Jabbour Highlights Ongoing Research, Current Treatment for ALL Subtypes

Elias Jabbour, MD

The treatment paradigm of acute lymphoblastic leukemia (ALL) has evolved with a number of advances over recent years, such as TKIs, antibody-drug conjugates, bispecific T-cell engager (BiTE) antibodies, and chimeric antigen receptor (CAR) T-cell therapy.

For example, the FDA granted an accelerated approval to the bispecific antibody blinatumomab (Blincyto) for the treatment of adult and pediatric patients with B-cell precursor acute ALL who are in remission, but still have minimal residual disease (MRD) in March 2018. This follows its prior approval as a therapy for adult and pediatric patients with relapsed/refractory B-cell precursor ALL.

“ALL is a rare disease; in a year, we see around 5000 cases,” said Elias Jabbour, MD, professor of medicine at The University of Texas MD Anderson Cancer Center. “It’s [important to] refer your patients to clinical trials so we can work together.”

Ongoing research with blinatumomab is focusing on the agent in combination. One phase II trial is exploring hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) in sequential combination with blinatumomab as a frontline treatment for adults with B-cell lineage ALL (NCT02877303).

Additionally, an ongoing phase I/II trial is evaluating inotuzumab ozogamicin (Besponsa) plus blinatumomab and combination chemotherapy for patients ≥60 years of age with treatment-naïve ALL (NCT01371630).

However, patients with Philadelphia chromosome (Ph)—positive disease require different treatment options, explained Jabbour. In addition, patients with Ph-like ALL also require alternative therapies. This subgroup is characterized by a similar genetic profile to Ph-positive ALL, but they do not share the BCR-ABL1 fusion. Also, in Ph-like disease, TKIs could be effective.

OncLive: What are the current treatment options for patients with ALL?

In an interview with OncLive during the 23rd International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma^®, Jabbour discussed the treatment options for patients with ALL across these various subgroups. Jabbour: In ALL, we are seeing a lot of evolution in a lot of great things. The major advances have been TKIs, monoclonal antibodies, BiTE engagers, and CAR T cells. In Ph-positive ALL, TKI added to chemotherapy showed that [it has a] great benefit in improving survival. Today, survival at 5 years is approaching 70%, and the idea that [stem cell] transplant is the only way to cure these patients is really a matter of debate. A patient can be cured without transplantation, which is really good. In this disease, we are moving away from chemotherapy by adding new drugs—such as a combination of blinatumomab with ponatinib (Iclusig), for example. It’s a chemotherapy-free regimen for these patients.

In relapsed disease, we have seen approvals of 3 drugs over the last few years. Inotuzumab ozogamicin, which is an anti-CD22 conjugate to calicheamicin; blinatumomab, which is a BiTE [antibody]; and CD19-targeted CAR T-cell therapies, as well. These drugs have shown great results in the lab setting with improvement in survival and higher response rate. Although it’s not what we want to do, we are using these drugs at the earlier stage because their efficacy is way more prominent earlier than later.

For example, blinatumomab has been approved by the FDA for [B-cell precursor ALL who are in remission] who have minimal residual disease (MRD); therefore, the use of the drug is more powerful if you use it earlier than later. At The University of Texas MD Anderson Cancer Center, we are using [blinatumomab] in the frontline setting, and in combination with other compounds in the relapse [setting]. Inotuzumab ozogamicin is also effective in the relapsed setting. At The University of Texas MD Anderson Cancer Center, we are using a strategy to combine low-dose chemotherapy with inotuzumab ozogamicin and blinatumomab for elderly people in the frontline setting and for the refractory setting. In the frontline setting for older people, we have a high response rate of 95%, MRD negativity approaching 95%, and the 3-year survival for these patients is 55%. This contrasts with historical data of only 15%, so it is a major advance that we are seeing.

In the relapsed setting, this combination has shown great results. For example, when you combine low-dose chemotherapy with inotuzumab ozogamicin and blinatumomab, we have a response rate of 85%. However, most importantly, the survival at 2 years and 3 years in the salvage setting is approaching 50%, which is a breakthrough. This combination has a median overall survival of 14 months, but is 25 months in the salvage setting, which is double and triple of what you could achieve with a single-agent drug.

How do these options differ for the patients with Ph-like ALL?

CAR T cells are available too. There was an approval for patients with ALL up until the age of 25. Of course, the game is not over. We are trying to optimize the use of CAR T cells. We are trying to minimize the safety concerns [associated with that treatment]. Hopefully in the future, we can rely less on chemotherapy and less on transplant by using a combination of inotuzumab ozogamicin, blinatumomab, and low-dose chemotherapy, and instead of using stem cell transplantation, use CAR T cells.Ph-like disease is a new entity over the last 10 years. It’s acknowledged by the World Health Organization classification as a provisional entity. These patients are characterized by having genetic profiling similar to the Ph-positive patients, but they don’t have the Ph chromosome. They are characterized by the presence of some recurrent fusion genes that may respond to TKI or may not.

Today, there is no standard test for Ph-like disease. However, one could check for CRLF2 overexpression, or a panel with certain genes. There are some data showing that TKIs may work. What we are doing at The University of Texas MD Anderson Cancer Center is combining chemotherapy with blinatumomab and inotuzumab ozogamicin in the frontline setting plus chemotherapy. Nevertheless, these patients are usually treated with standard chemotherapy, don’t achieve MRD negativity, and transplant should be offered for them.

How should patients with Ph-positive disease be treated?

What is the main take home message from your talk?

What unanswered questions still exist in this space?

The strategy for these patients should be to check back for MRD at 3 months. If it’s positive, go further with transplantation, otherwise at my institution, we are doing the combination of chemotherapy with blinatumomab upfront with inotuzumab ozogamicin.For Ph-positive disease, patients have the BCR-ABL1 fusion, which is different; for these patients, the standard of care is to use chemotherapy and a TKI. The best regimen thus far is hyper-CVAD and ponatinib. If they achieve a complete molecular response (CMR), transplant will not be needed. If no CMR at 3 months is achieved, then the patient should go for transplant.The key point is to think about Ph-like ALL. If you have a patient [with Ph-like disease], there are clinical trials. Assess for MRD-positivity. For Ph-positive disease, use the best TKI upfront, which is ponatinib, and chemotherapy. Asses for response at 3 months, and if a CMR is achieved, then you could put transplant on hold.We need to wait for the data to mature for combining chemotherapy and blinatumomab. If we show down the road that these results are sustained and we see noted success, one could easily move them to the younger patient population.

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