Chemotherapy

In the HISTSOC-LCH-II and HISTSOC-LCH-III (NCT00276757) studies, the standard treatment arm consisted of vinblastine and prednisone, as described above, but mercaptopurine was added to the continuation phase of the protocol.[27,76][Level of evidence A1]

In the HISTSOC-LCH-II and HISTSOC-LCH-III (NCT00276757) studies, the standard treatment arm consisted of vinblastine and prednisone, as described above, but mercaptopurine was added to the continuation phase of the protocol.[27,76][Level of evidence A1]

The standard therapy length recommended for LCH involving the spleen, liver, or bone marrow (high-risk organs) is now 12 months, based on the DAL-HX 83 and HISTSOC-LCH-III studies.

In the HISTSOC-LCH-II study, patients were randomly assigned to treatment with either vinblastine, prednisone, and mercaptopurine or vinblastine, prednisone, mercaptopurine, and etoposide.[28][Level of evidence A1]

In the HISTSOC-LCH-II study, patients were randomly assigned to treatment with either vinblastine, prednisone, and mercaptopurine or vinblastine, prednisone, mercaptopurine, and etoposide.[28][Level of evidence A1]

There was no statistically significant difference in outcomes (response at 6 weeks, 5-year probability of survival, relapses, and permanent consequences) between the two treatment groups. Hence, etoposide has not been used in subsequent Histiocyte Society trials.

In the HISTSOC-LCH-II study, patients were randomly assigned to treatment with either vinblastine, prednisone, and mercaptopurine or vinblastine, prednisone, mercaptopurine, and etoposide.[28][Level of evidence A1]

Late review of the results, however, reported reduced mortality for patients with risk-organ involvement in the etoposide arm.

Although controversial, a comparison of patients in the HISTSOC-LCH-I trial with patients in the HISTSOC-LCH-II trial suggested the following results:[26]

Although controversial, a comparison of patients in the HISTSOC-LCH-I trial with patients in the HISTSOC-LCH-II trial suggested the following results:[26]

Increased treatment intensity promoted additional early responses and reduced mortality.

Although controversial, a comparison of patients in the HISTSOC-LCH-I trial with patients in the HISTSOC-LCH-II trial suggested the following results:[26]

It is important to note that those studies included lungs as risk organs. However, subsequent analyses have shown that lung involvement lacks prognostic significance.

In the HISTSOC-LCH-III (NCT00276757) study, risk-organ–affected patients were randomly assigned to receive either vinblastine/prednisone/mercaptopurine or vinblastine/prednisone/mercaptopurine plus methotrexate (intravenous during the induction phase and oral in the continuation phase).[29]

In the HISTSOC-LCH-III (NCT00276757) study, risk-organ–affected patients were randomly assigned to receive either vinblastine/prednisone/mercaptopurine or vinblastine/prednisone/mercaptopurine plus methotrexate (intravenous during the induction phase and oral in the continuation phase).[29]

The response rates at 6 and 12 weeks and OS were no different between arms; however, there were significantly increased grade 3 and grade 4 toxicities in patients who received methotrexate.

In the HISTSOC-LCH-III (NCT00276757) study, risk-organ–affected patients were randomly assigned to receive either vinblastine/prednisone/mercaptopurine or vinblastine/prednisone/mercaptopurine plus methotrexate (intravenous during the induction phase and oral in the continuation phase).[29]

An important finding of the HISTSOC-LCH-III study was that the survival of patients with high-risk LCH on both arms of the study was significantly improved compared with that of patients on the earlier HISTSOC-LCH-II study, even though the standard arm used the same drugs. Possible explanations for better survival include the following:

In the HISTSOC-LCH-III (NCT00276757) study, risk-organ–affected patients were randomly assigned to receive either vinblastine/prednisone/mercaptopurine or vinblastine/prednisone/mercaptopurine plus methotrexate (intravenous during the induction phase and oral in the continuation phase).[29] › An important finding of the HISTSOC-LCH-III study was that the survival of patients with high-risk LCH on both arms of the study was significantly improved compared with that of patients on the earlier HISTSOC-LCH-II study, even though the standard arm used the same drugs. Possible explanations for better survival include the following:

A second 6-week induction phase of weekly vinblastine with oral prednisone was administered for 3 days per week. This reinduction phase was given to all patients who did not achieve an NAD status by the end of the 6-week induction phase, before going onto the every-3-weeks maintenance courses. The rate of NAD increased after the second induction phase; this course may have played a significant role in the improved survival rate.

In the HISTSOC-LCH-III (NCT00276757) study, risk-organ–affected patients were randomly assigned to receive either vinblastine/prednisone/mercaptopurine or vinblastine/prednisone/mercaptopurine plus methotrexate (intravenous during the induction phase and oral in the continuation phase).[29] › An important finding of the HISTSOC-LCH-III study was that the survival of patients with high-risk LCH on both arms of the study was significantly improved compared with that of patients on the earlier HISTSOC-LCH-II study, even though the standard arm used the same drugs. Possible explanations for better survival include the following:

Better supportive care.

In the HISTSOC-LCH-III (NCT00276757) study, risk-organ–affected patients were randomly assigned to receive either vinblastine/prednisone/mercaptopurine or vinblastine/prednisone/mercaptopurine plus methotrexate (intravenous during the induction phase and oral in the continuation phase).[29] › An important finding of the HISTSOC-LCH-III study was that the survival of patients with high-risk LCH on both arms of the study was significantly improved compared with that of patients on the earlier HISTSOC-LCH-II study, even though the standard arm used the same drugs. Possible explanations for better survival include the following:

Earlier change to an effective salvage strategy for nonresponsive lesions.

In the HISTSOC-LCH-III (NCT00276757) study, risk-organ–affected patients were randomly assigned to receive either vinblastine/prednisone/mercaptopurine or vinblastine/prednisone/mercaptopurine plus methotrexate (intravenous during the induction phase and oral in the continuation phase).[29]

It should be noted that although survival was improved in the HISTSOC-LCH-III study, only 60% of patients achieved an NAD status in risk organs after a year of therapy, and 25% to 29% of patients relapsed.

In the JLSG-96 trial, treatment included a 6-week induction regimen of cytarabine, vincristine, and prednisolone followed by 6 months of maintenance therapy with cytarabine, vincristine, prednisolone, and low-dose intravenous methotrexate. If patients had a poor response to the initial regimen, they were switched to a salvage regimen of intensive combination doxorubicin, cyclophosphamide, methotrexate, vincristine, and prednisolone.[125][Level of evidence B1]

In the JLSG-96 trial, treatment included a 6-week induction regimen of cytarabine, vincristine, and prednisolone followed by 6 months of maintenance therapy with cytarabine, vincristine, prednisolone, and low-dose intravenous methotrexate. If patients had a poor response to the initial regimen, they were switched to a salvage regimen of intensive combination doxorubicin, cyclophosphamide, methotrexate, vincristine, and prednisolone.[125][Level of evidence B1]

The 5-year response rate was 78%, and the OS rate was 95% for patients with multisystem disease.

In the JLSG-96 trial, treatment included a 6-week induction regimen of cytarabine, vincristine, and prednisolone followed by 6 months of maintenance therapy with cytarabine, vincristine, prednisolone, and low-dose intravenous methotrexate. If patients had a poor response to the initial regimen, they were switched to a salvage regimen of intensive combination doxorubicin, cyclophosphamide, methotrexate, vincristine, and prednisolone.[125][Level of evidence B1]

Diabetes insipidus occurred in 8.9% of patients with multisystem disease.

In the JLSG-96 trial, treatment included a 6-week induction regimen of cytarabine, vincristine, and prednisolone followed by 6 months of maintenance therapy with cytarabine, vincristine, prednisolone, and low-dose intravenous methotrexate. If patients had a poor response to the initial regimen, they were switched to a salvage regimen of intensive combination doxorubicin, cyclophosphamide, methotrexate, vincristine, and prednisolone.[125][Level of evidence B1]

Similar to the HISTSOC-LCH-III (NCT00276757) study, the important finding of this study was the increased survival compared with previous JLSG studies and the HISTSOC-LCH-II study. This was attributed to the early change to a more effective salvage therapy for patients with nonresponsive disease, as well as better supportive care.

In the JLSG-96 trial, treatment included a 6-week induction regimen of cytarabine, vincristine, and prednisolone followed by 6 months of maintenance therapy with cytarabine, vincristine, prednisolone, and low-dose intravenous methotrexate. If patients had a poor response to the initial regimen, they were switched to a salvage regimen of intensive combination doxorubicin, cyclophosphamide, methotrexate, vincristine, and prednisolone.[125][Level of evidence B1]

The study had a high reactivation rate, which prompted several changes, including an increase in the duration of the trial to 12 months and the addition of vinblastine, prednisone, mercaptopurine, and methotrexate.[62]

The JLSG-02 protocol was similar to the JLSG-96 study, except that cyclosporine was added to the reinduction of poor responders and the length of treatment was increased to 54 weeks for good responders and 60 weeks for poor responders.[136][Level of evidence B1]

The JLSG-02 protocol was similar to the JLSG-96 study, except that cyclosporine was added to the reinduction of poor responders and the length of treatment was increased to 54 weeks for good responders and 60 weeks for poor responders.[136][Level of evidence B1]

Despite a markedly increased intensity of treatment, the event-free survival (EFS) rates were only 46% for high-risk patients and 70% for low-risk patients. In the HISTSOC-LCH-III study, the EFS rates were 33% for high-risk patients and 50% for low-risk patients.[137]