 So, Dr. Aldoss, could you share with me what you think the future holds for patients with newly diagnosed pH-positive ALL? And can you share any unmet needs that these patients have?

 So, I really think this immune therapy as part of initial treatment for Philadelphia chromosome positive ALL will be a success in this population and we will have for the first time this scheme of therapy-free regimens for nearly diagnosed patient with ALL. The question is, with all these novel combination therapy, how durable these remissions and are the patient cure or not? And do we still need allergenic stem cell transplant as a consolidation or not? Until recently, allergenic stem cell transplant has been the standard of care for most adults with pH-positive ALL in contrast to children with pH-positive ALL. But now by learning which patient actually can be cured with tyrosine kinase regimens related to the early complete molecular emissions, lack of some high-risk genetics and maybe using more potent TKI in the frontline sitting, maybe we can spare some of these patients from the long-term complication of allergen stem cell transplant. So, this is a theme we have, all these encouraging data, but we need a longer follow-up to see that are these patients cured or not? Then I think one of the challenging subsets of pH-positive ALL is the patients who carry the IKZF deletion plus that has shown to adversely impact outcomes of patient treated with blinatumomab and dasatinib chemotherapy and dasatinib chemotherapy and ponatinib. We don't have enough data yet about ponatinib and blinatumomab if IKZF deletion plus still prognostic or not. But as of now, for this patient, because they seem to do poorly with current regimens, we still recommend transplant this patient when they achieve first remission. Another challenge with this disease is we're using more blinatumomab and third-generation tyrosine kinase inhibitors and the frontline sitting patient who relapse after these therapies, they will have limited options. We have CD19 CAR T-cell therapy, but since we're using blinatumomab as a frontline therapy subset of this patient, they will relapse as CD19 negative disease, and it'll be very challenging to treat these patients. So, we need clear novel therapies, a new generation of tyrosine kinase inhibitors that goes beyond ponatinib and can overcome the resistant to ponatinib. Now, there are some investigational agents are being used, there is third generation novel tyrosine kinase inhibitor like the HQP1351. There is more data actually in CML, but it seems it has also activity in relapse refractory pH-positive ALL for patients who fail prior ponatinib. What I see the futures, I think we going to keep actually bringing more novel therapy early in the treatment of pH-positive ALL-in adults with the goal that we can actually spare more patient from going through allogeneic stem cell transplant and avoid the complication of allogeneic stem cell transplant. For example, there is some early data from China looking at CD19 CAR T-cell therapy with tyrosine kinase inhibitor as a frontline therapy for nearly diagnosed pH-positive ALL. And although limited studies, limited follow-up, the data look very encouraging. So, this is where I see that as we have more successful treatment, salvage treatment, relapsed refractory sitting, are we able to move these medications as frontline therapy so we can actually prevent developing resistance mutation and curing more patients without transplant?

: And one of the trials that I'd like to highlight is the group at Dana-Farber is currently leading a phase one study evaluating asciminib, which is a potent specific inhibitor of the BCR-ABL domain. And this agent has a distinct allosteric mechanism of action, which is defined to demonstrate efficacy against patients with BCR-ABL mutations that confer resistant to the standard TKIs, just as you were saying. So, this agent is being evaluated in combination with dasatinib and prednisone for patients with newly diagnosed pH-positive ALL as well as those patients with CML and lymphoid blast crisis. So, this kind of a regimen is very attractive because it's all oral. The accrual right now is still in the early phases, but the responses do appear promising. So, I'm encouraged by that and looking forward to the data to be presented in full.

Videos

With their final thoughts, medical experts share unmet needs in the treatment landscape of Ph+ acute lymphoblastic leukemia.

Unmet Needs and Treatment Trajectory for Patients Diagnosed with Ph+ ALL

 Dr Przespolewski, can you discuss some of the most exciting advances in acute lymphoblastic leukemia and other hematological malignancies that were recently presented at ASCO 2023?

 So, I have a couple that I'd like to discuss.

The first one that I'd like to share with you is abstract number 7006, presented by Dr Matt Wieduwilt and colleagues, which was entitled "Chemotherapy-free Treatment with Inotuzumab Ozogamicin, and Blinatumomab for Older Adults with Newly Diagnosed pH-negative, CD22 Positive, B-Cell Acute Lymphoblastic Leukemia." So, this study sought to enroll patients that were 60 years of age or older, and those patients underwent induction with Inotuzumab following their initial induction course dependent on the degree of debulking that they achieved within their bone marrow. If they were in CR/CRi, they were able to go on to receive further Inotuzumab at a 0.5 mgs per meter squared dosing schema. But if patients did have adequate debulking and did not yet achieve CR/CRi, they got a slightly higher dose of Inotuzumab at 0.8 mgs per meter squared on days one, eight, and 15. If patients did not achieve adequate debulking with one cycle of Inotuzumab, they automatically went on to receive blinatumomab and did not receive any further Inotuzumab at that time. So, the primary endpoint for this study was one year event-free survival with a lower limit of a 90% confidence interval greater than 10%. So, when this abstract was presented, 33 patients had been treated to date with a median age of 71 years and a median white cell count of 3.2. Cumulative complete remission rates through course one with Inotuzumab were 85%, and those rates increased to 97% following course two with blinatumomab. The median follow up of this study was 22 months with a one-year event-free survival of 75%. and that two-sided 90% confidence interval was 63 to 89%, which did meet the primary endpoint. In total, nine patients relapsed, and one patient experienced sinusoidal occlusion syndrome of the liver, and the one-year overall survival was 84%. So, these authors were able to demonstrate that this chemotherapy-free regimen has significant activity in older adults with newly diagnosed pH negative acute lymphoblastic leukemia. And I look forward to more mature survival data. And I'm also interested to know the measurable residual disease status of these patients following treatment.

So next, I would like to move on to Abstract 7000, presented by Dr Claire Roddie and colleagues, entitled "The Safety and Efficacy of Obe-cel AUTO1, a Fast Off-Rate CD19 CAR in Patients with Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia." So, the agent that's being discussed in this clinical trial is an autologous CD19 CAR with a fast off-rate CD19 binding domain, which was designed intentionally to reduce the CAR-T immunotoxicity and to improve persistence of the CAR within circulation. So, this study was an open-label, multi-global, single arm, phase 1B2, study that enrolled patients into three cohorts based on their disease status. Those patients with fully relaxed refractory acute lymphoblastic leukemia with morphologic disease. The second cohort is aiming to study patients that are only MRD positive. And the third cohort is evaluating patients with only extra medullary disease at time of relapse. So, prior to being dosed with CAR-T patients underwent bridging therapy is necessary during the manufacturing process, and then patients underwent lympho depletion with fludarabine and cyclophosphamide. The target dose of the CAR was four times 10 to the six, and it was administered as a split dose on day one and day 10. The primary endpoint for this phase 1B2 study is overall remission rate. And the data that's presented in this abstract does reflect a pre-specified interim analysis of the first 50 patients that were treated in the first cohort, which were those patients with overt morphologic relapse. Those patients were followed for three months, or they were included in this interim analysis if they were discontinued prior to that third month. The median age of patients treated on this study was 50 years with a range of between 20 to 81 years. 42% of these patients had undergone a prior allergenic stem cell transplant, and the median number of lines of therapy in patients enrolled on this study was two. So impressively, the CR/CRi rate was observed to be 70% and the persistence of this product was noted to be ongoing and the majority of patients that were responding at their last follow-up with a median follow-up of 9.5 months. So, with regards to the safety analysis of total of 92 patients at the time of data cutoff were available for safety evaluation. 63% of these patients did develop any grade of CRS, but only 3% developed a grade three or greater CRS. And with respect to CNS toxicity in ICANS, ICANS of any grade was observed in 23% of patients, but only 8% of these patients developed a grade three or greater adverse event. So, the authors of this abstract were able to demonstrate that the obe-cel product for adults with relapsed refractory B-cell ALL is safe. And impressively it had demonstrated lower rates of ICANS in CRS, even in patients with a high burden of disease. Which is important for patients that are older, and this may have more general applicability. This agent is also effective, and I look forward to longer term follow-up of this agent.

Key advances in ALL treatment from ASCO 2023 are discussed by Dr Przespolewski.

Notable Advancements in Treatment for ALL

Dr Aldoss discusses the role ponatinib and blinatumomab in the management of Ph+ALL.

Ponatinib and Blinatumomab Use in Patients with Newly Diagnosed Ph+ ALL

Medical experts highlight recent findings from the PhALLCON study.

Recent Updates from the PhALLCON Study

Drs Aldoss and Przespolewski evaluate the changing treatment landscape for patients diagnosed with Ph+ ALL.

Evolving Standard of Care for Patients Diagnosed with Ph+ ALL

Amanda Przespolewski, DO, and Ibrahim Aldoss, MD define and discuss how to diagnose patients with Ph+ALL.

Amanda Przespolewski, DO

Articles

Unmet Needs and Treatment Trajectory for Patients Diagnosed with Ph+ ALL

Notable Advancements in Treatment for ALL

Ponatinib and Blinatumomab Use in Patients with Newly Diagnosed Ph+ ALL

Recent Updates from the PhALLCON Study

Evolving Standard of Care for Patients Diagnosed with Ph+ ALL

Defining and Diagnosing Philadelphia Chromosome-Positive (Ph+) ALL