TO THE EDITOR:

It is well known that patients with cancer may subsequently develop secondary/therapy-related neoplasms, generally exhibiting poorer prognosis than their de novo counterparts.1  Among patients with myeloproliferative neoplasms (MPN), there may be a higher rate of second malignancies before, concomitant with, or after their MPN diagnosis as compared with the general population2-9  (Table 1). We recently reported (and others confirmed) the association of lymphoid malignancies coexistent with an MPN diagnosis and found this to be an overall rare phenomenon that did not predict for worse clinical outcomes among MPN patients.10  The incidence and relative risk of post-MPN lymphoid neoplasms has been evaluated, and a 1.4- to 5-fold higher risk in this population has been identified, regardless of therapy received (Table 1). A recent important report in this area raises the possibility that those patients with MPN treated with a Janus kinase (JAK) inhibitor class of therapies may have a markedly higher rate of development of a subsequent lymphoma than patients who did not receive these therapies.11  Given the paucity of data sets that specifically focus on those patients with MPN treated with a JAK inhibitor subsequently diagnosed with a lymphoma, we sought to determine the characteristics and outcomes of this particular subset of patients in our large patient database.

Table 1.

Major studies of lymphoproliferative neoplasms in patients with MPN

StudyStudy typeLPN before, concurrent, or after MPNRR or SIR/SPR for secondary malignancyPatients with MPNNo. of LPNs detectedNo. with MPN firstNo. with LPN firstNo. with concurrent disease
Vannucchi et al18  Retrospective After 3.44 820 11 N/A N/A N/A 
Masarova et al10  Retrospective Before, concurrent, and after N/A 9866 15 15 16 
Masarova et al4  Retrospective After N/A 417 N/A N/A N/A 
Frederiksen et al3  Retrospective After 6203 152* N/A N/A N/A 
Palandri et al5  Retrospective Concurrent and after N/A 499 N/A 
Rumi et al6  Retrospective After 2.79 1915 22 N/A N/A N/A 
Pettersson et al19  Retrospective Before 1.49 2213 N/A N/A 30* N/A 
Brunner et al9  Retrospective After 2.27-3.14 20 250 124 N/A N/A N/A 
Landtblom et al7  Retrospective After 2.6 9379 90 N/A N/A N/A 
Marchetti et al8  Review Before, concurrent, and after N/A 214 214 105 43 65 
StudyStudy typeLPN before, concurrent, or after MPNRR or SIR/SPR for secondary malignancyPatients with MPNNo. of LPNs detectedNo. with MPN firstNo. with LPN firstNo. with concurrent disease
Vannucchi et al18  Retrospective After 3.44 820 11 N/A N/A N/A 
Masarova et al10  Retrospective Before, concurrent, and after N/A 9866 15 15 16 
Masarova et al4  Retrospective After N/A 417 N/A N/A N/A 
Frederiksen et al3  Retrospective After 6203 152* N/A N/A N/A 
Palandri et al5  Retrospective Concurrent and after N/A 499 N/A 
Rumi et al6  Retrospective After 2.79 1915 22 N/A N/A N/A 
Pettersson et al19  Retrospective Before 1.49 2213 N/A N/A 30* N/A 
Brunner et al9  Retrospective After 2.27-3.14 20 250 124 N/A N/A N/A 
Landtblom et al7  Retrospective After 2.6 9379 90 N/A N/A N/A 
Marchetti et al8  Review Before, concurrent, and after N/A 214 214 105 43 65 

LPN, lymphoproliferative neoplasms; N/A, not applicable; RR, relative risk; SIR/SPR, standard incidence ratio/standard prevalence ratio.

*

Lymphoid and myeloid malignancies were not separated.

We performed a comprehensive, multidisciplinary, retrospective chart review of all patients with diagnosis of MPN or lymphoma treated at our institution from May 1965 to November 2018. In order to ensure that all possible patients were captured for retrospective analysis, we queried 4 separate institutional patient data sets (cross-checked, with rigorous, continuous updated follow-up/outcomes) in the Departments of Leukemia, Pharmacy, Lymphoma, and Pathology. Overall, we identified 17 570 patients with lymphoma and 2583 patients with a diagnosis of MPN (including essential thrombocythemia [ET], polycythemia vera [PV], and myelofibrosis (MF; either primary or secondary to ET/PV). We then identified patients with both a confirmed diagnosis of MPN (ET, PV or MF) and lymphoma by World Health Organization criteria12,13  and age ≥18 years for a total of 21 patients (n = 13 lymphoma diagnosis prior to MPN, n = 9 lymphoma diagnosis after MPN). The focus of this analysis is the 9 patients with lymphoma diagnosed after the MPN diagnosis.

In total, we identified 2583 patients with MPN, including 1617 patients with MF (median follow-up time, 26 months; range, 0-348 months) and 966 patients with ET or PV (median follow-up time, 24 months; range, 0-345 months). Among the patients with MF, only 9 out of 1617 (0.56%) developed a subsequent lymphoma after the MF diagnosis. In the MF cohort (n = 1617), 623 patients had exposure to a JAK inhibitor and 994 did not. Among the 9 patients who went on to develop lymphoma, 6 had previous exposure to a JAK inhibitor and 3 did not, with a P value between the 2 groups that was not statistically significant (.082). In contrast, we found a slightly higher number of patients (n = 13) with a lymphoma diagnosis before the MF diagnosis.

The median age at the time of MF diagnosis among the 9 total patients was 63 years (range, 41-70 years); the median age of the 6 patients who had previous exposure to a JAK inhibitor was 64 years (range, 41-70) (P = .395, with no difference between the 2 groups). The median time from first exposure of a JAK inhibitor to the development of lymphoma was 3.5 years (range, 1.7-7.3 years). Three of the 6 patients who received JAK inhibitors were treated with ruxolitinib, and the remaining 3 patients were treated with other JAK inhibitors (Table 2) (CEP-701, n = 1; CYT387 [momelotinib], n = 1; and AZD1480, n = 1).

Table 2.

Characteristics of patients, MPN, and subsequent lymphoma

Patient no.SexMF Dx datePrior MPNMolecular (allele %)LDH at MF DxMarrow fibrosis gradeCytogenetics at time of MF DxPrior MPN therapies before JAK inhibitorJAK inhibitor receivedJAK inhibitor prior to lymphoma?Lymphoma Dx dateAge at lymphoma DxLymphoma stageLymphoma subtypeLymphoma treatmentOS from lymphoma Dx
8/14/2000 No Not done 569 MF-2 Diploid HU N/A 3/22/2010 62 Follicular lymphoma, grade 3A Observation 11 mo 
3/26/2012 No JAK2 (46.4%) 1107 MF-2 Diploid None N/A 4/12/2012 62 IV Enteropathy associated TCL Observation NR 
7/23/2013 PV JAK2 (42.1%) 949 MF-2 46,XX,t(9;15) (p24;q15) HU+ phlebotomy N/A 9/3/2013 63 IV TCL, anaplastic, ALK CHOP 1.6 mo 
3/9/2010 PV JAK2 (86%) 916 MF-2 46,XY,del(20) (q11.2q13.3) None Len + Rux 7/13/2015 54 IV DLBCL R-EPOCH Lost to follow-up 
11/30/2010 No Triple-negative MF 763 MF-2 Diploid None Rux 1/15/2017 69 Unknown NHL (scalp) Lost to follow-up Lost to follow-up 
2/21/2006 No Not done 1635 MF-2 Diploid None CEP-701 8/7/2014 49 IV DLBCL R-CHOP/HD MTX 5.5 mo 
6/27/2008 PV JAK2 (82%) 1134 MF-3 46,XY,del(13) (q12q14) HU Rux 2/2/2010 66 IV MCL R-hyper-CVAD/R-MTX/Ara-C 67 mo 
11/20/2009 No JAK2 (87.1%) 2463 MF-3 46,XY,del(20) (q11.2q13.3) HU CYT387 5/2/2017 77 IV MCL 5.7 mo 
12/23/2010 PV lJAK2 (87.85%) 1451 Not done Diploid Phlebotomy AZD1480 8/10/2018 72 II DLBCL R-CHOP NR 
Patient no.SexMF Dx datePrior MPNMolecular (allele %)LDH at MF DxMarrow fibrosis gradeCytogenetics at time of MF DxPrior MPN therapies before JAK inhibitorJAK inhibitor receivedJAK inhibitor prior to lymphoma?Lymphoma Dx dateAge at lymphoma DxLymphoma stageLymphoma subtypeLymphoma treatmentOS from lymphoma Dx
8/14/2000 No Not done 569 MF-2 Diploid HU N/A 3/22/2010 62 Follicular lymphoma, grade 3A Observation 11 mo 
3/26/2012 No JAK2 (46.4%) 1107 MF-2 Diploid None N/A 4/12/2012 62 IV Enteropathy associated TCL Observation NR 
7/23/2013 PV JAK2 (42.1%) 949 MF-2 46,XX,t(9;15) (p24;q15) HU+ phlebotomy N/A 9/3/2013 63 IV TCL, anaplastic, ALK CHOP 1.6 mo 
3/9/2010 PV JAK2 (86%) 916 MF-2 46,XY,del(20) (q11.2q13.3) None Len + Rux 7/13/2015 54 IV DLBCL R-EPOCH Lost to follow-up 
11/30/2010 No Triple-negative MF 763 MF-2 Diploid None Rux 1/15/2017 69 Unknown NHL (scalp) Lost to follow-up Lost to follow-up 
2/21/2006 No Not done 1635 MF-2 Diploid None CEP-701 8/7/2014 49 IV DLBCL R-CHOP/HD MTX 5.5 mo 
6/27/2008 PV JAK2 (82%) 1134 MF-3 46,XY,del(13) (q12q14) HU Rux 2/2/2010 66 IV MCL R-hyper-CVAD/R-MTX/Ara-C 67 mo 
11/20/2009 No JAK2 (87.1%) 2463 MF-3 46,XY,del(20) (q11.2q13.3) HU CYT387 5/2/2017 77 IV MCL 5.7 mo 
12/23/2010 PV lJAK2 (87.85%) 1451 Not done Diploid Phlebotomy AZD1480 8/10/2018 72 II DLBCL R-CHOP NR 

CHOP, cyclophosphamide, hydroxydaunorubicin (doxorubicin or adriamycin), oncovin (vincristine), prednisone; DLBCL, diffuse large B-cell lymphoma; Dx, diagnosis; F, female; HU, hydroxyurea; Len, lenalidomide; M, male; MCL, mantle cell lymphoma; MTX, methotrexate; NHL, non-Hodgkin lymphoma; NR, not reached; R-EPOCH, rituximab, etoposide phosphate, prednisone, vincristine sulfate (oncovin), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin); R-hyper-CVAD, rituximab plus hyper-fractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone; Rux, ruxolitinib; TCL, T-cell lymphoma.

We next examined our ET and PV cohorts, given that JAK inhibitors have also been investigated in clinical trials in ET14,15  and ruxolitinib is now approved in the advanced PV setting posthydroxyurea.16  A total of 966 patients comprised the overall ET/PV cohort, with a median follow-up time of 24 months (range, 0-345 months) and a median age of 52 years (range, 14-89 years) at diagnosis. Sixty patients had prior JAK inhibitor therapy; none of these 60 patients developed lymphoma after a median follow-up time of 51 months (range, 0-263 months). We did note, however, that 5 out of 906 patients who did not receive a JAK inhibitor developed lymphoma (0.55%); the P value not significant between these 2 groups.

Among the 6 patients with MF who were treated with a JAK inhibitor, we observed DLBCL (n = 3), MCL (n = 2), and other NHL (scalp) (n = 1). Among the 3 patients without prior JAK inhibitor therapy, we observed T-cell lymphoma (n = 2) and follicular lymphoma grade 3A (n = 1). The median age was 63 years (range, 41-70 years) at MF diagnosis and 68 years (range, 50-78 years) at lymphoma diagnosis. The majority of the patients diagnosed with lymphoma were male (Table 2). Though limited by a small sample size, the survival was relatively short following the lymphoma diagnosis for the majority of patients. The overall small numbers of patients and heterogeneity in lymphoma subtypes (including both B- and T-cell lymphomas) impairs our ability to draw any conclusions regarding the potential impact of JAK inhibitors on lymphomagenesis and outcomes.

In this large database review, we found no statistically significant difference in the incidence of a subsequent lymphoma diagnosis in patients with MPNs when comparing those who received prior JAK inhibitor therapy and those who did not. It is important to investigate this further, as we demonstrate different findings than Porpaczy et al.11  In the MPN literature, it is well known that there is a coincidence of other malignancies, including both solid tumors and lymphoid malignancies (Table 1). These reports did not have specific focus on JAK inhibitor therapy, however. In our analysis, importantly, we focused on this particular question, in a database consisting of 2583 patients with MPN (PV, ET, and MF), which represents approximately twofold more patients than in the Porpaczy et al study.11  Similar to that report, we also demonstrate a relatively short onset time to lymphoma development while on JAK inhibitor therapy of median 3.5 years; we also demonstrate a standard median age at the diagnosis of MF (63 years), and most of the patients identified with lymphoma to be JAK2 V167F mutated (6/9 [67%]). In contrast with the Porpaczy et al study, we demonstrated no significant increase in lymphoma rates in the JAK-inhibitor–treated population as compared with the non-JAK-inhibitor–treated group. Additionally, the rate of lymphoma after MPN diagnosis in our series is much lower (9/1617 [0.56%]) than that reported by Porpaczy et al (5.8% to 9.7%). There are several possible reasons for these 2 discrepant series. One, we have assembled a much larger data set, and larger numbers may diminish the relative effect of individual case observations. Second, the median follow-up time is critical to note, as in the present study, it is 26 months (0-348 months) in the MF cohort, and thus longer follow-up over time will be warranted. Additionally, in the Porpaczy et al study, it is notable that 2 out of 6 lymphoma cases (33%) received pipobroman as MF therapy prior to the lymphoma diagnosis, whereas none of our patients received prior pipobroman in the current study. (In a long-term follow-up study of MPN patients treated with pipobroman, the 10-year risk of second cancers was 4% to 8% with pipobroman.17 ) Finally, there may be important environmental, geographic, or other hitherto undetermined demographic factors that could be different in American vs European cohorts worthy of further analysis.

The authors thank Kelly Merriman (Director, Tumor Registry, Department of Tumor Registry), James M. Spence (Manager, Pharmacy Quality Improvement and Analytics, Department of Pharmacy), and Chun Feng (Senior Informatics Analyst, Department of Pharmacy Medication Management & Analytics) for their assistance.

This research is supported in part by MD Anderson Cancer Center Support Grant P30 CA016672.

Contribution: N.P. and S.V. designed the project; N.P., H.K., L.N., M.D., L.M., J.C., and S.V. evaluated/treated patients; L.Z., S.P., K.P.P., L.N., M.D., N.P., and S.V. contributed to data acquisition and analysis; and all authors wrote and edited the manuscript.

Conflict-of-interest disclosure: N.P. received consulting fees and honoraria from Celgene, Stemline, Incyte, Novartis, MustangBio, Roche Diagnostics, and LFB and research funding and clinical trials support from Stemline, Novartis, Abbvie, Samus, Cellectis, Plexxikon, Daiichi-Sankyo, Affymetrix, and the SagerStrong Foundation. H.K. received research funding and grants from AbbVie, Agios, Amgen, Ariad, Astex, BMS, Cyclacel, Daiichi Sankyo, Immunogen, Jazz Pharma, Novartis, Pfizer, and Incyte and honoraria from AbbVie, Actinium (advisory board), Agios, Amgen, Immunogen, Orsinex, Pfizer, and Takeda. L.N. received honoraria from Celgene, Genentech, Gilead, Janssen, Novartis, Spectrum, and TG Therapeutics. L.M. received research funding from Incyte. J.C. is a consultant for BMS, Novartis, Pfizer, Takeda, Astellas, Jazz, and Daiichi and received research support (for the institution) from BMS, Novartis, Pfizer, Takeda, Astellas, Jazz, Daiichi, Incyte, Immunogen, Merus, and Amphivena. S.V. received research funding and/or honoraria from Incyte, Roche, NS Pharma, Celgene, Gilead, Promedior, CTI BioPharma, Genentech, Blueprint Medicines, and Novartis and consulting fees and honoraria from Constellation, Pragmatist, Sierra, Incyte, Novartis, and Celgene. The remaining authors declare no competing financial interests.

Correspondence: Naveen Pemmaraju, Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, Unit 428, Houston, TX 77030; e-mail: npemmaraju@mdanderson.org.

1.
Takahashi
K
,
Pemmaraju
N
,
Strati
P
, et al
.
Clinical characteristics and outcomes of therapy-related chronic myelomonocytic leukemia
.
Blood
.
2013
;
122
(
16
):
2807
-
2811
,
quiz 2920
.
2.
Todisco
G
,
Manshouri
T
,
Verstovsek
S
, et al
.
Chronic lymphocytic leukemia and myeloproliferative neoplasms concurrently diagnosed: clinical and biological characteristics
.
Leuk Lymphoma
.
2016
;
57
(
5
):
1054
-
1059
.
3.
Frederiksen
H
,
Farkas
DK
,
Christiansen
CF
,
Hasselbalch
HC
,
Sørensen
HT
.
Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study
.
Blood
.
2011
;
118
(
25
):
6515
-
6520
.
4.
Masarova
L
,
Cherry
M
,
Newberry
KJ
, et al
.
Secondary solid tumors and lymphoma in patients with essential thrombocythemia and polycythemia vera: single center experience
.
Leuk Lymphoma
.
2016
;
57
(
1
):
237
-
239
.
5.
Palandri
F
,
Derenzini
E
,
Ottaviani
E
, et al
.
Association of essential thrombocythemia and non-Hodgkin lymphoma: a single-centre experience
.
Leuk Lymphoma
.
2009
;
50
(
3
):
481
-
484
.
6.
Rumi
E
,
Passamonti
F
,
Elena
C
, et al
.
Increased risk of lymphoid neoplasm in patients with myeloproliferative neoplasm: a study of 1,915 patients
.
Haematologica
.
2011
;
96
(
3
):
454
-
458
.
7.
Landtblom
AR
,
Bower
H
,
Andersson
TM
, et al
.
Second malignancies in patients with myeloproliferative neoplasms: a population-based cohort study of 9379 patients
.
Leukemia
.
2018
;
32
(
10
):
2203
-
2210
.
8.
Marchetti
M
,
Carobbio
A
,
Capitoni
E
,
Barbui
T
.
Lymphoproliferative disorders in patients with chronic myeloproliferative neoplasms: A systematic review
.
Am J Hematol
.
2018
;
93
(
5
):
698
-
703
.
9.
Brunner
AM
,
Hobbs
G
,
Jalbut
MM
,
Neuberg
DS
,
Fathi
AT
.
A population-based analysis of second malignancies among patients with myeloproliferative neoplasms in the SEER database
.
Leuk Lymphoma
.
2016
;
57
(
5
):
1197
-
1200
.
10.
Masarova
L
,
Newberry
KJ
,
Pierce
SA
, et al
.
Association of lymphoid malignancies and Philadelphia-chromosome negative myeloproliferative neoplasms: clinical characteristics, therapy and outcome
.
Leuk Res
.
2015
;
39
(
8
):
822
-
827
.
11.
Porpaczy
E
,
Tripolt
S
,
Hoelbl-Kovacic
A
, et al
.
Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy
.
Blood
.
2018
;
132
(
7
):
694
-
706
.
12.
Arber
DA
,
Orazi
A
,
Hasserjian
R
, et al
.
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia
.
Blood
.
2016
;
127
(
20
):
2391
-
2405
.
13.
Swerdlow
SH
,
Campo
E
,
Pileri
SA
, et al
.
The 2016 revision of the World Health Organization classification of lymphoid neoplasms
.
Blood
.
2016
;
127
(
20
):
2375
-
2390
.
14.
Harrison
CN
,
Mead
AJ
,
Panchal
A
, et al
.
Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide
.
Blood
.
2017
;
130
(
17
):
1889
-
1897
.
15.
Verstovsek
S
,
Passamonti
F
,
Rambaldi
A
, et al
.
Ruxolitinib for essential thrombocythemia refractory to or intolerant of hydroxyurea: long-term phase 2 study results
.
Blood
.
2017
;
130
(
15
):
1768
-
1771
.
16.
Vannucchi
AM
,
Kiladjian
JJ
,
Griesshammer
M
, et al
.
Ruxolitinib versus standard therapy for the treatment of polycythemia vera
.
N Engl J Med
.
2015
;
372
(
5
):
426
-
435
.
17.
Passamonti
F
,
Brusamolino
E
,
Lazzarino
M
, et al
.
Efficacy of pipobroman in the treatment of polycythemia vera: long-term results in 163 patients
.
Haematologica
.
2000
;
85
(
10
):
1011
-
1018
.
18.
Vannucchi
AM
,
Masala
G
,
Antonioli
E
, et al
.
Increased risk of lymphoid neoplasms in patients with Philadelphia chromosome-negative myeloproliferative neoplasms
.
Cancer Epidemiol Biomarkers Prev
.
2009
;
18
(
7
):
2068
-
2073
.
19.
Pettersson
H
,
Knutsen
H
,
Holmberg
E
,
Andréasson
B
.
Increased incidence of another cancer in myeloproliferative neoplasms patients at the time of diagnosis
.
Eur J Haematol
.
2015
;
94
(
2
):
152
-
156
.

Sign in via your Institution