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Findings from the phase 3 PhALLCON trial show that ponatinib plus reduced-intensity chemotherapy could be a new standard of care for patients with Philadelphia chromosome–positive acute lymphoblastic leukemia.

Phase 3 PhALLCON Trial of Ponatinib and Reduced-Intensity Chemo Shows Promise in Ph+ ALL

In a real-world population of patients with relapsed or refractory B-cell acute lymphoblastic leukemia, modest efficacy was demonstrated with brexucabtagene autoleucel.

ASCO Presentation Provides Real World Evidence of Brexu-cel’s Efficacy in R/R B-ALL

Phase 2 FELIX study results show 21.3% of the 94 patients infused with obecatagene autoleucel achieved a complete response or complete response with incomplete count recovery.

Obe-cel Induces 76% CR/CRi Rate With Compelling MRD Negativity in R/R B-ALL

The injectable formulation of nelarabine has been granted FDA approval to treatment 2 hematologic malignancies.

FDA Approves Nelarabine Injection for the Treatment of T-ALL and T-LBL

The phase 3 PhALLCON trial showed a trend toward event-free survival in patients with Philadelphia chromosome positive acute lymphoblastic leukemia when treated with ponatinib compared with imatinib.

Ponatinib Demonstrates Deep and Durable Responses vs Imatinib in Ph+ ALL

Fadi Haddad, MD, a leukemia fellow at The University of Texas MD Anderson Cancer Center, discusses the background of a phase 2 study of blinatumomab (Blincyto®; Amgen) in combination with ponatinib (Iclusig®; Takeda) in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

This chemotherapy-free regimen was designed as a result of the clinical activity shown with blinatumomab in relapsed/refractory ALL and the efficacy seen with ponatinib. Experts were hopeful that this option may offer patients higher chances of survival.

In the phase 2 study, 40 adult patients with newly diagnosed Ph+ ALL, 14 patients with relapsed/refractory Ph+ ALL, and 6 patients with chronic myeloid leukemia in lymphoid blast phase were treated with ponatinib plus blinatumomab.

during the Tenth Annual Meeting of the Society of Hematologic Oncology.

 Why [we presented] this study and why we believe this is important is because historically, the outcome of patients with Ph+ ALL has been poor with long-term survival around 10% to 15%. Throughout the years, the addition of tyrosine kinase inhibitors to chemotherapy significantly improved the survival of patients to up to 74% at 5 years with the combination of ponatinib and hyper-CVAD chemotherapy [cyclophosphamide, vincristine sulfate, doxorub icin hydrochloride, and dexamethasone].

We realize that many patients are still relapsing despite optimal therapy. Plus, they were having major [adverse] effects from the chemotherapy itself, which we all know, that's why we were thinking, why don't we design a protocol that is chemotherapy-free, and that might offer patients higher chances of survival. That's how we designed our trial, which is the combination of blinatumomab, which is a bispecific CD19 and CD3 antibody which is converted to the traditional chemotherapy, it stimulates the immune system to go out and fight leukemia, in combination with a potent third generation tyrosine kinase inhibitor on ponatinib.

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Fadi Haddad, MD, discusses the background of a phase 2 study of blinatumomab in combination with ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia. 


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Background on the Phase 2 Study of Ponatinib/Blinatumomab in Ph+ ALL

Mark R. Litzow, MD, chair and professor of medicine in the division of hematology at the Mayo Clinic, discusses the purpose of a trial of blinatumomab (Blincyto) for patients with newly diagnosed B-lineage acute lymphoblastic leukemia (B-ALL).

Blinatumomab is a bispecific T-cell engager approved by the FDA for patients with relapsed/refractory B-ALL and patients who are positive for measurable residual disease (MRD) with a morphological complete response (CR). Patients who respond to chemotherapy may still have relapsed disease even after displaying MRD-negative status by flow cytometry or molecular testing. Litzow says it has not yet been tested in patients who are MRD negative.

This phase 3 trial (NCT02003222) was designed to assess whether 

 negative patients with B-ALL who have a CR and are MRD negative after chemotherapy have improved outcomes with blinatumomab. Patients were randomly assigned 1:1 after chemotherapy to receive blinatumomab with consolidation chemotherapy or chemotherapy alone. The primary end point was overall survival, and secondary end points included relapse-free survival, MRD status, and incidence of adverse events.

 This was a trial to...see if blinatumomab would improve the outcome of newly diagnosed patients with B-lineage ALL who are 

 negative. Now blinatumomab…is already FDA approved for treatments with relapsed/refractory ALL, and also patients [who] are MRD-positive. So MRD can be measured by flow cytometry and also by molecular means. It's not been tested yet in patients who are MRD negative, so we didn't know whether it would be a benefit to those patients. We know those patients have a better prognosis overall than the MRD-positive patients. But they still relapse during the course of their treatment and after, so we know that they still have some leukemia in their system even though they're MRD negative. We wanted to add blinatumomab to chemotherapy in that group to see if we can improve their outcome.

Mark R. Litzow, MD, discusses the purpose of a trial of blinatumomab for patients with newly diagnosed B-lineage acute lymphoblastic leukemia. 

Rationale for a Trial of Blinatumomab in MRD-Negative ALL

Fadi Haddad, MD, leukemia fellow at The University of Texas MD Anderson Cancer Center, discusses the key points from the presentation he gave during the Tenth Annual Meeting of the Society of Hematologic Oncology (SOHO 2022).

At SOHO 2022, Haddad provided the results of a phase 2 study which evaluated adult patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL; n = 40), relapsed/refractory Ph+ ALL (n = 14), or chronic myeloid leukemia in lymphoid blast phase (n = 6). The combination of ponatinib (Iclusig®; Takeda) and blinatumomab (Blincyto®; Amgen) was administered to the enrolled patients.

Findings revealed that with this combination, patients with Ph+ ALL had deep responses and durable remissions.

The key takeaway message is that for patients with Ph+ ALL treated with intensive chemotherapy combinations, potent tyrosine kinase inhibitors [TKIs] are preferred over first- and second-generation TKIs. Those were treatments that were very effective when they were originally designed, but now we know there are more potent drugs. I will favor using ponatinib rather than first- or second-generation TKIs because most of the patients who relapse have T315I mutations. Using ponatinib can prevent the emergence of this resistant clone.

 The second recommendation is if [oncologists] are able to access more novel combinations strategies or refer their patients to receive blinatumomab combinations with a TKI, this will offer patients higher chances of success with limited toxicity. Again, we have a short follow-up so far on our study, and we’re reporting 1- to 2-year survival rates, but results look encouraging.

Fadi Haddad, MD, discusses the key points from the presentation he gave during the Tenth Annual Meeting of the Society of Hematologic Oncology.

Updated Findings of Ponatinib/Blinatumomab Combo in Ph+ ALL are Encouraging

Mark R. Litzow, MD, chair, professor of medicine, Division of Hematology, Mayo Clinic, discusses the talk he gave on initial treatment options for patients with acute lymphoblastic leukemia (ALL) during the National Comprehensive Cancer Network 2022 Annual Congress: Hematologic Malignancies.

After years of little to no new developments in the ALL space, experts have discovered that young adults up to the age of 40 with ALL can tolerate pediatric treatment regimens. When providing patients with additional doses of these agents, better survival outcomes have been observed.

As a result of young adult and pediatric patients being able to tolerate these intensive regimens, they are now beginning to be incorporated into treatment for this patient population.

I focused in my talk about initial treatment options for patients with acute lymphoblastic leukemia and risk stratification. Some of the new developments in ALL, and there have been many that have been very exciting for us after many years of stagnation where we did not have a lot of new treatments, one of the important things we learned is that in younger adults with ALL, they can tolerate treatment programs that have been used in children, so pediatric regimens. These regimens contain more drugs like vincristine, asparaginase, and corticosteroids.


It seems that additional doses of those drugs have helped improve the outcomes in children and now we have found in young adults. Young adults include patients up to 40 and in some circumstances, up to 50 or 55. They can tolerate these intensive regimens and we see better outcomes, so better survival, and less relapse. We have been incorporating those types of regimens into the treatment of younger patients with acute lymphoblastic leukemia.

Mark R. Litzow, MD, discusses the talk he gave on initial treatment options for patients with acute lymphoblastic leukemia during the National Comprehensive Cancer Network 2022 Annual Congress: Hematologic Malignancies.


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Incorporating Pediatric Regimens in the Treatment of ALL

Nitin Jain, MD, associate professor in the department of leukemia, division of cancer medicine, at The University of Texas MD Anderson Cancer Center, discusses clinical trials investigating allogeneic chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphoblastic leukemia (B-ALL) and other hematologic malignancies.

As opposed to autologous CAR T-cell therapies, allogeneic CAR T cells do not need to be derived from leukapheresis of the patient and can be made available more quickly. Jain highlights the CALM trial (NCT02746952) of UCART19, an anti-CD19 allogeneic CAR T-cell therapy, in which there was a 67% complete response rate among 21 patients with B-ALL. In this trial, the treatment served as a bridging therapy to hematopoietic cell transplant since the cells did not persist long term.

Another allogeneic CAR T product, PBCAR0191, was investigated in a trial (NCT03666000) of patients with ALL and non-Hodgkin lymphoma. Its results were presented at the 2021 American Society of Hematology (ASH) annual meeting and showed clinical activity in patients including some who had received prior autologous CAR T-cell therapy.

Other ongoing clinical trials noted by Jain include the phase 1/2 BALLI-01 (NCT04150497) trial of UCART22 for B-ALL, the phase 1 trial (NCT03190278) of UCART123 for acute myeloid leukemia, and a phase 1 trial (NCT04629729) of FT819 for B-cell malignancies. He says more data may be presented in the next year from various trials.

 One of the trials is [for] a product called UCART19, which I believe was the first trial in the United States with allogeneic CAR T cells for B-ALL. That was published last year in the journal 

 where 21 patients were treated with B-ALL. We saw that there were relatively high rates of responses in about 60% to 70% of the patients. And more so, I would say, it was a bridge to transplant because these CAR T cells do not last forever. Therefore, most of these patients then consulted with a transplant.

Another trial is by a company called Precision Biosciences. We had an oral presentation at ASH last year, where again these allogeneic CAR [T cells] derived from healthy human donors were able to show clinical activity, both for ALL as well as for non-Hodgkin lymphoma. I should say there are several other clinical trials in development, including for UCART22, UCART123 for AML, Fate Therapeutics [FT819]. There are many other companies which are developing off-the-shelf allogeneic CARs, and hopefully we'll see some data maybe at this upcoming ASH or in next year’s meetings as well.

Nitin Jain, MD, discusses clinical trials investigating allogeneic chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia and other hematologic malignancies.

Overview of Allogeneic CAR T-Cell Therapy Trials for ALL, AML, and NHL

Aaron Logan, MD, PhD, assistant professor of Clinical Medicine, University of California San Francisco, discusses some of the treatment options available for patients with acute lymphoblastic leukemia (ALL).

New therapies such as blinatumomab (Blincyto), inotuzumab (Besponsa), and chimeric antigen receptor (CAR)-T cells, have made the management of patients with ALL both complex and positive. Some agents, including blinatumomab, are even being moved into the frontline setting.

During a session at the National Comprehensive Cancer Network 2022 Annual Meeting: Hematologic Malignancies, experts, including Logan, further discussed the new and best strategies for managing patients with ALL.

The management of adults with ALL has become a bit more complex but thankfully more successful due to the availability of agents such as blinatumomab, inotuzumab, and we now have CAR T cells that are approved for adults of all age groups. We are now seeing that some of these agents are being moved to frontline therapy, in particular, blinatumomab, which is actually FDA approved for the management of minimal residual disease [MRD]-positive ALL.


 The NCCN guidelines now specify that it is an appropriate therapy for patients that have MRD positivity to get blinatumomab and then conventionally followed by an allogeneic stem cell transplant. There are potentially some patients that could remain in a long term remission after blinatumomab without transplant, but we currently are not able to prospectively identify those patients. The plan is generally to do blinatumomab followed by an allogeneic transplant. Then as far as the remainder of consolidation therapy for patients who achieved the milestone of MRD negativity after induction, or at least early in the course of therapy after initial consolidation, there are a few different options, including continuing multi-agent chemotherapy based on what protocol they're on.

Their protocol might be a pediatric inspired regimen, such as the CALGB 10403 regimen if they're in the adolescent or young adult group, or it might be hyper-CVAD depending on what institution they're being treated at. Another option per the NCCN guidelines would be to use blinatumomab as consolidation, even for patients who have achieved MRD negativity. That's based on some studies that have already demonstrated that blinatumomab is safe therapy after multi-agent chemotherapy, and is likely associated with long term remissions in that setting.

Aaron Logan, MD, PhD, discusses some of the treatment options available for patients with acute lymphoblastic leukemia.

Conference News

New Options Shape the Treatment Landscape of ALL

Bijal Shah, MD, MS, an associate member in the Department of Malignant Hematology at Moffitt Cancer Center, discusses the unmet medical needs in the T-cell acute lymphoblastic leukemia (T-ALL) space and what future research aims to examine.

During a session at The NCCN 2022 Annual Congress of Hematologic Malignancies, experts, including Shah, explained initial strategies, various treatment options, and future directions for patients with ALL.

According to Shah, while a lot of progress has been made in the field of ALL over time, a lot of questions remain when treating patients with T-ALL.

 Using immunotherapies, particularly using T Cells to target cells, has been hard. I think we are trying to find better ways of using molecularly-directed therapy and in some cases, certain kinds of immunotherapies like daratumumab [Darzalex] to try to improve outcomes in a very difficult-to-treat disease.

I think the key takeaway for T-ALL is that we are moving slowly to where we were 7 or 8 years ago in B-cell ALL. Now many people recognize that there is a big unmet medical need here. We are starting to see pharmacologists and the academician come together to begin to develop studies, this is a rare disease so often across several centers, to try and address this problem. Again, I am hopeful that the next time we meet, I am talking to you about some incredible advance that is going to shake up what we do in terms of that standard monolithic chemotherapeutic approach for T-ALL.

Bijal Shah, MD, MS, discusses the unmet medical needs in the T-cell acute lymphoblastic leukemia space and what future research aims to examine.


Future Directions and Unmet Needs in T-ALL

Hagop M. Kantarjian, MD, professor, and chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, and the Samsung Distinguished Leukemia Chair in Cancer Medicine, discusses what experts should know regarding ponatinib (Iclusig; Takeda) and blinatumomab (Blincyto; Amgen) in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

According to data discussed during the Tenth Annual Meeting of the Society of Hematologic Oncology, the combination induced deep responses and durable remissions in patients with Ph+ acute ALL.

Kantarjian notes how these findings may influence the future of this space as research pushes towards treating patients with non-chemotherapy regimens without the need of transplant, and with the use of ponatinib and blinatumomab.

Ponatinib has shown significant activity in Philadelphia-positive ALL. When we use it at only 30 mg in combination with blinatumomab, we're getting fantastic results. I think in Philadelphia positive ALL, the tradition has been to use intensive chemotherapy with the BCR-ABL tyrosine kinase inhibitor and then move the patients to transplant, what we find is with ponatinib and blinatumomab, we're inducing the best molecular responses we've ever seen and we're reporting an estimated 3-year survival of 95% without the transplant.

This is a major inflection point in the treatment of Philadelphia-positive ALL where we are advocating for a shift in the treatment from the combination of intensive chemotherapy TKI [tyrosine kinase inhibitor] and transplant to non-chemotherapy regimens without the need of transplant, and by using 2 targeted therapies, ponatinib and blinatumomab.

Hagop M. Kantarjian, MD, discusses what experts should know regarding ponatinib and blinatumomab in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Ponatinib and Blinatumomab Demonstrates Durable Responses in PH+ ALL

Nitin Jain, MD, associate professor in the department of leukemia, division of cancer medicine, at the University of Texas MD Anderson Cancer Center, explains the key takeaways from multiple discussions on acute lymphoblastic leukemia (ALL) which were presented at the 10th Annual Meeting of the Society of Hematologic Oncology.


During a session on the first day of the meeting, experts, including Jain, discussed different aspects of ALL, including pediatric data, minimal residual disease (MRD), and allogeneic chimeric antigen receptor (CAR) T cells within the space.

In the talk, Jain noted the evolving importance of allogeneic CAR T cells in ALL and how the future of this space aims to examine its efficacy compared with autologous CAR T.

 I think in the session this morning, we had 3 fantastic talks. One talked about the pediatric data and the younger data in ALL, another talk was on the MRD in ALL, and the third talk which I gave was in the allogeneic CAR T cells. Overall, I think it was good to see I think there are different aspects of things which are being developed. We learned the use that continues to be important for children and young adults. We learned that MRD techniques are being refined, and there are next generation sequencing technologies which are coming along more in the context of ALL.

The talk which I gave about allogeneic CARs, is a space which is evolving, and we have to see how things pan out in the next 1 to 2 years. But I think if allogeneic CARs were to show equal efficacy to autologous CARs, that will be a game changer in terms of how we are approaching CAR T for these patients.

Nitin Jain, MD, explains the key takeaways from multiple discussions on acute lymphoblastic leukemia which were presented at the 10th Annual Meeting of the Society of Hematologic Oncology.


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