Alemtuzumab for patients with chronic lymphocytic leukaemia

Skoetz, Nicole; Bauer, K. H.; Elter, Thomas; Monsef, Ina; Roloff, Verena; Hallek, Michael; Engert, Andreas

doi:10.1002/14651858.cd008078.pub2

Cited by 35 publications

(29 citation statements)

References 55 publications

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“…42,43 Therefore, we looked at previous therapy in relation to time of first measurable pEBVd to estimate if detection of pEBVd might be treatment-related. Supplemental Table 3 (in the online version) shows systemic therapies received in the pEBVd + cohort before the first measurable pEBVd compared with the EBV − cohort.…”

Section: Resultsmentioning

confidence: 99%

Increased Levels of Plasma Epstein Barr Virus DNA Identify a Poor-Risk Subset of Patients With Advanced Stage Cutaneous T-Cell Lymphoma

Haverkos

Gru

Geyer

et al. 2016

Clinical Lymphoma Myeloma and Leukemia

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Discovering prognostic factors that simultaneously describe tumor characteristics and improve risk stratification is a priority in cutaneous T-cell lymphoma (CTCL). More than a third of advanced stage CTCL patients in this cohort had detectable cell free plasma Epstein–Barr virus (EBV)-DNA (pEBVd) using quantitative real-time polymerase chain reaction. An increased level of pEBVd was highly concordant with EBV (ie, Epstein–Barr virus RNAs) in tumor tissue and was associated with inferior survival. Introduction Outcomes in advanced stage (AS) cutaneous T-cell lymphomas (CTCL) are poor but with great variability. Epstein–Barr virus (EBV) is associated with a subset of non-Hodgkin lymphomas. Frequency of plasma EBV-DNA (pEBVd) detection, concordance with EBV RNA (EBER) in tumor tissue, codetection of plasma cytomegalovirus DNA (pCMVd), and prognostic effect in AS CTCL are unknown. Patients and Methods Patients (n = 46; 2006–2013) with AS CTCL (≥IIB) were retrospectively studied. pEBVd and pCMVd were longitudinally measured using quantitative real-time polymerase chain reaction. EBER in situ hybridization (ISH) was performed on tumor samples. Survival from time of diagnosis (ToD) and time of progression to AS was assessed. Results Plasma EBV-DNA and pCMVd were detected in 37% (17 of 46) and 17% (8 of 46) of AS CTCL patients, respectively. pCMVd detection was significantly more frequent in pEBVd-positive (pEBVd+) than pEBVd− patients (35% vs. 7%; P = .038). Tumor tissue for EBER-ISH was available in 14 of 17 pEBVd+ and 22 of 29 pEBVd− patients; 12 of 14 (85.7%) pEBVd+ patients were EBER+ versus 0 of 22 pEBVd− patients. Frequency of large cell transformation (LCT) tended to be greater in pEBVd+ patients, but was not significant (10 of 14 pEBVd+ vs. 10 of 23 pEBVd−; P = .17). No notable differences in rates of increased levels of serum lactate dehydrogenase (LDH) were observed (17 of 17 pEBVd+ vs. 27 of 29 pEBVd−). pEBVd detection was associated with significantly worse survival from ToD (P = .021) and time of progression to AS (P = .0098). Conclusion Detection of cell-free plasma EBV-DNA was highly concordant with the presence of EBERs in tumor tissue, predicted survival independent of LDH and LCT, and should be further studied as a biomarker in AS CTCL.

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Section: Resultsmentioning

confidence: 99%

Increased Levels of Plasma Epstein Barr Virus DNA Identify a Poor-Risk Subset of Patients With Advanced Stage Cutaneous T-Cell Lymphoma

Haverkos

Gru

Geyer

et al. 2016

Clinical Lymphoma Myeloma and Leukemia

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“…Alemtuzumab is a humanized IgG1 monoclonal antibody that targets cells expressing the CD52 antigen, including T, natural killer, and B lymphocytes, and a proportion of monocytes and dendritic cells [7]. Alemtuzumab is licensed for use in fludarabine-refractory B cell chronic lymphocytic leukemia [8], but it has also found a role in T cell tumors in adults [9] and in autoimmune diseases [10]. Alemtuzumab is commonly used as part of reduced-intensity conditioning regimens for allogeneic HCT [11] and can decrease the incidence of aGVHD [12,13].…”

Section: Introductionmentioning

confidence: 99%

A Prospective Study of Alemtuzumab as a Second-Line Agent for Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric and Young Adult Allogeneic Hematopoietic Stem Cell Transplantation

Khandelwal

Emoto

Fukuda

et al. 2016

Biology of Blood and Marrow Transplantation

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We describe a single-center prospective study of alemtuzumab as a second-line agent for steroid-refractory (SR) acute graft-versus-host disease (aGVHD) in pediatric and young adult allogeneic hematopoietic stem cell transplant recipients. Alemtuzumab was administered for grades II to IV aGVHD if patients did not improve within 5 days or worsened within 48 hours after corticosteroids. Interim analyses of alemtuzumab levels and response were performed after every 5 patients enrolled, resulting in 3 dosing cohorts, as follows: (1) .2 mg/kg alemtuzumab subcutaneously on days 1 to 5 (maximum of 31 mg over 5 days) and .2 mg/kg/dose (not exceeding 10 mg/dose) on days 15, 22, and 29; (2) .2 mg/kg alemtuzumab subcutaneously on days 1 to 5 (maximum of 43 mg over 5 days) and .2 mg/kg/dose on day 7, 10, 15, 22, and 29; and (3) .2 mg/kg subcutaneously on days 1 to 5 and .2 mg/kg/dose on day 7, 10, 15, and 22. Alemtuzumab levels were assessed before starting alemtuzumab and at days 1, 3, 6, 10, and 14 and weekly until day 99, where day 1 was the day of first alemtuzumab dose. Fifteen patients (median age, 10 years; range, 1.4 to 27) received alemtuzumab for grades II (6%), III (74%), and IV (20%) SR-aGVHD. The overall response rate was 67%, with complete response (CR) in 40%, partial response (PR) in 27%, and no response in 33%. The median day 6 alemtuzumab level was 2.79 µg/mL (interquartile range, 1.34 to 4.89) in patients with CR compared with .62 µg/mL (interquartile range, .25 to 1.45) in patients with PR + no response (P < .05). Ninety percent (n = 9) of patients with a CR or PR reduced corticosteroid doses within 8 weeks from first alemtuzumab dose. Side effects included fever (26%) and transient thrombocytopenia (53%). Asymptomatic viremias occurred in all patients but invasive viral disease occurred in 2 patients. One patient developed Epstein-Barr virus–post-transplantation lymphoproliferative disorder. Eighty percent (n = 12) of patients were alive at 6 months, of whom 53% (n = 8) were free of GVHD whereas 13% (n = 2) developed chronic GVHD. Alemtuzumab is an effective second-line agent for children and young adults with SR-aGVHD. Higher alemtuzumab levels are associated with CR. A real-time dose adjusted alemtuzumab study is needed to further optimize the dose of alemtuzumab in aGVHD.

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“…The results of this trial led to the recent FDA approval of pembrolizumab for NSCLC. [Isfort et al 2014;Lindauer and Hochhaus, 2014;Ostendorf et al 2014;Waller, 2014;Wehrle et al 2014 [Sliwkowski and Mellman, 2013;Chen and Chen, 2015] CD33 AML Gemtuzumab ozogamicin [Sliwkowski and Mellman, 2013;Loke et al 2015] CD52 CLL Alemtuzumab [Skoetz et al 2012;Sliwkowski and Mellman, 2013] CTLA-4 Unresectable or metastatic melanoma Ipilimumab [Hodi et al 2010;Robert et al 2011;Hodi et al 2014] EGFR CRC Head and Neck Cetuximab Panitumumab [Cunningham et al 2004;Saltz et al 2004;Bonner et al 2006;Van Cutsem et al 2007;Vermorken et al 2008;Van Cutsem et al 2009;Douillard et al 2010;Price et al 2014] EpCAM Malignant ascites Catumaxomab [Seimetz, 2011] …”

Section: Immune Checkpoint Blockade: Ctla-4 and Pd-1mentioning

confidence: 99%

Novel cancer antigens for personalized immunotherapies: latest evidence and clinical potential

2015

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Abstract:The clinical success of monoclonal antibody immune checkpoint modulators such as ipilimumab, which targets cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and the recently approved agents nivolumab and pembrolizumab, which target programmed cell death receptor 1 (PD-1), has stimulated renewed enthusiasm for anticancer immunotherapy, which was heralded by Science as 'Breakthrough of the Year' in 2013. As the potential of cancer immunotherapy has been recognized since the 1890s when William Coley showed that bacterial products could be beneficial in cancer patients, leveraging the immune system in the treatment of cancer is certainly not a new concept; however, earlier attempts to develop effective therapeutic vaccines and antibodies against solid tumors, for example, melanoma, frequently met with failure due in part to self-tolerance and the development of an immunosuppressive tumor microenvironment. Increased knowledge of the mechanisms through which cancer evades the immune system and the identification of tumor-associated antigens (TAAs) and negative immune checkpoint regulators have led to the development of vaccines and monoclonal antibodies targeting specific tumor antigens and immune checkpoints such as CTLA-4 and PD-1. This review first discusses the established targets of currently approved cancer immunotherapies and then focuses on investigational cancer antigens and their clinical potential. Because of the highly heterogeneous nature of tumors, effective anticancer immunotherapy-based treatment regimens will likely require a personalized combination of therapeutic vaccines, antibodies and chemotherapy that fit the specific biology of a patient's disease.

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Alemtuzumab for patients with chronic lymphocytic leukaemia

Cited by 35 publications

References 55 publications

Increased Levels of Plasma Epstein Barr Virus DNA Identify a Poor-Risk Subset of Patients With Advanced Stage Cutaneous T-Cell Lymphoma

Increased Levels of Plasma Epstein Barr Virus DNA Identify a Poor-Risk Subset of Patients With Advanced Stage Cutaneous T-Cell Lymphoma

A Prospective Study of Alemtuzumab as a Second-Line Agent for Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric and Young Adult Allogeneic Hematopoietic Stem Cell Transplantation

Novel cancer antigens for personalized immunotherapies: latest evidence and clinical potential

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