New Treatment Approaches for Patients with LCH

Robert J. Arceci, M.D., Ph.D., Director of the Division of Pediatric Oncology, King Fahd Professor of Pediatric Oncology, Johns Hopkins Oncology Center, Baltimore, Maryland, USA
Discussion of treatment approaches for LCH

Should we treat this disease or not? While this may seem like an unusual question, LCH may in some instances regress on its own without treatment. In other situations, very minimal treatment will result in the resolution of symptoms and regression of the disease. One must therefore often try to balance the extent of medical intervention with the severity of the disease involvement.

For example, there may be little disagreement that an isolated bone lesion can usually be effectively managed initially with surgical curettage. Recurrent disease at the same site or a new lesion that appears in a different place may or may not require any intervention, depending upon their location and their extent. Under such circumstances, some patients will benefit from the use of nonsteroidal anti-inflammatory agents, such as Naprosyn or the local injection of steroids. The absolute, best therapeutic approach has not really been carefully studied, but clearly, most people agree that the treatment in these situations should not be worse than the disease.

For patients with more extensive disease, there is general agreement, based on many published studies of substance, that systemic chemotherapy will be beneficial. The exact type of chemotherapy that is best has not been completely worked out, although several different drugs and combinations have been shown to give excellent results with relatively minimal side effects. Such chemotherapeutic agents include steroids (e.g., prednisone), vinblastine, vincristine, etoposide or VP-16, 6-mercaptopurine, and methotrexate. While all of these agents have demonstrated good activity in treating LCH, the very best schedule and combination are still being explored.

One of the major challenges that we currently face is what type of treatment should be used for patients with extensive and/or progressive disease that is not responding to the "regular" recipe. Here, we are faced with significantly less information upon which to make the best decisions.

For example, LCH of the skin can be quite extensive and cause significant discomfort and disfigurement. With extensive involvement that is unresponsive to topical steroids, the use of topical nitrogen mustard or PUVA (a type of ultraviolet light treatment) may be effective, but these treatments carry some, albeit small, risk of developing skin cancer at a later date. There may even be circumstances when systemic chemotherapy needs to be used for the treatment of patients with very severe skin involvement.

For patients with refractory and/or progressive multifocal bone or multiorgan disease involvement, there are fewer very good treatments. The recent use of 2-chloro-2'- deoxyadenosine (2CdA) has shown some promising, early results. This drug was initially designed to treat patients with lymphoblastic leukemia but was found to be an excellent treatment for patients with other disorders, such as hairy-cell leukemia, chronic lymphocytic leukemia, and Waldenstrom macroglobulinemia. The initial use of 2CdA in patients with LCH arose out of the fact that it had several features that would potentially make it useful in that setting.

First, 2CdA is a potent immunosuppressive which would be likely to have a beneficial effect on ameliorating the symptoms associated with LCH. Secondly, 2CdA had been shown to be a very effective agent against acute myeloid and lymphoid leukemias. Thus, the hypothesis that this drug would be effective against LCH made a lot of sense, as Langerhans cells are close relatives to the other myeloid and lymphoid cell types. To this end, a relatively small group of patients with LCH were treated with 2CdA.

The results from these early studies were encouraging but not uniformly successful. For instance, it is still not clear why some patients simply do not respond to 2CdA, or for that matter, why some do respond. It is also not yet clear what the optimal dosing schedule is for patients. Furthermore, there is still insufficient information on long-term followup for patients treated with 2CdA. Thus, 2CdA is a drug that must be further studied in controlled clinical trials, so that careful and accurate information can be collected.

Another drug that is related to 2CdA is called "deoxycoformycin." Much less experience has been obtained with this agent, but it too may prove worth further studying. Other agents such as retinoic acid are also being studied, but no significant clinical trial has been done to date. The same can be said for the use of drugs like thalidomide, interleukin-2, oral 2CdA, cyclosporin, or FK-506. There is no solid evidence that supports the use of homeopathic or "over-the-counter" medicines or vitamins to offer any significant benefit.

Bone marrow transplantation has also been tried for patients who have progressive disease despite a variety of treatments. It is evident that in some children, bone marrow transplantation has been able to achieve a complete remission of disease.

Nevertheless, it is unclear just how effective this type of treatment is, because patients experiencing positive outcomes are usually the ones reported in the literature. In addition, while treatment-related morbidity and mortality have clearly improved for patients undergoing transplantation with matched family donors, there is still a significantly high risk for both acute and long-term problems. Furthermore, only a minority of patients will have such a matched family donor.

For the rest of patients, an alternative source of donor hematopoietic stem cells would need to be used, such as bone marrow from matched, nonfamilial members or cord blood samples. While the use of such alternative bone marrow sources is promising, major problems still remain in terms of treatment-related complications and mortality. Another approach to bone marrow transplantation is to use the patient's own hematopoietic stem cells in a procedure termed "autologous stem cell transplantation." This type of approach avoids the potential problems of graft-versus-host disease and usually decreases the chance of the bone marrow not engrafting. However, until more is learned about whether the cell causing LCH can be transferred from the patient's bone marrow back to the patient during the transplant procedure, the use of autologous transplantation may be problematic.

Much more information is needed concerning bone marrow transplantation for patients with LCH before it should be considered as an acceptable form of treatment. In addition, it is critical to better identify which patients would potentially benefit the most from bone marrow transplantation.

The possibility of developing very specific treatments for LCH is also being explored. For example, it is known that the abnormal Langerhans cell of LCH expresses a protein on its surface called "CD1a." Several years ago, investigators made antibodies (called "monoclonal antibodies") in mice, that could specifically detect this protein. Subsequently, Drs. Kelly, Pritchard, Chu, and Beverly tagged this mouse monoclonal antibody with a radioisotope and showed that when injected into patients, the radioactive antibody could find the active sites of LCH.

Unfortunately, patients had significant immune or allergic responses to the mouse antibody to make its use untenable. Recent efforts are now being made to develop this approach, using modified versions of the original antibody that will escape immune recognition and therefore can be safely used in patients for both diagnostic imaging and treatment.

A final area of particular need is how to manage patients with chronic, progressive involvement of the liver, lung, and central nervous system. In the case of liver and lung involvement of this type, a variety of immunosuppressive treatments can be used, but no curative therapy has yet been developed for this type of organ involvement. Sometimes these patients will ultimately need a liver or lung transplant. For patients with progressive involvement of the central nervous system, there is also a lack of effective therapeutic approaches. Recent work is suggesting that in some situations, the use of 2CdA may provide some benefit for patients with central nervous system involvement, but the type and extent of disease that will respond has not been clarified. This needs to be studied more in the context of a careful clinical trial.

Everyone's hope is that more effective and less toxic therapies will be forthcoming for patients with LCH. There is every reason to believe that this will occur by building on discoveries from solid laboratory research and rigorous clinical trials. While we would all want such curative therapies today, the reality is that such advances take a great deal of careful work that, in turn, takes time. Jumping to therapies before adequate testing is very tempting at times but is nearly always the wrong way to go, as we often find out too late that what we want is not always what we get. As Dr. Max Gottlieb said in Arrowsmith by Sinclair Lewis, "God give me unclouded eyes and freedom from haste. God give me a quiet and relentless anger against all pretense and all pretentious work and all work left slack and unfinished. God give me a restlessness whereby I may neither sleep nor accept praise till my observed results equal my calculated results, or in pious glee, I discover and assault my error. God give me strength not to trust to God."

Let us pursue the advancement of better treatments for all patients with LCH with this type of devotion and care.