Outcome of 136 Children with Advanced Lymphoblastic Lymphoma Receiving an BFM-Type Therapy with Intensified Maintenance: A Report from the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 Study

Abstract BACKGROUND: Lymphoblastic lymphoma (LBL) accounts for 30% of childhood non Hodgkin’s lymphoma in Japan. From European and North American groups, favorable results have been reported, using treatment strategies for acute lymphoblastic leukemia, over 80% of event free survival rate even in advanced LBL. However there were few data on Japanese or Asian patients with LBL. Here we report final outcome of first nation-wide prospective study over one hundred cases with advanced childhood LBL from Japan. PATIENTS & METHOD: Patients with stage 3 or 4 LBL received for 9 weeks induction phase, which consisted of 7 drugs and triple IT , followed by three courses of high dose MTX(5g/m2). After high dose MTX, re-induction, early maintenance, and late maintenance phase were administered. With an attempt to intensify maintenance therapy,early maintenance was consisted by two cycles of four courses of six drugs(MTX, PSL,VCR, L-ASP, 6MP, THP#) and late maintenance was five cycles of five drugs(MTX, PSL,VCR, 6MP,AraC). We omitted local radiotherapy including prophylactic cranial radiotherapy except patient with initial central nervous system (CNS) disease. The total duration of the treatment was 24 month. RESULTS: From November 2004 to October 2010, 154 children with newly diagnosed advanced stage LBL were entered in this study. A total of 136 cases were eligible. Ages ranged from four month to 15 years, with a median of 9.07 years. Of the 136 patients, 36 were girls and 100 were boys. The distribution of clinical stage 3 and stage 4 was 82 and 54 patients respectively. 94 patients had primary mediastinal disease. 41 patients had BM disease, 31 patients had CNS disease and 8 patients had BM and CNS disease. 104 patients (76.5%) had precursor T LBL (T-LBL), 31 patients (22.8%) had precursor B LBL (B-LBL), onepatient (0.7%) had bi phenotype LBL. The follow-up time ranged from 2.8 to 94 months, with a median 58 months. For the 136 patients analyzed in this study, 5-year OS was 82.9% and 5-year EFS was 77.9%. There was no significant difference in outcome by gender (5-year EFS, male 78.2% vs. female 73.0%), or by immunophenotype (5-year EFS, B-LBL 80.7% vs. T-LBL 76.9%). Of note, the 5-year EFS for stage 3 T-LBL patients were worse than that of stage 4 T-LBL patients (70.6% vs. 88.9%, P=0.031). There were also significant difference in 5-year EFS for T-LBL patients who achieved CR and CRu at end of induction, 86.9%, and 69.7% (P=0.034), respectively.Most events were observed as mediastinum enlargement before initiation of intensified maintenance therapy. CONCLUSIONS: Our firstnationwide study provided about 80% cure rate with only one case of toxic death in childhood advanced LBL. However, our intensified maintenance therapy could not improve survival outcome. Our result also emphasize the significant difference between T-LBL stage 3 and stage 4 and might suggest the difference in ethnicity for the composition of biological subgroup in T-LBL. THP: Pirarubicin Disclosures No relevant conflicts of interest to declare.

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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 ◽

10.1182/blood.v112.11.3610.3610 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3610-3610 ◽

Cited By ~ 13

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.

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Outcomes for Adult Lymphoblastic Leukemia (ALL) Are Mainly Influenced by Age and Status of Minimal Residual Disease (MRD) by Multiparameter Flow Cytometry (MFC) After Therapy with the Modified Hyper-CVAD (with or without Rituximab) Regimen

Blood ◽

10.1182/blood.v118.21.1524.1524 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1524-1524

Author(s):

Deborah A. Thomas ◽

Hagop M Kantarjian ◽

Jeffrey L. Jorgensen ◽

Stefan Faderl ◽

Elias Jabbour ◽

...

Keyword(s):

Maintenance Therapy ◽

Lymphoblastic Leukemia ◽

Adolescent And Young Adult ◽

Multiparameter Flow Cytometry ◽

High Dose ◽

Induction Phase ◽

Liposomal Daunorubicin ◽

Cns Disease ◽

Cd20 Expression ◽

Consolidation Phase

Abstract Abstract 1524 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 by early and late intensifications. The regimen was modified in 1999 to include use of laminar air flow rooms during the induction phase for pts aged 60 years or older. Rituximab 375 mg/m2 (Days 1 & 11 of hyper-CVAD, Days 1 & 8 of MTX-cytarabine for 8 total doses) was administered for CD20 expression > 20% to counteract increased propensity for relapse [Thomas D, Blood 113: 6330, 2009]. Early anthracycline intensification with liposomal daunorubicin and cytarabine was incorporated from 1999–2000 then omitted from the regimen [Thomas D, Cancer 116: 4580, 2010]. 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). Maintenance therapy was extended from 24 to 30 months inclusive of early and late intensifications (hyper-CVAD followed by weekly MTX and L-asparaginase mos 6 & 7 then mos 18 & 19) to reduce incidence of late relapses. Results in the CD20 positive B-lymphoblastic subset treated with hyper-CVAD and rituximab were encouraging; 3-yr rates of CR duration (CRD) and survival (OS) were 60% and 50% overall, respectively. In younger (age < 60 years) CD20-positive subset, rates of CRD and OS were superior compared with standard hyper-CVAD (70% v 38%; P <.001% and 75% v 47%, P =.003) [Thomas D, JCO 28: 3830, 2010]. Historical experience in the adolescent and young adult (AYA) subset aged 15 – 30 yrs with CD20 positive B-lymphoblastic leukemia (now treated with pediatric augmented BFM regimen) showed that the addition of rituximab improved the 3-yr CRD rates from 26% to 65% (P =.001) and 3-yr OS rates from 47% to 75% (P =.05) compared with standard hyper-CVAD. There were no significant differences in outcome for the AYA subset by regimen (standard or modified) for the CD20 negative groups (all 3-yr rates > 70%). In contrast to the Burkitt leukemia experience, elderly pts with CD20 positive B-lymphoblastic leukemia treated with hyper-CVAD and rituximab did not benefit (rates of CRD 45% v 50%, P = NS and OS 28% v 32%, P = NS, respectively), related in part to deaths in CR. For the modified hyper-CVAD regimen (no anthracycline intensification), the rate of MRD negativity by 4- or 6-color MFC (sensitivity 0.01%, assay now 8-color MFC) 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% v 21%, P =.01) and lower 3-yr CR duration rates (45% v 78%, P =.01). CD20 positive pts treated with rituximab had a higher rate of MRD negativity by MFC at CR than their CD20 negative counterparts (81% v 58%, P =.02). MRD positivity by MFC after hyper-CVAD and rituximab was associated with a significantly lower 3-yr CR duration rate (24% v 82%, P =.002), but survival rates were not statistically different (27% v 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 did not influence 3-yr CR duration rate (58% v 63%). Additional doses of rituximab have been added to the consolidation cycles (Day 1 of cycles 5 – 8) and during the maintenance phase. Upfront dose reductions have been implemented for the induction-consolidation phase according to age and performance status in order to reduce deaths in CR. MTX-cytarabine cycles now include vincristine. All pts receive 8 IT treatments in the absence of CNS disease. Younger pts age 40 – 50 yrs receive pegylated asparginase (2000 Units/m2 with capping) during the induction-consolidation phase and early/late intensifications (augmented hyper-CVAD). Elderly pts or younger pts with B-lymphoblastic leukemia with contraindications to asparaginase are now treated with the hyper-CVAD and ofatumumab regimen regardless of CD20 expression. The cumulative experience of the serial modifications to the hyper-CVAD regimen stratified by age/MRD status and the preliminary experience with the frontline version of the augmented hyper-CVAD regimen will be presented. Disclosures: Off Label Use: Rituximab in Lymphoblastic Leukemia.

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A Brief Use of Imatinib Immediately Before Hematopoietic Stem Cell Transplantation (HSCT) in Children with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL). Results of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Study Ph+ALL04

Blood ◽

10.1182/blood.v118.21.2554.2554 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2554-2554

Author(s):

Atsushi Manabe ◽

Hirohide Kawasaki ◽

Motoaki Chin ◽

Atsushi Sato ◽

Kimikazu Matsumoto ◽

...

Keyword(s):

Survival Rate ◽

Medical Information ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Cord Blood Transplantation ◽

High Dose ◽

Induction Phase ◽

Study Group ◽

Pediatric Leukemia ◽

Hematopoietic Stem

Abstract Abstract 2554 Aims: Children with Ph+ALL generally have a poor prognosis when treated with chemotherapy alone. The timing and duration of the use of imatinib has not been determined. We investigated a role of imatinib immediately before HSCT. Methods: All the patients with ALL were screened for diagnosis of Ph+ALL using RT-PCR. Children with Ph+ALL were enrolled on JPLSG Ph+ALL04 Study within 1 week of initiation of treatment for ALL. Treatment regimen consisted of 5 therapeutic phases: Induction phase (5-drug induction), Intensification phase (high-dose cytarabine and BFM Ib), Re-induction phase (4-drug re-induction), 2 weeks of Imatinib monotherapy phase (23 weeks after diagnosis), and HSCT phase (Etoposide+CY+TBI conditioning). Before and after each phase, minimal residual disease (MRD), the amount of BCR-ABL transcripts, was measured with the real-time PCR method (cut-off 50 copies/microgram RNA). The study was registered in UMIN-CTR (Medical Information, University hospital Medical Information Network - Clinical Trials Registry): UMIN ID C000000290. Results: During the period 2004–08, 42 patients were registered in the Ph+ALL04 study. Out of 42 patients, 37 patients (88%) achieved CR and 7 of 37 patients also achieved MRD-negative after induction phase. There were 13 patients who had no MRD at the beginning of imatinib monotherapy phase, and 14 patients were MRD-negative after imatinib phase, consequently, 14 patients were MRD-negative at the time of HSCT. Six patients relapsed before HSCT. In total, 31 patients received HSCT in 1st CR. All the patients had engraftment and no patients died because of complications of HSCT. Five patients relapsed after HSCT and 4 of the 5 patients were MRD-negative before HSCT and the other patient had detectable MRD although it was less than 50 copies. Twenty-six patients continue to be in 1st CR and MRD-negative for median of 3 years after diagnosis. The 3-year event-free survival rate and over-all survival rate for all the patients was 57% and 80%, respectively (figure 1). Five patients did not achieve CR after induction phase and they were treated with imatinib-contained chemotherapy. Four of the 5 patients achieved CR. All of the 4 patients received cord blood transplantation and remains in continued CR. Interpretation: The chemotherapy we employed was based on the previous high-risk regimen of TCCSG (Tokyo Children's Cancer Study Group) L-99-15 Study. The chemotherapy was intensive enough to induce MRD-negative in 13 at the time of imatinib phase and 31 of 42 patients were in CR at the time of HSCT (around 25–28 weeks after diagnosis). We planned to assess the efficacy of imatinib immediately before HSCT but it was not possible because of the low amount of MRD in most patients at the beginning of imatinib phase. Conclusion: Although EFS and OS was excellent in this study, 88% of induction rate appeared unsatisfactory and relapse occurred before HSCT in 6 out of 37 patients who achieved CR after induction phase. Earlier and longer use of imatinib may improve EFS in children with Ph+ALL and HSCT may be omitted in a subset of patients who achieve an early and deep remission status. Disclosures: No relevant conflicts of interest to declare.

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Lymphoblastic lymphoma in adults: results of a pilot protocol

Blood ◽

10.1182/blood.v57.4.679.679 ◽

1981 ◽

Vol 57 (4) ◽

pp. 679-684 ◽

Cited By ~ 55

Author(s):

CN Coleman ◽

JR Cohen ◽

JS Burke ◽

SA Rosenberg

Keyword(s):

Lymphoblastic Leukemia ◽

Abdominal Mass ◽

Lymphoblastic Lymphoma ◽

Myelogenous Leukemia ◽

High Dose ◽

Actuarial Survival ◽

Female Ratio ◽

Cns Disease ◽

Cns Relapse ◽

Male Female Ratio

Abstract Thirteen adult patients with histologically confirmed lymphoblastic lymphoma were treated with an intensive chemotherapy program consisting of induction with cyclophosphamide, adriamycin, vincristine, and prednisone (modified CHOP); consolidation and central nervous system (CNS) prophylaxis with methotrexate intrathecally and by high-dose intravenous injection, citrovorum factor and L-asparaginase; reinforcement with CHOP; and maintenance with 6-mercaptopurine and methotrexate. Treatment duration was 1 yr. A 14th patient with T-cell acute lymphoblastic leukemia was also treated at presentation by the same regimen. Thirteen patients had at least a mediastinal mass or abnormal cells in the bone marrow; one presented with CNS disease. The median age was 22 yr (range 16--50), and male--female ratio was 2.5:1. All patients had a rapid complete clinical response. Of the 13 patients without initial CNS disease, 4 have relapsed, 3 with primary CNS relapse and 1 with a recurrent abdominal mass. Five patients have died, 2 from drug toxicity, 2 from CNS relapse, and 1 from chronic myelogenous leukemia, which was diagnosed simultaneously with the lymphoblastic lymphoma. The median follow-up is 19 mo, and all patients have completed their planned therapy. At 3 yr, the actuarial survival is 61% and relapse-free survival is 56%.

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Long-Term Outcome for De Novo Lymphoblastic Lymphoma (LL) After Frontline Therapy with Hyper-CVAD Regimen and Variants.

Blood ◽

10.1182/blood.v116.21.2831.2831 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2831-2831

Author(s):

Deborah A. Thomas ◽

Stefan Faderl ◽

Susan O'Brien ◽

William G. Wierda ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Maintenance Therapy ◽

De Novo ◽

Lymphoblastic Leukemia ◽

First Line ◽

Term Outcome ◽

Long Term Outcome ◽

Cns Disease ◽

Mediastinal Disease

Abstract Abstract 2831 The long-term outcome for newly diagnosed LL has improved with use of intensive chemotherapy regimens designed for acute lymphoblastic leukemia (ALL) when compared to the historical experience with modified NHL regimens. An early report established the hyper-CVAD regimen (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high dose methotrexate (MTX) and cytarabine) as an effective first line therapy for LL [Thomas D, Blood 104:1624, 2004]. From April 1992 to March 2009, 49 patients (pts) with de novo LL were treated with hyper-CVAD (n=20) or modified hyper-CVAD regimens (n=11 anthracycline intensification with liposomal daunorubicin-ara-C for course 2 [regimen detailed in Thomas D, Cancer, e-pub], n=18 without anthracycline intensification). CNS prophylaxis alternated intrathecal MTX and ara-C on days 2 and 7 of the first 4 courses in the absence of CNS disease. Bulky (> 7 cm) mediastinal disease at presentation was an indication for consolidative XRT (after consolidation prior to maintenance therapy). POMP (6-mercaptopurine, vincristine, MTX, prednisone) maintenance therapy was administered for 24 months with standard hyper-CVAD (MTX-L-asparaginase intensifications mos 7 & 11); and extended to 30 mos with the modified hyper-CVAD regimens (hyper-CVAD followed by MTX-L-asparaginase mos 6 & 7 and 18 & 19). Allogeneic stem cell transplant (SCT) was performed in first complete remission (CR) only if inadequate response to therapy. Median age was 31 yrs (range, 17–59); 77% were males. Mediastinal disease was noted in 74%; 30% were associated with pericardial and/or pleural effusions. Two pts had superior vena cava syndrome and five had CNS disease. T-lineage disease was present in majority (79%). Eight (17%) pts had bone marrow involvement. Overall CR rate was 96% in 46 evaluable patients (3 in CR at start), with remainder achieving partial response (PET scan negative residual mediastinal disease not qualifying for CR). Of the 23 pts with bulky mediastinal disease at presentation, 74% underwent XRT as planned. With a median follow-up of 80 months (range 30–187+ months), 31 (66%) pts remained alive without disease. Overall 5-yr rates for CR duration and survival were 72% and 68%, respectively. Fourteen pts relapsed or progressed within a median of 13 months (6 with standard, 8 with modified hyper-CVAD); five pts were successfully salvaged with chemotherapy and allogeneic SCT. The hyper-CVAD is a highly active regimen for de novo LL with long-term follow-up confirming the earlier report. Early anthracycline intensification was clearly not beneficial. The treatment paradigm for LL has recently changed owing to availability of new agents and data supporting superior efficacy of pediatric regimens compared with conventional adult regimens. For older adults with de novo LL, the deoxyguanosine analog nelarabine has now been incorporated into the hyper-CVAD regimen as a single agent during consolidation (cycles 9 & 10) and maintenance (in lieu of the early intensifications) [Vigil CE, ASCO 2010, abstract 6524], whereas adolescents and younger adults are treated according to the pediatric-inspired augmented Berlin-Frankfurt-Muenster regimen. An augmented hyper-CVAD regimen (dose intensifying VCR/dexamethasone components and incorporating pegylated asparaginase) has been successfully piloted in the salvage setting. The optimal first line chemotherapy of LL continues to be refined; the role of autologous or allogeneic SCT for LL in first CR remains unclear since majority of patients can be cured without use of these modalities. Disclosures: Off Label Use: Nelarabine for de novo T-lymphoblastic leukemia/lymphoma Nelarabine for de novo T-lymphoblastic leukemia/lymphoma.

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Lymphoblastic lymphoma in adults: results of a pilot protocol

Blood ◽

10.1182/blood.v57.4.679.bloodjournal574679 ◽

1981 ◽

Vol 57 (4) ◽

pp. 679-684

Author(s):

CN Coleman ◽

JR Cohen ◽

JS Burke ◽

SA Rosenberg

Keyword(s):

Lymphoblastic Leukemia ◽

Abdominal Mass ◽

Lymphoblastic Lymphoma ◽

Myelogenous Leukemia ◽

High Dose ◽

Actuarial Survival ◽

Female Ratio ◽

Cns Disease ◽

Cns Relapse ◽

Male Female Ratio

Thirteen adult patients with histologically confirmed lymphoblastic lymphoma were treated with an intensive chemotherapy program consisting of induction with cyclophosphamide, adriamycin, vincristine, and prednisone (modified CHOP); consolidation and central nervous system (CNS) prophylaxis with methotrexate intrathecally and by high-dose intravenous injection, citrovorum factor and L-asparaginase; reinforcement with CHOP; and maintenance with 6-mercaptopurine and methotrexate. Treatment duration was 1 yr. A 14th patient with T-cell acute lymphoblastic leukemia was also treated at presentation by the same regimen. Thirteen patients had at least a mediastinal mass or abnormal cells in the bone marrow; one presented with CNS disease. The median age was 22 yr (range 16--50), and male--female ratio was 2.5:1. All patients had a rapid complete clinical response. Of the 13 patients without initial CNS disease, 4 have relapsed, 3 with primary CNS relapse and 1 with a recurrent abdominal mass. Five patients have died, 2 from drug toxicity, 2 from CNS relapse, and 1 from chronic myelogenous leukemia, which was diagnosed simultaneously with the lymphoblastic lymphoma. The median follow-up is 19 mo, and all patients have completed their planned therapy. At 3 yr, the actuarial survival is 61% and relapse-free survival is 56%.

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Intensification of Early-Phase Therapy to Diminish the Prognostic Effect of Myeloid Antigen Expression in Infants with KMT2A-Rearranged Acute Lymphoblastic Leukemia: A Report from the JPLSG MLL-10 Trial

Blood ◽

10.1182/blood-2021-145955 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2384-2384

Author(s):

Yuki Arakawa ◽

Takashi Ishihara ◽

Takako Miyamura ◽

Takao Deguchi ◽

Masashi Sanada ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Early Phase ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Age Distribution ◽

Central Nervous System Involvement ◽

High Dose ◽

Pediatric Leukemia ◽

Hematopoietic Stem ◽

Significant Difference

Abstract Background KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) is a rare and dismal disease in infants. Despite restriction of the indication of allogeneic hematopoietic stem cell transplantation to the high-risk group (patients aged <180 days with KMT2A-r ALL or central nervous system involvement), adoption of an Interfant-06-based induction therapy with stricter age-related dosing followed by COG AALL0631-based post-remission chemotherapy with additional administration of high-dose cytarabine in the early intensification phase led to rapid clearance of minimal residual disease (MRD) in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) MLL-10 trial. The MLL-10 trial demonstrated an improved outcome of 66.2% in 3-year event-free survival (EFS) among infants with KMT2A-r ALL (Tomizawa D. Blood 2021). As the Interfant-06 study showed an association between the expression levels of myeloid markers (MM) and poor MRD clearance at end of induction (EOI) and a high relapse rate (Stutterheim J, J Clin Oncol.2021), we analyzed the significance of MM expression in the MLL-10 cohort and its association with prognosis. Methods We analyzed and compared the MM expression (defined as at least one positive marker [with a positive blast subset ≥ 10%] among CD117, CD13, CD33, and CD65/CD15) by using flow cytometry (FCM) in infants with KMT2A-r ALL who were registered in the JPLSG MLL-10 trial. We also compared the results of immunoglobulin/T-cell receptor (Ig/TCR) gene-based polymerase chain reaction (PCR)-MRD analyses or 4-color FCM-MRD assay between the MM-positive and MM-negative groups at EOI and end of early consolidation. The Ig/TCR-MRD results were classified as negative if <5 × 10 −4 and positive if ≥5 × 10 −4, while the FCM-MRD results were classified as negative if <0.01% and positive if ≥0.01%. We prioritized PCR-MRD and used FCM-MRD when we could not make a primer for PCR-MRD. The presence of MRD was not used as a basis for choosing the appropriate therapy. Results and Discussion Among the patients with KMT2A-rALL, 74 were included in this study, excluding one who was not evaluated with FCM at diagnosis. Of these patients, 42 were MM-positive and 32 were MM-negative. The 3-year EFS rates of the MM-positive and MM-negative patients were 62.3% (95% confidence interval [CI], 45.5-75.3) and 70.0% (95% CI, 50.3-83.1), respectively (p = 0.61). Their 3-year overall survival rates were 80.6% (95% CI, 65.0-89.8) and 87.5% (95% CI, 70.0-95.1), respectively (p = 0.74). The numbers of MM-positive and MM-negative patients according to age group are summarized in Table 1, and the difference in age distribution between the two groups was not significant. The MRD statuses of the patients at EOI in the two groups are also summarized in Table 1. No significant difference in MRD clearance was found between the MM-positive and MM-negative groups. Conclusion In this study, we found no significant difference in survival rate between the MM-positive and MM-negative groups. The MM expression was not a prognostic marker in the infants with KMT2A-r ALL in the MLL-10 cohort. We believe that rapid MRD clearance in the early phase of treatment with enhanced chemotherapy would have the greatest contribution to the improvement of prognosis. In this study, the MM-positive patients from the MLL-10 cohort might have benefited from early-phase treatment intensification in terms of MRD clearance. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Phase II Study of Hyper-CVAD Plus Nelarabine in Previously Untreated Adult T-Cell Acute Lymphoblastic Leukemia and T-Lymphoblastic Lymphoma

Blood ◽

10.1182/blood.v128.22.177.177 ◽

2016 ◽

Vol 128 (22) ◽

pp. 177-177 ◽

Cited By ~ 2

Author(s):

Yasmin Abaza ◽

Hagop M. Kantarjian ◽

Elias J. Jabbour ◽

Deborah A Thomas ◽

Tapan M. Kadia ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Lymphoblastic Lymphoma ◽

Mediastinal Disease ◽

Significant Difference ◽

Cell Acute Lymphoblastic Leukemia ◽

Wbc Count ◽

T Lymphoblastic Lymphoma

Abstract Background: Despite the high complete remission (CR) rates, a significant proportion of adult patients (pts) with T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LL) treated with standard combination cytotoxic regimens will relapse underscoring the need for better therapeutic strategies. Nelarabine combined with intensive chemotherapy has been shown to be safe and effective in the frontline treatment of pediatric T-ALL. There is limited data on the use of nelarabine in the frontline setting in adult T-ALL and T-LL. Methods: This single-arm phase 2 study was designed to determine the CR rate, overall survival (OS), and safety of adding nelarabine cycles to the standard hyper-CVAD regimen in previously untreated or minimally pretreated (failure to 1 induction course or CR after ≤ 2 cycles) pts with T-ALL and T-LL. Treatment consisted of 8 induction/consolidation cycles of hyper-CVAD (odd courses 1, 3, 5, 7) alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C; even courses 2, 4, 6, 8) followed by 30 months of POMP (monthly vincristine, prednisone, 6-mercaptopurine, and MTX) maintenance therapy. Pts received nelarabine at a dose of 650 mg/m2 IV daily over 2 hrs for 5 days after the 8 cycles of induction/consolidation (Regimen 1). After 30 pts, the protocol was amended to deliver nelarabine after cycles 4 and 5 of induction/consolidation (Regimen 2). All patients also receive nelarabine instead of cycles 6 and 7 of POMP maintenance as early intensification. Late intensification consisted of MTX (100 mg/m2 IV on day 1) plus PEG-asparaginase (2000 IU/m2 IV on day 2) and hyper-CVAD given instead of cycles 18 and 19 of POMP maintenance. CNS prophylaxis consisted of 8 intrathecal treatments of MTX alternating with Ara-C. Pts with initial bulky mediastinal disease or with residual disease after induction were considered for local radiation therapy prior to the start of POMP maintenance. Results: To date, sixty-seven pts have been enrolled; 40 pts (60%) had T-ALL, 26 pts (39%) had T-LL, and 1 pt (1%) had biphenotypic disease. Median age was 37 years (range, 18-78) with 76% (N=51) of the pts males. Performance status was 2 in 9 pts (13%). Four pts (6%) had CNS involvement and 31 pts (46%) had mediastinal disease at diagnosis. Median WBC count at presentation was 8.1 x109/L (range, 0.8-309.2) and 11 pts (16%) had a WBC count > 100 x109/L. Based on immunophenotype, pts were categorized as thymic (N=24), mature (N=8), early T-cell precursor ALL (ETP; N=24), early non-ETP (N=2), and not otherwise specified (N=9). At diagnosis, 41 pts (61%) had diploid cytogenetics, 19 pts (28%) had miscellaneous karyotypic abnormalities, and 7 pts (10%) had indeterminate karyotype due to lack of testing and insufficient metaphases. Eleven pts were in CR at the time of initial presentation after having received 1-2 prior courses of therapy. Overall response rate was 96% (54/56 pts); with 52 pts (93%) achieving CR, 2 pts (4%) PR, and 2 pts (4%) no response. CR rates were similar for T-ALL and T-LL, 87% and 100%, respectively. There were no early deaths within the first month of treatment. With a median follow-up of 35 months (range, 2-98), 44 pts (66%) remain alive of which 41 pts (93%) are in remission. Ten pts (15%) received SCT after achieving CR and remain alive post-SCT; 8 remained in CR and 2 relapsed post-SCT. Nineteen pts relapsed with a median time to relapse of 6.5 months (range, 1.4-62). The site of relapses were: 10 hematologic (BM + blood), 5 extramedullary (EM), 3 BM + EM, and 1 BM + CNS. Twenty-three pts (34%) died including 17 pts with CR dying after relapse. Probability of CR duration at 3 years was 68% (95% CI 54-79 %). The 3-year probability of OS was 65% (95% CI 50-76 %) with a median OS of 82 months. There was no statistically significant difference in OS among the two different nelarabine regimens (Figure 1; p-value=0.93). Grade 3-4 nonhematological toxicity was reported in 60 (90%) pts, most frequent toxicities being infection (82%), elevated alanine aminotransferase (ALT) (16%), and thrombotic events (12%). Conclusion: Hyper-CVAD plus nelarabine is safe and effective in the frontline treatmentof adult T-ALL/T-LL and induces durable remissions. Administration of nelarabine earlier during the course of therapy does not appear to influence the outcome. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses; Portola: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding. Wierda:Gilead: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding. Jain:Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Novimmune: Consultancy, Honoraria; Infinity: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Honoraria; Incyte: Research Funding. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Daver:Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Sunesis: Consultancy, Research Funding. Thompson:Pharmacyclics: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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Randomized trial of r-metHu granulocyte colony-stimulating factor in an intensive treatment for T-cell leukemia and advanced-stage lymphoblastic lymphoma of childhood: a Pediatric Oncology Group pilot study.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.2.522 ◽

1998 ◽

Vol 16 (2) ◽

pp. 522-526 ◽

Cited By ~ 39

Author(s):

J Laver ◽

M Amylon ◽

S Desai ◽

M Link ◽

M Schwenn ◽

...

Keyword(s):

T Cell ◽

Lymphoblastic Lymphoma ◽

High Dose ◽

Induction Phase ◽

Advanced Stage ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Cell Leukemia ◽

Continuation Therapy ◽

Stimulating Factor

PURPOSE Contemporary chemotherapy has significantly improved the event-free survival (EFS) among patients with T-cell disease. However, myelosuppression has been a significant adverse effect of this approach. In this study, we assessed the impact of r-metHu granulocyte colony-stimulating factor (G-CSF) on the period of neutropenia, number of days of hospitalization, and delays in subsequent administration of chemotherapy in a cohort of patients with T-cell leukemia (T-ALL) or advanced stage lymphoblastic lymphoma (ASLL). PATIENTS AND METHODS This open-label, randomized trial incorporated r-metHuG-CSF into the induction and two consecutive continuation-therapy cycles of our intensive program for T-cell malignancies. In the induction phase, r-metHuG-CSF was given after two different combinations of chemotherapy, one of which included vincristine, prednisone, cyclophosphamide, and adriamycin and the other a continuous infusion of high-dose ara-C and L-asparaginase. In the two continuation-therapy cycles, r-metHuG-CSF was given following the combination of vincristine, adriamycin, prednisone, and 6-mercaptopurine (MP) and after continuous infusion of high-dose cytarabine (ara-C). RESULTS Fifty-six patients with T-ALL and 33 with ASLL were enrolled onto study from April 1994 to December 1995. Our data show no significant difference in number of days of absolute neutrophil count (ANC) less than 500/microL, hospitalizations, or delays in therapy in the induction phase. However, in the continuation-therapy phase the number of days of ANC less than 500/microL was significantly shorter (P = .017) on the G-CSF-arm without significantly affecting the number of days of hospitalizations or delays in therapy. CONCLUSION r-metHuG-CSF did not significantly affect the period of neutropenia, hospitalization, or delays in therapy in the induction phase, whereas in the two cycles of continuation therapy, it significantly shortened the period of neutropenia.

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Effect of glucocorticoid therapy on adrenal function in children with acute lymphoblastic leukemia

Paediatrica Indonesiana ◽

10.14238/pi54.1.2014.15-21 ◽

2014 ◽

Vol 54 (1) ◽

pp. 15

Author(s):

Gita Widyapuri ◽

Djajadiman Gatot ◽

Aman Bakti Pulungan ◽

Badriul Hegar

Keyword(s):

Hpa Axis ◽

Standard Dose ◽

Lymphoblastic Leukemia ◽

Adrenal Function ◽

High Dose ◽

Induction Phase ◽

Acth Test ◽

Before And After ◽

Response To Stress ◽

Cortisol Levels

BackgroundGlucocorticoids play an important role in thetreatment ofacute lymphoblastic leukemia (ALL), but can causeside effects such as suppression of the hypothalamic-pituitaryadrenal (HPA) axis. Suppression of the HPA axis causes adrenal insufficiency, disturbs the cortisol response to stress, and may be a cause of morbidity and mortality in children with ALL.ObjectiveTo evaluate adrenal function in children with ALL afterinduction chemotherapy with high dose glucocorticoids.MethodsThe adrenal function of 20 children with ALL wasevaluated using a standard dose (250 μ g) adrenocorticotropinhormone (ACTH) test performed before and after a 6 week oftreatment with glucocorticoids induction phase chemotherapy,which was followed by a week period tapering off. Adrenalinsuffien cy was defined as blood cortisol level of < 18 μg/dLResultsAdrenal insufficiency was found in 14/20 subjects afterthe induction phase followed by a week period of tapering off.Median cortisol levels pre- and post-stimulation before inductionphase were 14.72 (range 2.0 1- 46. 1) μg/dL and 29.29 (range 21.65 - 55 .15) μg/dL, respectively. Median cortisol levels pre- and poststimulation after induction phase were 5.87 (range 0.2 - 20.53)μg/dL and 10.49 (range 0.33 - 28.69) μg/dL, respectively. Clinicalsigns and symptoms did not differ between those with and withoutadrenal insufficiency.ConclusionOf 20 children with ALL, 14 develop adrenalinsufficiency after a 6-week induction therapy with glucocorticoidsand followed by a week period of tapering off. No specific clinicalsigns and symptoms are identified to be related to the adrenalinsufficiency.

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