Significance of Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) In Adults with De Novo Acute Lymphoblastic Leukemia (ALL) After Therapy with the Modified Hyper-CVAD Regimen

Abstract Abstract 2145 The hyper-CVAD regimen is an effective frontline program for de novo adult ALL [Kantarjian, JCO 18:547, 2000; Kantarjian, Cancer 101:2788, 2004]. Intensive cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternate with high dose methotrexate (MTX) and cytarabine every 21 days for 8 courses, followed by maintenance therapy with POMP (6-mercaptopurine, MTX, VCR, prednisone) interrupted with early and late intensifications. The regimen was modified in 1999 in order to improve on the results. Induction chemotherapy was administered in a laminar air flow room for pts aged 60 years or older owing to high induction mortality rate (17%). Rituximab 375 mg/m2 (days 1 & 11 of hyper-CVAD, days 1 & 8 of MTX-cytarabine for 8 total doses) was given if CD20 expression was > 20% owing to association with increased propensity for relapse [Thomas D, Blood 113:6330, 2009]. CNS prophylaxis alternated intrathecal MTX day 2 with cytarabine day 7 of the first 3 courses for low CNS risk and first 4 courses for high CNS risk (in the absence of CNS disease). The maintenance phase was extended from 24 to 30 mos with modifications of the early and late intensifications (hyper-CVAD followed by MTX-L-asparaginase mos 6 & 7 and 18 & 19) in order to reduce incidence of late relapses. Newly diagnosed or primary refractory (1 course only) pts with Philadelphia chromosome negative B-lymphoblastic leukemia (n=126) were treated with this modified hyper-CVAD regimen without anthracycline intensification (pts age 30 years or less have been allocated to treatment with the pediatric-inspired augmented Berlin-Frankfurt-Muenster regimen since 2006). Median age was 43 yrs (range, 15–83). CD20 expression was noted in 49%. Overall CR rate of the group was 93%; the rate of MRD negativity by 4- or 6-color MFC (sensitivity of 0.01%) at the time of CR in 95 evaluable pts was 72%. Overall, MRD positivity by MFC at the time of CR was associated with a higher relapse rate (52% versus 21%, p=.01) and lower 3-yr CR duration rates (45% versus 78%, p=.01). The CD20 positive pts (n=57) who were treated with rituximab had a higher rate of MRD negativity by MFC at CR than their CD20 negative counterparts (81% versus 58%, p=.02). MRD positivity by MFC after hyper-CVAD and rituximab was associated with a significantly lower 3-yr CR duration rate (24% versus 82%, p=.002), but survival rates were not statistically different (27% versus 70%) likely due in part to deaths in CR in the older subset of the MRD-negative group. In contrast, for the CD20 negative subset, presence of detectable MRD by MFC at the time of CR was not associated a with lower 3-yr CR duration rate (58% versus 63%). Dectectable MRD by MFC at the time of CR, despite subsequent eradication with consolidation chemotherapy in the majority of patients, predicts for increased risk of disease recurrence. Strategies to improve the MRD negativity rate at the time of CR (e.g., addition of monoclonal antibodies directed at other lymphoblast antigens such as CD22 for the CD20 negative subset and use of the newer anti-CD20 monoclonal antibodies for the CD20 positive subset) may further improve outcome after frontline therapy with the modified hyper-CVAD regimens. Disclosures: Thomas: Novartis: Honoraria; Bristol-Meyer-Squibb: Honoraria; Pfizer:; Amgen: Research Funding. Off Label Use: Imatinib for de novo Philadelphia positive ALL. Dasatinib for de novo Philadelphia positive ALL. Rituximab for CD20 positive ALL and Burkitt leukemia/lymphoma. Nelarabine for de novo T-lymphoblastic leukemia/lymphoma.

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

Blood ◽

10.1182/blood.v114.22.836.836 ◽

2009 ◽

Vol 114 (22) ◽

pp. 836-836

Author(s):

Deborah A. Thomas ◽

Hagop M. Kantarjian ◽

Stefan Faderl ◽

William G. Wierda ◽

Jorge Cortes ◽

...

Keyword(s):

B Cell ◽

De Novo ◽

Conflicts Of Interest ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Disease Free Survival ◽

High Dose ◽

Induction Phase ◽

Liposomal Daunorubicin ◽

Cd20 Expression

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

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Pediatric-Based Therapy for Young Adults with Newly Diagnosed Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v114.22.2037.2037 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2037-2037 ◽

Cited By ~ 2

Author(s):

Michael Rytting ◽

Deborah A. Thomas ◽

Anna R Franklin ◽

Elias Jabbour ◽

William Wierda ◽

...

Keyword(s):

Flow Cytometry ◽

Young Adults ◽

De Novo ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Unknown Origin ◽

High Dose ◽

Days Of Therapy ◽

Grade Iii

Abstract Abstract 2037 Poster Board II-14 Adolescents 14 to 21 years of age with de novo acute lymphoblastic leukemia (ALL) have improved outcomes if treated on pediatric chemotherapy regimens as opposed to adult regimens. Young adults with ALL may also benefit from chemotherapy modeled after pediatric regimens, though toxicities may be limiting. We report on 48 young adult patients between the ages of 12 to 40 years with de novo Philadelphia chromosome negative ALL treated with the augmented Berlin-Frankfurt-Munster (BFM) chemotherapy regimen. All patients have completed at least the initial 28 days of therapy (induction) consisting of high dose prednisone, pegylated asparaginase (PEG-asp), vincristine, daunorubicin and intrathecal treatments. The median age of the group was 20 yrs (14-36); 40 patients had pre-B ALL and 8 T-ALL, No infectious deaths were observed during induction. 45 (95%) patients achieved a remission by 29 days and 2 achieved remission after a 2 week extension of induction. One patient was refractory to therapy. 39 (81%) patients achieved a morphological marrow remission (<5% blasts) by day 15 of treatment (rapid early responders). Minimal residual disease (MRD) assessed by flow cytometry was negative at the end of induction for 30 (62%), positive in 10 (21%), suspicious in 6 (12%) and not available for 2 patients. In the 41 patients who completed 12 weeks of therapy, MRD was negative in 35 (85%) and positive in 6 (15%). 7 (15%) patients have relapsed or have refractory disease; 1 patient died in CR. Admission for fever of unknown origin with neutropenia occurred in 10 (21%) patients, an additional 10 (21%) patients had documented infections. Grade III-IV hepatic toxicity has been prominent: 22 (45%) increased transaminase, 14 (29%) hyperbilirubinemia. 9 (19%) patients had allergic reactions to PEG-asp, and 10 (21%) had thrombotic events. The majority of grade III-IV adverse events have been reversible. The median complete remission duration is 57 weeks (range 5-143). The overall survival at two years is 82%. In summary, this pediatric-based regimen for young adults with ALL effectively induces remission, both by morphology and by flow cytometry. Toxicity has been significant, but mostly transient and tolerable. Longer follow-up is needed to determine the long-term efficacy of this regimen in young adults with ALL. Disclosures: Rytting: Enzon: Speakers Bureau. Jabbour:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau.

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MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL

Cancers ◽

10.3390/cancers13092108 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2108

Author(s):

Manuela Tosi ◽

Orietta Spinelli ◽

Matteo Leoncin ◽

Roberta Cavagna ◽

Chiara Pavoni ◽

...

Keyword(s):

Residual Disease ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Philadelphia Chromosome ◽

Current Treatment ◽

New Drugs ◽

Term Survival ◽

Therapeutic Decisions ◽

Key Factor ◽

Combined Strategy

In many clinical studies published over the past 20 years, adolescents and young adults (AYA) with Philadelphia chromosome negative acute lymphoblastic leukemia (Ph− ALL) were considered as a rather homogeneous clinico-prognostic group of patients suitable to receive intensive pediatric-like regimens with an improved outcome compared with the use of traditional adult ALL protocols. The AYA group was defined in most studies by an age range of 18–40 years, with some exceptions (up to 45 years). The experience collected in pediatric ALL with the study of post-induction minimal residual disease (MRD) was rapidly duplicated in AYA ALL, making MRD a widely accepted key factor for risk stratification and risk-oriented therapy with or without allogeneic stem cell transplantation and experimental new drugs for patients with MRD detectable after highly intensive chemotherapy. This combined strategy has resulted in long-term survival rates of AYA patients of 60–80%. The present review examines the evidence for MRD-guided therapies in AYA’s Ph− ALL, provides a critical appraisal of current treatment pitfalls and illustrates the ways of achieving further therapeutic improvement according to the massive knowledge recently generated in the field of ALL biology and MRD/risk/subset-specific therapy

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

Blood ◽

10.1182/blood.v108.11.1858.1858 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1858-1858 ◽

Cited By ~ 3

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.

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Phase II Study of Combination of the HyperCVAD Regimen with Dasatinib in Patients with Philadelphia Chromosome (Ph) or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL) and Lymphoid Blast Phase Chronic Myeloid Leukemia (CML-LB).

Blood ◽

10.1182/blood.v110.11.2814.2814 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2814-2814 ◽

Cited By ~ 4

Author(s):

Farhad Ravandi ◽

Deborah Thomas ◽

Hagop Kantarjian ◽

Stefan Faderl ◽

Charles Koller ◽

...

Keyword(s):

Phase Ii ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Clinical Activity ◽

High Dose ◽

Cell Transplant ◽

Newly Diagnosed ◽

Blast Phase ◽

Platelet Recovery

Abstract Combination of cytotoxic chemotherapy with imatinib has improved the outcome for patients with Ph+ ALL and resulted in eradication of minimal residual disease and durable remissions without allogeneic stem cell transplant in some patients (Thomas D, Blood, 2004; Yanada M, JCO, 2006; Wassmann B, Blood, 2006; de Labarthe A, Blood, 2007). The dual Src and Abl inhibitor dasatinib has a significantly higher in vitro kinase inhibition against BCR-ABL and has demonstrated potent clinical activity in patients with imatinib-resistant lymphoid blast phase CML (CML-LB) and Ph+ ALL with over 50% complete cytogenetic responses (CG CR) in phase I and II trials but with median progression free survival of only 3 to 4 months. We are conducting a phase II trial in which patients with newly diagnosed or relapsed Ph+ ALL or CML-LB receive dasatinib 50 mg po bid for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Patients in complete remission (CR) continue to receive maintenance dasatinib 50 mg po bid daily and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. To date 15 newly diagnosed patients with Ph+ ALL (cohort I) and 4 patients with relapsed Ph+ ALL or CML-LB (cohort II) have received a median of 4 cycles (range 1 – 8); 4 patients are receiving maintenance in CR. Median age for cohort I is 55 years (range 23 – 79) and for cohort II, 43 years (range 26 – 69); 13 and 3 patients were older than 50 years, respectively. Median WBC at diagnosis for cohort I was 4.3 × 109/L (range, 0.8 – 203.4 x 109/L). Three patients had CNS involvement. Fourteen and 3 patients in the 2 cohorts are evaluable for response to induction; 2 are too early. Thirteen patients (93%) in cohort I and all evaluable patients in cohort II have achieved CR after the first cycle; 1 patient in cohort I died on day 20 from infections before response assessment; her bone marrow exam on day 14 showed no detectable disease. Ten of 11 (91%) patients in cohort I have achieved CG CR after 1 cycle; 3 are too early. Three of 4 patients in cohort II have achieved CG CR after 1 cycle; 1 had a new CG abnormality and 1 is too early. Six patients have achieved complete molecular remission after the first cycle with the lowest BCR-ABL/ABL in the other patients ranging from 0.01 to 1.91. Median time to neutrophil and platelet recovery for cohort I is 18 and 25 days and for cohort II 18.5 and 30.5 days. Grade 3 and 4 toxicity has included 7 episodes of GI bleeding as well as infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and acute renal failure unrelated to treatment. With a median follow up of 4 months (range, 0 – 10), 15 patients are alive and in CR; 1 died at induction, 1 died in CR from an unrelated cardiac event, and 2 are too early. No patient has relapsed and no patient has received an allogeneic transplant. We conclude that the combination of the hyperCVAD regimen with dasatinib is feasible and can achieve early molecular remissions in patients with Ph+ ALL and CML-LB.

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

Blood ◽

10.1182/blood.v110.11.587.587 ◽

2007 ◽

Vol 110 (11) ◽

pp. 587-587 ◽

Cited By ~ 16

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.

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Augmented Berlin-Frankfurt-Muenster Based Therapy For Young Adults With Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood.v122.21.1400.1400 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1400-1400 ◽

Cited By ~ 1

Author(s):

Michael E. Rytting ◽

Deborah A. Thomas ◽

Susan O'Brien ◽

Kurt Schroeder ◽

Rebecca Garris ◽

...

Keyword(s):

Young Adults ◽

Acute Lymphoblastic Leukemia ◽

De Novo ◽

Conflicts Of Interest ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Univariate Analysis ◽

Philadelphia Chromosome ◽

Significant Difference ◽

Grade Iii

Abstract Pediatric-based therapy of acute lymphoblastic leukemia (ALL) has been proposed as superior treatment for teen-agers and young adults with ALL. Several trials report improved survival rates in young adult ALL patients (pts) when treated with pediatric-based regimens. Augmented Berlin-Frankfurt-Muenster (ABFM) treatment is effective treatment for ALL in adolescents up to age 21. In an attempt to improve cure rates in AYA pts with ALL, we administered ABFM therapy to pts age 12 to 40 in a prospective, single institution trial. Results were then retrospectively compared to the HYPER CVAD regimen, the historical adult ALL regimen used at our institution. 85 pts with de novo Philadelphia chromosome negative ALL have completed at least 6 months of therapy. There are 69 (81%) pts with pre-B ALL and 16 (18%) pts with T-cell ALL/lymphoma. The age range is 13-39 with a median of 21. The median WBC at diagnosis is WBC=14 thousand/microliter (range 0.4-494). 80/85 (94%) pts entered remission (<5% blasts on day 29 marrow morphology). 1 patient died during induction. 61(72%) pts attained remission at day 15 of induction. 29 (22%) did not have morphological remission by day 15 of induction. At the end of induction, 46(58%) pts were minimal residual disease (MRD) negative by flow cytometry (<0.01% blasts). 25(31%) were positive for MRD and 6(7%) were not available or equivocal. By approximately day 84 of treatment, 55(69%) pts were negative for MRD and 13(16%) were positive or suspicious. Toxicities encountered include severe allergy to PEG-asparaginase in 17 (20%) pts, thrombosis in 18 (21%), hyperbilirubinemia grade III-IV in 31 (36%), elevated ALT grade III-IV in 28 (33%), hypofibrinogen grade III-IV in 30 (35%), pancreatitis in 9(11%), and avascular necrosis in 9 (11%). Grade III-IV hepatic toxicity is frequent but resolves within two weeks in almost all pts. For the entire cohort, the estimated 3 year overall survival (OS) is 75% and 3 year complete remission duration (CRD) is 71%. In univariate analysis, negative MRD at day 29 was associated with improved OS and day 84 negative MRD was associated with improved CRD. The presenting WBC was associated with OS and CRD. On multivariate analysis, only WBC over 50k/microliter maintained significance for OS and CRD. In comparing ABFM to HYPER CVAD, there is no significant difference in OS or CRD between the two regimens (fig. 1 and 2). This lack of difference in OS and CRD persists when patients are stratified for age > or </= 21 years, for presenting WBC over 50 thousand, and for MRD at the end of induction. In our hands, pediatric based therapy has significant though tolerable toxicity. Outcomes in AYA pts are similar but not superior to results obtained with historical ALL therapy. Disclosures: No relevant conflicts of interest to declare.

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T-cell acute lymphoblastic leukemia

Hematology ◽

10.1182/asheducation-2016.1.580 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 580-588 ◽

Cited By ~ 40

Author(s):

Elizabeth A. Raetz ◽

David T. Teachey

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

De Novo ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Disease Response ◽

Cell Acute Lymphoblastic Leukemia ◽

Relapsed Disease ◽

Modern Genomic

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is biologically distinct from its B lymphoblastic (B-ALL) counterpart and shows different kinetic patterns of disease response. Although very similar regimens are used to treat T-ALL and B-ALL, distinctions in response to different elements of therapy have been observed. Similar to B-ALL, the key prognostic determinant in T-ALL is minimal residual disease (MRD) response. Unlike B-ALL, other factors including age, white blood cell count at diagnosis, and genetics of the ALL blasts are not independently prognostic when MRD response is included. Recent insights into T-ALL biology, using modern genomic techniques, have identified a number of recurrent lesions that can be grouped into several targetable pathways, including Notch, Jak/Stat, PI3K/Akt/mTOR, and MAPK. With contemporary chemotherapy, outcomes for de novo T-ALL have steadily improved and now approach those observed in B-ALL, with approximately 85% 5-year event-free survival. Unfortunately, salvage has remained poor, with less than 25% event-free and overall survival rates for relapsed disease. Thus, current efforts are focused on preventing relapse by augmenting therapy for high-risk patients, sparing toxicity in favorable subsets and developing new approaches for the treatment of recurrent disease.

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Outcomes of Children with First Marrow Relapse: Results from Children’s Oncology Group (COG) Study AALL01P2.

Blood ◽

10.1182/blood.v108.11.1871.1871 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1871-1871 ◽

Cited By ~ 1

Author(s):

Elizabeth A. Raetz ◽

Michael J. Borowitz ◽

Meenakshi Devidas ◽

Stephen P. Hunger ◽

Naomi Winick ◽

...

Keyword(s):

Complete Remission ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Novel Agents ◽

Intrathecal Methotrexate ◽

Intrathecal Therapy ◽

High Dose ◽

Morphological Response ◽

B Lineage

Abstract Treatment of relapsed acute lymphoblastic leukemia (ALL) remains a significant challenge. Objectives of the COG AALL01P2 study were: a) to define a clinically acceptable re-induction platform to which novel agents might be added and b) to track response and minimal residual disease (MRD) through 4 months of treatment. The initial regimen consisted of 3, 35-day blocks of chemotherapy (block 1: vincristine, dexamethasone, PEG-asparaginase, idarubicin, and intrathecal cytarabine and methotrexate (CNS-negative), or triple intrathecal therapy (CNS-positive); block 2: etoposide, cyclophosphamide, 5 g/m2 methotrexate and intrathecal methotrexate (CNS-negative), or triple intrathecal therapy (CNS-positive); block 3: high dose cytarabine and L-asparaginase). Patients with Philadelphia chromosome positive (Ph+) ALL received imatinib mesylate in combination with all 3 blocks of chemotherapy. AALL01P2 opened in January 2003. The study was suspended in May 2003, however, due to unacceptable toxicity among the first 21 patients. Block 1 therapy was subsequently modified substituting doxorubicin for idarubicin, and prednisone for dexamethasone, and the study reopened accruing a total of 127 eligible patients (120 B-precursor-ALL, 7 T-ALL) from August 2003 through December 2005. Seventy-two patients had early marrow relapse (< 36 months from initial diagnosis) (ER) and 55 patients had late marrow relapse (LR). Four B-lineage patients were Ph+. Subsequent analyses include only patients enrolled following the modification in block 1 therapy. Complete remission (CR2) rates at the end of block 1 were 67% ± 5.9% for ER (n=63) and 96% ± 2.8% for LR (n=48). Patients with ≥ 5% residual blasts (M2 or M3 marrows) at the end of block 1 continued on protocol therapy. However, only 2 of 13 B-lineage patients with M2/3 marrows at the end of block 1 responded to subsequent chemotherapy. Event-free survival (EFS) at 4 months was 64% ± 6.7% for ER (n=72) and 93% ± 4.3% for LR (n=55). Outcome for T-ALL patients (n=7, 6 ER) was poor with complete remission achieved in only 2 of 7 patients. Toxicity was acceptable during all 3 blocks. The most common toxicities were hematopoietic and infectious, with the highest incidence during blocks 1 and 3. Five toxic deaths occurred (4%), all from infections: 3 during block 1, and 2 during block 3. MRD was measured by flow cytometry at the end of each block. MRD was detected in 79% ± 6.2% of ER (n=43), vs. 50%± 8.3% of LR (n=36) at the end of block 1 in an analysis restricted to B-lineage, CNS-negative, Ph-negative patients, regardless of their morphological response. Four month EFS was 95% ± 3.5% vs. 78% ± 5.3% in patients who were MRD-negative vs. positive at the end of block 1 (p<0.01). The AALL01P2 regimen is a tolerable and active re-induction platform, acceptable for testing in combination with novel agents. The COG ADVL04P2 study, which uses this regimen in combination with epratuzumab (anti-CD22), is currently underway. MRD measurements are also feasible at serial time points during re-induction, and early response is prognostic. Alternative strategies are urgently needed for patients with relapsed T-ALL and for early marrow relapse.

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Two Years Follow-up Results of Graspall/Graall-SA2–2008 Study: L-Asparaginase-Loaded Red Blood Cell Combined with Standard EWALL Chemotherapy in Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (Ph-ALL)

Blood ◽

10.1182/blood.v120.21.1473.1473 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1473-1473 ◽

Cited By ~ 1

Author(s):

Mathilde Hunault-Berger ◽

Thibaut Leguay ◽

Françoise Huguet ◽

Stéphane Leprêtre ◽

Eric Deconinck ◽

...

Keyword(s):

Red Blood Cells ◽

Blood Cells ◽

Older Patients ◽

Residual Disease ◽

Remission Rate ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

High Dose ◽

Newly Diagnosed

Abstract Abstract 1473 Introduction: L-asparaginase-loaded red blood cells (GRASPA®) has been shown to be a new available option for combining L-asparaginase with standard chemotherapy in different ALL population, including older patients with the disease. Tolerability and preliminary results of efficacy of GRASPA® in GRASPALL/GRAALL-SA2–2008 study have already been presented. We report below the 2-year follow-up efficacy results of this study. Methods: GRASPALL/GRAALL-SA2–2008 study aimed at determining optimal dose of GRASPA® that could be combined with standard EWALL chemotherapy backbone in patients aged >55y with newly diagnosed Ph-ALL. It was an open label Phase II dose escalation study. Primary endpoint combined tolerance and efficacy (asparagine depletion ≥7 days). Three doses of L-Asparaginase-Loaded Red Blood Cells (50, 100 and 150 IU/kg), infused twice during induction cycles, were investigated. EWALL backbone consisted of dexamethasone prephase followed by induction-1 (dexamethasone d1–2/8–11, vincristine d1,8, and idarubicine d1–2/8–9) and induction-2 (cyclophosphamide d15–17 and cytarabine d16–19/23–26). Consolidation consisted of 6 monthly alternating cycles with methotrexate (d1) / E.coli asparaginase (d2) and high-dose cytarabine (d1, 3, 5). Maintenance included mercaptopurine, methotrexate and vincristine/dexamethasone pulses for 2 years. Hematological and molecular Ig/TCR minimal residual disease (MRD) response rates, survival were secondary endpoints. Results: Between March 2009 and October 2010, 30 patients were recruited in 20 centres in France by the GRAALL network. The 50, 100 and 150 dose levels included 3, 13 and 14 patients, respectively. Median age was 67 years (range 59–77). No differences in baseline characteristics were observed across the 3 dose level groups. The tolerability with L-Asparaginase-related side effects is reported below: Overall L-asp expected adverse events tended to be lower in the 100 UI/kg group. Regarding the efficacy and benefit/risk, asparagines depletion, remission rate, EFS and OS are reported below: Three patients received the dose of 50 UI/kg but this dose was insufficient to reach a 7-day asparagine depletion. Survival analysis showed that the dose of 100IU/kg was associated with median OS of 15.6 months an absolute value that compared favorably with historical controls: 8,8 mo (Rousselot et al. Drugs Aging,2011) and 10,5 mo (Hunault et al. Haematologica,2011) Conclusion: GRASPA® at a dose of 100 UI/kg appears to be a safe and active manner to introduce L-asparaginase during initial induction chemotherapy of older patients with Ph- ALL with a sustained asparagine depletion and a good efficacy/safety profile. Disclosures: Godfrin: ERYTECH Pharma: COO Other.

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