Phase I trial of rituximab, cladribine, and temsirolimus (RCT) for initial therapy of mantle cell lymphoma.

BACKGROUND: We conducted this trial to determine the maximum tolerated dose (MTD) of temsirolimus added to an established regimen comprised of rituximab and cladribine for the initial treatment of mantle cell lymphoma. PATIENTS AND METHODS: A standard phase I cohort of three study design was utilized. The fixed doses of rituximab and cladribine were 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. There were five planned temsirolimus i.v. dose levels: 15 mg day 1; 25 mg day 1; 25 mg days 1 and 15; 25 mg days 1, 8 and 15; and 25 mg days 1, 8, 15, and 22. RESULTS: Seventeen patients were treated: three each at levels 1-4 and five at dose level 5. The median age was 75 years (52-86 years). Mantle Cell International Prognostic Index (MIPI) scores were low in 6% (1), intermediate in 59% (10), and high in 35% (6) of patients. Five patients were treated at level 5 without dose limiting toxicity. Hematologic toxicity was frequent: grade 3 anemia in 12%, grade 3 thrombocytopenia in 41%, grade 4 thrombocytopenia in 24%, grade 3 neutropenia in 6%, and grade 4 neutropenia in 18% of patients. The overall response rate (ORR) was 94% with 53% complete response and 41% partial response. The median progression-free survival was 18.7 months. CONCLUSIONS: Temsirolimus 25 mg i.v. weekly may be safely added to rituximab and cladribine at 375 mg/m(2) i.v. day 1 and 5 mg/m(2)/day i.v. days 1-5 of a 28-day cycle, respectively. This regimen had promising preliminary activity in an elderly cohort of patients with mantle cell lymphoma. CLINICALTRIALSGOV IDENTIFIER: NCT00787969.

Bowel perforation in intestinal lymphoma: incidence and clinical features.

BACKGROUND: Perforation is a serious life-threatening complication of lymphomas involving the gastrointestinal (GI) tract. Although some perforations occur as the initial presentation of GI lymphoma, others occur after initiation of chemotherapy. To define the location and timing of perforation, a single-center study was carried out of all patients with GI lymphoma. PATIENTS AND METHODS: Between 1975 and 2012, 1062 patients were identified with biopsy-proven GI involvement with lymphoma. A retrospective chart review was undertaken to identify patients with gut perforation and to determine their clinicopathologic features. RESULTS: Nine percent (92 of 1062) of patients developed a perforation, of which 55% (51 of 92) occurred after chemotherapy. The median day of perforation after initiation of chemotherapy was 46 days (mean, 83 days; range, 2-298) and 44% of perforations occurred within the first 4 weeks of treatment. Diffuse large B-cell lymphoma (DLBCL) was the most common lymphoma associated with perforation (59%, 55 of 92). Compared with indolent B-cell lymphomas, the risk of perforation was higher with aggressive B-cell lymphomas (hazard ratio, HR = 6.31, P < 0.0001) or T-cell/other types (HR = 12.40, P < 0.0001). The small intestine was the most common site of perforation (59%). CONCLUSION: Perforation remains a significant complication of GI lymphomas and is more frequently associated with aggressive than indolent lymphomas. Supported in part by University of Iowa/Mayo Clinic SPORE CA97274 and the Predolin Foundation.

Time of relapse after initial therapy significantly adds to the prognostic value of the IPI-R in patients with relapsed DLBCL undergoing autologous stem cell transplantation.

We explored the concomitant effect of the International Prognostic Index at the time of relapse (IPI-R) and the time from initial diagnosis to relapse (TTR) on outcome of 80 uniformly treated patients receiving BEAM conditioning followed by SCT for relapsed, chemosensitive diffuse large B-cell lymphoma. Median age at the time of transplantation was 62 years (range 26-77). Median follow-up of survivors was 31.4 months. Median overall survival (OS) from the time of transplant for patients with TTR >18 months vs < or =18 months was not reached and 50 months, respectively (P=0.01). Median OS for patients with IPI-R > or =3 was 23.3 months and not reached for patients with IPI-R <3 (P=0.01). These factors were independent in multivariate analysis with relative risk for death of 0.91 (0.80-0.99; P=0.04) for each 6-month increment in TTR and 0.63 (0.42-0.96; P=0.03) for IPI-R <3. TTR < or =18 months and IPI-R > or =3 were combined in a prognostic system where patients with none (n=32), one (n=39) or two (n=9) of these factors had median OS not reached, of 50 and 5 months, respectively (P<0.01). Patients with early, high IPI-R relapse after first-line therapy have a dismal outcome with SCT and should receive experimental therapies.

Infusion of autograft natural killer cell/CD14+HLA-DRDIM cell ratio predicts survival in lymphoma post autologous stem cell transplantation.

The infusion of autograft absolute lymphocyte count (A-ALC) and autograft natural killer cells (A-NKC) are prognostic factors for overall survival (OS) and PFS in non-Hodgkin's lymphoma (NHL) patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). The human monocytic CD14+HLA-DRDIM cells are associated with worse prognosis in NHL. Thus, we investigated whether the autograft A-NKC/A-CD14+HLA-DRDIM ratio predicts survival in NHL. In a total of 111 NHL patients, we analyzed apheresis collection samples for the content of A-NKC and A-CD14+HLA-DRDIM. With a median follow-up of 57.2 months (range: 2.1-84.6 months), patients with an A-NKC/A-CD14+HLA-DRDIM ratio of ⩾0.29 experienced superior OS (5-year OS rates of 84% (95% confidence interval (CI), 72-91%) vs 48% (95% CI, 34-62%), P<0.0002, respectively) and PFS (5-year PFS rates of 59% (95% CI, 47-71%) vs 32% (95% CI, 20-48%), P<0.002, respectively). Multivariate analysis revealed that A-NKC/A-CD14+HLA-DRDIM ratio was an independent predictor for PFS (hazard ratio (HR)=0.56, 95% CI, 0.32-0.96, P<0.03) and OS (HR=0.34, 95% CI, 0.16-0.68, P<0.002). The A-NKC/A-CD14+HLA-DRDIM ratio provides a platform to target specific autograft immune effector cells to improve clinical outcomes in NHL patients undergoing APBHSCT.

Vitamin D insufficiency is associated with an increased risk of early clinical failure in follicular lymphoma.

We evaluated whether vitamin D insufficiency (VDI; 25(OH)D <20 ng/ml) was associated with adverse outcomes among follicular lymphoma (FL) patients using an observational prospective cohort study of 642 FL patients enrolled from 2002-2012. The median age at diagnosis was 60 years. At a median follow-up of 59 months, 297 patients (46%) had an event (progression, treatment failure), 78 had died and 42 (6.5%) had a lymphoma-related death. VDI was associated with inferior event-free survival (EFS) at 12 months (EFS12, odds ratio (OR)=2.05; 95% confidence interval (CI) 1.18-3.54), overall survival (OS, hazards ratio (HR)=2.35; 95%CI 1.37-4.02), and lymphoma-specific survival (LSS, HR=2.97; 95% CI 1.52-5.80) for the full cohort. Among patients treated with immunochemotherapy (IC), VDI was associated with inferior EFS12 (OR=3.00; 95% CI 1.26-7.13), OS (HR=2.86; 95% CI 1.39-5.85), and LSS (HR=2.96; 95% CI 1.29-6.79). For observed patients, VDI was associated with inferior OS (HR=2.85; 95% CI 1.20-6.76). For other therapies, VDI was associated with inferior OS (HR=3.06; 95% CI 1.01-9.24). Our work is the first to reveal an association of VDI with early clinical failure, and to demonstrate an association of VDI with adverse outcomes among patients who are observed or treated with therapies other than IC. Our findings suggest a potentially modifiable prognostic factor to address in patients with FL.

A phase 1 trial of 90Y-Zevalin radioimmunotherapy with autologous stem cell transplant for multiple myeloma.

This phase 1 study (clinical trial NCT00477815) was conducted to determine the maximum tolerated dose (MTD) of yttrium-90 ibritumomab tiuxetan (90Y-Zevalin) with high dose melphalan (HDM) therapy in multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT). In a 3+3 trial design, 30 patients received rituximab 250 mg/m2 with indium-111 ibritumomab tiuxetan (111In-Zevalin) for dosimetry (day -22); rituximab 250 mg/m2 with escalating doses of 90Y-Zevalin (day -14); melphalan 100 mg/m2 (days -2,-1) followed by ASCT (day 0) and sargramostim (GM-CSF, day 0) until neutrophil engraftment. Each patient's 111In-Zevalin dosimetry data were used to calculate the dose of 90Y-Zevalin (in mCi) to deliver 10, 12, 14, 16, 18 or 20 Gy to the liver. Dose limiting toxicities were seen in 3 patients. The overall response rate was 73% (22/30) with stringent complete response in 2 patients; complete response, 5; very good partial response, 12; and partial response, 3. The median PFS was 16.5 months and the median overall survival was 63.4 months. In MM, the MTD of 90Y-Zevalin with HDM is 18 Gy to the liver. The addition of radiation with novel delivery methods such as radioimmunotherapy combined with standard transplant regimens warrants further study.

Early lymphocyte recovery after autologous stem cell transplantation predicts superior survival in mantle-cell lymphoma.

Autologous stem cell transplantation (ASCT) is an effective treatment strategy for mantle-cell lymphoma (MCL) demonstrating significantly prolonged progression-free survival (PFS) when compared to interferon-alpha maintenance therapy of patients in first remission. The study of absolute lymphocyte count at day 15 (ALC-15) after ASCT as a prognostic factor in non-Hodgkin lymphoma (NHL) included different lymphoma subtypes. The relationship of ALC-15 after ASCT in MCL has not been specifically addressed. We evaluated the impact of ALC-15 recovery on survival of MCL patients undergoing ASCT. We studied 42 consecutive MCL patients who underwent ASCT at the Mayo Clinic in Rochester from 1993 to 2005. ALC-15 threshold was set at 500 cells/microl. The median follow-up after ASCT was 25 months (range, 2-106 months). The median overall survival (OS) and PFS times were significantly better for the 24 patients who achieved an ALC-15 >or=500 cells/microl compared with 18 patients with ALC-15 <500 cells/microl (not reached vs 30 months, P<0.01 and not reached vs 16 months, P<0.0006, respectively). Multivariate analysis demonstrated ALC-15 to be an independent prognostic factor for OS and PFS. The ALC-15 >or=500 cells/microl is associated with a significantly improved clinical outcome following ASCT in MCL.

Autologous hematopoietic stem cell transplantation for older patients with relapsed non-Hodgkin's lymphoma.

To evaluate autologous stem cell transplant (ASCT) in older patients with intermediate grade non-Hodgkin's lymphoma (NHL), the Mayo Clinic Rochester BMT database was reviewed for all patients 60 years of age and older who received ASCT for NHL between September 1995 and February 2003. Factors evaluated included treatment-related mortality (TRM), event-free survival (EFS) and overall survival (OS). Ninety-three patients were identified, including twenty-four (26%) over the age of 70 years. Treatment-related mortality (5.4%) was not significantly different when compared to a younger cohort (2.2%). At a median follow-up of 14 months (0.6-87.6 months), the estimated median survival is 25 months (95% confidence interval (CI) 12-38) in the older group compared to 56 months (95% CI 37-75) (P=0.037) in the younger group. The estimated 4-year EFS was 38% for the older group compared to 42% in the younger cohort (P=0.1). By multivariate analysis, the only factor found to influence survival in the older group was age-adjusted International Prognostic Index at relapse, 0-1 better than 2-3 (P=0.03). Autologous stem-cell transplant can be safely performed in patients 60 years or older with chemotherapy sensitive relapsed or first partial remission NHL. The outcome may not be different from that of younger patients in terms of TRM and EFS.

Allogeneic stem cell transplantation and donor lymphocyte infusions for chronic myelomonocytic leukemia.

Prognosis in chronic myelomonocytic leukemia (CMML) is unfavorable and the optimal therapy remains uncertain. Currently, allogeneic stem cell transplantation is the only known curative therapeutic option. However, the data available are limited and restricted to small retrospective series. There is even less information on the use of donor lymphocyte infusions (DLI) for this disease. We reviewed our experience of allogeneic stem cell transplantation and DLI for adults with CMML. Seventeen consecutive adults underwent allogeneic stem cell transplantation from related (n=14) or unrelated (n=3) donors. Median age was 50 years (range 26-60). Seven patients (41%) demonstrated relapse or persistent disease at a median of 6 months (range 3-55.5). Five patients underwent DLI for morphologic relapse and one for mixed donor chimerism. Two patients achieved durable complete remissions of 15 months each. The overall transplant-related mortality was 41% (n=7). With a median follow-up of 34.5 months, three patients (18%) currently remain alive and in continuous CR. The current study demonstrates a graft-versus-leukemia effect in CMML, both for allogeneic stem cell transplantation and for DLI. Nevertheless, consistent with reported experience of others, overall outcomes remain less than optimal and unpredictable.

A phase I study of 153Sm-EDTMP with fixed high-dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma.

Despite response rates of 30% after high-dose chemotherapy with autologous hematopoietic stem cell transplant, patients with multiple myeloma are not cured. 153Samarium ethylenediaminetetramethylenephosphonate (153Sm-EDTMP; Quadramet) is a short-range, beta-emitting therapeutic radiopharmaceutical with avid skeletal uptake. In total, 12 patients were treated with escalating doses of 153Sm-EDTMP (N=3/group; 6, 12, 19.8, and 30 mCi/kg) and a fixed dose of melphalan (200 mg/m(2)). No dose limiting toxicity was seen. To better standardize the marrow compartment radiation dose, the study was modified such that an additional six patients were treated at a targeted absorbed radiation dose to the red marrow of 40 Gy based on a trace labeled infusion 1 week prior to the therapy. Despite rapid elimination of unbound radiopharmaceutical via kidneys and bladder, no episodes of nephrotoxicity, hemorrhagic cystitis, or delayed radiation nephritis were observed with a median follow-up of 31 months (range 8.5-44). Median times to ANC>0.5 and platelet >20 x 10(6)/l were 12 and 11 days, respectively, with no graft failures. Overall response rate was 94% including seven very good partial responses and five complete responses. Addition of 153Sm EDTMP to melphalan conditioning appears to be safe, well-tolerated and worthy of further study.

Predictive capacity of the International Prognostic Factor Index in patients with peripheral T-cell lymphoma.

PURPOSE: The International Prognostic Factor Index has been shown to predict the outcome of patients with predominantly B-cell lymphomas classified using traditional classifications, including the Working Formulation, but its prognostic importance has not been tested in a cohort of patients with exclusively T-cell lymphomas. This study was conducted to evaluate the prognostic significance of the International Prognostic Factor Index in patients with peripheral T-cell lymphoma (PTCL). PATIENTS AND METHODS: Seventy-eight patients (48 men and 30 women) with PTCL seen at a single institution between 1985 and 1995 were included in the analysis. The morphology and immunocytochemistry of all the original biopsy specimens were reviewed by a single pathologist and classified using the Revised European-American Lymphoma (REAL) classification. The International Prognostic Factor Index, as well as clinical and biochemical parameters, were evaluated by univariate and multivariate analyses to determine their association with patient outcome. RESULTS: The International Prognostic Factor Index strongly predicted survival when all patients were included in the analysis (P < .001). For patients < or = 60 years, the age-adjusted International Index significantly predicted long-term survival (P = .0218). For patients older than 60 years, the age-adjusted International Index also significantly predicted survival (P = .002). Liver involvement (P = .006) and bone marrow involvement (P = .014) were also significant prognostic factors in the univariate analysis, but only the International Index remained significant in the multivariate analysis (P = .001). CONCLUSION: The International Prognostic Factor Index, which significantly predicts outcome in patients with aggressive/intermediate-grade B-cell lymphomas, has similar prognostic importance in patients with PTCL.

Lymphocyte recovery after allogeneic bone marrow transplantation predicts risk of relapse in acute lymphoblastic leukemia.

Allogeneic blood and marrow transplantation (BMT) is curative for many patients with high-risk and relapsed acute lymphoblastic leukemia (ALL). However, relapse is an important cause of post-transplantation failure, and there are no reliable markers to predict relapse. A retrospective review of patients with ALL who underwent matched related allogeneic BMT was carried out to examine whether the rate of lymphocyte recovery after transplantation had any prognostic value in ALL. The absolute lymphocyte count (ALC) at days 21 and 30 after transplantation was obtained for 43 patients who received transplants during an 18-year period. Patients with an ALC of 175 x 10(6)/l or less on day 21 were more likely to relapse than those with ALC greater than 175 x 10(6)/l (relative risk, 4; 95% confidence interval, 1.5-11.2). Patients with slower lymphocyte recovery had significantly lower relapse-free survival than those with faster recovery (P=0.0028). There was also a trend toward poorer overall survival among those with a slow lymphocyte recovery (log-rank test; P=0.028). The rate of lymphocyte recovery is prognostic in patients with ALL undergoing allogeneic BMT, and this should be integrated with other predictors to identify patients at high risk of relapse. Such patients could be considered for interventions aimed at prevention of relapse, including rapid withdrawal of immunosuppressive medication or donor lymphocyte infusion.

A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma.

Autologous hematopoietic cell transplantation (AutoHCT) is a potentially curative treatment modality for relapsed/refractory Hodgkin lymphoma (HL). However, no large studies have evaluated pretransplant factors predictive of outcomes of AutoHCT in children, adolescents and young adults (CAYA, age <30 years). In a retrospective study, we analyzed 606 CAYA patients (median age 23 years) with relapsed/refractory HL who underwent AutoHCT between 1995 and 2010. The probabilities of PFS at 1, 5 and 10 years were 66% (95% confidence interval (CI): 62-70), 52% (95% CI: 48-57) and 47% (95% CI: 42-51), respectively. Multivariate analysis for PFS demonstrated that at the time of AutoHCT patients with Karnofsky/Lansky score ⩾90, no extranodal involvement and chemosensitive disease had significantly improved PFS. Patients with time from diagnosis to first relapse of <1 year had a significantly inferior PFS. A prognostic model for PFS was developed that stratified patients into low-, intermediate- and high-risk groups, predicting for 5-year PFS probabilities of 72% (95% CI: 64-80), 53% (95% CI: 47-59) and 23% (95% CI: 9-36), respectively. This large study identifies a group of CAYA patients with relapsed/refractory HL who are at high risk of progression after AutoHCT. Such patients should be targeted for novel therapeutic and/or maintenance approaches post-AutoHCT.

Modern chemotherapeutic regimens in the management of aggressive non-Hodgkin lymphoma: can they be improved?

Major advances in the treatment of aggressive NHL have occurred in the last 20 years. Modern combination chemotherapy provides a complete remission in a majority of patients and cures a significant number of these patients. Treatment failures are a consequence of the existence or development of resistant disease and regimen related toxicity. Identification of mechanisms of tumour resistance and prognostic factors, together with consideration of regimen related toxicity, should aid in the optimal application of currently available agents and regimens and guide the development of future regimens. Novel delivery systems may allow more tumour specific therapy in the future.

Primary pulmonary lymphoma.

Lymphoproliferative diseases affecting the lung occur over a broad clinical and pathologic spectrum. The clinical presentations and radiologic findings are nonspecific, entailing broad differential diagnoses. Accurate diagnosis requires adequate tissue sampling with appropriate ancillary pathologic studies. The recent delineation of new pathologic entities such as low-grade malignant lymphoma of mucosa-associated lymphoid tissue (MALT type) has aided in the understanding of the pathophysiology, clinical course, and management of patients with pulmonary lymphoma. Significant observations have been made in the clinical management and treatment of these disorders.

Malignant lymphoma of the bladder: evidence from 36 cases that low-grade lymphoma of the MALT-type is the most common primary bladder lymphoma.

Patients with malignant lymphoma of the bladder were studied, and three clinical groups were defined: those with primary lymphoma localized in the bladder, lymphoma presenting in the bladder as the first sign of disseminated disease (nonlocalized lymphoma), and recurrent bladder involvement by lymphoma in patients with a history of malignant lymphoma (secondary lymphoma). The differences in these groups regarding lymphoma type, clinical presentation, and clinical outcome were studied. Mayo Clinic Tissue Registry records from 1940 to 1996 were searched to identify patients with lymphomas involving the bladder. The lymphomas were classified based on review of the histology and immunophenotype performed by immunoperoxidase methods. Clinical records were reviewed. Presenting symptoms included urinary frequency, dysuria, hematuria, and lower abdominal and back pain. Primary lymphoma was present in six patients. All were B-cell lineage low-grade lymphomas of the mucosa-associated lymphoid tissue (MALT) type. No patient had recurrent lymphoma or died of lymphoma. Nonlocalized bladder lymphoma occurred in 17 patients; one with low-grade lymphoma of the MALT type, four with follicle center lymphomas, and 12 with large cell lymphomas. Excluding two patients who died postoperatively, median survival was 9 years. Six patients died of lymphoma in the follow-up period. Secondary bladder lymphoma occurred in 13 patients: two with low-grade lymphoma of the MALT type, one with follicle center lymphoma, one with mantle cell lymphoma, and nine with diffuse large cell lymphomas. Median survival in this group was 0.6 years. Low-grade lymphoma of the MALT type was the most frequent type of primary bladder lymphoma and was associated with an excellent prognosis. The bladder can be the presenting site of lymphomatous involvement in patients with more widespread disease. Survival in this group is quite favorable and is presumably dependent on lymphoma histologic type, stage of disease, and other prognostic factors. Bladder involvement by recurrent lymphoma is a sign of widely disseminated disease and is associated with a very poor prognosis.

Pathologic and clinical features of primary pulmonary extranodal marginal zone B-cell lymphoma of MALT type.

We reviewed pathologic, phenotypic, and clinical features of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type primarily involving lung to address unresolved questions regarding behavior and pathologic features of unambiguously diagnosed pulmonary MALT lymphoma. Lung specimens from 50 patients were reviewed. Forty-one had low-grade MALT lymphoma. Nine had low-grade MALT lymphoma and diffuse large B-cell lymphoma. The patients included 32 women and 18 men with a median age of 68 years (range 34-88 years). Half of the patients were asymptomatic at the time lymphoma was diagnosed. Radiographic abnormalities were more commonly unilateral (37 patients) than bilateral (12 patients). Localized masses or nodules occurred in 39 patients. Associated autoimmune disorders (29%) and monoclonal gammopathies (43%) were common. Low-grade lymphomas formed intraparenchymal masses composed of centrocyte-like cells, plasmacytoid lymphocytes, and plasma cells that formed lymphoepithelial lesions and exhibited a lymphangitic growth pattern. Mediastinal lymph nodes were involved histologically in 44% of cases. Lymphoma-specific survival was 71.7% at 10 years, and overall survival was significantly worse than age-and gender-matched control patients. None of the following features predicted those patients who had an adverse outcome: systemic symptoms, presence of autoimmune disorders or paraproteinemia, anatomic distribution and number of pulmonary lesions, lymph node involvement, or presence of anthracycline-treated large B-cell lymphoma.

Detection of t(2;5) in anaplastic large cell lymphoma: comparison of immunohistochemical studies, FISH, and RT-PCR in paraffin-embedded tissue.

Anaplastic large cell lymphoma (ALCL) is associated with the t(2;5)(p23;q35) translocation involving the anaplastic lymphoma kinase gene (ALK) and the nucleophosmin gene (NPM), which result in expression of a novel fusion protein, NPM-ALK (p80). Clinicopathologic studies have shown that ALK expression in ALCL is associated with improved 5-year survival rates when compared with ALCL lacking ALK expression. This study used paraffin-embedded tissue to compare interphase fluorescence in situ hybridization (FISH) and reverse transcriptase-polymerase chain reaction (RT-PCR) for the detection of t(2;5) with immunohistochemical analysis for the detection of ALK protein expression in 27 patients with CD30-positive ALCLs. ALK protein expression was detected with ALK1 antibody in 14 of the 27 patients. The neoplastic cells in 13 of these 14 lymphomas reacted with the p80NPM/ALK antibody. FISH, using a two-color ALK DNA probe, correlated 100% with the immunohistochemical results: a translocation involving the ALK gene was detected in all 14 lymphomas that reacted with anti-ALK1. RT-PCR, performed on 21 lymphomas, detected NPM-ALK mRNA in five of the lymphomas, all of which reacted with anti-ALK1 and showed ALK gene rearrangement by FISH. Lymphomas showing ALK1 reactivity occurred in a younger patient population (median age, 19.5 years) and were associated with improved 5-year survival rates (84%), as compared with lymphomas lacking ALK1 reactivity (median age, 68.0 years; 5-year survival rate, 35%; p = 0.008). We conclude that immunohistochemical studies, using antibody ALK1. and FISH for ALK gene rearrangement are equally effective for identifying patients with ALCL who have a favorable clinical outcome.

Immunomodulation of early engrafted natural killer cells with interleukin-2 and interferon-alpha in autologous stem cell transplantation.

High relapse rates during the first year after autologous stem cell transplantation (ASCT) for multiple myeloma or non-Hodgkin lymphoma are due to the failure of high-dose chemotherapy to eradicate minimal residual disease. Post-ASCT immunorecovery studies have shown that quantities of natural killer (NK) cells return to normal within 1 month post-ASCT in contrast to the recovery of T and B cell populations (up to 1 year). Preclinical studies have demonstrated that NK cells have potent antitumor activity. IL-2 and IFN-alpha enhance NK-cell activity. We investigated the efficacy of IL-2 and IFN-alpha to up-regulate NK-cell cytotoxicity at 14 days post ASCT. Twenty patients undergoing ASCT had PBMCs collected pretransplantation and at 14 days post transplantation. PBMCs (effector cells) from each blood sample were incubated in vitro with IFN-alpha and IL-2 at 10000 IU/ml. NK cell activity was determined by sodium chromate (51)Cr release assay for lysis of K562 target cells. IL-2 and IFN-alpha each increased lysis of K562 cells compared with placebo (effector-to-target ratio, 50:1, P < 0.001). Increased NK cell activity occurred in samples from all patients. IL-2 and IFN-alpha up-regulated NK cell activity at 14 days post ASCT. They may be useful as immunomodulators as early as 14 days post ASCT to eradicate or control minimal residual disease.