRD negative responders has not been reached but was 87 months for the 8 fludarabine-refractory patients achieving MRD negativity. Overall survival for the 18 patients with MRD-negative remissions was 66% at 72 months (see Figure). MRD positive CR patients had a median survival of 56 months, MRD positive PR patients a median survival of 42 months and non-responders a median survival of 14 months. The median treatment-free interval prior to alemtuzumab for the 18 MRD negative patients was 8 months (range 4 to 35). Excluding planned stem cell transplantation performed in CR, the median time to next treatment for the 18 MRD negative patients was 114 months and 72% (13/18) have required no further therapy. Therefore alemtuzumab can induce MRD negative remissions in CLL resulting in a clear survival advantage with 66% of MRD negative patients alive 6 years after alemtuzumab. The markedly increased treatment-free survival and excellent survival for MRD negative patients strongly suggests that achieving an MRD negative remission is an appropriate therapeutic end-point in relapsed CLL. Figure Figure

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