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Combination of cladribine, cytarabine improves survival for children with LCH
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The combination of cladribine and cytarabine conferred high survival rates among children with high-risk, risk organ-positive Langerhans cell histiocytosis, according to findings from an international phase 2 study.
However, the combination also resulted in a high rate of toxicity, results showed.
“Langerhans cell histiocytosis is known to be a very rare and very heterogeneous disease,” study researcher Jean Donadieu, MD, a pediatric oncologist at Hôpital Trousseau in Paris, told HemOnc Today. “Developing a trial is itself a challenge here, if we want to increase the degree of evidence. Most of the cases undergo a spontaneous remission or are eligible for a well-defined and safe chemotherapy regimen with two old drugs: vinblastine and a steroid. But its use remains somewhat limited in groups of patients with a poor outcome.
“Patients with hematological dysfunction and who are refractory to standard therapy are the main targets. … The historical survival of this group was about 30%,” Donadieu added.
Due to the promising results of a pilot study evaluating cladribine and cytosine-arabinoside as salvage therapy in 10 patients with Langerhans cell histiocytosis (LCH), Donadieu and colleagues conducted this phase 2 study of the drug combination in a cohort of 27 patients (median age at diagnosis, 0.73 years; range, 0.1-3.3).
The patients (20 boys, 7 girls) had a pathological diagnosis of LCH with the involvement of at least one risk organ — all patients had liver and spleen involvement — and had failed initial therapy. Twenty-five patients had hematological cytopenia.
Median follow-up was 5.37 years (range, 3.0-9.3 years).
Dosage varied depending on age and weight, but the initial course consisted of 500 mg/m² IV cytarabine twice daily for 5 days and 9 mg/m² IV cladribine daily for 5 days starting on day 2.
Ten patients underwent two courses of therapy, 12 patients had three courses, three patients had four courses and two patients had five courses.
Overall response rate (ORR) after two courses of therapy served as the primary endpoint.
Researchers defined patients’ disease status after two courses of therapy as non-active (n = 2), better (n = 23) or stable (n = 2). These data equated to an ORR of 92%.
The median disease activity score decreased from 12 at baseline to 3 after two courses of therapy (P ˂ .0001).
Among 21 patients with sufficient information, the median time to “non-active disease” status was 128 days (range, 52-1,971). Four patients did not achieve “non-active disease” status by the end of their intervention. One patient had a lethal viral infection and could not be assessed, and another patient experienced persistent pancytopenia and fever — considered disease-related — and died after five courses of treatment.
Six patients experienced disease reactivation with a median delay of 0.9 years. In two cases, the reactivation was limited to the skin and patients resumed conventional therapy. The other four patients had reactivation with involved risk organs, three of whom again received cladribine and cytarabine. One of these patients achieved complete response, and one patient achieved disease control after undergoing hematopoietic stem cell transplantation.
The 5-year survival rate was 85% (95% CI, 65.2-94.2). Four fatalities occurred at a median of 0.74 years (range, 0.21-1.6) after initiating therapy, two of which were considered therapy related (invasive varicella zoster virus infection and prolonged pancytopenia 9 months after the start of therapy).
All patients experienced grade 4 pancytopenia and fever. Additional toxicities included grade 3 to grade 4 enteritis and diarrhea (18%), septicemia (11%) and invasive pulmonary aspergillosis (11%). One patient experienced myalgia and tubulopathy.
Five patients were admitted to the ICU during the first two courses of therapy. The median duration of initial hospitalization — or time from the beginning of course one through discharge — was 65 days (range, 48-1,098).
Despite the efficacy, researchers identified substantial toxicity and the slow time to response as limitations of this therapy.
“These two limitations suggest that new therapeutic approaches are needed to help these children,” Donadieu and colleagues wrote. “Beyond a better understanding of the pathophysiology, the identification of a BRAF mutation in LCH and in Erdheim Chester disease offers the possibility of using BRAF inhibitors as targeted therapies in adults and also in infants if a therapeutic trial demonstrates the long-term safety of such therapy for young children. However, despite this promising perspective, the combination of cladribine and cytarabine can currently be considered the most effective salvage therapy for high-risk LCH.” – by Anthony SanFilippo
For more information:
Jean Donadieu, MD, can be reached Hôpital Trousseau, 26 Avenue du Dr Arnold Netter, 75012 Paris, France; email: jean.donadieu@trs.aphp.fr.
Disclosure: The researchers report no relevant financial disclosures.
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