Treatment Options Continue to Expand, Improving Survival Rates in ALL

Nicholas J. Short, MD

In the acute lymphoblastic leukemia (ALL) space, treatment options are moving away from chemotherapy and transplantation and in the direction of new agents and combinations.

Recent approvals in the field include chimeric antigen receptor (CAR) T cells which have offered improvements in survival and better remission rates, blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), and ponatinib (Iclusig), a tyrosine kinase inhibitor (TKI).

For patients with Philadelphia chromosome (Ph)-negative B-cell ALL, first-line treatment includes hyper-CVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride [Adriamycin], methotrexate, cytarabine and dexamethasone) with sequential blinatumomab plus inotuzumab. This combination was evaluated in a phase 1/2 study (NCT01371630) which demonstrated high efficacy at achieving minimal residual disease (MRD) negativity and prolonged overall survival.

There has also been a shift with cytopathic approaches due to the introduction of BCR-ABL TKIs in Ph-positive ALL and antibodies which targeted CD19 and CD22.

“We have great drugs available and hopefully there are more to come soon. But even with what we have, I think that we are going to be able to cure patients if we use them properly and ideally in the frontline setting,” said Nicholas J. Short, MD, in an interview with Targeted Oncology^TM.

In the interview with Targeted Oncology, Short of the University of Texas MD Anderson Cancer Center, discussed the evolution of the treatment landscape for ALL and what he hopes is next to come.

Targeted Oncology: Can you discuss the initial treatment strategies used in acute lymphoblastic leukemia management?

Short: With ALL, there is either Philadelphia chromosome-negative or Philadelphia chromosome-positive, and that is 1 of the big ways that we decide frontline treatment strategies. For the Philadelphia chromosome-negative patients, the options for patients who are adolescents and young adults would be either a pediatric-inspired regimen or generally, adult-inspired regimen such as hyper-CVAD. If patients are older in that patient population, it becomes much more difficult. Patients who are 16 years of age and older don't do as well with conventional chemotherapy. Many of us are now incorporating some novel monoclonal antibodies such as inotuzumab and blinatumomab in the frontline setting.

One thing that we've done at my institution at MD Anderson Cancer Center has been to use hyper-CVAD in combination with inotuzumab and blinatumomab for those older patients with some good results from patients with Ph-positive ALL. That's changed a lot in the last few years. Historically, the standard of care would be a combination chemotherapy along with a tyrosine kinase inhibitor. We now have chemotherapy-free regimens, for example, the dasatinib [Sprycel] and blinatumomab, which was published in the New England Journal [of Medicine] a couple of years ago. Now what we've been doing at my institution is ponatinib and blinatumomab.

This has rapidly revolutionized the treatment of Philadelphia chromosome-positive ALL in the sense that we now have chemotherapy-free regimens for these patients. Now, we're avoiding transplant for most of them. For patients with T-cell ALL, it's still the same as far as chemotherapy options, either pediatric-inspired regimens, potentially for wave populations, or you could also consider a hyper-CVAD regimen for those patients as well. Unfortunately, we have fewer novel therapies that we can integrate into the frontline setting than we have with the B-cell ALL. There's still a lot that needs to be done to improve the outcomes of those patients.

How have these treatment options changed over the past few years?

We've had a lot of changes in treatment of options for patients, particularly for B-cell ALL. In the relapsed/refractory setting, we have the approval of inotuzumab ozogamicin and we have 2 CAR T cell products. We're trying to now integrate these into the frontline setting with several ongoing clinical trials. For younger patients with Philadelphia-negative B-cell ALL, what we're doing at our institution is a combination of hyper-CVAD along with blinatumomab and we have integrated inotuzumab into that regimen. We do a similar regimen for patients who are 60 years of age and older. We give them mini hyper-CVAD, so a low intensity chemotherapy regimen along with inotuzumab and blinatumomab.

For patients with Philadelphia chromosome-positive ALL, that's where we've seen the biggest changes, at least in frontline management, with the use of now chemotherapy-free regimens with blinatumomab plus a TKI, either dasatinib or ponatinib, which we know is a very potent TKI. We've seen good results with that particular regimen of blinatumomab and ponatinib with a 2-year survival of over 90%. Importantly, we sent only 1 patient to transplant in our ongoing study and no patients have relapsed. It looks like a very deep and durable remission that can be attained with these chemotherapy-free regimens without the need for transplant in the vast majority of patients.

In the relapsed/refractory setting, we have these drugs which are approved as monotherapy, so inotuzumab, alemtuzumab [Lemtrada], and CAR T cells. I think we're seeing better activity or results when we combine these, and importantly, now we have CAR T cells, which we can potentially use even as consolidation. For patients who have MRD-positive disease, or patients that we otherwise would like to avoid doing a transplant for, we can send those patients potentially for CAR T-cell therapy. We have a lot of tools available, and I think the challenge moving forward is really just how to sequence these and how to combine them.

What is the role of MRD in the selection of consolidation therapy for patients with ALL?

Assessment of MRD is imperative for patients with ALL. Historically, we relied predominantly on flow cytometry for patients who hadn't Ph-negative ALL. Now we have better technology, we have next generation sequencing assays that can detect MRD at a level of 1 abnormal leukemia cell out of a million cells, so a much better discrimination for risk, for example. For Ph-positive ALL, typically we use [polymerase chain reaction (PCR)] for BCR-ABL, although I think there may be a role as well for these more sensitive next generation sequencing assays.

For patients who've had standard chemotherapy and still have persistent MRD, the standard of care would be to move them to receive blinatumomab. Blinatumomab was studied in patients with MRD positive B-cell ALL and has a very high rate of MRD conversion. About 80% of patients will convert from MRD positivity to MRD negativity with blinatumomab, and we know that those patients have better long-term outcomes. The question is when a patient converts from MRD-positivity to MRD-negativity with blinatumomab, will we still need to transplant them? I think that that's still an open question.

MRD is used across the board, both in the frontline setting and in the relapsed/refractory setting. For patients who have received CAR T-cell therapy, the persistence of MRD after CAR T-cells identifies those patients are at a very high risk of relapse after CAR T-cell therapy. Those patients may be selected for post CAR T-cell transplant. Those patients who clear their MRD by this highly sensitive next generation sequencing MRD assay, who clear that after CAR T-cell therapy in the relapsed/refractory setting, a significant proportion are cured even without transplant. We still need those studies, but I think that may be 1 way that we're going to stratify patients, even in the relapsed/refractory setting into who should undergo transplant and who may not benefit. Historically, we transplanted everybody with relapsed/refractory ALL and got them into remission, but I think that may not be the case now that we have better drugs and better tools for assessing MRD.

What unmet needs still exist in ALL?

We've made a lot of advances in the treatment of patients with ALL, but there's still several unmet needs. One major unmet need is for more effective treatments for patients with T-cell ALL. We've had a revolution in the management of patients with T-cell ALL as well with various immunotherapies blinatumomab, inotuzumab, and now 2 approved CAR T-cell products. We have all the tools that we need to cure the vast majority of patients with B-cell ALL, as long as we use these drugs appropriately, sequence them appropriately, and potentially use them in combination.

The challenge for T-cell ALL is that we don't have very good drugs in that setting. We have some good preclinical data suggesting that venetoclax [Venclexta] may be effective. There are several studies ongoing with that combination. Also, nelarabine is an effective drug in the relapsed/refractory setting, We and others have tried to move until nelarabine in the frontline setting to improve outcomes for these patients. We still struggle with management of patients with T-cell ALL because we don't have effective drugs.

For patients with B-cell ALL, fortunately, we made a lot of improvements. There are still certain subsets that don't do as well. For example, MLL or KMT2A-rearranged ALL, or any acute leukemias do poorly, even with our standard available therapies. Fortunately, we have new drugs called Menin inhibitors that are in clinical trials now in the relapsed/refractory setting. Hopefully, we'll see those be effective, integrated, and hopefully be used in the frontline setting in the future for patients with KMT2A-rearranged leukemias.

Patients who still do poorly with available therapies particularly have a JAK1 or JAK2 mutation. We certainly need better therapies for those patients. There's been some studies exploring JAK inhibition with ruxolitinib [Jakafi], but unfortunately, I don't think that the data is very impressive yet and we need better agents for those patients. There are still some patients who also have poor-risk cytogenetics, complex cytogenetics, or low hypodiploid ALL clinically with a TP53 mutation. Those patients still do relatively poorly.

The hope is that as we use these better agents, these tools that we have, blinatumomab, inotuzumab, CAR T cells, we might be able to overcome some of the negative prognostic implications of some of these genomic abnormalities, but we still have to show that with some prospective data. For now, patients are still recommended for transplant, but I think that hopefully, we can move fewer patients to transplant to avoid the potential morbidity and mortality of that procedure by getting very deep molecular responses with these available therapies, even for high-risk patients, and hopefully curing them without the need for transplant.

With the amount of change that has been seen in this space in the past decade, what do you think is next?

One of the most exciting things in ALL is the fact of how quickly things have moved in the last 10 years. I do think that we have the tools needed to cure many patients, certainly with B-cell ALL, with what we have. There are a number of studies ongoing which are looking at various sequences and combinations of these different immunotherapies. I think that the cure of most patients with B-cell ALL is with us and now we have to show in prospective studies that we can also cure these patients without the need for transplant.

The other exciting thing is the fact that we're a hope able to move away from transplant for many of these patients by using these effective therapies. We've seen that most clearly in the setting of Philadelphia chromosome-positive ALL, where when we use our most effective therapies, for example, ponatinib, which is a very potent TKI, in combination with blinatumomab, we see what looks like curative therapy in the with the absence of transplant. We have great drugs available and hopefully there are more to come soon. But even with what we have, I think that we are going to be able to cure patients if we use them properly and ideally in the frontline setting.