Researchers at the Medical College of Wisconsin recently found that mul­ti­ple myeloma patients are at an increased risk of engraftment syndrome following stem cell transplantation, compared to patients with lym­pho­ma. Engraftment syndrome is a complication that can occur soon after stem cell transplantation.

Within the myeloma population, the risk of engraftment syndrome was in­creased in patients who are over 60 years of age, have been treated with the novel agents Revlimid ^[1] (lenalidomide) and/or Velcade ^[2] (bortezo­mib), or have not been treated with cyclo­phos­phamide ^[3] (Cytoxan).

“The most important finding is the increased rate of engraftment syn­drome that is occurring after autologous stem cell transplantation when patients have been previously treated with novel agents,” said the study’s lead investigator, Dr. William Drobyski. “I think that this will impact patients in hopefully increasing aware­ness of this complication, which can be life threatening and fatal in some patients. This could lead to earlier inter­ven­tion with steroids, which can rapidly alleviate symptoms,” explained Dr. Drobyski.

Based on these findings,  Dr. Drobyski suggests that the addition of cyclophosphamide to induction therapy, prior to transplantation, may decrease the rate of engraftment syndrome in myeloma patients.

“There is debate in the field about the optimal induction regimen, and several may actually be equivalent. In that case, ones that include cyclophosphamide would be predicted from our data to be associated with a lower rate of this complication when patients do eventually undergo autologous stem cell transplantation, which most ultimately do.”

Background

Autologous stem cell transplantation is commonly used during the treatment of multiple myeloma patients who are eligible for the procedure. In this procedure, the patient’s stem cells are collected prior to high-dose chemotherapy, which kills off both tumor cells and healthy cells in the body. During transplantation, the har­vested stem cells are re-infused into the patient to replace the destroyed healthy cells.

Engraftment syndrome is a complication that may occur early after stem cell transplantation, when white blood cells begin to repopulate the patient’s bone marrow. Symptoms include fever, diarrhea, rash, and sometimes liver dysfunction, transient confusion, or a condition in which fluid leaks from the capillaries of the circulatory system.

Recent studies indicate that the rate of engraftment syndrome is increasing, particularly in the myeloma population. However, the reasons for the increase are unknown.

Researchers from the Medical College of Wisconsin therefore sought to define risk factors for the develop­ment of engraftment syndrome.

Study Design

The researchers retrospectively analyzed the records of 591 patients who underwent two consecutive autol­o­gous stem cell transplants at the Medical College of Wisconsin between 2001 and 2010. The patients had been previously diagnosed with multiple myeloma (71 percent), non-Hodgkin’s lymphoma (20 percent), or Hodgkin’s lymphoma (9 percent).

They identified patients with engraftment syndrome by the presence of a non-infectious fever and an addi­tion­al symptom of the syndrome, or else a combination of rash, diarrhea, and pulmonary infiltrates, during the three days prior or ten days after engraftment, which is when the transplanted stem cells begin pro­duc­ing new blood cells.

The median follow-up time was 49 months.

Study Results

Of the 591 transplants evaluated in the study, 22 percent developed engraftment syndrome at a median of 12 days after transplantation and one day after neutrophil engraftment. In particular, 27 percent of multiple myeloma patients developed engraftment syndrome, compared to 12 percent of non-Hodgkin’s lymphoma and 6 percent of Hodgkin’s lymphoma patients.

The most common symptoms observed in these patients included fever (90 percent), diarrhea (68 percent), and rash (50 percent).

Factors that increased the risk of developing engraftment syndrome included age greater than 60 years, transplant after 2005, diagnosis of multiple myeloma, treatment with Revlimid and/or Velcade, lack of ex­po­sure to cyclophosphamide, use of melphalan ^[4] (Alkeran) prior to transplant, and disease status of a partial response prior to transplant.

The researchers speculate that the increase in the rate of engraftment syndrome after 2005 is due to the use of novel agents, such as Revlimid and Velcade, after this time.

However, they did not observe an increased risk in patients who were previously treated with thalidomide ^[5] (Thalomid), another novel agent related to Revlimid. According to the researchers, this finding indicates that newer immunomodulatory agents, such as Revlimid and Pomalyst (pomalidomide) may have a more pro­found impact on the immune system than thalidomide. .

Pre-transplant exposure to cyclophosphamide was much higher in patients with non-Hodgkin’s disease be­cause it is a component of many common chemotherapeutic regimens used for the treatment of the dis­ease. These patients were subsequently found to have lower rates of engraftment syndrome.

The majority (81 percent) of patients who received cyclophosphamide received it as part of stem cell mobili­za­tion therapy, rather than as part of their induction therapy.

The researchers point out that there was no difference in progression-free and overall survival between pa­tients who developed engraftment syndrome and those who did not.

For more information, please refer to the study in the journal Biology of Blood and Marrow Transplantation ^[6] (abstract).