Treatment Challenges

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 approximately 2,400 children each year, most of whom are under the age of 10². Of those children, approximately 80% are event-free 5 years from diagnosis, due in large part to impressive advancement in treatments³. For the remaining 20% who don’t respond to treatment, however, the prognosis is bleak⁴.

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. 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 one⁵, 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.

The need for additional treatment options

In these relapsed or refractory patients, subsequent treatment to achieve or maintain remission is challenging. Heavily pretreated patients may have residual organ damage, which can limit the type of therapy they can receive upon relapse. New therapeutic options are necessary to address this need, and provide oncologists the means to offer their patients a chance to achieve a response and/or move to transplant.

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):554–7.
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. Gaynon PS, Trigg ME, Heerema NA, et al. Children’s Cancer Group Trials in childhood acute lymphoblastic leukemia; 1983-1995. Leukemia. 2000;14:2223–33.
4. Jeha S, Gandhi V, Chan K, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood 2004;103:784–9.
5. Steinherz PG. Acute lymphoblastic leukemia of childhood. Hematol Oncol Clin North Am 1987;1:549-66.

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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 Considerations

Clolar should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function, which is usually reversible and dose dependent, should be anticipated and is likely to increase the risk of infection, including severe sepsis. Administration of Clolar results in a rapid reduction in peripheral leukemia cells. Patients should be evaluated and monitored for signs and symptoms of tumor lysis syndrome and cytokine release (e.g., tachypnea, tachycardia, hypotension, pulmonary edema) that could develop into systemic inflammatory response syndrome (SIRS)/capillary leak syndrome, and organ dysfunction. Clolar should be discontinued immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and use of steroids, diuretics, and albumin considered.

The most common adverse effects after Clolar treatment, regardless of causality, were gastrointestinal tract symptoms, including vomiting (grade 3: 8%; grade 4: 1%), nausea (grade 3: 15%; grade 4: 1%), and diarrhea (grade 3: 10%); hematologic effects, including anemia (grade 3: 70%; grade 4: 18%), leukopenia (grade 4: 99%), thrombocytopenia (grade 3: 36%; grade 4: 64%), neutropenia (grade 3: 3%; grade 4: 7%), and febrile neutropenia (grade 3: 53%; grade 4: 3%); and infection (grade 3: 56%; grade 4: 18%).

Hepato-biliary toxicities were frequently observed in pediatric patients during treatment with Clolar. The most frequently reported cardiac disorder was tachycardia (34%), which was, however, already present in 27.4% of patients at study entry. Left ventricular systolic dysfunction was also noted. Since Clolar is excreted primarily by the kidneys, drugs with known renal toxicity should be avoided during the 5 days of Clolar administration. In addition, since the liver is a known target organ for Clolar toxicity, concomitant use of medications known to induce hepatic toxicity should also be avoided.

Severe bone marrow suppression, including neutropenia, anemia, and thrombocytopenia, have been observed in patients treated with Clolar. 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.

Pericardial effusion was a frequent finding in these patients on post-treatment studies. Careful hematologic monitoring during therapy is important. Hepatic and renal function should be assessed prior to and during treatment with Clolar, as the liver is a target organ for Clolar toxicity and the kidneys are the predominant mode of Clolar excretion.

Patients receiving Clolar may experience vomiting and diarrhea; they should therefore be advised regarding appropriate measures to avoid dehydration. Clolar may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant and avoid breastfeeding while receiving treatment with Clolar.

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