Looking Beyond Common Causes of Renal Dysfunction: Renal GVHD and Thrombotic Microangiopathy after Allogeneic Transplant

Thrombotic Microangiopathy in Patients with Allogeneic Hematopoietic Stem Cell Transplantation

Chronic Kidney Disease, Thrombotic Microangiopathy, and Hypertension Following T Cell-Depleted Hematopoietic Stem Cell Transplantation

EBMT Risk Score Predicts Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients Who Have Failed a Previous Transplantation Procedure

Improved Outcomes Using Tacrolimus/Sirolimus for Graft-versus-Host Disease Prophylaxis with a Reduced-Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplant as treatment of Myelofibrosis

Background Transplantation-associated thrombotic microangiopathy (TMA) is a feared complication of allogeneic hematopoietic stem cell transplantation (HSCT) owing to its high rate of mortality. The use of calcineurin inhibitors or sirolimus for graft-versus-host disease (GVHD) prophylaxis has been suggested as a potential risk factor. Purpose To analyse the incidence of TMA in patients undergoing HSCT who received ciclosporin as prophylaxis against GVHD; to investigate the cause of this phenomenon. Material and methods Retrospective observational study that reviewed the medical records of patients who had suffered from TMA after allogeneic HSCT in the haematology service of a tertiary hospital from 2010 to 2014. To obtain the results, the diagnostic criteria associating TMA with the bone marrow transplant of the International Working Group were measured. Results Of the 50 patients undergoing allogeneic HSCT, 10 suffered ciclosporin-associated TMA. In 4 TMA emerged with the addition of ciclosporin to sirolimus and in 6 when sirolimus was added to ciclosporin. The reason for the addition of these immunosuppressants was acute GVHD in 3 patients and in 7 due to chronic GVHD. The response to TMA was to suspend ciclosporin and maintain sirolimus and corticosteroids in 4 patients whereas in 6 both ciclosporin and sirolimus were suspended. In 4 patients phenytoin was added, in 2 haemodialysis was performed, in 3 plasmapheresis was done and in 1 rituximab was administered. In all the cases the duration of active levels of basal ciclosporin after it had been suspended was about two or four months. Conclusion The appearance of TMA in patients undergoing allogeneic HSCT is a concern. All cases present moderate to severe haemolytic anaemia, negative direct Coombs, thrombocytopenia, elevated LDH and creatinine, schistocytes >4% and kidney disorders. The cause of the sustained increase in the time of ciclosporin levels is still unknown, it is thought that an ABCB1 genetic polymorphism can produce this phenomenon. References and/or acknowledgements Pharmacogenetics No conflict of interest.

Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Thérapie Cellulaire

Impact of anti-HLA antibodies on allogeneic hematopoietic stem cell transplantation outcomes after reduced-intensity conditioning regimens

In March 2009, a 17-year-old woman was first diagnosed with acute myelogenous leukemia and myelodysplasia-related changes. She underwent chemotherapy and allogeneic hematopoietic stem cell transplantation, which resulted in complete remission. However, she experienced relapse, and remission was achieved each time with repeated transplantation. In September 2014, a human leukocyte antigen (HLA)-haploidentical transplantation, which was the fifth allogeneic transplantation, was performed to treat the third relapse. Platelet transfusion refractoriness, hemolytic anemia with schistocytes, and renal dysfunction were observed from approximately the day of engraftment; therefore, transplantation-associated thrombotic microangiopathy (TA-TMA) was diagnosed. Recombinant human soluble thrombomodulin (rTM) was administered, and fresh-frozen plasma (FFP) was infused; this resulted in gradual improvement of TA-TMA. Treatment with rTM and FFP was discontinued on the 70th day after transplantation. Because the HLA-haploidentical transplantation was the fifth allogeneic transplantation, the risk of aggravation of TA-TMA was very high. Combined treatment with rTM and FFP, however, resulted in improvement of TA-TMA. Further investigation of similar cases is necessary for clarifying the usefulness of rTM for TA-TMA.

The lack of an accepted definition of transplantation-associated thrombotic microangiopathy (TMA) has led the Blood and Marrow Transplants Clinical Trials Network (CTN) and International Working Group (IWG) to propose a definition for TMA with some differences. However, there have been few studies validating and comparing both newly proposed criteria for TMA. To validate recently proposed criteria for TMA by CTN and IWG, we analyzed 672 patients who underwent allogeneic stem-cell transplantation between January 2002 and December 2006. The cumulative incidences of TMA by CTN and IWG were 6.1% and 2.5%, respectively. The cumulative incidence of overall TMA (O-TMA) including probable-TMA defined as meeting CTN criteria without renal or neurologic dysfunction, as well as TMA by CTN (definite-TMA), was 12.7%. Sixty-six percent of TMA by CTN did not have any degree of schistocytosis by IWG criteria (≥4%), and 18% of TMA by IWG criteria did not have renal or neurologic dysfunction. On multivariate analyses, probable-TMA as well as definite-TMA adversely affected the survival of a cohort including all patients. In patients with O-TMA, the degree of schistocytosis (≥4% or not) failed to show prognostic significance, whereas renal involvement was a significant prognostic factor associated with poor survival. Both proposed consensus criteria have major pitfalls in their use as uniformly accepted diagnostic criteria for TMA. The use of O-TMA as a broad definition for TMA and the grading system by the presence of renal involvement may be a counterproposal for future trials.

The prevalence and clinical outcomes of microangiopathic hemolytic anemia in patients with biopsy-proven renal thrombotic microangiopathy.

Risk Factors and the Therapeutic Efficacy for Thrombotic Microangiopathy in Patients after Allogeneic Hematopoietic Stem Cell Transplantation - Results of the Multicenter Retrospective Cohort Study

Successful Reduced-Intensity Conditioning Allogeneic HSCT For HIV-Related Primary Effusion Lymphoma

We have previously reported that pre-transplant use of tyrosine kinase inhibitors (TKIs) is independently associated with the occurrence of transplant-associated thrombotic microangiopathy (TA-TMA). However, the precise TKI-related factors which predispose to TA-TMA are unknown. In this retrospective analysis, we identify the TKI-related factors that are associated with TA-TMA. This was a single center retrospective analysis of all patients with Philadelphia chromosome-positive (Ph+) malignancies who received BCR-ABL TKIs prior to transplant and underwent allogeneic hematopoietic stem cell transplantation (HSCT) between January 2008 and March 2019. Definite TA-TMA was defined as per Blood & Marrow Transplant Clinical Trials Network (BMT CTN) criteria and probable TMA as per Cho criteria. Details about the timing of the start and stop of TKI pre-transplant, the dose of TKIs used, and the number of TKIs exposed to pre-transplant were obtained. Imatinib > 400 mg/day, dasatinib > 100 mg/day, or nilotinib > 800 mg/day were considered as high dose TKI. Seventy-two patients with chronic myeloid leukemia (CML)/Ph+ acute leukemias underwent transplant in the above period. Patient, donor, and transplant characteristics are shown in Table 1 and were well-matched between those with and without TMA. Overall, 13 (18%) had TA-TMA (median day +128), with 9 definite and 4 probable. The only TKI-related factor significantly associated with TA-TMA was the use of high-dose TKI (p=0.04). Among non-TKI-related factors, acute graft versus host disease (GVHD) was associated with TA-TMA (p=0.01). On multivariate analysis, high dose TKI did not remain statistically significant (Odds Ratio (OR) 4.6, p=0.16). TA-TMA was associated with significantly worse long-term survival (6-year survival was 30% with TMA versus 62% without TMA, p=0.026). Pre-transplant use of TKI was associated with risk of TMA in about one-fifth of patients. High-dose TKI and acute GVHD increased the risk of TA-TMA. Prospective studies are warranted to confirm these findings. TA-TMA was associated with significantly worse long-term survival.

Transplant Associated Thrombotic Microangiopathy: Acomprehensive Review and Local Experience

A Pilot Trial of Pre-Transplant Risk Stratification and Prophylactic Defibrotide to Prevent Serious Thrombotic Microangiopathy in High-Risk Pediatric Hematopoietic Stem Cell Transplant Patients