Daratumumab monotherapy for refractory lupus nephritis

doi:10.21203/rs.3.rs-2472742/v1

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Daratumumab monotherapy for refractory lupus nephritis

https://doi.org/10.21203/rs.3.rs-2472742/v1

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published 10 Aug, 2023

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Refractory lupus nephritis (RLN) is a clinical condition with high risk of a poor outcome and often life-threatening. Six patients (one male and 5 females), aged 41.3 years (range 20 to 61 years) were treated with Daratumumab monotherapy, a monoclonal antibody targeting CD38 which is highly expressed on the surface of many immune cells, especially plasma cells. The treatment protocol consisted of 16 mg/kg daratumumab administered intravenously weekly for 8 weeks, then every two weeks 8 more times, and lastly monthly (maximum 8 infusions). All patients failed previous treatments with the Standard of Care (SOC) including mycophenolate mofetil (MMF), cyclophosphamide (CYC), azathioprine and rescue therapies including Rituximab (RTX), Ocrelizumab, Belimumab, and iv IgG. One out of six patients did not show clinical response after 6 months of therapy, and Daratumumab was discontinued. Five patients showing a clinical response over the same period continued to be treated and reached a 12-month observation. Renal biopsy performed before daratumumab administration revealed a class IV LN in 1 patient, class V LN in 1 patient, class III + V LN in 1 patient and class IV + V LN in the other 2. Three patients achieved a complete renal response and the other two a partial renal response. A significant decrease in proteinuria from 5.6 gr/24 hours to 0.8 g/24 hours (p = 0.001) was achieved at 12 months. The mean value of serum Creatinine (sCr) decreased from 2.3 to 1.5 mg/dl. Improvement of clinical symptoms was paralleled by seroconversion of anti-double-stranded DNA antibodies (p = 0.03), significant decrease in interferon-gamma values (p = 0.0006), BMCA-B-cell maturation antigen (p = 0.0005) and soluble CD163 levels (p = 0.045), and increase in C4 (p = 0.018) and IL 10 levels (p = 0.0006). Clinical remission was substantiated by improvement of SLEDAI-2K score (p = 0.03). Daratumumab was generally well tolerated.

These data suggest that Daratumumab administered alone (i.e., without any other immunosuppressant or agents targeting B-cell activating factor) is highly effective in RLN.

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease that results from an auto-immune dysfunction and is characterized by a variety of clinical manifestations with diverse severity (1). Potentially any organ can be affected. Lupus nephritis (LN) is a frequent organ manifestation occurring in 35–45% patients (2, 3) and is still associated with an increased morbidity and mortality (4). Despite the important advancements in the last years LN still represents a challenge to clinicians (5).

Prolonged immunosuppression is the treatment of choice to control systemic and renal inflammation, and is presently the first-choice strategy to preserve kidney function and improve survival. Both the EULAR/EDTA-ERA (6) and KDIGO (7) recommendations indicate either mycophenolate mofetil (MMF), given orally at the dose of 3 g/day for 4–6 months or 500 mg cyclophosphamide (CYC) given intravenously twice a month for three months (in combination with 3 pulses of methylprednisolone (0.25–0.5 g/day followed by slowly tapering oral prednisone) to be the standard of care (SOC) for remission induction. A 3-year regimen with MMF (if MMF was used in the phase of remission induction) or azathioprine (AZA) (if CYC was previously used) is recommended for maintenance. However, there is a consisting minority of patients who do not achieve complete renal response and are classified as refractory. These cases have a high risk of a poor outcome (8). It is worth to remind that there are no randomized controlled trials (RCTs) enrolling cases of refractory LN. While the issue of refractory SLE has been especially addressed for renal involvement, the definition of refractory LN is in itself a matter of debate since the standard parameters of response, i.e., proteinuria and renal function, do not clearly discriminate between activity and irreversible damage (9). Refractory LN is commonly defined as either no response to standard SOC, i.e., failure to improve within 3–4 months, or not achieving partial response after 6–12 months, or complete response to SOC after 2 years of treatment (10). A more comprehensive definition should include the double attempt with both MMF and CYC- based regimen (10). However, concerns arise on the possible adverse effects of a prolonged ineffective immunosuppression, even though LN must require a relatively long time to achieve response, especially in the patients with nephrotic-range proteinuria at baseline who often need up to 12 more months to achieve complete clinical response).

Developing specific treatment strategies for RLN is important to limit the risks of poor outcome.

Apart from autologous hematopoietic stem cell transplantation which implies specific expertise (11, 12), therapeutic approaches for RLN include new calcineurin inhibitors (i.e., Voclosporin) (13), B cell modulating therapies (i.e., Belimumab) (14), and B cell depleting agents (Obinotuzumab) (15), and proteasome inhibitors (such as Bortezomib) (16). Proteasome inhibitors deplete the whole memory plasma cell (PC) pool, including plasma cells that secrete protective antibodies. In the myeloma setting where the vast majority of plasma cells are involved in the production of a clonally restricted immunoglobulin, bortezomib revealed to be very effective, but an approach that more selectively depletes plasma cells secreting the pathogenic antibodies would be a substantial advance in the SLE setting. CD38 (also known as cyclic ADP ribose hydrolase) is highly expressed on the surface of many immune cells, especially plasma cells, and a cell type-specific dysregulation of CD38 expression has been observed in patients with SLE, Daratumumab, which is a recently emerged monoclonal antibody directed at the CD38, has been shown to deplete highly expressing CD38 PC in the bone marrow.

Data regarding the efficacy of Daratumumab in SLE are presently limited to two patients with refractory disease who have been reported to be successfully treated with this agent in addition to receiving continued immunosuppression, and complemented by maintenance therapy with the antibody belimumab (17).

In this pilot study we evaluated the efficacy and safety of Daratumumab given alone (i.e., without any other immunosuppressant or agents targeting B-cell activating factor) in a discrete cohort of patients with refractory Lupus nephritis, a still unexplored setting of difficult patients.

The entire series of patients comprises 6 adults with refractory lupus nephritis who received Daratumumab monotherapy. The results refer to the 5 patients reaching a 12-month follow-up from starting therapy and 1 patient who discontinued the treatment due to the absence of clinical response at month 6th .

All patients fulfilled the American College of Rheumatology classification criteria for SLE and had severe biopsy-proven renal involvement. Renal biopsy classification was performed as described in 2003 International Society of Nephrology/Renal Pathology Society (18).

All patients failed previous treatments with SOC (MMF, CYC, azathioprine) and rescue therapies (including RTX, Belimumab, Ocrelizumab, and iv IgG) (Tab.I). Treatment protocol of Daratumumab monotherapy consisted of 16 mg/kg weekly intravenous administrations for 8 consecutive weeks, then every two weeks for 8 more times, and lastly monthly for a maximum of 24t administrations. Premedication included paracetamol 1000 mg (oral), chlorphenamine 10 mg (intravenous), and methylprednisolone 125 mg (intravenous).

Renal response was stratified as: (i): complete renal response: proteinuria < 0.5 g/24 hours, normal or near-normal estimated glomerular filtration rate (within 10% of normal estimated glomerular filtration rate if previously abnormal); (ii): partial renal response: ≥50% reduction in proteinuria to sub-nephrotic levels (< 3.5 g/24 hours), and normal or near-normal estimated glomerular filtration rate; (iii) no renal response: all the other cases (19).

Daratumumab was obtained by the local hospital pharmacy for off-label use, according to the rules for the management of Rare Diseases of Piedmont (North-West Italy). All patients provided informed consent. No commercial sponsor was involved.

Cytokine and soluble receptor serum testing. The serum of enrolled subjects was collected at enrolment and during the follow and stored at − 20°C. Cycles of repeated freezing/thawing were avoided. serum B-cell maturation antigen (sBMCA) levels (detection limits 10 pg/mL) were assessed by ELISA (R&D Biosystems; MN, USA). The serum levels of soluble CD163, IL-10 and IFN-gamma were tested by a Bio-Plex Pro Human cytokine panel kit (Bio-Rad Laboratories, CA, USA) according to manufacturer’s protocols.

Statistical analysis.

Normality of data distributions was assessed by Shapiro-Wilk test. Categorical variables are shown as absolute values and percentages, and continuous variables are reported as medians and min-max range. Spearman’s rank correlation coefficient was used to assess correlations between parameters. Wilcoxon’s matched-pairs signed‐rank test was applied to investigate variations in parameters following treatment. Data analysis was completed using SPSS v.28 (IBM Corporation; Armonk, NY, USA) and GraphPad Prism 8.0 (GraphPad Software Incorporation; La Jolla, CA, USA). A p‐value ≤ 0.05 was considered significant.

We presented 6 cases of refractory LN (one male and 5 females), aged 41.3 years (range 20 to 61 years) treated with daratumumab monotherapy as a rescue therapy. One of them did not show clinical response after 6 months of therapy, and Daratumumab was discontinued. Five patients showing a clinical response over the same period continued to be treated and reached a 12-month observation. Renal biopsy performed before daratumumab starting revealed a class IV LN in 1 patient, class V LN in 1 patient, class III + V LN in 1 patient and class IV + V LN in the other 2. At the time of treatment beginning the mean sCr value was 2.3 mg/dl (range 0.6–7 mg/dl), mean estimated eGFR was 62 ml/minute/1.73 m² (range 9–111 ml/minute/1.73 m2) and the mean proteinuria was 5.6 g/24 hours (range 2-9.8 g/24 hours). At 3 months all patients achieved an overall response, specifically 3 patients achieved a complete renal response and the other two a partial renal response. A significant decrease in proteinuria from 5.6 gr/24 hours to 0.59 g/24 hours, 0.9 g/24 hours and 0.8 g/24 hours (p = 0.0010) at three, six and twelve months, respectively (Fig. 1a and b). The mean value of sCr decreased from 2.3 to 1.5 mg/dl (p = 0.98) (Fig. 2a and b). C3 and C4 levels increased from 72.8 (range 20–99) to 101.6 (range 7480 − 135) mg/dl (p = 0.16) (Fig. 3a and b) and from 9.4 (range: 5–14) to 20.4 (13–30) mg/dl (p = 0.0182) respectively (Fig. 4a and b). C3 and especially C4 (p = 0.0182) increased. The IgG levels decreased from 971.7 (560–1546) to 508.4 (192–957) mg/dl (P = 0.123).

The median interferon-gamma values decreased from 13.43 to 1.84 pg/ml (p = 0.0006). IL 10 level increased from 113,56 to 1123,5 pg/ml (p = 0.0005). sBMCA (serum B-cell maturation antigen) and soluble CD163 decreased from 451,34 to 64,45 ng/ml (p = 0.0005) and from 467,12 to71,45 pg/ml (p = 0.045) respectively (Fig. 5). Anti-DNA antibodies decreased from 157 IU/l to 12 IU/L (p = 0.03) (Fig. 6).

The SLEDAI-2K index (20) decreased from 10.8 at baseline to 3.6 at 12 months (p = 0.03).

As shown in Fig. 7, sBCMA had a good correlation (rs = 0.4539) with disease activity, while sCD163 (rs = 0.3851), IL-10 (rs = 0.3117) and IFN-gamma (rs = 0.2327) showed a lower correlation with SLEDAI-2K. The serum levels of sBCMA correlation with sCD163, IL-10 and IFN-gamma are shown in Fig. 7.E.

Two patients experienced an asymptomatic SARS-Co-2 infection (Pt#1 after the 12th administration, Pt#4 after the 10th administration) without effects on renal response. In one of them (Pt#4) following infection anti-dsDNA antibodies turned to positive. In the other one (Pt#1), a temporary increased of Ab anti-DNA titer and proteinuria level were observed after COVID-19 vaccination (after the 17th administration).

All five patients have a persistent response at the last visit. Patient #2 who achieved a complete renal response at 3 months, needed a temporary treatment discontinuation due to a miscarriage with subsequent new flare of the SLE. After restarting daratumumab the patient achieved a partial renal response with a progressive decrease in proteinuria level (from 5.3 to 0.8 gr/24 hours at the 18th administration) and persistent normal renal function.

Daratumumab was well tolerated. One patient (#4) reported mild redness of the face associated with a warm sensation during the first infusion. The symptoms resolved themselves without the need for specific treatments.

The residual dose of steroids at 12 months in these patients was prednisone 5 mg/day.

The main challenges in the treatment of severe Lupus Nephritis are achieving a prompt response within months, maintaining this response and avoid flares, preventing renal impairment in the long term, avoidting damage and co-morbidities, and fulfilling these objectives assuring a maximal quality of life.

Refractory Lupus Nephritis is defined as an inadequate response to SOC therapy (10). This condition is associated with poor outcome, including end stage renal disease (4). This is why it is of upmost importance to develop specific treatment strategies for these patients (21).

No agreement exists on the definition of “refractory LN”. Refractoriness should be fully determined by persistent histologic signs of activity despite putatively effective therapy. However, there is a latency between achieving clinical remission and substantial changes of histologic features. For this reason, RLN continues to be defined on a clinical ground. Several factors may contribute (22), such as poor medication adherence, poor tolerability of therapy and adverse events, delayed patient referral causing irreversible injuries prevailing in the clinical picture. Geographic, ethnic, genetic and other epidemiological factors can also influence treatment response. However, the choice of the immunosuppressive treatment plays an important role. For instance, protocols based on higher dose oral glucocorticoids have better response rates, but at the price of higher toxicity.

The equivalence between MMF and CYC-based regimens as a standard of care is still debated. Some evidence exists favouring a higher rate of efficacy of the MMF-based regimen in Blacks and Hispanics, while CYC-based regimens are assumed to be a better option for Caucasians (23). However, the equivalence of the EULAR scheme (24) and the NIH protocol (25) is a controversial topic. Patients who were treated with the NIH regimen in the original studies (monthly infusions of at least 1000 mg of CYC, followed by an infusion each three months) were more severe than patients treated in the trial that promoted the EULAR low-dose scheme. Low-dose MMF + tacrolimus has been shown to be as effective as intravenous CYC in induction and maintenance therapy in a Chinese cohort (26). Ongoing studies will clarify role of the multitarget therapy in ethnically diverse populations.

Proteasome inhibitors have been emerging as an alternative option (16). However, these agents are still unpopular among rheumatologists and nephrologists. Plasma exchange and Immune absorption (which has replaced plasma exchange in many countries due to better tolerance) has being extensively used in combination with immunosuppressive agents in the real life, especially in Chinese patients (27). Recruitment bias may be responsible for the disappointing results of the RCTs with these techniques (28).

Stem cell transplantation has been mainly used when damage accrual was already present. This option requires a robust expertise, explaining the high procedure-related mortality in the EULAR Registry (29).

In a recent RCT, the anti-BLyS monoclonal antibody belimumab has been evaluated as an add-on-therapy (30). This prompted consideration of the use of belimumab in combination with SOC in the management of difficult cases of lupus nephritis (14).

The type II MoAb anti-CD20 obinotuzumab was found to reduce CD20 internalization and not to elicit CD20 redistribution. It has a greater affinity for FcγRIII and a greater antibody dependent cytotoxicity compared to Rituximab, showing a more direct B-cell killing and a less reliance on complement dependent cytotoxicity. Obinotuzumab, used as an add-on-therapy on top of SOC provided a significant higher rate of complete renal response in proliferative lupus nephritis (15).

Voclosporin is a new generation calcineurin inhibitor that decreases interleukin-2, interferon gamma, and Tumor Necrosis Factor alfa production by T cells. In AURORA trial (13) patients given voclosporin on top of steroids and MMF achieved a significant higher rate of complete renal response compared to patient receiving placebo plus MMF-based SOC.

In the TULIP-LN trial (31) Anifrolumab, a monoclonal antibody directed at interferon alfa and beta receptor subunit 1, given at greater dose than that approved by FDA for the treatment of nonrenal SLE, was found to achieve more complete renal response that placebo when added to MMF-based SOC. A PHASE III trial is ongoing.

In LN patients treated with anti-CD20 depleting agents, a considerable variability in peripheral blood B cell depletion can be observed (32,33). Reaching complete peripheral depletion (#0), together with a prolonged duration of complete peripheral depletion (>71 days), have been associated with complete response (32). This goal has been obtained by a short-term intensified B cell depletion protocol (IBCDT) (34,35) consisting of a combination therapy of RTX (4 weekly doses of 375 mg/m2 followed by 2 further doses after 1 and 2 months) and CYC given at sub-immunosuppressive doses (10 mg/kg reduced by 30% in patients with impaired renal function) aimed at potentiating the B cell depleting effects of RTX. This regimen proved to be highly effective even in the long term (5.5 years, range 3.7-7 years) without immunosuppressive maintenance therapies (19).

However, none of the regimens mentioned above is able to assure long lasting complete response in the totality of patients, and the issue of refractoriness to both conventional and rescue therapy, albeit limited to a restricted number of cases, remains a challenge for clinicians.

A growing body of evidence is supporting the rationale of an anti-CD38 strategy in these cases. CD38 is a glycoprotein expressed on the surface of many leucocytes participating to different cellular activities, including signal transduction, cell adhesion, and calcium signalling (36). Patients with SLE has been observed to present with abnormalities of CD38 expression when analysed at cell type-specific level (37). Plasma cells (PC) express CD38, and the monoclonal antibody Daratumumab showed to be effective in depleting bone marrow CD38+PC.

The use of Daratumumab combined with belimumab in addition to continued standard immunosuppression has been recently explored in two patients with refractory SLE (17) with promising results.

In the present study 6 refractory lupus nephritis patients treated with Daratumumab monotherapy have been reported. They include 1 male and 5 females who had previously received SOC and several rescue therapies.

Five out of 6 patients had a clinical response and were followed for at least 12 months All five showed a significant reduction of proteinuria, an improvement of renal function, and an increase of complement component levels, especially C4. The evaluation of SLEDAI-2K profiles confirmed the clinical effectiveness of the treatment. As regard to other nonconventional biomarkers, the impressive decrease of INF-gamma levels was especially relevant. Due to the influence of endogenous IFN inducers (38), the activation of diverse IFN-producing cells (39), and a genetic setup favouring IFN production (40), SLE is characterized by an activation of the IFN system with an increased expression of IFN-regulated genes that promote a continuous stimulation of the immune system (41). Our data suggest that Daratumumab can interrupt the ongoing production of IFN that sustains the autoimmune process in SLE. Receptor sBCMA, which is known to be increased in SLE (together with its ligands sAPRIL and sBAFF) also dramatically dropped under Daratumumab. Receptor sBCMA is strongly related to disease activity (42). A significant decrease in IL10 levels have detected following Daratumumab. IL10 has pleiotropic effects in immunoregulation and inflammation. It downregulates the expression of Th1 cytokines and MCHC class II antigens, blocks NF-kB activity, regulates the JAK-STAT signalling and decreases the expression of co-stimulatory molecules on macrophages (43). Our data also showed a significant decrease in sCD163 following Daratumumab treatment. Soluble CD163 results from the enzymatic release of monocyte and macrophage cell membrane CD163 under inflammatory conditions (44). Notably, sCD163, IFN gamma, IL10 and BCMA were correlated with each other, and, most importantly, SLEDAI-2K values were directly correlated with IFN gamma, sBCMA and sCD163 levels and inversely correlated with IL10.

Anti-DNA antibodies showed a relative delay in dropping under Daratumumab, and a transitory increase in anti-DNA levels could be detected in coincidence with COVID infections and vaccinations. Anti-DNA antibodies are mainly produced by B lymphocytes and short-lived plasma cells which are targeted by anti-CD20 monoclonal antibodies, are strongly influenced by anti-BLISS monoclonal antibodies, but only indirectly influenced by anti-CD38 agents. That possibly explains the susceptibility of patients under Daratumumab treatment to develop anti-DNA antibodies following strong immunological triggers such as COVID infection or vaccination. Nevertheless, abolishing of the pleiotropic action of CD38 together with the decrease of IFN gamma production, sBCMA and sCD163 dropping and IL10 increase likely provide for a rebalancing of immune system and stabilization of clinical manifestations despite the latency of anti-DNA disappearance.

Daratumumab proved to be well tolerated and safe. Two patient who had a COVID 19-SARS infection during the treatment recovered without sequelae. That was not surprising since Daratumumab does not affect B cells which are the main defenders against the newly emerging infections. Finally, one patient, who completed the entire course of Daratumumab (i.e., 24 infusions) and has been further followed for 6 months after daratumumab discontinuation without receiving any further immunosuppressant regimen, still presents with stable renal function and a moderate proteinuria which may be the expression of residual fibrotic sequelae.

In summary, Daratumumab appears to be a new effective therapeutic tool for the management of Refractory Lupus Nephritis.

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	Age at the onset (yrs)	Previous treatments	LN Class	Daratumumab Administrations (N°)	Residual Steroid dose
Pt 1	41	GC-RTX+CYC- Bel-CYC-AZA	IV+V	23	Prednisone 5 mg/day
Pt 2	24	GC-MMF RTX + CYC	V	18	Prednisone 7.5 mg/day
Pt 3	61	GC-RTX (High doses)	IV+V	17	Prednisone 5 mg/day
Pt 4	20	MMF-RTX+CyA- Bel	III+V	17	Prednisone 5 mg/day
Pt 5	54	GC-MMF-IgG iv-Bel	IV	10	Prednisone 5 mg/day
Pt 6	28	GC-RTX-CYC- Ocre	V	6	Prednisone 5 mg/day

Table I. Patients treated with Daratumumab. MMF: mycophenolate mofetil, RTX: rituximab, CYC: cyclophosphamide, IgG: immunoglobulin, Bel: Belimumab, Dara: daratumumab, Ocre: ocrelizumab

There is NO Competing Interest.

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Daratumumab monotherapy for refractory lupus nephritis

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