Pneumocystis Jiroveci Pneunomia Prophylaxis during Maintenance Therapy with Hyper-CVAD Regimens for Adult Acute Lymphoblastic Leukemia

BACKGROUND: Pneumocystis jiroveci pneumonia (PCP) can be a deadly opportunistic infection in immunocompromised patients. Patients with acute lymphoblastic leukemia (ALL) are at risk for PCP due to their underlying disease, use of high doses of corticosteroids and receipt of lymphocyte-depleting chemotherapy. It is recommended that patients receive PCP prophylaxis during treatment for ALL. Trimethoprim/sulfamethoxazole (TMP/SMZ) is a common agent utilized but some practitioners are concerned about myelosuppression induced by TMP/SMZ. HyperCVAD regimens are the standard treatment strategy for ALL patients at our institution. Historically, PCP prophylaxis with TMP/SMZ was delayed until the beginning of maintenance therapy. This retrospective analysis evaluated PCP prophylaxis and incidence in ALL patients receiving maintenance therapy on a HyperCVAD regimen. Any influence of PCP prophylaxis on clinical outcomes was also evaluated.

METHODS: Newly diagnosed adult (≥ 18 yo) patients with ALL or lymphoblastic lymphoma who received at least one cycle of maintenance therapy on a HyperCVAD regimen between April 2000 to December 2016 were reviewed. Interim chart reviews were performed to identify the use of PCP prophylaxis and definite or suspected cases of PCP, as well as to document maintenance therapy doses or change in patient status, until the completion of maintenance therapy. Suspected PCP cases (missing microbiological documentation of Pneumocystis) were defined as those patients receiving PCP active therapy based on clinical presentation and imaging.

RESULTS: During the study period, 363 frontline ALL patients received at least one cycle of HyperCVAD maintenance therapy. 346 (198 males and 148 females) patients had sufficient documentation. Of these 346 patients, 145 never received PCP prophylaxis, 67 received i ntermittent PCP prophylaxis, and 134 received uninterrupted PCP prophylaxis throughout maintenance therapy. Only 3 cases of PCP (0.9%) were identified, one confirmed and 2 suspected. All cases occurred within the first 6 months of maintenance therapy and in patients never receiving PCP prophylaxis. The majority of patients receiving prophylaxis were on TMP/SMZ (97%); the most common regimen was 160 mg of the TMP component (1 DS tablet) twice daily two days per week. PCP prophylaxis rates have decreased over time - 55% of patients received uninterrupted PCP prophylaxis if initiated ALL maintenance therapy in 2000-2005 versus 10% of patients received uninterrupted maintenance if initiated ALL maintenance therapy in 2010-2016 (p=<0.001). Philadelphia-positive patients (106/346, 31%) received TKI-based maintenance therapy (TKI, corticosteroid, vincristine). Philadelphia-positive patients were less likely to receive uninterrupted PCP prophylaxis (p<0.0001). Doses of TKI were not statistically different between PCP prophylaxis groups. Philadelphia-negative patients received maintenance therapy containing mercaptopurine and methotrexate (plus corticosteroid, vincristine). Doses of mercaptopurine and methotrexate were not statistically different between PCP prophylaxis groups (p=0.75, p=0.4 respectively). ANC values were analyzed over time and were not significantly different between PCP prophylaxis groups (p=0.36 for never versus uninterrupted PCP prophylaxis). ALC values were also evaluated and were significantly lower in the uninterrupted PCP prophylaxis group at baseline, maintenance year 1 and maintenance year 2 (p=0.0464, p=0.0002, p=0.0001 respectively). Relapse rate, PFS and OS did not differ between the never, intermittent and uninterrupted PCP prophylaxis groups.

CONCLUSIONS: The rate of PCP was low in this group of adult patients with newly diagnosed ALL undergoing maintenance therapy as part of a HyperCVAD regimen. All PCP cases occurred in patients not receiving PCP prophylaxis. TMP/SMZ prophylaxis had no significant effect on doses of ALL maintenance therapy provided as well as PFS and OS. TMP/SMZ remains a safe, effective choice for PCP prophylaxis in adult ALL patients. Given the low incidence of PCP in this population, future studies are warranted to identify risk factors that allow selection of patients who would benefit the most from PCP prophylaxis.