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Ahead of the 2019 American Society of Clinical Oncology (ASCO) 

, we are speaking with Elizabeth Shpall, MD, of the University of Texas MD Anderson Cancer Center, about the management of cytokine release syndrome in patients receiving chimeric antigen receptor (CAR) T-cell therapy. Dr. Shpall will be speaking at an Education Session titled, “Assessment and Management of Cytokine Release Syndrome” on Friday, May 31, at the meeting, which is being held May 31–June 4 in Chicago.

Cytokine release syndrome needs to be assessed for and managed in patients undergoing chimeric antigen receptor (CAR) T-cell therapy. For which cancer types has CAR T-cell therapy been investigated? In addition, how many patients benefit from it, and how durable are their responses?

I think acute lymphoblastic leukemia (ALL) was the first cancer type for which CAR T-cell therapy was evaluated. The most stunning data come from individuals younger than age 26 years, in highly refractory situations where patients had failed many therapies, including an allogeneic transplant, which is the most aggressive option. In this setting, the use of CAR T–targeting CD19 produced a 90% complete remission rate, which is very impressive.

Depending on which studies you read, including the characteristics of the patients and the actual construct itself, about 60% of patients who achieved a complete remission appear to be in long-term remission at this time. Some studies found that this rate was lower, while other studies found it to be similar. So, I think the jury is still out on the long-term results, since many patients are still being followed and treated. That said, this research led to the US Food and Drug Administration (FDA) approval of the first CAR T-cell therapy, tisagenlecleucel, for the treatment of patients with ALL.

Research evaluating CAR T-cell therapy for non-Hodgkin lymphoma and diffuse large B-cell lymphomas in patients aged 18 to 75 years started shortly after the studies looking into this therapy for ALL. Now, even patients in their 80s are being treated. The categories of disease in this population include high-grade B-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large cell lymphoma, and diffuse large B-cell lymphoma arising from follicular lymphoma. These are the four subclassifications of patients who appear to benefit from CAR T-cell therapy. In clinical trials, approximately 70% of patients studied responded to axicabtagene ciloleucel, and the complete remission rate was about 54%. Long term, about 40% of these patients have remained in remission. Following critical studies led by Sattva Neelapu, MD, of MD Anderson Cancer Center, the FDA approved the CAR T-cell therapy axicabtagene ciloleucel for the previously listed individuals in October of 2017.

Researchers continue to evaluate tisagenlecleucel for various lymphoma categories and have seen good results. Many other therapies are being evaluated at different institutions across the country, including the TRANSCEND protocol, which is evaluating JCAR17 CAR T-cell therapy. The data look very promising so far, but it's not yet at the FDA for approval. In addition, there are some very impressive CAR T-cell constructs developed in individual academic centers that are moving forward and producing similar results to the ones I just discussed.

Lastly, data on the use of bb2121, a CAR T-cell therapy that targets B-cell maturation antigen, in multiple myeloma patients were just 

. The follow-up period was shorter, so it's not as robust as other studies and there's not as much information to tell us about the response durability, but the results are exciting.

Some patients taking CAR T-cell therapy experience cytokine release syndrome (CRS). Why does this happen, and what proportion of patients will experience CRS?

Although CAR T-cell therapy is very impressive and produces extraordinary results, it is also very potent in terms of the unique toxicities it produces. Cytokine release syndrome is the most common side effect associated with this treatment, and it is characterized by high fevers, hypertension, hypoxia, and multi-organ damage. About one-quarter to two-thirds of patients experience some sort of CRS. However, high-grade CRS-grade 4 or 5, which can be very dangerous or even fatal-is rare. Grade 3 and 4 CRS occurs in approximately 20% to 50% of patients.

Fortunately, the fatality due to CRS is very low, less than 5%-actually, less than 4% in most studies. But about half the patients who have been recorded in these early studies have required very intensive care management for at least a few days to ride out the cytokine release that has occurred. Management includes interleukin-6 inhibitors and corticosteroids. Neurotoxicity is fortunately not as common as CRS, but when it does occur, it has to be managed by a very astute team of investigators who understand how to diagnose and manage it (primarily with corticosteroids).

How are patients monitored for CRS and neurotoxicity during CAR T-cell therapy? What are the early symptoms?

The patients are followed very carefully. They need to be seen every day. Institutions often have a team in place to do so, including an evaluation for fever and monitoring of blood pressure and heart rate. These vital signs are very early signals that the patient may be developing CRS. Fever is typically the first warning sign of CRS followed by changes to blood pressure and heart rate. The patient’s respiratory status is also monitored because an increased use of oxygen and other clinical parameters can also indicate that a patient is developing CRS and needs immediate treatment.

For neurotoxicity, our team at MD Anderson and around the country has developed very simple neurologic testing to assess whether patients are developing any kind of neurologic compromise. It’s what we call the immune effector cell-associated encephalopathy (ICE) score, which is a simple 10-point score that involves asking the patient several questions (eg, name three objects, count backwards from 100 to 0, etc). If the patient can complete all of them and can write a sentence without any changes in handwriting, that confirms no early signs of neurotoxicity are present. Any perturbation in any of those parameters can heighten the team’s awareness that neurotoxicity may be developing, which can prompt more sophisticated testing such as electroencephalograms and scans of the brain.

Are there any predictive factors or biomarkers that might help identify which patients are at risk for high-grade CRS?

Many researchers are looking into this now. The academic centers are studying all of the different cytokines, including interleukin-6, interleukin-1, tumor necrosis factor alpha, and interferon gamma. However, baseline cytokine levels are not yet a perfect predictor.

Can you tell us a little about how CRS should be managed, including more about MD Anderson’s recently proposed guidelines for managing CRS and other CAR T-cell therapy toxicities?

It's important to underscore that published in the 

Biology of Blood and Marrow Transplantation

 in 2018 is the American Society for Transplantation and Cellular Therapy’s consensus grading by Lee et al. About 50 investigators from around the country were brought together to try to develop a now consensus screening criteria that will be used at every institution in the United States. This is a major improvement in the field, since before there were four or five different grading systems, and it was hard to compare patients and CAR T-cell products from different institutions. Now that this consensus grading is published, almost every center has adopting the criteria. At MD Anderson, we are also using this consensus grading.

In terms of how we evaluate for CRS, there are different symptoms that define grade 1, 2, 3, or 4 CRS, and these symptoms dictate the patient’s immune cell–associated neurotoxicity score. If patients have grade 1 CRS with a temperature, we watch them. If it's grade 2 CRS, we also continue to watch them, and if they develop more serious fevers or continued fevers, we may treat them with tocilizumab. For grade 3 and 4 CRS, we definitely treat patients with tocilizumab and corticosteroids.

We have been using tocilizumab and corticosteroids earlier in the course of CRS because studies have shown that they do not compromise the ultimate response rates in our patients, and they really do help abrogate early CRS and neurotoxicity. Patients developing grade 2 or 3 CRS are moved to the intensive care unit for careful monitoring and then are moved right back as soon as they are stabilized. If neurotoxicity alone is present without CRS, tocilizumab is not helpful, so we treat these patients with corticosteroids. Many groups in the country are looking at other potential blockades of these syndromes. One of them is the interleukin-1 inhibitor anakinra, which appears to be quite effective in mouse models; however, we don't have much clinical data yet.

What else would you like to tell readers about CAR T-cell therapy, CRS, and neurotoxicity?

I think it's a new day in the treatment of our patients. It's a gratifying time now to be able to achieve meaningful complete remissions and long-term responses when we have never had these opportunities in the past. However, we have to have the expertise in-house to be able to safely manage patients taking CAR T-cell therapy because, without that, we can have really unacceptable toxicities. So, clinical teams need to be trained, and clinicians from neurology, cardiology, and intensive care need to be part of a team that helps to manage these patients.

Many centers, including MD Anderson, are finding that the Foundation for the Accreditation of Cell Therapy (FACT) has developed very comprehensive standards to manage these patients. These are the 

, published a year and a half ago. These standards go through each section of treatment, including collection, processing, infusion, and management. They have been invaluable in getting our team organized, and in providing a roadmap of what things should be instituted to optimize the quality management and care of patients taking CAR T-cell therapy. I highly recommend the IEC Standards for any center entertaining treating patients with CAR T cells.

Centers can also become accredited by FACT to be an immune effector cells center when they meet certain standards, which can be downloaded on the FACT website. The FACT IEC inspection and accreditation program is going a long way to making this therapy safe for patients treated with CAR T-cell therapy throughout the United States.

American Society of Clinical Oncology Annual Meeting (ASCO)

Ahead of the ASCO Annual Meeting, we discuss the assessment and management of cytokine release syndrome in patients with cancer with Elizabeth Shpall, MD.

Managing Cytokine Release Syndrome in Patients on CAR T-Cell Therapy

Today we are discussing immunotherapy approaches for patients with acute myeloid leukemia (AML) with Dr. Naval Daver, MD, associate professor of leukemia at the MD Anderson Cancer Center in Houston. Daver leads several trials for patients with AML that are investigating the potential role of various immunotherapy approaches to better the outcomes of patients with this hematological malignancy. 

First, can you talk about the rationale for using immunotherapy to treat AML? Are there specific characteristics of AML that make it amenable to immunotherapy approaches?

Thank you for having me. AML is one of the diseases that is one of the first conditions for which we used immunotherapy in the form of allogeneic stem cell transplant. For almost four decades we have been using this as a modality to replace the patient’s immune system with a donor immune system, and we have seen that it is quite an effective approach for treating AML.

In addition, in the last 4 to 5 years, myself along with colleagues in the immunotherapy group at MD Anderson including Dr. Padmee Sharma and Jim Allison, have been interrogating acute myeloid leukemia patients’ blood and bone marrow samples to try to understand the nature of T-cells in AML. Our data will be published very shortly in an upcoming paper in the journal 

, and what we found when we looked at more than 100 patients with AML is that in fact, the T-cell population, both in the absolute numbers and the percentage, was quite preserved compared to healthy donors who had no disease. We did see that there was an upregulation of multiple different immune checkpoint co-receptors, the most striking being PD-1 and OX40.

Upregulation was highest in patients with relapsed AML compared to patients with new AML, but both sets of patients had a higher expression of PD1 and OX40 compared to healthy donors. This suggested that there is a favorable T-cell profile as well as expression of what we call inhibitory immune checkpoint receptors in the setting of AML, which may be one of the ways that AML tries to escape from being killed by the host defense immune system.  We could potentially activate these T-cells by blocking the inhibitory immune checkpoint receptors allowing them to fight the leukemia.

This form of immunotherapy, what we call T-cell-specific immunotherapy, such as immune checkpoint antibodies, bi-specific antibodies, CAR T-cells, enhance the patient’s own immune system.

There is another type of immunotherapy that is frequently used in patients with AML and that is called antibody-drug conjugates. This is an approach where we target leukemia-specific antigens and the most common ones have been CD33, CD133 and we now have newer ones like CLL1 (CLEC12a). We usually develop an antibody that also carries a toxic payload that is bacterial or chemical and these are delivered directly to the leukemia cells. It is important to know that there is a difference, when we talk about immunotherapy, namely T-cell based and the antibody-based immunotherapy. But both types seem to have efficacy, pre-clinical and clinical in AML.

On the T-cell based immunotherapy, you and your colleagues recently published positive results of a study at MD Anderson that tested the combination of azacitidine and nivolumab in patients with relapsed or refractory AML. Can you tell us about this trial and the results? Is this among the first positive immunotherapy clinical trials in AML?

We developed this trial a few years ago in a large collaboration that we had with BMS [Bristol Myers Squibb] to evaluate immunotherapies in different types of leukemia.  The conception of this trial actually came from some pre-clinical data that our colleagues at MD Anderson had generated that showed that azacitidine, which we have used for many years both in frontline AML and in relapsed AML and in MDS [myelodysplastic syndromes], upregulated the expression of PD1 and PDL1 on the surface of T-cells in patients with MDS and in those with AML. It was thought that we could use azacitidine as an immune-modulator in this situation and combine it with the anti-PD1 antibody and the one we used in this study is nivolumab.

The study was designed as most initial, first-in-human trials in any given malignancy are designed, to look at relapsed, AML patients and the idea is that if we found that the combination was safe and effective, giving us better efficacy than other contemporary azacitidine-based combination therapies or azacitidine single agent, then we would move it to the frontline.

We enrolled a total of 70 relapsed, AML patients and we allowed for both de novo and secondary AML and patients with different types of cytogenetics. The median age was 69. This is because we usually favor hypomethylating-based treatment approaches, whether in the frontline or relapsed setting, in elderly patients.

The study allowed patients of any age, but with younger patients we tend to try more intensive therapies both in the frontline and in relapse settings. We had one-third of patients who had adverse cytogenetics and about 22% of them had TP53 mutations. The primary endpoint of this study was to assess the response rate, which was defined by the European Leukemia Net (ELN) criteria to include complete remission (CR), complete remission with incomplete blood count recovery (CRi), as well as partial responses and hematological improvement.

The overall response that we saw was 34% in all relapsed AML patients. What was interesting was that the CR/CRi rate was 23%, but we had a number of non-traditional CR/CRi responses including hematological improvements and stable disease. These are not typically responses that we consider when we use high-dose, intensive cytotoxic therapies in AML, but these are responses that we are seeing can be quite important for quality of life, survival, transfusion-independence in elderly AML patients treated with azacitidine or with neither treatments such as IDH inhibitors.

With immunotherapy for solid tumors, we know that a number of responses could occur in the form of stable disease and that partial responses can last for many years. We are collecting these data and we showed that we had about 10%–12% additional stable disease responses in patients lasting for more than one year, in addition to the 34% response rate.

This is one of the first, larger studies using an immune checkpoint specific approach in AML showing that you can get an encouraging response rate in relapsed AML. To assess how these study results compared to what we were doing at MD Anderson with other azacitidine-based regimens, we developed a rigorous historical control that looked a 10 different trials of azacitidine or azacitidine combinations that we have done in the last 10 years.

We saw that this new combination regimen had better response rates and in fact, better survival, than all of those other combinations that we had done previously, suggesting that there is something specifically beneficial with this combination.

At the end of the day, the most important thing that we found was that it was specific subsets that seemed to have what we would consider the most clinically important benefit. Thirty-three percent is a reasonable response rate and the overall survival was 6 to 7 months, but that is not really a home run. What we also saw was that in salvage-1 patients who made up half of the study, we had an overall survival of almost 11 months, which is double the overall survival that we see with azacitidine combinations or azacitidine alone in salvage-1.

When we assessed biomarkers, we found clear biomarkers in the bone marrow or blood that could help select patients. For example, we found that pre-treatment CD3 levels in the bone marrow could predict for a higher response rate. Those patients who had more than 13% infiltrating CD3 in their bone marrow had a response rate of almost 56%, compared to those who had lower CD3 in their bone marrow initially, where the response rate was 23%.

We are thinking that the way these drugs need to be developed, which is already what is being done for solid tumors, is to use biomarkers to select the patients who are most likely to respond to these agents rather than exposing larger number of patients to see a benefit in only a small proportion. We think that if we use CD3 as a selection biomarker, which is a relatively simple assay that can be done using flow cytometry or immunohistochemistry, then we could actually have response rates of 50%–60%. So, we are basically trying to develop this combination therapy just like FLT3-mutation inhibitors and IDH inhibitors.

You’re also leading and taking part in several other immunotherapy AML trials, can you tell us about one or two of those?

We are conducting a number of different immune checkpoint based trials. In MDS we have a parallel study to the AML trial that was published in 

going on, looking at combination of azacitidine plus nivolumab. We're also looking at azacitidine with the anti-CTLA-4 antibody immune checkpoint inhibitor, ipilimumab in both frontline, high-risk MDS patients with high blasts and in MDS patients who have failed hypomethylating agents, azacitidine and decitabine. We presented this data last year as an oral abstract at the American Society of Hematology (ASH).

What we are seeing overall is that in the frontline setting, the combination of azacitidine with ipilimumab showed very encouraging response rates and survival, so we are expanding that cohort. Even in patients who have failed azacitidine, decitabine, which are the most difficult group of hematological malignancy patients who have dismal survival, we see that azacitidine with ipilimumab is showing us some interesting activity with high response rates of about 30%–40% as well as improved survival.

We think that in MDS, there may be a role for ipilimumab, which seems to have both single agent as well as combination activity with azacitidine. Learning from this experience, we are also going to be evaluating ipilimumab in AML. We have an ongoing study that is combining azacitidine with nivolumab and now adding to that ipilimumab at a low dose of 1 mg/kg, which is one-third of the standard dose and given every 6 weeks.

Just as has been seen in solid tumors where the combination of these two immune checkpoint inhibitors usually doubled or tripled response rates, we are hoping that this combination will further improve response rates and may even work in patients who have lower bone marrow CD3 infiltration and overcome what we consider the negative biomarker.

There are also a number of other phase II studies with other immune checkpoint inhibitors such as pembrolizumab, an anti-PD1 inhibitor, pidilizumab, and durvalumab, most in combination with azacitidine that we are also studying. One approach that I think will be very interesting, [which was] first shown by our colleagues at the Dana Farber Cancer Institute, is using an immune checkpoint inhibitor after a stem cell transplant. It was shown that this is quite an efficacious approach in patients who have relapsed AML post-transplant where single agent ipilimumab showed complete remission in 5 of 12 patients, including skin and lymph node clearance of disease.

So, we are looking at this combination of ipilimumab plus nivolumab in patients who have either relapsed or have high-risk features before or after transplant including adverse cytogenetics, TP53 mutation, MRD [minimal residual disease] positivity and we believe that in the setting of a transplant, enhancing immune surveillance with these drugs would potentially improve the relapse-free and overall survival of these high-risk patients who often do poorly even with transplant if you give some form of maintenance therapy.          

Are there other important immunotherapy modalities that are now being tested for AML patients that we haven’t discussed yet?

There are a number of other immunotherapy modalities that have been gaining traction in the last 3 to 4 years. I think we are seeing what was seen with solid tumors a few years ago, where initially the targeted approaches took precedence and these were developed and became mainstream but then quickly, there was a large onslaught of immunotherapy approaches that became a major part of therapy.

The other approaches that I think that are going to be important in hematological malignancies are the monoclonal antibodies. There will be updates on trials of monoclonal antibodies targeting CD33, as well as a CD123 antibody that we are working on at MD Anderson. Both of these are antibody drug conjugates so they carry a potent toxin on the antibody and both of these have been shown single agent complete responses in patients with AML who are relapsed after failing standard therapy.  We believe that when we combine these antibodies with azacitidine or with venetoclax or with other therapies, we could enhance their activity even more.

In ALL, we have the FDA-approved one, blinatumomab, which links to CD3 on T-cells and the CD19 antigen on the blast cell, and by doing that, brings the T cell in close proximity to the ALL blast cell resulting in T-cell mediated death of the blasts. Based on this concept, many companies, 2 to 3 years ago, started developing bispecific antibodies, including Amgen with AMG330 and Xmab with Xmab CD3-CD133 and MacroGenics also with a CD3-CD133 antibody. We are seeing with these agents, that they do have single agent activity in the relapsed AML setting.

The response rates have been lower than what we have seen with blinatumomab in ALL patients, and the responses do seem to be best in patients with low burden disease so we believe that these bispecific antibodies may actually play a role in low burden disease or minimal residual disease, which is also where they happen to work best in ALL patients.

Lastly, there is early development but not yet clear or large datasets of CAR T-cells in AML. In ALL and lymphoma, we have good data with CAR T-cells with high response rates. There are some early signals including a City of Hope study that showed that you could get responses in multiply relapsed AML with CD123 CAR T-cell and there are updates at this past ASH meeting, but I think the CAR T-cell therapy is about 4 to 5 years away from being mainstream and it’s more likely that the immune checkpoint inhibitors and the bispecific antibodies and monoclonals could be and commercialized in the early future for AML.

Thank you so much for joining us today Dr. Daver.

Cancer Network sat down with Dr. Naval Daver to discuss advancements and discoveries in immunotherapy for AML patients.

Immunotherapy Approaches in AML

Today, we are speaking with John F. Seymour, MBBS, PhD, the director of the department of haematology at the Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia. Dr. Seymour is the lead author on a paper of the results of the phase III MURANO trial, which studied venetoclax in combination with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

First, what are the current standard-of-care options for patients with advanced CLL who have already been treated with at least one therapy?

This is an area that is in a state of flux globally. In North America, ibrutinib has been well established in this setting, and I think is the most commonly used drug in that context. However, in many other parts of the world, chemoimmunotherapy remains the standard in the relapsed/refractory setting, particularly with bendamustine and rituximab, given that ibrutinib is not universally available or reimbursed for that indication.

Can you tell us about the MURANO trial’s design and the types of patients that were recruited? Were they the average types of patients with relapsed/refractory disease or was there something distinct about the particular patient cohort on this trial?

Sure. The eligibility required a maximum of three prior chemotherapy regimens. Unlike some other relapsed/refractory studies in which the patients could have had an unlimited number of prior treatments, this one was capped at three, although, they did need to have at least one prior chemotherapy-containing regimen. They could have had prior bendamustine, but, as it turns out, that was quite uncommon in the study. Patients with 17p deletions were allowed, but there was varying inclusion of these patients in geographic regions depending upon other therapies that were available. The median age of the patients was about 65 years. About one-quarter of the patients had a 17p deletion, with more than 80% of patients having prior fludarabine exposure-so a fairly standard cohort of patients. Adequate renal function was a requirement for study entry given the hydration and biochemical risk of tumor lysis syndrome with the venetoclax regimen.

What are the important results of this study?

 The most important result, and the primary endpoint, was progression-free survival and the bendamustine/rituximab arm performed somewhat better than expected. Despite a quarter of patients having deletion 17p, the median progression-free survival in the bendamustine/rituximab arm was 17 months. So, the control arm certainly performed adequately. But, the venetoclax/rituximab arm-the investigational arm-was far superior, with a hazard ratio of 0.17 for progression-free survival; the 

 value for superiority of venetoclax plus rituximab was < .0001. That translated into a 2-year progression-free survival improvement, from 36% in the bendamustine/rituximab control arm to 85% with venetoclax/rituximab, so a very profound improvement in progression-free survival with the investigational arm.

In subset analyses, that magnitude of therapeutic benefit was consistent across all clinical and biological subsets, including those either with or without deletion 17p. In some jurisdictions, some people would not consider bendamustine/rituximab as an appropriate treatment for those with a deletion 17p, but the benefit here of venetoclax was the same, regardless of deletion 17p status. The investigator-assessed progression-free survival benefit was confirmed by an independent review committee where the hazard ratio was pretty much identical, at 0.19. The overall response rate was substantially higher, and the complete remission rate as assessed by the investigators was also higher, at 27% compared with 8% for the bendamustine arm.

Two elements of the trial that are not yet fully mature but are showing very encouraging results are, one, that there was also an improvement in overall survival: the 2-year overall survival rate was 92% compared with 87% (

 = .018). Two, there was a very high rate of negativity of minimal residual disease (MRD) in the venetoclax/rituximab arm: 62% of patients were negative for MRD in the venetoclax arm compared with only 13% in the bendamustine/rituximab arm, so it’s likely that this depth of response as reflected by the investigator complete response and the MRD negativity rate is what accounts for the very durable response and the improved overall survival.

Is there anything notable about the differences in the safety profiles between the two treatment arms?

Yes, there are a few things. The first is that the rate of tumor lysis syndrome that had been a concern in the earlier development of venetoclax studies was quite low here, in this multinational setting: there were no incidences of clinical tumor lysis syndrome and the rate of biochemical tumor lysis was 3% in the venetoclax arm. Notably, a few cases were seen in the bendamustine/rituximab arm. The toxicity profile otherwise was consistent with what had been previously published for the regimen. The rate of grade 3/4 neutropenia was relatively high, nearly 60%, but infections were very infrequent, such that the febrile neutropenia rate was under 4% and the rate of serious infection such as pneumonia was around 5%. So, although the venetoclax arm had a relatively high rate of neutropenia, that did not translate into clinically significant infections throughout the study.

Do these results suggest that there would be a significant improvement in efficacy in the real-world setting for patients who could be treated with this combination outside of a clinical trial, if this regimen were to be approved by one or several health authorities? Could you put these results in context to other clinical trials in these patients that have been read out recently?

Yes, I do think the results are likely to be generalizable. This study was conducted in 109 sites in 20 countries, so there is very broad input from multiple investigators and clearly the regimen is safely and effectively deliverable in many geographic and healthcare settings. The nature of the population enrolled with the restriction of organ function are quite representative of relapsed/refractory CLL patients, and many practitioners now have very good experience with the package insert with venetoclax, with the weekly, graduated dose ramp-up and the need for hydration, uric acid control, and monitoring for potential tumor lysis. These precautions are now embedded in standard clinical practice, so I think the regimen is likely to be able to be delivered safely and effectively in the real-world setting.

Thank you so much for joining us today, Dr. Seymour. 

In this interview, we discuss the results of the phase III MURANO trial, which tested the combination of venetoclax with rituximab in relapsed/refractory CLL.

Venetoclax With Rituximab Improves Survival in Relapsed/Refractory CLL

As part of our coverage of the American Society of Hematology (ASH) Annual Meeting & Exposition held December 9–12 in Atlanta, we are speaking with Farhad Ravandi-Kashani, MD, professor of medicine and the chief of the section of developmental therapeutics in the department of leukemia at MD Anderson Cancer Center in Houston, about the management of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL). Dr. Ravandi-Kashani will lead a discussion titled, “Current Management of Philadelphia Chromosome–Positive ALL and the Role of Stem Cell Transplantation” during an education session at the meeting. 

First, what percentage of all ALL patients are positive for the Philadelphia chromosome and what does that mean in terms of the biology of this subtype compared with other subtypes of ALL?

The Philadelphia chromosome was originally described in chronic myeloid leukemia and is a translocation between chromosomes 9 and 22 that occurs in different percentages of patients with ALL depending on their age. It is fairly uncommon in children with ALL, only accounting for about 5% of patients. But in the adult population it accounts for about 25%; this proportion increases in the elderly, approaching as high as 40% or 45%. In terms of biology, this used to be one of the most difficult subtypes of ALL to treat with traditional ALL combination chemotherapy regimens. Prior to the introduction of tyrosine kinase inhibitors (TKIs), the literature always showed that the median survival with chemotherapy-based regimens was certainly less than 1 year and perhaps even shorter. The proportion of patients alive at 2 to 3 years was only about 15% to 20%, and perhaps a bit higher in the childhood population, but the majority of the patients who were alive longer term were those who were able to undergo an allogeneic stem cell transplant. Clearly, the introduction of TKIs has made a difference and has significantly improved the outcomes for both children and adults.

You already mentioned TKIs; can you talk about the options for patients who are newly diagnosed? Are the TKIs the mainstay of initial treatment for this subtype of ALL?

In my opinion, and I believe in the opinion of most physicians who treat this disease, the TKIs should be a part of the initial treatment in all patients, including children, adults, and the elderly. Now, there is some debate about whether these agents should be used as monotherapy or with minimal additional therapy, particularly in the older adult population, in the very elderly, or whether they should be combined with chemotherapy. I think there are a number of studies that have looked at this and have come up with somewhat different conclusions. However, I think the conclusion is unified-that in a younger patient who can tolerate the addition of ALL-type chemotherapy, that addition of chemotherapy to TKIs does improve the response, mainly the molecular response. However, in the older populations, in the elderly, there can be some argument for limiting traditional chemotherapy and just using TKI monotherapy because of the toxicity associated with chemotherapy. For example, the Italian groups have been conducting a number of studies using TKI monotherapy initially with imatinib, with dasatinib, and more recently with ponatinib, which have shown that you can actually achieve almost universal complete response with a TKI monotherapy plus some additional steroids. This is obviously very important because, again, in the older population, you are eliminating toxicity and early induction death.

Unfortunately, such a strategy does not lead to a long-term cure and long-term survival, and we certainly need to consolidate these remissions with additional therapy, whatever it may be-in the younger patients it can be the combination of chemotherapy and a TKI or allogeneic stem cell transplant or autologous stem cell transplant. In the older patients, it is best to perhaps reduce the chemotherapy and some of the newer agents that are becoming available. So, to answer your question, TKIs are definitely part of the initial treatment, but the form they take may depend on the age of the patient, and to some degree, on the desire to do an allogeneic transplant. Even in the younger patients, some experts suggest that you use minimal or no chemotherapy plus a TKI and then do an allogeneic stem cell transplant. That is a reasonable approach, but there could be a day when we completely eliminate stem cell transplants in these patients.

In regard to stem cell transplantation, where does the transplant fit into the course of therapy, and for which patients is it appropriate? 

As I mentioned, prior to the introduction of TKIs, without an allogeneic stem cell transplant, it would be extremely unlikely that you would achieve a long-term cure in Philadelphia chromosome–positive ALL. Allogeneic stem cell transplant has been considered standard therapy in first remission in all patients with Philadelphia chromosome–positive ALL who have a donor and are able to undergo transplantation. Also, as I mentioned, a lot of the patients with Philadelphia chromosome–positive ALL are older patients, people over the age of 60 and sometimes 65 and 70. Although there have been improvements in transplantation and there are now non-myeloablative regimens available, experts would agree that mortality and morbidity of transplant goes up significantly as the patient age increases. There have been attempts by some groups such as ours to try to see if we can actually do away with transplant initially, at least in some populations like the older patients or less fit patients, and if it is feasible, perhaps to even think about doing away with transplant in all patients. Even in the very young, there are still mortality and morbidity risks associated with transplant.

There are now very useful tools that can help us to achieve this. First, there are TKIs, which are very active; more importantly the newer third-generation TKIs are extremely potent and are active against resistance-inducing mutations such as T315I. Second, there are now agents that are becoming available such as monoclonal antibody–based therapies. We have shown that with the combination of chemotherapy and TKIs, there is a subset of patients who are cured without undergoing allogeneic stem cell transplant in first remission. Third, we now have surrogate markers specifically for minimal residual disease and molecular testing for the signature BCR-ABL translocation products, which can help us understand if the patient has achieved good enough remission that is unlikely to be associated with future relapse. Again, there have been many studies that have shown that achieving a complete molecular remission is certainly associated with a much higher likelihood of relapse-free and overall survival even without an allogeneic stem cell transplant. Overall, there is now an increased availability of effective tools for this disease, as well as better ways of monitoring for adequate therapy, specifically for eradication of minimal residual disease, that can hopefully allow us in the future to confidently decide that the patient does not need a transplant or that the patient is likely to relapse and we should consider transplant in first remission.

Thank you so much for joining us today, Dr. Ravandi-Kashani, and enjoy the conference.

ASH Annual Meeting & Exposition: Leukemia

In this interview ahead of the ASH Annual Meeting we discuss the current management of Philadelphia chromosome–positive acute lymphoblastic leukemia and the role of stem cell transplantation.

Management of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

The 2017 American Society of Clinical Oncology (ASCO) Annual Meeting is taking place June 2–6 in Chicago. As part of this year’s coverage, we are speaking with Ehab Atallah, MD, associate professor of medicine in the division of hematology and oncology at the Medical College of Wisconsin. At this year’s meeting, he will be speaking during an Education Session about discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia (CML).

What is the role of tyrosine kinase inhibitors-or TKIs-in the treatment of CML? How long do patients treated with TKIs remain on the drug? 

 TKIs have completely changed how we treat patients with CML. Currently, with this treatment, patients’ survival is almost very similar to patients who don’t have CML, which is pretty amazing. The only downside is that currently patients need to stay on treatment forever, as long as they are responding to it and tolerating it well.

What are some of the negative effects of the long duration of treatment with TKIs, physical or otherwise?

Ahead of the 2017 ASCO Annual Meeting, we discuss the discontinuation of TKIs in some chronic myeloid leukemia patients.

Leukemia

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