Intermediate Grade Non-Hodgkin Research Articles

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.

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.

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

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.

Phase I Study of Rituximab-Cyclophosphamide (R-CY) Stem Cell Mobilization and Rituximab-BEAM HDC with ASCT in Patients with Relapsed, Refractory or High Risk Intermediate Grade Non-Hodgkin's Lymphoma.

The addition of rituximab to mobilization regimens does not adversely affect collection of adequate numbers of CD34+ PBSC and may decrease tumor cell contamination. Prior administration of rituximab may sensitize lymphoma cells to chemotherapy, but its use with high dose chemotherapy has not been studied. In this study, eligible patients had intermediate grade NHL either primary refractory, relapsed or in CR1 with an intermediate/high risk IPI score. Eight patients with a median age of 49 years (28–61) were enrolled in this study. Four patients had relapsed disease, chemosensitive to salvage in 3 patients, and untested in 1 patient. Two patients had primary refractory disease, chemosensitive to salvage. Two patients had intermediate-high risk IPI scores and were in CR-1. One patient in CR-1 declined to undergo transplant following stem cell collection. All patients had received rituximab previously. Stem cell mobilization was rituximab 375mg/M2 followed by CY 2gm/M2/day for 2 doses and filgrastim 10ug/kg/d. High dose chemotherapy consisted of rituximab 375mg/M2 on day -8, carmustine 300mg/M2 on day -7, etoposide 200mg/M2/d on days -6 to -3, cytosine arabinoside 200mg/M2 on days -6 to -3 (8 doses) and melphalan 140mg/M2 on day -2. Patients received filgrastim post transplant.RESULTS: The median CD34+ cell dose collected was 12.5 x 106/kg (1.1 to 33.2). There was one inadequate CD34+ cell collection requiring bone marrow harvesting which yielded 0.72 x 106/kg CD34+ cells. Engraftment of neutrophils and platelets occurred at a median of 8 and 11 days post transplant respectively. Infectious complications included febrile neutropenia in one patient following mobilization and in 6 patients following R-BEAM. Transient grade I–II (common toxicity criteria) hepatic enzyme elevation occurred in 2 patients following R-CY. Following R-BEAM, 3 patients developed grade II-IV LFT elevation without evidence of VOD, which resolved. One patient developed moderate hemorrhagic cystitis which resolved. One patient developed bilateral pulmonary infiltrates of unkown etiology (BAL negative for organisms) which resolved. Immunoglobulin levels remained normal in two patients, but decreased in all other patients for up to a year post transplant. Peripheral blood flow cytometry and T cell subset analysis showed absent B cell populations, decreased CD4 cells and increased CD 8 cells in all patients up to a year post transplant. Five patients are alive with no evidence of disease 381 to 676 days post transplant. Three of these patients developed PET positive lymph nodes that showed florid follicular hyperplasia on biopsy, with no evidence of lymphoma. Two patients had persistent disease following transplant. One patient underwent a non-myeloablative allogeneic transplant and died of progressive disease.CONCLUSIONS: R-CY was well tolerated as a mobilization regimen and led to adequate stem cell collection. The addition of rituximab to the high dose chemotherapy regimen did not appear to increase the incidence of infections or peritransplant complications in this Phase I study. The effect, on disease free survival, of the addition of rituximab to the collection and preparative regimens requires further investigation.

Effect of High-Dose Rituximab on Peripheral Blood Stem Cell Mobilization in Intermediate Grade Non-Hodgkin's Lymphomas.

High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered to be standard therapy for patients with intermediate grade NHL (IGNHL) in chemosensitive relapse. In recent years rituximab has been widely used for in vivo purging of lymphoma cells from apheresis products, however its impact on kinetics of stem cell mobilization and engraftment are not well characterized. We studied 69 patients with IGNHL who were mobilized using rituximab plus chemotherapy or with chemotherapy alone. 31 patients (No-R group) were mobilized with ifosfamide (10 g/m2), and etoposide (150 mg/m2 every 12 hours for 6 doses) followed by G-CSF (12 mcg/kg/day). 38 patients (R group) also received 2 doses of rituximab (375 mg/m2 and 1000 mg/m2) on days 1 and 10. Patients underwent HDT following successful stem cell collection. HDT was standard BEAM (+ rituximab for patients in the R group) regimen in most patients. 15 patients received a cycle of CVP (cyclophosphamide, cisplatin, etoposide) prior to BEAM because of failure to achieve at least a PR following mobilization chemotherapy (all in the No-R arm).RESULTS: The baseline characteristics of the 2 groups are summarized in Table 1. Patients in the No-R group were more likely to have stage III/IV disease, and were more likely to have BM involvement with lymphoma, but had received fewer number of chemotherapy regimens received prior to mobilization. Failure to mobilize was defined as failure to reach a circulating CD34 count of 10/mcl. The target cell dose was a minimum of 4 x 106 CD34+ cells/kg. The apheresis data is summarized in Table 2. All 31 patients in the No-R group mobilized the target cell dose (NA-1). In the R group 7.9% did not reach the target cell dose (P=NS). Median time to neutrophil engraftment after ASCT was 10 (8–17) and 11 (9–37) days in the No-R and R groups respectively (P=0.01). The OS and DFS at 2 years were 45% (27–61) and 39% (22–55) and 78% (51–92) and 63% (38–51) respectively in the No-R and R group (P=0.001 and 0.01).CONCLUSION: High dose rituximab added to the mobilization regimen does not affect the ability to collect adequate number of stem cells for ASCT. Incidence of bacteremic episodes was higher in the rituximab group. The OS and DFS were significantly longer in patients receiving rituximab.Table 2. Apheresis DataRituximab group (N=38)No rituximab group (N=31)P=valueMedian days of apheresis (range)2 (1–5)2 (1–7)NSFailure to mobilize10NSFailure to collect 4 x 106CD34+cells/kg30NSMedian CD 34+cells/kg (range)6.5 (0–31.15) x 10613.7 (4.8–148) x 106<.0001PRBC transfusions median (range)1 (0–5)0 (0–8).01Platelet transfusions median (range)2 (0–6)1 (1–3).008No. of patients with infections1380.45Infectious episodes26 (22 bacterial)11 (6 bacterial)0.01Time to ANC > 500/mm3 after mobilization median (range)13 (11–18)14 (6–24) NA 30.7Table 1: Baseline characteristicsRituximab groupNo rituximab groupP valueN=38N=31Age years (range)49.9 (19–70 )48 (26–590.68Stage III/IV (%)9 (23.7%)13 (43.3%).003No. of prior chemoregimens (median, range)2 (1–5)1 (1–3).001IPI score (median, range)0 (0–2)1 (0–2) NA 5.03LDH ≥ normal (%)8 (21%)8 (30.7%)0.78BM involvement (%)0 (0)8 (25.8)

Phase I Study of Rituximab-Cyclophosphamide (R-CY) Stem Cell Mobilization and Rituximab-BEAM HDC with ASCT in Patients with Relapsed, Refractory or High Risk Intermediate Grade Non-Hodgkin's Lymphoma.

The addition of rituximab to mobilization regimens does not adversely affect collection of adequate numbers of CD34+ PBSC and may decrease tumor cell contamination. Prior administration of rituximab may sensitize lymphoma cells to chemotherapy, but its use with high dose chemotherapy has not been studied. In this study, eligible patients had intermediate grade NHL either primary refractory, relapsed or in CR1 with a high or intermediate/high risk IPI score. Five patients with a median age of 38 years (28–53) have been treated. All patients had rituximab previously. At transplant, 4 patients had relapse, chemosensitive to salvage in 3 patients, and untested in 1 patient. One patient had primary refractory disease, chemosensitive to salvage. Stem cell mobilization was rituximab 375mg/M2 followed by CY 2gm/M2/day for 2 doses and filgrastim 10ug/kg/d. Collection started when the CD34 count was ≥12/ul. High dose chemotherapy consisted of rituximab 375mg/M2 on day −8, carmustine 300mg/M2 on day −7, etoposide 200mg/M2/d on days −6 to −3, cytosine arabinoside 200mg/M2 on days −6 to −3 (8 doses) and melphalan 140mg/M2 on day −2. Patients received filgrastim post transplant and standard antibiotic prophylaxis. All patients are alive 11 to 306 days post transplant (median follow up 4.5 months). The median CD34+ cell dose collected was 8 x 106/kg (1.1 to 17.6). One patient had an inadequate CD34+ cell dose and required bone marrow harvesting which yielded 0.72 x 106/kg CD34+ cells. Engraftment of neutrophils and platelets occured at a median of 11 days post transplant. Infectious complications included febrile neutropenia in one patient following mobilization and in 4 patients following R-BEAM. Transient grade I–II (common toxicity criteria) hepatic enzyme elevation occurred in 2 patients following R-CY. Following R-BEAM, 3 patients developed grade II–IV LFT elevation without evidence of VOD, which resolved in two patients prior to discharge. The patient with grade IV hepatic toxicity had abnormal liver enzymes prior to study and known intrahepatic lymphoma. This patient continues to have grade III elevation of GGT 306 days post transplant with no evidence of infectious hepatitis or lymphoma (PET negative). One patient developed moderate hemorrhagic cystitis. One patient developed bilateral pulmonary infiltrates of unkown etiology (BAL negative for organisms) which resolved. R-CY was well tolerated as a mobilization regimen and led to adequate stem cell collection. R-BEAM HDC resulted in frequent elevations of LFTs. Further studies of rituximab with HDC warrant caution regarding hepatotoxicity.

Factors Associated with Early Termination of CHOP Therapy and the Impact on Survival among Patients with Chemosensitive Intermediate-Grade Non-Hodgkin's Lymphoma

Six to eight cycles of CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) is standard for intermediate-grade non-Hodgkin's lymphoma (NHL) but is associated with toxicity that may cause premature termination of therapy. We studied factors associated with premature termination of CHOP therapy (receiving fewer than 6 cycles) and the relationship of premature termination with survival. Subjects consisted of a population-based sample of Iowa residents with intermediate-grade NHL who were planned to receive > or = 6 or more cycles of CHOP and who were chemosensitive (ie, achieved a documented partial or complete response to CHOP). In a comparison with patients 18-59 years of age, the odds of premature termination of CHOP therapy was 2.6 (95% CI, 0.7-9.2) for those aged 60-74 and 6.2 (95% CI, 1.7-23.3) for those aged > or = 75. Patients with cycle 1 febrile neutropenia hospitalization (FNH) were 4.4 times (95% CI, 1.4-13.8) more likely to terminate CHOP prematurely than those without cycle 1 FNH. Among patients aged 60-74, but not those aged > or = 75, premature termination appeared to be associated with decreased 5-year survival (hazard ratio [HR] = 6.0; 95% CI, 2.4-15.2) compared with those completing CHOP therapy (HR = 2.1; 95% CI, 1.0-4.2). Findings for overall survival were similar. First-cycle FNH and age > or = 60 years were associated with premature termination of CHOP therapy. The association of premature termination with survival among chemosensitive patients differed by age.

First-Line Treatment with Brief-Duration Chemotherapy Plus Rituximab in Elderly Patients with Intermediate-Grade Non-Hodgkin's Lymphoma: Phase II Trial

This study was designed to evaluate the feasibility, toxicity, and efficacy of rituximab added to the VNCOP-B (etoposide/mitoxantrone/cyclophosphamide/ vincristine/prednisone/bleomycin) combination regimen for the treatment of elderly patients with large B-cell lymphoma. Previously untreated patients ≥ 65 years of age with stage II, III, or IV large B-cell non-Hodgkin's lymphoma were treated with a modified VNCOP-B regimen with weekly chemotherapy for 8 weeks. In addition, patients received rituximab 375 mg/m2 intravenously on weeks 1, 2, 3, 4, 6, and 8. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) during the 8 weeks of treatment. Between August 1999 and February 2002, 41 patients entered this multicenter phase II trial. The median age was 74 years, and 54% of patients had high-risk tumors (age-adjusted International Prognostic Index scores of 2 or 3). Sixty-eight percent of patients completed the 8 weeks of therapy. Overall response rate was 66%; actuarial progression-free survival rate at 2 years was 59%, with a 57% actuarial overall 2-year survival rate. Patients ≥ 75 years of age had similar treatment outcomes compared with younger patients. Toxicity with this regimen was predominantly related to chemotherapy; rituximab was well tolerated. Grade 3/4 neutropenia occurred in 83% of patients even with routine use of prophylactic G-CSF or GM-CSF. Treatment-related death occurred in 4 patients (10%). VNCOP-B plus rituximab is efficacious, producing 2-year progression-free survival rates that compare favorably with those of other active regimens in this patient group. Hematologic toxicity was increased compared with previous reports with VNCOP-B alone, as evidenced by the treatment-related mortality rate of 10% in the present study. Differences in toxicity may have been caused by the addition of rituximab, the modified etoposide schedule, or the differences in patient characteristics. This regimen provides a treatment option for elderly patients who are not considered candidates for standard CHOP/rituximab chemotherapy.

The Effect of Intensified Induction Using Vanderbilt Regimen in Patients with an Intermediate Grade Non-Hodgkin's Lymphoma Having 2 or 3 Adverse Factors on the Age-adjusted International Prognostic Index.

The purpose of our study was to evaluate the outcome of intensified induction therapy using the Vanderbilt regimen in patients with a poor prognosis non-Hodgkin's lymphoma (NHL). We retrospectively analyzed the results of two pilot studies, which enrolled the patients aged 60 years or less, with a previously untreated NHL of intermediate grade on the Working formulation, having 2 or 3 adverse prognostic factors on the age- adjusted International Prognostic Index. Patients received an intensified induction, with the regimen described by the Vanderbilt group. Thirty-five patients were analyzed. After induction, 29 patients (83%) achieved more than partial response (PR): 22 (63%) complete response (CR) and 7 (20%) PR. Three of the PRs were subsequently converted to CR following consolidation therapy. The overall CR rate, following the completion of treatment, was 71%. The 3-year overall survival (OS) rate of all patients was 53%. In the univariate analysis, age (<or=50 years vs. >50 years) was the only factor affecting the OS. The 3-year disease-free survival (DFS) rate of patients with CR was 68%. In the univariate analysis, age and bone marrow involvement were the factors affecting the DFS. Two patients died from the treatment-related toxicity of the induction therapy: one due to sepsis and the other due to congestive heart failure. Although the CR rate was relatively high, the OS or DFS of patients with a poor prognosis NHL, who had received the intensified induction using the Vanderbilt regimen, were no different from those that had received the conventional chemotherapy, as reported by the International Prognostic Index Project. However, the OS or DFS in the young patient groups were encouraging. To test the hypothesized benefits of our approach in the young patient groups, a larger cohort of patients aged 50 years or less should be studied.

Phase II Study of Sequential Topotecan and Etoposide in Patients with Intermediate Grade Non-Hodgkin's Lymphoma: A National Cancer Institute of Canada Clinical Trials Group Study

Preliminary results indicate that inhibitors of the nuclear enzyme topoisomerase (topo) I, such as topotecan, may be active in non-Hodgkin's lymphoma (NHL). Pre-clinical studies have shown sequential administration of a topo I and II inhibitor has supra-additive anti-tumor effects in some model systems, and that greater cytotoxicity occurs if the topo I inhibitor is given first. We enrolled 22 eligible patients with relapsed or refractory intermediate grade NHL in a phase II study of sequential administration of topotecan 1.25 mg/m 2 days 1-5 and etoposide 50 mg po b.i.d. days 6-12, every 28 days without G-CSF. Most patients had diffuse large B-cell lymphoma and all had received only one prior regimen (CHOP, 20 patients, or equivalent, 2 patients). Patients with stable or responding disease were allowed to proceed to high-dose therapy and autologous stem-cell transplant after 2 cycles of therapy. The 22 patients received a total of 62 cycles of topotecan+etoposide (median 2, range 1-6), and 4/22 completed all six planned cycles. Hematologic toxicity was significant and resulted in incomplete etoposide dosing in half of all cycles in 16/22 patients. Nineteen of twenty-two patients had grade 3/4 neutropenia, 12 had grade 3/4 thrombocytopenia, and 6 grade 3/4 anemia. Eleven patients had at least one episode of febrile neutropenia or had documented infection. Non-hematologic toxicity was mild. Four patients had a partial response (PR) (18.2%), nine had stable disease and seven progressed; three patients with stable disease went on to ABMT. The combination of topotecan and etoposide as given in this study has modest activity in relapsed/refractory aggressive histology NHL, and produces marked myelosuppression. Other doses and schedules combining topo I and II inhibitors, or topo I inhibitors with alkylating agents, should be explored with the addition of hematopoietic growth factors in this patient population.

Intrathecal Chemotherapy alone is Inadequate Central Nervous System Prophylaxis in Patients with Intermediate-grade Non-Hodgkin's Lymphoma

Central nervous system (CNS) relapse of non-Hodgkin's lymphoma (NHL) is usually fatal despite therapy and effective prophylaxis is desirable. Patients at high-risk usually receive intrathecal (IT) prophylaxis, although its efficacy is unproven. We therefore analyzed the outcome of all patients with newly diagnosed "intermediate-grade" NHL receiving IT prophylaxis from 1991 to 1999. Twenty-six patients were identified and analyzed. All were free of CNS involvement at diagnosis with negative cerebrospinal fluid (CSF) cytology. Disease stage was IE in 7, and IV in 19, with a median of two extranodal sites involved. Serum lactate dehydrogenase was elevated in 65%, and the median International Prognostic Factors Index score was 3 (range 0-5). Anthracycline-based chemotherapy was used in all cases and included high-dose methotrexate ± ara-C in six patients. The median number of IT treatments was 5 (range 1-12) and comprised methotrexate ± steroid in 15, together with ara-C in 11. The actuarial 3-year CNS-relapse rate was 26 ± 10%. Six CNS-relapses were observed and involved the spinal cord or brain parenchyma in two cases each, and the leptomeninges in four patients. Treatment-related variables associated with higher CNS-relapse rates (34-50%) were: delay of ≥ 14 days from diagnosis to first IT injection, <5 IT treatments, delay of IT prophylaxis until after attaining CR and systemic treatment lacking high-dose methotrexate ± ara-C (each P ≤ 0.17). IT CNS prophylaxis, as used here, was inadequate. Alternative approaches should be pursued.

Alternation of Epirubicin and Mitoxantrone in CHOP-like Regimens Retains Efficacy and Reduces Overall Toxicity in Elderly Patients with High and Intermediate Grade Non-Hodgkin Lymphomas

Mitoxantrone and Epirubicin are active agents in non-Hodgkin's lymphomas (NHL). These drugs have reduced cardiotoxicity and therefore are indicated in treatment of elderly patients. Cyclophosphamide, mitoxantrone, vincristine and methylprednisone (CNOP) and cyclophosphamide, epirubicin, vincristine and methylprednisone (CEOP) are combination chemotherapy and contain Mitoxantrone and Epirubicin that have been shown to be effective in treatment of NHL of intermediate and high grade of malignancy in the elderly. Since Mitoxantrone and Epirubicin are partially non-cross resistant their combined use may diminish emergence of resistant neoplastic clones and may be associated with enhanced anti-neoplastic activity. In this study, a polychemotherapy schedule alternating 3 cycles of CEOP and 3 cycles of CNOP, was used in a single center between December 1988 and April 1995 to treat 41 previously untreated patients, over 60 years of age affected by intermediate or high grade non-Hodgkin's lymphoma according to the Working Formulation. In treated patients, 57.5% achieved complete response, 35% partial response and 7.5% were non-responders. Overall survival was 52.4 % at 4 years, Disease free survival (DFS) for complete responders was 48.9%. Only one case of severe extrahematological toxicity (grade 3-4 WHO) was observed. Severe mucositis (grade 3-4 WHO) was absent, and delayed administration of chemotherapy was required in only 7/230 cycles. No treatment related deaths were registered. This regimen achieved results comparable to that of other anthracycline or mitoxantrone based chemotherapy, but determined lower toxicity. Alternating CEOP and CNOP may improve overall toxicity.

The Impact of Age on Delivered Dose Intensity and Hospitalizations for Febrile Neutropenia in Patients with Intermediate-Grade Non-Hodgkin's Lymphoma Receiving Initial CHOP Chemotherapy: A Risk Factor Analysis

The purpose of this historical case series study was to evaluate the association of age on delivered dose intensity of initial CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy and the occurrence of hospitalizations for febrile neutropenia for patients with intermediate-grade non-Hodgkin's lymphoma (NHL). Findings are reported for 12 managed community and academic practices. Medical records of 930 NHL patients not enrolled on clinical trial protocols were reviewed. We reported on 577 of the study patients (62%) who received initial CHOP chemotherapy. Median age of the patients was 65.1 years. Older patients (age ≤ 65 years) had more hospitalizations for febrile neutropenia (28% vs. 16%; P < 0.05) than younger patients (age, 18-64 years). In patients with advanced-stage NHL (stage III/IV), older patients received fewer cycles of CHOP (< 6 cycles, 35% vs. 22%; P < 0.05) than younger patients. Older patients were planned for lower average relative dose intensity (ARDI = 80%; P < 0.05) and had more heart disease and comorbid conditions (P < 0.05) than younger patients. Multiple logistic regression models showed that older patients were more likely to receive a lower dose intensity (ARDI ≥ 80%; odds ratio = 2.46, 95% confidence interval [CI]: 1.62-3.72) during their first 3 cycles of therapy and to experience more hospitalizations for febrile neutropenia (odds ratio = 2.17, 95% CI: 1.43-3.30). We found the dose intensity of delivered CHOP chemotherapy for elderly patients to be less than standard CHOP therapy and the risk of hospitalizations for febrile neutropenia to be greater than in younger patients. Prospective clinical trials examining supportive care measures, such as colony-stimulating factor, for elderly NHL patients are recommended.

Progressive Intermediate-Grade Non-Hodgkin's Lymphoma After High-Dose Therapy and Autologous Peripheral Stem-Cell Transplantation: Changing the Natural History with Monoclonal Antibody Therapy

The prognosis of patients with progressive intermediate-grade non-Hodgkin's lymphoma (NHL) after high-dose chemotherapy and autologous peripheral stem-cell transplantation (PSCT) is poor, with survival measured in months. The advent of monoclonal antibody therapy for NHL has created new options for effective therapy with relatively mild side effects. We report on two patients with progressive intermediate-grade NHL after PSCT who were treated with monoclonal antibody therapy. Both patients initially received rituximab (unlabeled anti-CD20 monoclonal antibody) and were subsequently treated with 90Y-epratuzumab (yttrium-90—labeled humanized anti- CD22 monoclonal antibody) at relapse. One patient received 90Y-epratuzumab alone while the other was treated with higher doses in combination with autologous peripheral stem-cell infusion. Both patients achieved a rapid response to the radiolabeled antibody with minimal toxicity. Monoclonal antibody therapy may be an effective and tolerable treatment for progressive NHL after PSCT.

A Multicenter Early Phase II Study of High-dose Chemotherapy with Autologous Peripheral Blood Stem Cell Transplantation for Treatment of Intermediate-grade Non-Hodgkin's Lymphoma

A Multicenter Early Phase II Study of High-dose Chemotherapy with Autologous Peripheral Blood Stem Cell Transplantation for Treatment of Intermediate-grade Non-Hodgkin's Lymphoma

Genomic DNA Amplification and the Detection of t(2;5)(p23;q35) in Lymphoid Neoplasms

Anaplastic large cell lymphoma (ALCL) is an intermediate grade Non-Hodgkin's lymphoma (NHL) characterized by the frequent presence of the t(2;5)(p23;q35). This translocation fuses the nucleophosmin (NPM) gene on chromosome 5q35 to a protein kinase gene (Anaplastic Lymphoma Kinase, ALK) on chromosome 2p23. In order to determine the frequency of t(2;5) we used a DNA polymerase chain reaction (PCR) amplification using genomic DNA, 5′-primers derived from the NPM gene, and 3′-primers derived from the ALK gene. The presence of amplifiable DNA in the samples was established with PCR and oligonucleotide primers designed to amplify a 3,016 bp fragment from the β-globin locus. The t(2;5) PCR assay was established using DNA isolated from three t(2;5)-positive ALCL cell lines. Its ability to amplify genomic DNA prepared for routine molecular diagnostic use was validated using archival DNA from four ALCL tumors known to be t(2;5)-positive. Its sensitivity was established by serially diluting t(2;5)-positive DNA in normal DNA: amplicons were generated in 100% of reactions diluted 104-fold (6–8 cells per tube) and in 30% of those diluted 105-fold (0.6–0.8 cells per tube.) We subsequently analyzed archival genomic DNA extracted from 38 ALCL, 77 NHLs, 37 Hodgkin's lymphomas, and 9 lymphomatoid papuloses. The t(2;5) was detected in 6 ALCLs (16%, 95% confidence intervals 6%-31%), but not in any other lymphoma, or in lymphomatoid papulosis. By using the published sequence of the fourth NPM intron that is involved in t(2;5) and by sequencing the individual tumor amplicons and also the normal ALK intron that is involved in t(2;5), we established that all breakpoints involve the same introns in the ALK and NPM loci. Detailed analysis demonstrated that each translocation generates a unique breakpoint sequence, and suggested that sequence homology between the ALK and NPM intron sequences may be involved in the translocation. We conclude that genomic DNA-PCR is useful for the detection of t(2;5) that in our patient population is restricted to ALCL and is not detectable in other NHL, Hodgkin's disease, or lymphomatoid papulosis. More work is needed to determine the prognostic significance of t(2;5), and to establish the utility of the genomic DNA PCR in monitoring minimal residual disease.