i. MALIGNANT DISORDERS Page 2

8. 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.

9. 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."

10. 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.

11. 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.

12. 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.

13. (The following citation includes data on malignant and non-malignant disorders.) Outcomes of unrelated cord blood transplantation in pediatric recipients. Styczynski J, Cheung YK, Garvin J, Savage DG, Billote GB, Harrison L, Skerrett D, Wolownik K, Wischhover C, Hawks R, Bradley MB, Del Toro G, George D, Yamashiro D, van de Ven C, Cairo MS. Bone Marrow Transplant. 2004;34:129-36.

The authors report results of unrelated cord blood transplants (UCBT) in 29 pediatric recipients in one center from August 1997 to September 2002, and the risk factors associated with survival. The median age of the patients was 9 years (0.5-20); diagnoses were ALL, AML, CML, HD, HLH, NHL, NBL, B-thal, FA, FEL, Krabbe, WAS, SAA; the median follow-up was 11 months; conditioning was total body irradiation (TBI)-ablative (14), chemotherapy-ablative (6) and reduced intensity chemotherapy (9). The median total nucleated cell (TNC) dose was 3.8 x 10(7)/kg (1.1-11); median CD34+: 2.3 x 10(5)/kg (0.2-9.9); and HLA match: 2 (6/6), 5 (5/6), 22 (4/6). The cumulative incidence estimate for neutrophil recovery at day +60 was 63%; two patients had neutrophil engraftment after day +60. Two patients had primary graft failure (2/23) (8.7%). Probability of >/=grade II aGVHD by day +60 was 27%, >/=grade III aGVHD was 20% and cGVHD 3%. Estimated 1-year overall survival (OS) 46% (95% CI 30-71) and for standard risk patients was 60% (95% CI 29-100%). Variables associated with improved survival by multivariate analysis include non-TBI-ablative conditioning (P=0.024), CD34+/kg (P=0.038) and gender (P=0.048).

The authors comment that their results indicating CD34 cell dose as a significant variable for hematopoietic reconstitution and for OS are complimentary to those of Wagner et al. The probability of aGVHD was strikingly lower than the results of less-HLA-disparate unrelated bone marrow transplants performed in children, and only one patient (cumulative incidence 3%) had extensive cGVHD. In comparison, cGVHD develops in 55-65% of patients receiving HLA-matched BMTs from unrelated donors. The authors suggest that the results should be viewed cautiously because of the small number of patients and events analyzed; the heterogeneity of the diagnoses, methods of conditioning and GVHD prophylaxis; and short follow-up.

14. First report of autologous cord blood transplantation in the treatment of a child with leukemia. Hayani A, Lampeter E, Viswanatha D, Morgan D, Salvi SN. Pediatrics. 2007; 119: e296-300.

The authors present the case of a 3-year-old girl with acute lymphoblastic leukemia who developed isolated central nervous system relapse while receiving chemotherapy 10 months after diagnosis. The child achieved a second remission on retreatment with systemic and intrathecal chemotherapy. She then underwent myeloablative chemotherapy and radiation therapy followed by infusion of her own umbilical cord blood, which the parents had saved after her delivery. Prior to transplantation, the authors used IgH receptor gene and T-γ JG receptor gene loci rearrangements as molecular markers of the leukemia clone. The negative rearrangement signal in UCB, although positive in the leukemic bone marrow, gave the authors some assurance that the cord blood did not contain the leukemia clone. Given the sensitivity limitation of the standard PCR testing, however, one cannot completely rule out the possibility that a low-abundance leukemia clone was present in the UCB.

The patient is now doing well and is in complete remission 20 months after cord blood transplantation.

This report is apparently the first report of autologous CBT for the treatment of childhood leukemia. Autologous UCB transplantation has been reported in 1 patient with neuroblastoma and another with severe aplastic anemia.

In considering the choice of an autologous cord blood unit rather than an allogeneic unit, the authors state that the decision was based on the assessment that the benefits of decreased transplant-related mortality and morbidity (especially the ~30% chance of GVHD) in autologous CBT outweighed the risks of possibly reinfusing the leukemia clone to the patient, and the absence of graft-versus-leukemia effect.

The authors add a disclaimer stating that it is not their intention in this report to advocate private UCB collection and its use but, rather, to report an isolated case and discuss some of the issues and uncertainties surrounding this procedure.

[Comment: The authors do not comment on the fact that the recurrence rate after autologous transplantation for leukemia is significantly higher than the recurrence rate after allogeneic transplantation and, as a result, overall survival is higher after allogeneic HSCT. The authors do not comment on whether a matched allogeneic unit was available but, instead, point out that they considered an autologous unit to be preferable. ]

15. Outcomes of unrelated umbilical cord blood transplantation in pediatric patients with myelodysplastic syndrome. Parikh SH, Martin PL, Szabolcs P, et al. Biol Blood and Marrow Transplant 2005;11(2, Suppl 1);80.

The authors point out that myelodysplastic syndromes (MDS) in children are associated with significant risk of leukemic transformation. Thirty children with MDS were transplanted with unrelated umbilical cord blood. Median age was 9.06 years and median weight was 28.4 kg. Eight patients had secondary MDS and 10 patients had bone marrow blasts >20%. The preparative regimen was TBI-based in 19 and chemotherapy-based in 11 patients. Grafts delivered a median of 4.12 x 10⁷ nucleated cells/kg precryopreservation, and the median CD34+ cell dose infused postthaw was 1.48 x 10⁵/kg. Median time to ANC >500/µL was 24 days and median time to platelet recovery (>50K untransfused) was 72 days. aGVHD grade III-IV occurred in 5 patients; limited cGVHD was seen in 4 patients.

Fifteen patients (50%) died and 15 are surviving in remission from 3.4 to 107 months (median, 50 months) posttransplantation. Six of 8 children with secondary MDS (75%) are alive compared to 13 of 22 (40%) with primary MDS, possibly due to the greater number of patients with >20% blasts in the latter group. These results, especially in patients with <20% blasts pretransplantation, are equivalent to matched allogeneic bone marrow transplantation data.

16. Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia. Sanders JE, Im HJ, Hoffmeister PA, Gooley TA, Woolfrey AE, Carpenter PA, Andrews RG, Bryant EM, Appelbaum FR Blood. Blood 2005;105:3749-3756.

The authors state that the role of transplantation in infants with acute lymphoblastic leukemia (ALL) is not defined. Accordingly, they analyzed results of 40 infants diagnosed before age 12 months who received a hematopoietic cell transplant (HCT) between July 1982 and February 2003 in CR1 (n=17), CR2/3 (n=7) or relapse (n=16). Patients were conditioned with cyclophosphamide with total body irradiation (n=39) or busulfan (n=1). Hematopoietic cell grafts included unmanipulated bone marrow from 24 related and 13 unrelated donors, peripheral blood stem cells from 1 unrelated donor and cord blood from 2 unrelated donors. Graft-versus-host disease (GVHD) prophylaxis was methotrexate or cyclosporine (7) or methotrexate plus cyclosporine (33). Thirty-nine engrafted, 20 developed acute GVHD, and 7 chronic GVHD. Sixteen relapsed and seven died of other causes. Patients in CR1 had disease-free survival (DFS) of 76% compared to 45% for CR2/CR3 and 8% for relapse (P=0.0001). Of 33 patients with cytogenetic data, 26 (79%) had MLL gene rearrangement. Fourteen of these 26 were in CR1 and 11 survive in remission. Outcome was associated with phase of disease, but having the MLL gene was not a factor predictive of outcome. Late effects included growth and other hormone deficiencies. The investigators concluded that their data demonstrate that infants with ALL and MLL gene have excellent DFS when transplanted in CR1 and consideration for transplantation in CR1 is warranted.

17. Unrelated cord blood transplantation for children with high risk myelodysplastic syndromes. Alessandra Picardi, Domenico Del Principe, Laura Cudillo, Teresa Dentamaro, Sergio Amadori and Paolo de Fabritiis. Haematologica 2004;89(5):ELT08 (e-letter)

The authors assessed the feasibility and toxicity of unrelated mismatched cord blood transplant in five pediatric patients with high-risk myelodysplastic syndrome. Four patients were at high-risk according to the FAB criteria and one because of age > 2 years, hemoglobin F level greater than 10%, low platelet count, associated immunodeficiency and hemolytic anemia. Before transplantation, two children were treated with chemotherapy: one failed 2 chemotherapy-induction cycles and one had a failure and disease progression after 1 locus mismatched allogeneic transplant from the mother.

Although all patients were considered at high risk of relapse because the proportion of marrow blasts ranged from 12% to 25% at transplant, full donor chimerism was achieved in 4/5 cases on day 28 and two patients are in continuous complete remission more than 5 years after no evidence of cGVHD.

On the basis of their study, the authors state that a search for an unrelated donor, including umbilical cord blood, should be mandatory for patients with MDS who lack an HLA-identical sibling, particularly in pediatric patients who have a longer life expectancy than adults.

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