LEUKEMIA: ACUTE LYMPHOBLASTIC ,Adult

 

Regimen/Number

Of Patients

Drug Dose and Route

Leukopenia/

Neutropenia

Toxicity

Anemia

Toxicity

Other

Grade III-IV Toxicities

Emetogenic

Potential

Consequences of

Adverse Event(s)

CALGB 9251

(Lee EJ, et al,

J Clin Oncol,

2001;19:4014-22)

 

 

N= 54

 

 

Cycle 1

Cyclophosphamide 200 mg/m2/d IV

days  1 – 5

Prednisone 60 mg/m2/d PO days 1 – 7

Neutropenia

Grade III 1%

Grade IV 93%

 

Infection

(Grade III) 57%

(Grade IV) 14%

(Grade V) 8%

Thrombocytopenia

(Grade IV) 85%

Diarrhea 13%

Stomatitis 66%

Esophagitis 36%

Anorexia 44%

Bilirubin 26%

Transaminase 22 %

Renal 9 %

Malaise 42%

Motor 28%

Cortical 14%

Other Neurologic 10 %

Days 1 – 5-

Level 3

 

 

 

 

 

 

 

 

Day 1 –

Level 5

Days 2, 3-

Level 3

Days 4, 5-

Level 4

 

79% of patients < 50 years old received 6 or 7 cycles of treatment, compared with only 32% of patients older than 50. Treatment was associated with higher rates of death (9% vs 21 %), disease progression (3% vs 32% ) , and toxicity (9% vs 16%) in older patients. 7% of patients died  of regimen toxicity between day 3  and day 105, 6 patients died of infection-related complications. Severe neurological toxicity occurred in   14% of patients . In 5 patients the toxicity  was transverse  myelitis, which was  progressive and  debilitating . In 2  patients the toxicity   was severe peripheral  neuropathy , in 3 patients the toxicity  was primarily central .

 

Cycle 2, 4, 6

Ifosfamide 800 mg/m2/ d  IV over 1 hour

days 1 – 5

Mesna 200 mg/m2/ d  IV at 0, 4, and 8 hours

after ifosfamide

Methotrexate 150 mg/m2/  IV

over 30 minuted day 1, followed by

methotrexate 1350 mg/m2/  IV over 23.5

hours (total dose 1500 mg/m2 ) day 1

Leucovorin 50 mg/m2/  IV, starting 36 hours

after the initiation of methotrexate,

then 15 mg/m2 q6h until methotrexate

is < 10-8 M

Vincristine 2 mg IV day 1

Cytarabine 150 mg/m2 /d IV continuous

Infusion on days 4, 5

Etoposide 80 mg/m2/d IV days 4, 5

Dexamethasone 10 mg/m2/d PO days 1 – 5

Intrathecal therapy

Methotrexate 15 mg on day 1 and day 5

Cytarabine 40 mg on day 1 and day 5

Hydrocortisone 50 mg on day 1 and day 5

Cycles 1 – 7 are administered at

21- day intervals

(continued)

 

Neutropenia

Grade III 1 %

Grade IV 93%

 

 

 

 

 

  

 

LEUKEMIA : ACUTE LYMPHOBLASTIC, ADULT  (continued ) : Page 2

 

Regimen/Number

Of Patients

Drug Dose and Route

Leukopenia/

Neutropenia

Toxicity

Anemia

Toxicity

Other

Grade III-IV Toxicities

Emetogenic

Potential

Consequences of

Adverse Event(s)

CALGB 9251

(Lee EJ, et al,

J Clin Oncol,

2001;19:4014-22)

 

 

N= 54

 

 

Cycle 3, 5, and 7

Cyclophosphamide 200 mg/m2/d IV

days  1 – 5

Methotrexate 150 mg/m2/  IV

over 30 minuted day 1, followed by

methotrexate 1350 mg/m2/  IV over 23.5

hours (total dose 1500 mg/m2 ) day 1

Leucovorin 50 mg/m2/  IV, starting 36 hours

after the initiation of methotrexate,

then 15 mg/m2 q6h until methotrexate

is < 10-8 M

Vincristine 2 mg IV day 1

Doxorubicin 25 mg/m2/d IV days 4, 5

Dexamethasone 10 mg/m2/d PO days 1 – 5

 

Intrathecal therapy

Methotrexate 15 mg day 1

Cytarabine 40 mg  day 1

Hydrocortisone 50 mg on day 1 and day 5

 

Cranial Irradiation

(see consequences section)

 

Cycles 1 – 7 are administered at

21- day intervals

 

 

 

 

Day 1 –

Level 5

Days 2, 3 –

Level 3

Days 4, 5 –

Level 4

Note: In the initial

regimen, intrathecal

therapy was

administered on day 1

and day 5 of cycles

2 – 7 , Due to a high

incidence of

neurotoxicity with

this regimen, it has

been subsequently

amended to give

only one IT injection

following cycles 2 to 7

(total of 6 doses ).

cranial irradiation is

reserved for those

patients with marrow

or CNS disease.

In this instance , the

irradiation is started

after the completion

of chemotherapy,

 

 

 


 

 

LEUKEMIA : ACUTE LYMPHOBLASTIC, ADULT  (continued ) : Page 3

 

Regimen/Number

Of Patients

Drug Dose and Route

Leukopenia/

Neutropenia

Toxicity

Anemia

Toxicity

Other

Grade III-IV Toxicities

Emetogenic

Potential

Consequences of

Adverse Event(s)

HD MTX – Ara-C

(Kantarjian HM, et al,

J Clin Oncol,

2000; 18: 547-61)

 

 

N= 204

 

Methotrexate 200 mg/m2 IV over 2 hours

day 1, followed by

Methotrexate 800 mg/m2 IV over 24 hours

day1

Calcium leucovorin 15 mg PO every 6 hours

x 8 doses starting 24 hours after completion

of the MTX infusion – dose adjusted

based on MTX levels .

Cytarabine 3000 mg/m2 IV over 2 hours

Every 12 hours on days 2 and 3 (4 doses

total)

Methylprednisolone 50 mg IV twice daily

days 1 – 3

G-CSF 5 mcg/kg SQ twice daily starting day

4 until ANC recovery

Cycle repeated when ANC > 3 x 109 / L and

platelets > 60x109 /L (approximately

3-4 weeks)

 

Notes:

Hyper-CVAD alternates with HD MTX-Ara-C

for a total of 8 cycles.

Corticosteroid eyedrops routinely

administered with cytarabine.

Refer to text for CNS prophylaxis and

maintenance therapy.

Refer to text for dose modification

of  MTX and Ara-C in patients with

renal dysfunction.

 

 

Sepsis 11%

Pneumonia 5%

Fungal Infections < 1 %

Fever of

Unknown Origin 23%

Rash 5%

Mucositis 5%

Neurotoxicity 5%

Rash and Desquamation

of Palms/ Feet 3%

Diarrhea 1%

Cytarabine- Associated

Fever 6%

Nephrotoxicity

(reversible ) 1.5%

Cytarabine

Neurotoxicity 2%

Day 1 –

Level 4

Days 2, 3 –

Level 5

Hospitalization for

adverse events in

42% of courses

MTX dose reduction

by 25% in 18% of

patients, by 50%

in 15% of patients

and by 75% in 3%

of patients

Median time to recovery

and delivery of the

next course was

22 days

 

 

LEUKEMIA : ACUTE LYMPHOBLASTIC, ADULT  (continued ) : Page 4

 

Regimen/Number

Of Patients

Drug Dose and Route

Leukopenia/

Neutropenia

Toxicity

Anemia

Toxicity

Other

Grade III-IV Toxicities

Emetogenic

Potential

Consequences of

Adverse Event(s)

Hyper – CVAD

(Kantarjian HM, et al,

J Clin Oncol

2000;18: 547-61)

 

N= 204

 

 

Cyclophosphamide 300 mg/m2 IV over

3 hours every 12 hours days 1 – 3

(total 6 doses )

Mesna 600 mg/m2 IV continuous infusion

days 1-3 - continue until 6 hours after

last dose of cyclophosphamide

Vincristine 2 mg IV days 4, 11

Doxorubicin 50 mg/m2 IV day 4

Dexamethasone 40 mg PO daily

days 1-4 and days 11-14

G-CSF 5 mcg/kg SQ twice daily starting 24

hours after the completion of chemotherapy

and continuing until ANC recovery

Altenate cycles of Hyper – CVAD with

HD MTX-Ara-C every 3-4 weeks

(when WBC> 3x 109 /L and platelet

Count > 60x 109/L)

 

 

Notes:

Antiviral, antibacterial, and antifugal

Prophylaxis routinely utilized.

Refer to reference text for CNS prophylaxis

and maintenance therapy.

Time to

granulocytes

1x109/L :

days after

the first cycle

 

Induction

Moderate – Severe

Mucositis 6%

Moderate –Severe

Diarrhea 3%

Disseminated Intravas-

cular Coagulopathy

Requiring Therapy 2%

 

Consolidation

Neurotoxicity 8%

G-CSF- Induced

Bone Pain 5%

 

Day 1-3-

level 3

Day 4 –

level 3

Day 11-

level 1

Induction

Hospitalization 63%

Documented infections:

Pneumonia 22%

Sepsis 15%

Fungal infection 4%

Other minor

infections 14%

Fever of unknown

Origin 45%

Median time to recovery

of granulocytes

days

 

Consolidation

Hospitalization 18%

Documented infections:

Pneumonia 2%

Sepsis 3%

Fungal infection 4%

Other minor

Infections 5 %

Fever of unknown

origin 8%

Median time to recovery

of granulocytes

days

 

 

 

LEUKEMIA : ACUTE LYMPHOBLASTIC, ADULT  (continued ) : Page 5

 

Regimen/Number

Of Patients

Drug Dose and Route

Leukopenia/

Neutropenia

Toxicity

Anemia

Toxicity

Other

Grade III-IV Toxicities

Emetogenic

Potential

Consequences of

Adverse Event(s)

Larson Regimen

(Larson RA, et al.

Blood.

1998;92:1556-64)

 

 

N= 198

(102 with G-CSF and

96 without G-CSF)

Course l : Induction ( 4 weeks )

Cyclophosphamide 1200 mg/m2 IV day 1*

Daunorubicin 45 mg/m2 / d IV days 1 -3 *

Vincristine 2 mg IV days 1, 8, 15, and 22

Prednisone 60 mg/m2/d PO days 1 – 21 *

L-Asparaginase (E coli) 6000 IU/m2 SQ/ IM

days 5, 8, 11, 15, 18, 22

G-CSF 5 mg/kg/d SQ, starting on day 4

and continuing until ANC ≥ 1000/mL on

2 consecutive days > 24 hours apart

 

For patients 60 years and older, reduce to

the following doses:

Cyclophosphamide 800 mg/m2 IV day 1

Daunorubicin 30 mg/m2/d IV days 1,2,3

Prednisone 60 mg/m2/d PO days 1 – 7

 

Course IIA: Early Intens : fication

(4 weeks ; repeat once for Course IIB)

IT methotrexate 15 mg day 1

Cyclophosphamide 1000 mg/m2 IV   day 1

5-Mercaptopurine 6 mg/m2/ d PO   days 1 – 14

Cytarabine 75 mg/m2/d SQ

days 1 – 4; 8 – 11

Vincristine 2 mg IV days 15, 22

L-Asparaginase (E coli) 6000 IU/m2 SQ /IM

days 15, 18, 22, 25

G-CSF 5 mcg /kg/d SQ, starting on day 2

and continuting for at least 14 days and

until ANC ≥ 5000/mL

(continued)

Leukopenia

(without G-CSF)

Grade III-V

97%

 

Leukopenia

(with G-CSF)

Grade III-V

98%

 

Grade III-V

With G-CSF

93%

With G-CSF

86%

 

 

Infection (Grade III-V)

with G-CSF 78%

withour G-CSF 87%

Thrombocytopenia

(Grade III- V)

With G- CSF 97%

Without G-CSF 95%

Nausea

( Grade III-V) 25.5%

Hyperbilirubinemia

(Grade III-V) 47.5

Transaminased

( > 5xULN) 35%

Malaise / Fatigue

(Grade III-V) 20.5%

 

 

Day 1 –

Level 5

Days 2-3-

Level 3

Days 5, 8,

11, 15,

18, 22

level 2

 

 

 

 

 

 

 

 

 

 

 

 

 

Day 1 –

Level 5

Days 2-4

and

11- 14-

Level 2

Days 5-11-

Level 1

Days 15, 18,

22, 25-

Level 2

Hematologic recovery

(G-CSF vs placebo):

ANC > 1000

16 vs 22 days

Duration neutropenia

vs 20 days

Platelets > 50,000

vs 19 days

Fever > 38.50C

3 vs 3 days

Hospitalization

22 vs 28 days

 

 

 

 

Hematologic recovery

(G-CSF vs placebo):

[median]):

ANC > 1000 /mL

vs 29 days

Duration  of

neutropenia

5 vs 13 days

Fever > 38.50C

0 vs 0 days

Hospitalization

7 vs 3 days

 

 

LEUKEMIA : ACUTE LYMPHOBLASTIC, ADULT  (continued ) : Page 6

 

Regimen/Number

Of Patients

Drug Dose and Route

Leukopenia/

Neutropenia

Toxicity

Anemia

Toxicity

Other

Grade III-IV Toxicities

Emetogenic

Potential

Consequences of

Adverse Event(s)

Larson Regimen

(Larson RA, et al,

Blood.

1998;92:1556-64)

 

 

N= 198

(102 with G-CSF and

96 without G-CSF)

Course III; CNS Prophylaxis  and

Interim Maintenance  (12 weeks)

Cranial irradiation 2400 cGy days 1 – 12

IT methotrexate 15 mg days 1, 8, 15, 22, 29

6- Mercaptopurine 60 mg/m2/d PO

days 1 – 70

Methotrexate 20 mg/m2 PO

days 36, 43, 50, 57, 64

 

 

Course IV; Late Intensification (8 weeks)

Doxorubicin 30 mg/m2 IV days 1, 8, 15

Vincristine 2 mg IV days 1, 8, 15

Dexamethasone 10 mg/m2/d PO days 1 – 14

Cyclophosphamide 1000 mg/m2 IV day 29

6- Thioguanine 60 mg/m2/d PO days 29-42

Cytarabine 75 mg/m2/d SQ days 29-32,

36-39

 

Course IV; Late Intensification (8 weeks)

(until 24 months from diagnosis )

Vincristine 2 mg IV day 1 of every

4 week period

Prednisone 60 mg/m2 /d PO days 1 – 5 of

every 4 – week period

6-Mercaptopurine 60 mg/m2/d PO days 1 -28

Methotrexate 20 mg/m2 PO days 1, 8, 15, 22

 

 

 

 

Days 1 -70-

Level 1

 

 

 

 

 

 

 

Days 1,8,15

level 3

Day 29 –

Level 5

Days 30-32

and 36-39

level 2

Days 34-35

and 40-42

level 1

 

 

Days 1-28 –

Level 1

 

 

Interval of study to the

beginning of Course III

106 vs 108 days