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ANTI‐INFECTIVE PROPHYLAXIS WITH ACICLOVIR AND COTRIMOXAZOLE SIGNIFICANTLY REDUCES THE RATE OF INFECTIONS AND THERAPY‐ASSOCIATED DEATHS IN ELDERLY PATIENTS WITH DLBCL UNDERGOING R‐CHOP IMMUNOCHEMOTHERAPY
Author(s) -
Murawski N.,
Amam J.,
Altmann B.,
Ziepert M.,
Haenel M.,
Viardot A.,
Neubauer A.,
Held G.,
Truemper L.,
Dreyling M.,
Kanz L.,
Hallek M.,
Schmitz N.,
Heintges T.,
Koelbel C.,
Poeschel V.,
Pfreundschuh M.
Publication year - 2017
Publication title -
hematological oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 44
eISSN - 1099-1069
pISSN - 0278-0232
DOI - 10.1002/hon.2438_63
Subject(s) - medicine , vincristine , rituximab , surgery , gastroenterology , leukocytopenia , lymphoma , chemotherapy , cyclophosphamide
lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We investigated the efficacy of dose‐dense chemoimmunotherapy and systemic CNS prophylaxis in two completed Nordic trials including patients less than 65 years with high‐risk DLBCL. We combined individual patient data from these studies to compare clinical outcome and prognostic factors in patients treated with CNS prophylaxis given in the beginning (CHIC) vs at the end (CRY‐04) of therapy. Patients and Methods: Inclusion criteria were age 18‐65 years, primary DLBCL or grade 3 follicular lymphoma without signs of CNS involvement, WHO performance score 0‐3, age‐adjusted International Prognostic Index (aaIPI 2‐3) and/or involvement of anatomical sites associated with an increased risk for CNS recurrence (e.g. testis, facial sinuses, orbita). In CRY‐04, six courses of R‐CHOEP14 were followed by HD‐Mtx and HD‐Ara‐C. In CHIC, treatment consisted of two courses of HD‐Mtx in combination with R‐CHOP14, followed by four courses of R‐CHOEP14 and one course of R‐HD‐AraC. In addition, liposomal AraC was administered intrathecally at courses 1, 3 and 5. Primary end points were failure free survival (FFS; disease progression, discontinuation of protocolled therapy due to toxicity, death from any cause) at 3 years and CNS progression rate at 1.5 years. Secondary end points included progression‐free survival (PFS; disease progression or death from any cause) and overall survival (OS) at 3 years. Results: Among 303 patients enrolled in the trials (CRY‐04, n = 160 and CHIC, n = 143), 295 (CRY‐04, n = 154 and CHIC, n = 139) met inclusion criteria and were evaluable for baseline characteristics and primary end points. Median age (54 and 56 years, p = 0.222), male/female ratio, stage and aaIPI scores were comparable in the two cohorts. Three‐year FFSwas 63% in CRY‐04 and 77% in CHIC (p = 0.018) after a median follow‐up of 5 and 3 years, respectively. Cumulative incidence rates of CNS progression were 5.0% and 2.4% (p = 0.22), and 3‐year OS 80% and 86% (p = 0.508), respectively. Treatment in the CHIC reduced the risk of systemic progression (aaIPI adjusted RR = 0.484, 95%CI 0.300‐ 0.782, p = 0.003). PFS benefit with CHIC vs CRY‐04 was observed across pre‐specified subgroups, and particularly in patients <60 years old (p = 0.007), with low proliferation index (Ki67 expression <75%, p = 0.029), and BCL2 positivity (p = 0.006). In the subsets of patients with available PET data, Deauville score 5 at the end of treatment was associated with increased rate of progression and death in both trials (p = 0.012). Only one out of 17 biopsies from PET positive lesions (DS 3‐5) contained vital lymphoma tissue. Conclusions: Our results derived from trial data with homogenous treatment support the use of HD‐Mtx in the beginning rather than at the end of therapy. Superior outcome seems to be primarily due to better systemic control of the disease. In addition, number of CNS recurrences is reduced.