Chapter 17: Leukemia, Acute Lymphoblastic (ADULT)

Michael M. Boyiadzis; Ivan Aksentijevich; Judith Karp

INTRODUCTION

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Epidemiology

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Epidemiology

Incidence:

6,020 (male: 3,140; female: 2,880. Estimated new cases for 2014 in the United States)

1.7 per 100,000 male and female per year (1.9 per 100,000 male, 1.5 per 100,000 female)

Deaths:

Estimated 1,440 in 2014 (male: 810; female: 630)

Median age:

B-cell lymphoblastic leukemia/lymphoma: 12 years

T-cell lymphoblastic leukemia/lymphoma: 18 years

Lymphoblastic leukemia/lymphoma unknown lineage: 12 years

Age-specific incidence patterns are characterized by a peak between the ages of 2 and 4 years and again during the sixth decade

Male to female ratio:

1.33

Dores GM. Blood 2012;119:34–43

Siegel R et al. CA Cancer J Clin 2014;64:9–29

Surveillance, Epidemiology and End Results (SEER) Program, available from http://seer.cancer.gov (accessed in 2013)

Work-up

H&P
CBC, leukocyte differential, platelets, electrolytes, liver function tests, PT, PTT, fibrinogen, LDH, uric acid
Bone marrow biopsy/aspirate
HLA typing for patients who are candidates for allogeneic hematopoietic cell transplantation
Cardiac scan if prior cardiac history or prior anthracycline use
CT/MRI of head if neurologic symptoms
CT chest for T-ALL patients

Pathology

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Pathology

Common Chromosomal and Molecular Abnormalities in ALL

Cytogentics

Gene

Frequency in Adults

Frequency in Children

Hyperdiploidy

–

25%

Hypodiploidy

–

t(9;22)(q34;q11) Philadelphia chromosome (Ph)

BCR-ABL1

25%

t(12;21)(p13;q22)

TEL-AML1

22%

t(v;11q23), e.., t(4;11), t(9;11), t11;19)

MLL

10%

t(1;19)

E2A-PBX1

t(5;14)(q31;q32)

IL3-IGH

<1%

t(8;14), t(2;8), t(8;22)

c-MYC

t(1;14)(p32;q11)

TAL-1^✫

12%

t(10;14)(q24;q11)

HOX11^✫

t(5;14)(q35;q32)

HOX11L2^✫

^✫Abnormalities observed exclusively in T-cell lineage ALL; all other occur exclusively or predominately in B-cell linage ALL

Prognostic Factors for Risk Stratification of Adult ALL

Characteristics

High Risk Factors

Age

>35 years

Leukocytosis

>30,000 mm³ (B lineage)

>100,000 mm³ (T lineage)

Karyotype

t(9;22), t(4;11) (q21;q23), complex, hypodiploid

Therapy response

Time to morphology CR >4weeks

Persistent minimal residual disease (MRD)

Expert Opinion

Treatment regimens for acute lymphoblastic leukemia (ALL) have evolved empirically into complex schemes that use numerous agents in various doses, combinations, and schedules, and few of the individual components have been tested rigorously in randomized trials. However, the backbone of chemotherapy for ALL remains the sequence of induction, consolidation, and maintenance

Remission induction: Most regimens include steroids, vincristine, an anthracycline, and usually asparaginase. Cyclophosphamide and cytarabine are often added. The combination of these agents results in CR rate to 80–90%; thus, treating physicians should use a regimen with which they are familiar and have experience in providing supportive care. See table below for different adult ALL regimens

Consolidation: Eradication of minimal residual disease during hematologic remission is the primary aim of the consolidation phase. It is difficult to assess the value of individual components of treatment because the number, schedule, and combination of antineoplastic drugs vary considerably among studies. Consolidation therapy typically consists of several cycles of treatment similar to, but often less intensive than, the drugs, dosages, and administration schedules given during induction, and consolidation usually is better tolerated than induction

Maintenance: Maintenance therapies are important for patients not undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Maintenance regimens consist of combinations of mercaptopurine, methotrexate, vincristine, and steroids given continually for 2–3 years. Patients with the genetic defect of thiopurine methyltransferase (TPMT) are more sensitive to myelosuppressive effects of mercaptopurine and should be consider for testing for TPMT gene polymorphisms

Myeloablative allo-HCT should be considered for adult patients with ALL in first clinical remission (CR) for all disease risk groups. Allo-HCT provides a significant improvement in overall and leukemia-free survival in younger patients (ages <35 years), standard risk, patients with Philadelphia chromosome (Ph)-negative ALL compared with less-intensive chemotherapy regimens. In older (ages >35 years) patients with standard risk, Ph-negative ALL, a higher treatment related mortality diminishes the significant survival advantage with allo-HCT

Cooperative group analysis have consistently demonstrated superior outcomes for adolescent and young adult (AYA) patients with ALL when treated with pediatric versus adult ALL regimens. Thus AYA patients should be treated with pediatric-based treatment protocols in clinical trials

Note: Mature B-cell ALL: Patients with mature B-cell ALL (Burkitt cell leukemia, L3) experience improvement in survival rate when high doses of cyclophosphamide, methotrexate, and cytarabine are incorporated early in treatment. The probability of leukemia-free survival improved with standard ALL induction from 35% to 60–70% with these agents. No maintenance therapy is given to patients with mature B-cell ALL since relapse occurs early and most patients are cured after approximately 1.5 years

Philadelphia chromosome-positive acute lymphoblastic leukemia: Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) are a distinct disease subgroup comprising 20–30% of adults. Chemotherapy regimens that have combined tyrosine kinase inhibitors (TKIs) offer enhanced CR rates and a greater opportunity for patients to proceed to allo-HCT. The potential benefits of allo-HCT in patients with Ph+ ALL have been described in several studies. For patients who receive allo-HCT DFS and OS always appear better than would be expected with chemotherapy alone. For patients who are too old or unfit for allo-HCT, TKIs should be continued without interruption in addition to whatever components of standard maintenance therapy can be tolerated

Patients with relapsed ALL have a poor prognosis with standard salvage therapy. Response rates to salvage chemotherapy range from 30–70% but are generally short-lived with a median survival of 6 months. Patients in second CR should be considered for allo-HCT

Studies in adults with ALL have demonstrated the strong correlation between minimal residual disease (MRD) and risks of relapse. The timing of MRD assessment varies depending on the ALL regimen protocol being used, and may occur during or after completion of initial induction therapy. For MRD evaluation by multicolor flow cytometry, sampling of bone marrow mononuclear cells is preferred over peripheral blood samples. For MRD evaluation by RQ-PCR, sampling of bone marrow mononuclear cells is preferred. The minimal limit of assay sensitivity (to declare MRD negativity) should be <1 × 10⁴, <0.01%)

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Results of Clinical Trials in Adult ALL

Rowe JM. Br J Haematol 2009;144:468–483

Study

Year

Median Age (range [Years])

SCT

CR Rate

Early Death

Survival

CALGB 9111, USA

1998

198

35 (16–83)

Ph+

85%

40% (3 years)

Larson RA et al. Blood 1998;92:1556–1564

LALA 87, France

2000

572

33 (15–60)

76%

27% (10 years)

Thiebaut A et al. Hematol Oncol Clin North Am 2000;1353–1366

NILG 08/96, Italy

2001

121

35 (15–74)

84%

48% (5 years)

Bassan R et al. Hematol J 2001;2:117–126

GMALL 05/93, Germany

2001

1163

35 (15–65)

83%

35% (5 years)

Goekbuget N et al. Blood 2001;98 [abstract 3338]

JALSG-ALL93, Japan

2002

263

31 (15–59)

78%

30% (6 years)

Takeuchi J et al. Leukemia 2002;16:1259–1266

UCLA, USA

2002

27 (16–59)

93%

47% (5 years)

Linker C et al. J Clin Oncol 2002;20:2464–2471

Sweden

2002

153

42 (16–82)

75%

28% (5 years)

Hallböök H et al. Br J Haematol 2002;118:748–754

GIMEMA 0288, Italy

2002

767

28 (12–60)

—

82%

11%

27% (9 years)

Annino L et al. Blood 2002;99:863–871

MD Anderson, USA

2004

288

40 (15–92)

Ph+

92%

38% (5 years)

Kantarjian H et al. Cancer 2004;101:2788–2801

EORTC ALL-3, Europe

2004

340

33 (14–79)

74%

36%^✫ (6 years)

Labar B et al. Haematologica 2004;89:809–817

LALA 94, France

2004

922

33 (15–55)

84%

36% (5 years)

Thomas X et al. J Clin Oncol 2004;22:4075–4086

GOELAL02, France

2004

198

33 (15–59)

86%

41% (6 years)

Hunault M et al. Blood 2004;104:3028–3037

MRC XII/ECOG E 2993, UK-USA

2005

1521

31 (15–64)

91%

4Æ8%

38% (5 years)

Rowe JM et al. Blood 2005;106:3760–3767

GIMEMA 0496, Italy

2005

450

16–60

80%

33% (5 years)

Mancini M et al. Blood 2001;98:[abstract 3492]

Pethema ALL-93, Spain

2005

222

27 (15–50)

82%

34% (5 years)

Ribera J-M et al. Haematologica 2005;90:1346–1356

PALG 4–2002, Poland

2008

131

26 (17–60)

90%

43% (3 years)

Holowiecki J et al. Br J Haematol 2008;142:227–237

Total of all studies (using weighted mean)

7393

84%

35%

Ph+, SCT in Philadelphia chromosome positive-ALL; PO, prospective SCT in all patients with donors; PR, SCT according to prospective risk model; HR, prospective SCT in a study for high-risk patients only; NR, not reported

Central nervous system involvement: Up to 10% of adults with ALL present with CNS involvement at the time of diagnosis. The cumulative risk of CNS leukemia in patients who do not receive prophylaxis can be as high as 50%. Factors associated with increased risks for CNS leukemia in adults include mature B-cell immunophenotype, T-cell immunophenotype, high presenting WBC count, and elevated serum LDH levels. CNS involvement should be evaluated by lumbar puncture at the appropriate timing in accordance with the specific treatment protocol used and when LP is performed intrathecal therapy administered concomitantly. Adult patients with ALL and CNS involvement at diagnosis require CNS-directed therapy starting at the same time as induction therapy. Treatment and prophylaxis of CNS involvement may consist of intrathecally administered methotrexate either alone or combined with intrathecally administered cytarabine or corticosteroids and/or intravenously administered high-dose cytarabine, high-dose cytarabine methotrexate. With the incorporation of adequate systemic chemotherapy and intrathecal chemotherapy regimens, it is possible to avoid the use of upfront cranial irradiation except for cases of overt CNS leukemia at presentation and reserve the use of irradiation for salvage therapy settings. Allo-HCT is indicated in patients with isolated CNS relapse and is probably the only curative approach for some patients, because of the high risk of occult marrow contamination at the time of CNS progression

Bassan R, Hoelzer D. J Clin Oncol 2011;29:532–543

Fielding AK. Blood 2010;116:3409–3417

Fielding AK. Hematol Oncol Clin North Am 2011;25:1255–1279

Gökbuget N, Hoelzer D. Semin Hematol 2009;46:64–75

Oliansky DM et al. Biol Blood Marrow Transplant 2012;18:18–36

Rowe JM. Br J HaematolBr J Hematol 2009;144:468–483

Rowe JM. Br J HaematolBr J Hematol 2010;150:389–405

PROPHYLAXIS AGAINST TUMOR LYSIS SYNDROME: HYDRATION, URINARY ALKALINIZATION, AND ALLOPURINOL ADMINISTRATION

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Prophylaxis Against Tumor Lysis Syndrome: Hydration, Urinary Alkalinization, and Allopurinol Administration

Hydration with 2500–3000 mL/m² per day as tolerated; administer intravenously to maintain urine output ≥100 mL/m² per hour (or ≥2 mL/kg per hour in persons whose body weight is <50 kg)

Urinary alkalinization with sodium bicarbonate injection added to intravenously administered fluids

The amount of sodium bicarbonate added to intravenously administered fluids should produce a solution with sodium content not greater than the concentration of sodium in 0.9% sodium chloride injection (≤154 mEq/L):

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Sodium Bicarbonate is Added to a Solution to Increase Urine pH within a Range 6.5 to ≤7

Base Solution Sodium Content

Sodium Bicarbonate Additive

Total Sodium Content

0.45% Sodium Chloride Injection (0.45% NS)

77 mEq/L

50–75 mEq

127–152 mEq/L

0.2% Sodium Chloride Injection (0.2% NS)

34 mEq/L

100–125 mEq

134–159 mEq/L

5% Dextrose injection (D5W)

125–150 mEq

125–150 mEq/L

D5W/0.45% NS

77 mEq/L

50–75 mEq

127–152 mEq/L

D5W/0.2% NS

34 mEq/L

100–125 mEq

134–159 mEq/L

Notes:

Hydration rate may be decreased at the completion of chemotherapy administration
Urinary alkalization increases the solubility and excretion of uric acid and its oxypurine precursors (hypoxanthine and xanthine) and helps avoid uric acid crystallization in renal tubules; however, alkalinization is not uniformly recommended because:
1. It favors precipitation of calcium phosphate in renal tubules, a concern in patients with concomitant hyperphosphatemia
2. A metabolic alkalemia may result from the administration of bicarbonate that can worsen the neurologic manifestations of hypocalcemia
Discontinue sodium bicarbonate administration (while continuing hydration) if serum bicarbonate concentration is >30 mEq/L (>30 mmol/L) or urine pH >7.5

Allopurinol

Administer orally or intravenously starting 12 hours to 3 days (preferably, 2–3 days) before starting cytoreductive chemotherapy
Hyperuricemia develops within 24 to 48 hours after initiating chemotherapy when the excretory capacity of the renal tubules for uric acid is exceeded
In the presence of an acid pH, uric acid crystals form in the renal tubules, leading to intraluminal renal tubular obstruction, an acute renal obstructive uropathy, and renal dysfunction
Initial dosage

Allopurinol 100 mg/m² per dose; administer orally every 8 hours (maximum daily dose = 800 mg), or

Allopurinol 3.3 mg/kg per dose; administer orally every 8 hours (maximum daily dose = 800 mg), or

Allopurinol 200–400 mg/m² per day; administer intravenously (maximum daily dose = 600 mg) in a volume of 5% dextrose injection or 0.9% sodium chloride injection sufficient to yield a concentration not greater than 6 mg/mL. The duration for administering individual doses should be informed by the volume to be given
- Allopurinol may be administered as a single daily dose, or the total daily dose may be divided equally for administration at 6-, 8-, or 12-hour intervals
Maintenance doses should be based on serum uric acid determinations performed approximately 48 hours after initiation of allopurinol therapy, and periodically thereafter
Continue administering allopurinol until leukemic blasts have been cleared from the peripheral blood

Notes:

Allopurinol dose adjustments for impaired renal function:

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Creatinine Clearance

Oral Allopurinol Dose

10–20 mL/min (0.17–0.33 mL/s)

200 mg/day

3–10 mL/min (0.05–0.17 mL/s)

100 mg/day

<3 mL/min (<0.05 mL/s)

100 mg every 36–48 hours

Allopurinol does not remove uric acid already present
The incidence of allergic reactions is increased in patients receiving amoxicillin, ampicillin, or thiazide diuretics

Rasburicase

Rasburicase is recombinant urate oxidase (uricase) produced by genetically modified Saccharomyces cerevisiae that express urate oxidase cDNA cloned from a strain of Aspergillus flavus
Uricase enzymes catalyze uric acid oxidation to allantoin, which is at least 5-times more soluble than uric acid

Rational utilization

Rasburicase should be considered among initial interventions against hyperuricemia in patients with high peripheral WBC counts, rapidly increasing blasts counts, high uric acid, or with evidence of impaired renal function; that is:

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Burkitt leukemia

WBC count ≥100,000/mm³

WBC count <100,000/mm³ + LDH ≥2 × ULN

WBC count <100,000/mm³ + LDH <2 × ULN +

acute kidney injury

normal renal function + uric acid > ULN, or potassium > ULN, or phosphorus > ULN

ULN, upper limit of normal

See Chapter 46, Oncologic Emergencies

Rasburicase 0.2 mg/kg per dose intravenously in a total volume of 50 mL 0.9% sodium chloride injection over 30 minutes once daily for up to 5 consecutive days is often used, but much less is usually sufficient (See Chapter 46, Oncologic Emergencies) (dosage and administration recommendations published in U.S. Food and Drug Administration product labeling, January 2011)

Rasburicase has demonstrated effectiveness in prophylaxis and treatment for hyperuricemia and acute increases in uric acid associated with cytoreductive therapies at dosages <0.2 mg/kg based on body weight, with fixed doses, and after administration of from 1–3 doses

See Chapter 46 for more information

Cairo MS, Bishop M. Br J Haematol 2004;127:3–11

Cairo MS et al. Br J Haematol 2010;149:578–586

Coiffier B et al. J Clin Oncol 2008;26:2767–2778

Klinenberg JR et al. Ann Intern Med 1965;62:639–647

REGIMEN: LARSON REGIMEN

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Regimen: Larson Regimen

Larson RA et al. Blood 1998;92:1556–1564

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Course I, Induction (1 course, 4 weeks in duration)

Treatment Stratified by Patient Age

<60 years

≥60 years

Cyclophosphamide 1200 mg/m²; administer intravenously in 100–250 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 15–30 minutes on day 1 (total dosage/course = 1200 mg/m²)

Daunorubicin 45 mg/m² per day; administer by intravenous injection over 3–5 minutes for 3 consecutive days, on days 1–3 (total dosage/course = 135 mg/m²)

Prednisone 60 mg/m² per day; administer orally, continually, for 21 consecutive days, on days 1–21 (total dosage/course = 1260 mg/m²)

Cyclophosphamide 800 mg/m²; administer intravenously in 100–250 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 15–30 minutes on day 1 (total dosage/course = 800 mg/m²)

Daunorubicin 30 mg/m² per day; administer by intravenous injection over 3–5 minutes for 3 consecutive days, on days 1–3 (total dosage/course = 90 mg/m²)

Prednisone 60 mg/m² per day; administer orally, continually, for 7 consecutive days, on days 1–7 (total dosage/course = 420 mg/m²)

All Patients

Vincristine 2 mg per dose; administer by intravenous injection over 1–2 minutes for 4 doses, on days 1, 8, 15, and 22 (total dose/course = 8 mg)

Asparaginase 6000 IU/m² per dose; administer intramuscularly, or intravenously in 10–50 mL 0.9% NS or D5W over at least 30 minutes for 6 doses, on days 5, 8, 11, 15, 18, and 22 (total dosage/course = 36,000 IU/m²)

Filgrastim 5 mcg/kg per day; administer by subcutaneous injection for at least 7 consecutive days. Start on day 4, at least 12 hours after the last dose of daunorubicin, and continue after the ANC nadir until the ANC is ≥1000/mm³ on 2 consecutive days (measurements ≥24 hours apart)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on day 1 is HIGH. Potential for delayed symptoms

Emetogenic potential on days 2 and 3 is MODERATE

Emetogenic potential on days with asparaginase ± vincristine is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with:

Filgrastim (G-CSF) 5 mcg/kg per day, by subcutaneous injection

Begin use on day 4
Continue daily filgrastim use for at least 7 days, and until ANC ≥1000/mm³ on 2 measurements separated temporally by ≥24 hours
Discontinue daily filgrastim use at least 24 hours before administering myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Courses IIA and IIB, early intensification (2 courses, each is 4 weeks in duration)

Methotrexate 15 mg; administer intrathecally via lumbar puncture in 3–15 mL preservative-free 0.9% sodium chloride injection (PF 0.9% NS) on day 1, every 4 weeks for 2 courses (total dose/course = 15 mg)

Cyclophosphamide 1000 mg/m²; administer intravenously in 100–250 mL 0.9% NS or D5W over 15–30 minutes on day 1, every 4 weeks for 2 courses (total dosage/course = 1000 mg/m²)

Mercaptopurine 60 mg/m² per day, administer orally, continually, for 14 consecutive days, days 1–14, every 4 weeks for 2 courses (total dosage/course = 840 mg/m²)

Cytarabine 75 mg/m² per dose; administer by subcutaneous injection for 8 doses on days 1–4 and days 8–11, every 4 weeks for 2 courses (total dosage/course = 600 mg/m²)

Vincristine 2 mg per dose; administer by intravenous injection over 1–2 minutes for 2 doses, on days 15 and 22, every 4 weeks for 2 courses (total dose/course = 4 mg)

Asparaginase 6000 IU/m² per dose; administer intramuscularly, or intravenously in 10–50 mL 0.9% NS or D5W over at least 30 minutes for 4 doses, on days 15, 18, 22, and 25, every 4 weeks for 2 courses (total dosage/course = 24,000 IU/m²)

Filgrastim 5 mcg/kg per day; administer by subcutaneous injection for at least 14 consecutive days. Start on day 2, and continue after the ANC nadir until the ANC is ≥5000/mm³ on 2 consecutive days (measurements ≥24 hours apart)

Note: In all cases, filgrastim should be discontinued at least 2 days before cyclophosphamide administration resumed on the first day of the second early intensification course

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on Day 1 is MODERATE

Emetogenic potential on days with cytarabine is LOW

Emetogenic potential on days with mercaptopurine alone is MINIMAL–LOW

Emetogenic potential on days with asparaginase ± vincristine is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with:

Filgrastim (G-CSF) 5 mcg/kg per day, by subcutaneous injection

Begin use on day 2
Continue daily filgrastim use for at least 14 days, and until ANC ≥5000/mm³ on 2 measurements separated temporally by ≥24 hours
Priority was given to starting the second course (Course IIB) 28 days after the first began
- For patients whose ANC recovers to ≥1000/mm³ and platelet count ≥50,000/mm³ 28 days after starting the first course (Course IIA), the second course of therapy began on the 29^th day of Course IIA even if they had not yet recovered an ANC ≥5000/mm³ by day 27
Discontinue daily filgrastim use at least 2 days before restarting myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Course III, CNS prophylaxis and interim maintenance (1 course, 12 weeks in duration)

Cranial irradiation 2400 cGy (total dose), delivered during 12 consecutive days, days 1–12

Methotrexate 15 mg per dose; administer intrathecally via lumbar puncture in 3–15 mL preservative-free 0.9% sodium chloride injection for 5 doses, on days 1, 8, 15, 22, and 29 (total dose/course = 75 mg)

Mercaptopurine 60 mg/m² per day; administer orally, continually, for 70 consecutive days, days 1–70 (total dosage/course = 4200 mg/m²)

Methotrexate 20 mg/m² per dose; administer orally, for 5 doses, on days 36, 43, 50, 57, and 64 (total dosage/course = 100 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Course IV, late intensification (1 course, 8 weeks in duration)

Doxorubicin 30 mg/m² per dose; administer by intravenous injection over 3–5 minutes for 3 doses, on days 1, 8, and 15 (total dosage/course = 90 mg/m²)

Vincristine 2 mg per dose; administer by intravenous injection over 1–2 minutes for 3 doses, on days 1, 8, and 15 (total dose/course = 6 mg)

Dexamethasone 10 mg/m² per day; administer orally, continually, for 14 consecutive days, days 1–14 (total dosage/course = 140 mg/m²)

Cyclophosphamide 1000 mg/m²; administer intravenously in 100–250 mL 0.9% NS or D5W over 15–30 minutes on day 29 (total dosage/course = 1000 mg/m²)

Thioguanine 60 mg/m² per day; administer orally, continually, for 14 consecutive days, days 29–42 (total dosage/course = 840 mg/m²)

Cytarabine 75 mg/m² per dose; administer by subcutaneous injection for 8 doses on days 29–32 and days 36–39 (total dosage/course = 600 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on Days 1, 8, 15, and 29 is MODERATE

Emetogenic potential on Days 30–32 and 36–39 is LOW

Emetogenic potential on days with thioguanine alone is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

During the intervals between doses of doxorubicin, and the interval from days 16 through 28
Discontinue daily filgrastim use at least 24 hours before administering myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Course V, prolonged maintenance (courses are 4 weeks in duration and are repeated until 24 months after diagnosis)

Vincristine 2 mg per dose; administer by intravenous injection over 1–2 minutes, on day 1, every 4 weeks (total dose/course = 2 mg)

Prednisone 60 mg/m² per day; administer orally, continually, for 5 consecutive days, on days 1–5, every 4 weeks (total dosage/course = 300 mg/m²)

Mercaptopurine 60 mg/m² per day; administer orally, continually, for 28 consecutive days, days 1–28, every 4 weeks (total dosage/course = 1680 mg/m²)

Methotrexate 20 mg/m² per dose; administer orally, for 4 doses, on days 1, 8, 15, and 22, every 4 weeks (total dosage/course = 80 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Patient Population Studied

102 patients (median age 35 years) with newly diagnosed ALL

Efficacy (N = 102)

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Efficacy (N = 102)

Induction Course

Complete CR (n = 97^✫)

90%

≥60 years (n = 21)

81%

<60 years (n = 76)

89%

Refractory disease (n = 102)

Died during induction (n = 102)

DFS, median

2.3 years

DFS Ph+ patients, median

0.8 years

Overall survival, median

2.4 years

^✫Among 102 patients randomly assigned to receive filgrastim during induction and early intensification courses, 97 patients were eligible for comparisons with patients who did not receive filgrastim

Adverse Effects of Remission Induction

Grades 3 & 4 or Grade 5 Toxicity

WBC (<1000/mm³)

Platelets (<25,000/mm³)

Hemoglobin (<6.5 g/dL)

Infection

Nausea

Bilirubin (>1.5 times NL)

Transaminase (>5 times NL)

Malaise/fatigue (PS >2)

Motor neuropathy

Pain

Hyperglycemia (>250 mg/dL)

Hypofibrinogenemia (<0.5 times NL)

Adverse Effects of Intensification and Maintenance

Grades 3 & 4 Toxicities

Intensification

Maintenance

Leucopenia

Thrombocytopenia

Anemia

Hemorrhage

Infection

Nausea/vomiting

Stomatitis

Diarrhea

Hepatic

Pulmonary

Cardiac

Genitourinary

CNS

Peripheral nervous system

Skin

Allergy

Data from 197 newly diagnosed ALL patients who were treated with the same chemotherapy regimen but did not receive filgrastim Larson RA et al. Blood 1995;85:2025–2037

Therapy Monitoring

CBC with differential daily during and after chemotherapy until recovery of ANC >500/mm³. Platelets every day while in hospital until patients no longer require platelet transfusions
Serum electrolytes, mineral panel, and uric acid, at least daily during active treatment until the risk of tumor lysis is past
Amylase and fibrinogen levels prior to asparaginase administration. If fibrinogen level is <100 mg/dL (<1 g/L) consider prophylactic administration of cryoprecipitate
Bone marrow aspirate and biopsy at day 29 of the initial induction course. After a patient achieves a CR, bone marrow biopsy and aspirate should be performed at the end of each consolidation cycle (or at the very least, every other cycle), and every 3 months during maintenance therapy

Treatment Modifications

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Treatment Modifications

Adverse Events

Treatment Modifications

Creatinine 1.5–2 mg/dL (133–177 μmol/L)

Reduce methotrexate dosage by 25%

Creatinine >2 mg/dL (>177 μmol/L)

Reduce methotrexate dosage by 50%

Creatinine >3 mg/dL (>265 μmol/L)

Reduce daunorubicin dosage by 50%

Total bilirubin 3–5 mg/dL (51–86 μmol/L)

Reduce daunorubicin dosage by 50%

Reduce methotrexate dosage by 25%

Total bilirubin >3 mg/dL (>51 μmol/L)

Reduce vincristine dosage by 50%

Total bilirubin >5 mg/dL (>86 μmol/L)

Hold daunorubicin

Hold methotrexate

Asparaginase Toxicity Management

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Asparaginase Toxicity Management

Stock W et al. Leuk Lymphoma 2011;52:2237–2253

Toxicity

Grade 2

Grade 3

Grade 4

Hypersensitivity Urticaria, wheezing, laryngospasm, hypotension, etc.

For urticaria without bronchospasm, hypotension, edema, or need for parenteral intervention, continue asparaginase

For wheezing or other symptomatic bronchospasm with or without urticaria, indicated parenteral intervention, angioedema, or hypotension, discontinue asparaginase. If erwinia asparaginase is available, replace pegaspargase with erwinia asparaginase

For life-threatening consequences or indicated urgent intervention, discontinue asparaginase. If erwinia asparaginase is available, replace pegaspargase with erwinia asparaginase

Hypertriglyceridemia

If serum triglyceride level <1000 mg/dL (<11.3 mmol/L), continue asparaginase but follow patient closely for evolving pancreatitis

Hold asparaginase for triglyceride >1000 mg/dL (>11.3 mmol/L); follow closely for pancreatitis; resume asparaginase at prior dose level after patient's triglyceride level returns to normal range

Hyperglycemia, ketoacidosis

Continue asparaginase for uncomplicated hyperglycemia

For hyperglycemia requiring insulin therapy, hold asparaginase (and glucocorticoid therapy) until blood glucose regulated with insulin; resume asparaginase at prior dose level

For hyperglycemia with life-threatening consequences or indicated urgent intervention, hold asparaginase (and glucocorticoid therapy) until blood glucose is regulated with insulin; resume asparaginase and do not make up for missed doses

Hyperammonemia-related fatigue

Continue asparaginase

Reduce asparaginase dose by 25%; resume full dose when toxicity is grade ≤2; make up for missed doses

Reduce asparaginase dose 50%; resume full dose when toxicity grade 2; make up for missed doses

Pancreatitis

Continue asparaginase for asymptomatic amylase or lipase elevation >3 × ULN (chemical pancreatitis) or only radiologic abnormalities; observe closely for rising amylase or lipase levels

Continue pegaspargase for non-symptomatic chemical pancreatitis but observe patient closely for development of symptomatic pancreatitis for early treatment. Hold native asparaginase for amylase or lipase elevation >3 × ULN until enzyme levels stabilize or are declining. Permanently discontinue asparaginase for symptomatic pancreatitis

Permanently discontinue all asparaginase for clinical pancreatitis (vomiting, severe abdominal pain) with amylase or lipase elevation >3 × ULN for >3 days and/or development of pancreatic pseudocyst

Increased hepatic transaminases

For alanine or glutamine aminotransferase elevation >3–5 × ULN, continue asparaginase

For alanine or glutamine aminotransferase elevation >5–20 × ULN, delay next dose of asparaginase until transaminasemia is grade <2

For alanine or glutamine aminotransferase elevation >20 × ULN, discontinue asparaginase if toxicity reduction to grade <2 takes >1 week

Hyperbilirubinemia

Continue asparaginase if direct bilirubin <3.0 mg/dL (<51 μmol/L)

If direct bilirubin is 3.1–5.0 mg/dL (53–86 μmol/L), hold asparaginase and resume when direct bilirubin is <2.0 mg/dL Consider switching to native asparaginase

If direct bilirubin is >5.0 mg/dL (>86 μmol/L), discontinue all asparaginase and do not make up for missed doses

Non-CNS thrombosis

For abnormal laboratory findings without clinical correlates, continue asparaginase

Withhold asparaginase until acute toxicity and clinical signs resolve and anticoagulant therapy is stable or completed. Do not withhold asparaginase for abnormal laboratory findings without a clinical correlate

Withhold asparaginase until acute toxicity and clinical signs resolve and anticoagulant therapy is stable or completed

Non-CNS hemorrhage

For bleeding in conjunction, with hypofibrinogenemia, withhold asparaginase until bleeding is grade ≤1. Do not withhold asparaginase for abnormal laboratory findings without a clinical correlate

Withhold asparaginase until bleeding is grade ≤1, until acute toxicity and clinical signs resolve, and coagulant replacement therapy is stable or completed

CNS thrombosis

For abnormal laboratory findings without a clinical correlate, continue asparaginase

Discontinue all asparaginase; if CNS symptoms and signs are fully resolved and significant asparaginase remains to be administered, may resume asparaginase therapy at a lower dose and/or longer intervals between doses

Permanently discontinue all asparaginase

CNS hemorrhage

Discontinue asparaginase; do not withhold asparaginase for abnormal laboratory findings without a clinical correlate

Permanently discontinue all asparaginase

Grade according to the National Cancer Institute Common Terminology Criteria for Advance Events version 4, with the exception of pancreatitis

Notes

An additional group of 96 patients in a study reported by Larson et al. (Blood 1998;92:1556–1564) did not receive filgrastim after assignment to treatment. The median time to recover neutrophils ≥1000/mm³ during the remission induction course was 16 days for patients assigned to receive filgrastim and 22 days for patients assigned to placebo. Patients who received filgrastim had significantly shorter durations of neutropenia and thrombocytopenia and fewer days in hospital compared with patients who received placebo
Among patients assigned to receive filgrastim, more achieved CR and fewer experienced death during remission induction than those who received placebo. Overall toxicity was not lessened by the use of filgrastim. After a median follow-up of 4.7 years there was no significant difference in the overall survival between the two groups
Larson et al. (Blood 1995:85:2025–2037) performed lumbar puncture at diagnosis of ALL only in symptomatic patients. Patients with CNS leukemia should receive intrathecal therapy via lumbar puncture or an intraventricular reservoir (eg, Ommaya) weekly until CNS clearance with Methotrexate 15 mg + Hydrocortisone sodium succinate 50 mg per dose; administer intrathecally once weekly, alternating with:

Cytarabine 100 mg + Hydrocortisone sodium succinate 50 mg per dose; administer intrathecally once weekly
- Doses may be given in a volume of 0.9% Sodium Chloride Injection WITHOUT antimicrobial preservatives (preservative-free) equal to the volume of CSF removed for chemical or cytological evaluations
- Intrathecal chemotherapy is given twice weekly; alternating doses of either methotrexate + hydrocortisone or cytarabine + hydrocortisone
- Alternating intrathecal chemotherapy doses are separated by at least 3 days
Patients should continue systemic treatment as specified in the regimen

REGIMEN: HYPER-CVAD

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Regimen: Hyper-CVAD

Kantarjian H et al. Cancer 2004;101:2788–2801

Kantarjian HM et al. J Clin Oncol 2000;18:547–561

Dose-intensive chemotherapy

The dose-intensive phase consists of 8 cycles of hyper-CVAD alternating with high-dose methotrexate and cytarabine every 3–4 weeks (when the WBC count is >3000/mm³ and platelet count is >60,000/mm³)

Hyper-CVAD (cycles 1, 3, 5, and 7)

Cyclophosphamide 300 mg/m² per dose; administer intravenously over 3 hours in 500 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) every 12 hours for 6 doses on days 1–3, for 4 cycles, cycles 1, 3, 5, and 7 (total dosage/cycle = 1800 mg/m²)

Mesna 600 mg/m² per 24 hours; administer by continuous intravenous infusion in 1000 mL 0.9% NS for approximately 69 hours for 4 cycles, cycles 1, 3, 5, and 7 (total dosage/cycle ~1725 mg/m²)

Mesna administration starts concurrently with cyclophosphamide on day 1 and continues until 6 hours after the last dose of cyclophosphamide is completed (69 hours)

Vincristine 2 mg/dose; administer by intravenous injection over 1–2 minutes for 2 doses, on days 4 and 11, for 4 cycles, cycles 1, 3, 5, and 7 (total dose/cycle = 4 mg)

Doxorubicin 50 mg/m²; administer intravenously via central venous access in 25–250 mL 0.9% NS or D5W over 2 hours on day 4, for 4 cycles, cycles 1, 3, 5, and 7 (total dosage/cycle = 50 mg/m²)

Dexamethasone 40 mg per day; administer orally, or intravenously in 25–150 mL 0.9% NS or D5W over 15–30 minutes for 8 doses, on days 1–4 and days 11–14, for 4 cycles, cycles 1, 3, 5, and 7 (total dose/cycle = 320 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on Days 1–4 is MODERATE

Emetogenic potential on Days 11 is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with:

Filgrastim (G-CSF) 5 mcg/kg per dose; administer by subcutaneous injection every 12 hours, starting on day 5 (24 hours after doxorubicin)

Continue filgrastim administration until postnadir WBC count >3000/mm³ and platelet count is >60,000/mm³. If platelet recovery is delayed, filgrastim is continued until the WBC count >30,000/mm³
Discontinue daily filgrastim use at least 24 hours before administering myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

High-dose methotrexate + cytarabine (cycles 2, 4, 6, and 8)

Hydration: with a solution containing a total amount of sodium not >0.9% NS (ie, ≤154 mEq sodium/1000 mL) by intravenous infusion during methotrexate administration and for at least 24 hours afterward

Commence fluid administration 2–12 hours before starting methotrexate, depending on patient's fluid status
Urine output should be at least 100 mL/hour before starting methotrexate infusion
Maintain hydration at a rate that maintains urine output ≥100 mL/hour until the serum methotrexate concentration is <0.1 μmol/L
Urine pH should be increased within the range ≥7.0 to ≤8.0 to enhance methotrexate solubility and ensure elimination
Adverse effects attributable to methotrexate are related to systemic methotrexate concentrations and the duration for which concentrations are maintained

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Sodium bicarbonate 50–150 mEq/1000 mL is added to parenteral hydration solutions to maintain urine pH ≥7.0 to ≤8.0

Base Solution Sodium Content

Sodium Bicarbonate Additive

Total Sodium Content

0.45% Sodium Chloride Injection (0.45% NS)

77 mEq/L

50–75 mEq

127–152 mEq/L

0.2% Sodium Chloride Injection (0.2% NS)

34 mEq/L

100–125 mEq

134–159 mEq/L

5% Dextrose injection (D5W)

125–150 mEq

125–150 mEq/L

D5W/0.45% NS

77 mEq/L

50–75 mEq

127–152 mEq/L

D5W/0.2% NS

34 mEq/L

100–125 mEq

134–159 mEq/L

Methotrexate 200 mg/m²; administer intravenously over 2 hours, on day 1, followed by:

Methotrexate 800 mg/m²; administer intravenously over 24 hours, on day 1, for 4 cycles, cycles 2, 4, 6, and 8 (total dosage/cycle, bolus + infusion = 1000 mg/m²)

Note: For logistical practicality and efficiency, parenteral admixtures containing methotrexate may include a portion or all of the fluid and sodium bicarbonate needed to meet hydration and urinary alkalinization requirements during methotrexate administration

Leucovorin calcium 15 mg per dose; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–30 minutes, starting 48 hours after methotrexate administration began (22 hours after methotrexate administration ends), every 6 hours for 8 doses (total dosage/cycle = 120 mg)

Note: If serum methotrexate concentrations are:

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Hours After Starting Methotrexate

Methotrexate Concentration

Leucovorin Regimen

Hour 24

>20 μmol/L (>2 × 10⁻⁵ mol/L)

Increase leucovorin dosages to 50 mg/dose; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–30 minutes every 6 hours until serum methotrexate concentrations are <0.1 μmol/L (<1 × 10²⁷ mol/L)

Hour 48

>1 μmol/L (>1 × 10⁻⁶ mol/L)

Hour 72

>0.1 μmol/L (>1 × 10⁻⁷ mol/L, or >100 nmol/L)

Cytarabine

Patient ages <60 years: Cytarabine 3000 mg/m² per dose; administer intravenously in 50–500 mL 0.9% NS or D5W over 2 hours every 12 hours for 4 doses on days 2 and 3, for 4 cycles, cycles 2, 4, 6, and 8 (total dosage/cycle [not including intrathecal cytarabine] = 12,000 mg/m²)

Patient ages ≥60 years: Cytarabine 1000 mg/m² per dose; administer intravenously in 50–500 mL 0.9% NS or D5W over 2 hours every 12 hours for 4 doses on days 2 and 3, for 4 cycles, cycles 2, 4, 6, and 8 (total dosage/cycle [not including intrathecal cytarabine] = 4000 mg/m²)

Methylprednisolone 50 mg; administer intravenously twice daily for 6 doses, on days 1–3 (total dose/cycle = 300 mg)

Filgrastim 5 mcg/kg per dose; administer subcutaneously, every 12 hours, starting on day 4 (24 hours after the last dose of chemotherapy) and continue until postnadir WBC count >3000/mm³ and platelet count is >60,000/mm³. If platelet recovery is delayed, filgrastim is continued until the WBC count >30,000/mm³

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on Days 1–3 is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with:

Filgrastim (G-CSF) 5 mcg/kg per dose; administer by subcutaneous injection every 12 hours, starting on day 4 (24 hours after the last dose of cytarabine)

Continue filgrastim administration until postnadir WBC count >3000/mm³ and platelet count is >60,000/mm³. If platelet recovery is delayed, filgrastim is continued until the WBC count >30,000/mm³
Discontinue daily filgrastim use at least 24 hours before administering myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Keratitis prophylaxis

Steroid ophthalmic drops (prednisolone 1% or dexamethasone 0.1%) administer by intraocular instillation daily until 24 hours after high-dose cytarabine is completed

Maintenance phase

Mercaptopurine 50 mg/dose; administer orally on an empty stomach, continually, 3 times daily for 2 years (total dose/4 weeks = 4200 mg)

Methotrexate 20 mg/m² per dose; administer orally, once weekly for 2 years (total dosage/4 weeks = 80 mg/m²)

Vincristine 2 mg; administer by intravenous injection over 1–2 minutes, once monthly for 2 years (total dose/month = 2 mg)

Prednisone 200 mg per day; administer orally, continually, for 5 consecutive days every month, starting on the day vincristine is given (total dose/month = 1000 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Patient Population Studied

288 newly diagnosed ALL patients (median age: 40 years)

Efficacy (N = 288)

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Efficacy (N = 288)

92%

CR <30 years

99%

CR>60 years

80%

Resistant disease

Died during induction

5-Year estimated survival rate

38%

5-Year CR rate

38%

CR for Ph+ ALL

91%

5-Year survival for Ph+ ALL

12%

Dose Modifications During the Induction Phase

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Dose Modifications During the Induction Phase

Adverse Effect

Dose Modification

Total bilirubin >2 mg/dL (>34 μmol/L)

Reduce vincristine doses to 1 mg

Total bilirubin 2–3 mg/dL (34–51 μmol/L)

Reduce doxorubicin dosage by 25%

Total bilirubin 3–4 mg/dL (51–68 μmol/L)

Reduce doxorubicin dosage by 50%

Total bilirubin 3–5 mg/dL (51–86 μmol/L)

Reduce methotrexate dosage by 25%

Total bilirubin >4mg/dL (>68 μmol/L)

Reduce doxorubicin dosage by 75%

Total bilirubin >5 mg/dL (>86 μmol/L)

Hold methotrexate

Creatinine 1.5–2 mg/dL (133–177 μmol/L)

Reduce methotrexate dosage by 25%

Bilirubin level 3–5 mg/dL (51–86 μmol/L)

Reduce MTX dose by 25%

Bilirubin >5 mg/dL (>86μmol/L)

Hold MTX

Creatinine >2 mg/dL (>177 μmol/L)

Reduce methotrexate dosage by 50% Reduce cytarabine dosage to 1000 mg/m²

Toxicity (N = 288)

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Toxicity (N = 288)

Induction Chemotherapy (First Course of Hyper-CVAD Therapy)

Myelosuppression

Median time to ANC >1000/mm³

19 days

Median time to platelets >100,000/mm³

22 days

Hospitalization

54%

Sepsis

11%

Pneumonia

16%

Fungal infection

Fever of unknown origin

37%

Neurotoxicity

64%

Moderate–severe mucositis

Moderate–severe diarrhea

Disseminated intravascular coagulopathy

Induction deaths

Consolidation Courses (Second Course of Hyper-CVAD Therapy)

Pneumonia

Hospitalization

16%

Neurotoxicity

Mucositis

Diarrhea

Sepsis

10%

Fever of unknown origin

High-Dose Methotrexate + Cytarabine Therapy

Sepsis

Pneumonia

Fever of unknown origin

22%

Neurotoxicity

Minor infections

Hospitalization

Mucositis

Rash and desquamation of palms and feet

Diarrhea

Therapy Monitoring

CBC with differential daily during and after chemotherapy until recovery of ANC >500/mm³. Platelets every day while in hospital until patient no longer requires platelet transfusions
Serum electrolytes, mineral panel, and uric acid, at least daily during active treatment until the risk of tumor lysis is past
Bone marrow aspirate and biopsy at day 29 of the initial induction course. After patient achieves a CR, bone marrow biopsy and aspirate should be performed at the end of each consolidation cycle (or at the very least, every other cycle), and every 3 months during maintenance therapy

Notes

1. In the studies reported by Kantarjian et al. (J Clin Oncol 2000;18:547–561), patients underwent a diagnostic LP on day 2 of the first course of treatment
- a. Patients with CNS disease at the time of diagnosis receive intrathecal therapy with:
  - • Methotrexate; administer intrathecally 12 mg/dose via lumbar puncture or 6 mg/dose intraventricularly via indwelling ventricular reservoir catheter (eg, Ommaya) twice weekly until cerebrospinal fluid cell counts normalize and cytology becomes negative for malignant disease, then:
  - • Methotrexate; administer intrathecally 12 mg/dose via lumbar puncture or 6 mg/dose intraventricularly via indwelling ventricular reservoir catheter on day 2 of each remaining treatment cycle, plus
  - • Cytarabine 100 mg/dose; administer intrathecally via lumbar puncture or intraventricularly via indwelling ventricular reservoir catheter on day 8 of each remaining treatment cycle
- b. Patients with cranial nerve root involvement received radiation 24–30 Gy in 10–12 fractions to the base of the skull or whole brain
- c. Patients with no evidence of CNS disease should receive intrathecal prophylaxis based on prognostic factors for CNS leukemia

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CNS Prophylaxis

Risk Factors

Risk Categories

High

Low

Unknown

LDH

>600 units/L

Within normal limits

unknown

Proliferative index (% S+G₂M)

≥14%

Histology

Mature B-cell ALL

Not applicable

Regimen for Intrathecal Prophylaxis

Administration Schedule by Risk Category

High Risk

Unknown Risk

Low Risk

Methotrexate; administer intrathecally 12 mg/dose via lumbar puncture or 6 mg/dose intraventricularly (via Ommaya reservoir) on day 2 of each cycle indicated, plus

Cytarabine 100 mg administer; intrathecally via lumbar puncture or intraventricularly on day 8 of each cycle indicated

For 8 cycles, cycles 1–8

For 4 cycles, cycles 1–4

For 2 cycles, cycles 1 & 2

2. Patients with mature B-cell ALL received no maintenance therapy
3. Patients who receive high-dose cytarabine need to be closely monitored for changes in renal function. Renal dysfunction is highly correlated with increased risk of cerebellar toxicity associated with cytarabine. Patients need to be monitored for nystagmus, dysmetria, and ataxia before each cytarabine dose
4. Hyper-CVDA+ Rituximab (Thomas DA et al. J Clin Oncol 2010;28:3880–3889): two hundred eighty-two adolescents and adults with de novo Philadelphia chromosome (Ph)–negative precursor B-lineage ALL were treated with standard or modified hyper-CVAD regimens. The latter incorporated standard-dose rituximab if CD20 expression ≥20%. The complete remission (CR) rate was 95% with 3-year rates of CR duration (CRD) and survival (OS) of 60% and 50%, respectively. In the younger (age <60 years) CD20-positive subset, rates of CRD and OS were superior with the modified hyper-CVAD and rituximab regimens compared with standard hyper-CVAD (70% v 38%; P <.001% and 75% v 47%, P = .003). In contrast, rates of CRD and OS for CD20-negative counterparts treated with modified versus standard hyper-CVAD regimens were similar (72% v 68%, P = not significant [NS] and 64% v 65%, P = NS, respectively). Older patients with CD20-positive ALL did not benefit from rituximab-based chemoimmunotherapy (rates of CRD 45% v 50%, P = NS and OS 28% v 32%, P = NS, respectively), related in part to deaths in CR. The incorporation of rituximab into the hyper-CVAD regimen improve outcome for younger patients with CD20-positive Ph-negative precursor B-lineage ALL.

REGIMEN: LINKER REGIMEN

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Regimen: Linker Regimen

Linker C et al. J Clin Oncol 2002;20:2464–2471

Treatment consisted of a total of 7 courses given in the order 1A → 1B → 1C → 2A → 2B → 2C → 3C, followed by maintenance chemotherapy

Induction (course 1A): DVP/Asp

Daunorubicin 60 mg/m² per day; administer by intravenous injection over 3–5 minutes for 3 consecutive days, on days 1–3 (total dosage/course after 3 doses = 180 mg/m²)

Note: If day 14 bone marrow evaluation reveals residual leukemia, give a fourth dose of daunorubicin on day 15 (total dosage/course after 4 doses = 240 mg/m²)

Vincristine

Patient age ≤40 years: Vincristine 1.4 mg/m² per dose; administer by intravenous injection over 1–2 minutes for 4 doses on days 1, 8, 15, and 22 (total dosage/course = 5.6 mg/m²)

Patient age >40 years: Vincristine 1.4 mg/m² per dose (maximum single dose = 2 mg), administer by intravenous injection over 1–2 minutes for 4 doses on days 1, 8, 15, and 22 (total dosage/course = 5.6 mg/m²; maximum dose/course = 8 mg)

Prednisone 60 mg/m² per day; administer orally, continually, for 28 consecutive days, on days 1–28 (total dosage/course = 1680 mg/m²)

Asparaginase 6000 IU/m² per day; administer intramuscularly, or intravenously in 10–50 mL 0.9% sodium chloride injection or 5% dextrose injection over at least 30 minutes for 12 consecutive days on days 17–28 (total dosage/course = 72,000 IU/m²)

CNS Prophylaxis and Treatment

Patients received CNS prophylaxis with methotrexate administered intrathecally during the initial diagnostic lumbar puncture. Five additional doses began with the first course of postremission chemotherapy with repeated doses delivered at weekly intervals as tolerated
Patients with CNS disease at diagnosis received intensified CNS therapy: 10 intrathecal treatments, and cranial irradiation 18 Gy was given after bone marrow remission was achieved

Methotrexate 12 mg per dose; administer intrathecally via lumbar puncture in 3–12 mL preservative-free 0.9% sodium chloride injection

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Prophylaxis

Treatment

Methotrexate (12 mg/dose)

Total number of doses

6^✫

10^✫

Total dose/all courses

72 mg

120 mg

Cranial irradiation

None

1800 cGy after bone marrow CR

^✫First dose is given at the start of Induction Course 1A

Second and subsequent doses start concurrently with post-CR chemotherapy, and continue on a weekly schedule

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days when daunorubicin is given is MODERATE–HIGH

Emetogenic potential on days when vincristine or asparaginase ± vincristine are given is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with:

Filgrastim (G-CSF) 5 mcg/kg per day, by subcutaneous injection

If only 3 doses of daunorubicin are given, begin filgrastim use on day 14. If a fourth dose of daunorubicin is given (on day 15) postpone instituting filgrastim use until 24 hours after daunorubicin was administered
Continue daily filgrastim use until ANC >1500/mm³ on two measurements separated temporally by ≥24 hours
Discontinue daily filgrastim use at least 24 hours before commencing the next course of myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Consolidation (courses 1B and 2B): high-dose cytarabine + etoposide (HDAC/etoposide)

Cytarabine 2000 mg/m² per day; administer intravenously in 100–1000 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 2 hours for 4 consecutive days on days 1–4 (total dosage/course = 8000 mg/m²)

Etoposide 500 mg/m² per day; administer intravenously diluted in 0.9% NS or D5W to a concentration within the range of 0.2–0.4 mg/mL over 3 hours for 4 consecutive days on days 1–4 (total dosage/course = 2000 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is at least MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

Filgrastim (G-CSF) 5 mcg/kg per day, by subcutaneous injection, or

Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL, by subcutaneous injection for 1 dose

Begin use from 24–72 hours after myelosuppressive chemotherapy is completed
Continue daily filgrastim use until ANC >1500/mm³ on 2 measurements separated temporally by ≥24 hours
Discontinue daily Filgrastim use at least 24 hours before commencing the next course of myelosuppressive treatment. Do not administer pegfilgrastim within 14 days before administering myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Keratitis prophylaxis

Steroid ophthalmic drops (prednisolone 1% or dexamethasone 0.1%); administer by intraocular instillation daily until 24 hours after high-dose cytarabine is completed

Consolidation (course 2A): DVP/Asp

Daunorubicin 60 mg/m² per day; administer by intravenous injection over 3–5 minutes for 3 consecutive days on days 1–3 (total dosage/course = 180 mg/m²)

Vincristine

Patients age ≤40 years: Vincristine 1.4 mg/m² per dose; administer by intravenous injection over 1–2 minutes for 3 doses on days 1, 8, and 15 (total dosage/course = 4.2 mg/m²)

Patients age >40 years: Vincristine 1.4 mg/m² per dose (maximum single dose = 2 mg); administer by intravenous injection over 1–2 minutes for 3 doses on days 1, 8, and 15 (total dosage/course = 4.2 mg/m²; maximum dose/course = 6 mg)

Prednisone 60 mg/m² per day; administer orally, continually, for 21 consecutive days on days 1–21 (total dosage/course = 1260 mg/m²)

Asparaginase 12,000 IU/m² per dose; administer intramuscularly, or intravenously in 10–50 mL 0.9% sodium chloride injection or 5% dextrose injection over at least 30 minutes, for 3 doses/week (eg, Monday, Wednesday, and Friday), for a total of 6 doses during 2 consecutive weeks (total dosage/course = 72,000 IU/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days when daunorubicin is given is MODERATE–HIGH

Emetogenic potential on days when vincristine or asparaginase ± vincristine are given is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is indicated with one of the following:

Filgrastim (G-CSF) 5 mcg/kg per day, by subcutaneous injection, or

Pegfilgrastim (pegylated filgrastim) 6 mg/0.6 mL by subcutaneous injection for 1 dose

Begin use from 24–72 hours after myelosuppressive chemotherapy is completed
Continue daily filgrastim use until ANC >1500/mm³ on 2 measurements separated temporally by ≥24 hours
Discontinue daily filgrastim use at least 24 hours before commencing the next course of myelosuppressive treatment. Do not administer pegfilgrastim within 14 days before administering myelosuppressive treatment

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Consolidation (courses 1C, 2C, and 3C): high-dose methotrexate + mercaptopurine

Hydration with methotrexate:

Administer 1500–3000 mL/m² per day. Use a solution containing a total amount of sodium not greater than 0.9% sodium chloride injection (ie, 154 mEq/1000 mL); administer by intravenous infusion during methotrexate administration and for at least 24 hours afterward

Commence fluid administration 2–12 hours before starting methotrexate, depending upon a patient's fluid status
Urine output should be at least 100 mL/hour before starting methotrexate infusion
Maintain hydration at a rate that maintains urine output of at least 100 mL/hour until the serum methotrexate concentration is <0.05 μmol/L
Adverse effects attributable to methotrexate are related to systemic methotrexate concentrations and the duration for which concentrations are maintained

Sodium bicarbonate 50–150 mEq/1000 mL is added to parenteral hydration solutions to maintain urine pH ≥7.0 to ≤8.0

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Base Solution Sodium Content

Sodium Bicarbonate Additive

Total Sodium Content

0.45% Sodium Chloride Injection (0.45% NS)

77 mEq/L

50–75 mEq

125–152 mEq/L

0.2% Sodium Chloride Injection (0.2% NS)

34 mEq/L

100–125 mEq

134–159 mEq/L

5% Dextrose Injection (D5W)

125–150 mEq

125–150 mEq/L

D5W/0.45% NS

77 mEq/L

50–75 mEq

125–152 mEq/L

D5W/0.2% NS

34 mEq/L

100–125 mEq

134–159 mEq/L

Methotrexate 220 mg/m²; administer intravenously over 1 hour (loading dose, or bolus), every 2 weeks on days 1 and 15, followed by

Methotrexate 60 mg/m² per hour; administer by continuous intravenous infusion for 36 hours, every 2 weeks on days 1 and 15 (total dosage/administration event, bolus + infusion = 2380 mg/m²; total dosage/course = 4760 mg/m²)

Leucovorin calcium 50 mg/m² per dose; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–30 minutes starting immediately after methotrexate is completed (37 hours after methotrexate administration began), every 6 hours for 3 doses, every 2 weeks on days 2 and 16, and then:

Leucovorin calcium 50 mg/dose; administer orally starting 6 hours after the last intravenously administered dose of leucovorin. Continue administration every 6 hours until serum methotrexate concentrations are <0.05 μmol/L (<5 ×10⁻⁸ mol/L, or <50 nmol/L), every 2 weeks

Mercaptopurine 75 mg/m² per day; administer orally, continually, for 28 consecutive days on days 1–28 (total dosage/course = 2100 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential on days when methotrexate is given is MODERATE

Emetogenic potential on days when mercaptopurine alone is given is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Maintenance Therapy

Mercaptopurine 75 mg/m² per day; administer orally, continually, until complete remission is sustained for 30 months (total dosage/week = 525 mg/m²)

Methotrexate 20 mg/m² per dose; administer orally once weekly until complete remission is sustained for 30 months (total dosage/week = 20 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—not indicated
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Patient Population Studied

84 newly diagnosed ALL adult patients (median age 27 years)

Efficacy (N = 84)

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Efficacy (N = 84)

Induction

Complete remission (CR)

1 Treatment-related death

5 Patients had resistant disease

93%

5-Year event-free survival

48% ± 13%

Overall survival

47%

5-Year event-free survival for patients achieving remission

52%

5-Year DFS for patients achieving remission

54%

Therapy Monitoring

CBC with differential daily during and after chemotherapy until recovery of ANC >500/mm³. Platelets every day while in hospital until patients no longer require platelet transfusions
Electrolytes, mineral panel, and uric acid at least daily during active treatment until the risk of tumor lysis is past
Amylase and fibrinogen levels prior to asparaginase administration. If fibrinogen level is <100 mg/dL (<1 g/L) consider prophylactic administration of cryoprecipitate
Bone marrow aspirate and biopsy at day 29 of the initial induction course. After a patient achieves a CR, bone marrow biopsy and aspirate should be performed at the end of each consolidation cycle (or at the very least, every other cycle), and every 3 months during maintenance therapy

Treatment Modifications

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Treatment Modifications

Adverse Events

Treatment Modifications

Creatinine 1.5–2 mg/dL (133–177 μmol/L)

Reduce methotrexate dosage by 25%

Creatinine >2 mg/dL (>177 μmol/L)

Reduce methotrexate dosage by 50%

Creatinine >3 mg/dL (>265 μmol/L)

Reduce daunorubicin dosage by 50%

Total bilirubin 3–5 mg/dL (51–86 μmol/L)

Reduce daunorubicin dosage by 50%

Reduce methotrexate dosage by 25%

Total bilirubin >3 mg/dL (>51 μmol/L)

Reduce vincristine dosage by 50%

Total bilirubin >5 mg/dL (>86 μmol/L)

Hold daunorubicin

Hold methotrexate

Adverse Effects

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Adverse Effects

Median Number of Days to Hematologic Recovery

Courses

Induction 1A DVP/Asp n = 84

1B HDAC/Etoposide n = 79

2A DVP/Asp n = 59

2B HDAC/Etoposide n = 53

ANC >500/mm³

ANC >1000/mm³

No. of days with ANC <500/mm³

Platelets

>20,000/mm³

>50,000/mm³

>100,000/mm³

No. of platelet transfusions

No. of RBC transfusions

11 Patients experienced a peak serum total bilirubin >3 mg/dL, 1 had a peak total bilirubin >10 mg/dL

Asparaginase Toxicity Management

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Asparaginase Toxicity Management

Stock W et al. Leuk Lymphoma 2011;52:2237–2253

Toxicity

Grade 2

Grade 3

Grade 4

Hypersensitivity Urticaria, wheezing, laryngospasm, hypotension, etc.

For urticaria without bronchospasm, hypotension, edema, or need for parenteral intervention, continue asparaginase

For life-threatening consequences or indicated urgent intervention, discontinue asparaginase. If erwinia asparaginase is available, replace pegaspargase with erwinia asparaginase

Hypertriglyceridemia

If serum triglyceride level <1000 mg/dL (<11.3 mmol/L), continue asparaginase but follow patient closely for evolving pancreatitis

Hold asparaginase for triglyceride >1000 mg/dL (>11.3 mmol/L); follow closely for pancreatitis; resume asparaginase at prior dose level after patient's triglyceride level returns to normal range

Hyperglycemia, ketoacidosis

Continue asparaginase for uncomplicated hyperglycemia

For hyperglycemia requiring insulin therapy, hold asparaginase (and glucocorticoid therapy) until blood glucose regulated with insulin; resume asparaginase at prior dose level

Hyperammonemia-related fatigue

Continue asparaginase

Reduce asparaginase dose by 25%; resume full dose when toxicity is grade >2; make up for missed doses

Reduce asparaginase dose 50%; resume full dose when toxicity grade 2; make up for missed doses

Pancreatitis

Continue asparaginase for asymptomatic amylase or lipase elevation >3 × ULN (chemical pancreatitis) or only radiologic abnormalities; observe closely for rising amylase or lipase levels

Permanently discontinue all asparaginase for clinical pancreatitis (vomiting, severe abdominal pain) with amylase or lipase elevation >3 × ULN for >3 days and/or development of pancreatic pseudocyst

Increased hepatic transaminases

For alanine or glutamine aminotransferase elevation >3–5 × ULN, continue asparaginase

For alanine or glutamine aminotransferase elevation >5–20 × ULN, delay next dose of asparaginase until transaminasemia is grade <2

For alanine or glutamine aminotransferase elevation >20 × ULN, discontinue asparaginase if toxicity reduction to grade <2 takes >1 week

Hyperbilirubinemia

Continue asparaginase if direct bilirubin <3.0 mg/dL (<51 μmol/L)

If direct bilirubin is 3.1–5.0 mg/dL (53–86 μmol/L), hold asparaginase and resume when direct bilirubin is <2.0 mg/dL

Consider switching to native asparaginase

If direct bilirubin is >5.0 mg/dL (>86 μmol/L), discontinue all asparaginase and do not make up for missed doses

Non-CNS thrombosis

For abnormal laboratory findings without clinical correlates, continue asparaginase

Withhold asparaginase until acute toxicity and clinical signs resolve and anticoagulant therapy is stable or completed

Non-CNS hemorrhage

For bleeding in conjunction, with hypofibrinogenemia, withhold asparaginase until bleeding is grade >1. Do not withhold asparaginase for abnormal laboratory findings without a clinical correlate

Withhold asparaginase until bleeding is grade >1, until acute toxicity and clinical signs resolve, and coagulant replacement therapy is stable or completed

CNS thrombosis

For abnormal laboratory findings without a clinical correlate, continue asparaginase

Permanently discontinue all asparaginase

CNS hemorrhage

Discontinue asparaginase; do not withhold asparaginase for abnormal laboratory findings without a clinical correlate

Permanently discontinue all asparaginase

Grade according to the National Cancer Institute Common Terminology Criteria for Advance Events version 4, with the exception of pancreatitis

REGIMEN: ALL TRIAL: MRC UKALL XII/ECOG E2993

Listen

Regimen: All Trial: MRC UKALL XII/ECOG E2993

Rowe JM et al. Blood 2005;106:3760–3767

Induction therapy

Induction—Phase 1 (weeks 1–4)

Daunorubicin 60 mg/m² per dose; administer by intravenous injection over 3–5 minutes for 4 doses on days 1, 8, 15, and 22 (total dosage/4-week course = 240 mg/m²)

Vincristine 1.4 mg/m² per dose; administer by intravenous injection over 1–2 minutes for 4 doses on days 1, 8, 15, and 22 (total dosage/4-week course = 5.6 mg/m²)

Prednisone 60 mg/m² per day; administer orally, continually, for 28 consecutive days on days 1 to 28 (total dosage/4-week course = 1680 mg/m²)

Daily prednisone doses may be given in a single dose or ≥2 divided doses

Methotrexate 12.5 mg; administer intrathecally in 3–12 mL preservative-free 0.9% sodium chloride injection on day 15 (total dose/4-week course = 12.5 mg)

Asparaginase 10,000 IU/dose; administer intramuscularly, or intravenously in 10–50 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) for 12 consecutive days, on days 17 to 28 (total dose/4-week course = 120,000 IU)

Induction—Phase 2 (weeks 5–8)

(Regardless of whether residual leukemia is present at the end of phase 1)

Cyclophosphamide 650 mg/m²; administer intravenously in 100–1000 mL 0.9% NS or D5W over 15–60 min for 3 doses on days 1, 15, and 29 (total dosage/4-week course = 1950 mg/m²)

Cytarabine 75 mg/m² per dose; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–60 min for 16 doses on days 1–4, 8–11, 15–18, and 22–25 (total dosage/4-week course = 1200 mg/m²)

Mercaptopurine 60 mg/m² per day; administer orally, continually, for 28 consecutive days on days 1 to 28 (total dosage/4-week course = 1680 mg/m²)

Methotrexate 12.5 mg per dose; administer intrathecally in 3–12 mL preservative-free 0.9% sodium chloride injection for 4 doses on days 1, 8, 15, and 22 (total dose/4-week course = 50 mg)

Notes: A diagnostic spinal tap was performed on all patients. If CNS leukemia was present at diagnosis, methotrexate was administered intrathecally via lumbar puncture or through a ventricular reservoir (eg, Ommaya) every week until blast cells were no longer present in the spinal fluid. In addition, 2400 cGy of cranial irradiation and 1200 cGy to the spinal cord were administered concurrently during induction, phase 2. For patients with CNS leukemia at presentation, intrathecal methotrexate was not administered during phase 2

Intensification therapy

Hydration for methotrexate: 6–18 hours before the anticipated start of methotrexate, start intravenous hydration containing sodium bicarbonate (NaHCO₃) to alkalinize a patient's urine to pH ≥7.0, but ≤8.0, at a rate that achieves a urine output ≥100 mL/hour

Options recommended to initially produce an alkaline urine, include:

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Fluid

Administration Rate

Sodium Bicarbonate Content (per 1000 mL)

0.45% NS

150–250 mL/hour

50–75 mEq

0.2% NS

100–125 mEq

D5W/0.45% NS

50–75 mEq

D5W/0.2% NS

100–125 mEq

D5W

150 mEq

D5W, 5% Dextrose injection; NS, sodium chloride injection

Notes: Urine alkalinization to pH ≥7.0 to ≤8.0 and urine output ≥100 mL/hour often initially require more NaHCO₃ and more rapid hydration rates than will be required to maintain either or both parameters after they are achieved

The amount of sodium bicarbonate added to intravenously administered fluids should produce a solution with sodium content not greater than the concentration of sodium in 0.9% sodium chloride injection (≤154 mEq/L)

Methotrexate 3000 mg/m²; administer intravenously in one of the solutions identified above in admixture with 25–75 mEq NaHCO₃ over 4 hours after urine pH ≥7.0 to ≤8.0 and urine output >100 mL/hour are confirmed for 3 doses on days 1, 8, and 22 (total dosage/course = 9000 mg/m²)

Temporarily interrupt hydration while methotrexate is administered
- The methotrexate product should contain volume and sodium bicarbonate content equivalent to what was being given in intravenous hydration to maintain urine pH ≥7.0 to ≤8.0 and output >100 mL/hour
Order daily serum methotrexate levels timed to start 24 hours after methotrexate administration begins and continue daily measurements until the serum methotrexate level is ≤0.05 μmol/L
Continue hydration with urine alkalinization (pH ≥7.0 to ≤8.0) until serum methotrexate level is ≤0.05 μmol/L

Leucovorin calcium 100 mg/m² per dose (preferred), or levoleucovorin calcium 50 mg/m² per dose; administer intravenously in 25–250 mL 0.9% NS or D5W over 10–30 minutes every 6 hours starting 24 hours after methotrexate administration began, and continue for at least 6 doses or until serum methotrexate concentrations are ≤0.5 μmol/L, whichever occurs later

When the methotrexate level is <0.5 μmol/L, parenterally administered leucovorin or levoleucovorin may be replaced with leucovorin administered orally (10 mg/m², or a fixed 25-mg dose for patients whose body surface area is <2.5 m²), until the serum methotrexate level is ≤0.05 μmol/L

Asparaginase 10,000 IU/dose; administer intramuscularly, or intravenously in 10–50 mL 0.9% NS or D5W intravenously or intramuscularly for 3 doses on days 2, 9, and 23 (total dose/course = 30,000 IU)

Consolidation therapy

Cytarabine 50 mg/dose; administer intrathecally in 3–12 mL preservative-free 0.9% sodium chloride injection weekly for 4 weeks, with:

Cranial irradiation 2400 cGy

Consolidation—Cycle 1

Cytarabine 75 mg/m² per day; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–60 minutes for 5 consecutive days on days 1–5 (total dosage/cycle = 375 mg/m²)

Etoposide 100 mg/m² per day; administer intravenously in a volume of 0.9% NS or D5W sufficient to produce a concentration within the range, 0.2–0.4 mg/mL over at least 60 minutes for 5 consecutive days on days 1–5 (total dosage/cycle = 500 mg/m²)

Vincristine 1.4 mg/m² per dose; administer intravenously over 1–2 minutes for 4 doses on days 1, 8, 15, and 22 (total dosage/cycle = 5.6 mg/m²)

Dexamethasone 10 mg/m² per day; administer orally, continually, for 28 consecutive days on days 1 to 28 (total dosage/cycle = 280 mg/m²)

Consolidation—Cycle 2 (starts 4 weeks after cycle 1)

Cytarabine 75 mg/m² per day; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–60 minutes for 5 consecutive days on days 1–5 (total dosage/cycle = 375 mg/m²)

Consolidation—Cycle 3 (starts 4 weeks after cycle 2)

Daunorubicin 25 mg/m² per dose; administer by intravenous injection over 3–5 minutes for 4 doses on days 1, 8, 15, and 22 (total dosage/4-week course = 100 mg/m²)

Cyclophosphamide 650 mg/m²; administer intravenously in 100–1000 mL 0.9% NS or D5W over 15–60 min on day 29 (total dosage/4-week course = 650 mg/m²)

Cytarabine 75 mg/m² per dose; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–60 minutes for 8 doses on days 31–34 and 38–41 (total dosage/4-week course = 600 mg/m²)

Thioguanine 60 mg/m² per day; administer orally, continually, for 14 consecutive days on days 29–42 (total dosage/4-week course = 840 mg/m²)

Consolidation—Cycle 4 (8 weeks after the conclusion of cycle 3)

Cytarabine 75 mg/m² per day; administer intravenously in 25–250 mL 0.9% NS or D5W over 15–60 minutes for 5 consecutive days on days 1–5 (total dosage/cycle = 375 mg/m²)

Maintenance therapy (continues for a total of 2.5 years after the start of intensification therapy)

Cytarabine 50 mg/dose; administer intrathecally in 3–12 mL preservative-free 0.9% sodium chloride injection on 4 occasions 3 months apart during maintenance therapy (total of 4 doses = 200 mg)

Vincristine 1.4 mg/m²; administer by intravenous injection over 1–2 minutes every 3 months (total dosage/3-month period = 1.4 mg/m²)

Prednisone 60 mg/m²; administer orally for 5 consecutive days every 3 months (total dosage/3-month period = 300 mg/m²)

Mercaptopurine 75 mg/m²; administer orally, continually each day (total dosage/week = 525 mg/m²)

Methotrexate 20 mg/m²; administer orally or intravenously once a week (total dosage/week = 20 mg/m²)

Supportive Care

Antiemetic Prophylaxis During Induction–Phase 1

Emetogenic potential on days 1, 8, and 15 is MODERATE

Emetogenic potential on days with asparaginase (days 17–28) is MINIMAL

Antiemetic Prophylaxis During Induction–Phase 2

Emetogenic potential on days with cyclophosphamide (days 1, 15, and 29) is MODERATE

Emetogenic potential on days with cytarabine without cyclophosphamide is LOW

Emetogenic potential on days with mercaptopurine alone is MINIMAL–LOW

Antiemetic Prophylaxis During Intensification

Emetogenic potential on days with methotrexate (days 1, 8, and 22) is MODERATE

Emetogenic potential on days with asparaginase (days 2, 9, and 23) is MINIMAL

Antiemetic Prophylaxis During Consolidation, Cycle 1

Emetogenic potential on days 1–5 is LOW

Emetogenic potential on days 8 and 15 is MINIMAL

Antiemetic Prophylaxis During Consolidation, Cycle 2

Emetogenic potential on days 1–5 is LOW

Antiemetic Prophylaxis During Consolidation, Cycle 3

Emetogenic potential on days 1, 8, 15, and 29 is MODERATE

Emetogenic potential on days with cytarabine is LOW

Emetogenic potential on days with thioguanine alone is LOW

Antiemetic Prophylaxis During Consolidation, Cycle 4

Emetogenic potential on days 1–5 is LOW

Antiemetic Prophylaxis During Maintenance

Emetogenic potential on days methotrexate is given is MINIMAL–LOW

Emetogenic potential all other days is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; Pneumocystis jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Population Studied

Of patients from 15 to 59 years of age newly diagnosed with ALL, 1521 received identical induction therapy, irrespective of risk assessment, including central nervous system (CNS) prophylaxis and treatment of CNS disease, if present at diagnosis. Philadelphia chromosome (Ph)-positive patients were considered the highest risk group. Patients who were Ph-negative were considered at high risk if any of the following were present: age ≥35 years; time to CR >4 weeks or WBC count >30 × 109/L for B-lineage ALL and >100 × 109/L for T-lineage ALL. Ph-negative patients who had none of these risk factors were considered at standard risk. After induction therapy, all patients younger than 50 years of age who had a human leukocyte antigen (HLA)–compatible sibling were assigned to undergo allogeneic transplantation. All other patients were randomly assigned between autologous transplantation and standard consolidation/maintenance therapy. Patients who were Ph-positive were offered a search for a matched unrelated donor if they did not have a histocompatible family donor

Efficacy

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Efficacy

No.

CR, %

5-Year Survival, %

5-Year Survival for Patients in CR, %

All patients

1521

Ph+

293

Ph–

1153

Standard risk^✫

533

High risk^✫

590

Unknown risk

^✫Risk stratification at diagnosis based on age and WBC count only

Overall survival (OS) rates at 5 years in this study were 38% for all patients, 41% for Ph-negative patients, and 25% for Ph-positive patients

In subsequent reports (Goldstone AH et al. Blood 2008;111:1827–1833), the 5 year OS in 1913 ALL patients was 39% and 43% for patients with Ph-negative ALL. In Ph-positive patients (Fielding AK et al. Blood 2009;113:4489–4496), the OS was 44% after sib allo-HSCT, 36% after MUD, and 19% after chemotherapy

Treatment Modifications

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Treatment Modifications

Adverse Events

Treatment Modifications

Creatinine 1.5–2 mg/dL (133–177 μmol/L)

Reduce methotrexate dosage by 25%

Creatinine >2 mg/dL (>177 μmol/L)

Reduce methotrexate dosage by 50%

Creatinine >3 mg/dL (>265 μmol/L)

Reduce daunorubicin dosage by 50%

Total bilirubin 3–5 mg/dL (51–86 μmol/L)

Reduce daunorubicin dosage by 50% Reduce methotrexate dosage by 25%

Total bilirubin >3 mg/dL (>51 μmol/L)

Reduce vincristine dosage by 50%

Total bilirubin >5 mg/dL (>86 μmol/L)

Hold daunorubicin

Hold methotrexate

Toxicity

Overall mortality rates for induction therapy were 4.7% (54 of 1153 patients) for Ph-negative patients and 5.5% (16 of 293 patients) for Ph-positive patients. Twenty-nine patients died of infection, most significantly caused by Aspergillus (7 patients). Five patients died of hemorrhage (3 pulmonary, 2 cerebral), 2 patients died of thromboses (possibly related to asparaginase), and 1 patient died from tumor lysis. The remaining 10 patients died of causes described as multiorgan failure, which might also have been related to an infectious etiology

Asparaginase Toxicity Management

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Asparaginase Toxicity Management

Stock W et al. Leuk Lymphoma 2011;52:2237–2253

Toxicity

Grade 2

Grade 3

Grade 4

Hypersensitivity Urticaria, wheezing, laryngospasm, hypotension, etc.

For urticaria without bronchospasm, hypotension, edema, or need for parenteral intervention, continue asparaginase

For life-threatening consequences or indicated urgent intervention, discontinue asparaginase. If erwinia asparaginase is available, replace pegaspargase with erwinia asparaginase

Hypertriglyceridemia

If serum triglyceride level <1000 mg/dL (<11.3 mmol/L), continue asparaginase but follow patient closely for evolving pancreatitis

Hold asparaginase for triglyceride >1000 mg/dL (>11.3 mmol/L); follow closely for pancreatitis; resume asparaginase at prior dose level after patient's triglyceride level returns to normal range

Hyperglycemia, ketoacidosis

Continue asparaginase for uncomplicated hyperglycemia

For hyperglycemia requiring insulin therapy, hold asparaginase (and glucocorticoid therapy) until blood glucose regulated with insulin; resume asparaginase at prior dose level

Hyperammonemia-related fatigue

Continue asparaginase

Reduce asparaginase dose by 25%; resume full dose when toxicity is grade ≤2; make up for missed doses

Reduce asparaginase dose 50%; resume full dose when toxicity grade 2; make up for missed doses

Pancreatitis

Continue asparaginase for asymptomatic amylase or lipase elevation >3 ×ULN (chemical pancreatitis) or only radiologic abnormalities; observe closely for rising amylase or lipase levels

Continue pegaspargase for non-symptomatic chemical pancreatitis but observe patient closely for development of symptomatic pancreatitis for early treatment. Hold native asparaginase for amylase or lipase elevation >3 ×ULN until enzyme levels stabilize or are declining. Permanently discontinue asparaginase for symptomatic pancreatitis

Permanently discontinue all asparaginase for clinical pancreatitis (vomiting, severe abdominal pain) with amylase or lipase elevation >3 ×ULN for >3 days and/or development of pancreatic pseudocyst

Increased hepatic transaminases

For alanine or glutamine aminotransferase elevation >3–5 ×ULN, continue asparaginase

For alanine or glutamine aminotransferase elevation >5–20 ×ULN, delay next dose of asparaginase until transaminasemia is grade <2

For alanine or glutamine aminotransferase elevation >20 ×ULN, discontinue asparaginase if toxicity reduction to grade <2 takes >1 week

Hyperbilirubinemia

Continue asparaginase if direct bilirubin <3.0 mg/dL (<51 μmol/L)

If direct bilirubin is 3.1–5.0 mg/dL (53–86 μmol/L), hold asparaginase and resume when direct bilirubin is <2.0 mg/dL

Consider switching to native asparaginase

If direct bilirubin is >5.0 mg/dL (>86 μmol/L), discontinue all asparaginase and do not make up for missed doses

Non-CNS thrombosis

For abnormal laboratory findings without clinical correlates, continue asparaginase

Withhold asparaginase until acute toxicity and clinical signs resolve and anticoagulant therapy is stable or completed

Non-CNS hemorrhage

For bleeding in conjunction, with hypofibrinogenemia, withhold asparaginase until bleeding is grade ≤1. Do not withhold asparaginase for abnormal laboratory findings without a clinical correlate

Withhold asparaginase until bleeding is grade ≤1, until acute toxicity and clinical signs resolve, and coagulant replacement therapy is stable or completed

CNS thrombosis

For abnormal laboratory findings without a clinical correlate, continue asparaginase

Permanently discontinue all asparaginase

CNS hemorrhage

Discontinue asparaginase; do not withhold asparaginase for abnormal laboratory findings without a clinical correlate

Permanently discontinue all asparaginase

Grade according to the National Cancer Institute Common Terminology Criteria for Advance Events version 4, with the exception of pancreatitis

Monitoring Therapy

CBC with differential daily during and after chemotherapy until recovery of ANC >500/mm³. Platelets every day while in hospital until patient no longer requires platelet transfusions
Metabolic panel and uric acid, at least daily during active treatment until the risk of tumor lysis is past
Amylase and fibrinogen levels prior to asparaginase administration. If fibrinogen level is <100 mg/dL (<1 g/L) consider prophylactic administration of cryoprecipitate
Bone marrow aspirate and biopsy after phase 1 and phase 2 of induction therapy. After a patient achieves a CR, bone marrow biopsy and aspirate should be performed at the end of each consolidation cycle (or at the very least, every other cycle), and every 3 months during maintenance therapy

Notes: A diagnostic spinal tap was performed on all patients

If CNS leukemia was present at diagnosis, methotrexate administered intrathecally via lumbar puncture or through a ventricular reservoir (eg, Ommaya) was given weekly until blast cells were no longer present in the spinal fluid. In addition, 2400 cGy of cranial irradiation and 1200 cGy to the spinal cord were administered concurrently during phase 2. For patients with CNS leukemia at presentation, intrathecal methotrexate was not administered during phase 2

In a subsequent analysis (Fielding AK et al. Blood 2007;109:944–950) of the MRC UKALL XII/ECOG E2993 study, among 1372 patients with ALL who entered remission, 609 (44%) relapsed at a median of 11 months after the start of treatment. Most (556 [91%]) patients relapsed within the bone marrow, the sole site of relapse in most (90%) of those patients. A group of 45 (8%) patients relapsed solely at extramedullary sites

Most patients (81%) relapsed within 2 years after diagnosis, although a significant minority (19%) relapsed >2 years after diagnosis. Of the 440 chemotherapy-treated patients, 349 relapsed within 2 years after diagnosis, and 87 relapsed later. Those on chemotherapy who relapsed within 2 years can be considered “relapses on therapy” because the duration of therapy was set to be 18 months from the point of initiation of the consolidation therapy (ie, 23 months)

The median survival after relapse was 24 weeks. Survival at 1 year was 22% (95% CI = 18–25%), and 7% (95% CI = 4–9%) at 5 years. Only 42 of 609 patients who relapsed remain alive without further relapse

Factors predicting a good outcome after salvage therapy were young age (OS of 12% in patients <20 years vs. OS of 3% in patients >50 years; 2P <0.001) and short duration of first remission (CR1) (OS of 11% in those with a CR1 >2 years vs. OS of 5% in those with a CR1 <2 years; 2P <0.001). Patients treated with HSCT had a superior OS (15% [95% CI = 0–35%] for autograft [n = 13], 16% [95% CI = 7–26%] for matched unrelated donor transplantation [n = 65], and 23% [95% CI = 10–36%] for sibling allograft [n = 42]) to those receiving chemotherapy alone (n = 182) whose OS was only 4% (95% CI = 1–7%) at 5 years

REGIMEN: LIPOSOMAL VINCRISTINE SULFATE

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Regimen: Liposomal Vincristine Sulfate

O'Brien S et al. J Clin Oncol 2013;31:676–683

Vincristine sulfate liposome injection 2.25 mg/m² per dose; administer intravenously in (total volume [q.s.]) 100 mL 0.9% sodium chloride or 5% dextrose injection over 60 minutes for 4 doses on days 1, 8, 15, and 22, every 28 days (total dosage/cycle = 9 mg/m²)

Liposomal vincristine sulfate doses are calculated from actual body surface area, and are not capitated

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Treatment Modifications

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Treatment Modifications

G ≥3 adverse effects (severe symptoms; limiting self-care activities of daily living [ADL]^✫) or persistent G2 (moderate symptoms; limiting instrumental ADL)^† peripheral neuropathy:

Interrupt vinCRIStine sulfate LIPOSOME

If the peripheral neuropathy remains at G ≥3, discontinue liposomal vincristine sulfate

If the peripheral neuropathy recovers to G ≤2, continue treatment with liposomal vincristine sulfate dosage decreased to 2 mg/m² per dose

Persistent G2 peripheral neuropathy after the first dose reduction to 2 mg/m²

Interrupt liposomal vincristine sulfate for up to 7 days

If the peripheral neuropathy increases to G ≥3, discontinue liposomal vincristine sulfate

If peripheral neuropathy recovers to G ≤1, continue treatment with liposomal vincristine sulfate dosage decreased to 1.825 mg/m² per dose

Persistent G ≥2 peripheral neuropathy after a second dose reduction to 1.825 mg/m²

Interrupt liposomal vincristine sulfate for up to 7 days

If the peripheral increases to G ≥3, discontinue liposomal vincristine sulfate

If the toxicity recovers to G ≤1, continue treatment with liposomal vincristine sulfate dosage decreased to 1.5 mg/m² per dose

If neutropenia, thrombocytopenia, or anemia G ≥3 develop, consider dose modification or reduction as well as supportive care measures.

Reduce liposomal vincristine sulfate dosages or interrupt treatment for hepatic toxicity

Severity grading for adverse events is based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_ applications/ctc.htm [accessed December 7, 2013]

^✫Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden

^†Instrumental ADL refers to preparing meals, shopping for groceries and clothes, using telephone, managing money, etc.

Patient Population Studied

Sixty-five adults (median age: 31 years; range: 19–83 years) with Ph-negative ALL in second or greater relapse, or whose disease had progressed following 2 or more leukemia therapies

Efficacy

CR/CRi rate was 20% and overall response rate was 35%

Median OS, overall, 4.6 months (range: <1 month to >25 months), and 7.7 months (range: 2.4 to >23.3 months) among patients who achieved a CR/CRi.

Therapy Monitoring

CBC with differential leukocyte count, renal and hepatic function tests prior to each dose of liposomal vincristine sulfate

Bone marrow biopsy on day 28 of treatment courses 1 and 2 and every second treatment course thereafter

Toxicity

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Toxicity

All Grades %

G3 %

G4 %

Any treatment-related adverse event

Nervous system disorders

Neuropathy peripheral

Hypoesthesia

Paraesthesia

Areflexia

Hyporeflexia

GI disorders

Constipation

Nausea

Vomiting

Abdominal pain

Diarrhea

Blood and lymphatic system disorders

Neutropenia

Anemia

Thrombocytopenia

Febrile neutropenia

General disorders and administration site conditions

Fatigue

Asthenia

Pyrexia

Metabolism and nutrition disorders

Decreased appetite

Tumor lysis syndrome

Investigations

Weight decreased

Notes:

Liposomal vincristine sulfate is a vinca alkaloid indicated for the treatment of adult patients with Philadelphia chromosome-negative (Ph−) acute lymphoblastic leukemia (ALL) in second or subsequent relapse, or whose disease has progressed following 2 or more antileukemia therapies
Liposomal vincristine sulfate is contraindicated in patients with demyelinating conditions including Charcot-Marie-Tooth syndrome
Neurologic toxicity: Monitor patients for peripheral, motor, and sensory, central and autonomic neuropathy, and reduce, interrupt, or discontinue treatment if signs or symptoms present
- Patients with preexisting severe neuropathy should be treated with liposomal vincristine sulfate only after careful risk-benefit assessment

REGIMEN: NELARABINE

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Regimen: Nelarabine

GöKbuget N Et Al. Blood 2011;118:3504–3511

Nelarabine 1500 mg/m² per dose; administer intravenously (without dilution) over 2 hours for 3 doses on days 1, 3, and 5, every 21 days (total dosage/cycle = 4500 mg/m²)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

Antimicrobial primary prophylaxis to be considered:

Antibacterial—not indicated
Antifungal—not indicated
Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

Efficacy (N = 126)

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Efficacy (N = 126)

Result after Cycle 1 (%)

Overall Result after 1–3 Cycles (%)

Failure

Death on therapy

Withdrawal

Patients with CR after 1 cycle (N = 36) tended to have a better 3-year survival (32% ± 8%) compared with those who later achieved a CR (N = 9; 11% ± 10%; P = 0.06)
The probability of survival after 1 year was 24% (SE ± 3%) and after 3 years 12% (SE ± 3%) with a median survival of 6 months
The 3-year survival of patients with failure or PR after nelarabine (N = 81) compared with patients who achieved a CR (N = 45) was 4% (SE ± 2%) versus 28% (SE ± 7%), respectively (P <0.0001)
A total of 36 of 45 patients (80%) who achieved a CR after nelarabine subsequently received stem cell transplantation (SCT) in continuous CR. Four patients died in CR (11%) related to transplantation (GVHD N = 1, infection N = 3) and 20 patients relapsed (56%). The probability of survival 3 years after transplantation in 36 patients transplanted in CR after nelarabine is 31% (SE ± 8%), and the relapse-free survival at 3 years is 37% (SE ± 9%). The median time to relapse after SCT was 4 months (range: 1–24) months. In patients alive after SCT, the median survival was 41 months (range: 13–85 months)
Survival probability at 3 years was 36% (SE ± 8%) in the 36 patients transplanted in CR after nelarabine. In comparison, CR patients without transplantation in CR after nelarabine (N = 9) survival probability was zero and failure or PR was 4% (SE ± 2%; N = 81) after 3 years (P <0.0001)

Patient Population Studied

Study of 126 relapsed/refractory patients (85% T-cell acute lymphoblastic leukemia (T-ALL),15% T-cell lymphoblastic lymphoma), median age 33 years (range: 18–81 years) treated with nelarabine

Treatment Modifications

Nelarabine administration should be discontinued for neurologic adverse reactions of NCI Common Terminology Criteria for Adverse Events grades ≥2. Treatment may be delayed for other toxicities

Therapy Monitoring

Weekly and before a treatment cycle: CBC with differential, renal, and hepatic function
Response evaluation: bone marrow biopsy every 2 cycles

Toxicity

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Toxicity

Hematologic

G 3–4 (%)

Leukopenia

Granulocytopenia

Thrombocytopenia

Neurotoxicity

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Neurotoxicity

Incidence, N (%) of Cycles

G 1

G 2

G 3

G 4

Number of Cycles

Cognitive disturbance

9 (4)

Confusion

9 (4)

Consciousness impaired

1 (0.5)

Dizziness

13 (6)

Fatigue

1 (0.5)

Guillain-Barré–like syndrome

1 (0.5)

Hallucination

4 (2)

Insomnia

2 (1)

Memory impaired

7 (3)

Mood alteration

12 (6)

Neuropathy increased

5 (2)

Restlessness

4 (2)

Somnolence

1 (0.5)

Tremor

4 (2)

Neurologic toxicities of any degree were observed after 26 cycles (13%) in 20 patients (16%). The majority of events were G1 or G2. In 4% of the cycles (N = 4) and 7% of the patients (N = 9), G3/4 neurotoxicities were observed
In 1 patient, treatment had to be stopped because of a Guillain-Barré–like syndrome with tetraparesis, hallucinations, and reduced vigilance, which developed at day 3 of the first cycle. The symptoms improved slowly after nelarabine was withdrawn

Notes

Nelarabine is indicated for the treatment of patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least 2 chemotherapy regimens
Severe neurologic adverse reactions have been reported with the use of nelarabine, including altered mental states, such as severe somnolence, central nervous system effects, such as convulsions, and peripheral neuropathy, ranging from numbness and paresthesias to motor weakness and paralysis. There have also been reports of adverse reactions associated with demyelination, and ascending peripheral neuropathies similar to Guillain-Barré syndrome

Full recovery from adverse reactions has not always occurred with cessation of therapy with nelarabine. Close monitoring for neurologic adverse reactions is strongly recommended
DeAngelo DJ et al. (Blood 2007;109: 5136–5142) also reported their experience with 26 refractory/relapsed patients with T-cell acute lymphoblastic leukemia (T-ALL) and 13 patients with T-cell lymphoblastic lymphoma whose median age was 34 years (range: 16–66 years). Treatment consisted of nelarabine 1500 mg/m² per dose intravenously over 2 hours for 3 doses on days 1, 3, and 5, every 21 days (total dosage/cycle = 4500 mg/m²). The investigators reported a complete remission rate of 31% (95% confidence interval [CI], 17%, 48%), and an overall response of 41% (95% CI, 26%, 58%). The principal toxicities were G3 or G4 neutropenia and thrombocytopenia, which occurred in 37% and 26% of patients, respectively. Only one G4 neurologic adverse event occurred, a reversible depressed level of consciousness. The median disease-free survival (DFS) was 20 weeks (95% CI, 11%, 56%), and the median overall survival was 20 weeks (95% CI, 13%, 36%). The 1-year overall survival was 28% (95% CI, 15%, 43%)

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Chapter 17: Leukemia, Acute Lymphoblastic (ADULT)

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INTRODUCTION

Expert Opinion

PROPHYLAXIS AGAINST TUMOR LYSIS SYNDROME: HYDRATION, URINARY ALKALINIZATION, AND ALLOPURINOL ADMINISTRATION

REGIMEN: LARSON REGIMEN

REGIMEN: HYPER-CVAD

REGIMEN: LINKER REGIMEN

REGIMEN: ALL TRIAL: MRC UKALL XII/ECOG E2993

REGIMEN: LIPOSOMAL VINCRISTINE SULFATE

REGIMEN: NELARABINE

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