Cladribine added to daunorubicin-cytarabine induction prolongs survival of FLT3-ITD+ normal karyotype AML patients

Libura, Marta; Giebel, Sebastian; Piątkowska−Jakubas, Beata; Pawelczyk, Marta; Florek, Izabella; Matiakowska, Karolina; Jaźwiec, Bożena; Borg, Katarzyna; Solarska, Iwona; Zawada, Magdalena; Czekalska, Sylwia; Libura, Jolanta; Jakóbczyk, Małgorzata; Karabin, Karolina; Paluszewska, Monika; Całbecka, Małgorzata; Gajkowska-Kulik, Justyna; Gadomska, Grażyna; Kiełbiński, Marek; Ejduk, Anna; Kata, Dariusz; Grosicki, Sebastian; Wierzbowska, Agnieszka; Kyrcz‐Krzemień, Sławomira; Warzocha, Krzysztof; Kuliczkowski, Kazimierz; Skotnicki, Aleksander B.; Hołowiecki, Jerzy; Jędrzejczak, Wiesław Wiktor; Haus, Olga

doi:10.1182/blood-2015-08-662130

Cited by 37 publications

(31 citation statements)

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“…NK AML accounts for 50% of all AML and represents the third and largest broad cytogenetic category in AML (26). FLT3-ITD has been recognized as a marker of poor prognosis in patients with NK AML, but FLT3-ITD mutations are also commonly observed in patients with AK AML (27,28), and the prognostic function of the FLT3-ITD mutation in these patients was unclear. A total of 23 FLT3-ITD mutated patients receiving treatment were analyzed; 6 patients were AK and 17 NK, and no significant differences in the OS and RFS were observed between these two groups.…”

Section: Discussionmentioning

confidence: 99%

Prognosis and outcome of patients with acute myeloid leukemia based on FLT3‑ITD mutation with or without additional abnormal cytogenetics

et al. 2019

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The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) gene mutation is present in ~20% of patients with de novo acute myeloid leukemia (AML). Patients with an FLT3-ITD mutation have a poor prognosis. However, the prognostic function of FLT3-ITD combined with other cytogenetic abnormalities are not clear. In the present study, a retrospective analysis of 103 newly diagnosed patients with AML was performed. The results revealed that the overall survival (OS) and recurrence-free survival (RFS) times were significantly longer in patients with an FLT3-ITD mutation combined with other favorable risk genes, compared with in those patients with a single FLT3-ITD mutation (P=0.0361 and P=0.0426). Sorafenib combined with chemotherapy significantly improved the overall response rate (ORR) when compared with mono-chemotherapy (P=0.039), but no significant differences were observed in the OS and RFS. In conclusion, favorable-risk cytogenetics may improve the clinical outcomes of patients with FLT3-ITD-mutated AML, but adverse-risk cytogenetics may not further worsen the prognosis. Sorafenib combined with chemotherapy may increase the ORR but would not result in a longer OS and RFS.

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Section: Discussionmentioning

confidence: 99%

Prognosis and outcome of patients with acute myeloid leukemia based on FLT3‑ITD mutation with or without additional abnormal cytogenetics

et al. 2019

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“…1 – 4 While gemtuzumab ozogamicin 5 and midostaurin 6 have now been approved in the U.S. as 7+3 adjuncts, these drugs provide incremental benefit and most patients who achieve a complete remission (CR) will relapse. 2 – 4 Studies reporting improved outcomes with higher doses of cytarabine during induction 7 or addition of cladribine (but not fludarabine) 8 – 10 led us to explore the combination of G-CSF, cladribine, cytarabine, and mitoxantrone (GCLAM). 11 Possibly more effective than mitoxantrone/etoposide/cytarabine (MEC) in relapsed/refractory AML, 12 only very limited data are available in upfront therapy.…”

Section: Introductionmentioning

confidence: 99%

Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms

et al. 2018

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Outcomes with “7+3” are often unsatisfactory in acute myeloid leukemia (AML). Trials demonstrating improved outcomes with high-dose cytarabine, addition of cladribine, or escalated anthracycline doses prompted a phase 1/2 study (NCT02044796) of G-CSF, cladribine, high-dose cytarabine, and dose-escalated mitoxantrone (GCLAM) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms. 121 patients, median age 60 (range: 21–81) years, were enrolled. In phase 1, cohorts of 6–12 patients were assigned to 12–18mg/m2/day of mitoxantrone as part of GCLAM. Because all dose levels were well-tolerated, mitoxantrone at 18mg/m2 was declared the recommended phase 2 dose (RP2D). 74/94 (79%) patients treated at the RP2D achieved a complete remission (CR; 67/74 without measureable residual disease [MRD]) for an overall MRDneg CR rate of 71% (primary phase 2 endpoint). Seven patients achieved a CR with incomplete blood count recovery (CRi; 7%, 5 MRDneg) for a CR/CRi rate of 81/94 (86%). 4-week mortality was 2%. After adjustment, the MRDneg CR and CR/CRi rates compared favorably to 100 matched controls treated with 7+3 at our center and 245 matched patients treated with 7+3 on a cooperative group trial. Our data indicate GCLAM with mitoxantrone at 18mg/m2/day is safe and induces high-quality remissions in adults with newly-diagnosed AML.

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“…Two patients experienced relapse and died, whereas three patients still showed no recurrence. Libura et al reported that cladribine added to daunorubicin–cytarabine induction prolongs the survival of patients with Fms‐like tyrosine kinase 3 internal tandem duplication (FLT3‐ITD) positive normal karyotype AML [12]. Thus, administering chemotherapy based on cladribine to patients with FLT3‐ITD + is reasonable.…”

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Cladribine with Granulocyte Colony-Stimulating Factor, Cytarabine, and Aclarubicin Regimen in Refractory/Relapsed Acute Myeloid Leukemia: A Phase II Multicenter Study

Wang

et al. 2020

The Oncologist

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Lessons Learned Studies targeting cladribine in combination with granulocyte colony‐stimulating factor, low‐dose cytarabine, and aclarubicin (C‐CAG) regimen in relapsed and refractory acute myeloid leukemia (R/R AML) are limited. The complete remission rate after two cycles of C‐CAG regimen was 67.6%, and 1‐year overall survival and disease‐free survival rates were 59.7% and 72.9%, respectively. The C‐CAG regimen is significantly effective against R/R AML with a low hematological toxicity and thus serves as an alternative treatment for R/R AML. Background The optimal salvage chemotherapy regimen for relapsed and refractory acute myeloid leukemia (R/R AML) remains uncertain. Therefore, a phase II study was conducted for the prospective evaluation of the efficacy and safety of the purine analog cladribine in combination with granulocyte colony‐stimulating factor (G‐CSF), low‐dose cytarabine, and aclarubicin (C‐CAG) regimen for patients with R/R AML. Methods A total of 34 patients received C‐CAG regimen for salvage treatment as follows: cladribine 5 mg/m2, days 1–5; G‐CSF 300 μg, days 0–9; aclarubicin 10 mg, days 3–6; cytarabine 10 mg/m2 every 12 hours, subcutaneously, days 3–9; 4 weeks per cycle. Patients were allowed to withdraw from the study if complete remission (CR) was not achieved after two courses of chemotherapy. If conditions were right, the patients achieving CR were recommended to receive allogeneic hematopoietic stem cell transplantation. Otherwise, they were treated for a total of six cycles unless disease progression or unacceptable side effects were observed or they withdrew their consent. Results All patients received at least two cycles of C‐CAG regimen chemotherapy. After two cycles of C‐CAG, 23 patients (67.6%) achieved CR, and 5 patients had partial remission (14.7%). At a median follow‐up of 15 months (range, 3–38 months), the 1‐year overall survival (OS) and disease‐free survival (DFS) rates were 59.7% (95% confidence interval [CI], 42.6%–76.8%) and 72.9% (95% CI, 54.3%–91.5%), respectively. The most common adverse effect was myelosuppression. Nonhematological toxicities were mild, and no treatment‐related deaths occurred. Conclusion Preliminary data indicate that the C‐CAG regimen chemotherapy is significantly effective against R/R AML with a high remission rate and a low hematological toxicity. Thus, it may serve as an alternative treatment for R/R AML.

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Cladribine added to daunorubicin-cytarabine induction prolongs survival of FLT3-ITD+ normal karyotype AML patients

Cited by 37 publications

References 15 publications

Prognosis and outcome of patients with acute myeloid leukemia based on FLT3‑ITD mutation with or without additional abnormal cytogenetics

Prognosis and outcome of patients with acute myeloid leukemia based on FLT3‑ITD mutation with or without additional abnormal cytogenetics

Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms

Cladribine with Granulocyte Colony-Stimulating Factor, Cytarabine, and Aclarubicin Regimen in Refractory/Relapsed Acute Myeloid Leukemia: A Phase II Multicenter Study

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