Depth of remission following first-line therapy | A prognostic marker in gastric mucosa-associated lymphoid tissue lymphoma

Mucosa-associated lymphoid tissue (MALT) lymphoma is a type of marginal zone lymphoma belonging to the indolent non-Hodgkin lymphoma (NHL) entity.¹ Histopathological markers of MALT lymphoma include the presence of lymphoepithelial lesions, follicular colonization and plasmacellular differentiation.² Although MALT lymphoma can affect any organ, gastric presentation is responsible for up to 50% of all cases.²

The impact of initial depth of remission to first-line therapy on progression-free survival (PFS) in patients with gastric MALT lymphoma has not yet been established. Barbara Kiesewetter-Wiederkehr, Medical University of Vienna, AT, and colleagues investigated patient responses to first-line therapy and subsequent relapse patterns. The study which was published in Cancers in February placed a major focus on a sub cohort of patients that had received Helicobacter pylori (H. pylori) eradication therapy.² The Lymphoma Hub hereby presents a summary of the results.  

Introduction

Chronic H. pylori gastritis has been associated with gastric MALT lymphomagenesis, and therefore H. pylori eradication is the standard of care (SoC) for patients with the condition.³ Antibiotic treatment demonstrates favorable outcomes in patients with gastric MALT lymphoma, inducing 5-year survival rates as high as 90%. However, follow-up biopsies uncover persistent disease in around one third of patients previously classed as being in complete remission (CR).² It has been suggested that persisting or residual disease may be affected by the level of remission following first-line treatment. Uncovering a relationship between depth of remission and patient outcome may influence the clinical management of patients with gastric MALT lymphoma.²

Study Design

• Retrospective evaluation of all patients treated for histologically verified primary gastric MALT lymphoma at the Medical University of Vienna between 1999 and 2019
• Outcome parameters: progression-free survival (PFS) and time to next treatment (TTNT), overall survival (OS) including cause of death
• An objective response to first-line treatment is defined as a partial remission (PR) or complete remission (CR)
• Patients with stable disease (SD) or no change (NC) are referred to as non-responders

Results

Patient characteristics

• Of the 412 patients diagnosed and treated for MALT lymphoma, 137 classified for primary gastric MALT lymphoma (Table 1)
• The majority of patients (68%) were H. pylori positive
• Median follow-up was 56.2 months

Table 1. Baseline characteristics of gastric MALT lymphoma patient cohort

MALT-IPI, MALT lymphoma prognostic index; IQR, interquartile range *IE, confined to the stomach †IIE, presenting with local lymph node involvement  ±IIIE, presenting with distant lymph node involvement §IV, disseminated disease
Characteristic	% of patients (n = 137)
Sex, Female	51
Median age, years (range)	63 (22 – 85 years)
Age ≥ 70 years	28
Stage of disease-Ann Arbor Ann Arbor IE* Ann Arbor IIE† Ann Arbor IIIE± Ann Arbor IV§	66 23 1 10
MALT-IPI (available in 122 patients) Low risk Intermediate risk High risk	62 33 6
Further clinical features Helicobacter pylori positive Plasmacellular differentiation Autoimmune disorder Paraproteinemia	68 22 20 27
Median follow-up time, months (IQR)	56.2 (26.3–111.6)

First-line treatment

• The nature of, and patient responses to first-line treatment are illustrated in Tables 2 and 3 respectively
• Due to conflicting treatment guidelines, 22 out of the 44 of H. pylori-negative patients were treated with antibiotics only
  • Overall response rates (ORR) to eradication treatment observed in H. pylori-positive versus H. pylori-negative patients: 62% vs 46%
• The mean time to an objective response was significantly prolonged by H. pylori eradication compared to upfront systemic or local therapy: 7.6 months vs 4.3 months (p = 0.002)

Table 2. Front-line treatment approaches

H. pylori, Helicobacter pylori
Treatment	% of patients
First-line treatment overall collective (N = 137) H. pylori eradication Systemic treatment (chemo-/immunotherapy) Local therapy (radiation, surgery) Watch and wait	70 23 4 3

Table 3. Patient outcomes to first-line treatments

CR, complete remission; H. pylori, Helicobacter pylori; ORR, overall response rate; PD, progressive disease; PR, partial remission; SD, stable disease
Response to treatment, %	ORR	CR	PR	SD	PD
Overall collective (n = 128)	67	48	19	30	3
H. pylori eradication therapy (n = 93)	58	38	20	39	3
Systemic treatment (n = 30)	90	77	13	7	3
Local treatment (n = 5)	100	80	20	-	-

Patient survival outcomes

• Patients achieving an objective response were significantly less likely to undergo second-line therapy compared to patients with SD as the best response (41% vs 63%, p=0.021)

• TTNT did not differ significantly between patients achieving a PR and CR in any cohort

Table 4. Patient survival outcomes at a median follow-up of 56.2 months

CI, confidence interval; CR, complete response; H. pylori, helicobacter pylori; PFS, progression-free survival; PR, partial remission; SD, stable disease; TTNT, time to next treatment *This difference remained significant after multivariate correction for MALT-IPI factors
Outcome	Overall collective (N = 137)	H. pylori eradication cohort (n = 96)
Relapse/progression, %	52	49
Median estimated PFS, months (95% CI)	34.2 (16.0–52.4)	27.6 (22.6–32.6)
PFS, months Objective response Non-responders p	68.3 17.3 < 0.001	49.0 17.3 < 0.001
Median estimated PFS CR vs PR, months CR PR p	94.8 28.5 0.007	109.4 27.6 0.020*
TTNT Objective response SD p	47.5 15.3 0.001	30.3 15.4 0.008

 Long-term outcome

• Five- and ten-year OS rates were 91% and 79% respectively
• OS did not differ significantly between patients achieving an objective response and non-responders
• Four patients died as a result of B-cell lymphoma:
  • Progression of MALT 302 months following initial diagnosis (n = 1)
  • Gastric bleeding (n = 1)
  • Progression of an unrelated Epstein-Barr virus (EBV)-associated B-cell lymphoma (n = 1)
  • Transformation to diffuse large B-cell lymphoma (n = 1)

Conclusions

• The depth of remission following first-line treatment significantly correlated with length of PFS and TTNT across the entire cohort and is a useful prognostic marker
• In contrast, OS was not influenced by the depth of remission
• PFS was not impacted by the diagnosis of autoimmune disorders, plasmacellular differentiation or the presence of paraproteinemia
• Limitations of this study:
  • lower than expected response rate to antibiotics in the unselected population, possibly due to the relatively large fraction of H. pylori-negative patients
  • response to eradication treatment was not correlated with translocation t(11; 18) (q21; q21) status, which has been associated with lack of response to antibiotics
• Although the data do not support early oncological intervention to force achievement of a complete remission, the authors suggest to develop risk-stratified follow-up algorithms, which would allow to reduce the number of endoscopic controls in patients with a good response to treatment and absence other risk factors such progression, transformation or death