Prognostic Value of Early Introduction of Second Line in Patients with Diffuse Large B Cell Lymphoma

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1 Med. J. Cairo Univ., Vol. 84, No., December: , 6 Prognostic Value of Early Introduction of Second Line in Patients with Diffuse Large B Cell Lymphoma HAMDY M. ZAWAM, M.D.; MENNAT ALLAH M.M. ABD EL-RADI, M.Sc. and EMAD M. HAMMADA, M.D. The Department of Clinical Oncology, Faculty of Medicine, Cairo University Abstract Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin Lymphoma (NHL). Although potentially curable, 4% of patients with DLBCL will die of relapsed or refractory disease. Many studies proved the correlation between achievement of early response to treatment and better survival. Our study aims to assess the prognostic of early introduction of second line chemotherapy. Methods: Randomized pilot trial of 5 adult patients with DLBCL conducted at Kasr Al-Ainy Oncology Department, ages 8-65 years, pathologically proven as DLBCL stages IIB-IV according to Ann Arbor classification, ECOG performance status <3. Patients were treated with standard dose 3- weekly R-CHOP for 3 cycles. Those achieved partial remission were randomized to either continue R-CHOP () or to shift to R-ESHAP (). Results: Fifty patients were enrolled between May 3 and September 4. Median age was 5 years. Better outcome with non shift group (response rate=9.9% Vs 66.67%). The month disease free survival in was 75% while in was 58% (=.49). The month overall survival was % in versus 68% in ( =.3). Conclusion: These results should be confirmed on larger scale studies. Key Words: DLBCL Early second line. Introduction DIFFUSE Large B-Cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin Lymphoma (NHL). It accounts for 3%-4% of all adult NHLs []. NHL was ranked as 5 th most frequent cancer in Egypt []. Although potentially curable, 4% of patients with DLBCL will die of relapsed or refractory disease. The standard of care for initial treatment Correspondence to: Dr. Hamdy M. Zawam, The Department of Clinical Oncology, Faculty of Medicine, Cairo University of DLBCL is R-CHOP- (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, prednisone on a -day schedule) []. Many studies proved the correlation between achievement of early response to treatment and better survival parameters in patients with DLBCL [3]. For patients with inadequate response at the interim treatment response evaluation, enrolment in a clinical trial including more intensified regimens is an option [4]. Early introduction of salvage therapy may allow restoring the chemo-sensitivity of the disease, saving the patient from ineffective therapy and may overcome the emerging resistant clones and, hence to improve the overall response. This represented the rationale of our study. Accordingly, our study aimed to assess the benefit of using intensified regimen (ESHAP) for patients with DLBCL having partial response at interim response evaluation. Patients and Methods This prospective randomized pilot trial included 5 patients with a proven pathological diagnosis of DLBCL presented to Kasr Al-Ainy Clinical Oncology Department during the period from May 3 till September 4. The study was conducted in accordance with the International Conference on Harmonization for Good Clinical Practice guidelines and the ethical principles outlined in the Declaration of Helsinki. All patients provided written, informed consent before undergoing any study-related procedures. Eligible patients were those with DLBCL stage IIB-IV according to Ann Arbor classification were candidate to receive immune-chemotherapy. The 443

2 444 Prognostic Value of Early Introduction of Second Line in Patients with DLBCL age range for 8-65 years, with ECOG performance status <3. The following data were collected from all recruited patients: History of smoking, and thorough physical examination including blood pressure, node bearing areas, performance status and constitutional manifestations. Laboratory assessment: Differential CBC, serum LDH, serum B macroglobulin levels, Uric acid, HBsAg and HCV antibody testing. Immunophenotyping: CD, CD45, CD3, CD5 at least. CT chest, abdomen and pelvis at the start and after 6 months. BM aspirate and biopsy. Lumbar puncture if indicated (high risk for CNS disease). All patients received the standard R-CHOP regimen every 3 weeks. Response was assessed after three cycles by CT scan of chest, abdomen and pelvis. Patients with negative scan (CR) completed six cycles of R-CHOP. Those with partial remission, were randomized into groups: continued R-CHOP and received second line chemotherapy R- ESHAP. Toxicity assessment: Every patient was assessed each cycle for toxicity and reported according to NCI-CTCAE v4. Statistical methods: All data were tabulated and statistically studied by descriptive analysis as well as survival analysis in relation to different prognostic factors. Comparison between the two groups was done using student test for continuous data and CHI square (χ) test for categorical data. Survival analysis was done according to Kaplan- Meier method and compared by log-rank test for significance. Univariate analysis using cox regression module was performed to test the power of relation between the independent variables and survival differences were considered significant if was less than.5. Results Of 5 patients included in the study, patients achieved partial remission after 3 cycles of R- CHOP and were eligible for randomization Fig. (). Eleven patients were randomized to (continue R-CHOP); while 9 patients were randomized to (shift to R-ESHAP), 5 of them did not to receive Rituximab due financial issues. Comparing the groups regarding the baseline characteristics, there was no statistical significant difference (Table ). Response evaluation: Comparing the randomized groups, the response rate for was 9.9% (/) while in it was 66.67% (3/9) with statistically significant difference ( p=.3). By comparing the factors affecting the response, the only contributing factor for response rate was the treatment regimen (Table ). Comparing factors affecting response rate at first assessment after 3 cycles of R-CHOP (CR and PR) including age, gender, ECOG performance status, bone marrow involvement, site of disease, IPI score, bulk of disease and stage; only disease stage was the only significant contributing factor for earlier and better response. Survival evaluation: At a median follow-up period of 6.3 months, year DFS in was 75% while in Group B was 58% which was statistically significant ( =.49). The year OS was % in Group A versus 68% in which was statistically significant (=.3). The median time to CR in was 7 weeks (-7), while in, the median time was 3 weeks (9-) (=). Toxicity evaluation: The grade 3 and 4 adverse events were consistent with the expected toxic effects of utilized regimens. Grade - fatigue and grade - vomiting are the most encountered toxicities, following total alopecia (was nearly universal after cycles of R- CHOP). Eight patients out of 5 patients (6%) experienced neutropenic fever along treatment course. One patient out of 5 patients (%) developed septic shock. One patient (%) developed neutropenic fever due to bacterial chest infection 3 times. Four patients (8%) developed neutropenic fever once. (4 received R-CHOP and 4 received ES- HAP+/-R).

3 Hamdy M. Zawam, et al. 445 Four patients developed grade 3 paraesthesia of both hands and feet. One patient (%) experienced it by the fifth cycle of R-CHOP. Two patients out of 5 patients (4%) developed asymptomatic scattered macular eruptions after second cycle R-CHOP. One patient out of 5 patients (%) developed scattered erythema with pruritis twice along he treatment course with R- CHOP. Two diabetic patients developed hyperglycemia needed increasing insulin doses in ESHAP group. Symptomatic hypocalcemia (<7) was seen in cases. Two out of nine patients (%) developed hypokalemia (.3-.7) after the second cycle of ESHAP despite the supplementations during treatment. Partial remission ( patients) Adult patients diagnosed with DLBCL (5 patients) Complete remission (9 patients) Continued on RCHOP ( patients) Shifted to R-ESHAP (9 patients) Progressed ( patient) Fig. (): Schematic presentation of results of a prospective study of 5 adult patients with DLBCL (NEMROCK). Cum survival R-ESHAP=9 patients R-CHOP= patients mo DFS=75% Vs 58% p= DFS ttt Group -Censored -Censored Fig. (): The difference in DFS between A & B groups (N= patients). Cum survival R-ESHAP=9 patients mo OS=% Vs 68% p=.3 R-CHOP= patients OS Fig. (3): The difference in OS between A & B groups (N= patients). Table (): General characteristics of partial responders (N=). Items Age: <4 4-6 >6 (N=) Gender: Female Male 7 PS: ttt Group -Censored -Censored Bm: Normal High 7 5 LDH: Normal 3.33 High 8 8 B symptoms: No Yes 4 5 Bulky: No 7.79 >=cm Yes Stage: Early Advanced 8 6 Site: Nodal Extranodal 3 BM infiltration: ve ve IPI score: Very good.9 Good 5 5 Poor 6 3 HCV: Negative Positive 3 4 HBV: Negative 9.33 Positive

4 446 Prognostic Value of Early Introduction of Second Line in Patients with DLBCL Table (): Patterns of response in patients randomized to R- CHOP or R-ESHAP. Items Complete remission Partial remission Stationary or refractory disease (N=) Table (3): Comparison of toxicity between different groups of response. Parameter (N=) Liver enzymes: No 9.56 Yes Neutrpenia: Nausea: Fatigue: Vomiting: Mucositis: Neuropathy: 7.76 Hypokalemia: No 7.9 Yes NF 4. Discussion The rationale of using early second line has been utilized by Sehn et al., in 4 who used PET scan to categorize the patients to early salvage by R-ICE. In spite of that, the response rate was 59% similar to our study and therefore the chemoimmunotherapy will not be enough to improve the action in partial responding cases. This study was conducted at Kasr Al-Ainy Oncology Department between May 3 and September 4. Fifty patients with DLBCL were recruited fulfilling the previously mentioned inclusion criteria. The main aim in this study was to assess the possibility of improving the prognosis of patients with DLBCL through early introduction of second line R-ESHAP, a non-cross resistant regimen for patients not achieving CR after third cycle. The initial CR rate to R-CHOP (after 3 cycles) in this study was 58% which is similar to that in other trials [3,5]. This consistency might be due to high IPI score that was found in our study and Sehn et al., 4 (44% and 4% respectively). The results of treatment with R-CHOP (for partially responding cases) appear to be better than ESHAP. The majority of patients in ESHAP cases did not receive rituximab (administrative problems). This seems to be the main factor behind the inferior results of ESHAP. Furthermore, larger scale studies will allow us to obtain a firm conclusion regarding which regimen is more effective. In Coral study, patients with DLBCL in first relapse or who were refractory after first line therapy were randomly assigned to either R-DHAP or R-ICE to be followed by ASCT for responding patients. The overall response rate was 63% with CR rate of only 4%. The results of ESHAP (even without rituximab) in our trial (CR 66%) are comparable to the results of R-ICE or R-DHAP in Coral trial (CR 4%). The month OS in the R-CHOP group was superior to that of ESHAP group which may be comparable to what is reported by Herbrecht et al., (3) study (the 3 year OS of R-CPOP 69% versus 84% of R-CHOP with p=.9) [6]. Compared to bortezomib plus R-CHOP in which mo OS was >8% [7] versus 64.7% for ESHAP +/-R in this study. Again despite poorer risk factors in Ruan et al., rendering ESHAP ± R a poorer option [7]. Another study done by P.J. Still et al., reported that upfront autotransplant improves PFS for responders in DLBCL patients, including those induced with CHOP-R, with a stronger outcome seen for those with High IPI where year OS was 8% [8]. This result is still higher than 64.7% in ESHAP use, but R-ESHAP is cheaper and more available with less side effects related to high dose therapy. The weakness in our study includes small sample size as well as the lack of molecular and cytogenetics based initial diagnosis to specify populations with poorer risk.

5 Hamdy M. Zawam, et al. 447 Among the adverse effects seen in both groups, grade III fatigue was statistically significant in which could be attributed to different mechanisms and effects of multiple drugs. Hypokalemia and hyperglycemia were seen in Group B due to cisplatin and higher doses of corticosteroids. Otherwise comparable adverse effects between the two randomized groups. One patient died of septic shock in this study versus 3 patients in GEL/TAMO study as R-ESHAP toxicity. While hypocalcemia and hypomagnesemia was encountered in % which is comparable to 5% in GEL/TAMO. These data might denote tolerability of Egyptians to R-ESHAP. As regard neuropathy % of patients who completed 6 cycles R-CHOP suffered grade III neuropathy versus 4% of patients who recieved bortezomib with R-CHOP regimen in Ruan et al., trial. No grade III neuropathy in ESHAP group [7]. Grade III and IV neutropenia was encountered in 33% of patients in ESHAP group versus 4% in bortezomib+r-chop study [7]. This makes ESHAP +/-R a more tolerable regimen. In conclusion, stage is an important factor affecting the initial response to chemotherapy; early introduction of a second line chemotherapy is not better than continuing R-CHOP which may be attributed to cumulative Doxorubicin dose efficacy. References - VAIDYA R. and WITZIG T.E.: Prognostic factors for diffuse large B-cell lymphoma in the R (X) CHOP era Annals of Oncology Advance, 4, accessed annonc. oxfordjournals.org/at Onco. Path. on October 5, 4. - AMAL S.I., HUSSEIN M., et al.: Cancer Incidence in Egypt: Results of the National Population-Based Cancer Registry Program, Journal of Cancer Epidemiology Volume, (4), Article ID 43797, HAIOUN C., LTTI ERAHMOUNI A., et al.: 8 fluoro- -deoxy-d-glucose positron emission tomography (FDG- PET) in aggressive lymphoma; an early prognostic tool predicting patient outcome. Blood, 6: 376-8, NCCN guidelines, version., National Comperehensive Cancer Network SEHN L.H., HARDY E.L.G., GILL K.K., et al.: Connors: 39 Phase Trial of Interim PET Scan-Tailored Therapy in Patients with Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL) in British Columbia (BC), ASH HERBRECHT R., CERNOHOUS P., ENGERT A., et al.: Comparison of pixantrone-based regimen (CPOP-R) with doxorubicin-based therapy (CHOP-R) for treatment of diffuse large B-cell lymphoma Annals of Oncology 4, (): 68-3, RUAN J., MARTIN P., FURMAN R.R., et al.: Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J. Clin. Oncol., 9: 69-7,. 8- STILL P.J., UNGER J.M., COOK J., et al.: Randomized phase III U.S./Canadian intergroup trial (SWOG S974) comparing CHOP±R for eight cycles to CHOP±R for six cycles followed by autotransplant for patients with highintermediate (H-int) or high IPI grade diffuse aggressive non-hodgkin lymphoma, Journal of Clinical Oncology, Vol. 9, abstract a8,.