Recent advances in adult acute lymphoblastic leukemia (ALL) treatment are rapidly reshaping clinical practice. At the Best of Hematology & Breast Cancer 2026 conference, Dr. Ryan Cassaday of Fred Hutchinson Cancer Center reviewed chemotherapy-free frontline regimens such as ponatinib plus blinatumomab, emerging data on inotuzumab-based strategies, CAR T-cell consolidation for older adults, and evolving approaches to measurable residual disease (MRD) risk stratification and transplant decision-making. These developments signal a shift toward more personalized, less chemotherapy-intensive care for adults with ALL.

Dr. Ryan Cassaday is a hematologist-oncologist specializing in the treatment and research of acute lymphoblastic leukemia (ALL) at Fred Hutchinson Cancer Center. At the Best of Hematology & Breast Cancer 2026 conference in Seattle, Dr. Cassaday presented a comprehensive overview of recent advances in the treatment of acute lymphoblastic leukemia in adults, with particular focus on chemotherapy-free approaches, risk stratification strategies, and emerging therapies.

The transcript below has not been reviewed by the speaker and may contain errors.

Chemotherapy-Free Frontline Treatment: The PANAM Study

Efforts to replace chemotherapy in the frontline setting have been a hot topic for several years. One of the most clinically relevant studies presented at ASH was a randomized trial performed in Italy that combined ponatinib and blinatumomab with no chemotherapy at all, compared to a regimen of imatinib and chemotherapy.

The trial used a 2-to-1 randomization in favor of the experimental arm. The survival results showed that both event-free survival and overall survival favored the ponatinib and blinatumomab arms. Of particular interest was the outcome of patients who crossed over from the chemotherapy arm to the blinatumomab-containing arm. These were patients who started on the chemotherapy arm and either did not achieve a deep response or had persistent disease, and were allowed to cross over to the blinatumomab-containing arm. Despite being a small number of patients, these crossover patients showed very good outcomes.

Key Questions Raised by the PANAM Study

Several important questions emerge from these data. First, imatinib is rarely used to treat adults with Philadelphia chromosome-positive ALL in the United States. Since a separate randomized controlled trial demonstrated that ponatinib is better than imatinib for newly diagnosed Philadelphia chromosome-positive ALL, the question arises: what if the control arm had included ponatinib? This study essentially compares two potent newer drugs versus an older combination approach. It probably would have been more informative to use blinatumomab and chemotherapy as the comparison arm, though this is not meant to suggest that's the crux of the difference.

Second, why did the crossover arm do so well? In most prospective clinical trials, crossover patients are typically not doing well on their assigned arm and are allowed to switch to the other arm. At least on the surface, these patients would not be expected to do quite as well. The fact that they appeared to do the best overall is striking and raises the question of whether the optimal approach, particularly for those who could tolerate it, would be a hybrid strategy like the crossover patients received: starting with some chemotherapy and then switching to blinatumomab-based treatment after achieving remission. This is similar to how Philadelphia chromosome-negative ALL is often treated now, with chemotherapy induction followed by blinatumomab consolidation.

Third, the authors didn't emphasize that about 20% of patients on the experimental arm actually consolidated with allogeneic transplant upfront. The role this plays with this approach remains unclear. There is still much to learn from this study, but it certainly raises interesting ongoing questions about the role of chemotherapy for this disease.

Inotuzumab and Dasatinib for Newly Diagnosed Philadelphia Chromosome-Positive ALL

Another study examined a chemotherapy-free approach using inotuzumab ozogamicin and dasatinib for newly diagnosed Philadelphia chromosome-positive ALL. While this might be argued as chemotherapy-free, technically inotuzumab ozogamicin uses chemotherapy to exert its effects against ALL, though it's not traditional cytotoxic chemotherapy.

The authors found that starting with dasatinib and steroids, then switching to inotuzumab, and then going back to dasatinib worked well for the majority of patients. An important footnote: the original schema actually combined dasatinib and inotuzumab together in induction in the first seven patients treated. Two patients developed sinusoidal obstructive syndrome (SOS), which is the most dreaded complication of inotuzumab ozogamicin. The study was stopped, a new schema was developed with alternating agents, and then the study proceeded from there.

The response rates were impressive, broken down by morphologic remission and depth of molecular response. The red sector of the response curve represented patients who had the deepest responses, constituting the vast majority of patients, indicating a very potent treatment approach.

Safety Concerns with TKI and Inotuzumab Combination

The overall conclusions showed high response rates with activity pretty comparable to TKI and blinatumomab, and durability of responses was argued to be comparable as well. The SOS that was seen during the initial schema was not seen at all after the schema was changed to alternating agents.

This presentation raises important questions about the safety of combining TKI and inotuzumab. This has been done in practice, mostly in the relapse-refractory setting with Philadelphia chromosome-positive ALL, where well-intentioned physicians will give both a TKI and inotuzumab. This study, at least in the frontline setting, found a pretty high rate of SOS, and importantly these patients weren't getting transplanted, so it was happening from that combination. With more mature and compelling data for ponatinib and blinatumomab in this setting, how this approach fits in the armamentarium is not clear. More follow-up and studies will be needed to make this a justifiable approach outside of very selective circumstances.

CAR T-Cell Consolidation for Older Adults with ALL

A consolidation CAR T-cell study for older adults with ALL was presented. These patients were all given chemotherapy induction, achieved deep remission, and then instead of continuing consolidation chemotherapy and maintenance, they went on to receive CAR T cells and were observed.

The results were very impressive with good toxicity rates. There were no grade 2 or higher cytokine release syndrome (CRS) events and no immune effector cell-associated neurotoxicity syndrome (ICANS). Based on these preliminary findings, the authors are planning a multicenter study using a commercially approved product.

More follow-up will be important. These patients by definition were all relatively favorable risk by virtue of having achieved deep remission, but the results still look promising.

Better Risk Stratification: Discordant MRD Results in Philadelphia Chromosome-Positive ALL

Risk stratification strategies are evolving, particularly for Philadelphia chromosome-positive disease and patients in first relapse. One important topic is the idea of discordant results of measurable residual disease (MRD) testing by either BCR-ABL RT-PCR or immunoglobulin or T-cell receptor-based next-generation sequencing testing.

BCR-ABL RT-PCR has been useful to risk-stratify patients with Philadelphia chromosome-positive ALL for years. It has been used for chronic myeloid leukemia and can be leveraged to identify patients thought to have the best overall survival. It can even help decide whether to refer patients for allogeneic transplantation based on larger retrospective studies.

However, when doing multiple different MRD assays, including some that are more lineage-specific (that identify lymphoblasts more specifically and not just the presence or absence of the BCR-ABL transgene), discordant results can often be seen. The lineage-specific test may be negative, meaning the assay looking specifically for ALL is negative, but detectable BCR-ABL transcript can still be seen in patients thought to have lymphoid blast crisis from CML. This can happen when persistent chronic-phase CML remains after achieving deep remission of the ALL, but it turns out this can be seen outside of that relatively well-defined clinical scenario.

Studies have suggested that the lineage-specific assays are more important and that BCR-ABL RT-PCR has less prognostic utility. Importantly, immunoglobulin and T-cell receptor rearrangement MRD testing is commercially available through assays like ClonoSEQ.

MD Anderson Retrospective Analysis

The group at MD Anderson looked at a large retrospective series of nearly 200 patients with Philadelphia chromosome-positive ALL subjected to this testing, where paired samples underwent both tests. They found that about a quarter of patients with Philadelphia chromosome-positive ALL were negative by next-generation sequencing (NGS) but still had detectable BCR-ABL transcript.

Since the NGS assay is about two orders of magnitude more sensitive, it doesn't make sense that the BCR-ABL signal would be coming from the ALL. They broke this down further by P190 versus P210 isoforms and the level of persistent disease by BCR-ABL transcript. Ultimately, they found that patients with discrepant results had basically the same prognosis, independent of the level of BCR-ABL transcript. If deep remission was achieved by NGS testing, the persistence of BCR-ABL no longer really mattered.

Transplant in Second Remission for Relapsed ALL

A retrospective analysis looked at the use of transplant in second remission—patients who relapsed and then achieved remission again. A multivariable analysis identified time to relapse, depth of response to salvage therapy, and age as the most important factors. A risk model incorporating these three variables was developed to examine how these patients do when they get back into remission.

Interestingly, for lower-risk patients (longer first remission, deep response to salvage therapy, and younger age), transplant didn't really help, which is somewhat counterintuitive. The typical thinking is that if a patient can get back into remission, they should get a transplant as soon as possible. For high-risk patients, however, it's a totally different story—essentially, the only survival is among patients who can get to a transplant.

Relapse Patterns After Frontline Blinatumomab

Patterns of relapse after treatment that includes blinatumomab in the frontline setting were examined, which is being done more routinely. The data showed relapse sites, including a relatively high number of extramedullary relapses as well as a not trivial percentage of patients who had CD19-negative relapses after receiving blinatumomab.

If blinatumomab is used upfront and a patient relapses, unfortunately the outcome is quite poor. The survival curves for patients with a short first remission resemble what outcomes looked like before immunotherapy was available for relapsed-refractory ALL.

CD19 CAR T Cells for Relapsed-Refractory B-Cell ALL

Consolidation Strategy for Isolated CNS Relapse

A study in children at the University of Pennsylvania used CAR T cells essentially as consolidation therapy for patients with isolated CNS relapse. This is a particularly challenging problem, where children are often subjected to very intense chemotherapy and CNS-directed radiation. In this study, patients received chemotherapy and then CAR T cells without radiation and had really good outcomes.

Predictors of Outcome with CAR T Cells

A study from the pivotal trial of brexucabtagene autoleucel used a test to detect the presence of CAR T cells at three months and stratified patients based on that result in a landmark analysis. The finding was that if patients still had persistent CAR T cells at that point, survival was much better. There may be a way this could be leveraged into a new commercial assay for this product.

Clinical Practice Changes

Based on these results, clinical practice considerations include the following. Before this meeting, the only data for ponatinib and blinatumomab in the frontline setting was from MD Anderson. Now with the large multicenter study from Italy, chemotherapy will likely still be used for younger patients who can tolerate it, probably switching to blinatumomab during consolidation.

For patients who are Philadelphia chromosome-positive, it's important to be mindful of the possible discrepancy that can occur between BCR-ABL and more lineage-specific assays, and probably favor the lineage-specific ones for prognostication.

The outcomes for patients in first relapse are evolving, and there may be ways to potentially justify deferring transplant in second remission, though this would probably be done only in select circumstances.

This doesn't happen frequently in adults, but for isolated CNS relapse in ALL, using CAR T cells is appealing. The idea of using frontline TKI or consolidated CAR T cells is certainly interesting, but much more follow-up is needed.

There are new CD19/CD3 bispecifics being developed that might prove to be a more convenient approach. While the idea of risk-stratifying with CAR T cells using T-cell persistence is appealing, the difference may not be enough to justify making major treatment decisions like subjecting someone to a transplant or not. It certainly suggests a difference, but it's not so different that it can be used to make definitive treatment decisions. More data are needed.