Vedolizumab as Rescue Therapy in Carboplatin-Gemcitabine-Induced Triggered Acute Severe Ulcerative Colitis Flare-Up

Abstract

Approximately 20% of patients with ulcerative colitis (UC) develop acute severe UC (ASUC), for which intravenous systemic steroid therapy and possibly infliximab-based rescue therapy are generally imposed. However, there are no significant guideline recommendations on ASUC regarding vedolizumab as an alternative in this setting. A case report was presented where a patient with steroid-dependent UC developed ASUC induced by second-line chemotherapy. Treatment with intravenous methylprednisolone was imposed, but there was no reduction in bowel movements in the days following admission. Rescue therapy with infliximab was contraindicated because of the oncologic history. Surgical consultation, contraindicated colectomy, and administration of vedolizumab 300 mg were initiated. After infusion with vedolizumab, there was a significant reduction in bowel movements starting the day after infusion until normalisation of bowel movements within three days and the concomitant normalisation of inflammatory indices. The patient is currently in clinical remission, on therapy with vedolizumab 108 mg subcutaneously every two weeks, and is in oncologic follow-up for pulmonary neoplasm. This case highlights the novel potential of vedolizumab as a possible rescue therapy in ASUC, especially in special populations, where it may offer a better safety profile. Although cyclosporine and infliximab still represent the mainstays of salvage therapy for steroid-refractory ASUC, new therapeutic agents may also be effective, such as vedolizumab, ustekinumab, and anti-Janus kinase agents.

1. Introduction

In the natural history of patients with ulcerative colitis (UC), about 20% go on to develop an episode of acute severe UC (ASUC) with the very often need to resort to hospitalisation [1].

The diagnosis of ASUC requires meeting a set of criteria that combine those related to a disproportionate increase in bowel movements (>5 per day) as well as several signs related to systemic toxicity (i.e., at least one out of body temperature greater than 37.8 °C, increased heart rate over 90 bpm, decreased haemoglobin (Hb) below 10.5 g/dL, and increased C-reactive protein (CRP) to a value greater than 30 mg/L) [2]. Systemic-acting parenteral steroids remain the mainstay of ASUC therapy. However, rescue therapy based on infliximab or cyclosporine is often required, while using other biologic drugs in this rescue setting, such as vedolizumab (VDZ), is not currently recommended by current practice guidelines [2].

VDZ is a humanised monoclonal antibody that targets the α4β7 integrin heterodimer by selectively blocking intestinal lymphocyte trafficking [3]. Initially available only intravenously, a subcutaneous formulation of VDZ is also now available [4]. VDZ is among the best biologics available for UC regarding safety profile. Lasa et al., in fact, in a network meta-analysis, ranked VDZ as the best biologic agent in terms of safety for both averse and serious adverse events by presenting the lowest surface under cumulative ranking (i.e., SUCRA, 0.184) [5]. In the UC registration trial, VDZ showed similar adverse event rates to a placebo with no particular red flags for hypersensitivity reactions [3].

VDZ does not require the monitoring of its metabolites, as with traditional immunosuppressants; however, a possible role of proactive or reactive monitoring of its trough levels is increasingly debated [6,7,8,9]. In addition, pharmacokinetics may play a part in the loss of response to VDZ, although this has yet to be fully demonstrated [9]. Not surprisingly, the European and British UC guidelines do not postulate recommendations regarding the proactive or reactive monitoring of trough levels [2,10].

VDZ also shows an advantage in the degree of immunosuppression that it causes. VDZ is a gut-selective biologic, and so it does not result in a particularly significant risk of systemic effects [11]. This is not true, for example, for other drugs used in the ASUC, such as systemic steroids, cyclosporine, or infliximab, which, in contrast, show a moderate-to-severe degree of immunosuppression [11]. This determines that it increases the risk of opportunistic infections as well as the risk of carcinogenesis.

Cancer management via chemotherapy, especially platinum derivatives (i.e., platinum-based therapy, PBT), may be associated with severe gastrointestinal toxicity [12]. Cases of toxic megacolon have been reported with chemotherapy [13]. Also extensive is the chapter on immunotherapy-induced colitis, i.e., immune checkpoint inhibitor (ICI)-induced colitis [14]. PBT may be associated with severe gastrointestinal symptoms in several cases accompanied by ulcerative damage noticeable via digestive endoscopy [15]. Platinum can, in fact, also result in severe gastrointestinal adverse events such as pseudomembranous colitis [16] or ischemic colitis [17,18] or even C. difficile fulminant colitis [19]. An additional case of severe ischemic colitis was described after the treatment of biliary cancer with gemcitabine (in combination with cisplatin) [20].

Because of this, adopting a chemotherapy regimen (including PBT and/or gemcitabine) in patients with cancer and concomitant chronic digestive damage (induced by inflammatory bowel disease) becomes a real and complex challenge from a clinical point of view.

In this report, we present the case of a man with ASUC triggered by chemotherapy for lung cancer recurrence and previous history of ICI colitis who was successfully treated both inducing the remission of UC and maintaining it via VDZ-based rescue therapy.

2. Case Presentation

We present the case of a 56-year-old male, who was white and a former smoker, with a previous UC diagnosis (20 years earlier) and subsequent developed steroid-dependence on therapy with mesalazine at the dosage of 4.8 g/day and with azathioprine at target posology. The only notable element of his family history was that a brother died of pancreatic cancer. The patient’s medical history was relevant to a previous left pneumectomy, performed five years earlier (i.e., in 2017), with hilum-mediastinal lymphadenectomy for a G3 lung pleomorphic carcinoma [pT3N0(0/15)cM0]. The patient underwent an adjuvant chemotherapy regimen with three cycles of cisplatin and gemcitabine.

Three years after surgery, the patient developed a recurrence in the right lung in the posterior and basal sites (standard uptake value > 6), detected via positron emission tomography plus computed tomography (CT) examination with subsequent salvage radiotherapy (September 2020). The oncologists proposed a fine needle aspiration cytology of the recurrence lesion for better histological framing, which the patient refused. However, a subsequent follow-up CT scan in November 2020 demonstrated right hilar (20 × 5 mm), paratracheal (14 × 7 mm), and pre-carinal (12 × 8 mm) neoplastic lymphadenopathies. Therefore, oncologists decided to set immunotherapy with pembrolizumab for only three cycles, but it was later discontinued due to the development of ICI colitis. The latter was treated with conventional therapy with a subsequent clinical resolution allowing immunotherapy restart, but the emergence of neurologic adverse events (i.e., debilitating paraesthesia and hypoesthesia) necessitated its new discontinuation in May 2021. Second-line chemotherapy with carboplatin in combination with gemcitabine followed. In June 2021, the patient was admitted to our Hepatogastroenterology Unit with a symptomatologic parade compatible with ASUC (>10 bowel movements of bloody liquid stool, even nocturnal per day, abdominal pain independent of evacuations, and heartbeat > 90 bpm). The patient underwent a recto sigmoidoscopy a week before admission to our hospital (see Figure 1A) with a picture of active UC (Mayo Endoscopic score of 3), also undergoing rectal biopsy on the worst affected tracts (on them, we tested for concomitant Cytomegalovirus infection, which then resulted in being negative).

On day 1, the patient underwent a complete physical examination (which showed abdominal pain with a treatable but painful abdomen and peristalsis present in all abdomen quadrants and, at the level of the residual right lung, posed a situation compatible with emphysematous chronic obstructive pulmonary disease). A 12-lead electrocardiogram was performed, which was normal. In addition, the patient underwent routine blood sampling and infectiology analysis to detect bacterial or viral opportunistic infections (i.e., stool culture and faecal parasitological exam, C. difficile stool test, QuantiFERON test, TORCH complex including HIV, and CMV blood tests), as shown in

Table 1. The main laboratory tests the patient underwent at the time of admission to our facility.

Parameter	Value	Normal Range
White blood cells	8.21 × 103/μL	4–11 × 103/μL
Red blood cells	4.8 × 103/μL	4.5–6 × 103/μL
Haemoglobin	10.9 g/dL	13–17.5 g/dL
Platelets	400 fL	150–450 fL
Blood glucose	68 mg/dL	70–100 mg/dL
Creatinine	1.31 mg/dL	0.67–1.17 mg/dL
Cholinesterase	5926 U/L	5320–12,920 U/L
Sodium	141 mEq/L	135–146 mEq/L
Potassium	3.4 mEq/L	3.5–5.3 mEq/L
Chlorine	104 mEq/L	98–111 mEq/L
Calcium	8.7 mg/dL	8.6–10.2 mg/dL
Lactate dehydrogenase	297 U/L	120–240 U/L
Blood iron	30 μg/dL	59–158 μg/dL
Transferrin	249 mg/dL	191–337 mg/dL
Ferritin	50 ng/mL	30–400 ng/mL
Creatine phosphokinase	31 U/L	60–190 U/L
C-reactive protein	3 mg/dL	0–1 mg/dL
ESR	40 mm/h	2–15 mm/h
Total proteins	7.3 g/dL	6.6–8.7 g/dL
Albumin	4 g/dL	3.5–5.5 g/dL
Aspartate aminotransferase	15 U/L	5–40 U/L
Alanine aminotransferase	42 U/L	5–41 U/L
C. difficile stool test	negative	negative
QuantiFERON test	negative	negative
Stool culture and faecal parasitological exam	negative	negative
TORCH complex, including HIV	negative	negative
CMV blood tests	negative	negative
Thyroid hormones	normal	normal

Note: ESR: erythrocyte sedimentation rate; HIV: human immunodeficiency virus; CMV: Cytomegalovirus.

, and abdomen and chest X-rays (see Figure 2A,B). As a result, intravenous methylprednisolone therapy (40 mg per day), intravenous pantoprazole (40 mg per day), and, under the guidance of the clinical nutritionist, fasting with parenteral nutrition were imposed. In detail, enteral nutrition could not be maintained because of the lack of control of bowel evacuations.

In addition, the patient was also hydrated intravenously while monitoring electrolytes and water balance. Over the next five days, the patient had more than eight bowel movements per day and verified that the surgeon did not intend to proceed with colectomy [21]; rescue therapy with VDZ was imposed in consultation with the patient and oncology colleagues. We recorded a worsening in this time window of the biochemical parameters compared with those of the entry (i.e., reduction in potassium values to 3.1 mEq/L, reduction in blood calcium to 8 mg/dL, reduction in cholinesterase to 5091 U/L, lowering of blood iron to 48 μg/dL, and elevation of C-reactive protein to 3.75 mg/dL).

Next, the patient was infused with 300 mg of VDZ intravenously. Due to the persistence of abdominal pain, abdominal CT was performed, ruling out megacolon. Over the next few days, there was progressive improvement in the number of bowel movements with normalisation within the next five days. There was also an improvement in the biochemical profile. Three days after the start of the VDZ infusion, a 50 mg dose of oral prednisone was switched (continued for the next few days and tapered by 5 mg each week until complete discontinuation). Oral feeding was also started simultaneously, and parenteral feeding was discontinued. The patient was discharged with a short outpatient follow-up, where it was decided to switch to subcutaneous VDZ administration (with 108 mg of VDZ every 14 days) at the patient’s request after the third intravenous infusion. Twelve months after starting therapy, the patient maintained clinical and biochemical remission and, in addition, recorded a Mayo Endoscopic score of 1 at the follow-up colonoscopy performed under conditions of optimal bowel preparation [22] (see Figure 1B). The histological picture related to sampling in the two endoscopic examinations conducted on the patient is exhibited in Figure 3.

The trends of the laboratory tests are presented in Figure 4. This case report was presented and written consistent with the CARE (for CAse REports) guidelines.

3. Discussion

This case report highlights the potential role of VDZ as rescue therapy in the ASUC of a patient with a complex oncological history (Figure 5). There are several elements for reflection. As the first one, VDZ leads to a clinical and biochemical response in a short amount of time, in our experience. Indeed, it is well known that the speed of VDZ in obtaining a clinical response can be activated even up to nine weeks [23]. The speed of response is one point that has been argued in favour of the current indication of infliximab in the ASUC [24]. However, the presence of active neoplasia, as well as the patient’s comorbidities, prevented us from the use of anti-tumour necrosis factor (TNF). Anti-TNF agents are determinants of moderate-to-severe immunosuppression, whereas VDZ, being colon-selective, is not weighed down by this issue, while increasing the risk of intestinal infections [11].

Secondly, it was associated with a good safety profile, a priority element in managing this oncological patient. Experiences of VDZ in ASUC are primarily anecdotal, although one successful case report has already been reported in a paediatric setting [25].

In addition, in our case, the absence of surgical indications for colectomy allowed us to start VDZ therapy more confidently. Certainly, the patient had albumin values > 3 g/dL, a normal C-reactive protein/albumin ratio, and no colic dilatation upon X-ray [2]. These would, if present, have been an element that would have made us lean more easily toward a surgical solution.

Moreover, improving the clinical picture with the reduction in the number of daily bowel movements allowed for the reintroduction of enteral feeding, which is associated with a better outcome [26]. The response has been sustained, and so the patient is continuing maintenance therapy with VDZ subcutaneously. Finally, this case report probably pushes for more study of VDZ as rescue therapy in ASUC and highlights its potential safety in order to be studied in a subgroup of oncology patients [27]. VDZ has recently been proposed in the ASUC as a “bridging” strategy in combination with cyclosporine in patients already failing anti-TNF agents or thiopurines [28]. However, this pathway would not have been applicable since cyclosporine, like infliximab, would have resulted in immunosuppression that was too severe to manage in a setting with a particularly tough concomitant oncologic component.

Certainly, VDZ is not an unknown therapeutic agent in managing lower gastrointestinal toxicity associated with cancer therapy. VDZ has shown promising efficacy compared with infliximab in ICI colitis (otherwise present in the patient’s history) [29]. The pathogenesis of ICI’s gastrointestinal damage differs from that induced by platinum and gemcitabine. ICI inhibitors block programmed death-1/programmed death-ligand 1 (i.e., PD-1/L1) or cytotoxic T-lymphocyte-associated protein 4 (i.e., CTLA-4) by causing the increase in effector T lymphocytes while reducing regulatory T cells, with a reduction in the intestinal microenvironment of anti-inflammatory cytokines, leading to histological and endoscopic pictures often tricky to distinguish from those of UC or Crohn’s disease [30]. VDZ’s role in managing non-ICU-induced gastrointestinal toxicity is much less clear. Mucosal insult resulting in damage (i.e., mucositis) also underlies the pathogenesis of PBT-derived gastrointestinal toxicity, but damage to intestinal innervation (especially in cases of persistence of symptoms after removal of PBT) is also not excluded [31]. In addition, chemotherapy develops a complex series of interactions with the gut microbiota leading to drastically adverse effects on the one hand; on the other hand, changes in the microbiota can also be harbingers of a predictive therapeutic response [32,33].

However, in the management of gastrointestinal toxicity associated with cancer therapy, the elimination of the therapeutic agent (e.g., ICI or PBT) generally results in an improvement in the clinical and endoscopic picture. Our patient had coexisting UC, resulting in chronic but mostly self-sustained inflammatory damage to the colon and rectum [34]. Therefore, PBT with gemcitabine triggered ASUC, which was self-sustained; consequently, using an immunosuppressive agent such as VDZ interrupted the inflammatory burden in the colon and rectum by blocking intestinal lymphocyte trafficking.

4. Conclusions

In conclusion, this case report highlights how VDZ was an effective and safe alternative to infliximab as rescue therapy for a complex case of ASUC triggered via chemotherapy for a relapse of advanced lung cancer. In addition, this report also points out that VDZ has shown, in this patient, relevant efficacy even in the setting of ASUC (as well as valid maintenance therapy past the stage of severity), where the significant guidelines on its management do not generally recommend VDZ. Studies evaluating the efficacy and safety profiles of VDZ in ASUC on a large scale and in randomised controlled settings are, therefore, desirable.