A Comparison of Two Induction Regimens for Older Patients with Acute Lymphoblastic Leukemia: Daunorubicin, Vincristine and Prednisone (DVP) is Worth Considering

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3252-3252
Author(s):  
Daniel Landsburg ◽  
David Porter ◽  
Edward Stadtmauer ◽  
Alison Loren ◽  
Donald Tsai ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Older Patients ◽  
Lymphoblastic Leukemia ◽  
Complete Response ◽  
High Dose ◽  
Treatment Groups ◽  
Social Security Death Index

Abstract Abstract 3252 Background: The prognosis for older patients with newly-diagnosed acute lymphoblastic leukemia (ALL) is generally poor, although a limited number of studies suggest that these patients can experience favorable outcomes when treated with standard intensive chemotherapy. However, a comparative analysis of curative regimens has not been performed to date. Here, we describe outcomes in patients diagnosed with ALL at age ≥60 who received induction at our institution with either hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine (hyperCVAD) or daunorubicin, vincristine and prednisone (DVP). Methods: Of the 44 patients diagnosed with ALL at age ≥60 who were treated at the University of Pennsylvania between July 2003 and June 2009, 38 received either hyperCVAD (n=24) or DVP (n=14). Induction regimens were chosen at the discretion of the treating physician. Patients in the hyperCVAD group received a median of 6 (range 1–8) cycles. Patients in the DVP group received a full course of induction therapy following the regimen used in the ECOG 2993/UKALL XII protocol with a majority receiving second induction, intensification and consolidation therapy. L-asparaginase was omitted from DVP therapy for all but 2 patients. Assessment for response or relapse was performed primarily via bone marrow biopsy as clinically indicated. If lost to follow-up, patients with previously documented remission were considered to remain in remission through the time of their last normal complete blood count. All deaths were confirmed through the Social Security Death Index. Categorical data was analyzed via the Fisher's exact test and survival times were calculated via Kaplan-Meier plots. Results: Table 1 reports baseline characteristics at diagnosis for patients in the hyperCVAD and DVP groups. Tables 2 and 3 report the rates of complete response (CR) and relapse as well as median progression free survival (PFS) and median overall survival (OS) for the two treatment groups. The median length of follow-up was 12.5 months for the hyperCVAD group (range 3–70) and 24 months for the DVP group (range 4–136). Five-year survival was 4% for hyperCVAD patients and 36% for DVP patients (p=0.019). No deaths occurred within the initial 2 months of treatment in either group. Maintenance chemotherapy was received by 50% of hyperCVAD patients and 70% of DVP patients. Of the Ph(+) patients in who received hyperCVAD, 75% received a tyrosine kinase inhibitor (TKI) with induction therapy and 50% with maintenance therapy. Of the Ph(+) patients in who received DVP, 29% received a TKI with induction therapy and 83% with maintenance therapy. All Ph(+) patients who experienced OS greater than the median OS for Ph(+) patients within their respective treatment groups received a TKI. These results did not achieve statistical significance unless otherwise noted. Conclusions: Older patients diagnosed with ALL can enjoy prolonged survival when treated with intensive induction regimens. While this has been previously described in patients receiving hyperCVAD, our analysis indicates that patients diagnosed with ALL at age ≥60 treated with DVP may experience longer OS compared to those treated with hyperCVAD despite an apparent lower rate of complete response and similar rate of relapse. Additionally, Ph(+) patients within this population may experience similar or better outcomes than Ph(-) patients when treated with either regimen, possibly related to the use of TKIs. Prospective trials are warranted to more rigorously evaluate these induction therapies in the older ALL population. Disclosures: No relevant conflicts of interest to declare.

Receipt of Maintenance Therapy Is Most Predictive of Survival in Older Acute Lymphoblastic Leukemia Patients Treated with Intensive Induction Chemotherapy Regimens.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2600-2600
Author(s):  
Daniel J. Landsburg ◽  
Edward A. Stadtmauer ◽  
Alison W. Loren ◽  
Steven C. Goldstein ◽  
Noelle V. Frey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Small Sample ◽  
Hazard Ratio ◽  
High Dose ◽  
Cox Regression Analysis

Abstract Abstract 2600 Background: Older patients diagnosed with acute lymphoblastic leukemia (ALL) receiving intensive induction therapy often suffer from poor outcomes due to therapy-related toxicity and high rates of relapse. We previously reported that patients age ≥60 diagnosed with ALL and treated at our institution with either hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine (hyperCVAD) or daunorubicin, vincristine and prednisone (DVP) induction therapies achieved comparable rates of survival. Now with longer follow-up and further analysis, we describe additional outcomes and factors predictive of survival in this patient population. Methods: Thirty-seven patients diagnosed with ALL at age ≥60 and treated at the University of Pennsylvania between July 2003 and June 2011 who received induction therapy with either hyperCVAD (≥1 A+B cycle) or DVP (phase I+II) were analyzed. HyperCVAD was administered as first described at the MD Anderson Cancer Center and DVP per the ECOG 2993/UKALL XII protocol. Therapy adjustments and bone marrow biopsy to confirm remission were performed at the discretion of the treating physician. Almost all Philadelphia chromosome (Ph) positive patients received a tyrosine kinase inhibitor. Event-free survival (EFS) was defined as the time from diagnosis to either relapse or death from any other cause. Results: Table 1 describes baseline characteristics. Table 2 describes outcomes. If achieved, morphologic remission was recognized upon the first bone marrow assessment performed while on therapy, which occurred after a median of 4 (2 A+B) cycles of hyperCVAD and by completion of phase II induction of DVP. EFS and overall survival (OS) trended in favor of DVP. HyperCVAD patients were more likely to complete intensive therapy but less likely to receive maintenance therapy, and more likely to relapse with the majority of relapses occurring off active treatment. Primary reasons for not starting or stopping maintenance therapy were infections and cytopenias. Relapsed disease was the most frequent cause of death. Table 3 describes univariate Cox regression analysis. Receipt of maintenance therapy demonstrated the strongest association with survival (p=0.0001, hazard ratio 0.06 for EFS; p=0.0002, hazard ratio 0.05 for OS). Valid multivariate analysis could not be performed due to small sample size. Conclusions: In older ALL patients treated with aggressive induction therapies and achieving remission, receipt of maintenance therapy appears to be most predictive of EFS and OS. Outcomes in the DVP and hyperCVAD groups were similar although a trend towards prolonged survival in the DVP group was seen, which may be explained by a lower rate of relapse due to a higher likelihood of remaining on therapy over time. Our findings suggest that these patients may benefit from attenuated courses of intensive initial therapy in order to avoid developing toxicities that may prohibit tolerance of prolonged maintenance therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals First Results of an Open Label Phase II Study to Evaluate the Efficacy and Safety of Inotuzumab Ozogamicin for Induction Therapy Followed By a Conventional Chemotherapy Based Consolidation and Maintenance Therapy in Patients Aged 56 Years and Older with Acute Lymphoblastic Leukemia (INITIAL-1 trial)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-13
Author(s):  
Matthias Stelljes ◽  
Simon Raffel ◽  
Ralph Wäsch ◽  
Sebastian Scholl ◽  
Mustafa Kondakci ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Induction Therapy ◽  
Older Patients ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Intrathecal Injection ◽  
Open Label ◽  
Inotuzumab Ozogamicin ◽  
Induction Cycle

Introduction: Acute lymphoblastic leukemia (ALL) represents around 5% of all newly diagnosed leukemia in patients between 55 and 70 years of age. Despite recent advances especially in younger patients, the prognosis of older patients with ALL remains dismal, even after moderately intensive chemotherapy. Due to increasing toxicity and infection rates in older patients, dose intensification of induction treatment often is no justifiable option. Consequently, new treatment options are needed to improve the survival of older ALL patients. Methods: This open label phase II study of the German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia (GMALL) is currently activated in 14 centers in Germany. Patients aged >55 years with newly diagnosed acute B lymphoblastic leukemia, with the exception of Philadelphia-chromosome or BCR-ABL positive ALL or Burkitt's or mixed phenotype acute leukemia, are eligible. Leukemic blasts must have CD22 surface expression of at least 20%. No previous ALL-specific treatment, with the exception of corticosteroids and/or single dose vincristine and/or up to 3 doses of cyclophosphamide (cycloph.) plus standard prephase treatment are allowed. The 1st induction cycle consists of inotuzumab ozogamicin (InO) 0.8 mg/m2 on day1 and 0.5 mg/m2 on days 8 and 15 together with dexamethasone 10 mg/m2 (days 7-8, days 14-17) and 1 intrathecal injection of methotrexate (MTX), cytarabine (AraC) and dexamethasone (Dexa). The 2nd and 3rd induction cycle consist of InO 0.5 mg/m2 on days 1, 8 and 15 plus intrathecal injection of MTX/AraC/Dexa. Response evaluation is scheduled after each cycle. Patients achieving a complete remission are offered to receive 5 conventional consolidation therapies (3 x ID-MTX/asparaginase; 2 x ID-AraC) and one reinduction therapy (idarubicine/AraC/cycloph./Dexa) in combination with rituximab (for CD20+ ALL), followed by a maintenance therapy with 6-mercaptopurine/MTX. The primary endpoint is is event free survival (EFS) at 12-months follow-up. An event is any of the following: persisting bone marrow blasts after 2 cycles of InO, relapse or death. An event rate of ≤40% at 12 months follow-up is considered to qualify the experimental treatment as very promising for additional testing. Under the assumption of one-sided type I error of 5% and 80% power, 42 evaluable patients were needed for primary endpoint analysis. The INITIAL-1 trial is registered with ClinicalTrials.gov, identifier: NCT03460522. Results: As of July 2020, 31 patients have been included, with induction results available for 29 patients. Median age at initial diagnosis was 64 years (range 56-80 years). Twenty-five patients were diagnosed with a common- and 4 with a pro-B lymphoblastic leukemia. Median CD22 expression on leukemic blasts was 70% (range 21-99%). Due to suspected therapy related liver toxicities, 1 patient received 1 induction cycle and 1 patient 2 induction cycles (both were in remission after the 1st induction). All other patients completed induction therapy and achieved complete remission (CR/CRi) mainly after the 1st induction. Results of minimal residual disease (MRD) measured by PCR are available for 23 patients, with 17 being MRD-negative after induction. So far, 4 events have been reported (2 deaths in remission and 1 relapsed ALL in the 1st year of treatment; one relapsed disease in the 2nd year). With a median follow-up of 242 days, the probability of OS at 1 year is 82.4 %. Two patients received an allogeneic stem cell transplantation in ongoing 1st remission. With regard to adverse events (AEs) during induction therapy 1, 2 and 3, most common AEs ≥CTC 3 reported were leukocytopenia (in 64%, 33% and 13% of all cases, respectively), anemia (54%, 28%, 13%), thrombocytopenia (68%, 17%, 26%) and elevation of liver enzymes (31%, 22%, 20%). Conclusion: Replacement of conventional induction chemotherapy by InO is feasible, results in promising remission rates, and may reduce the risk of early morbidity and lethality, particular in older patients with acute B lymphoblastic leukemia. Disclosures Stelljes: Amgen: Consultancy, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Wäsch:Pfizer: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Haenel:Amgen, Novartis, Roche, Celgene, Takeda, Bayer: Honoraria. Lenz:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios: Research Funding; AQUINOX: Research Funding; Novartis: Consultancy; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding. Brüggemann:Affimed: Research Funding; Regeneron: Research Funding; Celgene: Consultancy; Roche: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Goekbuget:Gilead: Consultancy; Kite: Consultancy; Servier: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Erytech: Consultancy; Amgen: Consultancy, Research Funding. Alakel:Pfizer: Consultancy. OffLabel Disclosure: Inotuzumab ozogamicin for induction therapy (1st line therapy)

scholarly journals ACUTE LYMPHOBLASTIC LEUKEMIA EXPERIENCE: EPIDEMIOLOGY AND OUTCOME OF TWO DIFFERENT REGIMENS

2013 ◽  
Vol 5 (1) ◽  
pp. e2013024 ◽  
Author(s):  
Salah Abbasi ◽  
Faten Maleha ◽  
Muhannad Shobaki
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Medical Records ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Complete Response ◽  
Cancer Center ◽  
Poor Prognostic Factor ◽  
Minimal Residual Disease Monitoring ◽  
Adult Acute Lymphoblastic Leukemia

Objectives. Accurate data about adult acute lymphoblastic leukemia (ALL) are lacking. We aim to assess demographics, prognostic factors, and outcome of ALL therapy at King Hussein Cancer Center (KHCC) in Jordan, and to compare the efficacy of two protocols.Methods. We reviewed medical records of adults diagnosed and treated for ALL at KHCC from January, 2006 to December, 2010.Results. Over a 5-year period, 108 patients with ALL were treated (66 with the Hyper-CVAD regimen, and 42 with the CALGB 8811 regimen). Median age at diagnosis was 33 years, with 63% males. The most common immunophenotype was CD10-positive common ALL, and 16% have BCR-ABL translocation. Complete response (CR) rate was 88%. After a median follow-up of 32 months (range, 10-72 months), the median survival (MS) was 30 months, and CR duration (CRD) was 28 months. In the multivariate analysis, the presence of BCR-ABL translocation was the only poor prognostic factor with lower MS of 23 months (p<0.01). There was no difference in MS or CRD between the two used regimens.Conclusion. International protocols for adult ALL were successfully applied to our patients. There is no difference in efficacy between Hyper-CVAD and CALGB 8811 regimens. Future protocols for adult ALL should incorporate new targeted agents and minimal residual disease monitoring to improve outcome.

Treatment Outcome and Prognostic Factors for Infants With Acute Lymphoblastic Leukemia Treated on Two Consecutive Trials of the Children's Cancer Group

1999 ◽  
Vol 17 (2) ◽  
pp. 445-445 ◽  
Author(s):  
Gregory H. Reaman ◽  
Richard Sposto ◽  
Martha G. Sensel ◽  
Beverly J. Lange ◽  
James H. Feusner ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Prognostic Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Cancer Group ◽  
Historical Controls

PURPOSE: Infants represent a very poor risk group for acute lymphoblastic leukemia (ALL). We report treatment outcome for such patients treated with intensive therapy on consecutive Children's Cancer Group (CCG) protocols. PATIENTS AND METHODS: Between 1984 and 1993, infants with newly diagnosed ALL were enrolled onto CCG-107 (n = 99) and CCG-1883 (n = 135) protocols. Postconsolidation therapy was more intensive on CCG-1883. On both studies, prophylactic treatment of the CNS included both high-dose systemic chemotherapy and intrathecal therapy, in contrast to whole-brain radiotherapy, which was used in earlier studies. RESULTS: Most patients (> 95%) achieved remission with induction therapy. The most frequent event was a marrow relapse (46 patients on CCG-107 and 66 patients on CCG-1883). Four-year event-free survival was 33% (SE = 4.7%) on CCG-107 and 39% (SE = 4.2%) on CCG-1883. Both studies represent an improvement compared with a 22% (SE = 5.1%) event-free survival for historical controls. Four-year cumulative probabilities of any marrow relapse or an isolated CNS relapse were, respectively, 49% (SE = 5%) and 9% (SE = 3%) on CCG-107 and 50% (SE = 5%) and 3% (SE = 2%) on CCG-1883, compared with 63% (SE = 6%) and 5% (SE = 3%) for the historical controls. Independent adverse prognostic factors were age less than 3 months, WBC count of more than 50,000/μL, CD10 negativity, slow response to induction therapy, and presence of the translocation t(4;11). CONCLUSION: Outcome for infants on CCG-107 and CCG-1883 improved, compared with historical controls. Marrow relapse remains the primary mode of failure. Isolated CNS relapse rates are low, indicating that intrathecal chemotherapy combined with very-high-dose systemic therapy provides adequate protection of the CNS. The overall unsatisfactory outcome observed for the infant ALL population warrants the future use of novel alternative therapies.

Adults with Acute Lymphoblastic Leukemia and T(1;19) Abnormality Have a Favorable Outcome with Hyper-CVAD Chemotherapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3955-3955
Author(s):  
Ravin Jain Garg ◽  
Hagop M Kantarjian ◽  
D. A Thomas ◽  
Stefan Faderl ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Response Duration ◽  
Complete Response ◽  
Cancer Center ◽  
P Value ◽  
Small Subset ◽  
High Dose ◽  
Cytogenetic Abnormalities

Abstract Among the well-described cytogenetic abnormalities in adults with acute lymphoblastic leukemia (ALL), a translocation involving chromosomes 1 and 19 [t(1;19) (q23;p13)] occurs in a small subset but has varyingly been associated with a good or bad prognosis in different studies. Adults with ALL and t(1;19) treated at M.D. Anderson Cancer Center were reviewed. Their clinical features and outcome were compared to those with other cytogenetic abnormalities. Endpoints included complete remission rate (CR), complete response duration (CRD) and overall survival (OS). Of 411 adults with pre-BALL, 12 patients had t(1;19). Ten of the 12 patients with t(1;19) received Hyper-CVAD (Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone alternating with Methotrexate and high-dose Cytarabine); the other 2 were treated with VAD (Vincristine, Adriamycin, Dexamethasone). All 12 patients achieved CR; the 3-year survival rate was 73%. Patients with t(1;19) had significantly better CRD and OS when compared to all other patients combined as well as individually to patients with Ph+, t(4;11), and lymphoma-like abnormalities [6q(−), 14q+, t(11;14), t(14;18)]. Adults with ALL and t(1;19) have an excellent prognosis when treated with the Hyper-CVAD regimen. Outcome of patients by cytogenetic group: t(1;19) vs. individual cytogenetic groups OVERALL SURVIVAL N Fail 3-Year % Median (weeks) P-value T(1,19) 12 3 73 Not recorded Diploid 138 72 52 179 0.09 Lymphoma-like 20 17 35 54 0.008 Ph+ 117 88 23 68 0.0002 Miscellaneous 112 56 56 236 0.17 T(4,11) 12 10 0 58 0.002 COMPLETE RESPONSE DURATION (CRD) N Fail 3-Year % Median (weeks) P-value T(1,19) 12 2 80 Not recorded Diploid 133 59 54 177 0.06 Lymphoma-like 16 13 34 89 0.009 Ph+ 102 52 42 63 0.006 Miscellaneous 100 41 59 401 0.16 T(4,11) 11 7 NR 45 0.018

Prognostic Value of Minimal Residual Disease (MRD) Detection in Adult Acute Lymphoblastic Leukemia (ALL) – HYPER-CVAD Protocol

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4870-4870
Author(s):  
Nikolaos Tsagarakis ◽  
Nektaria Kentrou ◽  
Mirsini Pergaminou ◽  
Theodore Marinakis ◽  
Stefanos I Papadhimitriou ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Induction Therapy ◽  
Treatment Time ◽  
Lymphoblastic Leukemia ◽  
Treatment Protocol ◽  
Disease Free Survival ◽  
Consolidation Therapy ◽  
Time Points ◽  
Time Point

Abstract Objective: HYPER-CVAD is an intensive treatment protocol of short duration, for ALL and other lymphoid neoplasms. It is consisted of 8 alternating cycles (parts A and B): in part A (cycles 1, 3, 5, 7) fractionated doses of cyclophosphamide, vincristine, doxorubicin and dexamethazone are administrated, while in part B (cycles 2, 4, 6, 8) high doses of methotrexate and aracytin. The two first cycles compose the induction therapy, while the next 6 cycles constitute the consolidation therapy, followed by two years of maintenance therapy. Protection of CNS is achieved with intradorsal injections, whereas in Ph+ ALL patients, imatinib is also administered. The aim of this study was the clinical evaluation of MRD detection in adult patients with ALL, during chemotherapy with HYPER-CVAD. Patients/Methods: During the period 1999–2008, 30 patients were hospitalized in our hospital for ALL and were treated with HYPER-CVAD therapeutic protocol. Among them, 14/30 (46,7%) were males and 16/30 (53,3%) females (median age 43,5 years, range 16–70). Median follow-up time was 12,8 months (range 0,5–100). ALL of T-origin had 8/30 patients and of B-origin, 22/30 (1 B1-EGIL/pro-B, 17 B2-EGIL/B-common, 4 B3-EGIL/pre-B). Caryotypic analysis and FISH was done in all patients (7/30 bcr/abl+). According to classical prognostic markers of ALL: 21/30 were classified as high, 4/30 as medium and 5/30 low risk, respectively. MRD presence was detected in bone marrow samples, with flow cytometric panels, at three particular treatment time-points: completion of induction therapy (T1), completion of consolidation therapy (T2) and at the end of maintenance therapy (T3). Overall survival (OS) and disease free survival (DFS) were investigated, especially in relation to the influence of MRD presence in (OS) and (DFS), respectively. For statistical analysis, Kaplan-Meier was used. Results: At treatment time-point (T1), MRD was detected in 10/28 (35,7%) patients, at time-point (T2) in 7/23 (30,4%) and at treatment-point (T3) in 9/17 (52,94%). The influence of MRD detection in (OS) was statistically significant (p&lt;0,05) at (T2) and (T3), while in (DFS) the detection of MRD presence in any of the standardized treatment time-points resulted in decreased DFS (T1/p&lt;0,05, T2 and T3/p&lt;0,001). Conclusions: Our results suggest that MRD detection during therapy of adult ALL is a negative prognostic indicator for (OS) and (DFS), the independency of which has to be confirmed after prolonged follow-up time and increased number of cases.

Nilotinib Combined with Multi-Agents Chemotherapy for Adult Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of a Prospective Study from a Single Center

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1301-1301
Author(s):  
Bingcheng Liu ◽  
Ying Wang ◽  
Chunlin Zhou ◽  
Hui Wei ◽  
Dong Lin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Maintenance Therapy ◽  
Prospective Study ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Induction Cycle

Abstract Background: Imatinib combined with conventional chemotherapy has significantly improved the prognosis of adults with Philadelphia-positive acute lymphoblastic leukemia ( Ph+ ALL ). Nilotinib, the second generation TKIs is approximately 30 fold more potent than imatinib and is active in vitro against multiple BCR/ABL mutations. Here, we report the efficacy and safety of nilotinib combined with multiple reagents chemotherapy in newly diagnosed patients with Ph+ ALL. Methods: Newly diagnosed Ph+ ALL patients aged 15 to 59 and with adequate organ function were recruited. The 4weeks induction cycle consist of vincristine, daunorubicin, cyclophosphamide and prednisone. After achieving hematological complete remission (HCR), patients received 2 years of consolidation and maintenance therapy. Consolidation therapy was including 7 courses of multiple drug chemotherapy or allogeneic/autologous hematopoietic cell transplantation (allo/auto HCT). Nilotinib was the only drug for maintenance therapy. Nilotinib 400mg was given orally twice daily along with combination chemotherapy starting from day 15 of induction until the initiation of conditioning for transplantation, hematological relapse or continuing for 2 years since achievement of hematological complete remission (HCR).Central nervous system (CNS) prophylaxis was performed by intrathecally administering triple agents. The data cut-off day was June 1st 2015. HCR and molecular complete remission (MCR), overall survival(OS), hematologic relapse free survival (HRFS), toxicity, nilotinib concentration in serum and cerebrospinal fluid(CSF) were evaluated. MCR was defined as Bcr-Abl fusion gene becomes negative in bone marrow using quantitative RT-PCR. Results: A total of 30 patients (19 males and 11 females) were enrolled from September 2011 to November 2013. The median age was 40 (range 21-57) years old. The type of BCR breakpoint was minor in 24 patients, major in 2 patients and both in 4 patients. All the 30 patients (100%) and 8 patients (26.7%) achieved HCR and MCR respectively after the induction cycle. Cumulative MCR rate was 80%. 17 patients underwent HCT, 14 patients with alloHCT and 2 patients with autoHCT in first HCR, 1 patient received alloHCT after relapse. 9 patients died from leukemia relapse and 4 patients died post-alloHCT without relapse. The median HRFS and OS were 20.7 and 34 months respectively. The 4 year HRFS rate was 41% and the 4 year OS rate was 48%. The molecular response after induction has no impact on HRFS and OS. Patients achieving MCR had better HRFS (32 vs 8.9 months, p=0.006) but not OS(33.3vs 17.2months, p=0.068) than those patient without MCR. During induction, 23 patients experienced infectious fever including 2 patients with septicemia and 6 patients with pneumonia needing antifungal therapy. Intestinal obstruction occurred in 7 patients during induction and relived by interrupting nilotinib treatment. The incidence of non-hematologic adverse events (AE) over grade 3 during the study was 23% jaundice, 10% rash, 6.7% arthralgia and bone pain, 6.7%headache, 3.3% ALT elevation. No QTc prolongation over 500ms happened. Grade 2 tachycardia and premature ventricular contraction occurred in 2 patients and 1 patient respectively. During the high-dose methotrexate treatment cycle, delaying of methotrexate metabolism happened in 20 patients (66.7%), increasing creatine occurred in 8 patients (26.7%, grade 3 in 3 patients), 1 patient received haemodialysis. Nilotinib serum level reached to stable concentration after 15 days of administration. Only traces of nilotinib was detected in CSF. Conclusion: In this prospective study, combination of nilotinib and cytotoxic drug was shown to be effective and tolerable for adult Ph+ALL. Nilotinib could not penetrate the blood brain barrier. (ChiCTR-ONC-12002469) Disclosures Off Label Use: nilotinib,the 2nd generation TKI, was approved for CML. Wang:Novarits and Bristol-Mayers squibb. G.S.: Consultancy.

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