**2.4 Solid tumors**

356 Advances in Hematopoietic Stem Cell Research

Autologous HSCT is the standard therapy for patients with HD in first chemosensitive relapse or second complete remission (CR) as shown by two prospective randomized

Currently, there is no indication for autologous HSCT in first CR, even in patients with bad

For primary refractory patients or for patients in chemorefractory relapse, autologous HSCT has only a small chance of inducing long-term remission (Lazarus et al., 1999; Sweetenham et al., 1999). As part of a clinical protocol for patients with resistant HD, autologous HSCT might be considered as an initial debulking therapy to be followed by an allogeneic HSCT as

Allogeneic HSCT has mainly been used as salvage therapy for multiply relapsed or refractory HD. A retrospective analysis indicates that reduced intensity conditioning allogeneic HSCT can improve the outcome of HD patients that relapse after an autologous HSCT (Thomson et al., 2008). Its impact in the long term outcome of these patients has still to be prospectively evaluated. HSCTs from HLA-identical sibling donors and well-matched

MDS is rare in children an allogeneic HSCT from a sibling donor or a well-matched unrelated donor is currently the only curative therapy that is available for children with de novo MDS, JMML or secondary MDS. MDS is a heterogeneous disorder, characterized by a clonal stem cell disease with ineffective hematopoiesis which is morphologically abnormal. MDS in children differs from MDS in adults, as children more frequently suffer from hypocellular MDS. De novo MDS can be further classified as refractory cytopenia (RC; previously known as refractory anemia or RA), RA with excess of blast (RAEB) and RAEB in

The European working party on myelodysplastic syndrome (EWOG-MDS) reported their retrospective results on 63 children with RC (Kardos et al., 2003). Over 40% of patients had hypocellular marrows. Almost 50% of children with monosomy 7 progressed to advanced MDS within 2 years from diagnosis. By contrast, patients with hypocellular RC with a normal karyotype, may experience a long stable course before progression to generalized marrow failure occurs. Therefore, in patients with monosomy 7, HSCT should be performed soon after the diagnosis has been established. This is also advised for patients with advanced MDS (RAEB or RAEBt), and for patients with hypercellular RC, or with other clonal aberrations. In some patients the differentiation between hypocellular RC with a normal karyotype and aplastic anemia may be difficult, and in such patients a "watch and wait" strategy may be considered with repeated bone marrow evaluation before a final

After the introduction of the new WHO definition of acute myeloid leukemia, which lowered the threshold to diagnose AML from 30 to 20% blasts, there has been a debate whether RAEBt should be classified and treated as MDS or AML (VArdiman, 2002). One approach is to build in some observation time to assess progression, and to look for signs

prognostic features at diagnosis (Federico et al., 2003; Proctor et al., 2002).

unrelated donors give a similar outcome (Anderlini et al., 2008).

**2.2.2 Hodgkin's disease (HD)** 

clinical trials (Linch et al., 1993; Schmitz et al., 2002)

consolidation therapy (Carella et al., 2000).

**2.3 Myelodysplastic syndrome (MDS)** 

decision on diagnosis and therapy is made.

transformation (RAEBt).

Neuroblastoma (stage IV beyond the age of 1 year, or high risk factors in lower stage) is still the only indication where the benefit of high-dose therapy with autologous HSCT has been shown by randomized trials (Ladenstein et al., 2008; Matthay et al., 2009).

Although to date the published results do not show an unequivocal benefit for consolidation with high-dose therapy, children and adolescents with solid tumors might undergo autologous HSCT after high-dose chemotherapy within clinical research trial, preferably as part of first –line treatment strategies in the following situations:


In general, allogeneic HSCT cannot be recommended in children with solid tumors. Allogeneic HSCT may be undertaken in the context of a clinical protocol in specialized centers.

#### **2.5 Bone marrow failure (BMF)**

BMF syndromes include a broad group of diseases of varying etiologies in which hematopoiesis is abnormal or completely arrested in one or more cell lines. BMF can be acquired aplastic anemia (AA) or can be congenital, as part of such syndromes as Fanconi anemia (FA), Diamond Blackfan anemia (DBA), and Shwachman Diamond syndrome (SDS). The estimated incidence of BMF is 2 per million in Europe, with higher rates in Asia, perhaps resulting from environmental factors.

#### **2.5.1 Acquired severe aplastic anemia (AA)**

HSCT using an HLA-matched related donor is the treatment of choice for severe acquired aplastic anemia, resulting in long-term survival rates of over 90% If an HLA-compatible

Hematopoietic Stem Cells Therapeutic Applications 359

and cGVHD and improved survival (Ayas et al., 2001). A recent series of 35 FA patients undergoing matched-related HSCT using this regimen along with peri transplantation ATG reported an excellent 10-year actuarial survival of 89%, with aGVHD in 23% of cases and

These studies have used low dose radiation because patients with FA have an increased risk of posttransplantation malignancy, but what about avoiding radiation altogether? A recent retrospective review of experience with matched related HSCT in FA patients in Saudi Arabia by Ayas et al (Ayas et al., 2008) found significantly greater OS in patients receiving non radiation, low dose cytoxan and ATG regimens compared with those undergoing preparative regimens with cytoxan and additional thoracoabdominal radiation (72.5% vs 96.9%; p=0.013). The availability of fludarabine, a highly immunosuppressive nucleoside analog that is well tolerated by patients with FA, has allowed the elimination of radiation with good results. Tan et al in 2006, recently reported an actual OS of 82%, transplant related mortality of 9% and minimal GVHD in a cohort of 11 patients who underwent transplantation with low dose cytoxan, fludarabine and ATG with T cell-depleted bone

HSCT from an unrelated donor for patients with FA remains a key treatment strategy. Historically, outcomes of alternative donor transplantation in FA have been discouraging, with high incidences of graft failure, aGVHD and cGVHD and organ toxicity related to preparative regimens. Many regimens have been looked at over the years for unrelated transplants including increasing the dose of radiation, adding ATG without significant improvement in overall survival. The advent of fludarabine based preparative regimens has resulted in considerable progress, improving engraftment without significant toxicity attributable to the drug. However, although fludarabine regimens have had some success in treating FA, concerns regarding reduced intensity conditioning (RIC) regimens persist; residual FA cells that survive the preparative regimen may present as AML as much as 10 years later (Ayas et al., 2001).Despite these data, (Chaudhury et al., 2008), in a study of 18 high-risk patients with transfusion dependent AA, MDS and AML receiving either related mismatched or unrelated matched or mismatched HSCT using fludarabine, TBI and cytoxan for preparative regimens with T-cell depleted stem cell sources, found 100% engraftment, OS 72.2% and DFS of 66.6% with a median follow up of 4.2 years, suggesting that a RIC preparative regimen might be sufficient to control malignancy in FA. Cord blood is an alternative stem cells source for patients with FA who lack an HLA-matched unrelated bone marrow donor, as umbilical cord blood transplant has decreased incidence of GVHD.

Despite the improved survival, identifying the ideal time for HSCT in FA patients requiring alternative donor transplantations remains challenging, given the still-significant peri transplantation mortality and the possibility of long lasting androgen response or survival with AA for a significant period without progression to MDS/AML. Referral and transplantation before exposure to large amounts of blood products or prolonged periods of

SDS is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, skeletal abnormalities and BMF with a predisposition to MDS and leukemia, especially AML. Although most patients with SDS have some hematologic abnormalities,

severe neutropenia are likely to lead to the best outcomes.

**2.5.2.2 Shwachman-diamond syndrome (SDS)** 

cGVHD in 12% of cases (Farzin et al., 2007).

marrow or umbilical cord cells.

family donor is not available, most patients are treated with high-dose immunosuppression, using antithymocyte globulin (ATG) plus cyclosporine, with or without granulocyte colonystimulating factor (G-CSF). Approximately 70-80% of patients respond to immunosuppression, although the actuarial 10-year survival rate is about 40%. Marrow transplantation from unrelated donors is reserved for those patients who do not respond to or who relapse after immunosuppressive therapy.
