Analysis of clinical characteristics of bone marrow proliferative tumor progression to acute myeloid leukemia

Abstract

OBJECTIVE:

This study aims to analyze Chinese patients who developed acute leukemia after being diagnosed and treated for Philadelphia chromosome (Ph)-negative chronic myeloproliferative neoplasms (MPNs), and compare the findings of this series with similar studies from literature.

METHODS:

Nine patients who progressed to leukemia after being diagnosed with MPN were included into the present study. Clinical data including age, treatment modalities and duration of use in the myeloproliferative phase, latency to leukemic transformation (LT), characteristics of leukemia, chemotherapy administration, and survival after LT were examined. Furthermore, factors associated with leukemia transformation were analyzed.

RESULTS:

Over a 13-year period, nine patients had LT in 192 Ph-negative MPNs. Among these patients, two patients had polycythemia vera (PV), three patients had essential thrombocythemia (ET), and four patients had myelofibrosis (MF). The median age at MPN diagnosis was 51 years old(range: 42–69 years old), and the median age upon reaching LT was 57 years old (range: 46–72 years old). Furthermore, the median latency to LT was 72.8 months (range: 7–144 months). Five patients had cytogenetic abnormalities (62.5%), with abnormalities in chromosomes $-$ 5, $+$ 8 and $-$ 7 being common. Eight patients underwent the JAK2 V617F gene test when diagnosed with MPN. The prognosis of patients with LT was poor, and the average survival time was 6.7 months.

This was not correlated with the treatment.

CONCLUSION:

LT in Ph-negative MPNs is rare, and has poor prognosis, which has been consistently reported in a number of studies, However, this needs to be further confirmed through larger studies.

1. Introduction

Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of diseases that originate from hematopoietic stem/progenitor cells and clonal diseases, and involves polycythemia vera (PV), primary extracorporeal thrombocytosis (ET) and primary myelofibrosis (PMF) [1, 2, 3, 4]. The discovery of the JAK2 V617F tyrosine kinase mutation in MPNs had a significant impact in altering the cognition of clinical and biological characteristics, treatment and other aspects [5]. However, few cases can be transformed into acute leukemia in the terminal stage. Leukemic transformation (LT) ratios for PV, ET and PMF are5–15%, 1–4% and 8–23%, respectively [6, 7, 8]. The average time from the diagnosis of MPN to LT is nearly 10 years. Furthermore, the prognosis of LT cases is always accompanied by extremely poor prognosis, merely a couple of months of surviving time, and frequent poor prognosis of chromosome karyotype or complex karyotype [9]. The mechanism of MPN cloning with relatively slow internal growth translating into the rapid proliferation of leukemia cloning has not been reported at present, both locally and abroad.

A total of nine MPN patients treated in our hospital over the past 10 years to the present gradually became acute myeloid leukemia (AML) after treatment. The following summary analysis focused on the clinical characteristics, therapeutic process and prognosis of these patients.

2. Materials and methods

2.1 Patient information

The data of 192 MPN admission cases in Qingdao Central Hospital from January 2001 to January 2016 were collected. Nine of these cases transformed into AML during the follow-up period. The initial diagnosis of these patients was strongly identified by bone marrow cytology and classified according to the present MPN diagnosis criteria. These nine cases underwent bone marrow cytology tests, and the bone marrow immunological classifications were totally in accordance with the World Health Organization (WHO) diagnosis criteria for AML [1]. The exact diagnosis period was from April 2009 to January 2015 (Table 1).

Table 1

MPN patient data

	Sex/age	Primary	Conversion	Splenomegaly	JAK2	Before conversion	Chromosome	AML	Survival time after
		disease	time (months)			treatment		type	conversion (months)
Case 1	Male/42	PMF	144	Yes		Hydroxyurea; interferon; thalidomide	Complex karyotype	AML	2
Case 2	Female/60	ET	72	Yes	$-$	Hydroxyurea	Complex karyotype	M5	5
Case 3	Male/44	ET	120	No	$+$	Hydroxyurea	$+$ 8	AML
Case 4	Female/54	PMF	12	Yes	$-$	Hydroxyurea	46, XY	M5	3
Case 5	Male/46	PMF	7	Yes	$+$	Hydroxyurea; interferon	$-$ 7, t(3; 3)	M5	4
Case 6	Female/69	PMF	36	Yes	$+$	Thalidomide	46, XY	AML	14
Case 7	Male/53	PV	108	No	$+$	Hydroxyurea	46, XY	M5	7
Case 8	Female/45	PV	95	Yes	$+$	Hydroxyurea	Complex karyotype	AML	10
Case 9	Female/46	ET	61	No	$-$	Hydroxyurea		AML	15

2.2 Methods

The clinical data of these patients, including gender, the number of years from the diagnosis of MPN, the number of years from AML transformation, the exact period for the transformation, the therapeutic method before and after transformation to AML, chromosome analysis results, and JAK2 V617F gene results were collected. The numerical variables and classified variables were described by description.

3. Results

Among the 192 MPN patients (MF, 68; PV, 57; ET, 67) who accepted treatment between January 2001 and January 2016, nine patients (MF, 4; PV, 2; ET, 3) transformed to AML during the follow-up period. These nine patients comprised of four male and five female patients. The mean age at MPN diagnosis was 51 years old (range: 42–69 years old), while the mean age at LT diagnosis was 57 years old (range: 46–72 years old). The mean time of conversion from MPN to AML was 72.8 months (range: 7–144 months).

In the MPN stage, eight cases were treated by hydroxyurea for an average of 53.9 months (range: 5–120 months). Furthermore, among these patients, two MF patients were treated by interferon associated with hydroxyurea, and one MF patient was treated by thalidomide for three months. The remaining patient was treated solely with thalidomide for one year after MF diagnosis. The hydroxyurea, interferon and thalidomide doses given to these patients were not different from those given to the rest of the MPN patients, while none of these patients were treated with alkylating agents or bauxin.

A total of nine patients were converted to AML. Among these patients, four patients developed to acute monocytic leukemia, while the remaining five patients were diagnosed with unclassified AML. None of these patients converted to acute lymphoblastic leukemia. Eight patients underwent bone marrow chromosome analysis during the diagnosis process. Among these patients, three patients had normal karyotypes, while the remaining five patients had abnormalities. Among these five patients, three patients had complex karyotypes (more or less than three chromosomal abnormalities). Furthermore, two patients underwent chromosomal analysis before and after LT. Among these patients, one patient had the same outcome, while the other patient had a normal karyotype with MPN diagnosis, which turned into a complex karyotype after conversion to AML. The general chromosomal abnormalities were $-$ 7 ( $n=$ 3), $+$ 8 ( $n=$ 2) and $-$ 5 ( $n=$ 3). Eight patients underwent JAK2 V617F gene analysis at the right time to confirm the MPN diagnosis. Five patients were detected with mutations. Among these patients, two patients underwent JAK2 V617F gene analysis before and after the transformation, while there were two ET patients and one MF patient for the remaining three patients.

The general prognosis was extremely terrible for these LT patients. Eight patients died, with an LT survival time of 6.7 months (range: 2–15 months). One patient underwent LT before 12 months, and is surviving with the tumor at present. These patients continuously had poor general status due to old age, masses of complications and survival with the tumor for a long time, and other reasons. Therefore, the therapy was really difficult for these patients. Four patients failed to receive regular chemotherapy, and solely received cytosine arabinoside to slowdown the disease progression, or component blood transfusion for support treatment. The remaining five patients received formal chemotherapy. Among these patients, two patients failed to induce therapy, while the remaining three patients re-emerged during or after the therapy. Thus, none of these patients attained long-term survival. The chemotherapy regimen comprised of deoxymycin daunorubicin $+$ cytosine arabinoside (IA regimen), daunorubicin $+$ cytarabine (DA regimen), acillamycin $+$ cytosine arabinoside $+$ granulocyte colony stimulating factor (CAG program), desilcinide, etc. Most of these patients died from infection or uncontrolled cancer progression.

4. Discussion

MPNs were derived from hematopoietic stem cell cloning disease, and the onset of occult, slow progression and advanced progression can be acute leukemia. However, few studies have been conducted on this field due to the low incidence of LT, long conversion time, and other reasons. During the follow-up period, the European Collaborative Group found that 1.3% of PV patients progressed to acute leukemia, with an average progression of 8.4 years [6]. In a study conducted by Passamonti et al., it was revealed that PV has a 5.3% chance of LT occurrence [10]. In recent years, a study conducted on ET patients revealed an incidence of 1.2–3.3% for LT [6, 11], and after alkylating agents were given to patients, ET reached 5–12% [12]. PMF patients had the highest incidence of LT, which can reach 8–23% within the initial diagnosis of 10 years [8]. At present, similar reports have been rarely reported in China. In the present study, the data of 192 MPN patients were reviewed. Among these patients, the disease progression of nine patients led to leukemia, which had an incidence rate of 4.7% and an average progression time of 72.8 months. These show that the progression of MPN patients to acute leukemia is not highly probable, and progression is very slow. In present study, the mean age at diagnosis of MPN was 51 years old, and the mean age at LT was 57 years old. These were largely consistent with foreign studies, and the incidence of LT was lower in younger MPN patients. In addition, patients in the present study had a lower incidence of LT, when compared to studies conducted by other countries.

The risk factors for LT are age, disease duration, as well as the use of alkylating agents, its association with chemotherapy, and LT before the first conversion to MF [6, 7, 8]. It remains controversial whether hydroxyurea should be used with LT [6, 8]. In the present study, eight of nine patients were treated with hydroxyurea in the MPN stage, and some patients treated with hydroxyurea were combined with other drugs, such as interferon. In addition, the hydroxyurea doses and effecting times differed, and were not exactly the same. Therefore, it is difficult to measure the use of hydroxyurea effecting time and dose related to LT. Due to the small number of cases of the present study, the analysis of LT-related risk factors was of little significance, and the survival analysis for age was not included.

The present study [9] revealed the following general chromosomal abnormalities: $+$ 1q, $-$ 5, 5q $-$ , $-$ 7, 7q $-$ , $+$ 8, $+$ 9, 11q $-$ , 13q $-$ and 20q $-$ . These were associated with abnormal chromosomes. Furthermore, $-$ 5/5q $-$ and $-$ 7/7q $-$ were the most common abnormal changes in patients who received multi-drug treatments, and approximately 5 and 5q $-$ abnormalities were observed in approximately half of the patients treated solely by hydroxyurea. The most common chromosomal abnormalities in patients who received bloodletting were $+$ 8 and $+$ 9. Chromosome 5 and 7 deletions were characteristic changes in treatment-related leukemia, which were also detected in LT patients, taking into account the likelihood of the occurrence of LT and the treatment of MPN. In recent years, the discovery of JAK2 V617F mutations has rapidly developed the diagnosis, typing and treatment of MPN patients [5, 13]. Two of the patients in the present study were detected with JAK2 V617F mutations before and after LT, indicating that leukemic cells developed from the same group of malignant cells.

Leukemia converted from MPN were mostly acute myeloid, and acute lymphoblastic leukemia were rarely observed, with a reported double phenotype of acute leukemia [14]. In our study, nine patients were all converted to AML, and none of these patients had lymphocytic leukemia and double phenotype acute leukemia. In addition, the AML in four patients were diagnosed with acute monocytic leukemia, which is the most common type of transformation.

The prognosis of leukemia converted from MPN was extremely poor. Masses of research institutions abroad have reported that the average survival time after the transformation was $<$ 6 months, with no correlation to the type of MPN before the transformation [8]. Approximately half of the initial treatments for LT patients can achieve complete remission, but the duration of the remission is short. The prognosis of this segment of patients was not correlated with the use of chemotherapy regimens, and hematopoietic stem cell transplantation was only performed for the survival of LT patients [15]. Furthermore, the prognosis of patients in the our study was poor, with an average survival time of 6.7 months after LT, and without long-term survival. Due to patient age, failure to induce therapy, severe general status and other reasons, none of these patients accepted hematopoietic stem cell transplantation therapy.

The present study revealed that the incidence of MPN transformation to leukemia is rare. These often undertake abnormal genetic changes and bad prognosis. Due to the rare number of cases studied, the intensity of the argument was limited to some extent. Therefore, there is an urgent need for further research on the assessment of patients with MPN conversion to leukemia.