Single-Center Experience With Epigenetic Treatment for Juvenile Myelomonocytic Leukemia

Marcu, Andra; Coliţă, Andrei; Radu, Letiţia Elena; Jercan, Cristina; Bica, Ana; Asan, Minodora; Coriu, Daniel; Tănase, Alina; Diaconu, Carmen C.; Marchini, Cristina; Botezatu, Anca; Pașca, Sergiu; Teodorescu, Patric; Anton, Gabriela; Gurban, Petruta; Coliţă, Anca

doi:10.3389/fonc.2020.00484

Cited by 9 publications

(5 citation statements)

References 42 publications

(36 reference statements)

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“…Following previous case reports, this is the first prospective study on azacitidine therapy in children with JMML. [20][21][22][23] Limitations of the study are the small sample size and short follow-up time. Whether a response to azacitidine prior to HSCT will translate into improved OS with longer observation time remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial

et al. 2021

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Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration-–time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.

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Section: Discussionmentioning

confidence: 99%

Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial

et al. 2021

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“…Low-dose intravenous cytarabine alone or in combination with 6-mercaptopurine, and high-dose cytarabine have been used. No standard chemotherapy protocol has proven to have an impact on relapse incidence after transplantation but the favourable toxicity of azacitidine (75-100 mg/m 2 on 5 to 7 days, repeated every 4 weeks) and its cytoreductive potential make it an attractive option prior to allo-HSCT [12,[24][25][26]. Patients with JMML who transform into acute myeloid leukemia (AML) generally have dismal outcomes following HSCT [10,27].…”

Section: Clinical and Hematologic Features (All 4 Features Mandatory)mentioning

confidence: 99%

Hematopoietic Stem Cell Transplantation in Juvenile Myelomonocytic Leukemia: A Case Report and Literature Review

Benakli¹,

Nacer²,

Mehdid³

et al. 2022

RGM

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Juvenile myelomonocytic leukemia (JMML) is a rare hematological malignancy of early childhood, classified by the World Health Organization as a myelodysplastic/myeloproliferative disease and is associated with a poor prognosis. Allogeneic hematopoietic stem cell transplantation is the only curative treatment. A two-year-old male child was diagnosed with JMML and was given induction chemotherapy. One year after diagnosis, the patient received allogeneic hematopoietic stem cell transplantation from an HLA sibling donor after a myeloablative conditioning regimen. The patient remained free of disease after 5 years of follow-up, healthy, with complete clinical, immunologic and hematologic recovery, without signs of JMML. Transplantation is the only modality to achieve a cure in JMML patients. The most widely practiced approach is the use of bone marrow or peripheral blood stem cells after a myeloablative conditioning regimen. Post-transplant monitoring chimerism can help identify the patients who are at risk of relapse.

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“…Although the clinical activity of azacitidine as a DNA hypomethylating agent appears to be promising, it is unlikely that azacitidine alone have the potential to cure JMML [29]. However, azacitidine as monotherapy is safe and effective in controlling disease both in upfront and relapsed patients in order to proceed to HSCT [30]. In fact, azacitidine is currently the gold standard bridge to HSCT in JMML.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Juvenile Myelomonocytic Leukemia (JMML): A Mimicker of KMT2A-Rearranged Acute Myeloid Leukemia (AML)

Saad¹

2021

Acute Leukemias

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Juvenile myelomonocytic leukemia (JMML) is the most confusing mimicker of KMT2A-rearranged acute myeloid leukemia (AML). Clinical presentation, age of susceptibility (infancy or early childhood) and abnormal monocytosis are common clinical features. To complicate matters, JMML morphologically resemble acute myelomonocytic leukemia (AML M4) and distinction must be made based on accurate blast and promonocyte counts. As treatment significantly varies, AML/JMML overlap can lead to catastrophic consequences that can be avoided by timely management. Therefore, meticulous knowledge of JMML is essential to treat patients with hematologic malignancies. The pathognomic feature of JMML is increased infiltration of the peripheral blood, bone marrow, and viscera by abnormal myelomonocytic cells. Molecular diagnostics has generated substantial dividends in dissecting the genetic basis of JMML. We can now molecularly confirm the diagnosis of JMML in approximately over 90% of patients who harbor driver mutations in KRAS, NRAS, PTPN11, NF1, or CBL genes. The presence of monosomy 7 is a classic feature of JMML that can support the diagnosis in many cases. On the other hand, cytogenetics and Fluorescence in situ hybridization analysis (FISH) are indispensable to differentiate KMT2A-rearranged AML from JMML. In particular, AML with t(9;11) is associated with monocytic features that can be easily mistaken for JMML.

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Single-Center Experience With Epigenetic Treatment for Juvenile Myelomonocytic Leukemia

Abstract: Conclusion: Our data show that AZA monotherapy is safe and effective in controlling disease both in upfront and relapsed patients in order to proceed to HSCT.

Cited by 9 publications

References 42 publications

Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial

Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial

Hematopoietic Stem Cell Transplantation in Juvenile Myelomonocytic Leukemia: A Case Report and Literature Review

Juvenile Myelomonocytic Leukemia (JMML): A Mimicker of KMT2A-Rearranged Acute Myeloid Leukemia (AML)

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