Risk Of Treatment-related Mortality Research Articles

Impact of Ethnicity and Socioeconomic Status on Outcome of Unrelated Donor (URD) Hematopoietic Cell Transplantation (HcT).

Prior studies suggest that success of HCT varies by race and ethnicity. This study examined whether disparate outcomes in URD-HCT are explained by socioeconomic status (SES), HLA disparity or other factors. Patients (n=6207) with acute or chronic leukemia or MDS, receiving myeloablative conditioning and URD HCT in the U.S., with available valid ZIP code, and reported to the CIBMTR between 1995–2004 were included. Patients were reported by the transplant center to be Caucasian (CC, n=5253), African American (AA, n=368), Asian/Pacific Islander (AP, n=141), or Hispanic (HS, n=445). We used 3 distinct HLA groupings with significantly different outcomes identified in another study to adjust for HLA disparity while accounting for best available resolution of typing. Well matched patients had no identified mismatches at HLA-A,B,C and DRB1 with low/intermediate or high resolution data available at HLA-A,B and high resolution DRB1. Partial matched patients had a single locus mismatch at any of the 4 loci and/or missing HLA-C data. Mismatched included any patient with 2 or more allele or antigen mismatches. Ethnic minorities were more likely than CC to have partially matched or mismatched donors. Patient income was estimated from reported residential ZIP code. The median follow-up of survivors ranged from 48 (AA and HS) to 66 months (CC). By Kaplan-Meier estimate, 1-year overall survival (OS) was 47% in CC, 32% in AA, 43% in AP, and 41% in HS (p<.001), and disease free survival (DFS) was 42% in CC, 28% in AA, 36% in AP, and 39% in HS (p<.001). These differences were sustained through 5 years post-HCT. Cox regression was used to examine the effect of study variables (age, performance status, income, co-morbidities, diagnosis, disease status, CMV status, stem cell source, HLA match, donor age and gender, year of HCT, conditioning regimen, cell dose, time from diagnosis to HCT, distance from patient ZIP code to transplant center) on the outcomes of interest between the 4 racial/ethnic groups. After adjusting for other significant factors, compared to CC, AA (but not AP or HS) were independently associated with worse OS (relative risk [RR] 1.46 (95% CI 1.28–1.66), P<.0001) and with worse DFS (RR 1.45 (1.27–1.64), P<.0001). The risk of treatment related mortality was higher in AA (RR 1.54, (1.33–1.79), P<.0001) and in HS (RR 1.23, (1.06–1.42), p=.005). HS had an increased risk of chronic GVHD (RR 1.24, (1.06–1.45), P=.008) compared to CC, otherwise there was no difference in the risk of acute or chronic GVHD among the racial groups. Race/ethnicity, median income and distance from transplant center were not associated with the risk of disease relapse. Greater distance to the transplant center (>175 miles) and higher median incomes (>$35,500) were associated with higher DFS (p=0.006, p=0.0002) and OS (p=0.001, p<0.0001) in all racial/ethnic groups. While this study is limited by the use of surrogate markers of SES and relatively small numbers of ethnic minority patients, the results suggest that the inferior outcomes after URD HCT detected primarily in AA patients are not fully explained by HLA disparity or SES indicators. Potential other mechanisms such as genetic polymorphisms that impact drug metabolism or the risk of TRM, as well as other pre- or post-transplant factors may be important.

Relevance of HLA-C Epitopes C1 and C2 for the Survival of Patients with AML and CML after Allogeneic Blood Stem Cell Transplantation.

BACKGROUND HLA-C epitopes can be grouped in C1C1, C1C2 or C2C2 ligands and mediate NK cell dependent immune response. Especially in haploidentical allogeneic stem cell transplantation a HLA-C ligand mismatch improves event free survival (EFS) in patients with AML known as Velardi effect. Recently, we could show in 109 CML patients that those with a C1C1 phenotype showed better overall survival (OS) and lower rates of treatment related mortality (TRM) (Fischer JC et al. J Immunology. 2007). But, the role of HLA-C ligands in allogeneic transplantations remains controversial.PATIENTS AND METHODS In this study we retrospectively analyzed a group of 88 patients with AML or CML (n=34), MDS (n=21) or lymphoid malignancies (Non-Hodgkin-Lymphoma or ALL) (n=31) receiving unrelated allogeneic blood stem cell transplantation after myeloablative and non-myeloablative conditioning regimens. HLA-C alleles were determined by DNA-based direct sequencing of all donors and recipients included into this study.RESULTS Looking at the group of 34 patients with AML or CML, the 13 recipients with a C1C1 phenotype showed increased OS compared to those with C1C2 and C2C2 phenotypes (all patients alive with a median follow-up of 154 days, range 90 to 665 days vs. a mean survival of 381 days, respectively; p=0.049). All recipients with a C1C1 phenotype received grafts with matched HLA-C alleles. Within the subgroup of patients with C1C2 or C2C2 phenotypes 6 patients had a HLA-C mismatch which was associated with significantly (p=0.016) increased OS (all patients alive with a median follow-up of 575 days, range 133 to 899) compared to matched HLA-C phenotypes (median survival of 254 days). In recipients with C1C1 phenotype the risk for TRM following HLA-C matched hematopoietic stem cell transplantation was reduced as reflected by an odds ratio of 0.13. In turn, the group receiving HLA-C mismatched grafts had a lower incidence of relapse. This effect was independent from the direction of the mismatch, graft vs. host or host vs. graft. The effects described above were not observed in patients with MDS, ALL or lymphoid malignancy.CONCLUSION The beneficial effects of a C1C1 HLA-C phenotype could be confirmed for patients with CML and AML in our patient cohort. Our data also suggest that patients with myeloid malignancies and an unfavourable C1C2 or C2C2 HLA-C phenotype benefit from a donor with HLA-C ligand mismatch.

Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-a and interferon-g was increased during pancytopenia as compared to in controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor.

Outcomes after autologous stem cell transplantation in relapsed or refractory Hodgkin disease: The Duke experience

8100 Background: High dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) offers patients with relapsed or refractory Hodgkin's disease (HD) the possibility of durable long term remission. We examined the characteristics and outcomes of patients treated at Duke University Medical Center between May 1997 and May 2006. Methods: We performed a retrospective chart review on all patients with relapsed or refractory HD who received HDT followed by ASCT at our institution. Various prognostic factors were also analyzed for their impact on overall survival (OS) and disease free survival (DFS). Results: Sixty-one patients received HDT followed by ASCT for relapsed or refractory HD. Median age was 33 years (range: 16 years to 64 years). The patient population was comprised primarily of males (64%), Caucasians (80%), and patients with nodular sclerosing histology (77%). Fifty-six percent of patients had primary refractory HD. At the time of relapse, 44% of patients had stage I-II disease, and 21% had B symptoms. For patients with relapsed disease, the median time from initial diagnosis to relapse was 17 months. Most patients (64%) received cyclophosphamide, etoposide, and BCNU chemotherapy as HDT. Thirty-one percent of patients received consolidative radiotherapy after HDT. Twenty-eight percent of patients had chemotherapy- responsive disease prior to undergoing HDT. Following ASCT, 46/61 (75%) of patients achieved a complete response. Transplant-related deaths occurred in 2/61 (3%) patients. With a median follow-up of 2.5 years (range: 3 months to 8.8 years), the actuarial 5-year OS and DFS were 79% and 50%, respectively. The most common post-therapy complication was pneumonitis, which occurred in 62% of patients. Three (5%) patients developed second malignancies. On univariate analysis, gender, stage at diagnosis, stage at relapse, presence of B symptoms at relapse, and the interval to first relapse did not significantly affect OS or DFS. Conclusions: Our results confirm that HDT followed by ASCT offers an excellent chance for long-term DFS and OS in patients with relapsed or refractory HD, with a low risk of treatment-related mortality. No significant financial relationships to disclose.

Superior Survival after Autologous vs. Allogeneic Hematopoietic Stem Cell Transplantation (HCT) for Diffuse Large B-Cell Lymphoma (DLBCL) Not Explained by Differences in Chemosensitivity.

No randomized trials have compared autologous HCT (autoHCT) to allogeneic HCT (alloHCT) for DLBCL. We analyzed the outcomes of 916 patients (pts) (837 autoHCT and 79 alloHCT) ages 18–60yrs after a first autoHCT or HLA-identical sibling alloHCT for DLBCL between 1995 and 2003 reported to the CIBMTR. Pts receiving T-cell depleted allografts or reduced-intensity conditioning were excluded. There were significant baseline differences between the groups in disease stage, B symptoms, extranodal disease and marrow involvement. AlloHCT pts were significantly more likely to have >3 chemo regimens prior to HCT (53 vs 40%), and resistant induction failure or relapse (39 vs 16%). At 1yr, treatment-related mortality (TRM) was higher after alloHCT (41%, 95% CI, 30–52%) than after autoHCT (11%, 95% CI, 9–14%, p<0.001), but risks of relapse/progression were similar (30%, 95% CI, 21–41%) and (33%, 95% CI, 29–36%, p=0.69), respectively. Cumulative incidence of outcomes and univariate probabilities of progression free (PFS) and overall survival (OS) at 5 yrs are summarized in table 1. In multivariate analysis, allo and autoHCT had differential early and late effects on outcomes. In the first 12 mo after transplant, alloHCT was associated with higher TRM (RR 4.76, 95% CI, 3.14–7.22, p<0.001), treatment failure (RR 2.08, 95% CI, 1.56–2.77, p<0.001) and mortality (RR 2.78, 95% CI, 2.06–3.77, p<0.001) but similar risk of progression (RR 1.14, 95% CI, 0.75–1.74, p=0.54) compared to autoHCT. Among pts surviving 12 mo post-transplant, no significant difference was observed between autoHCT and alloHCT for TRM, progression, PFS, or OS. Covariates that increased the risks of TRM and OS were older age (51–60 years), KPS <90%, chemoresistance at transplant, and earlier transplant yr (before 2001 vs later). Older age and chemoresistance were also associated with progression and lower PFS. There were no significant interactions between graft type and other prognostic variables; in particular, relative risk of outcomes with allo vs autoHCT were similar for patients with chemosensitive and chemoresistant disease. In summary, myeloablative alloHCT increased risks of early TRM and mortaliy without an effect on progression (compared to autoHCT). Transplant type did not affect outcomes after 12 months post-transplant. AutoHCT was associated with superior survival (fig 1), and the difference was not explained by differences in chemosensitivity at the time of transplant.AutoHCTAlloHCTOutcomes(95%CI)(95%CI)AGVHD @ day 100N/A42 (31–53)CGVHD @ 5yrsN/A27 (18–38)TRM @ 5yrs18 (15–20)45 (34–57)Relapse/progression @ 5yrs39 (36–43)33 (23–44)PFS @ 5yrs43 (40–46)26 (18–37)OS @ 5yrs49 (46–53)27 (18–27) [Display omitted]

Outcomes after HLA-Matched Sibling Transplants or Chemotherapy in Children with Acute Lymphoblastic Leukemia in a Second Remission after an Isolated Central Nervous System Relapse.

The optimal treatment for children with acute lymphoblastic leukemia (ALL) in second remission after an isolated central nervous system relapse is unknown. To address this question, we compared outcomes in 149 patients enrolled on Pediatric Oncology Group chemotherapy trials 9061 (n=79) and 9412 (n=70) and HLA-matched sibling transplant recipients (n=60) reported to the Center for International Blood and Marrow Transplant Research. Patients received treatment between 1990 and 2000. Median follow-up was 8 years and 9 years after chemotherapy and transplantation, respectively. Groups were similar with respect to sex and leukocyte count at diagnosis. Chemotherapy recipients were younger at diagnosis (5 vs. 7 years) and more likely to have had a longer duration of first remission (duration of first remission ≥18 months: 70% vs. 48%). All transplant recipients received bone marrow grafts and 83% received a total body irradiation containing preparatory regimen. The median time to transplantation after achieving a second remission was 2.5 months (range, <1 – 8). To adjust for time-to transplant bias, we used left-truncated Cox regression models to examine treatment outcomes. Risks of a subsequent leukemia relapse were similar in both treatment groups. As expected, risks of a subsequent leukemia relapse were significantly higher in older patients (11–17 years; relative risk [RR] 2.63, p=0.004) and those with a short duration of first remission (<18 months; RR 4.22, p<0.001) regardless of type of treatment. Relative to chemotherapy recipients, risks of treatment-related mortality (RR 4.29, p=0.001), treatment failure (RR 2.37, p=0.003) and overall mortality (RR 2.68, p=0.002) were significantly higher within the first 2 years after achieving a second remission in recipients of HLA-matched sibling transplants. Among transplant recipients who survived the first two years, subsequent mortality and treatment failure risks did not differ by treatment group. In both treatment groups, recurrent leukemia was the commonest cause of death (60% and 56% after chemotherapy and transplantation, respectively). The 8-year probabilities of leukemia-free survival (adjusted for age and duration of first remission) were 66% and 58% after chemotherapy and transplantation, respectively. These data support use of chemotherapy alone for patients with ALL and isolated central nervous system relapse who achieve a second remission regardless of duration of first remission.

Unrelated Donor Nonmyeloablative/Reduced Intensity (NST/RIC) Hematopoietic Stem Cell Transplantation (HCT) for Patients with Relapsed and Refractory Hodgkin's Lymphoma (HL).

Myeloablative allogeneic HCT salvages some patients (pts) with relapsed and refractory HL but has a high treatment-related mortality (TRM). NST/RIC conditioning regimens attempt to lower TRM, in particular after previous autotransplants. We studied the outcomes of 146 patients after unrelated donor (URD) HCT with NST/RIC conditioning for relapsed and refractory HL between 1999 and 2004 reported to the CIBMTR. NST/RIC was defined following established CIBMTR criteria as TBI < 500 cGy, busulfan < 9 mg/kg, melphalan ≤ 150 mg/m2 (RIC) or fludarabine without busulfan/melphalan, TBI = 200 cGy (NST). Median (range) age was 30 yrs (13–53), 69% had a Karnofsky score (KPS) ≥ 90%, 95% patients had ≥ 3 chemo regimens prior to HCT and 89% had undergone prior autotransplant. At transplant 57 (40%) had chemosensitive disease and 74 (51%) were chemoresistant. Conditioning was RIC in 95 (65%) and NST in 51 pts (35%). At a median follow-up of 25 mo (3–64) the probability of day 100 mortality was 18% (95% CI, 12–24%), acute GVHD grade 2–4 was 61% (95% CI, 51–70%), cGVHD at 2 years was 69% (95% CI, 60–77%) and TRM at 2 years was 33% (95% CI, 25–41%). Probability of progression free survival (PFS) was 31% at 1 year and 20% at 2 years. Probability of overall survival (OS) was 56% at 1 year and 38% at 2 years (fig 1). Relapse/progression was rare after 2 years with a plateau in the survival curve. Presence of extranodal disease (relative risk [RR] 2.43, 95% CI, 1.30–4.54, p=0.006) and KPS <90 (RR 3.13, 95% CI, 1.63–6.02, p<0.001) predicted TRM. Extranodal disease (RR 2.18, 95% CI, 1.38–3.42, p<0.001), elevated serum LDH at transplant (RR 1.92, 95% CI, 1.22–3.02, p=0.001) and KPS <90 (RR 2.37, 95% CI, 1.47–3.82, p<0.001) were associated with increased risk of death. The major cause of death (45%) was progressive HL. A comparison group of 38 patients after myeloablative URD HCT between 1996 and 2004 was also analyzed. The myeloablative HCT group did not differ in age, KPS or extranodal disease, but differed in GVHD prophylaxis, previous autologous HCT (74% vs. 89% in NST/RIC, p=0.02) and stem cell source (PBSC 45% vs. 73%, p<0.001). More myeloablative HCT pts (63%) were transplanted before 2003 and a yearly increase in proportion of NST/RIC transplants was seen. Use of donor lymphocyte infusions was similar (13% of myeloablative vs 14% in NST/RIC). There was a lower risk of TRM with NST (RR 0.52, 95% CI, 0.26–1.05) and RIC (RR 0.58, 95% CI, 0.31–1.07) compared to myeloablative HCT that did not reach statistical significance. However, the given sample size had only 49% (RIC) and 39% (NST) power to detect a 20% decrease in the 2 year TRM incidence compared to myeloablative transplants. Intensity of conditioning (myeloablative vs NST vs RIC) did not affect TRM, relapse/progression, PFS and OS or death. Chemosensitivity at transplant did not predict for relapse/progression. URD HCT using NST/RIC is associated with acceptable early TRM and can salvage some heavily pretreated pts with relapsed and refractory HL. [Display omitted]

Combined modality treatment for breast cancer: Justification for integration of transplants at diagnosis

10760 &gt;Introduction: In acute leukemia best therapy consist of fast remission-induction, consolidation of complete response and allogeneic transplantation to eradicate residual malignant cells. This therapeutic plan at diagnosis consists of three treatment combinations that have been proven to be most efficacious when administered consecutively according to protocol. Methods: The three treatment combinations were defined as independent entities and literature search was pursued to identify equivalent components for high risk and metastatic breast cancer. Results were tabulated. Results: First line combination treatment induces complete response rates that can be enhanced by dose density. This type of intensification does not change the risk of relapse although time to relapse may vary by a few months; survival in high risk breast cancer is about 50% and in early metastatic 10%. Failure to treat more aggressively induces respectively 50% and 90% relapse mortality. It is hidden treatment-failure related mortality. High-dose autologous transplants (HD-auto-tx) add a survival advantage of about 10% but this is statistically not considered significant. In large series treatment related mortality (TRM) of HD-auto-tx is 0–3%. Treatment integrating autologous transplantation reduce relapse mortality to respectively 60% and 80%. Allogeneic transplants induce an immune response in breast cancer that is comparable to the response observed in leukemia; micrometastatic bone marrow disease can be eradicated. After an autologous transplant risk of relapse is 80% and after an allogeneic transplant in first consolidated remission 20%. Allogeneic transplants make the combination attractive, despite the risk of TRM, mainly attributable to graft versus host disease. Selection of right treatment schedules and adequate prophylaxis for and treatment of graft versus host disease is emerging and may minimize the risk of TRM as result of this side effect to &lt;5%. Discussion: Optimization of treatment by integration of transplants in treatment at diagnosis is warranted to offer breast cancer patients the choice of cure at certain risks versus the standard chemotherapy resulting in remarkably higher disease driven mortality. Details will be presented. No significant financial relationships to disclose.

A computer program designed to assist in NSCLC adjuvant therapy decision making

7230 Background: The goal the computer program, Adjuvant! for NSCLC, is provide the health professional, and the NSCLC patient with information that might be helpful when deciding about adjuvant chemotherapy for completely resected Stage 1 to Stage 3A disease. The 4 elements of this decision are: estimates of prognosis, estimates of the efficacy of adjuvant chemotherapy, estimates of completing mortality, and estimates of toxicity. Methods: Estimates of prognosis are based on an analysis of 17, 130 patients in the SEER registry. Estimates for 5 year disease specific mortality for Stage 1A, 1B, 2A, 2B, and 3A disease are 22%, 37%, 51%, 63%, and 70%. Multivariate analysis justifies using tumor size, histologic grade, and BAC histology for refinement of prognostic estimates for Stage 1 patients. A small subgroup of Stage 1 patients (with tumors &lt; 10mm, low grade, BAC histology) could be identified with a 5 year disease specific mortality risk of &lt;10%. Estimates of the efficacy of chemotherapy were derived from meta-analyses. A proportional risk reduction of 20% is used by the program as the default efficacy estimate for platinum-based therapy. Pop-ups and help files discuss areas of uncertainty and controversy. The user has the option to adjust the default efficacy estimate to the more optimistic efficacy estimates of some of the recent trials, or to take into account some of the uncertainty as to whether adjuvant chemotherapy works as well in Stage 1 disease. SEER data shows the average NSCLC patient has competing mortality rates higher than would be suggested by chronologic age. Regimen specific risks of treatment related toxicity is given by the program. In the over 100 pages of help files there is a detailed discussion of the clinical evidence, adjuvant therapy guidelines, ongoing clinical trials, and corollary areas (radiotherapy, neoadjuvant therapy, biomarkers, etc.) Results: The program projects that for patients with favorable Stage 1 tumors the absolute OS benefit of therapy may be as low as 1% (of the same size as the risk of treatment related mortality), but for patients with Stage 2 and 3A disease the 5 yr OS benefit may be ∼10%. Conclusions: The impact of this tool on physician and patient knowledge about the adjuvant therapy of NSCLC will be presented. [Table: see text]

Increased risk for treatment-related mortality after bone marrow transplantation in GSTM1-positive recipients

Treatment-related mortality (TRM) is a major obstacle to successful allogeneic hematopoietic stem cell transplantation (HSCT). A variety of drugs are used in allogeneic HSCT, and a genetic polymorphism in metabolic enzymes could affect the metabolism of drugs and potentially influence TRM. Here, we focused attention on GSTM1 and GSTT1 enzymes, which metabolize chemotherapeutic agents, chemical carcinogens and by-products of oxidative stress and are absent from more than 50% of some populations. To assess the significance of homozygous GSTM1 and GSTT1 gene deletion in HSCT, we analyzed DNA from 373 patients with hematological disease and their HLA-identical unrelated bone marrow donors using PCR. Homozygous GSTM1 and GSTT1 gene deletions were observed in 56 and 45% of patients, respectively, and 57 and 46% of donors, respectively. There was no significant association between GSTT1 polymorphism and any outcome. However, a GSTM1-positive genotype in recipients was significantly associated with higher TRM and lower survival. These results suggest that a GSTM1-null genotype in recipients protects against TRM after allogeneic HSCT. Further studies are needed to elucidate a mechanism of increased risk for TRM in GSTM1-positive recipients.

Early treatment‐related mortality in adult autologous stem cell transplant recipients: a nation‐wide survey of 1482 transplanted patients

To evaluate early (<100 d) treatment-related mortality (TRM) in autologous stem cell transplant (ASCT) recipients. Altogether 1482 adult patients received ASCT in six Finnish centres 1990-2003. The most common diagnoses were non-Hodgkin's lymphoma (NHL) (n = 542), multiple myeloma (MM) (n = 528), breast cancer (BC) (n = 132), Hodgkin's lymphoma (n = 86) and chronic lymphocytic leukaemia (CLL) (n = 63). Forty-two patients (2.8%) died from treatment-related reasons <100 d from ASCT. The median time to death was 38 d from ASCT (0-99). The risk of TRM varied according to the diagnoses. The highest risk was observed in patients with AL amyloidosis (24%) followed by NHL (4.4%) and MM (1.9%). No early TRM was observed in patients transplanted for BC or CLL. Infections were the cause of death in 16 patients (fungal 7, bacterial 6, viral 3). Organ toxicity was responsible for early death in 26 patients (heart 9, lungs 7, other 10). This nation-wide survey indicated a low early TRM in ASCT recipients in general, but higher risks in patients with AL amyloidosis or NHL. In addition to patient selection, also optimization of transplant procedure may be needed in these patient groups to reduce early TRM.

Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults.

The prognosis for Philadelphia chromosome-positive ALL (Ph+ALL) is quite poor, and allogeneic hematopoietic stem cell transplantation (HSCT) is currently considered the only established procedure with curative potential. It is therefore quite important to clarify what are essential elements of the success of allogeneic HSCT. Thus, we performed a retrospective study covering 197 Ph+ALL cases aged 16 years or older who underwent allogeneic myeloablative HSCT to identify factors affecting the transplant outcome. The subjects comprised 120 males and 77 females, and their median age was 37 years (range, 16 to 59 years). Transplantation during complete remission (CR) accounted for 57% (112 cases), and only 19 patients received transplantation during their second or subsequent CR. The 5-year survival rates were 34% for patients in first complete remission (CR), 21% for those in second or subsequent CR, and 9% for those with active disease (p<0.0001). Multivariate analysis showed four pre-transplant factors as significantly associated with better survival: younger age, CR at the time of transplantation, conditioning with total body irradiation (TBI), and human leukocyte antigen (HLA)-identical sibling donor (p<0.0001, p<0.0001, p=0.0301, p=0.0412, respectively). Next, we investigated whether development of graft-versus-host disease (GVHD) had a significant influence on survival. The presence or absence of each type of GVHD (grade II-IV acute GVHD, grade III-IV acute GVHD, any form of chronic GVHD, and extensive chronic GVHD) was included separately in the Cox model containing the four significant pre-transplant risk factors. Although the survival rate was almost identical for patients with and without grade II-IV acute GVHD, grade III-IV acute GVHD had a significant impact on survival (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.34 to 0.98; p=0.0430). For patients developing any form of chronic GVHD, there was a non-significant increase in survival rate compared with those who did not (HR, 1.40; 95% CI, 0.85 to 2.32; p=0.1877). As for extensive chronic GVHD, the survival advantage was statistically significant (HR, 2.10; 95% CI, 1.13 to 3.88; p=0.0179). The 5-year survival rate was estimated to be 51% for those with extensive chronic GVHD, and 29% for those without. Chronic GVHD was associated with a lower risk of relapse without increasing the risk of treatment-related mortality (TRM), whereas acute GVHD was associated with a higher risk of TRM without diminishing the risk of relapse. From the analysis of the data for 197 Ph+ALL patients who had undergone allogeneic myeloablative HSCT, we identified four prognostic pre-transplant factors. Younger age, CR at the time of transplantation, TBI conditioning, and HLA-identical sibling donor were found to be associated with significantly better survival. Chronic GVHD reduces the risk of relapse without increasing the risk of TRM, and development of extensive chronic GVHD even prolongs survival. These findings should be helpful for achieving the success of allogeneic HSCT for Ph+ALL.

Use of Peripheral Blood Grafts Is Associated with Increased Acute and Chronic Graft-Versus-Host Disease without Improved Survival after Unrelated Donor Transplantation.

Data from the CIBMTR indicate that approximately 70% of unrelated donor hematopoietic stem cell transplants (HCT) in the U.S. utilize peripheral blood (PB) rather than bone marrow (BM) as a graft source. Comparative studies verifying its benefit, however, are lacking. We, therefore, performed a retrospective analysis comparing the results of 275 unrelated PB and 620 unrelated BM transplants in adults 18–60 years of age with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or chronic myeloid leukemia (CML), transplanted in 2000–2002. 73% of PB grafts were matched at HLA A, B, C (low resolution) and DRB1, 21% were mismatched at a single locus and 6% were mismatched at ≥ 2 loci. 69% of BM grafts were matched, 26% were mismatched at a single locus and 5% were mismatched at ≥ 2 loci. Median follow-up was 24 (range, 6–48) and 34 (range, 6–54) months for PB and BM recipients, respectively. Groups were similar except PB recipients were less likely to have CML, were more likely to have MDS and were transplanted more recently. Incidences of neutrophil recovery (95% vs. 90% at day 100, p=0.01) and platelets ≥20,000/ul (81% vs. 66%, at 1-year, p <0.0001) were significantly higher after PB than BM transplants. Incidences of grades 2–4 but not grades 3–4 acute graft-versus-host disease (GVHD) were significantly higher after PB than BM transplants (56% vs.45%, at day 100, p=0.003). Chronic GVHD was also significantly higher after PB transplants (54% vs. 39%, at 3 years, p<0.0001). Despite higher rates of grade 2–4 acute and chronic GVHD after PB transplantation, incidence of relapse was similar in the two groups for both early and advanced leukemia. In multivariate analysis, risks of treatment-related mortality (TRM), treatment failure (relapse or death) and overall mortality during the first 9 months after transplantation were similar. However, among patients surviving the first 9 months, subsequent risks of TRM (relative risk [RR] 1.90, 95% confidence interval [CI], 1.14–3.17, p=0.01) and treatment failure (RR 1.60, 95% CI 1.06–2.44, p=0.03) were significantly higher in the PB cohort. Three-year adjusted (from multivariate models) probabilities of leukemia-free survival were 29% and 31%, p=0.5, after PB and BM transplantation, respectively; corresponding probabilities of overall survival were 31% and 32%, p=0.8. While these data do not indicate a survival advantage with either stem cell source by disease or risk group, PB is associated with earlier engraftment. This advantage is offset by higher rates of grades 2–4 acute and chronic GVHD, leading to a higher risk of late adverse events. Randomized clinical trials are necessary to better define the relative risks and benefits of PB in the setting of unrelated donor HCT.

Myeloablative allogeneic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: significant roles of total body irradiation and chronic graft-versus-host disease

Disease-free survival in Philadelphia chromosome-positive ALL (Ph + ALL) is very poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently considered the only procedure with curative potential. To identify factors affecting transplant outcome, we analyzed the data from 197 Ph + ALL patients aged 16 years or older who had undergone allo-HSCT. The 5-year survival rates were 34% for patients in first complete remission (CR), 21% for those in second or subsequent CR, and 9% for those with active disease (P < 0.0001). Multivariate analysis showed four pre-transplant factors as significantly associated with better survival: younger age, CR at the time of transplantation, conditioning with total body irradiation, and HLA-identical sibling donor (P < 0.0001, P < 0.0001, P = 0.0301, P = 0.0412, respectively). Severe acute GVHD increased the risk of treatment-related mortality (TRM) without diminishing the risk of relapse, whereas chronic GVHD reduced the risk of relapse without increasing the risk of TRM. Thus, patients who developed extensive chronic GVHD had better survivals (P = 0.0217), and those who developed grade III-IV acute GVHD had worse survivals (P = 0.0023) than did the others.

Autologous and allogeneic stem cell transplantation in follicular lymphoma

Follicular non-Hodgkin’s lymphomas (NHL) usually present in advanced stage and although frequently are chemotherapy-sensitive remain incurable using conventional approaches. Treatment options are evolving rapidly and now include targeted therapies such as monoclonal antibodies. Recent studies, including the EBMTR-sponsored “CUP Trial” (conventional Chemotherapy, Unpurged autograft, Purged autograft), demonstrate that for patients under age 60 years with recurrent chemotherapy-sensitive disease, autologous stem cell transplantation (ASCT) provides a survival benefit over conventional therapy. Allogeneic stem cell transplantation (alloSCT) has become a more effective option. Although incorporation of TBI into the preparative regimen may increase treatment-related mortality (TRM), relapses appear to be reduced compared to a chemotherapy-alone regimen. Reduced-intensity alloSCT procedures now are being performed at an increasing rate, in part due to a lower risk for TRM. Until more data are available, however, reduced-intensity alloSCT should be considered only in cases where myeloablative conditioninig is contra-indicated. There are no clear means for choosing ASCT versus alloSCT, a decision influenced by amount of residual tumor, disease-responsiveness, degree of marrow involvement and extent of prior chemotherapy. ASCT or alloSCT in first remission remains an investigational procedure. Future considerations include incorporation of novel preparative regimens, in vitro purging techinques, anti-lymphoma vaccines, post-transplant immunotherapy and ex vivo-manipulated donor lymphocyte infusions.

Stem cell transplantation in follicular lymphoma: progress at last?

Follicular non-Hodgkin's lymphomas usually present in advanced stage and although frequently are chemotherapy-sensitive remain incurable using conventional approaches. Treatment options are evolving rapidly and now include targeted therapies such as monoclonal antibodies. Recent studies, including the EBMTR-sponsored 'CUP Trial' (conventional Chemotherapy, Unpurged autograft, Purged autograft), demonstrate that for patients under age 60 years with recurrent chemotherapy-sensitive disease, autologous stem cell transplantation (ASCT) provides a survival benefit over conventional therapy. Allogeneic stem cell transplantation (alloSCT) has become a more effective option. Although incorporation of TBI into the preparative regimen may increase treatment-related mortality (TRM), relapses appear to be reduced compared to a chemotherapy-alone regimen. Reduced-intensity alloSCT procedures are now being performed at an increasing rate, in part due to a lower risk for TRM. Until more data are available, however, reduced-intensity alloSCT should be considered only in cases where myeloablative conditioning is contra-indicated. There are no clear means for choosing ASCT vs alloSCT, a decision influenced by the amount of residual tumor, disease-responsiveness, degree of marrow involvement and extent of prior chemotherapy. ASCT or alloSCT in first remission remains an investigational procedure. Future considerations include incorporation of novel preparative regimens, in vitro purging techniques, antilymphoma vaccines, post transplant immunotherapy and ex vivo-manipulated donor lymphocyte infusions.

The impact of post transplant use of G-CSF on event free survival in AML patients undergoing allogeneic stem cell transplantation from unrelated donors and in vivo T-cell depletion with ATG

6637 Background: Allogeneic hematopoietic cell transplantation from matched unrelated donors (MUD-HSCT) may be curative for high risk AML patients. However, it carries a considerable risk of treatment related mortality. This study was performed to identify risk factors (RF) impairing event free survival (EFS) in patients (pts) with AML undergoing MUD-HSCT and in vivo T-cell depletion with ATG. Methods: In a retrospective analysis of all pts with AML undergoing MUD-HSCT we identified RF by Log-Rank analysis and performed a multivariate analysis of all RF being significant in univariate analysis. RF included were: disease status at transplant (DS); pts age; donor sex; transplant era; stem cell source; number of cells transplanted; HLA-match; ATG source; risk of cytomegalovirus infection; acute (a) and chronic graft vs host disease (GvHD); cytogenetics (CG); post transplant application of granulocyte colony stimulating factor (G-CSF). Results: Eighty-nine pts (47 m, 42 f), median age 42 y (18 –62 y), who underwent MUD-HSCT in the period from 1996 to 2003 were included. All pts received rabbit ATG (Fresenius: n=29, Merieux/Sangstat: n=60) during conditioning. 50 pts died after HSCT. Median EFS was 186 d (9 –2125 d). As significant risk factors we identified by univariate analysis: the occurrence of aGvHD (p=0.0000), CG (p=0.0375) and use of G-CSF (p=0.0001). The only RF remaining after cox regression analysis were aGvHD (p = 0.003, RR 1,544, CI 95%, 1,160 –2,056) and use of G-CSF (p = 0,000, RR 3,401, CI 95%, 1,712 –6,757). The mortality of pts receiving G-CSF was 77% as compared to 37% in pts not receiving G-CSF. This higher mortality was due to a higher transplant related mortality but also due to a higher relapse rate. Conclusions: In this cohort the occurence of acute GvHD and the application of G-CSF were independent negative predictors for EFS. Therefore the selection of pts for use of post transplant G-CSF should be done with due care, especially in AML pts receiving MUD-HSCT and in vivo T-cell depletion with ATG. No significant financial relationships to disclose.

The impact of post transplant use of G-CSF on event free survival in AML patients undergoing allogeneic stem cell transplantation from unrelated donors and in vivo T-cell depletion with ATG

6637 Background: Allogeneic hematopoietic cell transplantation from matched unrelated donors (MUD-HSCT) may be curative for high risk AML patients. However, it carries a considerable risk of treatment related mortality. This study was performed to identify risk factors (RF) impairing event free survival (EFS) in patients (pts) with AML undergoing MUD-HSCT and in vivo T-cell depletion with ATG. Methods: In a retrospective analysis of all pts with AML undergoing MUD-HSCT we identified RF by Log-Rank analysis and performed a multivariate analysis of all RF being significant in univariate analysis. RF included were: disease status at transplant (DS); pts age; donor sex; transplant era; stem cell source; number of cells transplanted; HLA-match; ATG source; risk of cytomegalovirus infection; acute (a) and chronic graft vs host disease (GvHD); cytogenetics (CG); post transplant application of granulocyte colony stimulating factor (G-CSF). Results: Eighty-nine pts (47 m, 42 f), median age 42 y (18 –62 y), who underwent MUD-HSCT in the period from 1996 to 2003 were included. All pts received rabbit ATG (Fresenius: n=29, Merieux/Sangstat: n=60) during conditioning. 50 pts died after HSCT. Median EFS was 186 d (9 –2125 d). As significant risk factors we identified by univariate analysis: the occurrence of aGvHD (p=0.0000), CG (p=0.0375) and use of G-CSF (p=0.0001). The only RF remaining after cox regression analysis were aGvHD (p = 0.003, RR 1,544, CI 95%, 1,160 –2,056) and use of G-CSF (p = 0,000, RR 3,401, CI 95%, 1,712 –6,757). The mortality of pts receiving G-CSF was 77% as compared to 37% in pts not receiving G-CSF. This higher mortality was due to a higher transplant related mortality but also due to a higher relapse rate. Conclusions: In this cohort the occurence of acute GvHD and the application of G-CSF were independent negative predictors for EFS. Therefore the selection of pts for use of post transplant G-CSF should be done with due care, especially in AML pts receiving MUD-HSCT and in vivo T-cell depletion with ATG. No significant financial relationships to disclose.

Allogeneic myeloablative transplantation for patients aged 50 years and over.

Allogeneic hematopoietic stem cell transplantation (HSCT) has been performed mainly for young patients due to concern about the high incidence of treatment-related mortality (TRM). Recent advances to reduce TRM by using peripheral blood stem cells or nonmyeloablative conditioning regimens have increased the age limit for this procedure, and correctly identifying the indication for transplant is essential for older patients. In this study, we analyzed data from 398 patients aged 50 or over selected from 5147 patients, who received conventional allogeneic HSCT (c-HSCT). Patients aged 50 or older showed inferior outcomes for TRM and overall survival (OS). Mulitivariate analyses confirmed that an age of 50 or over was an independent risk factor for TRM (P<0.0001) and OS (P<0.0001). Among patients aged 50 or older, increasing age remained an adverse factor for OS (P=0.0213). Regimens including total-body irradiation (TBI) correlated with a higher risk of TRM and a lower OS for older patients (P=0.0095 and 0.0303, respectively). These findings indicate that allogeneic c-HSCT should be offered to patients over 50 years only if the increased risk of TRM is acceptable, and that a non-TBI regimen is preferable when the transplant is performed.

The choice of allogeneic or autologous hematopoietic transplantation for NHL.

NHL constitutes the sixth most common malignancy diagnosed in the USA every year, accounting for approximately 24,400 deaths. Although a subset of patients can be cured with chemotherapy or radiation therapy, the outlook is generally poor for patients with refractory or recurrent disease. High-dose therapy supported by both autologous and allogeneic transplantation has been widely studied in this group of patients. Autologous transplantation may be considered standard therapy for patients with diffuse large-cell NHL in chemotherapy-sensitive relapse. Selected categories of patients with other histologic subtypes may also benefit from this strategy. Allogeneic transplantation using high-dose myeloablative conditioning regimen is an effective, yet hazardous approach. A GvL effect leads to a lower rate of disease recurrence than occurs with autologous transplants, but this benefit is offset by higher risk of treatment related mortality. The recent use of less toxic non-myeloablative conditioning regimens for allogeneic transplantation has reduced the risk of transplant-related mortality, allowing this approach even in older or medically infirm patients. Nonablative allogeneic transplants are a promising strategy, particularly for patients with indolent lymphoid malignancies.