38                                                                                                                                                 Histiocytoses  ______________________________________________________________________________________

7.    Histiocytoses

7.1       General considerations

            The term “ histiocytoses” was coined for a group of diverse disorders with the common 

 characteristic of an increased number of histiocytes – a variety of different cell type primarily

including macrophages and dendritic cells.

A (re)classification system for histiocytoses was established by the Histiocyte Society.

            Literature: for review

                        ARCECI, Eur. J. Cancer 35 (1999): 747 – 769 (incl. A commentary by

                        HENTER)

7.2       Langerhans cell histiocytosis

            Formerly described in the literature by a variety of eponymes, including

            histiocytosis X, Abt-

            Letterer- Siwe disease, Hand – Schueller – Christian disease, eosinophilic 

            granuloma.

7.2.1    General considerations

            LCH is a rare condition in which granulomas form in tissues through the

            accumulation of abnormal histiocytes( Langerhans cells), granulocytes and  

            lymphocytes. This can affect any organ of the body and patients of all ages.  

            Prognosis of patients with localized disease is known to be good, while

            disseminated disease has been associated with a chronic course, and  a high

            morbidity and mortality rate.

            In single system disease LCH may be treated with local therapy, Injections of methylprednisolone

            Into the lesions can be helpful in single system bone disease, and in isolated skin disease topical

            Administration of nitrogen mustard, or if not effective, psoralen with ultraviolet A (PUVA) may be considered.

            In multisystem disease or in resistant single system disease chemotherapy has been employed with a

            beneficial effect. Etoposide or vinblastine (with corticosteroids) are presently considered to be the

            most effective agents in monochemotherapy. An overall survival benefit for more intensive

            combination chemotherapy has not yet been proven definitively. At least some patients will profit

            from maintenance treatment.

            A variety of cytostatic and immunomodulatory approaches have been attempted to improve the

            results in recurrent or refractory LCH (incl. 2 – dechlorodeoxyadenosine or deoxycoformicin,

            thalidomide, and stem cell transplantation). Bisphosphonates ( pamidronate) were found useful in a         few  patients treated so far with bone pain unresponsive to chemotherapy, corticosteroids, anti-

            inflammatory drugs and narcotic analgesics.

Literature: for review e.g.

            ARCECI, Eur. J. Cancer 35 (1999): 747 – 769 (incl. a commentary by HENTER)

            COPPES- ZANTINGA and EGELER, Brit. J. Haematol 116 (2002): 3 – 9

(historical review)

Histiocytoses                                                                                                                                                  39 ________________________________________________________________________

first – line therapy

If systemic therapy is indicated, treatment with vinblastine and / or etoposide with prednisone (induction) with or without maintenance (mercaptopurine) and reinduction (prednisone, vinblastine, etoposide, methotrexate ). E.g.

Study LCH – I

or

• To be repeated every 3 weeks (for a total of 8 courses over 24 weeks)

    Response to treatment was assessed after 6 weeks and non-responders were    

    switched to the alternative cytostatic.

    Literature:

         GADNER et al, J. Pediatr, 138 (2001): 728 – 734

Study DAL – HX 90

With treatment intensification (additional doses of etoposide and vinblastine) in patients with organ dysfunction ( as defined by Lahey).

Literature:

      MINKOV et al, Klin. Pädiatr. 212 (2000): 139 – 144

7.2.2      Salvage therapy

Preliminary evidence indicates that 2- chlorodeoxyadenosine (cladribine) and 2- deoxycoformycin (pentostatin) may be effective in patients with Langerhans, cell histiocytosis refractory to or recurrent after standard therapy; e.g.

To be repeated every  3 – 4 weeks

Literature:

            RODRIGUEZ – GALINDO et al, Am. J. Hematol. 69 (2002): 179 – 184

            SAVEN and BURIAN, Blood 93 (1999): 4125 – 4130

            WEITZMAN et al, Med. Pediatr. Oncol. 33 (1999): 476 - 481

40                                                                                                                                               Histiocytoses  ______________________________________________________________________________________

or

            Maintenance therapy every 2 weeks for a period of 16 weeks

            Literature:

                        LOMBARDI et al, Hematology J. 3 (2002): 118 – 119

                        WEITZMAN et al, Med. Pediatr. Oncol. 33 (1999): 476 – 481

            Case reports indicate efficacy for other approaches including thalidomide* or

            pamidronate (for therapy – resistant bone pain)**.

            Literature:

                        * BERTOLINI et al, Ann. Oncol. 12 (2001): 987 - 990

                      ** FARRAN et al, J. Pediatr. Hematol. / Oncol. 23 (2001): 54 – 56

7.3             Hemophagocytic lymphohistiocytosis (HLH)

7.3.1      General considerations

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of infancy. It comprises familial

(or hereditary or primary) HLH (= FHL) and secondary HLH (= SHLH), both clinically characterized by fever, hepatosplenomegaly and cytopenia.

FHL is an autosomal recessive disease which is invariably fatal when untreated. It is associated with defective triggering of apoptosis resulting in a widespread accumulation of activated T-lymphocytes and histiocytes in the reticuloendothelial system. Moreover, immune system derangement with prominent secretion of inflammatory cytokines ( hypercytokinemia) and low or absent cytotoxic T- and natural killer cell activity is a consistent feature.

SHLH can be either infection- associated, malignancy-associated or idiopathic.

Regarding the therapeutic strategy, prompt differential diagnosis is essential and choice of treatment should be based on the risk of prognoss. Either cyclosporine A, steroids or i.v. immunoglobulin may be indicated as initial treatment for low-risk patients, and etoposide-containing regimens for high-risk patients. Immuno-chemotherapy and allogeneic hematopoietic stem cell transplantation have contributed significantly to further improved survival or cure of familial and refractory HLH.

Literature: for review e.g.

            ARCECI, Eur. J. Cancer 35 (1999): 747 – 769 (incl. A commentary by HENTER)

            DÜRKEN et al, Leuk. Lymphoma 41(2001): 89 – 95 (role of bone marrow transplantation)

            FADEEL et al, Leuk. Lymphoma 42 (2001): 13 – 20

            IMASHUKU et al, Expert Opin. Pharmacother. 2 (2001): 1437 – 1448

7.3.2      Study HLH 94

The treatment protocol includes 8 weeks of initial therapy followed (in case of familial disease or persistent nonfamilial disease) by a continuation therapy and if possible a bone marrow transplantation. Children with resolved nonfamilial disease ceased therapy after 8 weeks  and restarted only in case of reactivation.

Histiocytoses                                                                                                                                        41  _____________________________________________________________________________________

            Initial therapy

• Only in case of progressive  neurological symptoms or if an abnormal CSF has    

      not improved

    Continuation therapy ( starting week 9 )

• Aiming at trough levels of 200 µg / L

Literature:

      HENTER et al, Blood 100 (2002): 2367 – 2373