Abstract
The established treatment algorithms for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are currently challenged by novel classes of drugs, with ibrutinib being one of the most effective. Published data suggest that patients with early progression under ibrutinib often emerge as having Richter's transformation (RT) with a rapidly fatal prognosis, mostly developing diffuse large B-cell lymphoma (DLBCL). In this respect, it is known that RT to large DLBCL occurs in about 5% of patients with CLL during the disease course and less frequently to Hodgkin lymphoma (HL). Here, we report a patient with CLL who presented with HL transformation while still receiving therapy with ibrutinib stressing the need for clinical vigilance in any case with persisting or enlarging lymph nodes during treatment with this agent, as prompt modification of therapy is most important.
The management of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is undergoing significant changes. The established treatment algorithms are currently challenged by novel classes of drugs whose mechanisms of action are different from traditional cytotoxic agents and antibodies, with ibrutinib being one of the most effective (1-3).
Ibrutinib, an orally administered inhibitor of Bruton tyrosine kinase (BTK) that antagonizes B-cell receptor (BCR), chemokine, as well as integrin-mediated signaling agent, demonstrated high response rates and prolonged progression-free survival (PFS) in patients with CLL either as first-line therapy or at the relapse setting (4, 5). However, published data suggest that patients with early progression under ibrutinib often emerge as having Richter's transformation (RT) with a rapidly fatal prognosis, mostly developing diffuse large B-cell lymphoma (DLBCL) (6). In this respect, it is known that RT to large DLBCL occurs in about 5% of patients with CLL during the disease course but less frequently to Hodgkin lymphoma (HL) (7, 8).
CLL/SLL transformation into HL is observed in only about 0.5 % of patients and, until now, less than 100 cases have been reported (9-11).
Here, we report a patient with CLL who presented with Hodgkin transformation while still receiving therapy with ibrutinib highlighting the need for histological evaluation of any persisting or enlarging lymph node during treatment with this agent, as histology could reveal potential modification of treatment strategy.
Case Report
A 69-year-old male was diagnosed in 2009 with CLL stage B Binet stage. The patient was referred to us after a left cervical lymph node biopsy was performed. He was clinically fit, presenting with palpable left cervical and bilateral axillary lymphadenopathy (max diameter of 2 cm), as well as palpable splenomegaly (4 cm below left costal margin). His blood cell counts showed: White blood cells (WBCs): 16×109/l, lymphocytes: 12.2×109/l, granulocytes: 3.2×109/l, hemoglobin (Hb): 13 g/dl, hematocrit (Ht): 42.9%, platelets (PLTs): 142×109/l. No abnormal biochemistry was found and beta-2 microglobulin was within normal limits. Blood smear assessment disclosed a typical picture of CLL, while bone marrow examination revealed a diffuse pattern of infiltration. Both blood and bone marrow immunophenotypic analyses were consistent with typical CLL. Meanwhile, lymph node biopsy report was also consistent with CLL. As far as molecular prognostic factors were concerned, the patient was classified as unmutated type, while fluorescence in situ hybridization (FISH) analysis for 17pdel and 11qdel were both negative. The patient was placed on a watch-and-wait policy for 2 years until June 2011 when he developed massive splenomegaly, generalized lymphadenopathy and WBC count elevation (WBCs: 94×109/l, lymphocytes: 82×109/l, granulocytes: 8.4×109/l, Hb: 12.2 g/dl, Ht: 38%, PLTs: 145×109/l). Thus, he received immunochemotherapy with the combination of rituximab with chlorambucil and achieved a partial remission.
Later, in May 2014, at the age of 74, he relapsed showing similar clinical and laboratory characteristics as at initial presentation (WBCs: 100×109/l, lymphocytes: 95×109/l, granulocytes: 4.5×109/l, Hb: 12 g/dl, Ht: 36%, PLTs: 180×109/l). He was treated with a combination of rituximab, fludarabine and cyclophosphamide (FCR) receiving six cycles and he, again, achieved good partial response (PR) lasting until August 2016 when he relapsed again with generalized lymphadenopathy, splenomegaly and a WBC count of 40×109/l. Before new treatment initiation, FISH analysis for 17pdel was still negative. Since ibrutinib was commercially available, the patient was started on this agent at the standard dose of 420 mg/day in early September 2016. Gradually, all palpable lymph nodes decreased other than a right submandibular lymph node, which remained stable with a max diameter of 3 cm (Figure 1). Initially, this finding was considered as a reactive lymph node due to co-existence of herpes simplex lip infection and, therefore, acyclovir and antibiotics were administered without, however, any improvement.
In December 2016, after being on ibrutinib for four months, it was decided to perform a biopsy of this submandibular lymph node. The results showed HL with typical Reed-Sternberg, Hodgkin cells both CD30- and CD15-positive, mixed with lymphoid cells with immunophenotypic features of CLL. Antibody to LMP-1 antigen of Epstein-Barr virus (EBV) was also positive in these cells (Figure 1).
As a consequence, the patient was diagnosed with HL transformation of CLL and, thus, ibrutinib was discontinued and started receiving the adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) regimen that, after 2 cycles, shows a promising response.
Discussion
CLL is characterized by clinical and biological heterogeneity. The term Richter's syndrome (RS) or RT represents the development of lymphoma in a patient with CLL. Approximately 2-10% of patients with CLL will develop RS during the course of their disease and, in 85-90% of cases, histopathology shows aggressive DLBCL. Less frequently, CLL may progress into HL, now termed Hodgkin's variant (HV) of RS, which comprises only 10-15% of all RS cases (7-11). Two types of Hodgkin transformation of CLL/SLL have been described. Type 1 is characterized by Hodgkin-Reed Sternberg (H-RS) cells scattered in a background of CLL cells, which was the case of the patient described herein, while, in the type 2 transformation, H-RS cells are present in a typical polymorphous, inflammatory background that is separate from CLL (9-11).
The largest series of Hodgkin transformation in CLL/SLL was reported from M. D. Anderson Cancer Center (MDACC) where, among 4,121 patients, only 18 had (0.4%) transformed to HL (9).
Ibrutinib, an orally administered inhibitor of BTK that antagonizes BCR, has become a new standard-of-care in CLL, especially for patients with unfavorable genetic characteristics, such as 17p deletion (5). While ibrutinib therapy induces high response rates improving PFS even in high-risk CLL patients, one of the reasons for ibrutinib discontinuation is disease progression. Recently, it has been reported that, among 31 patients discontinuing therapy due to disease progression, in four clinical trials, 13 progressed with CLL and 18 with RT. Among patients with RT, 78% developed DLBCL, while one developed HL, one plasmablastic lymphoma, one composite B- and T-cell lymphoma and one peripheral T-cell lymphoma (6).
The patient of the current case presented with HL transformation 4 months after ibrutinib initiation, which is in line with published data that RT tends to occur early in the course of treatment with an estimated cumulative incidence of RT of 4.5 % at 12 months (6). Maddocks et al. showed that parameters, such as increased number of prior therapies, BCL6 and MYC abnormalities, presence of del(17p) and complex karyotype, were all significantly associated with a higher risk of progression- and disease-related discontinuation of ibrutinib, while, in multivariable analysis, presence of BCL6 abnormalities (p=0.012) and complex karyotype (p=0.007) remained independent risk factors (6). An increased baseline lactate dehydrogenase (LDH) also appeared to be associated with development of RT (6). The patient described here had received two prior lines of treatment and, from the available data, it is apparent that he had normal baseline LDH levels without TP53 abnormalities. It is noteworthy that, at the time of diagnosis of CLL transformation, the patient was clinically fit without any B-symptoms, in accordance with the observation derived from the Israeli CLL Study Group that clinical presentation during RT into HL is not as “stormy” as RT to DLBCL (12).
Another interesting finding relates to the fact that EBV was positive in the RT cells of the patient, thus supporting the hypothesis of a possible role of EBV infection in the etiology of RS-Hodgkin's variant of CLL (9, 12-13). The precise role of EBV infection still needs to be defined in RS and in HV-RS in particular. However, the biological rationale for this association may, indeed, relate to the degree of pre-existing immunosuppression in CLL, which may be enhanced by the use of agents with proven immunosuppressive effect(s) like fludarabine or other agents with yet unknown long-term immunological consequences due to BTK inhibition, such as ibrutinib.
Treatment of patients with Hodgkin RT in CLL/SLL is challenging. Our patient was placed on ABVD therapy with an initial response confirming the results of the MDACC study that showed that HL-type multiagent chemotherapy, such as ABVD, was effective (9). However, the same study also reported that the majority of patients eventually relapsed after a short period of time, thus emphasizing the need for a more specific treatment approach, considering the possible role of EBV in the pathogenesis of the disease as a potential therapeutic target (9).
To our knowledge, this is only the second case of CLL with RT into HL in a patient receiving ongoing ibrutinib therapy (6) highlighting the need for clinical awareness in cases of CLL with suspicious lymph node enlargement during ibrutinib therapy, as the prompt recognition of this extremely rare entity is of paramount importance in adapting the suitable therapy.
- Received March 31, 2017.
- Revision received April 18, 2017.
- Accepted April 19, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved