1-year Transplant-related Mortality Research Articles

Feasibility of clofarabine cytoreduction before allogeneic transplant conditioning for refractory AML

To control disease before allogeneic hematopoietic cell transplantation (HCT) for relapsed/refractory AML, we used clofarabine cytoreduction. Seventeen patients received clofarabine 30-40 mg/m(2) i.v. daily for 5 days with plans to initiate conditioning during the nadir, 14 days later. Bone marrow biopsy 12 days after clofarabine showed effective cytoreduction (that is,<20% cellularity with <10% blasts) in 10 of 17 patients (59%). Ineffective cytoreduction correlated with lower PFS (3.8 vs 6.4 months; HR=2.7, 95% CI=1.10-14.29, P=0.035) and OS (5.1 vs 16.6 months; HR=2.5, 95% CI=0.98-12.17, P=0.053). Significant toxicities before HCT, attributable to clofarabine, were grade 1-2 hyperbilirubinemia (18%); grade 1-2 (59%) or grade 3-4 (18%) transaminitis; and grade 1-2 (18%) creatinine elevation. Sixteen patients proceeded to HCT infusion 22 days (median) after initiation of clofarabine. Day 100 and 2-year transplant-related mortality were 6 and 36%. Nine patients relapsed. One year PFS and OS were 25 and 38%, respectively. Two patients are alive in remission at 18 and 52 months. Clofarabine cytoreduction followed by immediate HCT is feasible with acceptable toxicity and TRM. Outcomes for this cohort of patients with refractory AML remain poor and we are studying this approach in a prospective manner.

Mismatch at 1-2 HLA Loci Does Not Reduce Survival Following Alemtuzumab-Based Reduced Intensity Unrelated Donor Allogeneic Transplantation

Most candidates for reduced-intensity allogeneic stem cell transplantation (RIC) do not have a human leukocyte antigen (HLA)-matched sibling donor available. Improved HLA-typing techniques allow more stringent matching of unrelated donors (UD), but have reduced the likelihood of identifying a fully matched UD (MUD), defined as a 10/10 locus match by molecular typing. Whilst donors matching at 8–9/10 HLA loci (MMUD) are considered appropriate by some groups, it is unclear the degree to which HLA-mismatch increases procedural toxicity and how this is influenced by different regimens. Availability of alternative stem cell sources such as umbilical cord blood makes it important to clearly define such risks. We therefore analyzed outcomes of 99 consecutive patients who underwent RIC using an UD in our institution from October 1998 to July 2008. Donor selection was performed according to standard criteria, including molecular typing for HLA-A, -B, -C, DRB1 and DQB1. Donors were 10/10 HLA-matched (n=62) or mismatched at up to 2 HLA loci (n=37). Conditioning was 20mg/d alemtuzumab for 5 days, fludarabine 30mg/m2 for 5 days and melphalan 140mg/m2 for 1 day, with cyclosporine from day -1. Peripheral blood stem cells were used in 51 (30 MUD, 21 MMUD) and bone marrow in 48 (32 MUD, 16 MMUD). Median age was 47 years (13– 67), and underlying disease was AML (n=9), myeloma (n=13), Hodgkin (n=18) or non- Hodgkin lymphoma (n=40), and others (n=19). Patients had a median of 4 previous lines of treatment (0–9) and 49 had failed a prior autograft. There were no significant differences between the groups in terms of age, sex, prior autograft, number of treatment lines, or chemosensitivity at transplantation. There were significantly more CMV seropositive recipients in the MMUD group (P.002). Neutrophil recovery (>0.5 × 109/l) occurred at a median of 12 days (9–57) and did not differ between MUD and MMUD (median 11 vs 12 days). Two patients, both MUDs, had primary graft failure and engrafted following CD34 top-up. Three patients rejected the graft, all MMUDs (P.07 for MUD vs MMUD). Secondary graft failure occurred in 3 cases, all MMUDs (P.07 for MUD vs MMUD). All 3 received CD34 top-up with subsequent improvement in counts in one, another died shortly after infusion of cells and 1 remains cytopenic 4 years following the transplant. Of 40 at risk cases, CMV reactivation requiring treatment occurred in 35 (88%; 85% MUD and 90% MMUD). Donor lymphocyte infusions (DLI) were administered in 35 cases, 23 for disease relapse and 12 for mixed chimerism alone, with no significant difference between MUD (n=25, 40%) and MMUD (n=10, 27%, P.4). There was no difference in the incidence of grade 2–4 acute graft-versus-host disease (aGvHD) between MUD (27%) and MMUD (30%, P.7). Prior to DLI, only 3 cases of grade 3 aGvHD occurred (2 MUD and 1 MMUD) and no grade 4 aGvHD. Chronic GvHD (cGvHD) at 1 year occurred in 30%, with a non-significant trend for a lower incidence in MUD versus MMUD patients (24% vs 40%, P.1). Extensive cGvHD at 1 year was 15% (MUD 13% and MMUD 18%, P.6) excluding post-DLI GvHD, and was 26% at 1 year (MUD 26% and MMUD 27%, P.4) and 40% at 3 years (MUD 34% and MMUD 46%) including post-DLI GvHD. With a median follow-up of 3.0 years, transplant related mortality (TRM) for the whole cohort was 14% at 100 days and 28% at 1 year, with no significant difference between MUD (13% and 30%) and MMUD (16% and 27%). Overall survival (OS) at 3 years was 46% for the whole cohort (45% for MUD, 48% for MMUD). The outcome of 1 (n=20) versus 2 (n=17) locus mismatched transplants was also compared. There was a non-significant trend to increased grade 2–4 aGvHD (16% versus 39%, P.2) in the 2 locus MMUD group but extensive cGvHD (including post-DLI GvHD) at 1 year was not different (30% vs 24%, P.6). Survival was not inferior in the 2 locus MMUD group relative to the single mismatches, with 100 day TRM (20% 1 locus vs 13% 2 locus, P.5), 1-year TRM (43% 1 locus vs 19% 2 locus, P.5), and 3 year OS (32% 1 locus vs 63% 2 locus, P.3). We conclude that 8–9/10 MMUD-RIC is a viable option using T-cell depletion with 100mg alemtuzumab in vivo, without a significant adverse impact on TRM or OS compared with 10/10 MUD. The long-term OS of 48% following MMUD-RIC is encouraging given the inclusion mainly of patients with multiply relapsed/refractory hematological malignancy.

400 cGy TBI with fludarabine for reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation

Fludarabine and 200 cGy TBI are commonly used for reduced-intensity conditioning preceding allogeneic hematopoietic SCT (HSCT). However, graft rejection and disease relapse are significant causes of treatment failure with this regimen. We modified this regimen by escalating the TBI dose to 400 cGy in 40 patients with hematologic malignancies. Thirty-four patients achieved complete donor T-cell chimerism at a median of 40 days following HSCT. The incidences of grades II-IV and III-IV acute GVHD were 40 and 15%, respectively, whereas that of limited and extensive chronic GVHD were 12 and 20%, respectively. Two patients rejected their grafts and 12 relapsed. The 100-day mortality was 18%, 2-year transplant-related mortality 20% and overall survival was 58% at a median follow-up of 16 months. There were no significant survival differences between patients with lymphoid compared to myeloid malignancies. A dose of 400 cGy TBI administered with fludarabine is well tolerated and further study is needed to determine whether outcomes are superior to those with 200 cGy TBI.

Comparison of Two Doses of Antithymocyte Globulin in Patients Undergoing Matched Unrelated Donor Allogeneic Stem Cell Transplantation

Antithymocyte globulin (ATG) as part of conditioning regimens is known to reduce the incidence and severity of acute and chronic graft-versus-host disease (aGVHD, cGVHD). The influence of ATG on transplant-related mortality (TRM) and disease-free survival (DFS) is controversial, and may depend on the dose and timing of ATG. We retrospectively compared 2 doses of ATG-Fresenius (ATG-F) in patients undergoing matched unrelated donor allogeneic hematopoetic stem cell transplantation (HSCT) for hematologic malignancies. A dose of 60 mg/kg body weight has previously been recommended for ATG-F. All patients received cyclosporine A and short course methotrexate. ATG-F was administered at a dose of 30 mg/kg on day –1 (ATG-30 group, n = 34) or 20 mg/kg/day on days –3 to –1 (ATG-60 group, n = 49). There was no difference in time to leukocyte and platelet engraftment in the 2 groups. The incidence of aGVHD grade II-IV (50% versus 53%, P = .83) and grade III-IV (27 versus 20%, P = .60) was similar in the ATG-30 versus ATG-60 groups, respectively. There was a trend to a higher incidence of cGVHD in the ATG-30 group (59% versus 40%, P = .14). The estimated 3-year incidence of relapse was similar in the ATG-30 and ATG-60 groups (15% versus 16%, P = .84) whereas the 2-year TRM was lower for the ATG-30 group (12% versus 33%, P = 0.02), mainly because of a higher incidence of fatal infections in the ATG-60 group. This resulted in a better DFS (73% versus 51%, P = .07) for the ATG-30 group. ATG-F (30 mg/kg) administered as a single dose on day –1 may lead to better outcome in patients undergoing unrelated donor allogeneic HSCT compared to 60 mg/kg given in 3 equivalent doses. A prospective randomized study comparing these 2 doses of ATG-F is warranted.

SAFETY OF HEMATOPOIETIC STEM CELL TRANSPLANTATION IN CHILDREN LESS THAN THREE YEARS OF AGE

Allogeneic hematopoietic stem cell transplantation (HSCT) is a standard treatment for a variety of hematologic conditions. However, very young children may experience different complications of HSCT compared to older patients. The authors retrospectively analyzed the results of 51 transplants performed on children less than 3 years of age between June 1987 and October 2005. Donors were matched-related (n = 21), partially mismatched related (n = 3), and unrelated (n = 27). The majority of patients had one or more grade III organ toxicities, but all nonrelapse deaths were attributable to infection. Perineal dermatitis was found in a large number (73%) of recipients of cyclophosphamide-based conditioning regimens. The 1-year transplant-related mortality (TRM) was 14%, but significantly declined in the more modern period. Grades II–IV acute graft-versus-host-disease (GvHD) was seen in 22% of patients, while chronic extensive GvHD developed in only 7% of patients. Relapse was seen in 40% of transplants performed for a malignant condition, most commonly in those patients not in remission at time of HSCT. The 5-year event-free survival (EFS) and overall survival (OS) were 53 and 64%, respectively. Recipients of fractionated total body irradiation (fTBI) were more likely to have at least one long-term sequelae than patients who received chemotherapy-based regimens (p =. 014). These data demonstrate that HSCT can be performed safely in very young children, especially as supportive-care techniques improve. Cyclophosphamide-related perineal dermatitis is a unique complication in very young children. Finally, the incidence of acute and chronic GvHD in this population is low.

Prevention of graft vs. host disease with alemtuzumab ‘in the bag’ decreases early toxicity of stem cell transplantation and in multiple myeloma is associated with improved long-term outcome

Allogeneic stem cell transplantation in multiple myeloma (MM) is controversial because treatment-related mortality and relapse remain a substantial challenge. Patients with symptomatic MM responsive to therapy received myeloablative conditioning with radiotherapy (n=12) or chemotherapy (n=10) followed by infusion of HLA-identical grafts from a sibling. Graft vs. host disease (GvHD) prophylaxis consisted of 'ex vivo' T-cell depletion with CAMPATH-1 antibody. The objective of the study was to determine transplant-related mortality (TRM), GvHD, overall survival (OS) and Disease free Survival (DFS). Twenty-two patients, median age 45 (range 37-56) years, had a median performance status of 1 (0-2). Patients received a median of 23.8 x 10(4)/kg CFU-GM and 4.31 x 10(6)/kg CD34. Median time to engraftment was 13 days. The day-100 and 1-year TRM was 9% and 20%, respectively. Ten patients suffered disease recurrence. Four of eight patients remained in remission after infusions of donor lymphocyte (DLI) containing a median total of 0.67 x 10(8)/kg CD3 cells. Three-year OS was 56%, and 50% remained disease free at a median of 1101 days (range 385-5309). Multiple regression analysis showed that bone marrow (vs. peripheral blood stem cell) (P=0.03), presentation of low albumin (P=0.02) and a higher dose of CAMPATH-1H (P=0.01) were adverse factors for survival. Cox analysis confirmed that a lower CAMPATH-1H dose was associated with improved outcome. In chemotherapy-responsive patients with myeloma, T-cell depletion of allogeneic grafts was associated with an acceptable 1-year TRM and seemed to have a favorable impact on long-term survival.

Long-term follow-up of allogeneic bone marrow transplantation for patients with chronic phase chronic myeloid leukemia prepared with a regimen consisting of cyclophosphamide, cytarabine and single-dose total body irradiation conditioning

We evaluated long-term toxicities and outcomes in 96 patients with chronic phase chronic myeloid leukemia treated with a single bone marrow allograft regimen. Conditioning was cytosine arabinoside, cyclophosphamide (120 mg/kg) and single fraction total body irradiation (500 cGy). Median follow-up was 12.8 years (0.4-19.9 years). Graft failure occurred in one patient, nonfatal veno-occlusive disease in 13 patients (14%). Overall incidences of acute (a) and chronic (c) graft-vs-host disease (GVHD) were 77 and 63%. The 100-day and 1-year transplant-related mortality (TRM) were 1 and 9.2%, respectively, with no change through 5 years. Five- and 10-year event-free survival rates were 56 and 49%, overall survival (OS) rates 72 and 70%, respectively. Forty patients have relapsed: 8 cytogenetic (20%), 10 hematologic (25%) and 22 molecular (55%). Most have been salvaged with donor-leukocyte infusion, second transplants and/or imatinib therapy. Survival was worse for patients transplanted >2 years from diagnosis (10-year OS 56 vs 78%, P=0.01), for patients over 50 years old (10-year OS 44 vs 75%, P=0.05) and for patients without cGVHD (10-year OS 53 vs 86%, P<0.001). This regimen resulted in successful engraftment, low risk of TRM and long-term survival. In an era when imatinib is first line therapy, this regimen offers a potentially low-toxicity, highly successful alternative in the event of poor imatinib response.

Comparison of Reduced-Intensity and Conventional Myeloablative Regimens for Allogeneic Transplantation in Non-Hodgkin’s Lymphoma

Reduced-intensity regimens (RIRs) are being used with increasing frequency in patients with non-Hodgkin’s lymphoma (NHL) undergoing allogeneic transplantation. The impact of dose reduction on relapse and survival has not been extensively studied. We performed a retrospective analysis of 88 patients conditioned with conventional myeloablative regimens (CMRs) (n = 48) and an RIR (n = 40) of fludarabine 125 mg/m 2 and melphalan 140 mg/m 2. Compared with the patients receiving CMR, those receiving RIR were older, had more often failed autologous transplantation, and had more frequently received peripheral blood and unrelated donor transplants. Graft-versus-host disease prophylaxis was provided with cyclosporine + methotrexate ± prednisone for the CMR and with cyclosporine + mycophenolate ± methotrexate for the RIR. The relapse rate was significantly lower in the patients receiving CMR than in those receiving RIR (13% vs 28%; P = .05). The 1-year transplantation-related mortality rate was 33% for CMR and 28% for RIR ( P = .40). Kaplan-Meier 2-year overall survival and progression-free survival were 52% and 46% for CMR versus 53% and 40% for RIR ( P = not significant). Using cumulative incidence functions based on competing risks, univariate analysis, and treatment-related prognostic factors, we found that higher treatment intensity ( P = .03; relative risk [RR] = 35%) and absence of previous autologous transplantation ( P = .0007; RR = 20%) were associated with a lower relapse rate. Using a Cox univariate proportional hazards model, we found that chemosensitive disease at transplantation ( P = .05; RR = 57%) and absence of previous autologous transplantation ( P = .002; RR = 37%) were associated with improved survival. Our observation of similar survival in the patients receiving CMR and those receiving RIR confirms that RIRs are feasible alternatives for high-risk patients with NHL; however, the data suggest that reduced treatment intensity and previous autologous transplantation are associated with increased relapse.

In Multiple Myeloma (MM) CAMPATH-1 Antibodies “In the Bag” Reduce the Early Toxicity of Stem Cell Transplantation from Graft vs. Host Disease (GvHD) and Seem To Be Associated with Improved Long Term Outcome.

Introduction: Although allogeneic stem cell transplantation remains the only curative approach in patients with MM, its role remains controversial. Early high treatment related mortality, particularly from infections, GvHD and later, from disease recurrence remains substantial challenges. This study reviewed the outcome of consecutive patients who received T-cell depleted grafts from HLA identical siblings.Patients and Methods: Patients with symptomatic MM (stage II, n= 4 & III, n=17) who had an HLA identical sibling were initially treated until response with anthracycline or steroid based combinations. Three patients had, in addition, undergone autografting. Individuals who received cytokine mobilized peripheral blood progenitor cell (PBPC) grafts were also prescribed therapeutic serum levels of cyclosporine for 90 days post transplantation. The objective of the study was to determine transplant related mortality OS and DFS.Results: Twenty one patients with a median age of 44 (range 37– 56) years who had responded to chemotherapy (CR or VGPR) received stem cell enriched grafts from HLA identical siblings. Median performance status was 1 (0 – 2). Five individuals had significant organ dysfunction from effects of the disease. At presentation median albumin and β2MG blood levels were 30 g/L and 3.2 ng/mL, respectively. Myeloablative conditioning was radiotherapy (n= 12) or chemotherapy (n= 9) based. GvHD prophylaxis consisted of T-cell depletion with CAMPATH-1G (n=7) or H (n=14) antibodies “in the bag”. BM had all been treated with ex vivo with CAMPATH-1G (median 20 mg) while PBPC grafts in 14 patients were incubated with CAMPATH-1H (median 10 mg). Patients received a median of 23 ×104/kg CFU-GM in 0.87 BM mononuclear cells or 9.22 ×108/kg PBPC (CD34+: 4.46 ×106/kg). Median time to engraftment was 12 days. Two patients developed GvHD (grade 2) and 3 limited chronic form (1 progressed from acute). The 1 year non relapse mortality was 19%. Six patients suffered disease recurrence. One refused further therapy. Three of 5 responded to DLI and 2 remain in unsustained remission. Fatal events appeared lower in patients receiving chemotherapy based conditioning (mortality 11% vs. 50; p= 0.06), exposure of stem cells to CAMPATH-1H (15% vs. 62.5%; p= 0.04) and a lower median CAMPATH-1 dose given (p= 0.01). Cox analysis confirmed that lower CAMPATH-1 dose was associated with improved outcome. Fourteen (67%) patients survive at a median of 1101 days (range 385–5309) and 62% are disease free.Conclusions: In this cohort of chemotherapy responsive patients with advanced myeloma, ex vivo T-cell depletion of allogeneic grafts was associated with good protection from GvHD and 19% 1-year transplant related mortality. Low grades of GvHD post transplantation were associated with a favourable impact in the long term survival.

Two-Year Follow-Up Results at the M.D. Anderson Hospital with Reduced-Intensity Allogeneic Stem Cell Transplantation with Fludarabine-Melphalan as Preparative Regimen in Relapsed/Refractory Hodgkin's Lymphoma: Comparable Outcome with Matched Related and Unrelated Donors.

BACKGROUND: Allogeneic stem cell transplantation (allo-SCT) with reduced-intensity conditioning (RIC) is gaining increasing acceptance in relapsed/refractory (R/R) Hodgkin's lymphoma (HL), but there are little or no outcome data with matched unrelated donors (MUDs).METHODS: Fifty-eight patients with relapsed or refractory Hodgkin's lymphoma (HL) underwent allogeneic stem cell transplantation (allo-SCT) following a reduced-intensity conditioning (RIC) regimen from a matched related donor (MRD; n=25) or a matched unrelated donor (MUD; n=33). The median age was 32 years (range 19–59). The median number of chemotherapy regimens received prior to allo-SCT was five (range 2–9). Forty-eight (83%) patients had received a prior autologous (auto) SCT. The median time to progression after auto-SCT was five months (1–34). Disease status at SCT was sensitive relapse (n=30) or refractory relapse (n=28). The conditioning regimen employed was fludarabine (125–130 mg/m sq over 4–5 days), melphalan (140 mg/m sq IV over 2 days) (FM) and antithymocyte globulin (thymoglobulin 6 mg/kg over 3 days) was added for the most recent fourteen MUD transplants. Graft-vs-host disease (GVHD) prophylaxis included tacrolimus and mini-methotrexate.RESULTS: Chimerism studies indicated 100% donor-derived engraftment in all patients (100%). Cumulative 100-day and 2-year transplant-related mortality (TRM) were 7% and 15%, respectively, (100-day TRM MRD vs. MUD 6% vs. 8%, p=ns; 2-year MRD vs. MUD 13% vs. 16%, p=ns). The cumulative incidence of acute (grade II–IV) GVHD (first 100 days) was 28% (MRD vs. MUD 12% vs. 39%, p=0.04). The cumulative incidence of chronic GVHD at any time was 74% (MRD vs. MUD 57% vs. 89%, p=0.003). Fourteen pts (24%) received a total of 25 (range 1–5) donor leukocyte infusions (DLIs) for disease progression/relapse (PD). Five of them (35%) received salvage chemotherapy as well, and nine (64%) developed acute GVHD after the DLI. Thirty-six patients (62%) are alive (23 in remission) with a median follow-up of 24 months (4–78). The f/up is 23 months (4–53) for alive pts always in remission. Twenty-two patients (38%) expired, and relapse-related mortality was 24%. Projected 2-year overall (OS) and progression-free (PFS) survival are 64% (49–76) and 32% (20–45), with projected 2-year PD at 55% (43–70). There was no statistically significant difference between MRD and MUD transplants with regard to OS (p=0.1), PFS (p=0.9) and PD (p=0.8). There was a clear trend for the response status prior to allo-SCT (complete response, complete response undefined vs. all others) to favorably impact PFS (p=0.07) and PD (p=0.049), but not OS (p=0.4). Partial responders and patients with stable or refractory disease fared similarly with regard to OS and PFS.CONCLUSIONS: Despite the expected higher incidence of acute and chronic GVHD, MUD RIC allo-SCTs had TRM, PFS, and OS comparable to MRD allo-SCTs. Day 100, 2-year TRM and OS/PFS data appear very encouraging in these very high-risk, extensively pretreated patients. Response status at transplant seems to affect outcome, and PD remains a major obstacle. The use of unrelated donors would greatly expand donor availability for these patients.

Hematopoietic Stem Cell Transplantation (HSCT) for Benign Indications Using Umbilical Cord Blood Units (UCB) That Were Depleted of Plasma, but Not of Red Blood Cells.

Background: UCB is an attractive unrelated source for HSCT of benign indications such as hemoglobinapathies, genetic diseases and metabolic disorders, because of less stringent HLA matching requirements, lower incidence and severity of GvHD, and ready availability of a physical inventory; however, unlike BMT or PSCT, cell dosage is a critical factor in success of UCB HSCT. The red cell depletion (RCD) techniques that are widely used by UCB banks incur significant nucleated cell loss after processing. One method of minimizing cell loss during processing is to deplete plasma, but not the red blood cells (PD). A large racially diverse PD UCB inventory of 18,000 units is now available on stem cell registries. We now report our observations of using unrelated PD UCB HSCT for benign indications.Hypothesis: Usage of unrelated PD UCB for HSCT of benign indications will result in acceptable clinical outcome for myeloid (ANC 500) and platelet engraftment, overall survival (OS), and transplant related mortality (TRM).Methods: A retrospective analysis was performed on 28 patients with benign disorders who were transplanted with PD UCB in 15 centers and 7 countries, with 13 thalassemias, 5 SAA, 5 WAS, 2 SCID, 1 sickle cell disease, 1 osteopetrosis and 1 metabolic disorder.Results: The median age of patients was 3.7 years old (range 03–27 years old); median weight 16.0 kg (range 4.5–43 kg); male 57%. Transplant characteristics indicated a median # HLA ABDR matches of 4.0 (5 6/6; 7 5/6; 12 4/6; 3 3/6; 1NA); median pre-freeze TNC dose 7.7 x 107/kg; median post-thaw TNC dose as reported by TC 7.7 x 107/kg; median pre-freeze CD34 dose 3.1 x 105/kg; transplants performed outside of U.S. 68%; double unit transplant 13%; non-myeloablative 6%. The median time to engraftment for ANC 500 (n=21), platelet 20K (n=20), and 50K (n=18) are 14.5 days (range 11–41 days), 47.0 days (range 13–82 days), and 55.0 days (range 21–96 days) respectively. The unadjusted cumulative incidence (C.I.) of ANC500 and platelet 20K and 50K engraftment are 89±7%, 89±7%, and 87±8% respectively. The incidence of reported grade II–IV acute GVHD was 33%, and none had grade III–IV acute GVHD. 50% developed limited chronic GVHD (7/14), and so far only one patient was reported to have extensive chronic GVHD. With a median follow-up of 356 days (range 93–1,100 days), the Kaplan-Meier estimates of 1-year TRM, OS and disease-free survival were 11±6%, 89±6% and 89±6% respectively.Conclusion: These results demonstrate that HSCT using unrelated PD UCB can be performed safely and effectively in patients with benign disorders. Further study of HSCT using unrelated PD UCB in patients with non-malignant hematological disorders is warranted.

Reduced-Intensity Conditioning (RIC) Followed by Allogeneic Transplantation in Relapsed Lymphomas: Evidence for Graft-Versus-Lymphoma Effect in Low and High Grade Histologies, but Not in Hodgkin Disease.

Reduced intensity conditioning (RIC) followed by allogeneic stem cell transplantation (SCT) is associated with durable engraftment, low transplant-related mortality (TRM) and clinical remissions in hematologic malignancies. In addition, RIC followed by allograft is feasible also in patients who had failed previous autologous (auto) SCT. Here, we report the outcome of 118 lymphoma pts receiving RIC and allogeneic SCT from HLA-identical sibling donors. Histologic types included in the study were: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n=26), low-grade non-Hodgkin lymphoma (LG-NHL; n=24, 21 follicular NHL), high-grade NHL (HG-NHL, B cell n=28, T cell n=17), Hodgkin disease (HD; n=23). Median age was 50 years (range: 20–69). 47% of pts had refractory disease (46% CLL/SLL; 33% LG-NHL; 44% HG-NHL; 56% HD) and 48% have failed an auto SCT (15% CLL/SLL; 33% LG-NHL; 55% HG-NHL; 82% HD). All pts received debulkying chemotherapy followed by the same RIC regimen with thiotepa (10 mg/kg), fludarabine (60 mg/ms) and cyclophosphamide (60 mg/kg). GVHD prophylaxis consisted of cyclosporine A and short-course methotrexate. All pts engrafted. De-novo acute GVHD developed in 43% of pts and chronic GVHD in 45%. The 2-year TRM rate was 13% and was not influenced by previous auto SCT or hystological type. At a median follow-up of 20 months (range, 6–62 months), 91 pts (77%) are alive (n=69 CR, n=8 PR, n=14 with disease) and 27 died (23%) for disease (n=17) or TRM (n=10). The 2 years PFS rates for CLL/SLL, LG-NHL, HG-NHL, HD were 63%, 78%, 64%, 16%, respectively. Chemorefractory disease at time of SCT was associated with a worse 2-year PFS compared to chemosensitive disease (41% versus 74%, p<0.001). There was a trend toward lower relapse risk for pts developing acute or chronic GVHD (37% versus 50%, p=0.2). The 2-year OS rates for CLL/SLL, LG-NHL, HG-NHL, HD were 77%, 90%, 76%, 56%, respectively. Chemosensitive disease had significant impact on OS (84% 2-year OS compared with 64% for chemorefractory patients; p< 0.007) as well the occurrence of chronic GVHD (87% versus 57%; p<0.0059). Interestingly, previous auto SCT and age > 55 years did not influence OS. Among pts in clinical CR, 24 were suitable for PCR monitoring of residual disease and 17 pts (71%) are in continuous molecular remission. Our study indicates: 1) low TRM in a multicenter phase II study; 2) low risk of relapse and good survival rates in indolent lymphomas; 3) encouraging results in HG-NHL 4) disappointing results in HD

Addition of ATG to the conditioning regimen is a major determinant for outcome after transplantation with partially lymphocyte-depleted grafts from voluntary unrelated donors.

We retrospectively analysed the outcome of voluntary unrelated donor (VUD)-SCT in 56 patients after conditioning without or with ATG. All received partially lymphocyte-depleted grafts. Four of 17 patients (24%) who were not given ATG rejected their grafts, as did one of 33 (3%) conditioned with ATG (P=0.02). The incidences of acute graft-versus-host disease grade III/IV were 29 and 6%, respectively (P=0.02), and probabilities of 1-year transplant-related mortality were 64% (95% CI, 44-84%) and 27% (95% CI, 12-42%), respectively (P=0.004). Projected at 3 years, probability of survival was 18% (95% CI, 2-34%) after conditioning without ATG and 60% (95% CI, 43-70%) after conditioning with ATG (P=0.002). Probabilities of disease-free survival (DFS) were 18% (95% CI, 2-34%) and 45% (95% CI, 27-63%), respectively (P=0.005). Patients who did not receive ATG had a probability of current DFS of 18% (95% CI, 3-34%) and this was 60% (95% CI, 43-77%) for the patients conditioned with ATG (P<0.001). We conclude that the addition of ATG to the conditioning regimen is associated with a significantly more favourable outcome in recipients of partially T-cell-depleted grafts from VUDs.

BEAM-alemtuzumab reduced-intensity allogeneic stem cell transplantation for lymphoproliferative diseases: GVHD, toxicity, and survival in 65 patients

AbstractWe report the outcomes of reduced-intensity allogeneic stem cell transplantation using BEAM-alemtuzumab conditioning (carmustine, etoposide, cytosine arabinoside, melphalan, and alemtuzumab 10 mg/d on days –5 to –1) in 6 United Kingdom transplant centers. Sixty-five patients with lymphoproliferative diseases underwent sibling (n = 57) or matched unrelated donor (n = 8) transplantation. Sustained donor engraftment occurred in 60 (97%) of 62 patients. Of the 56 patients undergoing chimerism studies, 35 (63%) had full donor chimerism. Overall, 73% were in complete remission (CR) after transplantation. At a median follow-up of 1.4 years (range, 0.1-5.6 years), 37 remain alive and in CR. Acute graft-versus-host disease (GVHD) occurred in 11 (17%) of 64, grades I-II only. Estimated 1-year transplantation-related mortality (TRM) was 8% for patients undergoing first transplantation but was significantly worse for those who had previously undergone autologous transplantation. Six patients relapsed (estimated 2-year relapse risk, 20%). Histologic diagnosis (mantle cell lymphoma and high-grade non-Hodgkin lymphoma) and age at transplantation (> 46 years) were significantly associated with higher relapse risk and worse event-free survival. Relapse did not occur in any patient who developed acute or chronic GVHD. This study demonstrates that reduced-intensity allogeneic stem cell transplantation for lymphoproliferative diseases using a BEAM-alemtuzumab preparative regimen is associated with sustained donor engraftment, a high response rate, minimal toxicity, and a low incidence of GVHD.

Recent advances in stem cell transplantation. Abstracts from the 11th International Symposium. Del Mar, California, USA. May 8-10, 2003.

TANDEM AUTOLOGOUS FOLLOWED BY NON-MYELOABLATIVE ALLOGENEIC TRANSPLANTS FOR MYELOMA DG Maloney, Fred Hutchinson Cancer Research Center and the University of Washington High dose therapy and autologous BM or peripheral blood hematopoietic cell transplantation (HCT) has been associated with longer disease-free survival and improved overall survival compared with chemotherapy alone for patients with responding myeloma. While generally safe [transplant-related mortality (TRM) of generally B/5%], few if any patients are cured using these conventional approaches, and patients appear to face a continuing risk of relapse. Tandem autologous HCT may be superior to a single transplant. Recent analysis of the IFM94 trial [1] using tandem autologous transplants demonstrated a 7-year overall survival of 40% and a progression-free survival of 20%. Thus, even in patients with tandem autologous HCT the majority of patients eventually progress. The source of relapse following autologous HCT is likely due either to chemotherapy resistant disease left in the patient, or clonogeneic myeloma cells infused with the stem cell rescue. Current ‘purging’ methods have not improved outcome, suggesting that the former is the greater problem. In contrast, the use of allogeneic stem cells provides a tumor-free graft and, in addition, the opportunity to develop graft-versus-myeloma immune responses that can lead to prolonged myeloma-free survival in a minority of patients. Myeloablative allogeneic transplant regimens have been associated with a high mortality in myeloma patients, with Day 100 or 6 month TRM as high as 50%. The use of peripheral blood HCT rather than marrow may decrease TRM. Analysis of the European Bone Marrow Transplant (EBMT) Registry data demonstrates a 21% 6-month TRM and a 30% 1-year TRM for myeloma patients treated with conventional high-dose conditioning and allogeneic HCT. These patients were a median age of approximately 45, and were treated a median of 10 months from diagnosis. Thus, even in optimal situations, allogeneic transplantation can only be applied to a minority of patients with myeloma, due to age or co-morbid medical issues. In contrast to autologous HCT, following allogeneic HCT patients continue to be at risk for significant toxicity from GvHD, and infection and treatment is limited to younger, medically fit patients. The use of reduced-dose conditioning regimens (non-myeloablative conditioning) has allowed engraftment of donor cells with a lower TRM, using a wide variety of treatment regimens. This approach shifts the burden of anti-tumor activity from the conditioning regimen to that of the graft-versus-tumor effects of the donor immune system. As the development of graft-versus-myeloma activity takes time to develop, this limits the application of the lower intensity regimens to patients with significant disease cytoreduction prior to the allograft, and to diseases sensitive to graft-versus-tumor immune responses. In the Seattle consortium we have developed a non-myeloblative conditioning regimen for allografts using low-dose TBI (200 cGy) and immunosuppression with cyclosporine and mycophenolate mofetil (MMF). This has allowed the application 1 No abstract available. Cytotherapy (2003) Vol. 5, No. 6, 562 /580

Graft-vs.-Lymphoma Effect in Various Histologies of Non-Hodgkin's Lymphoma

Generally, there is a significantly lower risk of lymphoma relapse following allogeneic than after autologous stem cell transplant. Factors contributing to this lower risk of relapse include an absence of the use of ablative conditioning, with a tumor-free graft, and the generation of a graft-vs.-tumor (GVT) immune response. Allogeneic transplantation, however, has the possibility of graft-vs.-host disease (GVHD). The use of autologous and conventional allogeneic hematopoietic stem cell transplantation (HSCT) in follicular lymphoma, diffuse large cell lymphoma, chronic lymphocytic leukemia and multiple myeloma is discussed. Due to a 1-year transplant-related mortality of 30 – 40% and complications caused by GVHD, conventional, myeloablative, allogeneic transplantation is a high-risk option for low-grade lymphoproliferative disorders. Novel applications of allogeneic HSCT are described that take advantage of a GVT effect while reducing the risk of GVHD. Minimally myelotoxic pretransplant conditioning regimens allow host antigen-presenting cells to persist, enabling presentation of host minor histocompatibility antigens to donor T cells, causing a GVT response. Although complications may arise due to GVHD, non-myeloablative HSCT can be offered to patients previously ineligible for conventional high-dose treatment. A protocol developed in Seattle using a low-dose total body irradiation (TBI)-based conditioning regimen with immunosuppression using mycophenolate mofetil in combination with cyclosporin has been used in a multicenter trial. To overcome the problem of graft rejection fludarabine was later added to the protocol. A second protocol from a smaller trial used a preparative, conventional-dose regimen of fludarabine, given with cyclophosphamide. Rituximab was also given to provide synergistic action with the chemotherapy to enhance tumor control in the early post-transplant period to allow time for the establishment of the GVT effect. Following transplantation, GVHD prophylaxis was given using tacrolimus with methotrexate. A trial of a further variation of allogeneic HSCT, tandem auto/allo transplants, is described. First, high-dose therapy with autologous PBSC rescue was used to cytoreduce the disease. This was followed by a reduced-intensity or non-myeloablative allogeneic graft. This procedure was devised to take advantage of high-dose therapy and allogeneic HSCT. Results for non-myeloablative allogeneic HSCT are particularly promising in low-grade NHL and the GVT effect may augment response and delay or prevent relapse. However, for aggressive disease, non-myeloablative regimens are only indicated for patients with minimal disease, as the non-myeloablative regimens are unable to control the tumor before the generation of a GVT effect, and/or lack the ability to control rapidly proliferating disease. Patients with relapsed disease may require a higher-dose regimen or tandem transplant approach.

Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation

We report the outcome of reduced-intensity allogeneic progenitor cell transplantation (alloPCT) for 188 patients with lymphoma from the Working Party Lymphoma of the European Group for Blood and Bone Marrow Transplantation (EBMT). The median age of the patients was 40 years, the median number of prior treatment courses was 3, and 48% of patients had undergone a prior autologous transplantation. Eighty-four percent of the patients received conditioning with fludarabine-based regimens and 10% with the BEAM (BCNU, etoposide, cytosine arabinoside, melphalan) protocol. Full donor chimerism was confirmed in 71% of 100 patients assessed. Acute graft-versus-host disease (GVHD) developed in 37% of patients and chronic GVHD in 17%. A disease response to donor leukocyte infusion (DLI) was seen in 10 of 14 patients. With a median follow-up of 283 days, the overall survival rates at 1 and 2 years were 62% and 50%, respectively. The 100-day and 1-year transplantation-related mortality (TRM) rates were 12.8% and 25.5%, respectively, and were significantly worse for older patients. The probability of disease progression at 1 year for patients with chemoresistant and chemosensitive disease were 75% and 25%, respectively (P =.001). The progression-free survival at 1 year was 46% and was significantly better for those with chemosensitive disease, Hodgkin disease (HD), and low-grade non-Hodgkin lymphoma (NHL). Patients with high-grade NHL, mantle cell lymphoma, or chemoresistant disease had a poor outcome. Reduced-intensity progenitor cell transplantation is associated with a reduced TRM and may control advanced HD and low-grade NHL. A longer period of follow-up is required to determine the benefit of DLI and the graft-versus-lymphoma effect.

Reduced intensity thiotepa-cyclophosphamide conditioning for allogeneic haemopoietic stem cell transplants (HSCT) in patients up to 60 years of age.

Transplant-related mortality (TRM) remains a major problem in older patients undergoing allogeneic haemopoietic stem cell transplants (HSCTs). We have therefore explored a less intensive conditioning in 33 patients with a median age of 52 years (range 43-60) transplanted from human leucocyte antigen (HLA)-identical siblings. The underlying disease was chronic myeloid leukaemia (n = 15), acute myeloid leukaemia (n = 6), myelodysplasia (n = 7) or a chronic lymphoproliferative disorder (n = 5); 15 patients (45%) had advanced disease. The regimen consisted of thiotepa (THIO; 10 mg/kg) on day -5 and cyclophosphamide (CY; 50 mg/kg) on days -3 and -2 (total dose 100 mg/kg). The source was bone marrow (BM) (n = 17) or granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood (PB) (n = 16), which were infused without manipulation. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A (CyA) and a short course of methotrexate. Mean time to achieve a neutrophil count of 0.5 x 109/l was 17 d (range 11-23) and full donor chimaerism was detected in 79% of patients by day 100. Acute GVHD grade III or IV occurred in 3% of patients. Chronic GVHD was seen in 45% of patients, with a significant difference for PB (69%) compared with BM transplants (23%) (P = 0.009). For BM grafts, the actuarial 2-year TRM was 6%, the relapse 56% and survival 87%; for PB grafts, these figures were, respectively, 27%, 33% and 68%. Twenty-five patients are alive at a median follow-up of 762 d (range 216-1615) and 20 patients (60%) remain free of disease. Thirteen patients (39%) received donor lymphocyte infusion (DLI) either for persisting or relapsing disease and six patients had complete remission. (i) patients up to the age of 60 years can be allografted with reduced intensity conditioning; (ii) the procedure was associated with a low transplant-related mortality, particularly for bone marrow grafts, because of a lower risk of chronic GVHD; and (iii) DLI were required after transplant in half the patients for persisting disease or relapse.

Graft versus host disease prophylaxis with low-dose cyclosporine-A reduces the risk of relapse in children with acute leukemia given HLA-identical sibling bone marrow transplantation: results of a randomized trial

Leukemia relapse is a major cause of treatment failure for patients with acute leukemia given allogeneic bone marrow transplantation (BMT). This study evaluated whether a reduction of the dosage of cyclosporine-A (Cs-A) used for graft versus host disease (GVHD) prophylaxis could reduce relapse rate (RR) in children with acute leukemia given BMT. Fifty-nine children who had transplantation from HLA-identical siblings were randomized to receive Cs-A intravenously at a dosage of 1 mg/kg/d (Cs-A1) or of 3 mg/kg/d (Cs-A3) until patients were able to tolerate oral intake. Subsequently, both groups received Cs-A orally at a dosage of 6 mg/kg/d, with discontinuation 5 months after BMT. The probability of developing grade II-IV acute GVHD was 57% for the Cs-A1 group versus 38% for the Cs-A3 group (P =.06); the probability of developing chronic GVHD was 30% for the Cs-A1 group and 26% for the Cs-A3 group (P = NS). Three patients died of grade IV acute GVHD: 2 were in the Cs-A1 and the third in the Cs-A3 group. The RR was 15% for the Cs-A1 group and 41% for the Cs-A3 group (P =.034); 1-year transplant-related mortality estimates were 17% and 7%, respectively (P = NS). With a median observation time of 44 months from BMT, the 5-year event-free survival for children belonging to Cs-A1 and Cs-A3 groups was 70% and 51%, respectively (P =.15). Our data demonstrate that the use of low Cs-A doses is associated with a statistically significant reduction of leukemia relapse, probably due to an increased graft versus leukemia effect. (Blood. 2000;95:1572-1579)