Prognostic Impact of CNS-2 status in T-ALL: A report from the Children’s Oncology Group.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10003-10003
Author(s):  
Nathan Gossai ◽  
Stuart S. Winter ◽  
Meenakshi Devidas ◽  
Zhiguo Chen ◽  
Brent L. Wood ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Prognostic Impact ◽  
Early Closure ◽  
Children And Young Adults ◽  
Poor Outcomes ◽  
T Lymphoblastic Lymphoma ◽  
The Impact

10003 Background: In B-acute lymphoblastic leukemia (B-ALL), CNS2 was associated with inferior 5-year (yr) event-free and overall survival (EFS/OS) in recent trials. Here, we report the impact of CNS2 in T-ALL on AALL0434 and AALL1231, recently completed consecutive randomized phase 3 trials for children and young adults with T-ALL and T Lymphoblastic Lymphoma. This report is limited to T-ALL. Both trials used augmented Berlin Frankfurt Münster regimens. AALL0434 compared Capizzi escalating methotrexate+pegaspargase (C-MTX) vs High Dose MTX (HDMTX) +/- six nelarabine (Nel) courses; outcomes improved with CMTX and Nel. CNS1/CNS2 patients, except those defined as low risk (LR) received 12Gy cranial radiation (CRT); CNS3 patients received 18Gy CRT. AALL1231 randomized patients to +/- bortezomib (Bort). AALL1231 changed the AALL0434 backbone, using dexamethasone instead of prednisone throughout. CRT was given only to patients with CNS3 disease (18Gy) and those defined as very high risk (VHR) (12Gy). CNS2 patients could not be classified as LR on AALL0434 or standard risk (SR) on AALL1231. CNS1/CNS2 patients received the same intrathecal therapy frequency on both studies. Methods: CNS status was assigned at diagnosis. CNS2 defined as: presence of < 5/ μL WBCs and cytospin positive for blasts or ≥ 5/μLWBCs with negative Steinherz Bleyer algorithm. Outcomes by CNS status were compared between AALL0434 and AALL1231. Results: From 2007-2014, AALL0434 enrolled 1562 evaluable T-ALL patients, including 1128 (72.8%) CNS1, 306 (19.7%) CNS2 and 116 (7.5%) CNS3. 90.8% received CRT, including 90.4% of CNS1 patients. 5yr EFS rates for CNS1, 2, and 3 were 85.2±1.3%, 83.1±2.6%, and 71.4±5.2% (p = 0.0007); OS rates were 90.4±1.1%, 89.2±2.1%, and 83.1±4.3% (p = 0.0438). There were no differences in 5yr disease free survival (DFS) between CNS1 and CNS2 treated with CMTX (89.7% vs. 92.9%, p = 0.17) or CMTX+Nel (91.8% vs. 89.9%; p = 0.62). AALL1231 accrued 614 evaluable T-ALL patients [CNS1 437 (71.1%), CNS2 134 (21.8%), CNS3 43 (7.0%)] from 2014 to early closure in 2017. Of these, only 12% were scheduled to receive CRT. 3yr EFS rates for CNS1, 2 and 3 were 84.1±2.1%, 84.6±3.8% and 78.6±7.9% (p = 0.50). 3yr OS was: CNS1 87.5±1.9%, CNS2 92.2±2.8%, CNS3 78.5±7.9% (p = 0.017) . 3yr EFS was not statistically distinct without Bort in CNS1, 2 or 3 (85.3±2.9%, 81.4±5.6%, 71.9±13.4%) (p = 0.10) or with Bort (82.9±3.0%, 88.3±4.9%, 83.3±9,4%; p = 0.43). Intermediate risk (IR) CNS1 and CNS2 patients received identical therapy and had similar 3yr EFS (88.8±2.8% vs 88.8±3.5%, p = 0.98). Conclusions: Unlike in B-ALL, EFS/OS was similar for CNS1 and CNS2 on AALL0434 (with CRT) and AALL1231 (without CRT). Further, IR CNS1 and CNS2 on AALL1231 had similar outcomes with identical therapy. Thus, CNS2 status is non-prognostic in T-ALL on these contemporary COG regimens. CNS3 patients have poor outcomes in T-ALL despite CRT and intensive chemotherapy, novel approaches are needed. Clinical trial information: NCT00408005, NCT02112916.

scholarly journals Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia

2014 ◽  
Vol 32 (9) ◽  
pp. 949-959 ◽  
Author(s):  
Deepa Bhojwani ◽  
Noah D. Sabin ◽  
Deqing Pei ◽  
Jun J. Yang ◽  
Raja B. Khan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Brain Magnetic Resonance Imaging ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Asymptomatic Patients ◽  
A Genome ◽  
Increased Risk

Purpose Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

Intensive intravenous methotrexate and mercaptopurine treatment of higher-risk non-T, non-B acute lymphocytic leukemia: A Pediatric Oncology Group study.

1994 ◽  
Vol 12 (7) ◽  
pp. 1383-1389 ◽  
Author(s):  
B Camitta ◽  
D Mahoney ◽  
B Leventhal ◽  
S J Lauer ◽  
J J Shuster ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Lymphocytic Leukemia ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
Free Survival ◽  
Continuation Therapy ◽  
Potential Efficacy ◽  
Patients At Risk ◽  
B Lineage

PURPOSE To determine the potential efficacy and toxicity of intravenous (i.v.) methotrexate (MTX) and mercaptopurine (MP) as postremission intensification treatment for children with B-lineage acute lymphoblastic leukemia (ALL) at higher risk to relapse. PATIENTS AND METHODS Eighty-three patients (age 1 to 20 years) with higher-risk B-lineage ALL were entered onto this protocol. Following standard four-drug remission induction, 80 patients received 12 intensive 2-week cycles of MTX/MP: MTX 200 mg/m2 i.v. push, then 800 mg/m2 i.v. 24-hour infusion on day 1; MP 200 mg/m2 i.v. in 20 minutes, then 800 mg/m2 i.v. 8-hour infusion day 2; MTX 20 mg/m2 intramuscularly day 8; and MP 50 mg/m2 by mouth days 8 to 14. Age-based triple intrathecal therapy (MTX, hydrocortisone, and cytarabine) was administered for CNS prophylaxis. Continuation therapy was weekly MTX/MP (as on days 8 to 14) for 2 years. RESULTS Eighty-one patients (98%) entered remission. There were 28 relapses (marrow, n = 11; marrow and CNS, n = 2; isolated CNS, n = 9; testes, n = 5; ovaries, n = 1). No overt relapse occurred during the intensive phase of therapy. The event-free survival (EFS) rate at 4 years is 57.4% +/- 9.1% (SE). Hematologic, mucosal, and infectious toxicities were seen in 12%, 9%, and 5% of intensive MTX/MP courses, but were generally mild. CONCLUSION Combined data from this and our previous trial suggest that intensive MTX/MP may produce long-term disease-free survival in 70 to 75% of children with B-lineage ALL. In comparison to other intensive regimens, intensive MTX/MP is easy to administer, effective, and relatively nontoxic. If patients at risk for failure of MTX/MP can be identified prospectively, more aggressive regimens could be restricted to this smaller (25% to 30%) cohort.

A New Method To Evaluate the Prognostic Value of Response to Prednisone Pre-Treatment in Adult (15–60 Yrs) Patients with Acute Lymphoblastic Leukemia: Results of the GIMEMA LAL 2000 Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1829-1829 ◽  
Author(s):  
Giovanna Meloni ◽  
Simona Iacobelli ◽  
Paola Fazi ◽  
Marco Vignetti ◽  
Francesco Di Raimondo ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Reduction Rate ◽  
Disease Free Survival ◽  
Treatment Phase ◽  
High Dose ◽  
Blast Count ◽  
Pre Treatment ◽  
Wbc Count

Abstract The prognostic significance of the response to initial prednisone treatment in adult ALL has been recently emphasized. Prednisone response is usually defined on the basis of the peripheral leukemic blast count. The threshold value for the defintion as good or poor prednisone response is 1000 blasts/mmc on day 8 of prednisone pre-treatment. The drawback of this definition is the difficulty of classifying patients with less than 1000 blasts at diagnosis. In the LAL2000 GIMEMA study we therefore evaluated whether the blast reduction rate, which is not affected by the initial blast level, could be a factor with comparable prognostic value. The protocol design provided a 7-day (−6 to 0) pre-treatment phase with an escalating dose of prednisone up to 60 mg/sqm. On day 1 before starting the induction the response was assessed both according to the absolute blast count (&lt; versus ≥ 1000/mmc) (criterion 1) and according to the blast reduction rate ≥ 75% (criterion 2) in the peripheral blood. The induction included high dose Daunorubicin; for patients in complete remission (CR) this was followed by consolidation with high dose ARA-C, chemo and radio prophylaxis of the central nervous system, and periodical reinduction over a three years maintenance period. Patients with adverse cytogenetic features [i.e. t(9;22), t(4;11), t(1;19)] who achieved a CR were treated according to the HAM protocol that included high dose ARA-C and Mitoxantrone followed by Imatinib for Ph+ ALL and by allogeneic or autologous hemopoietic stem cells transplantation for the others. Between September 2000 and December 2003 a total of 368 patients were evaluable for response to induction. The median age was 35 years (15–60) and median WBC count 15′109/L (0.3–872); 72 (20%) were T ALL and 121 (33%) had cytogenetic high risk features (104 (86%) Ph+, 4 (3%) t(4;11) and 13 (11%) t(1;19)). Eighty-seven percent of the patients were evaluable for response to steroid pre-treatment: ’responders’ were 75% according to criterion 1 (blast &lt;1′109/L on day 0), and 80% according to criterion 2 (blast reduction rate ≤75% on day 0). The overall CR rate was 83%. The probability of response was significantly higher in prednisone responders with respect to non responders according to both criteria: 87% versus 63% (p&lt;0.0001) according to criterion 1, 85% versus 68% (p=0.001) according to criterion 2. Also the post CR outcome was better in steroid responders, regardless of the definition. Using criterion 1, median disease-free survival (DFS) was 24 months in responders and 11 months in non responders; using criterion 2, median DFS was 23 months in responders and 12 months in non responders. Both criteria were significantly related to DFS in a multivariate analysis adjusted for cytogenetic risk and WBC count at diagnosis (&gt;=/&lt;50). In conclusion, our study confirms that the sensitivity to steroids is an independent prognostic factor for the outcome of adult ALL; moreover, we propose an alternative method of its evaluation with respect to the one currently used. This method has the advantage of allowing to classify all patients, regardless of the initial blasts level, and shows a comparable prognostic value.

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.

A Multicenter Phase II Study Using a Dose Intensified Pediatric Regimen in Adults with Untreated Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1858-1858 ◽  
Author(s):  
Daniel J. DeAngelo ◽  
Lewis B. Silverman ◽  
Stephen Couban ◽  
Suzanne Dahlberg ◽  
Philip C. Amrein ◽  
...  
Keyword(s):  
Phase Ii ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Demographic Data ◽  
Philadelphia Chromosome ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Childhood All

Abstract Background: In children with ALL, current chemotherapy regimens produce an event-free survival (EFS) of greater than 80%. Adults with ALL have a much poorer prognosis, with EFS rates of 30–40%. Recent retrospective studies suggest that young adult patients may have superior outcomes when treated on more intensive pediatric regimens, but prospective studies are lacking. A phase II trial was performed in an effort to determine if an intensive pediatric regimen can be administered to adults with ALL. Methods: The therapeutic backbone of this protocol is based upon the high-risk arm of the DFCI Childhood ALL Consortium Protocol 00–01. Patients with newly diagnosed ALL were enrolled and received intensive multiagent remission induction chemotherapy, which included doxorubicin, prednisone, vincristine, high-dose methotrexate, high-dose asparaginase, and triple intrathecal therapy. CNS prophylaxis included triple intrathecal therapy and cranial radiation. Intensification therapy consisted of 3 week courses of doxorubicin, vincristine, dexamethasone, 6-mercaptopurine and 30 weeks of high-dose asparaginase that was individually dosed in order to maintain asparagine depletion. Continuation therapy consisted of 3 week courses of vincristine, dexamethasone, methotrexate and 6-mercaptopurine for a total of 2 years from an established complete remission (CR). Results: 71 patients have been enrolled to date. Although there was no initial upper age restriction, the protocol was amended to include only patients between the ages of 18–50 with de novo ALL; this amendment excluded 4 patients from the analysis. Two patients were enrolled but never received therapy. Demographic data are available for 61 evaluable patients. The median age was 28 years, (range, 18–50), 65% were male, 75% had B-lineage phenotype, and 13% were Philadelphia chromosome positive. In the 54 patients for whom response data was available, the 4 week CR rate was 82%. Among the patients who had the opportunity to complete Intensification therapy, asparaginase data was available for 23 patients, 18 (78%) of whom completed all 30 weeks. One death occurred during induction therapy from sepsis. Four patients developed grade 3 pancreatitis and one patient died of grade 5 pancreatitis. The latter case represented the only remission death on study. There were two cases of osteonecrosis, 10 cases of thrombosis/embolism and 12 cases of neutropenic infection that occurred during the post-remission period. At the median follow-up time of 18.4 months, the estimated EFS is 75% (95%CI: 61–89%) and the overall survival is 79% (95%CI: 65–93%). Conclusions: These results suggest that administration of a dose intensified pediatric-like strategy is feasible. Although the high EFS rate requires longer follow up and larger confirmatory studies, such intensive treatment of young adults with ALL could represent a major therapeutic advance.

Treatment Intensification of Traditional BFM Therapy with 3 Chemotherapy Blocks and Double Delayed Intensification (Protocol II) Improves Outcome in Infants with High Risk (HR) Acute Lymphoblastic Leukemia (ALL): Results of Two Consecutive AIEOP Studies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 871-871 ◽  
Author(s):  
Carmelo Rizzari ◽  
Maria Grazia Valsecchi ◽  
Paola De Lorenzo ◽  
Maurizio Aricò ◽  
Giuseppe Basso ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
High Dose Chemotherapy ◽  
P Value ◽  
High Dose ◽  
Treatment Intensification ◽  
Treatment Protocols ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Introduction: Cure rates of ALL in children aged less than one year (i.e. infants) at diagnosis are in the range of 35–40%. Encouraging results have been recently reported in infants by using intensified treatment, including high dose chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Aim: To evaluate the impact of the two treatment strategies adopted in the AIEOP ALL 91 and 95 studies on the outcome of ALL in infants. Patients and Methods: Fifty-two infants with ALL were enrolled between 1991 and 1999 in two consecutive studies, named AIEOP ALL 91 and ALL 95. Infants with an identified t(4;11) translocation had to be included in the high risk (HR) groups whilst those without this genetic abnormality could be treated in the intermediate (IR) or HR groups according to presenting features and treatment response. Patients belonging to the IR groups received a traditional BFM back-bone based treatment (protocols I, M and II), while those classified in the HR groups underwent an tensified treatment including induction (BFM protocol IA only, in study AIEOP ALL 91, and IA+IB in study ALL 95), consolidation with either 9 blocks of non-cross-resistant drugs (ALL 91) or 3 blocks followed by the 8-drug reinduction regimen - BFM protocol II - repeated twice (ALL 95). All patients were given a continuation phase (reinforced in HR patients of study ALL 95 by vincristine/prednisone pulses). Overall treatment duration was 2 years in both studies. Results: Infants in studies ALL 91 (n=21) and ALL 95 (n=31) had similar biological and clinical characteristics. The overall event-free survival (EFS) at 5 years was 45.0% (SE 7.0%). The EFS, after censoring for HSCT in 1st CR, was 38.1% (SE 11.4%) in ALL 91 and 51.6% (SE 9.9%) in ALL 95 (p-value=0.29). Patients treated in the IR arm of the two studies had a similar outcome. Better results were obtained in patients treated in the HR arm of ALL 95 study, where 9/17 chemotherapy-only patients and 3/4 HSCT patients are alive in CCR as compared to 1/7 and 0/2, respectively, in patients treated in the ALL 91 study. Discussion: These data show that full traditional BFM therapy intensified by 3 post-induction chemotherapy blocks and double protocol II (adopted in study ALL 95), is associated with a better outcome in infants with HR ALL.

A Multicenter Phase II Study Using a Dose Intensified Pediatric Regimen in Adults with Untreated Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 587-587 ◽  
Author(s):  
Daniel J. DeAngelo ◽  
Suzanne Dahlberg ◽  
Lewis B. Silverman ◽  
Stephen Couban ◽  
Philip C. Amrein ◽  
...  
Keyword(s):  
Young Adults ◽  
Phase Ii ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Treatment Strategies ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Childhood All

Abstract Background: Current chemotherapy regimens in children with ALL produce event-free survival (EFS) rates of greater than 80%. In contrast, adults with ALL have a much poorer prognosis, with EFS rates of 30–40%. Recent retrospective studies suggest that young adults may have superior outcomes when treated with intensive pediatric regimens. Unfortunately, prospective studies are lacking. This phase II trial was performed to determine if an intensive pediatric regimen could be administered to adults with ALL. Methods: The therapeutic backbone of this protocol is based on the high-risk arm of the DFCI Childhood ALL Consortium Protocol 00-01. Patients with newly diagnosed ALL received induction chemotherapy, which included doxorubicin, prednisone, vincristine, high-dose methotrexate, L-asparaginase (L-asp), and triple intrathecal therapy. CNS prophylaxis included triple intrathecal therapy and cranial radiation. Intensification therapy consisted of ten 3-week courses of doxorubicin, vincristine, dexamethasone, 6-mercaptopurine and 30 weeks of L-asp that was dosed to maintain asparagine depletion, defined as an L-asp level between 0.1 and 0.14. Continuation therapy consisted of 3 week courses of vincristine, dexamethasone, methotrexate and 6-mercaptopurine for a total of 2 years from an established complete remission (CR). Results: 89 patients have been enrolled and treated to date. The first 75 eligible patients were used for this analysis, 73 of whom had on-study data. Although there was no initial upper age restriction, the protocol was amended to include only patients between the ages of 18–50 with de novo ALL, which excluded 4 patients from the analysis. The median age was 28 years, (range, 18–50), 60% were male, 74% had B-lineage phenotype, and 20% were Philadelphia chromosome positive. The CR rate after 4 weeks was 84%. 39 patients had the opportunity to complete L-asp intensification therapy, and 27 (69%) completed all 30 weeks. The median L-asp dose was 16,582 U/m2 (starting dose was 12,500 U/m2). One death occurred during induction therapy (sepsis). Nine patients developed pancreatitis, one of whom died. This last case represented the only remission death on study. Two patients developed osteonecrosis, 14 thrombosis/embolism and 23 neutropenic infection during the post-remission period. With a median follow-up time of 15.3 months, the estimated 2-yr EFS is 72.5% (95%CI: 61–84%) and the estimated 2-yr overall survival (OS) is 77.1% (95%CI: 67–95%). Conclusions: The administration of a dose intensified pediatric regimen to adults with ALL is feasible. Although the high EFS and OS rates require longer follow up, such intensive treatment strategies for young adults with ALL could represent a major therapeutic advance.

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.

Increased Expression of Macrophage Migration Inhibitory Factor (MIF) Receptor CD74 Is Associated with Inferior Outcome in Younger Patients (Pts) with Cytogenetically Normal Acute Myeloid Leukemia (CN-AML): a Cancer and Leukemia Group B (CALGB) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1616-1616 ◽  
Author(s):  
Eyal C. Attar ◽  
Kati Maharry ◽  
Krzysztof Mrózek ◽  
Michael D. Radmacher ◽  
Susan P. Whitman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cellular Proliferation ◽  
Conflicts Of Interest ◽  
Advanced Pancreatic Cancer ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Free Survival ◽  
Expression Levels ◽  
The Impact ◽  
Disease Free

Abstract Abstract 1616 Poster Board I-642 CD74 is a type II integral membrane protein receptor that binds its ligand MIF to induce phosphorylation of the extracellular signal-regulated kinase-1/2 (ERK-1/2) and drive cellular proliferation via nuclear factor-kappa B (NF-kB) activation. CD74 expression has been identified in human solid tumors, and its expression is associated with adverse prognosis in advanced pancreatic cancer. As CD74 is expressed and NF-kB constitutively activated in myeloblasts, we hypothesized that CD74 expression might also be associated with adverse outcome in AML. To investigate the prognostic impact of CD74 expression in the context of other predictive molecular markers in CN-AML, we assessed CD74 expression levels by Affymetrix HG-U133 Plus 2.0 microarray in 102 younger [<60 years (y)] adults with primary CN-AML, treated on the front-line CALGB 19808 trial with an induction regimen containing daunorubicin, cytarabine, etoposide and, in some cases, the inhibitor of multidrug resistance valspodar, and consolidation with autologous stem cell transplantation. Microarray data were analyzed using the Robust Multichip Average method, making use of a GeneAnnot chip definition file, which resulted in a single probe-set measurement for CD74. At diagnosis, CD74 expression, when assessed as a continuous variable, was significantly associated only with extramedullary disease involvement (P=.006) among clinical features, and with none of the molecular prognostic variables tested, including NPM1, WT1, CEBPA, FLT3 (FLT3-ITD and FLT3-TKD) mutations, MLL partial tandem duplication, or differential BAALC and ERG expression levels. Although CD74 expression levels were not associated with achievement of complete remission (CR; 83% vs 81%), higher levels of CD74 were associated with shorter disease-free survival [DFS; P=.046, hazard ratio (HR) 1.85, 95% confidence interval (CI) 1.12-3.08] and with shorter overall survival (OS; P=.02, HR 1.32, CI 1.04-1.67). In multivariable analyses, higher CD74 expression was independently associated with shorter DFS (P=.045, HR 1.98, CI 1.16-3.40), after adjusting for WT1 mutations (P<.001) and FLT3-TKD (P=.04), and shorter OS (P=.01, HR 1.58, CI 1.11-2.25) after adjusting for FLT3-TKD (P=.02), WT1 mutations (P=.007), BAALC expression levels (P=.02), white blood counts (P=.007), and extramedullary involvement (P=.04). As quartiles 2-4 had similar expression levels distinct from the lowest quartile, to display the impact of CD74 expression levels on clinical outcome only, pts were dichotomized into low (the lowest quartile) and high (the top three quartiles) CD74 expressers. The Kaplan-Meier curves for DFS and OS (Figures 1 and 2) are shown below. In conclusion, our study identifies elevated CD74 expression as associated with adverse prognosis in younger CN-AML pts. Since we previously reported that higher CD74 expression was favorably associated with achievement of CR in AML patients receiving chemotherapy plus bortezomib, an inhibitor of the proteasome and NF-kB (Attar et al., Clin Cancer Res, 2008;14:1446-54), it is possible that in future studies elevated CD74 levels can be used not only for prognostication, but also to stratify CN-AML pts to study of bortezomib-containing chemotherapy regimens. Figure 1 Disease free survival Figure 1. Disease free survival Figure 2 Overall survival Figure 2. Overall survival Disclosures No relevant conflicts of interest to declare.

Increased Incidence of Osteonecrosis (ON) with a Dexamethasone (DEX) Induction for High Risk Acute Lymphoblastic Leukemia (HR-ALL): A Report from the Children’s Oncology Group (COG).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 898-898 ◽  
Author(s):  
Leonard A. Mattano ◽  
James B. Nachman ◽  
Meenakshi Devidas ◽  
Naomi Winick ◽  
Elizabeth Raetz ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Initial Study ◽  
Intrathecal Methotrexate ◽  
High Dose ◽  
Historical Comparison ◽  
Randomized Design ◽  
Age Cohort ◽  
Methotrexate Dose ◽  
Grade 3 ◽  
The Impact

Abstract Treatment with DEX, rather than prednisone (PRED), improves outcome for children with standard risk ALL. However, DEX exposure is strongly associated with the development of therapy-related ON, particularly in adolescents. Previous COG HR-ALL studies have shown a lower ON risk for patients receiving 1 vs. 2 delayed intensification (DI) phases, and for DI using discontinuous DEX (days 1–7 & 15–21) vs. continuous DEX (days 1–21), suggesting a strategy for giving the drug with acceptable toxicity. The HRALL study COG AALL0232 utilizes a modified augmented BFM backbone that compares in a 2x2 randomized design: induction DEX (10 mg/M2/day x14 days) vs PRED (60 mg/M2/day x28 days), and interim maintenance (IM) escalating-dose “Capizzi” methotrexate vs. high-dose (HD) MTX. Induction rapid early responders (RER) receive single DI while slow responders receive double DI; all patients receive monthly 5-day DEX pulses during maintenance. To limit ON risk in adolescents, in the initial study design children ≥ 13y received discontinuous DEX during single or double DI; those <13y received continuous DEX. In 10/2006 the study was amended due to an unexpectedly high ON incidence in patients 10–12y receiving continuous DEX (28% @ 18 months) compared with historical controls given discontinuous DEX (3.4%). Subsequently all patients ≥ 10y have received discontinuous DEX; it is too early to assess the impact of this change. A comprehensive interim ON analysis was completed 4/2008 (reported as 24-month cumulative incidences). Overall ON incidence is 10.4% (110/1647), and is higher for those age ≥ 10 vs. <10y (15.2 vs 2.6%, p<0.0001, RHR=6.38); 99/110 cases of ON occurred in the older cohort. Among all patients, ON incidence is higher in DEX vs. PRED regimens (11.6 vs 8.7%, p=0.014, RHR 1.64); rates are similar for Capizzi MTX vs. HD-MTX regimens (10.4 vs 9.8%). Among patients ≥ 13y, incidence is higher in DEX vs. PRED regimens (18.9 vs 9.9%, p=0.02, RHR 1.97). There is no difference between regimens for children <10y. Among randomized RER patients ≥ 10y, incidence is higher in DEX vs. PRED regimens (17.2 vs 12.6%, p=0.006, RHR=1.79). For historical comparison, ON incidences by age cohort for RER patients on AALL0232 regimen PC (PRED + Capizzi MTX) vs. CCG-1961 regimen D (double DI with discontinuous DEX) were: <10y 4.1±3.4 vs. 2.0±1.4%, 10–12y 21.9±10.6 vs. 7.1±2.8%, and ≥ 13y 7.1±10.1 vs. 6.6±3.8%. To address these findings, the study was amended 6/2008. Patients ≥ 10y will be non-randomly assigned to induction PRED; the induction steroid randomization will continue for younger patients. Patients of all ages will receive discontinuous DEX during DI and PRED pulses during maintenance. Of note, compared with CCG-1961 the AALL0232 augmented BFM backbone was non-randomly modified in several ways that may affect ON incidence, including the use of pegaspargase during induction, a higher 15 mg intrathecal methotrexate dose for those age ≥ 9y, and monthly DEX instead of PRED maintenance pulses. Heightened awareness among caregivers may also have led to increased recognition and reporting of this toxicity. Using CTCAE v3.0 criteria, clinical ON severity among the 110 patients is: 3% grade 1, 60% grade 2, 35% grade 3, and 2% grade 4. Data regarding surgical intervention are being collected. These findings will directly influence the design of future trials in an effort to lessen the incidence and burden of this toxicity.

Sign in / Sign up

Export Citation Format

Share Document