Azacitidine as post-remission consolidation for sorafenib-induced remission of Fms-like tyrosine kinase-3 internal tandem duplication positive acute myeloid leukemia

Gill, Harinder; Man, Cheuk-Him; Ip, Alvin H. W.; Choi, William W.L.; Chow, Howard C.H.; Kwong, Yok–Lam; Leung, Anskar Y.H.

doi:10.3324/haematol.2014.123034

Cited by 11 publications

(10 citation statements)

References 13 publications

(12 reference statements)

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“…As we suggested, we found that patients with low/intermediate DRI risk tended to benefit more from increasing the intensity of the chemotherapy regimen. As for patients with high/very high DRI, avoiding the toxicity of MAC and focusing on posttransplant strategies to help reduce relapse may be a more beneficial strategy [27][28][29]. There are a few limitations to the findings in the high/very high DRI risk group.…”

Section: Discussionmentioning

confidence: 97%

The Dilemma of Conditioning Intensity: When Does Myeloablative Conditioning Improve Outcomes for Allogeneic Hematopoietic Cell Transplantation

Solh

Solomon

Morris

et al. 2019

Biology of Blood and Marrow Transplantation

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The impact of conditioning intensity on different disease risk index (DRI) groups has not been evaluated. We retrospectively analyzed acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) hematopoietic cell transplantation (HCT) recipients in 2 groups based on DRI, to assess the impact of conditioning intensity on overall survival (OS), disease free survival (DFS), relapse, and nonrelapse mortality (NRM). A total of 380 patients with either high/very high (n = 148) or low/intermediate DRI (n = 232) myeloid malignancy (AML, n = 278; MDS, n = 102) were included in the analysis. Median follow-up for survivors was 35 months. Median age was 58 years (range, 18 to 75). Patient and transplant-related characteristics were 41% reduced-intensity conditioning (RIC), 59% myeloablative conditioning (MAC), 13% bone marrow graft, 29% matched related donor, 49% matched unrelated donor, 22% haploidentical donor, and 52% HCT-specific comorbidity index ≥ 3. Among patients with high/very high DRI, there was no difference in OS, DFS, relapse, and NRM between RIC and MAC conditioning groups. For low/intermediate risk DRI recipients of MAC had better 3-year OS estimate (69% versus 57%, P = .001), DFS (65% versus 51%, P = .003), and lower relapse (3-year cumulative incidence, 17% versus 32%; P = .01) but similar NRM (19% versus 17%, P = .04) to RIC recipients. On multivariable analysis MAC was associated with better DFS (hazard ratio [HR], .58; 95% confidence interval [CI], .39-.88; P = .01), lower relapse (HR, .56; 95% CI, .32 to .97; P = .038), and similar NRM (HR, 1.11; 95% CI, .54 to 2.26; P = .781) compared with RIC in the low/intermediate DRI group. Intensity had no impact on HCT outcomes in the high/very high DRI group. MAC improves DFS and relapse compared with RIC among AML/MDS patients with low/intermediate DRI. The finding of no such benefit in high/very high DRI needs to be further explored in a larger cohort with a longer follow-up.

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Section: Discussionmentioning

confidence: 97%

The Dilemma of Conditioning Intensity: When Does Myeloablative Conditioning Improve Outcomes for Allogeneic Hematopoietic Cell Transplantation

Solh

Solomon

Morris

et al. 2019

Biology of Blood and Marrow Transplantation

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“…Following one cycle of therapy, a marked discordance was observed with reduction in morphologic blasts to 12% but an increase in ‐7 FISH to 70%, suggesting that a majority of blasts differentiated into mature myeloid elements. While the observed response may be attributable to either sorafenib or azacitidine alone, the combination has demonstrated in vitro synergy in inhibiting cellular proliferation and inducing apoptosis, although the mechanisms underlying this synergy are not known . Subsequent cycles of therapy may have resulted in further reduction of blasts and eventual apoptosis of differentiating malignant cells; however, given the patient's favorable performance status, history of chemotherapy‐refractory leukemia, and risk of infection with ongoing myelosuppression, we elected to proceed to HSCT rather than additional cycles.…”

Section: Discussionmentioning

confidence: 99%

“…While the observed response may be attributable to either sorafenib or azacitidine alone, the combination has demonstrated in vitro synergy in inhibiting cellular proliferation and inducing apoptosis, although the mechanisms underlying this synergy are not known. [18,19] Subsequent cycles of therapy may have resulted in further reduction of blasts and eventual apoptosis of differentiating malignant cells; however, given the patient's favorable performance status, history of chemotherapy-refractory leukemia, and risk of infection with ongoing myelosuppression, we elected to proceed to HSCT rather than additional cycles. TBI-based conditioning was used because AML myeloablative conditioning regimens would be suboptimal for the persistent small population of lymphoid blasts.…”

Section: Discussionmentioning

confidence: 99%

Azacitidine and Sorafenib Therapy in a Pediatric Patient With Refractory Acute Myeloid Leukemia With Monosomy 7 and Somatic PTPN11 Mutation

Dahl

Michaels

McMasters

et al. 2015

Pediatr Blood Cancer

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Monosomy 7 is a well-documented cytogenetic aberration in pediatric acute myeloid leukemia (AML) and may occur in combinations with molecular abnormalities including PTPN11 mutation. PTPN11 mutations contribute to leukemogenesis through upregulation of Ras pathway signaling. We present the case of a 3-year-old female with AML with monosomy 7 and somatic PTPN11 mutation who was refractory to conventional AML chemotherapy but responded to a novel regimen of azacitidine and sorafenib followed by stem cell transplantation. Combination therapy with azacitidine and sorafenib may be an effective therapeutic strategy for patients with AML with Ras pathway abnormalities.

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“…Furthermore, combination of FLT3 inhibitors including sorafenib, quizartinib and gilteritinib with other low intensity treatment including azacytidine or decitabine, the hypomethylating agents, have been shown to be synergistic in laboratories [68][69][70] and appeared to be effective in Phase II clinical trials [19,71,72].…”

Section: Combination Of Flt3 Inhibitors With Low Intensity Regimenmentioning

confidence: 99%

Overcoming Resistance to FLT3 Inhibitors in the Treatment of FLT3-Mutated AML

Lam

Leung

2020

IJMS

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Acute myeloid leukaemia (AML) carrying internal tandem duplication (ITD) of Fms-Like Tyrosine kinase 3 (FLT3) gene is associated with high risk of relapse and poor clinical outcome upon treatment with conventional chemotherapy. FLT3 inhibitors have been approved for the treatment of this AML subtype but leukaemia relapse remains to be a major cause of treatment failure. Mechanisms of drug resistance have been proposed, including evolution of resistant leukaemic clones; adaptive cellular mechanisms and a protective leukaemic microenvironment. These models have provided important leads that may inform design of clinical trials. Clinically, FLT3 inhibitors in combination with conventional chemotherapy as induction treatment for fit patients; with low-intensity treatment as salvage treatment or induction for unfit patients as well as maintenance treatment with FLT3 inhibitors post HSCT hold promise to improve survival in this AML subtype.

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Azacitidine as post-remission consolidation for sorafenib-induced remission of Fms-like tyrosine kinase-3 internal tandem duplication positive acute myeloid leukemia

Cited by 11 publications

References 13 publications

The Dilemma of Conditioning Intensity: When Does Myeloablative Conditioning Improve Outcomes for Allogeneic Hematopoietic Cell Transplantation

The Dilemma of Conditioning Intensity: When Does Myeloablative Conditioning Improve Outcomes for Allogeneic Hematopoietic Cell Transplantation

Azacitidine and Sorafenib Therapy in a Pediatric Patient With Refractory Acute Myeloid Leukemia With Monosomy 7 and Somatic PTPN11 Mutation

Overcoming Resistance to FLT3 Inhibitors in the Treatment of FLT3-Mutated AML

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