How to manage prolonged immune effector cell-associated hematotoxicity (ICAHT) related to BCMA-directed myeloma therapy

KEYWORDS:

• ICAHT
• cytopenia
• stem cell boost
• CAR T

1. Introduction

B-cell maturation antigen (BCMA)-directed therapies including chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (BsAbs) represent promising treatment options for patients with relapsed refractory multiple myeloma (RRMM) [1–5]. BCMA is cell surface protein that regulates the life cycle of B-cells and is ubiquitously overexpressed on malignant plasma cells allowing tumor survival and proliferation, thus making BCMA an ideal target for treatment of RRMM [1,2]. Idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel), teclistamab, and elranatamab are the current BCMA-directed immune effector cell therapies approved by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treatment of patients with RRMM [1–4].

Common toxicities associated with BCMA-directed therapies include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hematotoxicity (ICAHT), and infections [6,7]. While treatment algorithms for CRS and ICANS have been well described, risk stratification and management of ICAHT are areas of ongoing investigation. In the pivotal trials and real-world studies of both ide-cel and cilta-cel, ICAHT (prolonged and profound cytopenias) occurred in up to 95% of patients and persisted after day 30 in over half of patients [1,2]. Infections due to prolonged ICAHT are also common and persist in many patients receiving BMCA-directed CAR T-cell therapy [1,2,6–8].

While the concept of ICAHT and its grading are well established following CAR T, data for ICAHT and infections due to BCMA-directed BsAbs are less mature. However, ongoing real-world data investigating BCMA-directed BsAbs outcomes confirm ICAHT, hypogammaglobulinemia, and infections commonly occur [9,10]. Until ICAHT grading can be validated for BsAbs, clinicians should continue to utilize the Common Terminology Criteria for Adverse Events (CTCAE).

Early ICAHT is defined as cytopenias that occur within 30 days of initiation of BCMA-directed therapy [6,7]. Early ICAHT after CAR T is typically severe (grade 3–4) with neutrophils being the most commonly affected lineage [6–8,11]. For patients undergoing CAR T-cell therapy, ICAHT typically occurs within 14 days due to lymphodepleting chemotherapy and most patients experience rapid count recovery by day 21 with varying median times to count recovery depending on the product [6,7]. After blood count recovery, some patients experience biphasic cytopenias with a second drop in counts between days 21 and 30 after cell infusion [6]. Patients receiving BsAbs may also experience early ICAHT which may be related to the number of prior lines of therapy at the time of initiation or baseline immune dysfunction due to heavy burden of disease [12].

Late ICAHT is described as prolonged cytopenias lasting longer than 30 days after BCMA-directed therapy initiation and may be associated with hypoplastic bone marrow after CAR T-cell therapy, CRS, use of tocilizumab and/or steroids, or the ongoing nature of treatment with BsAbs as these are typically administered weekly or biweekly until disease progression [8]. With the increasing adoption of BCMA-directed therapy, management of ICAHT is important for clinicians to understand. Here, we provide an overview of ICAHT and outline expert opinions on management of this common toxicity.

2. Risk factors and risk stratification

A plethora of factors can be related to the development of ICAHT with BCMA-directed therapy. Underlying myeloma, high baseline marrow plasma cell burden (≥50%) and circulating plasma cells have been associated with development of severe ICAHT after CAR T [8]. Prior therapy including alkylating agents, stem cell transplantation, or bridging therapy can damage and suppress bone marrow reserve which may be compounded by receipt of BCMA-directed therapy. Elevated inflammatory markers such as serum ferritin and C-reactive protein (CRP), CRS and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) have also been associated with ICAHT [6]. Age and/or frailty may also be related to prolonged ICAHT although several studies have shown there does not appear to be significant differences in safety outcomes in older/frail patients receiving BCMA-directed therapy [13]. Alternative etiologies for prolonged cytopenias including clonal hematopoiesis of undetermined potential (CHIP) and more importantly secondary malignancies including myelodysplastic syndrome/acute myeloid leukemia should also be considered.

The CAR-HEMATOX scoring system was developed by the German Lymphoma Alliance (GLA) to identify lymphoma patients who may be at risk of developing profound ICAHT and infections by using baseline blood counts, C-reactive protein (CRP), and ferritin levels [6,14]. This system has since been validated in patients with myeloma and may be a useful prognostic tool to risk stratify patients who are receiving BCMA-directed CAR T-cell therapy [14]. Patients with high CAR-HEMATOX scores are at high risk of severe pancytopenia, CRS, ICANS, and infections following CAR T. A high score could serve as an alert to clinicians to utilize earlier and broader prophylactic measures for both CRS, ICANS, and infections. Some clinicians may even choose to opt for alternative therapy to CAR T based on a high CAR-HEMATOX score in combination with the recently validated myCARe system, a prognostic utility to determine outcomes for patients receiving BCMA-directed CAR T [14,15].

2.1. Management of early ICAHT

The management of early ICAHT after CAR T involves support of the affected cell line with packed red blood cell (PRBC) transfusions, platelet transfusions, growth factor support, and infection prophylaxis (Table 1) [6–8]. Institutional practices regarding thresholds for transfusions are generally derived from guidelines used for hematopoietic stem-cell transplant supportive care protocols. PRBC and platelet transfusions administered per these institutional standards can temporarily boost hemoglobin and platelet counts but consideration should be given to avoid long-term complications such as iron overload and platelet refractoriness.

Table 1. Management of immune effector cell-associated hematotoxicity.

	Intervention	Details
Anemia	pRBC transfusions	–Hb < 7 for clinically stable –Hb < 8 for clinically unstable
Thrombocytopenia	Platelet transfusions TPO agonists	–PLT <10k for clinically stable –PLT <20k for clinically unstable –Consider TPO agonists for thrombocytopenia requiring frequent transfusions or bleeding complications
Neutropenia	G-CSF Stem-cell boost	–Prophylaxis: for patients at high-risk ANC <1000 μL –Avoid use during period with risk of exacerbation of CRS –Consider stem-cell boost for prolonged or refractory neutropenia
Antiviral (HSV/VZV)	Acyclovir or valacyclovir	–Consider at time of treatment initiation –Continue until one year post CAR T –While on BsAb and for three months after discontinuation
CMV	No prophylaxis	Monitor viral load by PCR if CMV suspected or patient at high risk
Antibacterial	Ciprofloxacin or levofloxacin	Initiate when ANC <500 μL or per institutional standards
Yeast/Mold	Fluconazole or posaconazole	Initiate when ANC <500 μL or per institutional standards
PJP	Sulfamethoxazole/trimethoprim or pentamidine or atovaquone	At therapy initiation or per institutional standards and continue until CD4 ≥ 200 μL
Hypogammaglobulinemia	IVIG 0.4 g/kg every 4 weeks	Consider if IgG <400 mg/dL or recurrent infections
Vaccinations	Pneumococcal, COVID-19, influenza, RSV	Per CDC or institutional guidelines

Key: pRBC, packed red blood cells; TPO, thrombopoietin receptor; G-CSF, growth colony stimulating factor; ANC, absolute neutrophil count; HSV, herpes simplex virus; VZV, varicella zoster virus; PJP, Pneumocystis jirovecii pneumonia; CMV, cytomegalovirus.

Granulocyte-colony stimulating factors (G-CSF) such as filgrastim are considered safe and effective to decrease rates of neutropenia and subsequent infections [16]. G-CSF may also be used as early as day + 2 post CAR T-cell therapy for patients at high risk for severe ICAHT, although optimal timing of initiation is an area of active investigation [6]. For patients undergoing CAR T, we recommend G-CSF for grade ≥ 3 neutropenia starting at day 14 after cell infusion. For BsAbs, we recommend considering G-CSF for grade ≥ 3 neutropenia with caution to avoid during periods of CRS due to potential exacerbation of CRS [12].

Infection prophylaxis is paramount for patients receiving BCMA-directed therapy (Table 1). For patients receiving CAR T, most clinicians use prophylaxis protocols which are similar to those used in patients undergoing hematopoietic stem-cell transplantation. Antiviral prophylaxis should be initiated at day 0 and continue for at least 12 months after CAR T infusion or indefinitely with receiving BsAb therapy and for 3 months after discontinuation. Antibacterial and antifungal prophylaxis are started as early as day 0 and are continued until ANC >500 μL. Pneumocystis jirovecii pneumonia (PJP) prophylaxis with pentamidine [those with sulfa allergies, cytopenia, renal impairment] or sulfamethoxazole/trimethoprim should be considered within 30 days of cell infusion and should continue until CD4+ T-cell count improves above 200 μL [6,7]. Patients should also receive vaccinations according to institutional protocols.

For patients receiving BCMA-direct BsAbs, we recommend consideration of antiviral and PJP prophylaxis at initiation and for the duration of treatment [12]. Antifungal and antibacterial prophylaxis should be considered in patients with prolonged neutropenia, those on prolonged corticosteroids, and those with history of recurrent infections (Table 1) [12].

2.2. Management of prolonged ICAHT

Prolonged neutropenia and infections after CAR T or during treatment with BsAbs may necessitate use of G-CSF; however, caution is advised to avoid use during periods of CRS given concerns for CRS exacerbation [16]. We recommend considering non-pegylated G-CSF for grade ≥ 3 neutropenia. Less frequent (biweekly and monthly) teclistamab dosing has also been shown to decrease the incidence of infections while maintaining efficacy and should be considered as a strategy to mitigate infection risk especially considering the risk of infection increases with the chronic nature of BsAb therapy [3,16]. Patients receiving BsAbs should be frequently monitored and encouraged to report any sign of symptoms of infection.

Thrombopoietin receptor (TPO) agonists, eltrombopag, or romiplostim have been shown to improve thrombocytopenia in patients with prolonged ICAHT in retrospective studies and may be considered for thrombocytopenia refractory to transfusions; however, prospective data are needed to confirm these results [17]. For patients receiving CAR T, we recommend considering a TPO agonist if patients remain transfusion-dependent with platelets < 30 k/cumm at day 21 post cell infusion.

Hypogammaglobulinemia and infections due to plasma cell depletion are important considerations for patients receiving BCMA-directed therapies. Prolonged hypogammaglobulinemia may predispose patients to viral, bacterial, or fungal infections. Hypogammaglobulinemia post-CAR T is transient and typically resolves within 6 months of infusion; however, persistent hypogammaglobulinemia beyond 6 months is not uncommon. In pivotal trials of BCMA CAR T, hypogammaglobulinemia and infections occurred most often within 8 weeks to 6 months after infusion and upward of 60% of the patients in the trials received IVIG [1,2]. Hypogammaglobulinemia with BsAbs worsens over time due to the ongoing nature of treatment [8,16,18]. For patients receiving CAR T, there are limited data to support prophylactic IVIG use; however, we recommend monitoring IgG levels monthly and consideration of IVIG supplementation in patients with recurrent infections and prophylactically to maintain levels ≥400 mg/dL [18]. It will be important for future prospective trials to incorporate the use of prophylactic IVIG to determine the true magnitude of infection prevention.

For patients receiving BsAbs, nearly three-quarters of patients experienced hypogammaglobulinemia in the MajesTEC-1 trial [16]. Evidence for use of prophylactic IVIG with BsAbs has been described; however, infections rates remain an area of concern [10,16,19]. In one retrospective study by Lancman and colleagues, all patients treated with BCMA-directed BsAb monotherapy experienced hypogammaglobulinemia, but intravenous immune globulin (IVIG) supplementation reduced serious infections by 90% when compared to those patients who did not receive IVIG [19]. We recommend monitoring IgG levels monthly and consideration of IVIG supplementation in patients with recurrent infections or prophylactically to maintain levels ≥400 mg/dL.

Infusion of previously collected CD34+ hematopoietic stem cells, also known as stem cell boosts, have been shown to be an effective method to alleviate prolonged ICAHT in patients undergoing CAR T-cell therapy [20]. One study in patients post-BCMA CAR T reported the median time for neutrophil, platelet, and hemoglobin recovery was 14 (range 9–39), 17 (range 12–39), and 23 (range 6–34) days after the infusion, respectively [20]. All but one patient recovered counts after stem-cell infusion. Stem-cell boosts require storage and acquisition of previous stem cells which may not be available for some patients. Optimal timing and dosing of stem-cell boost also remain unclear due to the retrospective nature of the available studies. Given the recent discussion regarding post-CAR T malignancies, consideration should be given to alternative etiologies for prolonged cytopenias including disease relapse and more importantly secondary malignancies (myelodysplastic syndrome/acute myeloid leukemia/T-cell malignancies) in heavily pretreated patients before proceeding with hematopoietic stem-cell boost. Although there are no published data regarding the use of stem-cell boosts in patients receiving BsAbs, boosts were well-tolerated post CAR T and their use should not preclude patients from receiving BCMA-directed BsAb.

3. Conclusion

Although the introduction of BCMA-directed therapies has transformed the way clinicians manage patients with RRMM, these novel therapies carry the burden of unique toxicities. Although ICAHT occurs in the majority of patients receiving BCMA-directed therapy, many of our current prevention and treatment strategies rely on retrospective evidence or individualized institutional protocols. Prospective clinical trials are needed to better understand the magnitude of benefit our current strategies offer. As these novel therapies become incorporated into community practice and move into earlier lines of treatment, it will be paramount for clinicians to understand prevention and management of ICAHT.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.