Low-dose alemtuzumab-associated immune thrombocytopenia in chronic lymphocytic leukemia

Authors


  • 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

Low-dose alemtuzumab-associated immune thrombocytopenia in chronic lymphocytic leukemia

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 [3]. Alemtuzumab is an anti-CD52 monoclonal antibody used in CLL both as first-line treatment 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 pathogenesis of ITP which could be related to its induced dysregulation of T-lymphocyte activity.

ITP is a common autoimmune complication in CLL, occurring in 2% to 5% of patients [1].

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 [3].

Alemtuzumab (Campath-1H) is an IgG1 kappa monoclonal antibody specific for the cell surface glycoprotein CD52 expressed on normal and malignant 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 Fondazione 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 preceded the treatment.

Supporting Information Table I summarizes the clinical characteristics (including HBV, HCV and HIV status), previous treatment and biological features 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 examination (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 P® Method, 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 × 109/L (range 3–70 × 109/L). During ITP, only two patients showed a clinically significant bleeding without any serious complications. In six patients, ITP was not associated to disease progression and they were treated with corticosteroids 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 alemtuzumab 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, ITP occurred 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 [3], suggesting an important role of alemtuzumab-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 conducted 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 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 lymphoproliferative 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.

Methods

We retrospectively analyzed a cohort of 64 patients affected by CLL, diagnosed according to NCIWG-CLL criteria and referred to the Hematology-BMT Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 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 × 109/L) of the platelet counts; (2) a normal or augmented number of megakaryocytes in the bone marrow; (3) no or limited (not palpable) splenomegaly, and (4) no cytotoxic treatment in the last month except for alemtuzumab. We also evaluated assays for antibodies to specific platelet glycoproteins, even if they are not routinely recommended, as platelet-associated IgG is elevated in both immune and non-immune thrombocytopenia [21].

Gianluigi Reda*, Francesco Maura†, Giuseppe Gritti‡, Anna Gregorini†, Francesca Binda†, Francesca Guidotti†, Alfonso Piciocchi§, Carlo Visco¶, Francesco Rodeghiero¶, Agostino Cortelezzi†, * Hematology and Transplantation Unit, Foundation IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy, † Hematology and Transplantation Unit, Foundation IRCCS Ca'Granda Ospedale Maggiore Policlinico and University of Milan, Italy, ‡ Ospedali Riuniti di Bergamo, Hematology, Bergamo, Italy, § GIMEMA Data Center, Rome, Italy, ¶ Department of Hematology, San Bortolo Hospital, Vicenza, Italy.

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