Review Series on Acute Lymphoblastic Leukemia (ALL)

Summary

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Blood Podcast: Review Series on Acute Lymphoblastic Leukemia (ALL)

American Society of Hematology
Episode Airdate: September 18, 2025
Host/Moderator: Dr. Herve Dombre (Associate Editor, Blood; Professor of Rheumatology, Institut de Leukémie, Hôpital Saint-Louis, Paris)
Guest: Dr. Mark Litso (Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN)

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Episode Overview

This episode of the Blood Podcast features a focused discussion on a new review series in Blood covering critical developments in acute lymphoblastic leukemia (ALL), with a spotlight on adult B cell precursor ALL. The conversation centers on the evolution of genetic subtyping, the shift toward immunotherapy—including blinatumomab and inotuzumab ozogamicin—frontline treatments, and future trends like CAR T-cell therapy and novel combinations, especially in the context of Philadelphia chromosome-positive ALL.

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Key Discussion Points & Insights

1. Structure of the Review Series

[00:39] Dr. Dombre outlines the four-article review series:

• Two reviews detail genetic classification for B cell precursor ALL and T-lineage ALL in adults, which now inform not only diagnosis and risk stratification, but also guide therapeutic decisions.
• A clinical review on the integration of immunotherapy (blinatumomab and others) into frontline regimens for adult B cell precursor ALL.
• An article examining the current and future role of CAR T-cell therapy.

Quote:
"All these new findings in terms of genetic classification are now used not only to classify but also to guide the treatment of those patients with ALL."
— Dr. Dombre [00:39]

2. Incorporation of Immunotherapy: Blinatumomab and Inotuzumab

[02:14] Dr. Litso provides an in-depth overview of immunotherapies entering the frontline:

• Blinatumomab: A bispecific T-cell engager (BiTE) with significant data (including the E1910 and MD Anderson regimens) supporting its use post-induction, leading to improved MRD negativity rates and survival.
• Inotuzumab Ozogamicin: Shows promise both in induction and in chemo-free regimens for older adults, as highlighted by US Alliance Cooperative Group trials.
• Rituximab: Early evidence from the GRAAL trial (French group) shows added benefit when combined with chemotherapy in CD20+ disease.
• CAR T-cell therapy: Touched on as a promising, though still investigational, frontline approach.

Notable Study Results:

• MD Anderson’s HYPERCVAD + blinatumomab regimen allows fewer chemotherapy cycles, high complete remission, and MRD negativity.
• LAL2317 Italian phase II trial: Blinatumomab + chemotherapy increases MRD negativity up to 90%.
• E1910 (US): Blinatumomab in consolidation yielded 85% 3-year OS vs. 68% with chemo alone in MRD-negative patients aged 30–70 (new FDA indication).

Quote:
"Blinatumomab has been studied extensively now in the frontline setting and shown very encouraging results... very high complete remission and MRD negative rates with this regimen in the phase two setting."
— Dr. Litso [02:54]

Chemotherapy-Free Approaches:

• In elderly (>65), inotuzumab followed by blinatumomab (with only intrathecal chemo) resulted in >90% CR, ~80% 1-year survival.

Quote:
"That bodes well for the potential for us to begin to significantly limit the amount of chemotherapy that particularly older patients need to receive."
— Dr. Litso [04:58]

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3. About the Optimal Number of Blinatumomab Cycles

[05:38] Dr. Dombre queries ideal cycle number for frontline treatment, noting previous approvals for MRD and relapsed/refractory settings.

[06:38] Dr. Litso responds:

• No definitive answer; trials have varied (Children’s Oncology Group: 2 cycles, E1910: up to 4 cycles).

Quote:
"Our data is with four cycles and so that's what I would recommend... It's conceivable that two cycles might be sufficient."
— Dr. Litso [07:14]

• Maintenance and minimization strategies are ongoing, including adding blinatumomab in maintenance to reduce chemotherapy exposure.

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4. Sequential Use of Inotuzumab and Blinatumomab (Debulking and MRD Eradication)

[07:51] Dr. Dombre probes “debulking” with inotuzumab followed by blinatumomab, referencing emerging trial strategies.

[08:21] Dr. Litso explains:

• Blinatumomab is less effective in high blast count settings; optimal in low MRD.
• Inotuzumab does not have this limitation—making it more suited for debulking, followed by blinatumomab for MRD eradication.
• Multiple studies (Alliance, MD Anderson, GMALL, EU-wide) are evaluating this sequencing.

Quote:
"A number of studies are focusing on giving inotuzumab for debulking...and then bringing in blinatumomab...to treat residual disease."
— Dr. Litso [09:04]

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5. Philadelphia Chromosome-Positive (Ph+) ALL: TKI-Immunotherapy Combinations

[10:08] Dr. Litso highlights:

• Tyrosine kinase inhibitors (TKIs) revolutionized Ph+ disease by improving outcomes when combined with chemo.
• New studies (Italian, MD Anderson, US) are comparing TKI+blinatumomab vs. TKI+chemo, potentially reducing/eliminating chemotherapy.
  • Ongoing randomized US trial: ponatinib/dasatinib + HYPERCVAD vs. ponatinib/dasatinib + blinatumomab.

Quote:
"Now we have studies that are combining tyrosine kinase inhibitors, particularly ponatinib with blinatumomab and also seeing very excellent outcomes."
— Dr. Litso [10:23]

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Notable Quotes & Memorable Moments

• “I think inotuzumab is probably more ideal for debulking and giving it early and then bringing in blinatumomab later is likely the way the field is moving.”
  — Dr. Litso [09:54]
• “There's definitely the potential to reduce the amount of chemotherapy we give...”
  — Dr. Litso [05:23]
• “The optimal treatment [for Ph+ ALL] is not yet determined and all the studies you mentioned are very important to help us to design the optimal treatment with these new agents.”
  — Dr. Dombre [11:28]

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Key Timestamps

• 00:39: Review series overview (genetic classification, immunotherapy, CAR T-cell therapy)
• 02:14: Immunotherapy: Blinatumomab and inotuzumab in the frontline; pivotal study discussion
• 05:38: Optimal number of blinatumomab cycles debate
• 07:51: Sequential therapy approaches—using inotuzumab for debulking, blinatumomab for MRD
• 10:08: Ph+ ALL: TKIs and immunotherapy—ongoing research and future paradigms

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Conclusions & Recommendations

The field of adult B cell precursor ALL is rapidly evolving, with genetic profiling closely linked to clinical management and immunotherapy reshaping frontline and consolidation strategies. Major takeaways:

• Blinatumomab and inotuzumab are improving outcomes, sometimes allowing significant reduction or even elimination of chemotherapy for select patient populations.
• The optimal sequencing and number of immunotherapy cycles remain under research.
• Integration of immunotherapy in Ph+ ALL, especially in TKI-based regimens, is poised to further improve results.
• Ongoing trials will better define best practices for combining and sequencing these agents.

Final Recommendation:
"I can strongly recommend the readers and the audience to go to your review and read the article if they want more detailed data on this very important topic."
— Dr. Dombre [11:45]

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Transcript

[Podcast Host]

Welcome to this week's bonus episode of the Blood Podcast, your source for innovative ideas and cutting edge information. In this episode, Associate Editor Dr. Herve Dombre discusses the review series on all with author Dr. Mark Litso.

[Dr. Herve Dombre]

I'm Herve, He's Associate Editor for blood, especially for acute leukemia. I'm professor of Rheumatology at the Leukemia institute at Hospitale St. Louis in Paris, France.

[Dr. Mark Litso]

I'm Dr. Mark Lidso. I'm a Professor of Medicine in the Division of Hematology at the Mayo Clinic in Rochester, Minnesota and the United States.

[Dr. Herve Dombre]

We do have a review series on acute lymphoblastic leukemia and this series includes four articles. Two articles are dedicated to the description of genetic subtypes and classification for B cell precursor all in adults and for a telineagic all as well. This is important because all these new findings in terms of genetic classification are now used not only to classify but also to guide the treatment of those patients with all. Then after we have one series one reviews on incorporation of immunotherapy into frontline treatment for adult patients with B cell precursor. All this is done by Dr. Badar, Dr. Luger and Dr. Mark Litzo. And the last article is about the present and future or CAR T cell therapy for adult patients, again with B cell precursor all. So this is a relatively well balanced series with two biological reviews and to more clinical reviews discussing the introduction of new treatments into the treatment of these patients. So we have the pleasure to have Dr. Lidsel today to discuss with us the incorporation of immunotherapy and mostly blenatimumab into frontline treatment for adult patients with B cell all.

[Dr. Mark Litso]

Thank you Harvey. Our publication on the incorporation of immunotherapy into frontline treatment of all focused primarily on the use of blinitumumab, the bispecific T cell engager molecule, and in atuzumab, the antibody drug conjugate targeting CD22. We also had some brief discussion about the potential role of CAR T cell therapy in the frontline treatment of all. That's an emerging area. And then we also commented on some of the early studies with rituximab, the CD20 antibody, and particularly the study that you and your colleagues did with the Graal trial showing the benefit of rituximab in addition to chemotherapy. Vinatumumab has been studied extensively now in the frontline setting and shown very encouraging results. The MD Anderson group has incorporated into their regimen with HYPERC and it's allowed them to lessen the number of cycles of hypercvad chemotherapy that they need to give to patients substituting ablinatumab and have seen very high complete remission and MRD negative rates with this regimen in the phase two setting. Now we briefly comment about an Italian trial, the LAL2317 trial, which is a phase two trial adding venatumumab to chemotherapy, which also increased the MRD rate up to 90% in patients. And then we focused on the E1910 trial, the upfront United States trial that I had the good fortune to lead that incorporated blinitumumab into consolidation therapy of adults with B cell, all between the ages of 30 and 70, and showed that in patients who achieved MRD negativity and then received blinitumumab plus chemother, they had a overall survival of 85% at 3 years as compared to the control arm of 68% in patients that received consolidation chemotherapy alone. This led to the new indication by the FDA for the use of ninatumumab in consolidation therapy. Inatuzumab has also been incorporated into frontline therapy in a number of studies. One that I'll just briefly mention that I'm excited about was a trial done by the Alliance Cooperative Group here in the United States, small study of some 30 patients that gave inatuzumab an induction in patients over the age of 65 and then added oblinatumab for consolidation and achieved over 90% complete remission rate with survival in the 80% range at one year. And this is exciting because there was no chemotherapy given with this regimen other than some intrathecal therapy. So I think that bodes well for the potential for us to begin to significantly limit the amount of chemotherapy that particularly older patients need to receive. I think we need to be more cautious in the younger adult setting, but I think there's definitely the potential to reduce the amount of chemotherapy we give in that setting.

[Dr. Herve Dombre]

Okay, thank you, Mark. I have a question concerning the use of blenatimumab frontline. As you know, blenatimumab was first developed in relapsed refractory patients and it was used with repeated cycles of blenatimumab until a total number of five cycles. And then blenatimumab was approved for patients with persistent minimal residual disease after frontline induction and consolidation, and again, the number of cycles was more than three. And in the ECOG study you mentioned focusing on patient who is achieving MRD negativity after induction and consolidation. If I remember well, you use three cycles of blenatimumab during the treatment. So could you comment about if there is an answer? I don't know, but about the optimal number of blenatimumab to give for frontline to a patient with B all that's.

[Dr. Mark Litso]

A key question and an important one and I'm afraid I don't have a clear answer about that. Most recently the children's oncology group here in the United States added two cycles of bletumumab to their chemotherapy regimen in standard risk children with all and showed a significant improvement in disease free survival. In our EcoCHG trial we actually gave four cycles or tried to give up to four cycles. We tried to look at whether the outcomes were similar between two cycles and four, but that analysis is confounded by too many variables for us to draw a clear conclusion about that. So I can't answer that question definitively. When people ask me, I say that our data is with four cycles and so that's what I would recommend. But I, I think it's conceivable that two cycles might be sufficient. You know there's also been studies beginning to look at adding glenitumumab in maintenance and potentially using that to minimize maintenance. So that would be another question about how many cycles to use in that setting and how much to add after say induction and consolidation.

[Dr. Herve Dombre]

Thank you Mark. I have another question which is quite obvious questions. I mean you mentioned several agents in autuzumab and binatumumab. I know there is some trials evaluating the use of both to treat frontline patients, maybe starting with inutuzumab in order to debulk the disease and following by blenatimumab after achievement of MRD response. So could you comment on maybe future options?

[Dr. Mark Litso]

Yes, I think that's an important point. The early studies with blenatumumab in the relapsedrefractory setting showed that patients with high blast counts had lower response than patients with lower blast counts. They used a 50% cutoff. And you mentioned the excellent results with blenatumumab in the MRD positive setting when patients have less than 5% blast but still have persistent MRD. And so I think the consensus is emerging that blonatumab is more effective in lower disease burden settings, whereas that doesn't seem to be the case with inatuzumab. And so a number of studies are focusing on giving inatuzumab for debulking, as you mentioned, and then bringing in blinitumumab to treat residual disease either MRD positive or MRD negative. I mentioned the alliance clinical trial in elderly patients that gave initial nutuzumab and then brought in blimatumumab more as a consolidation. The MD Anderson group is pursuing this as well. The gmal, the German all group published a paper last year, the initial one trial giving three cycles of inatuzumab and then coming in with consolidation and maintenance chemotherapy. They didn't add blenatumumab in that study. And then there's also the excellent study that the European group that was European wide study giving inatuzumab and low intensity chemotherapy in older patients. I think inatuzumab is probably more ideal for debulking and giving it early and then bringing in blenatumumab later is likely the way the field is moving.

[Dr. Herve Dombre]

Thank you very much Mark.

[Dr. Mark Litso]

Could I mention one more area that our article mentioned but I didn't get a chance to speak to and I think it's an important area and that's in Philadelphia. Chromosome positive, BCR ABL positive all where as we know the addition of tyrosine kinase inhibitors has revolutionized the treatment of PH positive all and significantly improved outcomes. And this is in the setting of combining with chemotherapy. But now we have studies from the Italian group and the MD Anderson group that are combining tyrosine kinase inhibitors, particularly nalponatinib with belinutumumab and also seeing very excellent outcomes in the United States. Here we have a randomized trial of ponatinib or dasatinib investigator Choice with HYPERCVAD vs. Ponatinib or Dasatinib and vinatumumab. And we're randomizing patients. And so that study may complete accrual this year and will give us a clearer focus on whether the TKI plus blenatumumab regimen is truly superior to TKI plus chemotherapy. And I know the Jemima group in Italy is doing a trial of ponatinib and blenatumumab versus amantinib and chemotherapy. And so we also await the results of that trial.

[Dr. Herve Dombre]

Very important point. Thank you Mark. I think concerning PH positive all maybe the the optimal treatment is not yet determined and all the studies you mentioned are very important to help us to design the optimal treatment with these new agents. So thank you very much Mark for being with us today and more discussing your excellent review on the introduction of this new agent immunotherapy into frontline treatment of patients with all. I think there is still some work to do in that field as you mentioned, but your explanation are very helpful for us, and I can strongly recommend the readers and the audience to go to your review and read the article if they want more detailed data on this very important topic.

[Podcast Host]

Thank you for listening to this review series on all. To read the articles, visit bloodjournal.org this presentation is copyrighted by the American Society of Hematology.