Prevalence of Large Granular Lymphocyte Proliferation in Chronic Myeloid Leukemia (CML) Patients Treated with Dasatinib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1111-1111
Author(s):  
Jason Valent ◽  
Charles A. Schiffer
Keyword(s):  
Flow Cytometry ◽  
Side Effects ◽  
Peripheral Blood ◽  
Chronic Phase ◽  
Cell Transplant ◽  
Pleural Effusions ◽  
Blast Phase ◽  
Number Of Patients ◽  
Dasatinib Treatment

Abstract Abstract 1111 Poster Board I-133 Dasatinib is a potent inhibitor of the BCR-ABL tyrosine kinase which is effective in the treatment of imatinib refractory CML. While hematologic toxicities of neutropenia and thrombocytopenia are well known, large granular lymphocytosis has been reported in only a small number of patients without prior allogeneic stem cell transplant treated with dasatinib for CML. During routine follow up of leukocyte counts in 15 consecutive patients (age range 27-77 years) treated with dasatinib, 4 patients (2 chronic-phase, 1 accelerated phase with clonal cytogenetic progression, 1 blast-phase) developed a lymphocytosis (> 3800/mm3). Peripheral blood smear and peripheral blood flow cytometry revealed a population of large granular lymphocytes (LGLs) expressing CD3, CD8, CD57, and variable expression of CD56. Lymphocytosis was first noted between 1 and 9 months after initiation of dasatinib and has persisted in 3 of the patients with a median follow up of 33 months from the onset of lymphocytosis. Peak absolute lymphocyte count ranged from 5000/mm3 to 6900/mm3 and approximately 40 to 60% of the lymphocytes were LGLs by flow cytometry with the remainder being predominantly T lymphocytes. These 4 patients with LGL lymphocytosis have all have major molecular responses and the patient with blast-phase has remained in a complete cytogenetic remission with a major molecular response 44 months after initiation of dasatinib. The 11 other patients (6 chronic-phase, 2 accelerated-phase, 3 blast-phase) treated with dasatinib for CML have not developed lymphocytosis. These patients have been followed for a median of 25 months (range 3-50 months) although some were treated with dasatinib for a relatively short period of time because of poor response of their advanced CML. Review of the peripheral blood smears from 3 of the 6 chronic phase patients without lymphocytosis who remain on dasatinib treatment did not reveal any LGLs. All of these 6 patients have had complete, sustained cytogenetic responses. A persistent pleural effusion developed in the blast phase patient with lymphocytosis approximately 12 months after lymphocytosis developed; no significant side effects were noted in the other 3 patients although one remains thrombocytopenic. Pleural effusions developed in 2 of the 6 patients without lymphocytosis who remain on dasatinib treatment. Previous reports have suggested an increased incidence of “inflammatory” type side effects such as pleural effusions and pneumonitis in patients with dasatinib related LGL proliferation, although the small number of patients in this series precludes analysis of this association. In summary, LGL proliferation was detected in a minimum of 27% of dasatinib recipients and may be associated with a beneficial response. While the mechanism of LGL proliferation has not been fully explained, it has been suggested that dasatinib mediated inhibition of immunoregulatory kinases such as Src is permissive of LGL proliferation. Further evaluation of the frequency and clinical impact of this phenomenon in the large clinical trials of patients treated with dasatinib is warranted. Disclosures Schiffer: Bristol Myers: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Association of Peripheral Regulatory T Cells with Achievement of Deep Molecular Response in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Treated with Dasatinib - the Final Results of D-First Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1916-1916 ◽  
Author(s):  
Chikashi Yoshida ◽  
Noriyoshi Iriyama ◽  
Yuho Najima ◽  
Shin Fujisawa ◽  
Hisashi Wakita ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Research Funding ◽  
Nk Cell ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Cumulative Rate ◽  
Dasatinib Treatment

Abstract Introduction Achievement of deep molecular response (DMR) has become an important treatment goal for patients with chronic phase chronic myeloid leukemia (CP-CML) since it is considered to be necessary for the challenge of stopping tyrosine kinase inhibitor (TKI) treatment. However, prognostic marker for prediction of DMR has not been established. We have previously reported the results of D-First study that shorter having time of BCR-ABL1 transcripts and early cytotoxic lymphocyte expansion were associated with achievement of DMR in newly diagnosed CP-CML patients treated with dasatinib. Here, the long-term follow-up results of the study were analyzed after a minimum 36 months follow-up. In this analysis, we mainly focus on dynamics of regulatory T cells (Treg) influencing patients' clinical course, as well as immunoprofiles during dasatinib treatment. Methods: A total of 52 patients with newly diagnosed CP-CML who were enrolled between June 2011 and June 2012 and treated with dasatinib 100 mg once daily on an open-label, multicenter, prospective phase II clinical trial (NCT01464411). All patients were followed-up for minimum of 36 months. Patients were assessed for molecular response before and 1, 3, 6, 9, 12, 15, 18, 24, and 36 months after starting dasatinib by real-time quantitative polymerase chain reaction analysis of BCR-ABL1 transcripts standardized on an international scale (BCR-ABL1 IS). A DMR was defined as less than 0.01% BCR-ABL1IS (MR4). The analysis of immunophenotyping of lymphocyte fractions in the peripheral blood samples was performed by flow cytometry before and 1, 2, 3, 6, 9, 12, 15, 18, 24, and 36 months after starting dasatinib treatment at a centralized laboratory (BML). Results: Patients' characteristic at diagnosis has been reported previously. Briefly, the median age was 52 years. High Sokal risk score was seen in 12% patients. With a minimum follow-up of 36 months, 12 (23%) patients have discontinued therapy. Reasons for treatment discontinuation includes: pleural effusion (N=3), pericardial effusion (1), proteinurea and systemic edema (1), pulmonary hypertension (1), malaise (1), elevation of intraocular pressure (1), interstitial pneumonia (1), and patient's requests (3). A cumulative rate of MMR was 75% by 12 months, 80% by 18 months, 86% by 24 months and 88% by 36 months. A cumulative rate of DMR was 49% by 12 months, 59% by 18 months, 59% by 24 months, and 65% by 36 months. Two patients died because of reasons unrelated to CML. No patients progressed to accelerated or blastic phase. Three-year overall survival was 96%. Flow cytometric analysis of peripheral blood revealed that average number of CD4+ T lymphocytes did not change over the course of 36 months. In contrast, ratio of CD4+CD25+CD127low Treg among CD4+ T cells decreased in a time-dependent manner during the follow-up. The ratio of Treg at 12 months of dasatinib treatment was associated with achievement of DMR, which was especially significant at 18 months (p<0.05). Differentiated NK cell represented a trend of increasing during the period of observation according to the analysis of CD3-57+/CD3-56+ ratio. In addition, differentiation degree in NK cells assessed by CD3-57+/CD3-56+ ratio was negatively associated with the probability of Treg through the treatment period, suggesting a critical role of Treg inhibition by dasatinib for the induction of NK cell differentiation. Conclusion: The long term results from this study of dasatinib as frontline treatment of newly diagnosed CP-CML showed the excellent results of achieving DMR. Inhibition of Treg in peripheral blood, possibly induced by dasatinib, was associated with the achievement of DMR, which could be one of the prognostic markers for predicting the important treatment goal. Disclosures Yoshida: Pfizer: Honoraria, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau. Iriyama:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Okamoto:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Teijin Pharma Limited: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Eisai Co., Ltd.: Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding. Kumagai:Pfizer: Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Ohyashiki:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Ariad: Consultancy. Morita:Bristol-Myers Squibb: Speakers Bureau. Sakamoto:Takeda Pharmaceutical: Consultancy; Yakult: Other: Remuneration. Inokuchi:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

Rituximab in Refractory Idiopathic Thrombocytopenic Purpura (ITP).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3979-3979
Author(s):  
Cristina Santoro ◽  
Francesca Biondo ◽  
Gioia De Angelis ◽  
Mariastefania De Propris ◽  
Annalisa De Vellis ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Platelet Count ◽  
Side Effects ◽  
Peripheral Blood ◽  
Complete Response ◽  
Early Response ◽  
High Dose ◽  
High Dose Dexamethasone ◽  
Anti Cd20

Abstract Background. Rituximab, a chimeric anti-CD20 monoclonal antibody effective in B-cell depletion, may be useful in autoimmune disorders by interfering with the production of auto-antibodies. Aims. To investigate the efficacy of Rituximab in patients with resistant ITP. Patients and Methods. Fourteen adult ITP patients (3 males, 11 females; median age 44.5 years [21.1–67.6]) were treated with Rituximab (375 mg/m2/weekly for four doses). The median time between diagnosis and start of Rituximab was 2 years (0.2–33.1 months). All patients had already received at least two lines of therapy (median 3; 2–6): prednisone, pulsed high-dose dexamethasone, azathioprine, immunoglobulins, interferon or splenectomy. At the start of Rituximab, the median platelet count was 10 x 109/L (3–20 x 109/L). Response definitions: complete response (CR), platelet count ≥150 x 109/L; partial response (PR), &gt;50 &lt;150 x 109/L; minimal response (MR), &gt;20 ≤50 x 109/L; no response (NR) ≤20 x 109/L. After completing therapy, patients were evaluated for platelet count after 1 and 3 months, and thereafter every 3 months until relapse or start of a different treatment. Peripheral blood B lymphocytes were evaluated by flow-cytometry as CD19+ cells before treatment, 1 and 3 months after stopping therapy, and then every 3 months up to recovery. Results. One month after Rituximab therapy, 7 responses (2 CR, 4 PR, 1 MR; 50%) and 7 NR (50%) were observed. Two relapses occurred 5 and 18 months after response. The median follow-up of all treated patients is 6 months (1.8–34.6), while the median follow-up of all responsive patients is 6.1 months (2–18.7). Before starting therapy, 11/14 cases were evaluable for flow-cytometry studies. The median baseline value of peripheral blood CD19+ B cells was 137 x 106/L (58–476). One month after completing therapy, 7/9 evaluable cases showed absence of CD19+ cells and 2/9 showed a count of 9 and 4.4 x 106/L CD19+ cells, respectively. At the last available control (median follow-up of 6.8 months; 1.9–32.5), 11/14 evaluable patients had still not recovered the baseline CD19+ cell count (median value: 5.5 x 106/L; 0–287). The following side effects were observed: 1 case of papulosquamous dermatitis, 2 cases of fever. Conclusions. Seven out of 14 (50%) ITP patients had an early response to Rituximab (2 CR, 4 PR, 1 MR), that persisted in 5 cases. No late responses were observed. The response was independent of the post-therapy CD19+ cell numbers. No serious infections were observed during the clinical follow-up. No patient had to stop therapy because of severe side effects.

Allogeneic Stem Cell Transplantation for Accelerated/Blastic Phase Philadelphia-Chromosome Negative MPN

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4532-4532
Author(s):  
Anjum Bashir Khan ◽  
Donal McLornan ◽  
Yogesh Jethava ◽  
Kavita Raj ◽  
Victoria T Potter ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Peripheral Blood ◽  
Research Funding ◽  
Myeloproliferative Neoplasm ◽  
Chronic Phase ◽  
Haematopoietic Stem Cell ◽  
Cell Transplant ◽  
Blastic Phase

Abstract Abstract 4532 Myeloproliferative Neoplasm (MPN)-Leukaemic Transformation (LT) uniformly carries a dismal prognosis. Effective therapy for such patients are currently lacking with no established evidence base to guide Allogeneic Haematopoietic Stem Cell Transplant (AHSCT) regimen. We report the outcome of a cohort of patients undergoing AHSCT at our 2 institutions over a 6-year period (2006–2012). 24 patients underwent AHSCT following diagnosis of MPN transformed to an accelerated phase (5–9% blasts on bone marrow (BM), n=9 & 10–19% BM blasts, n=2) or blastic phase (>20% blasts on peripheral blood or BM, n=13). Disease subtypes were: Polcythaemia Vera (PV, n=4), Essential Thrombocythaemia (ET, n=6), Primary Myelofibrosis (PMF, n=8), Myelodysplastic/Myeloproliferative neoplasm-Unclassified (MDS/MPN-U, n=6). Median age at diagnosis was 50 years (range 29–67) and median time to transformation was 50 months (range 0–271). Cytogenetics were abnormal at transformation in 11 patients (46%), with 6 (25%) demonstrating abnormalities of chromosomes 5, 7 or complex karyotype, and 5 displaying trisomy 8, whilst 1 had isolated chromosome 17p deletion. 13 patients harboured the JAK2V617F mutation. Patients received a median of 3 (range, 1–5) lines of therapy for chronic and acute phase prior to AHSCT, of which 20 patients received intensive AML-type induction therapy. Disease status at time of AHSCT was complete remission (CR) in 13 cases, partial response (PR) in 7, and 4 patients had persisting AML. Conditioning regimes were Reduced Intensity with T-depletion (Alemtuzumab or Anti-Thymocyte globulin) in 23/24 cases (Fludarabine/Busulfan-based n=12, FLAMSA (Fludarabine, Ara-C and Amsacrine, followed by TBI/Cyclophosphamide or Busulfan) n=9, Fludarabine Cyclophosphamide TBI haploidentical protocol n=1, Fludarabine/Melphalan n=1). Median CD34 dose was 6.48 × 10∧6 cells/kg (range 1.17 {BMH} −10.71). Stem cell source was Peripheral Blood in all but one case, from unrelated (n=17) or related (n=7) donors. Median time to both neutrophil and platelet engraftment was 13 days (range 9–25 and 7–68 respectively); 2 patients including the haploidentical transplant had Primary Graft Failure (8%). The incidence of severe (grade 3&4) acute GVHD was 3/24 (12.5%) and 10 patients developed NIH-defined chronic GVHD (8 moderate, 1 severe). Day 100 Non-relapse mortality was 12.5%. Patients underwent sequential chimerism monitoring. Median OS for the entire cohort was only 10 months with a median progression free survival (PFS) of only 6.5 months. 5 patients received therapeutic Donor Lymphocyte Infusion (tDLI) for relapse at a median dose of 1×10∧6 CD3+/kg. 2 patients received DLI alone for chronic phase relapse, of whom 1 achieved remission. 3 patients received chemotherapy + DLI and 1 achieved 2ndCR. At last follow-up, 11/24 patients were alive with median surviving patient follow-up of 25 months. The percentage of BM blasts at progression from chronic phase had a highly significant impact upon outcome post AHSCT, median OS 23 vs. 10 months for 5–9% BM blasts compared to 310% BM blasts (p=0.011) & PFS 11 vs 6 months respectively (p=0.033, Fig 1). This effect was replicated when considering disease response immediately prior to AHSCT, with a median OS of 28 months for those in CR, compared to 10 months for those with excess blasts (p=0.017) and median PFS 11 vs 6 months, p=0.019 (Fig 2). Disease duration, subtype, Jak2 status and age at allograft did not significantly affect survival. Of note for the 3 surviving patients with follow-up over 6 months, all received FLAMSA-RIC conditioning (n=9). 5 patients who received FLAMSA TBI; 2 died of treatment-related complications, and 2 with residual disease at time of AHSCT relapsed early. Of 4 patients who have received a hybrid FLAMSA-Busulfan regimen, 2 remain alive in CR and 2 achieved a relapse free period of 12 months. Interestingly, PFS for FLAMSA-Bu patients appears significantly improved compared to conventional RIC regimens (median PFS 12 vs. 6 months, p=0.035) on univariate analysis, although conclusions are limited by cohort size. Further work into optimising transplantation regimens for accelerated and blastic phase MPN is warranted. Early use of FLAMSA-Busulfan hybrid protocol, before transformation to overt blastic phase, in conjunction with early weaning of immunosuppressive therapy and prophylactic DLI may improve the proportion of long-term survivors. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures: Harrison: Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

Flow Cytometry in Bladder Tumours: Our Experience

1993 ◽  
Vol 60 (2) ◽  
pp. 158-161 ◽  
Author(s):  
M. De Siati ◽  
D. Grassi ◽  
N. Franzolin ◽  
F. Marchioretto ◽  
L.S. Azzolina
Keyword(s):  
Flow Cytometry ◽  
Initial Data ◽  
Patient Survival ◽  
Tumour Progression ◽  
Tumour Stage ◽  
Number Of Patients ◽  
Bladder Tumours

From January 1992 to January 1993, specimens from bladder tumours of 75 patients were analyzed by cytometry (FCM). Our data show a good correlation between tumour stage and grade, and tumour ploidy. Furthermore, aneuploid tumours showed progression more often than diploid tumours. A larger number of patients admitted to the study and a more prolonged period of follow-up will be necessary to confirm our initial data and to investigate whether a correlation exists between FCM and tumour progression and patient survival.

scholarly journals Study of Peripheral Mononuclear Cells and CD34 Levels as a Predictive Marker for Initiating Apheresis in Autologous Stem Cell Transplant

2021 ◽  
Author(s):  
Kiran PK ◽  
Vinu Sarathy P ◽  
Srinivas BJ ◽  
Girish V Badarkhe ◽  
Rajesh Kumar KS ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Stem Cell ◽  
Cell Count ◽  
Hodgkin Lymphoma ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cell ◽  
Blood Stem Cell ◽  
Optimal Time ◽  
Cell Transplant ◽  
Stem Cell Collection

Background: Autologous HCT in multiple myeloma is done as upfront treatment in newly diagnosed transplant eligible patients after induction chemotherapy. In addition, it is standard for relapsed, aggressive non-Hodgkin lymphoma (NHL) and classical Hodgkin lymphoma (HL), and is curative in ~40% to 45% of patients. Over a decade, many efforts were made to find helpful parameters to predict an optimal time for initiating an efficient peripheral blood stem cell collection so that adequate stem cells are collected.  It has been well accepted that CD34+ cell count in peripheral blood before leukapheresis is the best parameter to predict CD34 cell yield. However, white blood cell count, mononuclear cell count, and other easily obtained parameters are still used to guide the clinical practice of peripheral blood stem cell mobilization and collection.  Materials and Methods: In the present study, we analyzed the correlation between peripheral blood MNC and Apheresis CD34 levels and also between peripheral blood CD34 by flow cytometry and apheresis CD34 levels. Results: We found that there was a statistically insignificant weak correlation between peripheral MNC and apheresis CD34. There was a statistically significant strong correlation between peripheral CD34 and apheresis CD34. Conclusion: The results show that peripheral blood MNC was analogous indicating that no reliable prediction can be done for CD34 cells collected in apheresis while peripheral CD34 by flow cytometry is the strongest predictor for initiating stem cell collection.

Long-Term Follow-Up of Allogeneic Stem Cell Transplantation (SCT) with Reduced Intensity Conditioning (RIC) for Patients (pts) with Chronic Myeloid Leukemia (CML).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2898-2898
Author(s):  
Partow Kebriaei ◽  
Michelle Detry ◽  
Antonio Carrasco-Yalan ◽  
Athanasios Anagnostopoulos ◽  
Daniel Couriel ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Advanced Disease ◽  
Chronic Phase ◽  
Disease Stage ◽  
Disease Group ◽  
Blast Phase

Abstract Allogeneic SCT remains an effective strategy for inducing durable remission in CML. RIC regimens are less myelosuppressive, but adequately immunosuppressive, allowing for engraftment with acceptable treatment-related mortality (TRM) in older pts who otherwise would not be candidates for SCT. The long-term antitumor effect of this approach is not well-established. This is relevant in CML, since many pts present for SCT with advanced disease after failing tyrosine kinase inhibitors (TKI). Patients, Methods: We evaluated outcomes of 64 CML pts (40 M/24 F) with median age 52 yrs (range 18–72) treated from June 1996 to April 2005 with FAI (fludarabine 120 mg/m2, Ara-C 8 gm/m2, idarubicin 36 mg/m2), FM140 (fludarabine 120 mg/m2, melphalan 140 mg/m2 +/− Ara-C 2 gm/m2) or FM180 (fludarabine 120 mg/m2, melphalan 180 mg/m2) and unmanipulated stem cells. Disease stage at time of study entry was first chronic (n=13), second chronic (n=17), accelerated (n=29), or blast phase (n=5), with median time from diagnosis to SCT of 2.6 yrs (range 0.5–20.3). Stem cell source was bone marrow (n=38) or peripheral blood (n=26), and donor type was matched related (n=30), 1 Ag mismatched related (n=4), or matched unrelated (n=30). Graft vs. host disease (GVHD) prophylaxis consisted of tacrolimus and mini-dose methotrexate in all but 6 pts (CSA-based). Anti-thymocyte-globulin was added to all pts other than matched related. Maintenance therapy with TKIs following SCT was not used. Multivariate analysis was done using Cox proportional hazards regression. Results: 22 pts were alive at a median follow up of 7 yrs from SCT (range 0.8–9.8). OS and PFS were 48% and 30%, respectively, at 2 yrs, and 33% and 30%, respectively, at 5 yrs. The cumulative incidence of acute GVHD grades II–IV and III–IV were 31% and 14%, respectively, and chronic GVHD was 32% (22% for extensive). TRM at 100 days, 1-, 2-, and 5- yrs were 2%, 14%, 20%, and 33%, respectively. There was no association between pt age, donor source, preparative regimen, or time to SCT and TRM. Disease recurrence accounted for 12 of 42 deaths. There were 3 cases of graft rejection, with 1 death from graft rejection. Only disease stage at time of SCT was significantly predictive in multivariate analysis for both OS and PFS. Pts with advanced disease had worse OS (HR 2.36, 95%CI 1.25–4.46, p=0.008, see figure) and PFS (HR 1.91, 95%CI 1.05–3.49, p=0.035) than pts in chronic phase. In multivariate for PFS, pts who developed grade I or II acute GVHD were less likely to progress compared to pts who did not develop any GVHD: grade I (HR 0.324, 95%CI 0.13–0.84, p=0.027) and grade II (HR 0.286, 95%CI 0.11–0.78, p=0.014). Conclusion: RIC SCT provides adequate disease control in chronic phase CML pts. The development of some GVHD is protective in this setting. TRM rates are acceptable but continue to increase over time. Alternative treatment strategies need to be explored in pts with accelerated or blast phase disease. Results may be improved with addition of TKI therapy post SCT. Survival by Disease Group Survival by Disease Group

Dasatinib Efficacy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Pre-Existing BCR-ABL Mutations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 449-449 ◽  
Author(s):  
Martin C Müller ◽  
Jorge Cortes ◽  
Dong-Wook Kim ◽  
Brian J. Druker ◽  
Philipp Erben ◽  
...  
Keyword(s):  
Amino Acids ◽  
Median Time ◽  
Chronic Phase ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Imatinib Resistant ◽  
Dasatinib Treatment

Abstract Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Across a series of phase II and III trials, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal response, or intolerance to imatinib. BCR-ABL mutations are an important cause of imatinib failure and suboptimal response. Here, the efficacy of dasatinib in patients with CML-CP who had baseline BCR-ABL mutations following imatinib treatment was analyzed using data from three trials (CA180-013, -017, and -034). Mutational assessment of the BCR-ABL kinase domain was performed using RT-PCR and direct sequencing of peripheral blood cell mRNA. Hematologic, cytogenetic, and molecular response rates were reported after ≥24 mos of follow-up. Duration of response, progression-free survival (PFS), and overall survival (OS; in 013/034) were calculated using Kaplan-Meier analysis, and rates were estimated at the 24-mo time point. Of 1,150 patients with CML-CP who received dasatinib, 1,043 had a baseline mutational assessment and were analyzed further. Of these, 402 patients (39%) had a BCR-ABL mutation, including 8% of 238 imatinib-intolerant and 48% of 805 imatinib-resistant patients. Excluding known polymorphisms, 64 different BCR-ABL mutations were detected affecting 49 amino acids, with G250 (n=61), M351 (n=54), M244 (n=46), F359 (n=42), H396 (n=37), Y253 (n=26), and E255 (n=25) most frequently affected. Dasatinib treatment in patients with or without a baseline BCR-ABL mutation, respectively, resulted in high rates of major cytogenetic response (MCyR; 56% vs 65%), complete cytogenetic response (CCyR; 44% vs 56%), major molecular response (MMR; 33% vs 45%); PFS (70% vs 83%), and OS (89% vs 94%) (Table). After 24 mos, CCyRs in patients with or without a BCR-ABL mutation had been maintained by 84% vs 85%, respectively, of those achieving this response. Among patients with mutations who received dasatinib 100 mg once daily, which has a more favorable clinical safety profile, efficacy and durability were similar (MCyR: 55%; CCyR: 41%; MMR: 36%; PFS: 73%; OS: 90%). In general, high response rates and durable responses were observed in patients with different mutation types, including highly imatinib-resistant mutations in amino acids L248, Y253, E255, F359, and H396. When responses were analyzed according to dasatinib cellular IC50 for individual BCR-ABL mutations, dasatinib efficacy was observed in 44 patients who had any of 5 imatinib-resistant mutations with a dasatinib cellular IC50 &gt;3 nM (Q252H, E255K/V, V299L, and F317L, excluding T315I), including MCyR in 34%, CCyR in 25%, MMR in 18%, PFS in 48%, and OS in 81%. Among patients whose mutations had a dasatinib IC50 ≤3 nM (n=254) or unknown IC50 (n=83), responses and durability were comparable to patients with no BCR-ABL mutation. As expected, few patients with a T315I mutation (IC50 &gt;200 nM; n=21) achieved a response. Among 70 patients with &gt;1 mutation, a MCyR was achieved in 53% and a CCyR in 37%. Among patients with mutational analysis at last follow-up (n=162), 42 (26%) retained a BCR-ABL mutation (20 retained a mutation with IC50 &gt;3 nM), 42 (26%) lost a mutation (5 lost a mutation with IC50 &gt;3 nM), and 44 (27%) developed a new mutation (39 developed a mutation with IC50 &gt;3 nM), with some patients counted in more than one category. Overall, this analysis demonstrates that dasatinib has broad efficacy against all BCR-ABL mutations except for T315l. For patients with BCR-ABL mutations, dasatinib treatment is associated with durable responses and favorable long-term outcomes. Table Analysis by dasatinib IC50 No BCR-ABL mutation BCR-ABL mutation BCR-ABL mutation treated with 100 mg QD &gt;3 nM (excl. T315I) 3 nM* Unknown IC50** Some patients had &gt;1 mutation. *Excluding patients with a concurrent mutation with dasatinib IC50 &gt;3 nM. **Excluding patients with a concurrent mutation with known dasatinib IC50. Patients, n 641 402 49 44 254 83 Response rates (≥24 mos of follow-up), % CHR 93 90 90 82 94 96 MCyR 65 56 55 34 58 73 CCyR 56 44 41 25 47 54 MMR 45 33 36 18 34 43 Median time to MCyR, mos 2.8 2.9 2.8 5.7 2.9 2.8 Median time to CcyR, mos 3.0 5.3 3.0 5.7 5.4 3.4 24-mo PFS (95% CI), % 83 (79.8–86.5) 70 (65.3–75.2) 73 (60.1–86.3) 48 (31.2–64.7) 73 (66.6–78.9) 89 (82.3–96.3) 24-mo OS (95% CI), % 94 (91.4– 95.7) 89 (85.1– 92.1) 90 (81.2– 98.3) 81 (68.8– 93.8) 90 (85.8– 94.2) 96 (91.2–100)

The Vast Majority of CML-CP Patients Treated with Dasatinib (70 mg BID) Who Progress after Long-Term Follow-up (24 mo) Remain in Chronic-Phase

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4265-4265 ◽  
Author(s):  
Jorge Cortes ◽  
Michael Mauro ◽  
Susan O’Brien ◽  
Gautam Borthakur ◽  
William Wierda ◽  
...  
Keyword(s):  
Blast Crisis ◽  
Clinical Status ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Disease Stage ◽  
Second Line ◽  
Blast Phase ◽  
Line Therapy ◽  
Advanced Phase

Abstract Patients with Chronic Myeloid Leukemia (CML) who develop resistance to imatinib have poor clinical outcomes. The disease stage at the time of imatinib failure is an important prognostic factor for this outcome. Specifically, although patients with advanced-stage CML, particularly those in blast-crisis at the time of imatinib failure, had a high rate of cytogenetic response to second-line tyrosine kinase inhibitors (TKIs), these responses were not durable in most instances. In contrast, patients who remained in chronic-phase (CML-CP) at the time of imatinib failure substantially benefited from second-line TKIs, achieving PFS and OS that appear favorable compared to historical data of patients treated with non-TKI therapeutic modalities. Because the prognosis for those in chronic-phase is significantly better than patients who have progressed to accelerated- or blast-phase, it is important to examine the clinical status of patients at the time of TKI failure. This study examined the clinical status of patients in the START-C trial (CA180-013) at the time of disease progression after imatinib and dasatinib therapy. Progression was defined as: loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR), increasing WBC count, development of accelerated- or blast- phase CML, or death due to any cause. Of 387 participants, 322 (83%) were progression-free at the 2-year follow-up. Of the 65 patients with any criteria for progression as defined above, 46 subjects had progressive disease (loss of MCyR = 14, loss of CHR = 14, increasing WBC counts = 8, development of accelerated-phase CML = 10). The remaining 19 patients died. Thus, only 10 out of 65 (15%) progression events were due to the development of advanced disease and 36 patients (55%) remained in chronic-phase despite a loss or lack of therapeutic response to imatinib and subsequent dasatinib. In summary, 2.6% (10/387) of all patients analyzed transitioned to accelerated-phase CML after first- and second-line therapy. Importantly, development of blast-crisis CML was also not observed in our study population. In a 5-year follow-up of the IRIS trial comparing imatinib to interferon as first-line therapy, a projected 17% of subjects relapsed and 7% developed advanced-phase disease after imatinib. Despite the fact that patients analyzed in our study sequentially failed both imatinib and dasatinib, most remained in chronic-phase after dasatinib failure and are expected to benefit from additional therapeutic options.

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.

Imatinib Plasma Levels and Its Correlation with Response in Chronic-Phase Chronic Myeloid Leukemia: Experience of One Centre.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4284-4284
Author(s):  
J. Valentin Garcia. Gutierrez ◽  
Jesús Odriozola ◽  
Pilar Herrera ◽  
Javier Lopez ◽  
Maria Calbacho ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Plasma Levels ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Plasma Concentrations ◽  
Chronic Phase ◽  
Control Group ◽  
Treatment Optimisation ◽  
Number Of Patients

Abstract Abstract 4284 Introduction Imatinib (IM), 400 mg/d. induces durable responses in chronic myeloid leukaemia (CML) in chronic phase (CP). However, although IM-biodisponibility is fairly good, its plasma levels are variable and can not be predicted. Recently, these plasma concentrations have been related both to the dose being administrated and to the cytogenetic and molecular responses. Thus, Imatinib pharmacokinetics could be an issue towards treatment optimisation in CML patients. Recent studies suggest that therapeutic IM plasma levels should be above 1040 ng/dl. Aims To evaluate the association between IM dose and throughout plasma levels with different clinical outcomes. Results In this study, we looked for an association between plasma concentrations and clinical outcomes in 16/86 CML chronic phase patients who did not achieve optimal responses following the European Leukemia Net guidelines (ELN) (table 1). Patients with optimal responses and treated with the same standard doses were also analysed as a control group. Patients receiving doses above 400 mg showed throughout plasma levels considered as appropriate. In 7 of 16 patients (47.5%) not achieving optimal responses (ELN criteria), plasma levels were below the supposed therapeutic ranges. We have found no evidence for a correlation between clinical risk factors at diagnosis and the measurement of optimal plasma levels. Conclusions IM plasma levels are well correlated with IM dose administrated in the patients studied. In almost 50% of patients who did not achieve optimal responses, IM plasma levels were under the ranges considered therapeutic. Probably these are the patients who may benefit of a dose increase. Obviously, to learn more about the practical value of these measurements a longer follow up with a larger number of patients is needed. Disclosures: No relevant conflicts of interest to declare.

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