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).

scholarly journals 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 109 (2) ◽  
pp. 405-411 ◽  
Author(s):  
Neil E. Kay ◽  
Susan M. Geyer ◽  
Timothy G. Call ◽  
Tait D. Shanafelt ◽  
Clive S. Zent ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Color Flow ◽  
Significant Clinical Activity ◽  
Minimal Residual

Abstract Building on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (> 70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity.

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.

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.

Mcl-1 as a Possible Predictor of Progression-Free Survival in Previously Untreated Chronic Lymphocytic Leukemia Patients Treated with Pentostatin, Cyclophosphamide and Rituximab.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2105-2105
Author(s):  
Farrukh Awan ◽  
Neil E. Kay ◽  
Melanie Davis ◽  
Wenting Wu ◽  
Nelson Leung ◽  
...  
Keyword(s):  
Risk Factors ◽  
Flow Cytometry ◽  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Continuous Variable ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Color Flow ◽  
Free Survival ◽  
Pre Treatment

Abstract Myeloid cell factor-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 protein family that associates with tumor cell survival and drug resistance in chronic lymphocytic leukemia (CLL). Increased Mcl-1 expression is associated with failure to achieve remission after chemotherapy with fludarabine and chlorambucil in CLL patients. However, the influence of Mcl-1 expression has not been examined in CLL trials using treatment regimens that contain rituximab, which has shown substantially improved outcomes for a large subset of patients and have become a mainstay in the therapy of newly diagnosed CLL. We previously reported that combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab (PCR) has significant clinical activity with low accompanying toxicity in previously untreated CLL patients, and is especially well tolerated in older patients in whom the use of fludarabine may be associated with prohibitive toxicities. As part of this study, we prospectively investigated association of Mcl-1 protein expression with response and progression-free survival. Eligible patients received a regimen consisting of pentostatin (2 mg/m2), cyclophosphamide (600 mg/ m2), and rituximab (375 mg/m2) given intravenously on day 1 of a 21-day cycle for a maximum of 6 cycles. Responses were assessed according to NCI 1996 criteria and included bone marrow evaluation and two-color flow cytometry two months after completion of therapy. Flow cytometry-negative status was defined as less than or equal to 1% CD5+/CD19+ cells. Of the 64 patients evaluated in this trial, clinical responses were seen in 58 (91%), with 26 (41%) complete responses (CR), 14 (22%) nodular partial responses (nPR), and 18 (28%) partial responses (PR). Lysates from peripheral blood cells obtained pre-treatment were analyzed for Mcl-1 expression by immunoblot. Mcl-1 as a continuous variable was not found to be associated with other commonly described risk factors. However, Recursive Partitioning Analysis (RPA) was devised employing Mcl-1 expression as a continuous variable, which revealed an optimal cut point of 0.85. At this cutoff, flow cytometry-negative status was significantly different between the two groups (p=0.01) and median PFS was significantly higher (p=0.02) in patients with Mcl-1 levels of &lt;0.85 (50.8 vs. 18.7 months). No difference by Mcl-1 expression was noted in other pre-treatment or response parameters. Our data describes the first prospective validation of Mcl-1 over-expression adversely influencing both the likelihood of attaining a flow cytometry-negative complete remission and extended progression free survival. Mcl-1 expression was also independent of other risk factors, indicating additional benefit for this measure in assessing patients. Mcl-1 expression may therefore predict poor response to chemoimmunotherapy, and these findings advocate pursuing therapeutic agents targeting this important anti-apoptotic protein.

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.

Allogeneic Myeloma GVAX with Lenalidomide Enhances Progression Free Survival through the Generation of Tumor Specific Immunity in Patients in Near Complete Remission

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4238-4238 ◽  
Author(s):  
Ivan M. Borrello ◽  
Kimberly Noonan ◽  
Carol Ann Huff ◽  
Anna Ferguson ◽  
Amy Sidorski ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Response To Therapy ◽  
Clinical Activity ◽  
Free Survival ◽  
Specific Immunity ◽  
M Spike

Abstract Background: The depth of response to therapy in myeloma (MM) correlates with improved progression free survival. We have previously shown that lenalidomide (Len) can augment vaccine efficacy to the pneumococcal conjugate vaccine (PCV), PrevnarÒ. We extend those observations to examine whether vaccinating patients on Len in a near complete remission (nCR) (negative M-spike, IFE positive) could further deepen the clinical response and generate measurable myeloma specific immunity. Design: Patients on a Len-containing regimen (VRD, Rd, BiRD or R) that achieved and maintained a nCR for 4-6 months were eligible for the study. Patients continued only on single agent Len and received 4 GVAX vaccinations consisting of two allogeneic MM lines: H929, U266 admixed with K562 transduced to express GM-CSF as well as PCV. Patients received 3 monthly vaccines and a boost at 6 months. Immune monitoring was performed on BM samples obtained at baseline, 3 months and 1 year Results: To date 32 patients have been screened. 17 patients initially in a nCR were ineligible for vaccination: 3 (18%) had disease progression, 7 (42%) entered into an IFE negative CR, and 7 (42%) maintained a nCRduring the observation period but opted not to enroll. 15 patients have been enrolled and completed their vaccinations. Patient characteristics are shown in the Table. Of note, none possessed high-risk features by ISS or FISH. Median follow-up for the study is 34.0 months. Median progression free survival (PFS) of the cohort of vaccinated patients has not been reached whereas the PFS in the observation arm that remained on the multidrug Len-containing therapy was 17.9 months (p<0.001). Vaccination in the setting of a rising M-spike was less likely to induce a durable remission with a median PFS of 14.3 months (p<0.003). Laboratory analysis showed that the patients achieving a CR had greater expression of PD-1 on CD4 and CD8 cells at baseline in the BM. Furthermore, durable responses were associated with the development and persistence of MM-specific immunity. Conclusions: Vaccination in combination with Len in patients with minimal residual disease generates potent MM-specific immunity and appears to significantly extend the PFS. Vaccination in a nCR with a poly-antigenic approach such as GVAX in combination with Len-induced immunomodulation shows promising early clinical activity that warrants further investigation as an approach to inducing and maintaining durable clinical remissions. Table 1. Vaccination(n=15) Observation(n=16) Age 69 (55-81) 66 (40-83) FISH (high risk) 0% 0% ISS Stage III 2 (13%) 3 (19%) IFE negative 0 (0%) 7 (42%) Prior Therapies 1.8 (1-4) 1.8 (1-3) Disclosures Borrello: Celgene: Research Funding. Noonan:Celgene: Speakers Bureau.

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 Dose Intensive Rituximab and High-Dose Methylprednisolone in Elderly or Unfit Patients with Relapsed Chronic Lymphocytic Leukemia

Medicina ◽  
2019 ◽  
Vol 55 (11) ◽  
pp. 719
Author(s):  
Pileckyte ◽  
Valceckiene ◽  
Stoskus ◽  
Matuzeviciene ◽  
Sejoniene ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Meaningful Improvement ◽  
Free Survival ◽  
High Dose Methylprednisolone ◽  
Unfit Patients

Background and Objectives: BTK and BCL2 inhibitors have changed the treatment paradigms of high-risk and elderly patients with chronic lymphocytic leukemia (CLL), but their long-term efficacy and toxicity are still unknown and the costs are considerable. Our previous data showed that Rituximab (Rtx) and high-dose methylprednisolone (HDMP) can be an effective and safe treatment option for relapsed high-risk CLL patients. Materials and Methods: We explored the efficacy and safety of a higher Rtx dose in combination with a shorter (3-day) schedule of HDMP in relapsed elderly or unfit CLL patients. Results: Twenty-five patients were included in the phase-two, single-arm trial. The median progression free survival (PFS) was 11 months (range 10–12). Median OS was 68 (range 47–89) months. Adverse events (AE) were mainly grade I–II° (77%) and no deaths occurred during the treatment period. Conclusions: 3-day HDMP and Rtx was associated with clinically meaningful improvement in most patients. The median PFS in 3-day and 5-day HDMP studies was similar and the toxicity of the 3-day HDMP schedule proved to be lower. The HDMP and Rtx combination can still be applied in some relapsed high-risk and elderly or unfit CLL patients if new targeted therapies are contraindicated or unavailable. (ClinicalTrials.gov identifier: NCT01576588).

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.

Rituximab Plus Fludarabine and Cyclophosphamide Prolongs Progression-Free Survival Compared With Fludarabine and Cyclophosphamide Alone in Previously Treated Chronic Lymphocytic Leukemia

2010 ◽  
Vol 28 (10) ◽  
pp. 1756-1765 ◽  
Author(s):  
Tadeusz Robak ◽  
Anna Dmoszynska ◽  
Philippe Solal-Céligny ◽  
Krzysztof Warzocha ◽  
Javier Loscertales ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
B Lymphocyte ◽  
Response Rate ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Serious Adverse Events ◽  
Free Survival ◽  
Previously Treated

PurposeRituximab, a monoclonal antibody that targets the CD20 cell surface antigen, has clinical activity in patients with non-Hodgkin's lymphoma and other B-lymphocyte disorders when administered alone or in combination with chemotherapy. Promising results have previously been reported in nonrandomized studies in patients with chronic lymphocytic leukemia (CLL). This trial was designed to compare chemoimmunotherapy with chemotherapy alone in patients with previously treated CLL.Patients and MethodsThis international, multicenter, randomized trial compared six cycles of rituximab plus fludarabine and cyclophosphamide (R-FC) with six cycles of fludarabine and cyclophosphamide alone (FC) in patients with previously treated CLL. A total of 552 patients with Binet stage A (1%), B (59%), or C (31%) disease entered the study and were randomly assigned to receive R-FC (n = 276) or FC (n = 276).ResultsAfter a median follow-up time of 25 months, rituximab significantly improved progression-free survival in patients with previously treated CLL (hazard ratio = 0.65; P < .001; median, 30.6 months for R-FC v 20.6 months for FC). Event-free survival, response rate, complete response rate, duration of response, and time to new CLL treatment or death were also significantly improved. Although the rates of adverse events, grade 3 or 4 events, and serious adverse events were slightly higher in the R-FC arm, R-FC was generally well tolerated, with no new safety findings and no detrimental effect on quality of life.ConclusionR-FC significantly improved the outcome of patients with previously treated CLL.

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