1.         Acute Lymphoblastic Leukemia (ALL)

 

1.2                                     Pediatric patients

 

1.2.1                              General considerations

All is the most common childhood malignancy. As already presented in more detail for adult ALL, advances in the understanding of the biological features have provided a platform for the development of risk- directed protocols by collaborative groups in many countries. This progress together with improvements in the salvage of patients who have relapsed have resulted in 5 – year overall survival rates approaching 85%.

 

Literature ; for review and reprresentative group studies e.g.

ARICO et al, Blood 100(2002): 420 – 426 (Italian study AIEOP – ALL95 with double BFM protocol II        in high – risk patients)

      CHESSELS et al, Br. J. Haematol. 118(2002): 445 – 455 )MRC trial UKALL X and

      UKALL X1 ) and

      Br. J. Haematol. 117 (2002): 306 – 314 (Protocols Infant 87 and Infant 92)

      CHAN, Curr. Probl. Pediatr. Adolesc, Health Care 32 (2002): 40 – 49 (review)

      GREAVES, Br. Med. J. 324 (2002): 283 – 287 (review)

      HARMS and JANKA – SCHAUB, Leukemia 14(2000): 2234 – 2239 (German Co-

      operative Study  Group protocol ALL – 7 )

      KAMPS et al, Leukemia 16 (2002): 1099 – 1111 (Dutch DCLSG protocol ALL –8)

      LANGE et al, Blood 99 (2002): 825 – 833 (Children Cancer Group protocol CCG-

      1891 on effects of intensification after induction / consolidation)

      LAUER et al, Leukemia 15(2001): 1038- 1045 ( randomized Pediatric Oncology

      Group study POG

      9006 comparing two early intensifications)

      LeCLERC et al, J. Clin. Oncol. 20(2001): 237 – 246 (Dana – Farber ALL Consortium   

      Protocol 87- 01)

 

 

 

10                                                                                                       Acute Lymphoblastic Leukemia (ALL) ____________________________________________________________________________________

 

LIPSCHULTZ et al, J. Clin . Oncol. 20 (2002): 1677 – 1682 (Dana – Farber 91 – 01

Protocol of continuous vs bolus infusion of doxorubicin)

ORTEGA et al, Haematologica 86(2001): 586 – 595 (Spanish randomized

PETHEMA ALL – 89 trial of early and delayed consolidation chemotherapy)

OTTEN et al,Eur. J. Cancer 38 (Suppl 4) (2002): 44 – 49 (overview of the studies of the EORTC

Children Leukemia Group)

PATTE et al, Blood 97 (2001): 3370 – 3379 (Societe Francaise d’Oncologie

Pediatrique LMB 89 protocol)

PUI et al, Leukemia 14 (2000): 2286 – 2294 (long – term results of studies 11, 12 and

13 A at St. Jude Children’s Research Hospital ) and Lancet Oncol. 10

(2001): 597 – 607 (review)

RIZZARI et al, J. Clin. Oncol. 19 (2001): 1297 – 1303 (randomized study AIEOP

9102 of the Associazione Italiana Ematologia Oncologia Pediatrica)

VORA, pediatr. Drugs 4 (2002): 405 – 416 (review)

 

Remark : As for adult ALL treatment of childhood ALL should be performed by experienced and

specialized centers and  cooperative groups according to current protocols. The following outlines,

therefore, should only serve as illustrating examples.

 

 
1.2.2    ALL – BFM 90

Therapy was stratified into three therapy branches SR (standard – risk group). MR

(medium – risk group) and HR ( high – risk group):

 

  

 

 

 

 

*indicates no preventive radiotherapy if patient was under 1 year of age. Patients with central nervous system involvement received no radiation if they were under 1 year of age, 18 Gy if they were older than 1 of age but under 2 years of age, and 24 Gy  if they were 2 years of age or older

 

 

 

 

Acute Lymphoblastic Leukemia (ALL)                                                                                                 11

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Induction

 

Protocol 1

 

Phase A

Prednisone                              60 mg/m²    p.o                                             d 1 – 28 *

Vincristine                               1.5 mg/m²   i.v.                                            d 8, 15, 22, 29

                                                (max 2 mg)

Daunorubicin                          30 mg/m²      i.v.                                    d 8,  15 , 22 , 29

L – asparaginase                      10000 IU/m²  i.v.                                 d 12, 15 , 18 , 21 , 24

                                                                                                                        27 , 30 , 33 *

Methotrexate                            12 mg **     i.th                                              d  1, 15 , 29

 

Phase B (only in SR and MR)

Cyclophosphamide                     1000 mg /m²   i.v.                               d  36 , 64

Cytarabine                                    75 mg /m²      i.v.                              d 38 – 41 , 45 – 48

                                                                                                                 52- 55 , 59 –62

Mercaptopurine                           60 mg /m²      p.o.                              d 36 – 64

Methotrexate                                12 mg  **      i.th.                              d 45 – 59

 

Consolidation (in SR and MR)

 

Protocol M

Mercaptopurine                            25 mg /m²            p.o.                             d  1- 56

Methotrexate                                5000 mg /m²      i.v.(24 h ing)***           d 8 , 22 , 36 , 50

                                                      12 mg **           i.th.                               d 8 , 22 , 36 , 50

 

Protocol M – A ****

L- asparaginase                             25000 IU /m²      i.m.                           d 10 , 24 , 38 . 52

 

Reinduction (in SR and MR)

 

Protocol II

Dexamethasone                         10 mg /m²                     p.o.                      d  1- 21

Vincristine                                1.5 mg /m²                        i.v.                    d 8 , 15 , 22 , 29

                                                       (max 2 mg)

Doxorubicin                             30 mg /m²                         i.v.                   d 8 , 15 , 22 , 29

L – asparaginase                       10000 IU /m²                  i.v.                    d 8 , 11. 15 . 18

Cyclophosphamide                   1000 mg /m²                   i.v.                    d 36

Cytarabine                           75 mg /m²                      i.v.                         d 38 – 41 , 45 – 48

Thioguanine                         60 mg /m²                     p.o.                        d 36 – 49

Methotrexate                        12 mg **                       i.th.                        d 38 , 45

 

 

 

 

 

 

 

 

 

12                                                                                                       Acute Lymphoblastic Leukemia (ALL) ____________________________________________________________________________________

 

Intensive reconsolidation (HR only)

 

Element HR – 1

Dexamethasone                                        20 mg/m²         p.o.                               d  1- 5

Mercaptopurine                                        100 mg/m²       p.o.                               d 1- 5

Vincristine                                                1.5 mg/m²        i.v.                                 d 1, 5

Methotrexate                                             5000 mg/m²     i.v. (24 h inf)***          d 1

                                                                    12 mg **        i.th.

Cytarabine                                                  2000 mg/m²     b.i.d.i.v. (3 h inf)         d 5

                                                                    30 mg**           i.th                              d 1

L- asparaginase                                           25000 IU/ m²    i.m.                             d 6

Prednisolone                                                10 mg**           i.th.                             d 1

 

Element HR – 2

Dexamethasone                                            20 mg/m²         p.o.                            d 1 – 5

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

Vindesine                                                      3 mg/m²           i.v.                            d 1

Methotrexate                                                 5000 mg/m²     i.v. (24 h inf)***       d 5

                                                                       12 mg **         i.th.                           d 1

Ifofamide                                                      400 mg/m²      i.v. (1 h inf)               d 1- 5

                                                                                              With mesna uroprotection

Daunorubicin                                               50 mg/m²          i.v. ( 24 h inf)          d 5

L – asparaginase                                          25000 IU/m²     i.m.                           d 6

Cytarabine                                                    30 mg **          i.th.                          d 1

Prednisolone                                                 10 mg **          i.th.                          d 1

 

Element HR – 3

Dexamethasone                                            20 mg/m²           p.o.                          d  1- 5

Cytarabine                                                    2000 mg/m²       b.i.d.i.v. (3 h inf)      d 1 , 2

                                                                       30 mg **           i.th.                          d 5

Etoposide                                                       150 mg/m²         i.v. (1 h inf)             d 3 - 5

L – asparaginase                                             25000 IU/ m²    i.m.                          d 8

Methotrexate                                                  12 mg **           i.th.                          d 5

Prednisolone                                                   10 mg **           i.th.                          d 5

 

For induction, consoldation, and reinduction, the days given are the chronologic days of treatment , adjustments in time schedules were allowed if clinical condition and marrow recovery were inadequate ( according to protocol guidelines ). For intensive reconsolidation, the days given are the number of days of application per element . Each element was given 3 times unless otherwise indicated.

 

*In the HR, protocol I phase A had only 21 days of prednisone therapy and 6 doses of L-       asparaginase.

**Doses were adjusted for children < 3 years of age.

***Given with i.v. folinic acid rescue starting at hour 42 with 30 mg/m² ( or 15 mg/m² ) and with 2 more doses given at hour 48 and hour 54, respect. ( each 15 mg/m²).

****Only MR patients randomly assigned to M- A received additional L – asparaginase (4 doses starting 54 hours after starting high – dose MTX ) during consolidation. The addition of L-       asparaginase did not improve the outcome.

 

  

 

 

Acute Lymphoblastic Leukemia (ALL)                                                                                                 13

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For high – risk patients the outcome was inferior to that in the preceding trial ALL – BFM 86. In ALL – BFM 90 the HRG treatment regimen contained fewer alkylating agents, less prednisone, and no mitoxantrone, which probably could not be compensated by the use of more dexamethasone, etoposide, L – asparaginase, thioguanine, cytarabine and i.v. methotrexate. The respective treatment elements of ALL- BFM 86 can be found below :

 

Study ALL – BFM 86

 

Experimental  protocol E

Prednisone                          100 mg/m²        p.o.                               d  1- 7 , 15 – 21

                                                                                                           29 – 35 , 43 – 49

Cytarabine                          2000 mg/m²      b.i.d. i.v.(3 h inf)          d  1, 2 , 29 , 30

Ifosfamide                          1000 mg/m²      b.i.d. i.v. ( 1 h inf)       d 15 , 16 , 43 , 44

                                                                     With mesna uroprotection

Mitoxantrone                     10 mg/m²           i.v.                                d 1 , 15 , 29 , 43

Methotrexate                      5000 mg/m²       i.v. (24 h inf)                d 8 , 22, 36 , 50

                                                                        With folinic acid                                                                                

                                      12 mg *              i.gh.                              d 8 , 22, 36 , 50

 

Reinduction protocol II

Dexamethasone                                      10 mg/m²          p.o.                    d  1- 21

Vincristine                                              1.5 mg/m²         i.v.                 d 8 , 15 , 22 , 29

                                                        ( max 2 mg)

Doxorubicin                                            30 mg/m²          i.v.                d 8 , 15 , 22 , 29

L – asparaginase                                     10000 IU /m²     i.v.               d 8 , 11, 15 , 18

Cyclophosphamide                                 1000 mg/m²       i.v.               d 36

Cytarabine                                               75 mg/m²          i.v.               d 38 – 41 , 45 – 48

Thioguanine                                             60 mg/m²         p.o.              d 36 – 49

Methotrexate                                            12 mg*             i.th.             d 38 , 45

 

 

Literature :

REITER et al, Blood 84 ( 1994) : 3122 – 3133 ( ALL – BFM 86)

SCHRAPPE et al, Blood 95 (2000) : 3310 – 3322 ( ALL – BFM 90)

 

1.2.3                              Salvage therapy

        Literature : for review

                  UDERZO et al, Haematologica 85 ( Suppl.) (2000): 47 – 53

 

1.2.3.1                       Chemotherapy

        “ Late “ (> 30 months) extramedullary relapse , or late non T- marrow relapses or “  

         early” combined

           non  T – relapses might be rescued by salvage chemotherapy.

 

           Literature:

           BάHRER et al, Blood 83 ( 1994) : 3468 – 3472 ( study ALL – REZ BFM 85/87 )

 

 

 

 

14                                                                                                       Acute Lymphoblastic Leukemia (ALL) ____________________________________________________________________________________

 

 

1.2.3.2                       Allogeneic bone marrow transplantation

“ Early “ (< 30 months) relapses or T – immunophenotype ALL relapses can be recued only by        allogeneic BMT. It seems to be the best treatment option for patients in second CR ( in contrast transplantation in first remission seems to have no major impact on EFS in very high – risk ALL).

 

 

Literature :

BOULAD et al, j. Clin. Oncol. 17 (1999): 197 – 207 (retrospective analysis of allo BMT and salvage CT in CR 2)

DAVIES et al, J. Clin. Oncol. 18 (2000): 340 – 347 ( comparison of preparative regimens)

TESTI et al, Br. J. Haematol. 118 (2002): 741 – 747 (AIEOP study of a single high- dose of idarubicin combined with high – dose cytarabine as induction followed by intensive consolidation and stem cell transplant for treatment of first relapsed in high – risk ALL)

WHEELER et al, Blood 96 (2000): 2412 – 2418 (BMT vs. CT for very high – risk ALL in CR 1)