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Clinical

Andre H. Goy, MD; Sandra M. Swain, MD, FACP, FASCO Associate Dean for Research; Carolina Bernabe Ramirez, MD; Jonathan E. Rosenberg, MD; David H. Vesole, MD, PhD, FACP Director, Myeloma Program; Isabel Preeshagul, DO, MBS  
 

Community Practice Connections™: 5th Annual Precision Medicine Symposium – An Illustrated Tumor Board

Karen M. Winkfield, MD, PhD; Narjust Florez, MD, FASCO; Gilberto de Lima Lopes Junior, MD, MBA, FASCO; Coral Olazagasti, MD; Vonetta M. Williams, MD, PhD

 Fighting Disparities and Saving Lives: An Exploration of Challenges and Solutions in Cancer Care

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

In this feature, Memorial Sloan Kettering Cancer Center physicians explain what drives the collaborative process in their multidisciplinary graft-vs-host disease clinic. 

Learning From a Multidisciplinary Approach in Graft-Vs-Host Disease

In an interview, Colton Ladbury, MD, discussed new insights from a study and expanded on total marrow irradiation’s potential to transform transplant conditioning.

TMI Shows Potential Over Traditional TBI in Hematologic Malignancies

In an interview with Targeted Oncology, Josep Maria Ribera, MD, PhD, discussed the evolving treatment protocols for Philadelphia chromosome-positive acute lymphoblastic leukemia.

The Changing Landscape of Ph-Positive ALL

During a Case-Based Roundtable® event,  Michael R. Bishop, MD, moderated a discussion on monitoring and treatment of chronic graft-vs-host disease. 

Bishop Discusses Post-Steroid Treatment Approaches for Chronic GVHD

Findings from the phase 3 SIERRA study showed that Iomab-B was associated with a higher durable complete response rate vs allogeneic cell transplant in older patients with relapsed/refractory acute myeloid leukemia. 

Iomab-B Leads to More Durable Responses vs alloHCT in AML Treatment

Optimizing Transplant Timing in Acute Lymphoblastic Leukemia

Partow Kebriaei, MD, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, MD Anderson Cancer Center, discusses when the optimal time for transplant is in patients with acute lymphoblastic leukemia (ALL).


In recent years, advances in treatment have transformed options for patients with ALL, leading to deeper remissions and raising new questions around the optimal timing for bone marrow and stem cell transplants. Here, Kebriaei, provides insight into when transplant is most beneficial, emphasizing the importance of minimal residual disease (MRD) status and the effectiveness of chimeric antigen receptor (CAR) T-cell therapy in guiding these decisions.

For newly diagnosed patients with ALL, MRD status plays a pivotal role in determining the timing of transplant. Kebriaei notes that when MRD levels indicate minimal or no residual disease, patients are prime candidates for a stem cell transplant, maximizing their chances of long-term remission.

For patients with advanced ALL, they historically would not have been transplant candidates due to challenges in achieving deep remission. However, Kebriaei points out that CAR T-cell therapy has dramatically changed the prognosis for these individuals. By driving these advanced patients into deep molecular remission, CAR T-cell therapy can enable even patients with high-risk ALL to become eligible for stem cell transplantation.

So I think for upfront patients, we are using MRD to guide when to go forward. I think for advanced patients, and this is something that I touched on in my talk, we now can talk about the upfront patient, but what about that advanced patient, where in the past, we really did not even think about transplant because we could not get them into a deep enough remission? But now, we are able to get these patients, let us say, after CAR [T-cell] therapy, into a very deep molecular remission.

 So, should we then move very quickly with transplant as consolidation? I would posit that with the current data that we have, those patients, as soon as they achieve MRD negativity following CAR T therapy, as long as they are fairly fit, should then be considered for transplant. consolidation.



Videos

Partow Kebriaei, MD, discusses when the optimal time for transplant is in patients with acute lymphoblastic leukemia.


News

Evolving Strategies in Hematopoietic Stem Cell Transplant Conditioning

Sergio A. Giralt, MD, professor of medicine at Weill Cornell Medical College, attending physician in the Adult Bone Marrow and Transplant Service at Memorial Sloan Kettering Cancer Center (MSKCC), deputy division head of the Division of Hematologic Malignancies, and Melvin Berlin Family Chair in Multiple Myeloma at MSKCC, discusses what the most commonly used conditioning regimens for patients with myelodysplastic syndrome (MDS) undergoing transplants are.


According to Giralt, the majority of patients who are undergoing transplants today are older, which influences the type of conditioning they receive. Older patients with MDS often receive reduced intensity conditioning regimens. These regimens tend to be less aggressive than traditional myeloablative therapies.

: A combination of 2 drugs used for conditioning.

: Another combination that is commonly used.

In this video, Giralt further highlights the evolving landscape of conditioning regimens in stem cell transplantation, emphasizing the shift towards tailored approaches for older patients. He also acknowledges the promising data and ongoing research efforts in this space.

 Currently, most of the patients undergoing transplants are older patients, so many of them are getting reduced intensity conditioning with either fludarabine/melphalan or fludarabine/busulfan. We do know, based on a randomized trial, that myeloablative therapies are associated with better outcomes. So fludarabine/busulfan at full dose or fludarabine/melphalan have been probably the most common ones utilized.

 There is important data with fludarabine/treosulfan that seem to be emerging. Treosulfan is now commercially available in the US. Many of us are exploring investigational strategies with myeloablative therapies, combining alkylators like thiotepa with fludarabine and busulfan, or fludarabine and melphalan in conjunction with what we call CD34 engineered grafts. Then, there are the Memorial Sloan Kettering CD34 selection trials that have recently been published.

Sergio A. Giralt, MD, discusses what the most commonly used conditioning regimens for patients with myelodysplastic syndrome undergoing transplants are.


Mechanism of Action Influences Sequencing of Systemic GVHD Therapies

Noah M. Merin, MD, PhD, assistant professor at Cedars-Sinai Medicine and medical director of the Hematology and Cellular Therapy Disease Research Group at the Cedars-Sinai Cancer Institute, discusses the mechanisms of action and sequencing of oral therapies for chronic graft-vs-host disease (GVHD) in a live virtual event.

When looking at the cellular pathways involved in activating graft immune cells that cause GVHD, he first noted the role of ruxolitinib (Jakafi), a JAK1/JAK2 inhibitor, on the JAK/STAT pathway to downregulate cytokine production. Ruxolitinib would be his first choice for steroid-refractory acute GVHD or chronic GVHD. Next looking at ibrutinib (Imbruvica), he said it has a different adverse event profile from ruxolitinib and acts on the BTK (Bruton tyrosine kinase) signaling molecule to deactivate cytotoxic T cells responsible for GVHD. Merin said he would use it in patients whose disease did not respond to ruxolitinib.

The third approved therapy, belumosudil (Rezurock), is a ROCK2 inhibitor that acts downstream of integrins and growth factors that cause proliferation of T cells. Merin said he would normally use it after ruxolitinib and ibrutinib, but it is also especially effective in patients with GVHD of the lung, which would also be a sequencing consideration.

 Ruxolitinib is usually my first choice for acute GVHD that is steroid refractory, and often I'm using it again if patients develop chronic GVHD. It also [has] a different side effect profile than ibrutinib.

[The JAK/STAT pathway] is the first step of activation of immune cells [with] the cytokine receptors, and [ruxolitinib] inhibits that step. So if it doesn't work and I'm treating chronic GVHD, my next choice would be to work on—to use a drug that—this is the B cell receptor. Downstream from the B cell receptor is a signaling molecule called BTK. This is a T cell receptor, downstream from that is ITK [interleukin-2–inducible kinase] and ibrutinib blocks that. So if your B cell or T cell has already gotten exposed to cytokines, and it's destined to become an alloreactive immune cell; it's going to proliferate, it's going to put out antibodies, it's going to turn into a cytotoxic T cell, then ibrutinib can turn those cells off, because it's already cells that have already encountered their antigens and have been activated. So I use ibrutinib after patients progress on ruxolitinib for chronic GVHD.

Then the third drug in the lineup is belumosudil. So belumosudil is a ROCK2 inhibitor. ROCK2 is a signaling molecule that's downstream from integrins, which help immune cells bind to the vascular wall and migrate into areas where they're going to go and cause GVHD, and...growth factors that turn on T cells and make them proliferate. I use belumosudil in the third situation, if patients have progressed on ruxolitinib or ibrutinib, and it's particularly good for lung GVHD. It appears to have some benefit in lung GVHD. So in patients with lung GVHD, I'm trying to get them on belumosudil. That's how I divide up, [and] how I choose among the FDA approved oral therapies for chronic GVHD.

Noah M. Merin, MD, PhD, discusses the mechanisms of action and sequencing of oral therapies for chronic graft-vs-host disease (GVHD) in a live virtual event.

Giralt on MDS Transplant Timing and Candidacy

Sergio A. Giralt, MD, professor of medicine at Weill Cornell Medical College, attending physician in the Adult Bone Marrow and Transplant Service at Memorial Sloan Kettering Cancer Center, deputy division head Division of Hematologic Malignancies; Melvin Berlin Family Chair in Multiple Myeloma at Memorial Sloan Kettering Cancer Center, discusses how to determine which patient is a candidate for transplant and the optimal time to perform a transplant in patients with myelodysplastic syndrome (MDS).

Giralt covered this topic and more during a session at the 

2024 Society of Hematologic Oncology (SOHO) Annual Meeting

 where he delved into the role of transplant for patients with MDS.

0:09 | I think transplant candidacy is something that we think should be determined in the transplant center by a transplant physician, and they have teams of people who help him or her make this decision. For older patients, we think comprehensive geriatric assessment should be the standard-of-care, because our geriatricians can provide us enormous insight about what the risk of transplant may be for an individual patient.

 In general, we take into consideration disease risk characteristics, patient risk characteristics, and it is a conversation. We now know everybody has a donor. With post transplant cyclophosphamide, we can now do mismatched-unrelated donors and mismatch-related donors. In reality, what used to be a procedure that was only limited to people who had HLA identical donors within the family, and the registry is now open to everyone.

 High-risk [patients with] MDS should probably be transplanted as soon as the diagnosis is made. In patients with intermediate- or low-risk disease, it can be something where you can kind of see what the tempo of the disease is. But once again, when these patients develop high-risk molecular abnormalities, the data would show that the earlier they go to transplant, the better it is.

Sergio A. Giralt, MD, discusses how to determine which patient is a candidate for transplant and the optimal time to perform a transplant in patients with myelodysplastic syndrome.

Risk Factors and Indications for Stem Cell Transplants in MDS

Sergio A. Giralt, MD, professor of medicine at Weill Cornell Medical College, attending physician in the Adult Bone Marrow and Transplant Service at Memorial Sloan Kettering Cancer Center, deputy division head Division of Hematologic Malignancies; Melvin Berlin Family Chair in Multiple Myeloma at Memorial Sloan Kettering Cancer Center, discusses the current indications for considering stem cell transplants in patients with myelodysplastic syndrome (MDS).

In addition, Giralt delves into how factors like disease risk classification and patient characteristics influence this. Giralt presented on this topic at the 

Currently, the current indications for transplant in patients with MDS is in anybody with intermediate- to high-risk disease, or patients in which primary therapy is failing and they are still transfusion-dependent, in which it is felt that transplant will significantly improve their quality and quantity of life.

[It is] essential to be able to risk stratify patients, and we now know that some low-risk patients, because of molecular abnormalities, are actually high-risk patients because they will have a higher tendency to transform to acute leukemia. Then, we also know that patients who are scored as intermediate too may actually have lower propensity of progressing.

We also have to incorporate the patient specific factors we just heard in this [SOHO] meeting at 8 in the morning, Mohamed L. Sorror, MD, MSc, gave us an excellent presentation of the CHARM [composite health risk assessment model] score, where you could look at patients over the age of 65 and try to prognosticate what the risk of mortality is after transplant. Those types of scoring and risk stratification criteria are really essential for both the patients and the physicians taking care of them, to decide whether the risk benefit ratio of transplant is positive or whether they are a patient is better served by a more conservative approach.

Sergio A. Giralt, MD, discusses the current indications for considering stem cell transplants in patients with myelodysplastic syndrome.

Conference News

Buprenorphine for Refractory Pain in Patients Undergoing Bone Marrow Transplant

Mayuko Sakae, MD, City of Hope assistant clinical professor, Department of Supportive Care Medicine, discusses findings from her research presented at the 2024 Multinational Association of Supportive Care in Cancer Annual Meeting on refractory pain in patients who have undergone a bone marrow transplant.

, experts investigated the use of buprenorphine as a novel approach to help manage severe pain compared with traditional opioids during bone marrow transplant.

Our pilot prospective clinical trial was initiated after observing severe bone marrow transplant-related pain that our patients with sickle cell disease experienced. Their pain was uncontrolled even with the increasing use of multiple traditional opioid pain medications to high doses, which led to significant opioid side effects. Their pain was still uncontrollable by trying all the other pain management methods and techniques that we use when a specialty supportive medicine consult is requested for uncontrolled pain. This only changed when we introduced buprenorphine to the BMT pain management strategy for SCD patients in our pilot prospective clinical trial.

The number 1 key finding is that buprenorphine, an opioid pain medication with unique pharmacological properties, can provide effective pain management in patients suffering from uncontrolled pain with severe and complex pain history with significantly less opioid [adverse] effects. This means buprenorphine often causes less respiratory depression, less gastrointestinal adverse effects such as constipation, nausea, less euphoria and craving, and less depressant- and stress-causing neurotransmission compared with traditional full agonists.

Key point number 2 is that buprenorphine slows down the opioid tolerance development, meaning buprenorphine helps avoid further opioid dose-escalation, even in patients who have baseline hypersensitivity to pain. This would be an impossibility when we use traditional opioid pain medications like morphine, oxycodone, fentanyl, etc. [Our study suggests that a timely collaboration with a supportive medicine specialty earlier in the process, before the pain level escalation, is beneficial].

Mayuko Sakae, MD, discusses findings from research presented at the 2024 Multinational Association of Supportive Care in Cancer Annual Meeting on refractory pain in patients who have undergone a bone marrow transplant.

Advancements in Stem Cell Transplantation: Comparing Orca-T With PTCy

Alexandra Gomez Arteaga, MD, hematologist/oncologist in the bone marrow transplant and cellular therapy program at Weill Cornell Medicine in New York, New York, discusses the rationale behind a retrospective study comparing Orca-T with posttransplant cyclophosphamide-based hematopoietic cell transplantation using data from existing studies that involved similar patient populations.

Arteaga also discusses the mechanism of action of Orca-T, a novel cell therapy under investigation. The agent works by leveraging regulatory T cells from allogeneic donors to control graft-vs-host disease (GVHD).

 Our field in allogeneic stem cell transplantation is changing, and we now have new ways of doing GVHD prophylaxis. The posttransplant cyclophosphamide studies and the platform have shown significant reduction in chronic GVHD. There might be other ways that we can improve outcomes by reducing other important things such as toxicities and relapse.

 Orca-T is a high precision immunotherapy that is a more organized fashion to create immune reconstitution. Based on the new changes in post transplant cyclophosphamide, we wanted to compare Orca-T [with] posttransplant cyclophosphamide since we currently are doing a study with Orca-T against the standard of care.

 With the current allografts, there are over 50 cell types that are infused together, and we have no control over how these cells interact for engraftment. Orca-T immune reconstitution, on the other hand, is the high-precision immunotherapy where the cells are in manufacture and divided into 3 main components. The first component is hematopoietic stem cells. The second component is highly purified T regulatory cells. The third component is the conventional cells.

With this high precision immunotherapy, we can give the patient the exact number of cells at the exact time. On day 0, the patients get the stem cells from the T regulatory cells and these the regulatory cells are going to have an optimal immunomodulatory environment so that there's less GVHD. There is more organization of how the immune reconstitution happens.

Alexandra Gomez Arteaga, MD, discusses the rationale behind a retrospective study comparing Orca-T with posttransplant cyclophosphamide-based hematopoietic cell transplantation.

Exploring Subgroups of Patients Likely to Refuse HSCT for Myeloma Treatment

Chakra Chaulagain, MD, director of the multiple myeloma and amyloidosis program at Cleveland Clinic Florida, discusses findings from a comprehensive examination of National Cancer Database data from 2004 to 2020 regarding the utilization of autologous hematopoietic stem cell transplantation (HSCT) in patients with multiple myeloma.


The study found that a small yet significant percentage of patients with multiple myeloma are refusing this potentially life-saving procedure. Here, Chaulagain also discusses the subgroups of patients who were more likely to refuse HSCT.

We had 43,600 patients [with] newly diagnosed multiple myeloma, and they were recommended to undergo a stem cell transplantation after completing their initial induction therapy by their doctors. Ninety-eight percent of the patients did go and do the stem cell transplantation, but 2% refused. We analyzed the various socioeconomic, racial, ethnic, and geographic factors about what made them refuse the stem cell transplantation.

 We did find that older patients had a higher odds of refusing essential transplantation. Male [patients] had higher odds of accepting transplantation and females had higher odds of refusing it. Patients with more major medical comorbidities had higher odds of refusing it. Patients without insurance, or Medicare and Medicaid, had higher odds of refusing stem cell transplantation compared with patients who had private insurance. Median household income was also a significant predictor of whether the patient will go for a stem cell transplant or not. Those who were earning less than $63,000 annually had a higher odds of refusing autologous stem cell transplantation. Black patients, for example, had a higher odds of refusing transplantation, and Hispanic [patients] had a lower odds of refusing transplantation.

1. Chaulagain CP, Saba L, Sarna K, et al. Exploring autologous hematopoietic Stem cell transplantation (HSCT) utilization and HSCT refusal trends in multiple myeloma patients: A comprehensive examination of NCDB data from 2004 to 2020. 

. 2023;142 (Suppl 1): 532. doi:10.1182/blood-2023-182051

Chakra Chaulagain, MD, discusses findings from a comprehensive examination of National Cancer Database data from 2004 to 2020 regarding the utilization of autologous hematopoietic stem cell transplantation in patients with multiple myeloma.


Usmani on Indications and Timing of Autologous Transplant in Myeloma

Saad Z. Usmani, MD, MBA, FACP, FASCO, chief of the myeloma service at Memorial Sloan Kettering Cancer Center, discusses the specific patient subgroups for whom autologous transplant remains the best course of action for.

He then continues the conversation by discussing the current best practices for determining the optimal time for transplant in these patients.

Saad Z. Usmani, MD, MBA, FACP, FASCO, discusses the specific patient subgroups for whom autologous transplant remains the best course of action for.


Bone Marrow & Stem Cell Transplant

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