Early-stage mantle cell lymphoma: a retrospective analysis from the International Lymphoma Radiation Oncology Group (ILROG).

BACKGROUND: Mantle cell lymphoma (MCL) rarely presents as early-stage disease, but clinical observations suggest that patients who present with early-stage disease may have better outcomes than those with advanced-stage disease. PATIENTS AND METHODS: In this 13-institution study, we examined outcomes among 179 patients with early-stage (stage I or II) MCL in an attempt to identify prognostic factors that influence treatment selection and outcome. Variables examined included clinical characteristics, treatment modality, response to therapy, sites of failure, and survival. RESULTS: Patients were predominantly male (78%) with head and neck being the most common presenting sites (75%). Most failures occurred outside the original disease site (79%). Although the administration of radiation therapy, either alone or with chemotherapy, reduced the risk of local failure, it did not translate into an improved freedom from progression or overall survival (OS). The treatment outcomes were independent of treatment modality. The 10-year OS for patients treated with chemotherapy alone, chemo-radiation therapy and radiation therapy alone were 69%, 62%, and 74% (P = 0.79), and the 10-year freedom from progression were 46%, 43%, and 31% (P = 0.64), respectively. CONCLUSION: Given the excellent OS rates regardless of initial therapy in patients with early-stage MCL, de-intensified therapy to limit treatment-related toxicity is a reasonable approach.

Influence of new late effects on quality of life over time in Hodgkin lymphoma Survivors: a longitudinal survey study.

BACKGROUND: Long-term Hodgkin lymphoma (HL) survivors are known to have diminished quality of life (QoL). However, limited data are available on temporal changes in QoL and factors associated with the changes. METHODS: In 2010, we conducted a follow-up questionnaire study on 273 HL survivors who participated in a 2003 questionnaire study on late effects after HL. The questionnaire items were limited to new late complications and reassessment of QoL and fatigue level, using the Short Form 36 (SF-36) and the Functional Assessment of Chronic Illness Therapy-Fatigue instruments, respectively. We compared the results from the 2003 and the 2010 questionnaires, and QoL score changes between survivors with and without new late complications during the 7-year period. RESULTS: There was a significant decline in the SF-36 Physical Component Summary score (median change, -1.8; P<0.0001) over the time period. The decline was significantly greater among survivors with a new cardiac (P=0.005) or pulmonary (P<0.0001) complication, compared with those without any new complications. The survivors reporting new cardiac complications also experienced significantly greater worsening of fatigue scores (P=0.004). CONCLUSION: The significant association between the development of new cardiopulmonary complications and decline in QoL and energy level of HL survivors provides further support for current efforts to reduce treatment to limit late effects.

Lung malignancies after Hodgkin lymphoma: disease characteristics, detection methods and clinical outcome.

BACKGROUND: Hodgkin lymphoma (HL) survivors have an increased risk of secondary malignancies. We analyzed outcomes in patients with lung cancers following HL treatment. PATIENTS AND METHODS: Cases of thoracic malignancies were retrospectively identified from a multi-institutional database of 1976 patients treated for HL from 1969 to 2007. Data regarding risk factors, disease characteristics and outcomes were obtained from medical records. RESULTS: Lung malignancies were identified in 55 patients a median of 19.5 years after initial HL therapy. Thirty-one patients (56%) had a >10 pack-year history of tobacco use, 48 (87%) received thoracic irradiation and 26 (47%) received alkylating chemotherapy. Of the 42 patients with known stage at lung cancer diagnosis, 23 (55%) were stage IV and 5 (12%) were stage III. The method of lung cancer detection was known for 35 patients; of these, 12 (34%) were detected incidentally. Median survival time after diagnosis was 10 months for all 55 patients. Median survival time for patients with incidentally detected tumors has not been reached with a median follow-up of 39 months. CONCLUSIONS: Lung malignancies diagnosed in patients successfully treated for HL generally have a dismal prognosis. However, a subset of patients diagnosed incidentally may have potentially curable disease.

Salvage radiotherapy in patients with recurrent or refractory primary or secondary central nervous system lymphoma after methotrexate-based chemotherapy.

BACKGROUND: To assess the efficacy of salvage radiation therapy (RT) in patients with recurrent/refractory primary or secondary central nervous system lymphoma (CNSL) after initial methotrexate (MTX)-based chemotherapy and to identify factors associated with treatment outcome. PATIENTS AND METHODS: We reviewed 36 patients with primary or secondary CNSL who relapsed after MTX therapy and received salvage RT. Primary end points were radiographic response and overall survival (OS). RESULTS: After salvage RT, 18 patients (50%) achieved a complete radiographic response and 6 (17%) achieved a partial response, for an overall response rate of 67% [95% confidence interval (CI) 49% to 81%]. The median OS from start of salvage RT was 11.7 months (range: 0.6-94.7). Patients treated with less than five cycles of MTX before failure had a significantly shorter OS than patients who received five or more cycles (9.2 months versus not reached, P = 0.04). Patients with CNSL limited to brain only had a significantly longer OS than patients with disease in the brain and other central nervous system locations (16.5 versus 4.5 months, P=0.01). CONCLUSION: Salvage RT is effective for patients with recurrent/refractory primary or secondary CNSL after initial MTX therapy. Having received five or more cycles of MTX before failure and CNSL limited to the brain at relapse are associated with longer OS.

Prognostic significance of mid- and post-ABVD PET imaging in Hodgkin's lymphoma: the importance of involved-field radiotherapy.

BACKGROUND: Although positron emission tomography (PET) response to chemotherapy (CT) has prognostic significance in Hodgkin's lymphoma (HL), it is unclear whether patients with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG)-PET positivity during and/or after CT can be rendered disease free with consolidative involved-field radiotherapy (IFRT). METHODS: Patients with HL treated with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD)-based CT and radiotherapy (RT) at our institution from January 2000 to March 2007 were eligible. All patients had either a post-treatment PET or PET-CT before initiation of RT or a negative midtreatment PET or PET-CT. The primary end point was failure-free survival (FFS) for patients with and without residual FDG avidity after ABVD. The treatment outcome of patients with interim PET positivity during CT was also reported. RESULTS: Seventy-three patients were included in this study. Twenty patients (out of 46) were PET positive on interim PET, and 13 patients (out of 73) were PET positive at the conclusion of CT. At a median follow-up of 3.4 years for surviving patients, the 2-year FFSs for patients PET-negative versus PET-positive disease after ABVD were 95% and 69%, respectively (P < 0.01). On bivariable Cox regression, post-ABVD positivity (hazard ratio 4.8, P = 0.05) was predictive of disease recurrence after controlling for bulky disease. Of the 20 patients with interim PET positivity, three recurred, with a 2-year FFS of 85%. Among the 13 patients with interim PET positivity, but became PET negative at the completion of CT, the 2-year FFS was 92%. CONCLUSION: Sixty-nine per cent of patients with residual FDG avidity after ABVD were free of disease after consolidative RT, indicating a majority of patients with persistent lymphoma can be cured by sterilizing this PET-positive disease.

Response to low-dose involved-field radiotherapy in patients with non-Hodgkin's lymphoma.

BACKGROUND: The purpose of this study was to analyze response to palliative low-dose involved-field radiotherapy (LD-IF-RT) (two 2-Gy fractions), explore factors predicting for response, and determine the time course to subsequent treatment. PATIENTS AND METHODS: Thirty-three patients with advanced or recurrent indolent non-Hodgkin's lymphoma (NHL) received LD-IF-RT to 43 sites. Response was assessed by physical examination and radiographic studies. Median follow-up for individual sites was 14 months. Fisher's exact test was used to evaluate prognostic factors for response and in-field progression. RESULTS: Overall response was 95%. Thirty-six sites (84%) had a complete response (CR), five sites (12%) had a partial response, and two sites (5%) had progressive disease. The CR rate of head and neck sites was significantly higher than that of pelvic and/or inguinofemoral sites (95% versus 64%, P = 0.04). The CR rate was significantly higher for sites < or =40 mm than for sites >40 mm (90% versus 56%, P = 0.04). Ten sites (23%) had in-field progression diagnosed at a median of 9 months. Sixteen patients (48%) received systemic treatment at a median of 8 months. Fourteen patients (42%) did not require additional treatment. CONCLUSIONS: LD-IF-RT for selected NHL subtypes has excellent local CR and in-field control rates and may postpone the need for systemic therapy.

A prospective study of pulmonary function in Hodgkin's lymphoma patients.

BACKGROUND: To prospectively study changes in lung function in Hodgkin's lymphoma (HL) patients and to explore predictors for these changes over time. METHODS: In all, 52 patients with HL receiving bleomycin-based chemotherapy with (n = 23) or without (n = 29) mediastinal radiotherapy were enrolled. Pretreatment pulmonary function tests were carried out. These were repeated at 1 month, 6 months, and 1 year after therapy. RESULTS: With chemotherapy alone, the median %DLCO declined significantly at 1 month but returned to baseline by 6 months. The median %DLCO did not further decrease with radiotherapy, but remained persistently reduced at 1 year. In patients who received radiotherapy, having >33% of lung volume receive 20 Gy (V20) and a mean lung dose (MLD) of >13 Gy significantly predicted for persistently reduced %DLCO at 6 months (P = 0.035). Smoking significantly predicted for a persistently reduced %DLCO at 1 year (P = 0.036). On multivariable analysis, significant predictors for decline in %DLCO at 1 year were higher baseline %DLCO (P = 0.01), higher MLD (P = 0.02), and a smoking history (P = 0.02). CONCLUSIONS: Several factors contribute to decline in %DLCO in HL patients who received bleomycin-based computed tomography. The identification of threshold radiation dosimetric parameters for reduced lung function may provide guidance in the radiation planning of these patients.

Role of radiation therapy in the treatment of stage I/II mucosa-associated lymphoid tissue lymphoma.

BACKGROUND: Few large studies exist on the outcome of patients treated for stage I/II mucosa-associated lymphoid tissue (MALT) lymphoma. PATIENTS AND METHODS: We retrospectively reviewed the records of 77 patients consecutively treated for stage I (n = 66) or II (n = 11) MALT lymphoma at our institution. Progression-free survival (PFS), freedom from treatment failure (FFTF), and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: The median follow-up time was 61 months (range 2-177 months). Fifty-two patients (68%) received local radiation therapy (RT) alone, 17 (22%) had surgery followed by adjuvant RT, five (6%) had surgery alone, two (3%) had surgery and chemotherapy, and one patient had chemotherapy alone. The median RT dose was 30 Gy (range 18-40 Gy). The 5-year PFS, FFTF, and OS rates were 76%, 78%, and 91%, respectively. The 5-year PFS (79% versus 50%; P = 0.002) and FFTF (81% versus 50%; P = 0.0004) rates were higher for patients who received RT as compared with patients who did not. CONCLUSIONS: The prognosis following treatment of stage I/II MALT lymphoma is excellent. RT improves PFS and FFTF and has an important role in the curative treatment of patients with localized disease.

Long-term results of a prospective trial of mantle irradiation alone for early-stage Hodgkin's disease.

BACKGROUND: To determine the long-term treatment outcome and late effects of mantle irradiation alone in selected patients with early-stage Hodgkin's disease. METHODS: Between 1988 and 2000, 87 patients with pathologic stage (Ann Arbor) I-IIA or clinical stage IA Hodgkin's disease were entered on to a prospective trial of mantle irradiation alone. Patients with B symptoms, large mediastinal adenopathy, or subcarinal or hilar involvement were excluded. The median doses to the mantle field and mediastinum were 36 Gy (range 30.3-40) and 38.6 Gy (range 30.6-44), respectively. The actuarial freedom from treatment failure (FFTF) and overall survival (OS) rates were calculated using the Kaplan-Meier technique. RESULTS: The median follow-up was 107 months (range 23-192). Thirteen of 87 patients (15%) relapsed at a median of 30 months (range 5-62). The 5- and 10-year actuarial FFTF rates were 86% and 84.7%, respectively. All 13 patients who relapsed are alive without evidence of disease at a median of 84 months (range 30-156) post-salvage therapy. Five patients developed a second malignancy at a median of 93 months (range 27-131). The 10-year actuarial risk of a second malignancy was 4.5%. There have been two deaths to date, both due to second malignancies. The 10-year OS rate was 98.2%. CONCLUSION: In selected patients with early-stage Hodgkin's disease, mantle irradiation alone has an excellent long-term survival rate, comparing favorably with the previous standard treatment of extended-field radiation therapy and the current standard of combined modality therapy.

Computed tomography screening for lung cancer in Hodgkin's lymphoma survivors: decision analysis and cost-effectiveness analysis.

BACKGROUND: Hodgkin's lymphoma patients have an elevated risk of developing lung cancer and may be targeted for lung cancer screening. We used a decision-analytic model to estimate the potential clinical benefits and cost-effectiveness of computed tomography (CT) screening for lung cancer in Hodgkin's lymphoma survivors. MATERIALS AND METHODS: We developed a Markov decision-analytic model to compare annual low-dose CT screening versus no screening in a hypothetical cohort of patients diagnosed with stage IA-IIB Hodgkin's lymphoma at age 25, with screening starting 5 years after initial diagnosis. We derived model parameters from published studies and the Surveillance, Epidemiology and End Results (SEER) Program, and assumed that stage-shift produces a survival benefit. RESULTS: Annual CT screening increased survival by 0.64 years for smokers and 0.16 years for non-smokers. The corresponding benefits in quality-adjusted survival were 0.58 quality-adjusted life-years (QALYs) for smokers and 0.14 QALYs for non-smokers. The incremental cost-effectiveness ratios for annual CT screening compared with no screening were $34 100/QALY for smokers and $125 400/QALY for non-smokers. CONCLUSIONS: Our analysis suggests that if early promising results for lung cancer screening hold, CT screening for lung cancer may increase survival and quality-adjusted survival among Hodgkin's lymphoma survivors, with a benefit and incremental cost-effectiveness ratio for smokers comparable to that of other recommended cancer screening strategies.

Clinical course of thoracic cancers in Hodgkin's disease survivors.

BACKGROUND: Hodgkin's disease survivors have a high risk of subsequently developing thoracic cancers. Our goal was to evaluate the prognosis and treatment outcomes of thoracic cancers after Hodgkin's disease. PATIENTS AND METHODS: Thirty-three patients treated for Hodgkin's disease at Harvard-affiliated hospitals subsequently developed small-cell lung carcinoma, non-small-cell lung carcinoma (NSCLC) or mesothelioma. Information was obtained from medical records about the initial treatment for Hodgkin's disease, any salvage therapy, smoking history, and the stage, histology, treatment and survival for thoracic cancers. RESULTS: Of the 33 patients, 29 (88%) had a history of radiotherapy to the thorax, 17 (52%) had received alkylating chemotherapy, and 24 (73%) had a known history of smoking. The median time between diagnosis of Hodgkin's disease and diagnosis of thoracic cancer was 17.3 years (range 1.2-27.9 years). Among patients with NSCLC and a known stage, 85% presented with stage III or stage IV disease. Among patients whose treatment details were available, 40% underwent surgery, 40% received radiotherapy and 65% received chemotherapy. The median survival was 9 months (range 1-47 months). CONCLUSIONS: Most patients with thoracic cancers after Hodgkin's disease have a history of exposure to risk factors and present at an advanced stage. Patients with thoracic cancers after Hodgkin's disease have a poor survival.

Comparison of MOPP versus ABVD as salvage therapy in patients who relapse after radiation therapy alone for Hodgkin's disease.

BACKGROUND: The aim of this study was to determine salvage outcome in patients with Hodgkin's disease who relapse after radiation therapy, and to compare the efficacy of mechlorethamine, Oncovin, procarbazine and prednisone (MOPP) versus Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) as salvage treatment. PATIENTS AND METHODS: One hundred patients with Hodgkin's disease (97 with stage I-II disease at presentation) who relapsed after radiation therapy alone were salvaged with either MOPP or ABVD. Freedom from second relapse (FFSR) and overall survival (OS) were determined, and prognostic factors for salvage outcome were evaluated. RESULTS: The median follow-up time since salvage therapy was 12 years. The 10-year FFSR and OS rates were 70% and 89%, respectively. Forty-one patients were salvaged with MOPP and 59 received ABVD. The type of salvage chemotherapy did not significantly influence FFSR or OS. Age >50 years at initial diagnosis was the only significant predictor for an inferior FFSR and OS on both univariate and multivariate analyses. CONCLUSIONS: The two salvage regimens of MOPP and ABVD had similar efficacy in this group of patients with predominantly early-stage disease at initial radiation therapy. The inferior salvage outcome in patients aged >50 years is a contributing factor to the overall poor prognosis of patients presenting with Hodgkin's disease at an older age.

Costs and effectiveness of staging and treatment options in early-stage Hodgkin's disease.

PURPOSE: Using a cost-effectiveness analysis, to weigh the costs and benefits of the different staging and treatment options in early-stage Hodgkin's disease. METHODS: We constructed a decision-analytic model for a hypothetical cohort of 25-year-old patients with early-stage Hodgkin's disease. Markov models were used to simulate the lifetime costs and prognosis of each staging and treatment strategy. Baseline probabilities and cost estimates were derived from published studies and bills of relevant patient cohorts. RESULTS: Among the six management strategies considered, the incremental cost-effectiveness ratio of laparotomy and tailored treatment compared with mantle and para-aortic-splenic radiation therapy in all clinical stage I-II patients was $24,100/quality-adjusted life year, while that of the strategy of combined modality therapy in all clinical stage I-II patients compared with laparotomy was $61,700/quality-adjusted life year. All the remaining strategies were dominated by one of these three strategies. Sensitivity analysis showed that the cost-effectiveness ratios were driven predominantly by the effectiveness rather than the cost of each strategy. In particular, the analysis was heavily influenced by the utility of the post-laparotomy health state. CONCLUSIONS: In considering the various alternative management strategies in early-stage Hodgkin's disease, even very small gains in effectiveness were enough to justify the additional costs of more expensive treatment options.

Clinical and pathologic features of breast cancers in women treated for Hodgkin's disease: a case-control study.

The goal of this study was to assess whether there are clinical or pathologic differences between radiation-associated breast cancers developing after treatment for Hodgkin's disease and spontaneously arising breast cancers. Clinical and pathologic data were reviewed for 26 Hodgkin's disease patients who received irradiation and subsequently developed breast cancer (cases) and 26 age- and stage-matched patients with sporadic breast cancers (controls). The median age at diagnosis of Hodgkin's disease was 21 years (range 11-40 years), and the median interval between Hodgkin's disease and breast cancer diagnosis was 15 years (range 4-27 years). There were no differences between cases and controls with regard to clinical factors. Cases had a lower frequency of histologic grade III tumors (38% versus 65%, p = 0.09) and moderate to marked mononuclear inflammatory cell reaction (11% versus 35%, p = 0.03). When these covariates were combined, grade III tumors in conjunction with mononuclear inflammatory cell reaction were also seen less frequently in the case group than in the control group (11% versus 31%, p = 0.06). Seven cases developed additional cancers, but no additional cancers developed in the control group (p = 0.01). Patients who developed breast cancers after Hodgkin's disease did not differ from patients with spontaneous breast cancers, with regard to clinical factors. However, the lower frequency of high-grade tumors and moderate to marked mononuclear inflammatory cell reaction among the cases suggests that radiation-associated breast cancers may differ from spontaneously arising cancers in their pathogenesis. Cases appeared to be at increased risk of developing additional cancers, but we cannot exclude surveillance as a possible contributing factor.

Significance of epitrochlear lymph node involvement in Hodgkin disease.

BACKGROUND: Epitrochlear involvement in Hodgkin disease (HD) is a rare event, with only limited data available describing this unique presentation, its treatment, and long term outcome. METHODS: Between 1968 and 1997, 1180 patients with clinical stage (CS) IA-IIB HD were treated at the Harvard Longwood Area Hospitals, among whom 11 were identified to have presented with epitrochlear lymphadenopathy (1%). Together with 6 CS III-IV patients also with clinically involved epitrochlear lymph nodes at diagnosis, these 17 patients form the basis of the current study. The clinical characteristics, histopathologic distribution, and treatment details are described. Two radiation therapy techniques were used: the "single field" and "separate-field" techniques. The median dose to the epitrochlear region was 3600 centigrays. Survival outcome was calculated by the Kaplan-Meier method. The median follow-up was 17 years. RESULTS: The actuarial 15-year freedom from recurrence, cause specific survival, and overall survival (OS) rates for the 17 patients were 70%, 88%, and 70%, respectively. Among the CS IA-IIB patients, the 15-year OS rates of the 1169 patients and 11 patients without and with epitrochlear involvement were 80% and 90%, respectively. Two of the 11 CS IA-IIB and 3 of the 6 CS III-IV patients experienced recurrence. None of the recurrences involved the epitrochlear or ipsilateral brachial region regardless of the treatment technique, and no complications from the local radiation therapy were observed. CONCLUSIONS: Feasible and effective radiation therapy techniques are available for patients with HD with epitrochlear involvement. If appropriately treated, the prognosis of patients with this unique presentation appears to be similar to that of other HD patients.

Results of a prospective trial of mantle irradiation alone for selected patients with early-stage Hodgkin's disease.

PURPOSE: To determine the efficacy of mantle radiation therapy alone in selected patients with early-stage Hodgkin's disease. PATIENTS AND METHODS: Between October 1988 and June 2000, 87 selected patients with pathologic stage (PS) IA to IIA or clinical stage (CS) IA Hodgkin's disease were entered onto a single-arm prospective trial of treatment with mantle irradiation alone. Eighty-three of 87 patients had > or = 1 year of follow-up after completion of mantle irradiation and were included for analysis in this study. Thirty-seven patients had PS IA, 40 had PS IIA, and six had CS IA disease. Histologic distribution was as follows: nodular sclerosis (n = 64), lymphocyte predominant (n = 15), mixed cellularity (n = 3), and unclassified (n = 1). Median follow-up time was 61 months. RESULTS: The 5-year actuarial rates of freedom from treatment failure (FFTF) and overall survival were 86% and 100%, respectively. Eleven of 83 patients relapsed at a median time of 27 months. Nine of the 11 relapses contained at least a component below the diaphragm. All 11 patients who developed recurrent disease were alive without evidence of Hodgkin's disease at the time of last follow-up. The 5-year FFTF in the 43 stage I patients was 92% compared with 78% in the 40 stage II patients (P =.04). Significant differences in FFTF were not seen by histology (P =.26) or by European Organization for Research and Treatment of Cancer H-5F eligibility (P =.25). CONCLUSION: Mantle irradiation alone in selected patients with early-stage Hodgkin's disease is associated with disease control rates comparable to those seen with extended field irradiation. The FFTF is especially favorable among stage I patients.

Immunogenicity of Ly5 (CD45)-antigens hampers long-term engraftment following minimal conditioning in a murine bone marrow transplantation model.

Various techniques are available for distinguishing donor from host cells evaluating the efficacy of conditioning regimen for experimental bone marrow transplantation (BMT). Techniques include the use of extracellular immunological markers, such as Ly5 (CD45), and intracellular biochemical markers, such as glucose-phosphate-isomerase (Gpi). Because Ly5 is an extracellular protein, the disparity between donor (Ly5.1) and host (Ly5.2) antigens may induce a weak immune response whereas with Gpi, no immune response is expected. This difference may be of particular concern in experimental transplantation approaches that use minimal conditioning such as low-dose total body irradiation (TBI). Such mild conditioning may not induce the immunosuppression required to overcome host rejection of Ly5 disparate cells. To compare the relative engraftment of Ly5.1 and Gpi-1(a) donor marrow, B6 (Gpi-1(b)/Ly5.2) mice were irradiated with low-level TBI (0-6 Gy) and transplanted with several bone marrow (BM) doses (2 x 10(6)-5 x 10(7) cells). At 8, 26, and 52 weeks post-BMT, the level of donor engraftment was measured using flow cytometry (Ly5) or Gpi-electrophoresis. Lower engraftment levels were found in mice transplanted with Ly5 congenic BM in groups given low-dose TBI (< or = 4 Gy) and/or low doses of BM cells (BMC) (2 x 10(6)). However, when higher TBI or BMC doses were used, similar engraftment levels were found, suggesting sufficient immune suppression to allow equal engraftment of both sources of BM. These data suggest that even a minor phenotypic disparity between donor and host, such as Ly5, may necessitate high-dose TBI to prevent rejection. The combination of low-dose TBI or other nonmyeloablative conditioning strategies with small numbers of BMC may lead to reduced engraftment when extracellular immunological markers such as Ly5 are used for transplantation studies. Therefore, small immunological differences must be considered when using the Ly5 marker for engraftment.

Respiratory burst of neutrophils is not required for stem cell mobilization in mice.

It has been suggested that mature neutrophils may play an essential role in the cascade of events leading to egress of stem cells from the bone marrow to the peripheral blood. To investigate further the role of mature neutrophils and of reactive oxygen intermediates (ROIs), known to be involved in the signal transduction of neutrophils, we used mice deficient in respiratory burst, and thus the production of ROIs, to study the involvement of this activation pathway in stem cell mobilization. B6 mice with chronic granulomatous disease (CGD) received either cyclophosphamide (200 mg/kg) on day 1 and granulocyte colony-stimulating factor (G-CSF) (250 microg/kg/d) on days 3-6 or a single dose of interleukin 8 (IL-8; 30 microg/mouse) as a mobilization regimen. On day 7, the number of stem and progenitor cells in blood and bone marrow was compared with control B6 animals (with intact respiratory burst). White blood cell counts, bone marrow cellularity and the frequency of granulocyte-macrophage colony-forming cells (GM-CFC), and cobblestone area-forming cells (CAFC) on days 7 (CAFC-7) and 28 (CAFC-28) were determined. After cyclophosphamide and G-CSF (CY + G), both mouse strains showed considerable mobilization of CAFC-7 and CFU-GM to the blood. Normal mice showed up to a 1905-fold increase in progenitors per ml blood, whereas CGD mice showed up to a 264-fold increase in blood progenitors. IL-8 also induced mobilization in both mouse strains. In addition to progenitors, primitive stem cells measured as CAFC-28 and as CAFC at day 35 were also mobilized by both mobilization protocols in normal as well as in CGD mice. In conclusion, respiratory burst and the subsequent signal transduction pathway do not appear to be required for mobilization of stem cells. Accordingly, neutrophils either are not involved in stem cell mobilization or other signalling pathways within neutrophils must exist that lead to the release of factors which activate stem cell egress from the bone marrow.