First Results of the GRAAPH-2005 Study in younger Adult Patients with De Novo Philadelphia Positive Acute Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 12-12 ◽  
Author(s):  
Yves Chalandon ◽  
Xavier Thomas ◽  
Sandrine Hayette ◽  
Jean-Michel Cayuela ◽  
Claire Abbal ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
High Dose ◽  
Unrelated Donor ◽  
Molecular Response ◽  
Consolidation Chemotherapy ◽  
Significant Difference ◽  
Induction Regimen

Abstract The GRAAPH-2005 International study for adults with newly diagnosed chromosome Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) was designed to compare an imatinib-based induction regimen with an imatinib-HyperCVAD induction regimen and to evaluate the role of imatinib prior to stem cell transplantation (SCT). The protocol enrolled patients > 18 years and < 60 years. Among 118 enrolled patients from May 2006 onwards, 83 had a follow-up long enough to allow at least induction and consolidation evaluation. Median age was 42 years; 60% were male. A 7-day prephase steroid regimen (prednisone 60 mg/m2/day) allowed identification of the BCR/ABL transcript. In arm A (imatinib-based), imatinib 800 mg was given days 1–28, only combined with vincristine (2 mg at days 1, 8, 15, 22) and dexamethasone (40 mg at days 1–2, 8–9, 15–16, and 22–23). In arm B (imatinib-HyperCVAD), imatinib 800 mg was given days 1–14 of each course, combined with adriamycin (50 mg/m2 at day 4), cyclophosphamide (300 mg/m2/12h at day 1, 2, 3), vincristine (2 mg at days 4 and 11), and dexamethasone (40 mg at days 1–4 and 11–14) in the induction course, and combined with high-dose methotrexate (1 g/m2 at day 1) and high-dose cytarabine (3 g/m2/12h at days 2 and 3) in the salvage/consolidation course. Salvage/consolidation course was similar for patients initially following arm A. Four intrathecal infusions (methotrexate + cytarabine + methylprednisolone) were included within induction/consolidation courses. Complete hematological remission (CR) rate at the end of the two courses of induction/consolidation was 100% with arm A (42 patients of whom 2 after salvage course) and 95% with arm B (39/41 patients; all after induction course): overall 97.5% vs 70% in the pre imatinib era (LALA-94 trial). One patient died during the first course and 2 during the second course (of which 1 in CR after the induction course). Overall, median number of days to response was 37 (range, 28–136 days). Minimal residual disease (MRD) was centrally evaluated by quantitative RT-PCR at the end of induction (MRD-1) and at the end of salvage/consolidation chemotherapy (MRD-2). Molecular disease was undetectable in 11% at the time of MRD-1 and in 18% at the time of MRD-2, and at a level < 0.1% in 40% at the time of MRD-1 and in 60% at that of MRD-2. Although this did not translate into significant difference in terms of survival, monitoring of MRD (< 0.1%) documented that arm B was capable of inducing a deeper marked clearance of leukemic cells than arm A at the end of salvage/consolidation chemotherapy: 35% in arm A and 45% in armB (p = 0.3) for MRD-1, and 48% in arm A and 72% in arm B (p = 0.05) for MRD-2. After the two phases of induction/consolidation, patients received intensification by allogeneic SCT using related or unrelated donor stem cells or autologous SCT when a donor was not available and MRD < 0.1%. In absence of potential SCT, they underwent repeated cycles of imatinib-HyperCVAD regimen. Of the 61 patients with enough follow-up after induction/consolidation courses, 52 (85%) actually received SCT: 41 allogeneic SCT (of which 25 from related- and 16 from unrelated-donor) and 11 autologous SCT. Overall survival (OS) was 62% at 2-year (68% and 54% in arm A and arm B, respectively; p = 0.3), which differ significantly from the 29% observed in the pre imatinib era (LALA-94 trial). Disease-free survival (DFS) was 43% at 2-year (54% and 32% in arm A and arm B, respectively; p = 0.7). After a median follow-up of 12.6 months (95% CI, 10.6–15 months), 18 relapses (22%) were observed. Eighteen patients have died after induction/consolidation phase: 8 patients with progressive disease and 10 patients in CR (1 from septic shock waiting for allogeneic SCT, and 9 from toxicity during allogeneic SCT). The preliminary data of this study suggest that an imatinib-based regimen induces a high rate of hematological CR, similar to a more intensive (HyperCVAD) regimen. However the rate of molecular response has a tendency to be lower with imatinib-based regimen. The combination of imatinib with chemotherapy allows a majority of patient to have consolidation with SCT.

Influence of the fusion gene ETV6-RUNX1 in the prognosis of the Pediatric B- Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2515-2515
Author(s):  
Alejandro Contento-Gonzalo ◽  
Antonio Jimenez-Velazco ◽  
Alcala-Peña Magdalena ◽  
Manuel Barrios ◽  
Katie Hurst ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Rank Test ◽  
Prognostic Impact ◽  
Excellent Outcome ◽  
Log Rank Test ◽  
Significant Difference

Abstract Abstract 2515 INTRODUCTION AND OBJECTIVES: The ETV6-RUNX1 (TEL-AML1) rearrangement comes from the translocation of two chromosomes t(12;21)(p12;q22), and represents one of the most frequently detected anomalies (15–30%) in the B-precursor Acute Lymphoblastic Leukemia (B-ALL). It must be identified by polymerase chain reaction (PCR) or fluorescent in situ hybridization (FISH) methods, since this translocation is not detected by conventional cytogenetic techniques. The prognostic value of ETV6-RUNX1 is still a matter of controversy. Recently, the group of the St Jude Children's Hospital reported an excellent outcome in patients carrying the translocation, whereas the BMF group did not find any significant difference in the survival of ETV6-RUNX1 positive patients when compared to ETV6-RUNX1 negative. The aim of our study has been to determine the prognostic impact of the ETV6-RUNX1 rearrangement in patients diagnosed of B-ALL in our Hospital, after a long period of follow-up and with the same Spanish treatment protocols (from PETHEMA and SHOP groups). PATIENTS AND METHODS: All patients with B-ALL diagnosis from January 1997 to May 2011 were included in the study: in total, 114 patients with a mean of age of 6 ys (0.3–14). The type of leukemia was ALL common (83 patients), pro-B (17 patients), pre-B (13 patients) and mature (1 patient). All the children over 1 yr received treatment according to PETHEMA group protocols, adjusted to the risk. Children under 1 yr were treated following SHOP group protocols. Seventeen patients received an allogeneic transplantation. The main clinical features of the positive and negative patients for ETV6-RUNX1 are detailed in table 1. ETV6-RUNX1 assay was performed in our laboratory by RT-PCR, according to the European BIOMED project methodology. RESULTS: ETV6-RUNX1 was found in 31 of the 114 patients (27.2%). These patients showed a significantly higher frequency of myeloid antigens (p<0.001), and were always positive for CD10 (p=0.006). All cases of positive ETV6-RUNX1 were over 2 years old. No significant differences between positive and negative ETV6-RUNX1 were obtained when complete remissions (100 vs 80%), relapse (16 vs 20%) or deaths (10 vs 13%) were analyzed. Furthermore, estimation of disease free survival (DSF) at 14 ys for both groups were similar: 80 ± 8% for positive vs 66 ± 7% for negative (p=0.21, log-rank test). And the same happened for overall survival (OS): 87 ± 7% for positive vs 83 ± 5% for negative (p=0.4, log-rank test). DISCUSSION: In our series, including patients with B-ALL treated with similar protocols with long periods of follow-up, we could not find differences between positive and negative ETV6-RUNX1 patients. It is well known that the intensity of the chemotherapy regimen and the age of inclusion in different protocols may influence the prognosis. Therefore, at present, it is still a matter of discussion if previous reported differences in the B-ALL ETV6-RUNX1 positive group could be explained by a different stratification in risk groups or by different chemotherapy regimens. This work has been funded by a grant from AECC, Carmen Lavigne Prize 2010 Disclosures: No relevant conflicts of interest to declare.

Cytarabine with high-dose mitoxantrone induces rapid complete remissions in adult acute lymphoblastic leukemia without the use of vincristine or prednisone.

1996 ◽  
Vol 14 (9) ◽  
pp. 2480-2485 ◽  
Author(s):  
M Weiss ◽  
P Maslak ◽  
E Feldman ◽  
E Berman ◽  
J Bertino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Median Number ◽  
High Dose ◽  
Resistant Disease ◽  
Induction Regimen ◽  
Adult Acute Lymphoblastic Leukemia

PURPOSE To evaluate the efficacy and safety of a new induction regimen for adult acute lymphoblastic leukemia (ALL) that does not contain vincristine or corticosteroids. PATIENTS AND METHODS Thirty-seven adult patients with newly diagnosed ALL and lymphoblastic lymphoma were treated with a dose-intense induction regimen. This regimen was designed to increase the fraction of patients achieving an early complete remission (CR) in an attempt to increase long-term disease-free survival. The induction regimen was cytarabine (Ara-C) 3 g/m2/d for 5 days and mitoxantrone 80 mg/m2 as a single dose on day 3. Granulocyte colony-stimulating factor (G-CSF) 200 micrograms/ m2/d beginning on day 7 was used to promote early myeloid recovery. RESULTS There were 31 CRs (84%). Median time to CR was 34 days, median hospital stay was 28 days, and the median number of days with a neutrophil count less than 500/microL was 18. There were three patients with resistant disease who experienced treatment failure and three early deaths from sepsis. Four patients with Philadelphia chromosome-positive (Ph+) ALL achieved hematologic and cytogenetic CRs. CONCLUSION This dose-intense induction regimen produced a high incidence of CRs with acceptable toxicity without the use of vincristine or corticosteroids. Comparisons with our prior vincristine/prednisone-based induction regimen (the L-20 protocol) suggest that patients treated on the current study were more likely to achieve a CR and that they achieved this remission earlier than patients treated with a traditional four-drug (vincristine, prednisone, doxorubicin, and cyclophosphamide) induction regimen.

Effect of Protracted High-Dose l-Asparaginase Given as a Second Exposure in a Berlin-Frankfurt-Münster–Based Treatment: Results of the Randomized 9102 Intermediate-Risk Childhood Acute Lymphoblastic Leukemia Study—A Report From the Associazione Italiana Ematologia Oncologia Pediatrica

2001 ◽  
Vol 19 (5) ◽  
pp. 1297-1303 ◽  
Author(s):  
C. Rizzari ◽  
M.G. Valsecchi ◽  
M. Aricò ◽  
V. Conter ◽  
A. Testi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Randomized Study ◽  
Disease Free Survival ◽  
Experimental Treatment ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
High Dose ◽  
Intermediate Risk ◽  
Free Survival ◽  
Significant Difference

PURPOSE: To assess in a randomized study the therapeutic effect of the addition of high-dose l-asparaginase (HD ASP) in the context of a Berlin-Frankfurt-Münster (BFM)–based chemotherapy regimen for intermediate risk (IR) childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: From March 1991 to April 1995, a total of 705 patients, with 59% of the cohort of patients fewer than 15 years old, with newly diagnosed non-B ALL, enrolled onto the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-91 study, were assigned to the IR group. Patients in remission at the beginning of the reinduction phase were randomized either to the standard treatment (SD ASP arm) or the experimental treatment (HD ASP arm; weekly intramuscular administration of HD ASP 25,000 IU/m2 repeated for a total of 20 weeks). Most of the patients (90%) were treated with Erwinia chrysanthemi l-asparaginase product. RESULTS: Among the 610 patients randomized to the SD ASP arm (n = 322) or to the HD ASP arm (n = 288), relapse occurred at a median time of 24 months after randomization in 76 (24%) and in 64 children (22%), respectively. Most of the relapses occurred in the marrow (100 isolated, 21 combined). There was no significant difference between the disease-free survival in the two treatment arms (P = .64), with estimated values at 7 years from randomization of 72.4% (SE 3.1) v 75.7% (SE 2.6) in the SD ASP and HD ASP arms, respectively. CONCLUSION: No advantage was observed for IR ALL children treated with BFM-based intensive chemotherapy who received protracted E chrysanthemi HD ASP during reinduction and the early continuation phase.

scholarly journals Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2814-2822 ◽  
Author(s):  
CA Linker ◽  
LJ Levitt ◽  
M O'Donnell ◽  
SJ Forman ◽  
CA Ries
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Remission Induction ◽  
Cell Phenotype ◽  
Free Survival ◽  
Prognostic Features ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Disease Free

Abstract We treated 109 patients with adult acute lymphoblastic leukemia (ALL) diagnosed by histochemical and immunologic techniques. Patients were excluded only for age greater than 50 years and Burkitt's leukemia. Treatment included a four-drug remission induction phase followed by alternating cycles of noncrossresistant chemotherapy and prolonged oral maintenance therapy. Eighty-eight percent of patients entered complete remission. With a median follow-up of 77 months (range, 48 to 111 months), 42% +/- 6% (SEM) of patients achieving remission are projected to remain disease-free at 5 years, and disease-free survival for all patients entered on study is 35% +/- 5%. Failure to achieve remission within the first 4 weeks of therapy and the presence of the Philadelphia chromosome are associated with a 100% risk of relapse. Remission patients with neither of these adverse features have a 48% +/- 6% probability of remaining in continuous remission for 5 years. Patients with T-cell phenotype have a favorable prognosis with 59% +/- 13% of patients achieving remission remaining disease-free compared with 31% +/- 7% of CALLA-positive patients. Intensive chemotherapy may produce prolonged disease-free survival in a sizable fraction of adults with ALL. Improved therapy is needed, especially for patients with adverse prognostic features.

scholarly journals Comparison of chemotherapy with immunotherapy for maintenance of acute lymphoblastic leukemia in children and adults

Blood ◽  
1983 ◽  
Vol 62 (3) ◽  
pp. 606-615 ◽  
Author(s):  
PA Stryckmans ◽  
J Otten ◽  
MJ Delbeke ◽  
S Suciu ◽  
D Fiere ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Consolidation Chemotherapy ◽  
Disease Free Interval ◽  
Free Interval ◽  
Significant Difference ◽  
The Difference ◽  
To Receive ◽  
Disease Free ◽  
Leukemia In Children

Abstract Two hundred and seventeen patients, 1–50 yr old, with acute lymphoblastic leukemia in complete remission were randomized to receive a 1-yr consolidation chemotherapy of either type P, comprising 7 different drugs, or type M, consisting of methotrexate interspersed with prednisone and vincristine. Thereafter, they were randomized a second time to receive a 4-yr maintenance of either chemotherapy or immunotherapy, comprised of allogeneic blasts and bacillus Calmette- Guerin (BCG). Consolidation P caused more toxicity than consolidation M. However, comparison between the consolidation therapies P and M showed no significant difference, neither for disease-free interval nor for duration of survival. Chemotherapy showed more lethal toxicity in adults than in children. Comparison between chemotherapy (C) and immunotherapy (I) as maintenance treatment showed a significant (p = 0.016) superiority of C for disease-free interval (DFI). The difference was even more pronounced (p = 0.009) in the group with less than 8 g/dl of hemoglobin (Hb) at diagnosis before therapy. On the other hand, for patients with more than 8 g/dl Hb at diagnosis, presumably those with T- ALL, no difference in DFI was seen. No difference has been seen so far between maintenance therapies I and C concerning the duration of survival. The patients who were receiving maintenance I when they relapsed and who were consequently retreated by chemotherapy, survived longer from relapse than those patients retreated for relapse while receiving maintenance C.

Three-Drug Induction and BFM-Type Intensive Consolidation Chemotherapy for Treatment of Standard Risk Childhood Acute Lymphoblastic Leukemia Defined Also by DNA index. The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) Study ALL-9501.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1951-1951
Author(s):  
Maurizio Arico’ ◽  
Valentino Conter ◽  
Maria Grazia Valsecchi ◽  
Marie France Pinta Boccalatte ◽  
Elena Barisone ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Malignant Neoplasm ◽  
Small Subset ◽  
Unrelated Donor ◽  
Minimal Risk ◽  
Dna Index ◽  
Standard Risk

Abstract In this study, we tried to select a very small subset of children with acute lymphoblastic leukemia (ALL) at minimal risk of treatment failure - identified to not only by early response in vivo, one of the strongest predictors in the I-BFM-SG experience, but also by age, blood count and in particular high DNA content - which we treated with a reduced-intensity BFM schedule. The AIEOP-ALL 9501 study enrolled patients with standard-risk (SR) ALL, defined as: <20,000 WBC/mm3, age 1 to <6 years, non-T immunophenotype, DNA index between 1.16 and 1.6, non t(9;22), no extramedullary leukemia, good response to prednisone (PGR, defined as <1,000/mmc blasts in the peripheral blood after 7 days of prednisone and one injection of IT-MTX), CR at the end of induction therapy. Follow-up was updated at December,31st 2003 and median follow-up was 5.9 years. Treatment consisted of a modified BFM schedule: 3-drug (VCR + PDN + Erwinia ASP), 43-day induction, no phase IB, 4x2 g/m2 MTX, reinduction with protocol II followed by 6MP+MTX continuation therapy up to 2 years; CNS directed therapy consisted of IT-MTXx18. Between May 95 and August 2000, 137 patients were identified as SR (7.8% of the ALL-95 population), of whom 102 received the SR protocol and are here reported.Of them, 1 died in remission of septicemia, and 1 had developed a second malignant neoplasm (T-ALL after initial B-lineage ALL); 11 patients relapsed (bone marrow, n=8; central nervous system, n=1; marrow + testis, n=1; eye, n=1) and their re-treatment included chemotherapy only (n=3, 1 dead) or plus bone marrow transplant (n=8) either autologous (n=2) or allogeneic from matched (n=4, 1 dead) or partially matched (n=2) unrelated donor. The remaining 89 are in first CR; the probabilities (and related standard errors) of survival and event-free survival (EFS) were 97.0% (1.7) and 86.7% (3.5) at 5 years, 95.3% (2.4) and 86.7% (3.5) at 7 years, respectively. There was no difference in the outcome between the 56 females [7 events, 7-yrs EFS, 87.3 (4.5)] and the 46 males [6 events, 85.9 (5.4)]. Although most of the relapsed patients were rescued, the long-term EFS in this small, very selected group of patients remains inferior to expectance. Thus, alternative selection criteria, for instance related to minimal residual disease as in current AIEOP-ALL 2000, should be considered in order to address the issue of treatment reduction.

Intrathecal Liposomal Cytarabine (Depocyt) Is Safe and Effective for Prevention of Meningeal Disease in Patients with Acute Lymphoblastic Leukemia and High-Grade Lymphoma Treated with the HyperCVAD Regimen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4594-4594 ◽  
Author(s):  
Brian McClune ◽  
Francis Buadi ◽  
Naveed Aslam ◽  
Donna Przepiorka
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Liposomal Cytarabine ◽  
High Grade ◽  
Platelet Recovery ◽  
Significant Difference ◽  
Meningeal Disease

Patients with acute lymphoblastic leukemia (ALL) and high-grade lymphoma have a 10–20% risk of meningeal disease during induction and in remission when given standard-dose chemotherapy. This risk has been reduced to about 1% using intrathecal prophylaxis with cytarabine and methotrexate in addition to the systemic regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyperCVAD) alternating with high-dose methotrexate-cytarabine (MA). The discomfort and potential adverse events with frequent lumbar punctures may impair patient compliance. Liposomal cytarabine (Depocyt) is an intrathecal preparation of cytarabine with a prolonged half-life. Use of Depocyt could potentially reduce the number of lumbar punctures needed for routine neuroprophylaxis. We reviewed the tolerability and activity of Depocyt for neuroprophylaxis in 15 patients treated with the hyperCVAD regimen. The cohort included 12 males and 3 females of median age 48 years (range, 23–72 years) with precursor B-cell ALL (8), T-cell ALL (3), Burkitt lymphoma and HIV (2), Ph-positive ALL (1), and lymphoblastic lymphoma (1). The patients received a total of 65 cycles of systemic chemotherapy, 36 with hyperCVAD and 29 with MA. Depocyt was given IT or IO in 33 cycles, methotrexate IT in 5, and no intrathecal therapy in 27. When treated with Depocyt, patients also received dexamethasone pre- and postmedication.. The planned dose of Depocyt was 50 mg for all patients, but after one serious adverse event, the dose was reduced to 25 mg when administered by Omaya. Depocyt was instilled on a median of day 8 of the cycle (range, −4 to 13). To date, a meningeal relapse has not occurred in any of the patients. Although minor neurological events (transient headache or neckache) were not uncommon, there were two serious adverse events. One patient developed a severe but transient headache during the fourth cycle and was readmitted for pain control. A second patient received Depocyt four days prior to MA. Shortly after completing chemotherapy, this patient developed hyponatremia and somnolence. The neurological status normalized after several days with supportive care alone. Since leakage of Depocyt into the peripheral blood might cause myelosuppression, hematologic recovery was also assessed. There was a significant difference in time to ANC>500 (p=0.02) and platelets >20,000 (p=0.005) between hyperCVAD and MA cycles, so hematologic recovery was assessed separately for these regimens, as shown in the Table. Median Day of Hematopoietic Recovery Cycle Outcome All Cycles Depocyt No IT PX MTX IT “1” indicates the platelet count did not fall below 20,000 during that cycle. HyperCVAD ANC>500 15 15 14 16.5 Plts>20,000 1 1 1 1 MA ANC>500 16 16 16 15 Plts>20,000 13 13 14 15 There were no significant differences in time to neutrophil or platelet recovery between neuroprophylaxis regimens. Three patients received cranial or craniospinal radiation to compete neuroprophylaxis prior to allogeneic stem cell transplantation without notable neurotoxicity after transplantation. We conclude that it is safe to use a single dose of Depocyt (50 mg IT or 25 mg IO) following completion of administration of chemotherapy (around Days 6 – 8) during each cycle of the hyperCVAD regimen. This approach should be studied in a randomized trial to further assess its efficacy in comparison to more frequent instillations of methotrexate/cytarabine.

High-Dose Methotrexate and Early Intensification of Therapy Do Not Improve 3 Year EFS in Children and Adolescents with Disseminated Lymphoblastic Lymphoma. Results of the Randomized Arms of COG A5971

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3610-3610 ◽  
Author(s):  
Minnie Abromowitch ◽  
Amanda Termuhlen ◽  
Myron Chang ◽  
Sherrie L. Perkins ◽  
Thomas Gross ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymphoblastic Leukemia ◽  
Bone Marrow Involvement ◽  
Disease Free Survival ◽  
Lymphoblastic Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Disease ◽  
Dose Methotrexate ◽  
Significant Difference

Abstract The treatment of pediatric lymphoblastic lymphoma (LL) has developed in parallel with treatment strategies for childhood acute lymphoblastic leukemia using a BFM backbone. The excellent results of the NHL/BFM 90 trial prompted us to design this randomized factorial study to determine whether a regimen without high dose methotrexate (HDMTX) the CCG BFM will result in the same outcome as NHL/BFM-90 and whether intensification with anthracycline and cyclophosphamide would further improve disease free survival. From June 2000 to October 2005, 257 patients with Murphy’s Stage III and IV (excluding CNS disease) LL were randomized to one of the four regimens. All regimens used the BFM/NHL95 backbone. The CCG BFM regimen had intrathecal (IT) methotrexate throughout interim maintenance and maintenance without IV methotrexate. The NHL BFM utilized I.V. Methotrexate 5 Gms/m2 and intrathecal MTX every 2 weeks for four doses during interim maintenance without further intrathecal MTX during maintenance. One of each backbone regimens was further intensified with anthracycline and cyclophosphamide early in induction and delayed intensification. The median age was 10.3 years, 195 (76%) were males; 43 (17%) had >5% bone marrow involvement. Twelve patients with CNS disease were not randomized and received intensification and HD HDMTX with delayed CNS radiation (data not reported here). Major toxicities have been related to bone marrow suppression with 4 toxic deaths, 3 due to sepsis and 1 from cerebral hemorrhage. The frequency of grade III/IV neutropenia (alone, with fever or with infection), anemia, and thrombocytopenia were higher in the intensified arms during induction. Three of the four toxic deaths occurred on the intensified arms. The three years EFS of the HDMTX vs. none is 84.5% ± .3.5% vs. 82.7± 3.8 (ρ= 0.93) and the intensification vs. none is 83.4% ±3.7 vs 83.0% ± 3.6 (ρ= 0.66). Therefore, there was no significant difference between treatment arms. These results suggest that neither HDMTX nor early intensification improves EFS in LL. Future direction should focus on identifying biological factors early in therapy so alternative therapies may be investigated.

Pediatric Therapy In Adult Acute Lymphoblastic Leukemia: Updated Experience of a Single Centre

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4338-4338
Author(s):  
Stefania Paolini ◽  
Sarah Parisi ◽  
Ilaria Iacobucci ◽  
Cristina Papayannidis ◽  
Maria Chiara Abbenante ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hematological Toxicity ◽  
Induction Phase ◽  
Single Centre ◽  
Phase Ib ◽  
Small Series ◽  
Significant Difference

Abstract Abstract 4338 Background. Acute lymphoblastic leukemia (ALL) presents with different outcome in children and adults, with event-free-survival (EFS) rates of 70–80% and 30–40% at 5 years, respectively. This reflects both a different disease biology and different therapeutic approaches. Recently, results apparently improved in young adults/adolescents aged 15–21 years, with de novo ALL, when treated with pediatric intensive regimens rather than with typical adult regimens. Similarly, clinical studies are ongoing in older patients, toxicity related-therapy seeming the limiting issue. Aims. We report a single centre experience on adult ALL patients treated with an intensive pediatric-inspired schedule, designed to assess its tolerability and efficacy. Methods. From November 2007 to June 2010 seventeen ALL patients (M/F=12/5) were treated at our Center according to a modified AIEOP LAL2000 regimen. Treatment consisted of 7 days steroid pre-treatment, and four drugs 78-days induction (phase IA and phase IB) after which high risk (HR) patients were treated with three polychemotherapy blocks, while intermediate (IR) and standard risk (SR) patients went on 8-weeks consolidation and subsequent delayed intensification. Allo-SCT was planned for all patients with HLA-matched donor, as alternative to 2-years maintenance therapy. Median age was 31 years (range, 17–47). According to cytogenetic, response to steroid and minimal residual disease patients were classified into HR (n=7), IR (n=6) and SR (n=4). Results. 15/17 patients completed the induction phase IA, two being out for toxicity (grade IV infection and intestinal occlusion). Twelve (71%) obtained a complete remission (CR); three were refractory. However, one of them subsequently achieved CR after polychemotherapy blocks, for an overall response rate of 76% (13/17). Eleven patients then completed the 28-days induction IB. One patient is ongoing. Median induction duration was 92 days (range 82–136). Delays were mostly due to extra-hematological toxicity, the commonest being gastrointestinal (n=12), infective (n=7) and thrombotic (n=3). Delays were accumulated in both induction phases without significant difference between phase IA (median 18.5 days, range 4–37) and phase IB (median 17 days, range 9–66), despite an absolute number of moderate-severe AE superior in phase-IA versus phase-IB (12 vs 5). After induction, 4/12 patients already received consolidation therapy; 2/4 then received allo-SCT. The median duration of consolidation was 51 days (range 22–94). Conversely, 6/12 patients received polychemotherapy-blocks, one patient went directly on alloSCT and the remaining is ongoing. After polychemotherapy-blocks, five out six patients received allo-SCT. The median CR duration was 13 months (range 1+-42+); two patients relapsed, both after allo-SCT. With a median follow-up of 11 months (range 2–43) 11/17 (65%) patients are alive, 9 in CR (5 undergone allo-SCT). Six patients dead, three in CR for infectious complications, 3 for relapsed/refractory disease. Conclusions. Though in a small series, pediatric-like intensive chemotherapy seemed to be feasible in adult ALL. Extra-hematological toxicity, however, caused significant treatment delays during induction. Finally, the overall outcome appeared promising, though longer follow-up and larger populations are needed to draw definitive conclusions. Acknowledgments. BolognAIL, European LeukemiaNet, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO, Project of Integrated Program (PIO), Programma di Ricerca Regione – Università 2007–2009. Disclosures: No relevant conflicts of interest to declare.

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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