Important Safety Information
Clolar® should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. View additional Important Safety Information.

About Pediatric ALL

Acute lymphoblastic leukemia (ALL) is a clonal proliferation of early B- and T-lymphocyte progenitors. ALL is generally thought to arise in the bone marrow, but leukemic blasts may be systemically present at the time of presentation, found in the bone marrow, peripheral blood, thymus, liver, spleen, lymph nodes, testes, and central nervous system.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children and adolescents,1,2 and the leading cause of disease-related death in children, despite improvements in treatment outcomes.

ALL is diagnosed in over 2000 children each year, 80% of whom are between the ages of 2-3 and most are under the age of 10.3 Of these children, approximately 80% are event-free 5 years from diagnosis, due in large part to impressive advances in treatments.4 However, for the remaining 20% who fail to respond to treatment, the prognosis is poor.5 

An analysis of progression free survival data for 412 pediatric patients (< 21 years of age) with recurrent or refractory ALL registered in the Pediatric Oncology Group phase 2 studies between 1984 and 1994 indicate few of these patients achieve long-term, progression-free survival.
Adapted with permission from Weitman S, Ochoa S, Sullivan, J, et al.  Pediatric phase II cancer chemotherapy trials: a Pediatric Oncology Group study. J Pediatr Hematol Oncol. 1977; 19:187-191.

Overview of relapsed/refractory ALL

The American Cancer Society estimates that more than 95% of children with ALL achieve remission following standard first-induction regimens.6 Those who relapse can frequently achieve a second or third remission—often with the same therapeutic agents used previously. However, each remission is usually shorter than the previous one,7 and carries with it the toxic burden associated with multiple chemotherapies, including organ dysfunction. In addition, leukemia cells become resistant to these agents, particularly at relapse.

Treatment goals at relapse

In patients with ALL who have multiple relapses or have become refractory, bone marrow or allogeneic stem-cell transplantation may be considered the standard of care. For the transplant to be successful, however, remission must be sustained long enough to identify a donor and prepare the patient for transplant, so that the risk of post-transplant relapse is low.

References:

  1. McNeil DE, Cote TR, Clegg L, Mauer A. SEER update of incidence and trends in pediatric malignancies: acute lymphoblastic leukemia. Med Pediatr Oncol. 2002;39(6):554-557.
  2. Smith MA, Gloeckler Ries LA, Gurney JG, Ross JA. Leukemia: SEER pediatric monograph. In: Ries LAG, Smith MA, Gurney JG, et al. (eds). Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. NIH Pub. No. 99-4649. Bethesda, MD, 1999.
  3. CancerMPact®. The Mattson Jack Group, Inc. Available at: www.cancermpact.com.  Accessed Nov. 24, 2008.
  4. Gaynon PS, Trigg ME, Heerema NA, et al. Children’s Cancer Group Trials in childhood acute lymphoblastic leukemia; 1983-1995. Leukemia. 2000;14:2223-2233.
  5. Jeha S, Gandhi V, Chan K, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004;103:784-789.
  6. American Cancer Society Web site. Treatment of Children With Acute Lymphocytic Leukemia. Accessed March 20, 2009.
  7. Steinherz PG. Acute lymphoblastic leukemia of childhood. Hematol Oncol Clin North Am. 1987;1:549-566.

Clolar Resources

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Prescribing Information

Prescribing Information 
Clolar prescribing information (.pdf)

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Indication

Clolar is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.

Important Safety Information

Warnings and Precautions:

Clolar® should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

    Hematologic Toxicity

    • Monitor complete blood counts and platelet counts during and after Clolar therapy.
    • Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. Severe bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, has been observed in patients treated with Clolar. At initiation of treatment, most patients in the clinical studies had hematological impairment as a manifestation of leukemia.
    • Because of the pre-existing immunocompromised condition of these patients and prolonged neutropenia that can result from treatment with Clolar, patients are at increased risk for severe opportunistic infections.

    Infections

    The use of Clolar is likely to increase the risk of infection, including severe sepsis, as a result of bone marrow suppression. Monitor patients for signs and symptoms of infection and treat promptly.

      Hyperuricemia (Tumor Lysis)

      Administration of Clolar may result in a rapid reduction in peripheral leukemia cells. Evaluate and monitor patients undergoing treatment for signs and symptoms of tumor lysis syndrome. Provide intravenous infusion fluids throughout the five days of Clolar administration to reduce the effects of tumor lysis and other adverse events. Administer allopurinol if hyperuricemia (tumor lysis) is expected.

        Systemic Inflammatory Response Syndrome (SIRS) and Capillary Leak Syndrome

        • Evaluate and monitor patients undergoing treatment with Clolar for signs and symptoms of cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS), capillary leak syndrome and organ dysfunction.
        • Discontinue Clolar immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and consider use of steroids, diuretics, and albumin. Re-institute Clolar when the patient is stable, generally with a 25% dose reduction. The use of prophylactic steroids may be of benefit in preventing signs and symptoms of cytokine release.

        Hepatic Enzymes

        Hepato-biliary enzyme elevations were frequently observed in pediatric patients during treatment with Clolar. Some patients discontinued treatment due to hepatic enzyme abnormalities.

          Hepatic and Renal Impairment

          • Clolar has not been studied in patients with hepatic or renal dysfunction. Its use in such patients should be undertaken only with the greatest caution.
          • Patients who have previously received a hematopoietic stem cell transplant (HSCT) may be at higher risk for hepatotoxicity suggestive of veno-occlusive disease (VOD) following treatment with clofarabine (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). Severe hepatotoxic events have been reported in an ongoing Phase 1/2 combination study of clofarabine in pediatric patients with relapsed or refractory acute leukemia.

          Use in Pregnancy

          Clolar can cause fetal harm when administered to a pregnant woman. Intravenous doses of clofarabine in rats and rabbits administered during organogenesis caused an increase in resorptions, malformations, and variations. Women of childbearing potential should be advised to avoid becoming pregnant while receiving Clolar.

            Nursing Mothers

            Female patients should be advised to avoid breast-feeding during treatment with Clolar.

              Incidence of Treatment Emergent Laboratory Abnormalities (All Grades)

              ParameterAny gradeGrade 3 or higher
              Anemia 83% 75%
              Leukopenia 88% 88%
              Lymphopenia 82% 82%
              Neutropenia 64% 64%
              Thrombocytopenia 81% 80%
              Elevated creatinine 50% 8%
              Elevated SGOT 74% 36%
              Elevated SGPT 81% 43%
              Elevated total bilirubin 45% 13%

              Adverse Reactions:

              Most common adverse reactions with Clolar were nausea (73%), vomiting (78%), diarrhea (56%), febrile neutropenia (55%), headache (43%), rash (38%), pruritus (43%), pyrexia (39%), fatigue (34%), palmar-plantar erythrodysesthesia syndrome (16%), anxiety (21%), flushing (19%), and mucosal inflammation (16%).

              For more information, please consult the full Prescribing Information (PDF).