Probability Of Leukemia-free Survival Research Articles

Modified Donor Lymphocyte Infusion after HLA-Mismatched/Haploidentical T Cell-replete Hematopoietic Stem Cell Transplantation for Prophylaxis of Relapse of Leukemia in Patients with Advanced Leukemia

We evaluated the safety and efficacy of donor lymphocyte infusion (DLI) with granulocyte colony-stimulating factor priming and short-term immunosuppressive agents for prophylaxis of relapse in patients with advanced leukemia after human leukocyte antigen (HLA)-mismatched T cell-replete hematopoietic stem cell transplantation (HCT). Twenty-nine patients received prophylactic DLI at a median 75 (33-120) days after HCT. Acute graft-vs-host disease (GVHD) grades 3-4 occurred in six patients, and all cases were controlled. Eleven patients were alive and relapse-free with a probability of leukemia-free survival (LFS) of 37.3 +/- 9.6% at 3 years. Chronic GVHD was associated with a lower relapse rate and higher probability of LFS. Prophylactic-modified DLI is feasible in patients with advanced leukemia to prevent relapse after HLA-mismatched HCT.

Daunorubicin, cytarabine and fludarabine (DAF) for remission induction in relapsed or refractory acute myeloid leukemia. Evaluation of safety, tolerance and early outcome—Polish Adult Leukemia Group (PALG) pilot study

In 1992-1993, synergistic interaction of ribonucleotide reductase inhibitors (fludarabine, cladribine) and cytarabine (Ara-C) increasing Ara-CTP concentration in myeloblasts was proved. Based on these findings and encouraging results of the addition of cladribine to standard daunorubicin+Ara-C induction regimen (DAC) in acute myeloid leukemia (AML), the Polish Adult Leukemia Group (PALG) conducted a pilot study on the administration of cytarabine, daunorubicin, and fludarabine (DAF) as a reinduction treatment of AML to assess tolerance, toxicity, and early outcome. The DAF regimen consisted of daunorubicine 60 mg m(-2) day(-1) iv on days 1-3 and fludarabine 25 mg m(-2) day(-1) iv on days 1-5 given before cytarabine 200 mg m(-2) day(-1) in ci on days 1-7. Thirty-four AML patients with median age 39, 24% relapsed and 76% refractory, were included into the study between September 2003 and August 2004. Achieved response rate in the whole study population was 56%; n = 16 patients with complete remission (CR), and n = 3 patients with partial remission (PR). Fifteen of 16 patients achieved CR after the first course of therapy. Only 9% of total population died before the assessment of remission. All patients developed severe neutropenia. Serious infections were observed in 47% of the cases. Severe thrombocytopenia was observed in 72% of the patients. All patients required substitution of platelet concentrates (median 4), and PRBC (median 5). Severe alopecia, mucositis, vomiting were of low frequency. Liver, kidney, or circulatory failure, diarrhea, or polyneuropathy were not observed. The probability of overall survival (OS) for 1 year for the whole study population (34 patients) and the group of 16 patients in CR was: 44% (95% confidence interval [CI] 36-52%) and 69% (95% CI 55-83%), respectively. The probability of leukemia-free survival (LFS) for 1 year was 38% (95% CI 22-54%). Summarizing, DAF regimen used as the induction therapy in relapsed/refractory AML was well tolerated with acceptable toxicity and early efficacy.

Outcomes after HLA-matched sibling transplantation or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research

In children with acute lymphoblastic leukemia (ALL) with isolated central nervous system (CNS) relapse and a human leucocyte antigen (HLA)-matched sibling, the optimal treatment after attaining second remission is unknown. We compared outcomes in 149 patients enrolled on chemotherapy trials and 60 HLA-matched sibling transplants, treated in 1990-2000. All patients achieved a second complete remission. Groups were similar, except the chemotherapy recipients were younger at diagnosis, less likely to have T-cell ALL and had longer duration (> or = 18 months) first remission. To adjust for time-to-transplant bias, left-truncated Cox's regression models were constructed. Relapse rates were similar after chemotherapy and transplantation. In both treatment groups, relapse rates were higher in older children (11-17 years; RR 2.81, P=0.002) and shorter first remission (< 18 months; RR 3.89, P<0.001). Treatment-related mortality rates were higher after transplantation (RR 4.28, P=0.001). The 8-year probabilities of leukemia-free survival adjusted for age and duration of first remission were similar after chemotherapy with irradiation and transplantation (66 and 58%, respectively). In the absence of an advantage for one treatment option over another, the data support use of either intensive chemotherapy with irradiation or HLA-matched sibling transplantation with total body irradiation containing conditioning regimen for children with ALL in second remission after an isolated CNS relapse.

Haploidentical Hematopoietic Stem Cell Transplantation without In Vitro T Cell Depletion for Treatment of Hematological Malignancies in Children.

Objective: To evaluate the efficacy and safety of haploidentical hematopoietic stem cell transplantation (HCT) for children with donors from family members.Patients and methods: Forty-two children under fourteen years old with hematologic malignancies underwent haploidentical HCT. The outcome was analyzed.Results: Four (9.5%) of the forty-two patients/donor pairs mismatched in one HLA locus, fifteen (35.7%) pairs in two loci and twenty three (54.8%) in three loci. They were followed up for a median of 612 (40–1779) days. All patients achieved stable engraftment. The cumulative incidence of acute graft-versus-host disease (GVHD) grade 2–4 was 57.2%, and that of grade 3–4 was 13.8%. The cumulative incidence of total and extensive chronic GVHD was 56.7% and 29.5%, respectively. The probability of leukemia-free survival was 65.1% in standard-risk group and 49.6% in high-risk group. Fourteen patients died, four from infection, six from relapse of leukemia, two from heart failure, one from severe acute GVHD, and one from lymphoproliferative disorders. The probability of relapse was 13.8% at 1 year and 27.9% at 2 year after transplantation.Conclusion: The results in this study encourage extending the haploidentical HCT without T-cell depletion to children with an indication for transplantation.

Impact of FLT3 Internal Tandem Duplication (FLT3/ITD) on the Outcome of HLA-Identical Sibling Hematopoietic Transplantation for Adult Acute Myeloid Leukemia (AML) in First Remission: Substantial Probability of Leukemia-Free Survival Despite Increased Relapse Risk. A Retrospective Analysis of the EBMT-ALWP.

The prognosis of patients with AML and FLT3 internal tandem duplication (FLT3/ITD) is poor. It is unclear whether this mutation has impact on the outcome of allogeneic stem cell transplantation (Allo-SCT) for AML. Different cooperative groups have obtained controversial results. For this reason, registry data including large numbers of patients are of interest. We analysed the predictive value of FLT3/ITD on relapse incidence (RI), non-relapse mortality (NRM) and leukemia-free survival (LFS) in patients with AML in 1st CR who underwent a myeloablative allo-SCT from HLA-identical siblings and were reported to the EBMT. The series included 682 patients, 610 negative ITD/FLT3 and 72 FLT3/ITD positive reported between 1998 and 2007 with a median follow up time of 24 and 11 months, respectively. No significant differences were observed between the two groups regarding gender, median age (38 vs 40 yrs), FAB classification, cytogenetic distribution, number of induction courses to achieve CR, interval diagnosis to transplant (134 vs 133 days), source of stem cells (PB or BM) and CMV serostatus. In contrast, patients with FLT3/ITD had higher leukocyte counts at diagnosis (14 vs 65 × 109/L, p<0.0001), were transplanted with T-cell replete progenitors (78% vs 97%, p<0.0001) and more frequently a female donor to male recipient (yes: 31% vs 20%, p=0.04). Univariate (Table1) and multivariate analyses demonstrated the adverse impact of FLT3/ITD for LFS (HR 0.56, p=0.009) and relapse incidence (HR=2.9, p<0.001) but not for NRM (p=0.83). It is remarkable, however, 53% of FLT3/ITD positive patients transplanted for AML in first CR remain alive and disease-free at 2 years. Other independent prognostic factors for LFS and relapse were: T-cell depleted graft, poor cytogenetics and more than one induction course to achieve first CR. For NRM the only prognostic factor was age ≥ 45 years (HR=1.9, p=0.004). In summary, this analysis shows an adverse impact of FLT3/ITD on transplantation outcome. Despite this finding, half of FLT3/ITD positive AML patients in first CR remain disease-free at 2 years, a proportion that seems higher than with other treatment options.Table 1Two years outcomes of HSCT in adults patients with AML in CR1 according to the presence of FLT3/ITD.LFSRelapseNRMFLT3/ITD+ (n=70)53±7%36±7%17±7%FLT3/ITD-(n=610)64±2%20±2%19±2%P (log rank test)P=0.06P<0.0001P=0.49

Minimal Residual Disease Status Is the Most Important Preditive Factor in Adults with Acute Lymphoblastic Leukemia. Prospective, Multicenter PALG 4-2002 MRD Study.

Current therapeutic protocols for adult acute lymphoblastic leukemia (ALL) take into account the risk of relapse, in order adjust the treatment intensity to individual patient needs. It is postulated that in addition to “classical” risk criteria the status of minimal residual disease (MRD) should be considered for treatment decisions. The aim of this study was to prospectively evaluate the feasibility and prognostic significance of MRD detected with the use of immunophenotyping for outcome of ALL patients treated according to 4-2002 protocol of the Polish Adult Leukemia Group (PALG). Induction therapy included PDN, Asp and 4x epirubicin+VCR. Consolidation consisted of 2x high-dose AraC+Cy, 2x Mtx+Vep, 6MP, and CNS prophylaxis. Patients stratified to high risk (HR) group according to “classical” criteria based on those formerly developed by GMALL (bcr/abl(+), WBC>30 G/L, prepreB, early or mature T phenotype, age>35y, or prolonged time to achieve CR) were further referred for hematopoietic cell transplantation (HCT), whereas those assigned to standard risk (SR) group were treated with maintenance for 2 years. MRD was tested at the level of 0.1% after completion of induction and consolidation therapy in patients achieving CR, employing multicolor flow-cytometry, including a new “empty spaces” method taking into account an individual pattern of antigen expression on blast cells. 165 ALL pts (B-lineage 79%, T-lineage 21%), aged 29 y (17–60) were included. CR rate equaled 85,5%. 23% of CR pts were assigned to SR, 77%- to HR according to classical criteria. MRD evaluation was possible in all but 8 pts. After induction 37% of CR pts were found MRD(+). Among those who remained in CR, MRD after consolidation was detected in 26% of cases. 64% of patients were MRD(−) at both time-points, whereas in the remaining 36% of cases MRD was detected at least once. MRD status affected both relapse incidence (RI) and leukemia-free survival (LFS). After 3 years the RI was higher for pts with MRD(+) vs. MRD(−) if assessed after induction (82%vs.29%,p=0.00007) and after consolidation (62%vs.41%,p=0.05). For pts with MRD(−) at both study end-points the probability of LFS was 65% whereas for those with MRD(+) after either induction and/or consolidation − 26% (p=0.008). In the respective subgroups RI equaled 28% and 73% (p=0.004). The difference was observed for patients assigned to SR group (20%vs.92%,p=0.01) as well as to HR group (33%vs.70%,p=0.05). In a multivariate analysis including classical risk criteria the MRD status remained the only significant factor predictive for RI (HR: 2.5(1.3–4.8),p=0.006) and LFS (HR: 2.1(1.2–3.9),p=0.01). We conclude that immunophenotyping employing “empty spaces” method is feasible for MRD evaluation in adults with ALL. MRD stzatus after induction and consolidation is the most important predictive factor for RI and LFS. Based on our findings patients with MRD detected after induction and/or consolidation should be offered intensified treatment with the use of HCT irrespective of the absence of other risk factors.

Donor lymphocyte infusion for the treatment of leukemia relapse after HLA-mismatched/haploidentical T-cell-replete hematopoietic stem cell transplantation

In this study, we tested the efficacy and safety of donor lymphocyte infusion (DLI) with granulocyte colony-stimulating factor (G-CSF) priming in patients who relapsed after haploidentical hematopoietic stem cell transplantation (HSCT). Twenty patients received DLI at a median of 177 days after HSCT. Eight patients survived in complete remission for a median of 1118 days. The 2-year probability of leukemia-free survival was 40%. Acute graft-versus-host disease (GVHD) grade 3-4 occurred in six patients after DLI. GVHD prophylaxis reduced the incidence of acute GVHD. Our primary data showed that G-CSF-primed DLI with GVHD prophylaxis was a potentially effective therapeutic option for patients who relapsed after haploidentical HSCT.

Hematopoietic Cell Transplantation as Therapy for Pediatric Patients with Relapsed Acute Lymphoblastic Leukemia with and without CNS Involvement.

Allogeneic hematopoietic cell transplantation (HCT) is the standard of care for pediatric patients with acute lymphoblastic leukemia (ALL) with early bone marrow relapse. However, the role of HCT is less clear in patients with isolated central nervous system (CNS) relapse where intensive chemotherapy followed by craniospinal irradiation is often offered. To determine the potential role of HCT, we evaluated the transplant outcomes of 116 patients with relapsed ALL with and without CNS involvement, 1–18 years of age, treated at the University of Minnesota between 1991 and 2006. Patients not in remission at transplant, and those with isolated extramedullary disease not involving the CNS were excluded. Relapse site prior to HCT was CNS in 14 patients, bone marrow (BM) in 85 patients and both marrow and CNS (BM+CNS) in 17 patients. Forty-eight underwent HCT from 1991–1995, 39 from 1996–2000 and 29 from 2001–2006. There were no significant differences among groups in median age at diagnosis (CNS: 3.7 years, range 1.2–7.7; BM: 4.5, 1–16; BM+CNS 3.7, 1.4–17), median age at transplant (CNS: 8 years, range 3.2–17.3; BM: 8.3, 3.5–17.9; BM+CNS 7.8, 3–17.9), or length of CR1 (CNS: 22.8 months, range 8.6–58; BM: 26.9, 0.8–74; BM+CNS: 34.2, 3.3–74). Remission status was similar in all groups (CNS: 7 CR2, 14 CR3+; BM: 73 CR2, 92 CR3+; BM+CNS: 14 CR2, 17 CR 3+; p=.06). Graft source was also similar between groups with 44 patients (38%) having a related donor and 72 patients having an unrelated donor (36% marrow and 25% umbilical cord blood). The majority of patients received cyclophosphamide 120 mg/kg and total body irradiation 1320–1375 cGy alone (n=69), or with etoposide (n=38) or fludarabine (n=8). Preparative regimen had no effect on outcomes. The incidence of grade II–IV GVHD (CNS 51%, 95% CI 24–68; BM 36%, 26–46; BM+CNS 18%, 1–35; p=.27) and grade III–IV GVHD (CNS 21%, 95% CI 0–42%; BM 16%, 8–24%; BM+CNS 0%; p=.21) was similar between groups. Hazard ratios using Cox multiple regression analysis demonstrated reduced survival in recipients with T cell leukemia or BCR-ABL gene rearrangement, history of marrow relapse, or receipt of HLA mismatched marrow from an unrelated donor. Patients with isolated CNS relapse had the least transplant related mortality at 2 years (CNS: 0%; BM: 35%, 95% CI 11–59%, BM+CNS: 34, 24–44; p=.05) and the lowest incidence of relapse (CNS: 0%; BM: 12%, 95% CI 0–27%, BM+CNS: 30%, 20–40; p=.01). The probability of leukemia-free survival at 5 years was greatest for patients with isolated CNS relapse (CNS: 91%, 95% CI 51–99; BM: 35, 25–45; BM+CNS: 46, 22–.68; p<.05). Similarly, the probability of overall survival was also greatest for the CNS group (CNS 86%, 33–98%; BM: 38, 27–49; BM+CNS: 53, 28–73; p<.01). These data strongly support allogeneic hematopoietic cell transplantation as a viable therapeutic option for pediatric patients with isolated CNS relapse with a very high probability of survival. Furthermore, the data indicate that CNS disease in combination with marrow relapse does not adversely effect transplant outcome compared to results expected in those with marrow relapse alone.

Unrelated Allogeneic Stem Cell Transplantation with Myeloablative Preparative Regimen for Adult Patients with Acute Lymphoblastic Leukemia in CR: A Survey from the European Group for Blood and Marrow Transplantation (EBMT).

Data from the EBMT indicate that approximately 46% of Unrelated Allogeneic Stem Cell Transplantation (UD-SCT) in Europe utilize peripheral blood (PB) and 54% bone marrow (BM) as a graft source for adult patients with ALL since January 1998. However, prospective randomized trials comparing the two stem cell sources are lacking. This study describes the results of 782 adult patients with ALL in remission (422 BM and 360 PB) transplanted in different centers affiliated with the EBMT from 1998 to 2004 with an HLA identical unrelated donor (HLA-A and -B low resolution and HLA-DRB1 allelic typing). Median age was 27 years for BM (range 16–63, male 60%) and 30 years for PB (range16–63, male 62%), respectively. Fifty four (54%) and 64% of patients were transplanted in first complete remission (CR1) in the BM and PB groups, respectively. The frequency of female donor to male recipient was 18% in the BM and 15% in the PB group. Total Body Irradiation (TBI)-based preparative regimens were given in 85% and 88% of patients in the BM and PB group respectively. Graft-versus-Host Disease (GvHD) prophylaxis consisted of cyclosporine A (CsA) (6% and 4%), CsA and methotrexate (77% and 58%) or in vitroT-cell depletion (17% and 38% in BM and PB group, respectively). With the median follow-up of 17 (range 1–92) and 11,3 (range 1–71) months, the incidence of GvHD grade II–IV was 37% in the BM group and 39% in the PB group (p=0.39). Probabilities of LFS, TRM and relapse were calculated using the Kaplan-Meier estimate. LFS was 45+/−3% vs 36+/−3% (p=0.04) transplant related mortality (TRM) was 33+/−2% and 39+/−3(p=0.29 while incidence of relapse was 32+/−3% and 41+/−4%(p=0.06), in the BM and PB groups respectively. Two years leukemia-free survival (LFS) for the patients transplanted in CR1 was 48% (BM) and 42% (PB, p=0.48). However, 2-years LFS for patients transplanted in CR2 or CR3 was significantly higher in the BM compared to the PB group (42% and 26%, p<0.004). The probability of relapse was significantly lower in BM compared to PB (32% vs 54%, p<0.001) without there being a detectable difference in TRM at 2 years (38% vs 43%, p= 0.31).In conclusion, the results of this retrospective comparative study confirm that UD-SCT with BM and PB as a graft source have similar results for patients in CR1. However, patients transplanted in CR2 or CR3 with a bone marrow graft, have decreased relapse incidence and better LFS, probably reflecting disease and transplant related differences compared to PB transplants such as in vitro T cell depletion more used in those transplants.

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.

Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies

Many patients who require allogeneic hematopoietic stem cell transplantation (allo-HSCT) lack a human leukocyte antigen (HLA)-matched donor. Here, we report a protocol for haploidentical allo-HSCT that combines granulocyte-colony stimulating factor primed bone marrow (G-BM) and peripheral blood stem cells (PBSC) without in vitro T-cell depletion (TCD). In this study, 171 patients, including 86 in high-risk group, underwent transplantation from haploidentical family donors. All patients achieved sustained, full donor chimerism. One hundred and eleven patients were alive in remission at a median of 682 (253-1502) days. The cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) was 23% and that of extensive chronic GVHD, 47%; these were not influenced by HLA disparity. Patients younger than 15 years had less grade III-IV acute GVHD than older patients (P=0.044). The 2-year probability of relapse was 12% for standard-risk disease and 39% for high-risk disease. The 2-year probability of leukemia-free survival (LFS) was 68% for standard-risk patients and 42% for high-risk patients (P=0.0009). Grade III-IV acute GVHD was associated with better LFS (P=0.0017). The results require confirmation and show that G-BM combined with PBSC from haploidentical family donors, without in vitro TCD, may be used as a good source of stem cells for allo-HSCT.

Comparable Long-Term Survival After Unrelated and HLA-Matched Sibling Donor Hematopoietic Stem Cell Transplantations for Acute Leukemia in Children Younger Than 18 Months

To describe outcomes after unrelated donor stem cell transplantation (HCT) in children (< 18 months at diagnosis) with acute leukemia and compare these with outcomes after human leukocyte antigen (HLA)-matched sibling donor HCT. We compared the results of unrelated donor HCT with bone marrow (n = 85) or cord blood grafts (n = 81) and HLA-matched sibling donor HCT with bone marrow grafts (n = 101) for acute myeloid or acute lymphoblastic leukemia using Cox proportional hazards models. Unrelated donor HCT recipients were younger, more likely to have MLL gene rearrangement, to have advanced leukemia, and to receive irradiation before HCT. Treatment-related mortality rates were 6%, 15%, and 31% after matched sibling, unrelated donor bone marrow, and cord blood HCT, respectively. Risks of relapse, overall and leukemia-free survival were significantly associated with disease status at transplantation. Though leukemia recurrence was lowest after unrelated donor HCT in first clinical remission (CR), overall survival, and leukemia-free survival rates were similar after matched sibling and unrelated donor HCT, after adjustment for disease status. Relapse, overall and leukemia-free survival did not differ by graft type (bone marrow v cord blood) or type of leukemia. Three-year probabilities of leukemia-free survival were 49% and 54% after HLA-matched sibling and unrelated donor transplantation in first CR, respectively. Corresponding rates for those with advanced leukemia were 20% and 30%. Unrelated donor HCT should be considered for infants with acute leukemia in first CR using the same eligibility criteria as are currently used for those with HLA matched sibling donors.

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.

Outcomes after HLA-Matched Sibling Transplants or Chemotherapy in Children with Acute Lymphoblastic Leukemia in Second Remission: A Collaborative Study of the Children's Oncology Group (COG) and the Center for International Blood and Marrow Transplant Research (CIBMTR).

The best treatment for children with B-precursor acute lymphoblastic leukemia (ALL) in second remission after a marrow relapse is controversial. To address this question, we compared outcomes in 192 patients enrolled on COG chemotherapy trials 9110 (n=109), 9310 (n=59) and 9411 (n=29) and 189 HLA-matched sibling transplant recipients reported to the CIBMTR. Patients received treatment between 1991 and 1997. Patients with isolated extra-medullary relapse were excluded. Median follow-up was 103 (range 34–159) and 101 (16–160) months after chemotherapy and transplantation, respectively. Groups were similar with respect to sex, leukemia sub-type, leukocyte count at diagnosis and duration of first remission. Chemotherapy recipients were younger at diagnosis (5 vs. 8 years) and less likely to have combined marrow and extra-medullary site relapse (12% vs. 30%). To adjust for time-to transplant bias, we used left-truncated Cox regression models to examine treatment outcomes. The relative efficacy of chemotherapy and transplantation depended on the duration of first clinical remission and transplant conditioning regimen as shown in the Table below. Comparing children with early relapse (<36 months from diagnosis) the 5-year probabilities of leukemia-free survival (LFS) were 23%, 44% and 8% after chemotherapy alone, transplantation with a total body radiation (TBI)-containing regimen and a non-TBI regimen, respectively. In contrast to these findings, relapse and treatment failure were similar after transplantation with a TBI-containing regimen or chemotherapy after a late relapse (≥36 months from diagnosis). The 5-year probabilities of LFS were 61% and 60% after chemotherapy alone and a TBI-containing regimen, respectively and significantly lower at 30% after a non-TBI regimen. These data support HLA-matched related donor transplantation using a TBI-containing regimen in second remission for patients with ALL and early relapse.Early relapse (<36 months)Late relapse ≥36 months) (OutcomeNRelative Risk (95% CI)P-valueNRelative Risk (95% CI)P-valueLeukemia recurrenceChemotherapy1151.00811.00TBI-containing regimen920.50 (0.27–0.68)0.0004611.02 (0.62–1.68)0.91Non-TBI containing regimen191.36 (0.81–2.31)0.24142.51 (1.23–5.16)0.01Treatment failureChemotherapy1151.00811.00TBI-containing regimen920.53 (0.37–0.75)0.0003610.93 (0.63–1.37)0.70Non-TBI containing regimen191.49 (0.93–2.37)0.09142.87 (1.60–5.13)0.0004

Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT) in Children with Acute Leukemia: Risks and Benefits of Umbilical Cord Blood (CB) vs. Bone Marrow (BM).

Though CB is an accepted alternative to BM for HSCT, the selection of CB over BM remains controversial. Therefore, we compared the results of 492 unrelated donor BM and 508 CB transplants performed in children <16 years of age between 1995–2003. Median follow up was 45 and 59 months for CB and BM recipients, respectively. Compared to BM recipients, CB recipients were younger, less likely to be Caucasoid, more likely to have advanced disease, less likely to receive irradiation and more likely to receive cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Whereas, 7% of CB recipients were matched at HLA A, B (low resolution) and DRB1, 40%, 1-locus and 53%, 2 loci mismatched, respecively, 75% of BM recipients were matched and 25% mismatched at 1-locus. Neutrophil recovery at day 42 depended on graft type and cell dose: 97% with BM, 86% with matched CB, 79% with high cell dose (>0.3 x 108/kg) CB graft mismatched at 1 or 2 loci and 64% with low cell dose (≤ 0.3 x 108/kg) CB grafts. Rates of grades 2–4 acute GVHD were 70% with mismatched BM, 50% with matched BM, 40% with mismatched CB and 20% with matched CB. Corresponding rates of chronic GVHD were 35%, 33%, 17% and 27%. The relative efficacy of CB and BM transplantation depended on HLA disparity and CB cell dose as shown in the Table below. Children receiving matched CB had significanlty lower risks of treatment failure and overall mortality than those receiving matched BM; children receiving high cell dose CB mismatched at 1 locus had risks similar to those receiving matched BM. Children receiving low cell dose CB mismatched at 1 locus and CB mismatched at 2 loci (any cell dose) had higher risks of treatment failure and mortality than matched BM recipients during the first 3 months after transplantation; among children surviving the first 3 months, subsequent risks were similar to children receiving BM. The 3-year probability of leukemia-free survival was highest after matched CB transplants (60%); LFS probabilities were similar with matched BM and high cell dose CB mismatched at 1 locus (40% and 41%, respectively). Probabilities were lower after mismatched BM, low cell dose CB mismatched at 1 locus and CB mismatched at 2 loci (30%, 36% and 33%, respectively). These data support use of matched CB grafts or CB mismatched at 1 locus with a high cell dose for children needing HSCT, whether or not a matched BM donor is available; low cell dose or 2-loci mismatched CB grafts may provide a reasonable alternative when a matched BM donor is not available or for those whose disease requires immediate transplantation.Treatment failureOverall mortalityNRelative Risk (95% CI)P-valueRelative Risk (95% CI)P-valueBM Matched3681.001.00BM 1-Ag mismatched1231.26 (0.98–1.62)0.071.22 (0.93–1.59)0.15CB matched350.52 (0.30–0.92)0.020.54 (0.30–0.97)0.04CB 1-Ag mismatched, high dose1570.95 (0.75–1.22)0.710.96 (0.75–1.25)0.78CB 1-Ag mismatched, low dose44 ≤ 3 months1.85 (1.14–2.99)0.012.35 (1.44–3.83)0.001 >3 months0.69 (0.35–1.35)0.350.73 (0.37–1.42)0.35CB 2-Ag mismatched266 ≤ 3 months1.75 (1.36–2.60)<0.0012.06 (1.57–2.71)<0.001 >3 months0.87 (0.65–1.16)0.660.94 (0.70–1.25)0.66

Outcomes after HLA-Identical Sibling Allogeneic Peripheral Blood Stem Cell Transplantation Using Reduced Intensity Conditioning Compared to Autologous Peripheral Blood Stem Cell Transplantation for Elderly Patients with De Novo Acute Myeloid Leukemia.

Results of allogeneic hematopoietic stem cell transplantation (HSCT) in elderly patients are associated to high TRM mainly due to toxic effects of myeloablative preparative regimen allogeneic and GVHD. Therefore, chemotherapy or autologous (auto) HSCT are often treatment alternatives. Recently, allogeneic peripheral blood SCT (PBSCT) with reduced-intensity conditioning (RIC) has emerged as an alternative to decrease TRM and to add a GVL effect. We have conducted a registry-based retrospective risk-adjusted comparative analysis of outcomes of 204 RIC-PBSCT to those of 954 auto-PBSCT in adult patients aged 50 years or older with de novo AML. Transplants were performed from 1997 until 2003 and reported to the EBMT. Median age was similar in both groups (58 y in RIC and 57y auto PBST), however RIC patients were transplanted more recently, had more advanced disease at time of transplant and poorer cytogenetics compared to the auto-PSCT group (p<0.05). The majority of conditioning regimens used in the RIC group was fludarabine-based associated to low dose TBI or Busulfan (<8mg/kg). Median follow-up was 13 months in both groups. Median time to engraftment was 16 days in the RIC group and 12 days in the auto group (p <0.0001). Unadjusted one-year probability of TRM was 15 ±3% in RIC and 8±1% in auto (p=0.002) and one-year probability of relapse were 34 ±3% in the RIC group versus 40 ±2% in the auto group (p = 0.31). However after adjustment, multivariate analysis showed a lower risk for relapse (RR 0.75, p = 0.04) but a trend for a higher TRM (RR 1.57, p = 0.07) for RIC patients. Major causes of non leukemic death in the RIC group were infections and graft-versus-host disease; and in the auto group, infections. Unadjusted one-year probabilities of leukemia-free survival (LFS) and overall survival (OS) were not statistically different in both groups: LFS of 50±4% in the RIC group versus 52±2% in the auto group (p = 0.31), and OS of 62±4% versus 66±2% (p = 0.23), respectively. In a multivariate analysis, OS and LFS were not statistically different for both groups. In the subgroup analysis, unadjusted one-year probability of LFS was 62±8% for patients in 2nd complete remission receiving RIC transplants compared to 43±6% (p=0.02). Conclusion: Allogeneic HLA identical RIC PBSCT is an effective treatment option for older patients with AML, with acceptable overall survival and decreased relapse incidence compared to autologous PBSCT. These results suggest that RIC PBSCT are feasible in a high risk population and should be evaluated in prospective trials in elderly AML.

Time-Sequenced G-CSF (Lenograstim) for the Treatment of Adult Acute Lymphoblastic Leukemia - Seven Year Follow-Up of the Polish Adult Leukemia Group 4–96 Study.

The goal of the study was to evaluate long-term outcome of patients treated within 4–96 trial by the Polish Adult Leukemia Group (PALG). Sixty four patients with newly diagnosed acute lymphoblastic leukemia (ALL) (median age 26 years, range 16–58) were randomly assigned to receive chemotherapy alone (n=31) or chemotherapy and glucosylated G-CSF (lenograstim) (n=33). Both groups were well-balanced in terms of age, initial WBC, immunophenotype and bcr/abl positivity. Induction therapy consisted of epirubicin+vincristin (Epi/Vcr) on days 1, 8, 15, 22, prednisone on days 1–28, L-asparaginase 8 doses starting from day 13; consolidation treatment included twice methotrexate+etoposide (Mtx/Vep), twice high dose cytarabine and cyclophosphamide (HDAraC/Ctx), CNS irradiation and intrathecal Mtx. In T-derived ALL, additional HDAraC/Ctx was administered instead of the first Mtx/HDAraC. During induction patients received G-CSF 150 μg/m2 sc. on days 2–6, 9–13, 16–20, 23-until the neutrophil recovery >1.0x109/L, starting 36 hours after Epi/Vcr, finishing 48 hours before the next dose; in consolidation - following each HDAraC/Ctx course on days 5–16. High risk patients having a donor were performed allogeneic hematopoietic cell transplantation in first complete remission, whereas those without a donor were given autologous transplant. At seven years the overall survival rate equalled 42% for G-CSF group and 24% for the controls (p=0.11). There was also a trend to higher probability of leukemia-free survival in advantage of patients receiving the cytokine (38% vs. 20%, p=0.17). The above differences might have resulted from: 1) Higher CR rate in the G-CSF group compared to the controls (94% vs. 87%), 2) Better adherence to the chemotherapy protocol (faster completion of induction-consolidation programme by 19 days, p=0.005, less dose reductions or delays), which in turn might have influenced the risk of relapse.We conclude that time sequenced G-CSF administration may improve long-term outcome of adult ALL patients although the study including larger population is required to confirm this hypothesis.

Autologous hematopoietic stem-cell transplantation for children with acute myeloid leukemia in first or second complete remission: a prognostic factor analysis.

To determine prognostic factors correlated with outcomes after autologous hematopoietic stem-cell transplantation (HSCT) in children with acute myeloid leukemia (AML). We studied 219 children who received autologous HSCT for AML in first complete remission (CR) and 73 children in second CR and who were reported to the Autologous Blood and Marrow Transplant Registry. Among 29 of 73 patients who underwent transplantation in second CR, duration of first CR was > or = 12 months. Three-year cumulative incidences of relapse were 37% (95% CI, 31% to 44%), 60% (95% CI, 41% to 74%), and 36% (95% CI, 20% to 53%) for children in first CR, second CR after a short (< 12 months) first CR, and second CR after a long (> or = 12 months) first CR, respectively. Corresponding 3-year probabilities of leukemia-free survival were 54% (95% CI, 47% to 60%), 23% (95% CI, 10% to 39%), and 60% (95% CI, 42% to 75%). In multivariate analyses, risks of relapse, mortality, and treatment failure (relapse or death, inverse of leukemia-free survival) were higher for patients in second CR after a short first CR than for the other two groups. Transplant-related mortality, treatment failure, and overall mortality rates were higher in older (> 10 years) children. Duration of first CR seems to be the most important determinant of outcome. Results in children who experience treatment failure with conventional chemotherapy support the use of autologous transplantation as salvage therapy if such patients achieve a subsequent CR.

Omission of day +11 methotrexate does not appear to influence incidence and severity of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Objective: To explore the influence of omission of the day +11 dose of methotrexate (MIX) on the incidence and severity of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: From April 1997 to October 2002, 80 leukemia patients (46 men and 34 women aged from 12 to 56 years with a median age of 35) underwent allo-HSCT at our BMT unit. Among them, 58 patients received grafts from HLA-identical siblings, 8 from HLA one major antigen mismatched siblings and 14 from HLA-matched unrelated donors. All patients received a modified cyclosporine and short-course MTX regimen for GVHD prophylaxis, which included MTX 15 mg on day +1, and 10 mg on days +3 and +6 (MTX day +11 dose omitted) and cyclosporine given daily. Results: The overall incidence of grade I–IV acute GVHD was 57.5% (46/80 patients), with grade II–IV acute GVHD in 28 patients (35%) and grade III–IV acute GVHD in 7 patients (8.8%). Among 58 patients receiving grafts from HLA-identical siblings, 24 patients developed grade I–IV acute GVHD (41.4%), with grade II–IV acute GVHD in 13 patients (22.4%) and grade III–IV acute GVHD in 4 patients (6.9%). 21 out of 22 patients receiving grafts from HLA one major antigen mismatched siblings and HLA-matched unrelated donors developed grade I–IV acute GVHD (95.5%), with grade II–IV acute GVHD in 14 patients (63.6%) and grade III–IV acute GVHD in 3 patients (13.6%). Chronic GVHD occurred in 38 out of 56 evaluable patients (67.9%), with extensive form in 15 patients (26.8%) and limited form in 23 patients (41.1%). With a median follow-up of 960 days (range 180–1980 days), the probability of leukemia-free survival at 3 years was 61.3% for all patients. Conclusion: Our results suggest that the day +11 MTX can be omitted without a major deleterious effect on the incidence and severity of graft-versus-host disease after HLA-identical sibling transplantation as well as HLA one major antigen mismatched sibling and HLA-matched unrelated donor transplantation.

Factors influencing outcome and incidence of long-term complications in children who underwent autologous stem cell transplantation for acute myeloid leukemia in first complete remission

To evaluate factors influencing outcome and incidence of long-term complications, we analyzed, in a retrospective, multicenter study, 387 children who underwent autologous hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) in first complete remission (CR). Median follow-up time from transplantation was 60 months. Transplantation of bone marrow cells was performed in 318 children, whereas in 60 patients peripheral blood progenitor cells (PBPCs) were used. In multivariate analysis, we investigated the variables influencing probability of hematopoietic recovery, transplantation-related mortality (TRM), relapse, and leukemia-free survival (LFS). We found that use of PBPCs as stem cell sources and use of BCNU (N,N-bis[2-chloroethyl]-N-nitrosourea), amsacrine, VP-16, and cytosine arabinoside (BAVC) as a preparative regimen were associated with faster neutrophil recovery. Infusion of PBPCs, young age of patients, use of BAVCs, and absence of marrow purging predicted an accelerated platelet reconstitution. The 5-year Kaplan-Meier estimates of TRM, relapse, and LFS were 3% +/- 1%, 39% +/- 3% and 60% +/- 3%, respectively. Relapse probability was increased in children given the BAVC regimen, and it was decreased after in vitro purging of hematopoietic progenitors and in children with a French-American-British classification of M3 and a time interval of 170 days or more between CR and HSCT. These 2 latter variables favorably influenced the probability of LFS, which was, by contrast, reduced with the BAVC regimen. Thirty-three percent of patients surviving more than 18 months experienced at least one late sequela; use of total body irradiation was the only predictive factor. The results obtained in this analysis can be of help in designing prospective studies of autologous HSCT in children with AML in first CR.