Patients with Gaucher disease (GD) are prone to manifest various lymphoproliferative disorders (LPDs), and particularly non-Hodgkin's lymphoma, multiple myeloma (MM) and monoclonal gammopathy of undetermined significance. The occurrence of Hodgkin's lymphoma (HL) is rare. Among 137 and 126 cases of various malignancies identified in two large registries of 1525 and 2472 patients with GD, respectively, there were only two cases of HL,1, 2 and additional five cases of coexistent GD and HL have been previously described in the literature.3, 4, 5, 6 Moreover, only two cases of high-dose therapy and auto-SCT in patients with GD and MM or refractory/relapsed non-Hodgkin's lymphoma have been reported.7, 8 We describe here the first case of successful mobilization with the anti-CXCR4 chemokine plerixafor, after initial mobilization failure, and the first reported case of successful high-dose therapy and auto-SCT in a patient with multiply relapsed HL and type-I GD.
The patient was a female, diagnosed with type-I GD at the age of 15 years, during investigation for massive splenomegaly. She exhibited the N370S/N370S genotype and was homozygous for a deletional mutation of the chitotriosidase gene. As a consequence, we used serum levels of the chemokine CCL18/PARC, to evaluate the GD burden. She was splenectomized 3 years later, and started regular enzyme replacement therapy at the age of 28 years. When she was 38 years old, she presented with painless, hard, left cervical lymph node enlargement, fever and sweats. An initial lymph node biopsy was interpreted as reactive lymphadenopathy with many Gaucher cells. Because of clinical deterioration and manifestation of inguinal lymph nodes, a second biopsy confirmed the diagnosis of nodular-sclerosing classical HL. During that period, her median serum CCL18/PARC levels were 623 ng/mL (normal range 10–72 ng/mL), compared with a baseline level of 1837 ng/mL, estimated 8 years previously. She was profoundly anemic (Hb 8.5 gper100mL, serum ferritin 623 ng/mL, CRP 12.5 gper100mL) with leukocytosis (19.2 × 109 cells per L, neutrophils 82%), but platelet count was normal. The BM was normocellular, with 15% infiltration by Gaucher cells, without any evidence of involvement by HL. Therefore, the clinical stage was IIIB. She was treated with six cycles of adriblastina, bleomycin, vinblastine, dacarbazine (ABVD) and achieved a PR, with residual disease at the cervical areas. Local radiotherapy of 36 cGy was then offered, and a CR was attained. However, cervical lymphadenopathy reappeared 18 months later. Treatment with four cycles of DHAP was unsuccessful. At 7 months after her first relapse, she was referred to our department for further evaluation and treatment. She complained of fatigue and sweats and exhibited moderate hepatomegaly, anemia, leukocytosis, but no manifestation of bone or neurological involvement. A new lymph node biopsy confirmed the presence of refractory HL of stage IIIB, with an international prognostic score of 2. Treatment with three cycles of DICE (dexamethasone, ifosfamide, carboplatin, etoposide) resulted in a second CR, with a negative positron emission tomography scan. An effort to mobilize and collect hematopoietic progenitor cells with the fourth cycle of DICE yielded 0.5 × 106 CD34+ cells per kg of body weight. A second effort for mobilization 2 months later with CY plus G-CSF was again unsuccessful. Meanwhile, findings of a new relapse at the supraclavicular area appeared. Chemotherapy with three cycles of GVD (gemcitabine, vinorelbine and liposomal doxorubicin) was given and a third CR was achieved. A third mobilization course, this time by adding two s.c. doses of 240 μg per kg of body weight of the anti-CXCR4 chemokine, plerixafor (Mozobil, Genzyme Europe B.V., Gooimeer, The Netherlands), one administered soon after the last G-CSF dose (10 mg/kg × 5 days), that is, 14 h before collection and the second 2 h before starting collection, yielded a total of 3.61 × 106 CD34+ cells per kg in 2 consecutive days. The patient was then administered high-dose therapy with BEAM and was supported by her autologous graft. The post transplant period was uneventful. She engrafted well (day +13 neutrophils >1 × 109 cells per L, day +14 platelets >20 × 109 cells per L). At 17 months after auto-SCT, she remains in CR with a negative positron emission tomography computed tomography and continues enzyme replacement therapy. It is the first described case of successful auto-SCT in a patient with GD and multiply relapsed HL, as well as the first case of successful mobilization and hematopoietic progenitor cell collection using plerixafor in a patient with GD in whom the standard process was unsuccessful, suggesting that plerixafor may be effective in similar cases of patients with GD.
The occurrence of HL in patients with GD is uncommon, and to date, only six to seven cases have been reported. The diagnosis of HL may be difficult or delayed in view of the lymph node infiltration by GD macrophages, as was the case in our patient. BM infiltration, splenomegaly and chronic inflammation, which are typically present in patients with GD, may adversely affect hematopoiesis, leading to greater chemotherapy-induced myelosuppression, delays in chemotherapy administration and dose modifications, thereby increasing the likelihood of treatment failure.
The application of high-dose therapy and auto-SCT has been previously reported only in two patients with GD and MM.7, 8 In one of them, secondary autograft failure was observed.7 Secondary allograft failure has also been reported after allo-SCT in patients with GD.9 Finally, difficulties in obtaining sufficient PBSC number has been reported in GD patients, accrued to gene therapy protocols.10 The great majority of GD patients, who have developed a LPD, have been treated with conventional chemotherapy. Our patient, although neither elderly nor overtreated with chemotherapy and having received only stem cell sparing regimens (six cycles of ABVD, four cycles of DHAP and three cycles of DICE), was unable to effectively mobilize CD34+ cells. The possible contribution of GD per se in this inability, inducing an inflammatory marrow microenvironment and impairing the growing potential of multipotent stem cells cannot be ruled out. Therefore, the insufficient stem cell yield of our patient might at least in part be attributed to GD.
The administration of the mobilization enhancer plerixafor led to effective mobilization and collection of sufficient number of PBSCs, more than seven times higher, compared with the number of previous mobilization products. Plerixafor is a stem-cell adherence inhibitor and results in their easy detachment from the BM matrix. It has been used in many cases in which standard mobilization procedures are ineffective, particularly as a result of chemotherapy overtreatment or previous exposure to purine analogs. This is the first time that plerixafor was used in a patient with GD. As LPDs, and particularly MM and non-Hodgkin's lymphoma, are commonly encountered among patients with GD, and the optimal treatment strategy has not been outlined, this drug may permit the application of more effective strategies and particularly of high-dose therapy and auto-SCT.
In conclusion, our case shows that auto-SCT can be feasible in patients with GD who develop LPDs, and when mobilization is ineffective, plerixafor may help to overcome the problem, mobilizing sufficient number of PBSCs.
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We would like to thank Dr Helen Michelakakis, head of the laboratory of Metabolic Disorders, Institute of Child's Health, ‘St Sophia’ Children's Hospital of Athens, for her excellent support in monitoring the Gaucher disease burden of the patient. We also wish to thank Dr Panayiotis Tsaftaridis, Laikon Hospital of Athens and Dr George Katrinakis, University Hospital of Heraclion, Crete, for their contribution in the care of our patient.
The authors declare no conflict of interest.
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British Journal of Haematology (2013)