13.          Non-Hodgkin’s Lymphoma, extranodal primaries

13.1        Mucosa-associated lymphoid tissue (MALT)/marginal zone lymphomas (MALT/MZ NHL)

General considerations

Around 8% of all NHL arise from MALT which is provoked by pre-existing inflammatory responses. These lymphomas arise at numerous extranodal sites with gastric MALT lymphoma being the most common and best studied. Gastric MALT lymphomas are considered to be a consequence of a Helicobacter pylori infection and H. pylori eradication is the initial treatment of choice for localized disease. It can produce histologic regression of the lymphoma which can be maintained for years. For those not responding as well as for more advanced gastric MALT lymphomas and those at non-gastric sites treatment may include radiotherapy, chemotherapy, surgery, or a combination thereof. Single-agent therapy (e.g. chlorambucil or cyclophosphamide** or cladribine*) is usually, while combination chemotherapy (e.g. with CHOP) may have a role in the treatment of patients with a large tumor mass, or those with a significant proportion of large cells.

Literature:

CAVALLI et al, Hematology (Am. Soc. Hematol. Educ. Program) (2001): 241–258 (for review)

* JAGER et al, J. Clin. Oncol. 20 (2002): 3872-3877

MAES and De WOLF-PEETERS, Histopathology 40 (2002): 117 – 126 (review)

WOTHERSPOON et al, Curr. Opin. Hematol. 9 (2002): 50 – 55 (review)

** ZINZANI et al, J. Clin. Oncol. 17 (1999):  1254 – 1258 (non-gastrointestinal localization)

13.2        Primary cutaneous lymphomas

13.2.1 B- cell lymphoma

Primary cutaneous B-cell lymphoma (CBCL) is generally an indolent disease with a good prognosis. Although local cutaneous recurrences are often observed, dissemination outside the skin usually occurs late in the course of the disease.

The majority of cases is highly responsive to radiotherapy. Polychemotherapy (e.g. COP/CHOP) should, therefore, be reseved for involvement of non- contiguous anatomic sites or those with extracutaneous spread.

Literature: for review

            PANDOLFINO et al, J. Clin. Oncol. 18 (2000): 2152-2168

13.2.2 T-cell lymphoma

13.2.2.1                  General considerations

Cutaneous T-cell lymphomas (CTCL) comprise a number of clonal T-cell malignancies with primary manifestation in the skin.

The most common “ classical” subset of these diseases includes mycosis fungoides and Sezary’s syndrome, its aggressive variant that is characterized by erythroderma and leukemia.

Therapeutic options should primarily be determined by the clinical stage and extent of disease involvement. Patients with early patch/plaque mycosis fungoides are candidates for skin-directed therapies such as phototherapy with psoralen+ ultraviolet A (PUVA) with or without interferon alpha, topical chemotherapy (nitrogen mustard), ionizing radiation or systemic biological response modifiers including retinoids. Patients with IIB disease usually require more intensive therapy, like total skin electron beam radiation, retinoids (e.g. bexarotene) or the recombinant fusion toxin denileukin diftitox. Systemic chemotherapy may be required in patients with disease refractory to skin-directed treatment. Patients with stage III disease or Sezary’s syndrome who have leukemic involvement are often best treated with extracorporeal photopheresis as monotherapy or in combination with interferon, retinoids or radiation. Patients with advanced extracutaneous disease require more aggressive therapies such as systemic chemotherapy and/or investigational approaches (e.g. the anti-CD52 monoclonal antibody alemtuzumab). Allogeneic hematopoietic stem cell transplantation may have the potential for sustained remission and the possibility of cure for selected young patients with advanced or biologically aggressive CTCL.

            Literature: for review

                        APISARNTHANARAX et al, Am. J. Clin. Dermatol. 3 (2002): 193-215

GUITART et al, Arch. Dermatol. 138 (2002): 1359-1365 (allogeneic hematopoietic stem cell transplantation)

                        STADLER, Skin Pharmacol. Appl. Skin Physiol. 15(2002): 139 – 146

                        VONDERHEID, Recent Results Cancer Res. 160 (2002): 309 – 320

13.2.2.2                  Bexarotene

The capsules are taken as a once-daily dose with meals. The time to response is generally within 2 months. A topically applicable gel formulation is also available.

            Literature:

BRENEMAN et al, Arch, Dermatol. 138 (2002): 325-332 (phase I and II trial of  bexarotene gel)

DUVIC et al, J. Clin. Oncol. 19 (2001): 2456-2471 (multinational phase II and III trial results)

TALPUR et al, J. Am. Acad. Dermatol. 47 (2002): 672-684 (oral bexarotene as monotherapy and in combination with other active agents)

13.2.2.3                  Denileukin diftitox (DAB- IL2)

            Every 3 weeks (max 8 cycles or 6 months of therapy) with corticosteroid premedication.

For the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor.

            Literature:

                        DUVIC et al, Clin. Lymphoma 2 (2002): 222-228 (quality of life aspects)

                        OLSEN et al, J. Clin. Oncol. 19 (2001): 376- 388 (phase III pivotal trial)

13.3        Primay mediastinal B-cell lymphoma (PMBL)

PMBL is a rapidly proliferating aggressive tumor which arises in the thymus and mainly affects young adults. Conventional or dose-intensified, but nonmyeloablative anthracycline-containing chemotherapy (e.g. CHOP, CEOP-Bleo. VACOP-B or MACOP-B) is generally accepted as the initial management, which may be followed by consolidation (radiation or high-dose chemotherapy with stem cell support) in patients with a high risk for recurrence (e.g. those with pleural or pericardial effusions). High-dose chemotherapy with autologous transplantation has been successful in patients with recurrent/refractory disease.

Literature: for review

            AVILES et al, Ann. Hematol. 81 (2002): 368-373 (CEOP-Bleo)

CAIROLI et al, Bone Marrow Transplant. 29 (2002): 473-477 (VACOP-B with early intensification integrating chemotherapy, autologous stem cell transplantation and radiotherapy)

            Van BESIEN et al, J, Clin. Oncol. 19 (2001): 1855 – 1864 (review)

            ZINZANI et al, Haematologica 86 (2001) : 187-191 (MACOP-B)

13.4        Primary central nervous system NHL (PCNSL)

13.4.1 General considerations

The management of PCNSL is quite different from the usual treatment of systemic NHL. Standard chemotherapy regimens used in systemic NHL are ineffective, mainly due to the existence of the blood-brain-barrier. Whole brain radiation was therefore the cornerstone of the therapy for decades. It resulted in high response rates, however, of short duration and was burdened with delayed neurotoxicity. The combination of radio-and chemotherapy based on high-dose methotrexate proved very efficient in terms of survival rate, but again was overshadowed by a high incidence of delayed cognitive neurotoxicity (particularly in patients older than 60 years). Chemotherapy alone with protocols based on high-dose methotrexate (alone or in combination) thus far resulted in promising survival rates and quality of life in unicentric studies. Which need to be substantiated in larger multicentric trials. The role of myeloablative chemotherapy with  stem cell rescue is also under investigation.

Literature: for review e.g.

            AMBINDER and SPARANO, Cancer Treat. Res. 104 (2001): 231-246

            BASSO and BRANDES, Eur. J. Cancer 38 (2002): 1298 – 1312

            De ANGELIS, Curr, Treatm. Options Oncol. 2 (2001): 309-318

            FERRERI et al, J. Clin. Oncol. 21 (2003) 266-272 (prognostic scoring

            system)

            McALLISTER, Curr. Neurol. Neurosci, Rep. 2 (2002): 210 – 215

            PARK and ABREY, Expert Opin. Pharmacother. 3 (2002): 39 – 49

            PLASSWILM et al, Ann. Hematol. 81 (2002): 415- 423

RENI and FERRERI, Ann. Hematol. 80 (Suppl 3) (2001): 113- 117 (management of refractory/ relapsed PCNSL)

            RTOG study 93 – 10

*  16 mg/d for the first week, decreasing to 12, 8, 6, 4 and 2 mg/d over the next 5 wks

** Ommaya reservoir

Followed by whole brain radiotherapy (45 Gy in 1.8 Gy fractions, wk 11 – 15 )

Literature :

            De ANGELIS  et al , J . Clin . Oncol  . 20(2002) : 4643 – 4648 .