Progressive non-Hodgkin's Lymphoma Research Articles

Modified EPOCH for high-risk non-Hodgkin lymphoma in sub-Saharan Africa.

Aggressive non‐Hodgkin lymphoma (NHL) is among the most common cancers in sub‐Saharan Africa (SSA), where CHOP is standard treatment and outcomes are poor. To address this, we treated 17 newly diagnosed adult patients in Malawi with Burkitt (n = 8), plasmablastic (n = 8), and primary effusion lymphoma (n = 1) with a modified EPOCH regimen between 2016 and 2019. Twelve patients (71%) were male and the median age was 40 years (range 16‐63). Eleven (65%) were HIV infected, median CD4 count was 218 cells/µL (range 9‐460), and nine (82%) had suppressed HIV RNA < 400 copies/mL. Patients received a median of six cycles (range 2‐8) and median follow‐up was 14 months (range 2‐34) among patients still alive. Grade 3/4 neutropenia was observed in 26% of cycles and in 65% of patients. Sixteen (94%) responded to EPOCH and 10 (59%) achieved a complete response. One‐year overall survival (OS) was 62% (95% confidence interval [CI], 42%‐91%). Five patients (29%) died from progressive NHL and three (18%) from treatment‐related complications. These data suggest EPOCH with setting‐appropriate modifications may be a practical, safe, and effective option for improving high‐risk NHL outcomes in Malawi and comparable settings, which deserves further prospective evaluation.

Phase 2 Trial of Alisertib (MLN8237), An Investigational, Potent Inhibitor of Aurora A Kinase (AAK), in Patients (pts) with Aggressive B- and T-Cell Non-Hodgkin Lymphoma (NHL)

Abstract 95 Background:Aurora kinases are a family of oncogenic serine-threonine kinases that regulate multiple phases of the mitotic signaling cascade. Inhibition of aurora A kinase (AAK) leads to mitotic errors, followed by aneuploidy, apoptosis, and senescence. Investigational drug alisertib is an ATP-competitive, orally available inhibitor of AAK, that has been evaluated for safety and efficacy in Phase I hematological malignancies. We conducted the first phase II multicenter trial of alisertib in adult patients with aggressive B- and T- cell NHL. Methods: Eligible patients had normal organ function, ANC ≥1250/mm3, platelets ≥ 75,000/mm3 and no prior allogeneic transplant. Patients were treated with alisertib at a dose of 50mg twice daily for 7 days on 21 day cycles until either documented progression or unacceptable treatment-related toxicity. Using fluorescent in situ hybridization (FISH), gene amplification was assessed in archived tumors by a dual assay measuring AAK copy number on chromosome 20q13 as well as the ratio to a control probe located on chromosome 20q11. Immunohistochemistry (IHC) was performed on archived paraffin embedded diagnostic tissue using a dual assay measuring the protein levels of total AAK and that of phospho histone H3. PK sampling was performed with inclusion of steady-state trough plasma PK samples on the morning of Cycle 1 Day 8. Results: 48 pts were enrolled, including 41 response-evaluable. Histologies included DLBCL (n=21, 44%), mantle cell (MCL; n=13, 27%), peripheral T- cell (n=8, 17%), transformed follicular (n=5, 10%) and Burkitt (n=1, 2%). Median age was 68 y (range 32–85). Pts received median 3 prior regimens (range 1–11); 11 pts received prior ASCT. Most common Grade 3/4 adverse events were neutropenia (63%), thrombocytopenia (31%), stomatitis (15%), febrile neutropenia (13%) and fatigue (6%). Four deaths on study were attributed to progressive NHL (2), treatment-related sepsis (1), and unknown cause (1). 11 pts discontinued and 24 reduced dose due to adverse events (AEs). Evaluation of steady state trough concentration of alisertib (N=25) revealed that PK variability was consistent with that observed in other trials with alisertib, and there was a trend toward higher levels in patients who required AE-related dose reductions compared to those who did not (geometric mean 2375 nM [n=10, CV: 54%] vs. 1504 nM [n=15, CV: 35%]). FISH analysis for AAK gene amplification did not reveal differences between histologies (N=31). When total AAK protein was evaluated by immunohistochemistry (N=32), marked variability in both proportion of expression as well as intensity was observed both between and within histologies; there was no correlation of AAK protein expression and clinical response. The overall response rate (ORR) was 32% (95% CI 0.181–0.481); response by histology: DLBCL 20%; MCL 23% and T- cell NHL 57%. Conclusion: Current data suggests that alisertib is generally well-tolerated, with responses observed in heavily pretreated patients with aggressive NHL, including patients after ASCT. Emerging data supports single agent activity in several histologies, with proportionally more responses observed in relapsed/refractory T-cell NHL. Some patients have now been treated for up to two years with this agent, and the generally manageable toxicity profile suggests an opportunity to combine this drug with other agents. IHC of aggressive lymphoma histologies suggests heterogeneity in AAK protein expression and intensity. The geometric mean of alisertib steady-state trough concentration was 1.8 μM (CV= 47%, N = 25), which was above the 1 μM steady-state plasma concentrations associated with saturating levels of pharmacodynamics and antitumor activity in preclinical xenograft models. The observed trend for association between trough concentration of alisertib and AEs supports the dose modification scheme implemented in this trial. Based upon these results, planned future trials include a single-agent study in T-cell NHL, and a combination study exploring alisertib with rituximab and vincristine in aggressive B-cell NHL. Disclosures:Friedberg:Genentech: Consultancy; astellas:; Lilly:; Abbott/Trubion:; Seattle Genetics: Honoraria; Cephalon: Consultancy. Off Label Use: novel agents for relapsed DLBCL. Jung:Millennium: Employment. Danaee:Millennium Pharmaceuticals Inc.: Employment. Zhou:millennium: Employment. Leonard:millennium: Employment.

Reactivation of an occult hepatitis B virus escape mutant in an anti-HBs positive, anti-HBc negative lymphoma patient

Background Hepatitis B virus (HBV) often persists after resolution, but its replication is suppressed by antiviral T cells. Immunosuppressive treatment may lead to viral reactivation and severe hepatitis. Early antiviral therapy prevents reactivation but some occult HBV infections are not easily detectable. Results Here we describe a patient with a progressive non-Hodgkin lymphoma who had probably not been vaccinated against HBV and, before immunosuppression, showed antibodies (anti-HBs) against the viral surface antigen (HBsAg) as the only possible marker of occult HBV infection. Under immunosuppression he developed viremia (>10 8 copies/mL). The virus exhibited three S gene mutations (L109R, C137W, G145R) which led to false negative HBsAg results and diminished binding of vaccine-induced anti-HBs. Conclusions Reliable screening and monitoring of severely immunosuppressed patients for HBV should include, in addition to anti-HBc and HBsAg, anti-HBs and sensitive HBV DNA assays. Furthermore, active vaccination or hepatitis B immune globulin may not protect against such mutants.

A Phase II Trial of 90Y-Ibritumomab Tiuxetan-Based Reduced Intensity Allogeneic Peripheral Blood Stem Cell (PBSC) Transplantation for Relapsed CD20+ B-Cell Non-Hodgkins Lymphoma (NHL).

Reduced intensity allogeneic transplantation offers a potentially curative option to NHL patients with chemorefractory disease or relapse following autologous transplant. The efficacy of this approach relies on the development of a graft-vs-lymphoma (GVL) effect by establishment of donor chimerism. GVL, however, is most effective for NHL in settings of stable, chemoresponsive, and non-bulky disease. Anti-CD20 radioimmunotherapy (RIT) has been shown to be safe and effective in the treatment of B-NHL. This phase II clinical trial was designed to evaluate the safety and efficacy of administering 90Y-Ibritumomab Tiuxetan (Zevalin, Biogen-Idec) as part of reduced intensity allogeneic stem cell transplantation in order to safely provide disease control prior to the establishment of a GVL-effect that could maintain the remissions. Fourteen patients with relapsed or refractory CD20+ NHL and evaluable disease, who had too high-risk lymphoma for a routine non-ablative transplant and were not eligible for a traditional myeloablative transplant were treated with 0.4 mCi/kg 90Y-Ibritumomab Tiuxetan (maximum 32 mCi) on day −14, followed by fludarabine (30mg/m2 on days −7 to −5), 2 Gy TBI on day 0, and HLA-matched related (n=8) or unrelated (n=6) allogeneic PBSC transplantation. Cyclosporine and mycophenolate mofetil were employed for graft-vs-host disease (GVHD) prophylaxis. Patient characteristics included: median age=57y (range 33–69y), median # of prior regimens=6 (range 3–12), prior autologous transplant=5 (36%), chemoresistant=100%, median tumor bulk=3.7cm, elevated LDH=5 (36%), baseline cytopenia (ANC<1000, plts<100K)=7 (57%), and >25% marrow involvement with NHL=5 (ranging from 30–85% NHL involvement). Histologies included: mantle cell=5, diffuse large B-cell=4, follicular=3, small lymphocytic=1, hairy cell=1. There have been no non-relapse-related deaths in the first 100 days, no graft rejections or failures, and all patients achieved >80% donor CD3/CD33 chimerism by 28 days after transplant. No patients developed ≥ grade 3 acute GVHD, though 7 experienced grade 2 GVHD. Three patients died following progressive NHL and 2 died after day 100 from GVHD and infection-related complications. The median platelet and neutrophil nadirs were 9×103/μL and 50/μL, respectively. Responses to date include 3 complete responses (CR), and 4 partial responses (PR), including 1 CR, 6 PR, 3 stable disease by 1 month after transplant. With a median follow up of surviving patients of 6 months (range <1–18 months), 9/14 (64%) are alive and 7/14 (50%) are alive and progression-free. This study shows that standard-dose 90Y-Ibritumomab Tiuxetan can safely be delivered as part of reduced intensity allogeneic transplantation regardless of preexisting bone marrow involvement and cytopenias. One-month response data suggest that this strategy may also prove useful in early post-transplant disease control, though the ultimate impact on long-term disease-free survival remains to be determined.

Results of a Phase II Study of Pixantrone in Combination with Cyclophosphamide, Vincristine, and Prednisone in Patients with Relapsed Aggressive Non-Hodgkin's Lymphoma.

Background: Pixantrone is a novel aza-anthracenedione with less cardiotoxicity and superior activity compared to doxorubicin and mitoxantrone in murine leukemia and lymphoma tumor models. Pixantrone as single agent therapy led to major responses in patients (pts) with multiply relapsed aggressive non-Hodgkin's lymphoma (NHL), including diffuse large B-cell lymphoma (DLCL). In a phase I dose-ranging study of pixantrone (80 to 180 mg/m2) replacing doxorubicin (CPOP) in a CHOP-like regimen, the optimal dose (RD) from that study was found to be 150 mg/m2.Methods: In this international, multi-center, phase II study the primary objective was to assess the efficacy and safety of the CPOP regimen (cyclophosphamide 750 mg/m2d1, pixantrone 150 mg/m2d1, vincristine 1.4 mg/m2 d1, limited to 2 mg, and prednisone 100mg d1 to 5) in pts with relapsed DLCL, transformed follicular lymphoma (tFL) and mantle cell lymphoma (MCL) for a total of 6 cycles, given every 3 weeks. Response was assessed according to the standardized response criteria for NHL. Hematopoietic growth factors were not permitted for the first cycle and were used thereafter according to the ASCO guidelines. Main eligibility criteria included at least one but not more than two previous chemotherapy lines containing an anthracycline/anthracenedione with a cumulative dose of less than 450 mg/m2doxorubicin equivalent, a left ventricular ejection fraction (LVEF) > 50%, absence of CNS lymphoma, and negative HIV serology.Results: Thirty pts were included in this phase II study and are available for efficacy and safety assessment. Main baseline characteristics were: median age, 66 y (range 26–76); median baseline International Prognostic Index (IPI), 2 (11/30 pts had IPI 3 or 4); median number of previous therapy lines, 2 (1–7); median time since last chemotherapy, 14 months (1–202). Median number of cycles of study drug received was 6 (1–6). The overall response rate (ORR) was 73%, with 14 (47%) pts achieving complete response (CR/CRu) and 8 (26%) pts with partial responses (PR). For responses lasting at least 8 weeks (63%), the median duration of response was 10.3 months (range 2.5 to 27). The most common severe toxicities were gr 3/4 neutropenia, 29 (97%) pts; gr 3 febrile neutropenia, 6 (20%); gr 3 anemia, 9 (30%); gr 3/4 thrombocytopenia, 6 (20%); gr 3/4 infections, 5 (17%). Four pts had a decrease in LVEF >10% and ≤20% as determined by MUGA-scan. One of these patients developed symptomatic right heart failure classified by the investigator as related to progressive NHL. Two pts experienced transient LVEF decline > 20% during long-term follow up.Conclusions: The CPOP combination therapy with 150 mg/m2 pixantrone results in a high ORR (73%) with 47% CRs. Furthermore, it exhibits an acceptable toxicity profile and can be administered safely in an outpatient setting even in this cohort of elderly, anthracycline-pretreated patients. Based on these results, a randomized Phase II study comparing CPOP-rituximab with CHOP-rituximab in patients with untreated diffuse large-B-cell NHL has been initiated.

Antilymphoma Treatments Given Subsequent to Yttrium 90 Ibritumomab Tiuxetan Are Feasible in Patients with Progressive Non-Hodgkin's Lymphoma: A Review of the Literature

Yttrium 90–labeled ibritumomab tiuxetan is approved for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL). To date, the efficacy of repeated courses of radioimmunoconjugate treatment in patients whose disease has progressed has not been studied as a formal endpoint in a clinical trial setting. However, several clinical studies have been conducted in patients with progressive NHL who had previously received 90Y ibritumomab tiuxetan. A retrospective review of these studies has shown that clinical responses have been achieved with all types of subsequent treatment with no apparent impact on their efficacy. In addition, no significant differences in toxicities with subsequent therapies have been observed between patients who had previously received 90Y ibritumomab tiuxetan therapy and those who had not. These findings suggest that patients previously treated with 90Y ibritumomab tiuxetan can feasibly undergo other forms of treatment for progressive NHL, and that a clinical response to further treatment options is not precluded by administration of 90Y ibritumomab tiuxetan.

Comparison of the Sequential High-Dose Chemotherapy Followed by Autologous Stem Cell Support with and without Rituximab in Relapsed and Refractory Aggressive Non-Hodgkin's Lymphoma.

Introduction: Combination chemotherapy can cure patients (pts) with Non-Hodgkin's lymphoma (NHL), but those with relapse still have a poor prognosis. High-dose chemotherapy (HDCT) with autologous stem cell support (ASCT) can improve the outcome of these pts. Rituximab demonstrated encouraging activity in aggressive NHL and showed low toxicity in the setting of combined immunochemotherapy. To investigate the influence of addition of rituximab to the intensified salvage program followed by a final myeloablative course with stem cell reinfusion we compared the group of patients treated with this program - immuntherapy group (IT) with the standard therapy group (ST) of patients treated with the same program without rituximab.Patients and methods: Eligibility criteria for both groups were as follows: age 18–67 years, eligibility for HDCT, histologically proven CD20+ relapsed or progressive NHL. Treatment program starts with two cycles DHAP (dexamethasone, cytarabine, cisplatin); pts with PR or CR receive cyclophosphamide (4g/m2) followed by PBSC harvest; methotrexate 8g/m2 and vincristine 1,4mg/m2; and etoposide 2g/m2. The final myeloablative course is BEAM followed by ASCT. Pts in IT received additionally rituximab (375mg/m²) to the each chemotherapy cycle.Results: In the immuntherapy and standard therapy group were enrolled 23 and 57 pts, respectively. There were 18 (78%) IT and 34 (60%) ST pts with relapsed and 5 (22%) IT and 23 (40%) ST pts with refractory disease. The majority of pts in both groups received CHOP-like regimens as first line treatment (91% IT vs. 79% ST). The response rate at the final evaluation for all patients was in IT 61% (52% CR and 9% PR) and in ST 43% (32% CR and 11% PR). The overall response rate (OR) for patients who responded to 2 cycles DHAP was in IT 83% (71% CR and 12% PR) and in ST 59% (44% CR and 15% PR). The therapy toxicity was tolerable and comparable in both groups.Conclusion: The preliminary results suggest better therapy outcome in patient with sequential high-dose chemotherapy with rituximab compared to pts treated with the same therapy regimen without additional antibody. The combination regimen allows effective mobilization of stem cells. The tolerability of the final myeloablative BEAM was in both groups not affected by rapid sequential administration of DHAP and high doses of cyclophosphamide, methotrexate, etoposide and rituximab. The toxicity was tolerable in both groups. The full results of match pair and multivariate analysis as well as OS and FF2F will be presented.

Immunotherapy and Chemotherapy Can Result in Long-Term Survival for Patients with Recurrent or Progressive Non-Hodgkin's Lymphoma after Reduced-Intensity Allogeneic Stem Cell Transplantation.

Reduced-intensity allogeneic stem cell transplantation (RIST) has been demonstrated to clinically benefit patients (pts) with relapsed, chemotherapy-sensitive non-Hodgkin's lymphoma (NHL). The most significant challenge after RIST is treatment of recurrent or progressive disease, and the subsequent outcomes of NHL pts, who either have progressed or relapsed after RIST, have not been previously reported. To address this question we performed a retrospective analysis on 35 pts who had undergone RIST from HLA-matched siblings for refractory/relapsed NHL (excluding CLL/SLL). Outcomes were analyzed from Day +100 on, as all pts had achieved complete donor chimerism by this time point and this was a scheduled time of disease assessment as per protocol. All pts had received the identical reduced-intensity conditioning regimen consisting of fludarabine and cyclophosphamide and had received cyclosporine (CSA)-based GVHD prophylaxis. For pts with recurrent or progressive NHL, we employed a sequential approach of CSA withdrawal, followed by rituximab (ritux), followed by donor lymphocyte infusion (DLI), and then followed by chemotherapy +/− DLI; specific treatment was dependent upon the presence or absence of GVHD and CD20 expression. At Day +100 post-RIST 23/35 pts were in a complete remission (CR) of which 4 (DLC = 2, FCC = 1, MCL = 1) were subsequently observed to relapse. The disease status at Day +100 among the remaining 12 pts (DLC = 10, FCC = 1, PTCL =1) not in CR at Day +100 post-RIST was partial remission (PR) = 2, stable disease (SD) = 1, and progressive disease (PD) = 9, as compared to pre-RIST evaluation. Among the 4 pts who relapsed after an initial CR post-RIST, 3 had CSA withdrawn, 1 received ritux, 3 received DLI, and 2 received chemotherapy + ritux. There subsequently were 3 CR and 1 PR. CR were maintained 12, 24+, and 26+ months after intervention. Three of these 4 pts are alive, and the 12 month probability of survival beyond Day +100 post-RIST was 75%. Among the 12 pts who were not in CR at Day +100 post-RIST, all 12 subsequently had CSA withdrawn, 7 received ritux, 5 received chemotherapy, and 3 received DLI. For the 2 pts in PR at Day +100 both achieved a CR by 6 months post-RIST. The one SD patient achieved a PR and died +11 months post-RIST. Among the 9 pts with PD at Day +100, 2 achieved CR, which have been maintained for 22+ and 4+ months, respectively. The 12 month probability of survival beyond Day +100 post-RIST for the 12 pts not in CR at Day +100 was 44%. The 12 month probability of survival beyond Day +100 post-RIST for all 16 pts was 52%. These data demonstrate that relapse after achievement of CR post-RIST is low, and that the majority of these patients can achieve sustained survival with post-transplant therapies. For NHL pts who do not initially achieve a CR at Day +100 post-RIST, subsequent outcome appears to correlate with disease status at Day +100; however, sustained, complete remissions could be achieved for a minority of patients with progressive disease post-RIST. These data indicate that further immunotherapy and additional chemotherapy can result in significant long-term survival for NHL pts with recurrent or progressive disease post-RIST.

The effect of optimal treatment on elderly patients with aggressive non-Hodgkin's lymphoma: more patients treated with unaffected response rates.

A substantial part of elderly patients (with good performance) with intermediate or high-grade non-Hodgkin's lymphoma (NHL) are not treated with the standard chemotherapy of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). If NHL patients are not treated with CHOP, the outcome is inferior. By adding granulocyte colony-stimulating factor (G-CSF) to CHOP chemotherapy, we aimed at treating more patients with less toxicity. We performed a multicenter population-based study (in the southeast of the Netherlands) in which elderly patients (> or = 60 years) with intermediate or high-grade stage > or = IIB NHL were treated with CHOP chemotherapy and growth factor G-CSF to increase the number of patients treated according to standard protocols. We also evaluated elderly NHL patients who were not treated with CHOP chemotherapy. Adequate therapy was defined as > or = six cycles or a total of five cycles when complete remission was achieved after three cycles. Seventy-nine NHL patients fulfilled the selection criteria. The patients were treated with CHOP plus G-CSF (n=46), CHOP (n=19), cyclophosphamide, vincristine, and prednisone (COP) (n=2), chlorambucil and prednisone (n=2), or prednisone (n=1). Nine patients were not treated with chemotherapy. The median age was 72 years (60-87). Of the 79 NHL patients, 65 were treated with CHOP chemotherapy (82%); 38 of 65 patients (59%) were adequately treated. The complete remission rate in the NHL group treated with CHOP was 65% (42 of 65 patients). The overall 3-year survival was 50%. Most of the patients died from progressive NHL (53% in the CHOP and 77% in the group not treated with CHOP). The treatment-related mortality was 15% in the CHOP group. The most important reason for not treating patients with CHOP (with or without G-CSF) was poor performance (WHO > or = 2). A significant subset of patients can be treated with CHOP chemotherapy with acceptable toxicity. The combination of CHOP plus G-CSF increased the absolute number of treatable elderly patients, resulting in more (absolute) patients with complete remission and overall survival compared to our previous study.

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.

Treatment of primary progressive Hodgkin's and aggressive non-Hodgkin's lymphoma: is there a chance for cure?

To determine differences in prognosis between primary progressive Hodgkin's disease (HD) and aggressive non-Hodgkin's lymphoma (NHL), we retrospectively analyzed patients with progressive lymphoma who were treated with different salvage chemotherapy regimens including high-dose chemotherapy (HDCT) followed by autologous stem-cell support (ASCT). One hundred thirty-one patients with primary progressive lymphoma (HD, n = 67; NHL, n = 64) were enrolled. Primary progressive disease was defined as disease progression during first-line chemotherapy or only transient response (complete or partial response lasting </= 90 days) after induction treatment. Patients 60 years or younger with progressive lymphoma were eligible to receive HDCT with ASCT. The overall response rate after salvage chemotherapy for patients with primary progressive HD and NHL was 33% and 15%, respectively. Twenty-five HD patients (37%) received HDCT. Most patients with NHL had progressive disease under salvage treatment, with only six patients (10%) receiving HDCT. Of those, only two patients were alive and in continuous complete remission 3 and 12 months after HDCT. No patient with NHL survived longer than 26 months after first diagnosis. Actuarial OS after 5 years was 19% for all HD patients; 53% for HD patients receiving HDCT, and 0% for patients who did not receive HDCT. In HD patients, multivariate regression analysis identified chemosensitive disease on salvage treatment (P =.0001) and HDCT (P =.031) as significant prognostic factors for freedom from treatment failure. Significant prognostic factors for OS are chemosensitive disease (P =.0005), HDCT (P =.039), and B symptoms at the time of progress (P =.046). There are striking differences in the prognosis of patients with progressive HD and aggressive NHL. The prognosis of progressive NHL patients is dismal. Most patients have rapidly progressive disease after salvage treatment and are, therefore, excluded from HDCT programs. In contrast, progressive HD patients can achieve long-term survival after HDCT.

Long term follow-up and late complications of 2-chlorodeoxyadenosine in previously treated, advanced, indolent non-hodgkin's lymphoma

The aim of this study was to determine the long term outcome and toxicities after the administration of 2-chlorodeoxyadenosine (2-CdA) to patients with previously treated, advanced, indolent non-Hodgkin's lymphoma (NHL). Twenty-two patients (median age, 55 years) with relapsed or refractory low grade NHL (median disease duration, 2.8 years) were treated with 2-CdA by continuous infusion at 0.1 mg/kg/day over 5 or 7 days every 28 days, for a maximum of 6 cycles. The overall response rate was 45%. Two patients (9%) achieved a complete response (CR), 8 patients (36%) achieved a partial response, and 12 patients (55%) had no response. The two patients achieving CR have remained in CR for 46 and 38 months, respectively. Freedom from treatment failure at 24 months was 32%. Overall survival at 24 months was 59%. Three patients developed second malignancies: acute myelogenous leukemia (AML), myelodysplastic syndrome, and a cutaneous lymphoproliferative disorder. Fourteen patients have died after a median follow-up of 28 months (range, 3.9-49.2 months) due to progressive NHL (11 patients), infection (2 patients), and AML (1 patient). 2-CdA is an active agent for patients with previously treated, advanced, indolent NHL and may result in lasting remissions. Late complications following treatment may include delayed bacterial, fungal, or viral infection. Determination of whether the second malignancies that occurred in three patients reported herein were related to treatment with 2-CdA will require further study.

Adrenal Insufficiency as a Manifestation of Disseminated Non-Hodgkin's Lymphoma

To analyze the clinical characteristics, laboratory features, and outcome in five patients who had biochemically proven adrenal insufficiency attributable to pathologically confirmed non-Hodgkin's lymphoma (NHL). We retrospectively reviewed the medical records of all patients at Mayo Clinic Rochester during the period from 1976 to 1994 to identify those with both NHL, as listed in the surgical pathology tissue registry, and adrenal insufficiency. Histologically, the patients were classified on the basis of the working formulation and the revised European-American lymphoma classification. Three patients had diffuse large cell NHL, one patient had small noncleaved NHL, and one patient had cutaneous T-cell NHL. All five patients had stage IV disease. Adrenal insufficiency was confirmed by morning and evening determinations of serum cortisol levels and cosyntropin stimulation tests. All patients demonstrated loss of circadian rhythm. The median age of the patients was 77 years (range, 60 to 89). Three of the five patients died without treatment from 5 to 22 days after assessment. One patient died of a cerebrovascular accident. Despite initiation of chemotherapy, two patients died of progressive NHL at 7 weeks and 7 months. In our experience, biochemically proven adrenal insufficiency in patients with NHL is a manifestation of clinically advanced disease in elderly patients. A stepwise diagnostic approach is critical for the appropriate management of such patients.

The Treatment of Progressive Non-Hodgkin's Lymphoma With Intensive Chemoradiotherapy and Autologous Marrow Transplantation

Intensive chemoradiotherapy, with or without additional local radiotherapy, and unpurged autologous marrow transplantation was given to 68 patients with progressive non-Hodgkin's lymphoma. Responses were attained in 44 patients (65%, 95% confidence intervals [CI], 52% to 76%), including 37 who achieved complete responses. Fifteen patients (22%, 95% C.I. 13% to 34%) remain free of disease (including 11 continuously) at a median of 5.3 (range 3.1 to 9.1) years later. Higher Karnofsky scores (P less than .01, Mann-Whitney U test) and the absence of a history of prior radiotherapy (P = .02, chi 2 test) were associated with achievement of complete plus partial responses. Higher Karnofsky scores (P less than .01, Mann-Whitney U test) and less resistant disease status at transplantation (P = .04, chi 2 test) were significant when calculations were limited to complete responses. Karnofsky scores were also associated with the probability of freedom from progression (P = .02, log-rank) for responding patients. Also, Karnofsky scores and the absence of prior radiotherapy (P less than .01 and P = .01, respectively, log-rank) were associated with improved survival. Progressive lymphoma was the chief cause of failure; progression usually occurred less than 6 months after transplantation, most often at the sites of active disease before the transplant. However, five patients (including four with high-grade non-Hodgkin's lymphoma) suffered hematogenous patterns of relapse; four of these five patients had no prior history of marrow involvement. Other causes of mortality included interstitial pneumonitis, sepsis, hemorrhage and renal failure. Intensive chemoradiotherapy and autologous marrow transplantation produces durable remissions in some patients with progressive non-Hodgkin's lymphoma. Since such therapy is more effective when given to patients with signs of less advanced disease, earlier treatment would be the simplest way to produce improved results. However, improved conditioning regimens will also be needed, and measures to reduce occult lymphoma stem cell contamination with the autograft may also be required to increase the likelihood of cure in some patients.

Massive chemotherapy with autologous bone marrow transplantation in 50 cases of bad prognosis non-Hodgkin's lymphoma.

50 cases of advanced, intermediate (18) and high grade (32) non-Hodgkin's lymphoma (NHL) including 16 with Burkitt lymphoma have been treated with very high dose chemotherapy and autologous bone marrow transplantation (ABMT). These cases represent a retrospective analysis of the combined experience of a recently established collaborative group. 31 patients were treated with a protocol used in Lyon, 12 with that used in Marseille and seven with that used in London. Although the details of drug administration differed, each protocol was based on high dose alkylating agent (cyclophosphamide or melphalan), BCNU and cytosine arabinoside. 16 patients had drug resistant progressive NHL. Of these 11 responded to high dose treatment (nine CR, two PR). The duration of CR in this group was short (median 104d) and only one patient was in CR at 1 year. 19 patients had relapsed on previous therapy but were still responding to conventional rescue therapy. Following high dose therapy 47% of these patients are in continuous CR with a median time of observation of 300 d (73-962 d). Seven patients were partial responders to conventional induction therapy. Of these, six had a CR with high dose treatment and are still in CR (range 39-1230 d, median 200 d). Eight patients received high dose therapy as intensification after a long delay to CR with conventional treatment. Of these, four are alive and in remission 124-763 d after treatment. The high dose protocols produced significant morbidity with 25 patients (50%) having major or minor treatment-related complications, and there were seven treatment related deaths (14%). However, these results indicate that durable responses can be obtained with high dose chemotherapy in patients who have been heavily treated and indicate a role for this type of treatment at an earlier stage in advanced non-Hodgkin's lymphoma.