Specifically, the patients benefited from donor stem cell transplants without T-cells, a type of white blood cell.

Over 60 percent of patients experienced survival times greater than five years, and the rate of graft-versus-host disease, a common transplant-related complication, was low.

According to the researchers, these findings support the use of transplantation without T-cells in lower-risk myelodysplastic syndromes (MDS) patients.

The findings were presented at the 2011 American Society of Hematology (ASH) meeting last month.

Donor stem cell transplantation, also called allogeneic stem cell transplantation, is the only curative treatment for patients with MDS. However, this treatment is typically not considered early in the treatment plan for patients with lower-risk MDS due to the high risk of transplant-related complications.

Graft-versus-host disease is a common transplant-related complication, in which the donated stem cells attack the body’s cells. The rate of graft-versus-host disease decreases if mature T cells are removed from the donor cells before they are transplanted. T cells are a type of white blood cell that helps fight infections and tumor cells. They have also been identified as a cause of transplant rejection.

In the present study, researchers evaluated survival outcomes of 44 lower-risk MDS patients who underwent T cell-depleted stem cell transplantation early in their treatment plan. The median patient age was 37 years, and the median time from diagnosis to transplant was 0.6 years.

Prior to transplantation, patients received chemotherapy, with or without high-dose total body irradiation. Most of the patients also received anti-thymocyte globulin as preventative treatment for graft rejection. For 55 percent of patients, the transplant donor was a sibling, whereas 45 percent underwent transplantation with an unrelated donor.

The researchers found that the donated stem cells started producing white blood cells, a sign of a successful transplant, a median of 11 days after the transplant.

Five patients experienced graft failure, in which the body does not accept the donated cells. Four of these patients received second transplants, the common treatment for this complication.

The two-year and five-year survival rates were 70.1 percent and 63.3 percent, respectively.

Of the 44 patients included in the study, 14 percent developed graft-versus-host disease; half of the cases developed within the first 100 days after the transplant, the other half developed more than 100 days after the transplant.

As of May 2011, 36 percent of patients had died. Their causes of death included graft-versus-host disease (11 percent of patients), infections (11 percent), graft failure or poor graft function (7 percent), side effects of the preparative therapy prior to transplantation (5 percent), and lung cancer (2 percent).

For more information, please see abstract 3831 at the ASH 2011 meeting website.

The study authors concluded that early transplantation is not an appropriate treatment strategy for older, lower-risk patients unless quality of life is significantly impaired.

The findings were presented at the 2011 American Society of Hematology (ASH) annual meeting in San Diego on Sunday.

Donor stem cell transplantation is currently the only available cure for myelodysplastic syndromes (MDS). Patients undergo chemotherapy to destroy cancerous cells and then receive healthy stem cells from a donor to replace the patients’ stem cells that were destroyed during chemotherapy. Older patients frequently receive lower doses of chemotherapy, called reduced-intensity chemotherapy, to reduce the severity of treatment-related side effects.

Researchers designed a computer model to determine the role of donor stem cell transplantation with reduced-intensity chemotherapy in older MDS patients. They compared the survival outcomes of 92 older patients between the ages of 60 and 70 years who underwent reduced-intensity chemotherapy and transplantation to those of patients with similar levels of disease risk who did not receive transplants. The data for the comparison groups were provided from other clinical trials.

 For older patients with lower-risk MDS, the overall survival was 38 months for those who underwent transplantation and 77 months for those who instead received best supportive care or growth factors.

They also found that for transfusion-independent patients, the expected survival was 35 months for the transplanted group and 65 months for the non-transplanted group. For transfusion-dependent patients, the expected survival was 35 months for the transplanted group and 46 months for the non-transplanted group.

For older patients with higher-risk MDS, the overall survival was higher for patients who received an early transplant (36 months), compared to patients who received treatment with Vidaza (azacitidine) or Dacogen (decitabine) (28 months). 

For more information, please see abstract 115 at the ASH 2011 meeting website.

“In both [standard- and high-risk] MDS, elevated ferritin has a negative effect on the outcomes of transplantation,” said study author Dr. Takayoshi Tachibana of the Yokohama City University Medical Center in Yokohama, Japan.

Dr. Tachibana pointed out that patients with elevated ferritin levels should nevertheless undergo stem cell transplantation because “We think transplantation is the most promising therapy [for MDS patients].”

Instead he suggested that “The mechanism or nature of ferritin must be explored and a novel [approach] for reducing pre-transplant ferritin must be devised.”

Patients with MDS frequently have low red blood cell counts, a condition known as anemia. Red blood cell trans­fusions can be used to increase the cell counts. However, receiving repeated red blood cell trans­fusions can lead to excess iron in the blood, also known as iron overload.

Ferritin is an iron storage protein that can be used as an indicator for the amount of iron in a patient’s blood. “In most MDS patients, elevated ferritin [in the blood] is related to red blood cell trans­fusion,” explained Dr. Tachibana.

According to the Japanese researchers, elevated ferritin levels prior to stem cell transplantation have been shown to have a negative impact on outcomes in patients with higher-risk MDS.

“Elevated ferritin [in the blood] seems to be associated with a higher risk of complication after transplantation,” said Dr. Tachibana.

However, little is known about the effects of ferritin levels in lower-risk patients who undergo a stem cell transplant.

In this study, the researchers retrospectively analyzed data from 261 patients with different blood cancers of varying severity to determine the impact of pre-transplant ferritin levels on outcomes.

Of the 261 patients included in the analysis, 36 (14 percent) had MDS. The rest of the patients had either acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL).  (Unless otherwise specified, all results discussed in the rest of this article will be for patients with any of the three blood cancers covered by the study — not just for patients with MDS.)

The median age of the patients in the study was 43. All patients were treated at three hospitals in Japan between January 2000 and December 2008.

For their analyses, the authors of the study divided patients into two groups based on their disease severity: standard-risk and high-risk.

One quarter of the 36 MDS patients included in the analysis were categorized as having standard-risk disease, and three quarters were categorized as having high-risk disease.

Ferritin levels were measured one month before the patients began preparative chemotherapy for their stem cell transplants.

Patients were placed in the low ferritin group if they had less than 1,000 ng/mL ferritin in their blood or in the high ferritin group if they had 1,000 ng/mL or more ferritin in their blood.

The median ferritin level was 970 ng/mL. The researchers found that high-risk patients were significantly more likely to have high ferritin levels.

After five years, more patients with standard-risk disease were alive (60 percent) than patients with high-risk disease (25 percent).

Similarly, more patients in the low ferritin group were alive (54 percent) than patients in the high ferritin group (36 percent) after five years.

When the researchers divided the patients by disease-risk groups, they found that low ferritin levels had a positive impact on outcomes in both standard-risk and high-risk patients.

Standard-risk patients with low ferritin levels had significantly better overall survival after five years (64 percent) compared to standard-risk patients with high ferritin levels (54 percent).

In the high-risk group, patients with low ferritin levels also had significantly better overall survival compared to patients with high ferritin levels (35 percent versus 16 percent).

High-risk patients with low ferritin levels were also significantly less likely to experience disease relapse (50 percent) than high-risk patients with high ferritin levels (72 percent).

The impact of ferritin levels on survival remained statistically significant when the researchers controlled for a number of patient characteristics that also could affect survival.

In addition, the effect of ferritin levels stayed significant even when the analysis focused only on the 36 patients in the study who had MDS.

As the researchers explain in their article, “When subgroup analysis was done for the underlying diseases, pre-transplant [ferritin level] was a significant predictor of the outcome for patients with AML or MDS …”

Acute graft-versus-host disease, a transplant-related complication that develops within 100 days after transplantation, occurred in 107 of the 261 patients patients.   The development of acute graft-versus-host disease was not found to be related to a patient’s ferritin levels.

Patients who developed chronic graft-versus-host disease, which occurs more than 100 days post-transplant, had better overall five-year survival (67 percent versus 51 percent) than patients who did not have chronic graft-versus-host disease.

A total of 141 patients died during the study’s five years follow-up time; 43 percent died of disease relapse or disease progression and 57 percent died of other causes, including infection, organ failure, graft-versus-host disease, pneumonia, and transplant rejection or failure.

For more information, please see the study in the journal Leukemia & Lymphoma (abstract).

However, the study authors pointed out that this finding was only significant for patients with standard-risk disease. In patients with high-risk disease, the differences in survival were not statistically significant.

In addition, patients with standard-risk disease who received transplants from related donors with a mismatch at the HLA B gene experienced lower overall survival rates than patients who had related donors with mismatches at other HLA genes.

The study authors acknowledged that genetic similarities within the Japanese population might have contributed to a lower rate of treatment-related complications for patients who used matched unrelated donors. Previous studies conducted in other countries had found no difference in overall survival between the patients who received stem cell transplants from matched unrelated donors and those who received transplants from related donors with one mismatch.

Physicians have found that the selection of a stem cell donor plays a significant role in the success of stem cell transplants. In selecting a donor, physicians compare the genetic sequence of the human leukocyte antigen (HLA) from the recipient and from the donor. HLA is a cell surface protein that assists the immune system in differentiating between the body’s own tissues and foreign materials.

It is preferred for the donor to be a sibling with an identical HLA genetic sequence; however, not all recipients have a matched sibling donor. In these cases, an HLA-matched unrelated donor is often used for the transplant.

For patients with rare HLA genetic sequences, it still may be difficult to find an HLA-matched donor, related or unrelated. Previous studies have shown that patients who receive transplants from HLA-mismatched donors experienced higher rates of transplant failure and lower overall survival rates.

In the present study, the Japanese researchers compared clinical outcomes from transplants with a related donor with one HLA mismatch and from transplants with an HLA-matched unrelated donor.

They retrospectively analyzed data collected from patients with various blood cancers who had received transplants in Japan between 2001 and 2008.

Of the 779 patients included in the analysis, 327 received transplants from HLA-mismatched related donors, and 452 received transplants from HLA-matched unrelated donors.

The patients who used HLA-mismatched related donors were generally younger (median age of 45 years versus 48 years) and more likely to have high-risk disease (41 percent versus 29 percent) than those who used HLA-matched unrelated donors. Sixteen percent of the patients were diagnosed with myelodysplastic syndromes (MDS).

The two-year overall survival rate for patients who used HLA-matched unrelated donors was 59 percent, compared to 44 percent for patients who used HLA-mismatched related donors.

The study authors determined that the use of an HLA-mismatched related donor significantly shortened overall survival. Other factors that negatively impacted overall survival included patient age of at least 50 years and high-risk disease.

The impact of the HLA mismatch on outcome depended on whether the patients had standard-risk or high-risk disease. In patients with standard-risk disease, the overall survival was significantly higher for patients who received transplants from HLA-matched unrelated donors.

However, in patients with high-risk disease, there was no significant difference in overall survival between patients who received stem cell transplants from matched unrelated donors and those who received transplants from related donors with one mismatch.

The study authors also examined whether the specific gene at which the HLA mismatch occurs impacted overall survival. They found that patients who received transplants from related donors with a mismatch at the HLA B gene experienced the shortest overall survival and the highest rates of transplant-related death. However, the HLA B mismatch only affected overall survival significantly for patients with standard-risk disease.

For more information, please refer to the article in the journal Blood (abstract).

The study authors suggest that this protocol may be particularly useful for older, high-risk patients with advanced disease who cannot undergo conventional preparative therapy.

However, they point out that prospective trials are needed to confirm their findings.

High-dose chemotherapy is traditionally given to patients prior to stem cell transplantation in order to destroy their stem cells and minimize any immune reaction to the transplant. Due to the high intensity of this treatment, typically only young and healthy patients are eligible.

More recently, reduced-intensity preparative therapy has been used for older patients or patients with other diseases prior to transplant.

However, reduced-intensity preparative therapy alone is not sufficient to effectively control the disease. In these cases, reduced-intensity conditioning is frequently combined with therapy that reduces cell numbers prior to transplant.

Results from several Phase 1 and Phase 2 clinical trials have suggested that Clolar (clofarabine), a drug that suppresses cell production in the bone marrow, is effective in patients with acute leukemia.

In the United States, Clolar is approved by the Food and Drug Administration as a treatment for children who have acute lymphoblastic leukemia and have failed at least two prior therapies.  U.S. physicians may prescribe the drug for other patients, however, if they feel there is sufficient evidence to support such use.

In the current study, German researchers retrospectively analyzed data from 27 patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).  Their goal was to evaluate the effective­ness and safety of a combined Clolar-cytarabine regimen, followed by reduced-intensity preparative therapy prior to transplantation. Patients were treated during the period from May 2007 to October 2009. The median patient age was 58 years, and 22 percent were diagnosed with MDS.

Patients initially received five consecutive days of Clolar (30 mg/m²) and high-dose cytarabine (Cytosar-U) (1,000 mg/m²).  Cytarabine is a chemotherapy drug frequently used in the treatment of MDS.  It is chemically similar to Dacogen (decitabine) and Vidaza (azacitidine).

After five days of rest following treatment with Clolar and cytarabine, patients received reduced-intensity preparative therapy with total body irradiation, cyclophosphamide (Cytoxan), and antithymocyte globulin (ATG), followed by the transplant.

Patients also received cyclosporine (Sandimmune) and mycophenolate mofetil (Cellcept) for the prevention of graft-versus-host disease. Graft-versus-host disease is a common transplant-related complication in which the donated stem cells recognize the patient’s immune system as foreign material and attack it.

The median time for white blood cell and platelet recovery after transplantation was 16 days and 15 days, respectively.

At 30 days after the transplant, donor cell engraftment was 100 percent, which means that the donor stem cells produced healthy blood cells and none of the patient’s stem cells remained.

All patients who were alive 50 days after the transplant achieved a complete response.

At a median follow-up time of 36 months, the overall two-year survival rate was 56 percent. The two-year relapse-free survival rate was 52 percent.

All patients developed blood-related side effects after treatment with Clolar and cytarabine.  Fifty-five percent of patients developed skin-related side effects, which later disappeared without special treatment. Fifty-two percent of patients developed tissue swelling in the lower limbs after Clolar treatment, and three patients developed tissue swelling after receiving ATG.

Nearly all patients developed liver-related side effects, which in all cases but one resolved after Clolar treatment was completed. One patient developed severe liver side effects and died from multi-organ failure.

After transplant, 12 percent developed mild to moderate acute graft-versus-host disease, which occurs within 100 days of the transplant, and 26 percent developed chronic graft-versus-host disease, which occurs 100 days or longer after the transplant.

Nineteen percent of patients died due to disease relapse soon after transplant. Fifteen percent died from non-relapse causes  within 100 days of transplant. The non-relapse death rate increased to 35 percent two years after the transplant. Non-relapse causes of death included infections (22 percent), graft-versus-host disease (7 percent), bleeding (4 percent), and blood poisoning (4 percent).

For more information, please refer to the article in the European Journal of Haematology (abstract).

Based on their findings, the researchers conclude that umbilical cord blood transplantation with a mismatched donor is an effective treatment alternative if a matched donor for a bone marrow transplant is not available.

Furthermore, if transplantation is needed within a short time frame, the researchers recommended that umbilical cord blood transplantation be used over a mismatched bone marrow transplantation since little time is needed for an umbilical cord blood transplantation.

Stem cell transplantation is currently the only potentially curative treatment available for patients with myelodysplastic syndromes (MDS). In this procedure, a patient’s stem cells are destroyed with chemo­therapy or radiation and then replaced with stem cells from a healthy donor.

In order to increase the chances of a successful transplant, physicians search for a matched donor by comparing the genetic sequences for the human leukocyte antigen (HLA) of the recipient and potential donors. HLA is a cellular surface protein that plays a major role in the immune system’s identification of foreign materials.

According to the study authors, only 30 percent of transplant-eligible patients have a matched donor. In cases where an HLA-matched donor is unavailable, physicians frequently select a donor with a single HLA mismatch for the transplantation.

There are four protein variations of HLA: HLA A, B, C, and DRB1. A recent study showed that mismatches at HLA C and DRB1 result in the worst transplant outcomes (see related Beacon news).

Umbilical cord blood transplantation is increasingly being considered as an alternative to bone marrow transplantation for patients who cannot find a matched donor.

In the current study, Japanese researchers retrospectively analyzed data from 1,028 patients in Japan who underwent bone marrow transplantation and 351 patients who underwent umbilical cord blood trans­plan­tation to compare outcomes between the two procedures.

Of all the patients included in the analysis, 200 had MDS. The bone marrow transplants covered by the analysis took place between 2000 and 2005, while the umbilical cord blood transplants took place between 1996 and 2005.

The median age for patients who received umbilical cord blood transplants was slightly higher than that for patients who received bone marrow transplants (37 years versus 34 years).

The three-year survival rate for patients who received an umbilical cord blood transplant was 47 percent. This was similar to the three-year survival rate for patients who received single HLA-mismatched bone marrow transplants: 41 percent for mismatches at HLA DRB1 and 47 percent for mismatches at HLA A, B, or C. The survival rate for patients who received bone marrow transplants from donors with two HLA mis­matches was the lowest (38 percent).

Patients who received umbilical cord blood transplants had the slowest recovery of white blood cells and platelets. This, according to the Japanese researchers, is a major limitation of the umbilical cord blood procedure.

The researchers noted that several strategies have been investigated to speed up white blood cell recovery after transplantation, including screening patients for anti-HLA antibodies prior to transplantation, trans­plantation with two umbilical cord blood units, and direct injection of umbilical cord blood units into the bone marrow.

A common complication of stem cell transplants is graft-versus-host disease, in which the donor stem cells recognize the recipient’s immune system as foreign and attack it.

The rate of moderate to severe acute graft-versus-host disease was lowest in patients who received umbilical cord blood transplants (9 percent). By comparison, the rate in bone marrow recipients was 19 percent for mismatches at HLA DRB1, 18 percent for mismatches at HLA A, B, or C, and 22 percent for two HLA mismatches.

The researchers point out that the rates of acute graft-versus-host disease rates for umbilical cord blood transplants could actually have been even lower if it were not for the differences in preventative medication given to these patients. The majority of patients receiving umbilical cord blood transplants received cyclo­sporine A (Sandimmune), whereas the majority of patients receiving bone marrow transplants were given short-term methotrexate and Prograf (tacrolimus), which has been associated with reduced rates of severe acute graft-versus-host disease.

The risk of transplant-related death was also lower in patients who received umbilical cord blood trans­plants. The researchers speculated that the lower rates of acute graft-versus-host disease in patients who received umbilical cord blood transplants may have contributed to the decreased risk of transplant-related death.

For more information, please refer to the article in Biology of Blood and Marrow Transplantation (abstract).

The German regimen involves four days of treatment with fludarabine, amsacrine, and high-dose cytarabine followed, several days later, by a single high dose of melphalan.

The researchers investigating this regimen found that 97 percent of the patients who received it achieved complete remission within one month following their stem cell transplant.

Stem cell transplantation is currently the only potentially curative treatment available to patients with myelodysplastic syndromes (MDS).

In this procedure, patients first receive one or more drugs intended to either treat their MDS or kill off their existing stem cells, after which donor stem cells are transplanted into the patient.

Some patients also receive radiation therapy prior to transplant to help kill their existing stem cells.

There are differences of opinion, however, when it comes to what kind of preparative treatment should be used in MDS patients prior to stem cell transplantation.

In Europe, it is common for preparative treatment to include two types of therapies.

Initially, patients receive one or more rounds of “induction therapy,” which is intended to treat the patient’s MDS.  This therapy is continued until a patient’s MDS is in full or partial remission.

At that point, patients receive ”conditioning therapy,” which aims to kill off a patient’s existing stem cells.

In the U.S., physicians often skip induction therapy and instead go straight to conditioning therapy.  This approach shortens the time between diagnosis and transplant, which is considered important.

Previous research has shown that patients with higher-risk MDS experience the longest overall survival when transplants are performed soon after diagnosis.

In addition, higher-risk MDS patients often do not respond well to induction therapy, and they often get infections during induction therapy that can make them ineligible for a stem cell transplant.

An alternative approach to preparative therapy that is being explored is one that combines a brief round of induction therapy followed quickly by conditioning therapy and stem cell transplant.

One such approach that has been tried is a short induction regimen of fludarabine (Fludara), amsacrine (Amsidine), and high-dose cytarabine (Cytosar-U), followed by a conditioning regimen of low-dose total body irradiation and cyclophosphamide (Cytoxan) or busulfan (Busulfex).

According to the German authors of the current study, this quick sequential approach has shown promising results.

In the present study, the German researchers evaluated a modified version of the sequential regimen just described.  In their study, 30 previously untreated higher-risk MDS patients first received a four-day induction regimen of fludarabine, amsacrine, and high-dose cytarabine.

Then, to avoid the toxicity often seen with irradiation and cyclophosphamide or busulfan, the researchers used only high-dose melphalan (Alkeran), with or without thiotepa, as a conditioning regimen.

Following transplant, patients in the German study received granulocyte colony stimulating factor to stimulate the production of white blood cell counts. They also received Prograf (tacrolimus) and mycophenolate mofetil (Cellcept) to prevent graft-versus-host disease, a common transplant-related complication in which the donor stem cells recognize the patient’s immune system as foreign and attack it.

In addition, most of the 30 patients in the study received anti-thymocyte globulin (ATG)  for several days between induction and conditioning therapy to help prevent graft-versus-host-disease.

Patients received their transplants within a median of 134 days after diagnosis.

The German researchers found that all but one of the patients experienced improved blood cell counts after transplant. The median time for white blood cell and platelet recovery were 13 days and 17 days, respectively.

At 28 days after transplant, 97 percent of the patients were in complete remission.

At a median follow-up time of 28 months, 70 percent of patients were alive and disease-free.  Among those patients who received only melphalan during their conditioning regimen — as opposed to melphalan and thiotepa — 79 percent were alive and disease-free.

Thirteen percent of patients relapsed, but after receiving treatment with Vidaza (azacitidine) and white blood cell infusions, these patients are alive and disease-free.

Of the 30 patients included in the study, 73 percent experienced acute graft-versus-host disease, which develops within the first 100 days after the transplant; 63 percent of patients experienced chronic graft-versus-host disease, which occurs 100 days or longer after the transplant.

The most common severe, treatment-related complications were infections (53 percent), mouth ulcers (50 percent), and acute graft-versus-host disease (20 percent).

Thirty percent of patients died due to treatment-related complications. The researchers found that the risk of treatment-related death was related to the development of severe acute graft-versus-host disease.

Since the share of patients who died was particularly high among patients who received melphalan with thiotepa (67 percent), the study authors decided to remove thiotepa from the protocol early on in the trial.

For more information, please refer to the article in Biology of Blood and Marrow Transplantation (abstract).

Specifically, the study authors found that patients who matched their donors in the gene HLA C had a decreased risk of death compared to patients who did not match their donors in that gene.

Based on their findings, the study authors suggest that the current donor matching system should include matching at HLA C in order to minimize the risk of transplant-related death.

“When searching for an umbilical cord blood unit for transplantation, consider matching the unit and patient. If these [matching] units are unavailable, consider matching at HLA C and HLA DRB1. Having a mismatch at HLA C and HLA DRB1 had the worst outcome,” said the study’s lead author, Dr. Mary Eapen of the Medical College of Wisconsin.

Umbilical cord blood transplantation has recently been developed as a popular alternative to stem cell transplantation for patients with myelodysplastic syndromes (MDS) and other types of blood cancers who cannot find a matched donor.

“Not everybody has a fully matched donor,” explained Dr. Eapen.  “Most physicians look for a matched adult unrelated donor if there isn’t a matched family donor.  If a matched adult unrelated donor is not available, then they look for a cord blood unit.” 

In order to determine a matched donor for a stem cell recipient, physicians compare the genetic sequence for a cell surface protein called the human leukocyte antigen (HLA). This protein helps the immune system tell the difference between the body’s own tissues and foreign substances.

Previous research has shown that patients who undergo stem cell transplantation with an HLA-mismatched donor experience more serious transplant-related complications and are at a higher risk of death.

The authors of the current study found in earlier research that umbilical cord blood transplantation with an HLA-mismatched donor produces similar leukemia-free survival rates but is associated with more transplant-related deaths, compared to stem cell transplantation with an HLA-matched donor.

In order to decrease the high transplant-related death rate associated with umbilical cord blood transplantation, researchers are currently investigating the impact of improving matching between donor and recipient. The screening process for selecting a donor currently does not include matching at HLA C, one of the major classes of HLA proteins.

In the current study, researchers evaluated the impact of donor matching at HLA C on outcomes after umbilical cord blood transplantation. They retrospectively analyzed data from 803 patients with various forms of blood cancers, of which 9 percent had MDS. Ten percent were older than 41 years old.

Of the 803 patients included in the study, 9 percent had a donor matched at all four protein variations, HLA A, B, C, and DRB1. This population had a three-year transplant-death probability of 9 percent.

The rate of transplant-related death increased significantly with HLA C mismatching. In total, 68 percent of patients had a donor mismatched at protein HLA C. The three-year transplant-death probability for patients with no other mismatches besides HLA C was 26 percent. This probability increased to 31 percent for patients with one other mismatch besides HLA C.

Patients who underwent transplantation with an HLA C-mismatched donor also more commonly experienced graft failure, infections, and organ failure.

The three-year overall survival probability was 51 percent for patients with HLA C matched but another HLA class mismatched. This probability decreased to 37 percent for patients with HLA C mismatched and another HLA class mismatched.

The researchers found that the probability of overall survival improved with transplantation at an earlier disease stage and with younger patient age.

For more information, please refer to the article in The Lancet Oncology (abstract).

The researchers suggest that this approach be applied if a matched donor is not available or patients are unable to undergo preparative therapy at full intensity.

However, they also point out that further studies are needed in other ethnicities because their study included only Korean patients, who tend to have similar genetic makeup and experience fewer cases of graft-versus-host disease, a transplant-related complication in which the donor cells recognize the patient’s cells as foreign and attack them.

Stem cell transplantation from a matched donor may serve as a curative procedure for patients with myelodysplastic syndromes (MDS).

Physicians determine matched donors for stem cell recipients by comparing the genetic sequences for the human leukocyte antigen (HLA), a protein on the cellular surface that presents foreign materials to white blood cells in the immune system.

Previous research has shown that the rate of unsuccessful transplants increases as the number of HLA mismatches increases between the donor and the recipient.  In addition, transplantation with a mismatched donor may lead to serious complications, such as graft-versus-host disease, delayed recovery of the immune system, and transplant-related death.

According to the study authors, an HLA-matched donor exists for only 60 percent of patients who need a transplant. For certain minorities, this percentage is even lower.

The Korean researchers previously found that stem cell transplants with partially mismatched donors were successful in patients with MDS and acute myeloid leukemia after reduced-intensity preparative therapy with busulfan (Busulfex), fludarabine (Fludara), and anti-thymocyte globulin (ATG).

Based on these results, the researchers extended the trial by 53 additional patients and published their results based on data from a total of 83 patients.

After receiving reduced-intensity preparative therapy, patients in the Korean study underwent stem cell transplantation with partially mismatched donors.

Initial donor cell engraftment, a sign that the donated stem cells are reproducing and making new blood cells in the patient’s body, occurred in 92 percent of patients at a median of 13.5 days after transplant. The remaining 8 percent experienced disease progression.

At two weeks after transplant, 78 percent of patients had donor stem cells make up more than 90 percent of their total stem cells, which, besides donor cell engraftment, is another sign of a successful transplant. 

At a median follow-up time of 27 months, 53 percent of MDS patients were alive and disease free.

According to the researchers, the reduced-intensity conditioning therapy was well tolerated. The most serious side effects included diarrhea (19 percent), nausea/vomiting (10 percent), and mouth inflammation and ulcers (5 percent). Twenty-four percent of patients experienced acute graft-versus-host disease, which develops within 100 days after the transplant, and 34 percent experienced chronic graft-versus-host disease, which occurs 100 days or longer after transplant.

Eighteen percent of patients died due to transplant-relapsed causes, which the study authors attributed mostly to infections.

For more information, please refer to the article in the journal Blood (abstract).

“The study’s biggest implication is that we may choose a best bone marrow donor using granzyme B [genetic] analysis of donor candidates,” said the study’s lead author, Dr. Akiyoshi Takami of Kanazawa University in Japan.

However, since the study was small, Dr. Takami and his colleagues pointed out that additional studies are needed to confirm their findings.

Stem cell transplantation is currently the only potentially curative therapy for patients with myelodysplastic syndromes (MDS). In this procedure, chemotherapy or radiation destroys the patient’s stem cells, which are later replaced by stem cells from a matched donor. In most cases, the donor is a close relative; however, donors can also be unrelated if no close relatives are a match.

Granzyme B, an enzyme that breaks down proteins, plays a key role in cell death. Stored by certain types of white blood cells known as cytotoxic T cells and natural killer cells, granzyme B is released upon recognition of a target cell and induces cell death.

Previous research has shown that certain variants of the granzyme B gene are incapable of inducing cell death, which may negatively impact outcomes after transplantation.

In the present study, Japanese researchers compared transplant outcomes for patients with mutations of the granzyme B gene to determine their effects on outcome after transplantation.

They determined the genetic makeup of the granzyme B gene for 613 patients with various forms of blood cancer. Eighteen percent of the study participants had MDS. The median patient age was 36 years.

Genes can have various mutations. In this study, the researchers looked at one common mutation in the granzyme B gene.  The natural form of the gene is designated by the letter A, and the mutated form is designated by the letter G.  Since every individual has two copies of the gene, patients could have two copies of the natural granzyme B gene, notated as A/A, or at least one mutated form, notated as A/G or G/G.

Of the 613 patients included in the analysis, 38 percent of the patients had mutant granzyme B (G/G – 5 percent, A/G – 33 percent). Similarly, 36 percent of the donors had the mutated granzyme B gene (G/G – 4 percent, A/G – 32 percent).

For patients with acute myeloid leukemia (AML) or MDS, the five-year overall survival was significantly higher if the patients had the G/G or A/G genetic makeup compared to those who had the A/A makeup (52 percent versus 46 percent).

Five-year overall survival was also longer for patients who received cells from donors with G/G or A/G genetic makeup compared to those who received cells from donors with A/A genetic makeup (58 percent versus 42 percent, respectively).

In addition, the five-year relapse rate was lower for patients who received cells from donors with G/G or A/G genetic makeup compared to those with A/A genetic makeup (27 percent versus 37 percent).

The researchers did not observe any significant differences in the frequency of transplant-related deaths and the rates of acute and chronic graft-versus-host disease based on the genetic makeup.

According to the study authors, these results do not support the assumption that variants of granzyme B are unable to kill target cells. They suggested that the variants possess different biochemical properties that may be responsible for the improved transplant outcomes in AML and MDS patients.

For more information, please refer to the study in PLoS ONE.