Non-Hodgkin’s Lymphoma, aggressive and very aggressive                                                                    71

12.      Non-Hodgkin’s Lymphoma, aggressive and very

 aggressive (intermediate-to high-grade)

 

12.1        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 Eroup 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 .

 

Working Formulation categorles of Intermediate-and high-grade NHL

Intermeiate-grade

D         Malignant lymphoma, follicular, predominantly large cell

E          Malignant lymphoma, diffuse, small cleaved cell

F          Malignant lymphoma, diffuse, mixed small and large cell

G         Malignant lymphoma, diffuse, large cell

High-grade

H         Malignant lymphoma, large cell immunoblastic

I           Malignant lymphoma, lymphoblastic

J           Malignant lymphoma, small non-cleaved cell (Burkitt or non-Burkitt)

           

Kiel classification of high-grade NHL

B-cell lymphomas                                                      T-cell lymphomas

* Centroblastic                                         * Plemophic T-cell lymphoma, medium

* Immunoblastic                                         and large cells

* Large cell anaplastic Ki-1 lymphoma    * Immunoblastic

* Burkitt lymphoma                                  * Large cell anaplastic Ki-1 lymphoma

* Lymphoblastic                                        * Lymphoblastic

           

Finding the existing classifications at that 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 classification is basically identical to the REAL classification with minor changes.

 

Aggressive nodal or extranodal B-cell lymphomas adapted from the REAL and WHO classification (For extranodal entities see indication 13)

Diffuse large B-cell  lymphoma (DLBCL)

Variants:

* centroblastic lymphoma                          * anaplastic large B-cell lymphoma

* Immunoblastic lymphoma                      * Burkitt-like lymphoma

* B-cell lymphoma rich in T-cell               * lymphomatoid granulomatosis

* B-cell lymphoma rich in histiocyte         * Pyothorax-associated lymphoma

Subtypes:

* mediastinal lymphoma                            * serous lymphoma

* Intravascular lymphoma

Burkitt lymphoma / leukemia

Variant:                                                      * with plasma cell differentiation

 

 

 

 

 

 

72                                                                     Non-Hodgkin’s Lymphoma, aggressive and very aggressive

 

The staging should be given according to the Ann Arbor system and for prognostic purposes the International Prognostic Index (IPI) should be established.

 

Ann Arbor staging system
Stage I              Involvement of  a single lymph node region (1) or a single

                         extralymphatic organ or site (IE)
Stage II            Involvement of two or more lymph node regions on the same side

                        of the diaphragm (II) or localized involvement of an extralymphatic

                        organ or site (IE)
Stage III          Involvement of lymph node regions on both sides of diaphragm

                       (III) or localized involvement of an extralymphatic organ or site

                       (IIIE) or spleen (IIIS) or both (IIISE)
Stage IV          Diffuse or disseminated involvement of one or more

                        extralymphatic organs with or without associated lymph node

                        involvement
Identification of the presence or absence of symptoms should be noted with each stage designation
          A           asymptomatic
          B           Fever, sweats, weight loss > 10 % of body weight

 

IPI

Factor

Age                                                                    ≤ 60 vs > 60 years

Stage                                                                  I / II vs III / IV

Extranodal sites                                                 0, 1 vs ≥ 2

ECOG performance status                                0, 1 vx ≥ 2

Lactate dehydrogenase (LDH) level                  normal vs abnormal

Risk category

Low                                                                    0 or 1 factors

Low / intermediate                                             2 factors

High / intermediate                                            3 factors

High                                                                   4 or 5 factors

 

Diffuse large B-cell lymphoma (BLBCL) is the most common type of NHL. For patients with localized disease (stage I and non-bulky stage II) a combined chemoradiotherapy is the treatment of choice which results in cures for a large proportion of patients (for those with stage I non- bulky disease radiotherapy alone may also be adequate).

 

For patients with disseminated disease, who are not eligible for or do not wish to participate in a clinical trial, the CHOP-regimen remains the standard primary chemotherapy. One of three patients can be cured with 6 – 8 cycles of CHOP Consolidation by radiotherapy should be considered to sites of  bulky disease. A variety of strategies have been tested to improve these results. Intensification of the initial therapy either by administering higher doses or by shortening the cyclelength (both with growth factor support) has not uniformly shown a benefit in comparison to standard CHOP. However, it is possible that such regimens might be beneficial in subgroups of patients with high-risk disease. There has also been interest in integrating monoclonal antibodies into the initial therapy of aggressive NHL. Their full potential has still to be defined, but recent data strongly suggest that the combination of chemotherapy plus immunotherapy may significantly improve the outcome over chemotherapy alone. In young patients with poor prognosis a further intensification of induction chemotherapy with hematopoietic stem cell support has been suggested, but confirmatory controlled studies are still needed.

 

 

 

Non-Hodgkin’s Lymphoma, aggressive and very aggressive                                                                    73

 

For patients with refractory or relapsing disease after initial therapy a range of salvage combination regimens can be oftered which are composed of drug noncross resistant to standard first-line chemotherapy. Responses in general are relatively short-lived, however. For patients with a chemosensitive relapse subsequent high-dose therapy with stem cell support is therefore recommended since this may prolong survival .

 

            Literature: for review e.g.

                        ARMITAGE, Clin. Lymphoma 3 (Suppl 1) (2002): 5 – 11

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

                        COHEN and SCADDEN, Cancer Treat. Res. 104 (2001): 201 – 230

                        COIFFIER, Curr. Opin. Oncol. 13 (2001): 325-224 (DLBCL)

                        GODWIN and FISHER, Clin. Lymphoma 2 (2001): 155 – 163 (DLBCL)

                        KIMBY et al, Act Oncol. 40 (2001): 182-212 (systematic overview of

                        chemotherapy in aggressive NHL)

PHILIP and BIRON. Crit. Rev. Oncol./ Hematol. 41 (2002): 213 – 223 (high-dose chemotherapy with autologous bone marrow transplantation)

PRESS et al, Hematology (2001) American Society of Hematology Education Program Book: 221 – 240

                        TSANG and GOSPODAROWICZ, Ann. Hematol. 80 (Suppl 3) (2001):

                        66 – 72

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

                        (classification)

 

12.2        DLBCL and variants

 

12.2.1 First-line chemotherapy

 

12.2.1.1. CHOP standard chemotherapy

Cyclophosphamide                    750 mg /m2                    i.v.                          d 1

Doxorubicin                            50  mg /m2                    i.v.                          d 1

Vincristine                              1.4 mg / m2                   i.v.                          d 1

                                                (max 2 mg)

Prednisone                              100 mg /m2                    p.o.                          d 1 – 5

            To be repeated every 3 weeks (6 – 8  cycles)

 

Three to four cycles of CHOP followed by involved field radiotherapy were found to be superior to eight cycles of CHOP alone for the treatment of localized (stage I and IIa) intermediate and high-grade NHL.*

 

Literature:

FISHER et al, Ann. Oncol. 5 (Suppl. 2) (1994): 91 – 95 and N. Engl. J. Med. 328 (1993): 1002 – 1006

            JERKEMAN et al, Ann. Oncol. 10 (1999): 1079 – 1086 (CHOP vs  

            MACOP-B )

            KHALED et al, Ann. Oncol. 10 (1999): 1489 – 1492 (CHOP vs EPOCH)

*KROL et al, Radiother, Oncol. 58 (2001): 251 – 255

                  Mc KELVEY et al, Cancer 38 (1976): 1484 – 1493

MESSORI et al, Br. J. Cancer 84 (2001) : 303 – 307 (meta-analysis of survival in comparison to 3 rd generation regimens)

                  *MILLER et al, N. Engl, J. Med. 339 (1998): 21 – 26

                  MORENO et al, Oncologist 5 (2000): 238 – 249 (review of prednisone

                  schedules)

 

 

74                                                                     Non-Hodgkin’s Lymphoma, aggressive and very aggressive

 

12.2.1.2 CHOEP

Cyclophosphamide                  750 mg /m2                    i.v.                          d 1

Doxorubicin                             50  mg / m2                    i.v.                          d 1

Vincristine                               1.4 mg /m2                    i.v.                           d 1

                                                  (max 2 mg )

Prednisone                               100 mg /m2                   p.o.                          d 1 – 5

Etoposide                                 100 mg /m2                   i.v. ( 1 h inf)            d 3 – 5

            To be repeated every 3 weeks (CHOEP – 21) or every 2 weeks (CHOEP – 14   

           with G-CSF support).

 

            Literature:

                     PFREUNDSCHUH et al, 44 th Ann. Meet. Am. Soc. Hematol. (2002): 92  

                     a , abstr, 340 (randomized trial NHL-B – 1 of the German DSHNHL

                     group comparing CHOP –14 , CHOP- 21, CHOEP – 14,and CHOEP – 21 )

                       

12.2.1.3CNOP

Cyclophosphamide                          750 mg / m2                    i.v.                               d 1

Mitoxantrone                                   12 mg /m2                       i.v.                               d 1

Vincristine                                       1.4 mg / m2                     i.v.                               d 1

                                                      (max 2 mg)

Prednisone                                       100 mg / m2                    p.o.                              d 1 – 5

To be repeated every 3 weeks (stage I + II 4 cycles followed by involved field RT: stage III + IV 6 cycles)

 

Literature :

            VOSE et al, Leuk, Lymphoma 43 (2002): 799 – 804

 

12.2.1.4 PACEBOM

Prednisolone                                 50 mg /d                                      wks 1 – 4 and

                                                      50 mg alternate  d                        wks 5 – 12

Doxorubicin                                   35 mg /m2               i.v.                d 1

Cyclophosphamide                        300 mg /m2             i.v.                 d 1        

Etoposide                                       150 mg / m2            i.v.                 d 1

Bleomycin                                      10 mg /m2               i.v.                 d 8

Vincristine                                      1.4 mg /m2              i.v.                 d 8

                                                    (max 2 mg)

Methotrexate                                 100 mg /m2                i.v.                d 8

            Weekly alternating over 11 weeks

 

            Literature:

LINCH et al, Ann. Oncol. 11 (Suppl. 1) (2000) : 587 – 590 (randomized comparison with CHOP)

 

12.2.1.4Alternating triple therapy (ATT)

ASHAP

 

Doxorubicin                                  10 mg / m2          i.v. (cont inf)           d 1 – 4

Cisplatin                                        25 mg / m2          i.v.(cont inf)           d 1 – 4

Cytarabine                                     1.5 mg / m2         i.v. (2 h inf)            d 5

Methylprednisolone                         500 mg             i.v.(15 min inf)       d 1 - 5

m-BACOS

 

 

Non-Hodgkin’s Lymphoma, aggressive and very aggressive                                                                    75

 

           

Doxorubicin                         50 mg / m2                 i.v. (cont inf)                   d 1

Vincristine                           1.4 mg/ m2                 i.v.                                   d 1

                                           (max 2 mg)

Bleomycin                           10 mg /m2                  i.v.( 15 min inf)                d 1

Cyclophosphamide              750 mg /m2                i.v. (15 min inf)               d 1

Methylprednisolone            500 mg /m2                 i.v. (15 min inf)               d 1 – 3

Methotrexate                        1000 mg /m2              i.v. (3 h inf)                     d 10

Folinic acid                          15 mg                        p.o. q 6 h x 8                  d 11 – 12

 

            MINE

           

Ifosfamide                         1500 mg /m2               i.v. (1 h inf)                     d 1 – 3

                                                                             With mesna uroprotection

Mitoxantrone                    10 mg /m2                  i.v. (15 min inf)                 d 1

Etoposide                          80 mg / m2                 i.v. (30 min inf)                  d 1 – 3

Given in alternating fadhion for a total of 9 courses. ATT appears to be more effective than standard therapy for patients < 60 years old with unfavorable tumor scores.

 

Literature:

      CABANILLAS et al, Ann. Oncol. 9 (1998): 511- 518

 

12.2.2       First-line immunochemotherapy

Rituximab + CHOP (R-CHOP)

Rituximab                       375 mg /m2                 i.v.                                     d 1

Cyclophosphamide         750 mg /m2                 i.v.                                     d 1

Doxorubicin                    50 mg/m2                   i.v.                                     d 1

Vincristine                      1.4 mg /m2                 i.v.                                      d 1

                                        (max 2 mg)

Prednisone                      40 mg /m2                  p.o.                                     d 1 – 5

To be repeated every 3 weeks (8 cycles)

 

Literature:

COIFFIER et al, N. Engl. J. Med. 346 (2002): 235 – 242 (randomized comparison of CHOP with or without rituximab in elderly patients with DLBCL form the GELA group)

         VOSE et al, J. Clin. Oncol. 19 (2002): 389 – 397

 

12.2.3       Salvage chemotherapy

Also for cytoreduction and stem cell mobilization before high-dose chemotherapy in transplant-eligible patients with relapsed or refractory disease .

 

12.2.3.1ICE

Etoposide                      100 mg /m2                  i.v. ( 1 h inf)                  d 1 – 3

Carboplatin                   AUC = 5 *                  i.v.                                  d 2

                                             ( max 800 mg )

Ifosfamide                    5000 mg /m2                i.v. (24 h inf)                  starting d 2

                                                                          With mesna uroprotection

With G- CSF support, to be repeated at 2 week intervals ( 3 cycles)

 

            Literature:

 

 

76                                                                     Non-Hodgkin’s Lymphoma, aggressive and very aggressive

 

 

 

                        MOSKOWITZ, Cancer Chemother, Pharmacol, 49 (Suppl 1) (2002): 9- 12

                        MOSKOWITZ et al, J. Clin. Oncol, 17 (1999): 3776 – 3785

 

12.2.3.2IVE

Ifosfamide                      3000 mg /m2             i.v.                                   d 1 – 3

                                                                          With mesna uroprotection

Etoposide                      200 mg/m2                 i.v.                                    d 1 – 3

Epirubicin                     50   mg/m2                 i.v.                                    d 1

With G-CSF support

           

            Literature :

            McQUAKER et al, Bone Marrow Transplant. 24 (1999): 715 – 722

            ZINZANI et al, Haematologica 87 (2002): 816 – 821 (similar combination IEV)

 

12.2.3.3MINE / ESHAP

MINE

Ifosfamide                      1333 mg/m2                i.v. (1 h inf)                      d 1 – 3

                                                                         With mesna uroprotection

Mitoxantrone                  8 mg /m2                     i.v. (15 min inf)                d 1

Etoposide                       65 mg / m2                  i.v. (1 h inf)                      d 1 – 3

To be repeated every 3 weeks. For a maximum of 6 courses followed by

 

ESHAP

Etoposide                         60 mg /m2                    i.v. (1 h inf)                     d 1 – 4

Methylprednisolone         500 mg /m2                  i.v. (15 min inf)               d 1 – 4

Cytarabine                        2000 mg /m2               i.v. ( 2 h inf)                     d 5

Cisplatin                          25 mg /m2                   i.v (cont inf)                     d 1 – 4

To be repeated every 3 weeks. For 3 courses to consolidate a complete response or for a maximum of 6 courses after a partial response or no response to MINE.

 

Literature:

            RODRIGUEZ et al, J. Clin. Oncol. 13 (1995): 1734 – 1741

 

12.2.3.4  EPIC

Etoposide                       100 mg /m2               i.v. (1 h inf)                      d 1 – 4

Prednisolone                  100 mg /m2              p.o.                                   d 1 – 5

Ifosfamide                      1000 mg /m2            i.v. (15 min inf)                d 1 – 5

                                                                        With mesna uroprotection

Carboplatin                    240 mg/m2               i.v. (30 min inf)                d 12

            To be repeated every 4 weeks (outpatient treatment)

 

            Literature:

                        McBRIDE et al, Leuk, Lymphoma 35 (1999): 339 – 345

 

   12.2.3.5 DHAP

Dexamethasone                  40 mg                     i.v.                                     d 1– 4

Cytarabine                          2000 mg /m2           b.i.d. i.v.                            d 2

Cisplatin                            100 mg /m2              i.v.                                    d 1

To be repeated every 3 – 4 weeks

Literature:

 

Non-Hodgkin’s Lymphoma, aggressive and very aggressive                                                                    77

 

                        GUGLIELMI et al, J. Clin. Oncol. 16 (1998): 3264 – 3269

                        PHILIP et al, N. Engl. J. Med. 333 (1995): 1540 – 1545

                        VELASQUEZ et al, Blood 71 (1988): 117 – 122

 

12.2.3.6             Dexa-BEAM

Dexamethasone             8 mg                          t.i.d. p.o.                    d 1 – 10

BCNU                           60 mg /m2                  i.v. (30 min inf)          d 2

Etoposide                      75 – 150 mg /m2        i.v. (30 min inf)          d 4 – 7

Cytarabine                     100 mg /m2               b.i.d. i.v. (30 min inf)     d 4 – 7

Melphalan                      20 mg /m2                i.v. (30 min inf)              d 3

With G – CSF support. To be repeated after hematopoietic recovery

 

Literature:

            JOSTING et al, Onkologie 18 (1995): 246 – 250

            HOHAUS et al, Bone Marrow Transplant. 22 (1998): 625 – 630

 

12.2.4   Salvage immunotherapy and immunochemotherapy

 

12.2.4.1            Anti-CD20 monoclonal antibody (Rituximab)

Rituximab                              375 mg /m2                i.v.                                  d 1

To be repeated weekly (8 doses)

 

Literature:

            COIFFIER et al, Blood 92 (1998): 1927 – 1932

 

12.2.4.2            Rituximab + ICE (R-ICE)

Rituximab                      375 mg                      i.v.                                 d – 2 * , d 1

Ifosfamide                    5000 mg /m2             i.v.(24 h inf)                 starting d 4

                                                                       With mesna uroprotection

Carboplatin                    AUC = 5 **               i.v.                                   d 4

                                       (max 800 mg )

Etoposide                       100 mg /m2                i.v.                                   d 3 – 5

With G – CSF support. To be repeated at 2- week intervals (delay if ANC < 1000 and platelets < 50000).

* D – 2 prior to cycle 1 only                 **  Using the Calvert formula

 

Literature:

            KEWALRAMANI et al, 43rd Ann. Meet. Am. Soc. Hematol. (2001):

            abstr. 1459

            MOSKOWITZ, Cancer Chemother, Pharmacol. 49(Suppl 1)(2002): 9 –

            12

 

12.2.5   High-dose therapy with hematopoietic stem cell support

For patients with DLBCL in first or subsequent chemotherapy-sensitive relapse autologous stem cell transplantation is the treatment of choice. Frequently used preparative regimens are BEAM, CBV or high-dose ICE. The role and optimal approach to incorporating transplantation into the primary therapy is more uncertain because of conflicting results from randomized trials. High-risk patients who achieve a CR with conventional initial therapy but have a high-risk for relapse and patients who initially fail to enter a CR may benefit from consolidating autologous transplantation.

 

Allogeneic stem cell transplantation has been evaluated as well but it appears to be useful in only selected younger patients. If nonmyeloablative allogeneic stem cell transplantation will develop into a more feasible alternative approach has still to be evaluated.

 

 

78                                                                    Non-Hodgkin’s Lymphoma, aggressive and very aggressive

            Literature:

HAIOUN et al, J. Clin. Oncol. 18 (2000): 3025 – 3030 (consolidation, randomized study LNH 87 – 2 )

KLUIN-NELEMANS et al, J. Natl, Cancer Inst. 93 (2001): 22 – 30 (consolidation, randomized EORTC study)

KOGEL and McSWEENEY, Curr. Opin. Oncol. 14 (2002): 475 – 483 (nonmyeloablative allogeneic transplantation, review)

MINK and ARMITAGE, Oncologist 6 (2001): 247 – 256 (autologous and allogeneic transplantation, review)

PHILIP and BIRON, Crit. Rev. Oncol. / Hematol.41 (2002): 213 – 233 (autologous transplantation, review)

                        PHILIP et al, N. Engl. J. Med. 333 (1995): 1540 – 1545 (PARMA study)

ROBINSON et al, Blood 100 (2002): 4310 – 4316 (retrospective analysis of nonmyeloablative allogeneic transplantation from the EBMT registry)

SHIPP et al, Ann. Oncol. 10 (1999): 13 – 19 and J. Clin. Oncol. 17 (1999): 423- 429 (consensus report)

VELLENGA et al, Br. J. Haematol. 114 (2001): 319 – 326 (comparison of atologous peripheral blood stem cells and bone marrow, HOVON 22 study )

VOSE et al, J. Clin. Oncol. 20 (2002): 2344 – 2352 (randomized trial evaluating graft source and minimal residual disease in autologous transplantation)