In recent years, immunotherapy has emerged as one of the most promising therapeutic strategies in acute leukaemia. Antibody-drug conjugates are now recommended in combination with standard chemotherapy backbones in both acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). Immune cell engagers and chimeric antigen receptor (CAR) T-cells have been approved for relapsed/refractory B-cell ALL[3,4] and look promising as future treatments for AML. Our understanding of the biology and genomic architecture across all forms of acute leukaemia has also increased considerably, leading to the development of risk-assessment tools and risk-stratification guidelines incorporating a growing number of recurrent molecular aberrations.[2,6]
Evidence for the impact of these new advances on the diagnosis and treatment of acute leukaemia needs to be discussed and shared within the haematologic oncology community.
What are the latest developments in genetic testing in acute myeloid leukaemia (AML)?
Richard Dillon (RD): A range of genetic tests are now available in AML, but it is important to highlight which tests are required prior to commencing frontline treatment; this will vary depending on which treatments are available at individual centres and in different countries.
In the UK, we have access to three main treatment regimens that form current standard of care for younger, fitter patients with AML; standard DA (daunorubicin + cytarabine chemotherapy with gemtuzumab ozogamicin, GO), standard DA plus the FMS-like tyrosine kinase 3 (FLT3) inhibitor midostaurin, or CPX351, the liposomal formulation of daunorubicin + cytarabine. We can also refer patients to clinical trials investigating novel agents which increasingly focus on defined molecular subgroups.
Waiting days or weeks for cytogenetics results, next generation sequencing (NGS), or even whole genome sequencing (WGS) is becoming more common and, from our clinical practice, does not seem to have adverse impact on clinical outcomes. Cytogenetics testing, for example, which often reports within days, reveals the presence of myelodysplasia-related changes that makes patients eligible for CPX351. PCR testing can rapidly identify the commonest FLT3 mutations, allowing the incorporation of midostaurin alongside induction therapy, and the same methodology can also detect most NPM1 mutations, a group that appears to benefit from the addition of GO.
Beyond that we look at NGS results for mutations in CEBPA indicating favourable risk disease, and for the bank of mutations associated with secondary AML, as recommended by the European Leukaemia Net (ELN): ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, U2AF1, and ZRSR2. NGS can also detect non-canonical FLT3 and NPM1 mutations. These results inform decisions on post-remission therapy, such as whether patients should be referred for allogeneic transplantation in first remission. TP53 mutations are predictive of a poor response to all standard treatment options, so we would aim to place these patients into a clinical trial including novel therapies.
In older AML patients the situation is somewhat different as, currently, we have no treatment options beyond venetoclax and azacitidine (VEN+AZA). However, knowing a patient’s molecular profile is predictive of their likely response to VEN+AZA; patients with NPM1 or IDH mutations tend to do well while patients with FLT3, NRAS, or KRAS mutations may have a less durable response. Patients with TP53 mutations do very badly. This information is useful for counselling patients, and we hope it will be clinically actionable in the near future with emerging therapies.
NGS results are most useful in borderline older patients when making the difficult decision of whether they can tolerate VEN+AZA, or whether they should have monotherapy or supportive care. Here, the likely outcome based on molecular profile provides valuable context to support individualised decision making.
Marcos Garcia de Lima (MGL): In most situations today, I agree that we should wait for cytogenetics and molecular data from NGS panels before commencing therapy. In addition to providing information on the most suitable treatment regimen, the results are invaluable for monitoring treatment response. A dual NPM1 mutation, for example, may become your measurable residual disease (MRD) marker.
Nicholas Short (NS): In addition to cytogenetics and NGS panels, simple FISH tests should not be overlooked as they reveal the core-binding factor subtype of AML (e.g., t(8;21) or inv(16)). Core-binding factor AML has relatively favourable outcomes with cytarabine-based intensive chemotherapy but multiple studies, including a large meta-analysis, have demonstrated the importance of incorporating gemtuzumab ozogamicin into the treatment regimen for patients with favourable risk disease. We always offer gemtuzumab ozogamicin to patients with core-binding factor AML but, generally, not to intermediate-risk patients.
What are the latest developments in genetic testing in acute lymphoblastic leukaemia (ALL)?
NS: Our first step is to identify whether a new patient has B-cell ALL or T-cell ALL. A range of tests is then used to further subclassify and determine the best frontline treatment approach, as well as therapeutic options in the relapsed/refractory setting.
In B-cell ALL patients, we use FISH testing or PCR to look for the presence of a BCR-ABL1 fusion to determine whether a patient is Philadelphia chromosome-positive (Ph+ ALL) or negative (Ph- ALL). Ph+ ALL accounts for around 25–30% of all adult cases of B-cell ALL. Ph- ALL comprises the rest of cases of B-cell ALL, and within this group of patients with Ph- B-cell ALL, up to 50% of them have Ph-like ALL, a higher-risk subtype that is particularly common in young adults and in Hispanic patients.
Ph-like ALL is technically defined by gene expression profiling that is not used in clinical practice, so we include CRLF2 into our flow panel. Many patients with Ph-like ALL have rearrangements in CRLF2, and if a patient is CRLF2-positive by flow cytometry, that is suggestive of upregulation and therefore a rearrangement. We follow up with FISH testing for some of the common fusions, such as in the erythropoietin receptor gene EPOR and also JAK2, and then also send off for more comprehensive testing for other cryptic or less common fusions. One of the highest risk groups seems to be patients with CRLF2 rearrangements as well as a JAK1 or JAK2 mutation. These patients do very poorly and I always refer these patients for transplant. At the other end of the spectrum are patients with Ph-like ALL who have an ABL-class mutation who may be treated with the addition of an appropriate tyrosine kinase inhibitor, without need for transplant in first remission in most of them.
For further profiling beyond these major subtypes, assays such as SNP array can detect IKZF1 deletions or deletions in the Cyclin-dependent kinase inhibitor 2A/B genes (CDKN2A/B). It may not be immediately obvious how this information will be used therapeutically, but there is some data to suggest it could influence the decision of whether to send a patient to transplant or not.
CD20, CD19, and CD22 are also important markers to include. CD20 is definitely relevant to frontline treatment as we would add a CD20 antibody, typically rituximab, into our regimen for patients who are CD20-positive. CD19 and CD22 are more relevant in the relapsed/refractory setting, as they indicate the potential for using blinatumomab or inotuzumab ozogamicin, respectively. In addition, many clinical trials are now offering these immunotherapies in the frontline setting.
Genetic testing is also important for measuring MRD. Flow cytometry is typically still used in Ph- ALL disease monitoring in most centres. For Ph+ ALL we historically have used PCR for BCR::ABL1 to monitor MRD, but we now have more sensitive NGS-based assays that can detect MRD at the level of one in a million, which can be used for both B-cell and T-cell ALL. These assays are becoming increasingly important when making decisions about whether patients might be referred for transplant.
How should we use immunotherapy in the treatment of AML?
Martin S. Tallman (MST): If transplant-related mortality (TRM) were less than 5%, I think we would probably be offering allografting to almost every patient, even the favourable risk ones. It is, quite simply, the most potent anti-leukemic strategy we have. Sadly, TRM is much higher than 5%, and that precludes its use in many patients due to age or comorbidity. Have there been any recent advances that could reduce TRM?
MGL: I completely agree and would add that it is also crucial to know the TRM at your institution, because it can vary widely. If your institution has a TRM of over 20% at one year, you are starting out at a disadvantage when treating borderline cases of AML and patients over 60.
In terms of strategies to reduce TRM, advances have been made in patient management and management education, and we have new drugs available to treat graft-versus-host disease (GvHD). Ruxolitinib has become a new therapeutic option for steroid-refractory GvHD, with a substantial remission rate, and the benefit of post-transplant cyclophosphamide for GvHD prophylaxis has been demonstrated in a prospective, randomised study. Compared with tacrolimus, methotrexate, or other inhibitor-based prophylaxis used in standard reduced-intensity transplants, cyclophosphamide-based prophylaxis was clearly superior. It did not necessarily improve overall survival, according to the most recent analysis, but it did improve GvHD-relapse-free survival.
The shift in the standard of care that is gaining pace should decrease TRM in the future. In fact, I think the balance has already tipped since we now regard AML relapse as the number one threat to a successful transplant, not TRM.
Advances in maintenance therapy after transplant have also been made recently. Two studies have investigated sorafenib, both showing it to be highly protective against AML relapse, with measurable prolonged survival rates.[16,17] A UK-based clinical trial is currently investigating the use of oral azacitidine as a maintenance therapy. In the meantime, I would definitely recommend using FLT3 inhibitors post-transplant, albeit off-label.
Apart from gemtuzumab, which has a therapeutic role in patients not eligible for transplant, we currently have no other approved immunotherapies in AML. Several immunotherapies that harness T-cells against AML are in various stages of preclinical and clinical development, so there is great promise. These include bispecific and dual antigen receptor-targeting antibodies (targeted to CD33, CD123, CLL-1, and others), CAR-T cell therapies, and T-cell immune checkpoint inhibitors (including those targeting PD-1, PD-L1, CTLA-4, and newer targets such as TIM3 and STING).
RD: In the UK, all AML patients are given gemtuzumab, except those with an adverse risk karyotype. We give a maximum of two doses of 5 mg gemtuzumab with induction therapy to patients of all ages, based on the data from the ALFA study.
Once treatment has begun, if test results reveal an adverse karyotype, the second dose of gemtuzumab is withheld.
How should immunotherapy be used in the treatment of B-cell ALL?
NS: We know from randomised studies that the addition of rituximab improves outcomes for B-cell ALL patients who are CD20-positive. Although the best data we have is from patients under 60, our standard approach is to incorporate rituximab into frontline therapy across all age groups.
For relapsed/refractory B-cell ALL we have two approved antibody-based immunotherapies: inotuzumab ozogamicin, a CD22 antibody drug conjugate, and blinatumomab, a CD3/CD19 bi-specific T-cell engaging antibody. We also have two approved CAR-T cell products: tisagenlecleucel, a CD19 CAR-T cell approved for patients up to 25 years, and brexucabtagene autoleucel, which is approved for patients of all ages with CD19-positive relapsed refractory B-cell ALL.
Thinking first about on-label use of these therapeutics, if you have a patient with B-cell ALL who has relapsed, I do not see a role for chemotherapy alone, at least not until you have exhausted the immunotherapy options, or unless the patient has a contraindication to those agents. We also need to consider off-label use: should we be offering drug combinations in the relapsed/refractory setting? Although giving blinatumomab or inotuzumab ozogamicin certainly improves response rates and survival compared to conventional chemotherapy, both were approved as monotherapies. If we combine all effective therapies into an overall regimen, can we cure more patients, with or without subsequent transplant? Ongoing studies, including one here at the MD Anderson Center, are combining low-intensity chemotherapy (mini hyper-CVD, which is similar to hyper-CVAD but with dose reductions of all drugs, and the anthracycline is removed) with inotuzumab and, more recently, blinatumomab as well, for patients with relapsed/refractory B-cell ALL. This is supported, at least as an option, in the NCCN guidelines. We also need to investigate how to integrate CAR-T cell therapy into these new regimens.
Moving further into the arena of off-label use, we and others have been investigating inotuzumab and blinatumomab in the frontline setting for ALL patients over 60 years. We do not have good standard of care options in these older patients, who often cannot tolerate high-intensity chemotherapy. If you use low-intensity chemotherapy, this may induce a brief response, but the relapse rates are extremely high. We have therefore been using the mini hyper-CVD in combination with inotuzumab ozogamicin and blinatumomab as frontline therapy for older patients.
What treatment regimen is recommended for a patient aged 60 plus with B-cell Ph- ALL, and how does this differ from the approach used in a patient of the same age who is Ph+?
NS: In a patient with Ph- ALL over 60 years of age I would use a regimen of low intensity chemotherapy using mini hyper-CVD. We combine that with inotuzumab ozogamicin for four cycles. After that, patients receive four cycles of blinatumomab regardless of their MRD status. We have seen very encouraging outcomes with this approach with response rates of over 95%. Even in this older population, five-year survival rates are around 40% to 50%, which is approximately double the rates we previously achieved. My opinion is that using low-intensity chemotherapy plus immunotherapy drugs in the frontline setting is definitely a better approach than standard intensive chemotherapy.
For patients who are over 70 the approach is more investigational. I question whether we need a chemotherapy backbone at all in these patients. In the context of a clinical trial, we are exploring chemotherapy-free approaches for these patients with just a combination of inotuzumab ozogamicin and blinatumomab, some steroids, and a dose of vincristine.
For Ph+ ALL I think we are seeing a paradigm shift compared to where we were historically. This was once one of the most aggressive subtypes of ALL and patients were always referred to transplant but still had poor outcomes. Now, with the availability of better TKIs, our centre and some others are moving away from first- and second- generation TKIs and towards ponatinib, which seems to be a more potent TKI.
Many groups are still using intensive therapy for younger patients, but at my institution, we use chemotherapy-free approaches regardless of age. So, my approach for a Ph+ ALL patient would be immunotherapy in the frontline setting, and we would not send the patient to transplant. Using immunotherapy has produced such good and durable responses that less than 5% of our patients with Ph+ ALL are now sent to transplant.
MST: You made an interesting point about the first relapse of ALL. You said that, based on randomised data, you would consider inotuzumab and blinatumomab as opposed to salvage chemotherapy. There is some suggestion that blinatumomab does not work so well if you have more than 50% blasts in the bone marrow. So, if someone is in first relapse and they have 80% blasts, how would you treat them and how would you make that decision?
NS: I can tell you the way that I would treat it, but, again, this is from the perspective of practising in the US where we can access these drugs fairly easily.
If a patient has had only one chemotherapy before, we would salvage with low-intensity chemotherapy in combination with inotuzumab ozogamicin and blinatumomab. It is not really an either/or situation. If, for whatever reason, access limits me to a choice between the two, I think my main consideration would be based on disease burden. For patients with a very high disease burden, say over 50% blasts in the bone marrow and a very high circulating white count, I would prioritise the use of inotuzumab ozogamicin.
For patients with low-blast disease, typically, I would prefer blinatumomab because I think it elicits a longer duration of response in patients with low-burden disease. It would be advisable to repeat CD19 and CD22 testing at the time of relapse to make sure it still makes sense to give one or the other. Most ALLs are positive for both but there are some uncommon subtypes, particularly the KMT2A-rearranged ALL, in which CD19 and/or CD22 expression might be low. Some patients might even be CD19- or CD22-negative. It certainly makes no sense to give blinatumomab to someone who is CD19-negative.
I would also consider comorbidities and would be more hesitant about using inotuzumab in ozogamicin patients who have underlying hepatic dysfunction. Nor would I consider blinatumomab in a patient with underlying central nervous system pathology and usually not if they have active leukaemia in the CNS, for example.
Despite the remarkable advancements in B-cell ALL, the management of T-cell ALL that relapses or does not respond to frontline treatment is a significant challenge. What treatments are available for relapsed/refractory T-cell ALL?
NS: Unfortunately, I do not think there is anything yet. In the context of immune therapies, we certainly are getting closer to some sort of T-cell ALL CAR-T cell product. But it is lagging behind the advances in B-cell ALL.
We typically use hyper-CVAD, but we do incorporate asparaginase intercalated into a few cycles for patients with T-cell ALL because we do not have good drugs like inotuzumab ozogamicin or blinatumomab for those patients.
Nelarabine used in the frontline setting, particularly in children, seems to improve outcomes; it is approved in the relapsed/refractory setting, but some studies have evaluated it in the frontline setting. In the clinical trial setting we are incorporating nelarabine and asparaginase into the hyper-CVAD backbone for frontline treatment. We have also added in venetoclax because pre-clinical data suggests it may be of benefit in T-cell ALL.
Notably, none of these experimental therapies are immunotherapies. They are just different ways of combining chemotherapy approaches to find optimal combinations for T-cell ALL. In different clinical trials, for patients who have not already had venetoclax, we offer chemotherapy using a combination of venetoclax with the BCL-XL inhibitor navitoclax. Previous data have suggested this combined therapy is effective in both B- and T- cell ALL.
Genetic testing plays a crucial role in guiding treatment decisions for both AML and ALL, enabling the use of targeted therapies tailored to specific mutations. In ALL, targeted therapies such as TKIs have emerged as effective treatment options for Philadelphia chromosome-positive (Ph+) cases. Immunotherapy has transformed the management of both relapsed/refractory and frontline B-cell ALL, with approved antibody-based therapies and CAR-T cell therapies showing remarkable results across different age groups. The integration of low-intensity chemotherapy with immunotherapy is being explored as a potential approach for improving treatment outcomes in both AML and B-cell ALL.
Acknowledgement : Kathryn Senior, an independent medical writer, helped draft this article.
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Cite this: Advances in the Diagnosis and Management of Acute Leukaemia: AML and ALL - Medscape - Jun 28, 2023.