ABSTRACT
BACKGROUND: In order to promote widespread adoption of appropriate clinical practice, the Italian Society of Hematology (SIE), and the affiliate societies SIES (Italian Society of Experimental Hematology) and GITMO (Italian Group for Bone Marrow Transplantation) established to produce guidelines in the most relevant hematological areas. In this article, we report the recommendations for management of T/NK-cell lymphomas, excluding mature T-cell leukaemias. DESIGN: By using the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) system, we produced evidence-based recommendations for the key clinical questions that needed to be addressed by a critical appraisal of evidence. The consensus methodology was applied to evidence-orphan issues. RESULTS: Six courses of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone (CHOEP) chemotherapy were recommended for first-line therapy of patients with nodal, intestinal or hepatosplenic T-cell lymphomas (evidence: low; recommendation: do, weak). Except for ALK+ anaplastic large-cell lymphoma and elderly unfit patients, consolidation with high-dose chemotherapy was recommended (evidence: low; recommendation: do, weak). 50 Gy radiotherapy was the recommended first-line therapy for localized extranodal T/NK-cell lymphoma nasal type (evidence: low; recommendation: do, strong), while l-asparaginase-containing chemotherapy regimens were recommended for patients with systemic disease (evidence: very low; recommendation: do, strong). CONCLUSION: In adult T/NK-cell lymphomas, GRADE methodology was applicable to a limited number of key therapeutic issues. For the remaining key issues, due to lack of appraisable evidence, recommendations was based on consensus methodology.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/radiotherapy , Lymphoma, T-Cell/drug therapy , Lymphoma, T-Cell/radiotherapy , Practice Guidelines as Topic , Adult , Combined Modality Therapy , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Etoposide/therapeutic use , Evidence-Based Medicine , Humans , Prednisolone/therapeutic use , Prednisone/therapeutic use , Vincristine/therapeutic useABSTRACT
Since 2002, date of publication of the previous Italian Society of Haematology (SIE) practice guidelines for management of myelodysplastic syndromes (MDS), novel disease-modifying treatments have been introduced and the SIE commissioned an update. After a comprehensive review of the medical literature published since January 2001, the Expert Panel formulated recommendations for the management of adult and paediatric MDS, graded according to the available evidence. The major updates are: first-line hypomethylating agents in patients with INT2-high-risk disease; controlled use of first-line lenalidomide in low-INT1 risk transfusion-dependent patients with 5q deletion; deferasirox in low-INT1 patients with a relevant transfusional load; first-line high-dose ESA in low-INT1 patients with Hb <10 g/dl and endogenous EPO <500 U/l; allogeneic HSCT first-line therapy for INT2- and high-risk patients <65 years without severe co morbidities.
Subject(s)
Myelodysplastic Syndromes/therapy , Adolescent , Adult , Antineoplastic Agents/therapeutic use , Child , Child, Preschool , Humans , Lenalidomide , Middle Aged , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/mortality , Thalidomide/analogs & derivatives , Thalidomide/therapeutic useABSTRACT
BACKGROUND: Posttransplant lymphoproliferative disorders (PTLDs) are an uncommon but important cause of morbidity and mortality in solid organ transplant recipients. They are often the result of Epstein-Barr virus (EBV)-induced proliferation of B-lymphocytes in the setting of immunosuppression. PATIENTS AND METHODS: We retrospectively analyzed four cases of PTLD after liver transplantation. In all patients immunosuppression was reduced and anti-CD20 monoclonal antibody (rituximab) was administered. In two of four patients, EBV viral load was positive in the peripheral blood, and gancyclovir was therefore also prescribed. Chemotherapy (CHOP) was used as a rescue in the event of treatment failure. RESULTS: Even if no severe adverse events were observed during the treatment period, our treatment approach to PTLD was not effective, and only one patient out of four is still alive. CONCLUSIONS: Well-designed clinical trials are necessary to evaluate the role of this combined approach in the treatment of PTLD in liver transplant recipients.
Subject(s)
Immunosuppressive Agents/adverse effects , Liver Transplantation/immunology , Lymphoproliferative Disorders/chemically induced , Aged , Antibodies/therapeutic use , Antigens, CD20/immunology , Cyclosporine/adverse effects , Epstein-Barr Virus Infections/etiology , Female , Humans , Male , Middle Aged , Postoperative Complications/chemically induced , Retrospective Studies , Tacrolimus/adverse effects , Viral LoadABSTRACT
We analysed data for 213 patients with ALL and AML who received either peripheral blood stem cells (PBSC) (n=74) or bone marrow (BM) (n=139) from an HLA-matched unrelated donor (EBMT acute leukaemia registry; January 1994 to January 1999). The two groups of patients (by cell source) were comparable with respect to age, sex, disease status, year at transplant and graft T cell depletion. Engraftment was achieved in about 90% regardless of stem cell source or leukaemia type. Kinetics of neutrophil and platelet recovery, similar for both sources in ALL patients, were faster for PBSC in AML patients. The incidence of acute graft-versus-host disease was similar for both sources in AML patients, but higher for PBSC in ALL patients (74 vs 54%, P=0.05). The 1-year probability of chronic graft-versus-host disease was 40 and 45% (P=0.66) in ALL patients compared to 49 and 35% (P=0.13) in AML patients (PBSC vs BM). In AML patients, none of the following differed significantly with cell source: transplant-related mortality, relapse incidence, leukaemia-free survival and overall survival. In ALL patients, the transplant-related mortality for PBSC vs BM was 61 vs 47% (P=0.13), the relapse incidence was 47 vs 39% (P=0.17), the leukaemia-free survival was 21 vs 32% (P=0.04) and the overall survival was 24 vs 34% (P=0.04). These data suggest that the short-term outcome of allogeneic PBSC is not significantly different from that of BM in AML patients who underwent a transplant from a matched unrelated donor but, conversely, that survival with PBSC may be decreased in ALL patients. In conclusion, the source of transplant cells needs to be evaluated by disease, especially when dealing with unrelated donors.
Subject(s)
Bone Marrow Transplantation/methods , Leukemia, Myeloid, Acute/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Stem Cell Transplantation/methods , Adolescent , Adult , Bone Marrow Transplantation/adverse effects , Child , Female , Filgrastim , Follow-Up Studies , Graft vs Host Disease/epidemiology , Granulocyte Colony-Stimulating Factor/therapeutic use , Hematopoietic Stem Cell Mobilization , Humans , Leukemia, Myeloid, Acute/mortality , Living Donors , Male , Multivariate Analysis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Recombinant Proteins , Retrospective Studies , Stem Cell Transplantation/adverse effects , Survival Analysis , Time FactorsSubject(s)
Fusion Proteins, bcr-abl/metabolism , Interferon-alpha/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Pyrimidines/therapeutic use , Remission Induction , Benzamides , Humans , Imatinib Mesylate , Interferon alpha-2 , Interferon-alpha/administration & dosage , Male , Middle Aged , Piperazines , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/physiopathology , Pyrimidines/administration & dosage , Recombinant Proteins , RecurrenceABSTRACT
BACKGROUND: Anti-Helicobacter pylori therapy has been reported to cause regression of low-grade gastric mucosa-associated lymphoid tissue lymphoma in a high percentage of patients. However, in some patients, these lesions persist despite antibiotic treatment. AIM: To determine the various endosonographic findings that may predict the regression of low-grade gastric mucosa-associated lymphoid tissue lymphoma post-antibiotics. METHODS: Seventy-six patients with Helicobacter pylori-positive gastric mucosa-associated lymphoid tissue lymphoma were studied. Follow-up data were available on 51 patients. All patients were treated with antibiotics. Participants underwent pre- and post-anti-Helicobacter pylori therapy endoscopy with gastric biopsies, followed by endoscopic ultrasonography examination of the stomach. RESULTS: Helicobacter pylori was eradicated in 45 of 51 (88%) patients. At the 2-year follow-up, complete regression of mucosa-associated lymphoid tissue lymphoma was seen in 28 of 51 (55%) patients: 12 of 16 (75%) patients in stage T1m N0, 11 of 19 (58%) patients in stage T1sm N0, four of eight (50%) patients in stages T1m N1 and T1sm N1, and one of four (25%) patients in stage T2 N0. None of the stage T2 N1 patients achieved clinical regression. CONCLUSIONS: Endoscopic ultrasonography evaluation of gastric mucosa-associated lymphoid tissue lymphoma plays a pivotal role in the initial staging and post-treatment follow-up evaluation of these lesions. Accurate staging is essential in the determination of the optimal treatment modality.
Subject(s)
Endosonography , Lymphoma, B-Cell, Marginal Zone/diagnostic imaging , Stomach Neoplasms/diagnostic imaging , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents , Disease-Free Survival , Drug Therapy, Combination/therapeutic use , Female , Follow-Up Studies , Helicobacter Infections/complications , Helicobacter Infections/drug therapy , Helicobacter pylori , Humans , Lymphoma, B-Cell, Marginal Zone/microbiology , Lymphoma, B-Cell, Marginal Zone/pathology , Male , Middle Aged , Neoplasm Staging , Stomach Neoplasms/microbiology , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND: Among the third-generation chemotherapy regimens specifically adapted in the last decade for elderly aggressive non-Hodgkin's lymphoma (NHL) patients, we designed an 8-week cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin and prednisone (VNCOP-B) plus granulocyte colony-stimulating factor (G-CSF) regimen which, in a national multicenter trial, induced good complete response (CR) and relapse-free survival rates with only moderate toxic effects. Here we report a prospective, multicenter, randomized trial comparing the efficacy and toxicity of 8- and 12-week regimens of VNCOP-B plus G-CSF. PATIENTS AND METHODS: From February 1996 to June 2001, 306 consecutive previously untreated stage II-IV aggressive NHL patients > or =60 years of age were enrolled from 12 Italian cooperative institutions. Of the 297 evaluable patients, 149 and 148 received 8- and 12-week regimens, respectively, of VNCOP-B. RESULTS: The CR rates were 63% and 56% in the 8- and 12-week groups; at a median of 32 months (range 3-62 months), relapse-free survival rates were 59% and 55%, respectively. Hematological and non-hematological toxicities were similar in both treatment groups. CONCLUSIONS: Our data show that extending induction treatment with the VNCOP-B plus G-CSF regimen from 8 to 12 weeks does not raise the CR rate or provide a more durable remission.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Granulocyte Colony-Stimulating Factor/administration & dosage , Lymphoma, Non-Hodgkin/drug therapy , Aged , Aged, 80 and over , Bleomycin/administration & dosage , Cyclophosphamide/administration & dosage , Dose-Response Relationship, Drug , Drug Administration Schedule , Etoposide/administration & dosage , Female , Humans , Italy , Logistic Models , Lymphoma, Non-Hodgkin/mortality , Lymphoma, Non-Hodgkin/pathology , Male , Middle Aged , Mitoxantrone/administration & dosage , Neoplasm Staging , Prednisone/administration & dosage , Probability , Prognosis , Proportional Hazards Models , Survival Rate , Treatment Outcome , Vincristine/administration & dosageABSTRACT
Increased neoangiogenesis has been reported in myelofibrosis with myeloid metaplasia (MMM). Thus we studied the effects of thalidomide, an antiangiogenic drug, in 12 MMM patients. Before treatment, all the cases showed a significantly increased micro-vessel density (MVD); in all eight tested cases bFGF and VEGF plasma levels were higher than controls. All patients presented disease progression in the last 3 months with standard therapy, regarding splenomegaly, anemia and/or thrombocytopenia and/or hyperleukocytosis. Thalidomide was administered at daily doses increasing from 100 to 600 mg. Eleven out of 12 patients were evaluable. No progression of disease was seen during the treatment in any case. In particular, spleen size decreased in 7/11 patients, anemia improved in 3/4 (two are now transfusion independent), thrombocytopenia in 2/2 and hyperleukocytosis in 2/5 patients. Side-effects were frequent, although not severe. After treatment, VEGF and bFGF plasma levels varied widely and in selected cases decreased. In particular, VEGF and/or bFGF decreased in 4/5 responders and in 1/3 non-responders. Moreover, MVD significantly decreased in all the responders evaluated after treatment. We conclude that thalidomide is a feasible therapy in MMM patients and looks promising at least to control the growth progression of disease.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Primary Myelofibrosis/drug therapy , Thalidomide/therapeutic use , Adult , Aged , Bone Marrow/pathology , Endothelial Growth Factors/blood , Female , Fibroblast Growth Factor 2/metabolism , Humans , Lymphokines/blood , Male , Middle Aged , Neoplasm Staging , Neovascularization, Pathologic/drug therapy , Pilot Projects , Primary Myelofibrosis/pathology , Treatment Outcome , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
Although the transcription factor nuclear factor-erythroid 2 (NF-E2) is known to be functionally linked to the megakaryocytic lineage, little is known about its role in malignant megakaryocytes. We used real-time RT-PCR and Western blotting to investigate expression of NF-E2 and its partner, MafG, in CD34-derived normal (five cases) and malignant megakaryocytes from essential thrombocythemia (ET) patients (eight cases) and in megakaryoblastic cell lines. We also quantitated the mRNA of the thromboxane synthase (TXS) gene, which is directly regulated by NF-E2. Although real-time RT-PCR showed that both a and f NF-E2 isoforms were significantly reduced with respect to the normal counterpart both in ET megakaryocytes and in cell lines (P < or = 0.01), western blotting revealed decreased NF-E2 protein expression only in the latter. However, both the NF-E2a/MafG mRNA ratio (P < or = 0.01) and TXS (P< or = 0.01) mRNA expression were significantly reduced in megakaryocytes from ET patients and cell lines with respect to healthy subjects. These two findings provide strong indirect evidence of altered activity of the a isoform of NF-E2 in malignant megakaryocytes, raising the possibility that NF-E2 could play a role in megakaryocyte transformation.
Subject(s)
DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Megakaryocytes/metabolism , Thrombocytopenia/metabolism , Thrombocytosis/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Adult , Antigens, CD34/metabolism , Blotting, Western , Bone Marrow/chemistry , Case-Control Studies , DNA Primers/chemistry , Erythroid-Specific DNA-Binding Factors , Erythropoiesis , Female , Flow Cytometry , Humans , MafG Transcription Factor , Male , Middle Aged , NF-E2 Transcription Factor , NF-E2 Transcription Factor, p45 Subunit , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , RNA, Messenger/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Thrombocytopenia/genetics , Thrombocytopenia/pathology , Thromboxane-A Synthase/genetics , Thromboxane-A Synthase/metabolism , Tumor Cells, CulturedSubject(s)
Antibiotics, Antineoplastic/administration & dosage , Daunorubicin/administration & dosage , Leukemia, Myeloid/drug therapy , Meningeal Neoplasms/diagnosis , Acute Disease , Adult , Drug Carriers , Female , Humans , Liposomes , Male , Meningeal Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapyABSTRACT
For abdominal lymphoma patients, fluorine-18 fluorodeoxyglucose positron emission tomography (PET) provides unique information on the presence of residual active disease. We provide an update on the largest reported cohort of patients whose management following induction therapy was based on routine PET and computed tomography (CT) restaging. Fifty-nine patients with Hodgkin's disease or aggressive non-Hodgkin's lymphoma presenting abdominal involvement (35% with bulky disease) were studied with both PET and CT following combined chemotherapy/radiation treatment. After treatment, 3/3 (100%) patients who were PET+/CT- relapsed, compared with 0/7 patients in the PET-/CT- subset. Among the 49 patients who were CT+, six of the 10 (60%) who were PET+ relapsed, as compared with only two of the 39 (5%) who were PET-. The actuarial relapse-free survival (RFS) rates were 0 and 100% in the PET+/CT- and PET-/CT- subsets, respectively. In the PET+/CT+ subset, RFS was 94% at 5 years. PET restaging is very valuable for the identification of patients who would need appropriate second-line therapy because of the presence of residual active abdominal disease and should be made widely available in combination with CT.
Subject(s)
Abdominal Neoplasms/diagnostic imaging , Lymphoma/diagnostic imaging , Tomography, Emission-Computed , Tomography, X-Ray Computed , Abdominal Neoplasms/pathology , Abdominal Neoplasms/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Cohort Studies , Disease-Free Survival , Female , Fluorodeoxyglucose F18 , Follow-Up Studies , Hodgkin Disease/diagnostic imaging , Hodgkin Disease/pathology , Hodgkin Disease/therapy , Humans , Lymphoma/pathology , Lymphoma/therapy , Male , Middle Aged , Neoplasm, Residual , Radiopharmaceuticals , Recurrence , Remission Induction , Treatment OutcomeABSTRACT
TH2-inducing dendritic cells (DC2) are commonly identified as negative for lineage markers and positive for HLA-DR and CD123 expression. More recently, normal blood DC2 were shown also to be positive for BDCA-2 and BDCA-4 antigens. The aim of this study was to evaluate whether BDCA-2 expression on DC2 is impaired in patients undergoing an allogeneic hematopoietic stem cell transplantation (HSCT) and in healthy donors treated with G-CSF for HSC mobilization. Flow cytometry assays for DC2 detection using either a triple staining with anti-HLA-DR PerCP, anti-Lin(+) anti-CD34 FITC and anti-CD123 PE monoclonal antibodies (mAbs), or a double staining with anti-HLA-DR PE and anti-BDCA-2 FITC mAbs were compared in blood samples from patients who underwent an allogeneic HSCT (n = 30) or from healthy donors before (n = 11) and after (n = 8) G-CSF mobilization, as well as in healthy donors' leukapheresis products (n = 12) or bone marrow (n = 4). Staining of BDCA-2(+) cells with other markers such as anti-CD38, anti-CD54 and anti-CD58 were also performed. Median values of CD123(+) DC2 and BDCA-2(+) DC2 were not statistically different in the blood of patients previously treated with chemotherapy, nor in the blood or bone marrow of heathy donors. Also, a 5 day G-CSF treatment did not affect BDCA-2 or adhesion molecule expression on healthy donors' blood DC2 significantly. A correlation between all the results (n = 65) obtained with the two assays was demonstrated in a linear regression curve (r = 0.914) (P = 0.00001). BDCA-2 is a marker highly specific for DC2 that is not downregulated by chemotherapy or G-CSF treatment. Therefore, the anti-BDCA-2 mAb can be efficiently combined with other mAbs and used in studies addressing the role of DC2 in the allogeneic HSCT setting.
Subject(s)
Antibodies, Monoclonal , Dendritic Cells/immunology , Hematopoietic Stem Cell Transplantation/methods , Lectins, C-Type/metabolism , Biomarkers/analysis , Blood Cells/cytology , Blood Cells/immunology , Bone Marrow Cells/cytology , Bone Marrow Cells/immunology , Case-Control Studies , Cell Count/methods , Dendritic Cells/cytology , Dendritic Cells/pathology , Flow Cytometry/methods , Hematologic Neoplasms/blood , Hematologic Neoplasms/therapy , Humans , Lectins, C-Type/immunology , Leukapheresis , Membrane Glycoproteins , Receptors, Immunologic , Transplantation, Homologous/methodsSubject(s)
Myelodysplastic Syndromes , Age Factors , Antineoplastic Agents/therapeutic use , Combined Modality Therapy/trends , Cytogenetic Analysis , Hematopoietic Stem Cell Transplantation , Humans , Myelodysplastic Syndromes/classification , Myelodysplastic Syndromes/epidemiology , Myelodysplastic Syndromes/etiology , Myelodysplastic Syndromes/therapySubject(s)
Citrates , Gallium , Lymphoma/diagnostic imaging , Lymphoma/pathology , Mediastinal Neoplasms/diagnostic imaging , Mediastinal Neoplasms/pathology , Tomography, Emission-Computed, Single-Photon/methods , Adult , Aged , Combined Modality Therapy , Female , Gallium Radioisotopes , Humans , Lymphoma/therapy , Male , Mediastinal Neoplasms/therapy , Middle Aged , Neoplasm Staging/methods , RadiopharmaceuticalsABSTRACT
A single-center, retrospective study was conducted to evaluate therapeutic results of the MACOP-B third-generation chemotherapy regimen followed by involved-field radiation therapy in a stage I-II aggressive non-Hodgkin's lymphoma (NHL) patients. From 1986 to 1995, 118 consecutive patients with the diagnosis of aggressive NHL, stage I-IE or II-IIE, with or without bulky disease were treated with MACOP-B regimen followed, when appropriate, by 30-36 Gy involved-field radiation therapy. The complete response (CR) rate was 95% after the combined modality treatment (97% for stage I-IE and 93% for stage II-IIE). Patients with bulky disease had a CR rate of 92%. Treatment was well tolerated and no deaths occurred from acute toxicity. After a median follow-up of 68 months, 24 (21%) patients relapsed. The 14-year projected relapse-free and overall survival rates were 78% and d 69%, respectively. MACOP-B regimen with/without involved-field radiation therapy provides a safe and effective combined modality treatment for early-stage aggressive NHL, with the possibility to definitively cure two thirds of the patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/toxicity , Bleomycin/administration & dosage , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Female , Follow-Up Studies , Humans , Lymphoma, Non-Hodgkin/complications , Lymphoma, Non-Hodgkin/mortality , Male , Methotrexate/administration & dosage , Middle Aged , Prednisolone/administration & dosage , Radiotherapy, Adjuvant , Retrospective Studies , Survival Analysis , Vincristine/administration & dosageABSTRACT
Achieving a complete cytogenetic response (CCgR) is a major target in the treatment of chronic myeloid leukemia (CML) with interferon-alpha (IFN-alpha), but CCgRs are rare. The mean CCgR rate is 13%, in a range of 5% to 33%. A collaborative study of 9 European Union countries has led to the collection of data on 317 patients who were first seen between 1983 and 1997 and achieved CCgRs with IFN-alpha alone or in combination with hydroxyurea. The median time to first CCgR was 19 months (95% CI, 17-21; range, 3-84 months). At last contact, 212 patients were still alive and in continuous CCgR; 105 patients had lost CCgR, but 53% of them were still alive and in chronic phase. IFN-alpha treatment was discontinued permanently in 23 cases for response loss, in 36 cases for chronic toxicity (15 are still in unmaintained continuous CCgR), and in 8 cases because it was believed that treatment was no longer necessary (7 of these 8 patients are still in unmaintained continuous CCgR). The 10-year survival rate from first CCgR is 72% (95% CI, 62%-82%) and is related to the risk profile. High-risk patients lost CCgR more frequently and more rapidly and none survived more than 10 years. Low-risk patients survived much longer (10-year survival probability 89% for Sokal low risk and 81% for Euro low risk). These data point out that a substantial long-term survival in CCgRs is restricted mainly to low-risk and possibly intermediate-risk patients and occurs significantly less often in high-risk patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Immunologic Factors/therapeutic use , Interferon-alpha/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Biomarkers, Tumor/blood , Bone Marrow Transplantation , Cause of Death , Combined Modality Therapy , Europe/epidemiology , Female , Follow-Up Studies , Fusion Proteins, bcr-abl/blood , Humans , Immunologic Factors/administration & dosage , Interferon alpha-2 , Interferon-alpha/administration & dosage , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Life Tables , Male , Middle Aged , Recombinant Proteins , Remission Induction , Retrospective Studies , Risk Factors , Survival Analysis , Treatment OutcomeABSTRACT
All-trans retinoic acid (ATRA), alone or combined with chemotherapy (CHT) is widely used to induce complete remission (CR) in newly diagnosed acute promyelocytic leukemia (APL). If used alone, ATRA results in a substantial proportion of CRs. To maintain remission further, ATRA is commonly used with cycles of CHT, frequently followed by autologous (auto) or allogeneic (allo) stem cell transplantation (SCT), as early reports have shown that the continuous administration of ATRA as single therapy almost invariably leads to relapse in a short period of time (months). Pharmacokinetic studies have shown that induced resistance to ATRA is frequently suppressed by the intermittent use of the drug. In this study we applied an intermittent therapeutic protocol with ATRA in five APL patients who were either molecularly refractory after combined ATRA/CHT treatment, or relapsed, or at diagnosis, but not eligible for the combination treatment because of previous toxicity. They were treated with ATRA (45 mg/m2/day) for 21 days. The treatment was then prolonged continuously for 1 week every 2 weeks. Molecular analysis was performed by qualitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR). All patients obtained molecular remission, as assessed by qualitative RT-PCR, in a median of 3 months (range 1-15). Quantitative RT-PCR confirmed these data, showing a progressive reduction (1 or 2 logs) to a 'negligible quantity' of PML-RARalpha fusion transcript (ratio PML-RARalpha/ABL x 10(4) ABL < 10(-1)) in all but one patient treated with pulsed ATRA therapy. These data were confirmed with qualitative and quantitative RT-PCR. After a median follow-up of 17 months from the start of ATRA therapy, 4/5 patients (80%) are in continuous complete molecular remission. To our knowledge, this is the first clinical observation that intermittent ATRA therapy (without chemotherapy) is effective not only in inducing but also in maintaining long-term molecular remission in APL patients. This approach could therefore be effective, if confirmed in larger series, in relapsed/refractory patients unsuitable for high-dose therapy and SCT; it may be proposed as induction therapy for selected older APL patients if considered not to be eligible for combined ATRA/CHT due to inadequate performance status or concurrent disease.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Neoplasm Proteins/biosynthesis , Oncogene Proteins, Fusion/biosynthesis , Tretinoin/therapeutic use , Adult , Aged , Antineoplastic Agents/administration & dosage , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Kinetics , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/metabolism , Male , Middle Aged , Neoplasm Proteins/genetics , Neoplasm, Residual , Oncogene Proteins, Fusion/genetics , Pilot Projects , RNA, Neoplasm/biosynthesis , Remission Induction , Reverse Transcriptase Polymerase Chain Reaction , Tretinoin/administration & dosageABSTRACT
P21(Waf1/Cip1/Sid1) is a critical component of biomolecular pathways leading to the G(1) arrest evoked in response to DNA damage, growth arrest signals and differentiation commitment. It belongs to the Cip/Kip class of cyclin-dependent kinase inhibitors and is at least partly regulated by p53. P21(Waf1/Cip1/Sid1) functional inactivation possibly resulting from mutations of the gene itself or, more likely, from p53 mutations may be critical for either the cell fate following DNA-damaging insults or clonal evolution toward malignancy. In the study presented here we describe a competitive polymerase chain reaction (PCR) strategy whose sensitivity and reproducibility enable us to attain a precise quantitation of p21(Waf1/Cip1/Sid1) expression levels in hematopoietic progenitors, the cell compartment which mostly suffers from the side effects of genotoxic drugs in use for cancer cure. The strategy was set in the M07 factor-dependent hematopoietic progenitor cell line. We confirmed that its p21(waf1/cip1/sid1) constitutive expression level is very low and up-modulated by DNA-damaging agents: ionizing radiations and ultraviolet light. Gene up-modulation resulted in checkpoint activation and, in particular, in a significant G(1) arrest, required for either the repair of damaged DNA sequences or apoptotic cell death. Our competitive PCR strategy was further validated in CD34(+) purified hematopoietic progenitors from healthy donors mobilized into the peripheral blood by granulocyte colony-stimulating factor and intended for allogeneic bone marrow transplantation. The constitutive p21(WAF1/CIP1/SID1) expression levels, measured in three separate harvests, were very low and no significant differences were apparent. Our results support the use of a competitive PCR strategy as a useful tool for clinical purposes, to assess the individual biomolecular response of early hematopoietic progenitors to antiblastic drugs.
Subject(s)
Cyclins/genetics , Hematopoietic Stem Cells/metabolism , Cell Cycle/genetics , Cell Cycle/radiation effects , Cell Division/genetics , Cell Division/radiation effects , Cyclin-Dependent Kinase Inhibitor p21 , DNA Repair , Gene Expression , Gene Expression Regulation, Neoplastic/radiation effects , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/radiation effects , Humans , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, CulturedABSTRACT
BACKGROUND AND OBJECTIVES: Several molecular and cytogenetic advances have suggested novel therapeutic strategies that could help reach an eventual cure for multiple myeloma (MM). EVIDENCE AND INFORMATION SOURCES: Identification of novel, "MM-specific" molecular targets should pave the way for drugs that can specifically attack the neoplastic cells while sparing the normal ones. Drugs that alter the marrow microenvironment--such as bisphosphonates, proteasome inhibitors (e.g. PS-341/LDP341), lactacystin or LLNV compounds--induce apoptosis or G1 growth arrest and alter the adhesion of MM cells to marrow stroma. These drugs that modified microenvironment have a more solid scientific basis and may therefore have more realistic implications in MM treatment. Of these, novel vascular endothelial growth factor (VEGF) inhibitors, such as SU5416 and SU6668, block tumor-cell adhesion and could disrupt MM cell proliferation. Similar tyrosine kinase inhibitors (TKI) such as fibroblast growth factor receptor (FGFR) inhibitors may serve when the FGFR3 gene is overexpressed due to the t(4;14)(p16.3;q32) and/or is activated by point mutations. In cases carrying the translocation and expressing the IgH/WHSC1-MMSET hybrid transcripts, histone deacetylase (HDAC) inhibitors could be useful, but their possible clinical use need to be supported by more biological studies. Tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL) induces apoptosis in MM cell lines and primary cells. The proliferative signaling pathway of FGFR3 is mediated by Ras (Ras-activating mutations are frequently found in MM), which presents a possible target for farnesyltransferase inhibitors (used alone or in association with IFN-alpha). PERSPECTIVES: In several of these options, preclinical studies have proved encouraging, and clinical trials are now getting underway.