Long-term outcome of 487 patients with early-stage extra-nodal marginal zone lymphoma.

BACKGROUND: Localized early-stage extra-nodal marginal zone lymphoma (MZL) presents with heterogeneous organ involvement and is treated with various modalities, including resection, radiotherapy, and systemic therapy. We report the long-term outcome of a large cohort of extra-nodal MZL and assess the impact of patient and disease characteristics, organ site, and treatment strategy on disease control and survival. PATIENTS AND METHODS: We identified 487 consecutive patients with stage IE or IIE MZL referred between 1992 and 2012 to Memorial Sloan Kettering Cancer Center. Pathology was reviewed by hematopathologists at our institution. Patient and disease factors as well as treatment types were analyzed for association with relapse-free survival, overall survival, and cumulative incidence of relapse. RESULTS: Median follow-up after treatment was 4.7 years. Five-year relapse-free survival and overall survival were 60% and 89%, respectively. Cumulative incidence of disease-specific death at 5 years was 1.3%. Radiotherapy alone was the initial treatment in 50% of patients, followed by surgical resection (30%), observation (8%), immunotherapy (4%), and chemotherapy (2%). Initial treatment type, primary disease site, and number of involved sites were significant factors in multivariable analysis of relapse (all P < 0.05). When compared with stomach, MZL originating in other disease sites (HR > 2.0, P ≤ 0.001), except for thyroid, had higher risk of relapse. Strategies such as antibiotics or topical therapies were associated with higher risk of relapse when compared with radiation therapy (P < 0.001). Crude rate of transformation to pathologically confirmed large-cell lymphoma was 2% (11 patients). CONCLUSION: Overall and cause-specific survival are high in early-stage extra-nodal MZL. Curative-intent treatment led to fewer relapses and reduced the need for salvage. Stomach cases had lower risk of relapse than other anatomic primary sites. This study supports the use of local therapies to treat stage IE and IIE MZL.

Noninvasive Monitoring of Mantle Cell Lymphoma by Immunoglobulin Gene Next-Generation Sequencing in a Phase 2 Study of Sequential Chemoradioimmunotherapy Followed by Autologous Stem-Cell Rescue.

BACKGROUND: Minimal residual disease (MRD) monitoring has been used to identify early molecular relapse and predict clinical relapse in mantle cell lymphoma (MCL). Few published data exist in MCL on the performance of next-generation sequencing-based assay of immunoglobulin gene rearrangements for MRD assessment. PATIENTS AND METHODS: In a prospective clinical trial (NCT01484093) with intensive induction chemotherapy and autologous stem-cell transplantation, posttreatment peripheral blood samples were collected from 16 MCL patients and analyzed with an earlier version of the Adaptive Biotechnologies MRD assay. RESULTS: Of the 7 patients whose disease remained in remission, the MRD test remained negative in 5 (71%). Of the 9 patients who experienced relapse, the MRD test was positive at least 3 months before relapse in 6 patients (67%) and positive at the time of relapse in 1 patient (11%). All patients with at least 2 positive MRD tests experienced relapse. CONCLUSION: The next-generation sequencing-based MRD assay identified early molecular relapse, and we observed more sensitivity in the cellular (circulating leukocytes) versus acellular (plasma cell-free DNA) compartment. This observation may be due to availability of tumor target or a limitation of the assay.

Stanford V program for locally extensive and advanced Hodgkin lymphoma: the Memorial Sloan-Kettering Cancer Center experience.

BACKGROUND: The Stanford group has reported excellent results with the Stanford V regimen for patients with bulky and/or advanced Hodgkin lymphoma (HL). However, Gobbi reported markedly inferior failure-free survival (FFS) comparing Stanford V to other regimens but included major deviations from the original program. We retrospectively examined whether treatment at our institution carefully following Stanford V guidelines would confirm the original Stanford outcome data. PATIENTS AND METHODS: From June 1995 to May 2002, 126 patients with either locally extensive or advanced HL were treated with the 12-week Stanford V chemotherapy program followed by 36-Gy involved-field radiotherapy to sites initially > or =5 cm and/or to macroscopic splenic disease. Overall, 26% had stage IV disease and 20% had international prognostic score (IPS) > or =4. Overall survival (OS), disease-specific survival, progression-free survival (PFS), FFS, and freedom from second relapse (FF2R) were determined. RESULTS: The 5- and 7-year OS were 90% and 88%, respectively. The 5-year FFS was 78%. IPS > or =4 was a significant independent predictor of worse OS and PFS. The FF2R was 64% at 3 years. CONCLUSION: Stanford V with appropriate radiotherapy is a highly effective regimen for locally extensive and advanced HL.

Prognostic impact of proliferative index determined by quantitative image analysis and the International Prognostic Index in patients with mantle cell lymphoma.

BACKGROUND: The proliferative index (PI) is a powerful prognostic factor in mantle cell lymphoma (MCL); however, its utility is hampered by interobserver variability. The mantle cell international prognostic index (MIPI) has been reported to have prognostic importance. In this study, we determined the prognostic value of the PI as determined by quantitative image analysis in MCL. PATIENTS AND METHODS: Eighty-eight patients with adequate tissue were included in this analysis. Patients were treated with one of two treatment programs: sequential therapy with high-dose therapy consolidation or radioimmunotherapy followed by combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone. Patients were divided into four groups based on PI (<10%, 10%-29.9%, 30%-49.9%, and >50%), and outcomes were analyzed. RESULTS: Thirty percent was identified as the optimal cut-off for PI. By univariate analysis, intensive treatment and a low PI were associated with a superior progression-free survival (PFS); only PI was associated with overall survival. By multivariate analysis, both intensive treatment and PI correlated with PFS. The MIPI had no prognostic impact. CONCLUSIONS: PI is the most important prognostic factor in MCL. The cut-off of 30% is clinically meaningful and can be used to tailor the intensity of therapy in future clinical trials.

The majority of transformed lymphomas have high standardized uptake values (SUVs) on positron emission tomography (PET) scanning similar to diffuse large B-cell lymphoma (DLBCL).

BACKGROUND: We previously correlated non-Hodgkin's lymphoma (NHL) histology with (18)fluoro-2-deoxyglucose-positron emission tomography (FDG-PET) intensity: a standardized uptake value (SUV)>10 predicted aggressive lymphoma with >80% certainty and an SUV >13, with >90% certainty. PATIENTS AND METHODS: To evaluate SUV in transformed lymphoma, we identified all FDG-PET scans for NHL at Memorial Sloan-Kettering Cancer 1999-2007 with (i) biopsy-proven transformation, (ii) no therapy 60 days before PET scan and (iii) FDG-PET scans no more than 60 days before or 90 days after transformation. RESULTS: In 5 of 40 patients, the biopsy site was excised before PET; in two, only marrow was biopsied. In the remaining 33 patients, the SUV of the biopsy site ranged from 3 to 38, mean 14, median 12. Eighteen of 33 biopsies (55%) had an SUV>10 and 16 (48%)>13. The highest SUV in a transformed lymphoma PET scan (SUV(study-max)) ranged from 3.2 to 40, mean 15, median 12. Twenty-five of 40 patients (63%) presented with an SUV(study-max)>10 and 20 (50%)>13. CONCLUSIONS: Like de novo aggressive lymphomas, the majority of transformations have a high SUV(study-max) for a given pretreatment staging study, although many do not have very high values. Transformation should be suspected in indolent lymphoma with high SUVs on FDG-PET. Biopsies should be directed to the site of greatest FDG avidity.

Infectious disease associations in advanced stage, indolent lymphoma (follicular and nonfollicular): developing a lymphoma prevention strategy.

BACKGROUND: Eradication of Helicobacter pylori in gastric mucosa-associated lymphoid tumor can result in lymphoma remission. We prospectively identified/treated infections in nonbulky, advanced stage indolent lymphoma (follicular; nonfollicular lymphoma) eligible for observation. MATERIALS AND METHODS: Stool H. pylori, hepatitis C and Borrelia serologies, Borrelia and Chlamydia fixed tissue PCR, Chlamydia peripheral blood mononuclear cell PCR and hydrogen breath test for small bowel bacterial overgrowth (SBBO) were obtained. RESULTS: Fifty-six patients were enrolled. Positive infections: H. pylori (13); hepatitis C (3); SBBO (11). Negative: Borrelia (13); Chlamydophila psittaci (12, except one PCR). Lymphoma responses to antimicrobial therapy: H. pylori [one complete response (CR), 24+ months; one transient near CR]; hepatitis C [two CRs, 18+ and 30+ months; one partial response (PR) but hepatitis C virus persistent]; SBBO (one PR, 30+ months). Patients with associated infections, but without lymphoma CR, have required lymphoma treatment sooner than those without initial infections (treatment-free survival at 23.4 months median follow-up, 40.5% versus 74.7%, P = 0.01), indicating a different biology. CONCLUSION: Infections are common in advanced stage indolent lymphoma (37.5% in our series). Anecdotal lymphoma responses have been seen and three have been durable CRs (18 to 30+ months) with infection eradication alone. The identification and treatment of associated infections may be a first step towards developing a lymphoma prevention strategy.

Maintaining the dose intensity of ICE chemotherapy with a thrombopoietic agent, PEG-rHuMGDF, may confer a survival advantage in relapsed and refractory aggressive non-Hodgkin lymphoma.

INTRODUCTION: HDT/ASCT is standard for relapsed and refractory DLCL patients responding to second-line chemotherapy. We incorporated a thrombopoietic agent into the ICE chemotherapy program to potentially: decrease platelet associated toxicities, augment stem cell collection and maintain dose intensity. METHODS: This randomized, double-blind, placebo-controlled phase I/II trial examines PEG-rHuMGDF versus placebo with ICE chemotherapy. Phase I compared three cohorts and defined a clinically effective dose (CED). Phase II evaluated the CED versus placebo. Outcome measures included safety, hematological end-points, stem cell collection and the impact of dose-intensity on outcome. RESULTS: Forty-one patients with primary refractory (16) or relapsed DLCL (25) were treated; Response rates for evaluable patients are: 75% (12/16) for placebo and 82% (18/22) for PEG-rHuMGDF. PEG-rHuMGDF treated patients had significantly less grade IV thrombocytopenia, higher median platelet nadirs, and less platelet transfusion per cycle. ICE dose intensity was improved with PEG-rHuMGDF versus placebo: 75 versus 42% (P = 0.008). At 8.5 years median follow-up, overall and event-free survival are 47 and 31%, respectively. Patients treated on PEG-rHuMGDF versus placebo had improved survival (59 versus 31%, P = 0.06). CONCLUSION: PEG-rHuMGDF ameliorated thrombocytopenia, improved platelet recovery, and maintained ICE dose intensity. Potential survival advantages conferred by maintaining dose intensity require validation with newer thrombopoietic agents.

Randomized study of the duration of treatment with interferon alfa-2B in patients with hairy cell leukemia.

Several previous studies have demonstrated that both partially purified and recombinant alpha-interferons (alpha-IFNs) have high response rates in advanced hairy cell leukemia. However, the optimal dose and duration of therapy have not yet been defined. In this study, 90 patients were randomized after 12 months of IFN alfa-2b therapy with a standard dose of 2 X 10(6) U/m2 sc three times weekly to either no further therapy or an additional 6 months of therapy (18 mo total). There was no significant difference in the peripheral blood cell counts between the two groups (when analyzed) dating from the end of IFN therapy rather than from the time of randomization. Eighteen evaluable patients relapsed and were re-treated with IFN: 11 in the no-further-therapy group and 7 in the treated group. No patient was resistant to re-treatment with IFN. There was a significantly greater incidence of fatigue in the treated group (44% vs. 21%; P = .02) during the first 6 postrandomization months. We conclude that the duration of IFN therapy does not influence the clinical course after therapy is discontinued, but responses are maintained while patients receive therapy. However, because of a high incidence of fatigue with prolonged therapy and the ability to reinduce a second response, we recommend that IFN therapy be discontinued after 12 months in asymptomatic patients.

Endoscopic ultrasound in the evaluation of gastric small lymphocytic mucosa-associated lymphoid tumors.

PURPOSE: Low-grade, small lymphocytic lymphomas of the mucosa-associated lymphoid tissue (MALT) have recently been shown to be associated with Helicobacter pylori infections. Regression of these tumors has been reported with antibiotic therapy. Here we evaluate endoscopic ultrasound (EUS) as on objective method to evaluate pretreatment disease and posttherapy response. MATERIALS AND METHODS: We retrospectively reviewed 20 patients initially diagnosed elsewhere with MALT lymphoma. All patients had their initial endoscopic biopsies (EGDs) reviewed at Memorial Sloan-Kettering Cancer Center (MSKCC). All patients had EUS performed at the time of consultation and on completion of therapy if treated at our center. Antral biopsies were stained with a modified Steiner preparation to determine infection by H pylori. RESULTS: Gastric low-grade lymphoma was confirmed in 16 of 20 patients; 11 of 16 had previously received antibiotic therapy for biopsy-positive H pylori infection. All gastric lymphomas had an abnormal EUS: eight with discrete tumor masses and eight with gastric wall infiltration (submucosa, n = 4; muscularis propria, n = 3; serosa, n = 1). On completion of lymphoma treatment with chemotherapy, radiotherapy, or surgery, 11 of 16 patients underwent follow-up EUS. Five patients received care elsewhere and did not return for posttreatment EUS. The gastric wall was normal with no evidence of disease on EUS-guided biopsy in eight of 11 patients. The remaining three patients had abnormal gastric walls. One was biopsy-negative and two had residual lymphoma. Four patients were found to have benign lymphoid aggregates in association with H pylori on initial EGD and EUS biopsies. All four patients were previously untreated with antibiotics. EUS showed prominent mucosa, but no significant findings within the gastric wall. CONCLUSION: EUS appears useful to stage objectively and evaluate therapeutic outcome in the management of gastric, low-grade MALT lymphomas. It also helps to distinguish benign lymphoid aggregates from lymphoma associated with H pylori infection. EUS findings may have a significant impact on assessment and therapeutic recommendations.

Treatment of mucosa-associated lymphoid tissue lymphoma of the stomach with radiation alone.

PURPOSE: Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach (MLS) has recently been defined as a distinct clinicopathologic entity, often associated with Helicobacter pylori infection. Many regard antibiotic therapy as the primary treatment of MLS, but in the absence of H pylori infection, or when salvage of antibiotic failures is required, gastrectomy and/or chemotherapy have frequently been used. This study evaluates the efficacy of low-dose radiotherapy alone as an alternative to surgery. PATIENTS AND METHODS: Seventeen patients with stage I to II(2) low-grade MLS without evidence of H pylori infection or with persistent lymphoma after antibiotic therapy of associated H pylori infection were included in this series. Median age was 69 years (range, 39 to 84). Median total radiation dose was 30 Gy (range, 28.5 to 43.5 Gy) delivered in 1.5-Gy fractions within 4 weeks to the stomach and adjacent lymph nodes. Following treatment, all patients underwent endoscopic evaluation and biopsy at a median of 4 months, at 6-month intervals to 2 years, and annually thereafter. RESULTS: All obtained a biopsy-confirmed complete response. At a median follow-up time of 27 months (range, 11 to 68) from completion of radiotherapy, event-free survival was 100%. Treatment was well tolerated, with no significant acute side effects. All remained asymptomatic at last follow-up. CONCLUSION: These results suggest that effective treatment of MLS with low-dose radiation therapy alone is feasible and safe, and allows stomach preservation. Longer follow-up evaluation is required to determine the long-term efficacy of this treatment approach and its side effects. Further studies should clarify the indications for radiotherapy in H pylori-negative or antibiotic-resistant cases of MLS.

Accelerated hyperfractionated total-lymphoid irradiation, high-dose chemotherapy, and autologous bone marrow transplantation for refractory and relapsing patients with Hodgkin's disease.

PURPOSE: To evaluate the feasibility and therapeutic effect of accelerated hyperfractionated total-lymphoid irradiation (TLI), high-dose chemotherapy, and autologous bone marrow transplantation (AuBMT) in patients with relapsing or chemotherapy-resistant Hodgkin's disease (HD). PATIENTS AND METHODS: Forty-seven patients with HD who either relapsed after chemotherapy (n = 19), or failed to respond (n = 28) to at least two regimens of combination chemotherapy were studied. No patient received prior radiation therapy (RT). Treatment started with reinduction with standard-dose chemotherapy, followed by involved-field irradiation (15 Gy) to areas of relapsed or persistent disease and TLI (20.04 Gy given in 1.67 Gy fractions three times per day for 4 days). Subsequently, patients received etoposide and high-dose cyclophosphamide, followed by infusion of unpurged autologous bone marrow. All surviving patients had a minimum follow-up duration of 1 year. The median follow-up duration for survivors was 40+ months, and the maximum follow-up duration was 80+ months. RESULTS: Of the 47 patients treated, eight (17%) died of toxicity during the peritransplant period. Twenty-nine of the remaining 39 assessable patients (74%) attained a complete response (CR), while 10 remained with residual disease and progressed early after AuBMT. Four of the CR patients (14%) relapsed and 25 patients remained alive and free of disease. The actuarial disease-free survival (DFS) rate for the entire group at 6.5 years was 50%. Patients who received the protocol for relapsing HD had a significantly better DFS rate (79%) compared with patients treated for continuous refractory disease (DFS, 33%; P < .03). CONCLUSION: Previously unirradiated patients with relapsing or chemotherapy-resistant HD who have exhausted conventional chemotherapy may still respond to an aggressive therapeutic approach consisting of accelerated hyperfractionated TLI, high-dose chemotherapy, and AuBMT rescue. This program offers a potential for long-term DFS to approximately one half of patients who would otherwise have a dismal prognosis with standard-dose salvage therapy.

Second neoplasms in patients with Hodgkin's disease following combined modality therapy--the Yale experience.

From 1969 to 1982, 183 patients with previously untreated stages IIIB and IV Hodgkin's disease and relapsing Hodgkin's disease after radiation therapy were treated with combination chemotherapy plus low-dose irradiation (CRT). One hundred fifty patients who achieved a complete response (CR) were analyzed for risk of developing a second neoplasm. Median follow-up has been 8.3 years. Actuarial survival of all patients is 74% at 10 years with a relapse-free survival of 68%. An additional 24 patients with stage IIIA disease were also treated with CRT. There were 22 CRs at risk who were analyzed. Median follow-up has been 3+ years with an actuarial survival of 90% at five years and a relapse-free survival of 83%. Second neoplasms have developed in 14 of 172 patients at risk: acute nonlymphocytic leukemia (ANLL; five patients); aggressive histology non-Hodgkin's lymphoma (NHL; three patients); and a variety of solid neoplasms (six patients). Time to second neoplasm diagnosis after initial treatment ranged from 12 to 141 months. Five patients were older than 40 years. At the time of diagnosis of the second malignancy, 11 patients were free of Hodgkin's disease (for 36 to 141 months) and three were receiving therapy for recurrent Hodgkin's disease. The 10-year actuarial risk (%) of developing ANLL was 5.9 +/- 2.8; for NHL, the risk was 3.5 +/- 2.4, and for solid neoplasms, 5.8 +/- 3.0. Our results suggest that combination chemotherapy plus low-dose irradiation does not appear to significantly increase the risk of developing second neoplasms above that already reported for combination chemotherapy when administered as either initial or salvage treatment of Hodgkin's disease.

Alpha-2 interferon therapy of hairy-cell leukemia: a multicenter study of 64 patients.

Sixty-four patients with hairy-cell leukemia (HCL) (61 had undergone prior splenectomy) were treated with alpha-2 interferon (Intron A, Schering Corp, Kenilworth, NJ) subcutaneously three times per week at a dosage of 2 X 10(6) U/m2. Three patients (5%) demonstrated a complete response (CR) with apparent eradication of hairy cells from the bone marrow, 45 patients (70%) showed a partial response (PR) defined as normalization of all three blood counts associated with decreased involvement in the bone marrow, and nine patients (14%) showed a minor response that included improvement in at least one blood count. Three patients had no response, three patients died before completing 1 month of therapy, and one patient refused further therapy after 1 month of therapy. The median platelet count returned to normal by the second month of treatment. The median hemoglobin returned to greater than 12 mg/dL by the fourth month of treatment, and the median granulocyte count to greater than 1,500/mu by the fifth month of treatment. Bone marrow biopsy analysis during interferon therapy demonstrated a decrease in median hairy-cell index by more than half. Transfusion of both RBCs and platelets were decreased within 4 months of initiating treatment. Serious infections, which averaged four per month in 16 of the 64 patients before interferon therapy, were rarely observed after the first month of treatment. Treatment-induced toxicity was mild, consisting primarily of influenza-like symptoms, fatigue, and minor skin disorders. Alpha-2 interferon therapy is highly effective in reversing the course of progressive HCL and should be considered the treatment of choice for a minimum of 12 months in patients who have progressive disease post-splenectomy.

Effect of ABVD chemotherapy with and without mantle or mediastinal irradiation on pulmonary function and symptoms in early-stage Hodgkin's disease.

PURPOSE: To evaluate the effect of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy alone and of ABVD with mantle or mediastinal irradiation (RT) on the pulmonary function of patients with early-stage Hodgkin's disease. PATIENTS AND METHODS: Between 1989 and 1993, 60 patients with clinical stage I to IIIA HD enrolled onto randomized trials at Memorial Sloan-Kettering Cancer Center (MSKCC) underwent prospective evaluation of pulmonary function. All patients received six cycles of ABVD, and 30 patients received mantle or mediastinal RT. Pulmonary function tests (PFTs) and symptom evaluation were conducted before, during, and after completion of chemotherapy and RT, and at various intervals thereafter. The median follow-up time was 30 months. RESULTS: During chemotherapy, symptoms of cough and dyspnea on exertion developed in 32 of 60 patients (53%) and declines in pulmonary function occurred in 22 of 60 patients (37%). Discontinuation of bleomycin was necessary in 14 of 60 patients (23%). Following chemotherapy, there was a significant decline in median forced vital capacity (FVC) and diffusing capacity of carbon monoxide (DLCO). In patients who received mantle or mediastinal RT, there was a further decline in FVC following radiation therapy. At the most recent follow-up evaluation, five of 29 patients (18%) who received ABVD alone and nine of 30 (30%) who received ABVD and RT reported persistent mild pulmonary symptoms (P = .36), which did not significantly affect normal daily activity. CONCLUSION: ABVD chemotherapy induced acute pulmonary toxicity that required bleomycin dose modification in a substantial number of patients. The addition of RT resulted in a further decrease in FVC; however, this did not significantly affect the functional status of patients.

Resistance to methotrexate due to gene amplification in a patient with acute leukemia.

A patient is described with acute myelocytic leukemia refractory to conventional therapy, who also became highly resistant to methotrexate (MTX) after repeated courses of this drug. Leukemia cells from this patient were found to contain an elevated level of dihydrofolate reductase (DHFR) activity, with no change in the affinity of the enzyme for MTX. A sensitive "dot blot" assay revealed a fourfold increase in the gene copy number of DHFR. Southern blot analysis with a human DHFR cDNA probe confirmed this increase in the gene copy number, and demonstrated a similar restriction pattern with Eco R1, Hind III, and Pst 1 as seen with a highly amplified human leukemia cell line, K562. Additional DHFR fragments were detected, not seen in the K562 blot, suggesting the presence of pseudogenes, or a result of gene rearrangements occurring as part of the amplification process. Resistance to MTX in this patient was therefore ascribed to gene amplification and overproduction of DHFR.

Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin's lymphoma.

PURPOSE: To evaluate a chemotherapy regimen that consisted of ifosfamide administered as an infusion with bolus carboplatin, and etoposide (ICE) supported by granulocyte colony-stimulating factor (G-CSF) for cytoreduction and stem-cell mobilization in transplant-eligible patients with primary refractory or relapsed non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: One hundred sixty-three transplant-eligible patients with relapsed or primary refractory NHL were treated from October 1993 to December 1997 with ICE chemotherapy at Memorial Sloan-Kettering Cancer Center. Administration of three cycles of ICE chemotherapy was planned at 2-week intervals. Peripheral-blood progenitor cells were collected after cycle 3, and all patients who achieved a partial response (PR) or complete response (CR) to ICE chemotherapy were eligible to proceed to transplantation. Event-free and overall survival, ICE-related toxicity, and the number of CD34(+) cells collected after treatment with ICE and G-CSF were evaluated. RESULTS: All 163 patients were assessable for response, and there was no treatment-related mortality. A major response (CR/PR) was evident in 108 patients (66.3%); 89% of the responding patients underwent successful transplantation. Patient who underwent transplantation and achieved a CR to ICE had a superior overall survival to that of patients who achieved a PR (65% v 30%; P =.003). The median number of CD34(+) cells/kg collected was 8.4 x 10(6). The dose-limiting toxicity of ICE was hematologic, with 29.4% of patients developing grade 3/4 thrombocytopenia. There were minimal nonhematologic side effects. CONCLUSION: ICE chemotherapy, with ifosfamide administered as a 24-hour infusion to decrease CNS side effects, and the substitution of carboplatin for cisplatin to minimize nephrotoxicity, is a very effective cytoreduction and mobilization regimen in patients with NHL. Furthermore, the quality of the clinical response to ICE predicts for posttransplant outcome.

Nonhypoxemic hazards of prolonged myoclonus.

Hyperkalemia, hyperthermia, and systemic hypotension developed in a patient with generalized myoclonus. These disorders reached life-threatening proportions but were rapidly and completely corrected after the patient was paralyzed with pharmacologic agents. Induced neuromuscular blockade may be indicated when the systemic effects of pathologically contracting muscle become life-threatening.

Chemosensitive epidural spinal cord disease in non-Hodgkins lymphoma.

Epidural spinal cord disease (ESCD), an infrequent complication of systemic non-Hodgkins lymphoma (NHL), can occur at diagnosis or at relapse, and is usually treated with radiotherapy, or infrequently surgical decompression. We retrospectively analyzed 140 patients with intermediate-grade NHL (IG-NHL) who were treated on a dose-intense protocol using doxorubicin, vincristine, and high-dose cyclophosphamide (NHL-15). There were seven episodes of ESCD in six (4.3%) patients. Five episodes were asymptomatic at presentation; one patient had back pain, leg numbness, and tingling; and one had radicular pain and mild leg weakness. None had malignant cells in the CSF. One patient received high-dose dexamethasone after laminectomy for diagnostic biopsy; otherwise, dexamethasone was used only as an anti-emetic prior to chemotherapy. Patients who developed ESCD at diagnosis received the planned course of NHL-15 chemotherapy as treatment for ESCD, and those treated with NHL-15 who developed ESCD at relapse were given a regimen containing ifosfamide, carboplatin, and etoposide (ICE). After chemotherapy alone, five of seven episodes showed radiographic resolution of ESCD and improvement of neurologic deficits. One patient received consolidation radiotherapy (2,700 cGy) to the spine after ICE for relapsed ESCD and had a complete response. One patient had progression of systemic lymphoma and ESCD despite chemotherapy. These data suggest that chemotherapy may be effective as initial treatment of ESCD in IG-NHL and may reduce the potential complications of spinal surgery and radiotherapy.

Therapeutic approaches to the treatment of hairy cell leukemia.

Although a rare disease, hairy cell leukemia has great biologic and clinical significance. New therapeutic options of alpha-interferon and pentostatin have challenged the role of splenectomy in the overall management of the disease. alpha-Interferon can now be considered the treatment of choice for patients who progress after splenectomy, and it may also be considered as initial treatment in selected patients. Future clinical trials will focus on the relative efficacies of alpha-interferon and pentostatin, their potential for sequential or combined use, and the role of splenectomy.

Sequential evaluation of alpha-2b-interferon treatment in 128 patients with hairy cell leukemia.

This multicenter study reports on 128 patients with hairy cell leukemia (HCL) who were treated subcutaneously with alfa-2b interferon (Intron A, Schering Corp, Kenilworth, NJ), three times a week at a dosage of 2 megaunits/m2. Five patients (4%) had a complete response (CR) with virtual eradication of hairy cells from the bone marrow, 98 (77%) showed a partial response (PR), defined as hematologic normalization of all three blood counts associated with decreased hairy cells in the bone marrow, and nine (7%) showed a minor response (MR) that included improvement in at least one measurement of the blood count. Sixteen persons (12%) did not respond. Thirteen of the 128 had had neither a splenectomy nor a CR. Responders who completed 12 months of interferon therapy were randomized to either an additional 6 months of therapy or to observation only. Relapses occurred in six of 35 (18%) randomized to observation alone and in two of 29 (7%) who continued interferon therapy. The relapses are too few to draw conclusions; however, 27 responders have remained off interferon treatment for greater than 6 months; cessation of interferon therapy does not result in a rapid deterioration of peripheral blood counts. In HCL, interferon therapy produced a large percentage of durable objective responses in the majority of patients. The exact duration of this response and the results of retreatment are yet undetermined.