ALBERT

Description: A discordant lymphoma occurs where 2 distinct histologic subtypes coexist in at least 2 separate anatomic sites. Histologic discordance is most commonly observed between the bone marrow (BM) and lymph nodes (LNs), where typically aggressive lymphoma is found in a LN biopsy with indolent lymphoma in a BM biopsy. Although the diagnosis of discordance relied heavily on histopathology alone in the past, the availability of flow cytometry and molecular studies have aided the identification of this entity. The true prevalence and clinical ramifications of discordance remain controversial as available data are principally retrospective, and there is therefore little consensus to guide optimal management strategies. In this review, we examine the available literature on discordant lymphoma and its outcome, and discuss current therapeutic approaches. Future studies in discordant lymphoma should ideally focus on a large series of patients with adequate tissue samples and incorporate molecular analyses.

Description: Background There is an increasing amount of data showing that tumor microenvironment, host immunity and host inflammation response play an important role in determining the clinical course in patients with malignant lymphoma. Several investigators have considered the absolute monocytes count(AMC) as a surrogate biomarker of tumor associated macrophages, reflecting the tumor microenvironment, the absolute lymphocytes count (ALC) as a surrogate biomarker of tumor infiltrating lymphocyte, reflecting systemic host immunity, and absolute neutrophil count (ANC) as the host inflammatory response to cancer. Every of these parameters have been suggested to be a prognostic factor in diffuse large B-cell lymphoma (DLBCL). The aim of the present study was to verify whether neutrophil to lymphocyte ratio (NLR) is an independent prognostic factor in DLBCL. Patients and Method This retrospective analysis included data from 1050 patients diagnosed with diffuse large B-cell lymphoma according to the WHO criteria. We reviewed the clinical and laboratory data of consecutive "therapy-naïve" patients, treated in different centers in Italy and in Israel between 1993-2012, after approval by local institutional review boards. Patients had received treatment with combination chemotherapy: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), CHOP-like, or third-generation anthracycline-containing regimens, with or without rituximab. The cut-off for NLR was determined from the analysis of the log(HR) as function of NLR, by means of Cox cubic spline regression. The importance of the covariate was checked using the bootstrap inclusion frequency (BIF) with log-likelihood ratio test, considering a cut-off of 0.05, over 1000 resample of hierarchical Cox PH model, where NLR was added to IPI. Overall survival (OS) was assessed by Kaplan-Meier estimates and compared by risk groups using the log-rank test .We also performed Cox proportional hazard analysis. The effect size of risk was reported as a hazard ratio (HR) with the associated 95% confidence interval (CI95). Results Out of 1050 patients, 931 (89%)were completed for IPI and NLR. The median age was 60 years (range 18-89), 53% were males and 46% received chemotherapies with rituximab as part of the regimen. The 5-yr OS% after a median follow-up of 62 months (range 1-157 months) was 65% (95CI 61-68) for the entire cohort. The log(HR) vary linearly with the log(NLR) and the cut-off was selected at 3.6. Patients with NLR 〉3.6 showed a worst OS compared to those NLR ≤3.6 (58% vs 69%) with HR 1.54 (CI95 1.24-1.93, p3.6 maintain the prognostic value (HR 1.35, CI95 1.08-1.68, p=0.009) with a BIF of 73%. Also NLR in continuous form, log(NLR), showed a prognostic value, either in univariate (HR 1.28, CI95 1.12-1.48, p3.6, in patients population treated with CHOP or CHOP like without R and in patients population treated with CHOP and CHOP like plus R Figure 1. OS by NLR 〈 3.6 or NLR 〉3.6, in patients population treated with CHOP or CHOP like without R and in patients population treated with CHOP and CHOP like plus R Disclosures No relevant conflicts of interest to declare.

Description: BACKGROUND: The study of rare diseases is limited by the uncommon nature of the conditions as well as the widely dispersed patient populations. Current rare disease registries such as the National Organization of Rare Diseases utilize centralized platforms for data collection; however because of their broad nature, these do not always capture unique, disease specific elements. Hairy Cell Leukemia (HCL) is a rare leukemia globally with approximately 900 new cases diagnosed in the US each year. The HCL Foundation undertook creation of a Patient Data Registry that collects data from multiple HCL Centers of Excellence (COE) around the globe to better understand the complications, treatment outcomes, disease subtypes, comorbid conditions, epidemiology, and quality of life of patients with HCL. METHODS: Investigators at The Ohio State University Department of Biomedical Informatics and Division of Hematology in collaboration with the HCL Foundation developed a Patient Data Registry (PDR) for the longitudinal capture of high quality research data. This system differs from other registries in that it uses a federated( rather than centralized) architecture, wherein data is queried and integrated in an on-demand manner from local registry databases at each participating site. Further, the data collected for use in the registry combines both automated exports from existing electronic health records (EHRs) as well as additional data entered via a set of web-based forms. All manually entered data comes from source documents, and data provenance spanning electronic and manually entered data is maintained via multiple technical measures. Patients may be enrolled at HCL COE, or, if they do not have access to a COE they may enroll via a web-based portal (www.hairycellleukemia.org). At this time due to regulatory requirements the web-based portal is available to US patients only. All data are de-identified (see Figure 1: De-Identification Workflow) which reduces regulatory burden and increases opportunities for data access and re-use. End users have access to data via a project-specific query portal. RESULTS: The Patient Data Registry has been deployed at The Ohio State University, Royal Marsden Hospital, and MD Anderson Cancer Center, and is undergoing deployment at the University of Rochester. Up to 25 international HCL COE may participate. In addition, US patients are actively entering the registry via the web-based portal. To date, 227 patients have been consented to the registry with 119 of these being via the web-based entry point. CONCLUSION: We created an international and web-based patient data registry which will enable researchers to study outcomes in HCL in ways not previously possible given the rarity of the disease. This work was made possible by research funding from the Hairy Cell Leukemia Foundation. Figure De-Identification Workflow Figure. De-Identification Workflow Disclosures Andritsos: Hairy Cell Leukemia Foundation: Research Funding. Anghelina:Hairy Cell Leukemia Foundation: Research Funding. Lele:Hairy Cell Leukemia Foundation: Research Funding. Burger:Pharmacyclics: Research Funding. Delgado:Gilead: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Jones:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lozanski:Beckman Coulter: Research Funding; Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding. Montserrat:Morphosys: Other: Expert Testimony; Vivia Biotech: Equity Ownership; Gilead: Consultancy, Other: Expert Testimony; Pharmacyclics: Consultancy; Janssen: Honoraria, Other: travel, accommodations, expenses. Parikh:Pharmacyclics: Honoraria, Research Funding. Park:Genentech/Roche: Research Funding; Amgen: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tam:janssen: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heckler:Hairy Cell Leukemia Foundation: Research Funding. Payne:Hairy Cell Leukemia Foundation: Research Funding.

Description: Background There is an increasing amount of data showing that tumor microenvironment, host immunity and inflammatory responses play an important role in determining the clinical course and outcome in patients with malignant lymphoma. Several investigators have considered the absolute monocyte count (AMC) as a surrogate biomarker of tumor associated macrophages within the tumor microenvironment, the absolute lymphocyte count (ALC) as an important biomarker of tumor infiltrating lymphocytes, reflecting host immunity status, and the absolute neutrophil count (ANC) as indicative of the systemic inflammatory response to malignancy. All the above parameters have been suggested as significant prognostic factors in Hodgkin lymphoma (HL). The aim of the present retrospective study was to verify in whether neutrophil : lymphocyte ratio (NLR) can be utilized as an independent prognostic factor in a large cohort of patients with nodular sclerosis (NS) subtype HL. Patients and Methods This retrospective analysis included data from 1017 patients diagnosed with NS HL according to the WHO criteria. We reviewed the clinical and laboratory data of consecutive "therapy-naïve" patients, treated in different centers in Italy and in Israel between 1993-2012, after approval by local institutional review boards. Patients had received different combination chemotherapy regimens : doxorubicin, bleomycin, vinblastine and darcarbacine (ABVD), mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/epidoxirubicin, bleomycin, and vinblastine (EBV)/lomustine (CCNU), doxorubicin, and vindesine (CAD), Vinblastine, bleomycin, and methotrexate (VBM), bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) and Stanford V. The cut-off for NLR was determined from the analysis of the log (HR) as a function of NLR, using Cox cubic spline regression. The importance of the covariate was examined using the bootstrap inclusion frequency (BIF) with log-likelihood ratio test, (cut-off of 0.05), over 1000 resample of hierarchical Cox PH model, where NLR was added to IPI. Progression free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier estimates and risk groups compared using the log-rank test .We also performed Cox proportional hazard analysis. The effect size of risk was reported as a hazard ratio (HR) with the associated 95% confidence interval (CI95). Results Of the 1017 patients, 990 (97%) had data on both IPS and NLR. Median age was 31 years (range 17-69) and 49% were males. The 5-yr PFS and OS after median follow-up of 85 months (range 1-244 months) were 81% (95CI 78-84) and 91% (95CI 89-93), respectively, for all patients. The log(HR) for PFS and OS varied linearly for the function of NLR and the cut-off was selected at 6 for both outcomes. Patients with NLR 〉6 had a worse PFS and OS compared to NLR ≤6 (84% vs 75% and 92% vs 88% at 5-years, respectively). Figure 1). For PFS the HR for patients with NLR〉6 was 1.65 (CI95 1.25-2.18, p6 maintained it's prognostic value in both PFS (HR 1.49, CI95 1.12-1.98, p=0.006; with a BIF of 76%) and OS (HR 1.56, CI95 1.06-2.29, p=0.023; with a BIF of 64%). This was also evident in continuous form for NLR both s in PFS (HR adjusted by IPS 1.02, CI95 1.01-1.04, p=0.010) and OS (HR adjusted by IPS 1.02, CI95 1.01-1.05, p=0.039). Conclusion . Although the majority of patients with HL can be cured, about 1/3 of those with advanced stage disease relapse or progress after first line therapy. Several approaches have been employed to recognize high risk patients, including gene expression profiling and positron emission tomography. However these procedures are expensive and not always easy to perform and interpret. In conclusion, despite it is retrospective nature, our study shows that NLR can reliably identify high risk patients at the time of diagnosis. This easily obtainable simple prognostic parameter could well be utilized to improve the discriminating power of the IPS score in patients with NS HL. Figure 1. PFS and OS by NLR 〈 6 or NLR ≥ 6 Figure 1. PFS and OS by NLR 〈 6 or NLR ≥ 6 Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Chronic Lymphocytic Leukemia (CLL) is frequently accompanied by immune dysregulation. Hypogammaglobulinemia is one of the most important immune defects encountered, and all three classes of immunoglobulins (IgG, A and M) can be involved. Recently, novel heavy+light chain (HLC) immunoassays have become available that quantify the light chain types of each immunoglobulin class (e.g. IgGk and IgGl). These assays are measured in pairs and provide information on the isotype produced by a tumour (the "involved" HLC), the non-clonal ("uninvolved") HLC, and the ratio (e.g. IgGk/IgGl) - which indicates monoclonality. HLC assays have been shown to improve monitoring of plasma cell dyscrasias, but their role in CLL is yet to be studied. Methods This is a multi-center study performed in collaboration with the Israeli CLL Study Group and involved 10 medical centers. The cohort included 122 patients with CLL and 26 healthy controls. Baseline was defined as the time the blood sample was taken. Serum samples were analyzed for levels of IgG subclasses (IgG1, IgG2, IgG3, IgG4), heavy+light chains (HLC) (IgGκ, IgGλ, IgAκ, IgAλ, IgMκ or IgMλ) and free light chains (sFLC). HLC-pair suppression was defined as an abnormal HLC ratio and uninvolved HLC levels below the normal reference range (i.e. in g/L: IgGκ

Description: Introduction: Infections are a major cause of morbidity and mortality in patients with multiple myeloma (MM) and of these, one of the most frequent is gastroenteritis. This can be explained by immunoparesis, a known manifestation of MM and immunosuppression due to multiple lines of treatment. Other causes of diarrhea such as drugs or gastro-intestinal infiltration by plasma cells should also be excluded. Immunoglobulin A(IgA) is a major immunoglobulin on mucosal surface and defends the bowel from pathogens invasion. Data exists in literature about the protective role of IgA against Shiga toxin. Early isolation of pathogen and correct therapeutic intervention are important and can be lifesaving for MM myeloma patients. Until recently, diagnostic clinical laboratories utilized different methodologies to detect bacterial, parasitic, and viral causes of gastroenteritis. These tests have a number of disadvantages, including poor sensitivity, potentially long turnaround times, and complicated workflows. In addition, there are limited or almost no testing methods routinely available for most strains of Escherichia coli causing diarrhea. The Film Array GI Panel, is a relatively new method introduced recently, which provides comprehensive, simultaneous detection of 22 different enteric pathogens on stool specimens with a turnaround time as short as 1 hour . Because of its high cost it is not used routinely in all patients presenting to the emergency room with acute diarrhea. Here we summarize our real-life experience, using the BioFire PCR-Arrayfor 4 patients with relapsed /refractory MM who were admitted to our medical center with an acute presentation of gastroenteritis Methods: The Infectious Diseases Unit at our medical centre decided to introduce a strategic approach of the use of BioFire PCR-Array for the examination of stool samples, in immunocompromised patients who present to the emergency room with acute diarrhea. The panel used includes the following 22 pathogens: Campylobacter spp., Clostridium difficile(toxin A/B), Plesiomonas shigelloides, Salmonella spp., Vibriospp., Vibrio cholerae, Yersinia enterocolitica, enteroaggregative E. coli, enteropathogenic E. coli, enterotoxigenic E. coli, Shiga-like toxin-producing E. coli (stx1 and stx2) (including specific detection of E. coli O157), Shigella spp./enteroinvasive E. coli, Cryptosporidium spp., Cyclospora cayetanensis, Entamoeba histolytica, Giardia lamblia, adenovirus F 40/41, astrovirus, norovirus GI/GII, rotavirus A, and sapovirus. The assay is sent on the first day of patient admission, and results are reported to the Infectious Diseases Unit within one hour. Here we summarize the results obtained in four patients with MM treated at the Hemato-Oncology Unit in Bnai Zion Medical Centre , Haifa , who were hospitalized in 2018 due to acute diarrhea and had positive PCR-Biofire results; Results: All patients examined had relapsed/refractory MM and had received 2-5 treatment lines for MM. Two of the four patients had neutropenia on admission, two had low IgG level, three had low IgM level and all four had low IgA levels. Of the four patients with MM and acute diarrhea, evaluated by BioFire Film Array, one had two episodes of acute diarrhea on different occasions and was evaluated twice. Five pathogens were detected by BioFire FilmArray, STEC (Shiga-like toxin producing E. coli) was the most common bacteria encountered and was detected 3 times: EPEC (Enteropathogenic E. coli) and ETEC (Entertoxogenic E. coli) were detected one time each. Careful review of the literature did not identify any previous case report of patients with multiple myeloma who had Shiga-like toxin producing E. coli. All patients received antibiotics-Azithromycin and improved. Conclusion: In our experience using the PCR- Biofire assay we show that this approach is feasible and can be used safely to tailor therapy in immunocompromised patients. In all cases, E.Coli was found, most frequently STEC (Shiga-like toxin producing E. coli). Using this approach enable us to identify new pathogens causing diarrhea in immunocompromised patients, extremely quickly. These preliminary results reveal the need for more clinical experience using the Biofire FilmArray as a diagnostic test for patients with MM and other haematological malignancies, who present acutely with severe diarrhea. Disclosures Tadmor: NOVARTIS: Consultancy; ABBVIE: Consultancy; JNJ: Consultancy; PFIEZER: Consultancy; ROCHE: Research Funding. Polliack:ABBVIE: Consultancy; ROCHE: Research Funding.

Description: Chronic lymphocytic leukemia (CLL) occurs in older individuals with a median age at diagnosis of 72 years. In recent years, there has been considerable progress in the frontline therapy of elderly/physically unfit patients with CLL. The German CLL11 trial showed that addition of obinutuzumab to chlorambucil (G-Clb) prolongs progression free survival (PFS) and overall survival (OS) compared to chlorambucil alone or in combination with rituximab. More recently, obinutuzumab together with ibrutinib or venetoclax were shown to be superior to G-Clb with regard to PFS, but there was no advantage in terms of OS. In this retrospective, multinational and multicenter co-operative study the European Research Initiative on CLL (ERIC) and the Israeli CLL Study Group (ICLLSG) evaluated the efficacy of frontline treatment with G-Clb in patients with CLL, in a "real-world" setting. Our analysis excluded CLL patients with documented del(17p) or TP53 mutations since they are no longer treated with chemotherapy. Results: A total of 437 treatment-naïve patients with CLL from 51 medical centers located in 13 countries were included. The median age of this patient population was 75.9 years; 59.7% were men, median CIRS total score was 8 and estimated creatinine clearance 61.1 mL/min. Seventy four patients had Binet stage A (17.2%), 167 (38.8%) stage B and 190 (44.1%) stage C. Results of FISH and IGHV mutational status were available for 332 and 115 patients, respectively. High-risk cytogenetics, del(11q) was documented in 18.7% patients and IGHV-unmutated gene in 64.4%. The vast majority of patients were treated with G-Clb (N=408) and the rest with obinutuzumab monotherapy (G-monotherapy, N=29). The clinical overall response was 86.5%, including clinical complete and partial responses in 41.6% and 45.8% of cases, respectively. The median observation time was 14.1 months (m) and the median PFS of the entire cohort was 27.6m (95% CI, 24.2-31.0). The PFS for G-Clb was significantly better than G-monotherapy (P=0.001; HR=0.38, 95% CI: 0.22-0.67), being the 2-year PFS estimates 61.8% and 52.8%, respectively. The median PFS was significantly shorter for patients with del(11q) (19.2m) compared to those with normal FISH (not reached, P

Description: Novel therapies targeting BTK (ibrutinib), PI3Kδ (idelalisib) and BCL2 (venetoclax) are active in poor-risk chronic lymphocytic leukemia (CLL) and are widely administered to patients with relapsed/refractory (R/R)-CLL. Given the activity of ibrutinib in high-risk CLL patients, including those with del17p/TP53 mutation or germline IGHV genes, we assumed that this drug could diminish the prognostic utility of the CLL-IPI, because the outcome of patients with high- and very high-risk CLL-IPI scores may improve. Recently, Soumerai et al (Lancet Hematology, 2019) proposed a new risk score for overall survival (OS) based on four accessible markers, called BALL (β2-microglobulin, anemia, LDH, last therapy), in the setting of R/R-CLL patients receiving chemo-immunotherapy or targeted therapies in clinical trials. This model segregates CLL patients into three groups with significantly different OS. This multicenter, observational retrospective study aimed at validating the proposed BALL score for R/R-CLL real-world patients treated with ibrutinib. The primary objectives were to determine whether: i) the BALL score is of prognostic value for ibrutinib R/R-CLL patients, ii) the BALL score is predictive of progression-free survival (PFS); and iii) the CLL-IPI retains its prognostic power also in R/R patients treated with ibrutinib. This study, from an institutional Italian multicenter working group on CLL ('Campus CLL'), included CLL patients collected from 18 Italian centers and 1 Israeli center, who received ibrutinib 420 mg/day outside of clinical trials as salvage therapy with available data for the calculation of the BALL and CLL-IPI scores at the time of the start of treatment. OS was estimated for all subgroups according to both scores. Additionally, risk-specific PFS was assessed. Kaplan-Meier curve, log-rank test and Cox regression analyses were performed. The prognostic accuracy of the predictive model was assessed by the Harrell's C-index. Overall, 541 CLL patients were included in this analysis. The majority of patients were Binet stages B and C (87.2%). The median age was 70.4 years (range 37 - 88) and 353 cases (65.2%) were male. The median number of previous therapies was 2 (range 1-9). The baseline patients' features are listed in Table 1. After a median follow-up of 1.8 years (range 1 month to 5.8 years), 101 patients had died and 206 experienced an event (death or progression). According to the BALL score, 372 patients (68.8%) were classified as low-risk, 132 (24.4%) as intermediate-risk and 37 (6.8%) as high-risk. Stratification of patients according to the BALL score predicted significant differences in terms of OS. Thus, low-risk patients had a 2-year OS probability of 89.2% (HR=1), intermediate-risk of 79.9% (HR=2.8, 95%CI 1.8-4.4, P

Description: Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) primarily affects older patients (pts) who often have medical comorbidities along with disease-related immunosuppression and myelosuppression. Although alkylating agents such as chlorambucil (clb) have been commonly used in these pts, novel therapies are needed. Ibrutinib (ibr) is a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase FDA-approved for pts with CLL who received ≥1 prior therapy and for del17p CLL (including first-line). Ibr showed high activity in treatment-naïve pts age ≥65 years, with an overall response rate (ORR) of 84% (complete response [CR] in 23%) and 30-month progression-free survival (PFS) of 96% (Byrd et al. Blood 2015). We conducted a randomized, open-label phase 3 trial to evaluate efficacy and safety of single-agent ibr vs clb in treatment-naïve older pts with CLL/SLL. Methods: Pts aged ≥65 years with treatment-naïve CLL/SLL were randomized 1:1 to receive 420 mg ibr daily until progression or clb 0.5 mg/kg (up to maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Pts with del17p were excluded. Primary endpoint was independent review committee (IRC)-assessed PFS per iwCLL 2008 criteria, with 2012 clarification for treatment-related lymphocytosis. Secondary endpoints included overall survival (OS), ORR, event-free survival (EFS), rate of hematologic improvement, and safety. Pts with IRC-confirmed progression could transfer to an extension study where next-line therapy (including ibr) could be initiated if they had an iwCLL indication for treatment. Results: Among 269 pts enrolled, median age was 73 years (70% ≥70 years). Baseline characteristics were balanced between arms; 45% had advanced Rai stage, 20% had del11q, and 69% had comorbidities at baseline including CIRS score 〉6, reduced creatinine clearance, or ECOG status of 2. For pts treated with clb, 40% completed 12 cycles of therapy (mean dose 0.6 mg/kg). At a median follow-up of 18.4 months (mos), ibr significantly prolonged IRC-assessed PFS vs clb (median not reached [NR] vs 18.9 mos; HR 0.16, 95% CI 0.09-0.28, P

Description: Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. Despite the development of novel agents and new monoclonal antibodies, FCR still remains the combination chemoimmunotherapy of choice for fit patients with CLL, yielding the longest durations of remission. When this study was first started, no established chemo-immunotherapy regimen was unanimously regarded as standard therapy for less fit elderly patients with CLL; this category of patients had clearly been underrepresented in clinical trials utilizing chemo - or chemo-immunotherapy. Patients and Methods We conducted a single arm, phase II trial to assess the efficacy and toxicity of low dose fludarabine and cyclophosphamide in combination with a regular dose of rituximab (FCR-LITE) in elderly patients with therapy naïve CLL. Our intention was to deliver 6 courses of Fludarabine which was given intravenously (IV) at 12.5 mg/m2/day together with IV cyclophosphamide 150 mg/m2/day for 3 consecutive days. IV rituximab was administered on day 0 of cycle 1 at a dose of 375 mg/m2, and at 500 mg/m2 on day 1 of cycles 2-6. Categorical variables were compared in patients with and without CR using chi-square test or Fisher's exact test and continuous variables were also compared using Mann Whitney test. Duration of follow-up was recorded using reverse censoring method. Kaplan Meier curve was used to establish PFS during clinical follow-up. All statistical tests were two sided. P