1.         Acute Lymphoblastic Leukemia (ALL)

1.1             Adult Patients

1.1.1      General Considerations

Acute lymphoblastic leukemia ( ALL) is a clonal malignant disorder which is characterized by an execessive proliferation and arrest of differentiation of lymphoid cells at various stages of maturation and the loss of apoptosis.

The former French- American- British (FAB) classification of ALL – L1 / ALL- L2/ ALL- L3 has lost its importance, because the L1 and L2 morphology does neither reflect the immunophenotype and cytogenetics nor the clinic of ALL.

Several structural and numerical abnormalities of the karyotype now provide important prognostic. With regard to the structural chromosomal changes, a poor risk is associated e.g. with t (4; 11) or with t (9; 22) which gives rise to the BCR/ABL fusion and rearrangements ( Philadelphia [ph] ), whereas e.g. the translocation t(12;21) which results in the ETV6/ AML 1 fusion is probably associated with a good – risk prognosis. These abnormalities occur most frequently in B- lineage leukemias, while rearrangements of the T- cell receptor genes are associated with T – lineage ALL. High hyperdiploidy as a numerical abnormality is associated with a good risk, whereas the outlook for patients with near haploidy is grim.

The identification of ALL patients with different prognoses based on the biology of the malignant clone and new prognostic markers have led to emergence of risk – stratified therapies.

Approximately 70–75% of adult ALL are of precursor B-cell origin, 20 –25% are of T- cell origin, and < 5 %  are mature B- cell or burkitt- type (ALL – L3).

For precursor B- cell and T- cell ALL treatment is composed of several treatment phases. Intensive induction is usually based on vincristine, a glucocorticoid  and an anthracycline ( most often daunorubicin or doxorubicin) with or without asparaginase ( also PEG asparaginase) . Given the high CR rate observed it has been difficult to demonstrate further improvement with the addition of further drugs, including cyclophosphamide and cytarabine, except in T- lineage ALL where these two drugs appear to improve CR rate, disease- free survival and overall survival. Improved supportive care measures, incl., the use of antibiotics and growth factors, during remission induction may reduce mortality and improve prognosis in elderly ALL patients. Agents similar to those used during remission induction, with the addition of antimetabolites ( methotrexate, mercaptopurin or thioguanine) are elements of postremission treatment . Cyclophosphamide, high-dose cytarabine and other agents incl. topoisomerase-ll inhibitors ( etoposide, teniposide) have also been added. Since around one third of adult patients had developed CNS leukemia throughout the course of their disease resulting in poor long-term outcome despite treatment, a CNS prophylaxis has been incorporated into the postremission treatment. Measures include intrathecal therapy (methotrexate, cytarabine , steroids), high- dose systemic chemotherapy ( methotrexate, cytarabine, asparaginase, dexamethasone), and cranial irradiation ( increasingly abandoned because of the risks of acute and long – term toxicity). Long- term maintenance therapy which follows successful postremission treatment is usually given for 1-3 years and is based on a backbone of daily mercaptopurine and weekly methotrexate, often with the addition of monthly pulses of vincristine and prednisone.

High- risk patients, including those with ph- positive ALL or t(4; 11) abnormality, with an available donor should receive allogeneic stem cell trasplantaion in first remission, which demonstrated a survival benefit over autologous trasplantation or chemotherapy as postremission therapy.

4                                                                               Acute Lymphoblastic Leukemia (ALL) _______________________________________________________________________

An increasing experience with the use of nonmyeloablative preparative regimens provides a rationale for also testing the tolerability and efficacy of allogeneic stem cell transplantation in elderly high- risk patients with ALL.

Early studies demonstrated a lower CR rate and remission duration for patients with mature B-cell ALL, however, with the introduction of intensive cyclical, but shortterm, therapy adapted from pediatric studies the outcome improved substantially. Principles of this treatment include (1) a low – dose chemotherapy prephase to prevent an acute tumor lysis syndrome; (2) the incorporation of fractionated high-dose cyclophosphamide or ifosfamide, high-dose methotrexate, high-dose cytarabine and an anthracycline with or without etoposide; and (3) a focus on CNS prophylaxis by administering high doses of systemic methotrexate and cytarabine in addition to aggressive intrathecal therapy. There is no defined role for a prolonged maintenance therapy for mature B- cell ALL and allogeneic or autologous stem cell transplantation do not seem to be useful in first CR.

In relapsed ALL, many patients still achieve a second CR using drug combinations similar to those used for initial induction therapy. Currently, an allogeneic transplant in early relapse or following achievement of a second or later CR offers the best chance of a durable remission. Patients with refractory ALL have a poor prognosis and novel therapeutic agents are needed.

Overall in adult ALL contemporary intensive and tailored therapy programs are associated with CR rates of up to 90%, cure rates generally range between 30% and 45%. They can be as high as 50-70% in subsets such as T- cell and mature B-cell ALL but as low as < 10% in ph- positive ALL. A promising approach to treat Ph- positive ALL might be the use of imatinib mesylate in combination with chemotherapy.

Literature: for review and respresentative group studies e.g.

        ANNINO et al, Blood 99 (2002): 863 – 871 ( randomized study ALL 0288  

        of the Italian GIMEMA).

        CORTES , Hematol. / Oncol. Clin . North Am. 15 (2001): 145 – 162 ( CNS   

        leukemia)

                    DOMBRET et al, Blood 100 (2002) : 2357 – 2366 ( LALA -94 trial of the 

                    French GET- LALA Group in Ph- positive ALL)

        FENAUX et al, Hematol/ Oncol. Clin. North Am. 15 (2001): 37 – 50 (  

        Burkitt’s ALL)

        GARCIA – MANERO and THOMAS, Hematol/ Ocol. Clin. North Am. 15  

        (2001): 163- 205 ( salvage therapy for refractory or relapsed ALL)

        GÖKBUGET and HOELZER , Leuk. Res 26 (2002): 473-476 (role of hd

        cytarabine in induction therapy)

        HALLBÖÖK et al, Br. J. Haematol. 118 (2002) : 748-754 (Swedish Adult  

        ALL Group trial of inclusion of high-dose cytarabine in upfront therapy).

        HARRISON, Best Pract. Res. Clin. Haematol. 14 (2002): 593-607 (   

        cytogenetics)

        HOELZER and GÖKBUGET, Semin. Oncol. 27 ( 2000); 540-559

        KANTARJIAN, Hematol./ Oncol. Clin. North Am. 15 (2001): 207-211 (  

        future directions).

        LINKER et al, J. Clin. Oncol. 20 ( 2002): 2464 – 2471 ( Protocol 8707 of the  

        university  of California, San Francisco, of intensified and shortened   

        chemotherapy for B- precursor ALL)

        OTTMAN et al, Blood 100 (2002): 1965-1971 ( phase ll study of imatinib in   

        relapsed or refractory ph-positive ALL)

        PETERSDORF et al, Leukemia 15 (2001): 208-216 (SWOG study 8417/     

        8419 comparing two consolidation regimens of different intensity)

        TAKEUCHI et al, Leukemia 16 (2002): 1259-1266 (ALL 93 study of the  

        Japan Adult Leukemia Study Group [ JALSG])

       TODESCHINI, Hematol/ Oncol. Clin. North Am. 15 (2001): 9-20 (high-    

       dose anthracycline induction)

       VERMA and STOCK, Curr, Opin. Oncol. 13 (2001 ): 14-20

AcuteLymphoblasticLeukemia(ALL)                                                                                                  5

__________________________________________________________________________________

Remark: Treatment of ALL is very complex, risk- oriented and immunophenotype specific. Preferably it 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.

1.1.2    Precursor B- cell/ T- cell ALL

1.1.2.1 Remission induction

E.g. DVP

An additional dose of daunorubicin is given on d 14, if bone marrow examination reveals persistent leukemia.

Literature:

CASSILETH et al, Leukemia 6 (suppl 2) (1992): 178-181

or

Study ALL 06/99

Pre-induction ( big tumor mass, high leukocyte number)

Also with additional cyclophosphamide

Induction phase I

With G- CSF (starting on d 4 until granulocytes > 1500/µI)

Induction phase II

With G- CSF

CNS Prophylasix

Plus cranial irradiation

6                                                                               Acute Lymphoblastic Leukemia (ALL) ________________________________________________________________________

1.1.2.2.                     Postremission consolidation and reinduction

E.g. Study ALL 06/99

Consolidation I (for all risk groups): week  11

G-CSF (starting on d 7 until stem cell harvest d 15/16 for those  without a donor)

*    10 % of MTX in 30 min,  90 % in 23.5 h

Continuation according to risk group.

Standard risk group

Consolidation II , III, VI : starting week  16,  30,  46

*     10 % of MTX in 30 min, 90 % in 23.5 h

Reinduction Phase I : week  22 + 23

Plus intrathecal CNS prophylaxis on d 1, 15 (= d 1 of reinduction phase II)

*    Dosis reduction after  d 14, 3 days each  50 % , 25 % and  12.5 %

Reinduction Phase II : week  24 + 25 

Plus intrathecal CNS prophylaxis on  d 1 , 15

Consolidation IV : week  36

Plus intrathecal CNS prophylaxis on d 1

Consolidation v : week  41

Plus intrathecal CNS prophylaxis on  d  1

AcuteLymphoblasticLeukemia(ALL)                                                                                                  7

________________________________________________________________________

High and very high risk group

For those with a suitable donor after consolidation I: allogeneic stem cell transplantation. Otherwise

Consolidation II: Week 16

Plus intrathecal CNS prophylaxis on  d 1

or

G- CSF (starting d 7 until granulocytes > 1000/µI)

Plus intrathecal CNS prophylaxis on d 1

CNS Prophylaxis ( for all risk groups)

Day 15 only during reinduction

An additional 1 –d course of CNS prophylaxis is given in week 52

1.1.2.3                       Remission maintenance

E.g. Study ALL 06/99

To be given after reinduction and between consolidation III – VI as well as after VI till end of first year.

Therapy is to be continued according to the status of minimal residual disease (MRD):

Low risk :                     stop therapy

High risk :                     allogeneic or autologous stem cell transplantation or intensified        maintenance therapy for 1 year

Intermediate risk : intensified maintenance therapy for 1 year

1.1.3                              Mature B- ALL

1.1.3.1                       Study ALL 05/93

Prephase

Immediately followed by

8                                                                                                       Acute Lymphoblastic Leukemia (ALL) ____________________________________________________________________________________

Block A

G- CSF recommended. Plus intrathecal CNS- prophylaxis (Block A1 + A2) days 1+5 !

After 2 weeks

Block B

G- CSF recommended. Plus intrathecal CNS- prophylaxis (Block B1 + B2) days 1+5 !

Blocks A and B are alternatingly given 3 x each every 16 days.

For refractory or early relapsing patients (after A ⇚ B⇚ A)

Block C

1.1.3.2                       Hyper – CVAD

Course 1 , 3, 5, 7

Course 2 , 4 , 6 , 8

 All courses with G – CSF support, repeated every 3 (or 2 if count recovery allows) weeks

CNS prophylaxis

Of each course for all 8 courses

Acute Lymphoblastic Leukemia (ALL)                                                                                                  9

__________________________________________________________________________________

Literature :

         THOMAS et al, j. Clin. Oncol. 17 (1999): 2461 – 2470

The combination of Hyper – CVAD and highly active antiretroviral therapy (HAART)

Was found to be associated with long-term survival in patients with AIDS-related Burkitt’s lymphoma/ leukemia.

Literature:

         CORTES et al, Cancer 94 (2002): 1492-1499

1.1.4                              Hematopoietic stem cell transplantation

Allogeneic stem cell transplantation is the treatment of choice for those patients with a suitable donor who are at a high risk of relapse in first CR, or are in early relapse, or following a second or later CR.

Literature: for review and representative studies e.g.

ARNOLD et al, Leukemia 16 (2002): 2423 – 2428( nonmyeloablative stem cell transplantation)

ATTAL et al, Blood 86 (1995): 1619-1628(randomized comparison of allogeneic vs autologous BMT as consolidation).

EGERER et al, Leuk Lymphoma 44 (2003): 9 – 14 (review of autologous BMT)

FIERE et al, J. Clin. Oncol. 11(1993): 1990 – 2001 (randomized comparison of allo or auto SCT or conventional CT as postremission therapy)

GORIN, Stem Cells 20(2002): 3 – 10 (review of autologous stem cell transplantation)

MARTIN and GAJEWSKI, Hematol. Oncol. Clin. North Am. 15 (2001): 97 – 120

(review of allogeneic stem cell transplantation)

MARTIN and LINKER, Hematol./ Oncol. Clin. North Am. 15 (2001): 121 – 143

(review of autologous transplantation)

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

__________________________________________________________________________________

Induction

Protocol 1

Phase A

Phase B (only in SR and MR)

Consolidation (in SR and MR)

Protocol M

Protocol M – A ****

Reinduction (in SR and MR)

Protocol II