Significance of Missing Inhibitory KIR Ligands in Nonmyeloablative, HLA-Haploidentical (Haplo) BMT with Posttransplantation High-Dose Cyclophosphamide (PT/Cy)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 840-840 ◽  
Author(s):  
Yvette L. Kasamon ◽  
Leo Luznik ◽  
M. Sue Leffell ◽  
Hua-ling Tsai ◽  
Heather J. Symons ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Hematologic Malignancies ◽  
Donor Selection ◽  
Hla Typing ◽  
High Dose ◽  
Significant Difference ◽  
Grade Ii ◽  
The Impact

Abstract Abstract 840 Significance of Missing Inhibitory KIR Ligands in Nonmyeloablative, HLA-Haploidentical (Haplo) BMT with Posttransplantation High-Dose Cyclophosphamide (PT/Cy). Yvette L. Kasamon 1, Leo Luznik1, Mary S. Leffell1, Hua-Ling Tsai1, Heather J. Symons1, Javier Bolaños-Meade1, Gary Rosner1, Lawrence E. Morris2, Pamela A. Crilley3, Richard J. Jones1 and Ephraim J. Fuchs1, (1)Johns Hopkins University, Baltimore, MD, (2)Northside Blood and Marrow Transplant Program, Atlanta, GA, (3)Hahnemann University Hospital, Philadelphia, PA Introduction: NK cells can influence haplo BMT outcomes including risks of relapse and GVHD. Our group previously reported that, in allogeneic BMT for hematologic malignancies that incorporates PT/Cy, donor-recipient iKIR (inhibitory killer-cell immunoglobulin-like receptor) gene mismatches and having a KIR haplotype B donor were associated with improved outcomes (BBMT 2010;16:533). Because the reported impact of NK cell alloreactivity models in haplo BMT has been variable and some models are relevant to donor selection, we expanded our analysis of iKIR ligand status in this transplantation platform. Patients and methods: Outcomes of 212 uniformly treated patients (pts) enrolled on two similar clinical trials of related-donor, haplo BMT were retrospectively analyzed. Planned treatment consisted of fludarabine (30 mg/m2 IV on days −6 to −2), Cy (14.5 mg/kg IV on days −6 and −5), total body irradiation (200 cGy on day −1), and non-T-cell depleted bone marrow infusion. GVHD prophylaxis consisted of high-dose Cy (50 mg/kg IV on days 3 and 4), mycophenolate mofetil on days 5–35, and tacrolimus on days 5–180 without taper, with filgrastim begun on day 5. All pts (median age 51, range 1–73) had poor-risk hematologic malignancies; 60 (28%) had prior BMT. Diagnoses were Hodgkin lymphoma (31 pts), NHL (69), CLL (21), multiple myeloma (6), acute leukemia or lymphoblastic lymphoma (62), MDS (9), CML (9), CMML (4), PV (1). Missing ligands (ML; defined as absence in the recipient of one or more HLA ligands for iKIRs) and donor/recipient iKIR ligand incompatibility (LI; defined as presence of an iKIR ligand in the donor that is absent in the recipient) were determined using high-resolution HLA typing of class I alleles. For study purposes, HLA-A*2301, A*2402, and A*3201 were included in the Bw4 serologic group and effects attributable to HLA-A3 and A11 ligand groups were excluded. Results: With a median 2.9 year follow-up (range, 0.3–7 years) in pts without events, the actuarial 2-year progression-free survival (PFS) was 34%. On competing-risk analysis, cumulative incidences of grade II–IV acute GVHD and chronic GVHD were 28% and 14%, respectively; 1-year cumulative incidences of relapse and nonrelapse mortality (NRM) were 42% and 14%. Baseline characteristics in pts with ML (157 pts, of whom 76 had LI) and without ML were similar. On univariate analysis, pts with LI had no significant difference in PFS (figure A), grade II–IV acute GVHD, relapse or NRM compared to those without LI. In contrast, as compared to no ML, the presence of ML was associated with a statistically significantly improved PFS on univariate analysis (hazard ratio [HR] = 0.68, p = 0.03; figure B). This association was not identified in our previous analysis, potentially due to underpowering or inclusion of pts receiving one dose of PT/Cy. No statistically significant difference was detected according to the presence or absence of ML in the cumulative incidences of acute GVHD, relapse, or NRM, although presence of ML was associated with a tendency toward lower NRM risk (HR = 0.61, p = 0.17). On multivariate analysis, the presence of ML was found to be independently associated with a significant improvement in PFS (HR = 0.66, p = 0.03). This multivariate model also confirmed our previous observation (BBMT 2010;16:482) that greater donor-recipient HLA disparity was not detrimental to PFS (HR = 0.57, p = 0.04 for 3–4 antigen mismatches versus fewer at HLA-A, B, C, and DRB1 combined). We are currently investigating the impact of KIR haplotypes in this setting with the goal of optimizing donor selection. Conclusion: The presence of ML may be beneficial in haplo BMT with postgrafting immunosuppression that includes high-dose Cy. Further studies are needed to confirm and define the mechanisms of this effect. Our findings do not support selection of donors on the basis of LI in this transplantation platform. Disclosures: No relevant conflicts of interest to declare.

Antithymocyte Globulins (ATG) as Part of the Myeloablative Conditioning (MAC) Regimen Can Reduce the Risk of Severe Graft-Vs.-Host Disease (GVHD) after Allogeneic Stem Cell Transplantation (allo-SCT) from Matched-Unrelated Donors (MUD).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1151-1151
Author(s):  
Mohamad Mohty ◽  
Marie- Lorraine Balere ◽  
Gerard Socie ◽  
Noel-Jean Milpied ◽  
Norbert Ifrah ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Beneficial Effect ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Hla Typing ◽  
High Dose ◽  
Increased Risk ◽  
Grade 3

Abstract The use of ATG in the setting of standard MAC allo-SCT is still controversial. Some studies, however, suggested a beneficial effect of ATG in preventing acute GVHD. Here, we report the results of a large multicenter retrospective study analyzing the effect of ATG, incorporated within the MAC regimen for MUD-transplants in leukemic patients compared to patients not receiving ATG. The purpose of the study was to compare the incidence and severity of acute and chronic GVHD as well as non-relapse mortality (NRM), leukemiafree and overall survivals (LFS, OS). The study included 171 adult patients with acute leukemia and MDS (73% standard risk and 27% more advanced disease) reported to the registry of the SFGM-TC between 1998 and 2004, and for whom detailed allelic HLA typing (4 digits) for the recipient and the donor was available. Patients’ characteristics were as follow: median age: 33 (range, 15–67), 57% male recipients, 35% female donors, 44% AML, 43% ALL, 11% MDS and 2% unclassified leukemia. The stem cell source was bone marrow in 72.5% of patients, while PBSCs were used in 27.5% of cases. 81% of patients were transplanted from 10/10 allelic MUD, and 19% from a MUD with at least one allelic difference. A high dose TBI-based MAC regimen was used in 84% of cases, while 16% received a high-dose chemotherapy containing MAC regimen. 85% of the patients received the classical CsA and short course methotrexate GVHD prophylaxis regimen. In this series, 120 patients (70%) did not receive ATG (“no-ATG” group), while 51 patients received ATG (“ATG” group; Thymoglobuline*-Genzyme in all cases; total ATG dose: ≤5 mg/Kg, n=13; >5 and <10 mg/Kg, n=17; ≥10 mg/Kg, n=21) as part of the MAC regimen. Except for a significantly higher number of allelic differences between recipient and donor (33% vs. 13%; P=0.002), the “no-ATG” and “ATG” groups were strictly comparable as for patients, disease and transplant characteristics. 95% of patients had a sustained engraftment at a median of 20 (range, 9–41) days after allo-SCT with no significant differences between the 2 groups. With a median followup of 30.3 (range, 2.6–68.1) months after allo-SCT, grade 0–1 and 2–4 acute GVHD occurred in 74 (46%) and 88 patients (54%) respectively, with grade 3–4 acute GVHD being significantly lower in the “ATG” group as compared to the “no-ATG” group (18% vs. 32%; P=0.04). In this series, 142 patients (83%) were evaluable for chronic GVHD. Limited and extensive chronic GVHD were observed in 22 and 25% of assessable patients respectively, with extensive chronic GVHD being significantly lower in the “ATG” group as compared to the “no-ATG” group (5% vs. 33%; P=0.001). Interestingly, patients from the “ATG” group had a higher incidence of limited chronic GVHD (33% vs. 18%; P=0.06). The use of ATG was not associated with a higher risk of infections: infection-related mortality was comparable between both groups (23% vs. 27%, P=NS). Also, NRM was comparable between both groups (30% vs. 29%; P=NS). In multivariate analysis including all relevant risk factors tested in the univariate analysis, we found that an HLA allelic mismatch and the non-use of ATG were associated with an increased risk of severe grade 3–4 acute GVHD (RR=2.80, 95%CI, 1.5–5.3), P=0.001; and RR=2.4, 95%CI, 1.1–5.0, P=0.02 respectively). Similarly, multivariate analysis showed that the absence of use of ATG was the unique and strongest parameter associated with an increased risk of extensive chronic GVHD (RR=6.9; 95%CI, 1.7–29.0, P=0.008). Finally, LFS and OS at 2 years were not significantly different between the “no-ATG” and “ATG” group (48.8% vs. 41.3%, P=NS; and 53.6% vs. 54.3%, P=NS; respectively) Despite its retrospective nature, these results strongly indicate a global long-term beneficial effect of ATG when used as part of the MAC regimen prior to allo-SCT from MUD (especially in the HLA mismatch setting). Though prospective studies are needed to assess the optimal ATG dosing and administration schedule, such protective effect of ATG against severe acute and chronic GVHD, can be likely achieved without an increased risk of infections or leukemia recurrence.

Age and Disease Status Are Important Risk Factors for Outcome after Reduced Intensity Conditioning (RIC) Umbilical Cord Blood Transplantation (UCBT) in Adults

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4412-4412
Author(s):  
Sabine Fürst ◽  
Catherine Faucher ◽  
Jean El Cheikh ◽  
Jean Marie Boher ◽  
Patrick Ladaique ◽  
...  
Keyword(s):  
High Risk ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Disease Status ◽  
Significant Difference ◽  
Grade Ii ◽  
Grade Iii

Abstract UCBT in adult patients with hematological malignancies has significantly increased over the last 5 years. In addition, the introduction of RIC regimens can allow a decreased incidence of TRM. Thus, the use of UCBT after a RIC regimen can represent an attractive treatment modality for those high risk patients who lack a suitable HLA-matched donor. The aim of this analysis was to assess the outcome of 35 patients who received RIC UCBT in a single centre between 2005 and 2008. All 35 patients had high risk hematological malignancies (AML, n=19; ALL, n=9; NHL, n=5; CML, n=1; and Hodgkin disease, n=1). 27 patients (77%) were in CR (CR1, n=18; CR2, n=8; CR3, n=1), whereas 8 had a more advanced disease (PR, n=2; refractory, n=6) at time of UCBT. Of note, 12 patients (34%) have already received and failed prior autologous transplantation. The median age and weight was 44 (range, 17–62) years and 63 (range, 44–125) kg with 13 patients (37%) older than 50 years (range 51–62). The RIC regimen included Fludarabine 200 mg/m2, Cyclophosphamide 50 mg/kg and low dose TBI (2 Gy). All patients received CSA and MMF for GVHD prophylaxis. 13 patients (37%) received a single CB unit, whereas 22 (63%) received 2 CB units in order to achieve a minimum required cryopreserved cell dose of 3.0×10e7 TNC/kg. For the entire group, the median cryopreserved and infused cell doses were 4.8×10e7 TNC/Kg (range, 3.3–7.0) and 3.7×10e7/Kg (range, 1.9–5.5) respectively. 94% of the patients received 1–2 HLA mismatched grafts. Neutrophil engraftment (ANC>500/μL) occurred in 33 patients (94%) at a median of 20 (range, 6–45) days and a sustained platelets recovery (>50000/μL) was observed in 25 patients (71%) at a median of 36 (range, 23–136) days after UCBT. Hematological recovery was comparable between single and double CB unit recipients. Primary and secondary graft failure occurred in 4 and 1 patients respectively (AML, n=2; ALL, n=1; CML, n=1; NHL, n=1). Two out of these 5 patients underwent and failed a second UCBT. The overall incidence of grade II–IV acute GVHD was 54% (95%CI, 41–77%; 7 grade II, 10 grade III and 2 grade IV). 19 patients were evaluable for chronic GVHD for an overall incidence of 37% (8 limited and 5 extensive cases). 20 patients (57%; 95%CI, 42–76 %) with experienced at least one episode of a “serious” or “life-threatening” infectious complication (virus other than CMV reactivation, n=11; bacteria, n=10; fungal, n=4) at a median time of 74 (range, 0–595) days after UBCT, requiring long-term hospitalization, and of whom 8 patients were in grade III–IV acute GVHD. 7 patients (20%) experienced severe interstitial pneumonia, with 4 patients (11%) developing ARDS. Most importantly, 5 patients (14%) also required transfer to ICU. With a median follow-up of 468 (range, 105–1170) days, 10 patients (28%) had relapsed or progessed with this being significantly lower in those patients transplanted in CR (P=0.01), but without a significant difference between single and double CB recipients. 14 patients have died (infection, n=5; GVHD, n=3; relapse, n=6; TRM=23%). The KM estimate of OS and DFS was 61% (95%CI, 42–75%) and 52% (95%CI, 34–67%) at 2 years respectively for the entire population. On univariate analysis younger age at transplant and disease status in CR were the only factors associated with significantly better outcome. Although our patients population is small, we conclude that RIC UCBT is an efficient therapy for high risk hematological malignancies. Age and the disease status at transplant are crucial for patients outcome and further efforts are needed to define risk factor specific transplant procedures. Infectious complications and GVHD are still a matter of concern warranting better strategies to provide optimal prophylactic approaches.

Post-Transplantation High-Dose Cyclophosphamide (Cy) Is Effective Single Agent GVHD Prophylaxis That Permits Prompt Immune Reconstitution after Myeloablative HLA Matched Related and Unrelated Bone Marrow Transplantation (BMT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2891-2891 ◽  
Author(s):  
Luznik Leo ◽  
Chen R. Allen ◽  
Kaup Michele ◽  
Bright C. Emilie ◽  
Bolanos-Meade Javier ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Gvhd ◽  
Single Agent ◽  
High Dose ◽  
Post Transplantation ◽  
Cell Counts ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
The Impact

Abstract Prolonged pharmacologic immunosuppression is a major obstacle to early immunologic recovery after allogeneic BMT. Based on our results in animal models, we studied whether properly timed high-dose Cy post-HLA matched related and unrelated BMT is an effective strategy for limiting GVHD; we hypothesized that avoiding prolonged immunosuppression would speed immune recovery and reconstitution of regulatory T cells (T regs) thereby decreasing post-transplant complications. We are reporting results on 46 consecutive patients (median age 41, range 1–64) with high-risk hematologic malignancies (20 AML, 12 ALL, 6 NHL, 3 HD, 2 MM, 2 CML, 1 CMMoL); 28 received related and 18 unrelated unmanipulated HLA-matched BM (median of 2.2 x 108 MNC per kg) after conditioning with busulfan on days -7 to -3 and Cy (50 mg/kg/day) on days -2 and -1, and followed by Cy (50 mg/kg/day) on days +3 and +4 as the sole GVHD prophylaxis. All the patients had advanced disease (20 in advanced remission with the rest having refractory disease), and the median follow-up is 13 (range 6–24) months. All but two patients had sustained engraftment. The cumulative incidence of acute grades II–IV and grades III–IV GVHD were 41% and 9%, respectively. All patients with GVHD responded fully to standard therapy (steroids ± tacrolimus) or therapy per BMT CTN0302, and all except 2 patients were rapidly weaned from all immunosuppressive agents. Of the thirty-six patients alive after day 100, only 1 of the 23 patients that received HLA-matched related, and 3 of 13 patients that received unrelated allografts, developed chronic GVHD. Twenty-six (56%) patients are alive, of whom 21 (45%) are in complete remission. There were no deaths secondary to infection or GVHD. CMV reactivation was detected in 11 of 36 (31%) patients, of whom 9 had GVHD. There was no CMV infection. Median (± SEM) CD4+ T cell counts were 99 ± 16/mL and 209 ± 49/mL on days 60 (n = 23) and 180 (n= 8), respectively. Corresponding values for CD8+ T cells were 248 ± 132/mL and 228 ± 161/mL on days 60 and 180, respectively. Patients with grade II–IV GVHD had significantly fewer peripheral blood (PB) CD4+Foxp3+ T cells compared to patients with grade 0–I GVHD (p<0.05). Development of grade II–IV GVHD negatively correlated with the expression of the Foxp3 (p<0.05) and was associated with relatively higher expression of interferon-γ mRNA (p=0.08) in PB, suggesting higher effector function in the absence of Tregs in patients with grade II–IV GVHD. No differences in IL-10 mRNA expression between patients with or without GVHD were found, while significantly higher expression of interleukin-2 mRNA was detected in patients with grade II–IV GVHD (p<0.025). These results indicate that high-dose post-transplantation Cy is effective as a single agent strategy for limiting acute and chronic GVHD after myeloablative HLA-matched related and unrelated allografting; this approach also limits the need for prolonged immunosuppression, resulting in favorable immunoreconstitution with few opportunistic infections in this unfavorable group of patients. Longer follow-up and larger numbers of patients are needed to assess the impact of this strategy on survival.

Reduced Intensity Conditioning (RIC) with Cladribine, Busulfan and 4 Gy Total Body Irradiation (TBI) for Bone Marrow Transplantation (BMT) from an HLA-Matched Unrelated Donor (URD): A Prospective Multi-Institutional Clinical Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5397-5397 ◽  
Author(s):  
Sung-Won Kim ◽  
Masayuki Hino ◽  
Kazuo Hatanaka ◽  
Yasunori Ueda ◽  
Ryuji Tanosaki ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
High Response Rate ◽  
High Dose ◽  
Unrelated Donor ◽  
Grade Ii ◽  
Neutrophil Engraftment

Abstract [Background] We report the results of a prospective multi-institutional clinical trial of BMT from an HLA-matched URD following RIC. [Patients and Methods] The conditioning regimen included cladribine 0.11 mg/kg on day -8 to day -3, busulfan 4 mg/kg po on day -6 and day -5, and 4 Gy TBI on day -1. GVHD prophylaxis included cyclosporine and short-term methotrexate. Patients with hematologic diseases were eligible for this study if they were either older than 50 years or had significant medical contraindications to undergo conventional transplantation. Primary endpoints were neutrophil engraftment and achievement of complete donor-type chimerism (CD3+ cells >90%) on day 90. Regimen-related toxicities (RRT) between day -8 and day 28 were assessed by the NCI-CTC v2.0. A total of 27 patients were registered, but one patient was removed before transplant because of severe fungal infection. [Results] The median follow-up time was 722 days (range, 324–996) among survivors. The median age of patients was 56.5 years (36–64). Nine of the 26 patients (36%) had advanced-stage diseases and 3 (11%) had failed previous high-dose autologous or allogeneic transplantation. The diagnoses included AML (n=9), MDS/MPD (n=7), NHL (n=3), ALL (n=2), CML, ATLL, PCL, biphenotypic acute leukemia, and severe aplastic anemia (n=1). The median number of infused nucleated cells was 2.2 × 108/kg. After transplant, while one patient experienced engraftment failure and subsequent sepsis, and died on day 34, the remaining 25 patients achieved neutrophil engraftment (median, 17th day). Another patient was censored from the study due to grade 4 liver dysfunction, which developed on day 19, which left 24 patients for the chimerism analysis. The percentage of donor chimerism in CD3+ cells on days 28, 56 and 90 was, respectively, 88% (21/24), 100% (24/24) and 100% (24/24). Grade 3 RRT included arrhythmia (n=1), hypoxia (n=3), hyperbilirubinemia or hypertransaminasemia (n=7), stomatitis (n=18) and diarrhea (n=4), and grade 4 RRT included hypoxia (n=1) and hyperbilirubinemia (n=1). Acute GVHD of grade II, III and IV occurred in 27%, 27% and 4%, respectively. Ten of 15 evaluable patients (67%) had extensive chronic GVHD. CMV reactivation occurred in 23 patients (89%); 4 had histologically confirmed CMV colitis, 1 had CMV pneumonitis and 1 had CMV hepatitis, while the remaining patients had asymptomatic viremia. Of the 16 patients with measurable disease at the time of BMT, 15 achieved complete remission. The 100-day and 1-year cumulative incidences of non-relapse mortality (NRM) estimated by the Kaplan-Meier method were 20% and 54%, respectively. The cause of death that contributed to NRM was infection, with grade 0–I acute GVHD in 29% and grade II–IV acute GVHD in 71%. The 100-day and 1-year cumulative incidences of relapse were 8% and 35%, respectively, and the 1-year overall and progression-free survival rates were 42% and 30%, respectively. [Conclusions] The results support the feasibility of this procedure with a high response rate, but there is still a problem with the high NRM due to uncontrollable infections primarily associated with GVHD.

A Randomized 3-Arm Phase II Study to Determine the Most Promising Postgrafting Immunosuppression for Prevention of Acute Graft-Versus-Host Disease (GVHD) After Unrelated Donor Hematopoietic Cell Transplantation (HCT) Using Nonmyeloablative Conditioning for Patients with Hematologic Malignancies: A Multi-Center Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 348-348 ◽  
Author(s):  
Brenda M. Sandmaier ◽  
Michael Maris ◽  
Barry Storer ◽  
Lars Vindelov ◽  
Amelia Langston ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Phase Ii ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Unrelated Donor ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Sequential Trials

Abstract Abstract 348 We previously reported results of 3 sequential trials of GVHD prophylaxis with mycophenolate mofetil (MMF) BID/TID and cyclosporine (CSP) BID with various taper schedules in patients (pts) with advanced hematologic malignancies given unrelated G-CSF-mobilized peripheral blood stem cell (PBSC) grafts after fludarabine 90 mg/m2 and 2 Gray total body irradiation. Cumulative incidences of grades II-IV acute GVHD in the 3 trials were 52, 53 and 77%, respectively. The goal of the current protocol was to evaluate, in a phase II randomized 3-arm study, which drug combination or schedule was most promising in preventing acute GVHD. Tacrolimus (Tac) was used in place of CSP and each of the 3 arms used MMF TID until day 30 and then BID, but the subsequent duration of MMF varied. In Arm1, pts received Tac until day 180 and MMF until day 96. In Arm2, Tac was given until day 150 and MMF until day 180. In Arm3, Tac was given until day 150 and MMF until day 180 with the addition of rapamycin from days -3 through 80. One hundred seventy-five pts ineligible for myeloablative conditioning were enrolled on this multi-institutional study between Jan/05 and Aug/09, and results on the first 159 pts (Arm1 n=56; Arm2 n=51; Arm3 n=52) are reported here with a median follow-up of 18.4 months for surviving pts. The median age of pts was 60 (range 13-75) yrs. Sixty-six (42%) had previous autologous (n=55) or allogeneic (n=11) HCT. All pts were matched for HLA-DRB1 and -DQB1 at the allele level: 16 had single allele mismatches at HLA-A, -B or –C and the remainder (n=143) were fully HLA-matched. Diagnoses included AML (n=72), NHL (n=36), MM (n=19), ALL (n=10), CLL (n=9), MDS (n=8), HL (n=4), and CML (n=1). Randomization was based upon transplant center (FHCRC vs other), number of prior chemotherapy treatments (0-2 vs 3+), and age (<55 vs 55+ years). The pts received PBSC grafts containing a median of 7.9 ×106 CD34 and 2.8 × 108 CD3 cells/kg. Sustained donor engraftment occurred in 99.4% of pts. The day-150 cumulative incidences of grades II-IV (figure 1) and III-IV acute GVHD were as follows: Arm1: 56%, 9%; Arm2: 52%, 12%; and Arm3: 45%, 10%, respectively. Chronic GVHD requiring therapy was as follows: Arm1: 44%, Arm2: 35%, and Arm3: 55% of pts. The 6-month nonrelapse mortality was 6% in Arm1, 8% in Arm2, and 2% Arm3. The 2-year Kaplan-Meier estimates of relapse and nonrelapse mortality (figure 2) were as follows: Arm1: 27%, 24%; Arm2: 39%, 19%; and Arm3: 30%, 15%, respectively (overall 32% and 20%, respectively). The 2-year overall and progression-free survivals were as follows: Arm1: 49%, 41%; Arm2: 42%, 37%; Arm3: 55%, 41%, respectively (overall 48% and 40%, respectively). The addition of rapamycin to MMF and Tac (Arm3) resulted in the lowest incidence of grades II-IV acute GVHD (p=0.09 compared to reference Arm1), without a significant difference in chronic GVHD. While the phase II design of the study was not powered to show statistical differences between the 3 arms, the lower incidence of grades II-IV acute GVHD combined with the low morbidity and nonrelapse mortality in Arm3 using MMF, Tac and rapamycin is encouraging and warrants further study. Disclosures: Off Label Use: Fludarabine - conditioning prior to HCT. Mycophenolate mofetil - immunosuppression after HCT. Tacrolimus - immunosuppression after HCT. Rapamycin - immunosuppression after HCT..

Re-Exposure of Cord Blood (CB) to Non-Inherited Maternal HLA Antigens (NIMA) Improves Transplant Outcome in Patients (pts) with Hematologic Malignancies and May Reduce Relapse.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 661-661
Author(s):  
Jon J van Rood ◽  
Cladd E Stevens ◽  
Jacqueline Smits ◽  
Carmelita Carrier ◽  
Carol Carpenter ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Hla Antigens ◽  
Human Leukocyte ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Leukocyte Antigens ◽  
Grade Ii ◽  
The Impact ◽  
Related Mortality

Abstract Abstract 661 CB hematopoietic stem cell transplantation (CBT) can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result, at least in part, from tolerance-inducing events during pregnancy, but this concept has not been tested to date. Hence we analyzed the impact of fetal exposure to NIMA of the HLA-A, -B antigens or -DRB1 alleles on the outcome of 1121 pts with hematologic malignancies. All pts received single CB units provided by the NYBC, for treatment of ALL (N=451), AML (N=376), CML (N=116), MDS (N=79), other (N=99); 22% were transplanted in advanced stage. Median age was 9.7 years (range: 0.1-67); 29% of recipients were >16 years. Most pts (96%) received myeloablative cytoreduction. Sixty-two pts received fully matched grafts while 1059 received units mismatched (MM) for one or two HLA antigens. Of these, 79 (7%) had a MM antigen which was identical to a donor NIMA (Example: Pt: A1, A3; CBU: A1, A2; mother-CBU: A1, A3; A3 is NIMA). NIMA match was found in 25 recipients with one HLA MM and 54 of those with two MM. The NIMA match was identified after the transplant and was not used in unit selection. In multivariate analyses, NIMA matched transplants (NMTs), showed faster neutrophil recovery (RR=1.3, p=0.043), even for grafts with cell dose <3×107 (RR=1.6, p=0.053). There was no difference in the incidence of acute (grade II-IV) or chronic GvHD. 3-year relapse risk (cumulative incidence 22%) was reduced compared to 1 or 2 HLA MM no NIMA matched transplants, especially in pts with myelogenous malignancies given units with 1 HLA MM (RR=0.2, p=0.074). Further, 3-year transplant-related mortality was reduced (RR=0.7, p=0.034), particularly in pts ≥5 years old (RR=0.5, p=0.006), as was the 3-year overall mortality (RR= 0.7, p=0.029 and RR=0.6, p=0.015, respectively). As a result, in the NMTs, treatment failure (relapse or death) was significantly lower, particularly in pts ≥5 years (RR=0.7, p=0.019) and DFS was significantly improved (figure) and was similar to that of the 0 HLA MM group. These findings are the first indication that donor exposure to NIMA can improve post-transplant survival in unrelated CBT and might reduce relapse. We propose to include the NIMA of CB units in search algorithms. Thus, for pts lacking fully HLA matched grafts, HLA MM but NIMA matched CB units could be selected preferentially, since no adverse effects were seen. This strategy of selecting HLA MM grafts with optimal outcome effectively “expands” the current CB Inventory several-fold.Patient GroupNRR(95% Cl)p value0 MM360.5(0.3–0.8)0.0051 MM / NIMA Match180.4(0.2–0.9)0.0262 MM / NIMA Match400.8(0.5–1.2)0.3091 MM / No NIMA Match229reference group2 MM / No NIMA Match4871.1(0.9–1.3)0.365 Disclosures: No relevant conflicts of interest to declare.

Outcomes after Double Umbilical Cord Blood Transplantation in Children: A Survey on Behalf of Eurocord and PDWP-EBMT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2570-2570
Author(s):  
Federica Giannotti ◽  
Annalisa Ruggeri ◽  
Gerard Michel ◽  
Jean-Hugues Dalle ◽  
Tracey O'Brien ◽  
...  
Keyword(s):  
Single Unit ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Median Number ◽  
Cell Dose ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract Double UCBT (dUCBT) has been used in adults to reach an acceptable cell dose. For most children a single unit with a total nucleated cell (TNC) dose >3x107/Kg can be easily identified, but that is not always the case for heavier patients (pts). Use of dUCBT might decrease relapse and increase graft-versus-host-disease (GvHD). Data on dUCBT in children are scarce in the literature. A recent randomized study in children has described similar outcomes after double compared to single UCBT. Our study provides an overview of the use of dUCBT in the pediatric population reported to Eurocord. We retrospectively analyzed the outcomes of unrelated dUCBT in 177 children transplanted between 2002 and 2012 in 61 EBMT centres. Analysis was performed separately for pts with malignant (n=139) and non-malignant (NM, n=38) diseases. Among pts with malignancies, 76 had ALL, 40 AML, 6 MDS, 2 CML, 11 NHL, 3 Hodgkin Lymphoma and 1 Multiple Myeloma. Median age at dUCBT was 15 years (1.3-17.9) and median weight was 55 kg (13-97). Disease status at dUCBT was 1st complete remission (CR) (36%), ≥2nd CR (34%) or advanced (25%), and missing in 5% of the pts. In this group, 117pts received a myeloablative conditioning (MAC) and 22 a reduced intensity regimen (RIC). Cyclophosphamide+fludarabine+TBI was administered to 41% of the pts; 55% received ATG in the conditioning. Median number of collected TNC was 5.7x107/kg (3,6-12,8). Considering the unit with the higher number of HLA incompatibilities with the recipient, 56% had 2 mismatches. GvHD prophylaxis was cyclosporine-A (CSA) based in 93% of the pts (58% received CSA + mycofenolate mofetil). Median follow-up was 31 months. Cumulative incidence (CI) of neutrophil (PMN) and platelet (PLT) engraftment was 88% at 60 days and 64% at 180 days after dUCBT, and it was achieved with a median time of 24 and 45 days, respectively. Among the 122 pts with PMN engraftment, 85/94 with available data on chimerism were full donor and, of these, 20% had dual chimerism. CI of acute GvHD grade II-IV and grade III-IV at 100 days was 51% and 26%, respectively; it was significantly higher in pts who did not receive ATG (grade II-IV: 35% vs 67%, p=0.004; grade III-IV: 12% vs 37%, p=0.0075). Chronic GvHD was observed in 24/104 pts at risk (60% extensive; 2-year (yr) CI: 18%). The 2-yr CI of relapse was 31%. In univariate analysis, RIC, advanced stage at transplantation and a collected TNC dose lower than the median, were significantly associated with higher rates of relapse.The 2-yr CI of transplant related mortality (TRM) was 27%. Overall, 73 pts died: 35 of relapse, 15 of infections, 9 of GvHD and 14 of other causes. The 2-yr disease free survival (DFS) and overall survival (OS) were 42% and 45%, respectively. Among pts with NM disorders, 24 had bone marrow failure syndrome (BMFS) (10 Fanconi Anemia, 13 Acquired Aplastic Anemia and 1 other inherited BMFS), 2 hemoglobinopathies, 7 immune deficiencies and 5 metabolic disorders. Median age at dUCBT was 11 years (0.7-17.9) and the median weight was 40 kg (13-70). In this group, 27 pts received a RIC (40% TBI based), 10 a MAC (90% busulfan based), and 1 no conditioning regimen. ATG was administered to 82% of the pts and GvHD prophylaxis was CSA-based in 77%. The median number of collected TNC was 8.4x107/kg (1,2-11,2) and 60% of the grafts had ≥2 HLA mismatches with the recipient. Median follow-up was 39 months. Overall, 28 pts achieved PMN engraftment and 16 PLT engraftment, with a median time of 23 and 61 days, respectively. In univariate analysis, pts with BMFS compared to others had a significantly lower CI of PMN engraftment (58% vs 100%, p=0.002). Among the 10 pts who did not engraft, 3 had autologous reconstitution and 3 had a subsequent allogeneic HSCT. Forteen pts developed acute GvHD grade II-IV and 10/25 pts at risk had chronic GvHD (3 extensive). Overall 21 pts died (17 with BMFS): 9 of infections, 5 of GvHD and 7 of other causes. The 2-yr OS was 42% and it was significantly lower in pts with BMFS compared to those affected by other NM disorders (28% vs 70%, p=0.03). In pts with malignancies, despite a higher incidence of acute GvHD, DFS and OS seem to be comparable to those reported in the literature for single UCBT or HSCT from other alternative stem cell sources. In the NM disorders group, despite the high cell dose, dUCBT did not seem to improve results in pts with BMFS. This survey suggests that dUCBT is feasible in children and should be considered when a single unit with an adequate cell dose is not available. Disclosures No relevant conflicts of interest to declare.

scholarly journals Use of Partially Mismatched Related Donors Extends Access to Allogeneic Marrow Transplant

Blood ◽  
1997 ◽  
Vol 89 (10) ◽  
pp. 3864-3872 ◽  
Author(s):  
P. Jean Henslee-Downey ◽  
Sunil H. Abhyankar ◽  
Rudolph S. Parrish ◽  
Asim R. Pati ◽  
Kamar T. Godder ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Marrow Transplant ◽  
Successful Outcome ◽  
High Dose ◽  
Allogeneic Bone ◽  
Significant Difference

Most patients requiring allogeneic bone marrow transplant (allo-BMT) do not have an HLA-matched sibling donor. A phenotypically matched unrelated donor graft has been made available for approximately 50% of Caucasians and less than 10% of ethnic and racial minorities in need. However, almost all patients have a readily available partially mismatched related donor (PMRD). We summarize our experience with 72 patients who ranged from 1 to 50 years of age (median, 16 years) and who were recipients of a PMRD allo-BMT from haploidentical family members following conditioning therapy using total body irradiation (TBI) and multiagent, high-dose chemotherapy. T-cell depletion and post-BMT immunosuppression were combined for graft-versus-host disease (GVHD) prophylaxis. The probability of engraftment was 0.88 at 32 days. Six of 10 patients who failed to engraft achieved engraftment after secondary transplant. Grade II to IV acute GVHD was seen in 9 of 58 (16%) evaluable patients; extensive chronic GVHD was seen in 4 of 48 (8%) evaluable patients. There was a statistically significant difference in 2-year survival probability between low-risk and high-risk patients (0.55 v 0.27, P = .048). Prognostic factors that affected outcomes in multivariate analysis were (1) a lower TBI dose and 3-antigen rejection mismatch decreased stable engraftment (P = .005 and P = .002, respectively); (2) a higher T-cell dose increased acute GVHD (P = .058); (3) a higher TBI dose increased chronic GVHD (P = .016); and (4) a high-risk disease category increased treatment failure from relapse or death (P = .037). A PMRD transplant can be performed with acceptable rates of graft failure and GVHD. Using sequential immunomodulation, the disease status at the time of transplant is the only prognostic factor significantly associated with long-term successful outcome after PMRD allo-BMT. When allogeneic rather than autologous BMT is indicated, progression in disease status before transplant can be avoided using a PMRD with equal inclusion of all ethnic or racial groups.

Hyperglycemia and obesity in patients (pts) with acute lymphoblastic leukemia (ALL): Association with prevalence, response, and survival

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7074-7074
Author(s):  
K. D. Vu ◽  
V. R. Lavis ◽  
S. Strom ◽  
S. H. Faderl ◽  
M. Konopleva ◽  
...  
Keyword(s):  
Cox Regression ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Retrospective Chart Review ◽  
Hematologic Malignancies ◽  
Serum Glucose ◽  
High Dose ◽  
Baseline Serum ◽  
Significant Difference ◽  
The Mean

7074 Increasing evidence suggests associations between obesity, diabetes and/or hyperglycemia (DM/HG) and solid tumors. Less is known about the relationship of these metabolic factors to the hematologic malignancies. To determine the prevalence of DM/HG and obesity in pts with ALL and whether these are predictors of response and survival, we conducted a retrospective chart review of 299 pts with newly diagnosed ALL, who were evaluated at our institution between November 1999 and May 2005 and received hyper-CVAD therapy: fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and high-dose cytarabine. Median age was 43 yrs (range 15–83). Sixty-one percent of pts were male, and 39% female. Seventy-four percent had a diagnosis (dx) of precursor B cell ALL (22% Ph+), 18% Burkitt's ALL, 6% lymphoblastic lymphoma, 2% other. Prior to therapy, the overall prevalence of DM/HG (diabetes based on reported dx prior to ALL-dx, and hyperglycemia based on baseline serum glucose ≥200 mg/dL) was 16%. Pts with DM/HG were significantly older than those without DM/HG (median age 57 yrs vs. 40 yrs, p<0.001). Complete remission (CR) rate and the CR duration (CRD) were similar in the DM/HG vs. non-DM/HG group. However, the mean CRD was 80 wks in the HG separately group and 121 wks in the non-HG group (p=0.04). The mean CRD was 102 wks in the obese pts and 124 wks in the non-obese pts (p=.04). In univariate analysis, DM/HG, obesity, and older age were associated with shorter overall survival (OS). Mean OS of pts with DM/HG was 134 vs. 194 wks for pts without DM/HG, (p=0.2). Mean OS of obese pts was 136 vs. 199 wks for non-obese pts, (p=0.01). In a multivariable Cox regression model, the only factors that remained significant for survival were age, obesity, and white blood cell count (WBC). There was no significant difference in OS by leukemia diagnosis. In conclusion, the prevalence data suggests that DM/HG may be involved in the development of ALL. However, DM/HG has no impact on survival, probably because of its strong correlation with age. The association of obesity with shorter OS warrants further investigation. No significant financial relationships to disclose.

HLA-DP Mismatches Increase the Risk of Acute GVHD after Unrelated Donor Hematopoietic Transplantation (UDT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3125-3125 ◽  
Author(s):  
Marcos de Lima ◽  
Simrit Parmar ◽  
Ping Liu ◽  
Poliana A. Patah ◽  
Pedro Cano ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii

Abstract The HLA class II DP locus encode for both subunits of DPB1 heterodimers, which have low levels of expression on the cell surface of antigen presenting cells. We hypothesized that donor-recipient HLA-DP mismatch would lead to an increased incidence of acute (a) graft-versus-host disease (GVHD), and that 2 mismatches would likely be even more significant. Methods: We studied 84 consecutive patients (pts) with myeloid leukemias in complete remission (CR) transplanted from 01/02 to 02/06. Preparative regimens were ablative IV Busulfan-based (n=58) or Cy/TBI (n=2), and reduced intensity (Fludarabine (Flu)/Bu 130 mg/m2/2 doses plus Gleevec (n=8), and Flu/Melphalan 140 mg/m2 (n=16). Stem cell (SC) source was bone marrow (n=70) or peripheral blood (n=14). ATG was given in 78 cases. GVHD prophylaxis was tacrolimus and mini-methotrexate in all cases, with additional pentostatin in 31 pts. High-resolution typing was sequence-based for HLA-A, B, DRB1; SSP was used for DRB3/4/5, DQB1 and DPB1, and SBT/SSOP for HLA-C. A Cox proportional hazards regression model was used to study aGVHD-free and relapse-free (RFS) survival. Variables with a p-value <0.25 by univariate analysis were included in the multiple regression analysis (MV). Variables were age, gender, weight, conditioning regimen, GVHD prophylaxis, diagnosis, cytogenetics, SC source, ABO group, infused CD34 and CD3 cell dose, and HLA matching. AGVHD-free survival was calculated from transplant date to date of development of grade II–IV GVHD or completion of 100 days of follow-up. Results: Median age was 48 yrs (range, 14–72). Diagnoses were MDS (n=5), AML (n=58), and CML (n=21). 54 pts (64%) were beyond 1st CR; all CML pts were in >1st chronic phase (CP). Sixty-one pts were 10/10 HLA match (A, B, C, DRB1, DQB1), and 23 had one or more mismatches. All but one pt engrafted neutrophils at a median of 13 days. 33 pts (39%) and 13 pts (15%) developed grade II–IV and III–IV aGVHD, respectively. Chronic GVHD incidence was 51%. With a median follow-up of 18 mo. (range,1.3–52) 60 pts are alive; 40 pts have relapsed or died. Median survival has not been reached. Number of DP mismatches and incidence of aGVHD is shown in the table. The following covariates influenced aGVHD-free survival by MV analysis: Flu-based regimen (P=0.005; HR 0.25 (95%CI 0.1–0.66), reduced intensity regimens (p=0.02; HR 0.35 (95%CI 0.15–0.83) and presence of 2 DPB1 mismatches (p=0.02; HR 3.07 (95%CI 1.19–7.95). Presence of 1 DPB1 mismatch was not significantly associated with aGVHD. There was no statistically significant correlation between presence of 2 DP mismatches and RFS (P=0.17;HR 0.3 (95%CI 0.06–1.65);HR 0.75 for 1 mismatch) or with cGVHD. Actuarial 2-yr survival for 10/10 matched pts without DP mismatches (12/12) versus those with DP mismatches is 82% versus 71%(P=0.6). In the 10/10 matched group, GVHD was the cause of death only among recipients of 2 DP mismatches transplants (n=4). Conclusion: Mismatching at HLA-DPB1 may increase the risk of aGVHD following UDT. The role of DP in the development of GVHD and GVL effects merits future study. Incidence of acute GVHD 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 8% 0% 1 23% 8% 2 45% 18% < 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 45% 15% 1 82% 36% 2 80% 40%

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