Addition of Rituximab to Fludarabine Improves Progression Free Survival in Untreated ZAP-70 Negative Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 477-477
Author(s):  
Maria Ilaria Del Principe ◽  
Giovanni Del Poeta ◽  
Luca Maurillo ◽  
Adriano Venditti ◽  
Francesco Buccisano ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Monoclonal Antibodies ◽  
Mononuclear Cells ◽  
Residual Disease ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Free Survival ◽  
Grade 3

Abstract Clinical trials of monoclonal antibodies in combination with chemotherapy have reported previously unattained response rates in CLL because this approach reduces disease burden to levels detectable only by flow cytometry or molecular methods. The latest studies from CALGB have demonstrated that rituximab added concurrently or sequentially to fludarabine (Flu) for symptomatic, untreated CLL allows to achieve higher remission rates, longer progression free and overall survival. Nevertheless, the analysis of different biologic parameters could better explain the discordant outcome independent of treatment observed in these studies. Recent literature data indicate that unmutated VH genes, CD38 and/or ZAP-70 protein tyrosine kinase overexpression may predict both a lower response and a shorter survival. We performed at our Institution a phase II study that added rituximab sequentially to Flu as initial therapy for symptomatic, untreated CLL in order to evaluate either the toxicity or the clinical response or outcome. Complete remission (CR) was also assessed by a multiparametric flow cytometric method. ZAP-70 protein and CD38 antigen were determined before chemotherapy on mononuclear cells by flow cytometry using an anti-ZAP-70 and an anti-CD38 antibody, respectively. Forty-nine B-CLL patients, median age 59 years (range 37–74) received six monthly courses of Flu (25 mg/m2 for 5 days) and four weekly doses of rituximab (375 mg/m2) starting on an average of thirty days (range 5–180) after completion of the Flu therapy. According to modified Rai stages, 4 pts had a low stage, 42 an intermediate stage and 3 a high stage. Three out of 49 pts experienced fever, chills and rigors, during the first infusion of rituximab and only 1 patient presented grade 3 infective lung toxicity according to WHO. Hematologic toxicity included neutropenia (grade 1 and/or 2 in 12 pts, grade 3 and/or 4 in 22 pts), thrombocytopenia (grade 1 and/or 2 in 4, grade 3 and/or 4 in 3 pts) and anemia (grade 2 in 3 pts). Based on the NCI criteria, 45/49 (91.8%) pts achieved a CR, 3/49 (6.1%) a partial remission (PR) and 1/49 (2%) no response (NR). The median follow-up duration was 29 months. Median duration of CR and PR has not been reached. Noteworthy, our B-CLL pts treated sequentially with Flu and rituximab experienced a very long progression-free survival (PFS) from treatment (72% at 3 years). ZAP-70 and CD38 were positive (>20%) in 19/48 (39.5%) and in 13/48 (27%) pts, respectively. Minimal residual disease (MRD) performed on bone marrow by flow cytometry was positive (>5% CD19+CD5+CD79b- CLL cells) in 7/37 (19%) analysed pts. A significant shorter PFS was observed in ZAP-70+ pts (38% vs 100% at 3 years; P=0.003), in CD38+ pts (39% vs 92% at 3 years; P=0.007) and also in pts with higher MRD after treatment (50% vs 81% at 2 years; P=0.04). Therefore, the addition of monoclonal antibodies, such as rituximab, to chemotherapy allowed a better outcome in CLL, exerting a key role to eradicate MRD. Moreover, the stratification of pts within different risk classes using novel biologic predictive factors, such as ZAP-70 and CD38, might allow us to offer more tailored treatment strategies, reserving experimental approaches and/or transplantation procedures only to CLL subsets with proved adverse biologic and clinical features.

Combination Chemoimmunotherapy with Pentostatin, Cyclophosphamide and Rituximab Shows Significant Clinical Activity with Low Accompanying Toxicity in Previously Untreated B-Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 35-35
Author(s):  
Neil Kay ◽  
Susan Geyer ◽  
Timothy Call ◽  
Tait Shanafelt ◽  
Clive Zent ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Free Survival ◽  
Significant Clinical Activity

Abstract BACKGROUND: B-Chronic Lymphocytic Leukemia (CLL) is still uncurable but very powerful new tools are available with the use of chemoimmunotherapy (CIT). Purine nucleoside-based regimens that incorporate rituximab have generated very high levels of overall responses (OR) with significant percentage of those complete responses (CR) in previously untreated CLL. Here we report and update our experience with a phase 2 pentostatin-based CIT regimen for previously untreated CLL as conducted at 2 medical centers. We also studied the association of outcome based on risk stratification parameters and achievement of minimal residual disease. METHODS: Building on prior work of pentostatin in CLL by us (Kay ASH, 2004) and others, we initiated a trial of combined pentostatin (P)(2 mg/m2), cyclophosphamide (C)(600 mg/m2) and rituximab (R)(375 mg/m2) for symptomatic, previously untreated patients (n=65). This PCR regimen is given on a 21-day, 6-cycle schedule. However, the initial cycle of treatment uses thrice weekly rituximab as described by us earlier. In brief, this was rituximab at 100 mg/m2 on day 1, 375 mg/m2 on days 3 and 5 of the first week only. Prophylactic Sulfamethoxazole/Trimethoprim and Acyclovir were given to all patients for 1 year starting on the first cycle of therapy with PCR. All patients were risk stratified using CD38, ZAP-70, immunoglobulin heavy chain variable region gene (IgVH) and FISH panel assessments at entry. RESULTS: These patients were characterized as mostly in high-risk categories. Of 64 evaluable patients, 34 (53%) were high Rai risk (stage 3–4), 71% were non mutated for the IgVH gene, 34% were CD38+ and 34% were ZAP-70+. Thirty patients (52%) had one FISH anomaly, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs, and no major infections. NCI Working Group Criteria Responses occurred in 58 (91%) with 26 (41%) complete responses (CR), 14 (22%) nodular partial responses (nodular PR), and 18 (28%) partial responses (PR) patients. Outcome for all 64 patients demonstrates a median progression-free survival of 32.6 months. Importantly, no high risk factor (i.e., age, FISH, IgVH status, CD38+, ZAP-70+) except for del (17p) defect (n=3) precluded attaining a CR or NPR. In contrast, we found this regimen was equally effective in young vs. elderly (>70 yrs) patients and in del(11)(q22.3) vs. other favorable prognostic FISH factors. Examination of outcome among CR and nodular PR patients for PFS by flow cytometry status (negative vs. positive, i.e., ≤ 1 % CD5+/CD19+ vs. ≥ 1 % CD5+/CD19+) demonstrated improvement in progression free survival for patients who attained flow cytometry negativity (p = 0.009). Conclusion: This novel regimen of pentostatin, cyclophosphamide and rituximab for previously untreated CLL demonstrated significant clinical activity despite poor risk-based prognoses with minimal toxicity in terms of bone marrow suppression and/or infections. The additional feature of this approach is the ability to have durable responses for all age groups and even CLL patients with a del(11)(q22.3).

Consolidation Therapy with Subcutaneous (SC) Alemtuzumab After Fludarabine and Rituximab (FR) Induction Therapy Improves the Complete Response (CR) Rate in Chronic Lymphocytic Leukemia (CLL) and Eradicates Minimal Residual Disease (MRD) but Is Associated with Severe Infectious Toxicity: Final Analysis of CALGB Study 10101.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 210-210
Author(s):  
Thomas S Lin ◽  
Kathleen A Donohue ◽  
John C. Byrd ◽  
Margaret S Lucas ◽  
Eva Hoke ◽  
...  
Keyword(s):  
Residual Disease ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Consolidation Therapy ◽  
Varicella Zoster ◽  
Grade 3

Abstract Abstract 210 Background: Alemtuzumab (Campath-1H) is approved for the treatment of CLL. CALGB sought to determine whether alemtuzumab can improve the CR rate and eradicate MRD after induction chemoimmunotherapy by performing a phase II study administering FR followed by alemtuzumab consolidation to previously untreated, symptomatic CLL patients (pts). We previously reported preliminary toxicity data (Lin et al. ASH 2007) and now report final toxicity and response data. Methods: Pts received fludarabine 25 mg/m2 IV on days 1–5, and rituximab 50 mg/m2 IV on day 1, 325 mg/m2 on day 3, and 375 mg/m2 on day 5 of cycle 1 and then only on day 1 of cycles 2–6, repeated every 28 days for up to 6 cycles. Four months after the last fludarabine dose, pts with stable (SD) or responsive disease by NCI 96 criteria received SC alemtuzumab 3 mg on day 1, 10 mg on day 3, and 30 mg on day 5, and then thrice weekly thereafter for 6 weeks (18 total doses). Pts received standard Pneumocystis (PCP) and Varicella zoster virus prophylaxis and were monitored weekly by PCR for Cytomegalovirus (CMV) viremia. When unacceptable serious infectious toxicity was noted in pts who received alemtuzumab after achieving CR from FR induction, the study was amended so that only PR or SD pts received alemtuzumab after FR. Results: Median age of pts (n=102) was 61 years (range, 23–82), 74% were male, and 30% were Rai stage III/IV. FR was well tolerated; 93% of pts received at least 3 cycles, and 77% completed all 6 cycles. Overall, complete and partial response (OR, CR, PR) rates after FR induction were 90%, 29% and 61%, and 15% were MRD negative by flow cytometry. Fifty-eight pts received alemtuzumab, and 42 (72%) completed the planned 6 weeks of therapy. OR, CR, and PR rates after alemtuzumab (n=58) were 91%, 66% and 26%, and 50% were MRD negative. Twenty-eight of 45 pts (62%) in PR after FR who received alemtuzumab attained CR. Of 11 pts in CR after FR who received alemtuzumab, 5 were MRD negative prior to consolidation and 3 of the other 6 converted to MRD negative afterwards. By intent-to-treat for all patients enrolled, OR, CR, and MRD negativity were attained by 90%, 57% and 42% of pts. With a median follow up of 34 months, median progression free survival (PFS) was 37 months (95% CI, 33–43 months); PFS was 73% and overall survival (OS) 86% at 2 years. Two-year PFS (76% vs 70%, p=0.54) and OS (84% vs 88%, p=0.89) were similar for pts who did and did not receive alemtuzumab. Similarly, there were no differences in PFS or OS among the 30 pts in CR after FR whether or not they received alemtuzumab, although the numbers were small. Grade 3–4 neutropenia and thrombocytopenia were observed in 43% and 19% of pts during alemtuzumab therapy. Grade 3–4 non-hematologic toxicity was observed in 41% of pts, including 19% infections and 19% febrile neutropenia, during alemtuzumab therapy. As we previously reported, 5 pts in CR after FR who received alemtuzumab died from infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia), and one pt in PR after FR who received alemtuzumab died of Epstein-Barr (EBV) viremia without evidence of EBV lymphoma. These grade 5 toxicities occurred both during and for up to 7 months after alemtuzumab therapy. Conclusions: Alemtuzumab consolidation improved the CR and MRD negative rates after FR induction. However, alemtuzumab consolidation resulted in significant toxicity, particularly severe infections in pts who achieved a CR after FR induction. Longer follow up is needed to determine if the improved CR and MRD negative rates following alemtuzumab consolidation will eventually result in improved PFS or OS, especially among pts who achieved a PR after FR induction. Disclosures: Lin: GlaxoSmithkline: Consultancy, Employment; Genentech: Consultancy; Bayer: Consultancy. Off Label Use: Use of alemtuzumab as consolidation therapy. Byrd:Genentech: Consultancy, Research Funding. Link:Genentech: Consultancy. Rai:Genentech: Consultancy; Bayer: Consultancy.

scholarly journals Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 535-537 ◽  
Author(s):  
Farrukh T. Awan ◽  
Neil E. Kay ◽  
Melanie E. Davis ◽  
Wenting Wu ◽  
Susan M. Geyer ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Treatment Strategies ◽  
Myeloid Cell ◽  
Progression Free Survival ◽  
Poor Response ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Phase 2 Study ◽  
Significant Difference

Abstract Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. Increased Mcl-1 expression is associated with failure to achieve remission after treatment with fludarabine and chlorambucil in patients with chronic lymphocytic leukemia (CLL). However, the influence of Mcl-1 expression has not been examined in CLL trials using chemoimmunotherapy. We investigated Mcl-1 protein expression prospectively as part of a phase 2 study evaluating the efficacy of pentostatin, cyclophosphamide, and rituximab in patients with untreated CLL. No significant difference by Mcl-1 expression was noted in pretreatment or response parameters. However, in patients with higher Mcl-1 expression, both minimal residual disease-negative status and progression-free survival was found to be significantly reduced (57% vs 19%, P = .01; 50.8 vs 18.7 months; P = .02; respectively). Mcl-1 expression may therefore be useful in predicting poor response to chemoimmunotherapy. These findings further support pursuing treatment strategies targeting this important antiapoptotic protein. (Because the trials described were conducted before the requirement to register them was implemented, they are not registered in a clinical trial database.)

scholarly journals Response assessment in chronic lymphocytic leukemia after fludarabine plus prednisone: clinical, pathologic, immunophenotypic, and molecular analysis [see comments]

Blood ◽  
1992 ◽  
Vol 80 (1) ◽  
pp. 29-36 ◽  
Author(s):  
LE Robertson ◽  
YO Huh ◽  
JJ Butler ◽  
WC Pugh ◽  
C Hirsch-Ginsberg ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Gene Rearrangement ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Time To Progression ◽  
Free Survival ◽  
Biopsy Examination ◽  
Gene Rearrangement Analysis

Abstract The goals of this study were to evaluate the response to treatment in chronic lymphocytic leukemia (CLL) according to clinical, pathologic, immunophenotypic, and molecular features, as well as to address the clinical significance of each finding. One hundred fifty-nine CLL patients with either advanced Rai stage III or IV (81 patients) or progressive Rai stage 0 to II (78 patients) were treated with fludarabine (30 mg/m2/d intravenously every day for 5 days) plus prednisone (30 mg/m2/d orally daily for 5 days). Thirty-six patients were previously untreated. The response rates were 12% complete response (CR), 30% nodular complete response (nCR), and 18% partial response (PR). In all patients who achieved a complete response (both CR and nCR) less than 30% of nucleated cells were lymphocytes on marrow aspirate differential analysis; however, nCR patients had residual nodular and/or interstitial lymphocyte involvement on marrow biopsy examination. There was no evidence of leukemic infiltration on marrow biopsy examination in CR patients. With a median follow-up of 35 months, comparison of time to progression in the CR and nCR groups at 2 years showed a projected 87% versus 55% progression-free survival (P less than .03). Residual disease assessment by flow cytometry using simultaneous dual-color staining on blood and marrow lymphocytes was also performed on each patient. Residual disease was determined by the expression of CD5 on B lymphocytes and the monoclonality of surface light-chain expression. After six courses of fludarabine plus prednisone, no residual disease was detected by flow cytometry in 89% of the CRs, 51% of the nCRs, and 19% of the PRs. Clinical residual disease in PR patients with no residual disease detectable by flow cytometry was limited to lymph-adenopathy. Time to progression at 2 years was longer in CR and nCR patients having no residual disease detected by flow cytometry (84% v 39% 2-year progression-free survival, P less than .001). Posttreatment lg gene rearrangement analysis using JH, J kappa, and C lambda probes demonstrated no rearranged bands and a return to the germline configuration in five of seven CRs and two of eight nCRs studied. The molecular studies were concordant with the dual- parameter immunophenotype results and none of the patients who reverted to a germline DNA pattern after treatment have experienced relapse. The absence of detectable minimal residual disease by bone marrow biopsy, dual-color flow cytometry, and lg gene rearrangement analysis is achieveable in CLL with fludarabine and is predictive of the response duration.

Consolidation and Maintenance Immunotherapy with Rituximab Improve Progression Free Survival within ZAP-70 Positive Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2824-2824 ◽  
Author(s):  
Giovanni Del Poeta ◽  
Maria Ilaria Del Principe ◽  
Luca Maurillo ◽  
Francesco Buccisano ◽  
Adriano Venditti ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Progression Free Survival ◽  
Peripheral Blood Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Induction Treatment ◽  
Hematologic Toxicity ◽  
Free Survival ◽  
Mutational Status ◽  
Duration Of Response ◽  
Grade 3

Abstract Clinical studies of monoclonal antibodies combined with chemotherapy have attained more complete responses and longer duration of responses in CLL because this approach reduces disease burden to levels detectable only by immunological or molecular methods. Recent literature data indicate that VH genes, CD38, ZAP-70 protein, and cytogenetic status have a major impact on CLL prognosis. We performed a phase II study that added rituximab sequentially to fludarabine (Flu) as initial therapy for symptomatic, untreated CLL in order to evaluate both the clinical response and outcome. Remission status was also assessed by a multiparametric flow cytometric method based on the detection of CD19+CD5+CD79b− residual B-CLL lymphocytes. VH mutational status, CD38 and cytogenetics were obtained in all pts before treatment. ZAP-70 protein was performed by flow cytometry using an anti-ZAP-70 Alexa Fluor 488 conjugated antibody. Seventy-five CLL pts, median age 60 years, received six monthly courses of Flu (25 mg/m2 for 5 days) and four weekly doses of rituximab (375 mg/m2) starting on an average of thirty days after completion of Flu therapy. According to modified Rai stages, 6 pts had a low stage, 66 an intermediate stage and 3 a high stage. Based on NCI criteria, 61/75 (81%) pts achieved a complete remission (CR), 10/75 (13%) a partial remission (PR) and 4/75 (5%) no response. Three pts presented grade 3 (WHO) infective lung toxicity and 1 patient acute fatal B hepatitis. Hematologic toxicity included neutropenia (grade 3 and/or 4 in 38 pts) and thrombocytopenia (grade 3 and/or 4 in 4 pts). Twenty eight pts, either with CD5+CD19+CD79b− (MRD) bone marrow (BM) cells >1% (n=17 pts) or with CD19+CD5+CD79b− (MRD) peripheral blood lymphocytes (PBL) >1000/microl (n=11 pts) within six months after completion of the induction treatment, underwent consolidation/maintenance therapy with four monthly cycles of rituximab at 375 mg/m2 followed by twelve monthly doses of rituximab at 150 mg/m2. The median follow-up duration was 37 months. Noteworthy, all pts experienced a long progression-free survival (PFS) from treatment (67% at 5 years). Nevertheless, CLL pts that underwent consolidation therapy (n=28) showed a significant longer duration of response (75% vs 27% at 5 years, P=0.002) in comparison with the subset of not consolidated and BM or PBL MRD positive (n=18) CLL pts. Interestingly, BM and PBL MRD negative pts (n=26) showed a duration of response similar to that of the consolidated pts. Moreover, a significant shorter PFS was observed within CD38+ pts (29% vs 79% at 5 years, P=0.005), unmutated pts (0% vs 92% at 2 years, P=0.001), ZAP-70+ pts (29% vs 92% at 5 years; P=0.00003) and within the “poor risk” [trisomy 12 or del 11q or del 17p] cytogenetic subset (0% vs 79% at 2 years, P=0.03). Interestingly, within the ZAP-70+ subset (n=35), the consolidated pts (n=12) showed a longer duration of response (68% vs 0% at 2.6 years, P=0.007) in comparison with the unconsolidated pts (n=11). Therefore, the addition of a consolidation/maintenance therapy with rituximab prolongs significantly the duration of response allowing a better outcome. Moreover, rituximab improves significantly PFS of pts notoriously at worse prognosis, such as ZAP-70+ B-CLL.

Venetoclax plus Dose-Adjusted R-EPOCH (VR-EPOCH) for Richter's Syndrome

Blood ◽  
2021 ◽  
Author(s):  
Matthew S. Davids ◽  
Kerry A. Rogers ◽  
Svitlana Tyekucheva ◽  
Zixu Wang ◽  
Samantha Pazienza ◽  
...  
Keyword(s):  
Cellular Therapy ◽  
Residual Disease ◽  
Tumor Lysis Syndrome ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Phase 2 Trial ◽  
Grade 3 ◽  
Richter’S Syndrome

Richter's Syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS to chemoimmunotherapy and improve outcomes. We conducted a single-arm, investigator-sponsored, phase 2 trial of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) to determine the rate of complete response (CR). Patients received R-EPOCH for 1 cycle, then after count recovery, accelerated daily venetoclax ramp-up to 400 mg, then VR-EPOCH for up to 5 more 21-day cycles. Responders received venetoclax maintenance or cellular therapy off-study. Twenty-six patients were treated, and 13 of 26 (50%) achieved CR, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial response (overall response rate 62%). Median progression-free survival was 10.1 months, and median overall survival was 19.6 months. Hematologic toxicity included grade ≥3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38%. No patients experienced tumor lysis syndrome with daily venetoclax ramp-up. VR-EPOCH is active in RS, with deeper, more durable responses than historical regimens. Toxicities from intensive chemoimmunotherapy and venetoclax were observed. Our data suggest that studies comparing venetoclax with chemoimmunotherapy to chemoimmunotherapy alone are warranted. (Funded by Genentech/AbbVie; ClinicalTrials.gov number, NCT03054896).

scholarly journals Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2062-2068 ◽  
Author(s):  
Sameer A. Parikh ◽  
Michael J. Keating ◽  
Susan O'Brien ◽  
Xuemei Wang ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Color Flow ◽  
Free Survival ◽  
Phase 2 Trial ◽  
End Of Treatment ◽  
Grade 3

Abstract Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is associated with superior overall survival (OS) for patients with chronic lymphocytic leukemia (CLL). Alemtuzumab (A) was added to FCR (CFAR) in a phase 2 trial for high-risk untreated patients < 70 years with serum β-2 microglobulin (β2M) ≥ 4 mg/L. Sixty patients were enrolled; median age was 59 years (range, 42-69); 75% were male; median β2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 patients with 17p deletion, CR was achieved by 8 (57%). Of 57 BM samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable with historic high-risk FCR-treated patients. CFAR may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation.

scholarly journals Response assessment in chronic lymphocytic leukemia after fludarabine plus prednisone: clinical, pathologic, immunophenotypic, and molecular analysis [see comments]

Blood ◽  
1992 ◽  
Vol 80 (1) ◽  
pp. 29-36 ◽  
Author(s):  
LE Robertson ◽  
YO Huh ◽  
JJ Butler ◽  
WC Pugh ◽  
C Hirsch-Ginsberg ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Gene Rearrangement ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Time To Progression ◽  
Free Survival ◽  
Biopsy Examination ◽  
Gene Rearrangement Analysis

The goals of this study were to evaluate the response to treatment in chronic lymphocytic leukemia (CLL) according to clinical, pathologic, immunophenotypic, and molecular features, as well as to address the clinical significance of each finding. One hundred fifty-nine CLL patients with either advanced Rai stage III or IV (81 patients) or progressive Rai stage 0 to II (78 patients) were treated with fludarabine (30 mg/m2/d intravenously every day for 5 days) plus prednisone (30 mg/m2/d orally daily for 5 days). Thirty-six patients were previously untreated. The response rates were 12% complete response (CR), 30% nodular complete response (nCR), and 18% partial response (PR). In all patients who achieved a complete response (both CR and nCR) less than 30% of nucleated cells were lymphocytes on marrow aspirate differential analysis; however, nCR patients had residual nodular and/or interstitial lymphocyte involvement on marrow biopsy examination. There was no evidence of leukemic infiltration on marrow biopsy examination in CR patients. With a median follow-up of 35 months, comparison of time to progression in the CR and nCR groups at 2 years showed a projected 87% versus 55% progression-free survival (P less than .03). Residual disease assessment by flow cytometry using simultaneous dual-color staining on blood and marrow lymphocytes was also performed on each patient. Residual disease was determined by the expression of CD5 on B lymphocytes and the monoclonality of surface light-chain expression. After six courses of fludarabine plus prednisone, no residual disease was detected by flow cytometry in 89% of the CRs, 51% of the nCRs, and 19% of the PRs. Clinical residual disease in PR patients with no residual disease detectable by flow cytometry was limited to lymph-adenopathy. Time to progression at 2 years was longer in CR and nCR patients having no residual disease detected by flow cytometry (84% v 39% 2-year progression-free survival, P less than .001). Posttreatment lg gene rearrangement analysis using JH, J kappa, and C lambda probes demonstrated no rearranged bands and a return to the germline configuration in five of seven CRs and two of eight nCRs studied. The molecular studies were concordant with the dual- parameter immunophenotype results and none of the patients who reverted to a germline DNA pattern after treatment have experienced relapse. The absence of detectable minimal residual disease by bone marrow biopsy, dual-color flow cytometry, and lg gene rearrangement analysis is achieveable in CLL with fludarabine and is predictive of the response duration.

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.

Pharmacogenetic Assessment of Toxicity and Outcome in Patients With Metastatic Colorectal Cancer Treated With LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05

2010 ◽  
Vol 28 (15) ◽  
pp. 2556-2564 ◽  
Author(s):  
Valérie Boige ◽  
Jean Mendiboure ◽  
Jean-Pierre Pignon ◽  
Marie-Anne Loriot ◽  
Marine Castaing ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Tumor Response ◽  
Progression Free Survival ◽  
Hematologic Toxicity ◽  
First Line ◽  
Free Survival ◽  
Increased Risk ◽  
Grade 3 ◽  
Cancérologie Digestive

Purpose The aim was to investigate whether germline polymorphisms within candidate genes known or suspected to be involved in fluorouracil (FU), oxaliplatin, and irinotecan pathways were associated with toxicity and clinical outcome in patients with metastatic colorectal cancer (mCRC). Patients and Methods Blood samples from 349 patients included in the Fédération Francophone de Cancérologie Digestive 2000-05 randomized trial, which compared FU plus leucovorin (LV5FU2) followed by FU, leucovorin, and oxaliplatin (FOLFOX) followed by FU, leucovorin, and irinotecan (FOLFIRI; sequential arm) with FOLFOX followed by FOLFIRI (combination arm) in terms of progression-free survival (PFS) and overall survival, were collected. Twenty polymorphisms within the DPD, TS, MTHFR, ERCC1, ERCC2, GSTP1, GSTM1, GSTT1, and UGT1A1 genes were genotyped. Results The ERCC2-K751QC allele was independently associated with an increased risk of FOLFOX-induced grade 3 or 4 hematologic toxicity (P = .01). In the sequential arm, TS-5′UTR3RG and GSTT1 alleles were independently associated with response to LV5FU2 (P = .009) and FOLFOX (P = .01), respectively. The effect of oxaliplatin on tumor response increased with the number of MTHFR-1298C alleles (test for trend, P = .008). The PFS benefit from first-line FOLFOX was restricted to patients with 2R/2R (hazard ratio [HR] = 0.39; 95% CI, 0.23 to 0.68) or 2R/3R (HR = 0.59; 95% CI, 0.42 to 0.82) TS-5′UTR genotypes, respectively. Conversely, patients with the TS-5′UTR 3R/3R genotype did not seem to benefit from the adjunction of oxaliplatin (HR = 0.96; 95% CI, 0.66 to 1.40; trend between the three HRs, P = .006). Conclusion A pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.

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