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.

Detection and impact of minimal residual disease on outcome of chronic lymphocytic leukemia

2012 ◽  
Vol 153 (41) ◽  
pp. 1622-1628
Author(s):  
Márk Plander ◽  
Judit Skrapits ◽  
Tünde Bozsó ◽  
Tamás Szendrei ◽  
János László Iványi
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Minimal Residual

Introduction: Minimal residual disease is associated with longer overall survival in patients with chronic lymphocytic leukemia. Aim: The aim of the authors was to determine the clinical significance of remission and minimal residual disease on the survival of patients with chronic lymphocytic leukemia. Methods: Data from 42 first-line treated patients with chronic lymphocytic leukemia were analyzed. Minimal residual disease was determined by flow cytometry. Results: Overall response and complete remission was achieved in 91%, 86%, 100% and 87%, 0%, 60% of patients with fludarabine-based combinations, single-agent fludarabine and cyclophosphamide + vincristin + prednisolone regimen, respectively. Minimal residual disease eradication was feasible only with fludarabine-based combinations in 60% of these cases. The ratio of minimal residual disease was 0.5% on average. During a median follow-up period lasting 30 months, the overall survival of patients with fludarabine-resistant disease proved to be significantly shorter (p = 0.04), while complete remission without minimal residual disease was associated with significantly longer progression free survival (p = 0.02). Conclusion: Only fludarabine-based combinations were able to eradicate minimal residual disease in patients with chronic lymphocytic leukemia. Complete remission without minimal residual disease may predict longer progression free survival in these patients. Orv. Hetil., 2012, 153, 1622–1628.

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.

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.

Minimal Residual Disease Quantification Is an Independent Predictor of Progression-Free and Overall Survival in Chronic Lymphocytic Leukemia: A Multivariate Analysis From the Randomized GCLLSG CLL8 Trial

2012 ◽  
Vol 30 (9) ◽  
pp. 980-988 ◽  
Author(s):  
Sebastian Böttcher ◽  
Matthias Ritgen ◽  
Kirsten Fischer ◽  
Stephan Stilgenbauer ◽  
Raymonde M. Busch ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Surrogate Marker ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
High Level ◽  
Minimal Residual

Purpose To determine the clinical significance of flow cytometric minimal residual disease (MRD) quantification in chronic lymphocytic leukemia (CLL) in addition to pretherapeutic risk factors and to compare the prognostic impact of MRD between the arms of the German CLL Study Group CLL8 trial. Patients and Methods MRD levels were prospectively quantified in 1,775 blood and bone marrow samples from 493 patients randomly assigned to receive fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). Patients were categorized by MRD into low- (< 10−4), intermediate- (≥ 10−4 to <10−2), and high-level (≥ 10−2) groups. Results Low MRD levels during and after therapy were associated with longer progression-free survival (PFS) and overall survival (OS; P < .0001). Median PFS is estimated at 68.7, 40.5, and 15.4 months for low, intermediate, and high MRD levels, respectively, when assessed 2 months after therapy. Compared with patients with low MRD, greater risks of disease progression were associated with intermediate and high MRD levels (hazard ratios, 2.49 and 14.7, respectively; both P < .0001). Median OS was 48.4 months in patients with high MRD and was not reached for lower MRD levels. MRD remained predictive for OS and PFS in multivariate analyses that included the most important pretherapeutic risk markers in CLL. PFS and OS did not differ between treatment arms within each MRD category. However, FCR induced low MRD levels more frequently than FC. Conclusion MRD levels independently predict OS and PFS in CLL. Therefore, MRD quantification might serve as a surrogate marker to assess treatment efficacy in randomized trials before clinical end points can be evaluated.

Alemtuzumab Compared With Chlorambucil As First-Line Therapy for Chronic Lymphocytic Leukemia

2007 ◽  
Vol 25 (35) ◽  
pp. 5616-5623 ◽  
Author(s):  
Peter Hillmen ◽  
Aleksander B. Skotnicki ◽  
Tadeusz Robak ◽  
Branimir Jaksic ◽  
Anna Dmoszynska ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Alternative Treatment ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Line Treatment ◽  
First Line ◽  
Minimal Residual ◽  
First Line Treatment

Purpose We conducted a randomized trial to evaluate the efficacy and safety of intravenous alemtuzumab compared with chlorambucil in first-line treatment of chronic lymphocytic leukemia (CLL). Patients and Methods Patients received alemtuzumab (30 mg three times per week, for up to 12 weeks) or chlorambucil (40 mg/m2 every 28 days, for up to 12 months). The primary end point was progression-free survival (PFS). Secondary end points included overall response rate (ORR), complete response (CR), time to alternative therapy, safety, and overall survival. Results We randomly assigned 297 patients, 149 to alemtuzumab and 148 to chlorambucil. Alemtuzumab had superior PFS, with a 42% reduction in risk of progression or death (hazard ratio [HR] = 0.58; P = .0001), and a median time to alternative treatment of 23.3 versus 14.7 months for chlorambucil (HR = 0.54; P = .0001). The ORR was 83% with alemtuzumab (24% CR) versus 55% with chlorambucil (2% CR); differences in ORR and CR were highly statistically significant (P < .0001). Elimination of minimal residual disease occurred in 11 of 36 complete responders to alemtuzumab versus none to chlorambucil. Adverse events profiles were similar, except for more infusion-related and cytomegalovirus (CMV) events with alemtuzumab and more nausea and vomiting with chlorambucil. CMV events had no apparent impact on efficacy. Conclusion As first-line treatment for patients with CLL, alemtuzumab demonstrated significantly improved PFS, time to alternative treatment, ORR and CR, and minimal residual disease–negative remissions compared with chlorambucil, with predictable and manageable toxicity.

Validation of Minimal Residual Disease Flow Cytometry Method for Residual Disease Monitoring in Chronic Lymphocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4196-4196
Author(s):  
Shabnam Tangri ◽  
Annalee Estrellado ◽  
Julie Ranuio ◽  
Elisa Romeo ◽  
Jonathan Lawson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Chronic Lymphocytic Leukemia ◽  
Light Chain ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Normal Cells ◽  
Chain Analysis ◽  
Minimal Residual

Abstract Monitoring Minimal Residual Disease (MRD) of Chronic Lymphocytic Leukemia (CLL) patients who achieved complete remission has been difficult and challenging using flow cytometry detection methods in peripheral blood Earlier flow cytometry methods described for detection of MRD relied on the assessment of CD20 expression that maybe compromised during rituximab therapy (CD5/19/20/79B and light chain analysis) or were done using the classic CLL staining panel (CD5/19/23 and light chain analysis) that had a low sensitivity. To facilitate the development of methods that would be suitable for rituximab containing regimens and have better sensitivity, a panel of antibody combinations was identified for use in an internationally standardized flow cytometric approach for MRD detection in CLL-treated patients (Rawstron et al., 2007). This panel consists of 5 combinations of antibodies specific for 1-sIgKappa/sIgLambda/CD19/CD5, 2-CD45/CD14/CD19/CD5, 3-CD43/CD79b/CD19/CD5, 4-CD22/CD81/CD19/CD5 and 5-CD20/CD38/CD19/CD5 antigens. The first two combinations are utilized for confirmation of clonality and assessment of Tcell contamination rate within the B cell gate, whereas combinations 3, 4 and 5 are specific for MRD detection. This standardized 5-combination panel was technically validated by Genoptix Medical Laboratory for use in BiogenIdec’s clinical trials in CLL with Lumiliximab. To validate this panel assay, selected CLL samples were mixed with normal donor blood or “disease-free” bone marrow specimens, to achieve 1%, 0.1%, 0.05% and 0.01% of CLL cells in “non-CLL” leukocytes. Our results show that it is possible to identify up to 1 CLL cell in 10,000 normal cells in some but not all cases, and that on a consistent basis our analysis is able to identify 1 CLL cell in 1000 normal cells. In comparison, the classic screening panel commonly used to diagnose CLL has a limit of detection (LOD) of about 1% (1 leukemic cell in 100 normal cells); thus this new method provides a 10 to 100 fold improvement in sensitivity. The enhanced sensitivity and LOD of the new assay is mainly due to the reduction of the non-CLL cell background in peripheral blood and bone marrow Furthermore, to make analysis guidelines consistent among analysts, an internal semi-quantitative clustering scoring analysis system was developed for this assay. The cluster scoring scheme assigns a negative score to scattered events with no clearly visible clone; well grouped events with tight visible clones are assigned positive scores and those gated events are considered for MRD final call. To reliably define the presence of MRD, at least 2 of the 3 MRD specific antibody combinations must have a positive clustering score. Due to the small number of cells to be analyzed, collection of 500,000 events is recommended. Finally, the results of additional studies showed that the anticoagulant employed may impact the stability of the antigens over a period of 7 days, and for accurate MRD determination blood specimens should be drawn into Heparin vacutainer tubes when long shipping times are expected.

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.

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