*3.3.1 The immediate effectiveness of various therapies*

Various approaches have been used in treating patients, including anti-*Helicobacter pylori* therapy, surgery, and systemic chemotherapy. When using eradication antimicrobial therapy in the general population, the overwhelming majority of patients achieved a complete response (CR) - 87.5%, the median duration of CR - 51 months (range: 5 months - 81 months). The effect was realized quickly: the mediana of *Hp* eradication was 3 months, and the mediana of the CR observance was 5.5 months. Surgical treatment was performed for 28 patients (41.12%).

The efficacy of the therapy, depending on the morphological subvariant was evaluated (**Table 7**).

The efficacy of treatment in the group of patients with small cell subvariant of gastric MALT lymphoma was evaluated in all 31 patients. The median follow-up in this group was 64 months. Eradication anti-*Hp* therapy, which was used as the only method of treatment only in stage I (Lugano classification, 1993) of small-cell gastric MALT lymphomas, was performed for 16 patients (51.6%).

This approach allowed achieving CR in the vast majority of patients - 14 (87.5%), and the median duration of complete remissions was 51 months (5 - 81 months). Thus, anti-*Helicobacter pylori* therapy is competent and effective in primary small-cell gastric MALT-lymphomas of stage I with *H. pylori*, i.e. positive tumors with limited tumor lesion of the stomach (stage I) (**Figure 3a**, **b**).


*MALT Stomach Lymphomas: Aspects of Diagnosis and Treatment DOI: http://dx.doi.org/10.5772/intechopen.97865*

#### **Table 7.**

*Direct efficacy of various types of therapy depending on the morphological subvariant of gastric MALT lymphomas.*

In an earlier historical period (since 1973), 12 patients underwent surgical treatment of small-cell gastric MALT lymphomas: 11 patients underwent radical surgical treatment. The median duration of complete remissions in radically operated patients was 73 months (21 - 168 months), however, with a significant negative impact on the quality of life of patients.

The indication for chemotherapy (LVPP, COP, CHOP regimens) was the absence of *H. pylori* infection, while in all patients stabilization of the tumor process was only achieved. The efficacy of treatment in the group of intermediate subvariant of gastric MALT lymphoma was evaluated in 22 patients. The majority - 14 (63.7%) - received anthracycline-containing chemotherapy in combination with anti-*Helicobacter pylori* therapy. *H. pylori* eradication occurred in all patients within 1 to 8 months (median - 3 months), and complete remissions were achieved in 10 of them (71.4%). The median duration of CR was 37.5 months (1 - 53 months). Our experience of using induction standard chemotherapy in combination with anti-*Hp*-therapy for *H. pylori*, a positive MALT lymphoma of the intermediate subvariant, demonstrates a high frequency of achieving remissions and a stable long-term effect.

Radical surgical treatment was performed for 7 patients (31.8%): 2 - gastrectomy, 5 - distal subtotal gastrectomy were performed. The median duration of CR was 50 months (2–96 months).

The efficacy of treatment of the mixed subvariant MALT gastric lymphoma was assessed in all 15 patients, most of whom underwent surgical treatment at one of phase of disease (12/15) and only three received systemic chemotherapy alone. The immediate results of treatment of mixed gastric MALT lymphoma were better in 7 initially radically operated patients with subsequent adjuvant chemotherapy - the duration of CR was 57 months (mediana).

**Figure 3.**

*a) Endoscopic findings in subject with* Hp *+ MALT-lymphoma prior anti-*Hp*-therapy. b) -after anti-*Hp*therapy (from the archive of Malikhova O.A.).*

The results of standard anthracycline-containing chemotherapy turned out to be less impressive: out of 3 patients, complete remission at stage I of the process was achieved and persists for 39 months in 1 patient.

#### *3.3.2 Relapses*

With *H. pylori* - positive MALT gastric lymphomas of a small cell structure, out of 14 patients treated with antibiotics, relapse occurred only in 1 patient (7.1%) - 7 months after the CR. In this group, among radically operated patients, relapses were detected in 3 cases (27.3%).

In the group of patients with an intermediate variant, who received fundamentally different therapy (surgical treatment and systemic PCT (palliative chemotherapy)), the course of the disease was comparable in terms of the frequency of relapse: 30.0% and 37.5%, respectively. The difference is noted only in the timing of the detection of relapse: with conservative treatment, all relapses occurred in the first 2 years, and after surgical treatment later - in terms of 2 to 5 years (after 2, 3 and 5 years).

Attention should be paid to the predominant development of local recurrence in the stomach, regardless of the type of treatment and the type of NHL.

With the mixed sub-variant MALT, no relapses were detected.

#### *3.3.3 Long-term results*

Survival rates were calculated for 5-year and 10-year periods, which is explained by the long period of observation of patients. The overall 5-year survival rate (OS) was 96.8% in the case of MALT lymphoma of the small-cell subvariant. The indicators of 5-year OS are significantly lower with the intermediate subvariant - 71.4% (p = 0.008). These differences become even more pronounced to 10 years follow-up (**Table 8**). A small number of cases of mixed-type MALT lymphoma does not allow us to speak of significant differences.

The analysis of the influence of other characteristics on survival allowed us to establish that gender and age are not prognostically significant. Information about the further life of patients, depending on the methods of therapy used, is strategically important: a sparing conservative approach - anti-*H. pylori* antibiotic therapy - and an aggressive surgical method provide a high 5-year OS in the small


*MALT Stomach Lymphomas: Aspects of Diagnosis and Treatment DOI: http://dx.doi.org/10.5772/intechopen.97865*

#### **Table 8.**

*Long-term results of MALT lymphoma therapy depending on the morphological subvariant.*

cell subvariant of gastric MALT lymphoma, but with a significant deterioration in the quality of life in using a surgical approach.

Comparison of the conservative (chemotherapy + anti-Helicobacter antibiotic therapy) approach with the surgical approach in the intermediate variant demonstrates that OS indicators are comparable only in the first year of observation and amount to 83.8% and 80%, respectively; on the 3rd and 5th year of observation, the difference in these OS indicators increases by 25%: 81.8% and 55.8%, respectively. Disease-free survival is 15% higher with conservative therapy by the end of the first year (83.3% versus 67.5% with surgical treatment). This means that surgery for an intermediate variant of MALT lymphoma does not provide long-term control of the disease.

The analysis of survival rates in mixed gastric MALT lymphoma was not performed due to insufficient number of observations. Thus, the analysis of long-term results confirmed the clinical, morphological and prognostic heterogeneity of this tumor, a favorable prognosis of primary MALT gastric lymphoma in general, and significant differences in survival in different morphological subvariants.

### **4. Discussion**

Currently, according to practical recommendations, as a second-line treatment for patients in whom antibiotic therapy did not lead to remission, rituximab is prescribed as a monotherapy: 4 weekly administrations at a standard dose of 375 mg/m2 [9, 10].

In a study by G. Martineli, E. Zucca et al. 27 patients were enrolled exclusively with NHL gastric MALT lymphoma who received weekly rituximab injections [10]. In this work, the clinical activity of rituximab was confirmed in patients with gastric MALT lymphoma, refractory to antibiotic therapy or without association with *Helicobacter pylori*: the overall response (OR) was 77%, CR - 46%. With a median follow-up of 33 months, only 2 relapses were detected - after 26 and 14 months.

The IELSG-19 study as of today is the largest randomized trial comparing rituximab + chlorambucil with chlorambucil alone, in which the combination has shown the best results (OR) - 95% vs. 85%; CR - 79% vs. 63%). Based on data from this study (NCT 00210353) [11]. C. Thieblemont et al. the International Prognostic Index of Extranodal Lymphoma - MALT-IPI was developed [12]. Three factors were identified that influence event-free survival: age ≥ 70 years, Ann Arbor stage III or IV, and increased LDH levels. 5-year EFS in the low, intermediate and high risk groups was 70%, 56% and 29%, respectively.

The addition of rituximab to bendamustine provided significant advantages in a prospective study involving 60 patients with untreated extranodal MALT lymphoma: OR was 100, CR - 98%, 7-year EFS and PFS (progression-free survival) were 88% and 93%, respectively [13].

Fludarabine-containing regimens are excluded by most of the clinical recommendations from treatment standards and NHL due to the increased risk of developing second tumors [14].

In August 2020, a new treatment option for MZL relapses was registered in the Russian Federation - the lenalidomide + rituximab (R2) regimen. The high efficacy of this combination compared to rituximab + placebo was confirmed in the AUGMENT study for phase III, involving 358 patients with recurrent/refractory follicular lymphoma (295 patients) and marginal zone lymphoma (63 patients): median PFS was 39.4 months in the R2 group compared to 14.1 months in the placebo group [15].

The efficacy and safety of ibrutinib in relapses and refractory MZL was demonstrated in a st median udy of phase II involving 63 patients, of which 32 (51%) with extranodal MALT lymphomas [16]. With a median follow-up of 19.4 months median response time was not reached, and PFS - 14.2 months (mediana).

Blockade of the phosphatidylinositol 3-kinase (PI3K) pathway seems to be a very promising direction in the treatment of relapses or refractory MZL. However, drugs from this group are currently not registered in the Russian Federation.
