The acute leukemias, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), are rapidly progressing forms of leukemias defined by high percentages of blasts in the blood and bone marrow and by the predominant lineages of malignant cells.1 In 2020, an estimated 26,090 cases of acute leukemias will be diagnosed in the US and 12,700 deaths are anticipated.2 In children, leukemia is the most common hematologic malignancy, and the incidence of childhood leukemia has steadily increased every year.3 Advances in molecular diagnostics over the past several decades have further defined multiple disease subtypes, differentiated by the presence of specific genetic markers, which have informed risk-based treatment paradigms to reduce toxicity in low-risk patients while pursuing more aggressive therapies for those with a high risk of relapse.4–7

Standard treatment paradigms for acute leukemia have centered on high-intensity induction chemotherapy to achieve complete remission (CR) followed by allogeneic hematopoietic cell transplant (allo-HCT) in certain patients8–10 to eradicate residual disease through the “graft versus leukemia” effect mediated by the donor’s immune cells.11–13 However, allo-HCT is not indicated for all patients and a major ongoing challenge in the field is that few chemotherapy-based options are effective following relapse after allo-HCT or for patients who develop chemotherapy-refractory disease.13 14

Immunotherapeutic approaches have dramatically altered the treatment landscape across a variety of disease settings, including hematological cancers. In recent years, novel agents including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and engineered chimeric antigen receptor (CAR) T cells have been approved by the US Food and Drug Administration (FDA), offering additional options beyond standard regimens and deep and durable responses in some patients.15–18 Although ADCs may not be classified as a traditional form of immunotherapy, there is evidence of immunomodulatory activity by these agents.19

While immunotherapies for acute leukemia have demonstrated efficacy in a number of large-scale, randomized trials,15 20 21 clinical experience with some of these novel agents is still somewhat limited. To support the oncology community and provide expert, evidence-based recommendations, the Society for Immunotherapy of Cancer (SITC) published consensus recommendations in December 2016 on the role of immunotherapy in the treatment of hematological malignancies.22 Since 2016, however, rapid advances in the field have brought about a wider array of immunotherapy-based treatment options for each of the individual disease states discussed in the original guidelines: acute leukemia, lymphoma, and multiple myeloma. Thus, the SITC Cancer Immunotherapy Guidelines—Hematologic Malignancies Subcommittee determined that stand-alone guidelines are needed. To form up-to-date recommendations on the use of immunotherapy for the treatment of patients with acute leukemia, SITC convened a panel of experts to develop a new clinical practice guideline. This publication represents an update to the previously published consensus statement based on a more recent assessment of the peer-reviewed literature and the clinical experience of expert panel participants. These recommendations are not intended to supplant sound clinical judgment but rather to provide clinicians with the most current thinking on how experts integrate immunotherapy into the treatment of patients with acute leukemia.

A number of clinical guidelines have been developed for the workup and diagnosis of acute leukemia. Initial workup provides disease classification, risk stratification, and a better understanding of both disease biology and potential treatment options.1 5 6 24–26 Selection of appropriate diagnostics to initiate immunotherapies is under investigation. Only in a select few situations has consensus been achieved on how to determine whether a patient is a strong candidate for immunotherapy. Further, if a patient is eligible for two different immunotherapies, it is challenging to identify the treatment option that will provide maximal benefit. Potential diagnostic evaluations for patients with acute leukemia being considered for immunotherapy are discussed below.

A number of diagnostics are available for the initial workup of a patient suspected to have acute leukemia. Workup typically includes history and physical examination, complete blood counts (CBC) and leucocyte differential counts, platelets, electrolytes, liver function tests, prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio (INR), fibrinogen, lactate dehydrogenase (LDH), uric acid, human leucocyte antigen (HLA) typing for patients who are candidates for allo-HCT, chest X-ray and CT/MRI scans if clinically indicated, echocardiogram, and a lumbar puncture if neurological symptoms are present.5 6 24 27 Bone marrow biopsy/aspirate with cytogenetics (karyotype and fluorescence in situ hybridization (FISH)), immunophenotyping, and molecular studies including next generation sequencing, are performed to diagnose and classify disease characteristics. Cytochemical studies can also help to differentiate between ALL and AML, but do not traditionally replace immunophenotyping. Appropriate sensitivity of all assessment techniques must be verified to ensure that measurable/minimal residual disease (MRD) status can also be assessed in future management stages.24–26

Acute leukemia can be associated with a variety of genetic mutations that may serve as markers for MRD or be targetable with drugs. ALL can be associated with a variety of genetic mutations. The American Society of Clinical Oncology/College of American Pathologists/American Society of Hematology (ASCO/CAP/ASH) guidelines for the workup of acute leukemia recommend a number of genetic tests to identify different mutations. A summary of the recommended molecular tests for ALL and AML is provided in table 1.

While molecular characterization may identify actionable mutations for targeted therapies such as tyrosine kinase inhibitors, cell surface markers may be used to identify potential targets for immunotherapies. The National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) guidelines, in addition to molecular testing, also recommend assaying for specific cell markers, such as CD19, CD20, and CD22 for ALL and CD33 for AML to assess eligibility for potential antibody-based therapies.5 26 Importantly, however, current clinical pathology laboratories for CD19 and CD22 expression report only the presence or percent expression, which is often not an accurate representation of the number of molecules or the presence of subpopulations of leukemia cells that lack these markers.28 Subpopulations of CD19-negative or CD22-negative or low-expression leukemia cells may play an important role in eventual relapse. A retrospective analysis of flow cytometry archives found profound heterogeneity in CD22 and CD19 expression across 628 B‐ALL cases. 29 Although such analyses remain strictly for research use at this point, with the increasing use of CD19-specific or CD22-specific immunotherapies, the heterogeneity in cell surface marker expression is likely to become an important consideration in the future.

Certain FDA-approved immunotherapies for the treatment of patients with acute leukemia require specific disease characteristics for eligibility. For example, gemtuzumab ozogamicin (GO) for the treatment of patients with newly diagnosed or relapsed/refractory (RR) AML requires confirmation of CD33 positivity on malignant cells.30 The bispecific antibody blinatumomab that directs CD3 positive T cells to CD19-positive leukemia cells is approved for patients with B-cell ALCL (B-ALL) in first or second complete response (CR) with MRD positivity after induction therapy.16 20 31–35 Therefore, it is critical to perform phenotypic and molecular characterization of leukemic cells at diagnosis and to assist future MRD status assessment.6 24 25 36

Several ongoing clinical trials are evaluating the safety and efficacy of emerging immunotherapies directed against specific cell surface markers. For example, MGD006, a dual-affinity T cell retargeting molecule designed to target CD123-positive cells for recognition and elimination by CD3-expressing T lymphocytes, is currently being evaluated in a phase I dose-escalation and cohort expansion study in RR AML (NCT02152956).37 Additionally, the CD33-directed ADC IMGN779 is undergoing evaluation in a phase I trial (NCT02674763).38 Guidelines for these and other emerging therapies will be discussed in the emerging immunotherapies section of this manuscript. Although many targeted therapies have not yet been FDA approved, experimental diagnostics may assist in referring patients to an appropriate clinical trial. A summary of recommended immunotherapy-centric diagnostic markers for approved therapies is in table 2.

Treatment of acute leukemia has rapidly evolved since the publication of “The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of hematologic malignancies” in 2016.22 In the intervening years, novel immunotherapeutic approaches, such as ADCs, dual-affinity molecules such as bispecific T cell engagers (BiTEs), and highly successful CAR T cell therapies, have been approved by FDA and entered the clinic (table 3). Yet, these immunotherapies have specific indications that must be integrated with existing treatment modalities.

To date, relatively few immunotherapy approaches have been approved for the treatment of patients with AML compared with those available for the treatment of patients with ALL, although many are in clinical trials and some show promising preliminary results. One possible cause for this discrepancy is the difficulty in identifying targetable antigens on myeloid cells that allow for safe anticancer activity with defined long-term effects on the patient. Currently, the only approved immunotherapeutic strategies for treating AML are allo-HCT and the CD33-targeting ADC GO. However, several research programs and clinical trials are currently underway hoping to further the repertoire of therapies such as checkpoint inhibitors, unconjugated antibodies, BiTEs, and CAR T cell therapies in the treatment of AML.

A number of novel agents and strategies are being tested in preclinical and clinical settings. Promising results have been reported for both antibody-based and cell-based therapies, especially in the rapidly burgeoning CAR T cell field. As novel immunotherapies demonstrate safety and efficacy in clinical trials, more options will emerge for practicing clinicians. Because many of these agents have not yet been approved by the FDA, the committee emphasizes that new experimental drugs should only be administered at centers with proper support, infrastructure, and subspecialties in place to monitor outcomes and adverse events (AEs).

CAR T cell therapies have offered significant survival benefits for patients with ALL and data suggest that responses are durable. In some cases, however, CAR T cell therapy is ineffective due to either lack of the targetable antigen or antigen loss after initial therapy. Therefore, many novel CAR T cell therapies are under investigation to provide secondary options for these patients. In some cases, other immunotherapeutics may be options for patients who have relapsed or are refractory to FDA-approved CAR T cell therapies.

Although trials are underway for tisangenlecleucel as treatment for pediatric and young adult patients with B-ALL who received first-line treatment and are MRD positive at the end of consolidation therapy (CASSIOPEIA, NCT03876769), the current FDA approval is for refractory patients or in patients in second relapse or later. Relapse after CAR T cell therapy is sometimes due to the loss of the target antigen.28 45 The prognosis of patients who relapse post-CAR T cell administration is often considered poor, especially considering that the anti-CD19 blinatumomab is also rendered ineffective in patients with CD19 loss.

The availability of multiple CD19-targeting therapies including BiTEs and CAR T cells makes decisions on optimal treatment sequencing challenging, especially given the possibility for relapse mediated by antigen loss.95

Options for patients who relapse post-CAR T cell therapy include salvage chemotherapy, clinical trial enrollment, allo-HCT, or retreatment with CAR T cells (potentially targeting different antigens, depending on the mechanism of relapse). Allo-HCT transplant is potentially an option for patients who relapse after CAR T cell therapy, but these patients are often ineligible for transplant.

There are multiple studies investigating CAR T cell therapies that target antigens other than CD19 for the treatment of patients with CD19-negative ALL. There have been encouraging reports of therapeutic response in patients who have relapsed after CD19-targeted CAR T-cell therapy. For example, one study notes that patients with CD19-negative B-ALL displayed a median remission duration of 6 months after receiving anti-CD22 CAR T cell therapy. Of note, relapse due to loss of CD22 was also observed in this trial.28 As such, there are clinical studies investigating bispecific CAR T cell therapies that target two antigens concurrently to increase efficacy and reduce the risk of relapse.96 In one phase 1 trial of bispecific CD19/CD22 CAR T cells, CR was achieved in 5/7 (71%) RR ALL patients by day 21, 4 of which were minimal residual disease negative. Therapy was well tolerated with no dose limiting toxicities. CRS occurred in 5 subjects (Grade 1) with 2 of these subjects experiencing mild neurotoxicity. (Grade 1).97 Another study of the CD19/CD22 ‘cocktail CAR T cell’ approach for RR B-ALL demonstrated a 100% CR/CRi rate on day 20 to 30 after infusion in 15 patients with 14/15 (93.3%) achieving MRD negativity.98 A very low treatment-related toxicity was observed in this trial. Only 1 patient experienced grade 3 CRS and another patient (6.7%) developed grade 3 central nervous system toxicity; all other patients were CRS grade<2 and CNS grade 0.

Immune-related AEs are of significant concern in the field of immuno-oncology. Immunotherapies have distinct and significant toxicities requiring skilled management. SITC has published a textbook guide to managing immunotherapy toxicity as well as a consensus statement from the Toxicity Management Working Group concerning the management of toxicities after treatment with checkpoint inhibitors.99 Toxicity management after CAR T cell therapy for hematological malignancies is described in a 2018 review publication from SITC.17 At the time of publication, two additional SITC clinical practice guidelines for the recognition and management of immune-related AEs for immune effector cell and checkpoint inhibitor therapies are in preparation. Additionally, the American Society for Transplant and Cellular Therapy has published consensus guidelines for grading CRS and neurological toxicity after CAR T cell therapy.100

AEs arising during treatment for ALL with immunotherapy are distinctive and must be recognized early and managed appropriately. Concerning inotuzumab ozogamicin, 46% of patients treated with inotuzumab ozogamicin in the INO-VATE trial experienced ≥grade 3 AEs, similar to the rate and profile of ≥grade 3 AEs in patients who received SOC chemotherapy (43%). VOD occurred more frequently in the inotuzumab ozogamicin group than in the standard-therapy group (in 11% (15 patients) vs 1% (1 patient)). Of the 48 patients in the inotuzumab ozogamicin group who underwent stem cell transplantation after the trial, 10 had VOD after transplantation. The median time to the development of VOD associated with transplantation in the inotuzumab ozogamicin group was 16 days (range, 3 to 39 days).21 Recent consensus recommendations for the prevention and monitoring of VOD associated with inotuzumab ozogamicin include: avoid HCT conditioning regimens containing dual alkylating agents, use prophylactic medicines in patients proceeding to HCT, limit treatment with inotuzumab ozogamicin to 2 cycles, monitor patient weight for fluid retention, and frequently assess liver function.101

Both blinatumomab and CAR T cell therapies can result in serious AEs including CRS and neurotoxicities.102 103 These two events can be fatal if not properly managed. CRS was the most common AE reported across all CAR T cell clinical trials, with an incidence as high as 74% to 100% for CD19-directed CAR T cells.33 103–105 CRS can present with a variety of symptoms. Mild symptoms of CRS include fever, headache, rash, arthralgia, and myalgia. More severe cases are characterized by hypotension that can progress to an uncontrolled systemic inflammatory response with vasopressor-requiring circulatory shock, vascular leakage, disseminated intravascular coagulation, and multiorgan system failure.100 103 106–112

Several descriptions of management strategies for CAR T cell-associated CRS have been published, which generally encompass supportive care and anti-IL-6 therapies to break the cycle of inflammation.103 109 110 113–115 110 CRS toxicity may be mitigated by modifying the dosing of CAR T cells to attenuate peak expansion and proliferation, as was demonstrated in a recent report using fractionated dosing scheme of infused CAR T cells that demonstrated high response rates with acceptable tolerability in adult patients with ALL.116

Neurotoxicity has been reported in nearly every study involving CD19-directed T cells, including CAR T cells and blinatumomab. In the TOWER trial evaluating blinatumomab for the treatment of patients with ALL, 25/267 (9.4%) patients experienced neurotoxicities.20 Neurotoxicities were also observed in the ELIANA trial of tisagenlecleucel, where 40% of patients (30/75) experienced an event of any grade, and 13% of patients (10/75) experienced a grade 3 event.33 Risk factors for neurotoxicity after CAR T cell treatment include extramedullary disease younger age, pre-existing neurological comorbidities, higher total CAR T cell doses, early and/or severe CRS, and cytopenias.114 117 Unlike CRS, neurotoxicity secondary to CAR T cell treatment does not respond to tocilizumab.33 117–120

While immunotherapy may provide a significant and durable antitumor response for many patients, the appropriateness of any treatment option ultimately depends on patient-specific considerations. Although the likelihood for deep and durable response is the utmost priority in treatment selection, it is important to consider the potential effects on patient satisfaction and QoL for a planned intervention. Several analyses of QoL during chemotherapy in patients with acute leukemia have found that intensive induction regimens are linked to detrimental physical and psychological effects, such as fatigue, loss of physical function, and depression.121 122 However, several studies have also found that, in general, QoL improves significantly when patients are in remission.121 122

Immunotherapies offer the potential for prolonged remissions in some subsets of patients. Yet, although the side effects of immunotherapy might be more tolerable for patients than those that accompany cytotoxic drugs, the toxicities associated with immunotherapeutic approaches may be life-threatening in some cases; for example, CRS due to CAR T cell and BiTE therapies and VOD/SOS after some ADCs. Thorough patient education, as well as ongoing dialog among all members of a patient’s care team, is critical to ensure that the individualized and unique aspects of immunotherapy are understood, as well as the importance of promptly reporting any toxicity.

Due to the rapidly evolving nature of the field, relatively few large-scale QoL assessments directly comparing immunotherapeutic approaches with SOC treatment for patients with acute leukemia have been completed. From the available literature, however, recently approved immunotherapies compare favorably with intensive chemotherapy and allo-HCT in terms of patient-reported outcomes and QoL.

An analysis of patient outcomes in the phase III TOWER study of blinatumomab in adults with RR Ph− B-cell precursor ALL found patients who were treated with SOC chemotherapy (n=95) reported significant deteriorations in several functional measures (physical, role, and social) and symptoms as measured by the 30-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and markedly decreased overall global health status/QoL scores relative to blinatumomab. Furthermore, the time to clinically meaningful deterioration in HRQL or death was delayed for blinatumomab versus chemotherapy across all EORTC QLQ-C30 scales.123 n the phase III INO-VATE trial, patients with RR B-ALL who received inotuzumab ozogamicin 124reported better QOL, functioning, and symptom scores (except for constipation and emotional functioning).124 Similarly, an analysis of 58 patients with RR B-ALL aged 8–23 years treated with tisagenlecleucel in the phase II ELIANA trial demonstrated improvements in patient-reported QoL scores for all measures at month 3 after infusion with a mean change from baseline of 13.3 (95% CI, 8.9 to 17.6) for the pediatric quality of life inventory (PedsQL) total score and 16.8 (95% CI, 9.4 to 24.3) for the EQ-5D Visual Analogue Scale.20

Depending on the immunotherapeutic agent used, hospitalization and monitoring during dosing and in the subsequent weeks may be required, which can affect a patient’s QoL and ability to work. For example, blinatumomab requires continuous intravenous infusion over 4 weeks and hospitalization is recommended for the first 9 days of the first cycle for RR disease and 3 days of hospitalization for cycle 1 in the MRD setting. Additionally, patients are advised to refrain from driving and engaging in hazardous occupations or operating heavy or potentially dangerous machinery while receiving blinatumomab.31 Tisagenlecleucel requires patients to stay within proximity of their treatment center for the first month after infusion and, patients must be monitored two to three times during the first 7 days after treatment.46

Financial distress related to cancer also takes a substantial toll on patient QoL.125 Immunotherapies for leukemia are expensive. Importantly, patients may incur additional expenses, such as transportation to and from the hospital or accommodations nearby during treatment, further highlighting that unequal access to these emerging therapies.

Despite high prices, immunotherapeutic agents fare favorably in cost-effectiveness analyses, offering significant gains in life years and QoL years (quality-adjusted life years (QALYs)) for patients. A recent cost-effectiveness study of CAR T cell therapy versus SOC for pediatric patients with B-ALL found that tisagenlecleucel had a total discounted cost of US$667,000 (including hospital stays and other expenses), with 10.34 discounted life years gained and 9.28 QALYs gained, which amounted to an incremental cost-effectiveness ratio of approximately US$42,000 per life year gained and approximatelyUS$46,000 per QALY gained compared with clofarabine.126 In adults with RR Ph− B-ALL, blinatumomab was found to yield 1.92 additional life years and 1.64 additional quality-adjusted life years (QALYs) compared with SOC at an incremental cost of US$180,642. The incremental cost-effectiveness ratio for blinatumomab vs SOC was estimated to be $110,108/QALY gained in the base case.127 In the UK, the National Institute for Health and Care Excellence estimated substantial improvement in survival with inotuzumab ozogamicin compared with SOC, providing an additional 5.2 life years and 2.2 QALYs.128The deterministic incremental cost-effectiveness ratio was between £33,749 and £37,497 per quality-adjusted life-year gained compared with standard of care.

Once almost universally fatal, the 5-year survival rate for acute leukemia has risen to 63% in the US.129 The advent of immunotherapy has expanded the available options in the treatment repertoire for acute leukemia, although progress has been slower in the AML setting. Every year, novel agents including BiTEs, CAR T cell therapies, and ADCs continue to demonstrate impressive response rates with favorable toxicity profiles across a variety of disease states. Despite these advances, many patients remain ineligible for immunotherapeutic treatments, and relapses after some of the newer modalities remain associated with a very poor prognosis. In the future, the indications for existing therapies are likely to continue to expand and novel agents with potentially distinct mechanisms of actions will be approved. Promising areas for future research in leukemia include improvements in CAR constructs and combining CAR T cell therapies with other immunotherapy approaches as well as the development of additional bispecific monoclonal antibodies. In AML specifically, there is great potential in efforts aimed at targeting novel proteins that might be more effective or more specific to early leukemia progenitors for novel antibodies such as CLL1, WT1, and PR1 as well as the development of CAR T cells for myeloid leukemias with ‘off switches’ to minimize long-term myelosuppression. Therefore, as the field continues to develop, these recommendations will be updated.