Neutropenic events associated with new anticancer treatments, from pathophysiology to practice: a scoping review-NEW Group (Neutropenic Events Working Group).

Introduction

Along with surgery, radiotherapy and hormonal therapy, cytotoxic chemotherapy has long been one of the pillars of cancer treatment [ 1 ]. Advances in knowledge of immunology, genomics and molecular biology have led to the emergence of new therapies such as immunotherapy and targeted therapies, whose effectiveness has made it possible to reduce the use of chemotherapy and even, in some situations, to offer effective chemotherapy-free treatments [ 2 , 3 ].

The use of chemotherapy is largely limited by its toxic effects including febrile neutropenia, a potentially life-threatening complication that often leads to hospitalization, dose reduction, or even postponement of chemotherapy courses [ 4 ]. Neutropenia and neutropenic events definition refer to the Common Terminology Criteria for Adverse Events (CTCAE):

Grade 1, < Lower limit of normal—1500/mm 3 (1.5 × 10. 9 /L)

Grade 2, < 1500–1000/mm 3 (1.5–1.0 × 10. 9 /L)

Grade 3, < 1000–500/mm 3 (1.0–0.5 × 10. 9 /L)

Grade 4, < 500/mm 3 (0.5 × 10 9 /L).

Neutropenia is a well-recognized complication of chemotherapy, and is associated with an increased risk of infection, febrile neutropenia (FN), and can lead to mortality [ 5 – 8 ].

The incidence of neutropenia in the context of chemotherapy has been the subject of extensive research. It has been demonstrated that lower neutrophil counts are associated with a heightened risk of infection and an increased likelihood of death from infection. Febrile neutropenia (FN) is defined as an oral temperature of > 38.3 °C or two consecutive readings of > 38.0 °C for 2 h and an absolute neutrophil count (ANC) < 0.5 × 10 9 /l, or expected to fall below 0.5 × 10 9 /l (7) . International guidelines have been established to facilitate the management of FN, including the use of granulocyte colony-stimulating factor (G-CSF) in certain situations 5,6,7,8 . There is a clear relationship between the severity of neutropenia and the intensity of chemotherapy; the different chemotherapy regimens are classified as producing a high risk (> 20%), an intermediate risk (10%–20%) or a low risk (< 10%) of FN. In case of chemotherapy-induced febrile neutropenia, a primary prophylaxis with G-CSF is recommended by international guidelines (ASCO, ESMO, and EORTC) when the risk of febrile neutropenia is high (> 20%), or moderate (10–20% in patients with individual risk factors for FN (elderly (age ≥ 65 years) or comorbid patients)) 6,7,8 . However, neutropenia and neutropenic events associated with new anticancer drugs are less well-studied complications. There is a lack of data with neutropenia associated with novel anticancer agents (NAN), requiring a deeper understanding of the biological pathophysiology, pathways involved, and strategies to manage this complication [ 6 ]. This is particularly relevant in the case of older patients with reduced physiological reserves, given that the aging process affects the hematopoietic system and the production and functionality of neutrophils [ 9 ].

In this context, a Neutropenic Events multidisciplinary Working group (NEW) including hematologists, oncologists, geriatricians was gathered with the goal to compile latest available data on the pathophysiology, epidemiology, and management of NAN occurring during treatment with any of the following anti-cancer treatment: CDK4/6 inhibitors, PARP inhibitors, immune checkpoint inhibitors (anti-PD1, anti-PDL1 and anti-CTLA4), anti-CD20 and CAR T-cells. To this end, a scoping review was conducted to identify the available evidence on the occurrence and management of NAN, as well as gaps in knowledge in this area that may affect medical practice. The NEW Group identified the need to develop a new and modern approach for preserving the hematopoietic system in the context of chronicity, aging, comorbidity and multiple lines of treatment, such as chemoprotective agents or senolytics [ 4 , 10 , 11 ]. A specific focus was given on older patients, as they are at a higher risk of NAN. For each molecule of interest, recommendations for NAN management were suggested by the NEW Group following international guidelines if available or based on current evidence in the absence of international guidelines.

Cdk4/6 inhibitors

Cdk4/6 inhibitors mechanisms of action and effects on neutrophil lineage

Cyclin-dependent kinases (CDKs) are a family of enzymes that catalyze protein phosphorylation, upon binding of regulatory partners known as cyclins, during cell cycle progression and transcriptional regulation. More specifically, the G1 to S phase transition is controlled by CDK4 and CDK6 in conjugation with D1, D2, and D3 cyclins [ 2 ]. CDK4/CDK6 phosphorylate Rb proteins and CDK2 further phosphorylates Rb, blocking E2F binding to Rb and allowing the cell to enter in S-phase (Supplementary, Figure S1 ). Activation of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) have been implicated in cell proliferation and resistance to endocrine therapy in breast cancer, leading to the development of small molecule inhibitors (CDK4/6i—ciclibs). Ciclibs were shown to induce a G1 cell cycle arrest in tumor cells, indicating potential clinical applications (Supplementary, Figure S1 ).

In clinical trials, these molecules, in association with endocrine therapy, doubled the progression-free survival of estrogen receptor-positive/HER2-negative metastatic breast cancers, leading to their approval in the clinics, and their use as a gold standard in association with endocrine therapy in the current guidelines, and active research in other cancer types [ 12 ]. Three compounds, palbociclib, ribociclib, and abemaciclib, are currently available in breast cancer treatment, with distinct pharmacological targets and safety profiles [ 13 ], distinct from classical chemotherapy side effects. Ciclibs may cause on-target effects in non-cancer cells, such as cell cycle arrest in hematopoietic stem cells, which can result in reversible neutropenia.

Neutropenia associated with cdk4/6 inhibitors, data from clinical trials

Regarding neutropenia occurrence, in clinical studies, palbociclib, ribociclib and, to a lesser extend abemaciclib, were associated with a high frequency of neutropenic events [ 13 , 14 ]. However, in contrast to cytotoxic chemotherapy, that induces DNA damage and apoptosis of proliferating neutrophil precursors, ciclibs cause reversible cell cycle arrest but no death of proliferating neutrophil precursor cells (on-target effect of CDKs inhibition) [ 15 ]. This fundamental difference is associated, in the clinics, with extremely low rates of febrile neutropenia, below 3% in the pivotal clinical trials [ 14 ], however grade 3/4 neutropenic events are reported with frequencies ranging from 22% (abemaciclib) to 65% (palbociclib).

The induction of transient and reversible G1 cell cycle arrest of murine and human hematopoietic stem and progenitor cells (HSPCs) prior to chemotherapy with the use of CDK4/6 inhibitors has even been demonstrated to protect these HSPCs from chemotherapy-induced exhaustion [ 16 ].. Trilaciclib, a CDK4/6 inhibitor, has been approved by the United States Food and Drug Administration (FDA) in 2021 to reduce the frequency of chemotherapy-induced bone marrow suppression in adults receiving platinum and etoposide-based chemotherapy for extensive-stage of small cell lung cancer following the results of randomized trials [ 17 – 19 ]. Encouraging results were also reported in metastatic triple-negative breast cancer patients receiving a carboplatin – gemcitabine-based doublet [ 20 ].

Clinical risk factors with grade 3/4 neutropenia associated with CDK4/6 inhibitors have been reported in the literature. Probably due to its more pleiotropic anti-CDK activity, abemaciclib is associated with a lower frequency of high-grade neutropenia compared to ribociclib and palbociclib [ 13 ]. Recent bone irradiation due to bone metastasis has been reported to increase neutropenia frequency under palbociclib treatment [ 21 ], as well as high body-mass index, or statin use [ 22 ]. Baseline neutrophil count also increases the risk of high-grade neutropenia, as well as circulating palbociclib levels [ 23 ]. These pharmacokinetic parameters are modified by drug-drug interactions, especially with CYP3A4/P-glycoprotein inhibitors which increase palbociclib concentration by 25% and antacids that reduce palbociclib exposure by 20% [ 23 ]. Recent results from pharmacogenomics evaluations reported, in a series of 230 patients, an impact of genetic polymorphisms in ABCB1, an ADME responsible for multiple drugs absorption, distribution, metabolism, and elimination on grade 3/4 neutropenia at day 14 of the first treatment cycle [ 24 ].

Even if all these parameters are reported to modify the incidence of high-grade neutropenia, none have been associated to date with an increase in febrile neutropenia rate, probably due to the scarcity of this side effect under CDK4/6 inhibitors [ 14 ].

Neutropenia associated with cdk4/6 inhibitors, management and recommendations from the NEW group

Considering this extremely low rate of febrile neutropenia under CDK4/6 inhibitors [ 14 ] and the fundamental differences in physiopathology of the medullary toxicity, management of neutropenia under CDK4/6 inhibitors relies mainly on dose interruption and dose modification of the CDK4/6 inhibitors while continuing the endocrine agents, as per molecule labelling. In the rare situation of febrile neutropenia, the CDK4/6 inhibitors should be withheld and resumed at the next lower dose level. In cases of pancytopenia, bone marrow biopsy should be considered to rule out a bone marrow infiltration.

Concerning NEW Group recommendations, there are currently no published data on G-CSF use, primary or secondary, in the setting of neutropenia under CDK4/6 inhibitors. Considering the mechanism of action of these 2 drug families, physiopathology and clinical evidence, G-CSF agents should not be considered for the management of neutropenia induced by CDK4/6 inhibitors.

PARP inhibitors

PARP inhibitors mechanisms of action and effects on neutrophil lineage

Poly(ADP-ribose) polymerase (PARP) enzymes are a superfamily of enzymes involved in the DNA repair process. In the event of single-strand DNA damage, PARP enzymes are responsible for the synthesis of ADP-ribose polymer [ 25 ]. This polymer is then bound to the damaged DNA and acts as a signaling and chromatin-relaxing agent, allowing the repair process to take place [ 26 , 27 ].

In the presence of PARP inhibitors (PARPi), the PARP1 enzyme is trapped on damaged DNA, preventing this repair process and forcing the cell to recruit other repair mechanisms (such as homologous recombination—HR) to get round this blockage. HR-deficient cells cannot overcome PARPi’s effects, leading to apoptosis (Supplementary, Figure S2 ). The term “synthetic death” has been coined to describe this targeted phenomenon [ 28 , 29 ].

Breast cancer (BRCA) 1/2 are key genes involved in HR. PARPi were initially developed to enhance the cytotoxic effects of conventional anti-cancer therapies in BRCA 1/2-deficient tumors. The first trials of olaparib (first-in-class oral PARPi) in germline BRCA 1/2-mutated ovarian cancer were impressive and led to subsequent trials in breast, prostate and pancreatic cancer [ 30 , 31 ]. Since then, the efficacy of PARPi has been demonstrated in a wider range of cancers, including HR-proficient cancers, leading to subsequent Food and Drug Agency (FDA) approval in multiple indications [ 32 – 35 ].

The overall toxicity profile of PARPi is satisfactory, but the various clinical trials have revealed marked hematotoxicity, which can affect all lineages, especially neutrophils [ 36 ].

Data from fundamental work on PARPi might have suggested such toxicity on hematopoietic tissue.

Indeed, it has been shown in a mouse model that when haematopoietic stem cells (HSCs) are deficient in the base excision repair (BER) mechanism—as mediated by PARP inhibition—neutrophil production and proliferation is severely impaired compared to BER competent HSCs [ 37 ]. When HSC are exposed to DNA damage, such as radiation, this difference in neutrophil production is even more significant, mainly due to increased oxidative stress/TP-53 mediated apoptosis. One way for HSC to escape apoptosis seems to be through TP-53 inactivation. Therefore, it has been suggested that TP-53-mutant hematopoiesis may be selected by exposure of HSC to PARPi [ 38 , 39 ] (Fig. 1 ).

Neutropenia associated with PARP inhibitors, data from clinical trials

Neutropenia occurrence: to gain a better understanding of the association between neutropenia and PARPi therapy, the results of the major phase III PARPi trials published through November [ 40 ] were reviewed. Twenty trials (with a total of 6738 patients) were identified that investigating the main available PARPi (olaparib, veliparib, niraparib, rucaparib, talazoparib, iniparib, fluzoparib, pamiparib, ABT-767, and CEP-9722) [ 32 – 35 , 41 – 56 ]. Nine of these trials included olaparib and 16 (80%) reported the use of PARPi as monotherapy. Data on the occurrence of neutropenia were available in all but one of the trials, demonstrating the interest in this specific adverse event (Supplementary, Table S1 ).

Across these studies, any grade neutropenia occurred in 36% of patients and grade 3–4 neutropenia was reported in 22% of patients. Data on febrile neutropenia were available in 25% of the studies. This complication was much less common than grade 3–4 neutropenia, occurring in 0 to 2% of patients. One study reported death related to febrile neutropenia (Supplementary, Table S1 ).

Of the 16 studies evaluating PARPi as monotherapy, neutropenia was reported in 94% of the studies. Of these, 23% of patients experienced any grade neutropenia and 10% grade 3–4 neutropenia. Febrile neutropenia was reported in 25% of the studies, ranging from 0 to 2% with one related death (Supplementary, Table S1 ).

Neutropenia associated with parpi, management and recommendations from the NEW group

Data from these 20 studies suggests that the preferred approach for managing neutropenic events is to adapt or withhold PARPi doses until neutropenia is resolved [ 32 – 35 , 41 – 56 ]. Only one study, which evaluated the combination of veliparib with carboplatin, reported the use of G-CSF [ 41 ].

To date, no trial has assessed the effectiveness and safety of G-CSF use in PARPi-treated patients. However, findings from recent research studies indicate that treatment with PARPi may potentially contribute to the emergence of TP53-mutated clonal hematopoiesis. This observation could give rise to concerns that the simultaneous use of G-CSF might increase this risk by increasing the number of divisions in hematopoietic progenitors, and thus the possibility of a mutation affecting the TP53 pathway [ 38 ]. Lastly, none of the leading Phase III trials that evaluated PARPi as monotherapy reported the use of G-CSF. Based on data from both fundamental and clinical studies, there is currently no support for using G-CSF in cases of PARPi-related neutropenia. In such situations, the NEW group recommended approach is to careful dose management or withholding of PARPi therapy. In the event of neutropenia persisting for a period of four weeks or longer following the withdrawal of therapy, or in the presence of abnormal circulating immature white blood cells, a hematologic consultation for medullary evaluation is recommended.

Immune checkpoint inhibitors (anti-pd1, anti-pdl1, and anti-ctla4)

Immune checkpoint inhibitors mechanisms of action and effects on neutrophil lineage

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment by harnessing the body’s immune system to fight cancer. Key players in this therapeutic strategy are programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Twelve medications have been approved by the US Food and Drug Administration (March 2024) for the treatment of 14 solid tumors and 2 hematologic malignancies [ 57 ] (Supplementary, Table S2 ).

CTLA-4 is a protein receptor expressed by T lymphocytes CD4 + and CD8 + after their activation. This protein is also expressed by regulatory T lymphocytes CD4-CD25 +. By binding to the CD80-CD86 ligand of the antigen presenting cells (with higher affinity than the activating T lymphocyte receptor CD28), it downregulates antigen presentation to CD8 + T lymphocytes by affinity competition and induces endocytic degradation of CD80-CD86 on the antigen presenting cells. Both mechanisms lead to an immune suppressive effect [ 58 , 59 ].

PD-1 is expressed on activated CD4 + and CD8 + T lymphocytes, B lymphocytes, natural killer cells and myeloid-derived suppressor cells [ 3 ]. PL-L1 is a ligand expressed on antigen presenting cells and tumor cells (where it can be upregulated by oncologic signals and by interferon gamma) [ 60 ]. PD-1/PD-L1 binding leads to functional anergy on effector T lymphocytes, unactivated B lymphocytes, macrophages and natural killer cells [ 61 , 62 ].

Therefore, anti-CTLA-4, PD-1, and PD-L1 antibodies by blocking immune evasion tumor mechanisms help restore the immune response system towards neoplastic malignancies.

Hematological toxicities of ICI therapies are divided into immune and non-immune. Unfortunately, the distinction between those mechanisms remains vague and undiscernible by specific laboratory testing [ 63 ]. Steroids’ response in the majority of hematological adverse events supports the theory of a preponderant immune-mediated mechanisms [ 64 ]. Therefore, ICI toxicities are related to the removal of the immunological brake leading stochastically to autoimmunity.

Several putative mechanisms are suspected to lead to neutropenia in patients treated with ICI. The most accepted theories stand in (i) a change in the cytokines expression by helper T lymphocytes favorizing auto-antibody production and (ii) a direct CD8 + T lymphocyte cytotoxic effect [ 63 , 65 , 66 ],. Another suggested mechanism is an immune-mediated dysfunction in hematopoietic cell maturation and proliferation, but the exact mechanism is yet unknown [ 67 ]. Regarding anti-PD-1/PD-L1 therapies, another proposed mechanisms is the removal of the inhibitory signals in B lymphocytes possibly leading to an enhanced auto-antibody production; moreover the natural killer cells unleashed could also induce direct bone marrow toxicity [ 63 ] (Supplementary, Table S3 ).

Neutropenia associated with immune checkpoint inhibitors, data from clinical trials

The incidence rate of neutropenia adverse event secondary to ICI monotherapy has rarely been documented in trials on anti-PD-1/PD-L1 studies; its overall reported incidence was less than 1% [ 68 ] and the median time to onset was 3 cycles [ 69 ]. Although rare, these adverse events were severe, > 60% being grade 4 and > 60% being febrile neutropenia according to a French pharmacovigilance study [ 70 ]. The median time to onset of hematological toxicities tended to be shorter with anti-CTLA-4 monotherapy or a combination of anti-CTLA-4/anti-PD-1 therapies compared to anti-PD-1 monotherapy [ 64 ] (12 versus 25 weeks). Among patients who experience significant haematological toxicity, > 90% of those treated with anti-PD-1/PD-L1 and anti-CTLA-4 combination therapy experienced grade 3 + toxicity compared to 70% for those treated with monotherapy [ 71 ].

Regarding the impact of combining ICI with chemotherapy, a recently published meta-analysis from Ohashi et al. (29 articles included) evaluated the risk of grade I-IV neutropenia of systemic chemotherapy ± ICI: the addition of ICI to chemotherapy increased the risk by 10% (odd ratio 1.1; 95% CI [1.01–1.19] [ 72 ]. The incidence rate of grade 3 + leukopenia in regimens of ICI and chemotherapy alone were similar (Supplementary, Figure S3 ) according to Hou et al. (16 studies included) [ 73 ]. Interestingly, no differences were found between either the ICI type or the solid tumor subtype for grade I-V anemia, neutropenia, and thrombocytopenia [ 71 , 72 ].

Neutropenia associated with immune checkpoint inhibitors management and recommendations from the NEW group

Practical guidelines on the management of ICI toxicities have been published by various national and international societies such as ASCO, the American Society of Clinical Oncology [ 74 , 75 ], or ESMO, the European Society of Medical Oncology [ 71 ].

To date, no randomized trials or prospective studies evaluated management procedures to deal with ICI hematological adverse event and recommendations were based on retrospective cohort studies or expert opinion. All guidelines recommended early consultation with a hematologist and a rapid recourse to bone marrow examination [ 71 , 74 , 75 ]. When used in combination with chemotherapy: chemotherapy accountability should be first ruled out.

The NEW Group recommends for the management of ICI-induced neutropenia to use currently available guidelines [ 57 , 71 , 75 ] (Supplement, Figure S4 ):

− In case of neutropenia grade ≥ 2 ICI therapy should be withheld

− In case of grade ≥ 3 neutropenia: diagnostic work up should include complete blood count, blood smear, bone marrow aspirate and biopsy, vitamins, ferritin and triglycerides dosing and a consultation with hematologist if no response to first line treatment

In the absence of differential diagnosis first-line treatment includes the use of G-CSF in addition to IV steroids [ 71 ]. Second-line immunosuppressive treatment is less standardized and may involve IV immunoglobulins, mAb anti-CD20, and anticalcineurins [ 64 ].

About 2/3 of patients should recover within 1 month and ICI could be restarted when ANC are above 1G/L but 2/3 of patients will have a recurrence of neutropenia as AE [ 71 ].

Anti-cd20 therapies

Anti-cd20 mechanisms of action and effects on neutrophil lineage

Humanized anti-CD20 monoclonal antibody (mAb) rituximab has been registered by the FDA in 1997 in the treatment for relapsed/refractory Non-Hodgkin Lymphomas. Its use has greatly enhanced the response rate, progression-free survival and even longer overall survival [ 76 – 78 ]. As B-cell lymphocytes play an important role in auto-immune diseases, it has also been successfully used in various autoimmune diseases [ 79 – 81 ].

However, the concept of “rituximab resistance” emerged and a new “type 2” anti-CD20 mAb, obinutuzumab, was developed for patients with B-cell lymphomas who failed to achieve remission or experienced relapse [ 82 ]. This classification is based on the drug mode of action and CD20 properties. Type 1 (rituximab) relocates CD20 to lipid rafts and induces significant complement-dependent cytotoxicity (CDC) and antibody-dependent cellular toxicity (ADCC). On the other hand, type 2 (obinutuzumab) does not induce CDC, but by alternative binding to CD20 antigen, induces greater direct cell death (DCD) by caspase-independent mechanisms. In addition, its afucosylated Fc portion seems to confer more potent induction of ADCC and antibody-dependent phagocytosis than type 1 anti-CD20 mAb [ 82 – 84 ] (Supplementary, Table S4 ).

Classical anti-CD20 mAb toxicities are generally manageable infusion-related side effects, such as chills, rigors, fever, dyspnea and hypotension, and are usually transient [ 85 ].

Although occasional episodes of early onset neutropenia (defined by granulocytopenia occurring within 4 weeks) have been reported, this type of neutropenia usually transient and self-limiting was attributed to the accelerated destruction of neutrophils caused by binding of mAb-antigen complexes to neutrophil Fc receptors [ 86 ].

The majority of neutropenia associated with anti-CD20 mAb are late onset (defined by occurring at least 4 weeks after the last drug infusion), and several hypotheses have been proposed to explain mechanism involved (Fig. 2 ):

− Anti-neutrophil antibodies production: anti-CD20 mAb depletes the normal B-lymphocyte population needing 3 to 9 months to recover. During the recovery process, a new immune system is acquired in a non-physiological state. These conditions may lead to the production of some transient autoantibodies against neutrophils or their hematopoietic precursors [ 87 ].

− Expansion of T-LGL population: Fas ligands are members of the tumor necrosis factor family and induce neutrophil apoptosis by binding to their receptor Fas. In lymphoma patients treated with anti-CD20 mAb T-cell subset is unregulated due to the B-cell depletion leading to a dysfunctional crosstalk between B and T cells. In patients with neutropenia a significant T-LGL proliferation was demonstrated. Both activated and tumorigenic T-LGL expresses and secretes large amounts of Fas and Fas ligands leading lead to neutropenia [ 88 , 89 ].

− B-cell pool reconstitution and its consequences: B-cells depletion induces changes in hematopoietic growth factors especially B-cell activating factor (BAFF) and stromal-derived factor (SDF-1) whose chief receptor is CXC chemokine receptor 4 (CXCR4). Both those factors regulate B-cell development and lead to an outflow of neutrophils from bone marrow. DCXCR4/SDF-1 axis plays an important part in the regulation of neutrophils bone marrow development. SDF-1 is also implicated in cell division and migration of early lineage B cells. Rapid B-cell depletion disrupts the bone marrow SDF-1 gradient, thereby downregulating neutrophil efflux from the bone marrow [ 90 ]. BAFF is a cytokine that upregulates multiple B cell costimulatory molecules. Two mechanisms may contribute to increased serum BAFF levels following anti-CD20 mAb-induced B-cell depletion: the important reduction of B-cells BAFF receptors following their depletion, and the delayed regulation of BAFF mRNA levels. In the bone marrow, competition between B-cell lymphangiogenesis over granulocyte production is suspected: when BAFF levels reach a peak during B-cell division, dysplasia of granulocytes in the bone marrow occurs leading to disrupted granulopoiesis and delayed neutrophil maturation [ 91 ].

Neutropenia associated with anti-cd20, data from clinical trials

The incidence rate, time of onset, depth or duration of neutropenia during anti-CD20 mAb treatment are highly dependent on the setting (ranging from B cell malignancies to autoimmune diseases), the concurrent treatments (± chemotherapy or other concomitant systemic treatments) and the treatment line. The incidence rate specifically due to the anti-CD20 mAb is therefore hard to evaluate.

However, studies have shown that late onset neutropenia incidence is higher for patients with lymphomas (3–27%) [ 92 , 93 ], compared to autoimmune diseases (1.3–2.3%) [ 94 ]. Due to the lack of routine follow-up of neutrophil counts in most patients within a few months after anti-CD20 mAb treatment, this number may underestimate the true incidence rate.

Regarding the recurrence of neutropenic events, Zonozi et al. reported in a retrospective study 738 patients treated by rituximab for autoimmune disease who presented late onset neutropenia and were re-exposed to anti-CD20 mAbs, 21% of them had a recurrent neutropenia [ 95 ]. In a recent systematic review published by Zhang et al. identified various risk factors associated with anti-CD20 mAb late onset neutropenia: the use of combined chemotherapy especially purine drugs, specific polymorphisms at position 158V/F of the IgG and systemic lupus erythematosus (compared to other auto-immune diseases) [ 93 ].

Regarding the type of anti-CD20 mAb, Amitai conducted a systematic review and meta-analysis on randomized controlled trials with obinutuzumab and rituximab-based regimen, grade 3–4 neutropenia incidence rates were similar (RR 1.01 [95% CI 0.93–1.11], 4 trials, 3429 patients) but obinutuzumab was associated with an increased rate of febrile neutropenia (RR 1.23 [95% CI 1–1.51] [ 96 ]. Those data are concordant with previously published studies [ 97 ] and argue for possible class effect of anti-CD20 mAb (Supplementary, Figure S5 ).

Most late onset neutropenia cases are self-limiting or even asymptomatic, and a low incidence of serious infectious complications has been reported. Some manifestations of early onset neutropenia are more severe, ranging from sepsis-like manifestations of neutropenia to asymptomatic neutropenia [ 98 ]. To date, no deaths associated with early onset neutropenia have been reported [ 93 ].

Neutropenia associated with anti-cd20 management and recommendations from the NEW group

There are no specific recommendations for the management of late onset neutropenia associated with anti-CD20 therapies. Some patients may recover promptly with no specific treatment and some may need to be managed with granulocyte-colony stimulating factor (G-CSF), usually with a rapid response [ 99 ].

It is generally accepted that in most cases of grade 3 neutropenia, neutrophil recovery is self-limiting and patients recover rapidly without any specific therapy and do not require G-CSF administration [ 99 ]. Regarding grade 4 neutropenia, due to the high infectious complications risk, G-CSF use is justified for patients with risk factors with usually a rapid response [ 92 ] (Supplementary, Figure S6 ). Neutropenia under anti-CD20 unresponsive to G-CSF is rare and its management is currently controversial [ 100 ].

Recommendations from the NEW Group: to date, no trial has specifically assessed the effectiveness and safety of G-CSF for late onset neutropenia induced by anti-CD20 mAb.

Based on data both fundamental and clinical studies, there is currently no support for using G-CSF in anti-CD20 mAb related neutropenia. In case of grade 4 neutropenia, G-CSF use may be discussed regarding associated risk factors on a patient-by-patient basis (Supplementary, Figure S6 ).

Because of the risk of re-occurrence of late onset neutropenia, the need for re-treatment with anti-CD20 mA after recovery from late onset neutropenia should be determined on a patient-by-patient basis [ 85 ].

CAR T-cells (chimeric antigen receptor T-cell)

CAR T-cells mechanisms of action and effects on neutrophil lineage

Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy targeting the CD-19 B cell receptor in non-Hodgkin lymphoma/B-cell acute lymphoblastic leukemia or the B cell maturation antigen (BCMA) in multiple myeloma (MM) has emerged as an efficacious and life-extending treatment modality with high response rates and durable remissions in patients with relapsed and refractory non Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (B-ALL) or MM [ 101 – 110 ].

The process of making CART-cell constructs involve isolating the patient’s T-cells and using lentiviral or retroviral vectors to transfer genetic information to express new T-cell receptors that can identify a specific antigen on tumor cells while concurrently activating T-cells. These cells are then allowed to multiply in vitro (~ 14 days) and are infused into lymphodepleted patients. These CAR T- cells grow and multiply in the patient and function to identify and perform targeted destruction of the tumor cells. The treatment is both specific to the cancer cells, through amplified T-cell cytotoxic responses, and nonspecific, due to the release of cytokines which contribute to sustained and durable responses [ 111 ].

CAR T- cells are associated with some early-onset specific toxicities, such as cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis (HLH), and immune effector cell associated neurotoxicity syndrome (ICANS). While these toxicities can sometimes be life-threatening, they usually present early in the course of treatment, are well studied, and thus with appropriate management can be mitigated, thus making CAR-T cell therapy a safe treatment modality with low mortality rates [ 104 , 107 , 108 , 112 – 114 ]. With long term follow up of these patients, hematotoxicity (anemia, neutropenia, and/or thrombocytopenia) has emerged as an relevant adverse effect of CART-cell therapy.

Neutropenia associated with CAR T-cells, data from clinical trials

Neutropenia occurrence

Hematotoxicity has the highest cumulative toxicity incidence post CD19 CAR-T. Indeed, it is the most commonly observed grade 3 + immune-related adverse event, with a one-year cumulative incidence of 60% [ 115 ].

Based on CTCAE definition and grading, the incidence of grade 3 + neutropenia after CAR T-cells therapies was reported between 33 and 53% depending on the trials and the histological subtypes [ 102 , 105 – 108 , 116 ].

In DLBCL real-world study, a high incidence of neutropenia was observed; severe neutropenia concerned 91% of patients, approximatively 70% exhibited severe protracted neutropenia (≤ 500/µl and ≥ 7 days) and about a quarter of patients developed protracted, profound neutropenia (≤ 100/µl and ≥ 7 days). Importantly, 64% of patients displayed prolonged neutropenia – meaning an ANC < 1000/mm3 measured later than day 21 after CAR T-cell infusion, i.e., a long time after lymphodepleting chemotherapy and resolution of clinical CRS [ 117 ].

Clinical phenotypes of neutrophil recovery were described in three groups (Fig. 3 ):

First, patients with a quick neutrophil recovery following transient lymphodepletion-associated cytopenia

Second, patients with “intermittent recovery”, who developed a second dip below an ANC < 1000/µl after D21, often already post-discharge.

And third, the clinically challenging “aplastic” patients, who exhibited sustained severe neutropenia greater than 14 days.

Regarding the relative frequency of these phenotypes, the dominant phenotype was found to be the intermittent recovery (52% of all patients), followed by approximatively a quarter of patients fitting the “quick recovery” (25%) and “aplastic” category (23%) respectively [ 117 ]. Similar results were found in an updated analysis of 335 patients [ 118 ].

Regarding neutropenia risk factors, a prognostic score, the CAR-HEMATOTOX score (HT), was developed with the aim to stratify patients prior to CAR T transfusion into a high vs low risk group for clinically significant neutropenia. A neutrophil count below 500 for 14 days or longer was defined as a clinically meaningful endpoint to discriminate between the high vs low risk group. CAR-HEMATOTOX score was based on pre-CAR-T parameters (Fig. 4 ). Within the cohort with a low score, almost none of the patients developed an aplastic phenotype whereas within the high score group, 40% of the patients developed an aplastic phenotype with a median duration of ANC ≥ 14 days [ 117 ].

Regarding the distribution of phenotypes of neutrophil recovery by CAR-HEMATOTOX, the “aplastic” phenotype was found more frequently (36%) in the HT High patients compared to the HT low patients (1%). On the other hand, the “Quick Recovery” phenotype is more frequent in the HT low group. The clinical relevance of this finding was highlighted when the duration of neutropenia by phenotype was analyzed. Aplastic patients developed a median of 29 days of severe neutropenia when this median dropped to 10 days and 5 days in patients with intermittent recovery and quick recovery respectively. This may explain why the HT high patients have a longer median duration of neutropenia (13 days) compared to HT low patients (7 days) [ 117 ].

As already shown, hematotoxicity occurs independently of the disease or CART-cells construct, and similar results were found when applying CAR-HEMATOTOX score to mantle cell lymphoma and myeloma patients [ 119 , 120 ]. However, it is important to note that the score remains to be validated prospectively in adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia. Furthermore, the test characteristics (high sensitivity, but low specificity) indicate a low positive predictive value, meaning that not all patients deemed high risk will develop severe hematotoxicity. Conversely, the high negative predictive value suggests that the score is particularly helpful in ruling out patients at risk for severe hematotoxicity.

Interestingly, a prognostic impact of neutropenia profile was reported in the literature. Indeed, intermittent recovery is associated with independent positive prognostic marker for PFS (and trend for OS) while aplastic recovery was not an independent risk factor in PFS or OS when accounting for other established risk factors [ 118 ].

Aplastic phenotype seems to be characterized by profound baseline immune dysregulation and HLH-like inflammatory signature post CAR-T while biphasic neutrophil recovery is characterized by high CAR T-cell expansion and persistence—particularly in relation to baseline tumor load. However, more work needs to be done to understand the pathophysiological underpinnings of neutropenia.

Overall, a plethora of factors contribute to the development of cytopenias after CAR T-cell therapy, some of which remain incompletely understood [ 117 , 119 , 121 ] (Fig. 4 ).

Neutropenia associated with CAR T-cells, management and NEW group recommendations

Definition

A joint EHA/EBMT initiative has been proposed to define a new toxicity category corresponding to CAR T-cell-mediated hematotoxicity, which has been termed immune effector cell-associated hematotoxicity (or ICAHT). Based on a global survey involving 18 countries and more than 50 CAR-T centers, a novel consensus grading system and best practice recommendations were developed, and an international panel of CAR-T experts convened in Lille, France, in [ 40 ] to develop a standardized grading system [ 121 ].

For Early ICAHT, from day 0 to day 30, both the depth and duration of neutropenia were incorporated, based on the rationale that this is what really drives the risk of infection and is also correlated strongly with multilineage cytopenia (Fig. 5 ).

Late ICAHT was defined as non-transient neutropenia occurring after day + 30, with the severity grades mirroring CTCAE grading.

Diagnostic

An incremental approach to diagnostic work-up has been proposed, with two diagnostic tiers.

Tier 1 represents a "minimal" work-up and should be performed in patients with mild to moderate ICAHT.

In the case of G-CSF refractoriness, persistent cytopenia and/or the presence of relevant risk factors for ICAHT (e.g., high HT score), a second-tier diagnostic workup should be performed, including bone marrow analysis and extended viral studies (Fig. 5 ).

Neutropenia management and NEW group recommendations

Management of neutropenia associated with CAR T-cells therapies may need a combination of several modalities’ treatments given the considerable heterogeneity in the onset and duration of this toxicity.

Several recent reports have demonstrated an acceptable safety profile for the early use of G-CSF after CAR T-Cells infusion, with no increase in high-grade (grade ≥ 3) CRS/ICANS and a reduced risk of febrile neutropenia [ 40 , 122 – 124 ]. Notably, G-CSF was also safe in maintaining CAR T-cell expansion kinetics and anti-lymphoma activity, with no adverse effects on response quality and outcomes [ 40 , 123 ].

In grade I or II ICAHT, early or prophylactic G-CSF may be considered (from day + 2), especially in patients with a high-risk profile for developing hematotoxicity. Similarly, anti-infective prophylaxis, specifically antibacterial and antifungal prophylaxis can be applied in a risk-adapted manner [ 125 ].

Therapeutic G-CSF may also be considered for prolonged severe neutropenia (ANC < 500/µL) and may be of diagnostic value in identifying the aplastic neutrophilic recovery phenotype [ 117 ], which is often unresponsive to G-CSF. The vast majority (> 80%) of patients receiving CAR T-cell therapy ultimately respond to growth factor support [ 126 ]. A recurrent neutrophil drop may occur (biphasic course) and require intermittent application of therapeutic G-CSF. However, there is currently no consensus on the optimal treatment protocol for G-CSF (prophylactic vs. early, and pegylated vs. non-pegylated). A key point is the identification of GCSF-refractory patients, defined as lack of count recovery despite at least 5 days of G-CSF support. These challenging patients may benefit from additional treatments including anti-inflammatory measures, TPO agonists, or hematopoietic stem cell boost. Ultimately, allogeneic stem cell transplantation (allo-HCT) is the last resort. While we recommend initiating a donor search around day + 30 in very severe cases of ICAHT, the optimal trigger point for allo-HCT should be considered on a case by case basis and the possibility of spontaneous count recovery should be weighed against the risk of infection [ 121 ].

Persistent neutropenia after CAR T-cells therapy could be managed by Hematopoietic cell boost (HCB). Patients who are unresponsive and/or refractory to G-CSF beyond day + 14 after CAR T-cell infusion represent a clinically challenging subgroup of patients at high risk for severe and even fatal infectious complications. A promising strategy pertains to the use of cryopreserved autologous or allogeneic CD34 + hematopoietic cells from prior collection (either prior auto- or allo-HCT). Some recent case series shed light on both the safety and clinical feasibility of this approach [ 127 , 128 ]. High rates of sustained neutrophil engraftment were noted across studies. Because the earlier application of an available HCB was associated with superior survival outcomes [ 128 ], the expert panel recommends considering the application of an HCB without prior conditioning chemotherapy for grade ≥ 3 ICAHT beyond day + 14 if (1) a boost is readily available, and (2) G-CSF refractoriness has been established [ 121 ]. At the same time, the survey results highlighted that even when HCB was considered a viable treatment option in a patient with prior auto-HCT, the cell products were often not available.

Although prophylactic collection in high-risk candidates has been proposed as a potential mitigating strategy, the panel cautioned that the collection process may add to the already high logistic burden of CAR T-cell therapy (e.g., coordination of apheresis slots and storage capacity), which could negatively impact vein-to-vein times in a state of high disease burden. Furthermore, the process could incur unnecessary collection- and storage-associated costs. Ultimately, it was concluded that further research is needed to assess the number needed to treat for prophylactic stem cell collection [ 121 ].

Recommendations from the NEW Group: Hematotoxicity score after CAR T-Cells therapies is common and clinically relevant score but poorly understood with a high degree of heterogeneity in the grading and clinical management.

By clearly defining ICAHT, harmonized and severity-based recommendations for diagnostic work-up and management (G-CSF, prophylaxis, boosts) have been developed (Fig. 5 ). ICAHT grades should be reported in clinical trials to enable cross-trials comparisons and improve patient’s management.

Neutropenia in elderly, specific features of older patients

Impact of hematopoietic aging and inflammaging on neutrophils

Aging is associated with numerous changes is hematopoietic lineages, including decreased competences of the adaptive immune system (or immunosenescence), a systemic chronic inflammation (or inflammaging), and a higher susceptibility to infectious and noninfectious diseases [ 129 ]. In 2005, Rossi et al. demonstrated that cell intrinsic alterations participated to a so-called myeloid skewing of long-term hematopoietic stem cells, that is, the down-regulation of genes contributing to a lymphoid differentiation and the activation of genes involved in the myeloid fate [ 130 ] (Fig. 6 ). Among the myeloid lineages, neutrophils were classically considered as an homogeneous whole of terminally differentiated cells, but evidence has been progressively gathered, to show that the neutrophil pool is differently regulated depending on its localization (i.e., either circulating, into the bone marrow or marginated into different organs); moreover, different neutrophil populations co-exist, and contribute to the regulation of both innate and adaptive responses [ 131 ]. During aging, functional changes in the neutrophil pool may contribute to both the increased incidence and mortality of severe sepsis in the older population [ 132 ]. Strikingly, analyses of neutrophil heterogeneity in younger versus older populations during SARS-Cov-2 infections demonstrated that the excess pulmonary morbidity of the infection in older populations was not related to a defective neutrophil recruitment, but to the accumulation of dysfunctional neutrophils into neutrophil extracellular traps in the lungs, contributing more frequent acute respiratory distress syndrome [ 133 , 134 ]. In 2021, He et al. showed in primates (macaques) that age is associated with increased levels of G-CSF, decreased production of mature neutrophils, and increased rates of polymorphonuclear myeloid-derived suppressor cells (MDSC, Fig. 6 ) [ 135 ]. MDSC are immature cells of the myeloid lineage with immunosuppressive properties known to appear in cancer patients, in severe inflammatory conditions and infections, due either to an early escape of immature precursors from the bone marrow or a reprogramming/de-differentiation of differentiated cells (neutrophils or monocytes) in the context of acute or chronic inflammation [ 136 ]. An exponential piece of evidence places MDSCs at the crossroads of chronic diseases, aging, and inflammaging since, being immunotolerant, these cells limit the resolution of the immune response, leading to the maintenance of low grade inflammation, present in chronic diseases and during aging, and its consequences [ 137 , 138 ]. As G-CSF has been shown to favor an early escape of myeloid cells from the bone marrow [ 139 ], one may consider that G-CSF overexposure should be avoided in an older population.

HSC (hematopoietic stem cells) exhaustion and clonal hematopoiesis during aging: A place for the development of new therapeutic strategies

During aging, the concept of the antagonist pleiotropy [ 140 ] applies to the hematopoietic system: the destruction of altered hematopoietic progenitors – necessary to avoid leukemogenesis during the younger ages—contributes to a progressive clonally restricted hematopoiesis in the older populations, the long-term risk being bone marrow exhaustion. Clonal hematopoiesis is known to increase both with the exposure to agents interfering with homologous recombination [ 141 ] (like chemotherapy, or poly ADP ribose polymerase inhibitors) and age [ 142 ] and eventually leads to myelodysplasia and acute myeloid leukemia [ 143 ], leading the geriatric oncology community to promote strategies preventing the overstimulation of the hematopoietic system [ 4 , 144 , 145 ]. Among those, temporary cell-cycle arrest [ 146 ] and senotherapy [ 145 ] appear as promising strategies. The objective of temporary cell cycle arrest is the sparing of the stem cell reserve by the blockade of cycling cells – and particularly hematopoietic progenitors – during chemotherapy exposure. Several molecules have been evaluated to date: trilaciclib induces checkpoint inhibition in G1 by CDK 4/6 inhibition [ 147 – 150 ], plinbabulin prevents microtubule polymerization [ 151 , 152 ] and ALRN-6924 induces cell-cycle arrest by p53 activation (in p53-mutated cancers) [ 153 ]. Senotherapy is a promising new strategy aiming at reverting the deleterious effect of senescent sells, either intrinsically by the up-regulation of anti-apoptotic pathways and extrinsically by the senescent-associated secretion phenotype (SASP), consisting of secreted factors, able to promote chronic inflammation and tissue dysfunction [ 154 ]. Senotherapeutics aim either at the selective elimination (senolytics) or the suppression of the markers of senescence, and particularly the SASP (senomorphics) [ 155 , 156 ]. Strikingly, some classical therapeutics used in the treatment of cardio-vascular diseases (aspirin [ 157 ]), diabetes (metformin [ 158 ]), cancers (m-TOR inhibitors [ 159 ], JAK-STAT inhibitors [160], NF-КB inhibitors [161]) demonstrated senomorphic properties, leading to consider them as promising agents for the prevention of short-term and long-term hematotoxicities [ 145 ].

Discussion

Neutropenia is a well-known toxicity of chemotherapy. Its mechanism of occurrence is well described, enabling us to target precisely the type of patient population at risk, and to anticipate the onset of such toxicity as effectively as possible. Indeed, post-chemotherapy neutropenia is now considered to be a probabilistic event, occurring within a well-known time frame, which can often be prevented [ 6 ]. This probabilistic mechanism of occurrence has led to the development of clear guidelines on the prevention and management of chemotherapy-induced neutropenia [ 5 – 8 ].

Although the new anti-cancer therapies may appear to be better tolerated than conventional chemotherapy, they nevertheless share common toxicities, the most significant of which is neutropenia. This review has demonstrated that NAN (Neutropenia Associated with Novel-anticancer agent) can occurs with great frequency, for most of the molecule under consideration [ 14 , 115 ]. Conversely, the pathophysiological mechanisms underlying the occurrence of this toxicity exhibit considerable variation across different compounds, extending beyond direct cytotoxicity (a phenomenon observed in most chemotherapy agents) and remaining, at times, poorly understood [ 125 ]. The situation is further complicated by the fact that older patients with aging hematopoietic systems are more susceptible to bone marrow exhaustion in the event of excessive stimulation [ 130 , 142 ].

Consequently, the prevention and management of NAN cannot be approached with a universal strategy; rather, it must be tailored to the specifics of each treatment and patient. Consequently, clinicians are confronted with novel challenges, as treatment toxicities evolve into stochastic occurrences, and their management remains less well established.

A significant proportion of the research results presented in this review originate from clinical trials. It is therefore important to conduct further research using real-life data when available, in order to gain a deeper understanding of the mechanisms underlying the occurrence of NAN and to develop more effective strategies for its management outside the context of clinical trials.

Lastly, due to the disparate nature of the molecules involved in this review, as well as the still recent scientific data available, we deemed a scoping review to be an optimal method for taking stock of the current NAN landscape. This involved mapping the evidence currently available on the subject. To confirm these results with greater rigor, it would be beneficial to consider conducting systematic reviews dedicated to each of the molecules presented.

Conclusion

In the era of innovative new anti-cancer therapies and emergent treatment, neutropenia remains a major challenge for safe administration of these new drugs. It one of the most common toxicities that requires a better pathophysiological mechanism understand and an appropriate management diagnosis and treatment.

This literature review focuses on the main treatments which have been identified as significantly associated with neutropenia (CDK4/6 inhibitors, PARP inhibitors, immune checkpoint inhibitors (anti-PD1, anti-PDL1 and anti-CTLA4), anti-CD20 and CAR T cells). It provides an overview of the current understanding of the mechanisms of neutropenia, its epidemiology, and a management based on data from clinical trials and guidelines from academic societies.

The pathophysiological mechanisms of NAN are heterogenous and differ significantly between treatments, making it impossible to suggest a single management approach or strategy for this complication.

While G-CSF-type stimulating agents are commonly used and validated for the prophylaxis of chemotherapy-induced neutropenia, they may not be appropriate for managing NAN. Particular care is necessary when using these drugs in older patients, as they may increase adverse effects.

The generation of evidence-based recommendations with multicenter collaboration and registry data may fulfill the unmet need for practice guidelines for NAN.

Supplementary Information

Below is the link to the electronic supplementary material.

(DOCX 624 KB)

Author contribution

All authors participated in the design of the study and the design of the figures and reviewed the paper. GA obtained the data on PARPi and wrote the corresponding part, VT obtained the data on anti-CD20 and anti-PD1/CTLA and wrote the corresponding part, WJ obtained the data on CD/Ki and wrote the corresponding part, LB and CF obtained the data on older patients and wrote the corresponding part.

Funding

This article was funded and sponsored by Chugai Pharma France.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

CF, PS, WJ, GA, VT, LB. Received honoraria as members of the Scientific Committee of the NEW Group (Neutropenic Event Working Group). KM is a Chugai Pharma France employee. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

1/31/2026

The affiliations have been corrected.

References

1. Siamof CM, Goel S, Cai W (2020) Moving beyond the pillars of cancer treatment: perspectives from nanotechnology. Front Chem 8:598100. 10.3389/fchem.2020.598100

2. Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9(3):153–166. 10.1038/nrc2602

3. Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB (2020) Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers (Basel) 12(3):738. 10.3390/cancers12030738

4. Balducci L, Falandry C, List A (2022) New advances in supportive care: chemoprotective agents as novel opportunities in geriatric oncology. Curr Oncol Rep. 10.1007/s11912-022-01324-x

5. Rapoport BL, Cooksley T, Johnson DB, Anderson R, Shannon VR (2021) Treatment of infections in cancer patients: an update from the neutropenia, infection and myelosuppression study group of the Multinational Association for Supportive Care in Cancer (MASCC). Expert Rev Clin Pharmacol 14(3):295–313. 10.1080/17512433.2021.1884067

6. Smith TJ, Bohlke K, Lyman GH et al (2015) Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 33(28):3199–3212. 10.1200/JCO.2015.62.3488

7. Klastersky J. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol . 2016;27.

8. Aapro MS. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer . Published online 2010.

9. Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM (2010) Aging of the innate immune system. Curr Opin Immunol 22(4):507–513. 10.1016/j.coi.2010.05.003

10. Balducci L, Falandry C, Silvio Monfardini null. Senotherapy, cancer, and aging. J Geriatr Oncol . 2024;15(4):101671. 10.1016/j.jgo.2023.101671

11. Falandry C, List A, Balducci L (2023) Cell cycle arrest: a breakthrough in the supportive care of older cancer patients. J Am Geriatr Soc 71(7):2297–2307. 10.1111/jgs.18350

12. Mughal MJ, Bhadresha K, Kwok HF (2023) CDK inhibitors from past to present: a new wave of cancer therapy. Semin Cancer Biol 88:106–122. 10.1016/j.semcancer.2022.12.006

13. O’Leary B, Finn RS, Turner NC (2016) Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol 13(7):417–430. 10.1038/nrclinonc.2016.26

14. Ettl J (2019) Management of adverse events due to cyclin-dependent kinase 4/6 inhibitors. Breast Care 14(2):86–92. 10.1159/000499534

15. Hu W, Sung T, Jessen BA et al (2016) Mechanistic investigation of bone marrow suppression associated with palbociclib and its differentiation from cytotoxic chemotherapies. Clin Cancer Res 22(8):2000–2008. 10.1158/1078-0432.CCR-15-1421

16. He S, Roberts PJ, Sorrentino JA et al (2017) Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion. Sci Transl Med 9(387):eaal3986. 10.1126/scitranslmed.aal3986

17. Weiss JM, Csoszi T, Maglakelidze M et al (2019) Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial. Ann Oncol 30(10):1613–1621. 10.1093/annonc/mdz278

18. Hart LL, Ferrarotto R, Andric ZG et al (2021) Myelopreservation with trilaciclib in patients receiving topotecan for small cell lung cancer: results from a randomized, double-blind, placebo-controlled phase II study. Adv Ther 38(1):350–365. 10.1007/s12325-020-01538-0

19. Dómine Gómez M, Csőszi T, Jaal J et al (2021) Exploratory composite endpoint demonstrates benefit of trilaciclib across multiple clinically meaningful components of myeloprotection in patients with small cell lung cancer. Int J Cancer 149(7):1463–1472. 10.1002/ijc.33705

20. Tan AR, Wright GS, Thummala AR et al (2019) Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol 20(11):1587–1601. 10.1016/S1470-2045(19)30616-3

21. vasquez lea, coussirou julie, Arvers P, et al. palbociclib-associated-with-endocrine-therapy-in-patients-with-metastatic-breast-cancer-predictive-factors-of-severe-ear. J Cancer Sci Ther . 2019;11:290–294.

22. Kanbayashi Y, Sakaguchi K, Ishikawa T, Takayama K, Taguchi T (2021) Predictors for development of palbociclib-induced neutropenia in breast cancer patients as determined by ordered logistic regression analysis. Sci Rep 11(1):20055. 10.1038/s41598-021-99504-5

23. Leenhardt F, Fiteni F, Gauthier L et al (2022) Pharmacokinetic variability drives palbociclib-induced neutropenia in metastatic breast cancer patients: drug-drug interactions are the usual suspects. Pharmaceutics 14(4):841. 10.3390/pharmaceutics14040841

24. Peruzzi E, Gerratana L, Montico M et al (2023) Association of ADME gene polymorphisms on toxicity to CDK4/6 inhibitors in patients with HR+ HER2- metastatic breast cancer. Biomed Pharmacother 167:115479. 10.1016/j.biopha.2023.115479

25. Schreiber V, Dantzer F, Ame JC, de Murcia G (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7(7):517–528. 10.1038/nrm1963

26. Satoh MS, Lindahl T (1992) Role of poly(ADP-ribose) formation in DNA repair. Nature 356(6367):356–358. 10.1038/356356a0

27. Valerie K, Povirk LF (2003) Regulation and mechanisms of mammalian double-strand break repair. Oncogene 22(37 REV. ISS. 3):5792–5812. 10.1038/sj.onc.1206679

28. Lord CJ, Ashworth A (2017) PARP inhibitors: synthetic lethality in the clinic. Science 355(6330):1152–1158. 10.1126/science.aam7344

29. Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921. 10.1038/nature03445

30. Kaufman B, Shapira-Frommer R, Schmutzler RK et al (2015) Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33(3):244–250. 10.1200/JCO.2014.56.2728

31. Kim G, Ison G, McKee AE et al (2015) FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res 21(19):4257–4261. 10.1158/1078-0432.CCR-15-0887

32. González-Martín A, Pothuri B, Vergote I et al (2019) Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 381(25):2391–2402. 10.1056/nejmoa1910962

33. Ray-Coquard I, Pautier P, Pignata S et al (2019) Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med 381(25):2416–2428. 10.1056/nejmoa1911361

34. Mirza MR, Monk BJ, Herrstedt J et al (2016) Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 375(22):2154–2164. 10.1056/nejmoa1611310

35. Coleman RL, Oza AM, Lorusso D et al (2017) Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390(10106):1949–1961. 10.1016/S0140-6736(17)32440-6

36. LaFargue CJ, Dal Molin GZ, Sood AK, Coleman RL (2019) Exploring and comparing adverse events between PARP inhibitors. Lancet Oncol 20(1):e15–e28. 10.1016/S1470-2045(18)30786-1

37. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL (2007) Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447(7145):725–729. 10.1038/nature05862

38. Farreś J, Martín-Caballero J, Martínez C et al (2013) Parp-2 is required to maintain hematopoiesis following sublethal γ-irradiation in mice. Blood 122(1):44–54. 10.1182/blood-2012-12-472845

39. Farrés J, Llacuna L, Martin-Caballero J et al (2015) PARP-2 sustains erythropoiesis in mice by limiting replicative stress in erythroid progenitors. Cell Death Differ 22(7):1144–1157. 10.1038/cdd.2014.202

40. Effect of granulocyte colony-stimulating factor on toxicities after CAR T cell therapy for lymphoma and myeloma | Blood Cancer Journal. Accessed December 28, 2023. https://www.nature.com/articles/s41408-022-00741-2

41. Loibl S, O’Shaughnessy J, Untch M et al (2018) Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol 19(4):497–509. 10.1016/S1470-2045(18)30111-6

42. Tutt ANJ, Garber JE, Kaufman B et al (2021) Adjuvant olaparib for patients with BRCA1 - or BRCA2 -mutated breast cancer. N Engl J Med 384(25):2394–2405. 10.1056/NEJMoa2105215

43. Li N, Zhang Y, Wang J et al (2022) Fuzuloparib maintenance therapy in patients with platinum-sensitive, recurrent ovarian carcinoma (FZOCUS-2): a multicenter, randomized, double-blind, placebo-controlled, phase III trial. J Clin Oncol 40(22):2436–2446. 10.1200/JCO.21.01511

44. Golan T, Hammel P, Reni M et al (2019) Maintenance olaparib for germline BRCA -mutated metastatic pancreatic cancer. N Engl J Med 381(4):317–327. 10.1056/NEJMoa1903387

45. Moore K, Colombo N, Scambia G et al (2018) Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 379(26):2495–2505. 10.1056/NEJMoa1810858

46. Wu XH, Zhu JQ, Yin RT et al (2021) Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial☆. Ann Oncol 32(4):512–521. 10.1016/j.annonc.2020.12.018

47. Robson M, Im SA, Senkus E et al (2017) Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 377(6):523–533. 10.1056/NEJMoa1706450

48. de Bono J, Mateo J, Fizazi K et al (2020) Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 382(22):2091–2102. 10.1056/NEJMoa1911440

49. Pujade-Lauraine E, Ledermann JA, Selle F et al (2017) Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 18(9):1274–1284. 10.1016/S1470-2045(17)30469-2

50. Penson RT, Villalobos Valencia R, David Cibula ;, et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial. J Clin Oncol . 2020;38:1164–1174. 10.1200/JCO.19

51. Liu JF, Brady MF, Matulonis UA et al (2022) Olaparib with or without cediranib versus platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer (NRG-GY004): a randomized, open-label, phase III trial. J Clin Oncol 40(19):2138–2147. 10.1200/JCO.21.02011

52. Kristeleit R, Lisyanskaya A, Fedenko A et al (2022) Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial. Lancet Oncol 23(4):465–478. 10.1016/S1470-2045(22)00122-X

53. Litton JK, Rugo HS, Ettl J et al (2018) Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 379(8):753–763. 10.1056/NEJMoa1802905

54. Ramalingam SS, Novello S, Guclu SZ et al (2021) Veliparib in combination with platinum-based chemotherapy for first-line treatment of advanced squamous cell lung cancer: a randomized, multicenter phase III study. J Clin Oncol 39(32):3633–3644. 10.1200/JCO.20.03318

55. Diéras V, Han HS, Kaufman B et al (2020) Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21(10):1269–1282. 10.1016/S1470-2045(20)30447-2

56. Coleman RL, Fleming GF, Brady MF et al (2019) Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med 381(25):2403–2415. 10.1056/NEJMoa1909707

57. Kroll MH, Rojas-Hernandez C, Yee C (2022) Hematologic complications of immune checkpoint inhibitors. Blood. 10.1182/blood.2020009016

58. Sobhani N, Tardiel-Cyril DR, Davtyan A, Generali D, Roudi R, Li Y (2021) CTLA-4 in regulatory T cells for cancer immunotherapy. Cancers (Basel) 13(6):1440. 10.3390/cancers13061440

59. Qureshi OS, Zheng Y, Nakamura K et al (2011) Trans-endocytosis of CD80 and CD86: a molecular basis for the cell extrinsic function of CTLA-4. Science 332(6029):600–603. 10.1126/science.1202947

60. Ribas A (2015) Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov 5(9):915–919. 10.1158/2159-8290.CD-15-0563

61. Sage PT, Francisco LM, Carman CV, Sharpe AH (2013) PD-1 controls lymph node and blood T follicular regulatory cells. Nat Immunol 14(2):152–161. 10.1038/ni.2496

62. Park JE, Kim SE, Keam B et al (2020) Anti-tumor effects of NK cells and anti-PD-L1 antibody with antibody-dependent cellular cytotoxicity in PD-L1-positive cancer cell lines. J Immunother Cancer 8(2):e000873. 10.1136/jitc-2020-000873

63. Kroll MH, Rojas-Hernandez C, Yee C. Hematologic complications of immune checkpoint inhibitors.

64. Davis EJ, Salem J, Young A et al (2019) Hematologic complications of immune checkpoint inhibitors. Oncologist 24(5):584–588. 10.1634/theoncologist.2018-0574

65. Quirk SK, Shure AK, Agrawal DK (2015) Immune-mediated adverse effects of anti-CTLA-4 antibody therapy in metastatic melanoma. Transl Res J Lab Clin Med 166(5):412–424. 10.1016/j.trsl.2015.06.005

66. Omar NE, El-Fass KA, Abushouk AI, et al. Diagnosis and management of hematological adverse events induced by immune checkpoint inhibitors: a systematic review. Front Immunol . 2020;11. Accessed December 11, 2022. https://www.frontiersin.org/articles/10.3389/fimmu.2020.01354

67. Inadomi K, Kumagai H, Arita S et al (2016) Bi-cytopenia possibly induced by anti-PD-1 antibody for primary malignant melanoma of the esophagus. Medicine (Baltimore) 95(29):e4283. 10.1097/MD.0000000000004283

68. Petrelli F, Ardito R, Borgonovo K et al (2018) Haematological toxicities with immunotherapy in patients with cancer: a systematic review and meta-analysis. Eur J Cancer 103:7–16. 10.1016/j.ejca.2018.07.129

69. Naqash AR, Appah E, Yang LV et al (2019) Isolated neutropenia as a rare but serious adverse event secondary to immune checkpoint inhibition. J Immunother Cancer 7(1):169. 10.1186/s40425-019-0648-3

70. Delanoy N, Michot JM, Comont T et al (2019) Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study. Lancet Haematol 6(1):e48–e57. 10.1016/S2352-3026(18)30175-3

71. Haanen J, Obeid M, Spain L et al (2022) Management of toxicities from immunotherapy: ESMO clinical practice guideline for diagnosis, treatment and follow-up☆. Ann Oncol 33(12):1217–1238. 10.1016/j.annonc.2022.10.001

72. Ohashi T, Takase-Minegishi K, Maeda A et al (2023) Incidence and risk of hematological adverse events associated with immune checkpoint inhibitors: a systematic literature review and meta-analysis. J Hematol 12(2):66–74. 10.14740/jh1090

73. Hou J, Xie R, Zhang Z, Liu Q, Xiang Q, Cui Y (2023) Hematologic side effects of immune checkpoint inhibitor with or without chemotherapy in patients with advanced and metastatic gastrointestinal cancer: a systematic review and network meta-analysis of phase 3 trials. Front Pharmacol 14:1163971. 10.3389/fphar.2023.1163971

74. Brahmer JR, Lacchetti C, Schneider BJ et al (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol Off J Am Soc Clin Oncol 36(17):1714–1768. 10.1200/JCO.2017.77.6385

75. Schneider BJ, Naidoo J, Santomasso BD et al (2021) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 39(36):4073–4126. 10.1200/JCO.21.01440

76. Marcus R, Imrie K, Solal-Celigny P et al (2008) Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 10.1200/JCO.2007.13.5376

77. Coiffier B, Lepage E, Brière J et al (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346(4):235–242. 10.1056/NEJMoa011795

78. Zucca E, Conconi A, Laszlo D et al (2013) Addition of rituximab to chlorambucil produces superior event-free survival in the treatment of patients with extranodal marginal-zone B-cell lymphoma: 5-year analysis of the IELSG-19 randomized study. J Clin Oncol 31(5):565–572. 10.1200/JCO.2011.40.6272

79. Gómez-Puerta JA, Quintana LF, Stone JH, Ramos-Casals M, Bosch X (2012) B-cell depleting agents for ANCA vasculitides: a new therapeutic approach. Autoimmun Rev 11(9):646–652. 10.1016/j.autrev.2011.11.007

80. Gregersen JW, Jayne DRW (2012) B-cell depletion in the treatment of lupus nephritis. Nat Rev Nephrol 8(9):505–514. 10.1038/nrneph.2012.141

81. Sebastiani M, Anelli MG, Atzeni F et al (2014) Efficacy and safety of rituximab with and without methotrexate in the treatment of rheumatoid arthritis patients: results from the GISEA register. Joint Bone Spine 81(6):508–512. 10.1016/j.jbspin.2014.06.011

82. Mössner E, Brünker P, Moser S et al (2010) Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell–mediated B-cell cytotoxicity. Blood 115(22):4393–4402. 10.1182/blood-2009-06-225979

83. Herter S, Herting F, Mundigl O et al (2013) Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther 12(10):2031–2042. 10.1158/1535-7163.MCT-12-1182

84. Elias S, Kahlon S, Kotzur R, Kaynan N, Mandelboim O (2018) Obinutuzumab activates FcγRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL). Oncoimmunology 7(6):e1428158. 10.1080/2162402X.2018.1428158

85. Cattaneo C, Spedini P, Casari S et al (2006) Delayed-onset peripheral blood cytopenia after rituximab: frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk Lymphoma 47(6):1013–1017. 10.1080/10428190500473113

86. Davis TA, Grillo-López AJ, White CA et al (2000) Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: safety and efficacy of re-treatment. J Clin Oncol Off J Am Soc Clin Oncol 18(17):3135–3143. 10.1200/JCO.2000.18.17.3135

87. Voog E, Morschhauser F, Solal-Céligny P. Neutropenia in patients treated with rituximab. N Engl J Med . 2003;348(26):2691–2694; discussion 2691–2694. 10.1056/NEJM200306263482620

88. Liu JH, Wei S, Lamy T et al (2000) Chronic neutropenia mediated by Fas ligand. Blood 95(10):3219–3222. 10.1182/blood.V95.10.3219

89. Stamatopoulos K, Papadaki T, Pontikoglou C et al (2008) Lymphocyte subpopulation imbalances, bone marrow hematopoiesis and histopathology in rituximab-treated lymphoma patients with late-onset neutropenia. Leukemia 22(7):1446–1449. 10.1038/sj.leu.2405077

90. Ma Q, Jones D, Springer TA (1999) The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10(4):463–471. 10.1016/S1074-7613(00)80046-1

91. Terrier B, Ittah M, Tourneur L et al (2007) Late-onset neutropenia following rituximab results from a hematopoietic lineage competition due to an excessive BAFF-induced B-cell recovery. Haematologica 92(2):e20–e23. 10.3324/haematol.11031

92. Wolach O, Bairey O, Lahav M (2010) Late-onset neutropenia after rituximab treatment: case series and comprehensive review of the literature. Medicine (Baltimore) 89(5):308–318. 10.1097/MD.0b013e3181f2caef

93. Zhang X, Rao M, Xu G. An update on the incidence, risk factors and mechanisms of rituximab-associated neutropenia. Arch Med Sci . Published online September 15, 2022. 10.5114/aoms/152174

94. Salmon JH, Cacoub P, Combe B et al (2015) Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the autoimmunity and rituximab registry. RMD Open 1(1):e000034. 10.1136/rmdopen-2014-000034

95. Zonozi R, Wallace ZS, Laliberte K et al (2021) Incidence, clinical features, and outcomes of late-onset neutropenia from rituximab for autoimmune disease. Arthritis Rheumatol 73(2):347–354. 10.1002/art.41501

96. Amitai I, Gafter-Gvili A, Shargian-Alon L, Raanani P, Gurion R (2021) Obinutuzumab-related adverse events: a systematic review and meta-analysis. Hematol Oncol 39(2):215–221. 10.1002/hon.2828

97. Shimony S, Bar-Sever E, Berger T et al (2021) Late onset neutropenia after rituximab and obinutuzumab treatment – characteristics of a class-effect toxicity. Leuk Lymphoma 62(12):2921–2927. 10.1080/10428194.2021.1948037

98. Danés I, Agustí A, Vallano A et al (2013) Available evidence and outcome of off-label use of rituximab in clinical practice. Eur J Clin Pharmacol 69(9):1689–1699. 10.1007/s00228-013-1518-4

99. Diez-Feijóo R, Rodríguez-Sevilla JJ, Fernández-Rodríguez C et al (2022) Case report: high doses of intravenous immunoglobulins as a successful treatment for late onset immune agranulocytosis after rituximab plus bendamustine. Front Immunol 12:798251. 10.3389/fimmu.2021.798251

100. Rose AL, Forsythe AM, Maloney DG (2003) Agranulocytosis unresponsive to growth factors following rituximab in vivo purging. Blood 101(10):4225–4226. 10.1182/blood-2003-02-0450

101. Locke FL, Ghobadi A, Jacobson CA et al (2019) Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol 20(1):31–42. 10.1016/S1470-2045(18)30864-7

102. Neelapu SS, Locke FL, Bartlett NL et al (2017) Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 377(26):2531–2544. 10.1056/NEJMoa1707447

103. Jacobson CA, Hunter B, Armand P et al (2018) Axicabtagene ciloleucel in the real world: outcomes and predictors of response, resistance and toxicity. Blood 132(Supplement 1):92–92. 10.1182/blood-2018-99-117199

104. Nastoupil LJ, Jain MD, Feng L et al (2020) Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J Clin Oncol Off J Am Soc Clin Oncol 38(27):3119–3128. 10.1200/JCO.19.02104

105. Maude SL, Laetsch TW, Buechner J et al (2018) Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 378(5):439–448. 10.1056/NEJMoa1709866

106. Schuster SJ, Bishop MR, Tam CS et al (2019) Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 380(1):45–56. 10.1056/NEJMoa1804980

107. Berdeja JG, Madduri D, Usmani SZ et al (2021) Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet 398(10297):314–324. 10.1016/S0140-6736(21)00933-8

108. Munshi NC, Anderson LD, Shah N et al (2021) Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 384(8):705–716. 10.1056/NEJMoa2024850

109. Abramson JS, Palomba ML, Gordon LI et al (2020) Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 396(10254):839–852. 10.1016/S0140-6736(20)31366-0

110. Wang M, Munoz J, Goy A et al (2020) KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med 382(14):1331–1342. 10.1056/NEJMoa1914347

111. Sharma N, Reagan PM, Liesveld JL (2022) Cytopenia after CAR-T cell therapy—a brief review of a complex problem. Cancers 14(6):1501. 10.3390/cancers14061501

112. Bachy E, Le Gouill S, Di Blasi R et al (2022) A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma. Nat Med. 10.1038/s41591-022-01969-y

113. Jacobson CA, Hunter BD, Redd R et al (2020) Axicabtagene ciloleucel in the non-trial setting: outcomes and correlates of response, resistance, and toxicity. J Clin Oncol 38(27):3095–3106. 10.1200/JCO.19.02103

114. Inc MG. CAR T-cells associated acute toxicity in B-cell non-Hodgkin... by Dr. Pierre Sesques. Accessed December 28, 2023. https://library.ehaweb.org/eha/2022/eha2022-congress/357074/pierre.sesques.car.t-cells.associated.acute.toxicity.in.b-cell.non-hodgkin.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D2%2Asearch%3Dcar-t

115. Wudhikarn K, Pennisi M, Garcia-Recio M et al (2020) DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality. Blood Adv 4(13):3024–3033. 10.1182/bloodadvances.2020001972

116. Schuster SJ, Tam CS, Borchmann P et al (2021) Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 22(10):1403–1415. 10.1016/S1470-2045(21)00375-2

117. Rejeski K, Perez A, Sesques P et al (2021) CAR-HEMATOTOX: a model for CAR T-cell–related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood 138(24):2499–2513. 10.1182/blood.2020010543

118. Rejeski K, Perez A, Iacoboni G et al (2023) Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion. Sci Adv 9(38):eadg3919. 10.1126/sciadv.adg3919

119. Rejeski K, Wang Y, Albanyan O et al (2023) The CAR-HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL. Am J Hematol 98(11):1699–1710. 10.1002/ajh.27056

120. Rejeski K, Hansen DK, Bansal R et al (2023) The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma. J Hematol Oncol 16(1):88. 10.1186/s13045-023-01465-x

121. Rejeski K, Subklewe M, Aljurf M et al (2023) Immune effector cell–associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations. Blood 142(10):865–877. 10.1182/blood.2023020578

122. Galli E, Allain V, Di Blasi R et al (2020) G-CSF does not worsen toxicities and efficacy of CAR-T cells in refractory/relapsed B-cell lymphoma. Bone Marrow Transplant 55(12):2347–2349. 10.1038/s41409-020-01006-x

123. Liévin R, Di Blasi R, Morin F et al (2022) Effect of early granulocyte-colony-stimulating factor administration in the prevention of febrile neutropenia and impact on toxicity and efficacy of anti-CD19 CAR-T in patients with relapsed/refractory B-cell lymphoma. Bone Marrow Transplant 57(3):431–439. 10.1038/s41409-021-01526-0

124. Ma S, Li H, Zhou D et al (2023) Associations of granulocyte colony-stimulating factor with toxicities and efficacy of chimeric antigen receptor T-cell therapy in relapsed or refractory multiple myeloma. Cytotherapy 25(6):653–658. 10.1016/j.jcyt.2023.01.011

125. Rejeski K. Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations. CELL Ther . 2023;142(10).

126. Jain T, Knezevic A, Pennisi M et al (2020) Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic malignancies. Blood Adv 4(15):3776–3787. 10.1182/bloodadvances.2020002509

127. Rejeski K, Burchert A, Iacoboni G et al (2022) Safety and feasibility of stem cell boost as a salvage therapy for severe hematotoxicity after CD19 CAR T-cell therapy. Blood Adv 6(16):4719–4725. 10.1182/bloodadvances.2022007776

128. Gagelmann N, Wulf GG, Duell J et al (2023) Hematopoietic stem cell boost for persistent neutropenia after CAR T-cell therapy: a GLA/DRST study. Blood Adv 7(4):555–559. 10.1182/bloodadvances.2022008042

129. Santoro A, Bientinesi E, Monti D (2021) Immunosenescence and inflammaging in the aging process: age-related diseases or longevity? Ageing Res Rev 71:101422. 10.1016/j.arr.2021.101422

130. Rossi DJ, Bryder D, Zahn JM et al (2005) Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 102(26):9194–9199. 10.1073/pnas.0503280102

131. Silvestre-Roig C, Hidalgo A, Soehnlein O (2016) Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood 127(18):2173–2181. 10.1182/blood-2016-01-688887

132. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29(7):1303–1310. 10.1097/00003246-200107000-00002

133. Arcanjo A, Logullo J, Menezes CCB et al (2020) The emerging role of neutrophil extracellular traps in severe acute respiratory syndrome coronavirus 2 (COVID-19). Sci Rep 10(1):19630. 10.1038/s41598-020-76781-0

134. Barnes BJ, Adrover JM, Baxter-Stoltzfus A et al (2020) Targeting potential drivers of COVID-19: neutrophil extracellular traps. J Exp Med 217(6):e20200652. 10.1084/jem.20200652

135. He Z, Fahlberg MD, Takahashi N et al (2021) Declining neutrophil production despite increasing G-CSF levels is associated with chronic inflammation in elderly rhesus macaques. J Leukoc Biol 109(6):1033–1043. 10.1002/JLB.1HI1120-779R

136. Bergenfelz C, Leandersson K. The generation and identity of human myeloid-derived suppressor cells. Front Oncol . 2020;10. Accessed September 6, 2022. https://www.frontiersin.org/articles/10.3389/fonc.2020.00109

137. Salminen A, Kaarniranta K, Kauppinen A (2019) Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency. Cell Mol Life Sci 76(10):1901–1918. 10.1007/s00018-019-03048-x

138. Schroeter A, Roesel MJ, Matsunaga T, Xiao Y, Zhou H, Tullius SG (2022) Aging affects the role of myeloid-derived suppressor cells in alloimmunity. Front Immunol 13:917972. 10.3389/fimmu.2022.917972

139. Luyckx A, Schouppe E, Rutgeerts O et al (2012) G-CSF stem cell mobilization in human donors induces polymorphonuclear and mononuclear myeloid-derived suppressor cells. Clin Immunol 143(1):83–87. 10.1016/j.clim.2012.01.011

140. Williams GC (1957) Pleiotropy, natural selection, and the evolution of senescence. Evolution 11(4):398. 10.2307/2406060

141. Genovese G, Kähler AK, Handsaker RE et al (2014) Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 371(26):2477–2487. 10.1056/NEJMoa1409405

142. Zink F, Stacey SN, Norddahl GL et al (2017) Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130(6):742–752. 10.1182/blood-2017-02-769869

143. Trillsch F, Mahner S, Ataseven B et al (2022) Efficacy and safety of olaparib according to age in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer: analysis of the phase III SOLO2/ENGOT-Ov21 study. Gynecol Oncol 165(1):40–48. 10.1016/j.ygyno.2022.01.024

144. Balducci L, Falandry C, List A (2023) A proactive approach to prevent hematopoietic exhaustion during cancer chemotherapy in older patients: temporary cell-cycle arrest. Drugs Aging 40(3):263–272. 10.1007/s40266-022-01005-1

145. Balducci L, Falandry C, Silvio Monfardini. Senotherapy, cancer, and aging. J Geriatr Oncol . Published online November 2023:101671. 10.1016/j.jgo.2023.101671

146. Blayney DW, Schwartzberg L (2022) Chemotherapy-induced neutropenia and emerging agents for prevention and treatment: a review. Cancer Treat Rev 109:102427. 10.1016/j.ctrv.2022.102427

147. Daniel D, Kuchava V, Bondarenko I, et al. Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: a multicentre, randomised, double-blind, placebo-controlled Phase II trial. Int J Cancer . Published online December 21, 2020. 10.1002/ijc.33453

148. Hussein M, Maglakelidze M, Richards DA et al (2021) Myeloprotective effects of trilaciclib among patients with small cell lung cancer at increased risk of chemotherapy-induced myelosuppression: pooled results from three phase 2, randomized, double-blind, placebo-controlled studies. Cancer Manag Res 13:6207–6218. 10.2147/CMAR.S313045

149. Wang Y, Zhang H, Gigant B et al (2016) Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery. FEBS J 283(1):102–111. 10.1111/febs.13555

150. Tonra JR, Lloyd GK, Mohanlal R, Huang L (2020) Plinabulin ameliorates neutropenia induced by multiple chemotherapies through a mechanism distinct from G-CSF therapies. Cancer Chemother Pharmacol 85(2):461–468. 10.1007/s00280-019-03998-w

151. Guerlavais V, Sawyer TK, Carvajal L et al (2023) Discovery of sulanemadlin (ALRN-6924), the first cell-permeating, stabilized α-helical peptide in clinical development. J Med Chem 66(14):9401–9417. 10.1021/acs.jmedchem.3c00623

152. Lagoumtzi SM, Chondrogianni N (2021) Senolytics and senomorphics: natural and synthetic therapeutics in the treatment of aging and chronic diseases. Free Radic Biol Med 171:169–190. 10.1016/j.freeradbiomed.2021.05.003

153. Zhang L, Pitcher LE, Prahalad V, Niedernhofer LJ, Robbins PD (2023) Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. FEBS J 290(5):1362–1383. 10.1111/febs.16350

154. Aratani S, Nakanishi M (2023) Recent advances in senolysis for age-related diseases. Physiology 38(5):205–216. 10.1152/physiol.00003.2023

155. Feng M, Kim J, Field K, Reid C, Chatzistamou I, Shim M (2019) Aspirin ameliorates the long-term adverse effects of doxorubicin through suppression of cellular senescence. FASEB Bioadv 1(9):579–590. 10.1096/fba.2019-00041

156. Hu D, Xie F, Xiao Y et al (2021) Metformin: a potential candidate for targeting aging mechanisms. Aging Dis 12(2):480–493. 10.14336/AD.2020.0702

157. Awadalla A, Hussein AM, El-Far YM et al (2022) Rapamycin improves adipose-derived mesenchymal stem cells (ADMSCs) renoprotective effect against cisplatin-induced acute nephrotoxicity in rats by inhibiting the mTOR/AKT signaling pathway. Biomedicines 10(6):1295. 10.3390/biomedicines10061295

158. Shawky AM, Almalki FA, Abdalla AN, Abdelazeem AH, Gouda AM (2022) A comprehensive overview of globally approved JAK inhibitors. Pharmaceutics 14(5):1001. 10.3390/pharmaceutics14051001

159. Zhang Q, Lenardo MJ, Baltimore D (2017) 30 years of NF-κB: a blossoming of relevance to human pathobiology. Cell 168(1–2):37–57. 10.1016/j.cell.2016.12.012

Associated Data

Supplementary Materials

(DOCX 624 KB)

Data Availability Statement

No datasets were generated or analysed during the current study.