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D Marin,
I H Gabriel,
S Ahmad,
L Foroni,
H de Lavallade,
R Clark,
S O'Brien,
R Sergeant,
C Hedgley,
D Milojkovic,
J S Khorashad,
M Bua,
A Alsuliman,
A Khoder,
K Stringaris,
N Cooper,
J Davis, J M Goldman,
J F Apperley,
K Rezvani
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ABSTRACT: Natural killer (NK) cells are expanded in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitors (TKI) and exert cytotoxicity. The inherited repertoire of killer immunoglobulin-like receptors (KIR) may influence response to TKI. We investigated the impact of KIR-genotype on outcome in 166 chronic phase CML patients on first-line imatinib treatment. We validated our findings in an independent patient group. On multivariate analysis, KIR2DS1 genotype (RR=1.51, P=0.03) and Sokal risk score (low-risk RR=1, intermediate-risk RR=1.53, P=0.04, high-risk RR=1.69, P=0.034) were the only independent predictors for failure to achieve complete cytogenetic response (CCyR). Furthermore, KIR2DS1 was the only factor predicting shorter progression-free (PFS) (RR=3.1, P=0.03) and overall survival (OS) (RR=2.6, P=0.04). The association between KIR2DS1 and CCyR, PFS and OS was validated by KIR genotyping in 174 CML patients on first-line imatinib in the UK multi-center SPIRIT-1 trial; in this cohort, KIR2DS1(+) patients had significantly lower 2-year probabilities of achieving CCyR (76.9 vs 87.9%, P=0.003), PFS (85.3 vs 98.1%, P=0.007) and OS (94.4 vs 100%, P=0.015) than KIR2DS1(-) patients. The impact of KIR2DS1 on CCyR was greatest when the ligand for the corresponding inhibitory receptor, KIR2DL1, was absent (P=0.00006). Our data suggest a novel role for KIR-HLA immunogenetics in CML patients on TKI.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2011; 26(2):296-302. · 8.30 Impact Factor
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A Bazeos,
D Marin,
A G Reid,
G Gerrard,
D Milojkovic,
P C May,
H de Lavallade,
P Garland,
K Rezvani,
J F Apperley, J M Goldman,
L Foroni,
J S Khorashad
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2010; 24(6):1243-5. · 8.30 Impact Factor
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B E Shaw,
N P Mayor,
N H Russell,
J F Apperley,
R E Clark,
J Cornish,
P Darbyshire,
M E Ethell, J M Goldman,
A-M Little,
S Mackinnon,
D I Marks,
A Pagliuca,
K Thomson,
S G E Marsh,
J A Madrigal
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ABSTRACT: Disease stage and recipient/donor human leukocyte antigen (HLA) matching are important determinants of outcome in transplantation using volunteer-unrelated donors (VUD). Matching for HLA-A, -B, -C, -DRB1, -DQB1 is beneficial, whereas the importance of DPB1 matching is more controversial. The impact of HLA matching status may differ dependent on disease stage. We investigated the outcome according to the degree of HLA matching at 6 loci, in 488 recipients of predominantly T-cell depleted bone marrow VUD transplants for leukaemia. Survival was significantly better in 12/12-matched transplants in those with early leukaemia (5 years: 63 versus 41% in 10/10 matched, P=0.006), but not late stage disease. Conversely, within the HLA-mismatched group (< or =9/10), there was a significant survival advantage to DPB1 mismatching (5 years: 39 versus 21% in DPB1 matched, P=0.008), particularly in late leukaemia (P=0.01), persisting in multivariate analysis (odds ratio 0.478; 95% confidence interval 0.30, 0.75; P=0.001). These novel findings suggest that the best outcome for patients with early leukaemia, with a 10/10-matched donor, is achieved by matching for DPB1. Conversely, our results suggest that in patients receiving an HLA-mismatched graft, the outcome is significantly better if they are also mismatched for DPB1. We recommend validation of these results in independent datasets.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2009; 24(1):58-65. · 8.30 Impact Factor
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ABSTRACT: Ph-positive chronic myeloid leukemia (CML) and Ph-negative chronic myeloproliferative diseases (MPDs), characterized in many cases by the presence of the JAK2(V617F) mutation, have many features in common and yet also show fundamental differences. In this review, we pose five discrete and related questions relevant to both categories of hematological malignancy, namely: What are the mechanisms that underlie disease progression from a relatively benign or chronic phase? By what therapeutic methods might one target residual leukemia stem cells in CML? Is JAK2(V617F) the original molecular event in MPD? What epigenetic events must have a role in dictating disease phenotype in MPDs? And finally, Will the benefits conferred by current or future JAK2(V617F) inhibitors equal or even surpass the clinical success that has resulted from the use of tyrosine kinase inhibitors in CML? These and others questions must be addressed and in some cases should be answered in the foreseeable future.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2009; 23(10):1708-15. · 8.30 Impact Factor
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ABSTRACT: We designed experiments to study the effects on P210BCR/ABL expression of introducing antisense oligonucleotides into K562 cells. We used two antisense oligonucleotides: one (AS1) is complementary to the first coding codon of the BCR/ABL mRNA and the two 5′ and three 3′ codons, and the other (AS2) to BCR coding codons 5 to 11 inclusive. To facilitate entry of the oligonucleotides the K562 cells were subjected to electroporation on three occasions at 24 hr intervals (0, 24 and 48 hr). P210BCR/ABL expression was assayed by in vivo phosphorylation followed by immune precipitation with a BCR antibody. Introduction of AS1 inhibited P210BCR/ABL expression at 72 and 96 hrs, whereas AS2 and the control oligonucleotide had no effect. AS1 also killed K562 cells. We conclude that selected antisense oligonucleotides can modify leukaemia-specific protein expression in K562 cells. This approach could prove valuable for purging CML bone marrow cells in vitro.
06/2009; 3(3):201-208.
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A Hochhaus,
S G O'Brien,
F Guilhot,
B J Druker,
S Branford,
L Foroni, J M Goldman,
M C Müller,
J P Radich,
M Rudoltz,
M Mone,
I Gathmann,
T P Hughes,
R A Larson
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ABSTRACT: Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (n=553) or interferon-alpha (IFN) plus cytarabine (n=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82%; 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2009; 23(6):1054-61. · 8.30 Impact Factor
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Bone marrow transplantation 02/2009; 44(2):129-30. · 3.00 Impact Factor
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N C P Cross,
G Q Daley,
A R Green,
T P Hughes,
C Jamieson,
P Manley,
T Mughal,
D Perrotti,
J Radich,
R Skoda,
S Soverini,
W Vainchenker,
S Verstovsek,
J-L Villeval, J M Goldman
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2008; 22(11):1975-89. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2008; 22(9):1806-7. · 8.30 Impact Factor
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ABSTRACT: A significant minority of chronic myeloid leukaemia patients eventually develop resistance to imatinib, often as a result of point mutations within the BCR-ABL kinase domain. Second-line tyrosine kinase inhibitors (TKIs) are effective against mutations that confer imatinib resistance; however, the T315I BCR-ABL mutant has proved resistant to all available TKIs. An assay facilitating early identification of BCR-ABL(T315I) would therefore aid in identifying high-risk patients who may benefit from alternative therapy. This report describes the development of a sensitive T315I mutation detection methodology based on real-time PCR with self-probing fluorescent primers. The technique demonstrated complete concordance with direct sequencing, correctly identifying 34 T315I-positive samples from a total of 61 samples screened. In a limiting dilution assay, the mutated clone was detectable to a level of 1% of total cells. The data show that Scorpions PCR enables rapid screening for BCR-ABL(T315I) in chronic myeloid leukaemia patients and is appropriate for use in a clinical setting.
Journal of clinical pathology 08/2008; 61(7):863-5. · 2.43 Impact Factor
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M. E. Haines, J. M. Goldman,
A. M. Worsley,
D. M. McCarthy,
S. E. Wyatt,
C Dowding,
L. Kearney,
K. H. Th'ng,
N. J. Wareham,
A. Pollock,
M. C. Galvin,
D. Samson,
C G. Geary,
D. Catovsky,
D. A. G. Galton
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ABSTRACT: Between June 1977 and July 1983 51 patients with Ph1-positive chronic granulocytic leukaemia (CGL) in transformation were treated either by chemotherapy or by chemoradiotherapy followed by autografting with haemopoietic stem cells collected from their peripheral blood at the time of diagnosis. Forty-eight patients were restored to a second chronic phase. The median duration of survival after autografting was 26 weeks (range 2-152 weeks). Twenty-one patients with relatively long durations of second chronic phase were treated again by autografting as consolidation or when transformation recurred; this selected group of patients survived longer than the 30 patients treated by autografting only once (medians 52 v. 13 weeks respectively, P<0-01). There was no significant influence of the patients’ age, splenectomy status, type of transformation, treatment pre-autograft or number of nucleated cells autografted on the duration of survival. Three patients treated in myeloid blastic transformation were restored to partially Phnegative haemopoiesis. We conclude that this approach to the management of CGL in transformation can offer benefit for a minority of patients and that further chemotherapy and autografting for patients still in second chronic phase may be valuable.
British Journal of Haematology 03/2008; 58(4):711 - 721. · 4.94 Impact Factor
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ABSTRACT: Summary A cytogenetic analysis was carried out on bone marrow cells from 11 patients who presented with hypereosinophilia and the clinical features of the idiopathic hypereosinophilic syndrome. One of these patients was found to have trisomy 8 affecting the myeloid series, including eosinophils. In this patient, marrow eosinophils also showed asynchrony of nuclear-cytoplasmic maturation, and there were increased numbers of myeloid progenitor cells in the blood. Six months later, blast cell transformation occurred, and he died soon afterwards. These findings show that abnormalities in the karyotype of bone marrow cells and culture of blood progenitor cells may help to identity eosinophilic leukaemia among patients who present with features of the idiopathic hypereosinophilic syndrome.
British Journal of Haematology 03/2008; 62(4):659 - 669. · 4.94 Impact Factor
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T Mughal,
J Cortes,
N C P Cross,
N Donato,
O Hantschel,
E Jabbour,
H Kantarjian,
J V Melo,
T Skorski,
R T Silver, J M Goldman
Leukemia 08/2007; 21(7):1347-52. · 9.56 Impact Factor
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M P Simula,
S Marktel,
C Fozza,
J Kaeda,
R M Szydlo,
E Nadal,
M Bua,
A Rahemtulla,
E Kanfer,
D Marin,
E Olavarria, J M Goldman,
J F Apperley,
F Dazzi
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ABSTRACT: Donor lymphocyte infusions (DLI) are an effective treatment for patients with chronic myeloid leukemia (CML) in relapse after allografting but the optimal cell dose has yet to be identified. To address this question, we investigated the factors affecting the dose required to achieve remission (effective cell dose, (ECD)) in 81 patients treated with an escalating dose regimen. The overall proportion of patients who achieved a molecular remission was 88%. The cumulative proportion of remitters increased significantly at each dose level. With a CD3(+) cell dose < or =10(7)/kg, 56% of patients in molecular/cytogenetic relapse obtained molecular remission, whereas only 20% of those in hematologic relapse did so. At the same cell dose, 58% of patients who received lymphocytes from volunteer unrelated donors achieved remission, as compared to 29% of those who received DLI from sibling donors. We conclude that the response to DLI is dose-dependent and that the ECD is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility.
Leukemia 05/2007; 21(5):943-8. · 9.56 Impact Factor
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ABSTRACT: We investigated the risk factors for graft-versus-host disease (GVHD) in 82 patients treated with donor lymphocyte infusions (DLI) using an escalating dose regimen for chronic myeloid leukaemia in relapse following conventional allografting. Two factors emerged as predictors of both acute and chronic GVHD: the infusion of male recipients with lymphocytes from a female donor and the interval between transplant and last DLI, but only the first remained significant at multivariate analysis. Surprisingly, lymphocyte dose did not influence the incidence of GVHD. Our results suggest that DLI can be given in large cell doses without increasing the risk of GVHD.
British Journal of Haematology 04/2007; 136(6):833-6. · 4.94 Impact Factor
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R F Duarte,
D Pamphilon,
J Cornish,
B E Shaw,
D Samson,
C Craddock,
D Marks,
G J Mufti,
R L Powles,
J F Apperley,
J A Madrigal, J M Goldman
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ABSTRACT: Over more than three decades, The Anthony Nolan Trust (ANT) has provided an unrelated donor (UD) for over 4000 children and adults lacking a suitable family member donor, and has remained at the forefront of developments in haematopoietic stem cell transplantation (HSCT) and bone marrow register management. These three decades have seen major changes in clinical practice of UD-HSCT, including new indications, increased use of alternative haematopoietic cell sources, significant improvement of the outcome as a result of better support care, less-toxic conditioning regimens, and better donor selection, and expansion to older patients with higher comorbidities. In order to foster our goal of improving UD-HSCT availability and outcome in a progressively more complex clinical scenario, a new initiative from ANT was launched in 2005 to convene an experts workshop to address the topical issues in this field. Four consecutive panels addressed factors influencing donor selection and transplant outcome, the use of cord blood, regulatory and accreditation issues, and future developments in this field. This report summarizes the discussions held in this workshop, which will likely develop into a periodic event where transplant clinicians, scientists and registry members will meet to share their experience and vision in the field of UD-HSCT.
Bone Marrow Transplantation 06/2006; 37(10):901-8. · 3.75 Impact Factor
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J S Khorashad,
M Anand,
D Marin,
S Saunders,
T Al-Jabary,
A Iqbal,
S Margerison,
J V Melo, J M Goldman,
J F Apperley,
J Kaeda
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ABSTRACT: The expansion of a leukemia clone bearing a Bcr-Abl kinase domain mutation is associated with acquired resistance to imatinib and may also predict disease progression in patients with Philadelphia-positive chronic myeloid leukemia (CML). Here we report results of pyrosequencing to quantitate the non-mutated and mutant alleles in 12 CML patients monitored over periods ranging from 11 to 58 months, and describe three contrasting kinetic patterns: Group 1 - in four patients total BCR-ABL transcript numbers remained high with the mutant allele predominating; Group 2 - in four patients the total number of BCR-ABL transcripts fell to low levels but the mutant allele predominated; and Group 3 - in four other patients the total level of transcripts remained high (n = 2) or fell (n = 2) but the mutant clone persisted at relatively low level. In Group 2 the mutant leukemia clone was presumably still relatively sensitive to imatinib but in Group 1 the leukemia could be classified as resistant. In Group 3 patients the imatinib sensitivity of the leukemia was variable. We conclude that a mutant clone does not necessarily have a proliferative advantage and its presence does not always account for resistance to imatinib. Other mechanisms underlie resistance in at least some patients.
Leukemia 05/2006; 20(4):658-63. · 9.56 Impact Factor
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D Marin,
J Kaeda,
R Szydlo,
S Saunders,
A Fleming,
J Howard,
C Andreasson,
M Bua,
E Olavarria,
A Rahemtulla,
F Dazzi,
E Kanfer, J M Goldman,
J F Apperley
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ABSTRACT: We monitored BCR-ABL transcript levels by quantitative real-time PCR in 103 patients treated with imatinib for chronic myeloid leukaemia in chronic phase for a median of 30.3 months (range 5.5-49.9) after they achieved complete cytogenetic remission (CCyR). The patients could be divided into three groups: (1) in 32 patients transcript levels continued to decline during the period of observation (nadir BCR-ABL/ABL ratio 0.015%); in five of these patients BCR-ABL transcripts became undetectable on repeated testing, (2) in 42 patients the transcript levels reached a plateau and (3) in 26 patients transcript numbers increased and the initial CCyR was lost. Three patients were not evaluable. Patients who remained in CCyR for at least 24 months appeared to have a low risk of subsequent cytogenetic relapse. We conclude that the pattern of 'residual' disease after achieving CCyR on imatinib is variable: some patients in CCyR show a progressive reduction in the level of residual disease, some reach a plateau where transcript numbers are relatively stable and others relapse with Ph-positive metaphases.
Leukemia 05/2005; 19(4):507-12. · 9.56 Impact Factor
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ABSTRACT: The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) system has a major role in the pathogenesis of bone disease in myeloma (MM). The effect of autologous stem cell transplantation (ASCT) on bone turnover in MM was evaluated in 51 patients (35M/16F). Markers of bone resorption (NTX, TRACP-5b), bone formation (bone-alkaline phosphatase (bALP), osteocalcin), OPG and sRANKL were measured pre- and every month post-ASCT. The median follow-up period was 12 months. Four patients were transplanted in CR, 44 were transplanted in PR and three patients had progressive/resistant disease. All patients received bisphosphonates both pre- and post-ASCT. At baseline the majority of patients had increased NTX, TRACP-5b levels, and sRANKL/OPG ratio, while markers of bone formation were strongly suppressed. ASCT produced a significant reduction of sRANKL/OPG ratio, with a concomitant decrease of NTX, and TRACP-5b levels, starting the second month post-ASCT. Bone formation markers, osteocalcin and bALP, started to increase after the 9th and 11th month post-ASCT, respectively, while the increase of OPG preceded this. These results provide biochemical evidence that ASCT normalizes the abnormal bone resorption in MM patients possibly through the decrease of RANKL/OPG ratio, while bone formation requires a longer period to return to normal.
Leukemia 09/2004; 18(8):1420-6. · 9.56 Impact Factor
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ABSTRACT: Monotherapy of chronic myeloid leukemia (CML) with imatinib mesylate has been cast into shadow by the evolution of clinical resistance during therapy. Resistance to imatinib can arise by multiple mechanisms including amplification or mutation of Bcr-Abl, and continuity of imatinib therapy is probably a poor option for either of these patient groups. Recently, however, a structurally distinct new class of drugs, the pyrido[2,3-d]pyrimidines, has been described, and these compounds are predicted to make different molecular contacts in the Abl kinase domain. These drugs potently target both the Bcr-Abl and Src-family kinase activities, both of which are thought to be relevant to survival of the leukemic cell. We asked whether these drugs could selectively induce cell death in murine cell line models of CML cells sensitive and resistant to imatinib by different mechanisms. We show that whereas the pyrido[2,3-d] pyrimidines are indeed highly potent in suppressing proliferation of Bcr-Abl-overexpressing imatinib-resistant cells, they are almost completely ineffective against cells expressing the T315I mutant. This implies that despite structural differences from imatinib, these drugs are unlikely to be useful in patients expressing this mutant Bcr-Abl protein, but may be effective in cases where selection of cells overexpressing the oncoprotein leads to refractoriness to imatinib.
Leukemia 09/2004; 18(8):1352-6. · 9.56 Impact Factor
