Page 265 - 2021_07-Haematologica-web

Case Reports
a κ monotypic population consisting of 20% of mature plasma cells CD138+ and lymphoid cells CD20+ CD79a+ CD5+ CD10– CD23–. The screening for L265P mutation of MYD88 was positive. No adenomegaly nor splenome- galia was found on whole-body computed tomography scan. Cardiac markers were increased (troponin 199 ng/L and NT-pro BNP 13,664 ng/L) and echocardiography suggested infiltrative cardiomyopathy confirmed by car- diac magnetic resonance imaging. Although imaging fea- tures could not distinguish between amyloid and Randall-type light chain deposition (LCD), endomyocar- dial biopsy was not performed because of histological evidence of MIDD in the kidneys. This infiltrative car- diomyopathy was attributed to probable Randall-type LCD. A treatment combining rituximab 375 mg/m2 + cyclophosphamide 750 mg/m2 + dexamethasone 20 mg was initiated allowing partial hematological response after seven cycles. Weekly subcutaneous injections of bortezomib 1.3 mg/m2 were then added, leading to a κ/l ratio normalization after one cycle of bortezomib, so that cyclophosphamide was discontinued. At date of fol- low-up in October 2020, the patient had received 13 cycles of rituximab and eight courses cycles of borte- zomib and had achieved a sustained complete hemato- logical response.
Case 2: In March 2019, a 74 year-old woman presented at a rheumatologic clinic for diffuse pains associated with joints swelling leading to the diagnosis of articular chon- drocalcinosis. In the context of osteo-articular pains, a SPEP was performed revealing hypogammaglobulinemia at 2,7 g/L. sFLC-κ were elevated at 3,260 mg/L with a κ/l ratio of 14/61. The blood count was as following: hemo- globin 12 g/dL, platelets 374,000/mm3, neutrophils 7,660/mm3, lymphocytes 2,790/mm3. There was no hypercalcemia. Urine protein-to-creatinine ratio was at 29 mg/mmol (corresponding to 0,29 g/24 hours of pro- teinuria) and renal function was normal. Urine protein immuno-electrophoresis revealed Bence Jones protein- uria. β-2-microglobuline was 2,6 mg/L. Free light chain multiple myeloma was suspected and bone marrow aspi- ration was performed which revealed lymphocytic infil- tration consisting of 54% of mature lymphocytes associ- ated with 3% plasma cells frequently containing vac- uoles. This cytologic aspect of low-grade lymphoma was suggestive of Waldenström disease. Flow cytometry on bone marrow confirmed this diagnosis with a large mon- oclonal κ B-cell population CD19+, CD20+, CD22+, FMC7+, CD200+, CD5–, CD23–, CD10–, CD43–, CD38–. L265P mutation of MYD88 was detected.
A whole-body computed tomography scan and 18fluo- rodeoxyglucose-positron emission tomography scan showed no lytic bone lesion or hepatosplenomegaly or lymphadenopathy. Monoclonal IgM κ was detected on serum immunofixation (Figure 1C) and immuno-selec- tion confirmed the presence of m-HC (Figure 1D).
hypogammaglobulinemia, elevated sFLC and proteinuria revealing finally m-HCD. The dissociation between the sFLC level and the absence of a peak on SPEP was unusu- al. Moreover, the presence of vacuolated plasma cells in the bone marrow was highly suggestive of m-HCD. In order to detect heavy chains devoid of light chains on immuno-electrophoresis, immuno-selection techniques and the use of specific anti-light chains anti-serum are required. The serum samples were electrophoresed in agar containing anti-κ and anti-l antibodies trapping free lights chains and complete immunoglobulins. The throughs contained anti-m antiserum revealing mobile free μ-HC through precipitin line (Figure 1B and D). Bone marrow aspiration, immune phenotyping of B cells and the presence of monoclonal IgM on immunofixation eas- ily clarified the diagnosis of WM, in conjunction with the MYD88 mutation. Of note, this is to our knowledge the first report of such a mutation in patients with m-HCD. The association of these two conditions raises the ques- tion of the underlying pathophysiology and may suggest a continuum between WM and m-HCD: the secretion of truncated monoclonal IgM would be secondary to alter- ation of immunoglobulin gene within lympho-plasmo- cytic cells. Unfortunately we did not have sufficient bio- logical sample to perform DNA sequencing.
sFLC are part of the monitoring of multiple myeloma especially oligo-secretory myeloma and light-chain myeloma as well as amyloid light-chain amyloidosis. It has been recently suggested that sFLC could be a reliable marker in WM for prognosis and therapeutic response10,11 but currently, the routine use is not recommended in WM. Although m-HCD is a rare condition and renal com- plications are even more infrequent, it could be cost- effective to screen for proteinuria or even to measure sFLC and light chain proteinuria at diagnosis of lympho- plasmatic lymphoma, especially if the paraprotein is not detected on electrophoresis, because of the possible harmful renal and systemic consequences of sFLC increase. Indeed, cases of cast nephropathy12 and sys- temic amyloidosis13 associated with m-HCD have been reported and here we described the first case of MIDD.
Patient 1 presented Randall-type LCD disease with no HCD disease. Even though both conditions, HCD disease and HCD are due to CH1 deletion, m-HC protein never causes kidney or another organ damage. This difference could be explained by the fact that in m-HCD, the CH1 deletion is associated with deletions of a variable region which seems to be involved in tissue precipitation. Indeed, it has been reported that sequence analysis of HCD disease proteins revealed amino acid substitutions in the variable region responsible for charge and hydrophobicity modifications.4
Because of the rarety of this condition, there is no prospective studies and therefore no guidelines for the management of m-HCD which is based on case reports. In asymptomatic patients such as patient 2, simple mon- itoring seems reasonable. For symptomatic patients, the chemotherapy targets the underlying clone as proposed in the monoclonal gammopathy of clinical significance field.15 In this report the use of rituximab associated with bortezomib and cyclophosphamide + dexamethasone allowed a complete response in patient 1.
In summary, low levels of IgM protein with the pres- ence of light chain proteinuria and high level of sFLC in WM patients are highly suggestive of m-HCD, even more if bone marrow examination reveals vacuolated plasma cells, and should alert physicians to the possibility of kidney damage. Finally, our report suggests that m-HCD associated with lymphoplasmatic proliferation and MYD
In the absence of clinical impact, no specific treatment was introduced other than sodium bicarbonate to pre- vent cast nephropathy.
Few cases of γ-HCD at diagnosis or during the evolu- tion of WM have been described8 and Wahner-Roedler et al. reported in 1992 three cases of WM among the 27 first cases of m-HCD.11 Unlike γ-HCD and a-HCD, m- HCD is characterized by secretion of sFLC most often κ in the urine in one-half to two-thirds of patients with a risk of cast nephropathy or amyloidosis.4,5 However, the abnormal Ig is not detected by SPEP in two-thirds of m- HCD.5
These two new cases illustrated an uncommon presen- tation of WM like light-chain multiple myeloma with
haematologica | 2021; 106(7)
2035