Our main goal was to evaluate the CD34+ dose in patients undergoing haemotopoietic stem celltransplantation and its results in terms of recovery of neutrophile and platelet counts, transfusion requirements, days of fever, antibiotic requirements and length of hospital stay. We studied 38 consecutive patients with haematological malignancies transplanted at our Department, from Feb. 96 through Sept. 98. The CD34+ cell quantification technique was standardized, using a modification of the ISAGHE 96 protocol. Patients were sorted into three groups according to the CD34+ count administered: a) between 3 and 5 x 10(6) cells/kg; b) between 5 and 10 x 10(6) cells/kg; c) > 10 x 10(6) CD34+ cells/kg. As a secondary end point, results were assessed according to the number of aphereses required to arrive at the target count of CD34+, separating those patients that required only 1 or 2 aphereses versus those requiring 3 or more. Finally, an analysis was made of the results of transplantation comparing the different sources of stem cells (PBSC versus PBSC + B.M.). The best results were obtained in the group with cells between 3 and 5 x 10(6) CD34+. No statistically significant advantages were found in the group with cells over 5. The supra-optimal dose of more 10 x 10(6) would yield no additional beneficial results, while they can imply a greater infusion of residual tumor cells. The number of aphereses had no impact on engraftment. Results obtained with PBSC transplants were better than those with BM+PBSC in terms of neutrophile and platelet recovery. The number of CD34+ cells remains the main element in stem cell transplantation to evaluate the haematopoietic recovery after engraftment. Minimum and optimum yields remain unclear. Centers should establish their own optimal dose based on local methodologies and outcomes, maximizing costs and benefits.
No abstract
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.
The landscape of chronic myeloid leukemia (CML) has radically changed since the introduction of tyrosine kinase inhibitor (TKI), imatinib (IM), now considered as standard therapy. Although excellent cytogenetic responses are obtained, minimal residual disease still persists in a proportion of patients (pts) when measured by serial molecular monitoring by quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL transcript levels (Baccarani M et al. Blood2006; 108:1809–20). We monitored BCR-ABL transcript levels by RQ-PCR in 176 chronic phase (CP) –complete cytogenetic response (CCyR) CML pts treated with IM. Median follow-up from start of therapy with IM was 35 (6–80) months. Pts were recruited from 33 centers in Argentina and 2 in Uruguay. Median follow up from the first assessment at our Institution was 18 (6–32) months. Seventy nine patients (45%) had received interferon as 1st line prior to IM and 97/176 (55%) pts received imatinib as 1st line. Eighty eight percent (155/176) pts had received IM 400mg/d and 12% (21/176) 600–800mg at study initiation. Fifty four percent presented with low Sokal score at diagnosis. Peripheral blood samples were tested by RQPCR every 6 months. Major molecular response (MMR) was defined as BCR-ABL/ABL ratio of <0,1% on the Internationale Scale. Rise in transcript levels was immediately reconfirmed. Cytogenetic and mutational analyses were performed if rise in transcripts was confirmed. Overall, 48% had MMR at the initial evaluation (baseline), and this increased to 57% at last follow-up (month 18). No patient with MMR achievement lost CCyR. Only 5 pts lost CCyR, never having achieved MMR (p=0.01). All patients could be divided in 3 groups according to transcript level outcome: 61% decline (at least 1 log reduction of BCR-ABL/ABL ratio), 27% stable (no log variation), 13% rise (increasing 1 log of BCR-ABL/ABL ratio). Among 136 pts with follow up at month 18, we observed (Table 1): Molecular Response At baseline Decline in transcript levels %(pts) Stable transcript levels %(pts) Rise in transcript levels %(pts) Total %(pts) CMR: complete molecular response, U: undetectable CMR ≥ 4 log red <0,01%/U MMR ≥ 3 log red < 0,1% (N:60) 20(12) 63(38) 17(10) 44(60) No MMR > 0,1% (N:76) 47(36) 47(36) 5(4) 56(76) Total 35 (48) 55(74) 10(14) 100(136) From the group of pts with rise in transcript levels, 5 pts lost CCyR, none lost complete hematologic response. Overall, 5%(9/176) pts eventually changed therapy to a 2nd generation TKI: 5 pts with cytogenetic relapse and 4 pts with increase in transcript levels. Our results confirm that molecular responses continue improving over time and a significant number of pts achieve undetectable transcript levels with continued imatinib therapy. Achievement of MMR is associated with sustained cytogenetic response. These results emphasize the validity and feasibility of molecular monitoring in all areas of the world.
1701 Mutations within the BCR-ABL domain are the most frequent mechanism of imatinib (IM) resistance. The second generation inhibitors (SGI) are indicated for imatinib intolerance or resistance and the initials trials showed similar response rates in IM resistant patients after IM failure, independent of mutation status, with exception of T315I. The aim of this work was to report the frequency of BCR-ABL mutations in chronic myeloid leukemia (CML) patients of a Latin American population and to evaluate the clinical impact of the presence and type of mutations in overall survival (OS), progression free survival (PFS) and in the response to second generation inhibitors (SGI). Methods: retrospective analysis of 17 centers from Latin America. A total of 529 CML patients with mutation analysis performed in samples collected between 2002 and 2011 were included. Mutations were detected by direct sequencing from bone marrow or peripheral blood samples, collected from CML patients. After imatinib resistance, patients were treated with SGI (69%) or other treatments. Overall survival (OS) was calculated from date of mutation detection until last follow-up or death, and progression-free survival (PFS) from date of mutation detection until progression to accelerated phase or blast crisis, last follow-up or death. Survival curves were calculated using the log-rang test (SPSS 14.0 software).Results: the median age of patients at diagnosis was 45 years (5–87). 81% were in chronic phase (CP), 13% in accelerated phase (AP), 6% in blast crisis (BC). According to Sokal score, patients were stratified in low (36%), intermediate (30%) and high risk (34%); 36% had previously used Interferon. The median time from diagnosis until Imatinib treatment was 8 months (0–310) and from Imatinib start until mutation detection was 31 months (1–104). Mutations were found in 188 patients, in the following sites: P-loop (75/40%), nucleotide contact site (34/18%), catalytic domain (44/23%), A-loop (11/6%) and others (24/13%). The most frequent mutations detected were: T315I (30/16%), F359V/C/I (27/14%), M244V (18/9.6%), E255K/V (17/9%), G250E (17/9%), Y253H/F/Y (15/8%), M351T/L (12/6%); Ten patients presented concomitant mutations. On dasatinib treatment 29 mutations (27% T315I) were detected whereas 18 during nilotinib (16.5% T315I). Overall survival in the total group was 61% (95%CI: 51–71%) with a median time of 12 months. There was a significant difference in OS and PFS between non-mutated and mutated patients (76% vs 44% and 64% vs 44% respectively (P= 0.008 and P= 0.001). There was no difference in survival comparing P-loop mutations and others, excluding T315I. Patients with T315I mutations had a poorer outcome in comparison with other mutations (OS 21% vs 62%; PFS 35% vs 55%) (P= 0.04 and 0.06, respectively). In the group with BCR-AL mutations, OS was superior in patients that received a SGI in comparison with other treatments after resistance (50% vs 36% P= 0.007). One hundred patients (19%) died due to: disease progression (72), infections (8), graft versus host disease (2), central nervous system bleeding (2), cardiac failure (1), second neoplasia (1). 14 causes were not reported. Conclusions: Patients with BCR-ABL mutations had an inferior OS and PFS. T315I mutations were associated to a poor outcome. Treatment with SGI prolonged survival of patients after imatinib failure. Disclosures: Pagnano: Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Boquimpani:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Spector:Novartis: Membership on an entity's Board of Directors or advisory committees.
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