Pneumocystis jiroveci pneumonia prophylaxis during maintenance therapy influences methotrexate/6‐mercaptopurine dosing but not event‐free survival for childhood acute lymphoblastic leukemia

Abstract

Trimethoprim-sulfamethoxazole (TMP/SMX) is used in children with acute lymphoblastic leukemia (ALL) to prevent Pneumocystis pneumonia (PCP). We explored to which extent TMP/SMX influenced methotrexate (MTX)/6-mercaptopurine (6MP) dosage, myelosuppression, and event-free survival (EFS) during maintenance therapy. Of 447 study patients treated by the NOPHO ALL92 protocol, 120 patients received TMP/SMX continuously for 2-7 d/wk (TMP/SMX(2-7) ) and 287 patients never received TMP/SMX (TMP/SMX(never) ). Ten patients (all TMP/SMX(never) ) developed PCP, eight of which occurred within 7 months from the start of maintenance therapy. The TMP/SMX(2-7) group received lower oral 6MP doses than TMP/SMX(never) patients (50.6 vs. 63.9 mg/m(2) /d; P<0.001) but had lower absolute neutrophil counts (ANC) (median 1.7 vs. 2.0 × 10(9) /L; P<0.001). In Cox multivariate analysis, higher ANC levels (P=0.04) and male gender (P=0.06) were related to reduced EFS. ANC had no effect on EFS among TMP/SMX(2-7) patients (P=0.40) but did for TMP/SMX(never) patients (P=0.02). The difference in the effect on EFS between TMP/SMX(2-7) and TMP/SMX(never) patients was not significant (P=0.46). EFS did not differ between TMP/SMX(2-7) and TMP/SMX(never) patients (0.83 vs. 0.83; P=0.82). These results suggest that TMP/SMX is effective in preventing PCP and may have an antileukemic effect. TMP/SMX should be given the entire duration of maintenance therapy.

Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus

“…27 The PTWG consensus defi nition distinguishes between confi rmed and probable P jirovecii pneumonia.…”

Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

“…However, folate supplementation should probably be avoided during maintenance therapy, as it has been shown to influence both 6MP metabolism210 and myelotoxicity 211. Finally, trimethoprim-sulfamethoxazole given as Pneumocystis jiroveci pneumonia prophylaxis212 interferes with MTX213 and 6MP pharmacokinetics,214 and also enhances myelotoxicity leading to lower prescribed 6MP and MTX doses,215 but in spite hereof does not seem to increase relapse rates,215 and thus seems safe to prescribe to avoid this life-threatening infection.…”

Maintenance therapy of childhood acute lymphoblastic leukemia revisited—Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

“…First, the degree of leukopenia reflects both 6MP/MTX treatment intensity and children's normal WBC levels, which vary both between and within age groups, 35,36 by ethnicity, and by co-administration of trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis jiroveci. 37,38 Thus, two patients with the same mWBC during therapy could well have experienced different antileukemic treatment intensities depending on whether the off-therapy (i.e., "normal") WBC level was 8.5 or 4.5 × 10 9 /l. Second, other measures of myelosuppression, that is, Hb and TROM, did not seem related to risk of relapse, and it is yet to be determined why patients with low ANC levels do so much better than patients with higher levels.…”