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  • 1
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    Graft-Versus-Host Disease After Double-Unit Cord Blood Transplantation Has Unique Features and an Association with Engrafting Unit Recipient HLA-Match
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 4197-4197
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4197-4197
    Abstract: Abstract 4197 Background: Graft-versus-host disease (GVHD) has emerged as a major cause of morbidity and mortality after double-unit cord blood transplantation (DCBT), but data concerning its manifestations, treatment response, and risk factors are limited. Moreover, the incidence and clinical characteristics of GVHD after day 100 in DCBT recipients have not been well described. Methods: We evaluated the incidence and nature of GVHD in 115 DCBT recipients (median 37 years, range 0.9–69) transplanted for hematologic malignancies with either myeloablative (n = 88) or non-myeloablative conditioning (n = 27). CB units were 4–6/6 human leukocyte antigen (HLA)-A,-B antigen, -DRB1 allele match to the recipient, and all patients received calcineurin-inhibitor/mycophenolate mofetil immunosuppression without anti-thymocyte globulin. Results: With a median follow-up of 33 months (range 8–73), the cumulative incidences of grade II-IV and III-IV acute GVHD (aGVHD) at day 180 were 53% (95% CI: 44–62) and 23% (95% CI: 15–31), respectively. Among patients with grade II-IV aGVHD, the median onset was 40 days (range 14–169), but earlier for those with grade III-IV (median 35 days). The gastrointestinal (GI) tract was the most commonly affected organ (80%, 14 upper gut, 9 lower gut, 26 both), followed by skin (39%), and liver (18%). Among patients with grade II-IV aGVHD, 29 (48%) were treated with systemic corticosteroids, 27 (44%) with budesonide alone, and 4 (7%) with topical corticosteroids. Budesonide was used as the sole treatment exclusively in adults for grade II disease predominantly affecting the gut. Treatment response by day 28 was 79% and 85% to systemic corticosteroids or budesonide, respectively. Of 89 engrafted patients disease-free at day 100, 54% subsequently had active GVHD with 79% of those affected having persistent/recurrent aGVHD or overlap syndrome. Classical chronic GVHD was quite uncommon affecting only 10 patients (21%) in the study. To take into account potential confounding variables associated with day 180 grade III-IV aGVHD incidence, a multivariate Cox regression analysis was performed (Table). Grade III-IV aGVHD incidence was lower if the engrafting unit-recipient human HLA-A,-B,-DRB1 allele match was 〉 4/6 (HR 0.385, p = 0.031) (Figure), whereas engrafting unit nucleated cell dose and unit-unit HLA-match were not significant. Conclusions: GVHD after DCBT was common in our study, predominantly affected the gut, and had a high rate of successful response to treatment. Late GVHD frequently had acute features. Our findings support the consideration of HLA-A,-B,-DRB1 allele donor-recipient (but not unit-unit) HLA-matching in unit selection. This would represent a practice change for most transplant centers. Moreover, new prophylaxis strategies that target the gut are needed. Disclosures: Off Label Use: The use of Budesonide for acute gastrointestinal graft-versus-host disease. Giralt:Celgene: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.4197.4197
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 2
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    Adoptive Immunotherapy with Donor T Cells Sensitized with Overlapping Pentadecapeptides of the CMV-pp65 Protein for the Treatment of Persistent CMV Antigenemia Following Allogeneic Hematopoietic Stem Cell Transplants
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 351-351
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 351-351
    Abstract: Abstract 351 We have generated donor-derived T-cell lines specific for CMVpp65 peptides for use in a phase I, dose escalation trial of adoptive immunotherapy. T-cells were sensitized by autologous monocyte-derived DCs loaded with a pool of 138 pentadecapeptides (15-mers), with 11 amino acid overlaps spanning the entire 561 amino acid sequence of the CMV protein pp65. The 138 pentadecapeptides were synthesized and the T-cells were sensitized under GMP conditions. In preclinical studies we have been able to generate CMVpp65 specific T-cell lines from each seropositive donor tested, irrespective of HLA genotype. During the culture period of 21–35 days, populations of T-cells specific for CMV-pp65 selectively expanded 200–300 fold, while T cells reactive against major or minor alloantigens were depleted. Thirteen pts with persistent CMV viremia, refractory to at least 2 weeks of therapeutic doses of ganciclovir or foscarnet, have been enrolled: 3 pts at a T cell dose of 5×105/kg, 3 pts at 1×106 T cells/kg, and 7 pts at 2×106 T cells/kg. CMV specific cytototoxic T lymphocytes (CTLs) were generated from HLA-identical unrelated donors (3 pts) or from HLA-identical siblings (10 pts). Two pts received conventional transplants after non-myeloablative conditioning; 11 pts received myeloablative conditioning and T-cell depleted transplants. Pts were eligible if they had persistent CMV viremia despite 2 weeks' treatment with antiviral drugs or had toxicities precluding further treatment with antiviral agents. Prior to infusion, T cell specificity against CMV was confirmed by cytotoxicity, intracellular interferon gamma (IFN-g) production, and MHC-tetramer staining (if available). The HLA-restrictions, epitope specificities, and TCR Vβ repertoires of the T-cell lines were also characterized before infusion. Cells were also assayed to establish lack of alloreactivity, microbiological sterility, and low endotoxin levels. All CTLs demonstrated cytolytic activity against peptide-loaded autologous PHA blasts but no cytotoxicity against non-pulsed HLA-matched or peptide-pulsed HLA-mismatched target cells. The proportion of CMVpp65-specific CD8+ cells in the infused T-cells, measured by intracellular IFN-g or MHC tetramers, ranged from 2 – 20 % or 4 – 70%, respectively. Post infusion, an increase in the absolute lymphocyte count correlated with an increase in CMV-specific T-cell frequencies to levels as high as 14% of CD8+ cells. In one pt, the CTLs were monitored and persisted for more than 2 years (10% of CD8+ cells) after the infusion. Notably, the same pp65-derived epitopes and HLA-restrictions which characterized the infused CTLs were detected in the pt specimens post infusion. The same TCR Vβ repertoires of the CMVpp65-specific CTLs infused were also detected post infusion. Donors for three of the treated pts expressed HLA-A*0201 and HLA-B*0701 alleles. Epitope-specific T cells for the HLA-A*0201-restricted NLVPMVATV peptide and the B*0701-restricted RPHERNGFTV peptide were detected and monitored in pre and post infusion T-cell populations in these three pts. In all three pts, the B*0701 restricted RPHERNGFTV emerged as the dominant T-cell population. All 13 pts tolerated the infusions well without acute toxicities. None developed symptoms of GvHD at the dose levels tested. Twelve of the 13 pts cleared CMV viremia by 2–8 weeks following the CTL infusions. One of the pts died six weeks after the CTL infusion of respiratory failure despite clearing CMV from blood and bronchial aspirates. Another pt who initially remained viremic following the CTL infusion was restarted on oral valganciclovir and subsequently cleared CMV viremia. Only one pt had persistent viremia and died of pneumonia 31 days after CTL infusion. The results from this trial demonstrate that donor T cells, sensitized with this pool of overlapping CMV pp65 pentadecapeptides, are safe and clear CMV viremia resistant to standard therapy. A larger phase II trial for the treatment of persistent CMV viremia and CMV infections is currently ongoing at MSKCC. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.351.351
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 3
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    Double-Unit Cord Blood Transplantation (DCBT) for Acute Leukemia: High Disease-Free Survival in Adults and Children with Comparable Survival in European and Minority Patients
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3080-3080
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3080-3080
    Abstract: Abstract 3080 As compared to single-unit CBT, DCBT may improve engraftment and protect against relapse. Therefore, we have adopted DCBT for both children and adults with acute leukemia, myelodysplasia (MDS), and myeloproliferative diseases (MPD). However, determinants of disease-free survival (DFS) have yet to be fully established. Furthermore, whether DFS after DCBT is comparable in patients of European and non-European ancestry is of special interest. Therefore, we analyzed the DFS of 75 DCBT recipients with acute leukemia in morphologic remission or aplasia (n = 69), and MDS/MPD with ≤ 5% blasts (n = 6) transplanted from 10/2005-4/2011. Nearly all patients had high-risk disease. Children 0–15 years (n = 23) had the following characteristics: median age 9 years (range 0.9–15); median weight 37 kg (range 7–72); 30% European; and 26% CMV sero-positive. Diagnoses were 43% AML (or biphenotypic), 52% ALL, and 4% MDS/MPD, and all received high-dose conditioning. The children received grafts with a median infused TNC × 107/kg of 3.3 (larger unit) and 2.6 (smaller unit), and 2% of units were 6/6 HLA-A, -B antigen, -DRB1 allele matched, 63% 5/6, and 35% 4/6. Adults ≥ 16 years (n = 52) had the following characteristics: median age 41 years (range 16–69); median weight 69 kg (range 47–105); 48% European; 69% CMV sero-positive; and diagnoses were 63% AML (or biphenotypic), 27% ALL, and 10% MDS/MPD. Fifty percent received high-dose and 50% reduced intensity conditioning. Their units had a median infused TNC/kg of 2.7 and 1.9, and 3% were 6/6 HLA-matched, 47% 5/6, and 50% 4/6. All patients (pediatric and adult) received calcineurin-inhibitor/ mycophenolate mofetil immunosuppression, and none received anti-thymocyte globulin. Sustained donor neutrophil engraftment was seen in 91% of children and 94% of adults at medians of 20 and 26 days, respectively. The incidence of grade II-IV acute GVHD by day 180 was 44% in children and 58% in adults. Day 100 transplant-related mortality (TRM) was 9% in children and 19% in adults. The 2-year relapse incidence was 9% in children and 6% in adults. With a median follow-up of survivors of 26 months (range 4–70), 2-year Kaplan-Meier estimate of DFS was 78% in children and 64% in adults (Figure). Differences in survival by age did not reach significance. Univariate analysis of variables potentially influencing 2-year DFS (with log rank estimates of significance) in all patients is shown in the Table. There were no differences in 2-year DFS according to ancestry, remission status, and conditioning intensity. There was also no difference in 2-year DFS according to engrafting unit-recipient HLA-match (4-6/6 or 10 allele), or engrafting unit infused TNC dose/kg. However, patients who were CMV seronegative had a higher 2-year DFS (85% vs 55%, p = 0.018). Multivariate analysis revealed recipient CMV serostatus was a predictor of DFS independent of patient age, and its effect was mediated by an influence on TRM. We have previously shown that DCBT extends transplant access to minority patients. We now demonstrate that DCBT can achieve high and comparable DFS in both European and non-European pediatric and adult patients with acute leukemia and MDS/MPD. While these are very encouraging results further investigation in racial/ethnic sub-groups is needed. Nonetheless, our findings support DCBT as an immediate alternative therapy for high-risk acute leukemia in patients without suitable unrelated volunteer donors, especially given the very low incidence of relapse. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3080.3080
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
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  • 4
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    Graft-Versus-Host Disease (GVHD) After Double-Unit Cord Blood Transplantation (DCBT) Is Associated with Unique Clinical Features Including a Higher Incidence of Grade III-IV Acute GVHD in Children
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3044-3044
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3044-3044
    Abstract: Abstract 3044 While the GVHD incidence after unrelated donor CBT is lower than expected for the degree of human leukocyte antigen (HLA)-mismatch, GVHD can be a serious complication and at our center has been the second most common cause of transplant-related mortality after DCBT. However, relatively little is known about DCBT GVHD manifestations, treatment response, and risk factors. Therefore, we evaluated 108 DCBT recipients (median 37 years, range 0.9–69) transplanted for hematologic malignancies. The majority had acute leukemia and high-risk disease. Patients received either myeloablative (n = 81) or non-myeloablative (n = 27) conditioning and 4–6/6 HLA-matched grafts. GVHD prophylaxis consisted of a calcineurin-inhibitor with mycophenolate mofetil, and no patient received anti-thymocyte globulin (ATG). With a median follow-up of 28 months (range 9–64), the cumulative incidences of day 180 grade II-IV and III-IV acute GVHD (aGVHD) were 52% (95%CI :42–62) and 24% (95%CI :15–32), respectively. The median onset was 40 days (range 14–161); the gut was most commonly affected (43/54, 80%) followed by skin (35/54, 65%). Twenty-five patients with mainly grade II gut aGVHD were treated with budesonide alone, 26 patients with predominantly grade III-IV aGVHD received systemic corticosteroids, and complete or partial treatment response was achieved in over 80% by day 56 of therapy. However, 41 patients had active GVHD after day 100 with the majority (25/41, 61%) having aGVHD (persistent, recurrent or late onset), particularly of the gut. Overlap syndrome and classical chronic GVHD were uncommon. Only 1 patient had oral ulceration, and no patient had moderate or severe ocular or sclerotic skin involvement, joint, or pulmonary GVHD manifestations. Univariate analysis of the association between patient/ graft characteristics and grade III-IV aGVHD showed the only significant factor associated with a higher severe aGVHD incidence was age 0–15 years (Figure). Diagnosis, patient ancestry, cytomegalovirus seropositivity, conditioning intensity, and infused cell doses/kg (total graft and engrafting-unit nucleated cell, CD34+ and CD3+) were not significant. A higher engrafting unit-recipient HLA-match of 8–9/10 was associated with a lower incidence of severe aGVHD, and a better unit-unit HLA-match of 6–10/10 was associated with a higher incidence of severe aGVHD, although these differences were not significant (p = 0.128 and 0.266, respectively). To further investigate these findings multivariate Cox regression analysis was performed (Table). Younger age was independently associated with a higher incidence of severe aGVHD (p = 0.042) whereas better engrafting unit-recipient match at 8–9/10 HLA-alleles was protective (p = 0.053). There was a trend toward better unit-unit HLA-match being associated with a higher incidence of grade III-IV aGVHD, but, surprisingly, total infused TNC/kg had no relationship. The 2-year PFS of 72% (95%CI :51–94) in children was higher than the 56% (95%CI :45–66) in adults despite their greater incidence of severe aGVHD. Nine patients (all adult) have died of GVHD including 5 patients initially treated with systemic corticosteroids and 4 with budesonide. We conclude that aGVHD after DCBT is common in the absence of ATG, predominantly affects the gut, and has a high rate of treatment response. Furthermore, GVHD after day 100 frequently has acute features. While the GVHD incidence does not preclude a high rate of survival, improved prophylaxis and treatment are needed. Notably, in contrast to single-unit CBT and adult hematopoietic stem cell transplantation, children receiving DCBT are at a higher risk for severe disease. A possible approach to reduce aGVHD in pediatric DCBT recipients with adequate CB units doses would be to prioritize high resolution HLA-match. Moreover, our data does not currently support an upper limit of infused TNC/kg in DCBT recipients. Further investigation of the biology underlying these unique observations (including the role of specific cellular subsets) should be a major priority. Disclosures: Off Label Use: Mycophenolate Mofetil as GvHD prophylaxis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3044.3044
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 5
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    Adenovirus Viremia and Disease: Comparison of T Cell–Depleted and Conventional Hematopoietic Stem Cell Transplantation Recipients from a Single Institution
    Elsevier BV ; 2013
    In:  Biology of Blood and Marrow Transplantation Vol. 19, No. 3 ( 2013-03), p. 387-392
    Details
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 19, No. 3 ( 2013-03), p. 387-392
    Type of Medium: Online Resource
    ISSN: 1083-8791
    URL: Article
    DOI: 10.1016/j.bbmt.2012.10.014
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
    detail.hit.zdb_id: 3056525-X
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  • 6
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    Serious Infection Risk and Immune Recovery after Double-Unit Cord Blood Transplantation Without Antithymocyte Globulin
    Elsevier BV ; 2011
    In:  Biology of Blood and Marrow Transplantation Vol. 17, No. 10 ( 2011-10), p. 1460-1471
    Details
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 17, No. 10 ( 2011-10), p. 1460-1471
    Type of Medium: Online Resource
    ISSN: 1083-8791
    URL: Article
    DOI: 10.1016/j.bbmt.2011.02.001
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2011
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  • 7
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    Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation
    American Society of Hematology ; 2012
    In:  Blood Vol. 119, No. 11 ( 2012-03-15), p. 2644-2656
    Details
    In: Blood, American Society of Hematology, Vol. 119, No. 11 ( 2012-03-15), p. 2644-2656
    Abstract: We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2011-08-371971
    RVK:
    XA 33000
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 8
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    Third Party Donor Derived EBV Specific T Cells for the Treatment of Refractory EBV-Related Malignancies in Immunodeficient Recipients
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 577-577
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 577-577
    Abstract: Abstract 577 Adoptive immunotherapy is an effective strategy for the treatment of EBV+ lymphoproliferative diseases (EBV-LPD) arising after an allogeneic hematopoietic stem cell (HSCT) or solid organ transplant (SOT). This approach is, however, often limited by an inability to generate donor derived in vitro expanded EBV-specific cytotoxic T-lymphocyte (EBV-CTL) lines in a timely manner and/or the fact that EBV CTL lines derived from HLA non-identical donors may be restricted by non-shared HLA alleles. To date, we have treated 25 consecutive patients with an EBV LPD (N=20) or EBV Leiomyosarcoma (LMS) (N=5) with in vitro expanded EBV-CTLs derived from a donor other than the patient or their transplant (HSCT or SOT) donor. EBV CTLS were selected from a bank of 345 lines generated under GMP conditions from normal HSCT donors. Each donor was specifically consented for use of their T cells in patients other than their designated transplant recipient. Patients were recipients of unmodified (n=4), T cell depleted (n=5) or unrelated cord blood (n=5) HSCT, a solid organ transplant (n=6), a combined SOT and HSCT (n=1), or were non-transplanted patients with a primary immunodeficiency disease (n=4). EBV disease in transplanted patients was of host origin in 5 of 10 evaluable HSCT recipients, in 3 of 4 evaluable solid organ recipients, and in the one patient who underwent a combined HSCT/solid organ transplant. Third party EBV-CTLs were selected on the basis of HLA matching at a minimum of 2/8 recipient alleles. Where possible EBV-CTLs were selected that were restricted through HLA alleles present on the EBV+ tumor. HLA restriction was evaluated in vitro in 20 EBV-CTL donor lines. The restriction was at a single HLA allele (n=12), at two alleles (n=6) and at 〉 than two alleles (n=2). Patients received infusions of 3rd party EBV-CTLs after failing a median of 2 prior therapies including rituximab in all but one case of EBV LPD. Four patients failed prior infusions with EBV-CTLs which were autologous (n=1), derived from their original HSCT (n=2) or from their solid organ donor (n=1). In two patients who progressed after treatment with EBV CTLs generated from their HSCT or organ donor, it was demonstrated that the donor derived EBV CTLs were restricted by a non-shared HLA allele. Patients received a median of 5 infusions most at 1×106 EBV-CTL/kg/infusion. Four patients received EBV-CTLs from 〉 1 3rd party donor. Nine patients achieved a completed response. Nine patients died of progressive disease, 6 shortly after the first infusion (17–29 days). Two patients with LMS achieved long term stable disease (46 and 8 months); 5 achieved partial remissions which have been sustained in 4 (11- 68 months), and 1 patient progressed after 10 months in a partial remission. Response to EBV CTL therapy did not correlate with the degree of HLA matching between donor and recipient or donor and tumor. Radiographic and clinical responses correlated with detectable increases in the frequency of CTL precursors in the blood. However durable EBV CTL engraftment was not seen. One patient developed mild skin GvHD after infusion with 3rd party EBV-CTLs, but tolerated subsequent infusion of EBV-CTLs from an alternate 3rd party donor. Although no SOT recipient developed anti-HLA antibodies, one developed and episode of steroid responsive renal transplant rejection more than 6 months after infusion of EBV CTLs without evidence of donor (by STR analysis) in biopsied tissue. This study demonstrates a high response rate among patients with otherwise refractory EBV malignancy treated with EBV specific 3rd party CTLs restricted by HLA alleles shared by the tumor. Treatment failures correlated with the use of EBV CTLs restricted by HLA alleles not shared by the tumor. In addition two patients with a primary immunodeficiency disease who were unable to mount an endogenous EBV T cell response had transient but not durable responses to 3rd party cells. EBV CTLs can be effective when selected based on restriction to shared alleles despite significant HLA disparity. The bank of EBV specific T cells can provide an immediate source of HLA partially matched appropriately restricted T cells for adoptive immunotherapy to treat EBV associated malignancy. This enables treatment early in the course of disease and the use of EBV-CTL lines previously prepared and characterized in terms of HLA restriction. This is anticipated to maximize the response rate. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.577.577
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 9
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    Unrelated Donor T-Cell Depleted (TCD) Hematopoietic Stem Cell Transplantation (HSCT) for Patients with Advanced Myelodysplastic Syndromes (MDS): The MSKCC Experience
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1996-1996
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1996-1996
    Abstract: Abstract 1996 The outcomes of unrelated HSCT have markedly improved with the advent of high resolution HLA-typing. However, graft-versus host disease (GvHD) remains a limiting factor, particularly in mismatched transplants. Several studies have demonstrated that TCD reduces the incidence of acute and chronic GvHD, potentially allowing for improved outcomes in the mismatched setting. We have observed excellent long term survival in our early experience performing matched related TCD HSCT in patients with advanced MDS, particularly in patients who achieve a complete remission (CR) or second refractory cytopenia phase (RCy2) prior to transplant. We report here our experience performing unrelated TCD HSCT in 85 consecutive patients with advanced MDS. From 1989–2011, 85 patients with advanced MDS (IPSS Intermediate risk [IR]-1 or higher) and AML transformed from MDS underwent TCD HSCT (18 bone marrow [BM] , 67 mobilized peripheral blood [PB]) from unrelated donors following conditioning with a total body irradiation-based (25 patients) or a busulfan-based (60 patients) myeloablative regimen. 49 donors were fully matched and 36 were partially matched (9/10 HLA matched: 23; 8/10 HLA matched: 8; 7/10 HLA matched: 1; and 5/6 HLA matched: 4 [before high resolution typing] ). The median age was 55 (range 4–73). Prior to conditioning, 80 patients received chemotherapy (28 with a hypomethylating agent, 65 with intensive chemotherapy, and nine with both) and five patients did not receive chemotherapy. Prior to transplant, 34 of the 80 patients who received chemotherapy were in CR, 30 were in RCy2, and 15 failed to achieve remission (10 with RAEB, 5 with AML). Of the five patients who did not receive chemotherapy, two had refractory anemia and three had RAEB. The BM grafts were depleted of T-cells using the soybean agglutinin method followed by sheep RBC rosetting, and the G-CSF mobilized PB stem cell grafts were depleted of T-cells using immunomagnetic CD34+ selection (Isolex initially and CliniMACS after 09/2011). Rejection prophylaxis with ATG was used in all patients. No post-transplant pharmacologic prophylaxis for GvHD was given. 82 of 85 patients engrafted (92%). Three died before engraftment (3.5%, all 〈 28 d after transplant) and two developed late graft failure (2.4%). The day-100 cumulative incidence (CI) of grade II-IV aGVHD was 19% (95% confidence interval [95%CI] 11%-28%), and the 1-year CI of aGvHD, including the late onset form, was 28% (95%CI 18%-38%). When only including grade III-IV aGVHD, the day-100 CI was 9.4% (95%CI 4.3%-17%) and the 1-year CI was 16% (95%CI 9.4%-25%). The 2-year CI of cGVHD was only 3.5% (95%CI 0.9%-9.1%). The overall survival (OS) was 53% (95%CI 43%-63%) at two years and 44% (95%CI 35%-75%) at five years. The relapse free survival (RFS) was 46% (95%CI 36%-57%) at two years and 41% (95%CI 31%-52%) at five years. There was no significant difference in OS/RFS among patients transplanted with fully HLA-matched, 9/10 HLA-matched, or 7–8/10 HLA-matched grafts. There was a trend towards worse OS in patients who had a poor risk (HR) IPSS score at any time prior to transplant; the 2-year OS in this group was 43% (95%CI 32%-60%) versus 64% (95%CI 49%-82%) in the IR-1/IR-2 IPSS groups (p=0.08). Likewise, there was a trend towards worse OS in patients who failed to achieve CR or RCy2 prior to transplant (2-year OS 32% [95%CI 16%-64%] ), as compared with patients who achieved CR or RCy2 (2-year OS 58% [95%CI 48%-71%], p=0.25). The overall 1-year CI of relapse was low at 13% (95%CI 7%-21%). The 1-year CI of relapse was significantly higher in patients with IPSS poor risk cytogenetics (27%, 95%CI 5.2%-55%) as compared with intermediate (18%, 95%CI 0.1%-65%) and good (8.4%, 95%CI 0.04%-45%) risk cytogenetics (p=0.03). The 1-year NRM was 36% (95%CI 23%-49%) in those with HR disease and only 18% (95%CI 7%-33%) in those with IR-1/IR-2 risk disease. 5-year OS was superior in transplants done from 2000–2011 (48%, 95%CI 36%-59%) compared with 1989–1999 (25%, 95%CI 6%-50%, p=0.01), reflecting the availability of high resolution HLA-typing and improvements in supportive care. These results indicate that patients with advanced MDS can achieve durable remissions and long term survival after unrelated TCD HSCT with low rates of acute and chronic GVHD even with mismatched donors. Selecting patients for HSCT before progression to IPSS HR disease and induction into CR or RCy2 prior to transplant may maximize the efficacy of this approach. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1996.1996
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 10
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    Vaccine Response In Recipients of HLA Mismatched Unrelated Double Unit Cord Blood Transplantation (CBT).
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 1247-1247
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1247-1247
    Abstract: Abstract 1247 The use of CBT has increased steadily over the last decade, with recent studies showing long-term progression-free survival similar to that of unrelated volunteer donor transplant recipients. The ability of CBT survivors to respond to post-transplant immunizations may differ from other allogeneic transplant populations due to the lack of transfer of memory T- and B-cells with the graft. Limited data have been reported on vaccine responses following this treatment modality. We, therefore, analyzed responses to immunizations in 23 double-unit CB recipients (17 adults, 6 children) transplanted at our center from 10/05-12/08. Patients were transplanted at a median age of 34 years (range 7–61) for the treatment of acute leukemia (n=13), or lymphoma/CLL (n=8/2). They received high-dose myeloablative (n=11), reduced intensity myeloablative (n=5), or non-myeloablative (n=7) conditioning according to diagnosis, age, prior therapy, and co-morbidities. GVHD prophylaxis consisted of a calcineurin inhibitor and mycophenolate mofetil. No patient received ATG. The study patients had sustained engraftment with a 5/6 (n=12) or 4/6 (n=11) HLA-matched unit. Seven recipients received rituximab (median 4 doses, range: 4–8) as planned post-transplant therapy for B-cell malignancies (n=6) or treatment of an autoimmune hemolytic anemia (n=1). Eleven patients had a history of grade II-IV acute GVHD and 5 had ongoing late acute or chronic GVHD prior to vaccination. Criteria for vaccination were: CD4 cell count of at least 200 cells/ul, PHA of greater than 60% lower limit of normal and serum IgG level 〉 500 mg/dl at least 6 weeks following the last dose of IVIG. The median time to vaccination was 1.26 years post-CBT; this time was significantly longer in patients treated with Rituximab compared to those who were not (1.6 years versus 1.2 years, p=0.02), due to delayed normalization of B-cell numbers in the former group (449 days vs 108 days, p=0.004).Pre-vaccination titers obtained at a median of 1 year post-CBT demonstrated that over 85% of patients lacked protection against Pneumococcus, H. influenzae, and Pertussis, and at least 50% lacked immunity against tetanus, measles, and mumps. Seroconversion or 〉 3- fold rise in titer was observed in response to tetanus, diphtheria, H. influenzae, and Pneumococcus in 90% (18/20), 81% (13/16), 80% (16/20)and 90% (18/20) of patients and was not significantly different in patients with or without a history of acute or chronic GVHD. Whereas 90% (5/6) of patients without a history of GVHD responded to a series of Hepatitis B immunizations, only 22% (2/9) of those with prior acute and/or chronic GVHD did so (p=0.03). No patient was protected against pertussis following a single TDaP (n=14) and only 1 of 5 patients responded to the protein conjugated meningococcal vaccine. Immunization with a live attenuated vaccine was initiated in 7 seronegative patients, including all 6 children, at a median of 2.25 years (range 1.5–3.6) post-CBT (MMR, n=7, Varivax, n=3). Seroconversion against measles, mumps, rubella, or chickenpox was observed in 3/7, 2/7, 6/7, and 1/3 patients, respectively. There were no serious reactions to any vaccine. These data suggest that CBT recipients are capable of responding to tetanus, diphtheria, H. Influenza and pneumococcal vaccines similar to other transplant groups. Nonetheless, the sub-optimal response to pathogens associated with outbreaks in the community (Hepatitis B, Pertussis, meningococcus, measles, mumps, varicella) highlight the need to obtain pre- and post-vaccination titers to document response, as well as define the optimal schedule of post-transplant immunizations specifically in this transplant population. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.1247.1247
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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