Risk organ + LCH gets the one-two punch?

In this issue of Blood, Donadieu et al¹  present what may be the most encouraging data to date on a group of patients with Langerhans cell histiocytosis (LCH), which historically has poor disease-free survival and poor overall survival.

Since the beginning of the Histiocyte Society, when a small group of clinicians and scientists gathered in Philadelphia almost 30 years ago,²  investigators have been trying to understand this disease and its treatment and outcomes better through collaborative studies. During the past 3 decades, this small group of investigators has grown and reached out to an international contingent that recognized that any changes in the diagnosis and treatment of patients with such a rare disorder as LCH would require international collaboration. The group expanded in size and commitment, assembling clinical trials and gathering data on outcomes and late effects, and developing treatment algorithms. Over the next 20 years, several studies were completed that highlighted that children with disease involving the bone marrow, spleen, and liver (ie, risk organs) have a poor prognosis; children who failed to respond to induction therapy had a poor survival; children with disease affecting the facial bones would be at risk for a unique group of late effects including diabetes insipidus; and even with continued attempts to increase disease control, some children would inevitably develop recurrent disease.^3-5  The group with the worst prognosis and survival throughout these clinical trials has continued to consist of children with disease involving the bone marrow, liver, or spleen who did not respond to routine induction therapy or had a reactivation of their disease involving one of these high-risk organs. This group of patients has an overall 2-year survival rate of <30%.⁶  There have been a small series of reports suggesting that more aggressive therapy mimicking acute myeloid leukemia therapy may have an impact on this disease.^7,8  Bernard et al took this concept one step further and reported their results of a pilot study of 10 patients treated in France with the combination of high-dose 2-cladribine and cytosine arabinoside.⁹  The data were encouraging, and a phase 2 trial using the resources of the Histiocyte Society was initiated. The results of that study are reported in this issue. The intent of the study was to be an international collaboration with strict inclusion criteria and a well-defined treatment plan. The study was only able to accrue patients in Europe. A total of 27 patients were enrolled over the 5-year period. The primary end point was disease status after 2 courses of the 2-drug therapy.

LCH disease status has been reported since that initial meeting using a simple schema of nonactive disease, active disease better, active disease stable, and active disease worse.¹⁰  The problem for such an evaluation system was that LCH is not a simple disorder involving one organ or one site of one organ. The need for a system that might aid clinicians to grasp a more fluid and flexible disease evaluation system became apparent. Donadieu et al used a disease activity score (DAS) in this study to follow these patients. It is important to note that the primary objectives of the response to 2 courses of therapy and length of time to achieve complete remission were based on the standard LCH disease activity system. The investigators report that the use of this DAS will aid clinicians in better understanding the disease response or lack thereof in future clinical trials. The bottom line is that, of the 27 patients reported, the investigators report an overall response rate of 92% and a long-term survival rate of 85%. However, there is a caveat whenever a highly toxic regimen is used, and the investigators reported these acute and late effects.

For the first time since the founding of the Histiocyte Society, a regimen used in a multi-institutional trial demonstrates that children with disease of the bone marrow, liver, or spleen who do not respond to standard induction therapy can be treated with intensive chemotherapy. So what is next?

The Histiocyte Society has launched the LCH-IV study, with one of the strata addressing similar patients: risk organ–positive patients who do not respond to up-front induction. The treatment plan is a slight modification of the reported salvage therapy in an attempt to decrease toxicity yet maintain the improved overall survival seen in this phase 2 trial. Time, perseverance, and collaboration highlight the slow and steady progress in the treatment of this rare disease. Only time and collaboration will determine whether this type of therapy will have the long-lasting impact suggested by the results of Donadieu et al.