Delayed Platelet Engraftment and Early Increased Creatinine after Stem Cell Transplant Predicts Sustained Remission in Pediatric Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2159-2159
Author(s):  
Meera Sridhar ◽  
Christopher C. Dvorak ◽  
Rajni Agarwal ◽  
Joshua D. Schiffman
Keyword(s):  
Stem Cell ◽  
Acute Leukemia ◽  
Stem Cell Transplant ◽  
Sustained Remission ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Allogeneic Hsct ◽  
The Mean ◽  
The Difference

Abstract Background: Acute leukemia is the most common pediatric malignancy, and high risk or relapsed disease accounts for the most frequent need for pediatric hematopoietic stem cell transplant (HSCT). The 5-year Event Free Survival for acute leukemia following HSCT approaches 55%, and we currently cannot predict which children will relapse following transplant. Prognostic determinants for allogeneic HSCT recipients are limited to risk status of underlying disease, type of transplant received (matched sibling donor vs. unrelated donor), and severity of graft vs. host disease (GVHD). Although some clinicians believe that an increase in RRT may actually reflect a better outcome, the prognostic significance of engraftment and regimen related toxicity (RRT) remains to be investigated. Patients receiving similar preparative regimens respond with varying degrees of toxicity which may reflect individual genetic variations and ultimately may determine their treatment outcome. Objective: To determine whether engraftment or RRT correlates with outcome (sustained remission vs. relapse) in pediatric HSCT patients with acute leukemia. Methods: A chart review was conducted on 96 consecutive pediatric allogeneic HSCT recipients with acute leukemia at Stanford University from 1996–2006 treated with TBI/ VP or TBI/CY. The previously validated Common Terminology Criteria for Adverse Events v3.0 (CTCAE) was used to assess stomatotoxicity, hepatoxicity, and nephrotoxicity as indicators of RRT based on a 5-point Likert scale (0=no toxicity, 5=death). Toxicity scores were recorded within a 15 and 30 day period following HSCT to minimize toxicity attributed to GVHD. Time to hematological recovery also was assessed. An independent sample, two-tailed t-test was used to compare children in different outcome groups (relapse vs. sustained complete remission [CR]) for both combined total acute leukemia (TOTAL) and separate subtypes (ALL and AML). Finally, the percentage of patients with CR was calculated above and below the mean for any significant variables. Patients who died of treatment-related mortality (TRM) were removed from the analyses regardless of their remission status to avoid confounding. Results: Data were collected on 96 patients (ALL=53, AML=43). Twenty-one patients with TRM were removed, and the following number of HSCT patients analyzed: 75 TOTAL (CR=53, Relapse=22), 44 ALL (CR=29, Relapse=15), and 31 AML (CR=24, Relapse=7). CR patients took longer time to reach platelet recovery (P100) compared to relapsed pt’s for TOTAL (111 vs. 45 days, p=0.007), ALL (110 vs. 47 days, p=0.055), and AML (112 vs. 40 days, p=0.041). The TOTAL CR group also had higher creatinine-15 day scores (0.70 vs. 0.31, p=0.033) as did the AML CR group (0.83 vs. 0.28, p=0.05). This creatinine difference was no longer significant by Day-30. The percentage of CR patients above the mean P100 time to platelet recovery for each category was: TOTAL 89.5% (n=17/19, mean 97 days), ALL 82% (n=9/11, mean 92 days), and AML 100% (n=8/8, mean 104 days). The percentage of CR patients with creatinine-15 day scores above the mean was: TOTAL 79% (n=23/29, mean score 0.59) and AML 86% (n=12/14, mean score 0.7). The difference in denominators for each group is due to removal of patients without available data for specific variables or death due to TRM. Conclusion: This study represents one of the first attempts to methodically investigate whether engraftment and RTT are related to outcome in pediatric HSCT patients. Our retrospective analysis found delayed platelet engraftment (defined by platelet level of 100K/uL x 3 consecutive days) and higher creatinine-15 day values (less than 1.5 x normal) in leukemia patients who achieved sustained remission vs. those who ultimately relapsed. The difference in RRT scores between children who relapsed and those who did not may reflect differences in bone marrow and kidney exposure to previous chemotherapeutic agents; however, another explanation may be individual genetic variation in drug metabolism which leads to rapid drug clearance with lower RRT and subsequent relapse. Prospective studies are needed to validate our findings, in addition to high-throughput genomic screening to identify biological differences between children with different engraftment and RRT scores.

Platelet Release Occurs in the Bone Marrow Sinusoids and Spleen but Not in the Lungs Following Hematopoietic Stem Cell Transplant in the Mouse.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1710-1710
Author(s):  
Deanna Kreinest ◽  
Martha Sola ◽  
Xiao-Miao Li ◽  
Ronald Sanders ◽  
Marda Jorgensen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Platelet Release

Abstract The steps that lead to platelet production are poorly understood. Current theories suggest that megakaryocytes mature under the influence of contact with sinusoidal endothelium, and release platelets either in the sinusoids or in the lungs. We hypothesized that platelet release would be accentuated following hematopoietic stem cell transplant, and that sites of platelet release would be apparent during the period of platelet recovery. We transplanted highly purified hematopoietic stem cells based on lack of expression of markers for mature lineages (Linneg) and expression of Sca-1, c-kit, and Thy-1.1 (KTSL cells), and subfractionated these cells based on low expression of Rhodamine 1-2-3, into lethally irradiated hosts expressing an allelic version of glucose phosphate isomerase to identify donor and host-derived platelets. We collected bones, lungs, livers and spleens on day 7, 14, 21, and 28 post-tranplant, and stained formalin/fixed tissue with anti-Von Willebrand Factor antibody to identify megakaryocytes (5–10 animals per cohort, 2 separate experiments). We scored megakaryocytes based on their location relative to endothelial cells, and whether they were releasing platelets based on extension of proplatelet processes into the vascular spaces. Almost every megakaryocyte was associated with the endothelium during the period of platelet recovery, and we did not identify megakaryocytes that were migrating to the endothelium. We saw numerous megakaryocyte releasing platelets in both the bone marrow and the spleen during the time of platelet recovery, which occurred on days 13–28 following transplant of purified stem cells. Some of these megakaryocytes had disrupted the endothelium and were incorporated into the sinusoidal wall. Others were completely within the sinusoidal spaces. Between 30 and 50% of megakaryocytes were releasing platelets in the spleen and bone marrow at any given time following transplant, and platelet release did not correlate with the platelet counts. These levels were similar to levels of platelet release seen in healthy control mice. In contrast, we saw no identifiable megakaryocytes in the liver and lung during the period of platelet recovery. Our results suggest that in the mouse, the bone marrow and spleen, and not the lung, are major sites of platelet release following stem cell transplant.

Early Hematopoietic Stem Cell Transplant Is Associated with Improved Outcomes in Children with MDS,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4126-4126
Author(s):  
Ellen C Christianson ◽  
Barb Trotz ◽  
Qing Cao ◽  
Emily Lipsitz ◽  
Brenda Weigel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Factors Associated ◽  
Secondary Mds

Abstract Abstract 4126 Background: Childhood myelodysplastic syndrome (MDS) is a rare, heterogeneous disorder that is clinically distinct from adult MDS. Hematopoietic stem cell transplant (HSCT) is the treatment of choice, but there is no consensus regarding patient, disease, or treatment-related factors that predict outcomes after HSCT. Materials and Methods: We performed a retrospective review of 37 consecutive pediatric patients who received allogeneic HSCT for MDS at the University of Minnesota Amplatz Children's Hospital between 1990 and 2010. The median age at transplant was 11 years (range 1–21 years). Twenty patients had primary (de novo) MDS and 17 had secondary MDS (4 treatment-related, 8 with preceeding idiopathic aplastic anemia, 3 with Schwachman Diamond syndrome, and 2 familial). Those with Fanconi Anemia were excluded. Cytogenetics at diagnosis included monosomy 7 (n=21), trisomy 8 (n=7), normal/other (n=8). Thirty-one had refractory cytopenia (RC) and 6 had refractory anemia with excess blasts (RAEB) according to the modified WHO MDS classification. Patients were scored according to the International Prognostic Scoring System as low risk (n=1), intermediate-1 (Int-1; n=15), intermediate-2 (Int-2; n=21), or high risk MDS (n=0). Six patients received pre HSCT chemotherapy. Immediately prior to transplant, 27 had <5% bone marrow (BM) blasts and 10 had ≥ 5% blasts. Time from diagnosis to transplant was <140 days in 18 patients and ≥140 days in 19. Donor sources included umbilical cord blood (UCB; n=9), HLA-matched related donor (MRD; n=15), HLA-matched unrelated donor (MURD; n=7), and HLA-mismatched unrelated donor (MMURD; n=6). All patients received myeloablative conditioning prior to transplant (Cy/TBI n=35, Bu based n=2). The majority (70%) received cyclosporin based GVHD prophylaxis. Results: Neutrophil engraftment occurred in 89% (95%CI 77–97%) of patients at a median of 23 days (range 12–40). Patients transplanted after year 1999 were more likely to engraft (RR 2.27; 95% CI 1.06–4.88, p=.04). Overall survival (OS) was 70% (95%CI 53–82%) and 53% (95% CI 36–68%) at 1 and 3 years. In multivariate analysis (MVA), OS at 1 year was increased in patients who did not receive pre HSCT chemotherapy (RR of death 0.04; 95% CI 0–0.50, p=.01) and decreased in those with an IPSS score of Int-2 (RR of death 11.96; 95%CI 1.29–110.74, p=.03). Disease free survival (DFS) was 62% (95%CI 44–75%) and 48% (95% CI 31–63%) at 1 and 3 years. In MVA, factors associated with improved DFS at 3 years include having secondary MDS (RR of death or relapse 0.13; 95% CI 0.02–0.69 p=.02), undergoing HSCT after 1999 (RR 0.06; 95% CI 0.01–0.70, p=.02), not receiving pre HSCT chemotherapy (RR 0.06, 95% CI 0.01–0.36, p<.01), and a short interval (<140 days) from diagnosis to transplant (RR 0.21; 95% CI 0.05–0.85, p=.03). Those with an IPSS score of Int-2 had a significantly lower DFS (RR 3.96; 95% CI 1.12–14.00, p=.03). WHO classification, cytogenetics and pre HSCT blast percentage had no significant impact on either OS or DFS. The relapse rate at 2 years was 20% (95% CI 733%). Factors associated with decreased relapse include having secondary MDS (RR 0.04; 95% CI 0.01–0.21, p<.01) and not receiving pre HSCT chemotherapy (RR 0.21; 95% CI 0.05–0.85, p=0.03). Treatment-related mortality (TRM) was 25% (95%CI 11–39%) at 1 year. The risk of TRM was increased in patients with a pre HSCT blast count ≥ 5% (RR 6.65; 95% CI 1.60–27.67, p= 0.01) and was decreased in patients who did not receive pre HSCT chemotherapy (RR 0.07; 95% CI 0.01–0.69, P=.02). At 100 days the cumulative incidence of grades II-IV and III-IV acute graft versus host disease (GVHD) was 41% (95% CI 24–57%) and 16% (95% CI 5–28%), respectively. The incidence of chronic GVHD at one year was 19% (95% CI 6–32%). Conclusions: Our results suggest that in order to achieve optimal outcomes, children with MDS should be referred for allogeneic HSCT soon after diagnosis and that unlike in adult MDS, pre HSCT chemotherapy does not appear to improve outcomes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Nonmyeloablative Versus Myeloablative Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Deficiency

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1247-1247 ◽  
Author(s):  
Jennifer Cuellar-Rodriguez ◽  
Dennis D. Hickstein ◽  
Jennifer K. Grossman ◽  
Mark Parta ◽  
Juan Gea-Banacloche ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Conditioning Regimen ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Gata2 Deficiency ◽  
Related Donor

Abstract Background: Mutations in the zinc finger transcription factor GATA2 are responsible for: MonoMAC, monocytopenia with nontuberculous mycobacterial (NTM) infections; DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger's syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). Allogeneic hematopoietic stem cell transplant (HSCT) is the only definitive therapy for GATA2 deficiency. Methods: We used matched related donors (MRD), matched unrelated donors (URD), umbilical cord blood (UCB), and haploidentical related donors in allogeneic HSCT for GATA2 deficiency. Fourteen patients received a nonmyeloablative conditioning regimen (4 MRD, 4 URD, 4 UCB, and 2 haplo donors). Five patients received a myeloablative conditioning regimen (1 MRD, 2 URD, and 2 haplo donors). In the nonmyeloablative group, MRD and MUD recipients received fludarabine and 200cGy of total body irradiation (TBI), UCB recipients received cyclophosphamide 50mg/kg, fludarabine 150 mg/m2, and 200cGy of TBI, and haploidentical related donor recipients received cyclophosphamide 29 mg/kg, fludarabine 150 mg/m2, and 200 cGy TBI. In the myeloablative group, MRD and URD received busulfan 12.8 mg/kg and fludarabine 160 mg/m2, and haploidentical related donors received the same regimen as in the nonmyeloablative regimen except for the addition of two days of busulfan 6.4 mg/kg total dose. Nonmyeloablative MRD and URD recipients received tacrolimus and sirolimus post-transplant, and myeloablative MRD and URD recipients received tacrolimus and short course methotrexate post-transplant. All haploidentical related donor recipients received cyclophosphamide 50 mg/kg/day on days + 3 and +4 followed by tacrolimus and mycophenolate mofetil. Three patients in the nonmyeloablative cohort required one or more rounds of pre-transplant chemotherapy because of an increased number of blasts, whereas none of the 5 patients in the myeloablative arm required pre-transplant chemotherapy. Results: In the nonmyeloablative cohort, 8 of 14 (57%) of patients are alive at a median follow-up of 3.7 years (range 12 months to 5 years). One MRD recipient died of GVHD and one relapsed, one URD recipient rejected the donor stem cells and died, three UCB recipient died (one rejection, one early death, and one donor cell leukemia), and one haploidentical recipient died from regimen-related toxicity. All 5 patients (100%) in the myeloablative group, including two recipients of haploidentical related donors, are alive at a median follow-up of 9.2 months (range 6 to 12 months). All patients who survived had complete reconstitution of the monocyte, NK, and B-lymphocyte compartments, the three cell compartments that were severely deficient pre-transplant, and all had reversal of the infection susceptibility phenotype, characteristic of the disease. In particular, there were no recurrences of non-tuberculous mycobacterial (NTM) infections. Conclusions: Nonmyeloablative HSCT results in reversal of the hematologic and clinical manifestations of GATA2 deficiency. However, a more intensive conditioning regimen with busulfan resulted in more uniform engraftment, a reduced risk of relapse, avoidance of pre-transplant chemotherapy, and a low regimen-related toxicity. We anticipate that with the use of a high-dose regimen with busulfan, the replacement of UCB with haploidentical related donors, and HSCT earlier in the clinical course, before significant organ damage or clonal evolution of MDS to AML or CMML, the outcome of allogeneic HSCT in patients with GATA2 deficiency will continue to improve. Disclosures No relevant conflicts of interest to declare.

scholarly journals Relapsed Follicular Lymphoma Treatment - with or without Hematopoietic Stem Cell Transplant?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5893-5893
Author(s):  
Dulcineia Pereira ◽  
Carolina Teixeira ◽  
Sofia Ramalheira ◽  
Patricia Rocha ◽  
Claudia Moreira ◽  
...  
Keyword(s):  
Stem Cell ◽  
Treatment Strategy ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Histological Grade ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Autologous Hsct

Abstract BACKGROUND: The best treatment strategy in patients with relapsed Follicular Lymphoma (FL) remains controversial. The incorporation of rituximab (R) in the 1st line chemotherapy (CT) regimen and in treatment relapse resulted in better progression-free survival (PFS) but the benefit in overall survival (OS) was observed in only one trial (Hiddemann W. et al, Blood 2006). Hematopoietic stem cell transplant (HSCT) is the only treatment potentially curative, although the ideal time for its implementation remains undefined. AIM: Evaluation of the best treatment strategy and the impact of HSCT in PFS and OS in patients with relapsed FL. METHODS: Retrospective study including 85 patients with relapsed FL followed at a cancer care center between 2000-2012. Selection criteria: treatment naïve patients with the diagnosis of FL; absence of histological transformation at diagnosis and/or during the 1st line treatment. Survival analysis using the Kaplan-Meier method. Type of response defined according to NCCN criteria. RESULTS: Median follow-up of 64 months [4-158]. Disease progression after the 1st line CT was documented in 85 patients (median age 51 years [28-78], 42.4% male). 64 of the 85 patients had an Ann Arbor stage III-IV, of which 85.9% with follicular pattern, 95.3% grade 1/2 and 43.8% FLIPI ≥ 3. All patients underwent one or more CT regimens containing R, except in one case. In this study, 27.1% (n = 23) patients with age ≤ 60 years were submitted to HSCT (52.2% allogeneic HSCT from a related donor versus 47.8% autologous HSCT), almost all with ≥ 2 prior lines of CT (95.6%, n = 22). 78.3% (n = 18) had a CR or PR> 75% at the time of HSCT, and one death related to graft versus host disease was registered. Patients undergoing HSCT had a better PFS than those not transplanted (p = 0.022). A significant improvement in OS was observed in the HSCT subgroup (p = 0.007), especially in those with stage III-IV (p = 0.006). The type of HSCT had no impact on PFS and OS (p> 0.05), perhaps due to the small number of patients and short follow-up. By univariate Cox regression analysis, the number of regimens of CT before HSCT and the histological grade were independent predictors of PFS (p <0.05). The age and the histological grade were independent predictors of OS (p <0.05). CONCLUSION: In this study, HSCT improved PFS and also OS in patients with relapsed FL, especially in patients receiving less than 3 CT regimen, highlighting the importance of completing the HSCT earlier, during the disease’s chemosensitive phase. Our data suggest the curative potential of HSCT in these patients, due to the GVL effect in allogeneic HSCT and/or intensive high-dose CT in autologous HSCT. More studies are needed to validate these observations. Disclosures No relevant conflicts of interest to declare.

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