The measurement of whole blood pre-treatment cyclosporine A: metabolite ratios predicts the onset of renal dysfunction in recipients of allogeneic stem cell transplantation

Abstract Introduction: After allogeneic stem cell transplantation (allo-SCT), engraftment can be assessed by quantitative polymerase chain reaction (qPCR) using differing donor/recipient markers (Alizadeh et al. Blood, 2002), identified in peripheral blood DNA cells before transplant. We report here on the concomitant examination of the proportions of donor and recipient DNA in peripheral whole blood (WB) and sorted CD3+ T-cells on days +60 and +90, looking at their impact on survival. Patients, material and methods: This monocentric study evaluated the impact on outcomes of early WB and sorted CD3+ T cells chimerism independently and of the four possible combinations of chimerism between WB and sorted CD3+ T-cells. All follow-up chimerism samples from allo-SCT patients performed in adults at Nantes University Hospital between October 2009 and October 2016 were reviewed, focusing on those where both PB and/or CD3+ T-cells were evaluated on days +60 (45-75) and/or +90 (75-120) after allo-SCT. A global cohort of 229 patients (239 grafts) was retrieved, which includes 52 patients evaluable on day +60 only, 67 evaluable on day +90 only and 120 evaluable on both days +60 and +90. A threshold of >95% donor DNA was considered for complete chimerism. Disease free survival (DFS) was calculated from the date of graft until relapse, death or last follow-up. Overall survival (OS) was calculated from the date of graft until death or last follow-up. Chi square tests were used to compare incidences. Log rang test and Kaplan Meier were used to evaluate DFS and OS. Results: The whole cohort comprised 62% males and had a median age of 58 years old (20-74) at the time of allo-SCT. Patients were treated for myeloid-lineage disease in 59% of the cases. Reduced-intensity conditioning was used in 89% (n=212), donors were familial in 45% (n=107), registry in 48% (n=114). Unrelated cord blood units were used in 8% of the cases (n=18). Post-transplant cyclophosphamide (PTCY) was performed in 48 procedures including 33 and 15 with haplo (HG) and matched donors respectively. Considering the 239 allograft procedures, the median follow-up was 5.8 years (95% CI: 3.1-5.8), the rate of relapse 27% and the rate of death 31%. Complete WB chimerism was observed for 80% and 71% of the cases on day +60 and day +90 respectively. Complete CD3+ chimerism was present for 53% and 51% of the grafts at days +30 and +90 respectively. Thus, cases displaying both complete WB and CD3+ chimerism on days +60 and +90 were 53% and 51% respectively, while 27% and 20% were documented with full WB and mixed CD3+ chimerism on days +60 and +90. Mixed chimerism was observed in both WB and CD3+ cells in 14% of the cases on day +60 and 22% on day +90. Finally, a small proportion of patients (6% and 7% at days +60 and +90) displayed an intriguing complete chimerism in CD3+ cells yet mixed WB chimerism. None of these features appeared associated to disease lineage (lymphoid or myeloid) nor cord blood allo-SCT. Interestingly, of the 27 grafts with myeloablative conditioning, only 14 had full WB/CD3+ engraftment on day +60 or +90, and thus all 27 were retained for the study. None of the four WB/CD3 chimerism combinations at the two times considered had an impact on DFS in this cohort. Surprisingly, although full or mixed WB chimerism had no impact on DFS and OS at days +60 and +90, the presence of a mixed CD3+ chimerism (vs full) at day+90 was associated with a significantly better OS (median: 5.8 months years [95%CI: -not reached] versus 3.1 years [95%CI: 2.2- 3.1]; p=0.025). CD3+ chimerism at day+60 has no impact on OS. All HG resulted in full CD3+ chimerism at both time points compared to non HG (100% vs 52%, p<0.0001). The same was almost true when considering PTCY procedures: 90% at day+60 and 92% at day +90. Of note, there was no influence on DFS nor OS of WB or CD3+ chimerism status when considering only HG or PTCY grafts vs others in this series. Discussion: In this large series, early WB chimerism status did not predict outcome. Surprisingly, mixed CD3+ chimerism at day+90 appears to be significantly associated with a longer OS, suggesting that remaining recipient memory lymphocytes could be beneficial. This result has to be confirmed prospectively. It remains also to define the place of donor lymphocyte infusions (DLI) to prevent relapse in patients with full or mixed CD3+ chimerism post-transplant (analyses of DLI received in our patients are on-going). Disclosures Moreau: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria.

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Renal dysfunction after allogeneic stem cell transplantation: Risk factors and outcome

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2005.11.110 ◽

2006 ◽

Vol 12 (2) ◽

pp. 35-36

Author(s):

K. Oshima ◽

Y. Kanda ◽

H. Sato ◽

T. Watanabe ◽

N. Hosoya ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Renal Dysfunction ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation

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Comparison of Cyclosporine A and Mycophenolate Mofetil vs Cyclosporine A and Methotrexate in Reduced Intensity Conditioning HLA Sibling Allogeneic Stem Cell Transplantation. A Case-Match Single-Center Experience.

Blood ◽

10.1182/blood.v110.11.4994.4994 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4994-4994

Author(s):

Jose L. Piñana ◽

David Valcárcel ◽

Rodrigo Martino ◽

Rocio Parody ◽

Anna Sureda ◽

...

Keyword(s):

Stem Cell ◽

Mycophenolate Mofetil ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Cyclosporine A ◽

Allogeneic Stem Cell Transplantation ◽

Chronic Gvhd ◽

Reduced Intensity Conditioning ◽

Gvhd Prophylaxis ◽

Reduced Intensity

Abstract BACKGROUND: Graft-versus-host disease (GVHD) is the major obstacle to successful allogeneic stem cell transplantation (SCT) transplantation. Cyclosporine (Csa) in combination with methotrexate (MTX) is the most commonly used prophylactic regimen. The combination of CsA and Mycophenolate Mofetil (MMF) has recently been introduced. In this case-match study we retrospectively analyzed the introduction of MMF as GVHD prophylaxis in comparison with a short course of MTX in the setting of reduced intensity conditioning allogeneic SCT (Alo-RIC). PATIENTS AND METHODS: We analyzed 59 Alo-RIC recipients who received an Alo-HSCT from an HLA-identical sibling between April 2000 and June 2006. The median follow-up for the whole group was 473 days (8 to 2139 days). The study group included 40 males and 19 females. Median age was 59 years (range 43 to 72). Diagnoses were acute leukemia/myelodisplastic syndrome) (n=19/22), mutiple myeloma (n= 6), chronic myeloid leukemia (n=5) and non- Hodgkin lymphoma (NHL) (n= 4). GVHD prophylaxis consisted of Csa/MTX (MTX group) in 37 patients and Csa/MMF (MMF group) in 22 patients. The conditioning regimen was based on fludarabine in combination with busulfan (42 recipients) or melfalan (17 cases). RESULTS: The occurrence of mucositis grade 2–4 was higher in the MTX group than in the MMF group (62% vs 28% p= 0.015). No significant differences were found between MMF vs MTX groups in time to neutrophil recovery (16 +/−3 days vs 15 +/− 2days) (p= 0.5). Median time to the achievement of complete T-cell donor chimerism in the MTX and MMF groups was 79 days (range 19–740) and 76 days (range 24–223) respectively (P=0.4). The 1- year non-relapse mortality was similar in MTX and MMF groups 14% (95% C.L. 6–31%) vs 28% (95% C.L. 13–60%) respectively; P=0.2. Cumulate incidence of acute GVHD for MTX and MMF groups was 49% (95% C.L. 35–68%) and 68% (95% C.L. 51–91%) respectively (P= 0.6). Patients in the MTX group showed a trend to a higher incidence of chronic GVHD than the Csa/MMF group, 55% (95% C.L. 40–74%) vs 42% (95% C.L. 23–75%) (P=0.2). No differences were found between MTX vs MMF groups in 1-year overall survival [78%(64–92%) vs 53%(38–76%); P=0.1] nor in 1-year relapse incidence [37% (95%CI 21–64%) vs 19% (95%CI 10–37%) P=0.1) We conclude that the Csa/MMF combination appears to be equivalent to the standard Csa/MTX aGVHD prophylaxis in Alo-RIC. MMF showed significantly less mucositis.

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Pre-Transplant Predictors and Post-Transplant Sequels of Acute Kidney Injury After Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v116.21.4515.4515 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4515-4515

Author(s):

Yuki Kagoya ◽

Keisuke Kataoka ◽

Yasuhito Nannya ◽

Mineo Kurokawa

Keyword(s):

Acute Kidney Injury ◽

Multivariate Analysis ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Renal Dysfunction ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Cumulative Incidence ◽

Kidney Injury ◽

Post Transplant

Abstract Abstract 4515 Introduction: Acute kidney injury (AKI) is one of the most common complications after allogeneic stem cell transplantation (SCT). Although various post-transplant risk factors for AKI have been reported, there have been few studies which comprehensively assessed pre-transplant comorbidities and investigated their impact on the occurrence of AKI. Methods: We performed a retrospective analysis of 207 consecutive adult patients undergoing myeloablative or non-myeloablative SCT between 2001 and 2009. Cumulative incidence of AKI during the first 100 days was analyzed. AKI was defined and classified according to Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) criteria. Renal dysfunction considered to be associated with multiple organ dysfunction syndromes before death was excluded. The time to the development of severe AKI (defined as RIFLE class I or class F) was calculated and the multivariate analysis of pre- and post-transplant variables was performed by a Cox proportional hazards model. Post-transplant factors were assessed as time-dependent variables. As a representative of pre-transplant comorbidities, we used the hematopoietic cell transplantation-specific comorbidity index (HCT-CI). To analyze the outcomes of patients who developed AKI, the multivariate analysis of OS and NRM was carried out by a landmark approach, in which the follow-up was started at the onset of AKI class R or severe AKI in patients who developed AKI class R or severe AKI, and at the median time of the incidence of AKI in patients who did not develop AKI. Results: Among 207 patients, myeloablative SCT was performed in 149 patients and non-myeloablative SCT in 58 patients. Overall, 158 patients (76.3%) developed AKI, and 92 patients (44.4%) developed severe AKI. The median interval to the occurrence of severe AKI was 30 days after SCT. The cumulative incidence of severe AKI within 100 days in patients with a HCT-CI score 0, 1–2, and ≥3 was 21.3 %, 48.8%, and 73.9%, respectively. In a multivariate analysis, the HCT-CI was independently and most strongly associated with severe AKI (HCT-CI 1–2: adjusted hazard ratio [HR] 2.42, P<0.01; HCT-CI ≥3: adjusted HR 4.69, P<0.01), although no patients had renal dysfunction defined by the HCT-CI scoring system (pre-transplant creatinine > 2.0 mg/dl) before SCT in our cohort. Among post-transplant factors, sepsis (HR 2.66, P<0.01) and use of vancomycin (HR 1.79, P=0.04) were significantly associated with the development of severe AKI. In total, 101 of 207 patients (48.8%) died, of which 52 patients (51.5%) died of non-relapse causes. In a landmark analysis, the 3-year OS was 61.4% in patients without AKI, 53.9% in patients with AKI class R, and 39.3% in patients with severe AKI (P<0.01). The 3-year NRM was 5.6% in patients without AKI, 16.6% in patients with AKI class R, and 40.8% in patients with severe AKI (P<0.01). Multivariate analysis showed that severe AKI was a significant risk factor for worse OS (HR: 2.10, P=0.01) and NRM (HR: 6.15, P<0.01), while the occurrence of AKI class R did not have a strong impact on OS (HR: 1.14, P=0.69) or NRM (HR: 2.31, P=0.20). According to the cause of death, 24 patients died of severe AKI within 100 days after SCT, consisting of 2 on-disease patients (8.3% of the 24 patients who relapsed within 100 days after SCT) and 22 patients in remission (12.0% of the 183 patients who did not relapse within 100 days after SCT). There was no significant difference in the proportions of severe AKI as a mortality cause between patients with or without relapse (P=1.0). Conclusions: We found that high HCT-CI scores, particularly ≥3, were the most important pre-transplant predictor of severe AKI. The development of severe AKI within the first 100 days after SCT was independently associated with worse prognosis, irrespective of the status of the primary disease. Therefore, the strategy to prevent the occurrence of life-threatening severe AKI in patients with a high HCT-CI score would be imperative to improve their survival after allogeneic SCT. Disclosures: No relevant conflicts of interest to declare.

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Efficacy of Adoptive Immunotherapy By Donor Lymphocyte Infusions after Allogeneic Stem Cell Transplantation from Related an Unrelated Donors: A Single Center Retrospective Analysis

Blood ◽

10.1182/blood.v128.22.4556.4556 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4556-4556

Author(s):

Philipp Hemmati ◽

Christin Vogelsänger ◽

Theis Terwey ◽

Christian Jehn ◽

Lam G. Vuong ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Adoptive Immunotherapy ◽

Pre Treatment ◽

Active Disease ◽

Donor Lymphocyte Infusions

Abstract Introduction: Allogeneic stem cell transplantation (alloSCT) has become an integral part in the therapy of patients with malignancies of the lympho-hematopoietic system. One of the main reasons for treatment failure after alloSCT is relapse of the underlying disease, which, in the majority of cases, is associated with a poor prognosis. Adoptive immunotherapy by the use of donor lymphocyte infusions (DLI) was shown to be effective in this setting. However, the conditions and the optimal timing of DLI administration for prophylaxis or treatment of (impending) relapse remains controversial. Patients and Methods: We retrospectively analyzed 160 consecutive patients (median age: 48 (range: 17-69) years) who received DLI after previous alloSCT performed at our center between 1998 and 2014. Indications for alloSCT were: acute myeloid leukemia (AML) (N=68), acute lymphoblastic leukemia (ALL) (N=49), myelodysplastic syndrome/myeloproliferative neoplasia (MDS/MPN) (N=26), or myeloma/lymphoma (N=17). The disease risk index (DRI) was low (N=1), intermediate (N=101), high (N=43), or very high (N=6) (unknown: N=9). Comorbidities, as specified by the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), were low (N=38), intermediate (N=79), or high (N=38) (unknown: N=5). In N=71 patients a 10/10 human leukocyte antigen (HLA) matched-related donor was chosen, whereas N=89 patients were transplanted from an unrelated donor, either matched (N=73) or mismatched (N=16). Conditioning was either myeloablative (MAC) (N=71) or reduced-intensity (RIC) (N=89). The median interval from alloSCT to first DLI was 7.1 (range: 1.0-93.2) months. Indication for DLI was prophylactic (e.g. high-risk of relapse or active disease at the time of alloSCT) (N=28), pre-emptive (e.g. persistent or increasing mixed chimerism/molecular relapse) (N=86), or hematologic relapse (N=46). Pre-treatment before DLI was none/cessation of immunosuppression (N=129), lymphodepleting chemotherapy (N=16), or other (N=15). The median number of DLI units given was 2 (range: 1 - 6) and the median cumulative CD3+ cell dose/kg body weight given was 1.1 x 10E7 (range: 5.0 - 16.0 x 10E7). Results: The median follow-up of all patients from day of alloSCT was 37.3 (range: 3.0 - 202.6) months, whereas the median follow-up from day of first DLI administration was 21.2 (range: 0.3 - 200.5) months. Overall survival (OS) of the entire cohort at 1, 3, and 5 years after alloSCT was 80.5%, 63.8%, and 57.7%. Calculated from the day of first DLI OS at the same time points was 68.8%, 61.0%, and 55.8%. At five years after alloSCT OS in the group of patients with AML or ALL was significantly lower as compared to patients with MDS/MPN or myeloma/lymphoma, i.e. 52.0% versus 66.2% (p=0.043). Furthermore, OS in the group of patients receiving pre-emptive DLI was virtually identical to patients who received prophylactic DLI, i.e. 70.4% versus 69.8% at 5 years. In contrast, patients with hematologic relapse prior to DLI had an inferior outcome, i.e. an OS of 23.3% at 5 years. In addition to indication for DLI administration, i.e. prophylactic or pre-emptive versus therapeutic, the occurrence of chronic graft-versus-host disease (cGvHD) was the strongest predictor for outcome, i.e. long-term survival. Conclusions: Taken together, our data indicate that adoptive immunotherapy by the use of DLI is capable of inducing long-term remissions in patients after alloSCT. As pre-emptive and prophylactic treatment yielded virtually identical results, latter may be reserved for selected patients with (very) unfavorable disease characteristics, e.g. AML or ALL with active disease at the time of transplant. The optimal type of pre-treatment needs to be determined by investigating larger patient cohorts. Disclosures No relevant conflicts of interest to declare.

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