Sequential Therapy With Fludarabine, High-Dose Cyclophosphamide, and Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia Produces High-Quality Responses: Molecular Remissions Predict for Durable Complete Responses

Purpose Modern combination strategies are active in chronic lymphocytic leukemia (CLL) but can have significant myelosuppression and immunosuppression that may require dose attenuation for safety. We explored a sequential treatment strategy to allow safe delivery of active agents at full doses. Previously, we studied sequential therapy with fludarabine followed by cyclophosphamide (F→C). In that study, cyclophosphamide consolidation improved the frequency of complete response (CR) four-fold. Subsequently, rituximab was added to this regimen (F→C→R). Patients and Methods Thirty-six previously untreated CLL patients received therapy with fludarabine 25 mg/m2 on days 1 through 5 every 4 weeks for six cycles, followed by consolidation with cyclophosphamide 3,000 mg/m2 administered every 3 weeks for three cycles, followed by consolidation with weekly rituximab 375 mg/m2 for four cycles. Evaluation for minimal residual disease included flow cytometry and a highly sensitive clonotypic polymerase chain reaction (PCR). The median age was 59 years (range, 37 to 71 years), 61% of patients had high-risk disease, and 58% had unmutated IgVH genes. Results There were 32 responses (89%), including 22 CRs (61%). Consolidation with cyclophosphamide improved responses in 13 patients (36%); nine patients (25%) further improved their response with rituximab. Twenty patients (56%) achieved flow cytometric CRs, and 12 patients (33%) achieved a molecular CR (PCR negative). Patients achieving molecular CRs had an excellent prognosis with a plateau in the response duration curve, and 90% remain in clinical CR at 5 years. For the entire group, 5-year survival rate is 71% compared with a rate of 48% with our prior F→C regimen (P = .10). Conclusion Sequential therapy with F→C→R yields improvement in quality of response, with many patients achieving a PCR-negative state.

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Rituximab® and High Dose Methylprednisolone (HDMP) for the Treatment of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v104.11.2518.2518 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2518-2518

Author(s):

Januario E. Castro ◽

Jan Bole ◽

Carlos E. Prada ◽

Thomas J. Kipps

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Performance Status ◽

Variable Region ◽

Response Assessment ◽

Complete Response ◽

Lymphocytic Leukemia ◽

High Dose ◽

Ecog Performance Status ◽

Female Ratio ◽

High Dose Methylprednisolone

Abstract High-dose gluocorticoids and the anti-CD20 mAb Rituximab each can effect partial responses in patients with chronic lymphocytic leukemia (CLL), although complete and durable responses to treatment with either of these agents have not been reported. We examined whether patients with relapsed and/or refractory CLL could respond to these agents when used in combination in a pilot clinical trial. Fourteen patients with progressive, symptomatic, and relapsed/refractory disease were treated with three four-week cycles of high-dose Methylprednisolone (HDMP) at 1gr/m2 daily for 5 days and weekly Rituximab® at 375mg/m2 for four weeks. The median age of the patients was 60 years, the male to female ratio was 4:1, the ECOG performance status was < 2, and the average number of prior treatments was 2. All patients failed or were intolerant to fludarabine and 86% had high-risk disease by the modified Rai classification. Sixty-five percent of the patients had CLL cells that expressed ZAP-70 and unmutated immunoglobulin variable region genes. Response assessment was performed at the end of each cycle, two months after completion of treatment, and each 3–6 months thereafter until the patients experienced disease progression and/or required further treatment. Objective responses were observed in all 14 patients, with 6 patients achieving a complete response (CR) and the remainder a partial response (PR) as per the NCI-working group criteria. We observed a significant decrease in peripheral white blood cell (WBC) counts, increase in hemoglobin, elevation of platelet counts and a dramatic decrease in lymphadenopathy and splenomegaly. Five of the treated patients have not required further treatment with a median follow up of 26 months. Of these 5 patients 3 have maintain a CR. The median time to progression (TTP) was 12 months. Overall, the treatment was well tolerated and all the patients, except one, completed 3 cycles of therapy. The majority of adverse events were Grade I-II (fluid retention, cough, transient hyperglycemia, fatigue). In addition, we observed 7 episodes of grade III-IV toxicity secondary to (anemia, CMV esophagitis and GI bleeding with one case each and two cases each of thrombocytopenia and neutropenia). These data suggest that treatment with the combination of Rituximab® and HDMP has increased activity over treatment with either agent alone and may produce durable complete responses in patients with refractory and / or relapsed CLL.

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Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2019-01-896290 ◽

2019 ◽

Vol 133 (26) ◽

pp. 2765-2775 ◽

Cited By ~ 25

Author(s):

Ian W. Flinn ◽

John G. Gribben ◽

Martin J. S. Dyer ◽

William Wierda ◽

Michael B. Maris ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Residual Disease ◽

Standard Dose ◽

Tumor Lysis Syndrome ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Lymphocytic Leukemia ◽

Open Label ◽

Phase 1B ◽

Grade 3

Abstract This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (first line [1L]) chronic lymphocytic leukemia (CLL). Venetoclax dose initially was escalated (100-400 mg) in a 3 + 3 design to define MTD combined with standard-dose obinutuzumab. Patients received venetoclax (schedule A) or obinutuzumab (schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed duration 1-year treatment (1L). Fifty R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLSs per schedule). Schedule B and a 400-mg dose of venetoclax were chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%). Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% in R/R (complete response [CR]/CR with incomplete marrow recovery [CRi], 37%) and 100% in 1L (CR/CRi, 78%) patients. Rate of undetectable (<10−4) minimal residual disease (uMRD) in peripheral blood for R/R and 1L patients, respectively, was 64% and 91% ≥3 months after last obinutuzumab dose. Venetoclax and obinutuzumab therapy had an acceptable safety profile and elicited durable responses and high rates of uMRD. This trial was registered at www.clinicaltrials.gov as #NCT01685892.

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Randomized Comparison of Cladribine Plus Cyclophosphamide with Fludarabine Plus Cyclophosphamde in Untreated Patients with Chronic Lymphocytic Leukemia: Report of the Polish Adult Leukemia Group (PALG-CLL3).

Blood ◽

10.1182/blood.v112.11.2103.2103 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2103-2103 ◽

Cited By ~ 1

Author(s):

Tadeusz Robak ◽

Jerzy Z Blonski ◽

Krzysztof Jamroziak ◽

Joanna Gora-Tybor ◽

Beata Stella-Holowiecka ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Residual Disease ◽

Randomized Study ◽

Progression Free Survival ◽

Complete Response ◽

Lymphocytic Leukemia ◽

P Value ◽

Color Flow ◽

Significant Difference ◽

Adult Leukemia

Abstract Purine nucleoside analogues, cladribine(2-CdA) and fludarabine (FA), especially combined with cyclophosphamide (CY) are potent cytotoxic drugs for the treatment of chronic lymphocytic leukemia (CLL). In this randomized study we aimed to establish whether combination of 2-CdA plus CY (CC) with FA plus (FC) provide similar benefit to previously untreated patients with CLL. The trial was started in January 2004 and the recruitment was ended in May 2007. The study primary endpoints were overall response (OR) and complete response (CR). The secondary endpoints included progression free survival (PFS), overall survival (OS), minimal residual disease negativity (MRD/-/) and treatment related toxicity. Eligible patients were randomly assigned to receive 6 courses of either 2-CdA 0.12 mg/kg/d i.v. + CY 250 mg/m2/d i.v. or FA 25 mg/m2/d i.v. + CY 250 mg/m2/d, both combinations for 3 consecutive days. The treatment response and toxicity were evaluated according to NCI-WG guidelines. MRD was evaluated in patients with CR using four-color flow cytometry assay. There were no significant difference in the rates of OR, CR, MRD negativity, grade 3/4 neutropenia, thrombocytopenia and infections. PFS and OS were also similar in both groups. In conclusion, CC and FC regimens are similarly active and toxic in previously untreated CLL, however trend of longer OS in CC group is observed. Characteristic CC arm FC arm P value Pts enrolled 212 211 - Pts evaluated 184 187 - No of courses (median, range) 6 (2–6) 5 (2–6) 0.56 OR (%) 163 (88.6) 159 (85.0) 0.31 CR (%) 86 (46.7) 91 (48.7) 0.43 MRD/–/ (%) 33 (68.8) 44 (72.1) 0.70 PFS (median, years) 2.195 2.361 0.86 Thrombocytopania gr 3/4 (%) 23 (12.6) 22 (11.6) 0.77 Neutropenia gr 3/4 (%) 39 (21.4) 43 (22.8) 0.76 Infection gr 3/4 (%) 53 (29.1) 54 (28.6) 0.91 OS (median, years) 4.066 2.531 0.10 Death (%) 37 (20.2) 53 (27.9) -

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Ad-ISF35-Transduced Autologous Cells In Combination with Fludarabine, Cyclophosphamide, Rituximab (FCR) Induces Complete and Partial Responses In a Phase 1b Study for Patients with Fludarabine-Refractory and/or Del(17p)/p53-Defective Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v118.21.168.168 ◽

2011 ◽

Vol 118 (21) ◽

pp. 168-168

Author(s):

Januario E. Castro ◽

Lee Schwartzberg ◽

Javier Pinilla-Ibarz ◽

Johanna Melo-Cardenas ◽

Juan S. Barajas-Gamboa ◽

...

Keyword(s):

Adverse Events ◽

Cytotoxic Activity ◽

Residual Disease ◽

Complete Response ◽

Chemotherapeutic Agents ◽

Lymphocytic Leukemia ◽

High Dose ◽

Cell Transplant ◽

Phase 1B

Abstract Abstract 168FN2 CLL cells with del(17p) typically have loss of functional p53, rendering them refractory to chemotherapeutic agents. However, del(17p) CLL cells activated by CD40 ligand (CD154) are induced to express pro-apoptotic factors to overcome resistance to the cytotoxic activity of p53-dependent drugs, such as fludarabine. To examine whether a CD154-based therapeutic strategy can be developed in vivo for del(17p) and/or fludarabine-refractory CLL, a phase 1b clinical study evaluating an autologous cellular gene immunotherapy is being conducted. Autologous CLL cells transduced ex vivo with a replication-defective adenovirus vector encoding a membrane-stable, re-engineered form of CD154 (Ad-ISF35) are administered, followed by standard courses of FCR. Subjects with fludarabine-refractory and/or del(17p) CLL received three IV doses (one dose every two weeks) of 3×108autologous Ad-ISF35-transduced CLL cells. Two weeks following the third dose of Ad-ISF35-transduced cells, subjects receive up to six monthly cycles of FCR. Study endpoints include analysis of safety and efficacy. Nine (9) subjects have been enrolled and treated on study. Median age was 63 (range 48–70). All subjects were del(17p) (range 14–96%), and included treatment naïve (n=4) and previously treated (n=5) subjects. The number of prior treatments range from 0–5, including three subjects that previously received fludarabine-containing regimens. The overall response rate was 67% with 56% of subjects achieving a complete response (CR), including 3 CRu pending bone marrow assessment. Two subjects with a marked percentage del(17p) (range 63–66%) continue to have an ongoing complete response (CR) after a median follow up of >2 years, and no detectable minimal residual disease (MRD) in one subject. Three subjects that showed disease progression were treated with either alemtuzumab (1 subject) or ofatumumab plus high dose methylprednisolone therapy followed by allogeneic stem cell transplant (2 subjects). We observed clinical responses not only after FCR but also after infusion of Ad-ISF35-transduced cell. These ISF35-specific responses included reductions in absolute lymphocyte counts in all subjects (decrease from baseline 4–89%), and decreased lymphadenopathy (>50% reduction) in 78% of the subjects (decrease from baseline 19–100%). Infusion of Ad-ISF35-transduced cells plus FCR has been well-tolerated. The primary non-hematologic adverse events have been flu-like symptoms following infusion of Ad-ISF35 transduced cells. This includes transient grade I/II fever (89%), fatigue (56%) and chills (56%). The primary hematologic adverse events have been cytopenias following FCR treatment, including grade III/IV neutropenia (33%) and anemia (22%). Grade I/II hypophosphatemia (56%) following ISF35 has been observed and this might be related to increased serum cytokine levels following Ad-ISF35-transduced cell administration. Correlative studies on CLL cells obtained before and after infusions of Ad-ISF35-transduced CLL cells demonstrated that CLL cells prior to treatment were refractory to the cytoxic effects of P53-dependent drugs (e.g. F-ara-A). However, the CLL cells obtained after treatment with Ad-ISF35-transduced CLL had increases of p73, p21 and Bid and became sensitive in vitro to the cytotoxic activity of F-ara-A. We also observed up-regulation of costimulatory molecules (CD80, CD86, CD54) and death receptors (CD95). The majority of subjects developed antibodies against adenovirus with neutralizing activity. However, they did not developed antibodies against human CD154. Subjects also showed increases in TNFα, IL-6 and IL12 after infusion of Ad-ISF35 transduced cells. In conclusion, the combination of Ad-ISF35 transduced CLL cells plus FCR appears to be well-tolerated and highly effective in CLL patients with fludarabine-refractory disease and/or del(17p). The CR rate that we have observed in this high-risk CLL population is higher than those reported in the literature and makes our results very encouraging. Correlative data suggest that Ad-ISF35 promotes upregulation of costimulatory and death receptor molecules as well as pro-apoptotic proteins that may overcome resistance to FCR in vivo. These encouraging data suggest the combination of Ad-ISF35 plus chemoimmunotherapy could offer an effective treatment option for patients who otherwise would be resistant to standard forms of therapy. Disclosures: Cantwell: Memgen, LLC: Employment, Patents & Royalties.

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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 ◽

10.1182/blood.v118.21.2866.2866 ◽

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.

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Using the Biology of Chronic Lymphocytic Leukemia to Choose Treatment

Hematology ◽

10.1182/asheducation-2011.1.104 ◽

2011 ◽

Vol 2011 (1) ◽

pp. 104-109 ◽

Cited By ~ 20

Author(s):

Peter Hillmen

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Intracellular Signaling ◽

Residual Disease ◽

Lymphocytic Leukemia ◽

High Dose ◽

Signaling Mechanisms ◽

The Individual ◽

First Time ◽

Targeted Approach

AbstractIn recent years, our understanding of the pathophysiology of chronic lymphocytic leukemia (CLL) has advanced significantly. It is now clear that CLL is a relatively proliferative disorder that requires the help of its microenvironment to be maintained and to progress. The stimulation of the CLL cell occurs in most, if not all, patients through antigen stimulation via the BCR. In addition, there is now a clearer appreciation of the role of the p53 pathway leading to chemoresistance. These insights are allowing a more targeted approach with the use of p53-independent drugs such as mAbs and high-dose steroids to overcome genetically poor-risk CLL. The elucidation of the molecular and intracellular signaling mechanisms of disease is just beginning to facilitate the development of several targeted small molecules that promise to revolutionize the treatment of CLL. The measurement of the level of minimal residual disease (MRD) in CLL is becoming more available, facilitating approaches in which the aim of therapy is the eradication of detectable MRD. This also promises to improve personalization of therapy to the individual. Recently, the addition of rituximab to fludarabine plus cyclophosphamide (FCR) has improved overall survival in CLL for the first time, and it appears that this will only be the first small step on the path to much more effective therapies and, hopefully, less toxic targeted therapies.

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Rituximab, Fludarabine, Cyclophosphamide, and Mitoxantrone: A New, Highly Active Chemoimmunotherapy Regimen for Chronic Lymphocytic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2009.22.0442 ◽

2009 ◽

Vol 27 (27) ◽

pp. 4578-4584 ◽

Cited By ~ 97

Author(s):

Francesc Bosch ◽

Pau Abrisqueta ◽

Neus Villamor ◽

María José Terol ◽

Eva González-Barca ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Randomized Clinical Trials ◽

Residual Disease ◽

Clinical Stage ◽

Complete Response ◽

High Serum ◽

Lymphocytic Leukemia ◽

Severe Neutropenia ◽

Advanced Clinical Stage ◽

Β2 Microglobulin

PurposeThe addition of monoclonal antibodies to chemotherapy has significantly improved treatment of chronic lymphocytic leukemia (CLL). Based on excellent results with the chemotherapy-only regimen fludarabine, cyclophosphamide, and mitoxantrone (FCM), we built a new chemoimmunotherapy combination—rituximab plus FCM (R-FCM). We report a phase II clinical trial consisting of an initial treatment with R-FCM followed by rituximab maintenance.Patients and MethodsSeventy-two untreated CLL patients age 70 years or younger received rituximab 500 mg/m2on day 1 (375 mg/m2the first cycle), fludarabine 25 mg/m2IV on days 1 to 3, cyclophosphamide 200 mg/m2on days 1 to 3, and mitoxantrone 6 mg/m2IV on day 1, given at 4-week intervals with up to six cycles supported with colony-stimulating factor. Patients achieving response received maintenance with rituximab 375 mg/m2every 3 months for 2 years.ResultsThe overall response, minimal residual disease (MRD) –negative complete response (CR), MRD-positive CR, and partial response rates were 93%, 46%, 36%, and 11%, respectively. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Advanced clinical stage, del(17p), or increased serum β2-microglobulin levels correlated with a lower CR rate.ConclusionR-FCM is highly effective in previously untreated CLL, with an 82% CR rate and a high proportion of MRD-negative CRs (46%). Treatment toxicity is acceptable. Parameters correlating with a lower response rate were advanced clinical stage, high serum β2-microglobulin levels, and del(17p). Based on these results, R-FCM warrants further investigation in randomized clinical trials.

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Efficacy and Safety of Chimeric Antigen Receptor T Cell Therapy in Chronic Lymphocytic Leukemia: A Systematic Review

Blood ◽

10.1182/blood-2021-153595 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4822-4822

Author(s):

Rooma Habib ◽

Wajeeha Aiman ◽

Ishan Garg ◽

Rabiya Niaz ◽

Sigmone Khalid Butt ◽

...

Keyword(s):

Systematic Review ◽

Clinical Study ◽

Chronic Lymphocytic Leukemia ◽

Cell Therapy ◽

Clinical Studies ◽

Complete Response ◽

Lymphocytic Leukemia ◽

High Dose ◽

Efficacy And Safety ◽

Grade 3

Abstract Background: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults. Despite the advancements in drug therapies, CLL is largely incurable, and relapsed/refractory (R/R) patients have a very poor prognosis. Chimeric antigen receptor T (CART) cell therapy has shown promising results in B-cell malignancies. We conducted a systematic review to assess the efficacy and safety of CART cell therapy in patients with CLL. Methods: PRISMA guidelines were followed to perform the literature search and selection of articles for this systematic review. A search was performed using databases including PubMed, Cochrane, Web of Science, Embase, and clinicaltrials.gov. We used the following Mesh and Emtree terms, "Chronic lymphocytic leukemia" AND "Adoptive immunotherapy" from the inception of literature till 06/11/2021. Out of 1319 articles, we screened and included nine clinical studies (N=208) measuring the efficacy (i.e., complete response, partial response, etc.) and safety (adverse events ≥grade 3) in clinical terms. We excluded case reports, pre-clinical studies, review articles, and meta-analyses. Results: In 9 clinical studies, 158 patients with CLL were treated with anti-CD19 CART cell therapy. The range of age of the patients was 38-75 years. A high dose was used in 38 patients, and ibrutinib was added in 19 patients with CLL. The therapy was well tolerated with ≥grade 3 cytokine release syndrome (CRS) and neurological toxicity reported in 23/151 (15%) and 20/151 (13%) of the patients, respectively. Table 1. Complete response (CR), partial response (PR), and overall response (OR) were seen in 40% (54/134), 17% (22/126), and 56% (103/183). In the clinical study by Frey et al. (N=51)., progression-free survival (PFS) and ORR were significantly higher in the high dose (5x10 8 cells/kg) group as compared to the low dose (5x10 7 cells/kg) group (1.8 months vs. one month and 53% vs. 29%, respectively) without significantly increasing treatment-related adverse events (TRAE). In the clinical study by Gauthier et al. (N=38)., ORR was significantly high in the anti-CD19 CART cell therapy + ibrutinib group compared to the no ibrutinib group (83% vs. 56%). Neutropenia, infection, thrombocytopenia, leukemia, hypocalcemia, elevated ALT, and tumor lysis syndrome were common ≥grade 3 TRAEs reported in these patients (Table 1). More clinical trials are targeting CD-20, CD-137, CD-7, CD-28, ROR1, etc (Table 2). Conclusion: Anti-CD19 CART cell therapy was safe and effective in the treatment of CLL patients. A high dose of 5x10 8/kg CART cell therapy was well tolerated and had superior efficacy. Adding ibrutinib to CART cell therapy was safe and more effective than anti-CD19 CART cell therapy alone. More placebo-controlled randomized multicenter studies are needed to confirm these results. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Randomized Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen Sodium (Bcl-2 antisense) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2006.07.1191 ◽

2007 ◽

Vol 25 (9) ◽

pp. 1114-1120 ◽

Cited By ~ 216

Author(s):

Susan O'Brien ◽

Joseph O. Moore ◽

Thomas E. Boyd ◽

Loree M. Larratt ◽

Aleksander Skotnicki ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Opportunistic Infections ◽

Tumor Lysis Syndrome ◽

Chemotherapy Resistance ◽

Response Duration ◽

Fold Increase ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Response To Chemotherapy

Purpose Expression of Bcl-2 protein is associated with chemotherapy resistance and decreased survival in chronic lymphocytic leukemia (CLL). We evaluated whether oblimersen would improve response to chemotherapy in patients with relapsed or refractory CLL. Patients and Methods Patients had received at least one prior fludarabine-containing regimen and were stratified on the basis of prior fludarabine response, number of prior regimens, and duration of response to last prior therapy. Patients were randomly assigned to 28-day cycles of fludarabine 25 mg/m2/d plus cyclophosphamide 250 mg/m2/d administered intravenously for 3 days with or without oblimersen 3 mg/kg/d as a 7-day continuous intravenous infusion (beginning 4 days before chemotherapy) for up to six cycles. The primary end point was the proportion of patients who achieved complete response (CR) or nodular partial response (nPR). Results Of 241 patients randomly assigned, CR/nPR was achieved in 20 (17%) of 120 patients in the oblimersen group and eight (7%) of 121 patients in the chemotherapy-only group (P = .025). Achievement of CR/nPR was correlated with both an extended time to progression and survival (P < .0001). In patients who remained sensitive to fludarabine, oblimersen was associated with a four-fold increase in the CR/nPR rate and a significant survival benefit (P = .05). Oblimersen was frequently associated with thrombocytopenia and, rarely, tumor lysis syndrome and cytokine release reactions; the incidence of opportunistic infections and second malignancies was similar in both groups. Conclusion The addition of oblimersen to fludarabine plus cyclophosphamide significantly increases the CR/nPR rate in patients with relapsed or refractory CLL (particularly fludarabine-sensitive patients), as well as response duration among patients who achieve CR/nPR.

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Alemtuzumab As Consolidation After a Response to Fludarabine Is Effective in Purging Residual Disease in Patients With Chronic Lymphocytic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.6037 ◽

2006 ◽

Vol 24 (15) ◽

pp. 2337-2342 ◽

Cited By ~ 117

Author(s):

Marco Montillo ◽

Alessandra Tedeschi ◽

Sara Miqueleiz ◽

Silvio Veronese ◽

Roberto Cairoli ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Induction Therapy ◽

Residual Disease ◽

Plasma Concentrations ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Cytomegalovirus Reactivation ◽

Injection Site Reactions ◽

Prior Analysis

Purpose Treatment with alemtuzumab has resulted in negative responses for minimal residual disease (MRD) in patients with chronic lymphocytic leukemia (CLL). In a prior analysis we demonstrated that it is possible to achieved MRD negativity, as assessed by polyclonality of immunoglobulin heavy chain after consolidation with alemtuzumab. This phase II study evaluated 34 patients with CLL who received alemtuzumab consolidation in an effort to improve the quality of their response to fludarabine-based induction. Subsequent peripheral blood stem-cell (PBSC) collection and transplantation, tolerability, and pharmacokinetics also were assessed. Patients and Methods Thirty-four patients younger than 65 years who had a clinical response to fludarabine-based induction therapy received alemtuzumab 10 mg subcutaneously three times per week for 6 weeks. PBSCs were collected after mobilization with cytarabine and granulocyte colony-stimulating factor. Blood samples for pharmacokinetics study were taken between days 1 and 31. Results The complete response rate improved from 35% after fludarabine induction to 79.4% after alemtuzumab consolidation, including 19 patients (56%) who achieved MRD negativity. The most common adverse events were injection-site reactions and fever. Cytomegalovirus reactivation occurred in 18 patients, all of whom were successfully treated with oral ganciclovir. PBSC collection was successful in 24 (92%) of 26 patients, and 18 patients underwent autologous PBSC transplantation. Alemtuzumab plasma concentrations increased gradually during the first 2 weeks and accumulated more rapidly thereafter. Conclusion Subcutaneously administered alemtuzumab was effective, safe, and well tolerated as consolidation therapy in patients with CLL who responded to fludarabine induction therapy. Subsequent PBSCT was feasible thereafter.

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