Innovation

High-Dose Cyclophosphamide Holds Promise for Dogs with Lymphoma

For decades, the cornerstone of treatment for dogs with lymphoma has been chemotherapy employing five drugs: cyclophosphamide, doxorubicin, vincristine, L-asparaginase and prednisone.  Efforts to optimize these protocols by adjusting the doses and scheduling of drugs have not yielded significant improvement in remission rates or survival times.  In addition, the realization that discontinuous short chemotherapy protocols are as effective as traditional long protocols that include a lengthy maintenance phase has provided the opportunity to search for novel therapies to combat lymphoma before overt chemotherapy resistance develops.

Alternative modalities that have been studied include radiation therapy, chemotherapy agents traditionally reserved for rescue therapy, monoclonal antibodies, dose-intensified chemotherapy and bone marrow transplantation.  These approaches have yielded variable results, and some promising findings are under continued investigation.

An approach pioneered at Tufts was high-dose cyclophosphamide combined with a mini autologous bone marrow transplant.  The rationale for this treatment was that residual malignant lymphocytes present after initial therapy may be relatively more resistant to chemotherapy at conventional doses but retain susceptibility to higher drug doses.  Cyclophosphamide was considered an ideal drug to study since it has a steep dose-response relationship, and its dose-limiting effect is myelosuppression (largely neutropenia) without significant gastrointestinal toxicity.  Bone marrow harvested from patients prior to high-dose chemotherapy was reinfused intravenously after treatment in an effort to counteract severe myelosuppression.  The results of a preliminary dose-escalation study revealed that dogs that received the highest doses of cyclophosphamide (500 mg/m2) enjoyed remission times that were more than double those of dogs that received similar induction chemotherapy without high-dose cyclophosphamide (54 weeks vs 20 weeks, respectively).

These results are encouraging, particularly because the toxicity associated with this approach was minimal.  However, in an effort to simplify the protocol, we have replaced the bone marrow transplant with cytokine support using granulocyte-colony stimulating factor.  This change in protocol has allowed us to intensify the cyclophosphamide dose beyond 500 mg/m2, and dogs are currently receiving 650 mg/m2.  The treatment continues to be extremely well tolerated.  Although it is still too early to report remission durations for the new protocol, initial results are encouraging.

Reference:

Frimberger AE, Moore AS, Rassnick KM, et al.  A combination chemotherapy protocol with dose intensification and autologous bone marrow transplant (VELCAP-HDC) for canine lymphomaJournal of Veterinary Internal Medicine 20:355-364, 2006.