scholarly journals Outcomes after Donor Lymphocyte Infusion for Insufficient Donor Chimerism Following Hematopoietic Cell Transplantation for Non-Malignant Disorders

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1969-1969
Author(s):  
Carter Biewen ◽  
Angela R Smith ◽  
Jakub Tolar ◽  
Weston P Miller
Keyword(s):  
Epidermolysis Bullosa ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Donor Lymphocyte Infusion ◽  
Hla Typing ◽  
Junctional Epidermolysis Bullosa ◽  
Donor Chimerism ◽  
Cell Dose ◽  
The Impact

Abstract Background: Little is reported of the utility of donor lymphocyte infusion (DLI) following HCT for non-malignant disorders (NMD). We describe outcomes after DLI for insufficient donor chimerism after HCT in a large NMD cohort. Patients/Methods: We queried the Institutional BMT Database for patients with NMD receiving DLI for insufficient post-HCT donor chimerism. HLA typing, graft selection and conditioning were per institutional guidelines. The use, timing and dosing of DLI was at the discretion of the treating physician. Donor chimerism values on the myeloid fraction of peripheral blood at pre-DLI and most-recent time-points were reviewed. Patients were considered best DLI responders if donor chimerism improved (pre-DLI to most-recent) and most recent chimerism was ³ 80%. Results: Twenty-three patients (43% female) were identified. Table 1 shows patient, disease, transplant and DLI characteristics. The median zenith chimerism post-HCT (but pre-DLI) was 84% (IQR, 39 - 99%), observed at a median 28 days post-HCT. The median chimerism just prior to first DLI was 40%. The median time to first DLI was 90 days. Patients underwent a median 2 cycles (IQR, 2 - 3; maximum, 5) of DLI; the median cumulative per-patient CD3+ dose was 11.5 x 106/kg. Post DLI, two patients developed aGvHD and 2 patients developed cGvHD. Five patients (22%) were best DLI responders. At a mean 3.6 years post-HCT, they retained mean chimerism of 94% (mean increase from pre-DLI of 37%). Of the 18 non-best responders (78%), median chimerism at last follow-up was 10% (IQR, 2 - 25%). Seven patients underwent repeat HCT. Best response to DLI did not depend on HCT total nucleated cell dose, donor relatedness, serotherapy agent of HCT regimen, chimerism prior to DLI, or total DLI CD3+ dose. Best responders tended to have undergone myeloablative conditioning, be HLA-matched to the donor and receive first DLI later post-HCT (median 102 days, versus 83 days). Conclusions: In a large NMD cohort undergoing DLI after HCT, sustained high donor chimerism response was observed in 22%. Ongoing analyses aim to assess those with intermediate response (many of whom also enjoy improved or stable NMD), as well as the impact of peri-DLI immune suppression on outcomes. Table 1. Patient, Disease and Transplant Characteristics. ID Dx Age (y) at HCT Conditioning/ Serotherapy Donor / Graft HCT TNC(x 108 /kg) Days# to DLI DLI@ CD3+ (x106 /kg) % Chimerism Pre/MRFU aGvHD (grade) / cGvHD Re-HCT? Survival (y#) Notes / Cause of Death 1 ALD 8.1 MA / ATG R / BM 2.16 508 6 92 / 100 n/n n A (10) SD 2 ALD 8.3 NMA / C R / BM 3.17 73 9 59 / 27 n/n n A (6) SD 3 ALD 8.4 NMA / C R / BM 3.97 51 45 44 / 23 n/n n A (4.6) SD 4 ALD 9.9 NMA / C R / BM 2.13 44 17 43 / 17 n/n n A (7.2) SD 5 HLH 18 NMA/ Unk U / BM 1.94 102 1 75 / 100 Y(4)/n n D (0.6) Viral; Resp Failure 6 HLH 1 NMA / C U / BM 9.39 181 3 3 / 4 n/n Y D (1.9) Sepsis 7 Hurler 2.5 MA / ATG R / BM 5.05 193 16 67 / 58 n/n n A (8.3) SD 8 Hurler 1 MA / C R / BM 4.25 305 1 64 / 80 n/n n A (6.7) SD 9 IPEX 1.3 NMA / Unk U / BM 4.99 160 13 44 / 56 n/n n A( 6.4) SD 10 JEB 0.5 NMA / ATG U / BM 5.22 81 6 25 / 13 n/n n D (0.4) Sepsis 11 RDEB 2.8 NMA / ATG R / BM 6.21 274 11 17 / 25 n/n n A (2.1) SD 12 RDEB 6.3 NMA / ATG R / BM 7.28 167 Unk 17 / 6 n/n n A (3.1) SD 13 RDEB 0.9 NMA / ATG U / BM 9.91 98 16 12 / 87 n/n n A (2.7) SD 14 RDEB 3.3 NMA / ATG R / BM 3.53 48 16 10 / 0 n/n Y A (1.6) SD 15 RDEB 0.9 NMA / ATG R / BM 3.35 90 65 40 / 100 n/Y n A (1) SD 16 RDEB 4.9 NMA / ATG R / BM 4.27 133 65 41 / 25 n/n n A (0.8) SD 17 RDEB 0.5 NMA / ATG R / BM 5.5 85 30 71 / 45 n/n n A (0.7) SD 18 SCD 9.1 NMA / ATG U / BM 3.19 34 0.5 0 / 0 n/n n D (13.7) Progressive SCD 19 SCD 10.2 NMA / ATG U / PBSC 0.13 57 12 69 / 4 n/n Y A (10) Rejected re-HCT 20 Thal 2.3 NMA / ATG R / BM 3 84 Unk 15 / 0 n/n Y A (7.3) E, SD 21 Thal 2.8 NMA / ATG U / PBSC 0.22 48 1 40 / 0 Y(2)/Y Y D (2.2) cGvHD 22 Thal 1.7 NMA / C U / PBSC 0.17 69 5 11 / 2 n/n Y A (7.6) E, SD 23 Thal 2.6 MA / ATG R / BM 6.23 159 Unk 17 / 4 n/n Y A (5.3) E, SD # = time referenced to HCT; @ = cumulative CD3+ cell dose; ALD = adrenoleukodystrophy; HLH = hemophagocytic lymphohistiocytosis; IPEX = immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; JEB = junctional epidermolysis bullosa; RDEB = recessive dystrophic epidermolysis bullosa; SCD = sickle cell disease; Thal = thalassemia; y = years; MA = myeloablative; NMA - non-myeloablative; ATG = anti-thymocyte globulin; C = alemtuzumab; Unk = unknown; R = related; U = unrelated; BM = marrow; PBSC = peripheral blood stem cell; TNC = total nucleated cell dose; Pre = just prior to DLI; MRFU = most recent follow-up; n = no; Y = yes; A = alive; D = dead; SD = stable disease; E = engrafted. Disclosures No relevant conflicts of interest to declare.

Use of Pre-Emptive Donor Lymphocyte Infusions To Achieve Durable Remission Following Alemtuzumab Based Reduced Intensity Conditioning (RIC) Transplantation for AML or MDS.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1124-1124
Author(s):  
ZiYi Lim ◽  
Laurence Pearce ◽  
Wendy Ingram ◽  
Rafael Duarte ◽  
Stephen Devereux ◽  
...  
Keyword(s):  
T Cell ◽  
Advanced Disease ◽  
Disease Stage ◽  
Mixed Chimerism ◽  
Donor Chimerism ◽  
Significant Difference ◽  
Cell Source ◽  
Recipient Age ◽  
The Impact

Abstract Use of alemtuzumab in RIC HSCT reduces the incidence of graft rejection and graft vs host disease(GvHD). However, there can be a delay in full T-cell donor engraftment. As a dominant donor T-cell chimerism may be important to achieve a strong graft vs leukaemia effect(GvL), we examined the impact of pre-emptive DLI (pDLI) on patients with falling donor chimerism. 76 patients with AML or MDS were treated with RIC HSCT (fludarabine 150mg/m2, busulphan 8mg/kg, alemtuzumab 100mg). Complete sublineage chimerism data up to day +100 was available on all patients. The underlying diagnoses were AML n=27, MDS n=49. 33 patients had early disease vs 44 advanced disease (advanced disease as defined by AML >CR1, MDS RAEB or AML with multilineage dysplasia). The median recipient age was 51.6 years (range:19–72), with median follow-up of 526 days (range:137–1256). There were 30 sibling and 50 VUD allografts. Stem cell source was 61 PBSC vs 15 BM. 62 patients were fully HLA matched and 14 patients were HLA mismatched. CD15 engraftment occurred rapidly with 95% of patients achieving full donor chimerism(FDC) at day 30 and 96% at day 100. In contrast, CD3 engraftment was significantly delayed, with only 50% of patients FDC at day 30, 47% at day 100. Incremental doses of pDLI were considered for patients with falling donor chimerism (<50% donor) after day 100. Patients had immunosuppresion withdrawn, and had to have no GvHD. 20 patients received a total of 55 doses of pDLI. 10/20 had advanced disease, and 6/20 had unfavourable cytogenetics. Median donor CD3 chimerism at time of pDLI was 31.5%(range:7–59). The median CD3 dose of pDLI was 8.4x106/kg, with the first dose given at a median of day +176 (range:104–494). The median interval between pDLI was 8 weeks(range:4–22). 15 patients had FDC restored at median of 130 days following first doses of pDLI (range:36–523). 8/20 developed acute Gd II-IV GvHD following pDLI, with 2 patients dying of GvHD related complications. 2 patients relapsed with AML following treatment: with 1 death, and 1 patient currently undergoing treatment. 2 patients had not reached FDC at follow-up. A further 9 patients received DLI for cytogenetic or morphological relapse. Time to first dose of DLI was 257 days (range:76–837). The median CD3 dose was 1.67 x 107/kg. 3 patients were FDC and 6 patients MDC at time of relapse. All 3 patients with FDC failed to respond to DLI. Complete remission was seen in 3/6 patients with MDC. 4/9 patients developed acute Gd II-IV GvHD. 5/9 patients have died(all of underlying AML). The outcome of patients receiving pDLI was compared with patients with FDC(n=28), and stable mixed chimerism(defined as donor CD3 chimerism >70%) who did not receive DLI(n=18). There was no significant difference in recipient age, disease, disease stage, HLA type, cell source or cell dose between groups. However, there were more sibling donors in the group receiving pDLI(p=0.02). The 2 year DFS, OS and relapse rate was comparable between patients with FDC, stable chimerism and those receiving pDLI (59% vs 83% vs 67% p=0.22), (62% vs 88% vs 75% p=0.13), (12% vs 17% vs 15% p=0.74) respectively. In summary, pre-emptive DLI is effective in reversing falling donor chimerism, and can induce prolonged remission, even in a sub-group of patients with high risk disease. A dominant donor CD3 chimerism(>70%) may be sufficient to acheive an allo-immune effect in majority of patients.

Effect of T-Cell Dose On Outcomes After Peripheral Blood Allogeneic Hematopoietic Cell Transplantation in Hematological Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1171-1171
Author(s):  
Abraham S Kanate ◽  
Farhad Khimani ◽  
Aaron Cumpston ◽  
Kathy Watkins ◽  
Sonia Leadmon ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Hematopoietic Cell ◽  
Cell Dose ◽  
All Cause Mortality ◽  
Cd8 Cell ◽  
One Year

Abstract Abstract 1171 Poster Board I-193 Purpose: Peripheral blood allogeneic hematopoietic cell transplant (HCT) is used to treat various types of hematological malignancies. Current knowledge supports that increased CD34 + cell dose in the infusate is associated with earlier leukocyte recovery. The dose of CD3 +, CD4 + and CD8 + cells is largely disregarded except in T-cell depleted transplant. The correlation between various cell doses and outcomes is an area of great interest in HCT. Our analysis focuses on the impact of T-cell subset dosing, on outcomes after HCT, such as acute graft versus host disease (GVHD) and mortality. Methods: Retrospective analysis was conducted on 134 consecutive patients who underwent peripheral blood allogeneic HCT for various hematological malignancies in our institution between January 2003 and December 2008. Statistical analysis was performed using SPSS 15.0. The Chi - square test was used to determine any association between cell doses and the incidence of acute GVHD and all-cause mortality at one year of follow-up after transplant. Results were also compared with the association between CD3+ and CD8+ cell doses and incidence of acute GVHD as reported in 2007 by our institution. Results: A total of 134 patients were included in our analysis, consisting of 49 females and 85 males. The median age was 49 years (range 17-69). HCT was from matched related donors in 68 and from matched unrelated donors in 66 patients. A variety of conditioning regimens were used in preparation for the HCT. Overall survival at 1 year of follow-up was 60%, the incidence of acute GVHD was 52%, and chronic GVHD was 29%. All-cause mortality at one year follow up was found to be significantly higher when the CD3+ cell dose was < 30.5 × 107/kg IBW (49% vs. 29%, P = 0.018). All-cause mortality was also significantly increased when CD8+ cell dose was < 9.2 × 107/kg IBW (50% vs. 33%, P= 0.05). A CD8+ cell dose of < 9.2 × 107/kg IBW was also associated with an increased risk of grades 2-4 acute GVHD (48% vs. 22%, P = 0.026). There was no association of statistical significance between CD3+ and CD4+ cell doses and the incidence of acute GVHD. Conclusion: The data suggests a statistically significant inverse association between mortality and CD3+ cell dose of <30.5 × 107/kg IBW. A CD8+ cell dose of <9.2 × 107/kg IBW was also associated with increased all-cause mortality and acute GVHD (grades 2-4). Our institution reported in 2007, a significant association between the incidence of acute GVHD (grades 2-4) and CD3+ cell dose < 33.5 × 107/kg IBW and CD8+ cell dose of < 6.2 × 107/kg IBW, based on series of 66 patients. As we increased the sample size to 134, the association between CD3+ cell dose and acute GVHD was no more present. We conclude that T-cell dose is an important factor in terms of outcomes after all allogeneic HCT irrespective of preparative regimen. T-cell subsets likely play a pivotal role in transplant results, though it is not well described. Analysis of larger databases is required to substantiate our results. Disclosures: No relevant conflicts of interest to declare.

Monitoring of Minimal Residual Disease in NPM1 Mutated Acute Myeloid Leukemia (AML) – a Single Center Experience in 27 Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4672-4672
Author(s):  
Dana Dvorakova ◽  
Zdenek Racil ◽  
Ivo Palasek ◽  
Marketa Protivankova ◽  
Ivana Jeziskova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Npm1 Mutation ◽  
Mgb Probe ◽  
Minimal Residual

Abstract Abstract 4672 Background Mutations within NPM1 gene occurs in about 60% of adult cytogenetic normal AML (CN-AML) and represent the single most frequent molecular aberration in this subgroups of patients. These mutations usually occur at exon 12 and induce most frequently a net insertion of four base pairs. Aims To examine the applicability and sensitivity of DNA-based real-time quantitative polymerase chain reaction (RQ-PCR) with mutation-specific reverse primers and common minor groove binding (MGB) probe and to evaluate whether minimal residual disease levels are of prognostic relevance in CN-AML patients with NPM1 mutations. Methods Patients were treated within different AML trials and follow-up samples of peripheral blood or bone marrow were referred to perform an RQ-PCR. Samples were analysed at diagnosis, during, and after therapy. The NPM1 mutations were A (17 pts), B (1 pt), D (2 pts) and 7 patients with individual rare types. For all cases, levels of minimal residual disease were determined by DNA-based RQ-PCR with mutation-specific reverse primer, one common forward primer and one common MGB probe. The NPM1 mutation value was normalized on the number of albumin gene copies and expressed as the number of NPM1 mutations every 106 genomic equivalents. This assay is highly specific as no wildtype NPM1 could be detected. Maximal reproducible sensitivity was 10 plasmide molecules per reaction. Results A total of 950 samples of bone marrow and/or peripheral blood from 27 patients have been analyzed. Twenty of 27 patients (74%) achieved molecular remission (MR), twenty-six of 27 patients (96%) achieved hematological remission (HR). 6 of 27 (22%) patients achieved HR without MR and one patient failed therapy. 8 of 20 patients (40%) with MR after treatment relapsed at molecular level and except one in all these patients hematological relaps occured (one patient is still in HR with bone marrow blast present, but < 5%). Considering relapsed patients, time from molecular to hematological relapse was 1 to 5 months (median: 3 months). Considering all 14 patients with HR without MR (6 pts) or with molecular relapse (8 pts), in 11 of them hematological relaps occured (79%) and molecular positivity anticipating hematological relaps with median of 3,5 month (1-7 months). 3 of these 14 patients are still in HR. Conclusions Mutations within NPM1 gene are a sensitive marker for monitoring minimal residual disease in CN-AML patients. RQ-PCR using a MGB probe is an efficient approach to long-term follow-up of residual leukemia cells and frequent quantitative monitoring is useful for reliably predicting hematological relapse. Achievement of negativity appears to predict favorable clinical outcome. This work was partially supported by research grant No. MSM0021622430 Disclosures: No relevant conflicts of interest to declare.

The Addition of Thalidomide to the Induction Treatment of Newly Presenting Myeloma Patients Increases the CR Rate Which Is Likely to Translate Into Improved PFS and OS.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 352-352 ◽  
Author(s):  
Gareth J Morgan ◽  
Faith E Davies ◽  
Walter M Gregory ◽  
Susan E Bell ◽  
Alex J Szubert ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Response Rates ◽  
Multiparameter Flow Cytometry ◽  
Induction Treatment ◽  
Overall Response ◽  
Patient Pathways ◽  
The Impact

Abstract Abstract 352 We present updated results from MRC Myeloma IX study evaluating the role of the addition of thalidomide to the induction and maintenance of patients with myeloma. The study ran from May 2003 – November 2007 and randomised 1,970 patients and now has a median follow up of more than 3.5 years giving it improved power to detect changes in outcome developing later after treatment. Projected median OS younger fitter patients 66 months, median OS older less fit patients 32 months. The trial comprised of 2 patient pathways, one for younger fitter patients comparing CTD (cyclophosphamide, thalidomide, dexamethasone) with CVAD (cyclophosphamide, vincristine, adriamycin, dexamethasone), all patients going on to receive an ASCT – median age 59 years. In older less fit patients, melphalan and prednisolone (MP) was compared to CTD attenuated – median age 73 years. In both pathways following initial treatment, eligible patients were randomised to low-dose thalidomide or no maintenance. Patient's response was monitored using electrophoresis, serum free light chain and multiparameter flow cytometry. Cytogenetics was availabel on up to 60% of cases and gene expression on a subset of these. CTD is a well tolerated regimen with a good safety profile giving excellent survivals in both groups of patients despite a small increase in risk of VTE. Using modified EBMT criteria, the addition of thalidomide to induction treatment increases both response rates and depth of response for all age groups. Preliminary results as follows: overall response: CTD vs CVAD: 91% v 82%; CR 21% v 14% and 100 days post-HDM, better responses were seen in CTD with CR rates 65% v 48%. Remission depth was also greater in CTD with more patients achieving minimal residual disease negativity by flow cytometry. The addition of thalidomide increases response rates overall, and particularly complete response (CR) rates (a 17% increase in CR rates post HDM, p=.006). In older/less fit patients CTDa vs MP: overall response 83% v 46%; CR 21% v 4%. Definitive results of these analyses will be presented as well as how they translate into PFS and OS and by cytogenetic subgroup. There is a substantial increase in response with the inclusion of thalidomide but at a median follow-up of three years we are not as yet seeing a substantial increase in survival in either of the two broad patient groups. We have collected data on treatment at relapse to explore how this confounds OS data. Importantly modelling analyses indicate when and to what extent, with further follow-up, the survival differences that should accrue from this increase in CR rate are likely to translate into a survival benefit. These results have a number of important implications. We show the benefit of the addition of thalidomide to myeloma treatment but also highlight the importance of later analysis of such trials because of the emergence of significant changes at these later time points. We will present full updated results from the study including the impact of thalidomide on cytogenetic subgroups and in the maintenance setting. Disclosures: No relevant conflicts of interest to declare.

First Use of Allogeneic Stem Cells in the Treatment of Recessive Dystrophic Epidermolysis Bullosa: Demonstration of Biochemical and Clinical Improvement.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 660-660
Author(s):  
John E. Wagner ◽  
Akemi Ishida-Yamamoto ◽  
John A McGrath ◽  
Maria Hordinsky ◽  
Douglas R Keene ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epidermolysis Bullosa ◽  
Conflicts Of Interest ◽  
Dermal Matrix ◽  
Dystrophic Epidermolysis Bullosa ◽  
Type Vii Collagen ◽  
Male Sibling ◽  
Female Sibling ◽  
Recessive Dystrophic Epidermolysis Bullosa

Abstract Abstract 660 Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable, often fatal mucocutaneous blistering skin disease caused by mutations in the type VII collagen (C7) gene, COL7A1. These pathogenic mutations result in severely diminished expression of C7, a collagen localized at the dermal-epidermal junction (DEJ), and absence of anchoring fibrils (AFs) which are C7 containing structures that tether the epidermal basement membrane to the dermal matrix. From birth on, children with RDEB develop painful erosions and blisters on mucosal membranes and skin often resulting in esophageal strictures, mutilating scarring, joint contractures, fusion of fingers and toes and, aggressive squamous cell carcinomas. After first demonstrating that a stem cell enriched fraction of bone marrow (BM) rescued a proportion of RDEB mice from lethality and resulted in a) expression of C7 in skin and mucosal membranes, b) formation of new AFs, and c) resistance to blistering, a ‘first-in-human' phase I-II clinical trial was initiated in October 2007. To date, 7 patients have been treated with stem cells from BM from an HLA matched sibling donor (n=6) or unrelated cord blood (CB) donor (n=1). Follow-up data are reported through August 18, 2009. Conditioning consisted of busulfan 0.8 mg/kg per dose every 6 hours on days–9 to–6, fludarabine 25 mg/m2/day on days–5 to–3, and cyclophosphamide 50 mg/kg/day on days–5 to–2. After infusion of stem cells on day 0, immunoprophylaxis consisted of cyclosporine and mycophenolate mofetil. Patient and graft characteristics are shown in Table 1. Of the 4 patients with adequate follow-up, a progressive increase in C7 deposition by immunofluorescence (IF) at the DEJ, AFs or AF-like structures by electron microscopy, and wound healing with marked reduction in blister formation were documented. Unexpectedly, all patients had substantial chimerism in the skin (11-93%) that persisted over time. In 2 patients with a sex mismatched donor, perivascular localization of the donor cells in the dermis could be discerned using probes to the centromere regions of chromosomes X and Y. In summary, this is the first demonstration that the infusion of BM can ameliorate the severe systemic mucocutaneous manifestations of RDEB and sets the stage for using marrow stem cells in the treatment of a broad spectrum of extracellular matrix disorders. PtDonor (cell dose: NC × 108/kg)Transplant Related ToxicitiesC7 AssessmentAnchoring Fibril AssessmentClinical OutcomeSurvival Days1 15 mo maleHLA 8/8 male sibling BM/CB (3.04; 0.66)NoneIncreased by IF↑ Rudimentary AFsImproved but no change in use of dressingsAlive day 6592 9 mo femaleHLA 8/8 male sibling BMCardiomyo-pathyNot evaluableNot evaluableNot evaluableDied day 03 5.9 maleHLA 5/6 female unrelated CB (0.55)Graft rejectionIncreased by IF and Western↑ Rudimentary AFsNot evaluableDied day 1834 6.3 yo maleHLA 8/8 female sibling BM (3.76)Transient Dialysis ARDSNo change by IF° but WesternNormal AFs observedMarked reduction in blisters and dressingsAlive day 2475 6.2 yo femaleHLA 8/8 male sibling BM (3.07)Transient DialysisIncreased by IF and Western↑ Rudimentary AFsMarked reduction in blisters and dressingsAlive day 1286 6.0 yo femaleHLA 8/8 female sibling BM (3.11)EpistaxispendingpendingEarly reduction in blisteringAlive day 567 14.5 yo femaleHLA 8/8 female sibling BMToo early to evaluatependingpendingToo early to evaluateAlive day -9 Disclosures: No relevant conflicts of interest to declare.

Autologous Hematopoietic Stem Cell Transplantation (autoHSCT) in CLL: First Results of An EBMT Randomized Trial Comparing Autotransplant Versus Wait and Watch.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 877-877
Author(s):  
Mauricette Michallet ◽  
Peter Dreger ◽  
Laurent Sutton ◽  
Ronald Brand ◽  
Sue Richards ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Disease Status ◽  
Primary Objective ◽  
Phase Iii ◽  
Induction Treatment ◽  
Hematopoietic Stem ◽  
Binet Stage ◽  
The Impact

Abstract Abstract 877 This phase-III randomized EBMT-intergroup trial studied the impact of a consolidating autoHSCT vs no consolidation for patients with CLL in Binet stage A progressive, B or C , in CR, nodular PR or VGPR after first or second line therapy. The primary objective was to show that autoHSCT increased the 5-year progression-free survival (PFS) by 30%. Although it had been calculated that 270 patients were to be randomized, the study was terminated by the steering committee in July 2007 due to poor accrual. Here we present a first analysis based on 69% of expected follow-up forms. Results: Between November 2001 and July 2007, 223 patients were enrolled (SFGM-TC/FCLLG n=98, MRC n=62, GCLLSG n=32, SAKK n=10, other EBMT centers n=17). There were 74% males and 26% females. Binet stages were progressive A 13%, B 67%, C 20%; 59% were in CR, and 41% in very good or nodular PR. Of note, SFGM-TC/FCLLG included only patients in CR. 82% of the patients were enrolled in 1st, and 18% in 2nd remission. Patients were randomized between group 1 (autoHSCT n=112) and group 2 (observation n=111) after an induction treatment which was left at the discretion of the investigators. Median PFS was 43 months in the observation group but not reached in the autoHSCT group; 5-year PFS was 48% and 65%, respectively (p=0.005). Accordingly, autoHSCT halved the relapse risk (5-year relapse incidence 25% vs. 51%; HR 0.4 [0.23-0.71], p=0.002). Cox modeling for randomization arm, Binet stage, disease status, line of treatment, contributing group (country), and the interaction between randomization arm and contributing group confirmed that autoHSCT significantly improved PFS (HR 0.41 [0.23-0.75] p=0.004). The beneficial effect of autoHSCT was stable over all contributing groups although patients accrued by SFGM-TC/FCLLG overall had a significantly better PFS than patients from other countries (HR 0.2 [0.08-0.55], p=0.001). At 5 years, the probability of OS was 92% and 91% for autoHSCT and observation, respectively. Significant differences in terms of non-relapse death were not observed. At the last follow up, among 205 evaluable patients, 186 are alive (147CR, 39 relapse), 19 died (14 from relapse and 5 from non-relapse causes) . In conclusion, in patients with CLL in first or second remission, consolidating autoHSCT reduces the risk of progression (PFS) by more than 50%, but has no effect on overall survival. Disclosures: No relevant conflicts of interest to declare.

Day 100 PET Scan Positivity Predicts for Worse Survival in Lymphoma Patients Given Allogeneic Peripheral Blood Stem Cells After Non-Myeloablative Conditioning,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4155-4155
Author(s):  
Aurélie Jaspers ◽  
Pacome Fosse ◽  
Nadia Withofs ◽  
Marie Lejeune ◽  
Evelyne Willems ◽  
...  
Keyword(s):  
Ct Scan ◽  
Hodgkin’S Lymphoma ◽  
Conflicts Of Interest ◽  
Autologous Transplantation ◽  
Pet Scan ◽  
Hodgkin's Lymphoma ◽  
Myeloablative Conditioning ◽  
The Impact ◽  
Pet Scans

Abstract Abstract 4155 Background PET scan is increasingly used in the follow-up of lymphoma patients given allogeneic hematopoietic cell transplantation (Allo-HCT). However, whereas several studies addressed the question of the impact of PET positivity after autologous transplantation on transplantation outcomes, very few have been performed after allo-HCT. This is the aim of the current retrospective study. Methods We retrospectively analyzed data from 50 lymphoma patients who underwent an allo-HSCT after non-myeloablative conditioning between March 2000 and March 2009. The diagnoses were Hodgkin's lymphoma (n=8) and non-Hodgkin's lymphoma (n=42; 14 follicular, 11 mantle cell, 9 diffuse large B cell, 2 MALT, 1 Burkitt, 1 lymphocytic and 4 T-cell lymphomas). Patients were scheduled to benefit from a follow-up by PET scan on days 100, 180 and 365 and then yearly for a total of five years. Results Day 100 PET scans were not performed in 5/50 patients (4 patients died before day 100, while another onewas in intensive care unit at that time).Among the remaining 45 patients, 20 (44.4%) presented hypermetabolic lesions, including 9 patients(20%) who had hypermetabolic lesions evocative of lymphoma.One-year OS (Figure 1) was higher in patients whose PET scan was negative or positivefor infectious/inflammatory reasons than for those with typical lymphoma lesions (85% vs 44%, p=0.0013). Among patients with day-100 PET positivity evocative of lymphoma, 7 patients died, 5 of them of their lymphoma, while 2 patients remained alive. During further follow-up, twenty patients (44.4%) never presented hypermetabolic lesions after transplantation and 25 (55.6%) had at least one abnormal PET scan. Among the 25 patients, only 11 (24.5%) had probable/proven neoplasia: 1 died with residual disease, 2 had residual lymphoma that went into remission after GVHR, 5 had biopsy-proven relapse, 1 had non-biopsy proven progression, 1 had lung cancer and 1 lung PTLD. The other 14 patients (31.1%) had suspicious lesions at one of the follow-up PET scans, but after further work-up, none of these lesions proved to be a relapse, and all disappeared afterwards. Biopsies were performed in 6 of these cases, including 2 lymph node (1 normal and 1 lymphoid hyperplasia), 2 lung (1 normal and 1 aspergillosis) and 2 GI (1 normal and 1GVHD) biopsies. For 6 patients, imaging studies (CT scan, MRI or echography) were normal or demonstrated infectious or inflammatory (including gut GVHD) disorders. The last 2 patients were thought to relapse based on both PET and CT scans, but refused biopsies, but their lesions regressed spontaneously. Conclusion In our study, a positive PET scan at day 100 after transplant is predictive of poorer OS. However, there is a noteworthyincidence of false-positive PET scans after non-myeloablativeallo-HCT. We therefore recommend that every suspicious lesion,and particularly in areas not previously involved by lymphoma, should be explored at least by CT scan and/or biopsy, before initiating any new treatment. Disclosures: No relevant conflicts of interest to declare.

Impact Of Total Nucleated Cell and CD34+ Cell Dose On Transplant Related Outcomes In Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplants

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2048-2048 ◽  
Author(s):  
Paul Martin ◽  
Shuli Li ◽  
Edwin P. Alyea ◽  
Vincent T. Ho ◽  
Corey S. Cutler ◽  
...  
Keyword(s):  
Disease Risk ◽  
Conflicts Of Interest ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Reduced Intensity Conditioning ◽  
Allogeneic Hct ◽  
Cell Dose ◽  
The Impact ◽  
Reduced Intensity

Abstract Background Mobilized peripheral blood (PB) is the most common graft source for allogeneic hematopoietic transplantation (HCT) following reduced intensity conditioning (RIC). The impact, if any, of donor PB graft composition on major transplant outcomes in the RIC allogeneic HCT setting remains incompletely understood. Existing studies have focused primarily on CD34+ cell dose and report conflicting results, especially in relation to survival. The impact of total nucleated cell (TNC) dose has been less frequently evaluated, but limited studies with relatively small cohort sizes have reported higher TNC dose to be associated with improved survival. Methods In order to further explore the relationship between PB donor CD34+ cell dose, TNC dose and RIC HCT outcomes, we assessed 705 adult patients with hematological malignancies who underwent RIC allogeneic HCT at Dana Farber Cancer Institute/ Brigham and Women's Hospital (DFCI/BWH) between 2000 and 2010. The vast majority received a RIC regimen of fludarabine and busulfan (n=698). GVHD prophylaxis was tacrolimus based with or without sirolimus (524 vs. 171, respectively). Recipients of in vivo T-cell depletion (TCD) with antithymocyte globulin or ex-vivo TCD were excluded. The median age was 57 years (range,18-74). Patient's disease risk index (DRI) was categorized as low (n=164), intermediate (n=350), high (n=170) or very high (n=21) per Armand, et al (Blood, 2012). Transplants were categorized as matched (MRD n=273, MUD n=374) or mismatched (MMRD n=4, MMUD n=58). Results There was weak correlation between CD34+ cell dose and TNC (Spearman coefficient 0.25 [0.18-0.32]), and between CD34+/kg and TNC/kg with coefficient 0.25 [0.26, 0.39]. Cell doses for TNC effects were evaluated by quartiles. On multivariable analysis including age, DRI, donor source, gender, and CMV serostatus, higher TNC dose (top quartile, ≥10.8 x 10^10 cells) was independently associated with increased chronic GVHD (HR 1.33 [1.06-1.67], p=0.015) as well as decreased relapse (HR 0.74 [0.58-0.94], p=0.015). There was no effect on acute GVHD, engraftment, or non-relapse mortality. Importantly, higher TNC dose was associated with improved overall survival (HR 0.74 [0.59-0.94], p=0.014, Figure 1) and progression free survival, PFS (HR 0.76 [0.61-0.94], p=0.014). In contrast, although higher doses of CD34+ cells (> 10 x 10^6/kg vs. < 5 x10^6/kg) resulted in faster engraftment for both platelets and neutrophils (data not shown) and a decrease in non-relapse mortality ( HR 0.53 [0.30-0.93], p=0.027), there was no significant effect on acute or chronic GVHD incidence, relapse, PFS or survival. Conclusions These data suggest TNC dose is an important prognostic variable in T-replete RIC HCT with significant impact on survival and should, like CD34+ cell dose, be taken into consideration when planning donor graft infusions. Further studies are needed to confirm these data, and characterize the components of the PB graft that influence survival. Disclosures: No relevant conflicts of interest to declare.

CD34+ Selected Cells For The Treatment Of Poor Graft Function Following Allogeneic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3306-3306
Author(s):  
Alessandra Stasia ◽  
Anna Ghiso ◽  
Anna Maria Raiola ◽  
Federica Galaverna ◽  
Riccardo Varaldo ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Graft Function ◽  
Partial Recovery ◽  
Actuarial Survival ◽  
Cd34 Cells ◽  
Poor Graft Function ◽  
Disease Free

Abstract Background We have previously defined poor graft function (PGF) as 2 or 3 cytopenic lines (Hb<10 g/dl, neutrophil count <1,0 x 10^9/L, platelet count <30 x 10^9/L), lasting for at least 2 consecutive weeks post-transplant, beyond day +14, with transfusion requirement, associated with hypoplastic-aplastic bone marrow, in the presence of complete donor chimerism and in the absence of severe GVHD and relapse (Larocca 2006). We have also shown that PGF can be treated with the infusion of donor CD34+ cells, selected from mobilized peripheral blood. (Larocca 2006) . Aim of the Study To update the 2006 study in 41 patients. Methods All 43 patients received a boost of CD34+ selected peripheral blood stem cells (PBSC) without prior conditioning and without GvHD prophylaxis. The median age of patients was 37 years (18-60y). The median number of CD34+ PBSC infused was 3.45 x106/Kg at median days of 140 days from 1st HSCT. Complete response, or tri-lineage recovery was defined as achieving Hb >10 g/dl, ANC > 1000 x109/L, platelets > 100.000 x 109/L. A partial recovery was defined as transfusion independence, without a complete hematologic recovery. The median follow up was 1245 days. Results Tri-lineage recovery was seen in 31/41 (76%) and 3/43 patients became transfusion independent, for an overall response of 83%). The median time for complete hematological recovery from CD34+ boost infusion was 183 days. There was no influence on tri-lineage recovery of the following factors : dose of CD34 cells (</> 3.3) (78% vs 72%), nor patient age (</>35 years) 75% vs 76%, nor donor type (HLA id sib 83%, UD 79%, family mm 68%). All the patients who achieved tri-lineage recovery are alive and disease free (28/41 patients). In this cohort 13 patients died due to relapse 9/14 (64%) or GVHD 2/14 (14%) or other causes 2/14 (14%). The overall actuarial survival is 63% with a median follow up of 1245 days (94-4151 days). Interpretations and Conclusions We confirm that infusion of CD34+ selected PBSC is associated with a high rates of tri-lineage recovery, with low risk of acute or chronic GVHD in patients who develop poor graft function following an HSCT. Tri-lineage recovery or achieving transfusion independency have an interesting impact either on disease free and overall survival. Disclosures: No relevant conflicts of interest to declare.

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