Natasha Kekre

Hematopoietic stem cell transplantation donor sources in the 21st century: choosing the ideal donor when a perfect match does not exist

Most patients who require allogeneic stem cell transplantation do not have a matched sibling donor, and many patients do not have a matched unrelated donor. In an effort to increase the applicability of transplantation, alternative donors such as mismatched adult unrelated donors, haploidentical related donors, and umbilical cord blood stem cell products are frequently used when a well matched donor is unavailable. We do not yet have the benefit of randomized trials comparing alternative donor stem cell sources to inform the choice of donor; however, the existing data allow some inferences to be made on the basis of existing observational and phase 2 studies. All 3 alternative donor sources can provide effective lymphohematopoietic reconstitution, but time to engraftment, graft failure rate, graft-versus-host disease, transplant-related mortality, and relapse risk vary by donor source. These factors all contribute to survival outcomes and an understanding of them should help guide clinicians when choosing among alternative donor sources when a matched related or matched unrelated donor is not available.

Is Cytomegalovirus Testing of Blood Products Still Needed for Hematopoietic Stem Cell Transplant Recipients in the Era of Universal Leukoreduction

Hematopoietic stem cell transplantation (HSCT) recipients are a high-risk, immunocompromised group of patients who receive frequent transfusions after transplantation. Transfusion of cytomegalovirus (CMV)-negative blood products has long been the standard of care to prevent transfusion-transmitted CMV in this patient population. Leukoreduction of blood products before transfusion has been shown to significantly reduce the risk of transfusion-transmitted CMV. In the era of universal leukoreduction in Canada, the need for CMV testing of blood products remains unclear. We sought to identify whether there is a difference in transfusion-transmitted CMV viremia in patients receiving only leukoreduced versus CMV-negative and leukoreduced blood products in HSCT recipients. Patients who were CMV negative and received an allogeneic HSCT from a CMV-negative donor between October 1, 1999 and June 30, 2012 were included in the analysis. Transfusion data were collected from The Ottawa Hospital Blood Bank and Canadian Blood Services. CMV viremia was defined as PCR positivity. One hundred sixty-six patients were identified who met the inclusion criteria. Of these, 89 patients received an HSCT before January 2007, during the time when patients received leukoreduced and CMV-negative blood products. Seventy-seven patients received an HSCT after this time, receiving only leukoreduced blood products. The 2 groups did not differ in terms of age, gender, diagnosis, graft type, graft source, conditioning regimen, or ABO compatibility (P > .05). CMV viremia was detected in 3 patients who received CMV-negative leukoreduced blood products (3.37%) and in 1 patient who received only leukoreduced blood products (1.30%, P = .6244). Of the patients who developed CMV viremia, 2 developed suspected CMV disease. Both of these patients were transfused with CMV-negative blood products. Secondary outcomes, including total length of stay in hospital, admission to the intensive care unit, acute and chronic graft versus host disease, and 100-day nonrelapse mortality, did not differ between the groups. In the era of universal leukoreduction of blood products, this study demonstrates that testing for CMV-negative blood products is not needed for HSCT recipients.

The Impact of Prolonged Storage of Red Blood Cells on Cancer Survival

Background The duration of storage of transfused red blood cells (RBC) has been associated with poor clinical outcomes in some studies. We sought to establish whether prolonged storage of transfused RBC in cancer patients influences overall survival (OS) or cancer recurrence. Methods and Findings Patients diagnosed with cancer at The Ottawa Regional Cancer Centre between January 01, 2000 and December 31, 2005 were included (n = 27,591) where 1,929 (7.0%) received RBC transfusions within one year from diagnosis. Transfused RBC units were categorized as “new” if stored for less than 14 days, “intermediate” if stored between 14 and 28 days and “old” if stored for more than 28 days. Baseline characteristics between the comparative groups were compared by ANOVA test. Categorical variables and continuous variables were compared using Chi-squared and Wilcoxan rank-sum tests respectively. Overall survival was not associated with duration of storage of transfused RBC with a median survival of 1.2, 1.7, 1.1 years for only new, intermediate and old RBC units respectively (p = 0.36). Cancer recurrence was significantly higher in patients who received a RBC transfusion than those who did not (56.3% vs 33.0% respectively; p<0.0001) but was not affected by the duration of storage of transfused RBC (p = 0.06). In multivariate analysis, lung cancer, advanced stage, chemotherapy, radiation, cancer-related surgery and cancer recurrence were associated with inferior OS (p<0.05), while age, advanced stage, lung cancer, and more than 6 units of blood transfused were associated with cancer recurrence (p<0.05). The duration of storage of RBC before transfusion was not associated with OS or cancer recurrence in multivariate analysis. Conclusion In patients diagnosed with cancer, the duration of storage of transfused RBC had no impact on OS or cancer recurrence. This suggests that our current RBC storage policy of providing RBC of variable duration of storage for patients with malignancy is safe.

Storage time of transfused red blood cells and impact on clinical outcomes in hematopoietic stem cell transplantation.

BACKGROUND: Red blood cell (RBC) transfusion may prolong recovery in some patients, perhaps due to changes that occur during more prolonged RBC storage. We examined the impact of RBC transfusion and the age of transfused RBC units on clinical outcomes in hematopoietic stem cell transplantation (HSCT).

Infused total nucleated cell dose is a better predictor of transplant outcomes than CD34+ cell number in reduced-intensity mobilized peripheral blood allogeneic hematopoietic cell transplantation.

Mobilized peripheral blood is the most common graft source for allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning. In assessing the effect of donor cell dose and graft composition on major transplant outcomes in the reduced-intensity setting, prior studies focused primarily on CD34+ cell dose and reported conflicting results, especially in relation to survival end-points. While the impact of total nucleated cell dose has been less frequently evaluated, available studies suggest higher total nucleated cell dose is associated with improved survival outcomes in the reduced-intensity setting. In order to further explore the relationship between CD34+ cell dose and total nucleated cell dose on reduced-intensity transplant outcomes, we analyzed the effect of donor graft dose and composition on outcomes of 705 patients with hematologic malignancies who underwent reduced-intensity peripheral blood stem cell transplantation at the Dana Farber Cancer Institute from 2000 to 2010. By multivariable analysis we found that higher total nucleated cell dose (top quartile; ≥10.8 × 1010 cells) was associated with improved overall survival [HR 0.69 (0.54–0.88), P=0.0028] and progression-free survival [HR 0.68 (0.54–0.85), P=0.0006]. Higher total nucleated cell dose was independently associated with decreased relapse [HR 0.66 (0.51–0.85), P=0.0012] and increased incidence of chronic graft-versus-host disease [HR 1.4 (1.12–1.77), P=0.0032]. In contrast, higher doses of CD34+ cells (top quartile; ≥10.9 × 106/kg) had no significant effect on graft-versus-host disease or survival outcomes. These data suggest total nucleated cell dose is a more relevant prognostic variable for reduced-intensity transplant outcomes than the more commonly studied CD34+ cell dose.

Novel strategies to prevent relapse after allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia and myelodysplastic syndromes.

Purpose of reviewRelapse of haematological neoplasms after allogeneic haematopoietic stem cell transplantation (HSCT) remains one of the leading causes of death. Treatment of relapse post-HSCT is frequently ineffective and outcomes are poor, necessitating preventive strategies that are reviewed below. Recent findingsCurrent strategies to prevent relapse after HSCT are geared towards four general principles: improving the antitumour effects of conditioning regimens prior to HSCT, improving graft selection and engineering to augment the graft-versus-leukaemia effect, post-HSCT chemotherapeutic interventions to impair growth of residual clonal cells and post-HSCT immune-mediated interventions to enhance the graft-versus-leukaemia effect. Strategies based on cell manipulation, namely natural killer (NK) cell enrichment and adoptive T cell transfer, are emerging. Targeted therapies including vaccinations, FLT3 inhibitors, mAbs and chimeric antigen receptor T cell therapy represent a new avenue of treating acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Studies are underway to incorporate all of these strategies in the clinical setting to determine their impact on relapse and survival after HSCT. SummaryThe most recent evidence suggests that strategies using NK cell therapy and targeted immune therapies after HSCT may change the current landscape of HSCT for AML and MDS.

Effect of antithymocyte globulin source on outcomes of bone marrow transplantation for severe aplastic anemia

For treatment of severe aplastic anemia, immunosuppressive therapy with horse antithymocyte globulin results in superior response and survival compared with rabbit antithymocyte globulin. This relative benefit may be different in the setting of transplantation as rabbit antithymocyte globulin results in more profound immunosuppression. We analyzed 833 severe aplastic anemia transplants between 2008 and 2013 using human leukocyte antigen (HLA)-matched siblings (n=546) or unrelated donors (n=287) who received antithymocyte globulin as part of their conditioning regimen and bone marrow graft. There were no differences in hematopoietic recovery by type of antithymocyte globulin. Among recipients of HLA-matched sibling transplants, day 100 incidence of acute (17% versus 6%, P<0.001) and chronic (20% versus 9%, P<0.001) graft-versus-host disease were higher with horse compared to rabbit antithymocyte globulin. There were no differences in 3-year overall survival, 87% and 92%, P=0.76, respectively. Among recipients of unrelated donor transplants, acute graft-versus-host disease was also higher with horse compared to rabbit antithymocyte globulin (42% versus 23%, P<0.001) but not chronic graft-versus-host disease (38% versus 32%, P=0.35). Survival was lower with horse antithymocyte globulin after unrelated donor transplantation, 75% versus 83%, P=0.02. These data support the use of rabbit antithymocyte globulin for bone marrow transplant conditioning for severe aplastic anemia.

Cord blood versus haploidentical stem cell transplantation for hematological malignancies

Umbilical cord blood (UCB) and haploidentical donor stem cell sources represent common alternative donor strategies used when a matched sibling donor (MRD) or matched unrelated donor (MUD) is not available for hematopoietic stem cell transplantation (HSCT). Both donor sources require less stringent human leukocyte antigen (HLA) matching and thereby increase the donor pool for patients without a complete HLA-matched donor. Although a randomized trial comparing these donor sources is ongoing, currently available comparisons rely on observational data and small phase II trials. In hematologic malignancies, both donor sources offer the chance of eradicating disease, albeit with different results for engraftment time, graft failure, graft-versus-host disease (GVHD), transplant-related mortality (TRM), and relapse risk. This review focuses on comparing those outcomes and providing clinicians with evidence to help guide the decision between these alternative donor sources.

Impact of platelet transfusion on toxicity and mortality after hematopoietic progenitor cell transplantation

Thrombocytopenia occurs commonly after hematopoietic progenitor cell transplantation (HPCT) and is associated with potential morbidity and mortality. Few studies have examined the impact of platelet (PLT) transfusion on clinical outcomes in HPCT while optimal PLT transfusion strategies after HSCT remain uncertain.

Fludarabine/Busulfan versus Fludarabine/Melphalan Conditioning in Patients Undergoing Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation for Lymphoma

There is at present little data to guide the choice of conditioning for patients with lymphoma undergoing reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT). In this study, we compared the outcomes of patients undergoing RIC SCT who received fludarabine and melphalan (FluMel), the standard RIC regimen used by the Spanish Group of Transplantation, and fludarabine and busulfan (FluBu), the standard RIC regimen used by the Dana-Farber Cancer Institute/Brigham and Womens Hospital. We analyzed 136 patients undergoing RIC SCT for lymphoma with either FluBu (n = 61) or FluMel (n = 75) conditioning between 2007 and 2014. Median follow-up was 36 months. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 13% with FluBu and 36% with FluMel (P = .002). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 3.3% with FluBu and 31% with FluMel (P < .0001). The cumulative incidence of relapse at 1 year was 29% with FluBu and 10% with FluMel (P = .08). The 3-year disease-free survival rate was 47% with FluBu and 36% with FluMel (P = .24), and the 3-year overall survival rate was 62% with FluBu and 48% with FluMel (P = .01). In multivariable analysis, FluMel was associated with a higher risk of acute grades II to IV GVHD (HR, 7.45; 95% CI, 2.30 to 24.17; P = .001) and higher risk of NRM (HR, 4.87; 95% CI, 1.36 to 17.44; P = .015). The type of conditioning was not significantly associated with relapse or disease-free survival in multivariable models. However, conditioning regimen was the only factor significantly associated with overall survival: FluMel conditioning was associated with a hazard ratio for death of 2.78 (95% CI, 1.23 to 6.27; P = .014) compared with FluBu. In conclusion, the use of FluBu as conditioning for patients undergoing SCT for lymphoma was associated with a lower risk of acute GVHD and NRM and improved overall survival when compared with FluMel in our retrospective study. These results confirm the differences between these RIC regimens in terms of toxicity and efficacy and support the need for comparative prospective studies.