Physicians Discuss Treatment Preference in R/R B-Cell Precursor ALL

Nicholas Short, MD (MODERATOR)

Assistant Professor, Department of Leukemia

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX

EVENT REGION California, Nevada, and Arizona

PARTICIPANT LIST Alex Bataller, MD, PhD | Musa Yilmaz, MD | Arati Chand, MD | Preeti Chaudhary, MD | Michael R. Grunwald, MD

CASE SUMMARY

• A 72-year-old retired businessman was previously diagnosed with the following:
  • Philadelphia chromosome negative B-cell acute lymphoblastic leukemia (ALL)
  • CD22+; CD19+
  • Complex karyotype (≥ 5 chromosomal alterations)
• ECOG performance status: 0
• Medical history:
  • Type 1 diabetes mellitus
  • Hypertension (controlled)
  • Myocardial infarction at aged 63 years
• Induction/consolidation treatment:
  • Mini-hyper-CVD [cyclophosphamide and dexamethasone at 50% reduction, no anthracycline, methotrexate at 75% dose reductions, and cytarabine at 0.5 g/m2 × 4 doses]
  • Therapy well tolerated without major complications
• Response to therapy:
  • Achieved minimal residual disease–negative complete response (CR)
  • Relapsed during consolidation therapy 6 months after achieving first CR
  • Mildly neutropenic throughout the course of treatment
• Central nervous system (CNS) prophylaxis provided, negative for CNS disease

Presentation at first relapse

• Clinical presentation: pyrexia and fatigue
• Not eligible for stem cell transplant because of comorbidities
• Current disease assessment:
  • CD22+; CD19+
  • Complex karyotype (≥ 5 chromosomal alterations)
  • Bone marrow blasts: 65%
  • ECOG performance status: 1
• Additional laboratory values:
  • White blood cell count: 3.7 × 103/mm3
  • Hemoglobin: 7.2 g/kL
  • Hematocrit: 23%
  • Platelets: 14,000/μL
    

DISCUSSION QUESTION

• Considering the results of the INO-VATE ALL trial (NCT01564784) investigating inotuzumab ozogamicin (Besponsa),¹ which patients are you likely to treat or not treat with this drug: patients who are older, ineligible for transplant, proceeding to transplant, have high disease burden (> 50% blasts), other?

SHORT: Which patients are you most likely to treat with inotuzumab ozogamicin in practice? Are there any of these groups you would not treat with inotuzumab?

BATALLER: For a patient who has to go to transplant, [they can] have VOD [veno-occlusive disease] with inotuzumab—with blinatumomab [Blincyto]. You don’t have this VOD, so maybe that would be one situation that we would first think about another drug before using the inotuzumab in this scenario.

SHORT: That’s a good point. Patients who proceed to transplant are those who are the most likely to develop VOD because transplant already comes with a VOD risk. There are things that we can do to mitigate that; for example, you avoid dual alkylator conditioning and other things to make it less likely for the patient to develop VOD.

It’s interesting, because in the INO-VATE study, compared with chemotherapy, more patients were able to be bridged to transplant with inotuzumab.¹ In the TOWER study (NCT02013167) with blinatumomab, the transplant rates were similar between the blinatumomab and chemotherapy groups, so it suggested that blinatumomab didn’t increase the number of patients who went to transplant, at least in that study.²

If you want the patient to get to transplant, the phase 3 data suggest inotuzumab is maybe better to get them to transplant…but at the same time, you’re concerned about VOD, so these are all important things to think about. I wouldn’t use it as a contraindication, but to your point, these are all things to consider.

YILMAZ: Perhaps someone with nonalcoholic liver disease would be a concern.

SHORT: Exactly, that would be a patient who you would want to avoid with inotuzumab. It’s hard because it’s not a contraindication. It depends on the status of the liver disease. If someone has decompensated cirrhosis, that would be a contraindication.

For someone who has some fatty liver [disease] and their alanine transaminase or aspartate transaminase [level] is mildly elevated, you get nervous about it, but it’s not like you couldn’t use inotuzumab. I think it’s important to consider all these things, but in practice, it’s not as simple as: This patient is absolutely not a candidate for this, or this is the best treatment. It’s about making these decisions for an individual patient based on a lot of different factors.

DISCUSSION QUESTIONS

• What are the primary patient and disease factors in choosing a therapeutic approach in an older patient with relapsed/refractory B-cell ALL?
  • Physiological factors—performance status, comorbidities, etc
  • Laboratory factors—blast count, liver function tests
  • Lifestyle factors—transportation, insurance, financial, etc
  • Patient-informed choice
• For patients with bone marrow blasts of at least 50%, what is your preferred product? Why?
  

SHORT: CAR [chimeric antigen receptor] T-cell therapy is only approved for younger patients, so it’s not relevant to our patient case. Does anyone want to discuss specifically an older patient, so aged 60 years or older, and if that influences how you’re going to choose inotuzumab or blinatumomab?

When we’re talking about an older patient, do transportation, coming back and forth to the clinic, and other considerations in your practice sway you one way or another? Would anything else help you choose between these options for someone who is 60 years and older who’s not a transplant candidate?

CHAND: As far as the CAR T-cell therapy is concerned, the transportation may be an issue, but I think the bigger issue is the logistics of getting the patient to a cellular therapy center. If they’re [having a lot of disease burden], you can’t keep them without any treatment, because the CAR T-cell processes, commercially, can be time-consuming. You get them to a CAR T center, then they have to freeze [cells], and then they probably have to get some treatment before they get the T-cell infusion, so in the real world, there are a lot of things to consider.

I don’t think patients with high blast count can make it to a CAR T center in time without giving them bridging therapy, so the question is: Would you give them chemotherapy, inotuzumab, or blinatumomab? And if they have a complete response or a partial response, would you still take them to CAR T? That’s my question, because as far as ALL is concerned, I usually think of CAR T as a third-line treatment or later.

SHORT: Does anybody have any strategies or anything that has worked, thinking about a patient who might need CAR T-cell therapy or someone who has high blasts who’s more proliferative? Is that something you find to be feasible?

CHAUDHARY: I’m a community oncologist, so is there one treatment easier to give in a community setting vs another? I haven’t used these drugs, but I have a patient who’s currently in the hospital with ALL; does the setting in which you’re treating determine your decision on giving inotuzumab or blinatumomab?

SHORT: With blinatumomab, I’d be curious how many people get it outpatient. I’ve heard some places where you have to do it as inpatient treatment, which is not very feasible. If you give enough of it, a lot of institutions will have it set up where you can do these outpatient bag exchanges and keep patients out of the hospital. Inotuzumab, as long as you get an insurance approval, can be given as outpatient intravenously, so it’s simpler from that perspective. Has anybody had issues with giving blinatumomab from a logistical perspective?

CHAND: Usually, we start it as inpatient treatment and then transition to outpatient. First cycle, we keep them for 9 days, and subsequent cycles, for maybe 2 days, and then the home health [group] does the second-day bag exchange at home, and patients are usually able to stay home, unless they have adverse events or something.

With inotuzumab, I don’t think you can get it in the hospital. The only time I’ve been able to do it was outpatient, but then most of these patients will end up in the hospital with neutropenic fever or something like that.

SHORT: If you’re at a center that has never given blinatumomab, or very rarely, it might be difficult to get all this set up. If you don’t have a plan for setting up home health, bag changes, the pump, and all that, it might be challenging. From what I’m hearing, and maybe in a situation like that, inotuzumab might be simpler, but if any institution has treated multiple patients with blinatumomab, I think a lot of them will have that infrastructure set up to give [the agent], and then the logistics are probably less of an issue.

The patient case presented a blast percentage of 65%. Do you have any preference in that setting for inotuzumab vs blinatumomab?

GRUNWALD: I have a minor preference for inotuzumab in the high blast count setting. I could also envision a situation where I could use inotuzumab to debulk a patient before getting CAR T-cell therapy, so if the patient has a high blast count, they get inotuzumab for 1 or 2 cycles before CAR T.

SHORT: That’s a great point. I agree that if you are choosing between these and giving monotherapy, if you have a high blast percentage, the data are better for inotuzumab, if you can give it and they don’t have another contraindication to it.

Have you had a patient like that for whom you wouldn’t do the apheresis? If they come in with a high blast percentage, do you just give them a cycle of inotuzumab, [perform] apheresis when they’re in remission, and then give them CAR T-cell [therapy]? Or, if they’re in remission, do you say we don’t need CAR T-cell [therapy] anymore?

GRUNWALD: That’s a tough one. We know that the durability of inotuzumab is not necessarily always what we would want it to be. Most of the patients who are not receiving transplants don’t have a particularly long remission, and so I think you could infuse the CAR T when the patient is in remission, or you could wait for relapse and have it ready to go at the time of relapse. I haven’t used this strategy before, but I think it would be reasonable to give inotuzumab for debulking, and then to give CAR T.

SHORT: I agree. That’s something that we’ve adopted in our practice. When a patient clearly needs CAR T-cell therapy, which means their disease relapsed, that’s when it’s the hardest to give them the CAR T-cell because now they’re proliferative or something similar. We know that if patients receive inotuzumab and don’t go to transplant, the patient is going to relapse.

They’re either going to die from a complication, or they’re going to relapse and then die from leukemia, so I don’t think that we should think only when they’re relapsed, [give them CAR T-cell therapy]. I want to give CAR T-cell therapy immediately, so I should start bracing them and starting this process because it’s going to be challenging. If you give them inotuzumab and they’re not going to go to transplant, I would say to [perform] apheresis, knowing that you’re going to have to give CAR T-cell therapy. If that patient wants to receive further therapy, you’re going to want to have the CAR T cells available if you can get insurance approval.

This patient has relapsed/refractory ALL, even if they’re in a temporary remission, in theory, they’re relapsed/refractory, and I think that that’s the best way to make sure that you can get the patient the CAR T cells. Then when they relapse, you can admit them [to the hospital] and give them conditioning and the CAR T-cell product.

I don’t know if a lot of people have had experience with that, but we’ve done it in my institution, and it seems to work. It’s a much more orderly process, trying to [perform] apheresis on someone who’s in remission than someone who is proliferating.

CHAND: When you use inotuzumab in the relapsed setting, do you use it as a single agent or do you combine it with low-dose chemotherapy?

SHORT: What I use is the combination therapy because we did a lot of the trials that led to that. One of the National Comprehensive Cancer Network options is to give mini-CVD with inotuzumab.³ Usually, that’s our approach. Depending on the age, I would not [always] do the combination chemotherapy, depending on how fit they are, but for the average relapsed/refractory patient, I would use mini-CVD with inotuzumab.

Now there are published data following that up with blinatumomab….If you give mini-CVD with inotuzumab, give blinatumomab subsequently, and don’t go to transplant, there was a 3-year overall survival rate of 33%.⁴ That suggests if you give all of these best drugs in combination, sequence, or as 1 total regimen, you might have a curative approach for at least a substantial population of patients without needing to go to transplant.

We’re putting a lot of these patients on clinical trials, which has generated the data, but even outside a clinical trial, we still do use those, and we are usually able to get insurance approval to give all of those as part of 1 regimen. You don’t always ask for all of the drugs at once; you just give the mini-CVD and then you shift to blinatumomab and ask the insurance company, and usually we can get it approved.

Or you can give them mini-CVD alone. There’s also mini-CVD/inotuzumab without blinatumomab, although I prefer to give both agents as part of 1 regimen. If you sequence them, you give inotuzumab, then you wait for them to relapse, then you give blinatumomab, you’re less likely to have that potential survival.

CHAND: For neutropenic fever with inotuzumab, do you just treat them if it happens?

SHORT: For any patient who’s getting any myelosuppressive therapy, certainly, for durations of neutropenia, but usually across the board, I would give prophylaxis. We do triple prophylaxis and antibacterial, even antifungal and antiviral.

CHAND: But you don’t give granulocyte colony-stimulating factor [G-CSF]?

SHORT: You can give G-CSF as much as you want in ALL for neutropenic fever, so there’s no concern about stimulating the leukemia or anything. So yes, G-CSF, but in addition, you’d usually do prophylaxis, unless a patient has already been through a couple cycles, and they’re clearly not neutropenic. If they’re in a good complete response and they’re not neutropenic, then you don’t necessarily need to continue the prophylaxis. We usually continue antiviral for everyone, but…the antibacterial/antifungal are more relevant for neutropenia.

DISCUSSION QUESTION

• How do you prevent/minimize/manage toxicities?

SHORT: When you’re giving these drugs, inotuzumab, blinatumomab, or even CAR T cells, do you have any strategies to manage toxicities? I heard concerns about VOD if you are giving inotuzumab, although some of you haven’t given it that often. Do you give ursodiol, or if you were to have a patient you were going to give inotuzumab, would you give ursodiol?

GRUNWALD: I always give ursodiol. I can’t find a reason not to do it.

SHORT: I found out from a pharmacist that it’s expensive; I didn’t know this. For some reason, I just assumed it was a cheap drug, but it’s apparently not. But it’s low toxicity, so from that perspective, I agree—why not give it, so we do that.

REFERENCES:

1. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753. doi:10.1056/NEJMoa1509277

2. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847. doi:10.1056/NEJMoa1609783

3. NCCN. Clinical Practice Guidelines in Oncology. Acute lymphoblastic leukemia, version 2.2023. Accessed September 10, 2023. https://bit.ly/3ZkSoeL

4. Jabbour E, Sasaki K, Short NJ, et al. Long-term follow-up of salvage therapy using a combination of inotuzumab ozogamicin and mini-hyper-CVD with or without blinatumomab in relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic leukemia. Cancer. 2021;127(12):2025-2038. doi:10.1002/cncr.33469