News of the Week

Key points:

• After immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been excluded, the central clinical challenge is to determine which patients have a self-limited or trigger-driven thrombotic microangiopathy (TMA) and which have complement-mediated disease requiring urgent complement blockade.
• Complement-mediated TMA (CM-TMA), also known as atypical hemolytic uremic syndrome, results from dysregulation of the alternative pathway due to inherited or acquired defects in complement proteins. In practice, however, the diagnosis is rarely straightforward, because many recognized triggers, such as pregnancy, severe hypertension, autoimmune disease, and solid organ or stem cell transplantation, can either cause TMA independently or unmask CM-TMA in susceptible individuals. This distinction is difficult because CM-TMA is a diagnosis of exclusion. Unlike iTTP, a rapid confirmatory test is not available.
• Complement genetic testing is not immediately available, and many clinically convincing cases lack identifiable pathogenic variants. See Table 2 and Figure 4 in original paper.
• Genetic testing identifies a pathogenic variant in ~40% to 60% of CM-TMA cases; a negative result does not exclude the diagnosis. Interpretation of complement variants is often difficult because CM-TMA is characterized by incomplete penetrance, variable expressivity, and frequent dependence on a triggering event.
• In these situations, the critical question is not whether a trigger exists but whether it fully explains the syndrome and whether urgent complement blockade is warranted to prevent irreversible kidney injury.
• During anti-C5 therapy, monthly complete blood counts, lactate dehydrogenase, haptoglobin, creatinine, urinalysis/proteinuria, blood pressure, and CH50/AH50 or free C5 when available help detect breakthrough disease; incomplete blockade should prompt dose escalation or interval shortening.
• The duration of complement inhibition should be individualized according to relapse risk, recovery, trigger profile, and the ability to ensure close follow-up and immediate access to re-treatment.
• In patients with high-risk features, such as a pathogenic mutation, persistent factor H autoantibodies, previous relapse in the native kidney, recurrence after kidney transplantation, significant residual kidney injury, or barriers to rapid evaluation and drug access, should relapse occur, the authors generally favor long-term therapy.
• In contrast, in carefully selected patients with no pathogenic variant, a reversible trigger, and complete hematologic and renal recovery, discontinuation may be considered after shared decision-making, provided there is close laboratory surveillance and a clear plan for rapid reinstitution of therapy if relapse occurs. A variant of unknown significance should not automatically be treated as either benign or pathogenic, and available structural, functional, segregation, and antigenic data should be incorporated into the overall risk assessment of the variant.

Highlights:

• Primary central nervous system lymphoma (PCNSL) is an aggressive subtype of non-Hodgkin lymphoma with a poor prognosis, high rate of refractory or relapsed (R/R) disease, and no established standard of care for R/R PCNSL.
• This phase 2 study (PROSPECT) evaluated the efficacy and safety of tirabrutinib, a potent, highly selective, oral second-generation Bruton tyrosine kinase inhibitor, in patients with R/R PCNSL in the United States.
• Tirabrutinib monotherapy resulted in rapid and durable responses and demonstrated a favorable safety profile.

In the open-label PROSPECT study (www.clinicaltrials.gov, NCT04947319), adults with R/R PCNSL whose disease progressed on or after ≥1 high-dose methotrexate–based therapy received once-daily oral tirabrutinib 480 mg. The primary endpoint was overall response rate (ORR). Among 48 enrolled patients, median follow-up was 11.5 months, ORR was 67% (95% confidence interval [CI], 52-80), and CR rate was 44% (95% CI, 29-59). Median duration of response was 9.3 months (95% CI, 4.6-14.6), and median time to  response was 1.0 month (range, 0.9-3.7). Treatment-related treatment-emergent adverse events (TEAEs) occurred in 36 patients (75%), most commonly anemia (19%), maculopapular rash (17%), fatigue (15%), neutropenia (15%), lymphocytopenia (15%), pruritus (15%), and other rash (15%). Grade ≥3 treatment-related TEAEs occurred in 13 patients (27%), most commonly neutropenia (8%) and maculopapular rash (6%). One death (bronchopulmonary aspergillosis) was treatment-related.

Does high-dose therapy remain necessary for all patients with relapsed or refractory Hodgkin lymphoma (HL), or can selected subgroups be safely spared this intensive approach? This editorials presents both a pro and a con argument.

Key points:

• 10-20% of patients are refractory or will relapse following frontline therapy.
• High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has long been the cornerstone of curative therapy for eligible patients with relapsed or refractory HL who demonstrate treatment-sensitive disease.
• This is based upon two fairly historic studies that were conducted before novel agents, such as brentuximab vedotin (BV) and programmed death-1 (PD-1) blockade, were available. Both studies showed significant improvement in event-free survival or freedom from treatment failure. Based on those studies, the chance of cure in the second-line setting for HL was about 50%.
• Since the introduction of positron-emission tomography-adapted salvage as well as BV and PD-1 blockade, cure rates for relapsed/refractory HL have been much higher.
• The available evidence strongly supports the central role of ASCT as consolidative therapy for the majority of patients with relapsed or refractory HL in the current era.
• Several small studies evaluating salvage and radiation rather than transplant have demonstrated the potential of cure for patients with low-risk relapse. The cumulative results from these studies indicate that patients could consider one of these less aggressive approaches with the knowledge that if they experience a second relapse, additional salvage and ASCT consolidation is likely to be effective. See Figure 1 in original paper (“Proposed modern-era risk-adapted and response-adapted study for relapsed or refractory HL”).

Highlights:

• Kimura disease (KD), a rare chronic inflammatory disorder of unknown aetiology predominantly affecting young Asian males, manifests as a painless unilateral subcutaneous head/neck mass, blood/tissue eosinophilia and markedly elevated serum immunoglobulin E (IgE), with histopathology serving as the diagnostic gold standard.
• Due to the rarity of KD, no standardized treatment protocol exists, leading to highly variable local recurrence rates (8.3%-100%).
• Despite the favourable overall prognosis and long-term survival associated with KD, the disease can exhibit systemic involvement affecting multiple organs. Renal involvement may manifest concurrently with the initial mass lesions or emerge months to years afterwards.
• While surgery offers a higher rate of initial complete response (CR), it is associated with a greater risk of recurrence compared to glucocorticoid combined with other medication(s), which provide superior long-term control.

The whole cohort comprised 93 patients, including 82 (88.2%) males, with a median diagnosis age of 34 years, interquartile range (IQR 23-46.5). Pruritus was present at onset in 36 (38.7%) patients, and eczema was present in 18 (19.4%) cases. Laboratory findings revealed a median absolute eosinophil count of 0.79 × 10⁹/L (IQR 0.5–2.23) and serum IgE of 1205 IU/mL (IQR 557.75–2547.5). The neck was the most common site, constituting 28% of all involved sites, followed by the parotid gland (18%).

Laboratory analyses revealed that the parotid involvement group exhibited significantly higher white blood cell counts (8.55 vs. 7.4 × 10⁹/L, p=0.003), which was primarily driven by elevated eosinophil counts (2.01 vs. 0.66 × 10⁹/L, p=0.02). Renal comorbidities occurred in 14 (15.7%) patients, among whom three patients had elevated creatinine levels and 11 patients presented with nephrotic syndrome (due to minimal change disease). The CR rates across different treatment approaches were as follows: 76% (19/25) in patients receiving surgery alone, 79% (15/19) in those treated with surgery combined therapy, 53% (8/15) in the glucocorticoid monotherapy group and 38% (6/16) in the glucocorticoid combined with other medication(s) group. Compared to surgery alone, glucocorticoid combined with other medication(s) was associated with a significantly lower likelihood of achieving CR (odds ratio [OR] 0.19, 95% confidence interval[CI], 0.04-0.71; p=0.017). However, when assessing recurrence risk, non-surgical strategies including glucocorticoid monotherapy and glucocorticoid combined with other medication(s) showed significant protective effects relative to surgery alone. The most substantial reduction in recurrence risk was observed in the glucocorticoid combined with other medication(s) groups (OR 0.08, 95% CI, 0.01-0.43; p=0.007). Analysis via the log-rank test revealed that treatment with surgery alone (median events-free survival [EFS]: 48 months) was associated with significantly poorer EFS than other therapies (median EFS: 96 months) (p=0.024). The presence of pruritus at disease onset also correlated with worse survival (p=0.038).