Page 45 - 2022_01-Haematologica-web

Marginal zone lymphoma
Diagnosis and staging
Peripheral lymphadenopathy involving the head and neck is common at presentation, with up to one third of patients having bulky tumors (>5 cm) and about half hav- ing stage III/IV disease.43 Approximately 10% of patients will present with an IgM paraprotein,39 which can result in the diagnosis being confused with Waldenström macroglobulinemia. The absence of an MYD88 L265P mutation (a feature of Waldenström macroglobulinemia) supports the diagnosis of nodal MZL although this muta- tion may also be observed in less than 10% of cases of nodal MZL.38 PTPRD mutations are observed in 20% of patients with nodal MZL and the finding appears specific to this entity.44
Nodal MZL demonstrates similar cytological, immunophenotypic and genetic features to those of both splenic and extranodal MZL which may result in diagnos- tic difficulty, particularly in cases with involvement of the spleen or extranodal sites.39 Validated prognostic scoring systems are lacking in nodal MZL, with conflicting data regarding the applicability of the Follicular Lymphoma International Prognostic Index (FLIPI).45,46 Increased age and advanced stage have been associated with an adverse prognosis.47
Current treatment approaches
The standard therapy for nodal MZL is yet to be defined with many centers employing strategies used in follicular lymphoma. Patients with localized disease respond well to radiotherapy, and those with minimally symptomatic, low tumor burden, advanced stage disease are suitable for a strategy of watchful waiting.39 Reports of regression of MZL with eradication of hepatitis C infection support this strategy as an initial approach in hepatitis C virus-infected patients.48,49 Patients with dis- seminated disease and high tumor burden can be treated with chemo-immunotherapy.40
Chemo-immunotherapy
Despite the lack of prospective studies, chemo- immunotherapy with rituximab is generally considered standard treatment for patients with symptomatic advanced stage disease. Numerous regimens have been explored including R-CVP,50 rituximab, cyclophos- phamide, doxorubicin, vincristine and prednisone (R- CHOP),51 fludarabine and rituximab,52 fludarabine,
cyclophosphamide and rituximab53 and bendamustine and rituximab.51,54 Fludarabine regimens are not routinely utilized because of toxicities.
Splenic marginal zone lymphoma
Splenic MZL makes up less than 2% of all lymphoid malignancies, and 20% of all MZL. It is usually indolent, with a median survival of 8-10 years, but can transform to diffuse large B-cell lymphoma in approximately 5-10% of cases.2,55 Approximately one third of patients have no symptoms, and a watch and wait approach has no adverse impact on overall survival.56 The subtypes and the biology and function of the splenic marginal zone B cell remain poorly understood. Splenic marginal zone B cells bridge the gap between early innate immune responses and late adaptive immune responses. Marginal zone B cells are sustained in their local microenvironment by cytokine-secreting cells such as group 3 innate lymphoid cells, which produce copious amounts of the cytokine BAFF and induce IgM, IgG, and IgA production in margin- al zone B cells.
NOTCH pathway genes are mutated in splenic MZL and nodal MZL, in addition to other marginal zone differ- entiation-associated genes, in as many as 60% of patients.57 A common mutation in splenic MZL occurs in the KLF2 transcription factor, leading to activation of NF- kB signaling with further hits to TRAF3, MAP3K14, and BIRC3.11 Distinguishing splenic MZL from other CD5- and CD10-negative indolent B-cell lymphoproliferative disorders can be challenging, with a definitive diagnosis best achieved with spleen histology.55 However, in most patients, the diagnosis can be suggested by the character- istic morphology of peripheral blood lymphocytes with bipolar cytoplasmic villous projections and a round nucle- us (in contrast to hairy cell leukemia in which cells have circumferential projections and an ovoid nucleus).
Diagnosis and staging
Immunophenotyping of circulating or bone marrow lymphocytes demonstrates IgM +/- IgD, CD19, CD20, CD22 and BCL-2 expression. CD23, CD25, and CD103 and cyclin D1 negativity assist in excluding chronic lym- phocytic leukemia, mantle cell and hairy cell leukemia (which also causes prominent splenomegaly). In common
Table 1. Selected phase II studies evaluating novel agents in patients with relapsed/refractory marginal zone lymphoma. Efficacy data from the publica- tion with longest follow-up reported where available.
Class
BTK inhibitor PI3K inhibitor
Anti-CD19 CAR T-cell
Agent
ibrutinib zanubrutinib
idelalisib copanlisib
umbralisib parsaclisib
axi-cel
First author
Noy79, 80 Opat83
Gopal84 Martin85 Dreyling89 Panayiotidis90 Fowler91 Phillips92
Jacobson93
N. of MZL Median cases age
(years)
63 66 68 70
15 NA 23 69
69 67 99 71
22 66
Median prior lines
Extranodal / nodal / splenic (%)
ORR CR (%) (%)
Median DOR (months)
Median OS PFS (months)
(months)
2 51/27/22 2 38/38/18
NA NA
3 17/65/17
2
2 33/31/35
3 NA
58 3 27.6 15.7 NE 74 24 12m DOR 15m PFS NA
81% 68%
435NA6.6NA
70 13 17.4 24.1 2y OS 83%
49 16 NE 2y PFS 50.5% NE 5469.313.8NA
85 60 10.6 11.8 NE
MZL: marginal zone lymphoma; ORR, objective response rate; CR, complete response; DOR, duration of response; PFS, progression free survival; OS, overall survival; m: months; y: years: NA: not available; NE: not evaluable; BTK, Bruton tyrosine kinase; PI3K, phosphatidylinositol-3-kinase; axi-cel: . axicabtagene ciloleucel; CAR: T-cell: chimeric antigen receptor T-cell therapy.
haematologica | 2022; 107(1)
37