Carfilzomib-induced atypical haemolytic uraemic syndrome: a diagnostic challenge and therapeutic success

  1. Alicia Darwin 1,
  2. Leonger Malpica 2,
  3. Jugraj Dhanoa 3 and
  4. Hamza Hashmi 2 , 4
  1. 1 Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
  2. 2 Department of Blood & Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida, USA
  3. 3 Internal Medicine, University of Louisville, Louisville, Kentucky, USA
  4. 4 Department of Hematology Oncology, Medical University of South Carolina, Charleston, South Carolina, USA
  1. Correspondence to Dr Hamza Hashmi; hamzahashmi87@hotmail.com

Publication history

Accepted:04 Feb 2021
First published:26 Feb 2021
Online issue publication:26 Feb 2021

Case reports

Case reports are not necessarily evidence-based in the same way that the other content on BMJ Best Practice is. They should not be relied on to guide clinical practice. Please check the date of publication.

Abstract

Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy (TMA) that presents with renal insufficiency, thrombocytopaenia and microangiopathic haemolytic anaemia. Typical HUS is associated with Shiga toxin while atypical HUS (aHUS) is due to overactivation of the alternative complement pathway. aHUS has numerous causes, including drugs, with rare reports of carfilzomib, a proteasome inhibitor used in multiple myeloma, as causative agent. Cases vary in presentation, presenting a diagnostic challenge. Historically, TMAs were treated with plasma exchange. aHUS, however, is considered refractory to plasma exchange and best treated with eculizumab, a monoclonal antibody targeting C5, a terminal complement protein. We report a patient with history of multiple myeloma who presented with headaches, elevated blood pressure, petechiae, ecchymosis and haemolytic anaemia. His condition was determined to be carfilzomib-induced aHUS and he was successfully treated with eculizumab. Early detection and treatment of drug-induced aHUS is vital in reducing morbidity and mortality related to the condition.

Background

Thrombotic microangiopathies (TMAs) are a group of disorders that classically present with laboratory evidence of microangiopathic haemolytic anaemia (anaemia, elevated lactate dehydrogenase, low haptoglobin and evidence of schistocytes on peripheral blood smear), thrombocytopena and acute renal insufficiency. The main syndromes described within the TMA category are thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS).1 Advances in the understanding of pathophysiology have led to the classification of TMA based on underlying mechanism, rather than aetiology or clinical presentation. The pathogenesis of TTP involves a deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity. In contrast, typical HUS is associated with Shiga toxin infection. Atypical (aHUS) may have a similar clinical presentation to either condition but is caused by dysregulation of the alternative complement pathway and as such, ADAMTS13 activity may be elevated.2 aHUS is defined as a non‐Shiga toxin, non-immune TMA caused by uncontrolled activation of the alternative complement pathway. This entity is rare, with 1–3 cases reported per 100 000 people. Causes of aHUS vary, with less than half attributed to genetic abnormalities of the complement system and the remaining triggered by various factors including drugs, pregnancy, infection, malignancy or organ transplant.2 3 The pathophysiology of drug-induced aHUS is not well defined but mechanistic hypotheses include direct toxic effects, dose-related toxicity, immunological reaction or duration-related toxicity.4 Drug categories that have been associated with aHUS include antiplatelet agents, chemotherapeutic agents and immunosuppressants.2 4 Proteasome inhibitors (PI) agents, such as carfilzomib, bortezomib and ixazomib used in the treatment of multiple myeloma, have also been reported as causative agents in cases of both isolated renal thrombotic microangiopathy and complete aHUS.5–7

The treatment of TMA as a class has largely relied on plasma exchange. In aHUS, however, plasma exchange does not appear to restore renal function or improve thrombocytopenia and anaemia, resulting in poor outcomes.8 As such, aHUS is considered refractory to plasma exchange. With understanding of drug-induced aHUS as a complement-mediated process, prompt initiation of eculizumab, a monoclonal antibody that binds to terminal complement protein C5, is indicated. Early recognition and effective treatment of this entity is vital in preventing chronic renal damage and reducing relapse risk. Based on available data, eculizumab, a monoclonal antibody that binds to complement protein C5, is considered now the ‘gold-standard’ therapy of carfilzomib-induced aHUS. The agent is recommended to be used as first-line therapy as early as possible once the diagnosis is established to avoid life-threatening complications of TMA.

Case presentation

We present the case of a 53-year-old Caucasian man with a history of multiple myeloma status postallogeneic stem cell transplant who presented with fatigue, headache and easy bruising of 1-week duration.

The patient was diagnosed with IgG lambda multiple myeloma 3 years prior to presentation. On diagnosis, he was found to have 60% atypical plasma cells in the bone marrow and cytogenetic study was consistent with high risk disease (t(4;14) and gain of 1q). A patient underwent induction chemotherapy with lenalidomide, bortezomib and dexamethasone, followed by matched unrelated donor (8/8 human leucocyte antigen match) allogeneic stem cell transplant with fludarabine, melphalan, and bortezomib for conditioning chemotherapy and tacrolimus and methotrexate for graft-versus-host disease (GVHD) prophylaxis. Post-transplant course was complicated by acute GVHD of the skin (grade 2) and chronic GVHD of the eyes. Both resolved with a combination of prednisone, tacrolimus, sirolimus and mycophenolate. The patient experienced biochemical relapse of multiple myeloma 1 year prior to presentation and achieved complete remission with six cycles of salvage chemotherapy consisting of daratumumab, carfilzomib and dexamethasone. He was placed on maintenance chemotherapy with intravenous daratumumab (monthly), intravenous carfilzomib 56 mg/m² (every 2 weeks), and oral dexamethasone 40 mg (monthly). At the time of presentation, the patient had completed 18 cycles of maintenance therapy over 1.5 years. The last dose of carfilzomib was given 7 days prior to his presentation. He was also on a tapering dose of sirolimus for chronic GVHD of the eyes.

Investigations

On presentation, the patient was hypertensive with blood pressure of 170/100 mm Hg; other vital signs were normal. Physical examination revealed petechiae and ecchymosis. Complete blood count and comprehensive metabolic panel showed haemoglobin of 6.3 g/dL, platelet count 28x109/L, white cell count 2.62x109/L, creatinine 5.2, lactate dehydrogenase 1370 U/L, haptoglobin <10 mg/dL, total bilirubin 0.5 mg/dL, reticulocyte 2.9%, prothrombin time 12.5 s, activated partial thromboplastin time 41.6 s, international normalized ratio (INR) 1.1 and fibrinogen 480 mg/dL. Direct antiglobulin test (Coombs) was negative. Peripheral smear revealed more than 10 schistocytes (fragmented red blood cells) per high-power field. Serum and urine protein electrophoresis with immunofixation did not identify any monoclonal protein or Bence-Jones proteins in the serum or urine, respectively. Serum-free kappa, serum-free lambda and kappa lambda light chain ratio were 24.5 mg/dL, 10.8 mg/dL and 2.3 respectively. Bone marrow biopsy was performed and did not reveal any evidence of atypical plasma cells or myelodysplastic syndrome. Urinalysis revealed moderate amount of blood and 6–10 red blood cells per high-power field. A 24-hour urine protein was elevated at 1.8 g and fractional excretion of sodium was 1.8%. Renal ultrasound was without evidence of obstructive uropathy or medical renal disease. Testing for COVID-19 and viral respiratory pathogens via PCR were negative. Stool culture revealed 3+ enteric flora with no Escherichia coli 0157 isolated. Given headaches and elevated blood pressure, CT head and MRI of the brain were performed and did not reveal evidence of acute intracranial abnormalities.

Differential diagnosis

Drug-induced aHUS represents a diagnostic challenge as there are no biomarker or diagnostic tests to accurately identify the condition; therefore, it is a diagnosis of exclusion. While patients affected by aHUS may exhibit genetic mutations in the alternate complement pathway, confirmatory genetic results are not readily available during the window for diagnosis and treatment.9 To prevent progression of aHUS and associated end-organ damage, the differential diagnoses must be explored within hours to days to allow for prompt initiation of treatment.

Our patient presented with a clinical picture suggestive of a TMA including marked hypertension, intravascular haemolytic anaemia, thrombocytopaenia and non-descript fatigue and headache. Because of the patient’s history of multiple myeloma, it was prudent to ensure there was no disease recurrence causing haematological abnormalities via measurement of serum and urine proteins and immunoglobulins as well as bone marrow biopsy. The differential diagnoses of acute intracranial abnormalities and medical renal disease were explored and ruled out via head CT and MRI and renal ultrasound, respectively. TMA secondary to metabolic derangements, infection, autoimmune disease, malignancy, transplant and haemolysis, elevated liver enzymes and low platelets syndrome must also be explored as possible differential diagnoses.

Given negative workup for non-TMA causes of the patient’s presentation, further workup focused on determining the type and cause of his TMA. Stool culture was negative for E. coli 0157, reducing suspicion of typical HUS. ADAMTS13 activity level was drawn to explore the possibility of TTP and results returned 1 week later as normal, therefore, pointing to an HUS type of TMA. Other differential diagnoses included transplant-associated thrombotic microangiopathy and sirolimus-induced thrombotic microangiopathy. These entities present similarly, with renal impairment, evidence of microangiopathic haemolytic anaemia and normal to elevated ADAMTS13 activity. However, they tend to occur within 2 months after allogenic stem cell transplant.10

Treatment

With the clinical picture highly suggestive of TMA, patient was started on prednisone 80 mg (1 mg/kg) with daily plasmapheresis (one plasma volume per session) on day +1. ADAMTS13 activity level was drawn prior to initiation of plasmapheresis and reported on day +7 at 84%. Complement (C) levels were borderline low normal with C3 80 mg/dL (normal: 80–125 mg/dL), C4 15 mg/dL (normal: 15–42 mg/dL) and CH50 (total complement) 74 units/mL (normal: 60–144 units/mL). With little improvement in ongoing haemolysis and renal impairment as well as elevated ADAMTS13 activity, the patient was started on eculizumab on day +10, receiving 900 mg weekly for 4 weeks followed by 1200 mg every other week. Lab parameters showed improvement in haemolysis and renal impairment after one dose of eculizumab (table 1, figure 1). The patient received meningococcal vaccination prior to the first dose of eculizumab. The patient was started on amlodipine for new-onset hypertension and headaches resolved once blood pressure was adequately controlled.

Table 1

Change in haematological parameters and renal function with time

Days after presentation Haemoglobin
(g/L)		 Platelet
(K/uL)		 Lactate dehydrogenase
(U/L)		 Haptoglobin
(mg/dL)		 Serum creatinine
*Plasma exchange and corticosteroids were started on day +1.
* 63 28 1370 <10 5.2
+3 82 31 590 <10 4.7
+6 75 35 540 <10 4.2
+10†‡ 71 60 600 <10 3.6
+17§ 97 101 470 23 2.0
+24 100 163 315 45 1.2
+30 105 189 300 63 1.0
+37 110 200 250 60 1

Outcome and follow-up

Plasmapheresis was discontinued after 1 week of treatment. Prednisone was rapidly tapered with 2 weeks of treatment. Sirolimus, although initially held, was resumed on day +3 and continued at a dose of 1.5 mg daily and target therapeutic levels of 5–10 ng/mL. Given concerns for drug-induced aHUS, maintenance chemotherapy with daratumumab, carfilzomib and dexamethasone was discontinued. Haematological parameters including haemoglobin, lactate dehydrogenase and haptoglobin as well as serum creatinine continued to improve in the subsequent 2 weeks following weekly eculizumab (table 1, figure 1). The patient remains alive and well at the time of this report.

Discussion

We describe a patient with history of multiple myeloma status postallogenic stem cell transplant complicated by GVHD and eventual relapse who achieved second remission via salvage chemotherapy but developed carfilzomib-induced aHUS. This case illustrates an uncommon but serious complication of carfilzomib, a commonly used drug for patients with multiple myeloma. The true incidence of carfilzomib-induced aHUS remains unknown currently. Incidence is thought to be low as no aHUS occurred during clinical trials of carfilzomib but cases have been reported in literature.5–7 11–18 Additionally, drug-induced aHUS has been reported in patients receiving the PI agents bortezomib and ixazomib.18–23 Thus, aHUS is a class effect of PIs, and is an important clinical presentation to be aware of as new PIs such as marizomib and oprozomib are being investigated. It is not known whether certain PIs confer greater risk of aHUS than others.

A high index of suspicion is necessary for diagnosis of PI-induced aHUS due to varied clinical presentation often with confounding illness and polypharmacy, lack of specific diagnostic tests and rarity of the condition. Additionally, diagnosis is further complicated by the similar clinical presentation of TTP, typical HUS, aHUS and other entities in the TMA category.1–3 It is of vital importance to identify the type of TMA as diagnosis has implications on treatment. For example, while TTP is amenable to plasma exchange whereas aHUS is not.9 24 25 The presentation of PI-induced aHUS most commonly involves acute kidney injury and nonspecific symptoms including fatigue, lethargy, diarrhoea and vomiting.13 It is believed that new-onset hypertension or exacerbation of existing hypertension may be an early diagnostic clue to presence of aHUS.10 26 Time from initiation of PI to development of aHUS varies, with reports ranging from 1 day to 17 months.5 13 18 27 It is unclear whether cumulative PI dose is related to development of aHUS.13 15 Risk factors for PI-induced aHUS in multiple myeloma patients include tacrolimus-based GVHD prophylaxis, myeloablative conditioning, stem cell transplant, grade II–IV acute GVHD, hypertension, baseline renal insufficiency and concurrent treatment with cyclophosphamide, TMP/SMX, fluoroquinolones or acyclovir.26 27

Diagnosis of aHUS is supported by laboratory evidence of thrombocytopenia, non-immune mechanical haemolytic anaemia and renal dysfunction. Because aHUS is mediated by overactivation of the alternative complement pathway, it would be expected to cause low C3 and normal or elevated C4 levels. However, C3 and C4 levels are often normal in patients with aHUS confirmed via genetic testing, therefore, limiting the diagnostic and prognostic utility of these values.28 Our patient exhibited normal C3, C4, and CH50 levels. Investigation into alternative complement related protein levels including factor B, factor H, factor I, membrane cofactor protein and anti-factor-H antibodies should be considered in the workup of aHUS but were not conducted in our patient.29 30 An additional limitation of our workup was that no genetic testing of complement related genes was conducted. It is recommended that all genes identified as susceptibility factors for aHUS be screened using direct sequencing. There are numerous known pathogenic variants but lack of identification of a known variant should not call a clinical diagnosis of aHUS into question.29 The presence of certain mutations can confer negative prognosis with increased risk of relapse.30 Furthermore, genetic testing of these genes may provide insight into the mechanisms of PI-induced aHUS.

The pathogenesis of carfilzomib-induced aHUS is not known and the effect of carfilzomib on complement activity is poorly understood. Potential pathogenesis of PI-induced aHUS may involve decreased vascular endothelial growth factor (VEGF) production via nuclear factor kappa B (NF-κB) inhibition or the development of an inflammatory milieu with elevated interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) which permits the existence of drug-dependent platelet-reactive antibodies.5 18 The pathogenesis of aHUS as a broader category involves the unregulated activation of the alternative complement pathway. Complement dysregulation leads to thrombotic changes in microvasculature, ultimately causing microthrombosis, fragmentation of red blood cells, platelet consumption and multiorgan injury including renal failure.2 Given this pathogenesis, eculizumab, a monoclonal antibody that targets the terminal complement protein C5 and prevents further downstream generation of cytotoxic membrane attack complex and inflammatory molecules, is an effective treatment of aHUS.31

Eculizumab was granted accelerated FDA approval for treatment of aHUS in 2011 and has been effective in patients exhibiting all known complement protein genetic variants and also in those without identified variants. Use of this agent leads to improvement in both haematological parameters and renal function and appears to reduce the risk of chronic renal insufficiency and aHUS relapse.15 31–33 While other TMAs such as TTP are amenable to plasma exchange, this treatment is ineffective in aHUS with two-thirds of patients progressing to ESRD or death within 3 years.9 24 25 Although the efficacy of eculizumab has been established for aHUS, duration of treatment and cessation of therapy remains unclear. Eculizumab should be continued until haematological recovery, which typically occurs within weeks, but the necessity of continuing the agent until renal recovery, which can take months, is not clear. Current data are limited but suggests that relapse of drug-induced aHUS on stopping eculizumab is not common as it is in other aetiologies of aHUS. However, if discontinuing eculizumab, close monitoring of haematological and renal parameters should be continued.24 Additional treatment recommendations include holding of the offending agent and supportive care.9 Given that PIs are a component of numerous MM treatment regimens, withholding can put patients at risk of progression or relapse. Rechallenge with the offending PI can, but does not always, result in recurrence of the drug-induced TMA. Additionally, patients may be able to tolerate a different PI.20 Treatment decisions following PI-induced aHUS must be highly individualised, taking into account patient and disease characteristics, treatment history, patient preferences and goals of care and severity and course of PI-induced aHUS. Further research is needed to determine relapse rates of carfilzomib and PI-induced aHUS following cessation of eculizumab and the predictive characteristics associated with successful rechallenge with PI.

Learning points

  • Drug-induced atypical haemolytic uraemic syndrome (aHUS) is a rare condition where early diagnosis and treatment is important to avoid significant morbidity and mortality. It can be induced by carfilzomib and other proteasome inhibitors including bortezomib and ixazomib.

  • Patients with carfilzomib-induced aHUS may present with new or worsened hypertension, headaches, fatigue, easy bleeding/bruising and bloodwork indicating haemolytic anaemia, thrombocytopaenia and renal dysfunction. Risk factors for development of this condition may include tacrolimus-based GVHD prophylaxis, myeloablative conditioning, history of grade II–IV acute GVHD, hypertension and baseline renal insufficiency.

  • The pathophysiology of aHUS involves uncontrolled activation of the alternative complement pathway.

  • Eculizumab, a monoclonal antibody targeting the terminal complement protein C5, has shown efficacy in drug-induced aHUS and we recommend this as frontline treatment for carfilzomib-induced aHUS. Additionally, cessation of offending agent is necessary. The condition is refractory to plasma exchange. Optimal duration of treatment and recommended follow-up is not established.

Footnotes

  • Contributors AD: contributed to the writing and editing of report. LM: contributed to the writing and editing of report. JSD: contributed to the writing and editing of report. HH: contributed to the writing and editing of report. Patient was under the care of HH. Author team supervised by HH.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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