Efficacy and safety of combination therapies vs monotherapy of hypomethylating agents in accelerated or blast phase of Philadelphia negative myeloproliferative neoplasms: a systematic review and meta-analysis

Figures & data

Figure 1. Flow diagram for selection of studies included in the meta-analysis. *Three studies (Lancman et al. [22] USA, 2018; Yoon et al. [29] USA, 2021; Zhou et al. [10] USA, 2021) reported the results of combination therapy as well as monotherapy of HMAs simultaneously.

Table 1. Overview of the efficacy and safety of combination therapy with HMAs in Philadelphia negative MPN-AP/BP.

Source (author/ country)	Study type	Population	Number of men, n (%)	Median age (year, range)	Regimen	Number of cycles, median(range)	Efficacy	Median OS, Months (range)	Adverse events
Bose et al. [18] USA, 2016	Clinical trial	N = 12 Post-MPN AML	8(66.7)	70(32–92)	DEC plus RUX	4(1–7)	ORR:5/12, 42%; CR/CRi: 3/12,25%; PR:2/12, 16.7%	NA	Grade ≥3: pneumonia, febrile neutropenia, thrombocytopenia, neutropenia, infection, hypotension, fracture, fever, fatigue, anorexia, muscle weakness, confusion, ileus and transaminitis
Rampal et al. [19] USA (Phase I), 2016	Clinical trial	N = 21 MPN-AP 11 MPN-BP 10	NA	63(48–88)	DEC plus RUX	3(1–22)	ORR:12/21, 57.1%; CR/CRi:7/21, 33%; PR: 5/21, 24%	10.4(3.3–NR)	Grade ≥3: infection, anaemia, leukopenia, thrombocytopenia, haemorrhage
Rita Assi et al. [20] USA, 2017	Clinical trial	N = 19 Post-MPN AML	11(58)	71(32–92)	DEC plus RUX	2(1–7)	ORR: 4/14, 29%; CR/CRi: 4/14, 29%	8(1–20)	Grade ≥3: febrile neutropenia, myelosuppression, fracture, fatigue, anorexia, muscle weakness, confusion, ileus and transaminitis
Drummond et al. [21] UK, 2017	Clinical trial	N = 14 MPN-AP: 7 MPN-BP: 7	NA	72(62–81)	AZA plus RUX	3(0–7)	ORR:2/6, 33%, CR:1/6, 16.7%; PR: 1/6, 16.7%	NA	Grade 1/2: constipation, vomiting, anaemia, nausea, abdominal pain, injection site reaction, dyspnoea, fever and hyperkalaemia; Grade ≥3: anaemia, febrile neutropenia, neutropenia, abdominal pain, hypotension, infections, thrombocytopenia, pneumonitis and syncope
Rampal et al. [12] USA, 2018	Clinical trial	N = 21 MPN-AP: 8 MPN-BP: 13	13(61.9)	63(48–88)	DEC plus RUX	3(1–34)	ORR:9/17, 53%; CRi:4/17, 23.5%; PR:5/17, 29.4%	7.9(4.1–NR)	Grade ≥3 haematologic AEs: neutropenia (33.3%), lymphopenia (19%), thrombocytopenia (19%), anaemia (14%); Grade ≥3 nonhaematologic AEs: febrile neutropenia (33.3%), pneumonia (29%), sepsis (14%), respiratory failure (9.5%), hypertension (9.5%), cellulitis (9.5%), gastrointestinal bleeding (9.5%), squamous cell carcinoma of the skin (9.5%)
Lancman et al. [22] USA, 2018	Retrospective study	N = 57 MPN-BP	33(58)	68(40–92)	DEC +/- RUX	2.5(1–32)	HMAs with or without additional therapies: CR: 9/57, 15.8%;	6.7	NA
Bose et al. [23] USA, 2020	Clinical trial	N = 29 Post-MPN AML	NA	69(32–92)	DEC plus RUX	2(1–8)	ORR:13/29,45%; CR:12/29,41.4%; PR:1/29, 3.4%	6.9(0.4–42.6)	Grade 1/2: nausea, pruritus, fatigue, diarrhoea, dizziness
Gangat et al. [24] USA, 2020	Retrospective study	N = 12 MPN-BP	6(50)	71(48–81)	DEC/AZA plus Venetoclax	3(1–5)	ORR:5/12, 42%, CR:3/12, 25%, PR:2/12, 17%	6(2–NR)	NA
Mascarenhas et al. [25] USA, 2020	Clinical trial	N = 25 MPN-AP:10 MPN-BP:15	11 (44)	71.0 (46.7–85.6)	DEC plus RUX	4(2–11)	ORR:11/25, 44%, CRi:2/25, 8.0%; PR: 9/25, 36%	9.5(4.3–12)	Grade ≥3 haematologic AEs: neutropenia (16%), anaemia 4 (16%) and thrombocytopenia (8%); Grade ≥3 nonhaematologic AEs: febrile neutropenia (28%), pneumonia (24%), bone pain (8%).
Tremblay et al. [26] USA, 2020	Retrospective study	N = 9 MPN-AP:1 MPN-BP:8	7 (77.8)	69 (49–72)	DEC/AZA plus Venetoclax	NA	ORR:3/9, 33.3%; CR/CRi:3/9, 33.3%,	4.2(2.5–NR)	Grade ≥3: infections, intracranial haemorrhage
Gangat et al. [13] USA, 2021	Retrospective study	N = 32 MPN-BP: 32	19 (59)	69 (47–81)	DEC/AZA plus Venetoclax	3(1–7)	ORR: 18/32,56.3%; CR/CRi:14/32,43.8%; PR:4/32, 13%	8(1–24)	NA
Masarova et al. [27] USA, 2021	Retrospective study	N = 18 MPN-BP/post-MPN AML	19(61)	69(46–80)	DEC +  Venetoclax	5(1–14)	ORR:5/18, 27.8%; CR/CRi:4/18, 22.2%; PR: 1/18, 5.6%	NA	NA
King et al. [28] USA, 2021	Retrospective study	N = 27 MPN-AP: 6 MPN-BP: 21	18(66.7%)	72(55–82)	AZA/DEC +  Venetoclax	2(1–15)	ORR:14/24, 58.3%; CR:10/24, 41.7%; PR: 4/24, 16.7%	NA	NA
Yoon et al. [29] USA, 2021	Retrospective study	N = 39 MPN-BP:39	7(43.8)	HMA/Ven: 76(52–82)	DEC/AZA plus Venetoclax	NA	ORR:3/7, 42.9%; CR/CRi:3/7, 42.9%	5	Infection/fever(57.1%), haemorrhage(28.6%)
Zhou et al. [10] USA, 2021	Retrospective study	N = 42 MPN-AP: 14 MPN-BP: 16 MPN-HR: 12	16(61.5)	70.3(48.7–82.8)	DEC plus RUX	5.5(1–56)	NA	21(4.5–NR)	Bacterial infection, viral infection, fungal infection, arterial thrombus, venous thrombus, haemorrhage

Note: DEC: decitabine; AZA: azacytidine; HMAs: hypomethylating agents; GO: gemtuzumab ozogamicin; RUX: ruxolitinib; MOS: median overall survival; ORR: overall response rate; CR: complete remission; CRi: CR with incomplete count recovery; PR: partial remission; MLFS: morphological leukaemia free state; NR: not reach; NA: not available.

Table 2. Overview of the efficacy and safety of HMAs monotherapy in Philadelphia negative MPN-AP/BP.

Source (author/ country)	Study type	Population	Number of men, n (%)	Median age (year, range)	Regimen	Number of cycles, median (range)	Efficacy	Median OS, months (range)	Adverse events
Thepot et al. [11] France, 2010	Retrospective study	N = 26 Post-MPN AML	NA	NA	AZA	6(1–28)	ORR: 10/26,38.5%, CR/CRi:4/26, 15.4%; PR: 6/26, 23.1%	8	Not reported in post-MPN AML patients
Andriani et al. [30] Italy, 2014	Retrospective study	N = 19 MPN-BP	15(78.9%)	71.3(IQR: 64.5–77.7)	AZA	NA	ORR: 6/19, 31.6%; CR/CRi:5/19,26.3; PR:1/19, 5.3%	9.9(6.7–13.1)	grade 3/4 haematological AEs (21%), Non-haematological AEs: 1 episode of fever of unknown origin, 1 pulmonary fungal infection, 1 respiratory failure
Badar et al. [31] USA, 2014	Retrospective study	N = 43 MPN-AP: 19 MPN-BP: 24	31(72.1%)	MPN-AP: 66(50–77) MPN-BP: 63(22–82)	DEC	MPN-AP: 3(1–31) MPN-BP: 2(1–15)	MPN-AP: ORR: 6/19, 32% MPN-BP: ORR:6/24, 25% CR/CRi:5/24, 21% PR:1/24, 4%	MPN-AP:14.8 MPN-BP: 6.9	NA
Badar et al. [32] USA, 2015	Retrospective study	N = 45 MPN-AP 13 MPN-BP 21 DIPSS plus high risk PMF 11	32(71.1)	MPN-AP: 63(50–81) MPN-BP: 64(45–82) DIPSS plus high risk PMF: 67(55–77)	DEC(n = 24,12AP,12BP)	MPN-AP: 2(1–6) MPN-BP: 2(1–13)	MPN-AP: ORR:1/45, 8% MPN-BP: ORR:9/21, 41.7%	MPN-AP:9.7 MPN-BP:6.9 DIPSS plus high risk PMF:2.7	NA
Andriani et al. [33] Italy, 2016	Retrospective study	N = 16 MPN-BP	12(75%)	63.5(51–81)	AZA	NA	ORR: 7/16, 43.8%; CR/CRi:4/16, 25%; PR: 3/16, 18.8%	8.1(1–49.5)	NA
Chihara et al. [34] USA, 2016	Retrospective study	N = 273(total) Post-MPN AML	139 (50.9%)	67(28–92)	HMAs(N = 97) HDAC(N = 71) LDAC(N = 50)	NA	HMAs: ORR:29/97,30%; CR/CRi:29/97,30%	7.8	NA
Andriani et al. [35] Italy, 2017	Retrospective study	N = 32 MPN-BP	21(65.6%)	70.4(IQR:64.2–77.1)	AZA	NA	ORR:12/32,37.5%; CR/CRi:8/32, 25%; PR:4/32,15.6%	11.7(3.5–19.8)	NA
Dumas et al. [36] France, 2017	Retrospective study	N = 32 Post-MPN AML	17(53.1%)	70.5(61.2–83.3)	AZA(n = 18)	NA	ORR:3/18,16.7%	8.4(4.8–13.2)	NA
Venton et al. [37] France, 2017	Retrospective study	N = 73 Post-MPN AML	46(63%)	70(38–89)	AZA	NA	HMAs(n = 11): ORR:6/11,54.5%	7.9(2.3–24.3)	NA
Lancman et al. [22] USA, 2018	Retrospective study	N = 57 MPN-BP	33(58)	68(40–92)	AZA	2.5(1–32)	HMAs with or without additional therapies: CR:9/57,15%	6.7	NA
Mollard et al. [38] France, 2018	Retrospective study	N = 24 MPN-AP:10 MPN-BP:14	14(58.3%)	72.3(57.7–86.7)	AZA	1–18	ORR:12/24,50%; CR/CRi:8/24, 33%; PR:4/24, 17%	9	NA
Tefferi et al. [39] USA, 2018	Retrospective study	N = 26 MPN-BP	NA	NA	HMAs	NA	ORR:1/26,4%; CR:1/26, 4%	5.5	NA
Andriani et al. [40] Italy, 2019	Retrospective study	N = 39 MPN-AP:16 MPN-BP:23	NA	69.9(63.9‐76.9)	AZA	6(3–9)	ORR: 15/39,38.5%; CR/CRi:8/39,20.5% PR:7/39,18%,	13.5(8.2–18.7)	NA
Yoon et al. [29] USA, 2021	Retrospective study	N = 39 MPN-BP:39	7(43.8)	HMAs only: 72(62–83)	DEC/AZA (n = 9)	NA	ORR:1/9,11.1%, CR:1/9, 11.1%	1	Infection/fever (77.8%), haemorrhage (11.1%)
Zhou et al. [10] USA, 2021	Retrospective study	N = 42 MPN-AP: 14 MPN-BP: 16 MPN-HR: 12	16(61.5)	70.3(48.7–82.8)	DEC (n = 18, 7AP, 11BP)	5.5(1–56)	NA	12.9(6.1–NR)	Bacterial infection, fungal infection, arterial thrombus, venous thrombus, haemorrhage

DEC: Decitabine, AZA: Azacitidine, HMAs: Hypomethylating agents; MOS: Median overall survival, ORR: Overall Response Rate, CR: Complete Remission, CRi: CR with incomplete count recovery, PR: Partial Remission; HI: Haematologic Improvement; PD: Progress Disease; HDAC: High Dose Ara-c; LDAC: Low Dose Ara-c; NR: not reach; NA: not available.

Figure 2. The pooled ORR (a), CR/CRi (b) and PR (c) rates of HMAs plus venetoclax vs HMAs alone in patients with MPN-AP/BP.

Figure 3. The pooled ORR (a), CR/CRi (b) and PR (c) rates of HMAs plus ruxolitinib (Rux) vs HMAs monotherapy in patients with MPN-AP/BP.

Figure 4. The pooled rates of one-year OS and two-year OS of HMAs plus venetoclax vs HMAs alone (a, b) and HMAs plus ruxolitinib vs HMAs alone (c, d) in patients with MPN-AP/BP.

Lancman G, Brunner A, Hoffman R, et al. Outcomes and predictors of survival in blast phase myeloproliferative neoplasms. Leuk Res. 2018;70:49–55.

 PubMed Web of Science ®Google Scholar

Yoon JJ, Benitez LL, Bixby DL, et al. Efficacy of HMA +/- venetoclax or intensive chemotherapy in blast-phase myeloproliferative neoplasms [conference abstract]. Blood. 2021;138(Supplement 1):2569–2569.

 Google Scholar

Zhou S, Tremblay D, Hoffman R, et al. Clinical benefit derived from decitabine therapy for advanced phases of myeloproliferative neoplasms. Acta Haematol. 2021;144(1):48–57.

 PubMed Web of Science ®Google Scholar

Bose P, Verstovsek S, Gasior Y, et al. Phase I/II study of ruxolitinib (RUX) with decitabine (DAC) in patients with Post-Myeloproliferative neoplasm acute myeloid leukemia (post-MPN AML): phase I results [abstract]. Blood. 2016;128(22):4262–4262.

 Web of Science ®Google Scholar

Rampal RK, Mascarenhas JO, Kosiorek HE, et al. Safety and efficacy of combined ruxolitinib and decitabine in patients with Blast-Phase MPN and Post-MPN AML: results of a phase I study (myeloproliferative disorders research consortium 109 trial) [abstract]. Blood. 2016;128(22):1124–1124.

 Web of Science ®Google Scholar

Assi R, Bose P, Verstovsek S, et al. The combination of ruxolitinib (RUX) with decitabine (DAC) in patients (pts) with post-myeloproliferative neoplasm acute myeloid leukemia (post-MPN AML): interim report of a phase I/II trial [abstract]. Blood. 2017;130(Suppl_1):1379.

 Google Scholar

Drummond MW, Harrison CN, Vicente SM, et al. A phase Ib study to assess the safety and tolerability of ruxolitinib in combination with azacitidine in patients with advanced phase myeloproliferative neoplasms (MPN), including myelodysplastic syndromes (MDS) or ACUTE MYELOID LEUKAEMIA (AML) arising from MPN (the bloodwise/TAP PHAZAR study on behalf of the UK MPN CSG) [conference abstract]. Blood. 2017;130(Suppl_1):1649.

 PubMedGoogle Scholar

Rampal RK, Mascarenhas JO, Kosiorek HE, et al. Safety and efficacy of combined ruxolitinib and decitabine in accelerated and blast-phase myeloproliferative neoplasms. Blood Adv. 2018;2(24):3572–3580.

 PubMed Web of Science ®Google Scholar

Bose P, Verstovsek S, Cortes JE, et al. A phase 1/2 study of ruxolitinib and decitabine in patients with post-myeloproliferative neoplasm acute myeloid leukemia. Leukemia. 2020;34(9):2489–2492.

 PubMed Web of Science ®Google Scholar

Gangat N, Morsia E, Foran JM, et al. Venetoclax plus hypomethylating agent in blast-phase myeloproliferative neoplasm: preliminary experience with 12 patients. Br J Haematol. 2020;191(5):e120–e124.

 PubMed Web of Science ®Google Scholar

Mascarenhas JO, Rampal RK, Kosiorek HE, et al. Phase 2 study of ruxolitinib and decitabine in patients with myeloproliferative neoplasm in accelerated and blast phase. Blood Adv. 2020;4(20):5246–5256.

 PubMed Web of Science ®Google Scholar

Tremblay D, Feld J, Dougherty M, et al. Venetoclax and hypomethylating agent combination therapy in acute myeloid leukemia secondary to a myeloproliferative neoplasm. Leuk Res. 2020;98:106456.

 PubMed Web of Science ®Google Scholar

Gangat N, Guglielmelli P, Szuber N, et al. Venetoclax with azacitidine or decitabine in blast-phase myeloproliferative neoplasm: a multicenter series of 32 consecutive cases. Am J Hematol. 2021;96(7):781–789.

 PubMed Web of Science ®Google Scholar

Masarova L, DiNardo CD, Bose P, et al. Single-center experience with venetoclax combinations in patients with newly diagnosed and relapsed AML evolving from MPNs. Blood Adv. 2021;5(8):2156–2164.

 PubMed Web of Science ®Google Scholar

King AC, Weis TM, Derkach A, et al. Multicenter evaluation of efficacy and toxicity of venetoclax-based combinations in patients with accelerated and blast phase myeloproliferative neoplasms. Am J Hematol. 2022;97(1):E7–E10.

 PubMed Web of Science ®Google Scholar

Thepot S, Itzykson R, Seegers V, et al. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood. 2010;116(19):3735–3742.

 PubMed Web of Science ®Google Scholar

Andriani A, Montanaro M, Voso MT, et al. The experience of Gruppo Laziale for the study of Ph-, chronic myeloproliferative syndromes in the treatment of myeloproliferative neoplasms in blastic phase with azacytidine. Blood. 2014;124(21):3164–3164.

 Web of Science ®Google Scholar

Badar T, Kantarjian HM, Ravandi F, et al. Decitabine therapy for myeloproliferative neoplasm in accelerated (MPN-AP) or mastic (acute myeloid leukemia; MPN-AML) phase. J Clin Oncol. 2014;32(15_suppl):e18006.

 Web of Science ®Google Scholar

Badar T, Kantarjian HM, Ravandi F, et al. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase. Leuk Res. 2015;39(9):950–956.

 PubMed Web of Science ®Google Scholar

Andriani A, Latagliata R, Voso MT, et al. Azacitidine in the treatment of PH-myeloproliferative neoplasms in blastic phase - the experience of Gruppo Laziale for the study of PH-SMPC [abstract]. Blood. 2016;122(21):5270.

 Google Scholar

Chihara D, Kantarjian HM, Newberry KJ, et al. Survival outcome of patients with acute myeloid leukemia transformed from myeloproliferative neoplasms [abstract]. Blood. 2016;128(22):1940–1940.

 PubMed Web of Science ®Google Scholar

Andriani A, Montanaro M, Breccia M, et al. Treatment of myeloproliferative neoplasms in blastic phase with azacytidine. Clinical results and identification of prognostic factors [abstract]. Blood. 2017;130(Suppl_1):1635.

 Google Scholar

Dumas PY, Bertoli S, Bérard E, et al. Azacitidine or intensive chemotherapy for older patients with secondary or therapy-related acute myeloid leukemia. Oncotarget. 2017;8(45):79126–79136.

 PubMedGoogle Scholar

Venton G, Courtier F, Charbonnier A, et al. Impact of gene mutations on treatment response and prognosis of acute myeloid leukemia secondary to myeloproliferative neoplasms. Am J Hematol. 2018;93(3):330–338.

 PubMed Web of Science ®Google Scholar

Mollard LM, Chauveau A, Boyer-Perrard F, et al. Outcome of Ph negative myeloproliferative neoplasms transforming to accelerated or leukemic phase. Leuk Lymphoma. 2018;59(12):2812–2820.

 PubMed Web of Science ®Google Scholar

Tefferi A, Mudireddy M, Mannelli F, et al. Blast phase myeloproliferative neoplasm: mayo-AGIMM study of 410 patients from two separate cohorts. Leukemia. 2018;32(5):1200–1210.

 PubMed Web of Science ®Google Scholar

Andriani A, Elli E, Trapè G, et al. Treatment of Philadelphia-negative myeloproliferative neoplasms in accelerated/blastic phase with azacytidine. Clinical results and identification of prognostic factors. Hematol Oncol. 2019;37(3):291–295.

 PubMed Web of Science ®Google Scholar

Data availability statement

All data generated or analysed during this study are included in this article and its supplementary information files. The data that support the findings of this study are available from the corresponding author upon reasonable request.