|Photomicrograph of HE-stained small cell lymphocytic lymphoma. Click to enlarge.
||Photomicrograph of HE-stained lymphocytic lymphoma. Click to enlarge.
Small cell lymphocytic lymphoma (SLL) is far more rare than chronic lymphatic leukemia (CLL). The diagnosis is made from a lymph node biopsy. SLL and CLL are different clinical presentation of the same disease.
The disease has a very heterogeneous course; some patients have very aggressive disease leading to death within 2-3 years, while others never require treatment and the disease does not influence survival.
Treatment goal and the need for therapy for indolent non-Hodgkin lymphomas
Advanced stages of indolent non-Hodgkin lymphoma cannot be cured with today's treatment. Survival time is not changed whether treatment begins early or late, or on the treatment intensity. Observation, or "watch and wait" should therefore be chosen when the patient does not require treatment. Internationally, there is not clear consensus on how this group of patients should be treated when treatment is necessary. It is important to reach better treatment methods, and we recommend thereforethat patients with these lymphoma entities are included in ongoing studies. Factors which determine the need for treatment are, among others, general symptoms (B symptoms), secondary autoimmune conditions, threatening organ complications, bone marrow failure under progress (reduced levels of Hb, WBC, TPK), and progressing/symptomatic tumor. The patient's wishes should also be taken into consideration, since some patients find it a mental burden to not receive treatment.
Traditionally in Europe, clinical staging according to Binet has been used, which may be helpful prognostically and for decisions regarding therapy. In the last five years, new insight has been gained for some of the conditions leading to the great variation in disease courses. The extent to which the cells have undergone somatic hypermutation in the IgVh gene or not separates SLL/B-CLL in two most likely equal groups. Unmutated disease has a poor prognosis (median survival is about 90 months from diagnosis), while mutated disease has a good prognosis (median survival usually > 25 years). The cytogenetic deviations part 17p and 11q are also associated with poor prognosis. Expression of CD38 and/or ZAP-70 (confirmed using flow cytometry or immunohistochemistry) is correlated to unmutated disease, but the expression of these markers are not satisfactory surrogate markers for mutation status. Based on mutation status and/or cytogenetic deviations, SLL/B-CLL is separated into high risk and low risk disease, and this is on its way to being implemented in the choice of treatment for each patient. The background for this is that there are now indications that intense treatment, which gives a high response rate compared to monotherapy with alkylating drugs, improves survival with B-CLL. Multiple prospective multicenter studies have been started to verify this.
We emphasized that comprehensive and resource-demanding evaluations focusing on prognostic markers mentioned above are important for all patients with CLL/SLL. In elderly patients with an expected good prognosis, this can be excluded. Chlorambucil monotherapy is still the first choice treatment for such patients.
SLL in stage stadium I/II1 is treated with radiation therapy to the involved area with a margin. The dose is 2 Gy x 15 with a curative intention. Guidelines for radiation therapy are the same as described for confined follicular lymphoma. High-risk SLL/B-CLL necessitating treatment (unmutated IgVh gene, part 17p and/or part 11q) are candidates for combination therapy. These patients should preferably be treated from a protocol, and a Nordic/Dutch study for first line treatment of high-risk B-CLL is now active. This is a two-armed protocol comparing fludarabine and cyclophosphamide +/- low-dose alemtuzumab (MabCampath®). For younger patients needing treatment, the first choice outside of a protocol is fludarabine and cyclophosphamide possibly in combination with rituximab.
An oral formulation of flubarabine is now available that can replace intravenous administration, if desired. It is particularly important to be aware that this drug has a selective immune suppression targeting CD4 positive T-lymphocytes which causes the patient to be highly disposed to opportunistic infections such as pneumocystis jirovecii pneumonia and herpes zoster infections. GVHD (graft versus host disease) requiring transfusions is known and is may be fatal. Blood products should be filtered since this reduces the risk significantly. The risk is also eliminated by irradiation. Prophylaxis with trimethoprim should be used. Aciclovir may be considered.
In B-CLL patients with part 17p, it may be necessary to consider alemtuzumab as first line based on case reports. Monotherapy with fludarabin and alkylating drugs often have little effect in this patient group, while experience with combination therapy is currently sparse. Similar to fludarabine, this antibody also has a significant immunosuppressive effect. Patients are highly disposed for opportunistic infections.
In patients with low-risk SLL/B-CLL, chlorambucil is still considered standard first line therapy when there is an indication for treatment. The combination with corticosteroids is only indicated for immune-mediated subsequent conditions such as hemolytic anemia, erythroaplasia, and thrombocytopenia.
In patients who have received first line treatment with alkylating drugs, fludarabine is recommended as second line, possibly combined with cyclophosphamide. A protocol for second line therapy is available that is appropriate for inclusion of patients. This is a two-armed study comparing the effect of fludarabine and cyclophosphamide +/- rituximab. Bendamustin, COP or CHOP are also alternatives for second or third line therapy. Alemtuzumab and rituximab as monotherapy are options in certain situations. Rituximab monotherapy for SLL/B-CLL is less effective for follicular lymphomas, which may be associated with lower expression of CD20 in cells. Alemtuzumab monotherapy has a better effect on B-CLL than SLL, which is often dominated by nodal tumor. Rituximab may a good option if the patient has severe bone marrow failure. Treatment is usually tolerated well, and often improves blood values even if tumor reduction is limited. Treatment may also be reinforced with alkylating drugs such as purine analogs. Some cases with very serious prognoses may be included in studies with allogeneic stem cell transplantation and conditioning at Oslo University Hospital. This treatment has shown promising results in small studies and may be curative.