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Clinical

INC-22-TTD0622 - /clinical/bone-marrow-and-sct

In an interview with Targeted Oncology, Lori Muffly, MD, discusses the subanalysis of a phase 1 study of briquilimab plus low-dose total body radiation and fludarabine which was presented at 2023 Tandem Meetings on Transplantation and Cellular Therapy.


Briquilimab/Low-Dose TBI/Fludarabine Shows Promise in MDS/AML Undergoing AlloHCT

In an interview with Targeted Oncology, Yago Nieto, MD, PhD, discussed the full data from the phase 2 trial of panobinostat, gemcitabine, busulfan, and melphalan for patients with high-risk, relapsed/refractory myeloma.

Pano/GemBuMel May Be Safe/Effective for Treatment of High-Risk, R/R Myeloma

The phase 3 GRAPHITE study showed that vedolizumab plus standard prophylaxis after unrelated allogeneic hematopoietic stem cell transplantation was more effective vs placebo for the prevention of lower gastrointestinal graft-vs-host disease.

Vedolizumab and Standard Prophylaxis Proves Effective in Preventing GI aGVHD

In findings from the phase 3 SIERRA trial, Iomab-B-based conditioning for patients with relapsed or refractory acute myeloid leukemia provided significant efficacy and tolerable safety results over the current standard of care.  

Iomab-B Shows Significant Improvement in R/R AML Over Chemotherapy Prior to Allogeneic HCT

Tisagenlecleucel reinfusion shows promise as as an effective bridge to hematopoietic stem cell transplantation in pediatric B-cell acute lymphoblastic leukemia.

Second Tisa-cel Infusion Demonstrates Short MRD-Negative Responses in Pediatric B-ALL 

Samer A. Srour, MD, MS, of The University of Texas MD Anderson Cancer Center, in Houston, Texas, discusses some of the takeaways from the dose-expansion phase of an ongoing phase 1 trial (NCT03802695) evaluating Orca-Q in the haploidentical stem cell transplant (haplo SCT) setting for patients with high-risk hematologic malignancies.

Orca-Q had acceptable safety with myeloablative conditioning (MAC) with only tacrolimus monotherapy. There was a low incidence of acute graft-vs-host disease, only 8% (95% CI, 2%-27%) of patients had grade 2 or higher aGVHD, and 5% (95% CI, 0%-25%) of patients had grade 3 or higher aGVHD.

Though the follow-up was relatively short, findings showed that at a median of 211 days (range, 32-1125) and with 16 of the 23 patients past the 3-month mark, there was not any moderate-to-severe chronic GVHD (cGVHD) seen and only 1 patient (6%) developed mild cGVHD.

At 1 year, the GVHD-and–relapse-free survival achieved with Orca-Q was 75%, which was noted to compare favorably with prior data reported in context of MAC, haplo SCT, and posttransplant cyclophosphamide.

Further data from the study was presented by Srour during the 2023 Transplantation & Cellular Therapy Meetings.

One of the main outcomes in our study was graft-vs-host disease and the key always with it the transplant, generally speaking and more so in the haploidentical transplant, how can we decrease the graft-vs-host disease risk, and also the infections and the mortality without increasing the relapse. If we talk about the acute graft-vs-host disease, it was very low. Indeed, only 5% had severe acute GVHD, which is good for source disease in our patient population. That is encouraging compared with post transplant historical data.

 Then we looked at the chronic graft-vs-host disease. Immediate follow-up was around a little over 6 months in our patient cohort. We still need more follow-up, but at least it's a decent follow-up to start with. We didn't see any moderate or severe GVHD cases, which was also encouraging. Then, 1 of the most important outcomes to look at, regardless of everything I've said, is survival. Are patients alive? More important for me, are they alive with no complications? There's an interesting outcome we look at in the transplant. More and more these days are called graft-vs-host disease relapse-free survival, which means your patients are alive and without active disease without like they are in remission. This is a very good indicator or effective for a good quality-of-life if you can achieve a good number there.

In our cohort, graft-vs-host disease relapse-free survival was 75%. This is extremely encouraging because historically, if you achieve 40%-50%, you'll be happy with that. In our cohort it was 75% and then the overall survival, which means any patients are alive at 1 year, also was the same at 75%. These are some of the main key outcomes from our study.

Videos

Samer A. Srour, MD, MS, discusses some of the takeaways from the dose-expansion phase of an ongoing phase 1 trial evaluating Orca-Q.

News

Outcomes of Orca-Q in the Haplo SCT Setting for Hematologic Malignancies

Yago Nieto, MD, PhD, The University of Texas MD Anderson Cancer Center, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, discusses the findings from a phase 2 trial (NCT02506959) evaluating treatment with panobinostat, gemcitabine, busulfan, and melphalan (Pano/GemBuMel) for patients with high-risk or relapsed/refractory myeloma.

During the 2023 Transplantation and Cellular Therapy Meeting, Nieto presented data from the trial which showed the combination to be safe and effective in this patient population. Patients were enrolled in 2 separate cohorts, including autologous stem cell transplant (ASCT)-1 which consisted of 2 subgroups receiving a first frontline ASCT or a first salvage ASCT, and ASCT-2, which included those given second salvage ASCT.

Among patients, the overall response rate/complete response with measurable disease at ASCT were 67%/40% for patients receiving a frontline ASCT-1, and 93%/64% for second salvage ASCT. MRD negativity improved after ASCT-1 from 8.5 to 23% (P < .0001) and ASCT-2 from 34% to 55% (P = .02). Additionally, at a median follow-up of 51 months (range, 8-78), the median progression-free survival among patients receiving a frontline ASCT-1 was 45 compared with 21 for those with a 1st salvage ASCT-1, and 32 months with a second ASCT, respectively.

What we saw was that Pano/GemBuMel significantly improved progression-free survival when done as a first transplant compared with matched controls, but the outcomes were very similar when done as the second transplant. For overall survival, there were some numerical differences in favor of pano and GemBuMel, but they didn't reach statistical significance for overall survival.

 Our conclusion is that the panobinostat and GemBuMel is a safe regimen and is highly active. It leads to MRD negativity in a significant number of patients, even patients with relapsed and refractory disease, and it seems better in this non-randomized but concurrent match comparison with concurrent controls, and seems better when done as a first transplant.

Yago Nieto, MD, PhD, discusses the findings from a phase 2 trial evaluating treatment with panobinostat, gemcitabine, busulfan, and melphalan for high-risk or relapsed/refractory myeloma. 


Conference News

Pano/GemBuMel is Safe and Effective in High-Risk or Relapsed/Refractory Myeloma

Melhem Solh, MD, medical director for the Cellular Therapy Program at Northside Hospital, discusses what he is excited to see in the future for patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) that harbors a 

 gene mutation, gives his own recommendations to community oncologists who are treating patients with this disease.

Solh presented data on a group of patients who had AML or high-risk MDS with a 

 mutation who also underwent an allogeneic hematopoietic stem cell transplant at the 2022 Transplantation & Cellular Therapy Meetings

Data from his research showed that match-related donors were inferior to other groups of donors and about a third of patients with 

 mutations could be saved by getting a transplant. Among patients, the 3-year overall survival was 29%. Further research is warranted to gain more of an understanding on how to best treat this patient population.

With this specific population of patients, definitely the newer leukemia therapies that we have going on, another study for bispecifics, the natural killer cell treatment, and the chimeric antigen receptor T-cell therapy. It will be very interesting to see how we incorporate these types of therapy into transplant, pre or post, to help improve the outcome of this patient.

 It is very important with acute leukemias to be in touch with a tertiary center from the time of diagnosis, because with acute leukemia, getting these patients into donor typing and donor search and getting them to transplant in a timely fashion is very important. I can't stress that enough. Especially with a 

 del(17p), admission might be short, and you don't want to be delaying that. A quick referral to a transplant center is definitely helpful.

And 2, be sure that you are sending the markers of acute leukemia, as you're checking the chromosomes [and] next-generation sequencing to have all that data available at time of diagnosis, because that will help the transplant center make the best decisions and [know] how to proceed with those patients.

Melhem Solh, MD, discusses the future for patients with myelodysplastic syndrome and acute myeloid leukemia that harbors a TP53 gene mutation, and gives his own recommendations to community oncologists who are treating patients with this disease.


Recommendations for Treating Patients With TP53-Mutated AML or MDS

Robert J. Soiffer, MD, the chair, Executive Committee for Clinical Programs, vice chair, Department of Medical Oncology, chief, Division of Hematologic Malignancies and institute physician at Dana-Farber Cancer Institute, as well as the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology, Harvard Medical School, discusses the role of transplant in the post chimeric antigen receptor (CAR) setting for patients with hematologic malignancies.

According to Soiffer, transplant is a modality which has been used for over 40 years and remains the standard of care (SOC) for many hematologic malignancies.

However, increasing information and data regarding CAR T-cell therapy may change this SOC as the non-Hodgkin lymphoma, leukemia, and multiple myeloma settings have already had CAR T-cell products approved by the FDA.

This is an evolving area, and I think that if we were to have this discussion last year, the answer would have been different. And if we were to have this discussion again next year, the answer will be different again, so, this is a snapshot in time.

CAR T cells were approved for treatment in lymphoma and acute leukemia about 3 or 4 years ago, and these work for patients who either didn't have a transplant and were refractory, or who had relapsed after their transplant. CAR T cells are commonly used for patients who had an autologous transplant, say for lymphoma, or now for multiple myeloma, they relapsed after that and they may have had other therapies subsequent to that, but they can be treated with CAR T cells. There are a number of products out there that can be treated successfully, to induce remissions, and in many patients, long term remissions and what appears to be a cure. That is for patients with recurrent disease after an auto or an allo transplant.

Robert J. Soiffer, MD, discusses the role of transplant in the post chimeric antigen receptor setting for patients with hematologic malignancies.

The Use of Transplant in the Post CAR T Setting

Melhem M. Solh, MD, a blood and marrow transplant and leukemia program physician and medical director for the Cellular Therapy Program at Northside Hospital, discusses results of a study investigating allogeneic stem cell transplant (SCT) in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with a 

 mutation, previously presented at the 2022 Transplantation & Cellular Therapy Meetings.

Solh’s group at Northside Hospital looked at post-transplant outcomes for 30 patients in their SCT program, since 

 is associated with poor outcomes. When looking at outcomes, the 1-year overall survival (OS) rate was 62%, the 1-year disease-free survival (DFS) rate was 42%, 1-year rate of relapse was 51%, and the post-relapse survival rate was 19%. When looking at patients with both 

 mutations and deletion 17p (del[17p]), the 1-year OS rate was 73% and the DFS rate was 53%. The 3-year DFS rate was 27% for this subgroup.

The main reason for transplant failure was disease relapse, whether or not patients had both a 

 mutation and del(17p). When looking at factors related to outcomes, OS, DFS, and relapse rate appeared to be associated with disease risk. Notably, in this patient set, fully matched SCT recipients had poorer outcomes for relapse rate than those who received transplants from haploidentical or unrelated donors.

As we move into the outcomes for this patient population, the 1-year OS was 62%, DFS was 42%, relapse rate was 51%, and the post-relapse survival, patients who were alive post-relapse at 1 year, was 19%. Looking at the specific subgroups of patients who have a 

 mutation and del(17p), the numbers were similar with OS and DFS [at 73%] and 53%, [respectively] at 1 year, and that goes down to 27% at 3 years [for DFS]. The main reason for transplant failure was relapse in the 

When we looked at factors associated with outcomes and responses, we really didn't see [much]—No. 1, keep in mind, this is a small study, there are only 30 patients, so we may not have much power to detect any variability. But when you look at OS, the DRI or the Disease Risk Index was a main factor in picking [out] patients who did worse versus patients who did better. For DFS, it was the same story that disease risk was the main contributor to this. For relapse, we noticed 1 interesting finding, that patients who had a matched-sibling donors did poorly compared [with] patients who get either an unrelated-match donor or a haploidentical donor. Again, at relapse, the higher disease risk was correlated with a higher relapse. There was no difference in outcomes [whether] patients have del(17p) or if they did not have del(17p).

Melhem M. Solh, MD, discusses results of a study investigating allogeneic stem cell transplant in patients with myelodysplastic syndrome and acute myeloid leukemia with a TP53 mutation, previously presented at the 2022 Transplantation & Cellular Therapy Meetings.

Allogeneic SCT Shows Efficacy in TP53+ AML and MDS

Robert J. Soiffer, MD, the chair, Executive Committee for Clinical Programs, vice chair, Department of Medical Oncology, chief, Division of Hematologic Malignancies and institute physician at Dana-Farber Cancer Institute, as well as the Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology, Harvard Medical School, discusses the use of transplant in various hematologic malignancies.

Transplant is a modality that has been used for more than 40 years for many patients with hematologic malignancies. However, research is currently evaluating chimeric antigen receptor T-cell therapy as a possible replacement and new standard of care.

Here, Soiffer discusses the role of transplantation for patients with non-Hodgkin lymphoma, the use of autologous transplant for patients with multiple myeloma, and allogeneic transplant for patients with acute leukemia or myelodysplastic syndrome (MDS).

 I’ll put it in the context of different settings. Let’s talk about a non-Hodgkin lymphoma. It is now considered, or it has been considered standard of care for patients with non-Hodgkin lymphoma who’ve relapsed after their initial therapy, particularly patients with large-cell lymphoma, to once they achieve a second remission move into an autologous transplant. That's been able to result in cures anywhere between 40% and 60% of patients who are able to successfully undergo a transplant, and that's in the lymphoma setting.

In the world of multiple myeloma, autologous transplant again, using your own stem cells, is often used upfront. It may or may not really be a curative therapy, but it's certainly something that extends progression-free survival and allows patients to live for a long period of time without intervention.

On the acute leukemia side, and let's say marrow disorders like MDS, allogeneic transplant can be curative for a variety of these disorders. The likelihood of cure depends a lot on the molecular and genetic composition of leukemia itself. So, individuals with very high-risk leukemias will do poorly with standard therapy. They'll do somewhat better with allogeneic transplant. In patients with let's say intermediate-risk leukemias who do modestly well with chemotherapy alone, do even better with an allogeneic transplant.

Robert J. Soiffer, MD, discusses the use of transplant in various hematologic malignancies.

Role of Transplant Across Hematologic Malignancies

Salman Fazal, MD, a hematologist/oncologist in the Division of Hematology and Cellular Therapy at West Penn Hospital of Allegheny Health Network, explains how to lower the risk of graft-versus-host disease (GVHD) in patients who undergo allogeneic stem cell transplant or treat GVHD when it does develop.

To lower risk of GVHD, Fazal says that it is best to use a fully matched donor However, it is not possible to find a fully matched donor for every patient. Treatment with cyclophosphamide following transplant is another way to prevent GVHD.

For patients who do develop GVHD following their transplant, Fazal explains that new treatment options have been introduced for GVHD.

So, the graft-versus-host disease does present one of the transplant-related complications. And in order to lower the incidence of graft-versus-host disease, we like to use fully matched donors. [This] may not be possible for every patient, and in situations where we used haploidentical donor or a mismatched unrelated donor. We do use strategies such as post-transplant cyclophosphamide to lower the incidence of graft-versus-host disease.

We also have new treatment options for treatment of steroid-refractory acute and chronic graft versus host disease. So certainly, if the patients are developing signs and symptoms of graft-versus-host disease, we try to employ those therapies earlier in the in the complication to minimize worsening of their disease.

Salman Fazal, MD, explains how to lower the risk of graft-versus-host disease  in patients who undergo allogeneic stem cell transplant.

Mitigating Transplant-Induced GVHD

Chenyu Lin, MD, hematology/oncology fellow at the Duke Cancer Institute, discusses the significance of a 10-year follow up of a study of patients who underwent allogeneic stem cell transplant (ASCT) with the novel cell therapy omidubicel.

Finding an unrelated donor for ASCT is a major challenge for many patients, especially those in some ethnic minorities that are underrepresented in donor populations. Lin says this makes alternative stem cell sources critical.

The cell therapy omidubicel, a hematopoietic stem cell graft derived from umbilical cord blood, has shown efficacy over standard myeloablative umbilical cord blood in a phase 3 trial (NCT02730299), and the FDA has granted a priority review for its approval in patients with hematologic malignancies in need of ASCT.

A study Lin took part in at Duke Cancer Institute showed favorable long-term survival and manageable rates of graft-vs-host disease with omidubicel. Lin says this study shows the potential of cord blood expansion therapies to address the needs of patients with no adequate donor available, which will improve outcomes for patients as ASCT is the only curative therapy for many hematologic malignancies.

 With ASCT, one of the challenges is finding a donor. And we've been able to increase the diversity of our stem cell registries in the past decade. But there's still some healthcare disparities present in terms of being able to find an optimal match, [for an] unrelated donor. For an individual of Northern European descent, that's relatively easier. But for certain underrepresented ethnic and racial minority groups, the rates of being able to find an optimal match is much lower.

So this is where an alternative stem cell source like cord blood can come in. The hope—with the long-term safety data being reassuring for omidubicel—the hope is that we're going to be able to expand access to stem cell transplantation for patients who otherwise would not have an adequate donor, but who are nonetheless reliant on transplant as the only curative therapy for the disease, and especially for many racial and ethnic minority groups who may have a harder time finding a traditional donor. So I think it's an exciting time for cord expansion, and omidubicel is leading the way for potentially paradigm-shifting developments in the field.

Chenyu Lin, MD, discusses the significance of a 10-year follow up of a study of patients who underwent allogeneic stem cell transplant with the novel cell therapy omidubicel.

Omidubicel Increases Availability of Allogeneic Stem Cell Transplant

Chenyu Lin, MD, hematology/oncology fellow at the Duke Cancer Institute, discusses the results of a 10-year follow up of patients who underwent allogenic stem cell therapy with the novel cell therapy omidubicel.

The hematopoietic stem cell graft is derived from umbilical cord blood, composed of an 

 nicotinamide-expanded CD133-positive stem cell fraction, and a non-expanded CD133 T-cell-containing fraction. A previous phase 3 study (NCT02730299) showed that omidubicel fared better than other standard grafts derived from umbilical cord blood and reduced infections, leading to a FDA priority review of the drug’s biologics license application. However, there had not been a long-term analysis of the therapy.

At Duke Cancer Institute, Lin and his co-authors looked at 22 patients with hematologic malignancies given an omidubicel graft during the study period between November 2010 and January 2020. The most common disease types were acute myeloid leukemia (36%), myelodysplastic syndrome (32%), and acute lymphocytic leukemia (18%). Five patients were considered to have high risk disease, 13 were intermediate risk, 3 were low risk, and 1 was unevaluable. The estimated 10-years overall survival was 48.5% (95% CI, 31.0% - 75.7%) and estimated disease-free survival was 43.6% (95% CI, 26.8% - 70.9%). Eleven patients passed away due to disease relapse (64%), acute GVHD (27%), or infection (9%).

Lin highlights how these results show the long-term potential of adding this graft to allogenic stem cell therapy and how the complication profile of this therapy was also manageable.

Since this was a novel therapy, we looked at some of the long-term transplant related complications. We found that the cumulative incidence of chronic GVHD was 32%, but most of these patients had mild to moderate GVHD and were successfully weaned off systemic immunosuppression at last follow up. There were no secondary hematologic malignancies in our cohort, which is always a theoretical concern with these ex-vivo expansion technologies.

Notably, in terms of graph durability, we observed sustained trilineage hematopoiesis even at 10 years of follow up. This is also true for immune reconstitution. There were serial quantitative assessments that demonstrated the maintenance of normal levels of lymphocyte subsets for up to 8 years post-transplant. So, all this suggests that omidubicel can provide durable hematopoiesis and sustained immune competence, even on extended follow up, which does speak to the safety of the product in the long term. [This also] suggests that these expanded stem cells can retain their long-term repopulating ability.

Chenyu Lin, MD, discusses the results of a 10-year follow up of patients who underwent allogenic stem cell therapy with the novel cell therapy omidubicel.

Long-Term Follow Up Shows Potential of Omidubicel in Hematologic Malignancies

Robert J. Soiffer, MD, the chair, Executive Committee for Clinical Programs, vice chair, Department of Medical Oncology, chief, Division of Hematologic Malignancies and institute physician at Dana-Farber Cancer Institute, as well as the Worthington and Margaret Collette Professor of Medicine in the field of hematologic oncology, Harvard Medical School, discusses the use of stem cell transplant in treating hematologic malignancies prior to the availability of chimeric antigen receptor (CAR) T-cell products.

Prior to the development of CAR T-cell therapies, stem cell and allogeneic transplants have been the 2 main approaches for treating patients with hematologic malignancies, according to Soiffer. Transplant has been the standard of care for many hematologic malignancies and has been used for over 40 years.

Stem cell transplants are typically performed in patients with non-Hodgkin lymphoma and multiple myeloma, while allogeneic transplants typically are for patients with acute myelogenous leukemia, myelodysplastic syndrome, myelofibrosis, and more.

However, with developments focused on evolving CAR T-cell therapies, the main treatment approach for this patient population may change.

Robert J. Soiffer, MD, discusses the use of stem cell transplant in treating hematologic malignancies prior to the availability of chimeric antigen receptor T-cell products.