Response of factor X deficiency to darutumumab in the treatment of AL amyloidosis: a novel finding

Abstract

We report a case of progressive light-chain amyloidosis (otherwise known as AL amyloidosis) with acquired factor X (aFX) deficiency with a complete haematological response and rapid normalisation of FX levels following daratumumab monotherapy. To our knowledge, this is the first case report documenting successful treatment with daratumumab of aFX deficiency secondary to AL amyloidosis. The patient responded well to this therapy, with excellent symptomatic and quality of life improvements as well as a reduction in bleeding manifestations. This case highlights the value in considering daratumumab treatment when AL amyloidosis is complicated by FX deficiency.

Background

Systemic AL amyloidosis is a haematological disorder characterised by a monoclonal gammopathy leading to misfolding and deposition of immunoglobulin light chain proteins.¹ Aggregation of these light chains form amyloid fibrils and can deposit in various organ systems, most commonly the kidney and heart.^{1 2} Bleeding manifestations are also common and relate both to blood vessel fragility from amyloid deposition and coagulopathy.³ Coagulation abnormalities, with prolongation of both thrombin time and prothrombin time (PT), are thought to be multifactorial in aetiology with defects in synthesis and excess loss or consumption of clotting factors.³

An uncommon finding in patients with AL amyloidosis is acquired factor X (aFX) deficiency. Current literature postulates that the deposited amyloid fibrils adsorb FX from the circulation, leading to a reduction in FX half-life and subsequently FX levels.⁴ More recently, pentraxin-2 (PTX2) has been identified as a protein which binds and forms a complex with FX, preventing internalisation and depletion of FX; PTX2 has been described as a potential target of amyloid plaques.⁵ FX deficiency in patients with AL amyloidosis leads to frequent bleeding manifestations and sometimes catastrophic bleeding complications; therefore, highly effective treatment is imperative.^{6 7}

In this report, we describe a patient with AL amyloidosis and aFX deficiency treated with daratumumab monotherapy who achieved a complete haematological response leading to a rapid normalisation of FX levels with resolution of bleeding manifestations. To our knowledge, this is the first case report describing successful treatment of aFX deficiency with daratumumab.

Case presentation

A 67-year-old woman was diagnosed with AL amyloidosis in February 2014 on the basis of liver and gallbladder biopsies following cholecystectomy. Tandem mass spectrometry confirmed the amyloid to be of kappa immunoglobulin light chain type. She had multi-organ involvement at diagnosis with hepatomegaly with a liver span of 18 cm (normal 6–12 cm), normal liver function tests including an alkaline phosphatase (ALP) level of 118 IU/L (normal 44–147 IU/L), stage 1 kidney disease (creatinine of 92 µmol/L (normal 60–110 µmol/L), glomerular filtration rate (GFR) of >90 mL/min/1.73m², proteinuria of 1900 mg/24 hours; normal <30 mg/24 hours), and splenic involvement on serum amyloid P scintigraphy. There was no cardiac or neurological involvement and her coagulation studies were normal (international normalised ratio 1.1 (normal 0.8–1.1), PT 12 s (normal 11–12.5 s), activated partial thromboplastin time 28 s (normal 25–35 s), fibrinogen 3.96 g/L (normal 2–4 g/L) and platelet count of 251 x 10⁹/L (normal 150–350 x10⁹/L). FX level was not measured and gastrointestinal endoscopy was not performed. Assessment of the underlying monoclonal gammopathy demonstrated: serum free light chains (FLC) (Freelite assay)—kappa 156 mg/L (3.3–19.4 mg/L), lambda 15 mg/L (5.7–26.3 mg/L); no monoclonal bands on serum protein electrophoresis; a trace of kappa Bence-Jones proteinuria on urine protein electrophoresis, and 5% plasmacytosis on bone marrow examination.

There was no haematological response following five cycles of bortezomib, cyclophosphamide and dexamethasone therapy. This was shown by increased proteinuria and ALP levels although not meeting formal progressive organ disease criteria. The patient then had one cycle of cyclophosphamide, thalidomide and dexamethasone therapy which was poorly tolerated and proceeded to undergo high dose melphalan with autologous stem cell transplantation in 2015. At the 6-month post-transplant assessment, she had achieved a complete haematological response and over the subsequent 2 years achieved a hepatic organ response and while 24-hour proteinuria reduced to 3130 mg/24 hours (from 6740 mg/24 hours pretransplant) there was a slow deterioration in renal function. Towards the end of 2017, because of this deteriorating renal function (creatinine of 166 μmol/L, estimated GFR (eGFR) 27 mL/min/1.73m²), a renal biopsy was performed. This showed extensive amyloid deposition with 3 of 15 glomeruli sclerosed and 5% interstitial fibrosis. As her liver involvement had improved with reduction in hepatomegaly (span 28 cm pretransplant to 18 cm) and improvement in her ALP (200 IU/L pretransplant to 119 IU/L), and the FLC levels (NLatex assay) were normal, the appearance of renal amyloid deposition was assumed to be an old finding with the renal deterioration in keeping with chronic renal disease of any aetiology.

Throughout 2018, she developed recurrent gastrointestinal bleeding episodes necessitating multiple hospital admissions. These were characterised by a diarrhoeal illness or melaena, and a corresponding iron deficient anaemia sometimes with an acute haemoglobin drop. She was treated with blood transfusions and intravenous iron therapy. A subsequent upper endoscopy and colonoscopy were both macroscopically normal and no biopsies were taken. An enteroscopy revealed two non-bleeding angioectasias which were treated with argon plasma coagulation. No further gastrointestinal or muscosal biopsies were done so the possibility of gastrointestinal involvement by amyloidosis could not be determined.

Following these presentations, she was found to have haematological progression of her AL amyloidosis with deterioration in renal involvement and a new diagnosis of FX deficiency. The FLC showed a kappa of 107 mg/L and lambda of 31 mg/L with a kappa:lambda ratio of 3.5, abnormal even for the degree of renal involvement. The creatinine was now 241 μmol/L (eGFR 17 mL/min/1.73m² and 24-hour proteinuria was 5700 mg/24 hours. Her PT was 19 s and a diagnosis of aFX deficiency was made with an FX level of 13%. Interestingly, her hepatomegaly was continuing to improve (16.7 cm on ultrasound) and liver function tests had essentially normalised (ALP 108 IU/L). There was no evidence of cardiac amyloidosis.

At this stage she was referred to the Princess Alexandra Hospital Amyloidosis Centre where a decision was made to commence salvage chemotherapy for progressive disease. Lenalidomide and pomalidomide were considered relatively contraindicated given the need for thromboprophylaxis with these regimens and repeat autologous stem cell transplantation was not considered given the impaired renal function and relatively short duration of first remission. Daratumumab monotherapy was given according to a standard schedule with weekly intravenous infusions for eight doses, then fortnightly for eight doses and then monthly infusions.

Outcome and follow-up

The patient tolerated the therapy well and she has had over 12 months of treatment at the time of writing, with documented complete haematological and organ response. The difference in FLC fell from 70 mg/L to 11 mg/L after 4 weeks of daratumumab, and she remains in complete haematological response. Notably, her FX level improved to 39% after 6 months and to 90% after 12 months of daratumumab. Other coagulation studies normalised and there have been no episodes of gastrointestinal bleeding. Her renal function remains stable with a creatinine of 279 μmol/L with proteinuria reducing to 3400 mg/day. Her liver function tests also normalised and there was no hepatosplenomegaly.

At the time of writing, the patient is quite well and has had no further hospital admissions. Her quality of life is excellent; she can now exercise regularly. She has no symptoms suggesting progression of her amyloidosis. She will remain closely followed up with the haematology and renal teams at the local tertiary hospital.

Discussion

In AL amyloidosis, as opposed to myeloma, the disease is directly caused by the circulating monoclonal immunoglobulin light chain. The aim of treatment is to reduce the production of this amyloidogenic light chain as deeply, as quickly and for as long as possible to retard further amyloid fibrilogenesis and deposition. Should resorption of amyloid deposits exceed deposition then improvement in organ function can occur. Current initial standard therapy of AL amyloidosis is based on bortezomib-based regimens,⁸ or, for those who can tolerate it, autologous stem cell transplantation.^{9 10} Our case had no haematological response to bortezomib-based therapy and a 2-year complete haematological response following autologous stem cell transplantation.

Daratumumab, first approved for treatment of multiple myeloma in 2015, targets and binds to CD38, which is expressed by plasma cells in both multiple myeloma and AL amyloidosis.¹¹ Binding of daratumumab to CD38 initiates lysis of tumour cells through a multitude of mechanisms including complement-dependent cytotoxicity, phagocytosis and apoptosis, as well as augmentation of the immune response—elucidating on these is beyond the scope of this report.¹¹ Daratumumab has recently been approved for treatment of AL amyloidosis in the USA by the Food and Drug Administration, and there are encouraging data in the form of small phase II prospective trials in the relapsed setting, with a recent phase III trial demonstrating improved short-term outcomes when added to standard chemotherapy.^12–14

This case reports a complete and rapid improvement in FX levels and associated bleeding symptoms with daratumumab. This occurred because of daratumumab’s known ability to induce very deep and rapid (as early as 1 week after therapy) reductions in the pathological free light chain in AL amyloidosis.^{13 15} Achievement of complete haematological response halts overall amyloid deposition and allows resorption of amyloid deposits from target organs, in this case, presumably the liver and spleen.¹⁶ This was demonstrated in our case by an improvement in the patient’s hepatomegaly and proteinuria. As a result, because there is a reduction in total body amyloid load, there would be less adsorption of FX throughout the circulatory system, leading to an increase in FX half-life levels, absolute FX levels and restoration of normal coagulation.^{8 9}

Alternate, non-chemotherapeutic approached to the management of FX deficiency in AL amyloidosis are limited to case reports and small case series.⁷ Splenectomy, which removes a large amount of amyloid fibrils from the body, can improve FX levels although complications are significant.^{6 17} Takabe et al have successfully managed FX deficiency perioperatively with recombinant factor VIIa and an activated prothrombin complex concentrate, however, use of these agents in the operative setting carries with it risk of both bleeding and thrombosis, thought to be up to 44% of patients.¹⁷ More recently, there has been a report of using high purity FX concentrate to treat aFX and this is currently undergoing phase III clinical trials, although for patients with hereditary FX deficiency. This theoretically would negate the risk of fluid overload through using high volumes of FFP given variability of FX levels in FFP.¹⁸ These latter techniques are temporary measures and do not address the underlying cause of the FX deficiency.

In conclusion, we have demonstrated a remarkable response of FX deficiency to daratumumab in the treatment of AL amyloidosis. aFX deficiency secondary to AL amyloidosis can lead to a high incidence of bleeding manifestations, however, treatment is limited due to a paucity of evidence, limited eligibility of patients and unacceptable risk of adverse effects. This report highlights key advantages of daratumumab in this setting: the rapid and deep haematological response; no requirement for thromboprophylaxis which is a relative contraindication for the family of immunomodulatory drugs; the avoidance of thrombocytopenia which can complicate proteasome inhibitor therapy and high morbidity and mortality rates which can complicate autologous stem cell transplantation in this setting; and the ease of dosing in renal impairment which is a common situation in patients with AL amyloidosis. Thus, daratumumab should be strongly considered for treatment of AL amyloidosis complicated by FX deficiency given its tolerance and response profile.

Patient’s perspective.

The patient was kind enough to provide her own perspective regarding her experience:

I’ve had such a turbulent time with amyloidosis and suffered for many years with it. Daratumumab has given me my life back and I can actually do the things I’ve always wanted to do, it’s stopped any bleeding episodes that I used to have and I haven’t needed to go to hospital in a while. It’s always important to have hope, and with daratumumab it’s given me so much more hope about the future. I can’t fault any of the doctors who’ve helped me. Being in a case report would at least make me feel like I was helpful and if this report helps someone else then I would feel very appreciative of that.

Learning points.

• Suspect factor X (FX) deficiency in patients with AL amyloidosis who suffer from bleeding complications.

• Daratumumab is an effective therapy for AL amyloidosis, and has particular advantages if acquired FX deficiency is present.

• Daratumumab likely increases FX levels through a reduction in total amyloid load.

• Close follow-up and regular monitoring of organ biomarkers in AL amyloidosis is critical to assessing organ response.