Chronic graft‑versus‑host disease (cGvHD) is a major complication following allogeneic hematopoietic cell transplantation (allo‑HCT). More than half of transplant patients are diagnosed with cGvHD. Severe cases in particular are associated with a considerable burden of symptoms and reduced quality of life. On the other hand, patients with cGvHD suffer significantly less frequently from a relapse of the underlying malignant disease. This is ultimately reflected in a higher overall survival rate in patients with cGvHD.¹

The association between cGvHD and the occurrence of gammopathies has been known for many years. Already in 1989, Mitus et al² reported a significantly increased rate of monoclonal (MG) or oligoclonal (OG) gammopathies in patients with GvHD. Over the past 2 decades, several retrospective studies have been published on post–allo‑HCT gammopathies. The studies have shown that gammopathies occur with increased frequency following allo‑HCT.^3-5 They also reported a higher rate of cGvHD and improved survival rates in patients with post–allo‑HCT OG or MG. In this issue of Polish Archives of Internal Medicine, Karaszewski et al⁶ present important additional data on this topic based on a relatively large cohort of patients. In a retrospective analysis of 241 patients who underwent allo‑HCT at the Medical University of Warsaw between 2014 and 2024, 36 cases of gammopathy were identified. Of these, 16 patients had OG and 20 had MG, which together corresponded to an incidence rate of about 15%. These Figures corroborate the incidence of post–allo‑HCT gammopathy reported in earlier publications.^4,5 Also in line with previous studies,^3-5 the M proteins are mostly of the immunoglobulin (Ig)Gκ and IgGλ types. The value of this publication lies in a clear separation of the results for OG and MG. The authors were able to show that there is no significant difference between the patients with MG or OG in terms of the incidence of acute or chronic GvHD. Based on the Warsaw cohort, there was also no difference in overall survival (OS) or progression‑free survival (PFS) between the 2 variants of gammopathy. The data on the timing of OG and MG occurrence in relation to the onset of cGvHD are an exciting and important addition to the existing literature. While the patients developed OG a median of 6.3 months before the onset of cGvHD, MG occurred a median of 4.5 months after the diagnosis of cGvHD. Thus, the detection of OG could serve as an early indicator of the impending onset of cGvHD and can be used for preemptive decisions. For example, if OG is detected, consideration could be given to delaying the reduction of GvHD prophylaxis or refraining from the administration of donor lymphocytes. In earlier retrospective studies,^3-5 patients in a cohort with and without gammopathy were compared with regard to the incidence of cGvHD and in relation to PFS and OS. Karaszewski et al,⁶ on the other hand, chose to compare the group of patients with and without gammopathy in a matched‑pair analysis. This comparison showed that the patients with post–allo‑HCT gammopathy had a more than 4‑fold increased risk of developing cGvHD. With regard to the severity of cGvHD according to the 2014 National Institutes of Health criteria,⁷ the authors did not find an increase in patients with MG or OG. Based on the matched pair analysis, better 5‑year OS (hazard ratio, 3.05; P = 0.02) was demonstrated. These remarkable data corroborate the previous findings on post–allo‑HCT gammopathy mentioned above.

B lymphocytes play a critical role in the pathogenesis of cGvHD. This makes them an important target for therapeutic approaches.⁸ On the other hand, altered B‑cell homeostasis, mediated by B‑cell–activating factor, is a characteristic feature of cGvHD.⁹ It can be assumed that the occurrence of post–allo‑HCT OG and MG is a subaspect of altered B‑cell homeostasis. The observation of improved OS in the patients with OG and MG therefore probably reflects the positive effect of cGvHD on the relapses of the underlying disease and, consequently, the probability of survival.

Analyses of the influence of cGvHD on OS and PFS are usually complicated by the fact that the occurrence of cGvHD is a time‑dependent variable. The same applies to the post–allo‑HCT occurrence of gammopathy. Patients who die or relapse early do not have the opportunity to develop cGvHD or gammopathy. Early events are therefore under‑represented in the patients with these conditions. This statistical problem also relativizes the large difference in OS in the first years after transplantation and may explain the diminishing effect of gammopathy during longer follow‑up. Landmark analyses, for example 3 or 6 months post–allo‑HCT, could help to address the problem of time‑dependent variables for the analysis of OS and PFS.

The interesting phenomenon of post–allo‑HCT gammopathy and its association with the occurrence of cGvHD and survival probability would be worth investigating in a multicenter and, if possible, prospective approach.