Issue: March, 2021
Disclosures: Copelan reports no relevant financial disclosures. Cutler reports consultant/advisory board roles with Generon, Incyte, Jazz Pharmaceuticals, Kadmon, Medsenic and Mesoblast. Giralt reports research support from or scientific advisory board roles with Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Pfizer and Sanofi.
March 25, 2021
13 min read

Bone marrow transplantation enters ‘the dawn of a new era’

Issue: March, 2021
Disclosures: Copelan reports no relevant financial disclosures. Cutler reports consultant/advisory board roles with Generon, Incyte, Jazz Pharmaceuticals, Kadmon, Medsenic and Mesoblast. Giralt reports research support from or scientific advisory board roles with Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Pfizer and Sanofi.
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Although potentially curative for many hematologic malignancies, hematopoietic stem cell transplantation historically has been associated with substantial morbidity and mortality.

Now, based on decades of research into supportive care, conditioning regimens and posttransplant treatments, HSCT outcomes are improving, increasing access to patients who once would have been deemed illegible for the procedure.

Study results that showed improved outcomes with transplantation among older adults with myelodysplastic syndrome should have an immediate impact on clinical practice, according to Corey Cutler, MD, MPH, FRCPC.
Study results that showed improved outcomes with transplantation among older adults with myelodysplastic syndrome should have an immediate impact on clinical practice, according to Corey Cutler, MD, MPH, FRCPC. “We are hoping this will lead to greater acceptance of reduced-intensity transplantation by community hematologist-oncologists and will result in earlier referral for transplantation,” he said.
Source: Corey Cutler, MD, MPH, FRCPC.

“Most of the improvement has been in diminished rates of nonrelapse mortality, meaning that there are less deaths due to complications of the transplant,” Edward A. Copelan, MD, Kerry and Simone Vickar Family Foundation chair and chair of the department of hematologic oncology and blood disorders at Levine Cancer Institute at Atrium Health, and a HemOnc Today Editorial Board Member, told HemOnc Today. “Refinement of conditioning regimens and more effective and safer antimicrobials and other supportive medications have led to fewer and less severe liver, kidney and lung toxicities.”

Researchers also have focused on improving treatments for and prevention of acute and chronic graft-versus-host disease, a leading complication and cause of death following allogeneic HSCT.

Edward A. Copelan, MD
Edward A. Copelan

“The incidence of severe GVHD has improved immensely over the past 2 decades,” Copelan said. “Part of that is because of more effective prevention methods, such as posttransplant cyclophosphamide.”

HemOnc Today spoke with hematologist-oncologists and transplant physicians about improvements in posttransplant survival outcomes, decreases in HSCT complications based on advances in supportive care and conditioning regimens, promising treatments for GVHD, and how greater access to transplantation is now potentially providing a curative option for older and frailer populations.

Improvements in survival

A drastic reduction in the risk for nonrelapse mortality following HSCT has led to substantial survival improvements over the decades.

In a study published last year in Annals of Internal Medicine, George B. McDonald, MD, member emeritus at Fred Hutchinson Cancer Research Center and professor of gastroenterology at University of Washington, and colleagues found that patients who underwent allogeneic HSCT between 2013 and 2017 had fewer complications and better survival outcomes than those who underwent the procedure in the prior decade.

“The most striking improvement was the continuing fall in the risk [for] nonrelapse mortality — that is, deaths that occurred from complications of the transplant procedure, unrelated to the blood cancers for which the transplants were being carried out,” McDonald told HemOnc Today at the time the study was published. “There were also reductions in the risk [for] recurrence or progression of the cancers. The sum of these reductions was improved OS over the last decade, despite a patient population that was older and sicker in the most recent cohort.”

Researchers compared data of 1,148 patients (median age, 47.2 years) who underwent their first allogeneic HSCT between 2003 and 2007 and 1,131 patients (median age, 50 years) who received their first transplant between 2013 and 2017.

Results showed the most recent cohort had reduced risk for day-200 nonrelapse mortality (HR = 0.66; 95% CI, 0.48-0.89), relapse of cancer (HR = 0.76; 95% CI, 0.61-0.94), relapse-related mortality (HR = 0.69; 95% CI, 0.54-0.87) and overall mortality (HR = 0.66; 95% CI, 0.56-0.78).

“Of interest are data showing that the major causes of nonrelapse mortality in the early days of transplantation have greatly decreased in frequency or disappeared altogether — for example, intestinal bleeding, cytomegalovirus disease, mold infections and liver disease,” McDonald said. “Organ failure remains the most hazardous posttransplant complication, and an understanding of the pathobiology of liver, kidney and lung damage will be critical in designing preventive strategies.”

Also, the rate of grade 3 or grade 4 acute GVHD declined from 14% in the earlier cohort to 12% in the later cohort (adjusted OR = 0.63; 95% CI, 0.46-0.86), and frequency of chronic GVHD decreased by 60% (adjusted HR = 0.4; 95% CI, 0.33-0.48).

“This study shows that, since the early 2000s, results have improved significantly,” Copelan said. “We have better approaches to select appropriate conditioning regimens for individual patients, and more effective regimens to prevent GVHD, and the rate of severe GVHD has decreased. All this factors into fewer and less severe complications from transplants for patients. It’s become a less toxic procedure, which is leading to better results.”

A focus on technique

Experts with whom HemOnc Today spoke said the improvements in the study by McDonald and colleagues can be attributed to better reduced-intensity conditioning regimens and supportive care.

“We are in the dawn of a new era,” Sergio A. Giralt, MD, deputy division head of the division of hematologic malignancies and Melvin Berlin family chair in multiple myeloma research at Memorial Sloan Kettering Cancer Center, and a HemOnc Today Editorial Board Member, told HemOnc Today. “We are going from what I called the ‘triple-P transplant,’ which previously meant you pushed the drugs, poured the cells and prayed that it all worked out, to the modern triple P: precise, personalized and predictable.”

Sergio A. Giralt, MD
Sergio A. Giralt

Thirty years ago, high-dose total body irradiation and busulfan-based regimens were the only two preparative regimens available for HSCT, Giralt said.

“Now, with comorbidity scoring and geriatric assessment, we tailor the conditioning regimen to the patient,” he said. “Reduced-intensity conditioning has given us a broader palette of colors and flavors that allow us to tailor our approach. It is no longer one size fits all.”

The “extraordinarily high” doses of radiation once used have decreased, Copelan said, adding that dosing of busulfan based on plasma levels provides a safer and more effective alternative ablative regimen.

Improvements in antibiotics over the years, as well as drugs used for the prevention and treatment of cytomegalovirus, also have been key, Giralt said.

“The next revolution to come will be related to the precision dosing of the other drugs we use in transplant — melphalan, fludarabine and even antithymocyte globulin [ATG],” he added. “There are publications coming about that should hopefully impact outcomes.”

For instance, Giralt cited a study conducted by researchers in the Netherlands and published in The Lancet Haematology that evaluated 146 patients with acute lymphoid leukemia, acute myeloid leukemia or myelodysplastic syndrome undergoing allogeneic HSCT with ATG as part of a nonmyeloablative conditioning regimen. Results showed optimum ATG dosing — achieved by monitoring concentrations with a validated bioassay and pharmacokinetic exposure measures — was associated with improved 5-year OS compared with below-optimum exposure (69% vs. 32%; HR = 2.41; 95% CI, 1.15-5.06) and above-optimum exposure (48%; HR = 2.11; 95% CI, 1.04-4.27).

“The results showed we can precisely dose ATG and prevent overexposure of it in the posttransplant setting,” Giralt said. “It makes a huge difference in survival in pediatric transplants, and we are now going to do it in adults. We also are now looking at pharmacokinetic-directed therapy for melphalan, and that is going into a prospective trial.”

GVHD prevention, treatment

Overall improvements in HSCT outcomes also can be attributed to a focus on treatments to prevent and treat acute and chronic GVHD, which occurs when the donor’s immune cells attack the patient’s normal cells.

Acute GVHD typically occurs within 100 days of allogeneic HSCT, with grade 2 to grade 4 acute GVHD occurring in 34% to 51% of patients, even with a standard prophylaxis regimen of a calcineurin inhibitor with methotrexate or sirolimus. Chronic GVHD, on the other hand, can occur in up to 70% of patients 3 months to 2 years after transplant, and can affect many organ systems. Both types of GVHD can be life-threatening.

“Chronic GVHD usually occurs when a patient is coming off immunosuppressive therapy,” Giralt said. “The reality is that acute and chronic GVHD can occur at any time. We usually diagnose them based on the presentation of the disease.”

Managing GVHD, such as with the expanded approval of ibrutinib (Imbruvica; AbbVie, Janssen) in 2017, has been essential to improving HSCT outcomes. Typically, patients are treated with steroids, but not all patients respond to steroids, which carry their own risks.

Two studies presented in December at the virtual ASH Annual Meeting and Exposition showed two additional promising agents for the treatment of chronic GVHD.

In the randomized, phase 3 REACH3 trial, Zeiser and colleagues found ruxolitinib (Jakafi, Incyte) — an oral Janus kinase 1/2 inhibitor — conferred a higher overall response rate than best available therapy among patients with steroid-refractory or -dependent chronic GVHD.

The analysis included 329 patients (median age, 49 years; 61% male) who underwent allogeneic HSCT and developed moderate or severe chronic GVHD.

Results showed ruxolitinib was associated with a higher ORR at week 24 (49.7% vs. 25.6%; OR = 2.99; 95% CI, 1.86-4.8), as well as a higher complete response rate (6.7% vs. 3%), longer median failure-free survival (not reached vs 5.7 months; HR = 0.37; 95% CI, 0.26-0.51) and greater improvement in modified Lee Symptom Score response rate (24% vs. 11%; OR = 2.62; 95% CI, 1.42-4.82).

“Zeiser and colleagues have to be commended, because these are challenging studies to conduct,” Giralt said. “They noticed a significant benefit, and I think it establishes ruxolitinib as a standard of care for patients with chronic GVHD who are failing steroid therapy.”

In the phase 2 ROCKstar study, Corey Cutler, MD, MPH, FRCPC, medical director of the adult stem cell transplantation program at Dana-Farber Cancer Institute, as well as associate professor of medicine at Harvard Medical School, and colleagues evaluated belumosudil (KD025, Kadmon Holdings) — a novel oral selective rho-associated coiled-coil kinase 2 (ROCK2) inhibitor — which was developed specifically for the treatment of chronic GVHD.

“ROCK2 inhibition can do two important things in chronic GVHD,” Cutler told HemOnc Today. “It can rebalance STAT3/STAT5 signaling in the germinal center, reducing TH17 cells and increasing regulatory T cells. In addition, blocking ROCK2 signaling can prevent fibrosis and scarring, common occurrences in advanced chronic GVHD.”

The analysis included 132 patients (median age, 56 years; 57% men) with chronic GVHD who had received two to five prior lines of therapy and were assigned to a 200 mg daily or twice-daily dose of belumosudil. Most patients (72%) had received at least three prior lines of therapy, including ibrutinib (n = 46) or ruxolitinib (n = 38), and 73% were refractory to their last line of therapy.

Researchers reported an ORR of 73% (95% CI, 60-83) with the daily dose and 77% (95% CI, 65-87) with the twice-daily dose. Researchers also reported high ORRs combined for both doses among patients who previously received ruxolitinib (68%; 95% CI, 51-83) and ibrutinib (74%; 95% CI, 59-86).

Additional research should be conducted to evaluate belumosudil among more patients with chronic GVHD, Cutler told HemOnc Today.

“KD025 should be tested earlier in the chronic GVHD disease course and in patients with advanced fibrosis and sclerosis, as it might be able to reverse some of these manifestations,” he said.

The results of both trials raise important questions for future research, Giralt said, including whether these agents should be combined and how they should be sequenced.

“Considering these response rates, it makes sense to compare these agents head-to-head or, more importantly, combine them,” he said. “The biggest toxicities for patients with chronic GVHD are infectious complications that result from chronic steroid therapy. Having a steroid-free regimen will be a significant benefit to patients. We now have three, if you consider ibrutinib, belumosudil and ruxolitinib, that potentially can be steroid-free or steroid-sparing regimens for the treatment of chronic GVHD. That will make a significant impact on the quality of life for patients.”

Another area of focus has been the prevention of GVHD.

“A main factor in improved HSCT outcomes is prevention of severe acute and chronic GVHD,” Copelan said. “Treatment has improved a little bit, but not as much as prevention. It does still remain a problem, although many of us feel that the use of high-dose cyclophosphamide posttransplant has further reduced the incidence of severe acute and chronic GVHD.”

Research published in The New England Journal of Medicine showed that sitagliptin — a selective DPP-4 inhibitor approved for treatment of type 2 diabetes — in combination with sirolimus and tacrolimus significantly reduced incidence of acute GVHD in a cohort of 36 patients (median age, 46 years; 53% women).

Two patients developed acute GVHD by day 100, for a cumulative incidence of grade 2 to grade 4 GVHD of 5% (95% CI, 1-16) and cumulative incidence of grade 3 to grade 4 acute GVHD of 3% (95% CI, 0-12). These results suggested an improvement over the historical rate of 30%.

“Reducing the incidence and severity of acute GVHD would make transplants safer and potentially improve survival of patients,” Sherif S. Farag, MD, PhD, FRACP, FRCPA, Lawrence H. Einhorn professor of oncology at Indiana University School of Medicine, told HemOnc Today at the time of the study’s publication. “Although a number of other agents are being tested, sitagliptin is an already-approved drug, is much simpler to administer and relatively inexpensive — possibly the least expensive intervention in the transplant process.”

Relapse risk

Despite the overall progress made in HSCT, risk for posttransplant relapse remains a challenge.

Data presented at ASH by Sharplin and colleagues showed relapse was the most common cause of death in a cohort of 149 patients who underwent allogeneic HSCT for Hodgkin lymphoma between 2009 and 2019, occurring among 37% of patients. Relapse occurred after a median 8.5 months (range, 0.2-42), and 48% of patients who relapsed had been in complete remission at the time of HSCT.

Giralt agreed that relapse remains the most common cause of treatment failure.

“Second transplants are commonly performed, particularly if the patient achieved a long remission from the first transplant,” he said. “Many of us are exploring how to make second transplants better because it’s the only chance someone has for long-term disease control if they relapsed after an allogeneic transplant.”

However, for the first time in a generation, there are strategies that may impact relapse, Giralt added.

“The first is lenalidomide (Revlimid, Celgene) maintenance post-autologous transplant, which significantly delays relapse and improves survival,” he said. “Second, is rituximab (Rituxan; Genentech, Biogen) after autologous transplant for Hodgkin disease, which has an impact on PFS.

“There is nothing yet in the allogeneic setting, but in AML there is experience of giving azacitidine [Onureg, Bristol Myers Squibb] in a nontransplant setting that has clinical benefit,” he said.

Also, in a study published last year in Journal of Clinical Oncology, Gao and colleagues showed that recombinant human granulocyte colony-stimulating factor combined with minimal-dose decitabine reduced relapse incidence after allogeneic HSCT among patients with high-risk AML.

Results showed an estimated 2-year cumulative incidence of relapse of 15% among 100 patients who received G-CSF and decitabine compared with 38.3% among 102 patients who did not (HR = 0.32; 95% CI, 0.18-0.57).

The focus of research to address relapse has been to identify patients most at risk. Assessment of minimal residual disease (MRD) has been transformative in this regard, with studies showing that patients without MRD negativity at transplant are at greater risk for relapse following transplant.

“Years ago, we only knew if patients were in morphologic remission or not,” Copelan said. “Now, we know that the detection of MRD is a risk factor for relapse after transplant. MRD testing results may lead to additional therapy to achieve MRD negativity prior to transplantation or to favoring ablative rather than reduced-intensity conditioning.”

Measuring MRD is now standard at academic centers and is becoming more common at smaller centers to tailor posttransplant therapies, according to Giralt.

“We use it to determine whether to use donor lymphocyte infusions and for immune suppression withdrawal,” he said. “Donor lymphocytes work much better for patients who have measurable residual disease, and we can convert patients to MRD-negative status. But, we await data to show whether this really impacts relapse as the main cause of treatment failure.”

Copelan added that there are other factors under investigation to predict relapse risk.

“We know that high-risk disease — defined by cytogenetics and specific molecular abnormalities, which we weren’t even defining years ago in patients — can help predict risk for relapse,” he said. “Someone who has adverse predictors in terms of their molecular studies may require more aggressive treatment to get them into remission with negative MRD before transplant and/or targeted maintenance therapy following transplantation.”

Improved access

Historically, access to transplant may have been limited among patients due to a lack of insurance coverage. That especially has been true for older patients on Medicare.

“Access is a major issue and particularly if the Affordable Care Act gets revoked, access will worsen very quickly,” Giralt said. “The ACA allowed patients to access transplant centers and allowed transplant centers to take those patients. If there is a way that access improves for patients, if insurability improves, that will affect access positively.”

Moreover, improvements in transplant preparative regimens and supportive care have made the process of undergoing transplant more tolerable, opening the door to transplant for older patients.

“Recent studies have shown that some patients can tolerate transplants into their 70s,” Copelan said.

But, patients deemed eligible by their clinicians may have been denied insurance coverage for the procedure.

For example, Medicare historically did not consider transplant for myelodysplastic syndrome a covered benefit, Giralt said.

“So, patients with myelodysplastic syndrome aged older than 65 years often had to wait until their disease had evolved into an acute leukemia before they could undergo a transplant covered by Medicare,” he said. “This was absurd, because we know transplant before transformation was associated with better outcomes.”

After the National Marrow Donor Program and American Society for Transplantation and Cellular Therapy lobbied for access, CMS agreed to provide coverage with evidence determination, Giralt said, meaning that Medicare beneficiaries could be transplanted while a study was conducted to provide evidence showing that transplant is beneficial.

The results of that study, presented at ASH by Cutler and colleagues, showed older patients with myelodysplastic syndrome who underwent donor-matched allogeneic HSCT had significantly improved 3-year OS (47.9% vs. 26.6%) and leukemia-free survival (35.8% vs. 20.6%) than those who did not have a matched donor.

These results should have an immediate impact on clinical practice, as HSCT has been underutilized among this patient group, according to Cutler.

“We are hoping this will lead to greater acceptance of reduced-intensity transplantation by community hematologist-oncologists and will result in earlier referral for transplantation,” he said.

Giralt agreed.

“Now, we expect that CMS will consider transplant a covered benefit, and there will no longer be this coverage with evidence determination issue,” he said. “This provides strong data that should move the referring physicians, particularly those who are not closely linked to transplant centers, to consider their patients for transplant evaluation. Transplant evaluation earlier rather than later is important in order to catch patients earlier and increase access to transplant.”

Overall, this improved access is a product of widespread collaboration among transplant centers that has yielded incremental improvements in HSCT outcomes, Copelan said.

“Multiple studies showed huge improvement from the 1990s to the 2000s, but many wondered if that plateaued or whether outcomes would continue to improve,” he said. “The study by McDonald and colleagues, and implementation of better methods to prevent GVHD and relapse, indicate that results of transplantation continue to improve.

“We tend to look at this narrowly,” Copelan added. “We say the improvement in survival is from the preparative regimen, the improvement in the drugs we use, the prevention of GVHD, etc. But, if you view this progress from a broader perspective, it shows that meaningful collaboration between many centers across the world, including multicenter prospective randomized trials, is the most important ingredient in improved results.”

Previously, many centers performed their own phase 2 studies and used their own individual approaches, he added.

“Cooperation and large prospective trials have led to better and more broadly accepted standard approaches with improved outcomes, while also emphasizing the ongoing importance of participation in large collaborative studies,” he said.


Admiraal R, et al. Lancet Haematol. 2017;doi:10.1016/S2352-3026(17)30029-7.

Farag SS, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2027372.

Gao L, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.03277.

McDonald GB, et al. Ann Intern Med. 2020;doi:10.7326/M19-2936.

The following were presented at ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020:

Cuter C, et al. Abstract 353.

Nakamura R, et al. Abstract 75.

Sharplin KM, et al. Abstract 2435.

Zeiser R, et al. Abstract 77.

For more information:

Edward A. Copelan, MD, can be reached at Levine Cancer Institute at Atrium Health, 1021 Morehead Medical Drive, Building II, Suite 60200, Charlotte, NC 28204; email:

Corey Cutler, MD, MPH, FRCPC, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email:

Sergio A. Giralt, MD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: