1 Ematologia, Dipartimento di Biotecnologie Cellulari ed Ematologia, University La Sapienza of Rome; 2 Virology, Istituto Superiore di Sanità of Rome, Italy
*E-mail: gastaldi@bce.med.uniroma1.it
We have demonstrated previously the feasibility and efficacy of the CIOD (cyclophosphamide, idarubicin, vincristine, dexamethasone) regimen, including high dose idarubicin (IDA 2025 mg/m2 corresponding to doxorubicin 100125 mg/m2) plus granulocyte-colony stimulating factor and prophylaxis against infections in 14 diffuse large cell, AIDS-related, non-Hodgkins lymphoma (DLC AIDS-NHL) outpatients with a World Health Organization (WHO) performance score <3 and without prior illness due to AIDS at NHL onset. Nevertheless, a high frequency of opportunistic infection [(OI) 37%], an increase in HIV.1 RNA load and a marked lymphopenia were observed during chemotherapy; CIOD with IDA 20 mg/m2 was better tolerated than with 25 mg/m2 [1]. Until now, a total of 20 DLC AIDS-NHL patients [male/female ratio: 15/5; median age 37 years (range 2958); six of 20 patients on antiretroviral pretreatment at lymphoma onset; 14 of 20 with Ann Arbor stage III+IV disease; 11 of 20 with immunologic AIDS (CD4 <200 cells/µl) and with an overall median CD4 of 180 lymphocytes/µl (range 24900)] had been treated with CIOD, including a high dose of IDA. Complete response (CR) was achieved in 18 of 20 (90%) patients, with a median duration of 37.8 months (range 4104). One patient achieved a partial response and the other was not a responder. The median overall survival (OS) was 38 months (range 5108). Of 20 patients, three (15%) relapsed and nine (45%) died, five as a result of progressive NHL, three due to OI and the last one due to secondary acute myeloblastic leukemia in continuous CR of NHL. Cumulative 5-year disease-free survival and OS were 85% and 53%, respectively.
Among 12 of 20 patients treated, with CIOD including a well tolerated dose of IDA 20 mg/m2, six received nucleoside transcriptase inhibitors (NTRI) concomitant to chemotherapy with stavudine (d4T) and didanosine (ddI), two of whom were previously responders to highly active antiretroviral therapy (HAART), while the others were antiretroviral therapy (ART) naïve. All six patients received HAART with two NTRI and one protease inhibitor (PI)/or non-nucleoside transcriptase inhibitors (NNRTI) 1 month after CIOD discontinuation. The selection of d4T + ddI in combination with antineoplastic regimen was made on the basis of their sinergic in vitro action, a slow incidence of hematological toxicity and interaction with other drugs, and a low appearance of resistant HIV.1 strains.
A lower number of episodes of WHO grade 34 hematological toxicity (HT G34) and a significant higher mean nadir of hemoglobin (Hb), absolute neutrophil count (ANC) and platelet count (PLTC) were observed in six patients treated with CIOD + d4T + ddI in comparison to those six patients without ART [HT G34: 10 of 31 versus 22 of 28 CIOD courses (P = 0.0838), respectively; mean nadir of Hb: 10.6 ± 1.2 g/dl versus 9.4 ± 1.9 g/dl (P = 0.0094), respectively; mean nadir of ANC cells (per µl): 2290 ± 2110 versus 625 ± 760 (P = 0.0000), respectively; and mean nadir of PLTC (per µl): 136 000 ± 61 780 versus 700 714 ± 4000 (P = 0.0000), respectively]. Furthermore, no delay or drugs reduction and no case of OI occurred in patients treated with CIOD + d4T + ddI, while Cytomegalovirus retinitis was observed in two patients treated without ART, one of whom discontinued CIOD after three courses. An episode of pancreatitis was observed at the end of chemotherapy in a patient with chronic hepatitis C virus treated with d4T + ddI.
A significant virological response and a lower decrease of CD3, CD3CD4 and CD3CD8 lymphocytes were observed in patients treated with CIOD + d4T + ddI compared with those without ART (Table 1). Both patients, who were previously HAART responders, maintained viral suppression during d4T + ddI treatment.
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The majority of studies report the association of HAART with CHOP (cyclophosphamide, hydroxydoxorubicin, oncovin, prednisone) or with infusional CDE (cyclophosphamide, doxorubicin, etoposide) regimens [26]; in these studies, a significant decrease in AIDS-related complications was observed. Nevertheless, the association of HAART with antineoplastic agents may increase hematological and neurological toxicity, and may interfer with the optimal administration the various drugs. In particular, PI can increase the toxicity of doxorubicin and cyclophosphamide by blocking the metabolism of drugs by the cytochrome P-450 pathway. The median survival of CHOP with or without HAART remains in the range of 3556%, even if a better response and a longer survival were observed in patients responding to treatment with HAART compared with those treated without [3, 5]. HAART response was an independent positive factor on survival [26]. Recently, Little et al. reported a high CR and OS rates in patients treated with an infusional dose-adjusted EPOCH (96 h continuous infusion of etoposide, doxorubicin, and vincristine and oral prednisone with cyclophosphamide on day 5) with suspension of ART during chemotherapy [7].
The use of two NRTI is not a usually recommended guideline for HIV infection treatment; however, our preliminary data sugest that, in selected newly diagnosed NHL AIDS patients, the combination of two NRTI with antineoplastic agents, could be an alternative approach between ART discontinuation and toxicity due to HAART administration.
Acknowledgements
The authors would like to thank Silvana Bedini for English language revision of the manuscript. This work was supported by an AIDS National Project grant to the Istituto Superiore di Sanità of Rome, Italy.
R. Gastaldi1*, P. Martino1, G. Gentile1, M. S. De Propris1, M. F. Pirillo2, A. De Vellis1 & F. Mandelli1
1Ematologia, Dipartimento di Biotecnologie Cellulari ed Ematologia, University La Sapienza of Rome; 2Virology, Istituto Superiore di Sanità of Rome, Italy (*E-mail: gastaldi@bce.med.uniroma1.it)
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