Analysis of the Clinical Features and the Prognosis of Acute Lymphoblastic Leukemia with Complex Chromosomal Aberrations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4914-4914
Author(s):  
Xiujin Ye ◽  
Lixia Zhu ◽  
Li Li ◽  
Jie Zhang ◽  
Jingsong He ◽  
...  
Keyword(s):  
Chromosomal Aberrations ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Philadelphia Chromosome ◽  
Survival Outcome ◽  
Allogeneic Bone ◽  
Female Ratio ◽  
Laboratory Features

Abstract Abstract 4914 Background: Acute lympoblastic leukemia (ALL) with complex chromosomal aberrations (CCAs) which patients harboring three or more acquired chromosomal aberrations always have a poor outcome. Philadelphia chromosome–positive (Ph+) ALL is the largest genetically defined subtype in adult ALL with the most unfavorable prognosis. It is necessary to investigate the clinical and laboratory features of ALL patients with CCAs, analyze the distribution of Ph+ in these patients and assess the prognosis. Methods: In a retrospective follow-up study from 2005.1∼2011.6, 38 ALL patients with CCAs were investigated. All cases were diagnosed with morphological,immunological,cytogenetic classification and molecular biology. The karyotypes were interpreted according to the International System for Human Cytogenetic Nomenclature (ISCN). Clinical characteristics, laboratory features, treatment response and prognosis of ALL patients with CCAs were analyzed. Results: The study included 17 Ph+ ALL patients with an age range of 12 to 81 years (mean, 34.5 years) and a male to female ratio of 1:1. Ph+ ALL patients with CCAs were older than Ph- cases (P=0.096). The median survival time was 9.5 months (range, 1–44 months). The complete remission (CR) rate after two cycles of systemic chemotherapy was 53.6% (15/28) and the relapse rate was 53.3% (8/15). Ph+ ALL patients with CCAs showed a lower CR rate than Ph- cases. Eleven patients died during the follow-up period, six of them died within 2 months from the initial ALL diagnosis, and nine patients were failure to achieve CR. Three patients underwent allogeneic bone marrow transplantation (BMT): two of them presented Ph+ relapsed after 2 and 10 months, respectively. Using Kaplan-Meier survival analysis, we found the survival outcome of Ph+ ALL patients with CCAs is inferior to Ph- cases. Conclusion: Treatment outcomes of ALL patients with CCAs receiving chemotherapy or BMT are very poor. Ph+ as an unfavorable parameter influences on the CR rate and survival outcome. It is necessary to accumulate more clinical data to find innovative treatments that can improve the prognosis of this refractory leukemia. Disclosures: No relevant conflicts of interest to declare.

Philadelphia chromosome and terminal transferase-positive acute leukemia: similarity of terminal phase of chronic myelogenous leukemia and de novo acute presentation.

1983 ◽  
Vol 1 (11) ◽  
pp. 669-676 ◽  
Author(s):  
K Jain ◽  
Z Arlin ◽  
R Mertelsmann ◽  
T Gee ◽  
S Kempin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Leukocyte Antigen ◽  
Terminal Transferase

Twenty-eight patients with Philadelphia chromosome (Ph1)--positive and terminal transferase (TdT)--positive acute leukemia (AL) were treated with intensive chemotherapy used for adult acute lymphoblastic leukemia (L-10 and L-10M protocols). Fifteen patients had a documented chronic phase of Ph1-positive chronic myelogenous leukemia preceding the acute transformation (TdT + BLCML) while the remaining 13 patients did not (TdT + Ph1 + AL). An overall complete remission (CR) rate of 71% was obtained with a median survival of 13 months in the responders. Clinical presentation, laboratory data, cytogenetics, response to treatment, and survivals of the two groups of patients are compared. These results appear to be similar, suggesting a common or closely related origin. Since the overall survival of those receiving chemotherapy maintenance is poor, three patients underwent allogeneic bone marrow transplantation (BMT) from histocompatibility leukocyte antigen--matched siblings after they achieved CR. One of them is a long-term survivor (35 + months) with a Ph1-negative bone marrow. New techniques such as BMT should be considered in young patients with a histocompatibility leukocyte antigen--compatible sibling once a CR has been achieved.

scholarly journals Blinatumomab + Ponatinib for Relapsed Ph1-Positive Acute Lymphoblastic Leukemia: The French Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4014-4014 ◽  
Author(s):  
Marie-Anne Couturier ◽  
Xavier Thomas ◽  
Francoise Huguet ◽  
Céline Berthon ◽  
Célestine Simand ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
New Drugs ◽  
Molecular Response ◽  
Complete Molecular Response

Abstract Prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1+ ALL) has been considerably improved since the beginning of the BCR-ABL1 tyrosine kinase inhibitors (TKI) era 20 years ago. However, the prognosis of patients with a refractory/relapsed (including molecular relapse) disease is still very dismal. New drugs or combination of new drugs may improve outcomes of these patients. For example, ponatinib, a 3rd-generation oral TKI, known to have activity against BCR-ABL1 T315I mutations, has shown some efficacy in this context. Similarly, a recent study has reported very encouraging results of the bispecific anti-CD3/CD19 monoclonal antibody blinatumomab as single-agent in refractory/relapsed Ph1+ ALL. Data regarding the efficacy and tolerance of a combination of blinatumomab+ponatinib (blina/pona) are still scarce. This was a retrospective study with the aim to report outcomes of patients receiving a combination of blina/pona for refractory/relapsed Ph1+ ALL in France. Fifteen adults from 8 French centers were identified and data were collected by physicians of each centers, then gathered for the purpose of this study. There were 9 males and 6 females, with a median age of 53 years (range:17-72). All patients, but 2 with blast crisis of chronic myeloid leukemia, had de novo Ph1+ ALL. Four cases had BCR-ABL1 T315I mutation. Patients received the blina/pona combination, either after a first (n=8) or a second (n=7) cytologic relapse. There was no refractory patient in theses series. Previous allograft and autograft has been performed in 7 and 2 patients, respectively. The majority of patients (n=12) had previously received 2 or more lines of TKI. The median time between the first cycle of blina/pona and diagnosis was 14 months (range: 8-40). The median number of blinatumomab cycle (28 mg/day by continuous infusion for 28 days every 6 weeks) administered per patient was 3 (range: 1-6) while ponatinib was concomittantly administered continuously at an initial dose of 45 mg once daily in 11 pts (73%) and 30 mg in 4 pts (27%). Median duration of ponatinib administration was 4 months (range: 1.1-10.9) from first blinatumomab cycle. The toxicity profile was safe: all patients received a complete first cycle without grade 3-4 adverse events. After cycle 1, blinatumomab was stopped in 47% of cases because of neurologic events in 4 and infections in 3; ponatinib was stopped in 33% of cases because of neurologic events in 3, fluid retention in 1 and severe arteriopathy in 1 patient with other vascular disease risk factors. All neurologic events resolved after stopping blinatumomab or ponatinib. The majority of patients were evaluated after one cycle (n=11, after cycle 2 n=3, after cycle 3 n=1). All but one patients (93%) obtained a cytologic complete remission (CR), of whom 12/14 (86%) achieved a complete molecular response. However, 2 patients were documented with CNS relapse at the time of blina/pona evaluation although in bone marrow molecular remission. Both obtained clearance of leukemic blasts after intrathecal infusion of chemotherapy. Then, 5 patients underwent allogeneic transplant (including 2 patients already allotransplanted before blina/pona) and 1 patient received donor lymphocyte infusion. Seven cases pursued maintenance therapy with ponatinib as single agent after stopping blinatumomab. With a median follow-up of 8 months (range: 2.6-30.2) for alive patients, median overall and leukemia-free survivals from first cycle of blina/pona were 8.5 months (range: 1.7-30.2) and 8 months (range: 1.3-30.2), respectively. At last follow-up (July 2018), only 4 relapses had occurred at a median of 3.3 months (range: 1.3-8.3) from first blina/pona cycle and 6 patients had died (3 bacterial infections, 1 fungal infection, 1 secondary cancer and 1 ALL relapse). All alive patients (n=9) but one (cytologic CR but detectable minimal residual disease) are in complete molecular response. Four patients are still under ponatinib medication at last follow-up. The combination of blinatumomab+ponatinib appears effective and tolerable in relapsed Ph1+ALL patients and may replace chemotherapy salvage regimens. The combination should be tested in first-line therapy in the future. Our results have also to be confirmed prospectively on a larger cohort of patients. Disclosures No relevant conflicts of interest to declare.

Does Imatinib Change the Outcome in Philapdelphia Chromosome Positive Acute Lymphoblastic Leukaemia in Adults? Data from the UKALLXII/ECOG2993 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 8-8 ◽  
Author(s):  
Adele K. Fielding ◽  
Susan M. Richards ◽  
Hillard M. Lazarus ◽  
Mark R. Litzow ◽  
Selina M. Luger ◽  
...  
Keyword(s):  
Allogeneic Bone Marrow Transplantation ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
International Study ◽  
Treated Group ◽  
High Dose ◽  
Unrelated Donor ◽  
Allogeneic Bone ◽  
Phase 2

Abstract The UKALLXII/ECOG2993 international study for adults with acute lymphoblastic leukeamia (ALL) included a separate, single-arm study (still open) to evaluate the role of etoposide/TBI conditioned allogeneic bone marrow transplantation (BMT) in patients with Philadelphia chromosome positive (Ph pos) disease. Patients received 2 phases of induction, intensification with high dose methotrexate and BMT using unrelated donor stem cells where a matched sibling was not available. 267 patients with Ph pos ALL were treated from 1993 onwards, in the pre-imatinib era. The study was amended in 2003 to add imatinib 600mg per day following induction and after BMT for 2 years or until relapse. A subsequent amendment at the end of 2005, added imatinib 600mg per day also to phase 2 of induction. 153 patients have now been treated on the imatinib-containing protocol − 89 received imatinib following induction and 64 started imatinib with phase 2 induction. Complete remission (CR) rate at the end of 2 phases of induction was 91% with imatinib started in induction, 81% with imatinib started in consolidation only & 83% in the pre imatinib era. 128 of the 153 patients treated with any imatinib were eligible for BMT. Of the 98 patients with over 6 months follow-up, 57 (58%) actually received BMT. This transplant rate does not differ from the 62% in the pre-imatinib era although the data pertain mostly to those whose imatinib started later during therapy. Overall survival of the imatinib-treated group as a whole is 23% at 3 years, which does not differ from the 26% pre-imatinib rate as shown in the figure. Hence, imatinib started post-induction does not appear to improve survival. Imatinib given with induction may improve the CR rate, but there is insufficient follow up to assess transplant or survival rates. Earlier imatinib may be optimal but overall, our study does not provide evidence yet that imatinib alters the outcome of this disease. Figure Figure Patient characteristics Pre-imatinib (N=267) Post-imatinib (N=153) Gender: Male 150 (56%) 96 (63%) WBC (x 10 ^9/l) (2 unknown): <30 141(53%) 86 (56%) ≥ 30 124 (47%) 67 (44%) Median (range) 26.8 (1.5–438) 21.0 (0.5–491) Age: median (range) 40 (15–60) 42 (16–64) CNS disease (82 unknown) 14 (8%) 4 (3%)

Expression Level Of p-STAT5, c-MYC and IKZF1 By Immunohistochemistry Might Correlate With Adverse Clinic Outcome In Adult B- Lymphoblastic Leukemia (B-ALL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3875-3875
Author(s):  
Jiangchuan Tao ◽  
Bijal D. Shah ◽  
Xiaohui Zhang ◽  
Prerna Rastogi ◽  
Jianguo Tao ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Base Line ◽  
Allogeneic Transplant ◽  
Female Ratio ◽  
Cox Regression Analysis ◽  
Significant Difference ◽  
Jak2 Inhibitors

Abstract Background Molecular and cytogenetic abnormalities characterize the biologic heterogeneity of B-ALL and provide a strong and independent prognostic factor for treatment outcome. Emerging data highlight the role of tyrosine kinase inhibition (TKI) in those with Philadelphia chromosome positive (Ph+) B-ALL. A new high risk subset, so-called Ph-like ALL, has been recognized, comprising 10-15% of pediatric B-ALL. These cases show similar alterations in IKZF1, and are likely driven by alternative kinase rearrangements, including CRLF2, JAK2, ABL1, and others. Increased STAT5 phosphorylation may broadly classify such patients, and, also suggest a benefit with JAK2 inhibitors or TKI’s. Finally, c-MYC has been recognized as a high risk feature for both B- and T-ALL, though it is unclear whether the risk is similar among Ph+ and Ph- patients in the era of TKI-based therapy. Method and Materials A retrospective analysis was performed of a series of patients at Moffitt Cancer Center with B-ALL diagnosed between January 2003 and June 2012. Of them, paraffin embedded blocks from patients who had the first diagnostic bone marrow biopsy performed at MCC with a good biopsy quality (> 1.0 cm in length and tumor load over 70% of marrow cellularity) were selected for performing immunohistochemical (IHC) study. Ten normal bone marrows were also included as antibody base-line control. IHC stains were performed according to institutional standard protocol and modified based on the individually purchased antibody. Expression of pSTAT5, c-MYC, and IKZF1 on lymphoblasts was assessed semiquantitatively based on the expression score calculated with staining strength and multiplied by percentage positivity on tumor cells. Clinical outcomes were correlated to the IHC scores. Hazard ratios were generated using standard cox regression analysis. Patient survival was analyzed with Kaplan-Meier method from the date of diagnosis until death from any cause. Results 29 B-ALL patients, including 15 Ph+ and 14 Ph-, with median age 58years (19 - 72), median white blood cells (WBC) 10.1 k/uL (1.8-200), and male to female ratio of 2:1, were included in the study. 86% received HyperCVAD induction, and 93% of Ph+ patients received TKI therapy, most commonly with Imatinib (86%), and 32% received an allogeneic transplant in first remission. No significant difference in age, WBC, or receipt of allogeneic transplant, time to progression (TTP), or overall survival OS was apparent when comparing Ph+ to Ph- patients. The IHC staining results showed nuclear expression of pSTAT5 to be more frequently present in Ph+ B-ALL than in Ph- B-ALL (73% vs 33%, p = 0.0574), however, no differences in staining were observed with IKZF1 (80% vs 92%, p=0.61) or c-MYC (33% vs 50%, p=0.41). Overexpression of c-MYC was associated with decrease in OS (HR 4.1, 95%CI 1.2-13.9, p=0.02)(Figure 1), with a trend towards decreased TTP (HR 4.3, 95% CI 0.8-22.2, p=0.08). Neither pSTAT5 nor IKZF1 were predictive of OS or TTP when analyzing the entire cohort. Further analysis of the Ph+ group demonstrated a trend for impaired OS among c-MYC positive patients (HR 4.3, 95%CI 0.8-22.2, p=.08). There was no significant impact of c-MYC on TTP, and no impact of pSTAT5 or IKZF1 expression in regards to TTP or OS. 23% Ph+ patients and 7% Ph- patients showed loss of IKZF1 expression (p=0.61). Further analysis of the Ph- group demonstrated a trend towards impaired TTP among those with high expression of pSTAT5 (HR 9.4, 95%CI 0.8-105.8, p=0.07). There was no impact of pSTAT5 on OS, and no impact of IKZF1 or c-MYC expression in regards to TTP or OS. Conclusion Ph+ B-ALL patients more commonly expressed pSTAT5, but this did not influence outcome, perhaps due to TKI exposure. A subset of Ph- patients with high pSTAT5 had a trend towards lower OS in comparison to Ph- and pSTAT5 negative patients (figure 2). This may be a novel group for the study of TKI or JAK2 inhibitors. Expression of c-MYC was associated with impaired OS and a trend towards lower TTP, an effect which was most pronounced in the Ph+ group. Disclosures: No relevant conflicts of interest to declare.

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