Cladribine (Systemic)


VA CLASSIFICATION
Primary: AN300

Commonly used brand name(s): Leustatin.

Other commonly used names are
2-chlorodeoxyadenosine and 2-CdA .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Leukemia, hairy cell (treatment)—Cladribine is indicated for active treatment of hairy cell leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms {01} {05} {06} {08} {09} {10} {11} {12} {13} {14} {15} {16}.

[Leukemia, chronic lymphocytic (treatment)]1—Cladribine is accepted for treatment of B-cell chronic lymphocytic leukemia (CLL) in both previously untreated patients and patients refractory to previous treatment, based upon reports of objective tumor responses, most of which were partial, in noncomparative studies {21} {29} {32} {43} {48}.

[Lymphomas, non-Hodgkin's (treatment)]1—Cladribine is accepted for treatment of low-grade non-Hodgkin's lymphomas in patients refractory to previous treatment, based upon reports of objective tumor responses, most of which were partial, in two noncomparative studies {33} {34} {48}.

[Waldenstrom macroglobulinemia (treatment)]1—Cladribine is accepted for treatment of Waldenstrom macroglobulinemia, based upon reports of objective tumor responses in one noncomparative study {35} {48}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Synthetic {01}.

Chemical group—
    Cladribine is a halogenated {23} purine nucleoside analog {01} {05} of deoxyadenosine {40}.
Molecular weight—
    285.7 {02}

Mechanism of action/Effect:

Cladribine is an antimetabolite {18}. The exact mechanism of action in hairy cell leukemia is unknown {01} {07} {08}. Cladribine is resistant to the action of adenosine deaminase (ADA) {01} {05} {06} {07} {08}, which deaminates {01} {05} {07} deoxyadenosine to deoxyinosine {05} {08}. The phosphorylated metabolites of cladribine accumulate in cells with a high ratio of deoxycytidine kinase activity to 5´ nucleotidase activity {01} {05} {07} (lymphocytes {01} {05} {07} {08}, monocytes {01} {05}) and are converted to the active triphosphate deoxynucleotide {01}. Intracellular accumulation of toxic deoxynucleotides selectively kills these cells {01} {05}, which become unable to properly repair single-strand DNA breaks, leading to disruption of cell metabolism {01} {05} {07}. In addition, there is some evidence that deoxynucleotides are incorporated into the DNA of dividing cells and impair DNA synthesis {01} {05}. Cladribine also induces apoptosis (a form of programmed cell death in sensitive cells) {01} {05} {07}.

Cladribine's action is cell cycle–phase nonspecific {08}; cladribine equally affects dividing and resting lymphocytes {01} {05} {20}.


Other actions/effects:

Cladribine has immunosuppressant activity {05} {08} {17}; restoration of lymphocyte subsets after treatment takes at least 6 to 12 months {05} {08} {36}, although clinical immunocompetence is usually restored after about a month {05}. Significant reductions in T and B lymphocytes occur during treatment {08} (both CD4 and CD8 are affected {01} {08} {11}) and CD4 counts recover more slowly after treatment {01} {08} {11}.

Distribution:

Cladribine crosses the blood-brain barrier {18}.

Protein binding:

Moderate (approximately 20%) {01}.

Biotransformation:

Metabolized in all cells with deoxycytidine kinase activity {24} to 2-chloro-2´-deoxyadenosine-5´-triphosphate {01}.

Half-life:

Distribution—With continuous intravenous infusion: Approximately 30 minutes {01} {05} {07}.

Terminal—With continuous intravenous infusion: 7 hours {01} {05} {07}.

Onset of action:

Time to achieve response—Median 4 months {01}. (Response is defined as absence of hairy cells in bone marrow and peripheral blood together with normalization of peripheral blood parameters {01}.)

Pharmacologic—Toxicity to lymphocytes: 7 days {07} {20}.

Duration of action:

Median duration of response—Greater than 8 months (range, up to and greater than 25 months) {01}.

Elimination:
    Unknown {01}.
    In dialysis or hemofiltration—Unknown {01}.


Precautions to Consider

Carcinogenicity

No studies have been done with cladribine in animals {01}.

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents. {03}

Antimetabolites have been shown to be carcinogenic in animals and may be associated with an increased risk of development of secondary carcinomas in humans, although the risk appears to be less than with alkylating agents {03}.

Mutagenicity

In mammalian cells in culture, cladribine has been shown to cause an imbalance of intracellular deoxyribonucleotide triphosphate pools. This imbalance resulted in the inhibition of DNA synthesis and DNA repair, yielding DNA strand breaks and subsequently cell death. Inhibition of thymidine incorporation into human lymphoblastic cells was 90% at concentrations of 0.3 micromolar. Cladribine was also incorporated into DNA of these cells. Cladribine was not mutagenic to bacteria and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures. {01}

Pregnancy/Reproduction
Fertility—
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents. {03}

Intravenous administration of cladribine to Cynomolgus monkeys has been shown to cause suppression of rapidly generating cells, including testicular cells {01}.

Pregnancy—
Adequate and well-controlled studies in women have not been done {01}.

First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered. {03}

Other hazards to the fetus include adverse reactions seen in adults {03}.

In general, use of contraception is recommended during cytotoxic drug therapy {03}.

Cladribine has been shown to cause a significant increase in fetal variations in mice at a dose of 1.5 mg per kg of body weight (mg/kg) (4.5 mg per square meter of body surface) per day, and to cause increased resorptions, reduced litter size, and increased fetal malformations in mice at a dose of 3 mg/kg (9 mg per square meter of body surface) per day {01}. Cladribine was shown to cause fetal death and malformations in rabbits at a dose of 3 mg/kg (33 mg per square meter of body surface) per day {01}. No fetal effects were produced in mice at a dose of 0.5 mg/kg (1.5 mg per square meter of body surface) per day or in rabbits at a dose of 1 mg/kg (11 mg per square meter of body surface) per day {01}.

FDA Pregnancy Category D {01}.

Breast-feeding

Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended during chemotherapy because of the potential risks to the infant (adverse effects, mutagenicity, carcinogenicity) {03}. It is not known whether cladribine is distributed into breast milk {01}.

Pediatrics

No information is available on the relationship of age to the effects of cladribine in pediatric patients. However, phase I {01} {19} and phase II {28} studies in children have been reported {01} {19} and some studies of cladribine for acute myelocytic leukemia and acute lymphocytic leukemia have included children {21}.


Geriatrics


Although appropriate studies on the relationship of age to the effects of cladribine have not been performed in the geriatric population, clinical trials have included patients over 65 years of age {10} {12} and geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected {25}.


Dental

The bone marrow depressant effects of cladribine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks. {03}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Allopurinol or
Colchicine or
» Probenecid or
» Sulfinpyrazone    (cladribine may raise the concentration of blood uric acid {01}; dosage adjustment of antigout agents may be necessary to control hyperuricemia and gout; allopurinol may be preferred to prevent or reverse cladribine-induced hyperuricemia because of risk of uric acid nephropathy with uricosuric antigout agents)


Blood dyscrasia–causing medications (See Appendix II )    (leukopenic and/or thrombocytopenic effects of cladribine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of cladribine, if necessary, should be based on blood counts)

{03}
» Bone marrow depressants, other (See Appendix II ) or
Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)

{03}
Vaccines, killed virus    (because normal defense mechanisms may be suppressed by cladribine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors)

{03}
» Vaccines, live virus    (because normal defense mechanisms may be suppressed by cladribine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the cladribine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)

{03}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Uric acid concentrations in blood and urine    (may be increased as part of a tumor lysis syndrome, especially in patients with a large tumor burden {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression{01}
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease {03})


Gout, history of or
Urate renal stones, history of    (risk of hyperuricemia {01})


» Infection{03}
» Sensitivity to cladribine{01}
» Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy{03} .

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
CD4 T lymphocyte count and
CD8 T lymphocyte count    (recommended prior to initiation of therapy and at periodic intervals during and after therapy {44})


» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy {01}; frequency varies according to clinical state, agent, dose, and other agents being used concurrently {03})


Uric acid concentrations, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)

{26}


Side/Adverse Effects

Note: Percentage figures for frequency of side/adverse effects listed below are based on a single study of patients with hairy cell leukemia and are included only as an indication of relative frequency of reported side/adverse effects.
Cladribine has considerable hematopoietic stem cell toxicity {05}.
In patients with hairy cell leukemia, anemia, neutropenia, and thrombocytopenia may worsen during the first two weeks of cladribine therapy, before recovery begins {01} {10} {11}.
Prolonged bone marrow hypocellularity has been observed after treatment with cladribine {01}.
Administration of repeated courses for indications other than hairy cell leukemia has been associated with prolonged {29}, dose-limiting thrombocytopenia, occasional pancytopenia, and prolonged erythroid macrocytosis {05}.
Neurotoxicity (paraparesis/quadraparesis of upper and/or lower extremities consistent with a demyelinating disease) and acute renal failure (possibly necessitating hemodialysis {05}) occurred frequently in patients who received cladribine for indications other than hairy cell leukemia in doses above 0.26 mg per kg of body weight (mg/kg) per day for 10 to 14 days {05} (4 to 9 times the recommended dose for hairy cell leukemia) {01} in conjunction with alkylating agents, total body irradiation, and allogeneic bone marrow transplantation.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Anemia, severe (usually asymptomatic)—37%{01}
    
fever —40–70%{01}{08}{09}{10}{11}{12}{13}{14}{37}
    
infection (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—28%{01}{10}{14}{16}{17}
    
neutropenia, severe (usually asymptomatic)—up to 70%{01}{09}{11}{12}{13}
    
skin rash —27%{01}{11}{12}{15}{16}{47}
    
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—12%{01}{12}

Note: Anemia may increase transfusion requirements during the first month of therapy {01}; median time to normalization of hemoglobin has been reported to be 8 weeks {01}.
Fever (temperature above 100 °F [38 °C]) usually begins between the fifth and seventh day of therapy {05} {09} and lasts a few days {12}. Severe fever (temperature of 104 °F [40 °C] or higher) occurs in about 10% of patients {01}. In most patients, fever is associated with neutropenia {01} {08} {13}, although non-neutropenic fever may also occur {01}. Documented infections (including those related to central intravenous catheters) occur in fewer than one-third of patients who experience severe fever {01} {45}. Fever has generally not been reported when cladribine was used for indications other than hairy cell leukemia {05}.
Infections may be bacterial, viral, protozoal (e.g., Pneumocystis) {39}, or fungal {01} {10} {20}, may occur even in the absence of neutropenia, and may be life-threatening {01}. Cladribine causes prolonged depression of CD4 and CD8 lymphocyte subset counts {01}; recovery of counts takes at least 6 to 12 months {05} {08} {36}.
The highest incidence of severe neutropenia is in patients with pre-existing neutropenia related to prior therapy {38}. Median time to normalization of absolute neutrophil counts (ANC) has been reported to be 5 weeks {01}.
With thrombocytopenia occurring during cladribine therapy of hairy cell leukemia, median time to normalization of platelet counts has been reported to be 12 days {01}. However, thrombocytopenia may become prolonged {29} and dose-limiting with repeated courses (i.e., when cladribine is used for indications other than hairy cell leukemia) {05}.


Incidence less frequent
—less than 10%    
Cough{01}{46}
    
edema{01}{46} (swelling of feet or lower legs)
    
injection site reaction (pain or redness at site of injection)—9%{01}{12}
    
phlebitis (pain or redness at site of injection)—2%{01}{12}
    
shortness of breath{01}{46}
    
stomach pain{01}{46}
    
tachycardia{01}{46} (unusually fast heartbeat)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Anorexia (loss of appetite)—17%{01}{47}
    
headache —22%{01}{16}{47}
    
nausea —28%{01}{15}{47}
    
unusual tiredness —45%{01}{47}
    
vomiting —13%{01}{47}

Note: Nausea is usually mild and does not usually require treatment with antiemetics {01}.
Skin rashes are usually mild {01}.


Incidence less frequent
—less than 10%    
Constipation{01}{47}
    
diarrhea{01}{47}
    
dizziness{01}{47}
    
itching{01}{16}{47}
    
malaise{01}{47} (general feeling of discomfort or illness)
    
myalgia or arthralgia{01}{15}{47} (muscle or joint pain)
    
sweating{01}{47}
    
trouble in sleeping{01}{47}
    
weakness{01}{16}{47}

Note: Dizziness may be a neurologic effect {01}.






Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Treatment consists of:



• Withdrawal of cladribine {01}.


• Observation {01}.


• Supportive therapy.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Cladribine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to cladribine

Pregnancy—Use not recommended because of mutagenic, teratogenic, and carcinogenic potential; advisability of using contraception; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects
Other medications, especially probenecid, sulfinpyrazone, other bone marrow depressants, or other cytotoxic drug or radiation therapy
Other medical problems, especially chickenpox, herpes zoster, or infection

Proper use of this medication
Possibility of nausea and vomiting; importance of continuing medication despite stomach upset

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by the physician

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth {03}

Caution if bone marrow depression occurs {03}
» Avoiding exposure to persons with bacterial infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occur

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur


Side/adverse effects
May cause adverse effects such as blood problems; importance of discussing possible effects with physician

Signs of potential side effects, especially anemia, fever, infection, neutropenia, thrombocytopenia, cough, edema, injection site reaction or phlebitis, shortness of breath, stomach pain, and tachycardia

Asymptomatic side effects including anemia and leukopenia

Physician or nurse can help in dealing with side effects


General Dosing Information
Patients receiving cladribine should be under supervision of a physician experienced in cancer chemotherapy {01}.

Cladribine injection must be diluted prior to administration by intravenous infusion {01}.

If fever occurs, it is recommended that the patient be evaluated for possible infection {01}.

Development of uric acid nephropathy in patients with leukemia or lymphoma may be prevented by adequate oral hydration and, in some cases, administration of allopurinol {10}. Alkalinization of urine may be necessary if serum uric acid concentrations are elevated. {03}

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of cladribine. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required. {03}

Subsequent courses of cladribine should not be administered until hematological effects from the previous course have subsided {01} and then only with great caution {27}.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests. {03}

Red blood cell transfusions may be required for anemia {01}.

If neurotoxicity occurs, it is recommended that withholding or discontinuation of cladribine be considered {01}.

Safety considerations for handling this medication {03}
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include {01}:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Parenteral Dosage Forms

CLADRIBINE INJECTION

Usual adult dose
Hairy cell leukemia
Intravenous (by continuous infusion), 100 mcg (0.1 mg) per kg of body weight per day for seven days {41} {42}.


Note: Cladribine is usually given for only one course for treatment of hairy cell leukemia {05}.
Early studies used an actual dose of 0.09 mg per kg of body weight per day as a result of a slight calculation error during formulation, but in most recent studies the patients received the 0.1 mg per kg dose {41} {42}.


Usual adult prescribing limits
A dose of 0.1 mg per kg of body weight per day by continuous infusion for seven days has been established as the maximum-tolerated dose (MTD) in phase I studies {05} {07} {20} {42}.

Usual pediatric dose
Dosage has not been established {01}.

Strength(s) usually available
U.S.—


1 mg per mL (Rx) [Leustatin (sodium chloride 9 mg [0.15 mEq] per mL)]

Canada—


1 mg per mL (Rx) [Leustatin (sodium chloride 9 mg [0.15 mEq] per mL)]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F) {01}, unless otherwise specified by manufacturer. Protect from light {01}. Not adversely affected by freezing {01}; if freezing occurs, thawing naturally to room temperature is recommended (heat or microwave should not be used), and the solution should not be refrozen {01}.

Preparation of dosage form:
Cladribine injection must be diluted before administration {01}. (Since the product contains no antimicrobial preservative or bacteriostatic agent, proper aseptic technique and environmental precautions are necessary {01}.)

Cladribine injection is prepared for administration by a single 24-hour intravenous infusion (to be repeated daily for 7 days) by adding the calculated daily dose to an infusion bag containing 500 mL of 0.9% sodium chloride injection {01}.

Cladribine injection is prepared for administration by a continuous 7-day intravenous infusion by adding the calculated 7-day dose to the infusion reservoir through a sterile 0.22 micron disposable hydrophilic syringe filter. Then bacteriostatic 0.9% sodium chloride injection (0.9% benzyl alcohol preserved) is added through the filter, in an amount sufficient to make a total of 100 mL.

Caution—Use of diluents containing benzyl alcohol is not recommended for preparation of medications for use in neonates. A fatal toxic syndrome consisting of metabolic acidosis, CNS depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages has been associated with this use.

Stability:
Reconstituted solutions contain no preservative and should be used immediately or stored between 2 and 8 °C (36 and 46 °F) and used within 8 hours of reconstitution {01}.

Incompatibilities:
Use of 5% dextrose injection is not recommended for dilution of cladribine injection because increased degradation of cladribine will occur {01}.



Developed: 07/26/1994
Revised: 08/14/1998



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    1. Kay AC, Saven A, Carrera CJ, et al. 2-Chlorodeoxyadenosine treatment of low-grade lymphomas. J Clin Oncol 1992 Mar; 10: 371-7.
    1. Hickish T, Serafinowski P, Cunningham D, et al. 2´-Chlorodeoxyadenosine: evaluation of a novel predominantly lymphocyte selective agent in lymphoid malignancies. Br J Cancer 1993; 67: 149-53.
    1. Dimopoulos MA, Kantarjian H, Estey E, et al. Treatment of Waldenstrom macroglobulinemia with 2-chlorodeoxyadenosine. Ann Intern Med 1993 Feb 1; 118: 195-8.
    1. Per reviewer comment, 3/94.
    1. Per responses to panel question #2, 3/94.
    1. Per responses to panel question #3, 3/94.
    1. Per panelist comment, 3/94.
    1. Per panelist comment, 3/94.
    1. Per responses to panel question #10, 3/94.
    1. Saven A, Piro LD. 2-Chlorodeoxyadenosine: a newer purine analog active in the treatment of indolent lymphoid malignancies. Ann Intern Med 1994 May 1; 120: 784-91.
    1. O'Brien S, Kantarjian H, Estey E, et al. Lack of effect of 2-chlorodeoxyadenosine therapy in patients with chronic lymphocytic leukemia refractory to fludarabine therapy. New Engl J Med 1994; 330: 319-22.
    1. Per reviewer comment, 3/94.
    1. Per responses to panel question #4, 3/94.
    1. Side effects list confirmed per responses to panel question #5, 3/94.
    1. Side effects list confirmed per responses to panel question #7, 3/94.
    1. Accepted per Hematologic and Neoplastic Disease Advisory Panel consensus 8/12/94.
    1. Bryson HM, Sorkin EM. Cladribine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies. Drugs 1993; 46(5): 872-94.
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