Highlights from ASH 2024 – Updates in ALL
Updates in ALL
These research updates were presented at the 66th American Society of Hematology (ASH) Congress. The focus was on new treatments and approaches for acute lymphoblastic leukemia (ALL). ALL can sometimes return after treatment (relapse) or the leukemia can fail to respond to initial treatments (refractory disease), making it harder to achieve long-term remission. However, the studies presented at ASH highlight encouraging progress with targeted therapies, immunotherapies, and combination treatments. These advances aim to provide more effective, less toxic treatments, giving patients more options. Below is a summary of key studies and educational talks on these emerging approaches.
Poster: Chemotherapy-Free Treatment for Older Adults with ALL(1)
What was this study about?
Older adults with ALL often experience severe side effects from traditional chemotherapy, which can limit treatment options and impact survival.
A new approach using a chemotherapy-free combination of inotuzumab ozogamicin (a targeted therapy) and blinatumomab (a type of immunotherapy) aims to provide a safer, more effective treatment for older patients with B-cell ALL.
Study overview
Who participated in this study? 14 people (all aged 70 years or older; median age 76) with newly diagnosed Philadelphia-negative (Ph-ve) B-cell ALL.
What was studied? Treatment included cycles of inotuzumab ozogamicin and blinatumomab. Patients with CD20-positive disease also received rituximab (another targeted therapy).
Key results
Effectiveness:
• 92% (13 out of 14 patients) improved with treatment and had no visible signs of leukemia in their blood or bone marrow (complete remission or nearly complete remission)
• All 13 had no detectable cancer cells using sensitive tests (called MRD negative)
• After a median follow-up of 16 months, only 2 patients had relapsed
• At 1 year, 55% of patients had no signs of cancer growth or spread, 70% continued to have no visible signs of leukemia in their blood or bone marrow (remission), and 74% of patients were still alive
Safety:
• The most common side effects included mild to moderate confusion (36%), tremors (21%), and reversible neurological effects, such as one case of encephalopathy (a brain-related side effect) that resolved with treatment adjustments
• No cases of a serious liver condition called sinusoidal obstruction syndrome were reported
• Unlike traditional chemotherapy, this approach has not led to any cases of secondary cancers like myeloid neoplasms, a known risk with older chemotherapy regimens
• 3 patients died during remission (due to pneumonia, heart attack, or respiratory failure)
Key takeaway:
This chemotherapy-free treatment combination of inotuzumab ozogamicin and blinatumomab offers an effective option for older adults with ALL who may not be able to tolerate chemotherapy. The combination of inotuzumab ozogamicin and blinatumomab produced long lasting improvement with treatment for most patients, and a manageable side effect profile. Importantly, this approach avoids the toxic effects of traditional chemotherapy. Ongoing follow-up will provide more insights into long-term safety and the potential risk of secondary cancers.
Presentation: Targeted Treatment for Philadelphia-Positive (Ph+) ALL with ponatinib and blinatumomab(2)
What was this study about?
This study tested a new, chemotherapy-free treatment approach combining ponatinib (a targeted therapy) with blinatumomab (a type of immunotherapy) as an alternative to older treatment approaches. Researchers aimed to see if this combination could improve remission rates and reduce relapses.
Study overview
Who participated in this study? The study included 151 adults with newly diagnosed Ph+ ALL, ranging in age from 19 to 84 (average age 57), with 27% of participants aged 65 or older.
What was studied? Participants first received ponatinib (with doses adjusted based on age) followed by up to 5 cycles of blinatumomab.
Key results
Effectiveness:
• By the end of the initial treatment phase, 96% improved with treatment and had no visible signs of leukemia in their blood or bone marrow (complete remission or nearly complete remission)
• Only 4 patients experienced a relapse after an average of 5 months
• The number of patients predicted to be surviving at 12-months was 95%
Safety:
• Combining ponatinib and blinatumomab led to low rates of severe side effects (57 recorded in 40 patients)
• The most common were infections (19 cases), heart-related issues (5 cases) and general disorders (5 cases)
• 40% of patients required dose changes due to side effects
• Adjusting the dose of ponatinib for older patients appeared to prevent severe side effects
• 7 patients died during the study
Key takeaway
This study highlights a promising new approach for treating Ph+ ALL without chemotherapy. The combination of ponatinib and blinatumomab resulted in high remission rates, long-term survival, and a reduced need for transplants. Side effects were generally manageable, and older adults tolerated the treatment well. While longer follow-up is needed, these findings suggest a less toxic and highly effective option for adults of all ages with Ph+ ALL.
Presentation: Obe-cel CAR T-Cell Therapy in B-Cell ALL(3)
What was this study about?
This study investigated obecabtagene autoleucel (obe-cel) as a treatment for adults with relapsed or treatment-resistant (R/R) B-cell ALL. Obe-cel is a type of CAR T-cell therapy. CAR T-cell therapy is a treatment that uses a patient’s own immune cells, which are modified to better recognize and attack cancer cells.
Study overview
Who participated in this study? A total of 127 adults with R/R B-ALL received obe-cel treatment.
What was studied? The study aimed to understand how well obe-cel works and how safe it is. This study also carried out in-depth testing of how many cancer cells remained after treatment (called measurable residual disease or MRD). This summary reports the analysis of the study, which was done to see whether deeper MRD responses (fewer remaining cancer cells) were linked to better treatment outcomes.
Key results
Effectiveness:
• High remission rates: 76% (73 out of 96) of patients improved with treatment and had no visible signs of leukemia in their blood or bone marrow (complete remission or nearly complete remission) after obe-cel infusion.
• Deeper MRD response were associated with better outcomes:
o 84% of patients who improved the most with treatment had undetectable cancer cells at a very deep level (known as MRD negativity)
o Patients with the deepest MRD response had the best outcomes, including:
On average response to treatment lasted 18 months compared to 5 months for patients with higher levels of MRD
After an average of 21.5 months, 70% of patients with the deepest MRD response were still alive, compared to 16% of those with a less deep response
Key takeaway:
Obe-cel CAR T-cell therapy resulted in high remission rates for adults with R/R B-cell ALL. Achieving a deep MRD response (no detectable cancer cells) was linked to longer-lasting remissions and higher survival rates. These findings suggest that achieving this deep level of response may be an important goal for improving treatment outcomes in the future.
Educational session: Adult ALL Advancements: Optimizing Cure in 2024
This education session presented 3 talks that explored recent advances in the treatment and management of ALL in adults. Short summaries of each talk are provided below.
New approaches in Philadelphia positive ALL(4)
This talk provided some background on historical treatment strategies of adult Philadelphia-positive ALL (Ph+ ALL) and summarized recent developments.
Background: The BCR-ABL fusion protein is an abnormal protein found in Ph+ ALL that signals leukemia cells to grow uncontrollably. Tyrosine kinase inhibitors (TKIs) are targeted therapies that work by blocking this protein, stopping the signals that make the cancer cells grow and spread. TKIs are taken as tablets, making them more convenient than traditional chemotherapy.
This talk asked three questions about current treatments for Ph+ ALL.
1) Which TKI is the best for the treatment of Ph+ ALL?
Four TKIs were discussed:
a) Imatinib is the oldest and least effective TKI for this group of patients
b) Dasatinib has better outcomes but stops working if specific genetic changes/ mutations arise (T315l)
c) Ponatinib appears to be the most effective TKI and was approved by the FDA in March 2024 for the treatment of people with newly diagnosed Ph+ ALL. However, ponatinib does cause some issues like leakage of fluid from blood vessels or blood clots. These can be somewhat controlled by reducing the dose but remain a concern
d) Asciminib is a newer TKI that is still undergoing clinical testing, but may be gentler on the heart and blood vessels
2) What are the best treatments to use with a TKI to treat Ph+ ALL?
• TKIs used alone do not produce long lasting remission. Combing them with other drugs can greatly improve this
• Blinatumomab is currently recommended for use in combination with a TKI Blinatumomab is a type of immunotherapy that helps the body’s immune system find and destroy leukemia cells
o While this combination can produce good outcomes, neither agent targets the brain and spinal cord so these areas can be vulnerable to relapse
3) What is the role of stem cell transplantation in the treatment of Ph+ ALL?
• A stem cell transplant can be an effective treatment for Ph+ ALL
• For patients with no detectable leukemia cells by sensitive tests (known as MRD negativity), it’s unclear if a stem cell transplant is needed
• While a transplant can lower the chance of the leukemia coming back, it’s a very intensive treatment that comes with serious risks, including the possibility of life-threatening complications
• Research is underway to define exactly what role stem cell transplantation plays in the treatment of Ph+ ALL now we are in the era of immunotherapies such as blinatumomab
• Further study will need to explore which patients will benefit most from a stem cell transplant and this is discussed in more detail in the final talk The role of stem cell transplantation in ALL (see below)
Impact of immunotherapy in Philadelphia negative ALL(5)
This talk looked at the use of immunotherapies in B-precursor ALL. Unlike traditional chemotherapy, immunotherapy works by harnessing the body’s immune system to target and destroy cancer cells.
This talk focused on three main drugs. Rituximab, which targets specific proteins on cancer cells. Inotuzumab ozogamicin, a targeted drug that delivers a powerful cancer-killing agent directly to leukemia cells and blinatumomab which acts as a bridge, bringing immune cells and cancer cells together to help the immune system attack.
Rituximab
• Rituximab has been studied alongside chemotherapy and has shown positive results for treating B-precursor ALL
• However, it is not yet approved as a treatment for ALL and better results may be achieved with newer immunotherapies
Inotuzumab Ozogamicin (InO)
• InO is approved for patients with relapsed (disease has returned) or refractory (treatment-resistant) B-precursor ALL
• It works well as an initial (induction) treatment, especially for older patients, and is generally well tolerated
• InO can be used alone or with low-dose chemotherapy, but using it alone may be just as effective and causes fewer side effects
• Currently, InO is not approved for use as an initial (first-line) treatment for ALL
• Due to the potential for liver-related side effects, InO should be used cautiously in people with liver disease
Blinatumomab
• Blinatumomab is approved for 3 situations:
1. To treat relapsed or treatment-resistant (refractory) B-precursor ALL
2. To treat patients with measurable disease (detectable leukemia cells) after treatment
3. As a follow-up (consolidation) treatment for B-precursor ALL
• Blinatumomab is now the most commonly used treatment option for newly diagnosed B-precursor ALL
• It improves survival for patients with or without measurable residual disease after chemotherapy
• Further research is ongoing to find out what is the best order to use each therapy type in as well as to determine the optimal number of treatment cycles
Future directions
More clinical trials are needed to test treatment strategies that reduce or replace conventional chemotherapy with newer immunotherapy agents to improve the survival and quality of life of patients with B-precursor ALL.
The role of stem cell transplantation in ALL(6)
Advances in ALL treatment, especially for B-ALL, have led to more patients achieving remission with chemo-immunotherapy and CAR T-cell therapy (a treatment that uses modified immune cells to target cancer). For people with newly diagnosed ALL, even those at high risk, these treatments can clear detectable disease (known as MRD-negative remission). This raises the question of whether high-risk patients still need a stem cell transplant. In relapsed ALL, CAR T-cell therapy can also lead to deep remission, but it’s unclear if every patient should have a transplant afterward. Researchers are also exploring the best way to prepare the body for transplant (conditioning regimens) to improve outcomes.
Should high-risk patients still receive stem cell transplants during first remission?
• A stem cell transplant may still be recommended for patients with high-risk features, even if they are MRD negative (no detectable leukemia cells by sensitive tests)
• High-risk features include:
o Early T-cell precursor ALL
o Abnormalities in chromosomes (called a complex karyotype)
o Unfavorable genetic changes (like IKZF1; Ph-like; KMT2A rearranged; TP53; iAMP21; MYC rearranged; MEF2D rearranged)
o Slow response to therapy e.g., detectable disease (MRD positivity) after initial treatment or taking more than 4 weeks to reach complete remission
Should all patients receive a stem cell transplant after CAR T cell therapy?
• A stem cell transplant may benefit patients with high-risk features or MRD positivity after CAR T therapy
• With new treatments to prevent graft-versus-host disease (GvHD), like abatacept, outcomes for mismatched donors are now comparable to matched donors
• It is recommended to identify a potential donor for all patients, even if a transplant is not immediately planned
What is the best conditioning treatment before a stem cell transplant?
• Myeloablative conditioning (MAC) is a high-intensity form of treatment and is the current standard approach
• Total body irradiation (TBI) is a type of radiation therapy that targets the entire body to destroy cancer cells and suppress the immune system before a stem cell transplant. There is some evidence that it may offer better outcomes, especially for younger patients
• Patients who have no detectable disease by sensitive tests (MRD negative) may achieve similar outcomes with a low intensity treatment schedule (known as reduced-intensity conditioning regimen) instead of high-intensity one like MAC
What this means for patients
The latest advancements in ALL treatment offer hope for patients by providing more effective and less toxic options.
• For Ph+ ALL, newer TKIs like ponatinib, when combined with immunotherapy (blinatumomab), are improving outcomes and reducing the need for intensive treatments
• For Ph-negative ALL, immunotherapies like inotuzumab ozogamicin and blinatumomab are showing promising results and may reduce or replace the need for traditional chemotherapy
• Stem cell transplants remain an important option for high-risk patients, but ongoing research aims to better identify who will benefit most and when a transplant is needed
These updates show that researchers are working to make treatments more effective, less toxic, and better suited to each patient’s needs. More studies are underway to continue improving survival and quality of life for people with ALL.
References
1. Senapati J, et al. Poster presented at the 66th ASH Annual Meeting and Exposition, San Diego, December 7, 2024. Abstract #1442.
2. Chiaretti S, et al. Presentation at the 66th ASH Annual Meeting and Exposition, San Diego, December 9, 2024. Abstract #835.
3. Jabbour E, et al. Presentation at the 66th ASH Annual Meeting and Exposition, San Diego, December 9, 2024. Abstract #963.
4. Luskin M, et al. Presentation at the 66th ASH Annual Meeting and Exposition, San Diego, December 9, 2024. Education Session Adult ALL Advancements: Optimizing Cure in 2024
5. Stelljes M, et al. Presentation at the 66th ASH Annual Meeting and Exposition, San Diego, December 9, 2024. Education Session Adult ALL Advancements: Optimizing Cure in 2024
6. Kebriaei P, et al. Presentation at the 66th ASH Annual Meeting and Exposition, San Diego, December 9, 2024. Education Session Adult ALL Advancements: Optimizing Cure in 2024