Intermediate-grade non-Hodgkin's Lymphoma Research Articles

Head and Neck Lymphoma: Clinico-demographic Profile and Pattern of Presentations in a South Western Nigeria Tertiary Institution

Abstract
 Running title: A clinic-demographic profile and presentation of patient with head and neck lymphoma in a tertiary institution located in low-middle-income country.
 Introduction 
 Lymphoma is the second most common malignancy occurring in the head and neck region. It is broadly classified into Hodgkins lymphoma (HL) and non-Hodgkins lymphoma (NHL). It affects nodal and extra-nodal. The clinical presentation is largely determined by the anatomic distribution of the disease, clinical stage of the disease, age of the patients and presence of underlying diseases.
 Aims and Objectives
 This study aims to analyse the presentation of head and neck lymphomas over a fifteen years period at Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife. The objectives include; to determine the prevalence and demographic indices (age and gender) of head and neck, document the histopathologic types, and determine the association between the anatomical sites and histopathologic subtypes of lymphomas
 Materials and Method
 This is a retrospective study among patients seen and diagnosed histologically with head and neck lymphomas between 2005 – 2019 at the departments of Oral Medicine and Pathology and Morbid Anatomy and Forensic Medicine, OAUTHC. Relevant record were retrieve from patient record and histological register from the hospital registry. Patients with incomplete data were excluded. The study was conducted in accordance with the Declaration of Helsinki, and approved by our institution Ethics Committee Board.
 Results 
 A total number of 54 cases of head and neck lymphoma were analysed with a prevalence of 30.9%. Out of the 54 cases, 46 were NHL and 8 cases were HL with a ratio of 5.8:1 respectively. A male preponderance was observed (M: F; 2.4:1). The lesion commonly affects patients in 3rd and 4th decade of life. All the histologic variants were seen to affect males more than females except for the unclassified variant of HL which affected both sexes equally. Low-grade and intermediate grade NHL affected the older patients more while high grade and miscellaneous subtypes affected the younger males. The cervical lymph nodes were the most common nodal site while the jaw was the most common extra-nodal site. Eighteen (39.1%) cases of NHL were diagnosed histological as miscellaneous while high and low grade had seven (15.2%) cases each.
 Conclusion
 Head and neck lymphoma remain relatively rare. One of every six lymphoma seen was HL, with male preponderance. High grade lymphoma is seen more in the younger patient. Lymphoma affect cervical lymph node more while jaw was the most common extranodal site. Obesity may be a predisposing factor in our environment but require future study to confirm.

Activity and Event-Free Survival in Intermediate Grade Non-Hodgkin's Lymphoma Treated with Chemoimmunotherapy Utilizing Single Dose Intravenous Methylprednisolone in Lieu of Oral Prednisone

Schein et al first noted that patients with intermediate grade lymphoma treated with combination chemotherapy leading to complete response lasting 24 months were likely to remain relapse-free (Schein, Chabner, Canellos, Young, Berard, DeVita,1975). Subsequent changes in that original C-MOPP regimen have included the use of anthracyclines and rituximab. The University of Iowa/Mayo Clinic Molecular Epidemiology Resource and the Groupe d'Etude des Lymphomes de l'Adulte (GELA) program found that patients with diffuse large B-cell lymphoma achieving event-free status at 24 months with chemoimmunotherapy have subsequent overall survival equivalent to that of the general population (Maurer, 2014). While Rituximab, Cyclophosphamide, Hydroxydaunorubicin [doxorubicin], Oncovin [vincristine] and Prednisone (RCHOP) has served as the reference therapy for intermediate grade non-Hodgkin's lymphoma for two decades (Coiffier, 2002; Pfreundschuh, 2006), oral prednisone given daily for 5 days is problematic for individuals with underlying medical conditions such as diabetes, sleep or psychiatric disorders, or gastrointestinal symptoms. In this retrospective study between January, 2007 and March, 2023, 33 patients with intermediate grade Non-Hodgkin's Lymphoma, (26 with Diffuse Large B-cell subtype, 6 with follicular grade III, 1 with T-cell Immunoblastic) received Methylprednisolone 125 mg intravenously on day 1 instead of oral prednisone for 5 days as part of anthracycline-based treatment that consisted of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 2 mg (total dose) all given intravenously on day 1 with peg-filgastrim 6 mg subcutaneously on day 2 every 21 days. Three patients received mitoxantrone 12 mg/m2 intravenously on day 1 instead of doxorubicin. Patient characteristics: 23 males/10 females, median age-55 (range: 24-85), stages: IV (17 patients), III (4 patients), II (12 patients), B symptoms (16), subtypes: non-germinal center (13), germinal center (12), diffuse B-cell NOS (1), follicular grade III (6), T-cell Immunoblastic (1). Median cycles received (range): 6 (5-8). No patients required dose reduction or omission of methylprednisolone. Complete responses (determined by PET/CT) occurred in 26 (81%). 1 additional patient was PET negative but was lost to follow-up and is not counted as CR here. Three patients having PR after chemoimmunotherapy were converted to CR after involved site radiation. Two other patients achieved only short-lived PR. One patient is too early to evaluate. The median event-free survival has not been reached at 24.8+ months. Median overall survival exceeds 32.6+ months. Chemoimmunotherapy with the substitution of intravenous methylprednisolone on day 1 in place of 5 days of oral prednisone displays activity in intermediate-grade non-Hodgkin lymphoma and event-free survival beyond 24 months.

Substitution of single dose intravenous methylprednisolone (MP) for oral prednisone (Pred) in RCHOP in intermediate grade non-Hodgkin’s lymphoma (NHL).

e19019 Background: The regimen CHOP (cyclophosphamide, Hydroxydaunorubicin [doxorubicin], Oncovin [vincristine] and Pred) has been the basis of therapy given with curative intent for intermediate grade NHL for over 40 years. Rituximab added to CHOP (RCHOP) has been the standard for more than a decade. For patients (pts) with prior medical problems such as brittle diabetes, gastrointestinal bleeding, or psychiatric disorders, oral Pred given daily for 5 days is problematic. Methods: In this retrospective study between January, 2007 and September 2018, twenty pts, Diffuse Large B-cell (18) or grade III Follicular NHL (2), for whom standard oral Pred (100 mg daily for 5 days) was not felt to be medically well-suited or who refused or were not compliant with such therapy following an initial cycle, were treated with curative intent with the substitution of MP 125 mg IV (one received 60 mg IV) on day 1 (in place of oral Pred for 5 days) in combination with standard doses of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 2 mg (total dose) all given intravenously on day 1 with peg-filgastrim 6 mg subcutaneously on day 2 every 21 days. Results: Pt characteristics: 14 males/6 females, median age-56 (range: 24-76), stages: II (8), III (2), IV (10), B symptoms (12), subtypes: activated B-cell (11), germinal center (6), diffuse B-cell NOS (1), follicular grade III (2). Two were treated with 5 cycles. Fifteen received 6 cycles while three were treated with 8 cycles. Sixteen had complete responses (evaluated by PET/CT) following RCHOP. One pt with activated B-cell subtype had a short-lived partial response before experiencing disease progression. The three remaining pts had partial responses, all 3 of which were converted to complete responses following involved site radiation therapy. One with activated B-cell subtype relapsed at 68.2 months. Eighteen remain progression-free with the longest at 120.3+ months. Median progression-free survival has not been reached at 23+ months. Conclusions: RCHOP with the substitution of a single dose of MP in place of oral Pred has activity in intermediate grade NHL. Long-term disease-free survival may be seen.

English

INTRODUCTION: Lymphomas are heterogeneous group of malignant lympho- proliferative disorders. Broadly categorized into Non-Hodgkin's lymphoma (NHLs) and Hodgkin's lymphoma (HL). Decades back one of the challenging topics in morphologic pathology was accurate diagnosis and classification of lymphoma. Studies on lymphoma with clinicopathologic correlation were found to be much significant. STUDY OBJECTIVES: This was a retrospective study aimed to describe lymphomas on histo morphology and thus classify NHLs using working formulation for clinical usage (1982) and HL using Rye (1966) classification respectively. To attempt clinicopathologic correlation. METHODS: The study was done in the department of pathology, Mahadevappa Rampure Medical College, Gulbarga during the period 1989-1999. Formalin fixed paraffin wax embedded tissue blocks previously diagnosed as lymphomas in the department were used. Morphologic details by light microscopy on haematoxylin and eosin (H&E) stained sections were noted. Clinical history of each case were analysed from hospital records. Clinical and pathologic correlation was done. Special stains Reticulin (Gomori) and Periodic acid Schiff's stain (PAS) was done in relevant cases. RESULTS: Study of total 102 cases of lymphoma it was observed NHLs formed 70 cases with an incidence of 68.3%. HL accounted for 32 cases with incidence of 37.2%. NHLs commonly presented in fifth decade 24.2%, followed by fourth and sixth decade. Sex distribution showed Male: Female ratio as 2.5:1. Majority of cases presented with cervical and axillary lymphadenopathy at 41% and 20% respectively. The most frequent grade was clinically aggressive intermediate grade NHLs seen in 80% of all cases. 20 cases of NHLs were of extranodal in origin. The most common site was gastrointestinal tract (60%) and head and neck region with (30%). The major histologic type in both nodal and extranodal NHLs was diffuse small cleaved cell type (DSCC). HL showed sex ratio of 1.8:1.The common age group was in third and second decade. Mixed cellularity was most frequent type. No extranodal HL was noted. CONCLUSION: This study confirmed the usefulness of histomorphology in diagnosis of lymphomas and its basis used in the classification systems. Clinicopathologic correlation was significant. The Result was comparable with various author study series. A relook into the still clinical usefulness of the above classification system in this

Splenectomy for isolated splenomegaly; experience with twelve patients

Background: Changes in the indication for splenectomy in hematology, especially in hematological malignancies, has been observed in the last 10 – 15 years. Yet splenectomy, as a diagnostic tool, is still an option in the management of isolated splenomegaly.Objectives: to describe the outcome of diagnostic splenectomy in the management of 12 patients presenting with isolated splenomegaly.Patients and methods: Between August 2005 and July2012, Twelve patients underwent splenectomy for diagnostic purposes in the hematology unit / Baghdad Teaching Hospital. Analysis of these patients was done with a median follow up of 16 months (6 months -4 years).Results: The median age was 46 years (range 25-68). The median duration of symptoms was 6.8 months (range 3-12) months. The median duration of follow up was 16 months. We had 8 females, and 4 males. Three patients were asymptomatic, but they had progressive enlargement of spleen over one month. The most common symptoms were malaise and abdominal pain, seen in 8 patients. The other less frequent symptoms were fever (5 patients), weight loss (5 patients), arthralgia (4 patients), while the bleeding manifestation was seen in one patient only. Anemia was seen in 5 patients, two had leucopenia, and two had thrombocytopenia. Focal lesions in the spleen were seen in two patients by ultrasound and CT scan. The results of bone marrow aspirate and biopsy, upper gastrointestinal endoscopy and serological tests for collagen vascular diseases all were unrevealing prior to splenectomy. The histopathological results were; Hodgkin disease(1 patient), intermediate grade Non-Hodgkin lymphoma(1 patient) , splenic marginal zone NHL(2 patients),Diffuse Large B Cell Lymphoma(1 patient), Gaucher's disease(1 patient), favor myeloproliferative disorders(1 patients), one patient had tuberculosis, while 4 patients ended with non-diagnostic results. Laproscopic splenectomy was done in one patient only. Postoperative complications were seen in 4 patients which were grade 1-2 bleeding and simple wound infection. During follow up one patient with undiagnostic reports proved to have collagen vascular disease & two patients developed lymphoma, and the last one developed features of myeloproliferative disorder.Conclusion: splenectomy for isolated splenomegaly has a significant impact on the management of a significant proportion of those 12 patients. Other investigations which help in the diagnosis of collagen vascular diseases, myeloproliferative disorders& lymphoproliferative disorders are needed before proceeding for splenectomy.

Immunophenotyping of Non-Hodgkin's lymphomas in Sudan.

IntroductionNon-Hodgkin′s lymphomas (NHLs) are heterogeneous group of malignant lymphoproliferative disorders.Study objectivesThis was a retrospective study aimed to classify NHLs into B cell and T cell types; in addition to demonstrate the histological patterns and correlate it with gender, age and site of the biopsy.MethodsThe study was conducted in Histopathology Department, National Heath Laboratory, during the period 2007-2010. Formalin fixed paraffin wax embedded tissue blocks which were diagnosed as NHLs by routine Haematoxylin and Eosin (H&E) stain during the period 2000-2008 were used. Haematoxylin and Eosin (H&E) stain were done. Immunohistochemistry stains performed according to Dako cytomation protocol 2007. Lymphoid markers which were used in this study are CD45 (LCA), CD20 (B cell marker), CD3 (T cell marker), CD15 and CD 30. Epithelial marker which was used is CK MNF116. The total number of samples collected was 66; two of them were excluded because of poor processing. Another two specimens were excluded because they are non-reactive with lymphoid markers. The remaining 62 specimens were confirmed to be NHLs and classified into B cell and T cell types.ResultsThe study showed that B cell NHLs represented 87.1% while T cell NHLs were 12.9%. The Male: Female ratio was 1.6:1. The major affected age group was (47-67) years (38.1% of all specimens). The most frequent histological grade was intermediate grade NHLs (27% of all specimens). The most common site of NHLs in this study is the lymph node (40% of all specimens) followed by stomach (19.4%).ConclusionExtranodal locations are the most common sites affected with T cell NHLs. In conclusion; this study confirmed the fundamental role of immunohistochemistry in diagnosis and classification of NHLs.

A supplementary report on the toxic manifestations of CHOP regimen in subjects with intermediate grade NHL

Cancer chemotherapy engenders a gamut of unpredictable and perilous toxicities, which can cause substantialmortality, morbidity, and results in escalated healthcare costs due to increased requirement for ameliorative treat-ments and toxicity-related hospitalization. The main objective of this article is to report a range of adverse effects ofCHOP regimen in patients with intermediate grade Non-Hodgkin’s Lymphoma (NHL). This randomized prospective study was conducted on de novo intermediate grade NHL patients, aged >20?60 years, receiving CHOP chemotherapyregimen. Out of 30 patients who satisfied the inclusion criteria, only 25 patients completed 6 cycles of chemotherapy and were evaluated for various toxicities. Evaluation of all the 25 subjects showed that, in comparison with the baseline, most patients exhibited toxic damages. The hepatopancreatic, dermatological, vascular and nephrologicaldamages, eventually resulted in weight loss, hepatomegaly, alopecia, hypotension, as well as abnormal levels of serum liver markers, serum creatinine and blood glucose. But, the necessity to interrupt the CHOP treatment did not arise in any of the patients. Thus, in this study combination chemotherapy with CHOP protocol was well tolerated by majority of the subjects.DOI: http://dx.doi.org/10.3329/icpj.v1i10.11850 International Current Pharmaceutical Journal 2012, 1(10): 322-327

Results of treatment of 20 Iraqi Patients with Newly Diagnosed High and Intermediate grade Non-Hodgkin's Lymphoma with VACOP-B

Background: CHOP regimen was the standard treatment for patients with diffuse large and mixed cells Non-Hodgkin's lymphoma (NHL) even in comparison with second and third generation regimen. Recently Rituximab –CHOP is considered the standard treatment for aggressive B-cell NHL while CHOP (alone) is so for aggressive T-cell NHL, yet more than one study investigates another regimen which is VACOP-B and some showed its superiority over CHOP. Prior to the introduction of Rituximab, we used VACOP-B in the treatment of high &intermediate grade NHL in adult Iraqi patients as an alternative to CHOP. Patients and Methods:We performed a prospective analysis of 20 adult patients who, between April 2000 and October2005, received VACOP-B chemotherapy for high and intermediate grade NHL. The weekly regimen consisted of: doxorubicin50 mg/m2 i.v. weeks 1,3,5,7,9,11; cyclophosphamide350 mg/m2 i.v. weeks 1, 5, 9; etoposide 100mg/m2iv, weeks 3,7,11; vincristine1.4 mg/m2 i.v. (2 mg max.) weeks 2, 4, 6, 8, 10;bleomycin 10 mg/m2 i.v.(max. 15 mg) weeks 2,4, 6,8, 10; methotrexate12.5 mg intratheical was given in selected patients.; prednisolone 60mg p.o.daily for 2 weeks, reduced to 60 mg every other day for 10weeks.The patients treated were aged 25-50 years, 8(40%) had high grade (Working Formulation )NHL; 12 (60%) had intermediate grade NHL;seventeen patients(85%) had Stage III/IV disease; and 3 (15%) had stage II,bone marrow involvement seen in 3(15%)patients .patients distribution regarding age adjusted international prognostic index(aaIPI)was 8(40%)with aaIPI 0,1and 12(60%)with 2,3. Follow-up time from completion of VACOP-B chemotherapy ranged from 6 months to 40 months (median 22).Results: VACOP-B induced a complete response (CR) and partial response (PR) in 70% and 15% respectively, whilst one patient had no response to treatment and died due to progression of the disease, 2 patients died due to treatment related toxicity. The three year disease free survival (DFS) was 78%, where 4 patients relapsed, one of them in the central nervous system. This study showed 3-year overall survival (OS) 100% for those with a IPI 0-1and 48% for those with aa IPI 2-3. Tolerance to treatment was measured by WHO toxicity scores. The hemoglobin (Hb) toxicity median score for all patients was grade 1 (Hb 9.5-10.9 g/dl), and the white cell count (WCC), toxicity score was grade 2(WCC 2.0-2.9 x 109/1). No platelet toxicity was observed. Ten per cent of patients suffered grade 3 severity infections requiring antibiotics and there was two treatment related death. Conclusions: VACOP-B chemotherapy is an effective regimen for high and intermediate grade NHL, with an encouraging result in patients with aaIPI 0, 1. although chemotherapy was given weekly, the tolerance to treatment was acceptable. Studies comparing VACOP-B vs. CHOP chemotherapy to decide the exact role of the first in treating high grade &intermediate grade NHL, in the absence of Rituximab, are still needed.

Results of treatment of 20 Iraqi Patients with Newly Diagnosed High and Intermediate grade Non-Hodgkin's Lymphoma with VACOP-B

Results of treatment of 20 Iraqi Patients with Newly Diagnosed High and Intermediate grade Non-Hodgkin's Lymphoma with VACOP-B

Phase I trial examining addition of gemcitabine to CHOP in intermediate grade NHL

Gemcitabine induces a 20% response as single-agent therapy in patients with relapsed or refractory NHL. We report phase I findings of gemcitabine in combination with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. The protocol was modified during enrollment to include rituximab in CD 20+lymphomas. Patients received CHOP plus gemcitabine at 500mg/m(2) (Cohort 1) or 750mg/m(2) (Cohort 2) on days 1 and 4 of each 21-day cycle. Accrual was suspended once each cohort was filled. Dose escalation occurred after all patients in the cohort were determined to not have a dose-limiting toxicity. Between April 2002 and May 2004, 10 patients were enrolled and completed the study treatment (6 in Cohort 1, 4 in Cohort 2). In Cohort 1, grade 3 toxicities included neutropenia, anemia, neuropathy, and constipation. Grade 4 toxicities were febrile neutropenia and thrombocytopenia. In Cohort 2, grade 3 toxicities included neutropenia, thrombocytopenia, mucositis, anemia, and intestinal obstruction. Grade 4 toxicities included febrile neutropenia, neutropenia, and thrombocytopenia. One patient developed MDS 36months after chemotherapy. Three of four patients in Cohort 2 developed dose-limiting toxicities (mucositis and thrombocytopenia) requiring dose reduction in gemcitabine after cycle 1. Overall, the survival rate at 2.5years was 71%. This Phase I trial concludes that gemcitabine 500mg/m(2) on days 1 and 4 of each 21-day cycle is the maximum tolerated dose when combined with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL.

Body mass index and outcomes in patients receiving chemotherapy for intermediate-grade B-cell non-Hodgkin lymphoma

We conducted a retrospective cohort study examining the influence of obesity on treatment outcome and survival among 712 patients with intermediate-grade B-cell NHL receiving frontline therapy between 1988 and 2001. Baseline adiposity was approximated by body mass index categorized according to the World Health Organization schema. Logistic and Cox proportional hazards regression modeling was used to adjust for baseline patient demographic, disease, and treatment variables. Approximately 37% of cohort patients were overweight (BMI 25 to <30 kg/m2) and more than 23% were obese (BMI ≥ 30 kg/m2). Risk factors were similar across groups and treatment intensity did not vary by BMI. Median follow-up was 45.7 and 62.8 months for PFS and OS, respectively. After adjustment for other significant prognostic factors, BMI in the overweight range was associated with significantly reduced hazard for both PFS (OR 0.72, p = 0.011) and OS (OR 0.74, p = 0.030). Increased BMI is associated with significantly improved survival among patients with treatment-naive, intermediate-grade B-cell NHL. Prospective confirmation of these results is warranted given the increasing prevalence of both NHL and obesity.

Late phase II study of amrubicin in previously untreated patients with non-Hodgkin's lymphoma (NHL).

8097 Background: We evaluated the efficacy and safety of amrubicin, a third generation synthetic anthracycline, in combination with cyclophosphamide, vincristine and prednisolone (ACOP) in patients with previously untreated aggressive non-Hodgkin's lymphoma (NHL). Methods: Previously untreated patients with intermediate or high grade NHL were treated with 8 cycles of amrubicin, 100 mg/m2, cyclophosphamide, 750 mg/m2, and vincristine, 1.4 mg/m2 (maximum 2.0 mg), on day 1, and prednisolone, 60 mg/m2/day day 1-5 every 21 days. Patients were evaluated for response and left ventricular ejection fraction (LVEF) every 2 cycles, and electrocardiogram at every cycle. The primary endpoint was response rate; secondary endpoints were survival, cardiac safety, and general safety. Results: Fifty-six patients were eligible and received a median of 8 treatment cycles. The median follow- up period was 57.1 months. Most patients had diffuse large B-cell lymphoma (76.8%). The response rate was 92.9%; the complete response (CR) and CRu rate was 69.6%. The 2- and 5-years survival rates were 76.2% and 58.7%, respectively. Reversible myelosuppression was the most common adverse event. Grade 3/4 neutropenia, anemia, thrombocytopenia and febrile neutropenia were reported in 82.5%, 19.3%, 8.8% and 7% of patients, respectively. There were no treatment-related deaths or patients experiencing cardiomyopathy. LVEF did not change during the course of treatment. Conclusions: The response rate and survival in non-Hodgkin's lymphoma patients treated with ACOP were comparable to those achieved with CHOP in other studies, but ACOP had virtually no reduction of LVEF up to a cumulative amrubicin dose of 800 mg/m2. This suggests that amrubicin has little chronic cardiotoxicity. ACOP should be evaluated in combination with rituximab (R) and then compared to R-CHOP. No significant financial relationships to disclose.

Phase I Trial Examining Addition of Gemcitabine to CHOP in Intermediate Grade NHL.

Abstract 4765 BACKGROUNDGemcitabine induces a 20% response as single agent therapy in patients with relapsed or refractory NHL. We report phase I findings of gemcitabine in combination with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. The protocol was modified during enrollment to include rituximab in CD 20+ lymphomas. METHODSPatients received CHOP plus gemcitabine at 500 mg/m2 (Cohort 1) or 750 mg/m2 (Cohort 2) on days 1,4 of each 21 day cycle. Accrual was suspended once each cohort was filled. Dose escalation occurred after all patients in the cohort were determined to not have a dose limiting toxicity. RESULTSBetween 4/02 and 5/04 10 patients were enrolled and completed the study treatment (6 in cohort 1, 4 in cohort 2). In Cohort 1, grade 3 toxicities included neutropenia, anemia, neuropathy, and constipation. Grade 4 toxicities were febrile neutropenia, and thrombocytopenia. In Cohort 2, grade 3 toxicities included neutropenia, thrombocytopenia, mucositis, anemia and intestinal obstruction. Grade 4 toxicities included febrile neutropenia, neutropenia, and thrombocytopenia. One patient developed MDS 36 months after chemotherapy. Three of four patients in Cohort 2 developed dose limiting toxicities (mucositis and thrombocytopenia) requiring dose reduction of gemcitabine after cycle 1. Overall, the survival rate at 2.5 years was 71%. CONCLUSIONSThis Phase I trial concludes that gemcitabine 500mg/m2 on days 1 and 4 of each 21 day cycle is the maximum tolerated dose when combined with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. Response rates are encouraging for this novel chemotherapeutic regimen. Disclosures:Off Label Use: Gemcitabine was added to standard CHOP chemotherapy in this trial.. Sikov:Eli Lilly: Honoraria.

Alemtuzumab-Containing Allogeneic Hematopoietic Cell Transplant (HCT) for Relapsed Lymphomas: Prognostic Factors and Outcome.

Abstract 2247Poster Board II-224The role of allogeneic HCT for relapsed lymphomas remains imprecisely defined. Most pts considered for alloHCT are heavily pretreated and many have failed a prior autologous HCT. At The University of Chicago, 69 lymphoma pts (median age 54; range, 24-70) underwent allogeneic HCT after alemtuzumab-containing reduced intensity conditioning (RIC) regimens between 11/01 and 6/09. Ten had Hodgkin lymphoma (HL), 23 low-grade B-cell NHL (LGL), 17 intermediate-grade B-cell NHL (IGL), 9 mantle cell lymphoma (MCL), and 10 T-cell NHL (TCL). 25 pts (36%) had refractory disease and 17 pts (25%) had elevated LDH. Pre-HCT PET scans were performed in 48 pts and 31 (65%) were PET positive. Performance status (PS) was 0 for 45 pts (70%) and 1 for 18 pts (28%). 19 pts (27%) had failed a prior autologous transplant, and 4 pts had failed a prior allogeneic transplant. 31 pts (45%) had unrelated and 38 (55%) related donors. Conditioning regimens along with alemtuzumab included: fludarabine/melphalan (n = 40), clofarabine/melphalan (n = 20), fludarabine/busulfan (n = 5), and thiotepa/busulfan/cyclophosphamide (n = 4). GVHD prophylaxis consisted of single agent tacrolimus in all patients. With a median follow-up for survivors of 22 mos (range 2-94 mos), 2 yr overall survival (OS) is 53% (95%CI, 40-66). Progression-free survival (PFS) is 46% (95%CI, 34-58) at 1 yr and 38% (95%CI, 28-50) at 2 yrs. 11 pts had grade II-IV aGVHD and transplant-related mortality (TRM) was 20% at 1 yr. Disease responsiveness to salvage chemotherapy prior to transplant (as determined by CT scan) was highly predictive of PFS (p = 0.03). Pts with chemo-sensitive disease had a 2 yr PFS of 44% (95%CI, 28-60), those with chemo-refractory disease 30% (95% CI, 10-50). 2 yr PFS was 52% (95%CI, 30-74%) for LGL, 48% (95%CI, 12-84) for MCL, 28% (95%CI, 6-50) for IGL, 30% (95%CI, 0-60) for HL, and 34% (95%CI, 6-66) for TCL. Patient age, pre-transplant LDH, PS (0 vs 1), prior auto, donor type, and conditioning regimen did not correlate with outcome. Interestingly, a positive vs negative pre-HCT PET also did not correlate with outcome (p = 0.21). 23 pts (33%) relapsed. 13 of those have died, 2 are alive with disease, and 8 are in a durable subsequent remission lasting a median of 46 mos (range 8-69) after further chemotherapy (n=6) or DLI (n=2). Durable subsequent remissions were more common in those with late relapses (>6 mos after transplant) (Fig 1). Conclusion: Chemosensitivity by conventional CT scans remains the most important predictor of outcome. In contrast to other reports, neither the pre-HCT PET nor LDH correlate with outcome. Patients relapsing > 6 mos after alloHCT can re-enter durable remissions with chemotherapy alone. This suggests a favorable interaction between a persisting donor graft and salvage chemotherapy. [Display omitted] Disclosures:Off Label Use: off-label use of clofarabine and alemtuzumab. Kline:Genzyme corporation: Membership on an entity's Board of Directors or advisory committees. Stock:Genzyme: Research Funding.

Efficacy of modified Hyper-CVAD regimen on non-Hodgkin's lymphoma and safety evaluation

The efficacy of standard chemotherapy regimen on aggressive non-Hodgkin's lymphoma (NHL) of certain pathologic types is unsatisfied. This study was to evaluate the safety and efficacy of modified Hyper-CVAD regimen on Chinese patients with aggressive NHL. Clinical records of 31 NHL patients who received modified Hyper-CVAD regimen in Cancer Hospital of Chinese Academy of Medical Sciences from June 2004 to June 2008 were analyzed in terms of toxicity and response. The 31 patients totally received 91 cycles of regimen A and 41 cycles of regimen B with a median of 4 cycles (ranged 1-7 cycles). The major toxicity was myelosuppresion: the occurrence rates of neutropenia of grades III-IV, thrombocytopenia and febrile neutropenia were 49.5%, 3.3% and 12.1% during treatment of regimen A, and were 80.5%, 82.9% and 46.3% during treatment of regimen B. No treatment-related death was observed. The responses were assessable in 26 patients. The total response rate was 80.8%, and 12 patients achieved complete response (46.2%). Modified Hyper-CVAD regimen is a promising regimen for the patients with intermediate and high grade NHL.

Graft-Versus-Host Disease (Gvhd) Prophylaxis with Tacrolimus and Mycophenolate Mofetil (MMF) in 131 Matched Sibling Nonmyeloablative (NMA) Transplant Recipients: Long-Term Follow-up Confirms Extremely Low Incidence of Acute (a) Gvhd, High Incidence of Extensive Chronic (c) Gvhd and Favorable Disease Outcome.

Incidences of grade II–IV aGvhd in the range of 30–50% have been reported in sibling NMA transplant recipients despite prophylaxis with cyclosporine and methotrexate. To date, the ideal Gvhd prophylaxis regimen still remains undefined. Because tacrolimus is more potent than cyclosporine and MMF does not lead to mucositis, we hypothesized that early use of a combination of these two oral agents could offer an effective strategy to prevent Gvhd. We therefore designed an outpatient prospective phase II clinical trial with a NMA conditioning regimen consisting of daily fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 for 5 days, followed by infusion of at least 4 × 106 CD34+ cells/kg. All donors were 6/6 matched siblings. Tacrolimus 3 mg bid orally was started on day (D)-8, adjusted to achieve levels of 10–15 nmol/L until D+50, then tapered off by D+100 or +180 according to estimated risk of relapse. MMF 1000 mg bid was given between D+1 to D+50 without taper. Enrollment criteria included age >55 years, an estimated increased risk of toxicity with an ablative transplant or participation in a multiple myeloma (MM) sequential therapy. Between 07/2000 and 07/2007, 131 patients (M/F: 75/56) with a median age of 54 years (range: 20–66) have received an allogeneic transplant according to our protocol. Indication for transplant included age (26%), fear of toxicity (28%) or participation in the sequential therapy (48%). Overall, 101 (77%) patients had previously received an autologous transplant. Diagnoses included MM (N=62), non Hodgkin's lymphoma (NHL; N=46) including low grade (N=33), diffuse large cell (N=5), mantle (N=7) and Sezary (N=1), acute leukemia (N=10), and others (N=13). After infusion of a median of 6.8 × 106 CD34+ cells/kg (range 0.30 to 22.3), engraftment occurred in 95% of patients by D+180. Overall, 15 patients developed grade I–IV conventional aGvhd by D+120, with a Kaplan-Meier (KM) probability of 11.6% (95%CI: 7.1–18.5), a median of 64 (range: 31–120) days after transplant. At presentation, aGvhd grade was I in 5, II in 7, and III in 3 patients, respectively. No grade IV was observed. Organs involved included skin (13/15) or gastro-intestinal (GI; 4/15), but not liver. Additionally, 15 patients (12%; 95%CI: 7.4–19.2) developed an overlap syndrome consisting of clinical and histological features of both acute and cGvhd simultaneously, at a median of 140 (range 92–177) days post transplant. Altogether, the incidence of conventional II–IV aGvhd and overlap syndrome was 19.7% (95%CI: 13.7–27.7). In contrast, extensive cGvhd occurred in 84 patients surviving beyond D+80 (median D+148, range 83–1042), with a cumulative KM incidence at 7 years of 83.3% (95%CI: 74.3–90.6). Involved organs at diagnosis of extensive cGvhd included mouth (100%), skin (89%), liver (65%), eyes (51%), GI (20%), joints (6%) and lungs (6%), similar to other reported series. Nine of 76 (12%) patients at risk are still taking immunosuppressors after 5 years. To date, 37 patients have died; causes of death include relapse of initial malignancy (N=24), cGvhd (N=3), viral or fungal infection (N=3), or other (N=7). With a cohort median follow-up of 33 (range 2.7–86) months, KM probability of non-relapse mortality (NRM) is 15.5% (95% CI: 9.0–26.1) at 7 years. Overall survival (OS) at 1, 3 and 7 years are 88.5% (95%CI: 81.7–92.9), 71.0% (95%CI: 61.1–78.7) and 62.7% (CI: 51.4–72.1), respectively. Following NMA transplant, disease-free survival (DFS) at 3 years is highest in recipients with low-grade NHL (81.4%; 95%CI: 60.5–91.9) and lowest in intermediate grade NHL (40.0%; 95%CI: 6.6–73.4) or leukemia (35.7%; 95%CI: 13.0–59.4). We conclude that early use of tacrolimus and MMF is an effective strategy to prevent aGvhd and leads to very low NRM. Despite a high incidence of extensive cGvhd, OS, DFS and probability of discontinuing immunosuppression are excellent. Future strategies will need to focus on decreasing the incidence of extensive cGvhd without increasing the risk of relapse.

Long-Term Results of Dose-Intensive Chemotherapy With G-CSF Support (TCC-NHL-91) for Advanced Intermediate-Grade Non-Hodgkin's Lymphoma: A Review of 59 Consecutive Cases Treated at a Single Institute

We evaluated the long-term outcome of very dose-intensive chemotherapy (TCC-NHL-91) for advanced intermediate-grade lymphoma, in which an eight-cycle regimen with 11 drugs was given with granulocyte colony-stimulating factor (G-CSF) support (total 18 weeks). Fifty-nine patients were treated during February 1, 1991 and March 31, 2001 (median age: 48 years). Forty-three patients (73%) were in a high-intermediate risk or high-risk group (HI/H) according to the age-adjusted International Prognostic Index (aa-IPI). Forty-six patients received 7 or 8 cycles of therapy. Ten of 15 patients over age 60 stopped before 7 cycles. Forty-three patients with an initial bulky mass or a residual mass received involved-field radiation. Overall, 56 patients (95%) achieved complete remission (CR). Grade 4 hematotoxicity was observed in all patients. With a median follow-up of 128 months, the 10-year overall survival (OS) and progression-free survival (PFS) rates were 76% and 61%, respectively. Neither aa-IPI risk factors nor the index itself was associated with response, OS, or PFS. One patient died of sepsis during the therapy and one died of secondary leukemia. This retrospective study suggests that the TCC-NHL-91 regimen achieves high CR, OS, and PFS in patients with advanced intermediate-grade lymphoma up to 60 years old and may be a valuable asset in the management of this disease. Further evaluation and prospective studies of the TCC-NHL-91 are warranted.

Prognostic significance of early lymphocyte recovery after post-autografting administration of GM-CSF in non-Hodgkin's lymphoma

The purpose of this study was to analyze the prognostic significance of early lymphocyte recovery after autologous SCT (ASCT) in the setting of routine post transplant administration of GM-CSF in patients with non-Hodgkin's lymphoma (NHL). This is a single institution retrospective comparative outcome analysis in a cohort of 268 relapsed chemosensitive NHL patients divided into two groups (early and late lymphocyte recovery) based on absolute lymphocyte counts (ALC) obtained on post transplant day +15 (ALC > or = 500, n=151 (56%) and ALC < 500, n=117 (44%)). Patient's characteristics were well-balanced between the two groups with regard to age, sex, preparative regimen, prior therapy, time from diagnosis to transplant and number of CD34+ cells infused. Post transplant complications were comparable in the two groups. Late lymphocyte recovery (ALC < 500 on day +15) was independently associated with a delay in platelet recovery (29 vs 21 days, P=0.0003) in patients who have not received pre-transplant rituximab. With a median follow-up of 22 months, no associations between early lymphocyte recovery and improvement of disease-free and overall survival were observed for either low- or intermediate-grade NHL. In conclusion, in this large single-centered retrospective analysis, where patients received routine post transplant GM-CSF, early lymphocyte recovery was not associated with favorable outcomes.

Myeloablative Allogeneic Stem Cell Transplantation for Relapsed Composite Low and Intermediate Grade Lymphoma Is Not Superior to Autologous Stem Cell Transplantation - Reduced Relapse Risk Is Offset by Higher Treatment Related Mortality.

No reports compare autologous and allogeneic stem cell transplantation (auto-SCT vs allo-SCT) for patients (pts) with relapsed (REL) composite low and intermediate grade non-Hodgkin lymphoma (L/I-NHL). Fifty four pts with composite L/I-NHL (30 transformed, 16 composite(same site), 8 discordant(different sites)) who underwent allo (n=40) or auto-SCT (n=14) from Jan ‘89 to June ‘05 were evaluated (Table 1) to compare long-term results.Twenty pts (37%) (11/40 allo and 9/14 auto) are alive with median follow-up of 32 months (range 10–87). The 2 and 5-y OS for the whole group were 43% [95% confidence interval: 28–56%] and 29% [14–46%] respectively; the 2 and 5-y EFS 40% [26–53%] and 24% [11–39 %]. 5-y OS for the auto and allo-SCT were 51% and 23% respectively (p=.09)(Fig. 1). The 2 and 5-y EFS for the allo vs auto-SCT groups were 36% [24–55%] vs 54% [33–89%] and 27% vs 23% (p=0.4).Thirty four pts (63%) died; 18 (33%) with REL NHL and 16 (30%) with TRM. TRM was due to GVHD (n=7), infection (n=6), cerebral edema (n=1) and veno-occlusive disease (n=1). All but one (cerebral edema) TRM deaths occurred post allo-SCT. The cumulative incidence (CI) of TRM and REL for the whole group were 37% [17–57%] and 47% [30–64%]. The CI of TRM for allo and auto-SCT were 47% [20–74] and 8% [0–23%] respectively (p=.009)(Fig. 2).Twenty pts (37%) relapsed post SCT (14/40, 35% allo and 6/14, 43% auto). CI of REL NHL for allo and auto-SCT were 42% [23–61%] and 65% (p=.008)(Fig. 2).In conclusion EFS for composite L/I-NHL is low post auto-SCT due to a high relapse rate despite acceptable TRM. While relapse risk is significantly lower post allo-SCT, this advantage is offset by a higher TRM in these pts. Future attempts to reduce TRM while preserving the allogeneic graft vs lymphoma effect may be beneficial.Table 1The clinicopathological characteristics of 54 patients treated with auto and allo-SCT for relapsed composite L/I-NHLParameterAllo-SCT n=40(%)Auto-SCT n=14(%)Age: Range (Median)28–57(44)25–59(49)M:F2:11.3:1DiagnosisTransformed lymph.25(63)5(36)Discordant lymph.7(17)1(7)Composite lymph.8(20)8(57)Initial StageI/II4(10)6(42)III/IV36(90)8(58)B symptoms*11(28)6(43)BM involvement*29(73)3(21)IPI*0–118(45)11(79)2–321(53)3(21)4–51(2)0Prior treatmentCHOP33(83)14(100)Purine analogue17(43)2(14)Rituximab12(30)6(43)* at diagnosis [Display omitted] [Display omitted]

Prior Rituximab Reduces Relapse and Improves Survival Following High Dose Chemotherapy and Stem Cell Transplantation for Relapsed Composite Low and Intermediate Grade (Including Transformed) Lymphoma.

The effect of prior exposure to rituximab (ritux) on relapse (REL) and survival following stem cell transplantation (SCT) in patients (pts) with REL composite low and intermediate grade non-Hodgkin lymphoma (L/I-NHL) is unknown. Fifty-four pts with REL L/I-NHL underwent high-dose chemotherapy (CT) and SCT Jan '89 to June '05. Follow-up is complete to April '6 with a median of 32 mo. Ritux was added to CT regimens since 2001 and given at 375 mg/m2. Eighteen pts received ritux at initial diagnosis of NHL or after REL with salvage CT prior to SCT. Pts proceeded to high dose CT with allogeneic (allo) (n=12) or autologous (auto) SCT (n=6). This group was compared with a group of pts not receiving ritux pre-SCT (n=36)(Table 1).Eleven pts (61%) are alive in the ritux group compared with 11 pts (31%) in the non-ritux group. The 2 and 4-y OS for pts who received ritux were 52% and 52%, vs 36% and 24% (p=.12, RR=.52) for pts who did not receive ritux. The EFS were significantly different with 2 and 4-y EFS for the ritux group 56% and 56% vs 24% and 18% (P=.038, RR=.42) for the non-ritux group (figure 1). No effect was seen on TRM. The risk of REL post SCT was significantly lower in the ritux group (p=.017)(figure 2). Two of 18 pts (11%) had NHL REL in the ritux vs 18 of 36 (50%) in the non-ritux group. The hazard rate of REL in pts who received ritux was 20% that of pts in the non-ritux group. Significance maintained in multivariate analysis (p=.016).No impact was seen on graft-versus-host disease (GVHD). Fifty percent and 61% of pts developed acute GVHD grades 2–4 and 50% and 64% of pts developed chronic GVHD in the ritux and non-ritux groups respectively.In conclusion, prior treatment with ritux in pts with relapsed composite L/I-NHL undergoing SCT was associated with reduced risk of REL and improved survival without associated increase in toxicity. Further analysis is underway to clarify the nature of this important finding.Table 1:Clinicopathological characteristics of ritux and non-ritux groupsParameter$Rituximab group, n=18 (%)Non-rituximab group, n=36 (%)Median age at SCT48 y44 yM:F2.6:11.6:1Allo-SCT12(67)28(78)BM involvement*10(56)22(61)B symptoms*7(39)10(28)Prior purine analogue therapy8(44)11(31)Residual disease prior to SCT9(50)14(39)TBI in conditioning13(72)30(83)$ all p values are >0.1. *at diagnosis [Display omitted] [Display omitted]