In this multi-center, retrospective study of 88 patients with rel/rfr ARL, we described the outcomes after second-line chemotherapy with curative intent in patients who underwent ASCT and those who did not. The patients were not randomly assigned to ASCT. Rather, patients achieving CR/PR went on to ASCT based on regional availability and changing treatment paradigms. Surprisingly, ASCT was not associated with longer OS among patients achieving a CR/PR after second line therapy with more than 80% of patients surviving 1 year in both groups. However, the numbers in this subset were very small and the survival in the non-SCT group inexplicably high.
ICE was the most commonly used second line regimen in the current cohort. High-dose cytarabine and cisplatin based regimens, ESHAP and DHAP, were also commonly used. A recent multi-center prospective trial, the CORAL study, did not demonstrate any difference between R-ICE and R-DHAP regimens with regards to response, mobilization rates, and survival in HIV-negative patients with relapsed CD20-positive DLBCL[17
]. Therefore, it is not likely that switching from ICE to a different currently standard second line therapy would improve outcomes in rel/rfr ARL. The follow up Bio-CORAL study did suggest an advantage of DHAP for germinal center type DLBCL by Hans Criteria and this could be explored in HIV + patients[18
Rituximab was used in most of the patients with CD20 expressing lymphomas in accordance with the suggested improved response rates after addition of rituximab to the conventional chemotherapy regimens[20
]. However, CORAL demonstrated that R-ICE or R-DHAP was less efficacious in rituximab-experienced patients compared to historical controls[17
]. It is possible that using a different antibody as part of second-line combination chemoimmunotherapy may be advantageous.
The discouraging ORR of 37% in our patient cohort may be due to factors that cannot be ascertained within the limits of this retrospective study such as reduction of the chemotherapy dose intensity or excessive delays between the chemotherapy cycles. Regardless, the lower ORRs reported in our and previous studies in rel/rfr ARLs compared to those reported in HIV-negative patients demonstrate the need for better treatment strategies.
In our retrospective cohort, NHL histology vs. HL and refractory disease to the first-line therapy were independently associated with lower ORRs to the second-line therapy. Association of NHL with low CD4+ cell counts in contrast with HL, might have led to a higher prevalence of advanced HIV infection in the NHL group and a poorer prognosis. However, we did not find any impact of CD4+ cell count on the response to second-line therapy in univariate analyses. Additionally, those with relapse after CR to first line therapy rather than primary refractory disease had higher response rates to salvage therapy and longer OS suggesting that the nature of the lymphoma rather than the stage of HIV infection is the driving force behind the therapy failures. Although, International Prognostic Index (IPI) correlated with survival in HIV-negative patients with aggressive lymphomas[22
], we were unable to correlate the response to second line therapy with the IPI score as the performance status was not evaluable in one quarter of the patients. Specifically, amongst the 41 CD20+ DLBCL patients, only 31 had performance status available, which is an insufficient sample size for Cox modeling.
The hematologic toxicity rates in our study were comparable to those previously reported in patients with rel/rfr ARL treated with cyclophosphamide/doxorubicin/etoposide (CDE)[7
], DHAP, and ESHAP[8
] and those in HIV-negative patients treated with DHAP and ICE[17
]. Our number of chemotherapy-related deaths due to infections (n=6, 7%) appears higher than the 1% reported with DHAP and ICE, although our population may have been sicker than those admitted to a randomized trial with a minimum performance status requirement. Nonetheless, this demonstrates the importance of infection surveillance and treatment in these heavily pretreated, immunosuppressed patients undergoing intensive chemotherapy.
ASCT is considered to be the treatment of choice in patients with ARL since the demonstration of its feasibility[12
] and achievement of long-term results similar to those observed in HIV-negative patients[14
] despite the lack of any comparative studies.[23
]. Re et al. reported the largest prospective trial of ASCT in 50 patients with rel/rfr ARL, achieving a long-term OS and progression-free survival (PFS) of 50% where only 27 patients actually underwent ASCT[16
]. In a recent retrospective analysis of 68 patients with rel/rfr ARL reported to EBMTR, PFS and OS were 56% and 61%, respectively[24
]. Curiously, in those in CR/PR after second line therapy, ASCT did not affect outcome in our study. Specifically, with a median follow up of 117 weeks, we reported a 1-year OS of 88% for those who underwent ASCT and 82% for those who did not, among patients who achieved CR/PR after second-line therapy. We cannot easily explain this finding which flies in the face of randomized studies in HIV-negative patients[11
]. Regardless, currently ASCT remains the current standard of care in rel/rfr ARL when feasible. A joint AMC and Bone Marrow Transplant Clinical Trials Network study currently underway may shed some light on the feasibility of ASCT in a larger setting, though no comparator arm exists.
Finally, patients with rel/rfr BL and variants in our cohort neither underwent ASCT nor survived. In the post-HAART era, although survival in HIV-positive patients with DLBCL improved to be commensurate with HIV-negative patients, mixed results have been reported for BL, ranging from 6 month median survival using CHOP type regimens[25
] to one-year OS in the 80% range with dose-intense regimens such as CODOX-M/IVAC[26
] and variants[27
], or hyperCVAD[28
]. Our findings demonstrate a uniformly poor prognosis in HIV-positive patients with rel/rfr BL is poor, similar to those without HIV infection.
The major limitation of our study is its retrospective nature leading to reporting and selection biases with respect to treatment. Therefore, comparisons, particularly for those undergoing ASCT or not have to be interpreted with caution. Notably, almost half of the patients registered in the database were excluded either because they had not received any second-line therapy or received it palliative regimens inappropriate for transplant eligible patients. The underlying reasons likely include the reluctance of clinicians/patients to pursue aggressive therapy, poor performance status or comorbidities of HIV-positive patients. Although we found no differences between second line therapies with respect to ORR or OS, our power to detect relevant differences was limited by sample size. Finally, it is possible that the inclusion of patients treated in the early years of HAART, biased our study to include those with prior opportunistic infections and, hence, a poor prognosis.
In summary, the success of second-line chemotherapy is of utmost significance in the treatment of rel/rfr ARLs and prospective studies are desperately needed to improve salvage strategies. Whether ASCT is associated with a greater chance of survival cannot be addressed by our study due to its limitations, but some patients survived without transplant and the OS did appear surprisingly similar when one limited the analysis to patients who achieved CR/PR after second-line therapy.