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Is chronic lymphocytic leukemia curable? A clinical case relapsing 21 years after allogeneic stem-cell transplantation

Bone Marrow Transplantation volume 55, pages 1860–1861 (2020)Cite this article

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Allogeneic stem-cell transplantation (AlloSCT) continues being a therapeutic option in patients with high-risk chronic lymphocytic leukemia (CLL) failing to other therapies [1]. Importantly, disease relapse is infrequent after 6 years from transplantation and very rare beyond 10 years from the procedure. Because of this, these time points are frequently taken as a benchmark to consider CLL as potentially cured [2,3,4,5,6,7,8]. In this regard, in the update of the CLL3X study there were 23 patients observed for >10 years after transplantation, and only one of them relapsed after that time point [2] (P Dreger, personal communication, December 2019). In a Canadian report, no patient with  a follow-up ranging from 6 to 15 years (calculated number of patients: 10) had relapsed [3]. In a Polish study whose follow-up reached 16 years, none of the five patients followed for >4 years had relapsed [8]. Also, allogeneic stem-cell transplantation results in a high proportion of responses with undetectable residual disease (uMRD) [9, 10], a necessary condition to cure the disease. For all these reasons, AlloSCT is frequently considered as the only curative therapy for CLL. In most series, however, the median follow-up is around 6 years and there is only a small proportion of alive patients whose follow-up exceeds 10 years [2,3,4,5,6,7,8]. This hampers an accurate assessment of patients’ long-term outcome. Moreover, the existence of very late relapses should modulate the concept of cure in CLL.

In our center, 8 of 51 CLL patients allotransplanted between 1991 and 2019 had relapsed: 2 before 1 year, 2 at 2 years, 1 at 5 years, 2 at 10 years, and 1 at 21 years after transplantation. This later case is reported here. A 34-year-old man was diagnosed with CLL in December 1998. At the time of diagnosis the most relevant findings were generalized lymphadenopathy clinically and radiologically (CT scan) detected, WBC count 10.6 × 109/L (lymphocytes 65%), Hb 140 g/dL, and platelet count 98 × 109/L. The bone marrow examination showed a diffuse histological pattern with 80% lymphocytes. Cytogenetics, and fluorescence in situ hybridization (FISH) for CLL (13q, 11q, +12, 17p) were normal and IGHV (retrospectively assessed) was unmutated. The patient was treated with 2-CDA attaining a partial response. Because of this he was submitted to AlloSCT from  a human leukocyte antigen identical sibling. The conditioning regimen consisted of cyclophosphamide (60 mg/kg) and total body irradiation (13 Gy). Graft-versus-host prophylaxis consisted of cyclosporine and CD34-selected T-cell depletion. The number of CD34+ and CD3+ cells infused was 4.5 × 106/kg and 0.1 × 106/kg, respectively. The bone marrow function was recovered by day +16 after transplantation with full donor chimerism. The patient did not present GVHD. A clinical, radiological, and hematological evaluation at 60 days after transplantation demonstrated a complete response (CR) with uMRD as measured by flow-cytometry with a limit of detection of 0.01%. The patient was followed every 3–6 months and MRD was determined on a yearly basis. The uMRD CR status was maintained until December 2017 when 1% clonal CLL leukemic cells were detected. The patient was asymptomatic and no therapy was given. In December 2018, the patient presented with a WBC count of 16.4 × 109/L with 13% of lymphocytes of which 25% corresponded to clonal B cells with typical CLL immunophenotype. Cytogenetics showed 46XY, t(X,19) (p11-q13.3) [18]/46XY [2] and a monoclonal FR3 IGH rearranged. IGHV was unmutated. The clinical examination and a PET/CT scan demonstrated supra- and infra-diaphragmatic lymphadenopathy along with splenomegaly (12 cm). Molecular findings were consistent with a CLL relapse emerging from the same clone as the present at diagnosis (Table 1). In October 2019 because of enlarging lymphadenopathy treatment with ibrutinib was initiated, resulting in a very good partial response as determined in an interim evaluation in December 2019 and which is currently maintained.

Table 1 Main biological features during the course of the disease.
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Authors and Affiliations

  1. Department of Hematology, Hospital Clínic, Barcelona, Spain

    M. Rovira, F. Fernández-Aviles, T. Baumann & E. Montserrat

  2. Laboratory of Hematopathology, Hospital Clínic, Barcelona, Spain

    N. Villamor, M. L. López-Guerra & F. Guijarro

  3. Institute of Oncology Teknon, Barcelona, Spain

    F. Cobo & E. Montserrat

  4. University of Barcelona, Barcelona, Spain

    E. Montserrat

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Rovira, M., Villamor, N., Cobo, F. et al. Is chronic lymphocytic leukemia curable? A clinical case relapsing 21 years after allogeneic stem-cell transplantation. Bone Marrow Transplant 55, 1860–1861 (2020). https://doi.org/10.1038/s41409-020-0861-1

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