An amino-acid switch in the BCR-ABL kinase domain modifies sensitivity to imatinib mesylate.
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Amino Acid Substitution↗
Biomedical subjects
J Reiffers
Publications and source records attributed to J Reiffers.
Reassessing autotransplantation for acute myeloid leukaemia in first remission - a matched pair analysis of autologous marrow vs peripheral blood stem cells.
The role of autologous stem cell transplantation in adult patients with acute myeloid leukaemia (AML) in first remission is unclear, yet it has become standard treatment for myeloma and this paper explores whether the source of transplanted stem cells may explain this paradox. In total, 57 patients from the Royal Marsden Hospital who received an unpurged bone marrow transplant (ABMT) were matched with 114 patients from the EBMT registry who had undergone peripheral blood stem cell transplantation (PBSCT). Patients were matched for karyotype, FAB type, remission-autograft interval and age. In the PBSCT group, haematopoietic recovery was significantly faster and nonrelapse mortality at 4 years was significantly lower (13 vs 1%, P=0.04). The relapse rate and overall survival at 4 years (20 vs 31% and 77 vs 63%) were also better with PBSCT, although the differences were not statistically significant. Autografting should be reassessed in a randomised trial for first remission AML patients using peripheral blood as a source of stem cells rather than bone marrow.
Acute Disease↗
Higher doses of CD34+ peripheral blood stem cells are associated with increased mortality from chronic graft-versus-host disease after allogeneic HLA-identical sibling transplantation.
Allogeneic peripheral blood stem cell transplantation (PBSCT) has emerged as an alternative to bone marrow transplantation. PBSCT can be associated with a higher incidence of chronic graft-versus-host disease (cGVHD). In this study, we investigated whether there was a correlation between the composition of PBSC grafts (CD34+ and CD3+ cells) and hematological recovery, GVHD, relapse, and relapse-free survival (RFS) after myeloablative HLA-identical sibling PBSCT. The evolution of 100 acute or chronic leukemia patients was analyzed. Neither hematological recovery, acute or cGVHD, nor relapse, was significantly associated with CD3+ cell dose. Increasing CD34+ stem cells was associated with faster neutrophil (P=0.03) and platelet (P=0.007) recovery. Moreover, 47 of the 78 patients evaluable for cGVHD (60%; 95% CI, 49-71%) developed extensive cGVHD. The probability of extensive cGVHD at 4 years was 34% (95% CI, 21-47%) in patients receiving a 'low' CD34+ cell dose (<8.3 x 10(6)/kg), as compared to 62% (95% CI, 48-76%) in patients receiving a 'high' CD34+ cell dose (>8.3 x 10(6)/kg) (P=0.01). At a median follow-up of 59 months, this has not translated into a difference in relapse. In patients evaluable for cGVHD, RFS was significantly higher in patients receiving a 'low' CD34+ cell dose as compared to those receiving a 'high' CD34+ cell dose (P=0.04). This difference was mainly because of a significantly higher cGVHD-associated mortality (P=0.01). Efforts to accelerate engraftment by increasing CD34+ cell dose must be counterbalanced with the risk of detrimental cGVHD.
Acute Disease↗
Risk assessment in adult acute lymphoblastic leukaemia before early haemopoietic stem cell transplantation with a geno-identical donor: an easy clinical prognostic score to identify patients who benefit most from allogeneic haemopoietic stem cell transplantation.
In 1402 patients allografted in Europe during the period 1990-2000 with an HLA-identical sibling in first remission (CR1), the median interval from CR1 to allotransplant (96 days) was a major prognostic factor, patients transplanted earlier having a worse outcome. We studied in depth the 414 fully evaluable patients transplanted less than 96 days after achieving CR1; in these patients, only three factors predicted for the outcome by multivariate analysis: patient age, CR1 achievement with one or more induction courses and the recipient/donor sex combination. These three factors overcame the information from cytogenetics and source of stem cells. Three prognostic groups could be identified in relation to the outcome, using a prognostic score affecting 1 to each poor risk factor (total from 0 to 3): Group 1 (good prognosis) includes patients <35 years old, achieving CR1 with one induction course and to be transplanted with any other sex combination than female to male (score 0); group 2 (intermediate) with one adverse factor (score 1); and group 3 (bad prognosis) with two or three adverse criteria (scores 2 and 3). In these three groups, the 3-year leukaemia-free survival was 56+/-5%, 48+/-4% and 29+/-4% and the overall survival was 65+/-5, 53+/-4 and 29+/-5%, respectively. Therefore, adult patients with ALL and a score of 0 or 1 are good candidates for an early transplant if they have an identical sibling donor. Patient age, response to induction and the sex of the HLA-identical family donor (if existing) are the strongest easy predictors of the outcome for an early transplant in an adult patient with ALL. No additional information is mandatory.
Adolescent↗
Follow-up of complete cytogenetic remission in patients with chronic myeloid leukemia after cessation of interferon alfa.
PURPOSE: A small proportion of patients with chronic myeloid leukemia (CML) achieve a complete cytogenetic response (CCR), defined as the disappearance of Philadelphia (Ph) chromosome-positive metaphases, after treatment with interferon alfa (IFN). In this population of patients, the question of whether treatment should then be withdrawn is not yet resolved. PATIENTS AND METHODS: In the present study, we followed 15 patients who stopped IFN after achieving CCR. In nine patients IFN was stopped in view of adverse reactions (n = 8) or patient's choice (n = 1). For the remaining six patients, the treatment was stopped because no BCR/ABL rearrangement could be detected by reverse transcriptase polymerase chain reaction (RT-PCR) in four successive analyses using peripheral-blood samples. RESULTS: Loss of CCR and survival were not statistically different (P =.48; P =.7) for the 15 patients who stopped IFN compared with 41 other CCR patients who continued IFN therapy in our institution. The median follow-up after discontinuation of IFN treatment was 36 months (range, 6 to 108 months). Seven patients (47%) (females, or CCR > 24 months and RT-PCR negative before IFN cessation; P <.0001) did not relapse. Eight other patients (53%) relapsed (lost CCR) within 3 to 33 months of treatment discontinuation. One of them relapsed in major cytogenetic remission (MCR) and was still in MCR 87 months after stopping therapy without any treatment. CONCLUSION: It is possible to stop IFN treatment at least in some patients with CML who achieve a prolonged period of CCR. This study also illustrates the hypothesis that persistence of low numbers of Ph-positive cells does not necessarily imply hematologic relapse.
Adult↗
Nitric oxide induces the apoptosis of human BCR-ABL-positive myeloid leukemia cells: evidence for the chelation of intracellular iron.
Anti-leukemia activity of human macrophages involves the generation of nitric oxide (NO) derivatives. However, leukemic transformation may involve mechanisms that rescue cells from NO-mediated apoptosis. In the present work, we analyzed the effects of exogenous NO on the proliferation of BCR-ABL(+) chronic myelogenous leukemia (CML) cells. As normal leukocytes, the proliferation of leukemia cells was inhibited by SNAP (S-nitroso-N-acetyl-penicillamine), GEA (Oxatriazolium amino-chloride), and SIN-1 (Morpholino-sydnonimine), whereas SNP (sodium nitroprusside) had no effect on leukemia cell growth. SIN-1 induced higher anti-proliferation activity in BCR-ABL(+) cells, compared to normal hemopoietic cells. Inhibition of leukemia cell proliferation correlated with increased apoptosis and DEVDase activity. The simultaneous addition of exogenous iron reversed NO-mediated inhibition of cell growth, caspase activation and apoptosis in all BCR-ABL(+) cells tested. The quantification of intracellular iron levels in leukemia cells indicated that NO induced an early, dose-dependent decrease in ferric iron levels. Accordingly, elevation of intracellular iron protected leukemia cells from NO-mediated apoptosis. Together, the present work reveals the presence of an iron-dependant mechanism for leukemia cell rescue from NO-induced growth inhibition and apoptosis.
Apoptosis↗
Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon alpha-2b for the treatment of chronic myelogenous leukemia patients in chronic phase.
Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon alpha-2b (IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2-38 months). At 3 years the overall survival was 79% (95% CI, 70-88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.
Administration, Oral↗
Resistance to daunorubicin-induced apoptosis is not completely reversed in CML blast cells by STI571.
The leukemogenic property of BCR-ABL in chronic myeloid leukemia (CML) is critically dependent on its protein tyrosine kinase activity. STI571 inhibits the BCR-ABL kinase activity, the growth and the viability of BCR-ABL expressing cells. In this study, we report the apoptotic effect of STI571 in combination with daunorubicin (DNR) on peripheral blood mononuclear cells from 11 CML patients and four BCR-ABL-positive cell lines: AR230, LAMA84, K562 and KCL22. Primary blast cells were identified by flow cytometry on the basis of their low CD45 expression. Nucleus fragmentation, exposure of phosphatidylserines and decrease in mitochondrial membrane potential were measured using acridine orange, FITC-annexin V and DiOC6(3), respectively, to evaluate apoptosis. On cell lines, the effect of DNR was negligible, whereas STI571 induced 10 to 35% of apoptosis in 18 h. STI571 sensitized AR230, LAMA84 and K562 cells to DNR when apoptosis was measured at the mitochondrial and membrane but not the nuclear levels. On CML blast cells, phosphatidyl serine exposure was significantly induced by both DNR and STI571 and was higher when these drugs were used in combination (P < 0.0003). However, the effects of this drug combination were only additive and no sensitization of blast cells to DNR by STI571 was observed. Interestingly, sensitization was evidenced in CML but not normal lymphocytes. These results suggest that other mechanisms additional to Bcr-Abl tyrosine kinase activity could be responsible for DNR resistance, and further investigations are needed to understand its origin.
Antineoplastic Agents↗
Prior treatment with alpha interferon does not adversely affect the outcome of allogeneic transplantation for chronic myeloid leukaemia.
The timing of transplantation in chronic myeloid leukaemia is still debated and previous treatment with interferon (IFN) alpha has been reported to be deleterious. We have analysed the outcome of 438 allogeneic transplants performed between 1984 and 1995 and reported to the Société Française de Greffe de Moelle (SFGM) registry. One hundred and two patients (group I) received IFN for more than 6 weeks (median = 9 months) before transplant. Their outcome was compared with 336 other patients (group II) not pretreated with IFN. There were no significant differences between the groups for engraftment and chronic graft-versus-host disease (GVHD) incidence. However, other significant differences included the incidence of acute GVHD > or = 2 at 3 months which was higher in group I (65 +/- 10%) than in group II (38 +/- 5%; P = 0.01). Moreover, disease-free survival (DFS) and overall survival (OS) at 5 years were significantly shorter for group I than for group II (33 +/- 10% vs. 41 +/- 6%; P = 0.005)(95% CI) and (41 +/- 10% vs. 55 +/- 6%; P = 0.002)(95% CI) respectively. After adjustment for patient and transplant covariables in a multivariate analysis, prior IFN was not found to adversely affect transplant outcome.
Adolescent↗
Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders.
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.
Adult↗
Role of iron in tumor cell protection from the pro-apoptotic effect of nitric oxide.
F2The host defense against tumor cells is in part based upon the production of nitric oxide (NO) by activated macrophages. However, carcinogenesis may involve mechanisms that protect tumor cells from NO-mediated apoptosis. In the present study, we have assessed the effects of exogenous NO on the proliferation and survival of human liver (AKN-1), lung (A549), skin (HaCat), and pancreatic (Capan-2) tumor cell lines, compared with normal skin-derived epithelial cell cultures. Except to the HaCat cell line, all of the other human epithelioid cells were sensitive to the antiproliferation effect of S-nitroso-N-acetyl-penicillamine or Deta NONOate, whereas tumor cells had low if any response to sodium nitroprusside. Growth inhibition with exogenous NO correlated with increased apoptosis, but was not mediated by cyclic GMP, peroxynitrite generation, or poly(ADP-ribose) polymerase modulation, all of which involved in NO-mediated growth inhibition of normal skin-derived epithelial cell cultures. The simultaneous addition of iron-containing compounds protected tumor cells from NO-mediated growth inhibition and apoptosis. Intracellular iron quantification indicated that, as deferoxamine, exogenous NO significantly decreased intracellular ferric iron levels in tumor cells. Together, the current study reveals that intracellular iron elevation rescues tumor cells from NO-mediated iron depletion and subsequent growth inhibition and apoptosis.
Apoptosis↗
Expression of interferon-alpha (IFN-alpha) receptor 2c at diagnosis is associated with cytogenetic response in IFN-alpha-treated chronic myeloid leukemia.
For the management of chronic myeloid leukemia (CML), prediction or early determination of the response to interferon-alpha (IFN-alpha) treatment is important for identifying nonresponder patients to whom alternative therapy may be proposed. In this study, the levels of expression of both BCR-ABL and subunit 2c of IFN-alpha receptor (IFN-alphaR2c) genes were analyzed at diagnosis in 74 patients with chronic phase CML treated with an IFN-alpha monotherapy. By using blood samples, real-time quantitative polymerase chain reaction was performed to quantify BCR-ABL, IFN-alphaR2c, and G6PDH mRNA as external control. The results were compared with hematologic and cytogenetic responses to IFN-alpha. A wide variation in the BCR-ABL/G6PDH ratio was observed at diagnosis (median, 6.68%; range, 0.18%-41.31%), but no significant association with response to IFN-alpha was observed. In contrast, the variation of IFN-alphaR2c/G6PDH ratio at diagnosis was significantly associated with the achievement of major cytogenetic response (MCR; 34% or lower Ph(+) metaphases). Median values of IFN-alphaR2c/G6PDH ratio for patients achieving MCR and for those who did not achieve it were 110.75% (range, 9.47%-612.30%) and 64.42% (range, 5.96%-425.40%), respectively (P =.037). In addition, this novel molecular factor, combined with the achievement of complete hematologic response at 3 months, makes it possible to predict MCR achievement with high probability by Kaplan-Meier analysis (91% +/- 17% at 24 months; P =.0001). (Blood. 2001;97:3568-3573)
Adult↗
Long-term follow-up of a randomized trial comparing the combination of cyclophosphamide with total body irradiation or busulfan as conditioning regimen for patients receiving HLA-identical marrow grafts for acute myeloblastic leukemia in first complete remission.
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Bone Marrow Transplantation↗
Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure.
BACKGROUND: Avoiding intubation is a major goal in the management of respiratory failure, particularly in immunosuppressed patients. Nevertheless, there are only limited data on the efficacy of noninvasive ventilation in these high-risk patients. METHODS: We conducted a prospective, randomized trial of intermittent noninvasive ventilation, as compared with standard treatment with supplemental oxygen and no ventilatory support, in 52 immunosuppressed patients with pulmonary infiltrates, fever, and an early stage of hypoxemic acute respiratory failure. Periods of noninvasive ventilation delivered through a face mask were alternated every three hours with periods of spontaneous breathing with supplemental oxygen. The ventilation periods lasted at least 45 minutes. Decisions to intubate were made according to standard, predetermined criteria. RESULTS: The base-line characteristics of the two groups were similar; each group of 26 patients included 15 patients with hematologic cancer and neutropenia. Fewer patients in the noninvasive-ventilation group than in the standard-treatment group required endotracheal intubation (12 vs. 20, P=0.03), had serious complications (13 vs. 21, P=0.02), died in the intensive care unit (10 vs. 18, P=0.03), or died in the hospital (13 vs. 21, P=0.02). CONCLUSIONS: In selected immunosuppressed patients with pneumonitis and acute respiratory failure, early initiation of noninvasive ventilation is associated with significant reductions in the rates of endotracheal intubation and serious complications and an improved likelihood of survival to hospital discharge.
Acute Disease↗
[Molecular mechanisms controlling the cell cycle: fundamental aspects and implications for oncology].
INTRODUCTION: Comprehension of cell cycle regulation mechanisms has progressed very quickly these past few years and regulators of the cell cycle have gained widespread importance in cancer. This review first summarizes major advances in the understanding of the control of cell cycle mechanisms. Examples of how this control is altered in tumoral cells are then described. CURRENT KNOWLEDGE AND KEY POINTS: The typical mammalian cell cycle consists of four distinct phases occurring in a well-defined order, each of which should be completed successfully before the next begins. Progression of eukaryotic cells through major cell cycle transitions is mediated by sequential assembly and activation of a family of serine-threonine protein kinases, the cyclin dependent kinases (CDK). The timing of their activation is determined by their post-translational modifications (phosphorylations/dephosphorylations), and by the association of a protein called cyclin, which is the regulatory subunit of the kinase complex. The cyclin family is divided into two main classes. The 'G1 cyclins' include cyclins C, D1-3, and E, and their accumulation is rate-limiting for progression from the G1 to S phase. The 'mitotic or G2 cyclins', which include cyclin A and cyclin B, are involved in the control of G2/M transition and mitosis. The cyclins bind to and activate the CDK, which leads to phosphorylation (and then inhibition) of the tumor suppressor protein, pRb. pRb controls commitment to progress from the G1 to S phase, at least in part by repressing the activity of the E2F transcription factors known to promote cell proliferation. Both the D-type cyclins and their partner kinases CDK4/6 have proto-oncogenic properties, and their activity is carefully regulated at multiple levels including negative control by two families of CDK inhibitors. While members of the INK4 family (p16INK4A, p15INK4B, p18INK4C, p19INK4D) interact specifically with CDK4 and CDK6, the CIP/KIP inhibitors p21CIP1/WAF1, p27KIP1 and p57KIP2 inhibit a broader spectrum of CDK. The interplay between p16INK4A, cyclin D/CDK, and pRb/E2F together constitute a functional unit collectively known as the 'pRb pathway'. Each of the major components of this mechanism may become deregulated in cancer, and accumulating evidence points to the 'pRb pathway' as a candidate obligatory target in multistep oncogenesis of possibly all human tumor types. FUTURE PROSPECTS AND PROJECTS: Major advances in the understanding of cell cycle regulation mechanisms provided a better knowledge of the molecular interactions involved in human cancer. This progress has led to the promotion of new therapeutic agents presently in clinical trials or under development. Moreover, the components of the cell cycle are probably involved in other non-cancerous diseases and their role must be defined.
Animals↗
Primary digestive Richter's syndrome.
The clinical and morphologic transformation of 3 to 5% of chronic lymphocytic leukemia (CLL) to diffuse large-cell lymphoma (DLCL) is commonly referred to as Richter's syndrome. Richter's syndrome occurs mostly in lymph nodes and may represent a second neoplasm or a transformation from the same clonal population. Clinical features in six patients with digestive Richter's syndrome were recorded. Paired samples of CLL and DLCL were investigated by immunohistological analysis (n = 6) and by polymerase chain reaction (PCR) for immunoglobulin heavy-chain gene rearrangement (n = 4). Histological examination revealed the involvement of the gastrointestinal tract by DLCL of B-cell phenotype (n = 6). The same monoclonal rearrangement between CLL and DLCL was demonstrated by PCR and sequencing analyses in two patients. The monoclonal rearrangement was different between CLL and DLCL in only one case. Median survival was 22 months for five patients receiving chemotherapy, suggesting that digestive Richter's syndrome has a better prognosis than nodal Richter's syndrome. Indeed, appropriate surgical resection combined with chemotherapy led to partial or complete remission in four patients.
Aged↗
A comparison of toxicity following two different doses of cyclophosphamide for mobilization of peripheral blood progenitor cells in 116 multiple myeloma patients.
High-dose cyclophosphamide (HDC) has been shown to be an effective regimen for collecting PBPC in multiple myeloma (MM) patients, but the optimal dose to be used remains controversial. Two historical cohorts of MM patients who received G- or GM-CSF and HDC at the dose of either 7 g/m(2) (HDC7, n = 74) or 4 g/m (HDC4, n = 42) were compared. As patients in the HDC4 group were more likely to have received G-CSF than GM-CSF (P < 10(-3)) and fewer previous alkylating agents (P = 0.004), multivariate logistic regression analysis was performed. In the HDC4 group, patients had a shorter median duration of neutropenia (P < 10(-4)), fewer RBC (P < 10(-3)) and platelet transfusions (P < 10(-3)) with fewer patients with platelets <20 x 10(9)/l (P = 0.004). Moreover, fewer febrile episodes (P < 10(-3)) and less need of intravenous antibiotics (P < 10(-3)) were found in the HDC4 group. No statistical difference was observed with regard to CD34(+) cell collection efficiency. Thus, the use of HDC at the dose of 4 g/m(2) for the collection of PBPC in MM patients decreases hematological and extrahematological toxicity with an equivalent CD34(+) cell collection efficiency.
Adult↗
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.
Out of 690 allogeneic matched sibling donor transplants for multiple myeloma reported to the European Group for Blood and Marrow Transplantation (EBMT) registry, 334 were performed during the period 1983-93 (all with bone marrow) and 356 during 1994-98 [223 with bone marrow and 133 with peripheral blood stem cells (PBSCs)]. The median overall survival was 10 months for patients transplanted during the earlier time period and 50 months for patients transplanted with hone marrow during the later period. The use of PBSCs was associated with earlier engraftment but no significant survival benefit compared to bone marrow transplants during the same time period. The improvement in survival since 1994 with the result of a significant reduction in transplant-related mortality, which was 38%, 21% and 25% at 6 months and 46%, 30% and 37% at 2 years during the earlier period, and the later period with bone marrow and PBSCs respectively. Reasons for the reduced transplant-related mortality appeared to be fewer deaths owing to bacterial and fungal infections and interstitial pneumonitis, in turn a result of earlier transplantation and less prior chemotherapy. Better supportive treatment and more frequent use of cytokines may also play a role. The improvement in survival was not directly related to the increased use of PBSCs.
Adult↗