Recurrence of acute chest syndrome post stopping Crizanlizumab, the dilemma of stopping vs continuation in patient with sickle cell disease: case report

ABSTRACT

Sickle cell disease (SCD) is one of the most common hematological diseases, which results in variable complications. The treatment of SCD is evolving but limited options are available for now. Acute chest syndrome (ACS) is one of the serious complications observed in SCD and a challenging one in prevention. Crizanlizumab is a monoclonal antibody that binds to P-selectin and improves blood flow by preventing sickle cell adhesion to endothelium, resulting in improvement of vaso-oclusive crises (VOC). It is not well evaluated in terms of ACS prevention. Here we report a 23-year-old patient with SCD and recurrent ACS; she was started on Crizanlizumab and she had no more ACS, but once she was off Crizanlizumab she developed ACS again, later Crizanlizumab was re-started, and the patient has improved significantly.

KEYWORDS:

• Crizanlizumab
• sickle cell disease
• vaso-occlusive crisis
• acute chest syndrome
• hemoglobinopathies
• Hydroxyurea
• exchange transfusion
• Voxelotor‌

Introduction

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide [1]. It is estimated that 300,000 infants are born annually with SCD [2]. The substitution of glutamic acid to valine in the beta-globin chain results in the formation of sickle hemoglobin which contributes to the complications observed in such patients. Complications include vaso-occlusive crises (VOC), splenic sequestration, hemolysis, acute chest syndrome (ACS), and ischemic complication [3–5].

Apart from the economic burden of SCD which reaches one billion dollars annually in the United States [3]. The health burden of SCD is still challenging with the morbidity and mortality it causes, as treatment options are still limited [6,7].

Allogenic stem cell transplantation is the curative treatment option up to now, on the other hand, few drugs have been approved for the management and prevention of complications, including Hydroxyurea, L-Glutamine, Voxelotor, and Crizanlizumab [3,6].

Acute chest syndrome (ACS) one of the most common causes of death in SCD is defined by the presence of new chest infiltrate on imaging with respiratory symptoms and/or fever [1,8]. Three major causes have been proposed in ACS pathophysiology: pulmonary infection, bone marrow fat embolization, and pulmonary intravascular sequestration of sickled erythrocytes [9]. After VOC, ACS is the second most common cause of hospitalizations [1]. The Underlying pathophysiology of SCD complications is complex [10]. One of these involves P-selectin; an adhesion molecule found in platelets and endothelial cells. It is activated in response to inflammation and trauma. In SCD P-Selectin upregulation contributes to VOC by the adhesion of sickle red blood cells and leukocytes to the endothelial cells [11].

Crizanlizumab is a humanized monoclonal antibody that attaches to P-selectin and blocks its role in the adhesion of blood cells with endothelium. The net result is improved microvascular blood flow [12]. It is given in a standard schedule of 14 doses (first 2 doses every 2 weeks then maintenance every 4 weeks) as showed in the landmark study (SUSTAIN), no other proposed schedule addressed in the literature, more importantly in patients with severe VOC including ACS [10].

Herein we report a case of SCD patient with recurrent ACS and VOC who was started on Crizanlizumab and showed a significant improvement, but after the 13th dose she traveled and got ACS again, once resumed on Crizanlizumab no further ACS and the patient is doing well. This might suggest a potential benefit for Crizanlizumab in preventing further ACS events.

Case summary

A 23-year-old female known case of sickle cell anemia with recurrent VOC started on Hydroxyurea (HU) with a maximum tolerated dose of 1.5 g daily, despite being on HU the patient was admitted in the last two years twice to ICU with acute chest syndrome required intubation, antibiotics, and exchange transfusion.

The patient was offered a prophylactic exchange transfusion, but she refused. Moreover, she had 6 visits in the last two years to ED requiring admission from 5 to 10 days for pain crises. The patient was offered Crizanlizumab and started on 5 mg/kg loading dose over 2 weeks followed by 5 mg/kg maintenance every 4 weeks, the patient completed a total of 13 doses during this time she was admitted to the ward 3 times with VOC, and one of them was due to COVID infection few days before dose 11 Crizanlizumab, so it was postponed and resumed after recovery from COVID. There was no ACS during the time she was on Crizanlizumab (Table 1). After 13 doses, the patient traveled for vacation and after 2 months, she got a severe VOC abroad with fever and cough which required hospital admission, she was diagnosed with acute chest syndrome and required ICU care, intubation, and exchange transfusion. The patient recovered from the ACS episode and came back (6 months after the last dose of Crizanlizumab).

Table 1. VOC/ACS during Crizanlizumab period.

Crizanlizumab dose	VOC/ACS events
Dose 7 (9/2021)	1 VOC 1 day after Crizanlizumab dose
Dose 11 (1/2022)	1 VOC due to COVID infection
Dose 13 (4/2022)	1 VOC 2 weeks after Crizanlizumab dose

Crizanlizumab resumed as per the original schedule (the patient received again 2 loading doses followed by monthly maintenance), currently patient is on monthly maintenance and no VOC and no ACS (the patient received a total of 18 doses of Crizanlizumab so far).

Discussion

Despite the advancement in our understanding of SCD-related complications, treatment options are still limited [6,13,14]. Allogenic stem cell transplant remains the only curative treatment available till now, but it is limited by the availability of suitable donors as well as the cost. Gene therapy is a potential alternative that is still in the experimental phases and showing promising results [6]. Preventive treatment remains the major management for SCD, and it is an area of development and investigation. Currently, there are 4 FDA approved drugs to manage and prevent complications; starting with Hydroxyurea, which was approved in 1998, followed by L-Glutamine which got approval in 2017 and lately in 2019 both Voxelotor and Crizanlizumab were approved [3,10].

Crizanlizumab got its FDA approval after SUSTAIN trial. A phase 2 multicenter, randomized, double-blind, placebo-controlled trial, was conducted over 12 months and assessed the efficacy and safety of Crizanlizumab, a total of 14 doses of Crizanlizumab was given in the study period. The results showed a significantly decreased in sickle cell-related pain episodes by 45% in the Crizanlizumab group compared to the placebo and a doubling in the median time to the first and second vaso-occlusive pain events. As concluded, Crizanlizumab did not abolish completely the VOC, moreover, it showed up to 10% of patients who received Crizanlizumab developed infusion-related painful crises [15].

Further studies on Crizanlizumab are under investigation; however, none of them addressed the efficacy of Crizanlizumab in preventing acute chest syndrome [6,10]. Moreover, ACS was not meaningfully tested in the landmark SUSTAIN since their primary endpoint was to assess the annual rate of sickle cell-related pain crises which also included ACS. While all the patients in the trial did not experience any ACS events during the treatment duration, they did not mention that they did not have ACS before recruitment [12].

Awni et al. in 2022 addressed the benefit of continuation of Crizanlizumab in a SCD patient despite developing severe infusion-related painful crises; it also raised a potential preventive effect on ACS as the patient had previously 2 episodes of ACS in 3 years and after starting Crizanlizumab no further ACS episodes [11]. A further report from real-world data is necessary to establish the efficacy of Crizanlizumab in preventing acute chest syndrome.

Conclusion

There is a paucity of data regarding the potential benefit of Crizanlizumab in preventing ACS. Our case along with further case reports would raise a possible benefit of Crizanlizumab in preventing ACS. From our case, we can conclude that patients on Crizanlizumab and life-threatening complications (e.g. acute chest syndrome) might benefit from the continuation of Crizanlizumab beyond the standard 14-dose schedule.

Consent

Written informed consent was obtained from our patient to allow the publication of information.

Ethics statement

The case was approved by Hamad Medical Corporation Research Center with reference number MRC-04-23-135. Open Access funding provided by the Qatar National Library.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

We thank Qatar National Library for funding this article.