Intermediate dose methotrexate in childhood acute lymphoblastic leukemia resulting in decreased incidence of testicular relapse

Abstract

Six hundred thirty-four children with acute lymphoblastic leukemia (ALL) were randomized to receive sanctuary therapy consisting of either cranial irradiation (CRT) plus intrathecal (IT) methotrexate (MTX) or three courses of intermediate-dose methotrexate (IDM) plus intrathecal methotrexate. Two hundred sixty-six male patients achieved a complete response and were evaluable for the effects of prophylactic therapy on the duration of remission. There was one isolated testicular relapse (0.8%) in the IDM group compared with 14 (10%) in the CRT group. The incidence of testicular relapse was significantly lower in the patients treated with IDM (P less than 0.001). High plasma levels of MTX achieved during the 24-hour infusions may result in increased penetration of MTX into the interstitium of the testes, thus allowing for the eradication of sequestered leukemic cells and preventing the emergence of drug resistance resulting from exposure to sublethal concentration of MTX.

Isolated Extramedullary Relapse in Childhood Acute Lymphocytic Leukemia

“…For instance, it has been shown that methotrexate concentration in the testicular interstitial fluid is twofold to fourfold lower than in the serum. The concentration [23]. Though a physiologic barrier may explain these findings, other studies have suggested that the testes' external location may contribute to the decreased efficacy of leukemia therapy.…”

“…A barrier between the blood and the seminiferous tubules has been identified [22]. Leukemic cells, however, are usually found in the interstitial space, and a clear barrier between the blood and the interstitial space has not been well defined [22,23]. There is evidence, however, that systemic medications may not be equally distributed into the testes.…”

“…Marrow relapse is the most common second event for patients following an isolated extramedullary relapse [8]. Early theories suggested that a small population of blasts may evade destruction in these protected sites and then go on to reseed the bone marrow, but evidence is mounting that relapse in isolated sanctuary sites is actually an early manifestation of systemic relapse that is not yet apparent [17,23]. This theory is supported by minimal residual disease data at the time of isolated extramedullary relapse.…”

“…There are data, however, that support the existence of true isolated extramedullary relapse in the testes [26]. Patients with late ITR have been shown in some cases to respond to local irradiation and relatively nonaggressive chemotherapy [23,27]. Thus early and late ITR may in fact represent two distinct diseases.…”

High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia

“…21,22 In addition, high dosages of MTX offer the advantage of targeting extramedullary leukemia by producing cytotoxic concentrations in sanctuary sites where low-dose MTX does not readily distribute (eg, testes, cerebrospinal fluid). 10,23 However, the optimal dose of MTX, the adequate duration of the drug infusion, and the adequate folinic acid rescue remain controversial. 1,[24][25][26][27][28] While one randomized trial indicated that patients at increased risk of relapse treated initially with high-dose MTX (4 g/m 2 ) had significantly better event-free survival (EFS) rates compared with patients treated with low-dose MTX (40 mg/m 2 ), 24 ultra-high-dose MTX (12 g/m 2 ) at a 4-hour infusion and an intensive folinic acid rescue was not found to be beneficial in relapsed ALL children, compared with intermediate-dose MTX (1 g/m 2 ) at a 36-hour infusion and a reduced folinic acid rescue.…”