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 7075% 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 (  

        Burkitts ALL)

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

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

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

        cytarabine in induction therapy)

        HALLBK 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 GKBUGET, 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

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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

Daunorubicin                                 45 mg/m  i.v.                          d 1-3

Vincristine                                       2 mg         i.v.                          d 1,8- 15,22

Prednisone                                       60 mg/m  p.o.                       d  1- 35

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)

Dexamethasone                 10mg/m        p.o.(divided in                  d  1-3

                                                                  3 doses)

Also with additional cyclophosphamide

 

Induction phase I

Dexamethasone                 10mg/m        p.o.(divided in                  d  4, 5, 11-14

                                                                  3 doses)

Vincristine                           2 mg                i.v.                                  d 4, 11, 18

Daunorubicin                       45 mg/m        i.v. (15 min inf)              d 4 , 5, 11, 12

PEG- aspara-                       500-1000 IU/m i.v.(2 h inf)                  d 18

ginase

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

 

Induction phase II

Cyclophosphamide              1000mg/m      i.v.(1 h inf)                    d 24, 44

                                                                     With mesna uroprotection

Cytarabine                          75 mg/m         i.v. (1 h inf)                    d 26-29, 33-36,40-43

Mercaptopurine                  60 mg/m         p.o.                                 d 24- 44

With G- CSF

 

CNS Prophylasix

Methotrexate                      15 mg/m      i.th.                                d 1, 26, 33, 40

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

Dexamethasone             10mg/m             P.O.(divided in                d  1-5

                                                                   3 doses)

Vindesine                      3mg/m                i.v.                                  d  1

                                   (max 5 mg)

Methotrexate                 1500 mg/m         i.v.(24 h inf *)                d  1

                                                                   With folinic acid rescue

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

Etoposide                       250mg/m            i.v. (1 h inf)                   d 4+5

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

Methotrexate                1500 mg/m           i.v.(24 h inf *)              d 1+15

                                                                    With folinic acid rescue

PEG- asparaginase       500 IU/m              i.v. (2  h  inf)                d 2 + 16

Mercaptopurine            60 mg/m               p.o.                               d 1-7 , 15 21

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

 

Reinduction Phase I : week  22 + 23

Prednisolone *              20 mg/m               t.i.d. p.o.                      d  1 14

Vindesine                      3 mg/m                 i.v.                               d  1,7

                                      (max 5 mg)

Doxorubicin                  50 mg/m               i.v. (15 min inf)           d  1,7

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 

Cyclophosphamide           1000 mg/m          i.v. ( 1 h inf)                d 1

                                                                     With mesna uroprotection

Cytarabine                       75 mg.m              i.v. ( 1 h inf)                  d 3-6 , 10 13

Thioguanine                    60 mg/m              p.o.                                 d 1-14

Plus intrathecal CNS prophylaxis on  d 1 , 15

 

Consolidation IV : week  36

Cytarabine                      150 mg/m             i.v. (1 h inf)                    d  1-5 then

Teniposide                      100 mg/m             i.v. (1 h inf)                    d 1-5

Plus intrathecal CNS prophylaxis on d 1

 

Consolidation v : week  41

Cyclophosphamide         1000 mg/m           i.v. (1 h inf)                    d 1

                                                                      With mesna uroprotection

Cytarabine                      500 mg/m             i.v. (24 h inf)                   d 3-6, 10- 13 

Plus intrathecal CNS prophylaxis on  d  1

 

 

 

AcuteLymphoblasticLeukemia(ALL)                                                                                                  7

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High and very high risk group

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

 

Consolidation II: Week 16

Ifosfamide                        1000 mg/m           i.v. (1 h inf)                 d  1-5

                                                                        With mesna uroprotection

Cytarabine                        100 mg/m             i.v. (1 h inf)                d  1-5

Plus intrathecal CNS prophylaxis on  d 1

 

or

 

Idarubicin                         10 mg/m               i.v. (15 min inf)          d  1,3

Fludarabine                       30 mg/m              i.v. (1 h inf)                d 1-5(4 h before)

Cytarabine                        2000 mg/m          i.v.(2 h inf)                 d  1-5

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

Plus intrathecal CNS prophylaxis on d 1

 

CNS Prophylaxis ( for all risk groups)

Methotrexate                    15 mg                   i.th.                             d 1 (+15)*

Cytarabine                        40 mg                   i.th                              d 1 (+15)*

Dexamethasone                 4  mg                   i.th                              d 1 (+15)*

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.

Mercaptopurine                 60 mg/m             p.o.                            daily

Methotrexate                     20 mg/m             i.v.                             weekly

 

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

Prednisolone                    20 mg/m               t.i.d.p.o.                    d  1-5

Cyclophosphamide          200 mg/m             i.v.                            d  1-5

Immediately followed by

 

 

8                                                                                                       Acute Lymphoblastic Leukemia (ALL) ____________________________________________________________________________________

 

Block A

Vincristine                 2mg                     i.v.                                           d  1

Methotrexate              1500 mg/m        i.v.(cont inf )                            d 1

                                                               With folinic acid rescue

Ifosfamide                  800 mg/m           i.v. (1 h inf)

                                                                With mesna uroprotection     d 1 5

Teniposide                  100 mg/m           i.v. (1 h inf)                            d 4 + 5

Cytarabine                   150 mg/m          b.i.d.i.v. (1 h inf)                    d  4 + 5

Dexamethasone            10 mg/m           p.o                                          d 1 5

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

 

After 2 weeks

 

Block B

Vincristine                    2mg                     i.v.                                         d 1

Methotrexate                3000 mg/m         i.v.(cont inf)                          d 1

                                                                  With folinic acid rescue

Cyclophosphamide       200 mg/m           i.v.                                         d 1 - 5

Doxorubicin                  25 mg/m             i.v.(15 min inf)                     d 4 + 5

Dexamethasone             10 mg/m             p.o.                                       d 1 5

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

Vindesine                     3 mg                     i.v.                                         d 1

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

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

Dexamethasone             10 mg/m             p.o.                                       d 1 5

 

1.1.3.2                       Hyper CVAD

Course 1 , 3, 5, 7

Cyclophosphamide          300 mg/m        b.i.d.i.v. (2 h inf)                  d 1 - 3

                                                                   With mesna uroprotection

Vincristine                         2 mg                 i.v.                                        d 4 + 11

Doxorubicin                  50 mg/m            i.v.(2 h inf)                              d 4

Dexamethasone             40 mg              i.v. or p.o.                             d 1 4 , 11-14

 

Course 2 , 4 , 6 , 8

Methotrexate                  1000 mg/m          i.v.(24 h inf)                         d 1

                                                                     With folinic acid rescue

Cytarabine                      3000 mg/m          b.i.d. i.v. (2 h inf)                 d 2 +3

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

 

CNS prophylaxis

Methotrexate                  12mg                       i.th                                   d 2

                                                                        (6 mg via Ommaya)       

Cytarabine                      100 mg                    i.th                                   d 7

Of each course for all 8 courses

 

Acute Lymphoblastic Leukemia (ALL)                                                                                                  9

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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 Burkitts 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)