Early Response Dynamics Including Minimal Residual Disease (MRD) and Adherence to Risk/MRD-Oriented Therapy Are Major Outcome Determinants in Adult Ph-Negative Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2573-2573
Author(s):  
Renato Bassan ◽  
Orietta Spinelli ◽  
Elena Oldani ◽  
Manuela Tosi ◽  
Barbara Peruta ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Individual Response ◽  
Response Dynamics ◽  
Early Failure ◽  
Term Survival ◽  
Risk Class ◽  
Early Relapse ◽  
Clinical Risk

Abstract Abstract 2573 Introduction In adult Ph- ALL two major risk groups are generally identified on account of patient age, presentation white blood cell (WBC) count, disease immunophenotype and genetics/cytogenetics, with 5-year overall and disease-free survival (OS, DFS) rates of approximately 50% in standard-risk (SR) and 30% in high-risk (HR) patients, respectively. Although the difference is significant, this classification reflects a static risk assessment and does not recognize increasingly important factors such as individual response dynamics (complete remission [CR] vs induction failure or early relapse; MRD course) and risk-oriented treatment decisions with or without stem-cell transplantation (SCT). Aim To evaluate dynamic risk factors in association with adherence to risk-oriented therapy as major determinants of outcome. Patients and Methods OS and DFS rates were reanalyzed according to MRD-related risk definitions and risk-oriented treatment steps in a prospective clinical trial (Bassan et al, Blood 2009;113:4153). Different risk and treatment subsets were identified according to (i) achievement of CR vs early failure due to induction death, early relapse or toxicity precluding the application of MRD/risk-oriented therapy according to trial design, and (ii) adherence to planned MRD/risk-oriented chemotherapy or SCT vs non-adherence unrelated to early failure. Outcome results were compared with those obtained using traditional SR and HR definitions. Results Three-hundred and four patients with Ph- ALL were treated (age range 16–68 years, median 35 years; male 57%), of whom 258 (85%) entered CR and 18 and 28 proved refractory or died early, respectively. Among CR patients, 78 did not complete early consolidation and MRD study (50 relapse, 9 toxicity and 19 very HR to early SCT), while 144 did it and were allocated to MRD-oriented therapy and 36 without a sensitive probe for MRD analysis were allocated according to clinical risk class. Six-year OS and DFS were 44% (n=138) and 43% (n=122) in SR vs 28% (n=166) and 28% (n=136) in HR, respectively (P=0.0009). Instead, OS and DFS results according to early treatment response, completion of MRD study for risk re-stratification and adherence to MRD/risk-oriented therapy identified several distinct prognostic categories, in which survival, largely unrelated to age and clinical risk class, ranged from 0% at 2.8 mos. (early deaths) to 73% at 6–10 years (MRD-negative), as detailed in the table and figure. Conclusion In this study, long-term survival rates were about 50% in SR patients (MRD unknown), 70% in MRD-negative ones receiving chemotherapy, and 40%–50% in all those proceeding to allogeneic SCT because very HR, HR MRD unknown or MRD-positive. Therefore, using a risk/MRD-oriented strategy, the adherence to protocol design concurs to identify the patient subsets with the highest probability of cure. Disclosures: No relevant conflicts of interest to declare.

Short Chemotherapy-Phased Imatinib (IM) Pulses Improve Long-Term Outcome of Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2029-2029
Author(s):  
Renato Bassan ◽  
Giuseppe Rossi ◽  
Enrico Maria Pogliani ◽  
Eros Di Bona ◽  
Emanuele Angelucci ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Observation Interval ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Pcr Analysis ◽  
Remission Induction ◽  
Term Survival ◽  
Multicentric Study ◽  
Long Term Outcome

Abstract Abstract 2029 Poster Board II-6 In a prospective NILG (Northern Italy Leukemia Group) study, short IM pulses were added to chemotherapy in order to 1) reduce incidence of early failures, 2) obtain higher transfer rates to stem cell transplantation (SCT), and 3) improve survival in comparison with a prior patient cohort treated with the same chemotherapy program without IM. IM 600 mg/d was given orally for 7 consecutive dd. with each chemotherapy block, starting from day 15 of induction (IDR/VCR/PDN±ASP) and day –3 of the following consolidation courses (5x IDR/VCR/CY/DEXA; 2x HD-MTX/ARA-C). All pts. received CNS chemoradioprophylaxis and were eligible to allogeneic SCT, or alternatively to HD therapy with autologous SCT and long-term maintenance with 6MP/MTX and intermittent IM. Between April '00 and November '08, 100 out of 404 pts. registered in NILG study 09/00 had Ph+ ALL (Ph chromosome and/or BCR-ABL rearrangement). M/F ratio was 1.17 and median age 46 years (range 19-66). 35 pts. constituted the control cohort (IM-) while, starting December '02, 59 pts. were included in the modified protocol (IM+), and 6 were excluded from analysis because treated on a continuous IM schedule. Of 59 IM+ pts., 53 received IM during induction/consolidation as planned and 6 during consolidation only (included in IM- group for remission induction analysis). Outcome to induction therapy of IM+ vs. IM- group was: CR 49/53 (92%) vs. 33/41 (80%), NR 2 (3.7%) vs. 5 (12%), ED 2 (3.7%) vs. 3 (7%) (P=NS). With a median observation interval from diagnosis of 5 years (range 0.6-9.2 years), 21 IM+ vs. 6 IM- pts. are alive in remission (CR1 pts.: 43% vs. 18%, P=0.02), and both OS (Figure) and DFS (0.39 vs. 0.21, P=0.044) rates at 5 years are significantly improved in IM+ group, especially when IM was administered from the induction cycle. The ability to perform a SCT increased from 53%(n=15: 11 allogeneic, 4 autologous) to 68%(n=37: 22 allogeneic, 5 autologous), partly owing to lower incidence of early relapse (26% vs. 56% at 1 year, P=0.005). SCT-related mortality was not different (P=0.58) and postgraft survival probability at 5 years was 0.45 overall, again with no difference related to SCT source or IM. Use of IM was not associated with greater reduction of BCR-ABL transcripts: by PCR analysis of BM samples taken at weeks 10, 16 and 22 in pretransplantation pts., a major response (absent/<10-4 PCR signals) was documented in 13/27 (48%) determinations from 13 evaluable IM- pts. vs. 16/49 (33%) from 25 IM+ pts.(P=NS). The short IM schedule used in this multicentric study demonstrated synergy with chemotherapy, resulting for the first time in NILG studies in improved long-term survival for this adverse subset. Problems of SCT-related toxicity and postgraft relapse need to be addressed further, to confirm curability of Ph+ ALL in a greater proportion of cases. Disclosures: No relevant conflicts of interest to declare.

Prospective Exploratory Phase II Studies of A Rotating Regime of Nilotinib and Imatinib for Frontline Treatment of Philadelphia POSITIVE (Ph+) Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4972-4972 ◽  
Author(s):  
Giuseppe Saglio ◽  
Elisabetta Abruzzese ◽  
Giuliana Alimena ◽  
Monica Bocchia ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Chronic Phase ◽  
Disease Free Survival ◽  
Cytogenetic Response ◽  
Substantial Contribution ◽  
Free Survival ◽  
Complete Cytogenetic Response ◽  
Phase Ii Studies

Abstract Abstract 4972 The introduction of Imatinib (IM) and subsequently of Dasatinib and Nilotinib (NI) has made a substantial contribution to the therapy of all Ph+ leukemias. With IM alone, a complete cytogenetic response (CCgR) is achieved in about 75% of CML patients who are treated frontline, but about 15% of them loose the response in the first 3 years. A complete hematologic response (CHR) is achieved in almost all ALL patients, but about 50% of them relapse with BCR-ABL mutated clones within one year. With NI alone, a complete cytogenetic response is obtained in about 40% of Ph+ leukemia patients who are resistant to IM, and in more than 90% of early chronic phase, previously untreated, CML patients. NI is a derivative of IM, but has different pharmacokinetic and pharmacodynamic properties, and inhibits most of BCR-ABL mutants which are resistant to IM. Moreover, the toxicity profile of the two drugs is different. The administration of two tyrosine kinase inhibitors (TKIs) may increase the strength of initial therapy, so increasing the rate and the solidity of the response, and reducing the rate of failures. To test the feasibility and the validity of this hypothesis the GIMEMA CML WP designed a rotating regime of NI and IM to be tested front-line in patients with Ph+ CML, and in the patients with Ph+ ALL who are more than 60 years old. The first course is with NI 400 mg twice daily. The second course is with IM 400 mg once daily. A course lasts 3 months in CML, and 6 weeks in ALL. Treatment duration (study core) is 2 years in CML (8 courses), and 36 weeks in ALL (6 courses). The primary endpoint is event-free survival at 24 months in CML, and disease-free survival at 6 months in ALL. CML patients enrollment (n = 120) has been completed between February and August 2009. The results of the first interim analysis at 3 and 6 months will be presented. The enrollment of ALL patients will begin September 2009. Disclosures No relevant conflicts of interest to declare.

Chemoimmunotherapy with a Modified Hyper-CVAD and Rituximab Regimen Improves Outcome for Patients with De Novo Philadelphia Negative Precursor B-Cell Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 836-836
Author(s):  
Deborah A. Thomas ◽  
Hagop M. Kantarjian ◽  
Stefan Faderl ◽  
William G. Wierda ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
B Cell ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
High Dose ◽  
Induction Phase ◽  
Liposomal Daunorubicin ◽  
Cd20 Expression

Abstract Abstract 836 The hyper-CVAD regimen is an effective frontline program for de novo adult ALL and LL [Kantarjian, JCO 18:547, 2000; Kantarjian, Cancer 101:2788, 2004, Thomas, Blood 104:1624, 2004]. Intensive chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternates with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone). Historical CR rate was 92% with 3-year disease-free survival (DFS) rate of 38%. The regimen was modified in 1999. Induction chemotherapy was given in a protective environment owing to higher mortality in patients (pts) aged 60 years or older (17% vs 3%). Course 2 of liposomal daunorubicin and cytarabine was incorporated owing to reports suggesting benefit of early anthracycline intensification. Rituximab 375 mg/m2 (days 1 & 11 of hyper-CVAD, days 1 & 8 of methotrexate-cytarabine) was given if CD20 expression was 20% or greater due to its association with disease recurrence [Thomas, Blood 113:6330, 2009]. The maintenance phase was extended to 30 months with additional intensifications owing to late relapses after completion of POMP therapy. Newly diagnosed or primary refractory (1 course only) pts with ALL (n=204) or LL (n=27) were treated on the two sequential studies. Burkitt-type leukemia/lymphoma (BLL) and Philadelphia positive ALL were treated on alternative protocols. From May 2000 to December 2001, 69 pts were treated with modified hyper-CVAD with anthracycline intensification (9 induction-consolidation courses). Course 2 was then eliminated from the regimen (8 courses), with an additional 162 pts treated to date (pts age 30 years or less are now treated with augmented BFM). Median age was 43 yrs (range, 15–83). CD20 expression was noted in 49%. Overall CR rate of the evaluable group (n=225) was 93%; 7 pts achieved PR (LL with residual disease), five failed to respond, and 4 died during the induction phase. Three-yr CRD and OS rates were 70% and 62%, respectively after a median follow-up of 50 months (range, 2–106+). In the younger CD20 positive precursor B-cell ALL subset (n=99), rituximab improved outcome compared to historical experience with hyper-CVAD alone (n=127), with 3-yr CRD rates (75% vs 45%, p<.001) and OS rates (65% vs 38%, p<.001) approaching those of their CD20 negative counterparts. In contrast to the Burkitt experience, rituximab was not beneficial for the elderly subgroup (OS rates 28% vs 34%, p NS). Anthracycline intensification did not improve outcome. The addition of rituximab to the hyper-CVAD regimen appears to benefit the younger pts (age less than 60 yrs) with CD20 positive precursor B-cell ALL. Incorporation of rituximab and other monoclonal antibodies (e.g., ofatumumab, epratuzumab) into frontline chemotherapy regimens for ALL should be investigated systematically. Disclosures: No relevant conflicts of interest to declare.

Macrophages and Mast Cells Infiltration Are Biomarkers of Primary Refractory Hodgkin's Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3881-3881
Author(s):  
Deau Benedicte ◽  
Bachy Emmanuel ◽  
Ribrag Vincent ◽  
Delarue Richard ◽  
Rubio Marie-Therese ◽  
...  
Keyword(s):  
Mast Cells ◽  
Hodgkin’S Lymphoma ◽  
Conflicts Of Interest ◽  
Prognostic Score ◽  
Hodgkin's Lymphoma ◽  
Control Group ◽  
Tumor Associated Macrophages ◽  
Term Survival ◽  
Early Relapse ◽  
Hodgkin's Lymphomas

Abstract Abstract 3881 Classical Hodgkin's lymphoma is a highly curable lymphoma and about 80% of patients can be cured with modern treatment strategies. In spite of great clinical progress, a significant minority of classical Hodgkin's lymphoma experiences treatment failure after primary chemotherapy including a first line of anthracyclin-based regimen. Patients with refractory Hodgkin's lymphoma represent 5 to 10% of classical Hodgkin's Lymphoma. Many of these patients have a poor overall survival estimated at 25% at 5 years. A better biological characterization of such primary refractory patients might allow the use of early therapeutic intervention including targeted therapy. It remains, however, a challenge to identify patients whose disease will not be eradicated by standard therapy. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not yet been established to improve the International Prognostic Score. For these reasons, reliable biomarkers for predicting long term survival at diagnosis are needed for such patients. Steidl et al. (Nejm,2010) recently reported the prognostic value of tumor-associated macrophages in patients with classical Hodgkin's lymphoma, showing that higher infiltration is associated with a shortened survival. The value of tumor-associated macrophages in primary refractory Hodgkin's lymphomas has not been specifically assessed. In a retrospective study (Canioni et al., Plos one 2009), we previously evaluated 59 patients (18 with primary refractory or early relapse disease and 41 responders) collected from 1997 to 2004 in two hematology centres (Necker Hospital and Gustave Roussy Institute, Paris France) for c-kit expression by immunohistochemical analysis as a marker of mast cell infiltration and correlated the results with the response to treatment. All available poor prognosis patients were first identified (18 patients with primary refractory disease or early relapse (< 1year)) and the control group (47 responders) was randomly selected. Patients received conventional chemotherapy-based treatments [(MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), ABVD (doxorubicine, bleomycine, vinblastine, and dacarbazine) or the combination of both or BEACOPP (bleomycine, etoposide, doxorubicine, cyclophosphamide, vincristine, procarbazine, prednisone)] and radiotherapy in stages I and II. Most patients presented a nodular sclerosis subtype of Hodgkin's lymphoma regardless whether they were refractory (17/18cases, 94.5%) or responders (37/41cases, 90%). In this cohort, 44 (75%) patients had a localized stage, whereas 19 (25%) had a disseminated disease. The results showed that refractory Hodgkin's lymphoma were associated with an excess of mast cells infiltration in the tumor cells microenvironment. The number of mast cells stained was significantly higher in refractory Hodgkin's lymphoma (c-kit+ mast cells > 6 per field) than in responders (c-kit+ mast cells ≤ 6) (p=0.001 and 0.0194 in univariate and multivariate analysis, respectively). In this cohort of patients, using CD68 staining we also found a statistically significant higher proportion of tumor-associated macrophages in refractory Hodgkin's lymphoma as compared to responders in univariate and multivariate analyses (p=0.0048 and p=0.0041, respectively). Therefore, we confirmed a strong correlation between the number of CD68 positive macrophages in the tumor stroma and clinical outcome. The use of such markers (CD68 and c-kit) in combination with well-established clinical risk factors could improve on the predictive value of a single biomarker used alone. Therefore, in addition to mast cells, macrophages are also important players in refractory Hodgkin's lymphoma that may confer drug resistance to Hodgkin Reed Sternberg cells. Taken together, these data strongly suggest that microenvironment should be targeted in Hodgkin's lymphomas. In this regard, the use of kinase inhibitors that target both c-kit and M-CSF receptors could restore chemotherapy sensitivity in refractory Hodgkin's lymphoma and should be evaluated in clinical trials. Disclosures: No relevant conflicts of interest to declare.

Outcome of Second Allogeneic SCT Following Relapse of Hematological Malignancies After a First Allogeneic SCT

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3056-3056
Author(s):  
Guillermo Orti ◽  
Jaime Sanz ◽  
Arancha Bermudez ◽  
Dolores Caballero ◽  
Carmen Martinez ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Clinical Decision Making ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Disease Status ◽  
Late Relapse ◽  
Disease Relapse ◽  
Term Survival ◽  
Early Relapse ◽  
The Impact

Abstract Abstract 3056 Background: Disease relapse is the most frequent cause of treatment failure following allogeneic haematopoietic cell transplantation (allo-HCT), and carries a very poor prognosis. A second allo-HCT may be the only curative option for the majority of these patients. Patient and transplant factors that may associate with the outcome of a second allo-HCT are required for clinical-decision making in such high-risk patients. Aims and Methods: We performed a retrospective analysis of patients receiving a second allo-HCT for disease relapse after a prior allo-HCT reported by GETH centres. Our aim is to analyze our experience in this setting, and to identify factors associated with patient outcome. Results: We present data on 189 patients who underwent a second allo-HCT for disease relapse in Spain up to December 2010 (median year 2004), with a median follow-up for survivors of 54 months (3–224): median age 35 years (range 4–69); 113 male (60%); initial diagnosis AML 77, ALL 45, MDS/MPD 28, CML 23, lymphoprolipherative disorder 12, and others 4. Seventy-five (40%) received myeloablative conditioning. Donors for second allo-HCT were related in 158 cases (84%), and in 33 cases (17%) were new donors different from the donors in the previous allo-HCT. Only 23 cases (12%) had T-cell depletion. Median time from the first to the second allo-HCT was 19 months (1–151). The cumulative incidence of non-relapse mortality was 37%. Median overall survival (OS) was 297 days, with an OS at 1, 3 and 5 years of 39%, 28% and 25%, respectively. Type of donor (related versus unrelated and new donor versus same donor) and type of conditioning (myeloablative versus non-myeloablative) had no association with patient outcome. However, OS was significantly poorer in patients who underwent second allo-HCT in active relapse or progression than in those with low disease burden (complete response, good partial response, or chronic phase; 29% vs 52% at 1 year, 21% vs 39% at 3 years, 17% vs 35% at 3 years, respectively; p=0.001). Also, patients with early relapse after the first allo-HCT who underwent a second allo-HCT <1 year after first HCT also had a poorer OS than those with a later relapse and second allo-HCT (13% vs 53% at 1 year, 7% vs 40% at 3 years, and 5% vs 35% at 5 years, respectively; p<0.001). The impact of these two clinical factors in the outcome remained independent in the multivariate analysis (disease status at second allo-HCT: HR 1.8, 95% CI 1.2–2.6, p=0.002; time to second allo-HCT: HR 3.2, 95% CI 2.2–4.6, p<0.001). Time to second allo-HCT and disease status also have an independent association with the probability of progression free survival in this series (p <0.001 and p =0.001, respectively). In fact, while patients with late relapse who received a second allo-HCT in good response had a very encouraging probability of OS of 49% at 5 years, patients who had an early relapse and required a second allo-HCT in less than 1 year from their first allo-HCT and also had active disease at the time of second allo-HCT had very poor OS of only 8% at 1 year and no one survived beyond 3 years after the second allo-HCT. Conclusions: 25% of patients who relapse after an allo-HCT can achieve long-term survival of 5 or more years following a second allo-HCT. Donor type does not appear to influence the outcome. On the contrary, our data suggest that disease status at HCT and time to relapse between first and second HCT are two significant prognostic factors with independent impact on patient outcome. The indication of a second allo-HCT in this context should be thoroughly discussed for individual cases, in particular for patients with early relapse and refractory disease arriving to second allo-HCT, for whom the probability of prolonged survival is extremely low. Disclosures: No relevant conflicts of interest to declare.

Control of RAG Cleavage Activity Contributes to Maintaining Genome Stability During V(D)J Recombination

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2416-2416
Author(s):  
Susannah Hewitt ◽  
Suzzette Arnal ◽  
Ludovic Deriano ◽  
David Roth ◽  
Jane Skok
Keyword(s):  
B Cells ◽  
Genome Stability ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Double Strand Breaks ◽  
Chromosomal Translocations ◽  
Dna Double Strand Breaks ◽  
Term Survival ◽  
Strand Breaks ◽  
Cure Rates

Abstract Abstract 2416 Acute lymphoblastic leukemia (ALL) results from malignancy of lymphoid progenitor cells and affects both adults and children. It is the most common childhood cancer and despite advances in treatment that now result in above 80% cure rates for children, considerable problems remain with current therapies. These include low cure rates in children with high-risk ALL, the complexity and toxic effects of current treatments and the stubbornly poor prognosis of adults with ALL (with a less than 40% long-term survival rate). ALL can be initiated by errors in V(D)J recombination, a process which creates multiple combinations of receptor genes in B and T lymphocytes in order to target foreign pathogens. During recombination, DNA double strand breaks are introduced at the borders of two selected gene segments and repair creates a new gene combination. Chromosomal translocations can occur both by mis-targeting of the RAG recombinase proteins at cryptic recombination signal sequences, as well as illegitimate repair with a DNA break generated by alternative cellular processes. Our work has unveiled a remarkable and previously unknown control step which acts during V(D)J recombination to protect genome stability. We demonstrated that the key DNA damage response factor and serine/threonine kinase ATM (ataxia telangiectasia mutated), prevents aberrant cleavage during V(D)J recombination. In wild-type cells only one of the two homologous Ig alleles is normally cleaved at a time, whereas in ATM deficient cells both Ig alleles can be cleaved simultaneously and chromosomal aberrations are detected on two Ig alleles (Hewitt et al., Nature Immunology 2009). Our recent work has been directed at understanding how ATM and the RAG recombinase (RAG1 and RAG2 proteins) cooperate to implement allelic control of V(D)J recombination. We hypothesized that ATM may act to control RAG cleavage, either directly or indirectly. To test this, we investigated developing B cells from coreRAG1 or coreRAG2 mice; these are the shortest active forms of the proteins but lack regulatory domains. We assessed mono- versus biallelic cleavage using γH2AX to indicate repair foci and as a read-out for DNA double strand breaks. In pre-B cells from coreRAG1 mice, γH2AX foci were predominantly colocalized with only one Igk allele per cell, which indicates monoallelic cleavage. In contrast, biallelic colocalization was highly significant in coreRAG2 expressing pre-B cells. We have analyzed RAG2 mutants to precisely identify the protein motifs that regulate cleavage. These were introduced into Rag2-deficient pre-B cell lines by retroviral infection. Expression of a coreRAG2 construct in these cells recapitulated the biallelic cleavage seen in ex-vivo isolated pre-B cells. We found that mutation of putative serine/threonine phosphorylation motifs also resulted in significant biallelic colocalization of γH2AX with Igk alleles. This suggests that RAG2 performs a similar function to ATM in restricting simultaneous RAG cleavage on the antigen receptor loci and may indeed cooperate with serine/threonine kinases. These data provide a mechanistic basis for the similarities in chromosomal abnormalities between Atm–/– and coreRag2/p53–/– lymphomas and will contribute to our understanding of why recurrent chromosomal translocations and lymphoid cancers arise in ATM-deficient mice and humans. Disclosures: No relevant conflicts of interest to declare.

Second Malignancies After Treatment of AIDS-Related Non-Hodgking's Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4943-4943
Author(s):  
Jose Tomas Navarro ◽  
Maria Joao Baptista ◽  
Mireia Morgades ◽  
Cristina Tural ◽  
Evarist Feliu ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Conflicts Of Interest ◽  
Intravenous Drug User ◽  
Disease Free Survival ◽  
B Cell Lymphoma ◽  
Categorical Variables ◽  
Second Malignancy ◽  
Second Malignancies ◽  
Term Survival ◽  
Second Neoplasms

Abstract Abstract 4943 Background: The use of highly active antiretroviral therapy (HAART) has dramatically improved the prognosis of AIDS-related Non-Hodgkin lymphoma (NHL), causing a remarkable increase in patients' long-term survival. On the other hand, with the introduction of HAART, the incidence of non-AIDS-related malignancies is increasing among patients with HIV infection. The incidence of second neoplasms after treatment of aggressive NHL have been reported to be higher than in the general population. Nevertheless, there is scarce information regarding second malignancies occurring in HIV-infected patients after NHL treatment. We sought for second neoplasms among patients treated of AIDS-related NHL, hence suffering from 2 conditions which may predispose them to develop malignancies: therapy for lymphoma and HIV infection. Methods: We conducted a retrospective study of patient data on AIDS-related NHL individuals diagnosed between 1989 and 2010 in our institution. Demographic, HIV infection, and lymphoma data on each case were collected. Two groups were further considered: patients who did not take HAART at all, and those who started HAART at any stage of their HIV infection. Continuous and categorical variables are presented using descriptive statistics. Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. P-values of less than 0.05 were considered statistically significant. Results: Out of a series of 146 patients diagnosed with AIDS-related NHL, 138 patients were eligible for the study with a median follow-up of 8.24 years: 70 patients belonged to the no-HAART group, and 68 to the HAART group. Most interesting data regarding both groups are listed in table 1. Briefly, patients in the HAART group were older at the time of lymphoma diagnosis than those who did not receive it (p=0.024); in addition, there were more male patients in the no-HAART group (p=0.011). These differences show the demographic changes among HIV-infected patients in the HAART era. Furthermore, a higher number of complete responses (CR) to lymphoma treatment was observed in the HAART group (p<0.001). Overall survival (OS) and disease free survival (DFS) were significantly longer for patients who took HAART (p<0.001 and p<0.001 respectively). Four out of the 40 patients at risk (10%), developed a second malignancy in the HAART group, and none in the no-HAART one. However, no statistically significant differences were found, probably due to the low number of cases. The most important features of the 4 patients with a second malignancy are listed in table 2. All 4 patients were diagnosed with diffuse large B-cell lymphoma (DLBCL), were treated with CHOP, and had a prior diagnosis of AIDS. Two of the 4 were on HAART at lymphoma diagnosis (one of them in both virological and immunological response). The patient with hepatocarcinoma was HCV positive. As shown in table 1, three of the patients had responded to HAART when the second neoplasm (carcinoma) was diagnosed; and the reminder, who did not respond to HAART, developed a Kaposi sarcoma. All four patients died because of neoplasm progression. Conclusions: As expected, a higher frequence of second neoplasms was observed after treatment of AIDS-related NHL among patients who receive HAART. Second malignancies were non-HIV related neoplasms in patients with response to HAART. Abbreviations: CT, chemotherapy; RT, radiotherapy; IVDU: intravenous drug user. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Is Initial Dasatinib-Blinatumomab Therapy for Ph-Positive ALL in Adults Cost Effective?

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4962-4962
Author(s):  
Jacob D. Bitran ◽  
Edward Nabrinsky ◽  
Shams Bufalino ◽  
Phillip Knouse ◽  
Angel G. Galvez
Keyword(s):  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Cost Effective ◽  
Free Survival ◽  
New Therapy ◽  
The Cost ◽  
Disease Free ◽  
Yearly Cost

Abstract Adult, Philadelphia chromosome-positive, Acute Lymphoblastic Leukemia (Ph-positive ALL) had a poor prognosis, but with the use of an initial BCR/ABL tyrosine kinase inhibitor such as Dasatinib in conjunction with chemotherapy such as hyper-CVAD, the projected 24 month disease free survival is 64%. More recently Foa et al. on behalf of the GIMEMA investigators published a phase II trial of Dasatinib and Blinatumomab as initial therapy for adults with ALL. The complete remission rate was 98%, and the projected disease-free survival at 24 months is 88%. We wished to analyze the incremental cost-effectiveness ratio (ICER) of the Dasatinib and Blinatumomab therapy as compared to Dasatinib and hyper-CVAD. The comparison is based on retail costs of chemotherapy for Dasatinib, Blinatumomab and hyperCVAD and excluded hospital and outpatient charges. The cost of hyperCVAD is based on treatment of a person with a BSA I.8m2. The retail cost of therapy is shown below. Drug Dose Cost Dasatinib 100 mg $505.67 Blinatumomab 1 mg $126.81 Cyclophosphamide 1,000 mg $231.00 Mesna 1,000 mg $42.89 Vincristine 2 mg $18.52 Dexamethasone 40 mg $4.12 Cytarabine 100 mg $22.88 Leucovorin 25 mg $7.48 The ICER formula is the cost of new therapy minus (-) the cost of standard therapy/quality of adjusted life new therapy - the quality of adjusted life standard (QALY). The yearly cost of Hyper-CVAD and Dasatinib is $147,288.48 per QALY, whereas, the yearly cost of Dasatinib-Blinatumomab is $187,940.46 per QALY. The difference is $42,451.98 which is less than the 50,000-threshold using cost-effective analysis. In conclusion, the combination of Dasatinib-Blinatumomab appears to be cost effective. Disclosures No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) for Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3377-3377
Author(s):  
Michael Burke ◽  
Barb Trotz ◽  
Qing Cao ◽  
Brenda Weigel ◽  
Ashish Kumar ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
University Of Minnesota ◽  
Transplant Outcomes ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 3377 Poster Board III-265 Introduction: Allo-HCT with best available donor for children with Philadelphia positive (Ph+) ALL has previously been considered standard practice. Since the introduction of imatinib into the treatment of this disease, the role of allo-HCT is more uncertain. Patients and Methods: We investigated the impact of remission status, graft source, and imatinib use on transplant outcomes for thirty-seven children with Ph+ ALL who received an allo-HCT at the University of Minnesota between 1990 and 2006. The median age at HCT was 7.47 (range; 1.4 -16.4) years. Thirteen patients received imatinib therapy pre and/or post-HCT (imatinib group) and 24 patients, received either no imatinib (n=23) or only after post-HCT relapse (n=1) (non-imatinib group). Results: There was no difference in disease-free survival (DFS) or relapse between the imatinib and non-imatinib groups at 3 years (62% / 15% vs. 53% / 26%; p=0.99; 0.81, respectively). There was no significant difference in transplant outcomes between matched related donor or unrelated donor (umbilical cord blood or matched unrelated marrow) recipients whereas patients receiving allo-HCT in first remission (CR1) had superior DFS and less relapse compared to patients transplanted in ≥CR2 (71% / 16% vs. 29% / 36%; p=0.01; p=0.05). Conclusions: Based on this retrospective analysis at a single institution, the use of imatinib either pre and/or post-transplant does not appear to significantly impact outcomes for children with Ph+ ALL and allo-HCT with the best available donor should be encouraged in CR1. Disclosures: No relevant conflicts of interest to declare.

Thirty Percent Long Term Survival In Children with Acute Leukemia and Complications Requiring Mechanical Ventilation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3243-3243
Author(s):  
Daniel Steinbach ◽  
Bernhard Wilhelm ◽  
Hans-Rudolf Kiermaier ◽  
Ursula Creutzig ◽  
Martin Schrappe ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Intensive Care ◽  
Acute Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Serious Adverse Events ◽  
Term Survival ◽  
Long Term Survival ◽  
Cardiac Resuscitation

Abstract Abstract 3243 Objective: Previous reports indicated that short term prognosis for patients with malignant diseases and serious adverse events requiring mechanical ventilation (SAEV) is not dismal any more. The purpose of this study was to determine whether patients who survive such complications can also achieve long term cure from leukemia. It might influence end-of-live decisions on the intensive care unit if patients with an SEAV only survive intensive care to succumb to relapse. Patients and Methods: We report the outcome of children with SAEV treated in the multicenter studies ALL-BFM 95 and AML-BFM 98. Data from 1182 patients with acute lymphoblastic leukemia (ALL) and 332 patients with acute myeloid leukemia (AML) were analyzed. 88 patients (51 ALL; 37 AML) developed an SAEV. Results: The prognosis was almost identical in ALL and AML (50% survival of SAEV; 30% overall survival after 5 years). This was independent from the time between diagnosis of leukemia and SAEV. Even children who required hemodialysis (n=14) or cardiac resuscitation (n=16) achieved 20% long term survival but no patient survived (n=16) who fulfilled more than 3 out of 6 identified risk factors: age≥10 years, high risk leukemia, C-reactive Protein≥150mg/l, administration of inotropic infusion, cardiac resuscitation, and hemodialysis. Conclusions: To our knowledge, this is the first report about cure rates in a malignant disease after successful treatment of SAEV. Our results show that intensive care medicine contributes to short and long term survival of children with leukemia. Sixty percent of all children with acute leukemia who survive an SAEV achieve long term cure. However, we could also identify risk features that still indicate a devastating prognosis. Disclosures: No relevant conflicts of interest to declare.

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