Cell Transplantation For Hematologic Malignancies Research Articles

Is the Use of 9/10 HLA Unrelated Donors Still Acceptable in Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies? Comparison with Transplants from 10/10 HLA Unrelated Donors and Siblings

Is the Use of 9/10 HLA Unrelated Donors Still Acceptable in Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies? Comparison with Transplants from 10/10 HLA Unrelated Donors and Siblings

Hepatitis B Reactivation in a Multiple Myeloma Patient with Resolved Hepatitis B Infection during Bortezomib Therapy : Case Report

It has recently been reported that hepatitis B virus (HBV) reactivation in patients with hepatitis B surface antigen (HBsAg)-negative lymphoma during or after cytotoxic therapy occurs after the use of rituximab and stem cell transplantation for hematologic malignancies. However, clinical data on HBV reactivation in multiple myeloma patients have not been extensively reported. This is the first reported case of HBV reactivation in an HBsAg-negative myeloma patient treated with bortezomib (BOR) as salvage therapy and not stem cell transplantation. By closely monitoring HBV-DNA and early administration of entecavir, severe hepatitis was avoided and BOR therapy was continued. We suggest the importance of close monitoring of HBV-DNA for transplant-ineligible myeloma patients treated with BOR as salvage therapy.

Genetic Variation in Donor CTLA-4 Regulatory Region is a Strong Predictor of Outcome after Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies

Relapse remains a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Graft-versus-tumor effect is primarily mediated by donor T cells. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a critical inhibitor of T cell proliferation. Single nucleotide polymorphisms (SNPs) in CTLA-4 may affect immune responses. We hypothesized that CTLA-4 SNPs will be associated with disease control after allo-HCT. One hundred sixty-four adult patients with the availability of pretransplantation recipient and donor DNA samples were included in this analysis. Ten tagSNPs of the CTLA-4 gene were identified. Donor CTLA-4 SNP rs4553808 was associated with decreased relapse-free survival (RFS) (P = .019) and overallsurvival (OS) (P = .033). In multivariable analysis of an additive genetic model, genotype of CTLA-4 SNP rs4553808 was an independent risk factor for inferior RFS (hazard ratio [HR] = 1.73, 95% confidence interval [CI] 1.10-2.71, P = .017) and OS (HR = 1.84, 95% CI 1.13-3.0, P = .015). CTLA-4 SNPs can be used to identify high-risk patient subsets that may benefit from preemptive immunomodulation to decrease relapse rates and improve survival.

Is the Use of 9/10 HLA Unrelated Donors Still Acceptable in Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies? Comparison with Transplants From 10/10 HLA Unrelated Donors and Siblings

Abstract 3087 IntroductionAllogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only potential to cure wide types of hematological diseases. A patient has 30% of chance to find a HLA-identical sibling donor while the rest of patients should find an alternative unrelated donor. The use of 10/10 HLA matched unrelated transplants has been used as a main alternative and with its unavailability, when available, a 9/10 HLA mismatched unrelated transplant has been used. The outcome of this last mismatched transplant is not very clear and its use according to patient and disease conditions has not been well defined yet. AimsTo evaluate the outcome of allo-HSCT from 9/10 HLA mismatched unrelated donors compared to those from 10/10 HLA identical unrelated donors and siblings; and to define which category of patients can benefit the more in each alternative. Material and methodsWe have retrospectively studied the outcome of 213 patients who received allo-HSCT for different hematological malignancies, 121 (57%) from HLA identical siblings, 63 (29%) from 10/10 HLA identical unrelated donors and 29 (14%) from 9/10 HLA mismatched unrelated donors treated during the same period of time between 2006 and 2011 at our institution. In the mismatched group, 12 patients had the mismatch at HLA-A locus, 7 at the HLA-B, 7 at the HLA-C and 3 at the HLA-DQ. Characteristics between the 3 groups were comparable except for: disease type between the 2 unrelated groups, sex-matching, CMV-matching and ABO-matching. The different characteristics are detailed in Table 1. [Display omitted] [Display omitted] ResultsAfter HSCT, engraftment was significantly lower in the 9/10 HLA group (90%) than in the 10/10 HLA group (95%) than in the sibling group (99%), (p=0.03); the cumulative incidence of acute GVHD ≥2 at 3 months was 32% (23–41), 20% (15–26) and 27% (23–32) respectively; the cumulative incidence of extensive chronic GVHD at one year was 21% (13–30), 9% (5–13) and 17% (14–21) for the 3 groups respectively. After a median follow-up of 8 months (0–54) in the 9/10 HLA group, 10 months (0–60) in the 10/10 HLA group and 18 months in the siblings group, the median overall survival (OS) was 10 months (5–21), 18 months (11-NR) and 60 months (31-NR) respectively with a 2-years probability of 19% (8–44), 43% (31–59) and 63% (54–74) respectively. There was a higher but not significant relapse incidence at one year in the 9/10 HLA group compared to other groups while the transplant related mortality was significantly higher with a cumulative incidence at 1 year of 45% (35–55), (p<0.001) (Table1-results). In multivariate analysis, OS was negatively affected by unrelated donors [9/10 HR=5 (2.7–10), p=0.0001; 10/10 HR=2 (1.2–4), p=0.01], female donors [HR=2 (1.4–4), p=0.03] and disease status < CR1 or <chronic phase (CP) 1 [HR=3 (1.4–6), p=0.003]; while the TRM was negatively affected by unrelated donors [9/10 HR=9 (4–20), p<0.001; 10/10 HR=4 (1.2–10), p=0.03], female donors [HR=3 (1.2–7); p=0.01] and ABO minor incompatibility [HR=2.5 (1.2–5), p=0.01]. The funnel plot showing the adjusted TRM according to all covariates and comparing to the global population death rate, shows that the 9/10 HLA group has the worse TRM independently of any other factor. ConclusionWe showed that allo-HSCT from 9/10 HLA mismatched unrelated donors have a significantly worse OS than those from matched unrelated donors and siblings; this was mainly due to an increased TRM in this group. Patients in first CR or CP could benefit the more from matched or 9/10 unrelated allo-HSCT while the use of transplants from 9/10 HLA unrelated donors in patients not in CR1 or CP1 should be limited to clinical trials. In view of these results, we should consider and evaluate the use of cord blood as an alternative source of transplant according to patient and disease conditions. Disclosures:No relevant conflicts of interest to declare.

Outcome of Children Who Experience Disease Relapse Following Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies,

Abstract 4101 Introduction:According to the Center for International Blood and Marrow Transplantation and Research (CIBMTR) data, relapse accounts for 41% of deaths after matched sibling donor hematopoietic stem cell transplantation (HSCT) and 34% of deaths after unrelated donor HSCT. Overall long term survival of 25–30% has been reported in patients who relapse after HSCT. Most of these data are from adult studies. In a recent study, survival following a second allogeneic HSCT ranged from 25–50%. There are limited data on the treatment outcome of children who relapse after an allogeneic HSCT for hematological malignancies. Methods:This multicenter retrospective study was done with the primary objective to examine the incidence and outcome of children who experience relapse after allogeneic HSCT. Patients with a primary diagnosis of acute lymphatic leukemia (ALL), acute or chronic myeloid leukemia (AML or CML), juvenile myelomonocytic leukemia (JMML), biphenotypic leukemia (BL), acute undifferentiated leukemia (AUL), and myelodysplastic syndrome (MDS) were included. After IRB approval, data was collected from review of the medical charts of patients who underwent HSCT at 5 institutions across North America. Results:Data on 532 patients was analyzed; these included 328 males and 204 females. These included ALL (n=254), AML (n=187), MDS (n=35), CML (n=26), JMML (n=3), sAML (n=12), Biphenotypic leukemia (n=10), AUL (n=3) and 1 each with APL and secondary ALL. The median age at HSCT was 9.7 years (range 0.44 to 24.98). Four hundred and fifty (85%) of the 532 patients were in complete remission (CR) at the time of HSCT. Five hundred and fifteen (97%) underwent a myeloablative (MA) HSCT and 16 (3%) had a non-myeloablative (NMA) HSCT. Total body irradiation (TBI) was part of the conditioning therapy in 334 (63%) while 198 (37%) had chemotherapy based regimens. Standard graft versus host disease (GvHD) prophylaxis with calcineurin inhibitors and methotrexate was used in 76% of patients. Grade 1–2 acute GvHD developed in 180 (34%) of patients and 82 (15%) had grade 3–4 acute GvHD. Chronic GvHD was seen in 118 (22%) cases with half having extensive chronic GvHD. After HSCT, 85 (16%) patients died of transplant related complications at 1 year, with infection as the leading (26%) cause of death. The 2, 5 and 10 year overall survival for the entire group was 58.5%, 46% and 44% respectively. Following HSCT, 131 (25%) patients relapsed at a median duration of 7.7 months (range 0.6 to 66.4 months).Of the 131 patients who relapsed 80 (61%) received salvage therapy, 39(30%) did not get any therapy and data were not available for another 12 (9%) patients. Salvage therapy included a combination of withdrawal of immunosuppression, ALL or AML re-induction therapy, or other remission inducing agents, clofarabine, and/or donor lymphocyte infusions (n=22). After salvage therapy 46 (57.5%) patients achieved CR, 26 (32.5%) had no response, 3 (4%) partial response, 2 unknown and 4 (5%) had marrow aplasia and no recovery of counts.Sixty-three (48%) of the relapsed patients underwent a second HSCT: 26 (41%) received a MA, 21 (33%) NMA, 3 (5%) with no conditioning and in 13 (21%) conditioning therapy was unknown. Nearly 22 different conditioning regimens were used for the second HSCT. After the second HSCT 19 (41%) patients died because of transplant related mortality (TRM) and 24 patients died because of relapse. Seventeen (27%) patients are alive and disease free. Conclusions:Relapse remains a major complication following allogeneic HSCT for hematologic malignancies. Our data shows that patients who relapse after HSCT have poor prognosis. In our study 30 different salvage therapies were used for these patients. Currently there is no standard acceptable salvage therapy and most cooperative group or industry sponsored clinical trials exclude patients who underwent HSCT. In addition there are no standard conditioning regimens designed specifically for the second HSCT, which could contribute to the high TRM seen during second HSCT. There is urgent need to develop prospective clinical trials to better understand the optimal therapy for this group of patients. Disclosures:No relevant conflicts of interest to declare.

Comparison of Unrelated Cord Blood Transplantation and HLA-Mismatched Unrelated Bone Marrow Transplantation for Adults with Leukemia

Recent advances in unrelated cord blood transplantation (UCBT) and high-resolution typing of human leukocyte antigen (HLA) from an unrelated donor have increased choices in alternative donor/stem cell source selection. We assessed HLA-mismatched locus-specific comparison of the outcomes of 351 single-unit UCB and 1,028 unrelated bone marrow (UBM) adult recipients 16 years old or older at the time of transplantation who received first stem cell transplantation with myeloablative conditioning for acute leukemia or myelodysplastic syndromes. With adjusted analyses, HLA 0 to 2 mismatched UCBT showed similar overall mortality (relative risk [RR] = 0.85, 95% confidence interval [CI], 0.68-1.06; P = .149) compared with that of single-HLA-DRB1-mismatched UBMT. UCBT showed inferior neutrophil recovery (RR = 0.50, 95% CI, 0.42-0.60; P < .001), lower risk of acute graft-versus-host disease (RR = 0.55, 95% CI, 0.42-0.72; P < .001), and lower risk of transplantation-related mortality (RR = 0.68, 95% CI, 0.50-0.92; P = .011) compared with single-HLA-DRB1-mismatched UBMT. No significant difference was observed for risk of relapse (RR = 1.28, 95% CI, 0.93-1.76; P = .125). HLA 0 to 2 antigen-mismatched UCBT is a reasonable second alternative donor/stem cell source with a survival outcome similar to that of single-HLA-DRB1-mismatched or other 7 of 8 UBMT.

Stem Cell Transplantation for Hematological Malignancies: Prospects for Personalized Medicine and Co-therapy with Mesenchymal Stem Cells.

Bone marrow transplantation is a form of cell therapy that has been in practice for decades for the treatment of hematological disorders and solid tumors. Immunosuppressive therapy has been a mainstay for treatment, but the severity of the adverse effects has made it an undesirable choice. Mesenchymal stem cells (MSCs), which reside in the vascular regions of the bone marrow, have been shown to serve as cellular support for the hematopoietic stem cell (HSC) niche. Furthermore, the immune suppressive properties of MSCs have been explored in the treatment of inflammatory and autoimmune disorders. Thus, co-therapy with MSCs has been shown to facilitate engraftment of hematopoietic cells by suppressive graft versus host disease (GvHD). Although the mechanism by which MSCs suppress GvHD is unclear, the experimental evidence suggests that this partly occurs by modulation of immune response such as the induction of regulatory T cells. This paper discusses the role of MSCs as co-therapy for the future of stem cell transplantation, with the overarching theme of personalized medicine for cell-based health interventions.

Impact of immune modulation with anti–T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies

AbstractThe success of reduced intensity conditioning (RIC) transplantation is largely dependent on alloimmune effects. It is critical to determine whether immune modulation with anti–T-cell antibody infusion abrogates the therapeutic benefits of transplantation. We examined 1676 adults undergoing RIC transplantation for hematologic malignancies. All patients received alkylating agent plus fludarabine; 792 received allografts from a human leukocyte antigen-matched sibling, 884 from a 7 or 8 of 8 HLA-matched unrelated donor. Using Cox regression, outcomes after in vivo T-cell depletion (n = 584 antithymocyte globulin [ATG]; n = 213 alemtuzumab) were compared with T cell– replete (n = 879) transplantation. Grade 2 to 4 acute GVHD was lower with alemtuzumab compared with ATG or T cell– replete regimens (19% vs 38% vs 40%, P < .0001) and chronic GVHD, lower with alemtuzumab, and ATG regimens compared with T-replete approaches (24% vs 40% vs 52%, P < .0001). However, relapse was more frequent with alemtuzumab and ATG compared with T cell–replete regimens (49%, 51%, and 38%, respectively, P < .001). Disease-free survival was lower with alemtuzumab and ATG compared with T cell–replete regimens (30%, 25%, and 39%, respectively, P < .001). Corresponding probabilities of overall survival were 50%, 38%, and 46% (P = .008). These data suggest adopting a cautious approach to routine use of in vivo T-cell depletion with RIC regimens.

Phase II Prospective Multicenter Study of Treosulfan Based Reduced intensity Conditioning in Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies From 10/10 HLA Identical Unrelated Donor

Phase II Prospective Multicenter Study of Treosulfan Based Reduced intensity Conditioning in Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies From 10/10 HLA Identical Unrelated Donor

Clinical Outcomes of Haploidentical Donor Compared With Unrelated and Hla-Matched Related Donor Hematopoietic Stem Cell Transplantation for Hematologic Malignancies

Clinical Outcomes of Haploidentical Donor Compared With Unrelated and Hla-Matched Related Donor Hematopoietic Stem Cell Transplantation for Hematologic Malignancies

Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood

Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood

Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood

AbstractEffectiveness of double umbilical cord blood (dUCB) grafts relative to conventional marrow and mobilized peripheral blood from related and unrelated donors has yet to be established. We studied 536 patients at the Fred Hutchinson Cancer Research Center and University of Minnesota with malignant disease who underwent transplantation with an human leukocyte antigen (HLA)–matched related donor (MRD, n = 204), HLA allele–matched unrelated donor (MUD, n = 152) or 1-antigen–mismatched unrelated adult donor (MMUD, n = 52) or 4-6/6 HLA matched dUCB (n = 128) graft after myeloablative conditioning. Leukemia-free survival at 5 years was similar for each donor type (dUCB 51% [95% confidence interval (CI), 41%-59%]; MRD 33% [95% CI, 26%-41%]; MUD 48% [40%-56%]; MMUD 38% [95% CI, 25%-51%]). The risk of relapse was lower in recipients of dUCB (15%, 95% CI, 9%-22%) compared with MRD (43%, 95% CI, 35%-52%), MUD (37%, 95% CI, 29%-46%) and MMUD (35%, 95% CI, 21%-48%), yet nonrelapse mortality was higher for dUCB (34%, 95% CI, 25%-42%), MRD (24% (95% CI, 17%-39%), and MUD (14%, 95% CI, 9%-20%). We conclude that leukemia-free survival after dUCB transplantation is comparable with that observed after MRD and MUD transplantation. For patients without an available HLA matched donor, the use of 2 partially HLA-matched UCB units is a suitable alternative.

Low usage rate of banked sibling cord blood units in hematopoietic stem cell transplantation for children with hematological malignancies: Implications for directed cord blood banking policies

Directed sibling cord blood banking is indicated in women delivering healthy babies who already have a sibling with a disease that is potentially treatable with an allogeneic cord blood transplant. We evaluated the effectiveness of a national directed cord blood banking program in sibling HLA-identical stem cell transplantation for hematological malignancies and the factors influencing the usage rate of the stored cord blood units. Fifty families were enrolled from which, 48 cord blood units were successfully collected and 2 collections failed due to damaged cord/placenta at delivery. Among enrolled families 4 children needed transplantation; however, only one was successfully transplanted using the collected cord blood unit containing 2 × 10 7 nucleated cells/kg in conjunction with a small volume of bone marrow from the same HLA-identical donor. Two children received grafts from matched unrelated donors because their sibling cord blood was HLA-haploidentical, while the fourth one received bone marrow from his HLA-identical brother, since cord blood could not be collected due to damaged cord/placenta at delivery. With a median follow-up of 6 years (range, 2–12) for the 9 remaining HLA-matched cord blood units, none from the prospective recipients needed transplantation. The low utilization rate of sibling cord blood in the setting of hematopoietic stem cell transplantation for pediatric hematological malignant diseases necessitates the development of directed cord blood banking programs that limit long-term storage for banked cord blood units with low probability of usage such as non-HLA-identical or identical to patients who are in long-term complete remission.

Donor Lymphocyte Infusion After Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies.

AbstractAbstract 4511 Background:Hematologic relapse after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is associated with a dismal prognosis. Increasing minimal residual disease (MRD) after HSCT had been proved highly effective prognostic factor for post-treatment leukemia relapse. Savage chemotherapy or intensive conditioning followed by a second HSCT may be applied, but associated with a high mortality and a low rate of complete remission. Donor lymphocyte infusion (DLI) has been shown to exert a graft-versus-leukemia (GVL) effect and has been successfully used in patients who relapsed after HSCT. Objective:In this retrospective study, we sought to gain insights of the effect of DLI on clinical outcomes such as graft versus host disease (GVHD), overall survival (OS), disease free survival (DFS), and treatment-related mortality (TRM) in patients with either relapsed hematological malignancies or increasing MRD who underwent HSCT. Methods:DLIs were administered to 25 patients [10(40%) acute myeloid leukemia, 10 (40%) acute lymphoblastic leukemia, 5 (20%) chronic myeloid leukemia]. Patients with Acute leukemia had been treated with myeloablative conditioning (BuCy). Patients with chronic myeloid leukemia had been treated with non-myeloablative conditioning(Flu,ATG and Bu). Infusion of allogeneic hematopoietic stem cells are performed at our institution from 2005 to 2010. GVHD prophylaxis consisted of CsA, MMF and MTX.10 patients were diagnosed of hematologic relapse a median of 259 (30–850) days after HSCT. 15 patients had persistent increasing MRD(monitoring with flow cytometry or RT-PCR for Fusion Gene) after HSCT. DLIs were given to patients who had relapsed hematological malignancies or persistent increasing MRD. Patients with relapsed malignancies were performed reinduction chemotherapy simultaneously. A total of 57 DLIs were administered to 25 patients a median of 809 (92-1981) days after HSCT. The median transplant dose of CD3(+) cells is 4.12*10e7/kg (2.68*10e7/kg–7.97*10e7/kg). Results:The overall response rate of DLI was 80% for CML, 90% for ALL and 80% for AML.The response rate was 93.3% in patients with increasing MRD, whereas 60% in patients with relapsed malignancies. A total of 10 patients (40%,7 with increasing MRD, 3 with relapsed malignancies) developed acute GVHD. A complete response was achieved in 72% of the patients. TRM was 12% (3 patients with increasing MRD). The Kaplan-Meier estimate of OS and DFS at 3 years after DLI were 62.5% and 60.9%, respectively, with a median follow-up of 411 (32-1509) days for survivors. In patients with increasing MRD, the 3-year OS and DFS after DLI were 78.6% and 77.8%, respectively, with a median follow-up of 531(40-1509) days. In patients with relapsed malignancies,the 3-year OS and DFS after DLI were 40% and 36.8%, respectively, with a median follow-up of 469 (32-1393) days. Conclusion:Leukemia relapse is a serious therapeutic challenge following HSCT. In this retrospective study, DLIs was proved to be an effectively therapy to prevent relapse and get a better Clinical outcome in leukemia patients. Patients undergone DLI without leukemia relapse had a better outcome than the relapse group. Further strategies are required to detect early relapse in HSCT patients, and DLI may be a strategy to prevent relapse in high risk patients. Disclosures:No relevant conflicts of interest to declare.

Phase II Prospective Multicenter Study of Treosulfan Based Reduced Intensity Conditioning In Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies From 10/10 HLA Identical Unrelated Donor

AbstractAbstract 2353 Background:The key point in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to find the optimal balance between the graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect particularly in the unrelated HSCT settings, without forgetting the important role of conditioning. Objective:To evaluate the toxicity and efficacy of a new reduced intensity conditioning regimen including Treosulfan, followed by allo-HSCT from a 10/10 HLA identical unrelated donor. Materials and Methods:This prospective study included adult patients presenting a hematological malignancy in need of allo-HSCT using a 10/10 HLA identical unrelated donor. Accepted diagnoses were: CML in 1st chronic phase (CP) resistant to imatinib, in 2nd CP or in complete remission (CR) after blast crisis. Multiple myeloma (MM) or chronic lymphocytic leukemia (CLL) in stage B or C in response after relapse post-auto-HSCT. Acute lymphocytic or myeloid leukemia (ALL, AML) patients in CR1 at high risk or <CR1. Myelodysplasic syndrome (MDS) with poor prognostic factors. The conditioning included:Treosulfan 12g/m2/day intra-venous (day-6 to day-4), fludarabine 30mg/m2/day intra-venous (day-6 to day -2) and ATG 2.5 mg/kg/day (day-2 to day-1). GVHD prophylaxis used cyclosporine A oral (5mg/kg/day) or iv. (3mg/kg/day) from day-1. Peripheral stem cells after mobilization by G-CSF were used as HSC source. Results:Between February 2005 and July 2009, 56 patients were included in 5 different French centers, 30 (54%) males and 26 females with a median age of 57 years (18-65.5). There were 38 (68%) myeloproliferative disorders [29 AML (14 in CR1, 14 CR2 & 1<CR), 8 MDS (1CR1 and 7<CR) and 1 CML in CR1] and 18 (32%) lymphoprolifative disorders [9 MM in PR, 6 CLL (2CR1 & 4PR) and 3 ALL(1CR1 & 2CR2)]. Among 45 explored for cytogenetics, 23 (51%) were normal and 22 with poor prognostic. Before transplantation, two patients did not receive any previous treatment, 21 received 1 line, 22 two lines and 11 > 2 lines. For sex-matching, 49% of patients were sex-mismatched (half of them were F>M). For CMV, 43% were -/-, 25% +/+, 28% +/− and 1% -/+. For ABO matching, 52% were compatible, 24% major incomp. & 24% minor incopm. The median time between diagnosis and allograft was 15 months (4-168). The median number of infused CD34+ cells was 6.5 × 106/Kg(1-17.2)Fifty-four (96%) patients engrafted with a median time to neutrophils (>0.5G/l), and platelets (>50G/l) recovery of 16 days (4-86), 11 (4-82) respectively. Seventeen patients developed aGVHD grade ≥II (8 grade II, 2 grade III & 7 grade IV) with a cumulative incidence at 3 months of 31% (25-38). The cumulative incidence of cGVHD was, at 12 months: 32% (25-39) limited and 6% (2-10) extensive; at 18 months: 34% (27-47) limited and 8% (5-12) extensive. After a median follow-up of 13 months (1-57), the median overall survival (OS) was not reached with a 3 years probability of 52% (38-71). The median time of event free survival (EFS) was 15 months (8 - 57) with a 3-years probability of 47% (35-64). The cumulative incidence of relapse at 3 years was 25% (19-31) and the cumulative incidence of transplant-related mortality (TRM) at 12, 18 and 36 months was 20% (16-27), 23% (16-29) (same at 18 & 36 months) respectively. At the last follow-up, 22 patients died, 7 due to relapse and 15 due to TRM (5 pneumonia, 4 GVHD, 1 secondary malignancy and 6 other causes). We showed in a univariate analysis a higher 3-years OS of patients in CR1 (65%) compared to those <CR1 (44%) at transplantation with a significant better benefit for AML patients (76%). Patients with active cGVHD seem to benefit for the GVL effect on OS with a high significant difference (HR=0.2 (0.1-0.6) p=0.002). The multivariate analysis studying age, sex matching, ABO compatibility, CMV matching, type of disease, CD34+ cells number, cytogenetics, number of previous treatments, disease status and interval diagnosis-allo-HSCT showed: a negative significant impact of both minor ABO incompatibility (p<0.001) and CMV+/− (p=0.01) on OS, a negative significant impact of patients <CR (p=0.03) on relapse. There was no impact of studied factors on TRM. Conclusion:We showed very promising results in terms of OS, relapse and TRM with an impressive GVL effect, in heavily pre-treated patients and transplanted using unrelated donors. Treosulfan appears to be a good choice for conditioning especially with a better outcome in AML patients in CR1. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Interim Analysis of Randomized Phase II Study of Recombinant Human Epidermal Growth Factor on Oral Mucositis Induced by Intensive Chemotherapy with Stem Cell Transplantation for Hematologic Malignancies

AbstractAbstract 905Oral mucositis (OM) develops in 40–80% of patients undergoing intensive chemotherapy with stem cell transplantation (SCT) which is often debilitating and influences the quality of life (QoL). A novel drug, recombinant human epidermal growth factor (rhEGF), recently demonstrated promising efficacy and minimal toxicity in the prevention of OM in patients with head and neck cancer receiving radiotherapy (Wu HG et al, Cancer 2009). To evaluate the efficacy and safety of rhEGF for prevention and treatment of OM during SCT, a prospective randomized double-blind placebo-controlled phase II study is being performed (ClinicalTrials.gov identifier, NCT00845819). In this report, results of the scheduled interim analysis are presented. Patients for whom the procedure of SCT for hematologic malignancies was planned were eligible for this study. Patients were randomly assigned to either the rhEGF group or the placebo group, at a 1:1 ratio. Patients were instructed to spray either the 50 μg/mL rhEGF or the placebo over their entire oral mucosa twice daily and to swallow the residual. The rhEGF was administered at the start of intensive chemotherapy until the time of their recovery from neutropenia (absolute neutrophil count >1000 /μL for 3 consecutive days) and disappearance of OM. The severity of OM was assessed daily using the World Health Organization (WHO) scale. Patients also completed an Oral Mucositis Daily Questionnaire (OMDQ) to assess patient-reported QoL (Stiff PJ et al, J Clin Oncol 2006). A total of 138 patients are planned to be enrolled in this study. This interim analysis was performed after the acquisition of data on the 58 patients who were enrolled between March 2009 and June 2010. Twenty-nine patients were assigned to each group. Patient median age in the rhEGF group was 56 (range, 18–63) years and 51 (range, 19–65) years in the placebo group. Autologous SCT was performed on 26 patients (89.7%) from each group, and allogeneic SCT, in the rest (10.3%). Baseline characteristics were not significantly different between the 2 groups. The difference in the incidence of grade 3 or 4 OM between the 2 groups was not significant (p=0.283). The duration of OM in patients with grade 3 or 4 OM tended to be shorter, however, in the rhEGF group than in the placebo group (8.0 [range, 2.0–23.0] days vs. 18.5 [range, 2.0–34.0] days; p=0.108). This result is also supported by the significantly shorter duration of medication use in patients with grade 3 or 4 OM in the rhEGF group than in the placebo (28.0 [range, 17.0–44.0] days vs. 39.5 [range, 17.0–61.0] days; p=0.050). The OMDQ analysis using area-under-the-curve calculation (with a lower score for milder limitation) for patients with grade 3 or 4 OM also showed that rhEGF significantly reduced limitations in swallowing (26.0 [range, 8.0–75.0] vs. 51.5 [range, 19.0–92.0]; p=0.039) and drinking (25.0 [range, 7.0–73.5] vs. 55.5 [range, 20.0–86.0]; p=0.042) compared to placebo. The duration of administration of total parenteral nutrition (TPN) was significantly shorter in the rhEGF group than in the placebo group (7.0 [range, 0.0–25.0] days vs. 16.5 [range, 10.0–32.0] days; p=0.012) in patients with grade 3 or 4 OM. A similar result was observed for the duration of opioid analgesics use (6.0 [range, 0.0–25.0] days vs. 17.0 [range, 0.0–48.0] days; p=0.117). In patients with grade 3 or 4 OM, the rhEGF group showed a significantly shorter length of hospitalization than the placebo group (27.0 [range, 18.0–65.0] days vs. 41.5 [range, 27.0–94.0] days; p=0.022). Adverse events between the 2 groups were not statistically significant. The adverse events in the rhEGF group were nausea (n=2, 6.9%), oral pain (n=1, 3.4%), and taste alteration (n=1, 3.4%). No grade 3 or 4 adverse events developed. To summarize, in patients who received SCT for hematologic malignancies, rhEGF tended to reduce the duration of grade 3 or 4 OM and significantly reduced limitations in swallowing and drinking. In addition, rhEGF significantly reduced the duration of TPN use and hospitalization, and tended to reduce the duration of opioid analgesics use. The rhEGF was generally well tolerated with a favorable safety profile. The results of this interim report demonstrate that rhEGF has a role in the treatment of OM induced by intensive chemotherapy with SCT, and improves QoL. This study is still ongoing, and the final results are expected to be available within 2 years. Disclosures:Off Label Use: Recombinant human epidermal growth factor is a novel drug, which is officially approved for treatment of diabetic foot in Korea. This drug is currently not approved for treatment of oral mucositis by both the US FDA and the Korean FDA yet. In the present study, we used this drug to evaluate efficacy and safety of this drug for prevention and treatment of oral mucositis induced by intensive chemotherapy with stem cell transplantation.

Minimal Residual Disease following Allogeneic Hematopoietic Stem Cell Transplantation

Minimal residual disease (MRD), both before and after transplantation, is a clinically important yet relatively poorly defined aspect of allogeneic hematopoietic stem cell transplantation (alloHSCT). The clinical relevance of MRD in the context of alloHSCT has been demonstrated by its association with the development of clinical relapse. However, with the possible exception of chronic myeloid leukemia (CML), the specific techniques, timing, frequency, and clinical utility, relative to improvement in patient outcomes, for monitoring MRD in the setting of alloHSCT has yet to be clearly defined. A concise overview of monitoring techniques for detecting MRD, as well as treatment strategies and biological and clinical research initiatives for MRD suggested by the National Cancer Institute First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation, is covered in this article.

Future Perspectives: Therapeutic Targeting of Notch Signalling May Become a Strategy in Patients Receiving Stem Cell Transplantation for Hematologic Malignancies

The human Notch system consists of 5 ligands and 4 membrane receptors with promiscuous ligand binding, and Notch-initiated signalling interacts with a wide range of other intracellular pathways. The receptor signalling seems important for regulation of normal and malignant hematopoiesis, development of the cellular immune system, and regulation of immune responses. Several Notch-targeting agents are now being developed, including natural receptor ligands, agonistic and antagonistic antibodies, and inhibitors of intracellular Notch-initiated signalling. Some of these agents are in clinical trials, and several therapeutic strategies seem possible in stem cell recipients: (i) agonists may be used for stem cell expansion and possibly to enhance posttransplant lymphoid reconstitution; (ii) receptor-specific agonists or antagonists can be used for immunomodulation; (iii) Notch targeting may have direct anticancer effects. Although the effects of therapeutic targeting are difficult to predict due to promiscuous ligand binding, targeting of this system may represent an opportunity to achieve combined effects with earlier posttransplant reconstitution, immunomodulation, or direct anticancer effects.

A prospective study of serum soluble CD30 in allogeneic hematopoietic stem cell transplantation

The expression of CD30 is restricted to cells of the immune system and strictly regulated under physiological conditions. However, active immune cells express CD30 and soluble CD30 (sCD30) is released. Several investigators reported the relevance for sCD30 as a predictive marker for allograft rejection following organ transplantation. We investigated the role of sCD30 in 30 patients undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies. sCD30 was measured at different time points until day 120 post transplant. There was a great variety of sCD30 at baseline before transplantation. At time of engraftment, patients who developed no or only mild signs of acute graft-versus-host-disease (aGvHD) until day 120 had significant lower levels of sCD30 than patients who developed severe aGvHD. Moreover, all patients with aGvHD °III/IV showed a clear increase in sCD30 levels before clinical signs of aGvHD. Levels of sCD30 decreased if patients responded to aGvHD-therapy. We suggest a potential role of sCD30 serum levels in prediction of aGvHD following allogeneic stem cell transplantation.

Donor Cell Leukemia in Umbilical Cord Blood Transplant Patients: A Case Study and Literature Review Highlighting the Importance of Molecular Engraftment Analysis

Donor cell neoplasms are rare complications of treatment regimens that involve stem cell transplantation for hematological malignancies, myelodysplastic processes, or certain genetic or metabolic disorders. We report a case of donor cell leukemia in a pediatric patient with a history of acute myeloid leukemia that manifested as recurrent AML FAB type M5 fourteen months after umbilical cord blood transplantation. Although there was some immunophenotypic drift from the patient's original AML and their posttransplant presentation, the initial pathological impression was of recurrent disease. Bone marrow engraftment analysis by multiplex PCR of short tandem repeat markers performed on the patient's diagnostic specimen showed complete engraftment by donor cells, with a loss of heterozygosity in the donor alleles on chromosome 7. This led to the reinterpretation of this patient's disease as donor-derived leukemia. This interpretation was supported by a routine karyotype and fluorescence in situ hybridization analysis showing loss of chromosome 7 and a male (donor) chromosome complement in this female patient. Also noted was a loss of the patient's presenting chromosomal abnormality, t(11;19)(q23;p13). This case highlights the need for close coordination between all aspects of clinical testing for the transplant patient, including molecular engraftment studies, when distinguishing the very common complication of recurrent disease from the exceedingly rare complication of donor cell leukemia.