Reducing Toxicities in Allogeneic Hematopoietic Stem Cell Transplantation

By Michael Scordo, MD Miguel-Angel Perales, MD Thursday, March 15, 2018

Despite significant advances in supportive care and improvements in allogeneic hematopoietic stem cell transplantation outcomes, about one in every three patients succumbs to post-transplant toxicities, half of which are not related to graft-versus-host disease (GVHD).

While the use of ex vivo CD34⁺-selected stem cells for allogeneic hematopoietic stem cell transplantation (HCT) significantly reduces the risk of both acute and chronic GVHD, and eliminates the need for post-transplant immunosuppressive drugs, reducing post transplant toxicity burden remains a focal research point to improving patient outcomes.

CD34 is expressed on hematopoietic progenitor cells found in bone marrow and cord blood. CD34⁺Stem/ Progenitor Cells are multipotent and can give rise to all cell types in blood.

Memorial Sloan Kettering, one of the pioneers of myeloablative HCT with ex vivo CD34⁺-selected stem cells, has ongoing research efforts to characterize toxicities and identify risk factors that impact morbidity and mortality in adults undergoing this approach.

In our three recent papers published in Biology of Blood and Marrow Transplantation, we categorize the numbers and types of specific organ toxicities following CD34⁺-selected transplantation and describe the predictive factors.

Overall, we found that pretransplantation cytomegalovirus (CMV) seropositivity and a higher ferritin level were associated with poorer outcomes, while a pretransplantation higher absolute lymphocyte count and increased albumin level were associated with improved outcomes.

Minimizing Toxicities with CD34+-Selected Stem Cells

Managing the efficacy of intensive pretransplant conditioning and the graft-versus-tumor effect while minimizing the effects of GVHD and nonrelapse mortality is a challenging balancing act for clinicians treating patients undergoing allogeneic hematopoietic stem cell transplantation.

The current standard regimen to control GVHD is the administration of immunosuppressive agents — most commonly, the calcineurin inhibitors tacrolimus and cyclosporine — together with methotrexate This regimen, referred to as Tac/MTX, is administered for the first six to nine months after transplantation. While Tac/MTX can control acute GVHD well, it is less effective at managing chronic GVHD and may produce toxicities and side effects.

Memorial Sloan Kettering, one of the pioneers of myeloablative HCT with ex vivo CD34+-selected stem cells, has ongoing research efforts to characterize toxicities and identify risk factors that impact morbidity and mortality in adults undergoing this approach.

Miguel-Angel Perales Chief, Adult Bone Marrow Transplant Service

The use of ex vivo CD34⁺-selected stem cells involves depleting donor T cells from the graft. This approach has demonstrated significantly reduced acute and chronic GVHD while maintaining good outcomes in patients with acute leukemia or myelodysplastic syndrome in complete remission. The approach eliminates the need to treat patients with Tac/MTX post-transplantation and, accordingly, eliminates Tac/MTX-associated toxicities from occurring. However, patients receiving CD34⁺-selected stem cells still require pretransplant myeloablative conditioning that can influence the range of toxicities they experience post-transplant.

Recent Learning from MSK Patients

Memorial Sloan Kettering is one of 27 centers participating in the ongoing Blood and Marrow Transplantation Clinical Trials Network phase III randomized, controlled trial BMT CTN 1301, NCT0234580, co-chaired by Dr. Miguel Perales from MSK. The study is comparing two calcineurin inhibitor–free strategies for reducing GVHD in 345 patients randomized to three treatment groups: CD34⁺-selected stem cells with the CliniMACs CD34 Reagent System, bone marrow transplant followed by post-transplantation cyclophosphamide, and bone marrow transplant followed by standard Tac/MTX treatment.

While this large prospective trial is ongoing, we analyzed electronic health record data for our adult patients who had been enrolled in previous trials at MSK and had been treated with CD34⁺-selected stem cell transplants. We identified toxicities and associated risk factors and their impact on outcomes for three subgroups: first-year survivors, longer-term survivors, and adults over the age of 60.

Our findings for each subgroup are as follows:

One-Year Outcomes: The first study examined the impact of grade 3 or higher toxicities on first-year outcomes in 200 adult patients ages 19 to 73 years (median age 57 years). Overall, this group of patients experienced low rates of acute GVHD, in contrast to conventional transplants with myeloablative conditioning; low rates of sinusoidal obstruction syndrome; and good rates of nonrelapse mortality, progression-free survival, and overall survival. By the 100-day milestone, only six patients (3 percent) had developed grade 3 and 4 GVHD. One-year post-transplantation, 149 of 200 patients (75 percent) were alive. Of the 51 who had died, 17 died of disease whereas twice as many, 34, died of nonrelapse mortality. (1)

Patients experiencing pulmonary, renal, hepatic, and neurological toxicities had an increased risk of death and nonrelapse mortality. Our analysis revealed that CMV-positive patients who developed pulmonary and renal toxicities experienced a higher risk of poorer outcomes in the first year. High ferritin pretransplantation was significantly associated with serious hepatic complications. We also found that patients that had a higher level of busulphan than planned also had worse outcomes. (1)
Longer-Term Outcomes: In a second study, we analyzed late adverse effects among 131 patients who survived more than one year post-transplantation (median follow-up time of 36 months). Four-year overall survival for patients who survived one year was strong at 77 percent. The development of grade 3 or higher toxicities in the first year was associated with poorer outcomes, emphasizing the need for early identification and intervention strategies when toxicities arise. (2)

Among all of the toxicities recorded, 75 percent occurred within two years of transplantation. Cardiovascular, hematologic, hepatic, infectious, metabolic, neurologic, and pulmonary toxicities that occurred one year post-transplantation were independently associated with poorer outcomes, even after adjusting for higher scores using the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) pretransplantation and whether patients developed grades 2 through 4 acute GVHD within the first year of receiving transplants. (2)

Pretransplantation absolute lymphocyte count > 0.5 K/mL and serum albumin > 4.0 g/dL were associated with reduced risks of developing hematologic, infectious, metabolic, and pulmonary toxicities, as well as a reduced risk of death and nonrelapse mortality. Serum ferritin > 1,000 ng/mL was associated with a higher risk of toxicities and nonrelapse mortality after one year. (2)
Older Adults: In the third study, we examined the impact of toxicity on survival outcomes for older patients and compared results for 80 patients over 60 years with 120 patients ages 18 to 59 years. (3)

Overall survival and nonrelapse mortality were similar between patients over and under 60 years of age, with a one-year overall survival rate of 70 percent versus 78 percent (p=.07) and a one-year nonrelapse mortality rate of 23 percent versus 13 percent (p=.38) respectively. (3) These results suggest that many older patients who undergo allogeneic hematopoietic cell transplantation have favorable outcomes.

Patients in the older group had a higher risk of neurologic and cardiovascular toxicities but a lower risk of oral and gastrointestinal issues compared with those in the younger group. Overall, cardiovascular, hepatic, neurologic, pulmonary, and renal toxicities were independent risk factors for death and nonrelapse mortality, after controlling for higher comorbidity scores pretransplantation. (3)

CMV seropositivity in this patient group was associated with the development of several toxicities, suggesting that further research about the impact of CMV status is warranted. (3)

Few studies have systematically characterized specific organ toxicities after allogeneic hematopoietic stem cell transplantation. Our findings in these three recently published papers suggest that simple blood tests for CMV, ferritin, absolute lymphocyte count, and albumin may complement widely used prognostic tools, such as the HCT-CI, for risk assessment in patients receiving myeloablative allogeneic hematopoietic stem cell transplantation with ex vivo CD34⁺-selected stem cells. Earlier identification of toxicities and developing timely intervention strategies will help more patients achieve better, longer-term outcomes in the future.

At MSK, we treat hematologic cancers with advanced expertise and multidisciplinary collaboration. As leaders in the field, we are committed to pioneering advances in stem cell transplants that can reduce the risk of disease relapse, as well as the potential toxicities and symptom burden associated with bone marrow and stem cell transplantation in order to achieve the best possible outcomes for our patients.

In April this year we convened the first International Symposium on Hematopoietic Cell Transplantation-Related Toxicities. This symposium brought together thought-leaders and participants from around the world in the fields of hematopoietic cell transplantation and related medical subspecialties. Speakers discussed mechanisms of toxicities and symptom burden after hematopoietic cell transplantation that are not related to graft-versus-host disease in order to identify best practices to both prevent and treat these complications. Over the two day symposium, speakers and attendees also met in dedicated breakout sessions that facilitated collaborative efforts in planning future research aimed at mitigating serious toxicities, reducing symptom burden, and improving patients’ outcomes.

Learn more about patient eligibility for the BMT CTN 1301 study at MSK