Alemtuzumab in Combination With Methylprednisolone Is a Highly Effective Induction Regimen for Patients With Chronic Lymphocytic Leukemia and Deletion of <i>TP53</i>: Final Results of the National Cancer Research Institute CLL206 Trial

Pettitt, Andrew R.; Jackson, Richard E.; Carruthers, Stacey; Dodd, Julian; Dodd, Susanna; Oates, Melanie; Johnson, Gillian G.; Schuh, Anna; Matutes, Estella; Dearden, Claire; Catovsky, Daniel; Radford, John; Bloor, Adrian; Follows, George; Devereux, Stephen; Kruger, Anton; Blundell, Julie; Agrawal, Samir; Allsup, David; Proctor, Stephen J.; Heartin, Earnest; Oscier, David; Hamblin, Terry J.; Rawstron, Andy C.; Hillmen, Peter

doi:10.1200/jco.2011.35.9695

Cited by 150 publications

(78 citation statements)

References 49 publications

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“…20 Although the overall response rate (ORR) reported with standard-of-care first-line fludarabine, cyclophosphamide and rituximab (FCR) was 70%, the median progression-free survival (PFS) was short at 11.3 months. 21,22 Disappointing results were also described for first-line alemtuzumab, both as monotherapy (ORR 64%; median PFS 10.7 months) 23 and in combination with methylprednisolone (ORR 85%; median PFS 11.8 months) 24 or dexamethasone (ORR 97%; median PFS 17 months). 25 P53-independent mechanisms of action have been described for rituximab and lenalidomide, 26,27 but no complete remissions were reported with these agents as first-line treatment of patients with del(17p) CLL.…”

Section: Introductionmentioning

confidence: 99%

Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion

et al. 2014

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Although uncommon in treatment-naive patients with chronic lymphocytic leukemia, deletion 17p is a high-risk disease characteristic. We analyzed and reported outcomes for 63 patients with deletion 17p chronic lymphocytic leukemia who received first-line therapy at our institution; at time of first treatment, 81% had unmutated immunoglobulin heavy chain variable gene and 58% had complex karyotype. Forty-nine patients (76%) received first-line fludarabine, cyclophosphamide, rituximab-based therapy, 6 (11%) received rituximab-based and 8 (13%) received lenalidomide-based treatment. Overall, the complete plus nodular partial remission rate was 33%; on multivariable model, higher complete plus nodular partial remission rate was observed in patients with less than 50% cells positive for deletion 17p, and a higher probability of achieving at least a partial remission was observed with fludarabine, cyclophosphamide, rituximab-based treatment. After a median follow up of 33 months (range 1-89 months), the estimated median progression-free survival was 14 months (95% confidence interval 10-18) and estimated median overall survival was 63 months (95% confidence interval 43-83). In multivariable analysis, factors independently associated with longer progression-free survival were response to treatment and absence of complex karyotype. Achievement of complete plus nodular partial remission rate and mutated immunoglobulin heavy chain variable gene were independently associated with longer overall survival in multivariable model. Complex karyotype was associated with increased risk for Richter's transformation. New first-line strategies and agents must aim at both improving response and maintaining remission in patients with deletion 17p, particularly in the presence of complex karyotype.

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Section: Introductionmentioning

confidence: 99%

Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion

et al. 2014

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“…The larger the lymph node, the inferior the response. 48 The recent trials for 17p deleted CLL combine alemtuzumab with high-dose steroids, prednisone in the UK NCRI CLL206 trial, 49 and dexamethasone in the GCLLSG CLL2O trial, 50 and result in higher response rates compared with historical experience with conventional chemotherapy, even including rituximab-FC. Alemtuzumab has been now approved for use in previously untreated CLL, having been approved initially for fludarabine-refractory patients.…”

Section: New Monoclonal Antibodiesmentioning

confidence: 99%

A New Era is Coming up in the Treatment of Chronic Lymphocytic Leukemia

Montillo¹,

Frustaci²,

Picardi³

et al. 2014

Lymphoma and Chronic Lymphocytic Leukemias

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ABSTRACT:The survival of patients with chronic lymphocytic leukemia (CLL) has significantly improved in the last 30 years. The introduction of purine analogs in the treatment armamentarium followed by the combination of these compounds with alkylating agents first improved response rates and progression-free survival (PFS) when compared with alkylating agent-based therapy only. However, the great advance arrived with the development of a chemoimmunotherapeutic approach comparing this with chemotherapy alone demonstrating an improvement not only in terms of response rate and PFS but also, for the first time, in the rate of overall survival (OS). The last decade brought significant achievements in the understanding of CLL pathogenesis leading to the development of new agents targeting cell surface, intracellular pathways, and tumor microenvironment. As traditional chemotherapy is associated with acute and long-term toxicity, interest in these non-chemotherapeutic treatments has been constantly growing. The challenge will be to develop a rationale for non-chemotherapeutic approaches using these new agents as monotherapy, or in combination, with the aim of obtaining an individualized strategy based on disease characteristics and even patient basis. Hopefully, an increasing participation of ultra high-risk CLL patients in clinical trials evaluating the efficacy of these new treatments may lead to reasonable success, if not cure, in this unfavorable setting. KEY WORDS: chronic lymphocytic leukemia, chemoimmunotherapy, monoclonal antibodies, target therapyCC-By-nC 3.0 License. CORRESPONDENCE: marco.montillo@ospedaleniguarda.it this paper was subject to independent, expert peer review by a minimum of two blind peer reviewers. all editorial decisions were made by the independent academic editor. all authors have provided signed confirmation of their compliance with ethical and legal obligations including (but not limited to) use of any copyrighted material, compliance with ICMJE authorship and competing interests disclosure guidelines and, where applicable, compliance with legal and ethical guidelines on human and animal research participants. provenance: the authors were invited to submit this paper.

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“…Patients with del17p treated with alemtuzumab had threefold better ORR (64% vs 20%) and nearly fivefold improvement in median PFS (10.7 vs 2.2 months), although not statistically significant. NCRI CLL206 trial 59 and CLLSG CLL20 trial 60 evaluated alemtuzumab in combination with high-dose steroids, prednisone and dexamethasone, respectively, in 17p-deleted CLL patients. Results demonstrated higher response rates compared with historical experience with conventional chemotherapy, even including rituximab-fludarabine plus cyclophosphamide.…”

Section: Alemtuzumabmentioning

confidence: 99%

Monoclonal Antibodies in Chronic Lymphocytic Leukemia

2016

Lymphoma and Chronic Lymphocytic Leukemias

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Monoclonal antibodies (MoAbs) play a pivotal role in the treatment of chronic lymphocytic leukemia (CLL). Rituximab, a MoAb against CD20, was initially used as a single agent in the treatment of CLL before being incorporated into newer combination regimens. Integration of rituximab into chemotherapy regimens has led to an improvement in the response rate and overall survival when used in frontline therapy. Despite this, CLL remains an incurable disease, and treatment of relapsed CLL, particularly after failure of purine analog-based regimens, remains challenging. Technological advances relating to development of chimeric and humanized MoAbs are supporting the role of antibody-based regimens for many diseases, including CLL. Currently, MoAbs represent an integral component of CLL therapy. The antitumor efficacy of many therapeutic MoAbs can be potentially improved upon by their use in combination with new targeted therapy agents.

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Alemtuzumab in Combination With Methylprednisolone Is a Highly Effective Induction Regimen for Patients With Chronic Lymphocytic Leukemia and Deletion of TP53: Final Results of the National Cancer Research Institute CLL206 Trial

Abstract: Alemtuzumab plus methypredisolone is the most effective induction regimen hitherto reported in TP53-deleted CLL. The risk of infection is age related and, in younger patients, seems only marginally higher than that associated with rituximab, fludarabine, and cyclophosphamide.

Cited by 150 publications

References 49 publications

Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion

Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion

A New Era is Coming up in the Treatment of Chronic Lymphocytic Leukemia

Monoclonal Antibodies in Chronic Lymphocytic Leukemia

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