Hun J. Lee

Double hit lymphoma: The MD Anderson Cancer Center clinical experience

We report our experience with 129 cases of double hit lymphoma (DHL), defined as B‐cell lymphoma with translocations and/or extra signals involving MYC plus BCL2 and/or BCL6. All cases were reviewed for histopathological classification. Median age was 62 years (range, 18–85), 84% of patients had advanced‐stage disease, and 87% had an International Prognostic Index score ≥2. Fourteen patients (11%) had a history of low‐grade follicular lymphoma. MYC translocation was present in 81%, and extra signals of MYC in 25% of patients. IGH‐BCL2 translocation was present in 84% and extra signals of BCL2 in 12% of patients. Two‐year event‐free survival (EFS) rates in all patients and patients who received R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R‐EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and R‐HyperCVAD/MA (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine plus methotrexate) were 33%, 25%, 67% and 32%, respectively. In patients achieving complete response with initial therapy (n = 71), 2‐year EFS rates in patients who did (n = 23) or did not (n = 48) receive frontline stem cell transplantation were 68% and 53%, respectively (P = 0·155). The cumulative incidence of central nervous system involvement was 13% at 3 years. Multivariate analysis identified performance status ≥2 and bone marrow involvement as independent adverse prognostic factors for EFS and OS. Further research is needed to identify predictive and/or targetable biological markers and novel therapeutic approaches for DHL patients.

Management strategies and outcomes for very elderly patients with diffuse large B‐cell lymphoma

The number of elderly patients with diffuse large B‐cell lymphoma (DLBCL) in our aging society continues to rise, although the optimal management of very elderly patients with DLBCL is unknown.

The survival outcome of patients with relapsed/refractory peripheral T-cell lymphoma-not otherwise specified and angioimmunoblastic T-cell lymphoma

Survival outcome of patients with peripheral T‐cell lymphoma‐not otherwise specified (PTCL‐NOS) and angioimmunoblastic T‐cell lymphoma (AITL) who experience disease progression/relapse remains very poor. A total of 321 patients, newly diagnosed with PTCL‐NOS (n = 180) or AITL (n = 141) between 1999 and 2015, were analysed. Failure‐free survival (FFS) and overall survival (OS) were calculated from the time of first disease progression (FFS1, OS1), from second disease progression (FFS2, OS2) and from third progression (FFS3, OS3). With a median follow‐up duration of 52 months, 240 patients (135 PTCL‐NOS, 105 AITL) experienced progression/relapse. In patients with PTCL‐NOS, the median durations of FFS1, FFS2 and FFS3 were 3·1, 2·5 and 2·1 months, respectively. In patients with AITL, they were 5·5, 2·9 and 2·3 months, respectively. There was no improvement in FFS1 and OS1 by the time of recurrence during this period (1999–2004, 2005–2009 and 2010–2015). The median FFS after pralatrexate and romidepsin was only 3·0 and 2·5 months, respectively. The 5‐year OS rates after salvage autologous and allogeneic transplant were 32% and 52%, respectively; while the 5‐year OS rates for patients who did not undergo transplant was 10%. Further research for novel therapeutic approaches with higher efficacy and better safety profile are needed.

Encouraging activity for R-CHOP in advanced stage nodular lymphocyte–predominant Hodgkin lymphoma

Nodular lymphocyte Hodgkin lymphoma (NLPHL) is a rare disease for which the optimal therapy is unknown. We hypothesized that rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) could decrease rates of relapse and transformation. We retrospectively reviewed patients with NLPHL diagnosed between 1995 and 2015 confirmed by central pathologic review. Fifty-nine had sufficient treatment and follow-up data for analysis. We described progression-free survival (PFS), overall survival (OS), and histologic transformation according to treatment strategy and explored prognostic factors for PFS and OS. The median age at diagnosis was 41 years; 75% were male, and 61% had a typical growth pattern. Twenty-seven patients were treated with R-CHOP with an overall response rate of 100% (complete responses 89%). The median follow-up was 6.7 years, and the estimated 5- and 10-year PFS rates for patients treated with R-CHOP were 88.5% (95% confidence interval [CI], 68.4% to 96.1%) and 59.3 (95% CI, 25.3% to 89.1%), respectively. Excluding patients with histologic transformation at diagnosis, the 5-year cumulative incidence of histologic transformation was 2% (95% CI, 87% to 100%). No patient treated with R-CHOP experienced transformation. A high-risk score from the German Hodgkin Study Group was adversely prognostic for OS (P = .036), whereas male sex and splenic involvement were adversely prognostic for PFS (P = .006 and .002, respectively) but not OS. Our data support a potential role for R-CHOP in patients with NLPHL. Larger prospective trials are needed to define the optimal chemotherapy regimen.

Early-stage Hodgkin lymphoma outcomes after combined modality therapy according to the post-chemotherapy 5-point score: can residual pet-positive disease be cured with radiotherapy alone?

Early‐stage classical Hodgkin lymphoma (HL) patients are evaluated by an end‐of‐chemotherapy positron emission tomography‐computed tomography (eoc‐PET‐CT) after doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) and before radiation therapy (RT). We determined freedom from progression (FFP) in patients treated with ABVD and RT according to the eoc‐PET‐CT 5‐point score (5PS). Secondarily, we assessed whether patients with a positive eoc‐PET‐CT (5PS of 4–5) can be cured with RT alone. The cohort comprised 174 patients treated for stage I‐II HL with ABVD and RT alone. ABVD was given with a median of four cycles and RT with a median dose of 30·6 Gy. Five‐year FFP was 97%. Five‐year FFP was 100% (0 relapses/98 patients) for patients with a 5PS of 1–2, 97% (2/65) for a 5PS of 3, 83% (1/8) for a 5PS of 4, and 67% (1/3) for a 5PS of 5 (P < 0·001). Patients with positive eoc‐PET‐CT scans who were selected for salvage RT alone had experienced a very good partial response to ABVD. Risk factors for recurrence in this subgroup included a small reduction in tumour size and a ‘bounce’ in ≥1 PET‐CT parameter (reduction then rise from interim to final scan). Thus, a positive eoc‐PET‐CT is associated with inferior FFP; however, appropriately selected patients can be cured with RT alone.

TH‐CD‐BRA‐08: Novel Iron‐Based Radiation Reporting Systems as 4D Dosimeters for MR‐Guided Radiation Therapy

PURPOSE To compare novel radiation reporting systems utilizing ferric ion (Fe3+ ) reduction versus ferrous ion (Fe2+ ) oxidation in gelatin matrixes for 3D and 4D (3D+time) MR-guided radiation therapy dosimetry. METHODS Dosimeters were irradiated using an integrated 1.5T MRI and 7MV linear accelerator (MR-Linac). Dosimeters were read-out with both a spectrophotometer and the MRI component of the MR-Linac immediately after irradiation. Changes in optical density (OD) were measured using a spectrophotometer; changes in MR signal intensity due to the paramagnetic differences in the iron ions were measured using the MR-Linac in real-time during irradiation (balanced-FFE sequences) and immediately after irradiation (T1 -weighted and inversion recovery sequences). RESULTS Irradiation of Fe3+ reduction dosimeters resulted in a stable red color with an absorbance peak at 512 nm. The change in OD relative to dose exhibited a linear response up to 100 Gy (R2 =1.00). T1 -weighted-MR signal intensity (SI) changed minimally after irradiation with increases of 8.0% for 17 Gy and 9.7% after escalation to 35 Gy compared to the un-irradiated region. Irradiation of Fe2+ oxidation dosimeters resulted in a stable purple color with absorbance peaks at 440 and 585 nm. The changes in OD, T1 -weighted-MR SI, and R1 relative to dose exhibited a linear response up to at least 8 Gy (R2 =1.00, 0.98, and 0.99) with OD saturation above 40 Gy. The T1 -weighted-MR SI increased 50.3% for 17 Gy compared to the un-irradiated region. The change in SI was observed in both 2D+time and 4D (3D+time) acquisitions post-irradiation and in real-time during irradiation with a linear increase with respect to dose (R2 >0.93). CONCLUSION The Fe2+ oxidation-based system was superior as 4D dosimeters for MR-guided radiation therapy due to its higher sensitivity in both optical and MR signal readout and feasibility for real-time 4D dose readout. The Fe3+ reduction system is recommended for high dose applications. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. LH-102SPS.

Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/refractory mantle cell lymphoma (MCL).

Ibrutinib has shown significant activity in patients with relapsed or refractory mantle cell lymphoma (RR‐MCL). We report the long‐term outcome and safety profile of a single‐centre, single arm, open‐label, phase 2 study of RR‐MCL treated with IR. Overall, the median follow‐up time was 47 months (range 1–52 months), median duration on treatment was 16 months (range 1–53 months) and median number of treatment cycles was 17 (range 1–56). Twenty‐nine patients (58%) achieved complete remission and of these, 12 patients continue on study. Thirty‐eight patients discontinued treatment, 14 due to disease progression (2 transformed). Patients with blastoid morphology, high risk MCL International Prognostic Index score and high Ki67% had inferior survival. The commonest grade 1–2 toxicities were fatigue, diarrhoea, nausea, arthralgias and myalgias. None had long term toxicities. Median progression‐free survival was 43 months. Eighteen patients (36%) died (14 deaths were MCL‐related). The median overall survival has not been reached. Treatment with IR can provide durable remissions in a subset of patients with RR‐MCL, especially those with low Ki67%. The possible benefit of adding other therapies in combination with IR in RR‐MCL is under exploration.

TH-AB-BRA-11: Using 3D Dosimeters for the Investigation of the Electron Return Effect (ERE) in MR-Guided Radiation Therapy: A Feasibility Study

PURPOSE To demonstrate the capability of 3D radiochromic PRESAGE and Fricke-type dosimeters to measure the influence of magnetic fields on dose distribution, including the electron return effect (ERE), for MR-guided radiation therapy applications. METHODS Short cylindrical 3D dosimeters with PRESAGE and Fricke-type formulations were created in-house prior to irradiations in a 1.5T/7MV MR-linac. Each dosimeter was prepared with a concentric cylindrical air cavity with diameters of 1.5 cm and 2.5 cm, and the diameters of the dosimeters were 7.2 cm and 8.8 cm for PRESAGE and Fricke-type respectively. The dosimeters were irradiated within the bore of the MR-linac with the flat face of the dosimeters perpendicular to the magnetic field. Dosimeters were irradiated to approximately 9 Gy and 29 Gy to the center of dosimeters with a 15×15 cm2 field. The PRESAGE dosimeter was scanned using an optical-CT 2 hours post-irradiation; the Fricke-type dosimeter was immediately imaged with the MR component of the MR-linac post-irradiation. RESULTS Axial slices of the dose distributions show a clear demonstration of the dose enhancement due to the ERE above the cavity and the region of reduced dose below the cavity. The regions of increased and reduced dose are rotated with respect to the radiation beam axis due to the average directional change of the electrons. Measurements from line profiles show the dose enhanced up to ∼0.5 cm around the cavity by up to a factor of 1.3 and 1.4 for PRESAGE and Fricke-type dosimeters respectively. CONCLUSION PRESAGE and Fricke-type dosimeters are able to qualitatively measure the ERE with good agreement with previously published simulation and 2D dosimetry demonstrations of the ERE. Further investigation of these 3D dosimeters as promising candidates for quality assurance of MR-guided radiation therapy systems is encouraged to assess changes in response and measurement accuracy due to the magnetic field.

The risk of central nervous system relapses in patients with peripheral T-cell lymphoma

We performed a retrospective analysis to identify risk factors and survival outcome for central nervous system (CNS) relapse of peripheral T-cell lymphoma (PTCL) by histologic type. Records of 600 PTCL patients diagnosed between 1999 and 2014 were analyzed including PTCL not otherwise specified (PTCL-NOS, 174 patients), angoimmunoblastic T-cell lymphoma (AITL, 144), ALK+anaplastic large cell lymphoma (ALCL, 74), ALK-ALCL (103), extranodal NK-cell lymphoma (ENKL, 54), or others (51). With a median follow up of 57 months, 13 patients (4 PTCL-NOS, 1 AITL, 4 ALK+ALCL, 2 ALK-ALCL, 2 ENKL) experienced CNS relapse. One-year and 5-year cumulative incidence of CNS relapse were 1.5% (95%CI: 0.7–2.8%) and 2.1% (95%CI: 1.1–3.5%), respectively. The 5-year cumulative incidence of CNS relapse was 1.8% in PTCL-NOS, 0.7% in AITL, 5.4% in ALK+ALCL, 2.1% in ALK-ALCL and 3.7% in ENKL. Extranodal involvement >1 site was the only significant factor associated with higher chance of CNS relapse (HR: 4.9, 95%CI: 1.6–15.0, p = 0.005). Patients with ALK+ALCL who had extranodal involvement >1 (N = 19) had very high risk of CNS relapse with one year cumulative incidence of 17% (95%CI: 4%-37%), all occurring within six months after diagnosis. All patients with CNS relapse eventually died (median, 1.5 months; range, 0.1–10.1 months). CNS relapse in patients with PTCL is rare event but the risk varies by subtype. ALK+ALCL patients with extranodal involvement >1 site have a very high risk of early CNS relapse, and thus evaluation of CNS involvement at the time of diagnosis and possible CNS-directed prophylaxis may be considered.

A phase II study of carfilzomib in the treatment of relapsed/refractory mantle cell lymphoma

Velden, V.H., Brooimans, R.A., Pabst, T., Maertens, J., Boeckx, N., de Greef, G.E., Valk, P.J., Preijers, F.W., Huijgens, P.C., Dr€ager, A.M., Schanz, U., Jongen-Lavrecic, M., Biemond, B.J., Passweg, J.R., van Gelder, M., Wijermans, P., Graux, C., Bargetzi, M., Legdeur, M.C., Kuball, J., de Weerdt, O., Chalandon, Y., Hess, U., Verdonck, L.F., Gratama, J.W., Oussoren, Y.J., Scholten, W.J., Slomp, J., Snel, A.N., Vekemans, M.C., L€ owenberg, B., Ossenkoppele, G.J. & Schuurhuis, G.J. (2013) High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. Journal of Clinical Oncology, 31, 3889–3897. Venditti, A., Piciocchi, A., Candoni, A., Melillo, L., Calafiore, V., Cairoli, R., De Fabritiis, P., Storti, G., Salutari, P., Lanza, F., Martinelli, G., Luppi, M., Mazza, P., Falini, B., Cuneo, A., Specchia, G., Fabbiano, F., Tafuri, A., Ronci, B., Tieghi, A., Fracchiolla, N. S., Capelli, D., Fo a, R., Ronco, F., La Sala, E., Fazi, P., Maurillo, L., Buccisano, F., Del Principe, M.I., Lo Coco, F., Arcese, W. & Amadori, S. (2017) Risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia: results of the AML 1310 trial of the GIMEMA group. Haematologica, 102(s2), 6–7. (abstract s111).