Reviewing clinical strategies in the age of individualized medicine
Recently, ONCOLOGY discussed therapy options for adult acute lymphoblastic leukemia (ALL) with Dr. Elias Jabbour, MD, Professor of Medicine in the Department of Leukemia at the MD Anderson Cancer Center in Houston, Texas. Dr. Jabbour is involved in the development of chemotherapies and other therapies for leukemias, including ALL.
Q: What are the current standard-of-care therapy options for newly diagnosed patients with ALL, including newly approved therapies?
Dr. Jabbour: First, I think lots of progress has been made in therapies for adult ALL and believe we are going to improve the cure rate of this disease to levels achieved for pediatric ALL. I am confident of this because we don’t see every patient the same way and are moving to à la carte treatment. We do have many new drugs available, the first subset of which is tyrosine kinase inhibitors. When added to chemotherapy in Ph+ [Philadelphia chromosome-positive] ALL, these drugs lead to improvement in survival. In fact, the current 5-year survival rate of 75% has never been seen before. Then we have another group of drugs, the monoclonal antibodies, for the treatment of relapsed and refractory settings. In the frontline setting, rituximab, when added to chemotherapy, improved survival in the ALL 3b subtype. We also have other drugs like inotuzumab, ozogamicin, and blinatumomab that are approved in the relapsed setting. These drugs will be moving to the frontline setting and are very promising.
As there are different disease subsets of ALL, we rely heavily on their biology to identify certain subgroups of patients. This allows us to tailor our approach according to the baseline features of these disease subsets. Ten years ago, there was a publication describing what is now called Philadelphia-like ALL. These are patients with the same gene expression as Philadelphia-positive ALL but they don’t have the Philadelphia chromosome and therefore are Philadelphia-like. Patients who have this ALL subtype do poorly with chemotherapy, but with newly available approaches, we may be able to improve their outcome. At the T-cell level, we are looking into different subsets such as adenosine triphosphate (ATP) ALL, which has a poor prognosis. We are now testing new drugs to improve the outcome of these patients.
So, in treatment we have induction, consolidation, maintenance, and intrathecal chemotherapy to prevent CNS relapses. The consolidation therapy can be done with chemotherapy or a transplant and with maintenance therapy. We should not forget that we need to prevent CNS relapses by administering intrathecal chemotherapy.
This is what we have in the frontline setting for the management of ALL patients. Now, when we discuss the frontline setting, we also have to discuss biomarkers and how we choose therapy. So, what are the biomarkers that we use to distinguish the group of patients with ALL from each other? When you have a patient with ALL, it is important to identify the immune phenotype, whether it is a B-cell or T-cell subtype. Once we know it’s a B-cell ALL, for example, we need to know whether the patient is Philadelphia-positive. We check for the Philadelphia-like biology by checking the expression of certain markers such as cytokine receptor-like factor 2, overexpression involving checkpoint kinase 2 activation, or other arrangements including ABL1, ABL2, and cytokine receptors. Then we have the standard rubric of risk of ALL that usually has a good outcome. We look at CD20 expression, and we can add rituximab to frontline therapy for these patients. In T-cell ALL, we have to identify what we call the early T-cell precursor ALL, T-cell ALL, or Early T-precursor [ETP]-ALL. These include patients who have a certain immune phenotype, that is, CD1a-negative, CD5-dim (<75%), and CD8-negative, and one or more myeloid markers. These patients do not do well with a standard ALL regimen, and we are exploring new drugs such as venetoclax, but transplant should be offered in the frontline setting. In the past, we used to classify patients by WBC count, sex, and other factors. Today, based on biology, we are able to retune and redefine our ALL patient subgroups and design our treatment approach accordingly. When we have the diagnosis and baseline features, for example, we need to design a treatment approach for these patients.
Of course, the question of consolidation depends on the subtype of the patient. For example, in Philadelphia-positive ALL, we should offer transplantation up front, particularly in patients who cannot achieve complete molecular remission. Then we have Philadelphia-like ALL. Today, we are testing new drugs such as adding blinatumomab or inotuzumab to the frontline regimen, but standard of care remains transplantation. These Philadelphia-like patients usually remain minimal residual disease (MRD)-positive, and they should be treated for MRD positivity. Blinatumomab and/or transplantation should be considered. In ETP-ALL, we go for transplant after a patient achieves remission. Someone with 11q23 or MLL/copy serotype/hypodiploidy does not do well with the available regimens we have now and they should go for transplant. Transplant in first remission is reserved for patients who have bad features.
To summarize, we have different subsets of ALL. We identify the biology of the disease. We understand the severity of certain subsets and design consolidation and treatment approaches based on a patient’s baseline features.
Q: You mentioned minimal residual disease. Can you talk about how this is typically measured and if it is something now assessed in all patients? Or is this still only done at academic centers?
Dr. Jabbour: There’s nothing minimal about finding disease, because even having minimal disease is a sign of the cancer being refractory to treatment. If you look at the outcome with chemotherapy in ALL, if you give agent induction, about 90% of patients respond. But then, the vast majority do relapse, and our long-term outcome is only about 40% to 50% survival. This means there’s disease left that we may not be able to measure just based on morphology, indicating relapsed disease. Persistent minimal disease is the equivalent of relapse and treatment failure. This is not a biomarker but rather the persistence of disease whether detected at 4 weeks of a complete response or at 12 weeks. A meta-analysis with over 13,000 patients was published in 2017. It showed that pediatric or adult ALL patients, regardless of how you measure MRD, have poor outcomes. Therefore, we need to understand, whether we are in a community practice or in academia, that we cannot treat ALL without having in mind MRD assessment and how to address it. Finally, the US Food and Drug Administration approved a drug based on MRD last year. This was the approval of blinatumomab for the treatment of both pediatric and adult B-cell ALL in first or second complete remission with MRD > 0.1%. New trials are being designed taking into account MRD, because MRD can be a great target endpoint for long-term outcome. When you run a trial assessing a new drug, instead of waiting 7 years for survival results, you can use MRD as a surrogate endpoint because it coordinates with outcome.
In practice, we should test for MRD. Another question is how to test for it and when? The agreement is that within 12 weeks of starting treatment, patients should be MRD-negative. There is a lot of debate here because some clinicians say that maybe we should test for MRD at 4 weeks. That argument makes some sense, but it requires validation from different groups. For now, all of us who treat ALL have agreed that if you have levels of 10E-4 and above at 12 weeks, the outcome is really poor and these patients should be considered as refractory.
Of course, any time you have a patient who is MRD-positive is bad. How do we measure MRD? In the United States, the most common test is 6- to 8-color flow cytometry where we look at the expression of certain antigens on B cells and we define a normal population present. These tests require good expertise from the pathologist who reviews the flow cytometry results. We should send the first sample from the bone marrow to the pathologist. In Europe, they use a polymerase chain reaction (PCR)-based test with a look at the IgH [immunoglobulin heavy chain] receptor on the B cells. This requires a baseline clone and subsequent clones, and a good sample, to assess for MRD. This PCR-based assay is more time-consuming and expensive compared to flow cytometry. Flow cytometry doesn’t require a baseline sample, and the sensitivity is 10E-4 (1 leukemic cell/10,000). With the PCR-based test, the sensitivity is 10E-5 (1 leukemic cell/100,000). To go more in depth, we have a new test based on next-generation sequencing where we look at the sequence of the immunoglobulin receptor at a very low level and follow it. This is being standardized and is approved by the Food and Drug Administration as a reliable test for MRD. This test allows us to reach a sensitivity of 10E-6.
If you look at the data from the PCR test or from flow cytometry, patients who are MRD-negative can be positive by next-generation sequencing. It’s important because today if someone is MRD-negative, you may say that patient is doing well and that patient may not want to go for transplant. But there could be false-negative results. Having MRD assessed in more depth is one way to identify those patients who may not need to undergo a transplant.
So, next-generation sequencing is gaining more momentum today, but still the message I want to highlight is to check for MRD. Do not continue to treat ALL without assessing for MRD. Next-generation sequencing requires a baseline sample, as well as follow-up, just like the PCR-based test. One last test for MRD for Philadelphia-positive patients is to use PCR to check for BCR-ABL, and that has been standardized. The importance of MRD is that if you get to 3 months of treatment and a patient is in complete molecular response (CMR) with no disease left, this is great because we have shown that the outcome is excellent without transplantation in these patients. In contrast, if a patient is MRD-positive, you may need to go for transplant because the outcome is not so great.
Today, assessment for MRD and the results of MRD tests will dictate our approach to therapy moving forward. In the United States, we have a drug called blinatumomab, which is a CD3 bispecific engager that binds to CD19. The drug was approved based on multicenter phase II studies called the BLAST trial. Patients with MRD were given blinatumomab, and 80% responded. Today, someone with MRD-positive disease should be offered blinatumomab. They should not go for transplant unless they had blinatumomab and converting them to MRD-negative status had been tried, because we know outcomes with transplant are better in MRD-negative patients with ALL.
Q: It sounds like you are saying transplantation is not the goal for all patients. Can you talk in more detail about which patients are likely going to need a transplant versus those who will not?
Dr. Jabbour: Transplant is indicated in the frontline setting for patients who have hypodiploid ALL, for patients with 11q23 mutation, and for patients who have Philadelphia-like ALL, as well as for patients with Philadelphia-positive disease after blinatumomab who don’t achieve a CMR at 3 months, and finally, for patients with ETP-ALL. These are the patients for whom I would go to transplant in first remission.
Q: Can you talk about the different therapy options and for which patients these are appropriate in the relapsed, refractory setting?
Dr. Jabbour: In the relapsed setting, we’re making progress and have had several drugs approved in the last couple of years. One is inotuzumab ozogamicin, which is a CD22 antibody plus ozogamicin, a toxin. We also have blinatumomab, a bispecific engager antibody, and CAR [chimeric antigen receptor] T cells. Inotuzumab ozogamicin is targeted to CD22 expressed on B cells. When the drug binds to CD22, it is internalized and the ozogamicin is freed in the cell, and then causes double-stranded DNA breaks and kills the B cells. Blinatumomab is a bispecific engager that binds to CD3 on T cells and CD19 on B cells and activates T cells to kill the B cells. The CAR T cells are a big innovation in which a patient’s T cells are collected, re-engineered to express a receptor to CD19, and then infused back into the patient where they proliferate and kill the B cells.
Inotuzumab was approved based on a randomized trial that recruited patients who were refractory and randomized to either inotuzumab ozogamicin or standard of care. There was an improvement in responses of 80% and better overall survival of 7.7 months. Blinatumomab was first approved based on a phase II study, and then based on a trial in patients with Philadelphia-negative ALL randomized to either standard of care or blinatumomab. Patients on blinatumomab had higher response rates, higher MRD negativity, and better overall survival. That led to the full approval of this drug. In addition, the drug was tested in Philadelphia-positive disease. For both Inotuzumab and blinatumomab, better outcomes are obtained in first salvage compared to second salvage.
At MD Anderson, we took a step beyond that, knowing that these drugs are not myelossuppressive and can be combined with low with low-dose chemotherapy. When we did that, we had a response of 80% overall, and of 90% in first salvage; we improved survival as well: on average, the median survival was 14 months. If you look at first-salvage patients, survival at 2 years is beyond 50%, which is really good. With a 50% survival for patients at first salvage, and compared to historical data with inotuzumab or blinatumomab, the survival is about 7 months and here it’s 14 months, so we doubled the survival. I think the drugs are good, but it would be better to use them in combination, because we can have a better outcome and better safety profile.
For example, with inotuzumab, there is veno-occlusive disease (VOD). The combination allows us to use a lower dose of inotuzumab. Instead of using 1.8 mg/m2 per cycle, we now use the third of the dose with a total dose given of 2.7 mg/m2. With this kind of combination with the lower dose, we see less VODs. Furthermore, we use blinatumomab in a sequential fashion that allows us to distant transplant while deepening the responses and avoid VODs, and we have survival at 2 years of 50%. I don’t think these strategies are competing. Immunotherapies are great, but they can be used in combination.
This brings me to the last treatment strategy, which are CAR T cells. Again, these are T cells from the patient that are engineered to kill the patient’s B cells. Approval was based on a phase II multicenter trial with more than 100 patients screened, but not all were enrolled. The patients who did receive the infusion had responses that were still durable at 18 months and led to approval of the strategy. This therapy comes at the price of toxicities, mainly neurologic events, and cytokine syndrome. We see better efficacy in patients with minimal disease compared to patients with bulky disease. The approval is for patients only up to age 25, and we need more work on the adult patients. But I see a future role for the CAR T cells, maybe as a replacement for allogeneic stem cell transplantation. These are complementary approaches that will lead to significant improvement in outcomes for these patients.
Q: Finally, could you highlight some of the novel agents that are in the late stage of development for ALL?
Dr. Jabbour: We learned a lot from the relapsed, refractory setting experience with these drugs, and today we are testing these drugs in the frontline setting. We have an ongoing trial, for example, in older patients. Older patients do not do well because of bad organs and aggressive disease where survival is usually 4 to 6 months. We tested the combination of low-dose chemotherapy, inotuzumab, and blinatumomab in this group and found a highly tolerable regimen with a high response rate and a survival rate at 3 years of 54%, contrasting with 10% to 15% historically. Therefore, we are making progress by moving these drugs to the frontline setting and going into randomized trials to confirm their efficacy. Furthermore, we know that in young patients intensive chemotherapy can be toxic and can cause long-term complications. If these immunotherapy drugs are really well tolerated, maybe we can simplify the chemotherapy and use these drugs in the frontline setting.
FINANCIAL DISCLOSURES: Dr. Jabbour has received funding grants from Amgen, Pfizer, Takeda, Adaptive, Novartis, Spectrum, AbbVie, and BMS.
Kelly Valla, PharmD, BCOP
As illustrated throughout this conversation, the landscape and approach to treating ALL has seen changes related to a better understanding of disease biology, more sensitive tools to describe treatment responses with application of MRD-testing, and new agents incorporated into treatment algorithms. While inotuzumab ozogamicin, blinatumomab, and CAR-T cells are effective, consideration of their toxicity profiles and cost/access need to be taken into account.
The antibody-drug conjugate inotuzumab ozogamicin carries the risk of VOD – a risk also well described post-transplant. This risk should be factored into treatment planning; other non-modifiable risk factors, and those that may be modified, should be taken into account for patients who will move to transplant after receiving inotuzumab ozogamicin. Limiting pre-transplant exposure to inotuzumab, where possible, and selection of transplant conditioning therapy may be opportunities to reduce risk of VOD in this population.
Due to a short half-life of around 2 hours, blinatumomab administration consists of a continuous 28-day infusion of medication. In appropriate situations this can be managed in the ambulatory care setting after an initial hospitalization (7-day infusions may be prepared to reduce patient visits), but centers using this agent should establish clear transitions of care from the inpatient to outpatient setting to avoid interruptions in drug administration (unless, of course, drug administration is being held for toxicity). Blinatumomab administration requires close monitoring for cytokine-release syndrome (CRS) and neurotoxicity.
Speaking of CRS and neurotoxicity – these are also serious warnings associated with CAR-T therapy. At this time, centers must be certified and undergo training specific to the recognition and management of these complications in order to utilize CAR-T therapies. Patients and caregivers should be educated on the signs and symptoms of neurotoxicity as delayed onset in some patients has been described.
Financial Disclosure: The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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