Hematologic complications of immune checkpoint inhibitors

This Review Series, edited by past Associate Editor Catherine Bollard, looks at the role of immunotherapy in nonmalignant hematologic diseases. These 3 state-of-the-art reviews focus on the role of complement and complement inhibitors across a spectrum of diseases, the special immunologic challenges of hematopoietic stem cell transplant for nonmalignant diseases where patients have an intact immune system, and the hematologic complications of immune checkpoint inhibitors.


Introduction
Immune checkpoint inhibitors (ICIs) have transformed cancer care. 7 medications have been FDA approved for the treatment of 14 solid tumors and 2 hematological malignancies ( Table 1). They were considered to work primarily by overcoming tumor immune evasion by blocking inhibitory signals generated by ligand engagement of the lymphocyte receptors cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1), thereby unleashing clones of tumor-reactive CD8+ (or cytotoxic) T lymphocytes (CTLs). Clinical experiences have, however, expanded this simplistic model and introduced new information about how these systems operate within a complex immune response. Such "reverse translational studies" have in part been built upon a catalogue of immune checkpoint inhibitor toxicities, including hematological toxicities. This review will therefore approach the subject of hematologic complications of checkpoint inhibitors from an immunological point-of-view, aiming to identify putative mechanisms of hematological toxicities ( Figure 1). Its focus will be on hemolytic anemia, thrombocytopenia, neutropenia, bone marrow failure, hemophagocytic lymphohistiocytosis (HLH) and thrombosis. These problems will be examined focusing on autoreactive T cells, autoantibody production, and inflammatory signals. 1

CTLA-4, PD-1, and PD-L1
Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2020009016/1826266/blood.2020009016.pdf by guest on 06 October 2021 CTLA-4 is a protein receptor expressed following the activation of CD4+ and CD8+ T lymphocytes, and is expressed constitutively on CD4/25 + regulatory T lymphocytes (Tregs). The immunosuppressive function of CTLA-4 is due to its higher affinity than the activating T lymphocyte receptor CD28 for their shared ligand CD80/86 present on the antigen presenting dendritic cells and macrophages (antigen presenting cells or APCs - Figure 1). CD80/86 binding to CTLA-4 thereby subverts the stimulating CD28-mediated pathway, leading to CTL inhibition. 2 When CTLA-4 on Tregs engages CD80/86 on APCs it is immune-suppressive because it downregulates antigen presentation to CTLs by competition, as above, as well as through endocytic degradation by the APC of CD80/86 following CTLA-4 binding. 3 CTLA-4 gene deletion in mice leads to a rapid massive fatal lymphoproliferative disorder with spleen, lymph nodes, bone marrow, heart, lung, liver and pancreas infiltrated by activated lymphocytes. 4 PD-1 is expressed on activated CD4+ and CD8+ T lymphocytes (including tumorinfiltrating lymphocytes and Tregs), B lymphocytes, macrophages, natural killer (NK) cells, and myeloid-derived suppressor cells (MDSC). 5 Programmed deathligand 1 (PD-L1) is a ligand for PD-1 expressed on APCs and tumor cells. On tumor cells it can be upregulated by oncogenic signals and by interferon gamma (IFN-γ), whereby IFN-γ release by activated tumor-reactive lymphocytes leads to tumorassociated upregulation of PD-L1. 6 PD-L2 is a second ligand for PD-1; it is found mainly on hematopoietic cells. PD-L1 binding to PD-1 on effector T cells induces a negative regulatory signal that leads to functional anergy and decreases the immune Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2020009016/1826266/blood.2020009016.pdf by guest on 06 October 2021 suppressive function of follicular Tregs while it stimulates the immune suppressive function of blood Tregs, suggesting that these ICIs enhance autoantibody production in germinal centers. 7,8 PD-L1 binding to PD-1 mediates a similar inhibitory effect on unactivated B lymphocytes, macrophages and NK cells. 9 Various malignancies overexpress PD-L1, thereby escaping immune cell-mediated killing, and some malignancies stimulate PD-1 expression by MDSC, leading to MDSC proliferation and suppression of the local immune response. The broader array of PD-1 expressing cells suggests that its physiological role in immune suppression is more broadly fine-tuning of immune responses than is CTLA-4. Depending on strain, mice deficient in PD-1 develop varying degrees of arthritis, glomerulonephritis, cardiomyopathy, and a lupus-like phenotype over 6-12 months, indicating that PD-1 is a master regulator of self-tolerance and autoimmunity. 10

Targeted therapeutics
Ipilimumab is a human IgG4 monoclonal antibody to CTLA-4 that blocks it from binding CD80/86; it appears to work best in tumors with a high mutational burden, leading to greater neoantigens expression. This is why it is particularly effective in melanoma, a tumor with the highest burden of mutations. 11 About one-quarter of patients treated with ipilimumab experience serious toxicities of grade 3 or higher by the Common Terminology Criteria for Adverse Events (CTCAE). The CTCAE are a standard set of criteria for the general classification of adverse effects of antineoplastic therapy (i.e. "anemia" or "thrombocytopenia") and are not necessarily immune-related hematological adverse events (irAEs). CTCAEs usually develop within weeks to months of starting the medication. The most common ipilimumab toxicities are dermatological, gastrointestinal, liver, and endocrine, particularly hypophysitis. Fatal toxicity, usually from colitis, occurs in about 1.2% of patients, and usually develops early in the treatment program. 12 When ipilimumab is combined with the PD-1 inhibitor nivolumab the incidence of high-grade toxicities is roughly double that observed with single agent therapy. 13 All FDA-approved PD-1 inhibitors and the PD-L1 inhibitor durvalumab are human monoclonal IgG4 blocking antibodies. The PD-L1 inhibitors avelumab and atezolizumab are human monoclonal IgG1 blocking antibodies; only avelumab has a wild-type Fc receptor capable of mediating antibody-dependent cellular cytotoxicity (ADCC). These agents' anti-tumor activity correlates with the amount of PD-L1 expressed on tumor cells and tumor-associated stroma 14 , and measurement of PD-L1 mRNA or protein expression for some cancers, such as lung and urothelial, is predictive of responsiveness. About 10% of treated patients develop high-grade (CTCAE grade 3 and 4) ICI-related adverse events, usually in the first weeks to months after starting the medications, although toxicities have appeared more than a year after starting therapy. The profile of toxicities is similar to ipilimumab, except pneumonitis is notably more frequent and endocrine toxicities more often involve the thyroid, adrenal, and pancreatic β cell, rather than the pituitary gland. 11 Early lethal toxicity is most commonly attributable to pneumonitis, which occurs in about 0.4% of patients. The gut microbiome appears to influence both ICI efficacy and toxicity. 15 Preexisting lymphocyte counts are reported to be correlated with both efficacy and toxicity, presumably because of the dose-effect of unleashed lymphocytes ( Figure   1). 16 Mutation burden and PD-L1 expression influence ICI efficacy, but neither these factors nor tumor type affect the incidence of toxicity, with the exception that melanoma patients are more likely to develop vitiligo and colitis. Conversely, there are several factors that increase the risk of ICI toxicity without any apparent effect on efficacy: HLA-DR4/DRB1*04:05/DRB1*11:01 genotypes, a history of autoimmune diseases, baseline autoantibody or cytokine levels, and the ratio of neutrophils or platelets to lymphocytes. 11 There is also evidence that end-organ toxicity is triggered when an otherwise mild new insult is experienced, such as hepatitis or acute kidney injury when a potentially organ-toxic chemotherapy is started. This is the usual explanation for late-onset toxicities. Radiation therapy does not increase ICI toxicities. 17 The scope of hematological toxicities.
Hematological toxicities associated with ICI therapy are divided into non-immune and immune, but the distinction between them is vague and not discernable by any specific measures, although laboratory testing and clinical course are often used to define irAEs. The overall incidence of hematological toxicities was tabulated from 47 phase 1-3 clinical trials including 9,324 patients using different ICIs -although mainly PD-1 and PD-L1 inhibitors -to treat different tumor types. 18 The incidence of CTCAE high grade anemia was variable, 0.1%-17%. Other high-grade cytopenias were less variable: 0.4%-1.7% % for neutropenia; and ~ 1.2%-2.5% for thrombocytopenia. Mechanisms of these toxicities were not specified, but irAEs probably represented only a fraction of overall hematological toxicities.

The Registre des Effets Indésirables Sévères des Anticorps Monoclonaux
Immunomodulateurs en Cancérologie (REISAMIC), a prospective multicenter registry of patients treated with anti-PD-1 or anti-PD-L1 therapy, identified 4 hematological irAEs among 745 patients. 19 A recent meta-analysis of 14 case series and 66 individual case reports identified 145 total irAEs. 20 These studies fail to provide a denominator of all treated patients, but there are two studies that allow an estimation of the incidence of some hematological toxicities. The first examined 5,923 patients from 19 clinical trials and calculated an overall irAE rate of 3.6% (1% ITP, 0.6% aplastic anemia/pancytopenia, 0.6% neutropenia, 0.6% hemolytic anemia, 0.4% hemophagocytic lymphohistiocytosis (HLH), and 0.3% bicytopenia/pure red cell aplasia). 21 High-grade irAEs were 0.7% overall and mortality among all irAEs was 14%. The second study identified ITP in 11/2,360 patients (0.46%). 22 An examination of these reports also provides an estimate of natural history and outcomes: at least half of hematological irAEs appeared within the first 10 weeks after initiation of the ICI and most required about 1-2 months for resolution. [19][20][21][22] Comment [RHM1]: Did you mean to say 4 types of hematological irAEs?
The issue of thrombosis as an irAE is much less certain. While one study identified venous thromboembolism (VTE) in 47/672 ICI patients (~7%) 23 , another found that ICI-related VTE incidence was comparable to that for patients with similar cancers of similar stages not receiving an ICI 24 . Further evidence against the conclusion that ICIs are a clinically significant risk factor for cancer-associated VTE is presented in a retrospective analysis demonstrating that VTE occurred led frequently among lung cancer patients receiving an ICI than among those getting platinum-based chemotherapy. 25 It appears that, except for HLH (see below), PD-1, PD-L1 and CTLA-4 inhibitors are associated with hematological irAEs of similar rates, types, magnitudes and clinical courses. Because they are so infrequent, irAEs' predisposing factors, clinical presentations, mechanisms-of-toxicity, and management are uncertain. This fact underlies guidelines that are poorly evidence-based and built mainly on expert opinion. 26,27 Hemolytic Anemia REISAMIC included 9 cases of hemolytic anemia, identified by any CTCAE grade 2 or greater anemia and with clinical data consistent with a hemolytic anemia as reviewed by a board of experts in hematology and autoimmune disease. 19 A US multicenter retrospective cohort analysis included 14 cases identified by an abrupt decrease of serum hemoglobin concentration of 2 gm/dL associated with several laboratory parameters of red blood cell hemolysis. 26 The FDA Adverse Events Reporting System (an administrative data base of adverse events identified by terms "autoimmune hemolytic anemia" or "Coombs positive hemolytic anemia" and reported by individual practitioners) included 68 cases (with unknown overlap with the US multicenter cohort). 28 In REISAMIC all 9 cases had a positive direct antiglobulin test (DAT): 3 for IgG and 6 for complement factor 3d. Three of the latter 6 patients also had IgM autoantibodies in their serum (cold agglutinins). These results demonstrate that many cases of ICI-associated hemolytic anemia are due to autoantibody production, providing a reasonable template for diagnosis and treatment with the obvious caveat that one must ensure that serological testing is not cofounded by red blood cell alloantibodies. Mechanisms of autoantibody production are not understood but may involve decreased Treg-mediated immune suppression and/or B cell activation ( Figure 1).
Treatment begins with holding the ICI, which is recommended when the serum hemoglobin concentration (Hgb) is below 10 gm/dL. 26 After the ICI is held and because serology is often consistent with warm IgG or cold IgM autoimmune hemolytic anemia, clinical reports and guidelines have almost always described treatments that are routine for autoimmune hemolytic anemia: corticosteroids and rituximab, given simultaneously or sequentially, depending on the serological profile ( Table 2). Response rates -defined broadly in one analysis as complete (pre-ICI) and partial (Hgb within 2 gm/dL of pre-ICI) 28 -exceed 66% with corticosteroid responses expected to emerge within 2 weeks. 18,21 For those who respond, a slow corticosteroid taper is advised. For those who don't respond to corticosteroids and rituximab, second-line immunosuppression with IVIG, cyclosporine, or mycophenolic acid is recommended. 26 These latter two treatments target autoreactive CD8+ T lymphocytes (Figure 1), but to date there are no clinical or experimental data that validate this approach.

Immune Thrombocytopenia
Nine patients in the REISAMIC registry presented with thrombocytopenia. 17 Seven out of 9 patients had laboratory evaluations and bone marrow biopsies consistent with immune thrombocytopenia (ITP). Thrombocytopenia was severe with a median nadir platelet count of 5,000/µl. An antibody to platelet glycoprotein IIb/IIIa was identified in one patient's serum. Severe bleeding developed in 2/9 patients, but there was no fatal bleeding. Another small cohort (11 patients) found a median time to onset of 70 days, a median platelet nadir of 61,000/µl, no bleeding symptoms or signs among 8/11 and severe non-lethal bleeding in 2/11. 20 ITP is a diagnosis of exclusion. Guidelines for diagnosis and treatment of ICI-related ITP 21,26,30 are little different from long-standing 31 and recent 32 American Society of Hematology guidelines for non-ICI related ITP. One approach is to hold the ICI when the platelet count falls below 75,000/µl and begin immune suppressive therapy when the platelet count is below 30,000/µl. Treatment begins with corticosteroids for all -either dexamethasone 40 mg per day for 4 days or prednisone 1-2 mg/kg per day. 32 High dose IVIG should be added for patients who are bleeding, and we recommend rapidly introducing a thrombopoietic agent when corticosteroids and/or IVIG don't work (Table 2). We prefer a thrombopoietic agent to rituximab because it decreases immunosuppression, which may have an adverse effect on tumor progression. 33 In one survey, recovery occurred in 21/36 patients (58%). 20 Of note, drugs that target activated cytotoxic CD8+ T lymphocytes, such as cyclosporine or mycophenolate, have not been used in any of the published cases or series. One can speculate that these may be particularly useful for cases of severe refractory ITP, as data antecedent to the ICI indicate that cytotoxic T lymphocytes frequently mediate steroid-refractory ITP and that their inhibition leads to platelet recovery. 34,35

Neutropenia
The REISAMIC registry, a multicenter retrospective evaluation of three Israeli cancer centers, and two meta-analyses review case details for about three dozen total patients with ICI-associated neutropenia. 19,20,36,37 All patients suffered severe neutropenia (absolute neutrophil count [ANC] < 500/μl) or agranulocytosis within a few weeks of beginning therapy. A small percentage suffered additional ICI toxicities. Bone marrow biopsies were examined in most patients: about 45% were normal, 10% hyperplastic and 45% with myeloid hypoplasia or maturation arrest.
Two of four patients tested had positive anti-neutrophil antibodies; in one of these patients the bone marrow biopsy was normocellular and the patient recovered fully after stopping the ICI and beginning a corticosteroid. 36 About two-thirds of these patients developed neutropenic fever, which was the attributed cause-of-death in ~ 10%. 36 It is recommended that the ICI be held when neutrophils fall to below 1,500/μl and that active therapy begins when the ANC falls below 1,000/μl ( Table   2). 37 Treatment begins with corticosteroids and G-CSF, often given simultaneously or within days of each other if there is no early response to the single agent. When there is no early response, high-dose IVIG can be administered to those with normal or hypercellular bone marrow (considered to suffer peripheral autoantibodymediated immune destruction) and cyclosporine used for those with hypoplastic or maturation-arrested bone marrow (considered to suffer CD8+ T lymphocytemediated myeloid precursor destruction or suppression). Most patients recover within a month of treatment. 19

Cytopenias and Bone Marrow Failure
Less than 30 cases of bi-and tricytopenia are reported in the literature. [19][20][21]37 In the REISAMIC registry, 4/5 patients with pancytopenia whose bone marrow was examined showed severe trilineage hypoplasia; 1 patient's bone marrow was "nearnormal"; 1/5 died of neutropenic sepsis; and only 1/5 recovered over 8 months. 19 A summary of most of the reported cases is consistent with REISAMIC data; they report a broad range in the time of onset but usually within 2-3 months of starting the ICI, severe pancytopenia, most bone marrows examined showing severe aplastic anemia (some of which showed increased activated T lymphocytes), a low response rate (20-30%) and a comparably high death rate (5/17). 20 One should hold the ICI while providing transfusion and G-CSF support for patients with non-severe aplasia and begin immunosuppression when aplasia is severe (marrow cellularity < 25% with ANC < 500/μl, platelets < 20,000/μl and reticulocytes < 20,000/μl) ( Table 2). 26 Treatment includes corticosteroids with antithymocyte globulin (-/+ eltrombopag), with cyclosporine added for those with severe aplasia. 20,21 Similar parameters for treatment, based on the bone marrow cellularity and the myeloid:erythroid ratio, have been used for patients with pure red cell aplasia or bicytopenias. One case of amegakaryocytic thrombocytopenia has been reported; the patient responded to treatment with prednisone and eltrombopag. 38

Hemophagocytic Lymphohistiocytosis
About 25 cases have been reported, mainly with the most commonly used PD-1 inhibitors nivolumab and pembrolizumab, and none receiving anti-CTLA-4 therapy. 20,39 Their onset was anytime between 1 week and over a year after the ICI was begun. Most were accompanied by other irAEs. The most common presenting symptoms were fever and organomegaly, the mean ferritin level was 27,000 µg/l, and 16/18 examined patients had demonstrable hemophagocytosis in the bone marrow aspirate or blood smear, which in general fulfilled the diagnostic criteria of the HLH society. 39,40 In over half of the cases alternative potential predispositions or triggers for HLH were identified, such as progressive malignancy, infection, and one possibly deleterious perforin mutation. 41 Guidelines for managing ICI-related HLH are derived from HLH Society guidelines, which recommends starting corticosteroids and tocilizumab, and adding etoposide if there is no response after 48 hours (Table 2). 40 In the largest descriptive case series all patients were treated with ICI withdrawal and corticosteroids, 6/20 patients were treated with etoposide, and 1/20 patients were treated with either tocilizumab, anakinra, mycophenolate, cyclosporine or tacrolimus. 40 15/20 patients recovered, although the time to HLH resolution was not provided, and 3/20 patients died of complications of HLH.

Thrombosis
Baseline VTE risk among cancer patients is increased. It varies with cancer type, stage and treatment. Less clear is the baseline risk of arterial thromboembolic events (ATE) among cancer patients. 42 A systematic review of 20,273 patients treated with ICIs found 390 VTEs (1.8%) and 59 ATEs (0.3%), concluding that ICIs had no effect on the risk of thrombosis. 24 In contrast, single institution retrospective reviews of patients receiving ICIs identified 404/1,686 VTEs (24%) 43 ; and 47/672 VTEs (7%) and 9/672 ATEs (1.3%). 23 These disparate data force circumspection when addressing individual events and, until we have unambiguous data that ICIs are a risk for thrombosis, we do not advocate beginning pharmacological thromboprophylaxis when an ICI is started or discontinuing an ICI when an acute thrombosis develops. Of note, one retrospective cohort correlated IL-8 levels with ICI-associated VTE, introducing the previously uncatalogued cytokine IL-8 into the long list of cytokines involved in ICI irAEs that are being examined as potential therapeutic targets that could permit ICI continuation in the face of highgrade toxicities typically managed by stopping the ICI. 43,44

Miscellaneous Hematological Toxicities
Predispositions and triggers for non-ICI de-novo autoimmune hemolytic anemia, ITP, autoimmune neutropenia, severe idiopathic aplastic anemia, and HLH are often unknown, and mechanisms for the selective and rare expression of these same ICIassociated irAEs are similarly unknown. It is therefore likely some develop stochastically without any pathophysiological connection to the ICI. This is the likely basis for several life-threatening toxicities that were reported early in the ICI era but, since then, have not demonstrated an accumulation of cases that matches the accumulating -two orders of magnitude, in fact -use of ICIs, such as thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, acquired hemophilia, lymphopenia and hypereosinophilia. 26 Lymphopenia can, however, develop during treatment with an ICI, and when this happens it correlates with more rapid tumor progression. 16 The mechanism of lymphopenia is uncertain but could involve ADCC.
Each of the monoclonal antibody inhibitors of CTLA-4 and PD-1, and the PD-L1 inhibitor durvalumab is an IgG4 (which does not stimulate ADCC or activate the classical complement pathway) 45 . Each of the anti-PD-L1 antibodies except avelumab is an IgG engineered using an IgG frame with a Fc receptor binding site modified to prevent ADCC. There remain, however, concerns about this mechanism of toxicity as hypophysitis associated with ipilimumab is considered to be caused by ADCC. 1

Hematological Toxicity of ICI Treatment of Hematological Malignancies and After Stem Cell Transplant
Most clinical experiences with hematological irAEs derive from studies of solid tumors, but nivolumab is FDA-approved for relapsed and refractory Hodgkin's disease (HD) 46 and pembrolizumab is FDA-approved for this 47 and relapsed mediastinal B cell lymphoma 48 . Most hematological irAEs appear to not be increased in these conditions. Of note, however, is that when nivolumab was given to heavily pre-treated patients with HD, 1/23 developed myelodysplastic syndrome (MDS), possibly representing a distinct hematological irAE, although no MDS cases were reported with pembrolizumab treatment of similar patients with relapsed/refractory HD. 48 ICIs as single agents have not been effective in other lymphomas or in myeloid disorders, but they remain under active clinical investigation, often in combination with other mediations, for the treatment of lymphoma, myeloma, leukemia and post-allogeneic stem cell transplantation (SCT) for myeloid and lymphoid malignancies. 49,50 Because chronic lymphocytic leukemia (CLL), lymphoma and myeloma are associated with autoimmunity 51 and allogenic SCT is associated with graft-versus-host disease (GVHD) 50,52 , one must consider the risk of ICIs triggering or exacerbating these pathological immune phenomena. 53 To date, this risk remains theoretical except possibly for patients with progressive CLL and recipients of allogeneic SCT. In one clinical trial of pembrolizumab for patients with relapsed/refractory CLL or Richter transformation, about 20% of ICI-treated patients suffered drug-related -but not demonstrably immune-mediated -highgrade (CTCAE grade 3-4) anemia, thrombocytopenia and/or neutropenia 54 and acute GVHD was more frequent among patients with lymphoid malignancies who receive an allogeneic SCT after they have been treated with an ICI. 50 When acute GVHD develops in patients receiving an ICI post-SCT, routine therapy without ICI discontinuation has generally worked. 49,50 Nonetheless, ICIs are often held for weeks before SCT and they are not usually started when there is acute GVHD requiring treatment. 46,47 In one institution, post-SCT cyclophosphamide permitted the initiation of ICI therapy much earlier in the course of the relapse. 52

Re-challenging patients after hematological toxicity
There is almost always the desire to resume an ICI when it was working before an irAE forced its discontinuation, particularly because irAEs in response to the PD-1/PD-L1 inhibitors probably correlate with efficacy. 55,56 When and how to do this remains uncertain, however, with one central question being "should resumption occur while a patient is receiving immune suppressive therapy for an ICI-induced irAE?", because of the concern that immune suppression attenuates a therapeutic ICI effect, increases tumor progression and decreases patient survival. There appeared to be no adverse effect on melanoma responses when the dose of corticosteroid was reduced to the equivalent of prednisone 7.5 mg per day, but higher doses were associated with tumor progression. 33 Otherwise, there are no data to guide one when decreasing immune suppression. Of note, there is a counterpoint: some retrospective analyses and expert opinion conclude that immune suppression for ICI irAEs is not associated with worse cancer outcomes. 1 Our approach is to begin to reduce immune suppression therapy when the irAE has been improving for 48 hours, and to then taper it to the low dose prednisone equivalent over the next 4-6 weeks, at which time the ICI can be resumed (Table 2).
One group provides an algorithm for re-challenging patients; for hemolytic anemia and ITP they recommend waiting several months after the irAE and to re-challenge only while synchronously administering anti-CD20+ therapy +/-high dose IVIG. 57 No guidance is provided for other hematological toxicities.

The Future
Combination ICI therapy with anti-CTLA-4 and anti-PD-1 therapy could become the "base platform for future treatment strategies" because it will "unleash" both CD4+ and CD8+ T cells, leading to greater tumor cell killing and possibly attenuating resistance. 59 The combination of an anti-CTLA-4 antibody and an anti-PD-1 antibody is expected to increase the incidence and severity of hematological irAEs. When ipilimumab + nivolumab was used as first-line treatment for 94 patients with stage III or stage IV melanoma, however, no hematological toxicities were observed. 60 ICIs will be used to enhance therapeutic antibody-mediated ADCC by enhancing NK and CD8+ T lymphocyte activities 61 , and it is possible that new or worse hematological toxicities will emerge depending on the antibody target, whether it is conjugated to an anti-proliferative agent, and how it is distributed and cleared. For example, it is unlikely that adding an ICI to trastuzumab or cetuximab, neither of which has significant hematological toxicities, will result in worse hematological irAEs, while adding an ICI to rituximab or brentuximab-vedotin is likely to result in more, and possibly more severe, hematological toxicities. 62 New ICIs are being developed, including antibodies to lymphocyte-activation gene 3 Whether this approach is adequate, much less optimal, is unknown and could remain unknown because of the small number of recorded patients with hematological irAEs. In the face of uncertainty, one must attempt to identify putative pathogenetic mechanisms and then apply diagnostic and therapeutic interventions based on diseases in which the putative mechanism is better established. Inevitably, in doing this, clinical observations become hypothesisgenerating, triggering a "reverse translation" that will stimulate questions, ideas, and experiments revealing new insights into the complexities of human immunology. For example, do PD-1/PD-L1 blockers unleashing NK cells mediate specific hematological toxicities and, if so, can we predict a different toxicity profile when lirilumab is combined with ipilimumab rather than a PD-1/PD-L1 blocker? Just as we grow registries and develop multi-institutional clinical trials, we must grow our understanding of mechanisms of ICI-induced hematological toxicities by moving bidirectionally between bedside and bench. Only then will we begin the process of constructing rational management strategies that optimize cancer outcomes by improving immune checkpoint inhibitors' therapeutic indices.