Diagnosis and Treatment: Haematology Journal

Research Article

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

VA Shuvaev1,2*, IS Martynkevich1, MS Fominykh1,3, VY Udaleva1, EV Efremova1, AE Kersilova1, KY Krutikova1, A-PA Poshivay1, LB Polushkina1, EV Motyko1 and SV Voloshin1,4,5

1Russian Research Institute of Haematology and Transfusiology, Saint Petersburg, Russia

2City Clinical Hospital n.a. V.V. Veresaev of the Moscow Department of Healthcare, Moscow, Russia

3Saint-Petersburg State University, Saint Petersburg, Russia

4Military Medical Academy, Saint Petersburg, Russia

5North-Western State Medical University n.a. I.I. Mechnikov, Saint Petersburg, Russia

Received: 09 July 2019

Accepted: 09 August 2019

Version of Record Online: 19 August 2019

Citation

Shuvaev VA, Martynkevich IS, Fominykh MS, Udaleva VY, Efremova EV, et al. (2019) Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia. Diagn Treatment Hematol J 2019(1): 01-22.

Correspondence should be addressed to
Shuvaev VA, Russia

E-mail: shuvaev77@mail.ru
DOI: 
10.33513/DTHJ/1901-01

Copyright

Copyright © 2019 Shuvaev VA et al. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and work is properly cited.

Summary

Background: In recent years there has been significant progress in the diagnostic and treatment of Ph-negative myeloproliferative neoplasms. By the way, they remain heterogenous with great variability in clinical course for every patient. The individual choice from several available treatment methods should be based on balance between potential benefit and risk of adverse events and disease progression. There are some prognostic models for every classic Ph-negative myeloproliferative disease (Essential Thrombocythemia, Polycythemia Vera and Primary Myelofibrosis) that based on retrospective analysis. The implications of treatment algorithms based on such prognostic scales could apply for Ph-negative myeloproliferative neoplasms in routine clinical practice.

Aim: To compare results of diagnostic and treatment algorithms for Ph-MPN patient's management with previous experience.

Materials and methods: A database of Ph-MPN patients study group (97 ET patients, 174 PV patients, 94 PMF patients) and control group (116 ET patients, 265 PV patients, 182 PMF patients). Characteristics of the groups of patients were similar. The diagnosis and treatment of study group patients was conducted according to own risk-based algorithms since year 2012. We have applied different treatment algorithms to every Ph-MPN form (ET, PV, PMF), based on risks for survival and/or thrombosis.

Results: The implementation of diagnostic algorithm diminished the period between first hematologist referral to diagnosis established from 57 days in control group up to 16 days in study group. The use of risk-adapted approach led to two-times more frequent ET patient’s management without cytoreductive therapy (32% in study group vs 14% in control group). Five-year thrombosis-free survival was 91% in study group and 79% in control group. Relative risk for thrombosis was 0.34; 95% C.I. 0.15-0.81; p=0.01). Our ET management algorithm allowed to decrease thrombosis probability from 0.039 event per patient-year in control group to 0.032 event per patient-year in study group. Overall 5-year survival was 93% in study group and 80% in control group. The death probability was decreased from 0.026 event per patient-year in control group to 0.018 event per patient-year. The PV management was also improved with implementation of risk-based algorithm. The cytoreduction in total (drug + excessive red cell removal) were significantly (p=0.0001) rarer in study group (87%) than in control group (98%). HU was used significantly (p=0.0001) more frequent in control group (83%) than in study group (67%). HU as only monotherapy was significantly (p=0.0001) more frequently used in study group (24%) than in control group (11%). Despite of the rarer use of cytoreduction the complete responses almost two times were significantly (p=0.004) frequently achieved in study group (20%) with comparison to the control group (12%). Thrombosis-free survival and overall survival were also significantly higher in study group in comparison with control group: p=0.01 and p=0.02 respectively. Five-year thrombosis-free survival was 83% for study patients and 68% in control group, thus cumulative thrombosis rate was 17% in study group and 32% for control patients. The use of implemented program lowered thrombosis relative risk in two-times: from 0.067 event per patient-year in control patients to 0.033 event per patient-year for study group. Overall 5-year survival was also better in study group 95%, control group - 84%. The relative risk for death was also halved by the novel program (0.041 death per patient-year in control group and 0.0022 - for study patients. We have developed and adopted risk-based program for PMF patients management. The use of risk-adapted approach allowed to three-times more frequently (30% vs 10%, p=0.0001) use Ruxolitinib in study group in comparison to control group. Also, the rate of prescribing erythropoiesis stimulating agents was higher in study group than in control group: 22% vs 7%; p=0.0003. Despite that overall results were similar between groups there were some advantages developed program for PMF management over previous practice in more frequent responses with overall cytoreduction and hydroxycarbamide therapy in study group over the control. The patients in study group which were treated with Ruxolitinib had significantly (p=0.02) more clinical improvement (43% for study group vs 11% in control), the overall 5-year survival for Ruxolitinib treated patients was 78%, with beneficial influence of target therapy on survival. The survival analysis showed better results in study group. Five-year survival in study group was 82% in comparison to control group - 73% There was also decrease in cumulative death rate from 0.070 death per patient-year in control group to 0.058 in study group.

Conclusion: The results of our study showed the benefit of implementation risk-based approach for Ph-MPN patients management in clinical practice allow to use less frequently cytoreduction therapy and improve overall survival and complications risk.

Keywords 

Algorithm-Based Approach; Clinical Practice; Essential Thrombocythemia; Myeloproliferative Neoplasms; Polycythemia Vera; Primary Myelofibrosis

Introduction

The myeloproliferative neoplasms are consisted of the substantial part of hematological malignancies. The traditional of its division is on Chronic Myeloid Leukemia and Ph-negative myeloproliferative neoplasms (Ph-MPN). The most frequent Ph-MPN are Essential Thrombocythemia (ET), Polycythemia Vera (PV) and Primary Myelofibrosis (PMF). The US epidemiological data of incidence per 100 000 population based on previous diagnostic criteria are as follows: PV - 0.79, PMF - 0.25, ET - 0.53 and MPN-U - 0.41 [1]. In Russia there is only data for St. Petersburg with the incidence of each disease was registered in approximately 1 x 100 000 inhabitants per year [2]. There is much progress in its diagnostic and treatment in the last fifteen years. By the way, Ph-MPN remain heterogenous with great variability in clinical course for every patient. The investigation in molecular pathogenesis with detection of driver mutations (JAK2V617F, CALR, MPL) made diagnostic process simpler than before but some difficulties with identification of triple-negative cases and differential diagnosis with other hematologic malignancies and reactive blood changes are still remained [3-5]. The overall survival of Ph-MPN patient affected by thrombotic and leukemia progression risks with different balance from disease to disease [6]. The individual choice from several available treatment methods should be based on balance between potential benefit and risk of adverse events and disease progression. There are some prognostic models for every classic Ph-negative myeloproliferative disease (ET, PV and PMF) that based on retrospective analysis. The implications of treatment algorithms based on such prognostic scales could have of value to increase the overall survival and minimize of adverse events and complications. Several years ago, we have developed algorithms for use in own routine clinical practice for Ph-MPN patients management.

Aim: To compare results of diagnostic and treatment algorithms for Ph-MPN patients management with previous experience.

Materials and methods: We have created of database of Ph-MPN patients with two groups: study group (97 ET patients, 174 PV patients, 94 PMF patients) and control group (116 ET patients, 265 PV patients, 182 PMF patients), characteristics are presented in tables 1-3. The enrollment criteria were age more than 18 years at the time of database inclusion and diagnosis of MPN (by hematologist). The diagnosis was histologically proven in all ET and PMF patients. All the patients were treated at the same institution. There were no significant differences between control and study groups in ET patients with exception for higher erythrocyte count in study group and differences in patients’ proportion with unknown molecular status (more in control group) that led to several differences in molecular markers detection rates. The PV patients in study group were older than in control group with slightly lower level of hemoglobin, erythrocytes, hematocrit. The PMF patients were similar in the groups with exception for the rate of molecular assessment that led to several differences in molecular markers frequencies.

Characteristic

Patients, n (%)

p

control group
(n=116)

study group
(n=97)

Age at diagnosis, median (range), years

49.4

(18.4-82.8)

48.9

(19.0-79.0)

0.74

Gender, male/female

30/86

32/65

0.32

Thrombosis in anamnesis, n (%)

23 (20%)

12 (12%)

0.09

arterial, n (%)

15 (13%)

8 (8%)

0.38

venous, n (%)

8 (7%)

4 (4%)

0.56

Hemoglobin, g/dl, mean (95% C.I.)

13.7 (13.5-13.9)

14.2 (14.0-14.4)

0.05

Red cells, x1012/l, mean (95% C.I.)

4.7 (4.6-4.8)

5.0 (4.9-5.1)

0.002

Hematocrit, l/l, mean (95% C.I.)

0.42 (0.41-0.43)

0.44 (0.43-0.45)

0.05

White blood cells, x109/l, mean (95% C.I.)

9.4 (9.1-9.7)

9.7 (9.3-10.1)

0.81

Platelets, x109/l, mean (95% C.I.)

1017 (963-1071)

899 (869-929)

0.30

Bone marrow fibrosis by histology - MF0, n (%)

99 (85%)

86 (89%)

0.61

Genetic markers

JAK2V671F+, n (%)

47 (41%)

53 (55%)

0.06

JAK2V671F-, n (%)

34 (29%)

43 (44%)

0.03

CALR+, n (%)

10 (9%)

19 (20%)

0.0001

type 1, n (%)

5 (4%)

8 (8%)

0.36

type 2, n (%)

4 (3%)

9 (9%)

0.07

MPL+, n (%)

1 (1%)

1 (1%)

0,70

triple-negative, n (%)

1 (1%)

10 (10%)

0.002

genetic status unknown, n (%)

37 (30%)

1 (1%)

0.0001

Table 1: Characteristics of ET patients at the diagnosis.

Characteristic

Patients, n (%)

p

control group
(n=265)

study group
(n=174)

Age at diagnosis, median (range), years

58.6

(21.0-86.2)

65.0

(16.4-92.8)

0.0001

Gender, male/female

115/150

71/103

0.66

Plethora, n (%)

151 (57%)

104 (60%)

0.63

Thrombosis in anamnesis, n (%)

58 (22%)

51 (29%)

0.10

arterial, n (%)

45 (17%)

32 (18%)

0.80

venous, n (%)

8 (3%)

4 (2%)

0.88

Splenomegaly, n (%)

75 (28%)

39 (22%)

0.21

Hemoglobin, g/dl, mean (95% C.I.)

18.6 (18.5-18.8)

17.8 (17.6-17.9)

0.001

Red blood cells, x1012/l, mean (95% C.I.)

7.1 (7.0-7.1)

6.8 (6.7-6.9)

0.01

Hematocrit, l/l, mean (95% C.I.)

0.58 (0.58-0.59)

0.55 (0.55-0.56)

0.001

White blood cells, x109/l, mean (95% C.I.)

11,5 (11,2-11,9)

12,6 (12,1-13,1)

0.19

Platelets, x109/l, mean (95% C.I.)

515 (500-530)

575 (553-597)

0.05

Genetic markers

JAK2V671F+, n (%)

142 (92%)

151 (92%)

0.87

Mutations in JAK2 exon 12, n (%)

1 (1%)

1 (1%)

0.51

Table 2: Clinical signs in PV patients at the diagnosis.

Characteristic

Patients, n (%)

p

control group
(n=182)

study group
(n=94)

Age at diagnosis, median (range), years

57.2

(16.1-89.0)

58.4

(17.8-82.8)

0.46

Gender, male/female

67/115

38/54

0.47

Thrombosis in anamnesis, n (%)

39 (21%)

22 (23%)

0.82

arterial, n (%)

27 (15%)

16 (17%)

0.38

venous, n (%)

12 (7%)

6 (6%)

0.76

Hemoglobin, g/dl, mean (95% C.I.)

12.7 (12.4-12.9)

12.5 (12.2-12.8)

0.76

Red cells, x1012/l, mean (95% C.I.)

4.6 (4.5-4.8)

4.7 (4.5-4.9)

0.88

Hematocrit, l/l, mean (95% C.I.)

0.41 (0.40-0.41)

0.41 (0.40-0.41)

0.90

White blood cells, x109/l, mean (95% C.I.)

10.8 (10.3-11.4)

14.9 (13.5-16.3)

0.06

Platelets, x109/l, mean (95% C.I.)

599 (564-643)

615 (554-676)

0.59

Bone marrow fibrosis by histology

 

 

 

MF0, n (%)

29 (16%)

12 (13%)

0.60

MF1, n (%)

49 (27%)

21 (22%)

0.49

MF2, n (%)

60 (33%)

41 (44%)

0.11

MF3, n (%)

44 (24%)

19 (20%)

0.55

Genetic markers

JAK2V671F+, n (%)

84 (46%)

57 (61%)

0.03

JAK2V671F-, n (%)

70 (38%)

33 (35%)

0.68

CALR+, n (%)

10 (6%)

17 (18%)

0.002

type 1, n (%)

4 (2%)

13 (14%)

0.0003

type 2, n (%)

6 (3%)

4 (4%)

0.46

MPL+, n (%)

2 (1%)

1 (1%)

0.56

triple-negative, n (%)

8 (4%)

12 (13%)

0.02

genetic status unknown, n (%)

28 (15%)

4 (4%)

0.01

IPSS risk groups, n

low/int-1/int-2/high

64/58/25/35

34/28/19/13

ns*

DIPSS risk groups, n

low/int-1/int-2/high

64/68/36/14

34/39/19/2

ns*

DIPSS+ risk groups, n

low/int-1/int-2/high

16/23/19/16

12/14/15/8

ns*

IPSS risk groups, n

low/int-1/int-2/high

4/10/6/0

14/11/13/2

ns*

Table 3: Characteristics of patients and PMF clinical manifestation at the diagnosis.

*non-significantly; p>0.05 for all paired comparison 

The diagnosis and treatment of study group patients was conducted according to developed algorithms since year 2012 (Figures 1-4). Essential to our diagnostic process was initial concurrent molecular screening for BCR-ABL and JAK2V617F mutations. In case of BCR-ABL identification the CML diagnosis was made with further cytogenetic assessment, prognostication and treatment. Otherwise the JAK2V617F presence could give the base for initial Ph-MPN diagnosis with bone marrow biopsy verification. Negative cases for both aberrations were submitted to the second step of molecular screening with sequencing for the presence of mutations in CALR, MPL, JAK2 exon 12 genes and morphological assessment of bone marrow with karyotyping. According to the results of bone marrow biopsy the final step of prognostication was made in case of concrete Ph-MPN nosology or follow-up in case of unclassified form of Myeloproliferative Neoplasms (MPN-U) or check up for causes was done if reactive blood changes were suspected with MPN exclusion. For the assessment of our diagnostic algorithm efficacy we assessed a period from first referral to diagnosis established with our algorithm and compare with time needed to establish diagnosis in control group.

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 1: Myeloproliferative neoplasms diagnostic algorithm.

We have applied different treatment algorithms to every Ph-MPN form (ET, PV, PMF), based on risks for survival and/or thrombosis [7-9].

The management of ET patients had been founded on IPSET-thrombosis scale risks [10]. This simple scale based on age (>60 years), cardiological events risk factors (diabetes mellitus, arterial hypertension, smoking) - 1 score for each; JAK2V617F mutation presence and thrombosis in past - 2 scores for each. Risk category defines as low (0-1), intermediate (2) and high risk (3 and more).

The low-risk patients were kept at follow-up with receiving antiaggregant therapy only. The intermediate risk patients were classified depending on age (<60 years>) and platelet count (<1000x109/l>). Younger patients with low platelets could be managed with follow-up and antiaggregant. In younger patients with hyper thrombocytosis (>1000x109/l) the cytoreductive therapy was started with preference to Interferon-alfa (IFN) and Anagrelide (ANA) in first line and Hydroxyurea (HU) as second-line therapy. The older patients were treated with HU in first line and IFN and ANA in second line setting. High-risk patients usually have experienced previous thrombotic events with influence of life-term estimated. So, the age border for choice between IFN/ANA or HU for first-line therapy was decreased up to 40 years [8].

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 2: Essential thrombocythemia treatment algorithm.

We manage PV patients also with thrombosis risk-based approach using the scale from Marchioli R et al. [11]. This scale is very simple and consisted of age >65 years and previous thrombosis with 1 score for each factor, that constitute low (0), intermediate (1) and high (2) risk groups. In our own algorithm we differentiated treatment according to age (<50-70>) and presence of active cardiovascular pathology. For young (<50 years) and otherwise healthy patients we used antiaggregant and phlebotomy/red cell apheresis in order to maintain hematocrit <45%, IFN or HU as second-line and then Ruxoliinib (RUX) in third line settings. Young patients with cardiovaslular problems were mainly treated with IFN and then HU and RUX as second line. Intermediate (50-70) age patients without cardiovascular comorbidity were treated with HU and flebotomy/red cell apheresis in first and RUX and IFN as second line. In case of intermediate age patients with significantly cardiovascular diseases the treatment was similar with exception that flebotomy/red cell apheresis were tried to be avoided. Older (>70 years) patients were treated with HU as choice for first line, in case of resistance and/or intolerance the RUX or other chemotherapeutic agents or IFN were proposed [7].

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 3: Algorithm of treatment choice in Polycythemia Vera.

The risk-based approach was used in PMF management too [9]. The basis for the treatment modality choice was stratificaton by scoring systems: IPSS, DIPSS, DIPSS+, MIPSS information that we had. The scoring systems for PMF have different level of complexity and include various clinical, hematological, cytogenetic and molecular parameters with combinations that are special for every scale. The main advantage of these scales is its good corellation with PMF pateints survival, in addition some of them were used for comparison the results of allogeneic transplantation and conventionatal therapy of PMF [12-14]. The details of each risk stratification system could be found in references [15-18]. Low and intermediate-1 risk patients were treated mainly for symptom control and syndrome correction (anemia, cytoreduction, splenomegaly). The intermediate-2 and high risk patients should be initially discussed about allogeneic Stem Cells Transplantation (allo-SCT) possibility. Target therapy with RUX should initiated if drug available. The correction of clinical signs of disease (anemia, thrombocytopenia, cytoreduction, constitutional symptoms, splenomegaly) with best available therapy also was done.

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 4: Primary myelofibrosis management algorithm.

For our treatment algorithms efficacy assessment, we evaluated treatment responses according to ELN and IWG-MRT response criteria for ET and PV [19] and EUMNET and ELN criteria for PMF [20,21]. Also, we have compared overall and thrombosis-free survival and thrombotic and death risks.

Statistical methods include descriptive statistics, Mann-Whitney U test, Chi-square and Fisher exact tests, Kaplan-Meier curves with log-rank test.

Results

The implementation of diagnostic algorithm diminished the period between first hematologist referral to diagnosis established from 57 days in control group up to 16 days in study group. The shortening of diagnostic period was reached due to firs line concurrent molecular screening for CML and Ph-MPN.

Essential thrombocythemia: The results of ET patient’s management were as follows: thrombotic events in study group statistically significantly (p=0.02) differed depending on IPSET groups (Figure 5).

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 5: Thrombotic complications in Essential thrombocythemia patients according to IPSET thrombosis risk groups (n=97).

Overall Survival (OS) also significantly (p=0.005) differed in IPSET-thrombosis risk groups (Figure 6), 5-years OS was as follows:

  • low-risk - 97.5%;
  • intermediate-risk - 89.6%;
  • high-risk - 86.9%.

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 6: Overall survival in Essential thrombocythemia patients according to IPSET thrombosis risk groups (n=97).

ET patients were treated with antiaggregant and cytoreductive therapy (chemotherapeutic agents, interferon-alfa, anagrelide) (Table 4).

Therapy

Control group
(n=116)

Study group
(n=97)

p

Antiaggregant, n (%)

111 (96%)

93 (96%)

0.78

Acetylsalicylic acid, n (%)

110 (95%)

91 (94%)

0.98

median of dose, mg (range)

100 (50-150)

100 (50-150)

0.65

Clopidogrel, n (%)

1 (1%)

2 (2%)

0.88

Anticoagulant, n (%)

8 (8%)

2 (2%)

0.18

Warfarin, n (%)

5 (5%)

1 (1%)

0.31

Rivaroxaban, n (%)

2 (2%)

1 (1%)

0.87

No cytoredictive therapy, n (%)

17 (15%)

31 (32%)

0.01

Cytoreductive therapy, n (%)

99 (85%)

66 (68%)

0.01

Hydroxyurea, n (%)

58 (50%)

35 (36%)

0.06

median of dose, mg (range)

750 (250-2000)

500 (350-1500)

0.08

Interferon, n (%)

19 (16%)

24 (25%)

0.17

median of dose, mlnME/week (range)

9 (2-18)

9 (3-10,5)

0.95

Hydroxyurea + Interferon, n (%)

14 (12%)

-

0.001

Anagrelide, n (%)

8 (7%)

7 (7%)

0.86

Median of dose, mg (range)

3.0 (1.0-4.0)

2 (1.5-4.0)

0.10

 Table 4: Essential thrombocythemia patient treatment in control and study group.

The use of risk-adapted approach led to two-times more frequent ET patients management without cytoreductive therapy (32% in study group vs 14% in control group; p=0.01). The responses to the therapy according to ELN2013 [19] criteria are presented in table 5.

 

Control group

Study group

p

Cytoreductive therapy, n (%)

99 (100%)

66 (100%)

-

complete response, n (%)

18 (18%)

14 (21%)

0.78

partial response, n (%)

41 (41%)

32 (48%)

0.46

no response, n (%)

40 (40%)

21 (31%)

0.34

Hydroxyurea, n (%)

58 (100%)

35 (100%)

-

complete response, n (%)

6 (10%)

4 (11%)

0.86

partial response, n (%)

28 (48%)

22 (63%)

0.25

no response, n (%)

24 (41%)

9 (26%)

0.03

Interferon, n (%)

19 (100%)

24 (100%)

-

complete response, n (%)

3 (16%)

7 (29%)

0.50

partial response, n (%)

7 (37%)

7 (29%)

0.84

no response, n (%)

9 (47%)

10 (42%)

0.95

Hydroxyurea + Interferon, n (%)

14 (100%)

-

-

complete response, n (%)

4 (29%)

-

-

partial response, n (%)

5 (36%)

-

-

no response, n (%)

5 (36%)

-

-

Anagrelide, n (%)

8 (100%)

7 (100%)

 

complete response, n (%)

5 (63%)

3 (43%)

0.81

partial response, n (%)

1 (13%)

2 (29%)

0.90

no response, n (%)

2 (25%)

2 (29%)

0.67

 Table 5: Responses to cytoreductive treatment in Essential thrombocythemia patients in control and study group.

The therapy results were similar between groups. Despite the less frequent use of cytoreduction, the study group had beneficial over control group in time from diagnosis to thrombosis (p=0.03) and overall survival (Figures 7,8). Five-year thrombosis-free survival was 91% in study group and 79% in control group. Relative risk for thrombosis was 0.34; 95% C.I. 0.15-0.81; p=0.01). Our ET management algorithm allowed to decrease thrombosis probability from 0.039 event per patient-year in control group to 0.032 event per patient-year in study group. Overall 5-year survival was 93% in study group and 80% in control group. The cumulative mortality risk was significantly lower in study group than in control group (RR: 0.31; 95% C.I. 0.13-0.77; p=0.01). The death probability was decreased from 0.026 event per patient-year in control group to 0.018 event per patient-year.

Therefore, the use of risk-approached therapy algorithm could improve overall and thrombosis-free survival of ET patients.

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 7: Thrombosis free survival in Essential thrombocythemia patients in control (n=116) and study (n=97) group.

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 8: Overall survival in Essential thrombocythemia patients in control (n=116) and study (n=97) group.

Polycythemia vera: The PV management was also improved with implementation of risk-based algorithm. The PV-thrombosis score showed the evidence in 5-year follow up, the thrombosis rate was significantly differed according risk groups (p=0.005, figure 9):

  • low-risk - 7%;
  • intermediate-risk - 20%;
  • high-risk - 49%.

The relative thrombosis risk (event per patient-year) was as follows:

  • low-risk - 1.7%;
  • intermediate-risk - 5.0%;
  • high-risk - 38.7%.

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 9: Thrombosis free survival in Polycythemia Vera patients in study group according to risk groups by PV-thrombosis scale (n=174).

The PV-thrombosis scale also influenced on overall survival (p=0.05), 5-year OS was as follows (Figure 10):

  • low-risk - 95.2%;
  • intermediate-risk - 88.0%;
  • high-risk - 86.5%.

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 10: Overall survival in Polycythemia Vera patients in study group according to risk groups by PV-thrombosis scale (n=174).

The PV patients were treated with antiaggregant, removal of excessive red cell mass by phlebotomy or apheresis, cytoreduction with chemotherapy (mainly with HU), IFN. The frequency of different kind of treatment in study and control group are presented in table 6.

Treatment

Control group
(n=265)

Study group
(n=174)

p

Antiaggregant, n (%)

261 (98%)

166 (96%)

0.10

Acetylsalicylic acid, n (%)

261 (98%)

166 (96%)

0.10

median of dose, mg (range)

100 (50-200)

100 (50-150)

0.14

Anticoagulants, n (%)

7 (3%)

4 (2%)

0.93

Warfarin, n (%)

2 (1%)

-

0.67

Rivaroxaban, n (%)

3 (1%)

3 (2%)

0.92

Dabigatran, n (%)

1 (0.4%)

-

0.83

Cytoreductive treatment (drug and/or removal), n (%)

261 (98%)

151 (87%)

0.0001

Removal of excessive red blood cells (phlebotomy / red blood cells apheresis), n (%)

31 (12%)

31 (18%)

0.10

Cytoreductive drug therapy, n (%)

230 (87%)

120 (69%)

0.0001

Hydroxyurea, n (%)

28 (11%)

42 (24%)

0.0002

median of dose, mg (range)

1000 (500-2000)

750 (250-2250)

0.0001

Interferon, n (%)

1 (0.4%)

2 (1%)

1.0

median of dose, mlnME/week (range)

9 (9-9)

9 (9-9)

0.95

Hydroxyurea + Interferon, n (%)

38 (14%)

2 (1%)

0.0001

Hydroxyurea + phlebotomy / red blood cells apheresis, n (%)

153 (58%)

73 (42%)

0.004

Interferon + phlebotomy / red blood cells apheresis, n (%)

10 (4%)

1 (1%)

0.11

No cytoreductive treatment (drug and/or removal), n (%)

4 (2%)

23 (13%)

0.0001

 Table 6: Polycythemia Vera patients treatment in control and study group.

The use of our risk-based algorithm made possible to systemize process of choice therapeutic modality for every patient and to decrease toxicity with the lowering of doses and combination of different techniques. Antiaggregant were used in the vast majority of patients (96%-98%). Risk-based approach allowed more frequent to manage PV patients without cytoreduction (13% in study group and 25% in control group). Phlebotomy or red cell apheresis rates as monotherapy were similar (12%-18%) in patient groups. The cytoreduction in total (drug + excessive red cell removal) were significantly (p=0.0001) rarer in study group (87%) than in control group (98%). HU was used significantly (p=0.0001) more frequent in control group (83%) than in study group (67%). HU as only monotherapy was significantly (p=0.0001) more frequently used in study group (24%) than in control group (11%). The most frequent therapy modality was a combination of HU and phlebotomy/apheresis, by the way its need in study group (42%) was significantly (p=0.004) rarer than in control group (58%).

The responses to therapy according to ELN2013 criteria [19] are presented in table 7.

 

Control group

Study group

p

Cytoreductive treatment (drug and/or removal), n (%)

261 (100%)

151 (100%)

-

complete response, n (%)

31 (12%)

30 (20%)

0.04

partial response, n (%)

136 (52%)

63 (42%)

0.05

no response, n (%)

94 (36%)

58 (38%)

0.70

Removal of excessive red blood cells (phlebotomy / red blood cells apheresis), n (%)

31 (100%)

31 (100%)

-

complete response, n (%)

3 (10%)

1 (3%)

0.65

partial response, n (%)

12 (39%)

12 (39%)

0.79

no response, n (%)

16 (52%)

18 (58%)

0.80

Cytoreductive drug therapy, n (%)

230 (100%)

120 (100%)

-

complete response, n (%)

28 (12%)

29 (24%)

0.006

partial response, n (%)

124 (54%)

51 (43%)

0.06

no response, n (%)

78 (34%)

40 (33%)

0.99

Hydroxyurea, n (%)

28 (100%)

42 (100%)

-

complete response, n (%)

7 (25%)

14 (33%)

0.63

partial response, n (%)

18 (65%)

13 (31%)

0.01

no response, n (%)

3 (11%)

15 (36%)

0.40

Interferon, n (%)

1 (100%)

2 (100%)

-

complete response, n (%)

0 (0%)

1 (50%)

0,67

partial response, n (%)

1 (100%)

1 (50%)

0,83

no response, n (%)

-

-

-

Hydroxyurea + Interferon, n (%)

38 (100%)

2 (100%)

 

complete response, n (%)

3 (8%)

-

0.85

partial response, n (%)

21 (55%)

1 (50%)

0.70

no response, n (%)

14 (37%)

1 (50%)

0.58

Hydroxyurea+ phlebotomy / red blood cells apheresis, n (%)

153 (100%)

73 (100%)

-

complete response, n (%)

17 (11%)

14 (19%)

0.15

partial response, n (%)

79 (52%)

36 (49%)

0.50

no response, n (%)

57 (37%)

23 (31%)

0.49

Interferon + phlebotomy / red blood cells apheresis, n (%)

10 (100%)

1 (100%)

 

complete response, n (%)

1 (11%)

0 (0%)

0.91

partial response, n (%)

5 (44%)

0 (0%)

0.55

no response, n (%)

4 (44%)

1 (100%)

0.45

Table 7: Responses to treatment of Polycythemia Vera patients in control and study group.

Despite of the rarer use of cytoreduction (as with drug as with red cell removal) the complete responses almost two times were significantly (p=0.004) frequent achieved in study group (20%) with comparison to the control group (12%). According to kind of treatment there were found next significant:

  • drug cytoreduction - more complete responses in study group (24%) than in control group (12%);
  • HU - more partial responses in control group (65%) with comparison to study group (31%) without difference in complete responses rate.

Target therapy with Ruxolitinib (RUX) was used in 5 PV patients with previous resistance to HU: there were achieved partial response in 3 patients and 1 patient reached a complete response.

Thrombosis-free survival and overall survival were also significantly higher in study group in comparison with control group: p=0.01 and p=0.02 respectively (Figures 11,12).

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 11: Thrombosis free survival in Polycythemia Vera patients in study (n=174) and control (n=265) group.

Five-year thrombosis-free survival was 83% for study patients and 68% in control group, thus cumulative thrombosis rate was 17% in study group and 32% for control patients. The use of implemented program lowered thrombosis relative risk in two-times: from 0.067 event per patient-year in control patients to 0.033 event per patient-year for study group. Overall 5-year survival was also better in study group 95%, control group - 84%. The relative risk for death was also halved by the novel program (0.041 death per patient-year in control group and 0.0022 - for study patients.

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 12: Overall survival in Polycythemia Vera patients in study (n=174) and control (n=265) group.

The recent years have yielded a great success in the field of molecular pathogenesis of PV with identification of JAK-STAT signal pathway. Nevertheless, the majority of PV patients still suffered and died from thrombotic events that occurred in these patients significantly more frequent than in general population. The implementation our algorithmic thrombosis risk-based program in clinical practice showed benefit as in improvement of responses to therapy as in thrombosis-free and overall survival of PV patients.

Primary myelofibrosis: We have developed and adopted risk-based program for PMF patients management. The diagnostic workup for PMF is including cytogenetic and molecular (JAK2V617F, CALR, MPL, ASXL1, EZH2, IDH1/2, SRSF2) genetic assessment that make possible to stratify patients in risk groups according to IPSS, DIPSS, DIPSS+, MIPSS, MIPSS70(+) [15,17,18,22,23]. The prognostic scales are very useful in PMF as for prediction survival as for choice of treatment between conventional therapy and allogeneic stem cells transplantation [12].

In our program at the end of diagnostic stage we have stratified PMF patients according to risk groups and submit kind of treatment by weighting balance between risk of adverse events and benefit for survival. The main purposes of PMF treatment are survival and quality of life. The only one curative method is allo-SCT has its own risks, some of them enhanced by PMF nature, and could not be done for the vast majority of patients due to comorbidity, donor availability, etc

The scheme of our algorithm for treatment choice for PMF patients in clinical practice is presented in figure 4.

Low and intermediate-1 risk: These risks are identified in majority of patients at diagnosis. Commonly, the patients have normal or subnormal hemoglobin without transfusion dependency, there are no severe WBC elevation and blastemia. The projected OS for this group of patients is 7-15 years with low risk of blast phase transformation [15,22,24]. The aggressive treatment in this case could result to adverse events more significant in long term than risk of progression. Given absence of constitutional symptoms and complications, patients could be managed under follow up and special treatment should be started only when clinically significant symptoms will arise. The symptoms mainly treated symptomatically: erythropoiesis stimulating agents, androgens, steroids. The target therapy with RUX in this stage is limited to cases with massive splenomegaly, constitutional symptoms that have resistance or intolerance to conventional therapy.

The minority of patients has intermediate-2 and high risk at diagnosis, but the fact that OS in this case is already shortened in comparison to general population should be taken onto account. Typically, the patients have significant anemia, severe leukocytosis with left shift to blasts, sometimes with thrombocytopenia, severe bone marrow fibrosis and clonal cytogenetic aberrations. This group of patients could be progressed to more severe cytopenia’s and blast transformation in recent years.

The target therapy with RUX indicated to all patients if access to drug is available due to its beneficial effect on OS [25-28]. The first question that should be clarified in first year from diagnosis for young fit patients (younger 65 years) is the suitability to undergo allo-SCT. In case of allo-SCT unavailability (older or unfit patients) the conventional therapy with HU, IFN, steroids, erythropoiesis stimulating agents or blood transfusion depending on clinical situation is prescribed. The monitoring of response to therapy and adverse events is essential in PMF patients and should be done every 3 months or more frequently. In our program we assessed responses to therapy according to EUMNET [20] or IWG-MRT (ELN2013) criteria [21]. The ELN2013 response assessment have some difficulties for use in clinical practice, that related to the need of periodic bone marrow examination and symptom assessment with standardized questionnaire MPN10, its Russian version only undergone validation process and is not completely ready for use.

In our study we have compared the results of our program application in 94 PMF patients (study group) with retrospective analysis of 182 PMF patients outcomes that were treated previously at our institution (control group). The PMF in both groups did not differ by age, gender, disease symptoms or blood count levels. There is only one significant difference in rate of molecular genetic assessment (more thoroughly in study group 96% vs 85% in control group) that led to some differences rate of molecular driver gene mutations detection. The most frequent mutation was JAK2V617F, then CALR and MPL, that fully consistent with other studies [29].

There was not any significant difference in the rate of risk groups according to prognostic scoring systems (IPSS, DIPSS, DIPSS+, MIPSS) between study and control groups patients. The OS was statistically significant differed between risk groups according to all used prognostic systems (IPSS, DIPSS, DIPSS+, MIPSS), 5-year OS in study group are presented in table 8.

Risk group

IPSS
n=94

DIPSS
n=94

DIPSS+
n=49

MIPSS
n=40

Low

79%

79%

100%

85%

Intermediate-1

71%

63%

74%

82%

Intermediate-2

64%

58%

67%

55%

High

32%

0%

43%

0%

Table 8: Overall 5-year survival in PMF patients in different risk groups by IPSS, DIPSS, DIPSS+, MIPSS prognostic scales.

During our prospective study we have registered thrombotic complications in 16 (17%) patients in study group: arterial - 7 (7%) and venous - 9 (10%), including 3 cases of myocardial infarction and stroke in one patient. Five-year thrombosis-free survival was 58%.

Transformation to the blast phase was occurred in 7 (7%) patients in study group and 8 (4%) in the control group (p=0,47). Five-year blast-free survival was 89% in study group and 92% in control group (p=0.13). In study group six out of 7 patients who progressed were died, whereas in control group all patients were died with the equal medians of 6 months from blast transformation.

PMF patients were treated with antiaggregant, cytoreduction with monochemotherapy (mainly HU), IFN, janus kinase inhibitors (RUX), steroids, hemopoiesis stimulators, blood components transfusions. The rate of prescription antiaggregant and different kind of cytoreduction as first line therapy in study and control groups are presented in table 9.

Treatment

Control group
(n=182)

Study group
(n=94)

p

Antiaggregant, n (%)

116 (64%)

60 (96%)

0.65

Acetylsalicylic acid, n (%)

112 (62%)

54 (94%)

0.98

median of dose, mg (range)

100 (50-150)

100 (50-150)

0.54

Clopidogrel, n (%)

4 (2%)

2 (2%)

0.69

No cytoreductive therapy, n (%)

30 (16%)

22 (23%)

0.39

Cytoreductive therapy, n (%)

152 (84%)

72 (77%)

0.39

Hydroxyurea, n (%)

103 (57%)

54 (57%)

0.99

median of dose, mg (range)

750

(143-1750)

500

(250-2000)

0.81

other chemotherapeutic agents (Busulfan, Mercaptopurine, Cytarabine)

6 (3%)

4 (4%)

0.23

Interferon, n (%)

20 (11%)

9 (10%)

0.45

median of dose, mlnME/week (range)

9 (6-18)

9 (3-9)

0.95

Hydroxyurea + Interferon, n (%)

23 (13%)

5 (5%)

0.07

Ruxolitinib, n (%)

19 (10%)

28 (30%)

0.0001

Glucocorticoids, n (%)

38 (21%)

17 (18%)

0.70

Erythropoiesis stimulating agents, n (%)

12 (7%)

21 (22%)

0.0003

Transfusions, n (%)

47 (26%)

21 (22%)

0.62

Red blood cells

47 (26%)

21 (22%)

0.62

Platelets

3 (2%)

3 (3%)

0.33

 Table 9: Treatment of PMF patients in control and study group.

The rate of antiaggregant and cytoreduction kind in first line did not significantly differ between groups of patients. The use of risk-adapted approach allowed to three-times more frequently (30% vs 10%, p=0.0001) use RUX in study group in comparison to control group. Also, the rate of prescribing erythropoietin preparation was higher in study group than in control group: 22% vs 7%; p=0.0003.

The responses to therapy according to EUMNET (20) and ELN2013 (19) are presented in tables 10,11.

 

Control group

Study group

p

Cytoreduction therapy, n (%)

152 (100%)

72 (100%)

-

complete response, n (%)

4 (3%)

5 (7%)

0.08

major response, n (%)

18 (12%)

9 (13%)

0.87

moderate response, n (%)

5 (3%)

8 (11%)

0.02

minor response, n (%)

21 (14%)

12 (17%)

0.97

no response, n (%)

68 (45%)

23 (32%)

0.06

progression, n (%)

36 (24%)

15 (21%)

0.85

Hydroxyurea, n (%)

103 (100%)

54 (100%)

-

complete response, n (%)

0 (0%)

3 (6%)

0.04

major response, n (%)

12 (12%)

7 (13%)

0.99

moderate response, n (%)

0 (0%)

8 (15%)

0.0001

minor response, n (%)

15 (15%)

8 (15%)

0.85

no response, n (%)

48 (47%)

16 (30%)

0.06

progression, n (%)

28 (27%)

12 (22%)

0.63

Interferon, n (%)

20 (100%)

9 (100%)

-

complete response, n (%)

2 (10%)

1 (11%)

0.69

major response, n (%)

2 (10%)

1 (11%)

0.69

moderate response, n (%)

1 (5%)

0 (0%)

0.69

minor response, n (%)

2 (10%)

3 (33%)

0.55

no response, n (%)

10 (50%)

4 (44%)

0.16

progression, n (%)

3 (15%)

0 (0%)

0.31

Hydroxyurea + Interferon, n (%)

23 (100%)

5 (100%)

 

complete response, n (%)

1 (4%)

1 (20%)

0.33

major response, n (%)

2 (9%)

1 (20%)

0.46

moderate response, n (%)

3 (13%)

0 (0%)

0.54

minor response, n (%)

4 (17%)

0 (0%)

0.43

no response, n (%)

9 (39%)

2 (40%)

0.67

progression, n (%)

4 (17%)

1 (20%)

0.66

other chemotherapeutic agents (Busulfan, Mercaptopurine, Cytarabine)

6 (100%)

4 (100%)

-

complete response, n (%)

1 (17%)

0 (0%)

0.60

major response, n (%)

2 (33%)

0 (0%)

0.33

moderate response, n (%)

1 (17%)

0 (0%)

0.60

minor response, n (%)

0 (0%)

1 (25%)

0.40

no response, n (%)

1 (17%)

1 (25%)

0.67

progression, n (%)

1 (17%)

2 (50%)

0.33

Ruxolitinib, n (%)

19 (100%)

28 (100%)

-

complete response, n (%)

0 (0%)

1 (4%)

0.60

major response, n (%)

4 (21%)

6 (21%)

0.74

moderate response, n (%)

2 (11%)

5 (18%)

0.40

minor response, n (%)

1 (5%)

2 (7%)

0.65

no response, n (%)

8 (42%)

7 (25%)

0.36

progression, n (%)

4 (21%)

7 (25%)

0.52

Table 10: Responses to cytoreduction therapy in PMF patients in control and study group according to EUMNET criteria (20).

 

Control group

Study group

p

Cytoreduction therapy, n (%)

152 (100%)

72 (100%)

-

complete response, n (%)

2 (1%)

2 (3%)

0.39

partial response, n (%)

4 (3%)

7 (10%)

0.03

clinical improvement, n (%)

21 (14%)

14 (19%)

0.38

stable disease, n (%)

115 (76%)

38 (53%)

0.001

progressive disease, n (%)

20 (13%)

11 (15%)

0.82

Hydroxyurea, n (%)

103 (100%)

54 (100%)

-

complete response, n (%)

0 (0%)

0 (0%)

-

partial response, n (%)

0 (0%)

5 (9%)

0.004

clinical improvement, n (%)

14 (14%)

12 (22%)

0.25

stable disease, n (%)

87 (84%)

28 (52%)

0.0001

progressive disease, n (%)

12 (12%)

9 (17%)

0.53

Interferon, n (%)

20 (100%)

9 (100%)

-

complete response, n (%)

1 (5%)

1 (11%)

0.53

partial response, n (%)

3 (15%)

2 (22%)

0.50

clinical improvement, n (%)

2 (10%)

1 (11%)

0.69

stable disease, n (%)

11 (55%)

5 (55%)

0.71

progressive disease, n (%)

3 (15%)

0 (0%)

0.31

Hydroxyurea + Interferon, n (%)

23 (100%)

5 (100%)

 

complete response, n (%)

1 (4%)

1 (20%)

0.33

partial response, n (%)

0 (0%)

0 (0%)

-

clinical improvement, n (%)

3 (13%)

0 (0%)

0.54

stable disease, n (%)

14 (61%)

4 (80%)

0.40

progressive disease, n (%)

5 (22%)

0 (0%)

0.34

other chemotherapeutic agents (Busulfan, Mercaptopurine, Cytarabine)

6 (100%)

4 (100%)

-

complete response, n (%)

0 (0%)

0 (0%)

-

partial response, n (%)

1 (17%)

0 (0%)

0.60

clinical improvement, n (%)

2 (33%)

1 (25%)

0.67

stable disease, n (%)

3 (50%)

1 (25%)

0.45

progressive disease, n (%)

0 (0%)

2 (50%)

0.13

Ruxolitinib, n (%)

19 (100%)

28 (100%)

-

complete response, n (%)

1 (5%)

1 (4%)

0.65

partial response, n (%)

4 (21%)

3 (11%)

0.61

clinical improvement, n (%)

2 (11%)

12 (43%)

0.02

stable disease, n (%)

13 (68%)

3 (11%)

0.0002

progressive disease, n (%)

1 (5%)

7 (25%)

0.08

Table 11: Responses to cytoreduction therapy in PMF patients in control and study group according to ELN2013* [19].

*the response assessment did not include control bone marrow examination and dynamic symptom assessment by MPN10.

Despite that overall results were similar between groups there were some advantages developed program for PMF management over previous practice.

According to EUMNET criteria:

  • the overall cytoreduction therapy had significantly (p=0.02) more frequent moderate response in study group (11%) than in control patients (3%), also there was a statistical tendency (p=0.06) for more high no response rate in control group (45%) in comparison to study group (32%);
  • HU treatment significantly (p=0.04) had more frequent complete and moderate responses in study group (6%  15%) than in control (0%  0%), whereas no response rate also statistical tendency (p=0.06) in control group (47%) in comparison study group (30%).

According to ELN2013 system:

  • the overall cytoreduction had significantly (p=0.03) more partial response in study group (10%) than in control patients (3%), stable disease was observed significantly (p=0,001) more frequent in control group (76%) in comparison to study group (53%), the differences was due to patients in study group were more frequent than control group had various responses to treatment, whereas rates of progression were similar (15% vs 13% respectively);
  • HU treatment statistically significant (p=0.004) had more partial response in study group (9%) in comparison to control patient (0%), as a result significantly (0,0001) less patients (52%) in study group than in control (84%) had stable disease whereas progression rates were similar (17% vs 12% respectively);
  • target therapy with RUX had different profiles of responses in study and control groups: significantly (p=0.02) more patients in study group had clinical improvement (43% for study group vs 11% in control) that resulted to stable disease more rare (p=0.0002) was registered in study group (11%) than in control patients (68%), the overall 5-year survival for RUX treated patients was 78%, the regression analysis showed statistically significant (p=0.0001) beneficial influence RUX on survival with patients stratification by DIPSS as a covariate.

Allo-SCT was done for 6 patients (for 3 patients in both groups). The mortality was similar (one patient in every group): the patient in control group was died from chronic graft versus host disease, whereas in study group patient had a primary graft failure.

The survival analysis showed better results in study group. Five-year survival in study group was 82% in comparison to control group - 73% (RR 0.60; 95% C.I. 0.41-0,87; p=0.01) (Figure 13). There was also decrease in cumulative death rate from 0.070 (95% C.I. 0.045-0.103) death per patient-year in control group to 0.058 (95% C.I. 0.047-0.70) death per patient-year in study group.

Implementation of Algorithm-Based Approach for Ph-Negative Myeloproliferative Neoplasms in Routine Clinical Practice in Russia

Figure 13: Overall survival in Primary myelofibrosis patients in study (n=94) and control (n=182) group.

Therefore, the experience of risk-adapted approach in PMF management showed its possibility to prognose the survival and suitability for treatment individualization with improvement in overall 5-year survival from 73% to 82%. The janus kinase inhibitors are beneficial for 37-58% of patients with previous resistance to conventional therapy.

Discussion and Conclusion

Myeloproliferative neoplasms are substantial part of hematologic diseases. Until recently, the MPN diagnosis was based on empiric exclusion of other diseases and therapy had restrictive intention without systematic approach.

The advances of recent years associated with molecular pathogenesis investigation allowed to substantially wide the knowledge about mechanisms of MPN development, create of new diagnostic criteria, prognostic scales and therapy algorithms based on evidence medicine. Nowadays MPN from unclear diseases turned into accurate nosology. Diagnostic criteria by World Health Organization could make accurate and reproduced diagnosis with specific list of work up methods. The retrospective and prospective studies were served as foundation for prognostic scales that could predict survival and probability of complications.

The standardization of diagnosis allowed to conduct multicenter international trials and create target drugs with better tolerability and efficacy than conventional therapy that allowed to prolong term of life and preserve its quality.

In our study we have analyzed the experience of implementation the own algorithm for MPN management in clinical practice. The morphology and genetic-based diagnostic algorithm have substantially shortened period for verification of concrete form of MPN and individualize treatment according to needs of every patient.

The risk-based algorithm for ET management in clinical practice resulted to safe decrease of cytoreduction therapy prescription. The individual thrombosis risk assessment led to decline of thrombotic complications rate, increase of time from diagnosis to thrombosis, improvement in overall survival and diminish thrombotic and death risks.

The personalized program for PV diagnosis and treatment with algorithm for individual treatment choice was also was developed in our study. The risk-adapted approach could decrease cytoreduction therapy prescription as in case for ET, whereas efficacy in complete response rate was significantly improved. All of these led to improvement in overall and thrombosis free survival as a result of halved risks for thrombotic complications and death. The target therapy gave possibility to have response in majority of PV patients with previous resistance to conventional therapy.

For PMF management first time in Russia we have implemented in clinical practice the diagnostic program that included as driver genes mutations detection as identification mutations in epigenetic regulators genes. Newly created algorithm allowed to stratify patients according to modern prognostic scales and personalized treatment between risks of adverse events and death probability. The implementation of own PMF management program improved response rates for HU treatment and for cytoreduction in total. The Ruxolitinib use was also more effective within algorithm-based approach. The overall results of adoption PMF management program in clinical practice were overall survival improvement and decrease of death risk in PMF patients.

Therefore, our study showed the benefit of implementation risk-based approach for Ph-MPN patients management in clinical practice as for overall survival as for complications risk with less treatment toxicity.

Acknowledgement

The research did not have funding support.

Conflicts of Interest

All authors declare no conflicts of interest in this article.

References

  1. Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, et al. (2008) Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood 112: 45-52.
  2. Shuvaev V, Martynkevich I, Abdulkadyrova A, Udaleva V, Zamotina T, et al. (2014) Ph-Negative Chronic Myeloproliferative Neoplasms - Population Analysis, a Single Center 10-years’ Experience. Blood 124: 5556.
  3. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, et al. (2013) Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2. New England Journal of Medicine 369: 2391-2405.
  4. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, et al. (2013) Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms. New England Journal of Medicine 369: 2379-2390.
  5. Lundberg P, Karow A, Nienhold R, Looser R, Hao-Shen H, et al. (2014) Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood 123: 2220.
  6. Hultcrantz M, Kristinsson SY, Andersson TM-L, Landgren O, Eloranta S, et al. (2012) Patterns of Survival Among Patients With Myeloproliferative Neoplasms Diagnosed in Sweden From 1973 to 2008: A Population-Based Study. Journal of Clinical Oncology 30: 2995-3001.
  7. Abdulkadyrov KM, Shuvaev VA, Martynkevich IS (2015) All we know about polycythemia vera: literature review and own experience. Oncohematology 10: 28-42.
  8. Abdulkadyrov KM, Shuvaev VA, Martynkevich IS (2015) Modern Approaches to Diagnosis and Treatment of Essential Thrombocythemia: Literature Review and Own Experience. Klinicheskaya onkogematologiya 8: 235-247.
  9. Abdulkadyrov KM, Shuvaev VA, Martynkevich IS (2015) Primary myelofibrosis: own experience and news from diagnostic and treatment. Oncohematology 10: 25-35.
  10. Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, et al. (2012) Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood 120: 5128-5133.
  11. Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, et al. (2005) Vascular and Neoplastic Risk in a Large Cohort of Patients With Polycythemia Vera. Journal of Clinical Oncology 23: 2224-2232.
  12. Gupta V, Hari P, Hoffman R (2012) Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood 120: 1367.
  13. Kröger N, Giorgino T, Scott BL, Ditschkowski M, Alchalby H, et al. (2015) Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood 125: 3347.
  14. Stewart WA, Pearce R, Kirkland KE, Bloor A, Thomson K, et al. (2010) The role of allogeneic SCT in primary myelofibrosis: a British Society for Blood and Marrow Transplantation study. Bone Marrow Transplantation 45: 1587.
  15. Gangat N, Caramazza D, Vaidya R, George G, Begna K, et al. (2011) DIPSS Plus: A Refined Dynamic International Prognostic Scoring System for Primary Myelofibrosis That Incorporates Prognostic Information From Karyotype, Platelet Count, and Transfusion Status. Journal of Clinical Oncology 29: 392-397.
  16. Hussein K, Pardanani AD, Van Dyke DL, Hanson CA, Tefferi A, et al. (2009) International Prognostic Scoring System-independent cytogenetic risk categorization in primary myelofibrosis. Blood 115: 496-499.
  17. Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, et al. (2009) A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 115: 1703-1708.
  18. Vannucchi AM, Guglielmelli P, Rotunno G, Pascutto C, Pardanani A (2014) Mutation-Enhanced International Prognostic Scoring System (MIPSS) for Primary Myelofibrosis: An AGIMM & IWG-MRT Project. Blood 124: 405.
  19. Barosi G, Mesa R, Finazzi G, Harrison C, Kiladjian J-J, et al. (2013) Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood 121: 4778-4781.
  20. Barosi G, Bordessoule D, Briere J, Cervantes F, Demory J-L, et al. (2005) Response criteria for myelofibrosis with myeloid metaplasia: results of an initiative of the European Myelofibrosis Network (EUMNET). Blood 106: 2849.
  21. Tefferi A, Cervantes F, Mesa R, Passamonti F, Verstovsek S, et al. (2013) Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood 122: 1395-1398.
  22. Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, et al. (2008) New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 113: 2895-2901.
  23. Vannucchi AM, Guglielmelli P, Lasho TL, Rotunno G, Mannarelli C, et al. (2017) MIPSS70: Mutation-Enhanced Prognostic System for Transplant Age Patients with Primary Myelofibrosis. Blood 130: 200.
  24. Shuvaev V, Abdulkadyrova A, Udaleva V, Golovchenko R, Zotova I, et al. (2013) Primary myelofibrosis - a survey based on the 20-years’ experience of a single center. Haematologica 98: 624.
  25. Al-Ali HK, Griesshammer M, le Coutre P, Waller CF, Liberati AM, et al. (2016) Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica 101: 1065-1073.
  26. Harrison CN, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Gisslinger H, et al. (2016) Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia 30: 1701-1707.
  27. Vannucchi AM, Kantarjian HM, Kiladjian J-J, Gotlib J, Cervantes F, et al. (2015) A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica 100: 1139-1145.
  28. Verstovsek S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, et al. (2017) Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. Journal of Hematology & Oncology 10: 55.
  29. Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, et al. (2013) JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 123: 1544-1551.
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