Biomedical subjects
Publications and source records attributed to Eduardo Olavarria.
In 37 adults with chronic myeloid leukemia undergoing allogeneic stem cell transplantation imatinib prior to transplant had no discernible negative impact on 100-day mortality (13%) and severe acute (22%) or extensive chronic graft-versus- host disease (31%). After a median of 203 days (range: 18-1419) overall and progression-free survival rates are 62% and 54%, respectively.
We identified 243 patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) who had BCR-ABL transcripts monitored by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) after allogeneic stem cell transplantation for a median of 84.3 months. Individual patients were regarded as having achieved molecular relapse (MR) if the BCR-ABL/ABL ratio exceeded 0.02% on 3 occasions or reached 0.05% on 2 occasions. Patients were allocated to 1 of 4 categories: (1) 36 patients were "persistently negative" or had a single low-level positive result; (2) 51 patients, "fluctuating positive, low level," had more than 1 positive result but never more than 2 consecutive positive results; (3) 27 patients, "persistently positive, low level," had persisting low levels of BCR-ABL transcripts but never more than 3 consecutive positive results; and (4) 129 patients relapsed. In 107 of these, relapse was based initially only on molecular criteria; in 72 (67.3%) patients the leukemia progressed to cytogenetic or hematologic relapse either prior to or during treatment with donor lymphocyte infusions. We conclude that the pattern of BCR-ABL transcript levels after allograft is variable; only a minority of patients with fluctuating or persistent low levels of BCR-ABL transcripts satisfied our definitions of MR, whereas the majority of patients who did so were likely to progress further.
BACKGROUND AND OBJECTIVES: Imatinib is an effective treatment for chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, relapse is common in patients with advanced or high risk disease. Such patients may be eligible for allogeneic stem cell transplantation (SCT), raising the question whether imatinib therapy may compromise the outcome of subsequent SCT. DESIGN AND METHODS: We retrospectively analyzed 70 patients with CML and 21 with Ph+ ALL who had received imatinib prior to SCT. Data were retrieved by directly contacting centers. Multivariate analysis was used to define factors associated with major outcomes (engraftment, graft-versus-host disease, relapse, non-relapse mortality) in addition to descriptive statistics. For the CML patients major outcomes were compared with those of historical controls drawn from the EBMT registry. RESULTS: At SCT, 44% of CML patients were in accelerated phase or blast crisis and 40% of ALL patients had active disease compared to 84% and 95% prior to imatinib. At 24 months, estimated transplant-related mortality was 44% and estimated relapse mortality 24%. Factors associated with shorter overall and progression-free survival were advanced disease at SCT and a female donor/male recipient pairing. No unusual organ toxicities were observed. Compared to historical controls, prior imatinib treatment did not influence overall survival, progression-free survival or non-relapse mortality, while there was a trend towards higher relapse mortality and significantly less chronic graft-versus-host disease. INTERPRETATION AND CONCLUSIONS: Within the limits of a heterogeneous and relatively small cohort of patients, we found no evidence that imatinib negatively affects major outcomes after SCT, suggesting that imatinib prior to SCT is safe.
Stem cell transplantation is used widely in the management of a range of diseases of the hemopoietic system. Patients are immunosuppressed profoundly in the early posttransplant period, and reactivation of cytomegalovirus (CMV) remains a significant cause of morbidity and mortality. Adoptive transfer of donor-derived CMV-specific CD8+ T cell clones has been shown to reduce the rate of viral reactivation; however, the complexity of this approach severely limits its clinical application. We have purified CMV-specific CD8+ T cells from the blood of stem cell transplant donors using staining with HLA-peptide tetramers followed by selection with magnetic beads. CMV-specific CD8+ cells were infused directly into nine patients within 4 h of selection. Median cell dosage was 8.6 x 10(3)/kg with a purity of 98% of all T cells. CMV-specific CD8+ T cells became detectable in all patients within 10 d of infusion, and TCR clonotype analysis showed persistence of infused cells in two patients studied. CMV viremia was reduced in every case and eight patients cleared the infection, including one patient who had a prolonged history of CMV infection that was refractory to antiviral therapy. This novel approach to adoptive transfer has considerable potential for antigen-specific T cell therapy.
BACKGROUND: A Phase I/II study was designed to show whether the addition of semisynthetic homoharringtonine (sHHT) would reduce the level of residual disease in patients with Ph-positive chronic myeloid leukemia who appeared to have achieved a suboptimal response to imatinib alone. METHODS: Patients with CML who had achieved >/= 35% Ph-negativity on imatinib were included. All patients had been treated with imatinib at >/= 400 mg/day for at least 2 years and had achieved a plateau in BCR-ABL transcripts defined by measuring BCR-ABL transcripts on at least 4 occasions over a minimum period of 1 year with the latest value not lower than the previous minimum value. Initially sHHT was given subcutaneously at a dose of 1.25 mg/m(2) twice daily for 1 day. Courses were repeated every 28 days. The dosage of sHHT was escalated by adding one day of treatment every two days. Efficacy was assessed by serial monitoring of blood levels of BCR-ABL transcripts. RESULTS: Of 10 evaluable patients, 7 had an appreciable decline in BCR-ABL transcript levels; in 5 cases the reduction was greater than 1 log. Asthenia (n = 10) and cytopenias (n = 3) were prominent side-effects, but the drug was generally well tolerated. Mutations in the P-loop of the BCR-ABL kinase domain were found in 2 of the patients who responded to the addition of sHHT. CONCLUSIONS: The addition of sHHT should be considered for patients on imatinib who fail to obtain low levels of minimal residual disease.
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There never has been a more difficult time to advise patients newly diagnosed with chronic myeloid leukemia (CML). Until recently,the options comprised noncurative but relatively nontoxic chemotherapy or potentially curative allogeneic stem cell transplantation,with its attendant morbidity and mortality. There now is the additional option of the tyrosine kinase inhibitor imatinib mesylate that has been in clinical practice for almost 5 years. Although data are emerging regarding the efficacy of imatinib, solid evidence of any prolongation in survival will be delayed for several years. Future management of CML will continue to depend on a combination of approaches that use allografting and targeted drug therapy. The next decade undoubtedly will witness the introduction of a number of agents capable of inhibiting signal transduction pathways,perhaps controlling CML in cases of primary or acquired imatinib resistance. In the absence of long-term outcome data for imatinib,it remains reasonable to propose that young patients with newly diagnosed CML who have HLA-identical or well-matched unrelated donors should undergo allogeneic transplantation using a standard or nonmyeloablative conditioning regimen. Similarly,patients who fail to respond to imatinib should be rescued with a transplant strategy. The role of molecular monitoring in these two strategies cannot be underestimated.
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Until the recent introduction of imatinib, interferon alfa was the standard treatment for patients in the chronic phase of chronic myeloid leukaemia. We compared survival of 143 such patients, who did not respond to interferon alfa and were treated with imatinib, with that of 246 historical controls who received conventional treatment. Patients on imatinib showed an overall survival advantage (relative risk 0.54, 95% CI 0.31-0.93). However, although patients on imatinib who achieved at least some degree of cytogenetic response after 6 months had better survival than controls (0.13, 0.05-0.39), those with no cytogenetic response to imatinib had significantly worse survival (1.69, 1.09-2.64). Our findings suggest that cytogenetic responders obtain benefit from imatinib but patients who show no cytogenetic response should be given alternative treatment without delay. We confirmed these results in a case-matched analysis.
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Imatinib is clearly an important contribution to the management of patients with chronic myeloid leukemia (CML). Based on the available data, it seems reasonable to conclude that this exciting new agent is the best primary treatment for the newly diagnosed chronic-phase patient who is not immediately eligible for allogeneic stem cell transplant (allo-SCT). However, the definition of response or failure to respond is not straightforward and the extent to which imatinib prolongs life when used as a single agent cannot yet be estimated with any accuracy. This means that decisions on how best to continue treatment can be extremely difficult. Moreover, the decision whether and when to offer the patient treatment by allo-SCT has become especially complicated in the last 2 years. Imatinib seems to be generally less effective when used to treat patients in advanced phases of CML, although some patients treated in accelerated phase may achieve prolonged disease control. It is likely that the role of imatinib, used alone or in combination with other agents, will be more clearly defined in the near future.
BACKGROUND AND OBJECTIVES: The acquisition of additional cytogenetic changes (clonal evolution, CE) during treatment of chronic myeloid leukemia (CML) with imatinib mesylate is currently regarded as an index of increasing resistance to imatinib. Therefore, to investigate whether CE as an isolated event increases the risk of disease progression during imatinib treatment, we compared the outcome of patients with CML in chronic phase (CML-CP) who developed CE whilst in complete hematologic remission with the outcome of comparable patients in complete hematologic remission who showed no evidence of CE. DESIGN AND METHODS: We serially studied cytogenetic findings in 102 patients receiving the Abl-tyrosine kinase inhibitor, imatinib mesylate, as sole agent to treat CML-CP who had no evidence of CE before initiation of imatinib treatment. RESULTS: CE was identified during treatment with imatinib in 15 patients, 10 of whom were in complete hematologic remission. In most cases these changes occurred exclusively in the Ph+ population but in three patients additional changes occurred in a co-existing Ph-negative population. Patients with de novo CE in the absence of any other sign of disease progression had a significantly higher incidence of progression by 18 months than did non-CE patients (progression-free survival 34.3% (CI 10.5-69.8%) vs. 94.1% (CI 80.6-98.4%), p<0.0001). INTERPRETATION AND CONCLUSIONS: Based on this relatively small series of patients, we conclude that acquisition of clonal evolution increases the risk of subsequent disease progression also in CML patients in complete hematologic remission on imatinib.
BACKGROUND: A small proportion of patients with chronic myeloproliferative diseases have constitutive activation of the gene for platelet-derived growth factor receptor beta (PDGFRB), which encodes a receptor tyrosine kinase. The gene is located on chromosome 5q33, and the activation is usually caused by a t(5;12)(q33;p13) translocation associated with an ETV6-PDGFRB fusion gene. The tyrosine kinase inhibitor imatinib mesylate specifically inhibits ABL, PDGFR, and KIT kinases and has impressive clinical efficacy in BCR-ABL-positive chronic myeloid leukemia. METHODS: We treated four patients who had chronic myeloproliferative diseases and chromosomal translocations involving 5q33 with imatinib mesylate (400 mg daily). Three of the four patients presented with leukocytosis and eosinophilia; their leukemia cells carried the ETV6-PDGFRB fusion gene. The fourth patient had leukocytosis, eosinophilia, and a t(5;12) translocation involving PDGFRB and an unknown partner gene; he also had extensive raised, ulcerated skin lesions that had been present for a long time. RESULTS: In all four patients, a normal blood count was achieved within four weeks after treatment began. In the patient with skin disease, the lesions began to resolve shortly after treatment began. The t(5;12) translocation was undetectable by 12 weeks in three patients and by 36 weeks in the fourth patient. In the three patients with the ETV6-PDGFRB fusion gene, the transcript level decreased, and in one patient, it became undetectable by 36 weeks. All responses were durable at 9 to 12 months of follow-up. CONCLUSIONS: Imatinib mesylate induces durable responses in patients with chronic myeloproliferative diseases associated with activation of PDGFRB.
Donor lymphocyte infusion (DLI) can restore durable molecular remission in a high percentage of patients with chronic myeloid leukemia (CML) who have relapses after allogeneic stem cell transplantation, but for patients who do not respond survival is poor. Imatinib mesylate (STI571) is a specific inhibitor of BCR-ABL tyrosine kinase that can induce hematologic and cytogenetic remissions in patients with CML. We report here a male patient who had a relapse to chronic phase after stem cell transplantation for CML, did not benefit from treatment with DLI, and then was administered STI571 at a dose of 400 mg daily. There was a rapid, complete hematologic response, and complete restoration of donor-type hematopoiesis (100% 46, XX marrow metaphases) was achieved after 6 months of therapy, though RT-PCR studies still detected BCR-ABL transcripts in the blood at low level. This case demonstrates that imatinib mesylate can be highly effective in the management of patients who have relapses after allograft for CML.
We analyzed factors having an impact on response to treatment and survival in 78 consecutive patients with chronic myeloid leukemia (CML) in blastic transformation (BT) referred to the Hammersmith Hospital from January 1995 to December 2000. BT was defined as the presence of at least 30% blasts in blood or marrow or extramedullary blastic deposits. Immunophenotyping of blasts showed 57 myeloid, 19 lymphoid, and 2 biphenotypic. The median age of the patients was 39.1 years (range, 11.3-73.4 years), with 55 males and 23 females. The median survival for all patients after onset of BT was 8.2 months (95% CI, 6.4-10). Patients in lymphoid BT survived longer than those in myeloid BT (median, 11.2 months versus 6.9 months, P =.052). Initial treatment varied; 41 patients received cytotoxic drugs, 8 underwent allogeneic or autologous transplantation procedures, 21 received STI571 (imatinib mesylate, Gleevec), 1 received radiotherapy, and 7 received no therapy. Of the 25 (32%) patients who achieved a "second chronic phase" with first therapy, 6 of 21 (29%) were treated with STI571 and 19 of 50 (38%) were treated with chemotherapy, transplantation, or radiotherapy. Patients who achieved a second chronic phase survived longer than those who did not (median time from onset of BT 12.0 months versus 6.3 months, P =.0004). In multivariate analysis the finding of more than 50% blast cells in the blood and the presence of cytogenetic progression were independent adverse prognostic variables for survival. We conclude that survival after onset of BT has improved in recent years but is still unsatisfactory. We speculate that the combined use of STI571 with cytotoxic drugs may offer additional benefit.
We have analysed the outcome of 581 autologous stem cell transplants (SCT) for chronic myeloid leukaemia (CML) in first chronic phase reported to the European Group for Blood and Marrow Transplantation between 1983 and 1998. Out off 207 patients evaluable for cytogenetics within 6 months of SCT, 36 patients (17%) were in complete cytogenetic remission (CCR), 34 (16%) in major remission (MCR), 74 (36%) in minor remission (mCR) and 63 (31%) had no cytogenetic response (NR). Interferon (IFN) was given post SCT to 267 patients. Results of the cytogenetic analysis within 1-2 years from SCT were available for 117 patients, the majority of whom (n = 101) received IFN post SCT: 17 (15%) were in CCR, 18 (15%) in MCR, 24 (20%) in mCR and 58 (50%) NR. The median survival in this series was 96 months (71-125) from SCT. There was no difference in survival according to cytogenetic status pre- and immediately post SCT. However, patients in CCR or MCR at 1-2 years post SCT had a 10-year survival of 66% compared with 36% for patients in mCR or NR (P = 0.003). The 5-year survival for patients receiving IFN post SCT was 72% compared with 61% for patients not treated with IFN (P = 0.01). Out of 155 patients refractory to IFN pre SCT, 70% achieved a cytogenetic response post SCT, which was complete or major in 31%. IFN refractory patients who sustained a CCR or MCR for 1-2 years after SCT had an excellent outcome.
The tyrosine kinase inhibitor STI571 (imatinib mesylate, Gleevec) is an effective treatment for chronic myeloid leukemia (CML). We examined bone marrow samples from 53 patients with CML who were receiving STI571 in 3 multicenter phase 2 trials to assess morphologic changes and cytogenetic response to this drug. In most patients with initially increased blasts, the bone marrow blast count rapidly decreased during STI571 therapy. Reductions in cellularity, the myeloid/erythroid ratio (commonly with relative erythroid hyperplasia), and reticulin fibrosis (if present pretreatment) also were seen in most patients, resulting in an appearance resembling normal marrow in many cases. Eighteen patients (34%) had some degree of cytogenetic response. Surprisingly, these striking morphologic changes occurred irrespective of any cytogenetic response to STI571. Thus, STI571 seems to affect the differentiation of CML cells in vivo, causing even extensively Philadelphia chromosome-positive hematopoiesis to exhibitfeatures resembling normal hematopoiesis.
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