CD19-directed chimeric antigen receptor T-cell therapy: what can we learn from the haematologist?

WHAT IS ALREADY KNOWN ON THIS TOPIC

Chimeric antigen receptor (CAR) T -cell therapy is a revolutionary cellular therapy that modifies patient’s T-cells to target and eliminate specific cells. Originally developed for the treatment of haematological malignancies, CAR T-cell therapy is now explored as a potential therapy for autoimmune diseases.

WHAT THIS STUDY ADDS

We discuss the clinical experience of hematologists in managing patients during their CAR T-cell therapy journey, including patient selection, timing, potential side effects, and follow up.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

These insights are relevant for advancing the use of CAR T-cell therapy in patients with auto-immune disease.

Introduction

Chimeric antigen receptor (CAR) T-cell therapy, targeting CD19, has revolutionised therapy for patients with a haematological malignancy, such as B-cell lymphoma and B-acute lymphoblastic leukaemia (B-ALL), it is estimated that tens of thousands patients have been treated with CAR T-cell therapy to date. 1 , 8 This novel treatment option involves T-cells that are genetically engineered to express a receptor that recognises CD19, binds CD19 on B-cells and becomes activated and then selectively eliminates CD19-positive B-cells. The success of this therapy was most evident in patients with relapsed refractory (R/R) large B-cell lymphoma (LBCL) and B-ALL, where prior therapies failed and CD19 CAR T-cells showed the potential to induce complete remission and possibly even cure. 1 , 10 To date, therapeutic applications are expanding to other areas and small studies have provided encouraging evidence of its efficacy in patients with severe, treatment-refractory autoimmune diseases which are characterised by an autoreactive B-cell and/or plasmablast-mediated pathophysiology. A recent case series of five patients with severe SLE and multiple organ involvement, who had not responded to at least five other immunosuppressants, were treated with CD19 CAR T-cell therapy. 11 This resulted in deep B-cell depletion and clinical remission with seroconversion of autoantibodies in all patients. 11 Therapy-free remission even persisted after B-cell recovery. In line with these results, a small trial with eight patients with SLE, four with systemic sclerosis and three with myositis also demonstrated encouraging results. With a median follow-up of 15 months, all patients with SLE and myositis had clinical remission, and all patients with systemic sclerosis showed a clear reduction in disease activity and only minimal toxicity was observed. 12 CD19 CAR T-cell therapy appears to ’reset’ the immune system by depleting autoreactive B cells and potentially offers long-term remission from disease activity. Although these results are promising, given the limited treatment options some patients have, larger clinical trials are needed to fully understand long-term efficacy and safety. Table 1 provides an overview of registered clinical trials investigating various CAR T-cell therapies for the treatment of adults with SLE and other autoimmune diseases, highlighting the growing and expanding field of research in this area. Furthermore, a novel advancement is the use of chimeric antigen antibody receptor T-cell therapy, which are T cells tailored to eliminate specific autoantibody-producing B cells.

Haematologists have developed expertise in managing patients during their CAR T-cell therapy journey, including patient selection, timing, follow-up and mitigation of potentially severe side effects such as cytokine release syndrome (CRS), immune cell-associated neurotoxicity syndrome (ICANS) and infections. These insights may help the development of CAR T-cell therapy in the context of autoimmune diseases, where the therapeutic goal shifts from eliminating malignant cells to a reset of the immune system.

What are CAR T-cells?

CAR T-cells are T-cells that are transduced ex vivo with a lentivirus or retrovirus encoding a receptor which consists of the variable part of an antibody recognising a surface antigen coupled to the intracellular signalling part of the CD3zeta chain. First-generation CAR T-cells contained a single intracellular domain which provided activation, proliferation however was limited and the lifespan was short. Second-generation CAR constructs also contain a costimulatory signal, usually either CD28 or 4-1BB. This approach significantly enhanced proliferation, cytotoxicity and persistence in vivo. CD19-directed CAR T-cells were the first to be tested in large pivotal trials in several B-cell malignancies, such as B-acute lymphoblastic leukaemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia, followed by B-cell maturation antigen (BCMA)-directed CAR T-cells which have shown great promise in multiple myeloma. 1 , 1013 14 For this review, we will focus on CD19-directed CAR T-cells. Currently, four products (axicabtagene ciloleucel (axicel) Yescarta, tisagenlecleucel (tisacel), Kymriah, lisocabtagene maraleucel (lisocel) Breyanzy and brexucabtagene ciloleucel (brexucel) Tecuartus) are Food and Drug Administration (FDA) and European Medicine Agency (EMA) approved for B-cell NHL and/or B-ALL. Their main characteristics are shown in table 2 and figure 1 .

What are the main results in lymphoma?

Results of the pivotal phase II trials in different types of B-NHL are summarised in table 3 . In general, overall response and complete response rates are high, with obtaining a complete remission after infusion being of great importance. Cross-trial comparison of results is difficult given the differences in patient baseline characteristics, CAR T-cell dose and use of bridging therapy. Whereas the use of axicel is associated with higher response rates than tisacel, it is also carries a higher risk of (severe) ICANS. 15

What are the main results in acute lymphoblastic leukemia?

Tisacel is FDA and EMA approved for children and young adults ≤25 years, based on the pivotal phase II ELIANA trial. 6 In this phase 1–2a study, 75 patients received a single infusion of tisacel with an overall response rate (ORR) of 81% and all responding patients were negative for minimal residual disease. At a median follow-up of 38 months, the median event-free survival (EFS) was 24 months, and the median overall survival was not reached. At 3 years, the EFS was 44% (95% CI 31% to 57%) with an overall survival (OS) of 63% (95% CI 51% to 73%). Some of the patients were consolidated in remission with an allogeneic stem cell transplantation (alloSCT).

More recently, brexucel was approved for adult patients with B-ALL, based on the ZUMA-3 trial. In this phase II trial, 65 adult patients were treated with an ORR of 71% and a CR rate of 56%, a median relapse-free survival of 11.6 months and a median OS of 18.2 months. 8 Of those patients, 18% subsequently underwent a consolidation therapy with an alloSCT.

What are the main new developments in B-cell-directed CAR T-cell therapy?

To date, CAR T-cell treatment is studied for earlier lines of treatment and in other haematological malignancies. Other several new developments should be mentioned. First, non-viral transduction methods are being explored, such as Sleeping Beauty transposon and Piggy-bac technologies. A transposon is a jumping gene, a mobile genetic element, both technologies offer an alternative manner of gene editing using with unique strengths in cargo size, precision and stability and also possible risks. 16 Second, instead of autologous CAR T-cells, allogeneic CAR T-cells can be used, which offer the advantage of being available off-the-shelf, but also carry additional risks such as graft versus host disease (GVHD). 17 To avoid GVHD, several risk mitigation strategies are being used, such as knocking out the endogenous T-cell receptor. Third, to decrease the risk of antigen escape, which is one of the causes of failure of CAR T-cell therapies, targeting of multiple antigens, such as CD19-CD20, CD19-CD22 or even triple targeting, is being explored. 17 There are several ways to target multiple antigens, such as co-administration of transduced cells, co-transduction, tandem CARs and bicistronic CARs. Co-administration of transduced cells involves the production of two distinct CAR T-cell populations that are infused together. Co-transduction refers to the generation of CAR T-cells using CAR constructs on different vectors, resulting in some cells expressing both CARs and others expressing only one. In contrast, tandem CARs have both CAR constructs on a single vector, leading to the production of CAR T-cells with both CARs integrated into the same chimeric protein. Bicistronic CARs, however, use a single gene construct to produce two separate CAR molecules that are not part of the same chimeric protein but are expressed within the same T-cell. Finally, more rapid production platforms and point-of-care production, which can considerably shorten the vein-to-vein time between apheresis and administration of the final product, show promise in making the therapy available for patients with aggressive disease requiring rapid treatment. Thus far, none of these approaches have been tested head to head in clinical trials against registered CARs.

Patient eligibility and leukapheresis

Selecting the appropriate patient for CAR T-cell therapy is an important first step (see figure 2 for the CAR T-cell journey). For each individual patient, the potential benefit/risk ratio should be assessed based on patient and disease characteristics. A patient with an aggressive haematological malignancy may be rapidly progressive and become ineligible between leukapheresis and CAR T-cell infusion, as the production of CAR T cells takes several weeks. Also, some patients have severe comorbidities and are at high risk for CAR T-cell-related toxicities. The European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA) have summarised recommendations, also for the autoimmune disease setting. 18 19 Patients should have a good performance status and have an adequate bone marrow reserve ( table 4 ). Heart, lung, liver and kidney function should be sufficient to withstand potential complications. Importantly, there is no age limit and age should be considered in conjunction with overall fitness and comorbidities. Those with active infections or uncontrolled autoimmune diseases may not be eligible, as these conditions can exacerbate the side effects of CAR T-cell therapy. For latent hepatitis B prophylaxis is required. In patients with other malignancies requiring active treatment, a careful consideration of benefit-risk ratio is essential.

In the Netherlands, nationwide referral, eligibility assessment and data collection for CAR T-cell therapy are centralised through a national tumour board and registry called ‘Follow that CAR!’. The Dutch CAR-T tumour board was established in May 2020, coinciding with the commercial availability of the first CAR-T product, axicel, in the country. The primary goal of this initiative is to optimise (cost-)effective, high-quality CAR-T care by streamlining patient evaluation, treatment decisions and data tracking across the healthcare system. 20 Once a patient is referred, even while the outcome of the screening phase may still be pending, advanced planning for each step of the CAR T-cell therapy process starts. Baseline evaluations are conducted during the first visit to the CAR T-cell centre, and when necessary, patients are referred to specialists for assessment of specific comorbidities. The possible impact of lymphodepleting (LD) chemotherapy on reproductive function is also discussed, and fertility preservation should be considered where applicable. The doctor provides detailed information about each phase of the CAR T-cell therapy process to patients and their caregivers. It is crucial that patients understand the treatment and its potential side effects; also, it is often an intense period with multiple hospital visits in a short time. Patients have an additional appointment with the CAR T-cell nurse to repeat the information, assess informal caregiver availability and address any potential logistical challenges. We advise patients to have a caregiver 24/7 available for up to 28 days after the infusion during the outpatient follow-up period. This ongoing support is necessary due to the continued risk of (neurological) toxicities during this period. This person should be in physical proximity and could be a partner, spouse, child or friend. Patients are also required to stay close to the CAR T-centre during this period. Once deemed eligible, patients are scheduled for leukapheresis to begin the cell collection process.

Leukapheresis

To ensure optimal T-cell fitness, cancer and auto-immune disease-related treatments should be discontinued, taking into account their respective washout periods, see Greco et al for recommendations. 19 Corticosteroids and other immunosuppressive therapies are avoided in the week before apheresis, although prednisone doses of up to 10 mg/day are acceptable. Rituximab causes B-cell depletion and is therefore irrelevant for T-cell apheresis and CAR T-cell production. 19 The day before apheresis, patients undergo clinical (no signs of active infection?) and laboratory evaluations ( table 3 ) to confirm patient eligibility. Nasopharyngeal PCR is performed in patients with respiratory symptoms to rule out infections. Serological testing for hepatitis B, C, HIV, human T-lymphotropic virus-1 (HTLV-1) and syphilis must be completed within 28 days prior to leukapheresis. 18 We also perform serology tests for cytomegalovirus (CMV), Epstein-Barr virus, varicella-zoster virus (VZV) and herpes simplex virus (HSV) to assess the risk of reactivation. If a blood transfusion is required in the days before apheresis, the use of irradiated blood products is recommended. 21

Lymphodepleting chemotherapy and CAR T-cell infusion

The production time for each CAR T-cell product varies from 1 to 6 weeks, and keeping a patient with a haematological disease stable during this period can be challenging. In patients with progressive disease, we often use radiotherapy, chemotherapy or a combination to control the disease. 20 The optimal bridging strategy to guide patients toward CAR T-cell therapy is not yet clearly established. Once the CAR T-cell product is ready, we initiate LD chemotherapy. At this point, the patient must still meet the eligibility criteria (see table 3 ) and show no signs of active infection.

LD chemotherapy, typically a combination of fludarabine and cyclophosphamide, is administered over 3 days (day −5 to day −3). Dose reduction of fludarabine is advised in case of renal impairment. 19 LD chemotherapy is a crucial component of CAR T-cell therapy, as it reduces endogenous lymphocytes and creates an optimal microenvironment for CAR T-cells, enhancing engraftment. 22 Prophylaxis for nausea and vomiting should be considered. CAR T-cell infusion (day 0) is performed in-hospital via a central venous catheter (PICC line), with pre-medication given according to product-specific guidelines; corticosteroids are avoided. Patients are hospitalised for at least 7 days following the CAR T-cell infusion. Tocilizumab should be readily available on the ward for managing potential side effects. If no severe symptoms develop (see below), patients are discharged on day 7 and continue intensive outpatient monitoring until day 28 ( table 5 ). In anticipation of the growing use of CAR T-cell therapy and refined management protocols, more institutions are also developing outpatient programmes for select patient groups. 23

CRS and ICANS

CAR T-cell therapy has diverse toxicities for which early recognition and treatment is needed. It is important to have a neurologist and intensive care specialist in the CAR-T team in case of serious adverse events. CRS is the most common CAR T-related toxicity and has been reported for all products. 1 , 1013 14 However, comparing CARs in lymphoma, CARs that incorporated 4-1BB as costimulatory domain have lower toxicity rates as compared with CAR products with CD28. 1 , 324 Typically, CRS starts within 1–14 days after CAR T-cell infusion and it is triggered by the immune response that occurs when the infused CAR T-cells proliferate in vivo and start targeting cancer cells (see figure 3 ). 25 Interferon-γ is released from activated immune and malignant cells, and stimulates macrophages to produce inflammatory mediators such as interleukin (IL)-6, tumour necrosis factor-α and IL-10. The IL-6/soluble IL-6R complex activates cells lacking IL-6R through gp130. Additional cytokines such as IL-1, IL-5, IL-8 and granulocyte macrophage-colony stimulating factor (GM-CSF) further amplify the inflammatory cascade characteristic of CRS. These large number of cytokines and chemokines produced may cause fever, low blood pressure, low oxygen level and other influenza-like symptoms. Severe CRS can cause organ failure and can even be fatal. 25 CRS-related symptoms are graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading, ranging from mild fever and fatigue (grade 1) to life-threatening organ dysfunction (grade 4). CRS can be managed with close monitoring and supportive care for mild cases and with immune suppressive medication such as corticosteroids and tocilizumab for more severe cases. 26 Timing and dosing may differ for each CAR T-cell product as every product has its unique cytokine activation pattern and risks. Additionally, severity of CRS and ICANS can vary according to the underlying disease and disease burden. Generally, in autoimmune diseases, CRS and ICANS appear to be quite mild. Fever in the days to weeks following CAR T-cell infusion is most commonly attributed to CRS. However, infection and progression of the underlying disease remain top differential diagnoses. A full infectious workup is recommended, including blood cultures, urine cultures and PCR testing for respiratory viruses. Imaging, such as chest and abdominal CT scans, should also be considered. 27 Broad-spectrum antibiotics are typically started, as most patients are neutropenic due to prior LD chemotherapy. CRS is graded and commonly treated with tocilizumab (up to 4 doses of 8 mg/kg). In patients with high risk for CRS or requiring repeated doses of tocilizumab, steroids (dexamethasone 10 mg) are also commonly incorporated. 27 Dexamethasone may be escalated up to 4 times daily 10 mg or methylprednisolone in grade 3–4 CRS. Once a response is achieved, steroids are tapered within days. 26 In patients with refractory CRS to whom 2 doses of tocilizumab are already given repeat doses are generally not recommended and alternative etiologies or treatment options should be considered. 27 Anakinra (anti-interleukin 1 receptor antagonist) 100 mg intravenously every 6 hours might be added to steroid treatment. 27 However, additional exposure to immunosuppressive medications also brings a greater risk for infections.

ICANS is also an early toxicity and usually develops days after (or at the same time) with CRS. Initial symptoms are usually non-specific and may include lack of concentration and language deficits. On progression of ICANS aphasia, apraxia and somnolence may develop, but also seizures, focal motor weakness, cerebral oedema and coma have been described. 28 To diagnose, grade, monitor and treat encephalopathy, the 10-point Immune Effector Cell-Associated Encephalopathy (ICE) score is used containing questions about orientation, naming objects, following commands, writing and attention. The ICE test is done daily up to day +28 post CAR T-cell infusion. ICANS is graded and treated according the ASTCT guidelines. 26 Risk factors are patient related (high tumour burden, young age (ALL) and early onset CRS), treatment related (more at risk are CAR T products with CD28) and high baseline inflammatory markers. 28 Whether neurological comorbidities increase the risk for ICANS is not completely clear; however, CAR T-cell treatment often worsens chronic neurological conditions. 28 Dexamethasone is first-line treatment because it crosses the BBB, more severe cases with refractory ICANS receive methylprednisolone possibly combined with anakinra. 27 For isolated ICANS, tocilizumab is usually avoided because there are concerns that it could worsen neurotoxicity. 28 It is important to consult a neurologist when ICANS is suspected. When it is not rapidly resolving or is severe, other possible causes should be ruled out such as bleeding, epilepsy or infection. Neuroimaging, cerebrospinal fluid analysis (to rule out (opportunistic) infections) and electroencephalography are advised. In ICANS, the MRI may reveal non-specific signs such as T2-FLAIR hypersignals, diffusion restriction, diffuse pachymeningitis or cerebral oedema. Antiseizure prophylaxis should be considered.

CRS and ICANS are usually reversible if promptly recognised and managed. In the pivotal trials, tocilizumab and corticosteroids were reserved for severe cases. However, early and even prophylactic protocols with dexamethasone/tocilizumab/anakinra have now been tested in small cohorts. These strategies have proven effective in mitigating both CRS and ICANS, although they seem more effective for CRS. 27 Some caution remains regarding potential impacts on CAR T-cell efficacy. To date, we assess the risk of CRS and ICANS in patients prior to infusion and attempt to mitigate this risk through strategies such as reducing disease burden and/or CAR T product selection. Additionally, we opt for an early steroid protocol in older patients, those with comorbidities and/or patients with a high tumour burden to mitigate CRS and ICANS during low-grade toxicity. 29 Patients who have shown no signs of CRS or ICANS in the past 48 hours and have not required immunosuppressants may be discharged at day 7. We recommend daily temperature monitoring and ICE score until day +28. Patients are also seen weekly during the first 28 days. If lab results remain stable and the patient has no side effects, the frequency of visits is reduced in the second month. In the small case series in patients with autoimmune disease and CD19 CAR T-cell treatment, no grade 3–4 CRS and or ICANS were observed; however, monitoring and management according to the EBMT guidelines are recommended. 11 12 18 19 Thus far, no grade 3/4 CRS and/or ICANS has been described in patients with severe autoimmune disease treated with CAR T-cells.

Immune effector cell-associated haematotoxicity

Haematological toxicity is common after CAR T-cell therapy. Most cytopenias improve in weeks but in some patients they can be profound and long lasting. 30 Recently, immune effector cell-associated haematotoxicity (ICAHT) was presented as a novel toxicity category and a grading system with recommendations for its management was reported. 31 Although the exact pathophysiology is not known, haematology patients at risk usually have a poor bone marrow reserve before start of LD chemotherapy (pre-existing anaemia, leucopenia and or thrombopenia) and a high inflammatory state (high C-reactive protein (CRP) and ferritin level), resulting in a high CAR-HEMATOX score. 30 31 Additionally, type of previous chemotherapy, bone marrow infiltration, type of disease (ALL>lymphoma) and type of CAR T-cell product (CD28>41BB) add to the risk profile for ICAHT. 31 In high-risk patients, early (day+2) start of growth factor support is recommended. However, alternative diagnoses should be considered such as (viral) infections or reactivations (CMV), myelosuppressive medication, bone marrow disease, deficiencies and immune effector cell-associated hemophagocytic lymphohistocytosis-like syndrome. 31 Most patients eventually recover from ICAHT. In severe prolonged ICAHT, a stem cell boost is optional, if stem cells were collected before CAR T-cell therapy. Although only small numbers of patients with auto-immune disease have been treated with CAR T-cell therapy, severe ICAHT has thus far not been described. 19 Possibly, the younger age of the patients, a better bone marrow reserve and the use of a 4-1BB CAR T-cell products play a role. As G-CSF may cause a flare of autoimmune disease, prophylactic G-CSF is not recommended. 19

Infections and preventive measures

Infections are a well-known complication post CAR T-cell therapy, and most recipients have a plethora of factors that may contribute to an increased infection risk. Their haematopoietic reserve may be reduced due to previous lines of (chemo) therapy resulting in neutropenia, lymphopenia (both B-cells and T-cells) and low immunoglobulin levels. In addition, disease burden and baseline inflammatory state are associated with an increased risk for infection. 32 A recent meta-analysis reported that 45% of haematological CAR T-cell patients experienced an infection post-treatment, with 25% of these being a severe infection (need for hospital admission/intravenous antibiotics). 33 The most commonly observed were bacterial infections (Gram-negative and Gram-positive bloodstream infections) and viral infections (primarily upper respiratory tract infections). Additionally, reactivations of HSV, VZV and CMV were reported. Invasive candidiasis/yeast infections were uncommon. Patients receiving BCMA CAR T-cell therapy had the highest rate of infection, which may be attributed to high rates of previous autologous stem cell transplantation and significant hypogammaglobulinaemia. 33 The infection risk rates for R/R CAR T-cell patients compared with those who receive CAR T-cell treatment in first line are not well established. That infections have emerged as one of the most critical side effects was also demonstrated by Cordas Dos Santos et al . 34 They reported non-relapse mortality rates in CAR T-cell therapy varying from 5.7% to 10.6%, depending on type of CAR T treatment and underlying disease. 34 More than half of non-relapsed reported deaths were attributed to infections, among the deaths with a reported pathogen, a substantial number was due to COVID-19 (53%) and, although rare post CAR T, fungal infections (19%). To date, antimicrobial prophylaxis, intravenous immunoglobulin, post cellular therapy vaccinations and early antimicrobial therapy are used to prevent severe infection. 35 International guidelines advise to screen patients for hepatitis B and C, HIV, CMV, HTLV1 and syphilis, on indication also for tuberculosis, and strongyloidiasis. HSV/VZV prophylaxis with valacyclovir is recommended for at least 6 months post infusion. 35 Also, prophylaxis for pneumocystis infection with trimethoprim/sulfamethoxazole is advised to be initiated and continued for at least 6 months, as well as entecavir for patients with latent hepatitis B. Other antimicrobial prophylaxes are not standardly recommended, also not during the phase of neutropenia. Vaccinations for pneumococcus, recombinant zoster vaccine, influenza and COVID vaccination are recommended post CAR T-cell treatment and may start after at least 3 months post CAR T therapy, preferably in patients with demonstrated immune reconstitution (defined as CD4 >0.2×10 9 /L, CD19 or CD20 positive B cells >0.2×10 9 /L). 35 COVID-19 vaccination relies not only on antibody response but also on T-cell-mediated immunity, and therefore, B-cell aplasia is not considered a contraindication. Additionally, no specific T-cell threshold has been defined. 19 35 Additional research is needed to identify patients who would benefit the most, to study the duration of antimicrobial treatment, the benefit of IVIG, and the optimal timing for vaccinations pre or post CAR T-cell therapy. In patients with autoimmune disease, it was shown that antibody levels induced by vaccines pre CAR T-cell therapy remained stable for months after CAR T-cell treatment. However, it is also important to note that also these CAR T-cell patients may have impaired serological responses to new vaccines.

Secondary malignancies?

In November 2023, the FDA issued a warning regarding a potential risk of T-cell malignancies in patients treated with CAR T-cell therapy. 36 This warning was based on 20 reports of T-cell malignancies, including one confirmed case where the CAR transgene was detected in the T-cell clone. However, with over 34 000 CAR T-cell-treated patients, the overall risk appears to be quite low. 36 A study by researchers at the University of Pennsylvania examined their cohort of 449 patients treated with commercial CAR T-cell therapy for secondary malignancy. They found solid secondary malignancies in 2.7% of the patients and haematological secondary malignancies in 1.1% of the patients, including a single case of T-cell lymphoma. 37 A recent analysis of the FDA’s Adverse Event Reporting System (FAERS) reported secondary cancers in 4.3% of the CAR T-cell-related adverse event reports, T-cell lymphomas were reported in 0.1%. Most common secondary malignancies were leukaemia (2.7%) and skin cancer (0.4%). 38 While the risk of secondary malignancies appears to be rare, it is also important to realise that most CAR T-cell patients have a history of multiple prior treatment lines with (high-dose) chemotherapy, which may contribute to the risk of secondary cancers. The exact role of CAR T-cell therapy in this context is still being investigated, life-long monitoring is advised. 39

Discussion

CAR T-cell therapy is a relatively new technology that has demonstrated enormous potential in the treatment of patients with haematological malignancies. The therapeutic field continues to expand and the experience in haematology and possible new CAR T-cell therapy indications in autoimmune diseases brings different disciplines together. In this paper, we summarised our experiences and insights in CAR T-cell therapy, focusing on patient selection, timing, possible side effects, their treatment and follow-up. At this moment, long-term outcomes of efficacy and safety for haematology patients treated with CAR T cell therapy are very good and outweigh the associated risks. However, as this treatment is expanding beyond the relapsed refractory setting to a much broader patient population, the balance may be different. Dedicated long-term follow-up for CAR T-cell patients is therefore essential. Small studies in patients with severe treatment refractory autoimmune disease have shown very promising results, including therapy-free interval. More studies are needed to position this therapy within current treatment guidelines.

Footnotes

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.

Patient consent for publication: Not applicable.

Ethics approval: Not applicable.

Provenance and peer review: Commissioned; externally peer reviewed.

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