Clinical, pathological, and genetic features of patients who developed aggressive B-cell lymphomas during JAK1/2 inhibition
| . | Patient 1 (Vienna) . | Patient 2 (Vienna) . | Patient 3 (Vienna) . | Patient 4 (Vienna) . | Patient 5 (Paris) . | Patient 6 (Paris) . |
|---|---|---|---|---|---|---|
| Sex | Female | Female | Female | Male | Female | Female |
| MPN | PV post-PV MF | PMF | PMF | PMF | ET post-ET MF | PMF |
| Age at MPN | 22 (PV) | 45 | 71 | 70 | 66 (ET) | 50 |
| 54 (post-PV MF) | 69 (post-ET MF) | |||||
| JAK2 V617F mutation in MPN | Positive | Positive | Positive | Positive | Negative (CALR mutation) | Positive |
| Treatment before JAK1/2 inhibition | Phlebotomy | Anagrelide Hydroxyurea | Hydroxyurea | None | Anagrelide | None |
| Intron A | Hydroxyurea | |||||
| Pipobroman | Pipobroman | |||||
| Hydroxyurea | EPO | |||||
| JAK1/2 inhibitor | Ruxolitinib | Ruxolitinib | Fedratinib Ruxolitinib | Ruxolitinib | Ruxolitinib | Ruxolitinib |
| Time from diagnosis of MPN to diagnosis of NHL, years | 35 (PV to NHL) | 14 | 2 | 4 | 6 (ET to NHL) | 3 |
| 3 (post-PV MF to NHL) | 3 (post-ET MF to NHL) | |||||
| Time (months) from JAK1/2 inhibition to diagnosis of NHL | 20 | 35 | 13 | 30 | 17 | 28 |
| Age at NHL | 57 | 59 | 73 | 74 | 72 | 53 |
| NHL | HGBL | DLBCL | DLBCL | DLBCL | DLBCL | DLBCL |
| Antilymphoma treatment | Burkitt Protocol, Buparlisib (BKM120) | EPOCH-R R-CHOP | R-CHOP | R-CHOP | R-CHOP | R-CHOP |
| Outcome | PD, Death | CR ongoing | CRu, early relapse, death | CRu, sAML, death | CR | PR, Death |
| NHL manifestation | BM, PB, LN | BM, PB, LN | Mammary gland; at relapse: BM, PB | Mucosa | LN | BM |
| COO | Not applicable | GCB | Non-GCB | Non-GCB | Non-GCB | Non-GCB |
| CS/IPI | IV E / 4-5 | IV E / 2 | II E / 3 | I E / 2 | II / 2 | IV E / 2 |
| DHS | 2 | 2 | 2 | 1 | ||
| IHC | Negative | |||||
| MYC (40%) | 85% | 80% | 80% | 70% | Negative | |
| BCL2 (50%) | 100% | 100% | 100% | 5% | Positive | |
| BCL6 (30%) | 2% | 80% | 40% | 40% | Positive | |
| p53 (30%) | 100% | 80% | 80% | 70% | ||
| FISH | ||||||
| MYC | Translocation | Translocation | Normal | Normal | ||
| BCL2 | Amplification | Translocation | Normal | Normal | ||
| BCL6 | Normal | Translocation | n.d. | Translocation | ||
| TP53 | Deletion | Normal | Normal | Normal | ||
| Targeted sequencing | TMB: low (2 m/mb) | TMB: high (22 m/mb) | n.d. | n.d. | n.d. | n.d. |
| IGH-MYC rearrangement | IGH-BCL2 rearrangement | |||||
| CDK6 amplification | MYC A59T, SOCS1-MYC rearrangement | |||||
| MLL2 R5086* | CDKN2A p14ARF C15fs*28, p14ARF M1V | |||||
| TP53 A159P | BCL2 P59S, R129H | |||||
| TNFRSF14 T169fs*65 | ||||||
| KRAS G13D | ||||||
| B2M L15fs*41 BCL7A splice site 92+1G>A | ||||||
| FAS splice site 664_676+36del49 | ||||||
| TAF1 R1049H | ||||||
| JAK2 V617F Mutation in NHL | Negative | Negative | Negative | Negative | n.d. | n.d. |
| Detection of preexisting B-cell clone | Yes | Yes | Not applicable | Yes |
| . | Patient 1 (Vienna) . | Patient 2 (Vienna) . | Patient 3 (Vienna) . | Patient 4 (Vienna) . | Patient 5 (Paris) . | Patient 6 (Paris) . |
|---|---|---|---|---|---|---|
| Sex | Female | Female | Female | Male | Female | Female |
| MPN | PV post-PV MF | PMF | PMF | PMF | ET post-ET MF | PMF |
| Age at MPN | 22 (PV) | 45 | 71 | 70 | 66 (ET) | 50 |
| 54 (post-PV MF) | 69 (post-ET MF) | |||||
| JAK2 V617F mutation in MPN | Positive | Positive | Positive | Positive | Negative (CALR mutation) | Positive |
| Treatment before JAK1/2 inhibition | Phlebotomy | Anagrelide Hydroxyurea | Hydroxyurea | None | Anagrelide | None |
| Intron A | Hydroxyurea | |||||
| Pipobroman | Pipobroman | |||||
| Hydroxyurea | EPO | |||||
| JAK1/2 inhibitor | Ruxolitinib | Ruxolitinib | Fedratinib Ruxolitinib | Ruxolitinib | Ruxolitinib | Ruxolitinib |
| Time from diagnosis of MPN to diagnosis of NHL, years | 35 (PV to NHL) | 14 | 2 | 4 | 6 (ET to NHL) | 3 |
| 3 (post-PV MF to NHL) | 3 (post-ET MF to NHL) | |||||
| Time (months) from JAK1/2 inhibition to diagnosis of NHL | 20 | 35 | 13 | 30 | 17 | 28 |
| Age at NHL | 57 | 59 | 73 | 74 | 72 | 53 |
| NHL | HGBL | DLBCL | DLBCL | DLBCL | DLBCL | DLBCL |
| Antilymphoma treatment | Burkitt Protocol, Buparlisib (BKM120) | EPOCH-R R-CHOP | R-CHOP | R-CHOP | R-CHOP | R-CHOP |
| Outcome | PD, Death | CR ongoing | CRu, early relapse, death | CRu, sAML, death | CR | PR, Death |
| NHL manifestation | BM, PB, LN | BM, PB, LN | Mammary gland; at relapse: BM, PB | Mucosa | LN | BM |
| COO | Not applicable | GCB | Non-GCB | Non-GCB | Non-GCB | Non-GCB |
| CS/IPI | IV E / 4-5 | IV E / 2 | II E / 3 | I E / 2 | II / 2 | IV E / 2 |
| DHS | 2 | 2 | 2 | 1 | ||
| IHC | Negative | |||||
| MYC (40%) | 85% | 80% | 80% | 70% | Negative | |
| BCL2 (50%) | 100% | 100% | 100% | 5% | Positive | |
| BCL6 (30%) | 2% | 80% | 40% | 40% | Positive | |
| p53 (30%) | 100% | 80% | 80% | 70% | ||
| FISH | ||||||
| MYC | Translocation | Translocation | Normal | Normal | ||
| BCL2 | Amplification | Translocation | Normal | Normal | ||
| BCL6 | Normal | Translocation | n.d. | Translocation | ||
| TP53 | Deletion | Normal | Normal | Normal | ||
| Targeted sequencing | TMB: low (2 m/mb) | TMB: high (22 m/mb) | n.d. | n.d. | n.d. | n.d. |
| IGH-MYC rearrangement | IGH-BCL2 rearrangement | |||||
| CDK6 amplification | MYC A59T, SOCS1-MYC rearrangement | |||||
| MLL2 R5086* | CDKN2A p14ARF C15fs*28, p14ARF M1V | |||||
| TP53 A159P | BCL2 P59S, R129H | |||||
| TNFRSF14 T169fs*65 | ||||||
| KRAS G13D | ||||||
| B2M L15fs*41 BCL7A splice site 92+1G>A | ||||||
| FAS splice site 664_676+36del49 | ||||||
| TAF1 R1049H | ||||||
| JAK2 V617F Mutation in NHL | Negative | Negative | Negative | Negative | n.d. | n.d. |
| Detection of preexisting B-cell clone | Yes | Yes | Not applicable | Yes |
COO, cell of origin; CR, complete remission; CRu, complete remission unconfirmed; CS, clinical stage according to Ann-Arbor classification; DHS, double-hit protein score; DLBCL, diffuse large B-cell lymphoma; E, extranodal; EPOCH-R, immunochemotherapy (etoposide, doxorubicin, cyclophosphamide, vincristine and prednisone with rituximab); FISH, fluorescent in-situ hybridization; GCB, germinal center B-cell like; HGBL, high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement; IHC, immunohistochemistry; IPI, international prognostic index; LN, lymph node; m/mb: mutations per megabase; n.d., not done; NGS, new-generation sequencing; non-GCB, nongerminal center B-cell like; PD, progressive disease; post-ET MF, postessential thrombocythemia myelofibrosis; post-PV MF, postpolycythemia vera myelofibrosis; R-CHOP: immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone); sAML, secondary acute myeloid leukemia; TMB, tumor mutation burden.