Low-dose alemtuzumab-associated immune thrombocytopenia in chronic lymphocytic leukemia.
ABSTRACT Chronic lymphocytic leukemia (CLL) is frequently complicated during its course by autoimmune disorders (from 2 to 12% of cases), such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). In particular, ITP has been reported in about 2–5% of CLL population. Recently, Cuker et al. reported the occurrence of ITP in 6/216 patients with relapsing-remitting multiple sclerosis in a phase 2 clinical trial of annual alemtuzumab. Alemtuzumab is an anti-CD52 monoclonal antibody used in CLL both as first-line treatment and in relapsed/refractory patients. We evaluated a cohort of 64 consecutive patients affected by relapsed-refractory CLL treated with low-dose alemtuzumab and we observed a incidence of ITP higher than predicted. Our data, associated with the report of Cuker et al., seem to suggest an important role of alemtuzumab in the pathogenesis of ITP which could be related to its induced dysregulation of T-lymphocyte activity.
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ABSTRACT: The expanding therapeutic use of high-dose intravenous immunoglobulin (IVIg) in autoimmune diseases has raised important practical and conceptual issues over the last few years. These have prompted a number of research efforts aimed at characterizing aspects of the mechanism of action of current IVIg preparations, which might lead to the development of standardized, more cost-effective agents. Although polyclonal IgG in these preparations are mostly thought to act via direct interference with disease-specific, pathogenic autoantibodies, evidence from clinical and experimental work points to the involvement of crucial checkpoints upstream of self-reactive B-cell activation and autoantibody production. Reviewed herein are the results of the most recent studies documenting the crucial role of regulatory T cells (Treg) in the immunomodulatory activity of IVIg, and the molecular mechanisms mediating the effect of specific IgG fragments and glycoforms on Treg activity and the ensuing downregulation of T-cell effector responses of different sign and magnitude. Further progress in this area of translational research may lead to the development of innovative strategies aimed at restoring tolerance in autoimmune diseases.Current Opinion in Pharmacology 05/2014; 17C:1-11. · 5.44 Impact Factor
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ABSTRACT: A series of monoclonal antibodies (mAbs) are commonly utilized in renal transplantation as induction therapy (a period of intense immunosuppression immediately before and following the implant of the allograft), to treat steroid-resistant acute rejections, to decrease the incidence and mitigate effects of delayed graft function, and to allow immunosuppressive minimization. Additionally, in the last few years, their use has been proposed for the treatment of chronic antibody-mediated rejection, a major cause of late renal allograft loss. Although the exact mechanism of immunosuppression and allograft tolerance with any of the currently used induction agents is not completely defined, the majority of these medications are targeted against specific CD proteins on the T or B cells surface (e.g., CD3, CD25, CD52). Moreover, some of them have different mechanisms of action. In particular, eculizumab, interrupting the complement pathway, is a new promising treatment tool for acute graft complications and for post-transplant hemolytic uremic syndrome. While it is clear their utility in renal transplantation, it is also unquestionable that by using these highly potent immunosuppressive agents, the body loses much of its innate ability to mount an adequate immune response, thereby increasing the risk of severe adverse effects (e.g., infections, malignancies, haematological complications). Therefore, it is extremely important for clinicians involved in renal transplantation to know the potential side effects of monoclonal antibodies in order to plan a correct therapeutic strategy minimizing/avoiding the onset and development of severe clinical complications.Toxins 01/2014; 6(3):869-91. · 2.13 Impact Factor
*Correspondence to: Christine L. Kempton, MD, MSc, 2015 Uppergate Drive,
Atlanta, GA 30322, USA
Conflict of interest: C.K. receives research support from Novo Nordisk, Inc,
has been a consultant for Inspiration Biopharmaceuticals and has
participated in an advisory board for Baxter Biopharmaceuticals.
All other authors have no conflict of interest.
Published online 21 May 2012 in Wiley Online Library
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Low-dose alemtuzumab-associated immune thrombocytopenia
in chronic lymphocytic leukemia
Gianluigi Reda,1Francesco Maura,2Giuseppe Gritti,3Anna Gregorini,2Francesca Binda,2
Francesca Guidotti,2Alfonso Piciocchi,4Carlo Visco,5Francesco Rodeghiero,5and Agostino Cortelezzi2*
Chronic lymphocytic leukemia (CLL) is frequently complicated during
its course by autoimmune disorders (from 2 to 12% of cases), such as
autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic
purpura (ITP). In particular, ITP has been reported in about 2–5% of
CLL population [1,2]. Recently, Cuker et al. reported the occurrence of
ITP in 6/216 patients with relapsing-remitting multiple sclerosis in a
phase 2 clinical trial of annual alemtuzumab . Alemtuzumab is an
anti-CD52 monoclonal antibody used in CLL both as first-line treat-
ment and in relapsed/refractory patients [4,5]. We evaluated a cohort
of 64 consecutive patients affected by relapsed-refractory CLL treated
with low-dose alemtuzumab and we observed a incidence of ITP
higher than predicted. Our data, associated with the report of Cuker
et al., seem to suggest an important role of alemtuzumab in the patho-
genesis of ITP which could be related to its induced dysregulation of
ITP is a common autoimmune complication in CLL, occurring in 2% to 5%
of patients .
Recently, Cuker et al., in a Phase 2 clinical trial of annual alemtuzumab
for the treatment of relapsing/remitting multiple sclerosis, reported a total of
six cases of ITP out of 216 alemtuzumab-treated patients (2.8%). Of the
alemtuzumab-associated cases, 2/108 (1.9%) occurred in the 12 mg/day
group and 4/108 (3.7%) occurred in the 24 mg/day group .
Alemtuzumab (Campath-1H) is an IgG1 kappa monoclonal antibody spe-
cific for the cell surface glycoprotein CD52 expressed on normal and malig-
nant B and T lymphocytes [4,5].
Over the last decade, alemtuzumab as single agent has been utilized in
CLL as first-line treatment [6–9] and in relapsed/refractory patients [10–15].
ITP has never been reported so far as a significant event complicating
alemtuzumab treatment of CLL patients in clinical trials [16,17].
We investigated the incidence of ITP in a cohort of 64 consecutive
relapsed/refractory CLL patients referred to the Hematology Unit of Fonda-
zione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan and treated
with low-dose alemtuzumab. Low-dose alemtuzumab was defined as a total
weekly dose lower than 45 mg and a cumulative dose inferior to 600 mg,
given for a maximum of 18 weeks [18–20].
ITP was diagnosed in 12 (18.7%) patients: in nine patients (14%) ITP
developed during or after treatment with alemtuzumab (median observation
time 30 months, range 9–23), whereas in the remaining three patients it pre-
ceded the treatment.
Supporting Information Table I summarizes the clinical characteristics
(including HBV, HCV and HIV status), previous treatment and biological fea-
tures of the nine patients with ITP secondary to alemtuzumab treatment.
Splenomegaly was absent in all the patients and peripheral blood smears
examination did not reveal schistocytes or myelodysplastic features in all the
patients. ITP diagnosis was supported by consistent bone marrow examina-
tion (no myelodysplastic aspects with normal or increased megacaryocytes)
in eight of nine patients; seven patients showed platelet-bound antibodies
specific for platelet glycoproteins IIb/IIIa or Ib/IX (Capture P1Method,
ImmucorGamma, Norcross GA). Patients with latent HBV infection received
preventive treatment with lamivudine during alemtuzumab administration and
for at least 6 months after the end of the therapy. No HBV reactivation or
hepatitis flare was observed during follow-up.
Concomitant hemolytic anemia (Evans syndrome) was observed in one of
these patients. Median platelet count at ITP diagnosis was 11 3 109/L
(range 3–70 3 109/L). During ITP, only two patients showed a clinically sig-
nificant bleeding without any serious complications. In six patients, ITP was
not associated to disease progression and they were treated with corticoste-
roids with or without intravenous immunoglobulins. Five of these patients
achieved a complete ITP remission, while one patient did not respond. Three
patients showed ITP during progressive disease, respectively after 3, 4, and
13 months from beginning of Alemtuzumab, and were therefore treated with
chemo-immunotherapy. One patient achieved a CLL partial remission with ITP
resolution, while two patients were treatment refractory and died because of
disease progression (Supporting Information Table II, Fig. 1).
Only three patients (4.7%) in the study developed ITP before starting alem-
tuzumab therapy (median observation time 76 months, range 6–280) and no
relapses of the autoimmune disorder were observed during the treatment.
In our cohort of CLL patients treated with low-dose alemtuzumab, ITPoccurred
in 9 of 64 patients (14%) with an incidence of 5.7 events/100 patient-year. This
result is higher than previously reported in CLL patients [16,17]. These figures
are in line with recently published data , suggesting an important role of alemtu-
zumab-induced T- lymphocyte dysregulation in the pathogenesis of ITP.
Median time to ITP development from initial alemtuzumab exposure was
12 months (range 1–42 months), with a median cumulative dose of 510 mg
administered in 18 weeks (10 mg three times a week). In the study con-
ducted by Cuker et al., median time to ITP (from first dose of Alemtuzumab)
was 24 months (range 3–39 months), with a median cumulative dose of 192
936American Journal of Hematology
mg administered during two or three annual cycles (12 mg or 24 mg, 3
times a week). The shorter time to ITP development observed in our study
may be related to the different cumulative dose and to the different schedule
of drug administration.
It has been previously suggested that ITP secondary to lymphoprolifera-
tive disorders could be ascribed to autoreactive non-malignant B-cell clones,
favored by the loss of immune tolerance due to T-cell dysfunction and/or
inappropriate pathological (auto)antigen presentation by CLL cells [16,17].
During alemtuzumab treatment, immune-dysregulation of T lymphocytes
may further favor autoimmunity.
In conclusion, while reporting for the first time the association between low-
dose alemtuzumab treatment and ITP in a cohort of CLL patients, we would also
suggest to maintain a high level of vigilance and to strongly consider routine
monitoring for ITP in patients treated with this agent for any pathologic condition.
We retrospectively analyzed a cohort of 64 patients affected by CLL, diag-
nosed according to NCIWG-CLL criteria and referred to the Hematology-
BMT Unit of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policli-
nico, Milan between 2003 and 2010. Median age of patients was 68 years
(range: 40–83 years).
Patients had been treated with low-dose Alemtuzumab, defined as a total
weekly dose lower than 45 mg and a cumulative dose inferior to 600 mg,
administered for up to 18 weeks [18,19,20].
The diagnosis of ITP was based on (1) an otherwise unexplained, rapid
(<2 weeks) and severe fall (at least half of the initial level and below 100 3
109/L) of the platelet counts; (2) a normal or augmented number of mega-
karyocytes in the bone marrow; (3) no or limited (not palpable) splenome-
galy, and (4) no cytotoxic treatment in the last month except for alemtuzu-
mab. We also evaluated assays for antibodies to specific platelet glycopro-
teins, even if they are not routinely recommended, as platelet-associated
IgG is elevated in both immune and non-immune thrombocytopenia .
1Hematology and Transplantation Unit, Foundation IRCCS Ca’Granda Ospedale
Maggiore Policlinico, Milan, Italy;2Hematology and Transplantation Unit,
Foundation IRCCS Ca’Granda Ospedale Maggiore Policlinico and University of
Milan, Italy;3Ospedali Riuniti di Bergamo, Hematology, Bergamo, Italy;4GIMEMA
Data Center, Rome, Italy;5Department of Hematology, San Bortolo Hospital,
Contract grant sponsor: Assistenza Studio Malati Ematologici (ASME-Milan) and
Associazione Italiana Leucemie Milan (AIL) to A.C.
*Correspondence to: Agostino Cortelezzi, Hematology and Transplantation Unit,
Foundation IRCCS Ca’Granda Ospedale Maggiore Policlinico and
University of Milan Via F. Sforza 35, Milan 20122, Italy
Additional Supporting Information may be found in the online version of this article.
Conflict of interest: Nothing to report.
A.C., G.R., C.V., and F.R. designed the research study; F.M., G.G., G.R., A.G.,
F.B., and F.G. performed the research; F.M., G.G., A.G., and A.P. analyzed the
data; A.C., G.R., F.M., G.G., C.V. wrote the paper. All authors reviewed the
manuscript critically for important intellectual content and approved the final version
Published online 21 May 2012 in Wiley Online Library
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The impact of baseline and interim PET/CT parameters on
clinical outcome in patients with diffuse large B cell lymphoma
Silvia Park,1Seung Hwan Moon,2Lee Chun Park,1Deok Won Hwang,1Jun Ho Ji,1Chi Hoon Maeng,1
Su-Hee Cho,1Hee Kyung Ahn,1Ji Yean Lee,1Seok Jin Kim,1Joon Young Choi,2*and Won Seog Kim1*
Taking a step forward from the IPI, attention is focused on the role of
18F-FDG PET/CT as a tool for guidance in risk stratification in patients
with aggressive non-Hodgkin’s lymphoma (NHL). Here, we analyzed
the predictive value of various PET/CT parameters in patients with
DLBCL. Particularly, we were interested in patients with an IPI score of
1, 2, or 3, whose prognosis are confusing. Between Jul 2008 and Feb
2010, a total of 100 patients (including 57 patients with an IPI score of
1-3) who were treated with R-CHOP for DLBCL, and had assessable
PET/CT parameters were analyzed in this study. Absolute value of
SUVmax, SUVsum(sum of SUVmax) and TLGsum(SUVmean x Volumemeta)
from baseline and interim PET/CT, and DSUVsum, DSUVmax, and
DTLGsumbetween baseline and interim PET/CT were selected as PET/
CT parameters. The median number of R-CHOP cycles was 6, and
interim PET/CT was performed after 2 or 3 cycles. None of the parame-
ters which showed percentile change between initial and interim PET/
CT were associated with prognosis. Instead, absolute value of SUVsum
American Journal of Hematology937