scholarly journals Amsacrine with high-dose cytarabine is highly effective therapy for refractory and relapsed acute lymphoblastic leukemia in adults

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 433-435
Author(s):  
ZA Arlin ◽  
E Feldman ◽  
S Kempin ◽  
T Ahmed ◽  
A Mittelman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Side Effects ◽  
High Risk ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Primary Treatment ◽  
High Dose ◽  
Refractory Disease ◽  
High Dose Cytarabine ◽  
Adults And Children

Abstract Thirty-six patients with relapsed acute lymphoblastic leukemia (ALL) and four with primary refractory ALL were treated with a regimen that included amsacrine, 200 mg/m2, intravenously daily for three days with cytarabine, 3 gm/m2, by infusion over three hours daily for five days. There were 27 remissions in the 36 relapsed patients and two in the four patients with primary refractory disease. Seventeen of the 23 patients with common ALL, four of the six with T-cell ALL, one of the three with B-cell ALL, and seven of eight whose cells were not characterized responded. Toxicity of this regimen was comparable to other reinduction regimens for ALL, but the side effects characteristic of high-dose cytarabine therapy were absent. Since these results compare favorably with conventional induction regimens, its use in the primary treatment of adults and children with high-risk ALL is proposed.

scholarly journals Amsacrine with high-dose cytarabine is highly effective therapy for refractory and relapsed acute lymphoblastic leukemia in adults

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 433-435 ◽  
Author(s):  
ZA Arlin ◽  
E Feldman ◽  
S Kempin ◽  
T Ahmed ◽  
A Mittelman ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Side Effects ◽  
High Risk ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Primary Treatment ◽  
High Dose ◽  
Refractory Disease ◽  
High Dose Cytarabine ◽  
Adults And Children

Thirty-six patients with relapsed acute lymphoblastic leukemia (ALL) and four with primary refractory ALL were treated with a regimen that included amsacrine, 200 mg/m2, intravenously daily for three days with cytarabine, 3 gm/m2, by infusion over three hours daily for five days. There were 27 remissions in the 36 relapsed patients and two in the four patients with primary refractory disease. Seventeen of the 23 patients with common ALL, four of the six with T-cell ALL, one of the three with B-cell ALL, and seven of eight whose cells were not characterized responded. Toxicity of this regimen was comparable to other reinduction regimens for ALL, but the side effects characteristic of high-dose cytarabine therapy were absent. Since these results compare favorably with conventional induction regimens, its use in the primary treatment of adults and children with high-risk ALL is proposed.

Clofarabine in the Frontline Treatment of Childhood Acute Lymphoblastic Leukemia. Results of the COALL 08–09 Study Regarding Safety and Efficacy of Clofarabine in Combination with Asparaginase During Consolidation Therapy.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2606-2606
Author(s):  
Gabriele Escherich ◽  
Martin Zimmermann ◽  
Martin A. Horstmann
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Side Effects ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Historical Control ◽  
High Dose ◽  
Consolidation Therapy ◽  
Safety And Efficacy ◽  
High Dose Cytarabine ◽  
Grade 3

Abstract Abstract 2606 Background Since the FDA approval for clofarabine in the treatment of childhood relapsed or refractory acute lymphoblastic leukemia (ALL) several studies have been launched which put clofarabine under scrutiny in combination with other cytostatic drugs as second or third line therapy. As a novel treatment strategy we introduced the combination of clofarabine with asparaginase into the frontline management of ALL. To assess safety and efficacy of clofarabine in combination with PEG-ASP, high risk B- progenitor and T-ALL patients received this regimen as a postinduction treatment within the CoALL 08–09 protocol. Patients and methods In October 2010 the CoALL trial 08–09 was opened for enrollment of patients under 18 years with confirmed diagnosis of acute B-progenitor or T-cell leukemia. Until December 2011 109 patients were accrued as study patients. Patients being identified for a high risk of relapse by PCR based MRD at the end of induction were stratified to receive the combination of clofarabine 5 × 40 mg/m2 and pegylated asparaginase (PEG-ASP) 2.500 IU/m2 at the beginning of consolidation therapy. Criteria for eligibility were cytomorphologic remission and an MRD load ≥ 10−4for B-progenitor patients and a MRD load ≥ 10−3 at day 43, after they had already received one cyclophosphamide and methotrexate containing consolidation cycle for T-ALL patients. All other patients received the standard treatment of high dose cytarabine 4 × 3g/m2(HIDAC) in combination with PEG-ASP 2.500 IU/m2. For comparison a historical control cohort from the predecessor CoALL 07-03 trial were analyzed who fulfilled the same MRD criteria. In this trial all patients received the standard postinduction therapy with high dose cytarabine and asparaginase. Results Forty-two out of 109 patients of the CoALL 08–09 trial (39 B-progenitor and 3 T-ALL) fulfilled the inclusion criteria, were stratified and received the clofarabine/PEG-ASP treatment. No unknown or unexpected severe side effects were observed after the treatment of clofarabine with PEG-ASP. No grade 3 or 4 skin, central or peripheral neurological or renal toxicity occurred. In 13/42 patients grade 3 and in 6/42 patients grade 4 elevation of transaminases were reported, which were all reversible. There was a remarkable response to the treatment of clofarabine/PEG-ASP measured by MRD. In comparative analysis the MRD response to clofarabine/PEG-ASP was superior to that reached after HIDAC/PEG-ASP as it is shown in Figure 1. A logistic regression analysis of the MRD response with the MRD level at end of induction as covariable showed an odds ratio of 0.26 (95% CI 0.9-0.8, p=0.02) for clofarabine vs HIDAC. Conclusion In this cohort of high risk ALL patients clofarabine in combination with PEG-ASP given as the first postinduction treatment in the frontline management of acute lymphoblastic leukemia was well tolerated without severe or persistent side effects. Moreover, the antileukemic effect of this combination appears to be superior compared to the historical control group treated with high dose cytarabine and PEG-ASP at the same time point of treatment which warrants further investigation in a randomized fashion. Disclosures: No relevant conflicts of interest to declare.

Effect of Polymorphisms in Folate Related Genes on Side Effects of High Dose MTX Treatment in Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1961-1961
Author(s):  
Wim Tissing ◽  
Lisha Huang ◽  
Robert de Jonge ◽  
Rob Pieters
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Side Effects ◽  
High Risk ◽  
Methylenetetrahydrofolate Reductase ◽  
Lymphoblastic Leukemia ◽  
Methionine Synthase ◽  
Hematological Toxicity ◽  
High Dose ◽  
Childhood All ◽  
Methionine Synthase Reductase

Abstract Introduction. High dose (2 – 3 g/m2) methotrexate (MTX, an anti-folate) is used in the treatment of pediatric acute lymphoblastic leukemia (ALL) with side effects in a considerable number of children. We studied the prevalence of MTX related side effects and a possible relation with common polymorphisms in folate metabolism related genes in the treatment of childhood ALL. Methods. In this retrospective study, DNA was isolated from leukemic samples of 81 children with ALL. High risk (HR) ALL patients were treated with 4 courses of 3 g/m2, non-high risk (NHR) patients with 3 times 2g/m2. The following effects were monitored: serum MTX levels, transfusion need, liver toxicity, skin toxicity and hematological toxicity. Common gene mutations in methylenetetrahydrofolate reductase (MTHFR 677C>T and MTHFR 1298A>C), methionine synthase (MS 2756A>G), methionine synthase reductase (MTRR 66A>G), serine hydroxymethyl transferase (SHMT 1420C>T), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), thymidylate synthase (TS 2R3R) and reduced folate carrier (RFC 80G>A) were detected by PCR-RFLP. Results. 57% of the patients had prolonged increased serum levels of MTX in at least 1 course. 59% patients had the MTX courses at the scheduled time, 35% had one course postponed and 6% 2 courses. Mucositis was observed in 22% patients after 1 out of 3 courses, 19% after 2 and 20% after 3 courses. 28% patients had 1 transfusion, 6% had 2 and 1% had 3 transfusions during the MTX courses. Transaminases were elevated 2 times above the normal upper level in 25% of the patients. Skin rash was observed in 32% patients. Using Mann Whitney analysis we found a significant relation between polymorphisms of the MTHFR 1298A>C and for the MTRR 66A>G genes and side effects. The MTHFR 1298A>C polymorphism was related to less transfusions (p<0.05). Recovery of WBC count in HR ALL patients tended to be slower in patients with a MTHFR 1298AA genotype (P=0.053). HR patients with a MTRR 66AG genotype had a slower recovery of platelet count (p=0.004) Conclusion. Common polymorphisms in the MTHFR (677C>T), MS, SHMT, TS, RFC, and MTHFD1 genes are not related to the occurrence of side effects of MTX treatment in childhood ALL. Polymorphisms in the MTHFR (1298A>C) and MTRR (66A>G) gene are related to hematological toxicity.

scholarly journals Inotuzumab Ozogamicin Is an Effective Salvage Therapy in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia with High-Risk Molecular Features, Including TP53 Loss

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3888-3888 ◽  
Author(s):  
Xiaochuan Yang ◽  
Amber C. King ◽  
Charlene C. Kabel ◽  
Christopher J. Forlenza ◽  
Jae H. Park ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Response Rate ◽  
Lymphoblastic Leukemia ◽  
Advisory Board ◽  
Inotuzumab Ozogamicin ◽  
Ras Mutations ◽  
Molecular Features ◽  
Cell Acute Lymphoblastic Leukemia

Introduction: Adults with (w/) B-cell acute lymphoblastic leukemia (B-ALL) exhibit high rates of complete response (CR) to induction chemotherapy, but relapse is common. Inotuzumab ozogamicin (IO), an antibody-drug conjugate targeting CD22, achieves high rates of CR in patients (pts) w/ relapsed/refractory (R/R) B-ALL and is FDA-approved for R/R B-ALL in adults. It remains unknown whether cytogenetic and molecular features associated w/ decreased response rate and poor prognosis following conventional chemotherapy are associated w/ response to IO. As such, we investigated the relationship between several high-risk genetic alterations and outcome following IO treatment in pts w/ R/R B-ALL. Methods: We reviewed electronic medical records of pts of all ages w/ R/R B-ALL or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) receiving IO at Memorial Sloan Kettering Cancer Center (MSK) between January 2011 and April 2019. The primary objective was to assess whether recurrent cytogenetic or molecular features were associated w/ achievement of CR or CR w/ incomplete hematologic recovery (CRi), w/ or w/o measurable residual disease (MRD), and disease-free (DFS) and overall survival (OS) following IO. Secondary objectives included association of baseline clinical features, including central nervous system (CNS) or other extramedullary (EM) disease, w/ outcomes post-IO. MRD was defined as any unequivocal evidence of B-ALL detectable by RT-PCR (Ph+ ALL) or flow cytometry (FACS). Genomic alterations were defined by MSK IMPACT-Heme (Cheng, J Mol Diagn, 2015), FoundationOne Heme, or similar platforms. A set of selected high-risk (HR) features in Philadelphia chromosome-negative (Ph-) B-ALL was defined prior to the analysis (HR: mutations/loss of TP53, IKZF1/3, CDKN2A, CREBBP; activating RAS mutations; "Ph-like" profile). DFS and OS were computed using Kaplan-Meier methods and compared between groups using log-tank tests. Results: 32 pts (13F, 19M) w/ R/R B-ALL (n=31) or CML-LBP (n=1) treated w/ IO were identified. IO was given as monotherapy in 27 pts and w/ other systemic therapy in 5 pts (mini-hyper-CVD-like regimen, n=4; ponatinib, n=1). Median age at start of IO was 45 years (range 3-78). 10 pts had undergone prior allogeneic hematopoietic cell transplantation (alloHCT). Seven and 15 pts had a history of CNS disease or other EM involvement by B-ALL, respectively, including 3 and 6 pts immediately prior to IO, respectively. Pts received a median 3 lines of salvage prior to IO, including prior CD19-targeted immunotherapy (blinatumomab and/or CAR-T cells) in 24 pts(Table 1). Among 27 pts w/ Ph- B-ALL, 12 had the selected HR features (Table 2). Five pts had Ph+ ALL (n=4) or CML-LBP (n=1) and 5/5 harbored ABL1 kinase domain point mutations (4/5 w/ T315I mutation). 22 pts had at least one successful molecular profiling panel.29 patients had initial cytogenetic studies, of whom 28 patients had evaluable karyotypes. 23 pts had best response to IO of CR/CRi (MRD-, n=15; MRD+, n=8). 9 pts had no objective response to ≥1 cycle of IO. Of the 12 Ph- pts w/ selected HR mutations, 11 achieved CR/CRi. Notably, 6/6 pts w/ TP53 mutation/deletion and 5/5 pts w/ IKZF1/3 mutations (3/3 pts w/ both TP53 & IKZF mutations) achieved CR/CRi. Both pts w/ Ras mutations and 2/3 w/ Ph-like B-ALL achieved CR/CRi. 7/11 HR responders underwent alloHCT post-IO (3 had undergone pre-IO alloHCT). Pts w/ Ph- B-ALL w/ HR mutations demonstrated similar CR/CRi rate and OS to pts w/ Ph- B-ALL w/o defined HR mutations (Fig 1A-B). In contrast, only 1/5 pts w/ Ph+ ALL achieved CR/CRi (was MRD+) and 4/5 showed persistent B-ALL. OS was superior among pts w/ Ph- vs Ph+ B-ALL post-IO (8.0 vs 1.9 months, p=0.0068, Fig 1C). Among pts w/ EM disease immediately prior to IO, 3/6 achieved CR/CRi, including CR in 1 pt w/ a cardiac mass. Median DFS was 3.2 months vs. not reached following achievement of MRD+ vs MRD- CR, respectively (p=ns, Fig 1D). Conclusions: HR molecular features associated w/ poor response to chemotherapy were not associated w/ inferior response rate and overall prognosis following IO in this small series. Notably, pts w/ Ph+ ALL (all w/ ABL1 mutations) exhibited suboptimal response, possibly as pts received IO only in advanced disease states following TKI failure. This small report supports investigation of IO in frontline therapy for pts w/ B-ALL w/ HR mutations to spare unnecessary toxicities of chemotherapy and bridge successfully to alloHCT. Disclosures King: Genentech: Other: Advisory Board ; Astrazeneca: Other: Advisory board; Incyte: Other: Advisory Board. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin is not FDA approved for pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia.

scholarly journals Interleukin-4 induces programmed cell death (apoptosis) in cases of high-risk acute lymphoblastic leukemia

Blood ◽  
1994 ◽  
Vol 83 (7) ◽  
pp. 1731-1737 ◽  
Author(s):  
A Manabe ◽  
E Coustan-Smith ◽  
M Kumagai ◽  
FG Behm ◽  
SC Raimondi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Programmed Cell Death ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Fatal Outcome ◽  
Interleukin 4 ◽  
B Lineage

Abstract We investigated the effects of interleukin-4 (IL-4) on the survival of leukemic and normal B-cell progenitors cultured on bone marrow stroma. IL-4 (at 100 U/mL) was cytotoxic in 16 of 21 cases of B-lineage acute lymphoblastic leukemia, causing reductions in CD19+ cell numbers that ranged from 50% to greater than 99% (median 83.5%) of those in parallel cultures not exposed to the cytokine. All nine cases with the t(9;22)(q34;q11) or the t(4;11)(q21;q23), chromosomal features that are often associated with multidrug resistance and a fatal outcome, were susceptible to IL-4 toxicity. IL-4 cytotoxicity resulted from induction of programmed cell death (apoptosis); there was no evidence of cell killing mediated by T, natural killer, or stromal cells. IL-4 cytotoxicity extended to a proportion of normal B-cell progenitors. After 7 days of culture with IL-4 at 100 U/mL, fewer CD19+, CD34+ normal lymphoblasts (the most immature subset) survived: in five experiments the mean (+/- SEM) reduction in cell recoveries caused by IL-4 was 60.0% +/- 6.0%. By contrast, reductions in recovery of more differentiated bone marrow B cells (CD19+, CD34-, surface Ig+) were low (6.6% +/- 2.2%; P < .001 by t-test). Our findings indicate that IL-4 is cytotoxic for human B-cell precursors and support clinical testing of IL-4 in cases of high-risk lymphoblastic leukemia resistant to conventional therapy.

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