Monitoring Of Bcr-abl Levels In Chronic Myeloid Leukemia Patients Treated With Imatinib In The Chronic Phase - The Importance Of A Major Molecular Response

Background: Real time PCR has become the most common technique to monitor BCR-ABL transcript levels of patients treated with kinase inhibitors. The aim of this study was to evaluate BCR-ABL levels of chronic myeloid leukemia patients treated with imatinib in the chronic phase and correlate the response to therapy and event-free survival. Methods: BCR-ABL levels were measured in peripheral blood cell samples using Real time PCR at diagnosis and then every 3 months after starting therapy with imatinib. Major molecular response was defined as a three-log reduction from the standardized baseline value. Major molecular response values were adjusted to international scale using a conversion factor of 1.19. The results are reported as a BCR-ABL/ABL ratio (%). Results: Hematological, major cytogenetic and complete cytogenetic responses were achieved by 57 (95%), 45 (75%) and 38 (63%) patients, respectively. Twenty-four out of sixty patients achieved a major molecular response (40%) in a median time of 8.5 months. Overall survival and event free survival were higher for patients with (100%) versus patients without (77%) a complete cytogenetic response (p-value = 0.01) at 48 months. Patients with complete cytogenetic response and major molecular response had a higher event free survival compared to patients with complete cytogenetic response but without major molecular response (p-value = 0.007). Conclusion: In conclusion, the prognostic impact of achieving complete cytogenetic response and a major molecular response and also the importance of molecular monitoring in the follow-up of chronic myeloid leukemia patients were demonstrated.333211215Melo, J.V., The molecular biology of chronic myeloid leukaemia (1996) Leukemia, 10 (5), pp. 751-756Wang, L., Pearson, K., Pillitteri, L., Ferguson, J.E., Clark, R.E., Serial monitoring of BCR-ABL by peripheral blood real-time polymerase chain reaction predicts the marrow cytogenetic response to imatinib mesylate in chronic myeloid leukaemia (2002) Br J Haematol, 118 (3), pp. 771-777Muller, M.C., Gattermann, N., Lahaye, T., Deininger, M.W., Berndt, A., Fruehauf, S., Dynamics of BCR-ABL mRNA expression in firstline therapy of chronic myelogenous leukemia patients with imatinib or interferon alpha/ara-C (2003) Leukemia, 17 (12), pp. 2392-2400Branford, S., Hughes, T.P., Rudzki, Z., Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics (1999) Br J Haematol, 107 (3), pp. 587-599Radich, J.P., Gooley, T., Bryant, E., Chauncey, T., Clift, R., Beppu, L., The significance of bcr-abl molecular detection in chronic myeloid leukemia patients late, 18 months or more after transplantation (2001) Blood, 98 (6), pp. 1701-1707Hughes, T.P., Kaeda, J., Branford, S., Rudzki, Z., Hochhaus, A., Hensley, M.L., Frequency of major molecular responses to imatinib or interferon-alpha plus cytarabine in newly diagnosed chronic myeloid leukemia (2003) N Engl J Med, 349 (15), pp. 1423-1432Press, R.D., Love, Z., Tronnes, A.A., Yang, R., Tran, T., Mongoue- tchokote, S., BCR-ABL mRNA levels at and after the time of a complete cytogenetic response predict the duration of CCR in imatinib mesylate-treated patients with CML (2006) Blood, 107 (11), pp. 4250-4256Cortes, J., Talpaz, M., O'Brien, S., Jones, D., Luthra, R., Shan, J., Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate (2005) Clin Cancer Res, 11 (9), pp. 3425-3432Iacobucci, I., Saglio, G., Rosti, G., Testoni, N., Pane, F., Amabile, M., Achieving a major molecular response at the time of a complete cytogenetic response (CCgR) predicts a better duration of CCgR in imatinib-treated chronic myeloid leukemia patients (2006) Clin Cancer Res, 12 (10), pp. 3037-3042Baccarani, M., Saglio, G., Goldman, J., Hochhaus, A., Simonsson, B., Appelbaum, F., Evolving concepts in the management of chronic myeloid leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet (2006) Blood, 108 (6), pp. 1809-1820Hughes, T., Deininger, M., Hochhaus, A., Branford, S., Radich, J., Kaeda, J., Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: Review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results (2006) Blood, 108 (1), pp. 28-37Branford, S., Cross, N.C., Hochhaus, A., Radich, J., Saglio, G., Kaeda, J., Rationale for the recommendations for harmonizing current methodology for detecting BCR-ABL transcripts in patients with chronic myeloid leukaemia (2006) Leukemia, 20 (11), pp. 1925-1930Cortes, J., Baccarani, M., Fea, G., (2008) A Phase III, Randomized, Openlabel Study of 400 Mg Versus 800 Mg of Imatinib Mesylate (IM) in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase (CML-CP), Using Molecular Endpoints: One Year Results of TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) Study, , 50th ASH Annual Meeting and Exposition Online program and Abstracts. San Francisco, CABranford, S., Fletcher, L., Cross, N.C., Muller, M.C., Hochhaus, A., Kim, D.W., Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials (2008) Blood, 112 (8), pp. 3330-3338O'Brien, S.G., Guilhot, F., Larson, R.A., Gathmann, I., Baccarani, M., Cervantes, F., Imatinib compared with interferon and lowdose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia (2003) N Engl J Med, 348 (11), pp. 994-1004Marin, D., Milojkovic, D., Olavarria, E., Khorashad, J.S., de Lavallade, H., Reid, A.G., European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor (2008) Blood, 112 (12), pp. 4437-444

The availability of full match sibling donors and feasibility of allogeneic bone marrow transplantation in Brazil

The feasibility of allogeneic bone marrow transplantation (alloBMT) in a developing country has not yet been demonstrated. Many adverse factors including social and economic limitations may reduce the overall results of this complex and expensive procedure. Our objective was to characterize the most important clinical, social and economic features of candidates for transplantation and their potential donors as well as the influence of these factors on overall survival in a retrospective and exploratory analysis at a university hospital. From July 1993 to July 2001, candidates for BMT were referred to the Bone Marrow Transplantation Unit by Hematology and Oncology Centers from several regions of Brazil. A total of 1138 patients were referred to us as candidates for alloBMT. Median age was 25 years (range: 2 months-60 years), 684 (60.1%) were males and 454 (39.9%) were females. The clinical indications were severe aplastic anemia and hematological malignancies. From the total of 1138 patients, 923 had HLA-typing; 497/923 (53.8%) candidates had full match donors; 352/1138 (30.8%) were eligible for alloBMT. Only 235 of 352 (66.7%) were transplanted. Schooling was 1st to 8th grade for 123/235 (52.3%); monthly family income ranged from US$60 (7$400 (36%). Overall survival for patients with chronic myeloid leukemia, severe aplastic anemia and acute myeloid leukemia was 58, 60 and 30%, respectively. Thus, overall survival rates for the most frequent hematological diseases were similar to those reported in the International Registry, except for acute myeloid leukemia. This descriptive and exploratory analysis suggests the feasibility of alloBMT in a developing country like Brazil.31532

Correlation of mixed lymphocyte culture with chronic graft-versus-host disease following allogeneic stem cell transplantation

The purpose of the present study was to evaluate the mixed lymphocyte culture as a predictive assay of acute and chronic graft-versus-host disease (GVHD). We studied 153 patients who received a first bone marrow transplantation from human leukocyte antigen-identical siblings. Acute GVHD was observed in 26 of 128 (20.3%) patients evaluated and chronic GVHD occurred in 60 of 114 (52.6%). One-way mixed lymphocyte culture (MLC) assays were performed by the standard method. MLC results are reported as the relative response (RR) from donor against patient cells. The responses ranged from -47.0 to 40.7%, with a median of 0.5%. The Kaplan-Meier probability of developing GVHD was determined for patients with positive and negative MLC. There was no significant difference in incidence of acute GVHD between the groups studied. However, the incidence of chronic GVHD was higher in recipients with RR >4.5% than in those with RR 4.5%), 2.9 for those who received peripheral blood progenitor cells as a graft, and 2.2 for patients who developed previous acute GVHD. MLC was not useful for predicting acute GVHD, but MLC with RR >4.5% associated with other risk factors could predict the development of chronic GVHD, being of help for the prevention and/or treatment of this late complication.56757

The Effect Of Prior Exposure To Imatinib On Transplant Outcomes And Its Effectiveness For Relapse Treatment [influência Do Imatinibe No Resultado Do Tmo E Sua Eficácia No Tratamento Da Recaída]

Imatinib mesylate (IM) has become the first-line therapy for chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly chosen as salvage therapy for patients who are intolerant of IM, fail to achieve a complete cytogenetic response (CCR) or relapse. The first part of this review will discuss the effect of prior exposure to IM on transplant outcomes and the impact of a poor or a loss of response at the time of transplantation on post-transplantation survival of patients who underwent transplantation in a chronic phase (CP). The second part will discuss the management of relapse disease after transplant. Donor lymphocyte infusion (DLI) has become the treatment of choice for patients who relapse. The response to DLI is dose-dependent and the effective cell dose is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility. IM is now an alternative to DLI as it can be used to achieve remission without graft-versus-host disease and may be effective when DLI has failed. It can also be used in combination with lower doses of DLI to maximize responses. IM is safe and well tolerated in combination with DLI, patients achieve molecular response more rapidly, are able to stop IM without recurrence of molecular disease and this treatment has a higher disease free survival rate after transplantation.30SUPPL. 14751Oehler, V.G., Gooley, T., Snyder, D.S., The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia (2007) Blood, 109, pp. 1782-1789Hochhaus, A., Druker, B.J., Larson, R.A., IRIS 6-year follow-up: Sustained survival and declining annual rate of transformation in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with Imatinib (2007) Blood, 110, pp. 25aKantarjian, H.M., Cortes, J., OBrien, S., Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase (2002) Blood, 99, pp. 3547-3553Kantarjian, H.M., Talpaz, M., OBrien, S., Imatinib mesylate for Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon-alpha: Follow-up results (2002) Clin Cancer Res, 8, pp. 2177-2187Sawyers, C.L., Hochhaus, A., Feldman, E., Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: Results of a phase II study (2002) Blood, 99, pp. 3530-3539Talpaz, M., Silver, R.T., Druker, B.J., Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: Results of a phase 2 study (2002) Blood, 99, pp. 1928-1937Cortes, J., Giles, F., OBrien, S., Result of high-dose imatinib mesylate in patients with Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-alpha (2003) Blood, 102, pp. 83-86Radich, J.P., Gooley, T., Bensinger, W., HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen (2003) Blood, 102, pp. 31-35Hansen, J.A., Gooley, T.A., Martin, P.J., Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia (1998) N Engl J Med, 338, pp. 962-968Barrett, J., Allogeneic stem cell transplantation for chronic myeloid leukemia (2003) Semin Hematol, 40, pp. 59-71Clift, R.A., Buckner, C.D., Thomas, E.D., Marrow transplantation for patients in accelerated phase of chronic myeloid leukemia (1994) Blood, 84, pp. 4368-4373Hughes, T.P., Kaeda, J., Branford, S., Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia (2003) N Engl J Med, 349, pp. 1423-1432Radich, J.P., Gehly, G., Gooley, T., Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: Results and implications in 346 patients (1995) Blood, 85, pp. 2632-2638Radich, J.P., Gooley, T., Bryant, E., The significance of bcr-abl molecular detection in chronic myeloid leukemia patients "late," 18 months or more after transplantation (2001) Blood, 98, pp. 1701-1707Zander, A.R., Zabelina, T., Renges, H., Pretreament with glivec increases transplant-related mortality after allogeneic transplant (2003) Blood, 102, pp. 468aShimoni, A., Kroger, N., Zander, A.R., Imatinib mesylate (STI571) in preparation for allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusions in patients with Philadelphia-positive acute leukemias (2003) Leukemia, 17, pp. 290-297Zaucha, J.M., Prejzner, W., Giebel, S., Imatinib therapy prior to myeloablative allogeneic stem cell transplantation (2005) Bone Marrow Transplant, 36, pp. 417-424Deininger, M., Schleuning, M., Greinix, H., The effect of prior exposure to imatinib on transplant-related mortality (2006) Haematologica, 91, pp. 452-459Wassmann, B., Pfeifer, H., Scheuring, U., Therapy with imatinib mesylate (Glivec) preceding allogeneic stem cell transplantation (SCT) in relapsed or refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) (2002) Leukemia, 16, pp. 2358-2365Kim, D.W., Chung, Y.J., Lee, S., Pretransplant imatinib can improve the outcome of nonmyeloablative stem cell transplantation without increasing the morbidity in Philadelphia chromosome-positive chronic myeloid leukemia (2004) Leukemia, 18, pp. 1907-1909Bornhauser, M., Kroger, N., Schwerdtfeger, R., Allogeneic haematopoietic cell transplantation for chronic myelogenous leukaemia in the era of imatinib: A retrospective multicentre study (2006) Eur J Haematol, 76, pp. 9-17Seggewiss, R., Lore, K., Greiner, E., Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner (2005) Blood, 105, pp. 2473-2479Appel, S., Balabanov, S., Brummendorf, T.H., Brossart, P., Effects of imatinib on normal hematopoiesis and immune activation (2005) Stem Cells, 23, pp. 1082-1088Kolb, H.J., Mittermuller, J., Clemm, C., Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients (1990) Blood, 76, pp. 2462-2465Guglielmi, C., Arcese, W., Dazzi, F., Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: Prognostic relevance of the initial cell dose (2002) Blood, 100, pp. 397-405Gilleece, M.H., Dazzi, F., Donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukaemia (2003) Leuk Lymphoma, 44, pp. 23-28Simula, M.P., Marktel, S., Fozza, C., Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: The importance of escalating the cell dose to maximize therapeutic efficacy (2007) Leukemia, 21, pp. 943-948Guglielmi, C., Arcese, W., Hermans, J., Risk assessment in patients with Ph+ chronic myelogenous leukemia at first relapse after allogeneic stem cell transplant: An EBMT retrospective analysis. The Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (2000) Blood, 95, pp. 3328-3334Olavarria, E., Ottmann, O.G., Deininger, M., Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia (2003) Leukemia, 17, pp. 1707-1712DeAngelo, D.J., Hochberg, E.P., Alyea, E.P., Extended follow-up of patients treated with imatinib mesylate (gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: Durable cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease (2004) Clin Cancer Res, 10, pp. 5065-5071Savani, B.N., Montero, A., Kurlander, R., Childs, R., Hensel, N., Barrett, A.J., Imatinib synergizes with donor lymphocyte infusions to achieve rapid molecular remission of CML relapsing after allogeneic stem cell transplantation (2005) Bone Marrow Transplant, 36, pp. 1009-1015Weisser, M., Tischer, J., Schnittger, S., Schoch, C., Ledderose, G., Kolb, H.J., A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem cell transplantation (2006) Haematologica, 91, pp. 663-66

Hematopoietic Stem Cell Transplant And Recovery Of Hematopoiesis [transplante De Células-tronco Hematopoéticas E A Regeneração Da Hematopoese]

Mobilized peripheral blood has replaced the use of bone marrow as a source of hematopoietic stem cells in most autologous transplants and is increasingly used in allogeneic transplants. The hematopoietic reconstitution after using mobilized peripheral blood is faster compared to bone marrow. Umbilical cord blood has emerged as another rich source of hematopoietic stem cells for transplantation. The minimal risk to the donor and the rapid availability are among the great advantages of this stem cell source. The slow recovery of neutrophil and platelet counts is the major clinical concern. Bone marrow biopsy is an important tool for obtaining information regarding the hematopoietic recovery after hematopoietic stem cell transplantation. The histopathological hematopoietic reconstitution of the bone marrow after umbilical cord blood transplantation is delayed compared to bone marrow transplantation. However, gradual hematopoietic recovery is seen, and afterwards no other differences comparing bone marrow and umbilical cord transplants are observed. Bone marrow histology does not elucidate the genotypic origin of post-transplant hematopoiesis. Hence, chimerism analysis has become an important instrument for engraftment surveillance, and is the basis for treatment intervention to avoid graft rejection, to maintain engraftment, and to treat clinical imminent relapse by immunotherapy. This review focuses on the hematopoietic recovery after hematopoietic stem cell transplantation.314280284van den Berg, H., Kluin, P.M., Vossen, J.M., Early reconstitution of haematopoiesis after allogeneic bone marrow transplantation: A prospective histopathological study of bone marrow biopsy specimens (1990) J Clin Pathol, 43 (5), pp. 365-369Fyles, G.M., Messner, H.A., Lockwood, G., Curtis, J.E., Rider, W., Minden, M.D., Long-term results of bone marrow transplantation for patients with AML, ALL and CML prepared with single dose total body irradiation of 500 cGy delivered with a high dose rate (1991) Bone Marrow Transplant, 8 (6), pp. 453-63Petz, L.D., Yam, P., Wallace, R.B., Stock, A.D., de Lange, G., Knowlton, R.G., Mixed hematopoietic chimerism following bone marrow transplantation for hematologic malignancies (1987) Blood, 70 (5), pp. 1331-1337Yamasaki, K., Solberg Jr., L.A., Jamal, N., Lockwood, G., Tritchler, D., Curtis, J.E., Hemopoietic colony growth-promoting activities in the plasma of bone marrow transplant recipients (1988) J Clin Invest, 82 (1), pp. 255-61Cairo, M.S., Suen, Y., Sender, L., Gillan, E.R., Ho, W., Plunkett, J.M., Circulating granulocyte colony-stimulating factor (G-CSF) levels after allogeneic and autologous bone marrow transplantation: Endogenous G-CSF production correlates with myeloid engraftment (1992) Blood, 79 (7), pp. 1869-73Li, S., Champlin, R., Fitchen, J.H., Gale, R.P., Abnormalities of myeloid progenitor cells after successful bone marrow transplantation (1985) J Clin Invest, 75 (1), pp. 234-41Arnold, R., Schmeiser, T., Heit, W., Frickhofen, N., Pabst, G., Heimpel, H., Hemopoietic reconstitution after bone marrow transplantation (1986) Exp Hematol, 14 (4), pp. 271-277Messner, H.A., Curtis, J.E., Minden, M.D., Tritchler, D., Lockwood, G., Takahashi, T., Clonogenic hemopoietic precursors in bone marrow transplantation (1987) Blood, 70 (5), pp. 1425-32Vellenga, E., Sizoo, W., Hagenbeek, A., Löwenberg, B., Different repopulation kinetics of erythroid (BFU-E), myeloid (CFU-GM) and T lymphocyte (TL-CFU) progenitor cells after autologous and allogeneic bone marrow transplantation (1987) Br J Haematol, 65 (2), pp. 137-42Turhan, A.G., Humphries, R.K., Phillips, G.L., Eaves, A.C., Eaves, C.J., Clonal hematopoiesis demonstrated by X-linked DNA polymorphisms after allogeneic bone marrow transplantation (1989) N Engl J Med, 320 (25), pp. 1655-61Devetten, M., Armitage, J.O., Hematopoietic cell transplantation: Progress and obstacles (2007) Ann Oncol, 18 (9), pp. 1450-1456Dexter, T.M., Haemopoiesis in long-term bone marrow cultures. A review (1979) Acta Haematol, 62 (5-6), pp. 299-305Amos, T.A., Gordon, M.Y., Sources of human hematopoietic stem cells for transplantation - a review (1995) Cell Transplant, 4 (6), pp. 547-69Sheridan, W.P., Begley, C.G., Juttner, C.A., Szer, J., To, L.B., Maher, D., Effect of peripheral-blood progenitor cells mobilised by filgrastim (G-CSF) on platelet recovery after high-dose chemotherapy (1992) Lancet, 339 (8794), pp. 640-644Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: An individual patient data meta-analysis of nine randomized trials (2005) J Clin Oncol, 23 (22), pp. 5074-87. , Stem Cell Trialists' Collaborative GroupRussel, N., Gratwohl, A., Schmitz, N., The place of blood stem cells in allogeneic transplantation (1996) Br J Haematol, 93 (4), pp. 747-53Bender, J.G., Unverzagt, K.L., Walker, D.E., Lee, W., van Epps, D.E., Smith, D.H., Identification and comparison of CD34-positive cells and their subpopulations from normal peripheral blood and bone marrow using multicolor flow cytometry (1991) Blood, 77 (12), pp. 2591-2596Tjønnfjord, G.E., Steen, R., Evensen, S.A., Thorsby, E., Egeland, T., Characterization of CD34+ peripheral blood cells from healthy adults mobilized by recombinant human granulocyte colony- stimulating factor (1994) Blood, 84 (8), pp. 2795-801To, L.B., Haylock, D.N., Dowse, T., Simmons, P.J., Trimboli, S., Ashman, L.K., A comparative study of the phenotype and proliferative capacity of peripheral blood (PB) CD34+ cells mobilized by four different protocols and those of steady-phase PB and bone marrow CD34+ cells (1994) Blood, 84 (9), pp. 2930-2939Körbling, M., Huh, Y.O., Durett, A., Mirza, N., Miller, P., Engel, H., Allogeneic blood stem cell transplantation: Peripheralization and yield of donor-derived primitive hematopoietic progenitor cells (CD34+ Thy-1dim) and lymphoid subsets, and possible predictors of engraftment and graft-versus-host disease (1995) Blood, 86 (7), pp. 2842-2848Scott, M.A., Apperley, J.F., Bloxham, D.M., Jestice, H.K., John, S., Marcus, R.E., Biological properties of peripheral blood progenitor cells mobilized by cyclophosphamide and granulocyte colony stimulating factor (1997) Br J Haematol, 97 (2), pp. 474-80Gordon, M.Y., Lewis, J.L., Marley, S.B., Grand, F.H., Goldman, J.M., Stromal cells negatively regulate primitive haemopoietic progenitor cell activation via a phosphatidylinositol-anchored cell adhesion/ signalling mechanism (1997) Br J Haematol, 96 (3), pp. 647-53Rocha, V., Wagner Jr., J.E., Sobocinski, K.A., Klein, J.P., Zhang, M.J., Horowitz, M.M., Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources (2000) N Engl J Med, 342 (25), pp. 1846-54Rubinstein, P., Carrier, C., Scaradavou, A., Kurtzberg, J., Adamson, J., Migliaccio, A.R., Outcomes among 562 recipients of placentalblood transplants from unrelated donors (1998) N Engl J Med, 339 (22), pp. 1565-77Laughlin, M.J., Eapen, M., Rubinstein, P., Wagner, J.E., Zhang, M.J., Champlin, R.E., Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia (2004) N Engl J Med, 351 (22), pp. 2265-75Dercksen, M.W., Rodenhuis, S., Dirkson, M.K., Schaasberg, W.P., Baars, J.W., van der Wall, E., Subsets of CD34+ cells and rapid hematopoietic recovery after peripheral-blood stem-cell transplantation (1995) J Clin Oncol, 13 (8), pp. 1922-32Lee, Y.H., Lee, Y.A., Noh, K.T., Kim, K.H., Han, J.Y., Seo, S.Y., Homing-associated cell adhesion molecules and cell cycle status on the nucleated cells in the bone marrow, mobilized peripheral blood and cord blood (2004) J Korean Med Sci, 19 (4), pp. 523-528Maeda, T., Shiozawa, E., Mayumi, H., Usui, T., Nakashima, H., Hattori, N., Histopathology of bone marrow reconstitution after umbilical cord blood transplantation for hematological diseases (2008) Pathol Int, 58 (2), pp. 126-123Bader, P., Niethammer, D., Willasch, A., Kreyenberg, H., Klingebiel, T., How and when should we monitor chimerism after allogeneic stem cell transplantation? (2005) Bone Marrow Transplant, 35 (2), pp. 107-19McCann, S.R., Lawler, M., Mixed chimaerismdetection and significance following BMT (1993) Bone Marrow Transplant, 11 (2), pp. 91-94Bader, P., Hölle, W., Klingebiel, T., Handgretinger, R., Niethammer, D., Beck, J., Quantitative assessment of mixed hematopoietic chimerism by polymerase chain reaction after allogeneic BMT (1996) Anticancer Res, 16 (4 A), pp. 1759-63Bader, P., Hölle, W., Klingebiel, T., Handgretinger, R., Benda, N., Schlegel, P.G., Mixed hematopoietic chimerism after allogeneic bone marrow transplantation: The impact of quantitative PCR analysis for prediction of relapse and graft rejection in children (1997) Bone Marrow Transplant, 19 (7), pp. 697-702Ramírez, M., Díaz, M.A., García-Sánchez, F., Velasco, M., Casado, F., Villa, M., Chimerism after allogeneic hematopoietic cell transplantation in childhood acute lymphoblastic leukemia (1996) Bone Marrow Transplant, 18 (6), pp. 1161-1165Boder, P., Beck, J., Schlegel, P.G., Handgretinger, R., Niethammer, D., Klingebiel, T., Additional immunotherapy on the basis of increasing mixed hematopoietic chimerism after allogeneic BMT in children with acute leukemia: Is there an option to prevent relapse? (1997) Bone Marrow Transplant, 20 (1), pp. 79-81Thiede, C., Bornhäuser, M., Ehninger, G., Strategies and clinical implications of chimerism diagnostics after allogeneic hematopoietic stem cell transplantation (2004) Acta Haematol, 112 (1-2), pp. 16-2

Allogeneic Hematopoietic Stem Cell Transplant For Multiple Myeloma [o Transplante Alogênico De Células-tronco Hematopoé Ticas No Tratamento Do Mieloma Múltiplo]

Multiple myeloma (MM) is a incurable hematological malignancy with an average survival of 3 years with conventional therapy. Allogeneic hematopoietic cell transplantation (allo - HCT) may cure some patients, but has been associated with a high transplantation-related-mortality (TRM) of over 40%. The potential advantages of allo - HCT are the ability to collect myeloma free stem cells and the graft - versus - myeloma effect. But, despite these factors, long term cure is rare. Relapse continues at a rate of approximately 7% per year with long term follow-up. The graft-versus-host disease (GVHD) can also be a problem, requiring therapy and impairing quality of life. Approaches to improve the outcome of allo - HCT for MM include consideration of patient status, efficacy and toxicity of induction therapy, source of hematopoietic graft, and conditioning regimens. Recent attempts to improve outcome include autologous hematopoietic cell transplantation (AHCT) followed by non - myeloablative allogeneic transplantation, and allo-HCT with T depletion and subsequent donor lymphocyte infusions. With the use of strategies directed at cell signaling, patients' lives can be prolonged, and the quality of their lives can be improved compared with the current approach that transplantation provides, despite its survival benefit.2914247Gratwohl A, Baldomero H, Frauendorfer K, Urbano-Ispizua A. EBMT activity survey 2004 and changes in disease indication over the past 15 years. Bone Marrow Transplant 2006;37:1.069-85Bjorkstrand, B., European Group for Blood and Marrow Transplantation Registry studies in multiple myeloma (2001) Semin Hematol, 38, pp. 219-225Gahrton G, Tura S, Ljungman P, et al. Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 1995;13:1.312-22Bensinger WI, Buckner CD, Anasetti C, et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood 1996;88:2.787-93Mehta, J., Tricot, G., Jagannath, S., Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft? (1998) Bone Marrow Transplant, 21, pp. 887-892Gahrton, G., Svensson, H., Cavo, M., Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: A comparison between transplants performed 1983-93 and 1994-8 at European Group for Blood and Marrow Transplantation centres (2001) Br J Haematol, 113, pp. 209-216Catley, L., Anderson, K., Strategies to improve the outcome of stem cell transplantation in multiple myeloma (2004) Hematol J, 5, pp. 9-23Bird, J.M., Russell, N.H., Samson, D., Minimal residual disease after bone marrow transplantation for multiple myeloma: Evidence for cure in long-term survivors (1993) Bone Marrow Transplant, 12, pp. 651-654Corradini, P., Voena, C., Tarella, C., Molecular and clinical remissions in multiple myeloma: Role of autologous and allogeneic transplantation of hematopoietic cells (1999) J Clin Oncol, 17, pp. 208-215Martinelli G, Terragna C, Zamagni E, et al. Molecular remission after allogeneic or autologous transplantation of hematopoietic stem cells for multiple myeloma. J Clin Oncol 2000;18:2.273-81Gahrton, G., Svensson, H., Bjorkstrand, B., Syngeneic transplantation in multiple myeloma - a case-matched comparison with autologous and allogeneic transplantation. European Group for Blood and Marrow Transplantation (1999) Bone Marrow Transplant, 24, pp. 741-745Gahrton G, Tura S, Ljungman P, et al. Allogeneic bone marrow transplantation in multiple myeloma. European Group for Bone Marrow Transplantation. N Engl J Med 1991;325:1.267-73Bensinger WI, Buckner CD, Clift RA, et al. Phase I study of busulfan and cyclophosphamide in preparation for allogeneic marrow transplant for patients with multiple myeloma. J Clin Oncol 1992;10:1.492-7Cavo, M., Benni, M., Cirio, T.M., Gozzetti, A., Tura, S., Allogeneic bone marrow transplantation for the treatment of multiple myeloma (1995) An overview of published reports. Stem Cells, 13 (SUPPL. 2), pp. 126-131Bensinger, W.I., Buckner, D., Gahrton, G., Allogeneic stem cell transplantation for multiple myeloma (1997) Hematol Oncol Clin North Am, 11, pp. 147-157Bensinger, W.I., Maloney, D., Storb, R., Allogeneic hematopoietic cell transplantation for multiple myeloma (2001) Semin Hematol, 38, pp. 243-249Bjorkstrand BB, Ljungman P, Svensson H, et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 1996;88:4.711-8Arora M, McGlave PB, Burns LJ, et al. Results of autologous and allogeneic hematopoietic cell transplant therapy for multiple myeloma. Bone Marrow Transplant 2005;35:1.133-40Bellucci R, Alyea EP, Weller E, et al. Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma. Blood 2002;99:4.610-7Lokhorst HM, Schattenberg A, Cornelissen JJ, Thomas LL, Verdonck LF. Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood 1997;90:4.206-11Alyea, E., Weller, E., Schlossman, R., T-cell - depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: Induction of graft-versus-myeloma effect (2001) Blood, 98, pp. 934-939Collins Jr., R.H., Shpilberg, O., Drobyski, W.R., Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation (1997) J Clin Oncol, 15, pp. 433-444Majolino, I., Corradini, P., Scime, R., High rate of remission and low rate of disease recurrence in patients with multiple myeloma allografted with PBSC from their HLA-identical sibling donors (2003) Bone Marrow Transplant, 31, pp. 767-773Blade J, Vesole DH, Gertz M. High-dose therapy in multiple myeloma. Blood 2003;102:3.469-70Giralt, S., Thall, P.F., Khouri, I., Melphalan and purine analog-containing preparative regimens: Reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation (2001) Blood, 97, pp. 631-637Badros A, Barlogie B, Morris C, et al. High response rate in refractory and poor-risk multiple myeloma after allo transplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions. Blood 2001;97:2.574-9Badros A, Barlogie B, Siegel E, et al. Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 200220:1.295-303Lee, C.K., Badros, A., Barlogie, B., Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after reduced intensity conditioning (2003) Exp Hematol, 31, pp. 73-80Barlogie, B., Shaughnessy, J., Tricot, G., Treatment of multiple myeloma (2004) Blood, 103, pp. 20-32Giralt, S., Aleman, A., Anagnostopoulos, A., Fludarabine/ melphalan conditioning for allogeneic transplantation in patients with multiple myeloma (2002) Bone Marrow Transplant, 30, pp. 367-373Einsele, H., Schafer, H.J., Hebart, H., Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning (2003) Br J Haematol, 121, pp. 411-418Crawley C, Lalancette M, Szydlo R, et al. Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT. Blood 2005;105:4.532-9Kroger N, Sayer HG, Schwerdtfeger R, et al. Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality. Blood 2002;100:3.919-24Maloney, D.G., Molina, A.J., Sahebi, F., Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma (2003) Blood, 102, pp. 3447-3454Kroger, N., Schwerdtfeger, R., Kiehl, M., Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma (2002) Blood, 100, pp. 755-760Hari, P., Pasquini, M.C., Vesole, D.H., Cure of multiple myeloma - more hype, less reality (2006) Bone Marrow Transplant, 37, pp. 1-18Kroger N, Schilling G, Einsele H, et al. Deletion of chromosome band 13q14 as detected by fluorescence in situ hybridization is a prognostic factor in patients with multiple myeloma who are receiving allogeneic dose-reduced stem cell transplantation. Blood 2004;103:4.056-61Garban F, Attal M, Michallet M, et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood 2006;107:3.474-80Badros A, Barlogie B, Morris C, et al. High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions. Blood 2001;97:2.574-9Perez-Simon, J.A., Martino, R., Alegre, A., Chronic but not acute graft-versus-host disease improves outcome in multiple myeloma patients after non-myeloablative allogeneic transplantation (2003) Br J Haematol, 121, pp. 104-108Peggs KS, Thomson K, Hart DP, et al. Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses. Blood 2004;103:1.548-56Vesole DH. Transplantation for multiple myeloma: who, when, how often? Patient selection and goals. Blood 2003;102:3.471-2Smith, A., Wisloff, F., Samson, D., Guidelines on the diagnosis and management of multiple myeloma 2005 (2006) Br J Haematol, 132, pp. 410-45

Primary Oral And Perioral Amyloidosis Associated With Multiple Myeloma

Three years after being diagnosed with multiple myeloma, a patient sought treatment for swelling on the floor of the mouth, associated with hardening of the soft tissues on the right perioral region, loss of facial expression, and difficulty opening his mouth. The patient reported improvement following an incisional biopsy for microscopic diagnosis. Eighteen months later, the patient showed no clinical alterations.535340341Stoopler, E.T., Sollecito, T.P., Chen, S.Y., Amyloid deposition in the oral cavity: A retrospective study and review of the literature (2003) Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 95, pp. 674-680Kyle, R.A., Linos, A., Beard, C.M., Linke, R.P., Gertz, M.A., O'Fallon, W.M., Kurland, L.T., Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989 (1992) Blood, 79, pp. 1817-1822Virchow, V.R., Ueber einem Gehirn and Rueckenmark des Menschen auf gefundene Substanz mit chemischen reaction der Cellulose (1854) Virchows Arch Pathol Anat, 6, pp. 135-138Raubenheimer, E.J., Dauth, J., De Coning, J.P., Multiple myeloma presenting with extensive oral and perioral amyloidosis (1986) Oral Surg Oral Med Oral Pathol, 61, pp. 492-497Salisbury III, P.L., Jacoway, J.R., Oral amyloidosis: A late complication of multiple myeloma (1983) Oral Surg Oral Med Oral Pathol, 56, pp. 48-50Raubenheimer, E.J., Dauth, J., Pretorius, F.J., Multiple myeloma and amyloidosis of the tongue (1988) J Oral Pathol, 17, pp. 554-559Flinck, W.G., Lawrence, F.R., Oral amyloidosis as initial symptom of multiple myeloma. A case report (1980) Oral Surg Oral Med Oral Pathol, 49, pp. 18-20Van Der Waal, R., Van Der Waal, R.I., Van De Scheur, M.R., Huijgens, P.C., Starink, T.M., Van Der Waal, I., Amyloidosis of the tongue as a paraneoplastic marker of plasma cell dyscrasia (2002) Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 94, pp. 444-447Loh, F.C., Ravindranathan, N., Yeo, J.F., Amyloidosis with oral involvement. Case report (1990) Aust Dent J, 35, pp. 14-18Tongue, primary amyloidosis, and multiple myeloma (1994) Oral Surg Oral Med Oral Pathol, 77, pp. 121-125Van Der Wal, N., Henzen-Logmans, S., Van Der Kwast, W.A.M., Van Der Waal, I., Amyloidosis of the tongue: A clinical postmortem study (1984) J Oral Pathol, 13, pp. 632-639Rocken, C., Shakespeare, A., Pathology, diagnosis and pathogenesis of AA amyloidosis (2002) Virchows Arch, 440, pp. 111-122Kyle, R.A., Greipp, P.R., Amyloidosis (AL). Clinical and laboratory features in 229 cases (1983) Mayo Clin Proc, 58, pp. 665-683Kyle, R.A., Bayrd, E.D., (1976) The Monoclonal Gammopathies: Multiple Myeloma and Related Cell Disorders, , Springfield, IL: Charles C. Thoma