Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma.

Lymphomas express a tumor-specific antigen which can be targeted by cancer vaccination. We evaluated the ability of a new idiotype protein vaccine formulation to eradicate residual t(14;18)+ lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission. All 11 patients with detectable translocations in their primary tumors had cells from the malignant clone detectable in their blood by PCR both at diagnosis and after chemotherapy, despite being in complete remission. However, 8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissions. Tumor-specific cytotoxic CD8+ and CD4+ T cells were uniformly found (19 of 20 patients), whereas antibodies were detected, but apparently were not required for molecular remission. Vaccination was thus associated with clearance of residual tumor cells from blood and long-term disease-free survival. The demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte-monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting.

Rapid, high-yield production in plants of individualized idiotype vaccines for non-Hodgkin's lymphoma.

BACKGROUND: Animal and clinical studies with plant-produced single-chain variable fragment lymphoma vaccines have demonstrated specific immunogenicity and safety. However, the expression levels of such fragments were highly variable and required complex engineering of the linkers. Moreover, the downstream processing could not be built around standard methods like protein A affinity capture. DESIGN: We report a novel vaccine manufacturing process, magnifection, devoid of the above-mentioned shortcomings and allowing consistent and efficient expression in plants of whole immunoglobulins (Igs). RESULTS: Full idiotype (Id)-containing IgG molecules of 20 lymphoma patients and 2 mouse lymphoma models were expressed at levels between 0.5 and 4.8 g/kg of leaf biomass. Protein A affinity capture purification yielded antigens of pharmaceutical purity. Several patient Igs produced in plants showed specific cross-reactivity with sera derived from the same patients immunized with hybridoma-produced Id vaccine. Mice vaccinated with plant- or hybridoma-produced Igs showed comparable protection levels in tumor challenge studies. CONCLUSIONS: This manufacturing process is reliable and robust, the manufacturing time from biopsy to vaccine is <12 weeks and the expression and purification of antigens require only 2 weeks. The process is also broadly applicable for manufacturing monoclonal antibodies in plants, providing 50- to 1000-fold higher yields than alternative plant expression methods.

Anti-idiotype antibodies in cancer treatment.

As a cancer immunotherapy tool, idiotypes (Ids) have been used in different ways over the last three decades, depending on the actual human tumor cell target. It all started with passive, monoclonal, anti-Id antibody treatment of B-cell lymphoma, a setting in which results were tantalizing, but logistics unsustainable. It then moved toward the development of anti-Id vaccines for the treatment of the same tumors, a setting in which we have recently provided the first formal proof of principle of clinical benefit associated with the use of a human cancer vaccine. Meanwhile, it also expanded in the direction of exploiting the antigenic mimicry of some Ids with Id-unrelated, tumor-associated antigens for the immunotherapy of a number of solid tumors, a setting in which clinical results are still far from being consolidated. All in all, over the years Id-based immunotherapy has paved the way for a number of seminal therapeutic improvements for cancer patients, including the development of most if not all Id-unrelated monoclonal antibodies that have recently revolutionized the field.

[Anemia in chronic lymphatic leukemia: is erythropoietin the solution?]. / La anemia en la leucemia linfática crónica: Es la eritropoyetina la solución del problema?

Anemia is a common complication in the clinical course of chronic lymphocytic leukemia. Low hemoglobin levels both correlate with an adverse prognosis and adversely affect the quality of life of chronic lymphocytic leukemia patients. Different physiopathological phenomena may lead to anemia: marrow infiltration, hypersplenism, immune hemolysis or toxicity of chemotherapy. Treatment with human recombinant erythropoietic agents has been shown to be effective for anemia associated with different lymphoproliferative syndromes. This paper analyses the available evidence on erythropoietic agent treatment for chronic lymphocytic leukemia associated anemia. The comparative effect of different dosage schemes, the role of possible response-prediction factors such as the endogenous erythropoietin level and the results achieved using darbopoietin alpha are reviewed.

[The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases]. / El potencial de la inmunomodulación con anticuerpos monoclonales anti-CD137 (4-1BB) para terapia de enfermedades malignas e infecciones virales crónicas.

Pharmacological intervention on the immune system to achieve more intense lymphocyte responses has potential application in tumour immunology and in the treatment of chronic viral diseases. Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4) that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start.

Gemcitabine treatment in pretreated cutaneous T-cell lymphoma: experience in 44 patients.

PURPOSE: To evaluate the efficacy and toxicity of gemcitabine, a novel pyrimidine antimetabolite with a low-toxicity profile and activity in several solid tumors, in patients with relapsed or refractory cutaneous T-cell lymphomas. PATIENTS AND METHODS: Between May 1997 and February 1999, 44 previously treated patients with mycosis fungoides (MF; n = 30) and peripheral T-cell lymphoma unspecified (PTCLU) with exclusive skin involvement (n = 14) were enrolled onto a two-institution, phase II trial and treated with gemcitabine. This drug was given on days 1, 8, and 15 of a 28-day schedule at a dose of 1,200 mg/m(2) intravenously over 30 minutes for a total of three courses. RESULTS: Of the 44 patients, five (11. 5%) achieved complete responses (CRs), 26 (59%) partial responses (PRs), and the remaining 13 showed no benefit from the treatment. Two of the CRs were histologically confirmed. The CR and PR rates were the same for patients with MF and those with PTCLU, respectively. No difference in terms of overall response rate was observed between relapsed and refractory patients. The median durations of CR and PR were 15 months (range, 6 to 22 months) and 10 months (range, 2 to 15 months), respectively. Treatment was well tolerated; hematologic toxicity was mild, and no nausea/vomiting or organ toxicity was recorded. CONCLUSION: The results of the present phase II study show activity of gemcitabine as a single agent in patients with pretreated cutaneous T-cell lymphoma. Further studies that use gemcitabine alone or in combination with other drugs in earlier stages of the disease are needed.

Clinical implications of serum levels of soluble CD30 in 70 adult anaplastic large-cell lymphoma patients.

PURPOSE: In the last few years, the search for new biologic markers in high-grade non-Hodgkin's lymphomas has provided important results. In particular, soluble CD30 (sCD30) levels were elevated in most patients with Hodgkin's disease (HD) and anaplastic large-cell lymphoma (ALCL). PATIENTS AND METHODS: From September 1988 to October 1993, treatment was completed in 70 previously untreated patients with ALCL, of whom 38 had the common type (ALCL-CT) and 32 had the Hodgkin's-like subtype (ALCL-HL). Serum sCD30 levels were measured at the time of diagnosis and after induction polychemotherapy in all patients; in addition, the initial sCD30 levels were compared with those obtained from 50 stage-matched patients with HD. RESULTS: Pretreatment levels of sCD30 were highly elevated in the stage-matched group of HD patients compared with healthy controls; median sCD30 levels in patients with ALCL-CT and ALCL-HL were 18 and seven times higher, respectively, than in patients with HD. The sCD30 level normalized on achievement of complete response (CR). The risk of lower relapse-free survival was associated with bulky disease, advanced stage, and high pretreatment sCD30 levels; the risk of lower overall survival was associated with advanced stage and pretreatment levels of sCD30 in both univariate and multivariate analysis. CONCLUSION: The results of this study suggest that sCD30 is a specific prognostic indicator of the risk for lower complete response rate and relapse-free expectancy for patients with ALCL.

Anaplastic large-cell lymphoma: clinical and prognostic evaluation of 90 adult patients.

PURPOSE: During the last few years, the application of CD30 monoclonal antibodies has led to the identification of a new lymphoma entity, termed anaplastic large cell lymphoma (ALCL). This tumor includes four distinct histologic subtypes, among which the Hodgkin's-like/Hodgkin's-related one (ALCL-HL) shares morphologic and phenotypic features with Hodgkin's disease (HD). PATIENTS AND METHODS: From September 1988 to October 1993, 90 ALCL patients were treated with third-generation chemotherapy regimens (either vincristine, cyclophosphamide, fluorouracil, cytarabine, doxorubicin, methotrexate with leucovorin, and prednisone [F-MACHOP] or methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B]) during the course of an Italian multicentric randomized trial on high-grade non-Hodgkin's lymphomas (HG-NHL). In particular, 47 patients had ALCL of the common type (ALCL-CT) and 43 ALCL-HL. Null phenotype was the most common (39.8%), while T-cell, B-cell, and hybrid forms accounted for 35.5%, 22.2%, and 2.5%, respectively. RESULTS: Complete remission (CR) was achieved in 66 of 90 (73.5%) patients (33 of 47 [70%] with ALCL-CT and 33 of 43 [77%] with ALCL-HL). The majority of the patients in CR (56.5%) were alive and well at a median follow-up time of 38 months; no significant differences were observed between the two histologic groups, with the rate of complete responders being 49% and 65% in ALCL-CT and ALCL-HL, respectively. The probability of relapse-free survival (RFS), projected at 63 months, was 67% for ALCL-CT and 82% for ALCL-HL. The risk of lower CR and RFS rates was associated with the presence of bulky disease, advanced stage, and B symptoms. CONCLUSION: The data of the present study confirm that ALCL responds to third-generation chemotherapy regimens similarly to other aggressive malignant lymphomas in terms of both CR and RFS rates.

Nongastrointestinal low-grade mucosa-associated lymphoid tissue lymphoma: analysis of 75 patients.

PURPOSE: Nongastrointestinal locations represent about 30% to 40% of all low-grade mucosa-associated lymphoid tissue (MALT) lymphomas. We report a retrospective analysis of 75 patients with nongastrointestinal low-grade MALT lymphoma, presenting their clinical, therapeutic, and follow-up data with respect to the initial location of the lymphoma. PATIENTS AND METHODS: From January 1988 to October 1997, 75 patients with untreated nongastrointestinal low-grade MALT lymphoma were subjected to treatments ranging from local radiotherapy and local interferon alfa administration to chemotherapy. The lymphomas were located in the lung (19 patients), orbital soft tissue (16 patients), skin (seven patients), thyroid (seven patients), lachrymal gland (six patients), conjunctiva (six patients), salivary gland (six patients), breast (three patients), eyelid (two patients), larynx (one patient), bone marrow (one patient), and trachea (one patient). RESULTS: Complete and partial remissions were achieved in 59 (79%) and 16 (21%) of the 75 patients, respectively, with an overall response rate of 100%. All but two of the patients are still alive, with a median follow-up of 47 months; these two patients died from other causes. The estimated time to treatment failure rate is 30% at 5 years. In the thyroid and lachrymal gland sites, no relapses were reported. CONCLUSION: Our data regarding the largest reported series of nongastrointestinal MALT lymphomas confirm the good prognosis of this particular clinicopathologic entity and the significant efficacy of different therapeutic approaches to specific sites.

Randomized trial of fludarabine versus fludarabine and idarubicin as frontline treatment in patients with indolent or mantle-cell lymphoma.

PURPOSE: A first comparative trial of fludarabine (FLU) alone versus FLU plus idarubicin (FLU-ID) for indolent or mantle-cell lymphomas. PATIENTS AND METHODS: From September 1995 to July 1998, 199 patients aged 25 to 65 years (median, 54 years) with newly diagnosed stages II to IV indolent or mantle-cell lymphomas (standard risk according to the International Prognostic Index) were enrolled onto a multicenter, 1:1 randomized study. Of the 199 patients who were able to be assessed, 101 were assigned to the FLU group (six monthly cycles of FLU 25 mg/m(2)/d on days 1 through 5) and 98 to the FLU-ID group (six monthly cycles of FLU 25 mg/m(2)/d on days 1 through 3 and idarubicin 12 mg/m(2) on day 1). RESULTS: In the FLU group, complete response (CR) and partial response rates were 47% and 37%, respectively, whereas in the FLU-ID group, they were 39% and 42%, respectively. In-depth analysis of the CR rate with respect to histologic type showed that FLU seemed to be superior to FLU-ID in treating follicular lymphomas (60% v 40%, respectively), whereas FLU-ID seemed to be more effective than FLU in treating nonfollicular lymphomas (small lymphocytic, 43% v 29%, respectively; immunocytoma, 38% v 23%, respectively; P = not significant), excluding the mantle-cell subset (in which there was no difference between the two groups). No striking differences were observed between the two protocols in terms of overall response or toxicity, which was generally mild. However, with a median follow-up of 19 months, only 29 patients (62%) who received FLU alone have maintained their initial CR, compared with 32 (84%) of those who received FLU-ID therapy (P =.021). CONCLUSION: Although the FLU-ID regimen may not significantly improve the induction of CR in most indolent-lymphoma patients, our preliminary data do suggest that, with respect to FLU alone, it may be capable of conferring a longer-lasting CR and that it might be superior in terms of CR rate in small lymphocytic and immunocytoma subtypes.

Anti-idiotype vaccines for human follicular lymphoma.

Cancer vaccines are conceived as therapeutic tools, in contrast to the prophylactic vaccines that have resolved the problem of a number of infectious diseases in a highly cost-effective way. Over the last decade, anti-idiotype vaccines for human follicular lymphoma have started to come into their own. Whereas 10 years ago it was not even known whether patients could be immunized against an antigen of their own tumor, a phase III clinical trial based on this finding is now already underway. The rapidity of this development encourages the hope that active immunotherapy may become decisive in oncology sooner than expected. Many important results have already been achieved. These include evidence of vaccine-induced, tumor-specific humoral and cellular responses along with the first documented molecular remissions following vaccination. Crucial questions still awaiting an answer include: do Id vaccines actually cure at least a fraction of FL patients? What is the most effective vaccine formulation? Is it possible to reduce the workload involved in producing an effective Id vaccine?

A single prior course of BCNU-cisplatin chemotherapy has a significant deleterious effect on mobilization kinetics of otherwise untreated patients.

Extensive prior treatment with cytotoxic agents is associated with impaired mobilization of hematopoietic cells. To assess the effect of a single course of standard-dose chemotherapy (CT), we compared the results of filgrastim-induced mobilization among two sequential groups of grade III-IV malignant glioma patients included in a hematopoietic transplantation program. The first group (21 patients) had never been treated with CT until 2 days after surgery, when they received a course of 100 mg/m2 BCNU (i.v.) and 100 mg intracarotid cisplatin for cytoreduction (not for mobilization). At 1 month after this CT, they were mobilized with 12 microg/kg filgrastim. The second group (22 patients) was mobilized with the same dose of filgrastim directly after the surgery, without having ever received any prior CT. The blood level of CD34+ cells was significantly lower in the CT-treated patients, both on the fourth day of filgrastim (15 vs 36 cells x 10(6)/l; P=0.01) and on the fifth (25 vs 58 cells x 10(6)/l; P=0.003), as it was the number of CD34+ cells collected per apheresis (1.3 vs 3.5 x 10(6)/l; P<0.0005). The toxic effect of a single course of BCNU-cisplatin CT led to significant impairment of the filgrastim-induced mobilization response.

Adult Burkitt's lymphoma: clinical and prognostic evaluation of 20 patients.

Burkitt's lymphoma (BL), a rapidly growing lymphoma, is recognized by its aggressive course, brief median survival, and low rates of long-term survival for patients. Several polychemotherapeutic approaches are utilized. Twenty adult patients with BL identified according to the Kiel classification were analysed retrospectively. Therapeutic modifications depended upon the different times of the diagnosis. Eight patients received the LSA2-L2 regimen, 11 patients were treated with third generation polychemotherapeutic regimens for high-grade non-Hodgkin's lymphomas: F-MACHOP and MACOP-B, and 1 elderly patient was given the COP regimen. Of the 11 patients treated with cyclic conventional therapy (7 with F-MACHOP and 4 with MACOP-B), 8 achieved a complete response (CR). Of the 8 patients who were given the LSA2-L2 protocol, 4 obtained a CR. One elderly patient treated with the COP regimen obtained a partial response. Early stage of disease, low levels of LDH, and the absence of bone marrow involvement were characteristics of patients with good prognoses. Effective conventional third-generation polychemotherapy regimens (F-MACHOP and MACOP-B), normally used for high-grade non-Hodgkin's lymphomas, were equally effective for a large fraction of adults with BL. Furthermore, our study confirms the important role of LDH level, stage, and bone marrow involvement as prognostic factors in BL as well as the roles of tumor burden in the CR rate and relapse-free survival.

All-trans retinoic acid in the treatment of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a group of hematopoietic disorders characterized by uni- or multilineage maturation defects of the bone marrow. Controversial therapeutic results have been obtained using growth factors or differentiating agents such as 13-cis retinoic acid. In this pilot study we evaluated the effects of all-trans retinoic acid (ATRA) in 10 MDS patients (5 male, 5 female). Six patients had refractory anemia (RA), 1 had refractory anemia with excess of blasts (RAEB), and 3 had refractory anemia with excess of blasts in transformation (RAEB-t). All patients received the same dose of ATRA (45 mg/sqm/day) orally for 6 weeks. A rise in hemoglobin concentration > 1g/dl was observed in 3/10 patients, while 5/10 patients showed an increase in granulocyte count > 0.5 x 10(9)/l without concomitant increase in the percentage of blast cells in the bone marrow. A rise in the platelet count > 50 x 10(9)/l was observed in 1/10 patients. All the effects were transient and maximal responses were obtained by the fourth week of treatment. Thereafter, the peripheral blood counts started to drop again, reaching pre-therapy values by the end of the treatment. This phenomenon could be attributed either to the exhaustion of an ATRA-responding cell pool, the development of cellular resistance to ATRA or to a reduction of plasma ATRA levels after prolonged treatment. According to our results, it seems that ATRA might have therapeutic efficacy in MDS, particularly if its effect could be improved by combinations with other differentiating agents or growth factors.

Massive mediastinal involvement in stage I-II Hodgkin's disease: response to combined modality treatment.

Thirty-seven patients with stage I-II Hodgkin's disease and massive mediastinal involvement, observed between June 1981 and November 1989, underwent combined modality treatment. This treatment included: 3 cycles of mechlorethamine, vincristine, procarbazine, and prednisone followed by mantle-field irradiation, and subsequently by 3 additional cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Thirty-five (95%) patients achieved complete responses and only 2 (5%) had partial responses. All the complete responders are living and relapse-free at a median follow-up of 62 months; no major toxic reactions were recorded. These data suggest, as did those of other studies, that combined modality therapy is superior to either radiotherapy or chemotherapy alone for patients in stage I-II with bulky disease, especially in the mediastinum. In fact, in these particular patients, if adequately treated with a combination of chemotherapy and radiotherapy, the role of massive mediastinal involvement as a poor prognostic factor appears to be less significant.

Adult lymphoblastic lymphoma: clinical features and prognostic factors in 53 patients.

Lymphoblastic lymphoma (LBL) in adult patients is recognized as a particular entity in the high-grade non-Hodgkin's lymphoma (HG-NHL) group with characteristic clinical and prognostic features. Initially, polychemotherapy normally used in HG-NHL failed to produce long-term relapse-free survival because of progression disease in the CNS and in the bone marrow. Subsequently, the intensification of therapy using multimodality aggressive acute lymphoblastic leukemia (ALL) treatments led to an increase in long-term relapse-free survival. We analyzed retrospectively 53 adult patients with LBL according to the Kiel classification and the criteria by Nathwani et al. Therapeutic modifications depended upon the different times of diagnosis. Twenty-one patients received the modified L17 regimen, 13 patients were treated with the L0288 regimen, and 19 patients were submitted to the L20 protocol. There was no significant differences in CR rates among the three protocols: 48% vs 54% vs 63%, respectively. Nineteen of 29 patients who achieved CR were alive and relapse-free at a median follow-up of 84 months. Ten of the CR patients underwent autologous bone marrow transplantation (ABMT) to consolidate the first response and 7 of them are alive and relapse-free. Early stage of disease, age < 30 years, low LDH levels, the absence of leukemic phase at diagnosis, and, in particular the attainment of CR were all features of patients with good prognosis. Our study confirms the role of intensive polychemotherapeutic regimens including CNS prophylaxis, the significance of a score model of prognostic factors, and of the role of ABMT (or allogeneic bone marrow transplantation) in the treatment of adult LBL.

Primary gastric lymphoma: a clinical and therapeutic evaluation of 82 patients.

Eighty-two patients with primary gastric (IE, II1E, and II2E) non-Hodgkin's lymphoma according to the Musshoff's staging system were treated with combined modality including surgery with/without radiotherapy between January 1985 and December 1991. According to the Updated Kiel classification 54 had high-grade histologic subtypes and 28 low-grade. The strategy throughout the study was to resect primary tumor: all patients underwent gastrectomy, 40 subtotal and 42 total gastrectomy. The resection permitted complete surgical staging utilizing three pathologic features: disease confined within or beyond the serosa, negative/positive regional lymph nodes, and negative/positive surgical margins. If there was no evidence of these pathologic factors, the patients who underwent surgery alone received no further radiotherapy. On the other hand, all patients who presented at least one of three pathologic factors were treated with adjuvant radiotherapy after the resection. All except 14 patients presented at least one of the pathologic features and 50 (61%) patients had involvement of the whole gastric wall. Radiotherapy included the gastric bed and para-aortic lymph nodes and, for the patients, who had positive regional lymph nodes in combination with the complete involvement of the gastric wall, the irradiation included the whole abdominal approach. The complete response rate was 97% and the 9-year disease-free survival was 93%. All but one of the 5 relapses occurred within 18 months stressing the need for more specific staging. Gastric resection with/without radiotherapy may still represent the primary therapeutic procedure in early stage gastric non-Hodgkin's lymphoma.

Radiotherapy in early stage Hodgkin's disease.

Ninety-nine patients with "standard risk" Stage IA-IIA Hodgkin's disease observed between January 1983 and December 1990, received radiotherapy only. The complete response rate was 98% (97/99). Twenty-one patients (21%) relapsed, 17 of whom (81%) obtained a second complete remission. The projected 9-year overall survival and disease-free survival were 95% and 78%, respectively. In this study our goals were to reduce the irradiation volumes, to decrease the number of splenectomies performed at diagnosis, and to utilize radiotherapy alone in these patients. We were able to reduce the irradiation volumes in over 50% and 80% of the patients with disease in the upper torso and subdiaphragm, respectively. Furthermore, this therapeutic approach permitted us to reduce the acute and long-term toxic effects related to splenectomy and combined modality treatment.

Primary Mediastinal B-cell lymphoma with sclerosis: clinical and therapeutic evaluation of 22 patients.

In the last decade, there have been several reports on what is now recognized as a new clinical and pathological entity termed primarily mediastinal B-cell lymphoma (PMBCL) with sclerosis. This lymphoma presents unique clinical characteristics with an aggressive outcome and, at present, the best approach seems to be a combination of chemotherapy and radiotherapy. Between June 1989 and September 1994, twenty-two previously untreated patients with PMBCL with sclerosis were treated with a combination of third-generation chemotherapy regimen (MACOP-B or F-MACHOP) and mediastinal irradiation. All the patients presented with bulky mediastinal involvement; the radiologic clinical stage with evaluation of tumor size included computed tomography and Gallium-67-citrate SPECT. Twenty-one patients (95%) achieved a complete response and only one was resistant to treatment. Regarding 67Ga SPECT, 6 patients, including the nonresponder, showed persistent abnormal 67Ga uptake after chemotherapy; however after the mediastinal radiotherapy, all the patients except for the nonresponder were 67Ga-negative. The overall survival was 87%, with a median follow-up of 24 months from the time of diagnosis. Two of the patients who achieved complete response relapsed 7 and 10 months after completion of treatment, respectively. The relapse-free survival rate was 89% at 62 months (median 20 months). In patients presenting with bulky mediastinal PMBCL with sclerosis combined modality treatment using third-generation chemotherapy regimens and radiotherapy induces a good remission rate with greater than 80% chance of surviving disease-free, at 2 years. A longer follow-up before definitive conclusions are drawn is still warranted.

Factor VIII inhibitor prior to and during secondary acute nonlymphocytic leukemia in a patient with cured Hodgkin's disease.

We report a 54-year-old patient with Hodgkin's disease who achieved a complete remission after combined modality treatment. Three years later the patient developed a severe hemorrhagic syndrome, concomitant with the onset of a factor VIII inhibitor in plasma. The control of very proteiform bleedings was extremely difficult, even with plasmaphereses, as well as with immunosuppressive and substitutive therapies. Two years later, a secondary acute nonlymphocytic leukemia (ANLL) was diagnosed. Two courses of chemotherapy with fludarabine, cytosine arabinoside and G-CSF (FLAG) were able to obtain a complete remission. Hemorrhagic complications were mainly linked to thrombocytopenia and continued until recovery of thrombopoiesis. Factor VIII inhibitor levels and related clinical symptoms decreased progressively. In conclusion, we suggest that FLAG succeeded in inhibiting an abnormal lymphoid clone responsible for factor VIII inhibitor production, suggesting a possible role for intensive chemotherapy in similar situations, which are often refractory to conventional immunosuppressive and depletive therapy.