i. MALIGNANT DISORDERS Page 2

9. Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies. Petropoulos D, Worth LL, Mullen CA, Madden R, Mahajan A, Choroszy M, Ha CS, Champlin RC, Chan KW. Bone Marrow Transplant. 2006; 37:463-7.

The authors evaluated the efficacy and toxicity of adding 9 Gy of total body irradiation (TBI), in three single daily fractions of 3 Gy, to the reduced intensity regimen of fludarabine 30 mg/m2 i. v. x 4 days and melphalan 140 mg/m2 i. v. x 1 day in advanced pediatric hematologic malignancies. Twenty-two acute lymphoblastic leukemia (ALL), six acute myeloid leukemia (AML), and one non-Hodgkin lymphoma patients were transplanted. Of these, 13 were beyond second remission, and five had prior hematopoietic stem cell transplant (HSCT). Twenty-one donors were unrelated, of which 19 were from cord blood (CB) units. Three of the eight related donors were genotypically disparate. Oral mucositis and diarrhea were the most common toxicities.

Twenty-seven patients achieved neutrophil engraftment (median 16 days), and 23 had platelet engraftment (median 42 days). One patient had primary graft failure. Seven patients died of non-relapse causes in the first 100 days. With a median follow-up of 52 months, seven of 22 ALL, five of six AML, and one of one lymphoma patients are alive and in remission.

The authors concluded that the regimen of TBI, fludarabine, and melphalan allows the engraftment of allogeneic hematopoietic stem cells (including mismatched CB). It was fairly well tolerated in pediatric patients, even for second transplants. Its efficacy requires further evaluation.

10. Busulfan/Melphalan/Antithymocyte Globulin Followed by Unrelated Donor Cord Blood Transplantation for Treatment of Infant Leukemia and Leukemia in Young Children: The Cord Blood Transplantation Study (COBLT) Experience. Wall DA, Carter SL, Kernan NA, Kapoor N, Kamani NR, Brochstein JA, Frangoul H, Goyal RK, Horan JT, Pietryga D, Wagner JE, Kurtzberg J. Biol Blood Marrow Transplant. 2005;11:637-46.

Although allogeneic transplantation offers potentially curative therapy to children and adults with otherwise untreatable malignancies, only a fraction of patients will have an HLA-matched donor in their family. Networks of unrelated volunteer donors have been established to provide an alternative donor source for those without family donors. However, with current HLA matching requirements, there remain a large proportion of patients for whom an unrelated volunteer donor is not identified in a timely fashion. Allogeneic transplantation from unrelated marrow donors is more frequently complicated by severe graft-versus-host disease (GVHD) or graft rejection.

Most prior studies with CBT have focused on total body irradiation (TBI)-based preparative regimens. There was interest in evaluating a non-TBI regimen for patients unable to tolerate TBI because of pretransplantation toxicity and leukemia patients <4 years of age. One stratum of the COBLT trial was to investigate the safety and efficacy of busulfan, melphalan, and antithymocyte globulin (ATG) as an alternative conditioning regimen to TBI.

Thirty-eight patients with leukemia or myelodysplastic syndrome (MDS) were enrolled in the study. The article presents the outcome of transplantations in the 32 children <4 years old who were enrolled on the trial. Within that subset, infant leukemia was defined as all cases diagnosed as leukemia before 6 months of age or diagnosed before 12 months of age with cytogenetic rearrangements carrying the mixed lineage leukemia gene.

The cumulative incidence (CINC) of neutrophil recovery (absolute neutrophil count >500/µL) at day 42 was 0.59 (95% confidence interval [CI], 0.44-0.78) at a median of 31 days (range, 23-55 days). The CINC and Kaplan-Meier estimates of platelet engraftment at day 180 were 0.53 (95% CI, 0.34-0.69) and 0.82 (95% CI, 0.61-1.00), respectively. CINC estimates of grade III/IV acute GVHD at day 100 and chronic GVHD at 1 year were 0.25 (95% CI, 0.09-0.41) and 0.26 (95% CI, 0.09-0.44), respectively. The CINC estimate of relapse was 0.31 (95% CI, 0.16-0.47) at 2 years. With a median follow-up of 27.8 months (range, 23.4-46.7 months), the probability of survival at 1 year was 0.47 (95% CI, 0.30-0.64).

The authors state that, in this small cohort, relapse and relapse-free survival were similar between patients in CR1 and those in CR2 and beyond. On the basis of current results with improved outcome in front-line chemotherapy and the reasonable salvage with CBT in CR2, it is reasonable to consider CBT for infant acute leukemia in CR1 for those who are at high risk for relapse and who would be unlikely to enter a second remission should relapse occur. The benefit of CBT over a volunteer unrelated stem cell donor is that the time to donor identification is short, thus allowing transplantation immediately after reinduction/consolidation.

[Note: As an incidental finding, these authors found that high-resolution molecular HLA typing for HLA-A, -B, and -DRB1, performed in retrospect, correlated with improved survival. Such a finding is in apparent disagreement with the data presented by Kogler et al (See Annotated Bibliography IX, HLA, citation #6) who reported that high-resolution HLA typing by sequencing for HLA-A, -B, -C, -DR, -DQ in 122 unrelated cord blood/patient pair transplants hardly improves long-term clinical outcome.]

11. Outcomes of unrelated cord blood transplants and allogeneic-related hematopoietic stem cell transplants in children with high-risk acute lymphocytic leukemia. Jacobsohn DA, Hewlett B, Ranalli M, Seshadri R, Duerst R, Kletzel M. Bone Marrow Transplant. 2004;34:901-7.

The authors pointed out that, in publications describing outcomes of children with leukemia who underwent unrelated cord blood (UCB) transplants compared to results using unrelated donor marrow transplants, the results are similar. In this study, the authors compared outcomes using UCB vs. allogeneic-related hematopoietic stem cells in pediatric ALL patients since 1992. A total of 49 patients were analyzed. All patients were either in CR1 with high-risk features (n=21) or in CR2 (n-28). In all, 23 patients underwent allogeneic-related bone marrow transplants and 26 underwent UCB transplantation. Other than increased time to engraftment for the UCB recipients, results are equivalent. The 3-year overall survival is 64% and 3-year event-free survival is 60% for both groups. Rates of GVHD and transplant-related mortality are also equivalent. The delayed hematopoietic reconstitution did not appear to adversely affect these patients, as the TRM was not statistically different when compared to the allogeneic-related transplants.

Notably, most UCB grafts were mismatched at one or two HLA alleles, with almost half of them being two allele mismatches. The median nucleated cell dose or UCB transplants was 0.58 x 10⁸/kg and the median neutrophil and platelet engraftment was 29 and 51 days, respectively. The authors suggest that their favorable results may be due to the strategy (since 1988) of selecting UCB units with a high cell count.

The authors concluded that for children with high-risk ALL in CR1 or children with ALL with initial remission less than 36 months in CR2, an unrelated cord blood transplant provides equivalent long-term results when compared to the gold standard – a matched-sibling transplant.

The policy at the authors' institution for patients without an HLA-identical sibling is that if there is a UCB unit that has 2 or fewer HLA mismatches and a cell count greater than 4.0 x 10⁷ TNC/kg, the patient will receive a UCB transplant instead of an unrelated donor marrow transplant.

12. Favorable Outcome for Infant Acute Lymphoblastic Leukemia after Hematopoietic Stem Cell Transplantation. Jacobsohn DA, Hewlett B, Morgan E, Tse W, Duerst RE, Kletzel M. Biol Blood Marrow Transplant. 2005;11:999-1005.

Infants with acute lymphoblastic leukemia (ALL) have a poor prognosis when treated with standard chemotherapy. A subset of these infants, particularly those with mixed-lineage leukemia (MLL) rearrangements, has a high likelihood of relapse. Hematopoietic stem cell transplantation (HSCT) performed early in first remission may improve outcome. This article presents results of 16 patients with infant ALL who were treated with HSCT in first remission.

Six patients were </=6 months of age at diagnosis, 11 had an initial white blood cell count of >50,000/µL, and all patients with determinable cytogenetics had a high-risk karyotype [t(4:11) abnormality or other MLL rearrangement]. All patients received 150 cGy of total body irradiation for 8 doses (1200 cGy). Fifteen of 16 patients received etoposide at 1000 mg/m² as a continuous infusion over 24 hours and cyclophosphamide at 60 mg/kg/d for 3 days. Eight patients received HSCT from an HLA-identical sibling, and 8 from unrelated cord blood.

The HSCT was well tolerated; 15 patients achieved neutrophil engraftment at a median of 16 days. Two patients, one of whom had minimal residual disease at HSCT, died after relapse following HSCT. Two patients died of transplant-related causes (TRM = 12%). Other than these 2 deaths, there were no major complications, such as fungal infection or veno-occlusive disease. Twelve (75%) patients remain long-term survivors (median follow-up, 4.7 years). The fact that there were no late deaths suggests good immune reconstitution and minimal chronic GVHD.

More data are needed regarding the late sequelae after using TBI in infants. The risks and benefits, therefore, need to be clearly weighed before infants with ALL are submitted to HSCT. Nevertheless, it does seem that infants with very-high-risk leukemia, mainly those with MLL gene rearrangements, benefit from high-intensity allogeneiic HSCT.

These results support the use of HSCT in the treatment of infant ALL, especially when used as consolidation in first remission. The risk of relapse seems to be decreased with this approach. Further work is being performed to determine the long-term effects from this therapy.

13. Unrelated cord blood transplantation for childhood acute myeloid leukemia: a Eurocord group analysis. Michel G, Rocha V, Chevret, et al. Blood 2003;102:4290-4297.

The authors reported results of unrelated cord blood transplantation in 95 children with AML (20 in CR1, 47 in CR2 and 28 in more advanced stage). Poor prognosis cytogenetic abnormalities were identified in 29 cases. Most patients had a 1 or 2 HLA antigen mismatched cord blood transplant. The median number of collected nucleated cells (NC) was 5.2 x 10⁷/kg. Cumulative incidence of neutrophil recovery was 78±4%, acute GVHD was 35±5% and 100-day transplant-related mortality (TRM) was 20±4%. In multivariable analysis, a collected nucleated cell dose of higher than 5.2 x 10⁷/kg was associated with a lower 100-day TRM. The two-year cumulative incidence of relapse was 29±5% and was associated with disease status. The 2-year leukemia free survival (LFS) was 42±5% (59±11% in CR1, 50±8% in CR2, and 21±9% for children not in CR). Children with poor prognosis cytogenetic features had similar LFS to other patients. In CR2, LFS was not influenced by the length of CR1. The authors concluded that unrelated cord blood transplantation is a good therapeutic for children with very poor prognosis AML and who lack an HLA-identical sibling.

(NOTE: The median dose of nucleated cells "collected" (5.2 x 10⁷/kg) seems generous and is likely to be an important factor regarding the good results obtained by these investigators. The median "infused" nucleated cell dose was 4.4 x 10⁷/kg, indicating about 85% recovery of "collected" cells after processing, cryopreservation, and thawing. An important comment by the authors is that the TRM was 17±5% in transplants carried out after January 1998 whereas it was 30±9% before that date. Moreover, when the "collected" nucleated cell dose was above the median, the 100-day TRM decreased to 9±4%.)

In a commentary regarding this article (Blood 2003;102:4249), Dr. Przepiorka points out, "With intensive chemotherapy alone, children with AML who achieve a second remission following a long first remission have a prolonged survival, whereas those with a short first remission have a poor prognosis. In contrast, the good disease-free survival following unrelated donor cord-blood transplantation was independent of the duration of first remission. Moreover, a 2-year disease-free survival was 21% for children who underwent transplantation in relapse, a group with little chance of survival with chemotherapy alone. Thus, there appears to be a substantial graft-versus-leukemia effect with unrelated-donor cord-blood transplantation for patients with high-risk second remission and relapsed AML."

14. Cord blood transplantation for children with acute leukaemia: a Eurocord registry analysis. Gluckman E, Rocha V. Blood Cells Mol Dis. 2004;33:271-3.

This report provices results of unrelated cord blood transplants collected by Eurocord Registry in children with acute leukemia. Children with AML: 95 children were analyzed. The two year leukemia free survival was 42% in patients transplanted in first remission, 50% in second remission and 21% in children not in remission. Children with poor prognostic cytogenetic features had the same survival compared to other patients. Children with ALL: 195 patients with ALL were analyzed. The two year leukemia free survival was 36% in patients transplanted in remission and 15% in patients transplanted in relapse. Results of unrelated cord blood transplants compared to unrelated bone marrow transplants in children with acute leukemia: 416 children with acute leukemia received a HLA matched unrelated bone marrow transplant and were compared to 99 children transplanted with an unrelated HLA mismatched cord blood. The long term outcome between these groups were comparable with delayed engraftment in cord blood transplant, more relapse in T cell depleted bone marrow transplant and more GVH in the unmanipulated bone marrow transplant resulting in similar 5 years leukemia free survival.

The authors concluded that the results show that use of unrelated cord blood transplant is an option in patients lacking an HLA identical sibling donor.

15. Survival after transplantation of unrelated donor umbilical cord blood is comparable to that of human leukocyte antigen-matched unrelated donor bone marrow: results of a matched-pair analysis. Barker JN, Davies SM, DeFor T, Ramsay NK, Weisdorf DJ, Wagner JE. Blood 2001; 97:2957-2961.

A matched-pair analysis compared the outcomes of recipients of hematopoietic cell transplants using 0 to 3 HLA-mismatched cord bloods vs. HLA-A, -B, and DRB1-matched bone marrow as a source of stem cells. Patients were predominantly children (median age, 5 years) undergoing transplantation for malignancy, storage diseases, BM failure and immunodeficiency syndromes between 1991 and 1999. Although neutrophil recovery was significantly slower after cord blood transplantation, the probability of engraftment at day 45 was 88% in cord blood vs. 96% in BM-MTX recipients (n = 26 pairs), and 85% in cord blood vs. 90% in BM-TCD recipients (n = 31 pairs). The authors concluded that despite increased HLA disparity, probabilities of engraftment, GVHD, and survival after cord blood transplantation are comparable to those observed after HLA-matched marrow transplantation.

16. Cord blood transplantation from HLA-mismatched unrelated donors as a treatment for children with haematological malignancies.  Ohnuma K, Isoyama K, Ikuta K, Toyoda Y, Nakamura J, Nakajima F, Tsuchida M, Ohira M, Suminoe A, Hara T, Nishihira H.   Br J Haematol. 2001;112:981-987.

Factors influencing the outcome for 39 children with haematological malignancy who were subjected to a cord blood transplantation (CBT) from genotypically HLA-mismatched unrelated donors were analysed. This retrospective study included 21 children with acute lymphoblastic leukaemia, 15 with acute myelogenous leukaemia and one each with chronic myelogenous leukaemia, refractory anaemia with myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukaemia (JMML). Those subjected to CBT during the first or second complete remission (CR) and MDS without blasts were assigned to the standard-risk (SR) group (n = 16). Patients in third or subsequent remission, relapse or partial remission with refractory leukaemia at the time of CBT were considered to be in advanced phase, and placed in the high-risk (HR) group (n = 11). JMML and the second CR after a relapse (n = 8), or bone marrow failure after a rejection (n = 3), following haematopoietic stem cell transplantation (HSCT) in the first CR were included in the high-risk group. Kaplan-Meier estimates for neutrophil and platelet recovery were 83.7 +/- 12.2 at d 60 and 55.4 +/- 16.6% at d 100 respectively. The incidence of grades II-VI acute graft-versus-host disease was 58.5 +/- 16.8%. The Kaplan-Meier estimate for 3-year event-free survival (EFS) was 49.2 +/- 16.6. From multivariate analysis, the most important factor influencing EFS was disease status at CBT: SR patients had a 3-year EFS of 75.0 +/- 21.6%, compared with 29.6 +/- 20.6% for those with HR disease (P = 0.013, RR 4.746, 95% CI 1.382-16.298). These data confirm that HLA-mismatched, unrelated CBT is a feasible procedure to cure a significant proportion of children with leukaemia, especially if conducted in a favourable phase of the disease.

Page 1 | 2 | 3