11.        Non-Hodgkin’s Lymphoma, indolent (low grade)

11.1        General considerations

Non- Hodgkin’s lymphomas (NHL) are a heterogenous group of lymphoproliferative malignancies that originate from B- or T-lymphocytes, and , rarely, also from natural killer (NK-) cells.

Several competing lymphoma classifications have been proposed over the years with the Kiel classification and the Working Formulation having had the highest impact in Europe and the United States , respectively. The delineation of lymphoma types into low-grade and high-grade or low-grade, intermediate-grade and high-grade, respectively, in these classification systems was primarily based on survival data but not on the biology and natural history of the entities.

*   For extranodular entities see indication 13

CLL = chronic lymphocytic leukemia (see indication 4), PLL= prolymphocytic leukemia,

HCL= hairy cell leukemia (see indication 6), LgX= lymphogranulomatosis X

Finding the existing classifications at the time not entirely satisfactory and corresponding only incompletely with each other, the Revised European –American Lymphoma (REAL) classification was proposed by the International Lymphoma Study Group in 1994. It consists of a number of biological entities defined by clinicopathologic and immunogenetic features. Finally the WHO classification in hematopoietic and lymphoid tumors was published in 2001, its lymphoma classifi-cation is basically identical to the REAL classification with minor changes.

*   For extranodal entities see indiction 13

            Follicular lymphoma (FL) is the most prevalent indolent lymphoma. For the minority of patients

with localized stage I and II disease involved field radiotherapy has the potential of cure should be initiated without delay. The addition of systemic therapy to local irradiation or wider field radiotherapy may improve the results, but this has not been finally proven.

The majority of patients has advanced stage III and IV disease at the time of diagnosis, however, which is essentially incurable. In the absence of symptoms and/or of adverse prognostic factors treatment is not mandatory and can be deferred without a negative impact or overall survival until there is evidence of disease progression with emergence of adverse prognostic factors.

Palliative treatment of advanced indolent NHL has been based for decades on alkylating agents, resulting in improved well-being for most patients. There is no proof that initial combination chemotherapy (e.g. COP = CVP, CHOP) results in more or longer lasting remissions or prolonged survival in comparison with mono-chemotherapy.

Patients with relapsing disease may repeatedly respond to alkylating agents or combinations containing alkylating agents, although the proportion responding and the response duration decrease with each  relapse. The majority finally die from progressive disease often accompanied by transformation to aggressive lymphoma.

More recently a number of new substances have been introduced for the treatment of indolent lymphoma.

Interferon alpha combined with initial chemotherapy or as maintenance therapy seems to augment the response rate, decrease the relapse rate prolong the progression-free and overall survival.

Nucleoside analogs (most experience has been gained with fludarabine) as single agent and in combination yield high remission rates including remarkable molecular remissions (clearance of bc1-2-positive cells from blood and/or bone marrow) in patients with newly diagnosed but also with relapsed or refractory disease. It remains to be proven whether molecular remissions will translate into cure or prolongation of survival when compared with conventional chemotherapy. Treatment with nucleoside analogs is associated with the risk of opportunistic infection.

Monoclonal antibodies, given alone and especially combined with chemotherapy, as well as immunoconjugates have also been recognized as very promising approaches for the first-line and salvage therapy of indolent lymphomas.

The role of high-dose therapy in indolent lymphomas is still controversial both in first-line and subsequent therapy.

Literature: for review e.g.

            BRANDT et al, Acta Oncol. 40 (2001): 213-223 (systematic overview of           

            chemotherapy)

            CHAN, Hematol. Oncol. 19 (2001): 129 – 150 (classification)

            CZUCZMAN, Semin, Oncol. 29 (Suppl 6) (2001): 11 – 17

            (immunochemotherapy)

            LINCH, Anti-Cancer Drugs 12 (Suppl 2 ) (2001): 5 – 9

            MacMANUS and SEYMOUR, Australasian Radiol. 45 (2001): 326 – 334

            (management of localized low-grade follicular lymphomas)

            McLAUGHLIN, Oncologist 7 (2002): 217 – 225

            REISER and DIEHL, Eur. J. Cancer 38 (2002): 1167- 1172 (follicular

            lymphoma)

            SOLAL-CELIGNY, Semin. Oncol. 29 (Suppl 6) (2002): 2- 6

            UPPENKAMP and FELLER, Onkologie 25 (2002): 563 – 570

            (classification)

11.2        Generally applicable

(E.g. FL, B-cell, prolymphocytic leukemia, lymphoplasmacytoid lymphoma/immunocytoma, nodal marginal zone B-cell lymphoma)

11.2.1 Alkylating agents

E.g. chlorambucil, cyclophosphamide or trofosfamide, also combined with prednisone.

Chlorambucil + prednisone (CP)

            To be repeated every 2 weeks

            or

            Cyclophosphamide

            With dose modification for hematologic toxicity

            Literature: e.g.

LICHTMAN et al, Leuk. Lymphoma 42 (2001): 1255 – 1264 (CALGB study 9150 of high-dose cyclophosphamide + G-CSF)

PETERSON et al, J. Clin. Oncol. 21 (2003): 5-15 (CALGB study 7951 of prolonged oral cyclophosphamide vs combination chemotherapy)

                        SUMMERFIELD et al, Br. J. Haematol. 116 (2002): 781-786 (high-dose

                        chlorambucil)

                        WIST and RISBERG, Acta Oncol. 30 (1991): 819 – 821 (trofosfamide)

11.2.2  Purine nucleoside analogs

As salvage therapy for relapsed/refractory disease and as first-line therapy.

To be repeated every 4 weeks

Or

To be repeated every 3 weeks

Literature:

            CABANILLAS, Oncology 14 (Suppl 2) (2000): 13 – 15 (review)

KLASA et al, J. Clin. Oncol. 20 (2002): 4649-4654 (randomized comparison of fludarabine vs COP)

TONDINI et al, Ann. Oncol. 11 (2000): 231- 233 (randomized comparison of cladribine and fludarabine, relapsed/refractory disease)

11.2..3 Combination chemotherapy

11.2.3.1 COP (CVP)

            To be repeated every 3 (-4) weeks

            Literature:

                        BAGLEY et al, Ann. Intern. Med. 76 (1972): 227 – 234

            or

To be repeated every 3 weeks (with a minimum of 4 and a maximum of 10 cycles in responding patients)

Literature:

KLASA et al, J. Clin. Oncol. 20 (2002): 4649-4654 (randomized comparison of CVP vs fludarabine)

11.2.3.2 CHOP/CHOP-B*

            To be repeated every 3 weeks

* In the CHOP-B regimen bleomycin is added at a dose of 10 units/m² and prednisone is reduced to 60 mg/m²/d

            Literature:

                        DANA et al, J. Clin. Oncol. 11 (1993): 644-651

PETERSON et al, J. Clin. 21 (2003): 5-15 (CALGB study 7951 of prolonged oral cyclophosphamide vs CHOP-B with improved disease control and survival in patients with follicular mixed lymphoma who received CHOP-B)

11.2.3.3 Purine nucleoside analog-based combinations

Often fludarabine + cyclophosphamide (with or without a corticosteroid or mitoxantrone). As salvage therapy for relapsed/refractory disease and as first-line therapy; e.g.

            FC

            To be repeated every 4 weeks

            or

            To be repeated every 3 weeks

            Or

            FMD

            To be repeated every 4 weeks (total 8 cycles)

            Literature:

                        FLINN et al, Blood 96 (2000): 71- 75 (FC, first- line)

                        HOCHSTER et al, J. Clin. Oncol. 18 (2000): 987 – 994 (FC, first-line)

LAZZARINO et al, Ann. Oncol. 10 (1999): 54 – 64 (FC + dexamethasone, pretreated disease)

SANTINI et al, Haematologica 86 (2001): 282 – 286 (FC± mitoxantrone, relapsed refractory disease)

TSIMBERIDOU et al, Blood 100 (2002): 4351-4357  (FMD as initial therapy in patients with  stage IV indolent lymphoma)

11.2.4  Combined chemo-radiotherapy

The combination of involved field radiation and chemotherapy produced a high complete remission rate, lower rate of relapse and better overall survival than IF radiation alone in patients with stage I-II low grade FL.

The addition of adjuvant radiotherapy in patients with poor-prognosis FL was also reported to increase event-free and overall survival with minimal toxicity .

Literature:

AVILES et al, Eur. J. Haematol. 68 (2002): 144 – 149 (adjuvant radiotherapy in advanced stages)

SEYMOUR et al, Ann. Oncol. 7 (1996): 157 – 163 (conbined chemo-radiotherapy for localized stages)

11.2.5 Interferon alpha

In meta- analyses interferon alpha was found to dealy disease progression and probably to improve overall survival when administered either with chemotherapy or as maintenance therapy after induction treatment  for FL. The benefits were most pronounced at higher doses (≥ 5 x 10⁶ IU/month). e.g.

CHVP + interferon alpha *

To be repeated every 4 wks (x 6), then every 8 wks (x 6)

Literature:

            ALLEN et al, J. Immunother. 24 (2001): 58-65 (meta-analysis)

*COIFFIEER et al, Ann.Oncol 10 (1999): 1191 – 1197

                  FISHER et al, J. Clin. Oncol 18 (2000) : 2010 – 2016 (randomized study   

                  of the SWOG which found no advantage of interferon alpha consolidation)

                        SMALLEY et al, Leukemia 15 (2001): 1118 – 1122  (final analysis of the  

                        ECOG randomized trial E6484 of COPA vs I-COPA)

11.2.6 Monoclonal antibodies

11.2.6.1 Uncojugated anti-CD20 monoclonal antibody (Rituximab)

After premedication with a non-steroidal anti-inflammatory drug and an antihistamine a solution of rituximab in physiologic saline (1 mg/ml) is infused at an initial rate of 50 ml/h. Every 30 min the dose is increased by 50 ml/h up to maximum of 200 ml/h.

Either as single agent salvage or first-line therapy or in combination with standard chemotherapy (e.g. CHOP or fludarabine).

            Literature:

COLOMBAT et al, Blood 97 (2001): 101 – 106 (single, first-line for patients with low tumor burden)

CZUCZMAN et al, J. Clin. Oncol. 17 (1999): 268 – 276 (combination with CHOP) and Semin. Oncol. 29 (Suppl 2) (2002) 36-40 (review)

HAINSWORTH et al, J. Clin. Oncol. 20 (2002): 4261 – 4267 (single, first-line and maintenance )

                        JÄGER et al, Eur. J. Haematol. 69 (2002): 21-26 (consolidation of first-

                        line CHOP)

                        McLAUGHLIN et al, J. Clin. Oncol. 16 (1998): 2825 – 2833 (single

                       agent, salvage)

11.2.6.2  lodine-131 radiolabeled murine anti-CD20 monoclonal antibody (tositumomab)

            For the treatment of relapsed/refractory low-grade and transformed low-grade  

            NHL.

Before the dosimetric and therapeutic doses, patients are premedicated with 650 mg of acetaminophen and 50 mg of diphenhydramin. To prevent uptake of iodine-131 by the thyroid, the patients received a saturated solution of potassium iodide beginning at least 24 h before the dosimetric dose and continuing for 14 days after the therapeutic dose.

Literature:

DILLMAN, J. Clin. Oncol. 20 (2002): 3545-3557 (review of radiolabeled anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoma)

            KAMINSKI et al, J. Clin. Oncol. 19 (2001): 3918 – 3928

            VOSE et al, J. Clin. Oncol. 18 (2000): 1316 – 1323

11.2.6.3 Yttrium 90 labeled murine anti-CD 20 monoclonal antibody

( 90 Y –ibritumomab tiuxetan)

Patients were to receive an initial infusion of rituximab (250 mg/m²) to deplete B cells from the peripheral circulation, bone marrow and lymph nodes to optimize ibritumomab distribution. Immediately thereafter an i.v. image dose of 111 in ibritumomab (5 mCi, 1.6 mg) is given. One week later, patients meeting dosimetry requirements were to receive a second infusion of rituximab and a therapeutic i.v. injection of 90Y-ibritumomab. The dose is capped at a maximum of 32 mCi.

Literature:

DILLMAN, J. Clin. Oncol. 20 (2002): 3545-3557 (review of radiolabeled anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoma)

         GRILLO-LOPEZ et al, Expert Rev. Anticancer ther, 2 (2002): 485 – 493 (review)

WISEMAN et al, Blood 99 (2002): 4336 – 4342 (phase II multicenter trial) for patients with relapsed or refractory indolent or transformed lymphoma and mild thrombocytopenia)

WITZIG et al, J. Clin. Oncol. 20 (2002): 3262 – 3269 (refractory follicular lymphoma) and J. Clin. Oncol. 20 (2002): 2453 – 2463 (randomized comparison of rituximab vs ibritumomab for patients with relapsed or refractory low-grade, follicular, or transformed b-cell NHL)

11.2.7        High-dose therapy with stem cell rescue

High-dose therapy followed by allogeneic transplantation from HLA-identical siblings may lead to prolonged survival in some patients with advanced low-grade lymphoma. This approach is still investigational , however. The same considerations apply to high-dose therapy with autologous transplantation as a treatment option for chemosensitive transformed low-grade follicular NHL.

Literature:

HORNINNG et al, Blood 97 (2001): 404 – 409 (autologous bone marrow transplantation in first CR or PR)

            HUNAULT-BERGER et al, Blood 100 (2002): 1141-1152 (review)

            KHOURI et al, Blood 98 (2001): 3595 – 3599 (nonmyeloblative

            allogeneic  transplantation)

LADETTO et al, Blood 100 (2002): 1559 – 1565 (high-dose sequential chemotherapy and autografting at diagnosis) and leukemia 15 (2001): 1941-1949 (rituximab-supplemented high-dose sequential  chemotherapy and autografting as frontline or salvage therapy)

            MOUNIER et al, Crit. Rev. Oncol./Hematol. 41 (2002): 225 – 239

            (review)

SCHMITZ, Anti-Cancer Drugs 12 (Suppl 2) (2001): 21 – 24 (rituximab in autologous stem cell transplantation)

SCHOUTEN et al, Ann. Oncol. 11 (Suppl 1) (2000):  591 – 594 (randomized comparison of standard-vs high-dose chemotherapy followed by unpurged or purged autologous stem cell transplantation)

VERDONCK, Leuk. Lymphoma 34 (1999): 129 – 136 (allogeneic vs autologous transplantation)

WILLIAMS et al, J. Clin. Oncol. 19 (2001): 727 – 735 (autologous transplantation for transformed low-grade follicular NHL)

11.3               Mantle-cell lymphoma (MCL)

11.3.1 General considerations

Mantle cell lymphoma (MCL) is a distinct subtype of NHL. Long time being considered as being a low-grade and indolent lymphoma, this entity combines unfavorable clinical features of the indolent and the aggressive lymphomas as it is generally incurable and grows rapidly. It is characterized by dissemination, usually involving lymph nodes, bone marrow and spleen and frequent extranodal involvement including the gastrointestinal tract.

Currently there is no convincing evidence that any conventional chemotherapy regimen is curative. In contrast to aggressive NHL, the CHOP regimen has not been successful in inducing a meaningful response rate in curing patients with MCL.

The introduction of newer regimens including high-dose methotrexate and/or cytarabine as preconsolidation seems to improve the outcome to a certain extent, however. High-dose regimens with autologous or allogeneic stem cell support have been tested in younger MCL patients but generally yieded rather disappointing results. Trials aimed at defining the role of monoclonal antibodies, both as single agents and in combination with conventional or myeloablative chemotherapy regimens are ongoing. Because no therapy can be considered standard, patients with MCL should be best treated within clinical trials, whenever feasible.

Literature: for review

            BARISTA et al, Lancet Oncol. 2 (2001): 141 – 148

            BERYONI et  al, Clin Lymphoma 3 (2002): 90 – 96

                        CABANILLAS et al, ASCO Educational Book (2002): 416 – 419

                        DECAUDIN, Leuk Lymphoma 43 (2002): 773 – 781

                        LEONARD et al, Curr. Opin. Oncol. 13 (2001): 342 – 347

                        PRESS, ASCO Educational Book (2002): 407 – 415

SWEETENHAM, Bone Marrow Transpl. 28 (2001): 813 – 820 (role of stem cell transplantation)

11.3.2 HYPER -CVAD and high-dose methotrexate/cylarabine followed by stem cell transplantation

Course 1, 3 …

With growth factor support

Course 2 , 4 … (after clinical and hematological recovery)

* Decreased to 1000 mg/m² per dose in patients older than 60 years, or if serum creatinine > 1.3 mg/dl. With growth factor support.

Courses to be repeated every 21 days, with evaluation after 2 and 4 courses.

Appropriate patients with at least PR were to receive allogeneic stem cell transplantation (age ≤ 55 years, HLA-identical or one-antigen-mismatched related donor) or autologous stem cell transplantation (age ≤ 65 years without donor, provided that the bone marrow had < 10% malignant cells on biopsy and < 30 % clonal cells by immunophenotyping).

Literature:

            KHOURI et al, J. Clin. Oncol. 16 (1998): 3803 – 3809

11.4        T-cell prolymphocytic leukemia (T-PLL)

11.4.1 General considerations

T-cell prolymphocytic leukemia (T-PLL) is a rare chronic lymphoproliferative disease of mature, post-thymic T-cells, characterized by a high white blood cell count and splenomegaly. It typically is a disease of the elderly, for which currently no approved standard treatment exists. T-PLL either may initially present as indolent disease but eventually progresses or is resistant to conventional chemotherapy from the beginning .

The most investigated treatment  is pentostatin with few other therapeutic approaches reported (incl.

Chlorambucil + prednisone, fludarabine, combination chemotherapy, allogeneic bone marrow transplantation, or splenectomy).

More recently the monoclonal antibody Campath- 1H was reported to be an effective therapy, but T-PLL remains incurable and new therapeutic approaches are therefore badly needed.

            Literature:

                        MATUTES et al, Blood 78 (1991): 3269 – 3274 (clinical and laboratory

                        features of T-PLL)

11.4.2 Anti-CD52 monoclonal antibody Campath- 1H (alemtuzumab)

* An initial dose of 3 mg is administered and, if tolerated, the dose is increased to 10 mg, and then to 30 mg on 3 consecutive days. Diphenhydramine and acetaminophen preced the Campath – 1H infusions.

            Literature:

                        DEARDEN et al, Blood 98 (2001): 1721 – 1726

                        KEATING et al, J. Clin, Oncol, 20 (2001): 205 – 213