Ablative Stem Cell Transplantation Research Articles

Cytomegalovirus and Effect on Early Chimerism in Patients with Myeloid Disorders Undergoing Stem Cell Transplantation Using Reduced Toxicity Ablative Conditioning Regimen

Cytomegalovirus (CMV) remains a significant cause of morbidity after allogeneic hematopoietic stem cell transplantation (SCT). The influence of CMV on the chimerism in reduced toxicity ablative conditioning SCT in myeloid disorders is ill defined. A recent report published in Blood by Sellar et al showed that in patients who received alemtuzumab-based regimen, the group of patients who were recipient positive (R+)/ Donor negative (D-) had CMV-specific T cells that are exclusively of recipient origin and significantly influenced the chimerism status toward recipients. To explore the impact of seropositivity and seronegativity of CMV in recipients and donors on early chimerism, we undertook a retrospective analysis of patients with myeloid disorders who received four days of fludarabine and busulfan with or without anti-thymocyte globulin (ATG) at our center in the last 10 years.Methods: Chimerism assay was performed using a quantitative fluorescence-based short tandem repeat-polymerase chain reaction (STR-PCR) with capillary electrophoresis for PCR product resolution.Results: 42 patients were identified and included in the study. All patients received fludarabine (40 mg/m2/day x 4 doses), busulfan (3.2mg/kg/dose IV x 4 doses). Of these 42 patients, 25 had anti-thymocyte globulin. There were 28 male and 14 female patients with a median age of 62 years (range 48-74yrs). Median time to follow up was 8 months (0.8-54 months). Disease risk was considered advanced in 21 patients, intermediate in 4 and early in 17. Median blast number at time of SCT was 5%. Stem cell source included peripheral blood in all patients. There were no primary graft failures. Total recipient cell chimerism showed increase or persistence of recipient chimerism in 5/11 (45%) of R+D- vs 2/6 (33.3%) of R-D- in the group of patients who received ATG, p=1.0, with a mean of recipient chimerism at day 100 of 20.4% in the R+D- group compared to a mean of 17% in the R-D- group. In the group who did not get ATG, recipient chimerism persistence or increase was not that different between the R+D- patients 3/4 (75%) compared to 4/4 (100%) in patients who were seronegative for CMV (R-), p=1.0. The mean of recipient chimerism at day 100 in the R+D- no ATG group was 23.25% with a median of 12% while the mean and median at day 100 in the R- no ATG group were 35.25% and 19.5% respectively (p=0.573).When looking at the persistence or increase in recipient chimerism in the group of patients who were R+D-, in those who got ATG it was 45% increase vs 75% increase in those who did not get ATG (p=0.569) with a median of 12% vs 0% respectively (p=0.49). Also increase or persistence of recipient chimerism was 33.3 % in patients who were R- and got ATG vs 100% in R- no ATG patients (p=0.076)with median at day 100 of 0 vs 19.5% (p=0.098).Conclusion: In this small cohort from a single center, we found that in patients with myeloid disorders who received reduced toxicity ablative conditioning regimen, the group of patients who received ATG, there was no statistically significant increase in recipient chimersim in the R+D- group compared to R-D- group. This is different from what Sellar et al found in a small group of patients who received alemtuzumab. These results may indicate a difference between ATG and alemtuzumab in the effect of CMV seropositivity and negativity on the recipient chimerism, which need to be studied further in a larger retrospective or prospective study. This is especially important in myeloid disorders since persistent or increase in recipient chimerism may identify high-risk patient cohorts who may benefit from additional therapeutic interventions. DisclosuresNo relevant conflicts of interest to declare.

Effectiveness of Reduced Toxicity Conditioning Regimen with Intravenous Busulfan Plus Pentostatin (BUPENT) in Patients Older Than 50 Years with Advanced Hematologic Malignancies.

Abstract 3331Poster Board III-219 IntroductionCurrent data suggests that recipient age above 50 is associated with an inferior outcome after myeloablative allogeneic stem cell transplantation (SCT). Overall survival (OS) of 31%, and transplant related mortality (TRM) of 17% at 100 days have been reported in this population (Ditchkowski, et al 2005; Yanada, et al. 2004). Encouraging results are observed with non-myeloablative conditioning regimens. However, for patients with a high relapse risk, this approach may not be sufficient to achieve long term disease control. In these cases, a reduced toxicity, yet ablative stem cell transplantation (RT-SCT) may give adequate time to the transplanted cells to mature and mount an immune-mediated antitumor response. This study evaluated the outcome after RT-SCT using a conditioning regimen consisting of intravenous busulfan (Bu) and pentostatin (Pent). MethodsConsented adult patients up to 70 years with a fully-matched related (MRD) or unrelated donor (MUD) were screened for enrollment. Conditioning consisted of Bu 1.6 mg/kg every 12 hours days -7 to -4, and Pent 4 mg/m2 on day -3 and -2 prior to stem cell infusion on day 0. GVHD prophylaxis was methotrexate 10 mg/m2 on day 1, and 5 mg/m2 on days 3, and 6. Tacrolimus was started on day -2, and then tapered over 1 month after day +100. CharacteristicsTwenty six patients were analyzed. Male to female ratio was 1:1. Stem cell source was from MRD in 15 patients and MUD in 11. Median age was 62, with 92% of patients being older than 50 years. Indications for treatment were AML (35%), MDS (42%), Refractory CLL (23%), Relapsed NHL (12%), and Philadelphia (+) ALL (4%). All AML patients were high risk either due to poor cytogenetic, transformation, or relapse and only two of them were transplanted in first complete remission. MDS patients were RAEB (36%), secondary MDS (36%), or multilineage dysplasia (18%). Two patients had prior autologous transplants. ResultsNo graft failure was observed. All patients achieved neutrophil (NEU) engraftment. Two patients expired prior to platelet (PLT) engraftment. Median engraftment days for NEU and PLT were 13 days. At a median follow up of 25 months, the OS and progression free survival for the entire group was 40% and 38% respectively. The OS in the MRD group was 58%. TRM at 100 days was seen in one patient (4%) due to veno-occlusive disease (VOD). Limited chronic GVHD was the most common observed toxicity (54%), followed by diarrhea (30%) and mucositis (23%). Mucositis was mainly grade 1 (8%) and grade 2 (8%). No grade 3 mucositis was observed. There was only one case of VOD and one case of acute GVHD. ConclusionTo our knowledge, this is the first report of a RT-SCT using BuPent. This study demonstrates the efficacy of the regimen in patients older than 50 years. No graft failure was observed and the regimen related toxicity was acceptable in this high-risk population. The overall survival of 40% at a median follow up of 25 months compares favorably with prior reports of myeloablative allogeneic stem cell transplatation in patients older than 50 years. This regimen provides an exciting opportunity to extend the benefits of allogenic transplant to an older population, and warrants replication with larger controlled trials. DisclosuresRodriguez:Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vesole:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Millenium: Speakers Bureau; Centocor Ortho Biotech: Speakers Bureau.

A Prospective Study of Iron Overload in Patients Undergoing Ablative Stem Cell Transplantation.

Abstract 3332Poster Board III-220 IntroductionIron overload is a recently recognized problem for patients undergoing hematopoietic stem cell transplantation (HSCT). Hyperferritinemia is common and is associated with significantly increased treatment-related mortality (TRM) and poorer overall survival after HSCT. However, serum ferritin may be a poor surrogate for total body iron burden, and no prospective study of parenchymal iron overload has yet been reported. We initiated a prospective study of adult patients with acute leukemia or myelodysplastic syndrome (MDS) undergoing myeloablative HSCT, in order to estimate the prevalence of iron overload in this population. We measured pre-HSCT serum ferritin, C-reactive protein (CRP), iron, total iron binding capacity, and genotyped patients for HFE mutations. All patients also underwent liver and cardiac MRI with measurement of T2*, from which liver iron content (LIC) and cardiac iron loading were inferred. Results41 of 45 planned patients have been enrolled to date. Median age was 46 years (range, 18-63). 24 patients had AML, 11 had ALL, and 6 had MDS. They had received a median of 2 prior chemotherapy courses (range, 0-6). Among the 39 patients with available transfusion history, the median number of prior RBC transfusions was 19 (range, 0-59). 88% of patients had a pre-HSCT serum ferritin above normal; the median value was 1432 (range, 20-6989). Higher ferritin values were associated with more advanced disease stage, number of prior chemotherapy regimens, and number of transfusions. The median LIC was 3 g/g dry weight (g/gdw) (range, 0.6-12.9). 85% of patients had an LIC above the upper limit of normal (1.8 g/gdw), and 17% had an LIC above 7 g/gdw. Only 1 patient had cardiac iron overload (cardiac T2*<20 msec). Pre-HSCT LIC correlated best with serum ferritin (r=0.7), although it also correlated with transfusion history (r=0.56) and with transferrin saturation (r=0.50). The correlation improved further (r=0.76) when ferritin was divided by log(CRP), when CRP was above normal (see Figure). [Display omitted] Median follow-up after HSCT is 4.5 months (range, 0.2-13.5), precluding full analysis of clinical outcomes at this point. ConclusionHepatic iron overload is very common in patients with acute leukemia or MDS undergoing HSCT, and is strongly correlated with transfusion history. Cardiac iron overload is rare. Pre-HSCT serum ferritin, adjusted for CRP, is a good surrogate marker for hepatic iron overload. This close relationship lends support to prior studies that used serum ferritin to assess the impact of pre-HSCT iron overload on transplantation outcome. Moreover, it provides the basis for the assessment of iron chelation strategies to reduce TRM. DisclosuresArmand:Novartis: Consultancy, Research Funding.

Enhanced Engraftment of a Very Low-Dose Cord Blood Unit in an Adult Haemopoietic Transplant by Addition of Six Mismatched Viable Cord Units

The report describes the feasibility of the addition of multiple viable HLA-mismatched unrelated cord blood units, to a low cell number matched unrelated cord, to assist clinical engraftment. An ablative stem cell transplant was performed in an adult with relapsed acute lymphoblastic leukaemia (ALL), using a single HLA-matched cord blood unit (mononuclear cell dose 0.8 × 107), supported by six mismatched cord blood units (one unit per 10 kg recipient weight). No adverse reaction occurred following the infusion of mismatched units and engraftment of the suboptimal-dose matched unit occurred rapidly, with no molecular evidence of engraftment of mismatched cords. Early molecular remission of ALL was demonstrated using a novel PCR for a mitochondrial DNA mutation in the leukaemic clone. The cell dose of the matched cord was well below that recommended to engraft a 70 kg recipient. We suggest that a factor or factors in the mismatched cords enhanced/supported engraftment of the matched cord.

Comparative Outcome of Myeloablative and Reduced Intensity Allogeneic Stem Cell Transplantation for Chronic Lymphocytic Leukemia.

Allogeneic stem cell transplantation (SCT) remains the only potentially curative modality for patients with CLL. Reduced intensity conditioning (RIC) approaches are commonly used because of lower initial toxicity and the belief that cure is primarily mediated by a GVL effect. However, the role of dose intensity in these patients has not been fully explored. We analyzed the outcomes of 88 CLL patients undergoing a first allogeneic SCT from a HLA-matched (6/6) donor at DFCI between 1998 and 2007. 26 patients receiving ablative transplants were conditioned either with standard doses of cyclophosphamide and total body irradiation (96%), or cyclophosphamide and oral busulfan (4%). 62 patients receiving RIC were conditioned with fludarabine 30 mg/m2 and intravenous busulfan 0.8 mg/kg/d, both for 4 days. GVHD prophylaxis regimens consisted mostly of tacrolimus/ sirolimus +/− MTX (35% ablative, 63% RIC), cyclosporine with prednisone or MTX (15% ablative, 23% RIC) and T cell depletion (31% ablative, 0% RIC). 50% of the ablative SCTs were performed after 2002, compared to 90% of the RICs (p < 0.001). RIC patients were older, with a median age of 55 (36–55), compared to 47 (27–60) for the patients having ablative SCTs (p < 0.001). Virtually all RIC patients (98%) received PBSC, compared to 54% of patients undergoing ablative SCT (46% bone marrow) (p < 0.001). 66% of RIC patients had unrelated donors, compared to 42% of patients undergoing ablative SCT (p = 0.06). No differences between groups were observed for patient gender, donor-patient sex matching, or disease status at conditioning (56% CR/PR for RIC, 58% for ablative SCT). No significant difference in rates of acute GVHD (grade 2–4, 34% in RIC and 48% in ablative SCT; p = 0.23) and chronic GVHD (72% in RIC and 55% in ablative SCT; p = 0.18) was observed. The median follow-up of survivors was 3.3 years for the RIC patients and 5.1 years for the ablative SCT patients. No statistical difference between RIC and ablative SCT was noted in PFS or OS, with 3 year PFS 54% for RIC and 38% for ablative SCT (p=0.30 from stratified log-rank test, by year of transplant before or after 2002) and 3 year OS 65% for RIC and 50% for ablative SCT (p=0.19 from stratified log-rank test by transplant year). As anticipated, the 3 year cumulative incidence of transplant related mortality (TRM), reflecting relapse as a competing risk, was 15% for RIC, compared to 54% for ablative SCT (p < 0.001, Gray's test). The 3 year cumulative incidence of relapse following RIC was 30%, compared to 8% after ablative SCT (p=0.038, Gray's test). In Cox proportional hazards regression analysis considering type of conditioning regimen (RIC vs ablative), age, donor patient sex mismatch, PBSC vs BM, matched related vs unrelated donor, disease status at conditioning (CR/PR vs other), GVHD prophylaxis (sirolimus vs non-sirolimus), and transplant year (before, or 2002 and after), only disease status at conditioning was an independent predictor of OS (CR/PR, HR=0.30 (95% CI 0.13–0.66), p = 0.003) and PFS (CR/PR, HR=0.48 (95% CI 0.25–0.93), p = 0.03). The type of transplant conditioning did not reach statistical significance for OS (ablative SCT HR=2.36, p = 0.07) or PFS (HR=1.28, p = 0.58). In a competing risks regression model evaluating the same factors, significant predictors of TRM included disease status at conditioning (CR/PR, HR=0.27 (95% CI 0.09–0.78), p = 0.02), and conditioning type (ablative SCT, HR=7.69 (2.97–19.92), p < 0.001). The only significant predictor of relapse was type of conditioning (ablative SCT, HR=0.11 (95% CI 0.03–0.39), p < 0.001). Although the patients undergoing RIC likely differ systematically from the patients undergoing ablative SCT, these data suggest that, although TRM is, as expected, higher following ablative SCT in CLL, relapse is also significantly lower, suggesting that dose intensity may play a role in disease control. Given the counterbalancing factors of TRM and relapse, PFS and OS are similar following the two approaches. Future research could focus on efforts to enhance GVL or dose intensity without increasing TRM.

Campath-1H-Containing Reduced Intensity Regimen Followed by Unrelated Allogeneic Stem Cell Transplantation in Patients with Advanced Hematologic Malignancies.

BACKGROUND: Graft versus host disease (GVHD) remains a major cause of mortality after unrelated transplants. Reduced intensity conditioning regimens (RIC) followed by allogeneic stem cell transplantation (SCT) with in vivo T-cell depletion using Campath-1H have been shown to decrease the incidence of GVHD. We report our experience with such an approach in 19 patients (pts) with advanced hematologic malignacies who undergone unrelated SCT.PATIENTS AND METHODS: Between October 2001 and June 2003, 19 pts with a median age of 56 years (range 18–70) not eligible for ablative SCT received Campath-1H 20 mg/m2, fludarabine 25 mg/m2 × 5 days and either cyclophosphamide 1 g/m2 × 2 days (n=16pts), melphalan 140mg/m2 (1 pt) or busulfan 0.8 mg/m2 × 8 doses (n=2pts) followed by G-CSF stimulated peripheral blood (n=13) or unmanipulated bone marrow (n=6). GVHD prophylaxis consisted of cyclosporin at least until T+60 and mycophenolate mofetil through T+30. DLI was allowed for residual disease/progressive disease or mixed chimerism after T+ 60, in the absence of acute GVHD. Seven pts had a previous autologous transplant. Ten pts had myeloid diseases (AML=6, CML Ph negative=1, CML accelerated phase =1, therapy related MDS=1, myelofibrosis=1); 9 pts lymphoid (HD=3, NHD=5, PLL=1); Only 5 pts were in CR at transplant. Six pts received bone marrow witha median CD34+ cells infused of 3.7 × 106/Kg, and 13 pts received peripheral blood with a median of 4.5 × 106/Kg CD34+ cells infused.RESULTS:19 pts achieved ANC>0.5 × 106/L within a median of 12 days (range 8–16); 2 pts rejected the graft and 1 had autologous reconstitutuion; 10/19 pts achieved sustained platelet engraftment at a median of 16 days (range7–27). 2/17 pts with sustained engraftment developed acute GVHD (grade IV T+30 and grade III T+53); 7/14 at risk pts had CMV reactivation; TRM at T+100 was 16% (disease progression in 2 and GVHD in 1). Nine pts received DLI (5 for mixed chimerism and 4 pts for persistent/progressive disease). After DLI, 5 pts had GVHD limited to skin. None of the pts receiving DLI for persistent/progressive disease responded. Response to transplant was as follows: CR in 3/6 AML pts, CR in 1/1 pt with myelofibrosis, CR in 3/3 HD pts, CR in 3/5 NHL pts. Five pts (26%) remain alive in CR at T+ 36, 42, 50, 56 and 66 months. Causes of death include disease progression/relapse in 7 pts, CMV disease in 1 pt, sepsis in 2 pts, GVHD in 3 pts (2 underwent a second transplant), other malignancy in 1 pt.CONCLUSION: These results confirm that unrelated SCT with in vivo T -cell depletion using Campath-1H is well tolerated. This approach is associated with low TRM even in pts with advanced disease, and some can achieve long-term disease control. Disease progression/relapse remains a major impediment to this approach.

A Pilot Trial of Two Dose Levels of Rabbit Antithymocyte Globulin, (rATG), Thymoglobulin, as Part of a Myeloablative-Conditioning for a HLA Identical Matched Related Donor Stem Cell Transplant (SCT) with Cyclosporine (CsA) as Graft Versus Host Disease (GvHD) Prophylaxis.

To determine the role of rATG to modify the development of acute GvHD we conducted a randomized, prospective, open-label, multi-center pilot study in patients with ALL or AML in first or second remission. CsA was the only agent used for GvHD prophylaxis. Patients (N=22) were randomized (1:1) to receive either 4.5 mg/kg or 8.5 mg/kg of ATG during the preparative regimen. The rATG infusions were completed on Day -1, within 18 hours prior to SCT on Day 0. The low (N=11) and high dose groups (N=11) were comparable for age, diagnosis and remission status. The mean age was 41.4 and 39.6 years in the low and high dose groups respectively. In both groups 6/11 patients had AML and 5/11 had ALL. All patients received a fully ablative preparative regimen from a HLA matched related donor. Results: Mean time to neutrophil engraftment was 6.5 and 7.3 days for the low and high dose arms, respectively. The incidence of Grade &amp;gt; II acute GvHD was 0/11 for the low dose arm and 3/11 for the high dose arm. Infections were seen in 9/11 patients in both groups. The cumulative number of hospitalization days was 30.4 and 47.6 days (p=n.s.) in the low and high dose groups respectively. The overall survival at 180 days was 63.6 % in the low dose group and 54.5 % in the high dose group (p=n.s.). The disease free survival (DFS) at day 180 was 54.5% in both groups. The treatment related mortality (TRM) was 18.2 % in the low dose and 45.5 % in the high dose (p=n.s.) The relapse rate was 18.2 % in the low dose group and 0% in the high dose group (p=n.s). Conclusion: This pilot study suggests that rATG may modify the development of serious acute GvHD in patients who received a fully ablative SCT. The low, combined, 3/22, incidence of acute GvHD (13.6%) in patients who received rATG(Thymoglobulin) and post transplant CsA suggests that this combination is an acceptable regiment for GvHD prophylaxis. The lower dose of rATG, 4.5 mg/kg, was as effective and was associated with a lower TRM as compared to the higher, 8.5mg/kg dose. The use of rATG administered during the preparative regimen was well tolerated and may provide an effective alternative to methotrexate when used as part of an ablative conditioning regimen in HLA identical related donor SCT.

Incidence and outcome of idiopathic pneumonia syndrome in pediatric stem cell transplant recipients

Idiopathic pneumonia syndrome (IPS) is a rare complication following stem cell transplant (SCT) and its incidence among pediatric SCT recipients is not known. To assess the incidence of IPS, we retrospectively reviewed the incidence of IPS at our center. IPS is defined as the presence of multilobar infiltrates by chest radiograph or computed tomography scan, need for supplemental oxygenation with declining pulse oximetry and no identifiable pulmonary infection. Between July 1999 and August 2005, 11 of 93 children who received a fully ablative allogeneic SCT (11.8%) developed IPS. All 11 patients had normal pulmonary evaluation before transplant. IPS developed at a median of 17 days (range 8-42 days) after transplant. Recipients of unrelated donor transplant had increased risk of developing IPS. There was a significant association between acute or hyperacute graft-versus-host disease (GVHD) and IPS (P=0.035). All patients had significant hypoxia and five patients required assisted ventilation. IPS was the cause of death in two patients. Although there was complete resolution of respiratory symptoms in the other nine patients, overall transplant-related mortality was significantly higher among patients with IPS (64 vs 17%, P=0.002). IPS is a relatively common complication in pediatric SCT recipients and acute GVHD is an important associated factor.

The Different Dynamics of Chimerism Evolution Determines the Success of Myeloablative, Reduced Intensity Conditioning and T-Cell Depleted Allogeneic Stem Cell Transplantation.

Background: The dynamics of chimerism evolution determines the success of allogeneic stem cell transplantation (SCT). Several factors such as the intensity of the conditioning regimen, the T-cell content of the graft or the GVHD prophylaxis, influence the degree of chimerism after SCT. Objective: To evaluate the dynamics of chimerism after different SCT settings (ablative, reduced intensity conditioning -RIC- and T-cell depleted -TCD-) and its influence in the success of the procedure.Patients and Methods: The study includes 68 SCT: 32 ablative (including 7 from HLA matched unrelated donors -UD-), 19 RIC and 17 TCD (including 8 from haploidentical donors and 2 from UD with 1 HLA disparity). Chimerism analysis was performed by FISH for the sex chromosomes or STR-PCR (sensitivity 1 Samples obtained on days +30, +100, +180, +365 and once a year thereafter, included bone marrow (BM) and peripheral blood (PB). Moreover, chimerism was analyzed in PB and leukocyte lineages (T lymphocytes CD3+, B lymphocytes CD19+ and myeloid cells CD15+ isolated (purity >95%) by immunomagnetic means, AutoMACS, Miltenyi Biotec), every 2 weeks, starting on day +15 (except in ablative), and until complete chimerism (CC) was achieved. Results of chimerism follow-up were censored once the diagnosis of relapse or rejection was established.Results: The incidence (% patients) of mixed chimerism (MC) on day +30 (ablative: BM 27%, PB 15%; RIC: BM 40%, PB 41%, CD3 40%; TCD: BM 31%, PB 33%, CD3 54%), as well as its dynamics (MC on day +100: ablative BM 8%, PB 4%; RIC BM 8%, PB 15%, CD3 22%; TCD BM 20%, PB 40%, CD3 37%) were different in the three SCT settings. All except 2 CD15 samples analyzed showed CC. Moreover, the percentage of recipient cells (%R) was significantly higher after RIC and TCD than after ablative SCT, as well as in T lymphocytes than in BM or PB (7/8 cases with simultaneous studies showed MC in T lymphocytes and CC in PB). All RIC SCT evolved to CC by day +180 while TCD SCT showed persistent MC (2 patients with stable MC after one year). The incidence of rejection was greater after RIC (2/19) and TCD (4/17) than after ablative SCT (2/32). All these patients showed MC, mainly in T lymphocytes, which allowed early diagnosis and successful treatment with immunosuppression withdrawal and donor leukocyte infusion. Patients with CC in PB/T lymphocytes on day +30 had a higher incidence of GVHD>I than those with MC. In the present series, however, a relationship between chimerism and relapse, disease free survival or overall survival, was not observed.Conclusions: SCT with greater incidence of MC (RIC and TCD) favor immune tolerance between donor and recipient which reduces the risk/severity of GVHD at the expense of a higher incidence of graft rejection.

In vivo T cell depleted unrelated allogeneic stem cell transplantation with a reduced intensity regimen in patients with advanced hematologic malignancies

Background: Graft versus host disease (GVHD) remains a major cause of mortality after transplantation. Reduced intensity conditioning (RIC) regimens followed by allogeneic stem cell transplantation (SCT) with in vivo T-cell depletion using Campath-1H have been shown to decrease the incidence of GVHD. We report our experience with such an approach in 19 patients (pts) with advanced hematologic malignancies undergoing unrelated SCT. Patients and Methods: Nineteen pts with a median age of 56 years (range 18–70) not eligible for ablative SCT received Campath-1H 20 mg/m2, fludarabine 25 mg/m2× 5 days and either cyclophosphamide 1 g/m2× 2 days (n=16 pts), melphalan 140 mg/m2 (n=1 pt) or busulfan 0.8 mg/m2× 8 doses (n=2 pts) followed by G-CSF stimulated peripheral blood (n=13) or unmanipulated bone marrow(n=6).

Acute Graft-Versus-Host Disease: Clinical Presentation and Response to Therapy Following Umbilical Cord Blood Transplant.

The nature of aGVHD after umbilical cord blood transplant (UCBT) has not been well characterized. We analyzed acute graft-versus-host disease (aGVHD) incidence and response to therapy in 136 recipients of unrelated UCBT. aGVHD developed in 72 receiving myeloablative (MA) (n=39) and non ablative stem cell transplant conditioning (NST) (n=33) (indicated if age >45 years, prior transplant and major co-morbidity). MA transplant recipients were significantly younger (median age 14 years, range 0.8–50) than NST transplant recipients (median 48 years, range 0.7–59), p < 0.0001 and had fewer advanced malignant disease at transplant (8% versus 24%), p = 0.09. At diagnosis of aGVHD, the clinical grades and organ involvement were similar in the 2 groups. Grade II–IV aGVHD developed in 34% of MA transplant recipients and 45% (p = 0.1) of NST transplant recipients at a median of 35 days (12–137) and 30 days (15–96) post transplant whereas grade III–IV aGVHD developed in 9% and 13% (p=0.6), respectively. 87% of MA vs. 85% of NST recipients (p=0.8) had skin involvement; 39% vs. 49% had GI disease (p=0.4); and 10% vs.9% (p=0.9) had liver GVHD, respectively. Response to therapy was assessed at 28 and 56 days after diagnosis of aGVHD. A high frequency of complete response (CR) was seen across all grades at day 28 (47%, 48% and 43% CR in grades I, II and III–IV, respectively). At day 56, CR was more frequent in grade I aGVHD (68% vs 64% and 50% in patients with grade II and III–IV disease, respectively, p 0.08). Response rates were similar in MA and NST transplant recipients (CR in 49% vs 46% by day 28, p=0.1, and 64% vs 61% by day 56, p=0.5. Age < 20 years (CR or PR 82% vs 64%, p = 0.09) and single organ GVHD (81% vs 52%, p=0.01) were associated with a higher response. A higher response rate was seen in patients with skin GVHD (85%) vs GI disease (63%) vs skin + GI (56%) vs liver involvement with skin/GI (43%), p=0.04. After a median follow up of 1.0 year (0.8–7 years) in both groups, 67% (95% CI 52%–81%) of MA versus 45% (95% CI 28%–62%) of NST patients survive (p=0.05). Higher 1 year survival of 70% (95% CI 58%–83%) was seen in patients with day 28 CR or PR to treatment versus non responders (24%, 95% CI 6%–42%), p<0.0001.This data suggests that among unrelated UCBT recipients using either MA or NST preparative regimens, similar incidence, clinical presentation and response to therapy of aGVHD was seen. Early identification of high risk group (age >20, multiorgan disease, GI or liver GVHD) should facilitate timely assignment of intensified therapy.