Can Targeted Therapy for CML Still Learn From Transplant? Using Post-transplant RQ-PCR monitoring to Clarify the Importance of the Depth of Molecular Remission On the Risk of Subsequent Relapse.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2789-2789
Author(s):  
Frederick Pimm ◽  
Richard Szydlo ◽  
Letizia Foroni ◽  
Francesco Dazzi ◽  
Jaspal S Kaeda ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Residual Disease ◽  
Unrelated Donor ◽  
Molecular Response ◽  
Molecular Remission ◽  
Post Transplant ◽  
Long Term Treatment ◽  
Risk Of Relapse

Abstract Abstract 2789 The use of tyrosine kinase inhibitors (TKI) in the management of chronic myeloid leukemia (CML) has dramatically improved survival, with some 80% of patients achieving a deep and durable molecular remission (MR). The current focus for these patients is the ability to withdraw long-term treatment and a number of ‘stopping’ studies have been initiated worldwide. Many of these approaches are derived from the French STIM study which showed that 40% of patients who had been real-time quantitative PCR (RT-qPCR) negative for BCR-ABL1 for two years could cease treatment without experiencing disease relapse. However, the RT-qPCR assay used in this study was particularly stringent with a sensitivity of 10−5, compatible with a five log reduction in BCR-ABL1 transcripts (MR5), and it is not clear that the same level of success will result from studies using MR4 and MR4.5 as the indication for treatment cessation. Furthermore, because of the lack of accuracy in RT-qPCR assays when the number of BCR-ABL1 transcripts approach zero, some laboratories report as undetectable, transcript numbers <6 or even <11. In order to investigate the importance of the depth of molecular response on the risk of subsequent disease recurrence, we studied the long-term follow-up of, and RT-qPCR results from, patients who received allogeneic stem cell transplantation as treatment for CML at a time when minimal residual disease detection was performed by RT-qPCR using ABL1 as the control gene. We analysed data from 180 patients transplanted from January 1998 onwards who received an allo-SCT from an HLA-identical sibling or a matched unrelated donor and who had survived for at least 6 months post-transplant with a consistent sequence of 5 or more RT-qPCR results from the time of transplant to the end of follow-up. Patients were assessed on the depth of their MR; 9 categories of ‘complete’ MR were defined based on BCR-ABL1 transcript threshold for negativity (BCR-ABL1=0, BCR-ABL1>0 but <6, BCR-ABL1>5 but <11) and control transcript number (CTN) (CTN>104 but <104.5, CTN>104.5 but <105, but CTN>105). We ranked these categories, firstly by BCR-ABL1 transcript threshold, defining negativity at a lower threshold as a deeper response, and then sub-ranked by CTN, defining a larger CTN as a deeper response. Of the 180 patients, 49 (27%) did not achieve ‘complete’ MR by any definition and for the 131 (73%) patients who did reach some degree of ‘complete’ MR, the median time from transplant to best molecular response was 8.7 months (range, 1.0–103 months). We defined relapse as progression to an RT-qPCR level that triggered the use of donor lymphocyte infusions i.e. BCR-ABL1/ABL ratio exceeded 0.02% in 3 samples, or exceeded 0.05% in 2 samples, or showed rising levels with the last 2 samples higher than 0.02%, or worse (loss of cytogenetic or haematological remission). The 2 year relapse incidence post SCT was 94% in the group who did not achieve any degree of ‘complete’ MR, 94% in the group who achieved MR with BCR-ABL1<11 and >0, CTN>104 (n=32, 17.8%), 55% in the group BCR-ABL1=0, CTN>104 and <104.5 (n=19, 11%), 26% in the group BCR-ABL1=0, CTN>104.5 and <105 (n=47, 26%), and 6% in the group BCR-ABL1=0, CTN>105 (n=33, 18%) (p<0.0001). In multivariate analysis with adjustment for donor type, classifying the 33 patients who achieved BCR-ABL1=0, CTN>105 as the optimal molecular responders the relative risk of relapse was 90.1 in 49 patients who never achieved MR by any definition, (p<0.0001), 21.7 in the group BCR-ABL1<11 and >0, CTN>104 (n=32) (p<0.0001), 8.1 in the group BCR-ABL1=0, CTN>104 and<104.5 (n=19) (p<0.0001), and 2.11 in the group BCR-ABL1=0, CTN>104.5 and <105 (n=47) (p=0.002). In conclusion, fewer detectable BCR-ABL1 transcripts with larger numbers of control transcripts, i.e. a deeper response, predict a lower risk of relapse in post-transplant survivors and may have important implications for the ability to stop long-term TKI therapy. Disclosures: No relevant conflicts of interest to declare.

Attempt to Discontinue Imatinib Following Interferon Alfa Pre-Treatment In Chronic Phase CML Patients Achieving Stable Complete Cytogentic Responses (CCyR)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4898-4898
Author(s):  
Izhar Hardan ◽  
Yulia Volchek ◽  
Tali Tohami ◽  
Ninette Amariglio ◽  
Luba Trakhtenbrot ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Interferon Alfa ◽  
Cytotoxic T Cell ◽  
Molecular Response ◽  
Molecular Remission ◽  
Line Therapy ◽  
Pre Treatment

Abstract Abstract 4898 Imatinib (IM) has been shown to induce sustained clinical responses and stable remissions resulting in improved survival in chronic phase (CP) CML patients (pts.). Currently the state of the art is life long continuation of IM therapy which raises issues like the emergence of drug resistance, long-term safety and tolerability, compliance and costs. Interferon Alfa (IFNα), which has anti-CML activity and may induce major cytogenetic responses (MCyR), has in contrast to IM, immunoregulatory properties including the induction of anti-CML cytotoxic T-cell activity. Moreover, in initial studies of IM discontinuation it seemed that previous IFNα exposure was beneficial for the maintenance of molecular remission after IM cessation. We, therefore, hypothesized that adding IFNα to IM prior to IM discontinuation will increase the proportion of pts. remaining in continuous molecular response. We report on the long term, median follow up of 40 months (range, 33–41), outcome of CP CML pts. who discontinued IM after the addition of IFNα. CP CML pts. in CCyR for ≥2 years on IM were included. Study pts. received a combination of PegIFN (Pegasys, Roche) (180 μg/week, sc) and IM (400 mg) for 9 months followed by 3 months of PegIFN monotherapy, and were followed up thereafter without any anti leukemia therapy. Twelve CP CML pts. were included, 9 males and 3 females. Median age was 50.5 years (range, 33–67). Disease duration was 67 (18-96) months. Eight of the pts. (67%) received IFNα prior to IM as first line therapy. Eight of the patients had a major molecular response (MMR), 2 were in complete molecular response (CMR) (of 48 and 10 months duration) and 2 had less than a MMR. Of the evaluable pts. only 1 had a BCR ABL KD mutation (E373D). IFNα dose had to be reduce to 90–135 μg/week, sc due to intolerance in 10/12 pts. Median duration of CCyR (n=12) and MMR (n=8) at the time of IM discontinuation was 47.5 (21-86) months and 19.5 (9-84) months, respectively. Cytogenetic relapse occurred in 8 pts. 8 (2-38) months after IM discontinuation. Loss of molecular responses could be detected in all 8 pts. during follow up, and prior to the cytogenetic relapse at 8 (1-25) months post IM discontinuation. An additional 1 pt. had a molecular relapse but has maintained his CCyR 20 months post IM discontinuation. IM (400 mg/day) was reintroduced in all 8 pts. with loss of CCyR and they all re-achieved a CCyR 3.5 (3-7) months after IM re initiation. Five of the 8 pts. (62%) achieved also a MMR at 5, 7, 8, 10, and 11 months post IM re- administration, respectively. After a median follow up of 40 (range 33–41) months, 4 of the 12 study pts. (33.3%) are in persistent molecular remission. These 4 pts. achieved a CMR (n=1) (of 10 months duration) or MMR (n=3) (of 8, 14 and 19 months, respectively) prior to IM discontinuation. Notably, 2 of these 4 pts. had IFNα exposure as front line therapy pre-IM initiation. In summary, only a minority of CML pts. with stable MMR or CMR have a long lasting remission and will not relapse following IM discontinuation. Pts. having a cytogenetic relapse after IM discontinuation respond to IM re-administration by re-achieving CCyR and mostly MMR. The role of IFNα pre treatment, as well as the depth of molecular response needed to be achieved pre-IM discontinuation, should be further evaluated in a well designed 2 arms controlled randomized studies. Disclosures: No relevant conflicts of interest to declare.

Minimal Residual Disease and Normalization of the Bone Marrow after Long-Term Treatment with Alpha-Interferon2b in Polycythemia Vera. A Report on Seven Patients in Sustained Complete Hematological Remission with Major Molecular Responses.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1744-1744 ◽  
Author(s):  
Thomas Stauffer Larsen ◽  
Michael Boe Møller ◽  
Karin de Stricker ◽  
Peter Nørgaard ◽  
Jan Samuelsson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Term Treatment ◽  
Alpha Interferon ◽  
Molecular Response ◽  
Molecular Responses ◽  
Long Term Treatment ◽  
Minimal Residual

Abstract Background : Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by the presence of the JAK2V617 mutation in virtually all patients. Recently several studies have shown that the JAK2V617F mutational load decreases during treatment with alpha-interferon2 (1–6). Aim: To report on molecular and histomorphological bone marrow responses in seven PV patients with complete molecular remissions during and after long-term treatment with alpha-interferon 2b. Patients: Seven patients treated with alpha-interferon2b for a median of 84 months (range 31–120) are reported. In four of the patients alpha-interferon2b was started at the time of diagnosis and in three patients 9, 36 and 42 months from the time of diagnosis, respectively. Methods: The mutation was determined by allele specific PCR (n=2 only) (7) and quantitative PCR (qPCR) (n=5) (8). In three out of these patients qPCR JAK2V617F was performed on archived bone marrow from diagnosis (2 patients) and on peripheral blood (one patient) prior to treatment with alpha-interferon2b. A complete molecular remission (CMoR) was defined by less than 2 % JAK2 V617F mutated alleles (7). Results: Molecular Responses. All patients obtained a CMoR after a median of 84 months (29–120 months) of treatment with alpha-interferon2b. Subsequently all patients have discontinued alpha-interferon with a follow-up period of median 10 months (range 4–30 months) and sustained complete hematological remission. Furthermore, in three patients molecular responses have recently been updated – April and May 2008 - showing CMoRs in all (1,2 %, 0,9 % 0,1 % mutated alleles, respectively). Bone Marrow Responses. Follow-up bone marrow biopsies were available in five patients. Complete normalization of the bone marrow was seen in three patients after treatment with alpha-interferon2b for 84, 132 and 132 months, respectively. In the bone marrow from the patient being treated with alpha-interferon for 132 months a qPCR JAK2V617 analysis was performed detecting the mutation at a very low level (0,5 % mutated alleles). In two other patients, being treated with alpha-interferon2b for 24 and 120 months, respectively, and having obtained a CmoR in peripheral blood the bone marrow histomorphology showed marked regression of PV-features but in both patients still with focal areas displaying an increased number of morphologically abnormal megakaryocytes. Updated histomorphological and molecular response patterns will be presented. Discussion and Conclusion : Previous studies on the molecular response during alpha-interferon2a treatment have shown that a substantial proportion of patients achieve a significant molecular response after 12 months with a continuous decrease in the JAK2V617F mutation load at 24 and 36 months (1,5,6). This report confirms and extends preliminary data, showing that long-term treatment with alpha-interferon 2b in a subgroup of PV-patients is able to induce complete molecular remissions with normalization of the bone marrow morphology, which may even be sustained after discontinuation of alpha-interferon2b for up to 20 months (5). Prolonged treatment for several years seems necessary to induce such sustained responses, since treatment for only a few months has been reported to be followed by rapid recurrence of clonal hematopoiesis (9). In conclusion, a state of “minimal residual disease” may be achieved in PV by long-term immune therapy using alpha-interferon 2. Our observations call for large prospective clinical studies in which treatment with alpha-interferon is initiated up-front in patients with JAK2-positive PV and allied diseases. These studies should also aim at exploring the minimal dose of alpha-interferon needed to elicit complete molecular responses in order to minimize side effects of the drug and accordingly diminish the high drop-out rates reported in most previous studies.

Molecular Long-Term Surveillance of CML Patients on Imatinib Therapy. Follow-Up of German Patients Treated within the IRIS Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1003-1003
Author(s):  
Martin C. Mueller ◽  
P. Paschka ◽  
T. Lahaye ◽  
Ch. Lorentz ◽  
N. Gattermann ◽  
...  
Keyword(s):  
Median Time ◽  
Nested Pcr ◽  
Residual Disease ◽  
Response To Therapy ◽  
Imatinib Therapy ◽  
Interferon Α ◽  
Tyrosine Kinase Domain ◽  
Molecular Response

Abstract High rates of complete cytogenetic response (CCR), the availability of sensitive methods to detect residual disease, and direct therapeutic consequences are leading motives to integrate regular molecular monitoring into the standards for the management of patients (pts) with chronic myeloid leukemia (CML). We sought to determine long-term dynamics of BCR-ABL mRNA expression levels in 132 CML pts (75 m, 57 f, median age 51, range 20–71 yrs) recruited into the IRIS study in 17 German centers. Pts were randomized to receive imatinib (n=69) or interferon α+Ara-C (IFN, n=63). Due to intolerance or lack of response 41 pts crossed over from IFN to imatinib. Response to therapy was sequentially monitored by conventional cytogenetics from bone marrow metaphases (n=806). BCR-ABL transcripts were determined in 1414 peripheral blood samples by quantitative real time RT-PCR (RQ-PCR) using the LightCycler technology. In case of low level (&lt;10 transcripts/2μl cDNA) or neg RQ-PCR, nested PCR was performed. Total ABL transcripts were quantified as internal controls. A single series of BCR-ABL plasmid dilutions served as standard for both BCR-ABL and ABL transcripts. In pts on 1st-line imatinib therapy median ratios BCR-ABL/ABL gradually decreased: 4.8% at mo 3, 0.88% at mo 6, 0.22% at mo 12, 0.17% at mo 18, 0.058% at mo 24, 0.066% at mo 30, and 0.023% at mo 36. After crossover to imatinib results were not significantly different: 15.5% at mo 3, 1.6% at mo 6, 0.28% at mo 12, 0.068% at mo 18, 0.045% at mo 24, and 0.041% at mo 30. After a median follow-up of 40 mo (1–47) 31/69 pts (45%) on 1st-line imatinib were still RQ-PCR pos, 20 pts (29%) were RQ-PCR neg and nested PCR pos, and in 4 pts (5.8%) BCR-ABL became undetectable by RQ- and nested PCR. After a median time of 25 mo (3–43) on 2nd-line imatinib therapy 19/41 pts (46%) were RQ-PCR pos, 9 pts (22%) were RQ-PCR neg and nested PCR pos, and in 5 pts (12%) BCR-ABL was undetectable by RQ- and nested PCR. Considering adequate RNA quality BCR-ABL became repeatedly undetectable in 4 pts after 18–33 mo of 1st-line imatinib therapy and in 5 pts 9–33 mo after crossover from IFN to imatinib. In one patient, BCR-ABL remained undetectable after a treatment free interval of 4 weeks. After achieving CCR, 5 pts (7.2%) on 1st-line and 2 pts (4.9%) on 2nd-line imatinib therapy experienced cytogenetic relapse after a median time of 10 mo (4–21). In none of these pts mutations of the tyrosine kinase domain of BCR-ABL were detected. BCR-ABL/ABL ratios after 12 mo of imatinib therapy were significantly lower in pts in continuous CCR vs pts with subsequent relapse (0.18 vs 0.60%, respectively, p=0.04). None of the relapsing patients had achieved a ratio BCR-ABL/ABL &lt;0.12% after 12 mo, which represents a 3-log reduction from baseline. During total follow-up ratios BCR-ABL/ABL &lt;0.12% have been achieved in 51 pts (74%) on 1st-line and in 21 pts (51%) on 2nd-line imatinib therapy. We conclude that (i) treatment with imatinib in newly diagnosed CML pts is associated with a rapid and steady decrease of BCR-ABL transcript levels, (ii) a short trial of IFN does not jeopardize molecular response to subsequent imatinib therapy, (iii) an increasing minority of pts achieve complete molecular remission, and (iv) ratios of BCR-ABL/ABL &lt;0.12% after 12 mo of therapy predict for long-term response.

Molecular Remission to Imatinib in Patients with Chronic Myeloid Leukaemia (CML) Is Less Durable Compared to Patients after Allografting.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 276-276
Author(s):  
Thoralf Lange ◽  
Thomas Bumm ◽  
Marc Mueller ◽  
Sandra Otto ◽  
Haifa K. Al-Ali ◽  
...  
Keyword(s):  
Nested Pcr ◽  
Bone Marrow Cells ◽  
Residual Disease ◽  
Standard Dose ◽  
Healthy Individuals ◽  
Rt Pcr ◽  
Molecular Remission ◽  
Conventional Cytogenetics ◽  
Risk Of Relapse

Abstract Objectives: Patients with CML who achieve molecular remission (MR, defined as a RT-PCR negativity for BCR-ABL transcripts) after myeloablative stem cell transplantation (SCT) have a low risk of relapse, and the majority may be cured. The frequency of MR on imatinib varies greatly and the durability of these responses has not been reported. To investigate if MR after SCT and on imatinib are equally stable, we directly compared two cohorts of patients treated with imatinib or SCT, respectively, from the time of their first negative RT-PCR result. Patients and Methods: One hundred and forty-four CML patients in chronic (n=104) or accelerated phase (n=40) treated with standard dose imatinib were routinely monitored by conventional cytogenetics, quantitative RT-PCR (qPCR) and conventional nested PCR in case of negative qPCR results. Nineteen patients (13.2%) had at least 1 negative nested PCR. To assess the level of residual disease in patients with a single negative RT-PCR result, 10 replicate reactions were performed, each corresponding to &gt; 106 white bone marrow cells. Thirty-six samples (median 3, range 1–4) from patients in MR on imatinib and 45 samples (median 2, range 1–3) from patients in MR after SCT were available. Twenty samples from healthy individuals were tested as controls. Results: The first negative result was noted after a median of 16.8 months (range 11.5–36.1) of imatinib therapy and 6.6 months (range 4.7–9.5) after SCT, respectively. The projected risk of molecular relapse at 12 months after the first negative RT-PCR result was 83% in patients on imatinib but only 20% in patients after SCT (P = 0.0001). Only two patients on imatinib remained in molecular remission at 13.8 and 16.6 months. While none of the patients with molecular relapse after allograft lost CCyR, one patient on imatinib progressed to cytogenetic relapse. The replicate assay was positive in 18/36 samples (50%) from patients on imatinib, 8/46 (17.4%) after allografting and 4/20 (20%) from healthy individuals. These differences were significant between patients on imatinib and after allografting (P = 0.003) and between patients on imatinib and healthy individuals (P = 0.005), but not between patients after allografting and healthy individuals (P = 0.9). Negativity by replicate testing was more stable in patients after allografting, although, even in these patients, positive replicate reactions continued to occur with longer follow-up. Conclusion: Imatinib-induced MR is usually not durable, in contrast to MR after transplant. Consistent with this, the level of residual disease in samples negative by single nested PCR is higher in patients on imatinib compared to patients after SCT. These results suggest that disease eradication with imatinib monotherapy may be rare. Patients on imatinib followed by PCR should be made aware of the fact that a single negative test does not have the same significance as in patients after SCT.

Peptide-Vaccine Treatment Associated with TKI Therapy in Patients with CML Is Able to Induce Immunologic, Cytogenetic and Molecular Responses: a Single Center Experience with Long-Term Follow up.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2185-2185 ◽  
Author(s):  
Elisabetta Abruzzese ◽  
Malgorzata Monika Trawinska ◽  
Angela Coletta ◽  
Serena Zaza ◽  
Roberta Giovagnorio ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Residual Disease ◽  
Treatment Plan ◽  
Peptide Vaccine ◽  
Chronic Phase ◽  
Intradermal Injection ◽  
Variable Degree ◽  
Molecular Remission ◽  
Number Of Patients

Abstract Abstract 2185 Poster Board II-162 Introduction: The main objective in the intent to “cure” chronic myeloid leukemia (CML) is to obtain complete cytogenetic remission (CCR) and molecular remission. Tyrosin kinase inhibitors (TKI) treated patients (pts) achieve CCR, but BCR-ABL transcripts can still be detectable, and complete molecular remission (CMR), intended as undetectable transcript, are rare. Moreover about 10% of up-front treated patients show resistance to Imatinib, that reaches 30% in late chronic phase, loss of response during treatment is not negligible, and treatment cannot be stopped. Thus the eradication of residual disease still appears a difficult goal for a TKI alone. An alternative approach to target the residual disease is an active specific immunotherapy. We associated TKI therapy and immunogenic peptides derived from the p210 b3a2 and b2a2 fusion protein (developed by M. Bocchia et al. University of Siena) in pts with chronic phase (CP) CML with stable disease in trying to obtain a specific immunologic activation able to induce a measurable clinical response. Patients population and methods: 17 pts (11 M:6 F) with CP CML, median age 55,5 (range 30-68) treated with Imatinib (16) or Dasatinib (1) were enrolled in the studies. All patients but one were in late chronic phase and had been treated with 2 (2 pts), 3 (11 pts) or >3 (4 pts) lines of therapies. Median time from diagnosis was 64.1(16-143) months, and patients were treated for a median of 30.8 months with TKI before peptide vaccination. 15 pts had b3a2 and 2 a b2a2 transcript. Pts presented with stable, measurable disease at cytogenetic or molecular level from at last 6 months. Vaccination included GM-CSF pre treatment and administration of 5 p210 b3a2 (CMLVAX100) or 1 b2a2 (CMLVAX25) derived peptides. Treatment plan consisted of an induction plan of 6 vaccinations every two weeks, followed by additional boosts every 3-6 months for responding patients. During vaccination, patients continued their conventional treatment with Imatinib/Dasatinib. Prior to vaccine all patients were tested with an intradermal injection of peptides (DTH) to evaluate their sensitivity to the CML antigens, and all of them resulted negative. Cytogenetics, FISH and molecular biology, peptide-specific immune responses (DTH, CD4+ proliferation, immunophenotype) were analyzed before and during treatment. Results: 15/17 pts are evaluable (2 patients had just completed the first 3 months and were not considered for their short follow up), and all patients but one showed a variable degree of response. All patients presented with some degree of DTH indicating the “recognition” of peptides by effector T cells (biologic response). 5/9 pts with positive cytogenetic (2-66% Ph+) reached CCR, and 3 also CMR, while 1 patient did not respond (the one with high tumor burden, 66% Ph+). 3/6 pts in CCR at time of vaccination reached CMR. The majority of responses were rapidly reached (after the induction) and were long lasting. After 69 month follow up 6/15 patients are still treated. Patients suspended vaccination due to: no response (1), lost CCR (5), progression (1), 2nd neoplasm (1), allergic reaction (1). One patient that reached CCR and MCR after vaccination stopped imatinib and was closely monitored thereafter. She is now treated with only vaccine boosts twice/year and still in CMR after 28 month. Specific immune response will be described. Conclusions: These data suggest that addition of b3a2 or b2a2-specific vaccine may have synergistc effect with TKI favouring reduction of residual disease and increasing the number of patients that reach CMR. A multicentric trial is ongoing through the GIMEMA CML study group, and a pilot study to stop TKI in long lasting CMR is in preparation. Disclosures: No relevant conflicts of interest to declare.

Treatment Results and Malignant Complications in Patients on Long-Term Treatment with Tyrosine Kinase Inhibitors(TKIs) for Chronic Myeloid Leukemia(CML)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3767-3767
Author(s):  
Taiichi Kyo ◽  
Kouhei Kyo ◽  
Takesi Okatani ◽  
Mitsuhiro Itagaki ◽  
Ryouta Imanaka ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Malignant Neoplasm ◽  
Incidence Rates ◽  
Term Treatment ◽  
Molecular Response ◽  
Malignant Diseases ◽  
Expected Number ◽  
Long Term Treatment

Abstract Abstract 3767 Background With the introduction of imatinib (IM) and subsequent TKIs such as nilotinib (NI) and dasatinib (DA), deaths due to progression of chronic myeloid leukemia (CML) have decreased dramatically. In such circumstances, the new occurrence of other malignant diseases in patients with CML on treatment with TKIs always causes distress. With the increase in long term surviving patients with CML, there is concern over whether these malignancies are related to treatment with TKIs or not. We investigated the improved prognosis in patients with CML on long-term treatment with TKIs and the occurrence of complicating malignancies. Methods We evaluated 173 patients (101 males, 72 females) in the chronic phase of CML, all of whom had CML diagnosed at our hospital between January 1990 and June 2011 and received treatment with TKIs for at least 1 year. The median age at the start of treatment with TKIs was 57 (19 – 92) years. Patients aged 60 years and older accounted for 72 (42%). The median follow-up period after the start of treatment with TKIs was 68 (12 – 128) months. Before the onset of CML, 11 patients had prior malignancies. Treatments for CML administered before use of TKIs were hydroxyurea (HU) alone 3, HU + interferon-α (IFN-α) 47, IFN-α alone 7, chemotherapy for AML + IFN-α 2 and chemotherapy for ML + IFN-α 1. TKIs were used as frontline therapy in 113.TKI treatment of all patients initially consisted of IM at the dose of 100 mg per 12 kg body weight. We switched the drug to NI when complete molecular response (CMR) was not achieved after long-term treatment with IM. In addition, a switch to DA was used to consolidate CMR. Treatments that contained TKIs consisted of IM alone in 42, IM → NI in 46, and IM →NI → DA in 85. Two patients with a complete cytogenetic response (CCR) underwent bone marrow transplantation. Results Among 173 patients, the best response to treatment in patients treated with TKIs was CMR in 72, a major molecular response (MMR) in 84, CCR in 15, and refractory CML in 2. Currently, 22 have maintained CMR for 6 to 111 months after discontinuation of TKIs, and 19 (11%; 17 males, 2 females) have developed new onset of a malignancy. In these 19, the median age at the onset of cancer was 70 (31 – 85) years. Patients aged 60 years and older accounted for 15 (79%). The median period from the start of TKIs to the onset of cancer was 38 (10 – 117) months. Affected organs were bladder 5; stomach 3; rectum 3; large intestine 2; lung 2; and esophagus, appendix, prostate, and pancreas each in 1. The TKIs given to the patients with malignant diseases were IM alone in 13, IM → NI in 4, and IM → NI → DA in 2. Prior treatments included HU + IFN-α in 8 and IFN-α alone in 1. The observed number of patients who were diagnosed as malignant neoplasm was compared with the expected number. The expected number was obtained through integration of age specific incidence rate of malignant neoplasm from the start age taking medicine to the age at which the diagnosis as malignancy was made or the follow up was finished for censoring. The age specific incidence rates were estimated by interpolating five year old specific incidence rates from of the 2007's survey that was conducted by Center for Cancer Control and Information Services, National Cancer Center, Japan. The observed number/expected number (O/E) ratio for the occurrence of all malignant diseases was 1.00 (19/18.97), and the O/E for gastrointestinal cancer was 1.118 (11/9.84). Therefore, no increase in the incidence of malignant diseases was observed in patients treated with TKIs. However, the O/E for bladder cancer was 4.525 (5/1.11) with a 95% confidence interval of 1.42 – 9.32 (P = 0.0002), which means that the incidence of bladder cancer in patients treated with TKIs was higher than that in the general Japanese population. So far 19 patients have died and the median age at death was 79 (59 – 94) years. In these patients, 8 deaths were related to cancer and the others were caused by diseases associated with old age that were unrelated to the worsening of CML. Conclusion The introduction of TKIs has undoubtedly improved the prognosis of patients with CML. Based on the results of this investigation, the apparent increase in malignant diseases observed during the long-term follow-up of patients treated with TKIs was generally considered to be attributable to the aging of patients. We should however further investigate whether the higher incidence of bladder cancer seen in patients treated with TKIs is incidental or not. Disclosures: No relevant conflicts of interest to declare.

Imatinib Mesylate Discontinuation in Patients with Chronic Myelogenous Leukemia in Complete Molecular Remission: An Update Follow Up.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2154-2154 ◽  
Author(s):  
Francois-Xavier Mahon ◽  
Francoise Huguet ◽  
Gabriel Etienne ◽  
Delphine Réa ◽  
Jean-Michel Cayuela ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Quantitative Polymerase Chain Reaction ◽  
Leukemic Cell ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Molecular Remission

Abstract The BCR-ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec) induces complete cytogenetic responses (CCR) in more than 85% of patients with chronic myelogenous leukemia (CML). However, patients in CCR relapse after imatinib interruption in case of detectable residual disease. In fact, less than 10% of patients achieve a molecular remission, defined by an undetectable residual disease using real time quantitative polymerase chain reaction (RTQ-PCR). We previously reported the outcome of CML patients in CCR after cessation of interferon-alpha during the pre-imatinib era. Seven (all with a negative PCR) out of 15 patients did not relapse (J Clin. Oncol.,20,2002:214–220). In the present study, we address the issue of the discontinuation of imatinib in CML with undetectable residual disease for more than 2 years in 15 patients. The median duration of RTQ-PCR negativity and imatinib therapy were respectively 32 months (24–46) and 45 months (32–56) before imatinib interruption. Eight patients displayed a molecular relapse with a detectable BCR-ABL transcript appearance between the first 6 months. Imatinib was then re-introduced and led to a novel molecular response in most patients. Seven other patients have still an undetectable level of BCR-ABL transcript after a median follow up of 20 months (9–24). With the assumption that the doubling time of a proliferative CML cell is 8 days, it will take a maximum of 6 months if only one leukemic cell persists and proliferates to reach 107 cells i.e corresponding to a residual disease detectable by RTQ-PCR. Relapses observed within 6 months may reflect the kinetic of undetectable dividing CML cells. Those cells may be eradicated or controlled in long term non relapsing patients described in our study.

Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia

2017 ◽  
Vol 35 (3) ◽  
pp. 298-305 ◽  
Author(s):  
Gabriel Etienne ◽  
Joëlle Guilhot ◽  
Delphine Rea ◽  
Françoise Rigal-Huguet ◽  
Franck Nicolini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Treatment Discontinuation ◽  
Molecular Response ◽  
Long Term Follow Up ◽  
Study Population ◽  
Analysis Point

Purpose Imatinib (IM) can safely be discontinued in patients with chronic myeloid leukemia (CML) who have had undetectable minimal residual disease (UMRD) for at least 2 years. We report the final results of the Stop Imatinib (STIM1) study with a long follow-up. Patients and Methods IM was prospectively discontinued in 100 patients with CML with UMRD sustained for at least 2 years. Molecular recurrence (MR) was defined as positivity of BCR-ABL transcript in a quantitative reverse transcriptase polymerase chain reaction assay confirmed by a second analysis point that indicated an increase of one log in relation to the first analysis point at two successive assessments or loss of major molecular response at one point. Results The median molecular follow-up after treatment discontinuation was 77 months (range, 9 to 95 months). Sixty-one patients lost UMRD after a median of 2.5 months (range, 1 to 22 months), and one patient died with UMRD at 10 months. Molecular recurrence-free survival was 43% (95% CI, 33% to 52%) at 6 months and 38% (95% CI, 29% to 47%) at 60 months. Treatment was restarted in 57 of 61 patients with MR, and 55 patients achieved a second UMRD with a median time of 4 months (range, 1 to 16 months). None of the patients experienced a CML progression. Analyses of the characteristics of the study population identified that the Sokal risk score and duration of IM treatment were significantly associated with the probability of MR. Conclusion With a median follow-up of more than 6 years after treatment discontinuation, the STIM1 study demonstrates that IM can safely be discontinued in patients with a sustained deep molecular response with no late MR.

Long-Term Molecular Results Of The Gimema VEL-03-096 Trial: Molecular Remission Achievement and Loss Are Major Outcome Predictors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2077-2077
Author(s):  
Simone Ferrero ◽  
Marco Ladetto ◽  
Daniela Drandi ◽  
Federica Cavallo ◽  
Elisa Genuardi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Salvage Treatment ◽  
Clinical Relapse ◽  
Molecular Remission ◽  
Advisory Committees ◽  
Risk Of Relapse

Abstract Background and aims The extensive use of new drugs in multiple myeloma (MM) allowed the achievement of unprecedented levels of cytoreduction and major advantages in survival rates, though almost all patients still relapse after a successful treatment. PCR-based minimal residual disease (MRD) studies are powerful prognostic tools, able to indentify patients at high risk of relapse. Thus, there is a growing interest in MRD to modulate therapy also in MM, as already happens in other lymphoid neoplasms. However available reports have a too short follow-up to be conclusive. In particular some points need to be addressed: 1) which is the long-term outcome of patients achieving molecular remission (MR) in the absence of further treatment? 2) What is the prognostic impact of MR loss? 3) How long is the window between MR loss and clinical relapse? These issues have been addressed based on the mature results of the GIMEMA VEL-03-096 trial [EudraCT Number 2004-000531-28], which currently has a median follow-up (mFU) of 93 months. Patients and methods Inclusion criteria and treatment schedule have been already reported [Ladetto et al., J Clin Oncol 2010]. MRD was assessed on bone marrow at diagnosis, study entry, after two VTD courses, at the end of treatment and then every six months up to clinical relapse. Patients underwent MRD detection using both qualitative nested PCR and Real Time Quantitative (RQ)-PCR, employing immunoglobulin heavy chain-derived patient specific primers, as described [Voena et al., Leukemia 1997; Ladetto et al., Biol Bone Marrow Transpl 2000; van der Velden et al., Leukemia 2007]. MR was defined as negative MRD results by nested-PCR or less than 1EE-04 by RQ-PCR. Loss of MR was defined as an increase of MRD levels of at least one log in consecutive samples at whenever timepoint. For survival analysis duration of response (DOR), progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS) rates were used, as detailed in IMWG criteria [Rajkumar et al., Blood 2011]. Results Thirty-nine patients were enrolled. So far 27 serological progressions, 22 clinical relapses needing salvage treatment and 12 deaths (two non-MM-related) were observed. Median PFS was 60 months, median TNT 67 months and OS at mFU was 64%. 270 of the planned samples for MRD monitoring (86%) were actually received by the centralized lab. Currently, 26 MR and 11 MR losses have been registered. The achievement of MR was strongly associated with a better outcome, in terms of median DOR (62 vs 9 months, p<0.001), PFS (67 vs 22 months, p<0.001), TNT (108 vs 30 months, p<0.001) and resulted significant for OS, too (72% vs 48% at mFU, p=0.04, Figure 1A-B). Moreover, patients with ongoing MR, MR loss or not achieving MR at all showed increasing risk of relapse, respectively (DOR not reached vs 38 vs 9 months, PFS 92 vs 63 vs 22 months, TNT not reached vs 72 vs 30 months, each p<0.001, Figure 2). Interestingly, the time lag between MR loss and clinical relapse for patients achieving and then loosing MR was comparable to that between end of consolidation and clinical relapse for patients never obtaining MR (TNT 19 vs 11 months p=0.34). Finally, analyzing the relationship between MR achievement, MR loss and need for a salvage treatment, of the 26 patients who obtained MR only 11 (42%) received a retreatment at a median time of 42 months (range: 22-87 months). Of these 11 clinical relapses, 7 were anticipated by a molecular relapse (64%), occurring at a median time of 9 months (range: 2-39 months). The 4 relapses not anticipated by MR loss occurred in cases with inadequate follow-up sampling or at least two years after the end of the planned molecular follow-up. Conclusions Besides confirming the strong prognostic value of PCR-based MRD monitoring in MM, our long-term results indicate the following: 1) the 42 months TNT of patients achieving MR underlines the excellent disease control of MM patients once obtained MR; 2) the occurrence of MR loss heralds relapse, with a TNT from MR loss comparable to TNT of patients not achieving MR; 3) there is a 9 months lag between MR loss and need for salvage treatment. These observations will have increasing relevance considering that ongoing methodological developments will allow effective MRD monitoring in the vast majority of MM patients. Disclosures: Off Label Use: Bortezomib and thalidomide as post-transplant consolidation during first-line treatment of multiple myeloma. Ladetto:Celgene: Research Funding, Speakers Bureau; Jannsen Cilag: Research Funding, Speakers Bureau; Mundipharma: Research Funding, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Cavallo:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Jannsen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Caravita:Celgene: Honoraria, Research Funding; Jannsen Cilag: Honoraria. Guglielmelli:Celgene: Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Jannsen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

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