Sokal Index Research Articles

Combined Chemotherapy (daunorubicin + cytarabine) and Dasatinib as Salvage Therapy of Chronic Myeloid Leukemia (CML) in Myeloid Blast Crisis, a Pilot Study.

Abstract 2195Poster Board II-172The results of the treatment of blast crisis CML remain still disappointing with poor overall survival rates, despite the introduction of imatinib (IM) in the therapeutic arsenal of Ph+ leukemias. This compound alone provides 24% of overall initial hematologic responses in myeloid blast crisis (MBC) IM-naive patients (pts), with 7 months of median overall survival rates. Dasatinib remains disappointing with 34% of major hematological responses (MaHRs, Cortes, Blood, 2007) in IM-resistant pts. The combination of IM to daunorubicin (3 days) and cytarabine (7 days) AML schedule (“3+7”) might improve responses and survival rates with 55.5 % of complete remissions (CR) and a median overall survival of 15.9 months (B. Deau, submitted).In this preliminary pilot study, we proposed to test the combination of daunorubicin + cytarabine to dasatinib in MBC CML in order to improve outcome. Fifteen patients have been enrolled [8M, 7F, median age at diagnosis 45 (28-64) years]. Prior to enrollment, 5 pts were in chronic phase (CP), 2 in accelerated phase (AccP) on IM. Eight pts were in MBC at diagnosis, and IM-naive. Additional chromosomal abnormalities (ACA) were present at diagnosis in 5 pts [+8 (2 pts), +21 (2 pts), t(3;21) (1 pt), add(1) (1 pt), complex abnormalities (1 pt), variant Ph (2 pts)]. For CP pts Sokal index was low for 2, intermediate for 1, unknown for 2, and none had any additional chromosomal abnormality at diagnosis. One patient had an e1a2 transcript, others a M-BCR transcript. Nine pts/15 had IM prior to combined therapy [best responses to IM prior to MBC were for 5 pts in CP: 3 complete hematologic remissions (CHR), 2 major molecular responses (MMR), for 2 pts in AccP: 2 CHR, for 2 in MBC: 1 complete cytogenetic remission (CCR) and 1 hematologic response (HR)]. In these 9 pts, 1 developed IM hematologic resistance in CP, 5 cytogenetic resistance, 1 molecular progression, and 2 entered MBC. Nine were screened for BCR-ABL mutations and only one was harboring a G250E mutation. The median interval between IM start and progression to MBC was 27 (1.1-65) months. Only 2 pts were exposed to dasatinib prior to combined therapy.At MBC, 7/15 pts had ACA, 10/15 screened were unmutated, 3 mutated (G250E, and 2 unknown). The pts received a median dose of 60 mg/m2/d of daunorubicin 3 days + a median dose of 200 mg/m2/d of cytarabine for 7 days and a median dose of 140 mg/d of dasatinib starting at day 1. Eight pts/15 had G-CSF after induction chemotherapy as planned by the study, for a median of 18 (5-28) days. The induction chemotherapy was well tolerated with no pleural effusions or other particular toxicities. A median of 37 days of neutropenia (<0.5 G/l) and 27 days of thrombocytopenia (<20 G/l) since day 1 were observed, and a median of 8 (3-38) RBC transfusions and 10 (4-45) platelets transfusions were necessary. One patient remained aplastic until allogeneic transplantation. No particular infection occurred. Complete remission (CR) was obtained in 8/15 and non evidence of leukemia in 3/15 resulting in a MaHR rate of 73%. The median BCR-ABL/ABL (IS) ratio was 6 (0.04-62)% and CCR was documented in 3/15 pts. Six pts had various courses of consolidation therapy (dasatinib in all cases + anthracyclin + cytarabine in 5). Ten pts/15 could be referred for allogeneic stem cell transplantation (5 MUD, 1 haplo-identical, 3 cord blood, 1 related, 6 conventional, 4 reduced intensity). The median delay between day 1 combined therapy and transplant was 5 (2.9-5.4) months. In evaluable pts, acute GVHD did not occur in 4 pts (1 grade 2, 4 unknown). At 3 months post-transplant 4/8 evaluable pts were in CHR, 3 in complete molecular remission, 2 in CCR. With a median follow-up since combined chemotherapy of 8 (1-20.9) months, 6/15 (40%) pts are alive (4 in CMR, 2 in MMR). The median overall survival (OS) since MBC onset was 12.3 months as shown in figure 1 (dashed lines are 95% CI), but did not significantly differ between transplanted and untransplanted patients (12.3 vs 4.8 months respectively, p=0.604) in this small series of pts heterogeneously transplanted. In addition the OS was not different between pts previously submitted to IM or not (p=0.87). [Display omitted] This strategy provides encouraging initial results compared to TKIs alone, without specific toxicity, however, it does not translate into survival improvement, but might still represent a suitable preparative regimen for allogeneic transplant whenever it is possible. Disclosures:No relevant conflicts of interest to declare.

Reduced Expression Level of SHP1 Gives An Additive Survival Advantage to the Ph+ Cells of Chronic Myeloid Leukemia (CML) Patients and Provides a Novel Pretreatment Predictor of Major Molecular Response Achievement in CML Patients.

Abstract 2212Poster Board II-189Treatment of Chronic Myeloid Leukemia (CML) has shown an outstanding progress while new understanding of the disease has increased significantly. Nevertheless in the era of targeted therapy, Sokal index remains a dominant prognostic determinant of newly diagnosed CML patients. Our study has aimed to identify novel prognostic indicators to improve both an initial assessment and subsequent monitoring of CML patients. Initially, we have found that the protein-tyrosine phosphatase SHP1, that has a tumour suppressor activity, may play an important role in the resistance to imatinib treatment. We applied gene profiling and proteomic bidimensional electrophoresis to compare the differential pattern of gene and protein expression between KCL22s (imatinib-sensitive) and KCL22r (imatinib-resistant) cell lines. We found SHP1 to be one of the most differentially expressed genes. By ESI-TRAP MS technique, we found that one of the main interactors of SHP1 is SHP2, a protein phosphatase well known as positive regulator of oncogenic pathways, including the Ras/MAPK pathway. Gain-of-function mutations in SHP2 gene, have been described in various haematopoietic neoplasias and myeloproliferative disorders including Juvenile Chronic Myelomonocytic Leukemia. This protein is regulated throw phosphorylation on 542- and 580-Tyr, and unlike SHP1, acts as a positive regulator of the same oncogenic pathways. We found that KCL22r cell line, that has low SHP1 levels, showed complete phosphorylation of both SHP2 tyrosine residues, while these residues are not phosphorylated in the KCL22s line, which could explain an important mechanism for imatinib sensitivity. Consistently with this hypothesis, knock-down of SHP2 phosphatase in KCL22r by a specific shRNA resulted in 60% inhibition of KCL22r proliferation. Furthermore, the KCL22rSHP2- cells showed significant reduction in STAT3 (60%) and ERK1/2 (70%) phosphorylation. Our initial results from CML patients (Esposito et al , ASH 2008 Abs 1106) have suggested a differential expression of SHP1 in patients with different response to imatinib treatment. To further explore the role of SHP1 as a determinant of imatinib sensitivity we evaluated the expression of SHP1 in 93 newly-diagnosed CML patients enrolled into the TOPS trial investigating 400mg versus 800mg imatinib (Cortes et al, EHA 2008). The results of this study indicate that the mRNA levels of SHP1, as assessed by QPCR in peripheral blood of patients at the time of enrolment, are significantly different between patients who do or don't achieve Major Molecular Response (MMR) by 12 months (7.9±4.0 vs. 5.9±3.4; p=0.01). Logistic regression was used to estimate regression coefficients and corresponding odds ratio using MMR by 12 months as outcome variable in our model. Since the 25th and 75th percentiles of SHP1 were 4.3 and 8.4, respectively (resulting in an interquartile range of 4.1), statistical analysis shown that a value of 4.1 or more in SHP1 is associated with almost 2-fold odds of achieving MMR by 12 months (OR=1.92; 95% CI=1.12, 3.29; p=0.018). Moreover, in a contingency table, chi-square analysis has been shown a high risk of not achieving MMR by 12 month in those patients with either low SHP1 expression and high Sokal score, when compared with patients with high-intermediate SHP1 expression and low-intermediate Sokal score (p=0.0068).In conclusion, these results suggest that, measuring expression levels of SHP1 could be of value in assessing newly diagnosed CP-CML patients and estimating treatment response, which could help optimizing Gleevec treatment, or recommending patients to more potent TKIs.Supported by Novartis Oncology, Clinical Development, TOPS Clinical Correlative Studies Network Disclosures:Saglio:Novartis: Honoraria; Celgene: Honoraria. Pane:Novartis: Research Funding; Ministero dell'Università/PRIN: Research Funding; Regione Campania: Research Funding; Ministero della Salute/Progetto integrato Oncologia: Research Funding.

Imatinib mesylate experience of young patients with chronic myeloid leukemia in chronic phase—Care to cure

7072 Background: Chronic myeloid leukemia (CML) with introduction of imatinib has been transformed into a chronic illness. The options of treatment in a patient less than 35 years include imatinib or allogenic stem cell transplantation. Hence we studied this unique subset to look at the response rates, adverse effects, progression free survival, and overall survival with imatinib mesylate. Methods: 477 patients with Philadelphia positive CML in chronic phase were retrospectively analyzed from January 2002 to December 2007 at Cancer Institute (WIA), Chennai, India. Standard criteria were used for response evaluation and adverse effects. Results: A total of 248 young CML patients with age less than 35 years (51.9%) were diagnosed in chronic phase. The median age of study population was 27 years (4–35). The male to female ratio was 1.9: 1. Risk stratification was done using Sokal index and were classified into low (32.3%), intermediate (50.4%), and high (17.3%). All patients received imatinib 400 mg as the initial dose. Complete hematological remission (CHR) was seen in 96.7%.Cytogenetic (FISH) and molecular (RTPCR) monitoring was possible in 53.2% and 17.3%, respectively. 72% of the patients had major cytogenetic response. Major molecular response was seen in 34.8% while complete molecular response occurred in 23.2% of the patients. Primary and secondary imatinib failure was seen in 3.1% and 16.9%, respectively. 6.7% had grade 3 and grade 4 hematological toxicities. The other common non hematological toxicities included pedal edema (13.7%), hypo or hyper pigmentation (60.0%), hyalgia (14.5%), diarrhea (1.6%), and liver dysfunction (1.6%). None of the patients discontinued imatinib due to toxicities. The 3-year DFS and OS was 86.2% and 89.5%, respectively. Patients with male sex (p = 0.04), spleen &gt; 8 cm (p = 0.02), high sokal index (p = 0.02), and loss of CHR (p &lt; 0.001) were associated with poor outcome. Conclusions: Imatinib in young patients have an excellent tolerance and response. A small subset does not respond to therapy or develop resistance during treatment. Hence it is essential to identify these poor responders and to offer stem cell transplantation at the earliest. No significant financial relationships to disclose.

Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study

AbstractImatinib mesylate (IM), 400 mg daily, is the standard treatment of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML). Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. To investigate whether the systematic use of a higher dose of IM could lead to better results, 216 patients with Ph+ CML at high risk (HR) according to the Sokal index were randomly assigned to receive IM 800 mg or 400 mg daily, as front-line therapy, for at least 1 year. The CCgR rate at 1 year was 64% and 58% for the high-dose arm and for the standard-dose arm, respectively (P = .435). No differences were detectable in the CgR at 3 and 6 months, in the molecular response rate at any time, as well as in the rate of other events. Twenty-four (94%) of 25 patients who could tolerate the full 800-mg dose achieved a CCgR, and only 4 (23%) of 17 patients who could tolerate less than 350 mg achieved a CCgR. This study does not support the extensive use of high-dose IM (800 mg daily) front-line in all CML HR patients. This trial was registered at www.clinicaltrials.gov as #NCT00514488.

The Expression of shp-1 and SHP-2: A Novel Powerful Predictor of Major Molecular Response (MMR) Achievement in Chronic Myeloid Leukemia Gleevec-Treated Patients Enrolled into the TOPS Clinical Trial.

Imatinib (Ima) has dramatically improved the outcome of patients affected by chronic myeloid leukemia (CML) and became the standard care for patients with newly diagnosed CML in chronic phase (CP). In spite of treatment progresses and novel biological findings, Sokal index is still a dominant prognostic determinant of newly diagnosed CML patients also in the era of targeted therapies. In this study we investigated the predictive role of the levels of expression of two SHP-constitutive non receptor protein tyrosine phosphatase, the SHP-1 and SHP-2, in leukemia cells obtained from 48 newly diagnosed CML patients enrolled into the TOPS (Tyrosine kinase inhibitor Optimization and Selectivity) trial. TOPS is a prospective, open-label, randomized (2:1) Phase III trial that compared Ima 800mg/d to 400mg/d in CP-CML. The findings end point of the trial is the rate of major molecular response (MMR) indicated by several reports as a parameter that predict a benefit for progression free survival (PFS). Results indicate that the mRNA levels of both SHP1 and SHP2 assayed by QPCR in peripheral blood of newly diagnosed the patients and expressed as ratio to ABL, are significantly different between those patients who do and do not achieved MMR by 12 months (7.4 ± 3.8 vs 6.0 ± 3.2, p = 0.017 for SHP1/Abl % and 0.19 ± 0.15 vs 0.10 ± 0.12, p = 0.017 for SHP2/ABL%). There is not statistical evidence that patients who achieved MMR earlier than 12 months i.e. at 6 and 9 months, have different baseline levels of SHP1 or SHP2, however the data are suggestive of a difference which might become statistically significant with a larger sample size. Complete cytogenetic response, CCyR, was a secondary end point of the TOPS study, overall, 65% have achieved CCyR by 6 months, and 85% by 12 months, and although not statistically different, results indicate that both SHP1 and SHP2 levels tended to be higher in patients who obtained CCyR, and the our further study with a larger sample size will show if the differences might become significant. .SHP1/ABL % and SHP2/ABL % are weakly correlated each other in the patients, therefore each independently acts as predictor of MMR at 12 months and logistic regression indicated that the combination increases their prognostic value for predicting MMR in the first 12 months and using logistic regression, Sokal score does not add any discriminating power to either of those markers (either alone or in combination). In conclusion, our results indicate, that the levels of expression of SHP1 and SHP2 are useful predictors of MMR in newly diagnosed CP-CML patients. These data confirm our prior findings from “in vitro” studies, which investigated the role of SHP1 and SHP2 phosphatases in mechanisms which regulate Imatinib sensitivity.

Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation

We analyzed 27 CML patients treated with imatinib (IM) who developed a BCR-ABLT315I mutation. These patients had poor prognostic features: High or intermediate Sokal index (82%), and lack of CCyR under IM (59%). At T315I discovery, patients were in advanced phase (59%), with clonal evolution (84%). Median time since diagnosis was 39 months, and progression occurred 13 months after IM initiation, regardless of disease phase. Overall survival since IM initiation was 42.5 months for chronic, and 17.5 months for advanced phases, and all patients progressed. This mutation seems related to or (partially?) responsible for progression and poor survival.

A Retrospective 20-Year Survey of the Incidence of Chronic Myeloid Leukemia in the Northern France Region.

Purpose: To assess the incidence of chronic myeloid leukemia (CML) in the Nord-Pas de Calais Region in Northern France (~ 4 millions inhabitants) and to describe the patients (pts) characteristics and evolution.Methods: A retrospective study was conducted to record all confirmed diagnosis of CML that occurred during the period 1985–2004. All pts were actually living in the region at the diagnosis. CML was diagnosed by cytogenetic and molecular tests (Philadelphia chromosome and/or BCR-ABL fusion gene). Pts were screened through the results of the two cytogenetic and molecular laboratories of the region. The possibility of pts diagnosed outside the region is negligible and under study. Age-standardized incidence rate calculation was based on the standard world population.Results: 783 pts with confirmed diagnosis of CML were included. Age-standardized incidence rate is 0.82/100,000 people during the 1990–2004 period, with a raw incidence rate of 1.02/100,000 people during the same period. In the whole 20 years cohort, 55.7% of the pts are of male gender and the median age at diagnosis is 55.3 years (5.4–93.4). Haematological status at diagnosis was available for 83.5% of pts: chronic phase (CP) for 623 pts (95.3%), accelerated phase (AP) for 21 pts (3.2%), and blastic crisis (BC) for 10 pts (1.5%). Sokal index was available for 67% of pts, and was low for 40.5%, intermediate for 35.9%, and high for 23.6% of them. At December 31th 2004, 331 (42.3%) pts were still alive, 370 (47.2%) were deceased and 82 (10.5%) of unknown status. Taking into account the patients who have left the region, the raw prevalence rate is 8.1/100,000 people at this date. During the follow-up, an advanced phase was documented for 206 pts (26.5%) of the whole cohort and 189 (48.5%) of deceased patients. Allogeneic bone marrow transplantation was performed in 140 (17.9%) pts with a 5-years overall survival rate of 60%. 354 pts (45.2%) received interferon alfa (IFN) (median treatment duration 13.5 Mo (0.5–157.1)) with 24.6% pts achieving a major cytogenetic response (MCyR). 302 pts (38.6%) were treated by imatinib mesylate (IM) (median treatment duration 31.3 Mo (0.5–72.3)) with a rate of MCyR of 75.2% for pts in CP at IM initiation (206 informative pts). The overall median survival of the whole cohort was 72 months. For the diagnosis periods 1985–1989, 1990–1994, 1995–1999, and 2000–2004, the 5-years overall survival rates were respectively 41.6%, 51%, 57.5%, and 78.5% (p<0.0001).Conclusion: our findings in a well defined region corroborate the results of other cancer registries for the CML incidence. The prognosis of this disease has been modified by bone marrow transplantation and the use of interferon alfa but the major survival improvement seems related to the large use of tyrosine kinase inhibitors since 2000–2001, suggesting a great increase of CML prevalence in the future. [Display omitted]

Monitoring Response to Imatinib by Fluorescence In Situ Hybridization (FISH) and Real-Time Quantitative Polymerase Chain Reaction (RQ-PCR) in Chronic Myeloid Leukemia (CML) Patients in Chronic Phase. Experience of Argentina and Uruguay.

Introduction: The evaluation of response to imatinib in CML patients (pts) as guide to clinical management is undergoing substantial changes of criteria. The degree of reduction of total leukemia cell mass by imatinib as measured by FISH and RQ-PCR studies, correlates with progression-free survival. Therapeutic decisions, as dose scalation, is mandatory in pts with rising level of bcr/abl transcripts.Purpose: To determine the potential of RQ-PCR to predict the duration of response in pts in complete cytogenetic remission (CCyR).Patients and Methods: A total of 160 CML pts in first chronic phase, in CCyR treated with imatinib 400mg daily were studied prospectively since November 2005 (147 pts from 30 hematology centers in Argentina and 13 pts from 2 centers in Uruguay). According to previous treatment they were divided in two groups: 83 pts (51%) received as first line treatment IFN/Cytarabine and 77 pts (49%) received imatinib as first line. According to Sokal Index, 72% were low risk, 19% intermediate risk and 9% high risk. At baseline all pts were first evaluated by FISH and RQ-PCR under EAC program protocol and recommendations of T.P. Hughes, et al (Blood 108:28–37, 2006). Only RQ-PCR is being performed at 6 and 18 months from the beginning of the study. The median duration since beginning with imatinib treatment was 28 months (range 6–58).Results: At the time of first RQ-PCR evaluation, 93% had undetectable bcr/abl fusion gene by FISH and 7% had low level FISH positivity ( 0,1 – 5%). The distribution of the type of molecular responses (MR) in the 160 pts was: Complete (CMR)≥4 log red, U/<0.01% bcr-abl/c-abl : 23%; Major (MaMR) ≥ 3log red, <0,1%bcr-abl/c-abl : 17%; Minor (MiMR) >2 log red, 1–0,1 % bcr-abl/c-abl : 34%; MiMR < 2log red, 10–1% bcr-abl/c-abl : 15%; Nule (NuMR) <1 log red, > 10%bcr-abl/c-abl : 11%. Pts with Fish (+) showed association with MiMR. Thirty eight percent of pts with a follow-up between 6–24 months since the beginning of imatinib treatment achieved MaMR and CMR, similar rate as the observed in the group with > 24 months on imatinib (42%). Up to July 2006, 53 pts underwent a 2nd RQ-PCR evaluation at 6 months: 15% of pts improved molecular response, 68% maintained it while 17% showed worse response. The 87.5% of pts with decreasing bcr-abl transcripts level at 2nd evaluation corresponded to imatinib treatment as first line. The 78% of pts with rising levels at 2nd evaluation showed MiMR at beginning of this study. Up to now, no pts showed hematological relapse.Conclusion: This is an on-going study in CML pts in CCyR, where 93% showed a negative FISH study, and 7% had low FISH positivity. By RQ-PCR, 40% of pts presented CMR or MaMR (≥3 log red). In 2nd RQ-PCR evaluation, 83% of pts improved or maintained the molecular response. Up to now all pts remain in hematological remission.

USING CHLOROPLAST DNA MARKERS TO UNDERSTAND ANANAS AND PSEUDANANAS GENETIC DIVERSITY

Diversity has been examined in Ananas and Pseudananas using PCR-RFLP of chloroplast DNA (cpDNA). Ninety-seven accessions representing all valid species of both genera were included in the study, and 13 accessions of other bromeliads were added to constitute, out-group and study phylogenetic relationships. Eight primers designed from cpDNA were used to generate fragments. Restriction by 18 endonucleases generated 255 variable fragments for the whole sample and 52 for Ananas and Pseudananas. Dissimilarities were calculated from the resulting matrix using the Sokal & Michener index and the Neighbour-Joining method was used to reconstruct the diversity tree. Phylogenetic reconstruction was attempted using Wagner Parsimony. Phenetic and cladistic analyses gave consistent results. Ananas and Pseudananas form a monophyletic group, in which chloroplast data allow three strongly supported sub-groups to be identified, two of which are geographically consistent. The majority of A.parguazensis accessions constitute a northern group restricted to the Rio Negro and Orinoco basins. The tetraploid Pseudananas sagenarius joins the diploid A.fritzmuelleri to constitute the southern group. The third and largest group is the most widespread, as its distribution encompasses those of the northern and southern groups, and gathers all remaining species plus some A.parguazensis and other accessions of intermediate phenotypes. A.ananassoides is dominant in this sub-group and highly variable. Its close relationship to all cultivated species supports the hypothesis of this species being the progenitor of the domesticated pineapple. The data indicate the existence of gene flow, common within this group and scarcer with both the first and second groups. Comparison of cpDNA data with genomic DNA point to the hybrid origin of A.bracteatus and support the autopolyploidy of Pseudananas. The comparison between molecular and collecting of data point to the Guyana region as the probable center of domestication of A.comosus indicates a second diversity center in the western region of the Amazon. (Resume d'auteur)

Efficacy and Safety of Imatinib Treatment in Elederly Patients with Chronic Myeloid Leukemia.

The increase of median survival of the general population results in a higher incidence of Chronic Myeloid Leukemia (CML) in the elderly. In our series of 260 cases from a single institution the mean age of CML cases was 52.5 from 1977 to 1987 and 61.9 from 1999 to 2003; in other words, in the last 5 years 39.6% of our CML cases was over 70 years of age. The introduction of Imatinib (STI) has changed the treatment strategy in CML elderly patients, previously treated with hydroxyurea (HU). Efficacy, tolerability and cost of STI therapy in this CML setting are worth to be considered. For this purpose we retrospectively evaluated our elderly CML patients treated with STI. Our series consists in 24 cases, M/F 18/6, with a median age at diagnosis of 70.1 yrs (60–83), and 73.4 (65–83) at time of STI therapy; Co-morbidity included hypertension (5 cases), renal failure (2), cardiovascular diseases (4), diabetis (1), psoriasis (1), B-cell chronic lymphocytic leukaemia (B-CLL) (1).The mean interval from diagnosis to STI was 2.6 yrs (0-7). Sokal index was low in 4 cases, intermediate in 18, high in 2; Euro index was low in 15, intermediate in 7, high in 2. All cases were bcr/abl positive (p210), 19 Ph1+, 4 Ph1-. Four patients, one in AP, were untreated. Six cases had received HU, 3 in accelerate phase (AP). Out of 14 cases previously treated with interferon (IFN) for 1 to 43 months, 5 patients were intolerant, 7 resistant (1 in AP), while 2 patients obtained haematological and cytogenetic complete response and received IFN treatment for 24 and 29 months, respectively. STI was administered at 400 mg/day in CP and 600 mg/day in AP, for a mean period of 2 yrs (1 to 46 months). All cases but 3, 2 in AP and 1 in chronic phase (CP), either obtained or maintained the hematological response. After 6 to 12 months of STI therapy, out of 24 cases, 11 obtained complete cytogenetic (CG) response (1 case in AP), 1 minor, 3 no CG response; in the remaining cases CG response was not evaluable, in 2 cases because CG response was already obtained after IFN therapy, in 3 because of short period of therapy, and in 4 because Ph1 negative at onset. Quantitative molecular response, evaluated in 9 out of 11 patients achieving CG response, was obtained in 8 cases; notably, in 4 cases bcr/abl was so low to become undetectable. Tolerability was generally good in all but 2 cases, requiring STI permanent withdrawal; one patient presented subdural hemorrage needing surgery, the other one presented hepatic failure The remaining toxicity consisted of grade 3 cough, scrotal oedema, reversible lethargy because of cerebral oedema; and fatigue requiring temporary withdrawal or dose reduction in 7 patients. Also hematological toxicity required temporary drug withdrawal 2 cases. Out of 4 patients requiring permanent dose reduction to 300 mg/day, 3 are maintaining CG and molecular response, while one patients lost CG response. In detail, out of 5 cases in AP, 3 died of progressive disease, one maintains haematological and the last CG complete response. Interestingly the patients affected by psoriasis demonstrated a clear improvement of skin lesions and the patient with concomitant B-CLL achieved a response at phenotypic level.At the time of the present report 3 patients died, all in AP because of disease progression. According to the present data STI therapy is indicated in CML elderly patients.

Autologous stem cell transplantation in chronic myeloid leukemia: a single center experience.

Between 1980 and 1996, we transplanted 72 patients with CML using blood stem cells collected at diagnosis before treatment and without any mobilization. The median age of patients at diagnosis was 47.5 years (range 20.5-59.5). The median numbers of nucleated cells and CFU-GM transplanted were 10 x 10(8)/kg and 97 x 10(4)/kg, respectively. The median duration to reach more than 0.5 x 10(9)/l neutrophils and 50 x 10(9)/l platelets was 12 (range 5-19) and 11 days (range 0-79), respectively. Twenty patients (group I) were transplanted in chronic phase either for resistance to IFN (14 patients) (group IA) or because the Sokal index was more than 1.2 (six patients) (group IB). All those patients had preparative regimen with busulfan (4 mg/kg/day x 4) and melphalan (140 mg/m2). They were treated with recombinant alpha-interferon (IFN) after transplant. The cumulative incidence of major cytogenetic response (MCR) at 12 months was 25 +/- 21% (95% CI), the 5-year survival was 75 +/- 42% (95% CI). These results (observed in patients with bad prognosis factors) are similar to those usually observed in CML patients treated by IFN, whatever the Sokal risk. Thus autologous transplantation is able to reproduce for poor prognosis patients the results observed in standard risk patients treated with IFN. This suggests that it could prolong survival. Fifty-two other patients (group II) were transplanted for CML in transformation (accelerated phase = 32; blast crisis = 20) after a preparative regimen containing either total body irradiation (TBI) or busulfan. The median survival was short (10.4 months) and only 21 patients survived more than 1 year. The survival was longer for patients transplanted in accelerated phase (vs blast crisis), those who were due to receive a double transplant (vs single) (34 patients), those who were treated with IFN after transplant (vs hydroxyurea) and for the patients who obtained a complete hematologic response.

Chronic myeloid leukemia in first chronic phase not responding to alpha-interferon: outcome and prognostic factors after autologous transplantation. EBMT Working Party on Chronic Leukemias.

We report the data obtained from the European Bone Marrow Transplant Registry for patients with CML who received autologous transplantation (AT) in chronic phase (CP) because alpha-IFN was ineffective. Forty-one CML patients (median age: 40.5 years; median Sokal index: 0.78) were included in this study. Bone marrow (16 cases) or blood (25 cases) progenitor cells were collected at diagnosis in 19 patients, during stable chronic phase or while the patient had cytogenetic (Cy) or complete hematologic response (CHR) in the other 22, and were manipulated ex vivo in 10 cases. The conditioning regimen consisted of busulfan associated with other chemotherapeutic regimens in 36 cases. Two patients died from interstitial pneumonitis (one case) and hemorrhage (one case). From the date of AT, the estimated probability of survival for the 41 patients was 84 +/- 13% and 51 +/- 29% at 2 and 4 years, respectively. Considering the 39 evaluable patients, the actuarial probability of achieving CHR, major and complete CyR 2 years after AT was 92 +/- 9%, 46 +/- 17%, and 30 +/- 15%, respectively. The Sokal score at diagnosis and the achievement of hematologic response after transplant were of prognostic importance. We suggest that a significant proportion of CML patients not responding to alpha-IFN may benefit from AT.

Mobilization of predominantly Philadelphia chromosome‐negative blood progenitors using cyclophosphamide and rHUG‐CSF in early chronic‐phase chronic myeloid leukaemia: correlation with Sokal prognostic index and haematological control

Mobilization of Philadelphia chromosome (Ph) negative blood progenitors was attempted in 23 newly diagnosed chronic myeloid leukaemia (CML) patients using a regimen of cyclophosphamide (CY) 5 g/m2 and rHUG-CSF 150 microg/m2 daily. This regimen was well tolerated with no major adverse events reported. More than 2 x 10(6)/kg CD34+ cells were collected in 21 patients (91%). Predominantly Ph-negative mobilization (0-25% Ph-positive) was seen in 30% of cases overall and was confined to patients with a Sokal prognostic score < 1 (7/11 with Sokal score <1; 0/12 with Sokal score > or = 1). Within the low Sokal index group, a low WBC count pre-mobilization and a low WBC nadir both correlated strongly with Ph-negative mobilization (P = 0.006 and 0.02 respectively). Five of 19 patients receiving at least 6 months of Roferon A therapy post mobilization achieved a major cytogenetic response; all five patients were Ph-negative mobilizers. Therefore CML patients can be divided into a good-prognosis group in whom predominantly Ph-negative progenitors can be mobilized using a regimen of moderate intensity if haematological control is achieved pre-mobilization, and a poor-prognosis group for whom predominantly Ph-positive cells are mobilized with this regimen regardless of haematological control.

Long‐term survivors in chronic granulocytic leukaemia: a study by the International CGL Prognosis Study Group

The purpose of the present work were to identify the initial characteristics associated with long-term survival in chronic granulocytic leukaemia (CGL) and to analyse the accuracy of prognostic models in identifying long-term survivors. 813 Philadelphia (Ph) chromosome-positive, nonblastic CGL patients from six American and European institutions, the majority treated conventionally, with a minimum follow-up > 10 years, were studied. Stepwise logistic regression was performed to ascertain the association between the initial clinicohaematological variables and survival > or = 8 years, and a prognostic index was derived. The usefulness of both Sokal's and the new prognostic index to identify long-term survivors was assessed by calculating their positive and negative predictive accuracies, sensitivity and specificity. Median survival of the series was 45 months (range 1-255), with 784 patients (96.4%) having died and 109 (13.4%) surviving 8 years or longer. Younger age, smaller spleen, platelets < or = 600 x 10(9)/l, and lower blood blast percentage were associated with survival > or = 8 years; platelets < or = 600 x 10(9)/l and lower blood blast percentage were the predictive factors in patients 50 years old or younger. Two-thirds of long survivors belonged to Sokal's low-risk group, but the positive predictive accuracy and specificity for prolonged survival of Sokal's index were very low. This was also the case for the new predictive index.(ABSTRACT TRUNCATED AT 250 WORDS)