Evaluation of Different Treatment Regimens for Relapsed and Refractory NHL: Single Institute Experience

Background and Aim: The treatment of choice for relapsed or refractory Non-Hodgkin Lymphoma (NHL) mainly, is High dose chemotherapy with autologous stem cell transplantation. However, its use is mostly restricted to patients responding to salvage chemotherapy. In this study, our aim was to evaluate outcome and toxicity of different treatment modalities of relapsed and refractory NHL. Patient and Methods: This retrospective study included 217 patients were diagnosed as refractory or relapsed NHL. Those patients received different treatment modalities as GDP (Gemcitabine, dexamethasone, cispla-tin), DHAP (Dexamethasone, Cytarabine, and Cisplatin), MINE (Mitoxan-trone, ifosfamide, etoposide and mesna), CHOP (Cyclophosphamide, Dox-orubicin, Vincristine and Prednisone), and CVP (Cyclophosphamide, vincristine and prednisone). Results: The median age of patients in the study was 50 years. Patients who received DHAP showed ORR of 62%, which was the highest response. The most common adverse effects were hematological which were more noticed in patients, received CHOP. Sixty one patients (54.5%) had anemia, 54 patients (48.2%) had neutropenia and 55 patients (49.1%) had thrombocytopenia, but the difference between the different lines of treatment wasn’t significant p value of 0.95. The median time to relapse is 10 months and the median survival time is 40 months. The 3-year PFS rates of all patients were 49.3%, while the 3 year OS rates were 54.8%. Conclusion: The overall and PFS didn’t show any difference between different lines of treatment.

ative disorders originating in B-lymphocytes, T-lymphocytes or natural killer (NK) cells. NK/T-cell lymphomas are very rare [1]. NHL includes many clinicopathologic subtypes, each with distinct epidemiologies; etiologies; morphologic, immunophenotypic, genetic, and clinical features; and responses to therapy.
With respect to prognosis, NHLs can be divided into two groups, indolent and aggressive [2]. Indolent NHL types have a relatively good prognosis with a median survival as long as 20 years, but they usually are not curable in advanced clinical stages [3]. The aggressive NHLs grow faster and have shorter survival; the number of patients cured with intensive chemotherapy currently has been increasing [4]. A large number of new therapeutic protocols based on a combination of multi-drug chemotherapy, have been introduced for the treatment of patients with high-grade NHL [5]. Multi-drug chemotherapy produces an overall survival of 50% -60% at five years in aggressive NHL [6]. However, a significant proportion of patients relapsed, experiencing either failure after prolonged treatment, known as refractory disease, or relapsed after initial response, known as a relapsing disease [7]. The strategy for management of relapsed or refractory disease is to deliver salvage chemotherapy, followed by high dose chemotherapy and autologous stem-cell transplantation in responding patients [8]. There is no optimal salvage regimen for relapsed or refractory B-cell lymphoma; also there are no standard options of treatment for patient's response to second line regimens, nor for patients who are not eligible for transplant [9].

Study Type and Duration
The current retrospective study included 217 patients who were diagnosed as refractory or relapsed NHL (B or T) at Medical Oncology Department, Assiut University Hospitals from January 2011 to December 2015.

Exclusion Criteria
• Prior history of cardiac disease (serious arrhythmia, heart failure, myocardial

Study Design
Patients were divided into 6 groups: Lugano response criteria for NHL [10] observed at the end of treatment of 6 cycles as complete response, partial response, stable disease, progressive disease.

Statistical Analysis
The results of study were tabulated and statistical analysis was carried out using statistical package spss version 23. using significant level (p < 0.05), chi square test was used to compare frequencies, M ANOVA, Survival curves were estimated with Kaplan Mayer method [11] and compared using Log-rank test.

Patient Characteristics (n = 217)
The median age of patients in the study was 50 years old with 116 (53.5%) of patients were females. One hundred and twelve patients (51.6%) were with ECOG

Treatment Outcome
Response to 2nd line was shown in Table 3. Table 4. Figures 1-4.

Discussion
Several attempts have been made to prolong survival of patients with relapsed and refractory NHL [12]. Refractory or progressive disease is identified during the post-treatment response evaluation. The treatment of patients with relapsed or refractory lymphomas remains challenging. In general, the standard care is high-dose chemotherapy followed by autologous stem cell transplant (ASCT) for patients who are sensitive to salvage chemotherapy. There are no standard options of treatment for patients who show no response to second-line regimens, nor for patients who are not eligible for transplants [13]. In developing countries with limited resources as Egypt, high dose chemotherapy followed by ASCT is not always an option of treatment in relapsed and refractory lymphomas due to a small number of transplant centers across the country, long waiting lists and limited resources [14].
Regarding the response rate, the ORR in this study was higher in patients receiving DHAP and GDP but there was no statistical difference between the different lines of treatment. These findings were in agreement with that of Ismaeil., et al. who reported that the ORR was 65% and 67.6% in patients who had received GDP and DHAP respectively [15]. Conversely, this finding was higher than that of Abali, et al. who reported ORR of 48% in the DHAP group [16].
As regard treatment toxicity, the most common adverse effect was hemato-  [18].
As regard the non-hematological toxicities, nausea, vomiting, and diarrhea were the most common adverse effect which were more in patients who had received DHAP, but the difference wasn't significant. This finding was in agreement with that of Ismaeil, et al. who reported that nausea and vomiting were the most common non-hematologic toxicities in the majority of patients who received GDP and DHAP with a non-significant difference [15].

Conclusion
From the results of the current study, we conclude that relapsed and refractory disease continued to represent the most significant challenge in treating NHL with no difference between different lines of treatment. The hematological toxicity, GIT toxicity, hepatoxocitiy, neurotoxicity and renal toxicity didn't show a significant difference between investigated lines of treatment. The overall and PFS didn't show any difference between different lines of treatment while the low response and survival rates mandate the need to add rituximab to 2nd line treatment and to proceed to bone marrow transplantation in eligible patients.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.