Sandro Dallorso

STROMAL DAMAGE AS CONSEQUENCE OF HIGH-DOSE CHEMO/RADIOTHERAPY IN BONE MARROW TRANSPLANT RECIPIENTS

Bone marrow transplant (BMT) relies on the engraftment of donor hemopoietic precursors in the host marrow space. Colony forming units-fibroblasts (CFU-f), the precursor compartment for the osteogenic lineage, are essential to hemopoietic stem cell survival, proliferation and differentiation. We have studied CFU-f in donors (aged 5 months to 62 years) and in patients who had received allogeneic BMT (aged 2 months to 63 years). In donor marrows we found an inverse correlation between CFU-f frequency and age. In BMT recipients CFU-f frequencies were reduced by 60%-90% (p < 0.05) and the numbers did not recover up to 12 years after transplant. Stromal reconstitution to normal levels was found only in patients < 5 years old. In all patients studied CFU-f post-BMT were of host origin. Patients with low CFU-f levels displayed also a decreased bone mineral density (p < 0.05) and significantly reduced levels of long-term culture-initiating cells (LTC-IC) (p < 0.05). Our study demonstrates that the marrow stromal microenvironment is seriously and irreversibly damaged after BMT. Donor cells do not contribute to reconstitute the marrow microenvironment, whose residual CFU-fs remain of host origin.

Treatment of relapsed Wilms tumors: lessons learned

Treatment regimens for recurrent Wilms tumor (WT) are currently designed to include drugs that are not used during primary chemotherapy, using a risk-stratified approach. Therapy of recurrent disease depends on the nature of initial treatment, and of recognized prognostic indicators inherent in the primary tumor. Several highly effective chemotherapy regimens, including ifosfamide–carboplatin–etoposide, cyclophosphamide–etoposide and carboplatin–etoposide, are considered first treatment choice for recurrent disease. While intense-dose chemotherapy is uniformly accepted to treat high-risk recurrent WTs, the optimal therapy for standard-risk children has yet to be defined, owing to the small number of such patients and their relatively better prognosis compared with high-risk recurrences. Recurrent tumors among those defined as very-high risk are likely to develop chemoresistant disease, and novel therapeutic strategies will be necessary to cure these patients. Evidence on how to properly administer surgery and radiotherapy at relapse is more fragmentary. The authors have reviewed the available experiences concerning the treatment of recurrent WT, and have attempted to provide the most up-to-date recommendations regarding the optimal risk-based treatment for these patients.

An international strategy to determine the role of high dose therapy in recurrent Wilms' tumour

PURPOSEnTo review event-free (EFS) and overall survival (OS) from publications describing outcome for children with relapsed Wilms tumour. Comparisons are made between those receiving myeloablative high dose chemotherapy with autologous stem-cell rescue (HDT) and those not (NoHDT).nnnMATERIALS AND METHODSnRelevant information was extracted from individual patient or summary data and 3-year EFS and OS rates established. These rates were combined in a weighted manner to derive hazard ratios (HRs).nnnRESULTSnNineteen publications were identified (5 HDT, 6 NoHDT, 8 both). Pooling all studies suggested an advantage to HDT with a hazard ratio (HR) for EFS of 0.87 (95% confidence interval (CI) 0.67-1.12) and 0.94 (0.71-1.24) for OS. A stratified analysis confined to studies that provided individual patient data on both HDT and NoHDT gave HRs of 0.83 (0.56-1.24) and 0.92 (0.59-1.41). Further, analyses of risk groups, defined by treatment and/or histology prior to first relapse, suggested a HR for EFS of 0.90 (95% CI 0.62-1.31) for those of high and 0.50 (CI 0.31-0.82) for the very high risk patients.nnnCONCLUSIONnThe evidence suggests, although there are many caveats since the information summarised here is not from randomised trials, a great deal of uncertainty concerning the role of HDT in patients following relapse after treatment for their Wilms tumour. For each risk group we propose a randomised trial comparing a standard with a more intensive therapy with specific choice of regimen tailored to the risk group (and co-operative groups) concerned. A synthesis of updated evidence from studies in this overview together with any emerging studies and future trial information will form the basis for future evidence-based clinical decision-making.

Treatment of high‐risk relapsed Wilms tumor with dose‐intensive chemotherapy, marrow‐ablative chemotherapy, and autologous hematopoietic stem cell support: Experience by the Italian association of pediatric hematology and oncology

We evaluated an intensified chemotherapy strategy in children with Wilms tumor who relapsed with high‐risk features.

High‐dose vincristine, fractionated total‐body irradiation and cyclophosphamide as conditioning regimen in allogeneic and autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission: a 7‐year Italian multicentre study

We investigated the feasibility and efficacy of high‐dose vincristine (4 mg/m2 over 4 d) combined with fractionated total body irradiation (F‐TBI) (200 cGyx2 over 3 d) and cyclophosphamide (60 mg/kg for 2 d) as a preparative regimen in allogeneic (AlloBMT) and autologous (ABMT) bone marrow transplantation for 75 consecutive children (median age at transplant 8‐5 years) with acute lymphoblastic leukaemia in second complete remission (CR). Median duration of first CR was 26 and 25 months in the AlloBMT and ABMT group, respectively. Of the 46 patients who underwent AlloBMT, 33 had isolated or combined marrow relapse and 13 isolated extramedullary relapse. Of the 29 patients given ABMT, 23 had preBMT isolated or combined marrow relapse and six isolated extramedullary relapse. 44/75 patients are alive and in CR at a median follow‐up of 35 months (range 10‐90 months). Seven children given AlloBMT (15.8%) and two given ABMT (7%) died from transplant‐related causes. No major early organ toxicity, including vincristine‐related toxicity, was recorded. The overall 3‐year EFS estimate (95% CL) was 53.8% (42‐66%): in particular, 58.2% (40‐76%) for AlloBMT and 27.6% (9‐46%) for ABMT patients who experienced a marrow relapse before transplant. The overall 3‐year relapse rate estimate (95% CL) was 39.2% (27‐51%): in particular, 30.1% (12‐49%) in the AlloBMT group and 72% (54‐91%) in the ABMT group (P < 0.01) who presented a preBMT isolated or combined marrow relapse. We conclude that the conditioning regimen with high‐dose vincristine combined with cyclophosphamide and F‐TBI is feasible and promising, although its therapeutic advantage should be tested in larger series of patients enrolled in randomized studies.

Lipoblastoma: a case with t(7;8)(q31;q13).

Lipoblastoma is a rare benign adipose tumor which, in all of the cases so far described, presents an involvement of chromosome 8 in the region 8q11-13. We hereby report the results of the second case of lipoblastoma studied by fluorescence in situ hybridization (FISH), in a 13-month-old boy. An abnormal karyotype 46,XY,t(7;8)(q31;q13) was found in 90% of the metaphases examined, in agreement with the previously reported observations. We suggest the region 8q11-13 may contain a relevant locus for lipoblastoma origin.

Improved survival for children with parameningeal rhabdomyosarcoma: Results from the AIEOP soft tissue sarcoma committee

Parameningeal rhabdomyosarcoma (PM‐RMS) is a rare, highly malignant pediatric tumor arising from locations adjacent to the meninges, from where it can spread intracranially.

Secondary acute promyelocytic leukemia with t(8;21) and t(9;22) at onset and loss of the philadelphia chromosome at relapse

The translocation (8;21) is a typical marker of the M2 subtype of acute nonlymphocytic leukemia, whereas the Philadelphia (Ph) chromosome is predominantly associated with chronic myelogenous leukemia, and seldom with immature acute leukemias, either lymphoblastic or nonlymphoblastic. Furthermore, the association between t(8;21) and a Ph in the same cell is extremely rare. We present a case of secondary acute promyelocytic leukemia with a karyotype 46,XY,t(8;21), t(9;22) at onset. At relapse the patient lost the Ph, while maintaining the t(8;21). This apparently paradoxical pattern of cytogenetic features and evolution is discussed.

Uneventful outcome of unrelated hematopoietic stem cell transplantation in a patient with leukemic transformation of Kostmann syndrome and long-lasting invasive pulmonary mycosis

Abstract: Kostmann syndrome (KS) is an inherited hematological disorder characterized by an absolute neutrophil count (ANC) <0.2u2003×u2003109/L and life‐threatening bacterial infections. Granulocyte‐colony stimulating factor (G‐CSF) makes it possible to reach an ANC of 1.0u2003×u2003109/L and consequently to reduce significantly the occurrence of severe infections. Absence of response to G‐CSF, G‐CSF receptor mutation, and leukemic transformation are absolute indications to perform hematopoietic stem cell transplantation (HSCT). Pulmonary mycosis does not represent an absolute contraindication to bone marrow transplantation (BMT), although a relapse rate of 30–50% has been reported, despite adequate medical and surgical treatment. Mycotic pneumonia recurrence shows a mortality rate above 80%, especially in the presence of persisting immunosuppression. We report on a KS patient with long‐lasting fungal pneumonia who developed myelodysplasia and subsequent acute myeliod leukemia (AML) conversion resistant to antiblastic therapy. Despite surgical excision and secondary prophylaxis, recurrence of the pulmonary lesion occurred prior to the unrelated HSCT. In spite of these poor prognostic characteristics, outcome was uneventful and the patient is alive and well in continuous complete remission with no signs of fungal infection.

Unrelated HSCT in an adolescent affected by congenital erythropoietic porphyria

Abstract: CEP is a rare inborn error of porphyrin–heme synthesis. Clinical manifestations can range from mild to severe and include erythrodontia, reddish‐colored urine, and hemolytic anemia that can be mild or severe and may result in splenomegaly. Completely avoiding exposure to the sun is crucial. Attempts to reduce erythropoiesis and to lower circulating porphyrin levels by means of erythrocyte transfusions have been successful in reducing the expression of the disease. However, the complications of a chronic transfusion regimen are potentially severe. Successful bone marrow transplantation has been reported in CEP. We report a case of successful bone marrow transplantation and prolonged follow‐up in an adolescent CEP patient.