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  • 1
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    A Phase II Trial of Peri-Transplant Palifermin with Busulfan, Melphalan and Fludarabine Followed by T-Cell Depleted Hematopoietic Stem Cell Transplants in Patients with Advanced Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) Evolved From MDS
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1935-1935
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1935-1935
    Abstract: Abstract 1935 Introduction: The success of allogeneic HSCT in the treatment of advanced MDS has been limited by high incidence of relapse and transplant-related mortality (TRM). The main complications contributing to TRM are graft-vs-host disease (GvHD) and infections. Although T cell depletion has successfully reduced the incidence of GvHD, slow immune reconstitution and high rate of infections have compromised its full potential. T cell reconstitution after transplant requires a functional thymic epithelium. Transplant conditioning regimens damage the thymus and impair the production de novo of T cells. Keratinocyte growth factor (KGF) has an important role in healing the epithelium after injury. Palifermin, a human recombinant form of KGF, decreases the incidence and duration of mucositis after total body irradiation and has been approved by the FDA for this purpose in autologous and allogeneic HSCT. In murine models, KGF given before allogeneic transplant has a protective effect on the thymus and accelerates T cell reconstitution. The aim of this study was to assess whether administration of palifermin peri-transplant decreases TRM and improves the overall and disease-free survival (OS and DFS). This study was designed to reduce one- year TRM from 30% and 35% to 10% in HLA matched and mismatched arms, respectively. Patients: Between 11/2009–05/2012, 42 patients (advanced MDS: 26 or AML evolved from MDS: 16) enrolled on this trial. At transplant, 23 were in CR1, 3 were in second refractory cytopenia phase, and 16 had limited disease ( 〈 5% circulating blasts and 〈 9% marrow blasts). The median age was 57.5 years (1–65), with 22 males and 20 females. Conditioning consisted of busulfan (12 doses over three days of 0.8 mg/kg IV for patients 〉 4 years old or 1.0 mg/kg IV for patients 〈 4 years old), melphalan (70 mg/m2 IV × 2 days), fludarabine (25 mg/m2 IV × 5 days), and rabbit ATG pre-transplant (2 doses and 3 doses for HLA matched and mismatched recipients, respectively). Palifermin was given according to the approved dose for mucositis prevention: 60 mcg/kg/day IV for 3 consecutive days before the preparative regimen, and 3 doses post transplant (day 0, +24hours, +48hours). Donors were HLA matched (31; 13 related and 18 unrelated) or unrelated mismatched (11). G-CSF mobilized donor peripheral blood stem cells underwent CD34+ selection and depletion of T cells using CliniMACS immunomagnetic selection columns (Milteny Biotec). Results: All 42 patients engrafted, 1 patient developed secondary graft failure. The cumulative incidence of grade III-IV aGvHD at day +100 and 1 year were 4.8% and 10.5%, respectively. The latter increase was due to late-onset acute GvHD. Only 1 of 33 patients at risk developed moderate chronic GvHD. The 2-year OS and DFS were 77% and 65%, respectively, and similar in the two arms (HLA matched and mismatched). The CI of relapse at 1-year was 12 % (similar in the two arms). The 1-year TRM was 20%; 18.4% in the HLA matched group (accrual met) and 22% in the mismatched arm (accrual ongoing). Causes of death were: infections (N=5; 3 HLA matched, 2 HLA mismatched), regimen related toxicity (N=2, liver VOD) and relapse (N=1). The frequency of infections was similar to historical controls; at 3 months post transplant, 30% of patients developed active CMV, EBV, or adenovirus infections, at 6 months 16.6%, and at 12 months 7.1%. The 6-month CI of CMV viremia in CMV seropositive patients was 75% and the 6-month CI of EBV viremia was 31%. Immune reconstitution as measured by CD4 count was slow, similar to historical controls, with median absolute CD4 count at 3 months of 77 cells/μl and 200 cells/μl by 1 year posttransplant. Other parameters to assess safety of this regimen, namely duration of narcotics use and days on TPN to measure severity of mucositis were similar to historical controls (same preparative regimen without palifermin). Conclusion: In this ongoing phase II trial the addition of peri transplant palifermin to a chemotherapy only myeloablative conditioning regimen in recipients of TCD HSCT for advanced MDS decreased the TRM, although did not meet the primary objective of this study (reduction to 10%). Also, there was no reduction in the incidence of viral infections and no improvement in immune reconstitution. The reduction in TRM resulted from early detection of infection and improved treatment options. Disclosures: Perales: SOBI Biovitrum, pharma company: SOBI Biovitrum, pharma company Other. Goldberg:SOBI Biovitrum: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1935.1935
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 2
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    Reduced-intensity conditioning hematopoietic stem cell transplantation for chronic lymphocytic leukemia and Richter’s transformation
    American Society of Hematology ; 2021
    In:  Blood Advances Vol. 5, No. 14 ( 2021-07-27), p. 2879-2889
    Details
    In: Blood Advances, American Society of Hematology, Vol. 5, No. 14 ( 2021-07-27), p. 2879-2889
    Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) may potentially cure patients with chronic lymphocytic leukemia (CLL) and Richter’s transformation (CLL-RT) or CLL without RT, but the impact of novel agents on HSCT is unclear. CLL-RT patients have a grave prognosis, and their outcomes after HSCT are uncertain. We conducted a retrospective analysis of all 58 CLL patients, including 23 CLL-RT patients, who underwent reduced intensity conditioning (RIC) HSCT at Memorial Sloan Kettering Cancer Center (New York, NY) between September 2006 and April 2017. With a median follow-up of 68 months (range, 24-147 months), 5-year progression-free survival (PFS) was 40% (95% confidence interval [CI] , 28%-56%), and overall survival (OS) was 58% (95% CI, 48%-74%). The 1-year graft-versus-host disease/relapse-free survival (GRFS) was 38% (95% CI, 25%-50%). Patients with CLL-RT and CLL patients without RT had comparable outcomes. In both cohorts, treatment-sensitive response and ≤3 previous lines of therapy produced superior PFS and OS. Outcomes were agnostic to adverse cytogenetic and molecular features. Novel agents did not have a negative impact on HSCT outcomes. Total body irradiation (TBI)-containing RIC yielded inferior PFS, OS, and GRFS. CLL-RT patients older than age 55 years who had an HSCT Comorbidity Index score of ≥2 demonstrated inferior OS. This study, which is the largest series of RIC-HSCT for patients with CLL-RT, provides evidence supporting RIC-HSCT in early remission courses for patients with CLL-RT and poor-risk CLL patients. TBI-containing RIC should be considered with caution.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2020003726
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 3
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    Pilot Study To Evaluate The Prevalence Of Actionable Oncogenic Mutations In Patients With Relapsed Refractory Multiple Myeloma
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 755-755
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 755-755
    Abstract: Patients with multiple myeloma (MM) have realized improved survival with the development of multi-drug combinations using immunomodulatory drugs (IMiDs), proteasome inhibitors, and alkylating agents. Nevertheless, all MM patients eventually become refractory to available therapies, underscoring the importance of identifying additional rational therapeutic targets. Recent genomic studies using exome/copy number analysis have demonstrated that, at presentation, multiple myeloma is characterized by a dominant plasma cell clone and a heterogeneous group of subclones, with resistance emerging due to altered clonal dominance driven by therapeutic selective pressure or clonal evolution through the acquisition of additional mutational events. This suggests oncogenic mutations in dominant plasma cell clones in multiply relapsed disease may not only be involved in resistance, but should also be prioritized for further clinical development. Methods We performed a pilot study by sequencing DNA from cryopreserved whole bone marrow aspirate samples obtained pre-treatment from 28 patients with newly diagnosed myeloma (Cohort A) and 27 heavily pre-treated patients enrolled on a phase II clinical study of infusional carfilzomib (NCT01351623), a selective 2nd generation proteasome inhibitor (Cohort B). Genomic DNA and total RNA was isolated from all patient samples. Adaptor ligated sequencing libraries were captured by solution hybridization using two custom baitsets targeting 374 cancer-related genes and 24 genes frequently rearranged for DNA-seq, and 258 genes frequently rearranged for RNA-seq. All captured libraries were sequenced to high depth (Illumina HiSeq), averaging 712X for DNA and 〉 20,000,000 total pairs for RNA, to enable the sensitive and specific detection of genomic alterations. Results Median follow-up for both cohorts was 21 months (26.3m for A; 15.6m for B). Cohort B patients were treated with a median of 5 prior therapies, with 74% refractory to the non-selective 1st generation proteasome inhibitor bortezomib, 70% refractory to IMiD therapy, and 55% refractory to both therapies. 44% had high-risk cytogenetics. Responses to initial therapy in Cohort A demonstrated that 21%, 7%, and 7%, respectively harbored bortezomib--resistant, IMiD-resistant, or double-resistant myeloma at presentation. 28% of cohort A patients had high risk cytogenetics. We obtained high coverage, high quality sequence data for 54/55 cases and examined alteration prevalence in the 35 samples with sufficient plasma cell content. We observed a high frequency of mutations in the MAPK pathway, including mutually exclusive mutations in NRAS and KRAS in 48% of cases and BRAF V600E mutation in 3%. 14% of cases had TET2 frameshift/nonsense mutations or IDH2 mutations, suggesting the DNA hydroxymethylation pathway is targeted by recurrent somatic mutations in MM. Given that MEK/RAF inhibition has demonstrated efficacy in a spectrum of human tumors and that there are emerging data that epigenetic (decitabine and 5-azacytadine) and targeted (IDH2) therapies offer significant benefit in patients with TET2/IDH mutations, these data demonstrate that mutational profiling can identify patients with actionable mutations that can lead to novel therapies, including mechanism-based clinical trials. Taken together, we identified mutations in epigenetic modifiers in 41% of the patients in our cohort, including mutations in TET2/IDH, in chromatin modifying enzymes/scaffolds (ARID1A, ASXL1), and DNA methyltransferases (DNMT3A). Moreover, we identified novel mutations in DNA repair pathways (ATM, FANCA, FANCD2) and in FAT3, suggesting there are novel disease alleles, which require functional investigation for their role in MM pathogenesis. No differences in mutation frequency were found between bortezomib sensitive vs resistant MM cases present in either cohort. We did not identify mutations, which impacted progression free and overall survival in this small sample set. Conclusions We demonstrate next generation sequencing of unsorted bone marrow samples is feasible in MM and can rapidly identify actionable mutations based on genetic profiling of limited clinical isolates. These include the identification of mutations, which can guide therapeutic trials of clinically targeting specific oncogenic pathways (ex, MAPK or TET2/IDH) on an individual patient level. Disclosures: Lesokhin: Janssen Pharmaceuticals, Inc: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Foundation Medicine, inc: Consultancy. Brennan:Foundation Medicine, Inc: Employment. Wang:Foundation Medicine, Inc: Employment. Sanford:Foundation Medicine, Inc: Employment. Brennan:Foundation Medicine, Inc: Employment. Otto:Foundation Medicine, Inc: Employment. Nahas:Foundation Medicine, Inc: Employment. Lipson:Foundation Medicine, Inc: Employment. Stephens:Foundation Medicine, Inc: Employment. Yelensky:Foundation Medicine, Inc: Employment. Miller:Foundation Medicine, Inc: Employment. Levine:Foundation Medicine, Inc: Consultancy. Dogan:Foundation Medicine, Inc: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.755.755
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 4
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    Two Chemotherapy-Based Conditioning Regimens Compared To TBI-Based Conditioning Secure Consistent Engraftment Of T-Cell Depleted Allogeneic HSCT, Similarly Low Incidences Of Gvhd and Favorable Rates Of Disease-Free Survival (DFS)
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 546-546
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 546-546
    Abstract: To ascertain the therapeutic potential of non-TBI-based conditioning for CD34+ HPC-selected , T cell-depleted allografts, we conducted a trial comparing our standard regimen, arm (A) 1375cGy HFTBI+ thiotepa,5 mg/kg/day x 2 days + cyclophosphamide 60 mg/kg/day x 2 days vs. arm (B) Busulfex 0.8 mg/kg/6h x12 (dose adjusted) + melphalan 70 mg/kg/day x 2 + fludarabine 25 mg/m2/day x5 and arm (C) Clofarabine 20 mg/m2/day x 5 + melphalan 70 mg/m2/day x 2 + thiotepa 5 mg/kg/day x2, as preparation for T-cell depleted CD34+ PBSC transplants from GCSF-mobilized leukocytes fractionated with the CliniMACS device. Primary endpoints were engraftment, GVHD, transplant-related mortality (TRM) and 2 yr OS and DFS (Confer Table). Stratification of pts to arms A (standard), B or C was based on the patient’s disease, disease stage and clinical factors such as age, prior therapy or comorbidities enhancing risks of TBI. Arm B was the non-TBI arm predominantly used for myeloid and Arm C for lymphoid malignancies. Prior to transplant, recipients of HLA-matched or non-identical transplants received rabbit thymoglobulin at 2.5 mg/kg/day x2 or 3 days respectively, to prevent graft failure. No GVHD drug prophylaxis was given post transplant. A total of 181 consecutive patients, accrued between 5/13/2010 and 6/12/2013, were analyzed (81 in arm A, 78 in arm B, 22 in arm C). These pts have been followed for a median of 12.1 months. Donors were related or unrelated and HLA-matched for 74% of the patients and 1-2 HLA allele disparate for 26%. Median age for the entire group was 50.5 years, with older pts predominating in the non-TBI groups (medians arm A ,31.9 yrs; arm B , 61.9 yrs; arm C, 44.6 yrs). The CD34+ PBSC transplants provided a mean dose of 9.7x106 CD34+ progenitors/Kg (range 1.4-89.7) and 4.5x103 CD3+ T-cells/Kg (range 0.6-25.3). All pts engrafted; but 2 pts (2.5%) in arm B experienced late graft failure, one of whom was reconstituted after a secondary graft. Overall the incidence of grade II-IV acute GVHD was 18%, and 14% for recipients of HLA-matched grafts. TRM at 1 year was 10% in Arm A, and 15% in Arms B and C. Two year OS and DFS for each arm are: arm A, 66.7% and 58.4%; arm B 62.3% and 59.5%; arm C 52% and 53%. For the 101 pts who received standard risk transplants (i.e., pts with high risk forms of AML, ALL or NHL in 1o CR, AML in 2o CR, MDS RA/RCMD, CML in 1o CP or MM in CR1, VGPR or first PR ), 2 year OS and DFS are: arm A 68% and 62%; arm B 67% and 66%; arm C 86% and 86%, with relapse rates at 2 yrs of: arm A 23%, arm B 15%, and arm C 14%. These results thus identify two non-TBI-based conditioning regimens that secure consistent engraftment of rigorously T-cell depleted allogeneic HSCT and can yield favorable long-term DFS and OS with low incidences of GVHD and relapse. Table 1 Overall Results Graft 1 Year Acute GVHD II – IV 2 Year PTs ENG Failure TRM ALL HLA-Matched O.S. DFS ARM A 81 81 0 10% 23% 17% 66.7% 58.4% ARM B 78 78 2 15% 12.3% 13% 62.3% 59.5% ARM C 22 22 0 15% 27% 20% 52% 53% Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.546.546
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 5
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    The Disease Risk Index Predicts Outcomes Including Relapse and Survival in CD34-Selected Allogeneic HCT for Acute Leukemia and Myelodysplastic Syndrome
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 3498-3498
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3498-3498
    Abstract: INTRODUCTION: T-cell depleted allogeneic peripheral blood stem cell transplant (TCD PBSCT) using CD34 selection achieves relapse rates comparable to those of unmodified grafts (Pasquini et al., JCO 2012), but disease-related predictors of outcome have not been fully characterized in the TCD setting. We evaluated the prognostic utility of the refined Disease Risk Index (DRI; Armand et al., Blood 2014) in TCD PBSCT. METHODS: This was a retrospective analysis of patients who underwent first allogeneic HCT with TCD PBSCT for AML, ALL, or MDS at a single center between 1/2000 and 12/2015. Overall survival (OS), relapse-free survival (RFS), and chronic GVHD/relapse-free survival (CRFS) were estimated by the Kaplan-Meier method. Cumulative incidence of relapse, non-relapse mortality (NRM), acute GVHD (aGVHD), and chronic GVHD (cGVHD) were estimated using the cumulative incidence method for competing risks. The univariate association between variables of interest and OS/RFS/CRFS was evaluated using the log-rank test; Cox regression models assessed the adjusted effect of significant covariates on OS and RFS. Given only 1 patient with very high DRI, the high/very high DRI groups were combined. Similarly, given few patients with low DRI, the low/intermediate groups were combined in multivariate analysis. RESULTS: The analysis comprised a total of 519 patients. Median age was 55 years (range 18-73). There were 302 patients (58%) transplanted for AML, 144 (28%) for MDS, and 73 (14%) for ALL. Seventeen patients had low DRI scores (3%), 431 intermediate (83%), and 71 high/very high (14%). Median follow-up among survivors was 53.1 months (range 4.6-171.0). Two-year estimates for outcomes of interest were OS 62.8% (95% CI 58.5, 66.9), RFS 58.1% (95% CI 53.7, 62.3), and CRFS 54.0% (95% CI 49.5, 58.2). The cumulative incidence of relapse at 2 years was 17.3% (95% CI 14.2, 20.7). There were 0 relapse events in patients with low DRI, whereas intermediate and high/very high DRI scores were associated with a significantly increased incidence of relapse (p & lt; 0.001), with 2 year estimates 14.7% (95% CI 11.5, 18.3) and 37.1% (95% CI 25.8, 48.4), respectively. The cumulative incidence of NRM was 24.6% (95% CI 20.9, 28.4) at 2 years. The cumulative incidence of aGVHD at 100 days was 12.5% (95% CI 9.8, 15.5) for grade 2-4 and 2.5% for grade 3-4 (95% CI 1.4, 4.1); with a cumulative incidence of cGVHD of 4.7% (95% CI 3.1, 6.7) at 1 year. NRM, aGVHD, and cGVHD did not vary with DRI. In univariate analysis, DRI was associated with significant differences in OS, RFS, and CRFS (Table 1; Figure). Additional factors associated with poorer OS in univariate analysis were HCT-CI score & gt; 0, KPS & lt; 90, donor type (matched unrelated or mismatched vs. matched related donor), and age & gt; the median of 55.3 years; HCT-CI and KPS also correlated with significant differences in RFS. On multivariate analysis (Table 2), high/very high DRI corresponded to significantly greater risk of death (HR 1.72 for OS, [95% CI 1.24, 2.40]) and relapse or death (HR 1.86 for RFS [95% CI 1.35, 2.55] ), compared with low/intermediate DRI. Multivariate analysis also showed that KPS & lt; 90 was associated with worse OS and RFS, as did a higher HCT-CI score. Neither age nor donor type was significantly associated with OS in multivariate analysis. CONCLUSION: In a large cohort of patients undergoing first TCD PBSCT at a single center for acute leukemia or MDS, DRI score significantly correlated with relapse incidence as well as OS, RFS, and CRFS. We have previously shown that the HCT-CI score, which incorporates patients' baseline comorbidities, is also predictive of outcomes after TCD PBSCT. Combining these prognostic tools will serve to better select appropriate patients for TCD PBSCT, a transplant approach currently under investigation in a multicenter phase 3 trial (BMT CTN 1301). Disclosures Koehne: Atara Biotherapeutics: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.3498.3498
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 6
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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
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    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 7
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    Double-Unit Cord Blood (CB) Transplantation Combined With Haplo-Identical CD34+ Cell-Selected PBSC Results In 100% CB Engraftment With Enhanced Myeloid Recovery
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 298-298
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 298-298
    Abstract: Double-unit CB transplantation (DCBT) has provided high rates of sustained donor engraftment in patients with hematologic malignancies. However, delayed engraftment is frequent with a median neutrophil & platelet recovery of 25 & 48 days, respectively, in adult DCBT recipients at our center. This delay is associated with increased transplant-related mortality (TRM). It is also associated with prolonged hospitalization with a median discharge time of +42 days (range 25-76) in recent adult myeloablative DCBT recipients. Methods We investigated the combined transplantation of a 4-6/6 HLA-A,-B antigen, -DRB1 allele matched double-unit CB allograft (infused on day 0) with peripheral blood stem cell derived Miltenyi column selected haplo-identical CD34+ cells (haplo-CD34+, infused on day 0 or +1) to speed myeloid recovery. We used DCB grafts to facilitate comparison with historic/concurrent DCB controls transplanted without haplo-CD34+. Results Of 23 protocol eligible patients, 6/23 (26%) underwent DCBT only due to the lack of any suitable haplo-identical donor. Thus, 17 patients [median 39 years (range 16-69), median 78 kg (range 63-133)] were transplanted 9/2012-6/2013 with DCB plus haplo-CD34+ cells for high-risk hematologic malignancies. Diagnoses included 12 acute leukemias & 5 lymphomas. Conditioning was myeloablative with CSA/MMF immune suppression & no ATG. Median infused CB TNC x 107/kg was 2.29 (larger unit, range 1.73-2.95) & 1.82 (smaller unit, range 1.26-2.48). Haplo-identical donors (median 37 years, range 19-71) had a median donor-recipient HLA-match of 5/10 (range 5-7). 15 patients received the targeted infused haplo-CD34+ cell dose of 3 x 106/kg whereas 2 each received haplo-CD34+ cell doses of 1 x 106/kg. The median infused haplo-CD3+ dose was 0.6 x 103/kg (range 0.3-1.6). One patient died on day 14. Of 16 remaining evaluable patients, all (100%) engrafted with a median neutrophil recovery of 13.5 days (range 11-31) in 14 patients who received 3 x 106/kg haplo-CD34+ cells, and 26 and 18 days in the 2 patients who received 1 x 106/kg haplo-CD34+ cells. Platelet recovery ≥ 20 × 109/l has occurred in 12/15 patients (median 27 days, range 18-46) to date. Serial chimerism results demonstrating the contribution of haplo-CD34+ cells & each CB unit to date is shown (Table). While myeloid recovery on day 14 was predominantly haplo-CD34+ cell mediated, one CB unit dominated by day 28 in both neutrophil & T-cell subsets. The median total donor chimerism was 100% the dominant CB unit by day 100. With a median follow-up of survivors of 5 months (range 1-10), to date 9 of 15 evaluable patients have developed grade II-IV aGVHD by day 100 (7 grade II, 1 grade III, 1 grade IV). One patient with refractory leukemia transplanted with disease has relapsed, & 4 have died of TRM (2 organ failure, 1 grade IV aGVHD, 1 CMV infection). Excluding early deaths, of patients who were discharged in the first 100 days (n = 13), the median day of discharge was day +33 (range 21-60). Conclusions Double-unit CBT supplemented by haplo-CD34+ cells is safe. The incidence of neutrophil engraftment is high & the speed of neutrophil recovery is enhanced compared with recent DCBT controls. A shorter time of initial hospitalization (9 days) has offset the cost of the addition of haplo-CD34+ cells. It is intriguing that the dominant CB unit can rapidly reject the haplo-identical donor. This may be facilitated by omission of ATG, and the determinants of the speed of haplo-donor rejection are under investigation. Whether the same results could be achieved with a single CB unit plus haplo-CD34+ cells requires investigation. Addition of haplo-CD34+ cells is also an alternative to expansion, although expansion remains an important strategy to augmenting myeloid recovery given some patients do not have any suitable haplo-identical donors. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.298.298
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 8
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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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  • 9
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    T-Cell Depleted (TCD) Hematopoietic Stem Cell Transplantation (HCT) For Adult Patients With Acute Myelogenous Leukemia (AML) In First and Second Remission: Long-Term Disease Free Survival(DFS) With a Significantly Reduced Risk Of Graft-Versus-Host Disease(GvHD)
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 3387-3387
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3387-3387
    Abstract: Allogeneic-HCT is recommended for AML patients (pts) in CR2, in CR1 with poor-risk cytogenetics, and should be considered for those in CR1 with intermediate-risk. Non-relapse mortality (NRM) and GVHD remain major causes of treatment failure. Ex vivo TCD can prevent GvHD but large case series have not been published. Methods A retrospective chart review was conducted to evaluate 178 pts with AML in CR1 and CR2 undergoing TCD-HCT between 2001 and 2011. All pts received myeloablative-conditioning. The majority received ATG for graft rejection prophylaxis. Acute (A) and chronic(c) GVHD were assessed by standard criteria. No GVHD prophylaxis was administered post-transplant. Soybean agglutination+sheepRBC rosetting (sRBCR) was used for BM TCD. CD34+ selection +/- sRBCR was used for PBSC TCD. Pt characteristics were compared using Pearson's chi-squared and Fisher's exact tests. Prognostic factors relating to overall survival (OS) and DFS, including age, gender, leukemia etiology, cytogenetic-risk group, donor-type, TCD-method, conditioning-regimen, HLA match grade, HCT-specific comorbidity index and immune reconstitution were evaluated using log-rank test statistics. Differences in cumulative incidence (CI) rates were evaluated using Gray's test. Cox proportional-hazards regression was used to further adjust for pt risk factors for OS and DFS. Results Pt characteristics and outcomes are summarized in Tables 1 and 2. Median follow-up of survivors is 52 mo (12-134). 177 pts engrafted. One died pre-engraftment, 7 developed late graft-failure (GF), and 3 are alive after a 2nd HCT. One yr incidence of aGVHD was low (grade 2-4 13%, 3-4 3%). Only 1 pt developed cGVHD by NIH consensus criteria. Univariate association between CR status (1 vs 2), OS and DFS was not statistically significant (p=0.17 and 0.16, respectively). After adjusting for HLA status, age, sex, cytogenetic risk, and regimen, CR2 pts had an increased risk of death (HR: 1.90 (1.14-3.16), p= 0.014). In CR1 pts, cytogenetics was associated with relapse incidence (p=0.003) and was highest in patients with adverse cytogenetics (31%, 95%CI 16-48) and 〈 10% in intermediate I-II risk pts. Overall CI relapse at 1 and 2 yrs was 13% and 16%, respectively. Causes of death were: relapse (n=29), infection (n=25), GVHD (n=7), organ toxicities (n=5), GF (n=2) and other (n=7). Female gender was significantly associated with decreased OS and DFS (p 〈 0.002 and 0.003, respectively). Two yr estimates of OS and DFS in females vs males was 51% vs. 71% and 49% vs. 69%, respectively. These differences were due to a higher NRM in females receiving the chemotherapy based regimen (p 〈 0.001). Gender difference was not observed in pts receiving TBI-based regimens (p=0.599). This difference persisted after adjusting for other common prognostic factors in a multivariate model. For the entire group, 2yr OS and DFS was 67% and 62%, respectively. For CR1 pts, 2 yr OS and DFS was 70% and 64%, respectively (Fig.1). Conclusion These results support the use of TCD HCT in AML pts in CR. Durable DFS and long-term OS can be achieved with low rates of GVHD without compromising the graft-vs-leukemia effect. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.3387.3387
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 10
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    The Hematopoietic Cell Transplant-Co-Morbidity Index (HCT-CI) Predicts Outcomes After T Cell Depleted (TCD) Allogeneic HCT For AML and MDS
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 2045-2045
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2045-2045
    Abstract: Ex vivo TCD Allogeneic-HCT results in long-term relapse-free (RFS) and overall survival (OS) in patients with AML in CR or MDS, with a low incidence of acute and chronic graft-versus-host disease (GVHD). The HCT-CI predicts non-relapse mortality (NRM) and 1-year survival in recipients of conventional grafts. We investigated whether HCT-CI also predicted outcomes in ex vivo TCD-HCT in order to improve patient selection. Methods A retrospective chart review was conducted to evaluate 218 pts (median age 50.4) with AML in CR (n=155) or MDS (n=63) undergoing TCD-HCT between 1997-2008. All pts received myeloablative conditioning. The majority received ATG for graft rejection prophylaxis. No GVHD prophylaxis was administered post-transplant. TCD of BM utilized soybean agglutination+sheepRBC rosetting (sRBCR). CD34+ selection +/- sRBCR was used for PBSC TCD. HCT-CI was determined according to Sorror et al. (Blood 2005). Prognostic factors relating to OS and RFS, including age, conditioning-regimen (TBI vs. chemo), HLA match (identical vs. other), and HCT-CI were evaluated using log-rank test statistics. Univariate and multivariate Cox proportional-hazards regression were performed for OS & RFS. Results The median HCT-CI score was 2 (range 0-9). HCT-CI score was 0 (low) in 25% patients, 1-2 (intermediate) in 36% and ≥3 (high) in 39%. Median follow-up of survivors is 70 months (range 6.1-182.6). Outcomes of the univariate and multivariate analysis are summarized in Table 1. Age and HCT-CI score were significantly associated with OS and RFS by univariate and multivariate analysis. In addition, in the multivariate analysis, HLA-match was associated with OS and RFS, while regimen was only associated with RFS. Patients with a high HCT-CI had significantly lower OS and RFS than those with a low or intermediate HCT-CI (Figure 1). Furthermore, while the cumulative incidence of relapse did not differ based on HCT-CI, patients with a high HCT-CI had a significantly higher incidence of NRM compared to patients with low or intermediate HCT-CI (not shown). Conclusions These results support the use of the HCT-CI to stratify patients with AML and MDS who are eligible for myeloablative TCD-HCT and identify patients who are candidates for other approaches. Interestingly, unlike conventional grafts, we do not see worse outcomes (OS/RFS/NRM) in patients with intermediate vs. low HCT-CI, suggesting that patients with intermediate HCT-CI may better tolerate a TCD-HCT than a conventional HCT. A planned prospective three arm randomized Phase III, comparing two calcineurin inhibitor-free strategies for GVHD prophylaxis (CD34-selection and post-HCT Cy) to standard tacrolimus and methotrexate (BMT-CTN 1301) will further address these questions. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.2045.2045
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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