Hun Ju Lee

hnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies.

hnRNP K regulates cellular programs, and changes in its expression and mutational status have been implicated in neoplastic malignancies. To directly examine its role in tumorigenesis, we generated a mouse model harboring an Hnrnpk knockout allele (Hnrnpk(+/-)). Hnrnpk haploinsufficiency resulted in reduced survival, increased tumor formation, genomic instability, and the development of transplantable hematopoietic neoplasms with myeloproliferation. Reduced hnRNP K expression attenuated p21 activation, downregulated C/EBP levels, and activated STAT3 signaling. Additionally, analysis of samples from primary acute myeloid leukemia patients harboring a partial deletion of chromosome 9 revealed a significant decrease in HNRNPK expression. Together, these data implicate hnRNP K in the development of hematological disorders and suggest hnRNP K acts as a tumor suppressor.

Ibrutinib-related atrial fibrillation in patients with mantle cell lymphoma

Ibrutinib is a Bruton tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration for the treatment of refractory mantle cell lymphoma (MCL). It has shown promising results in MCL,[...

Factors influencing outcome in advanced stage, low-grade follicular lymphoma treated at MD Anderson Cancer Center in the rituximab era

BACKGROUNDnThe optimal initial therapy of follicular lymphoma (FL) remains unclear. The aims of this study were to compare primary treatment strategies and assess the impact of maintenance rituximab and patterns of treatment failure.nnnPATIENTS AND METHODSnWe retrospectively analyzed patients with treatment-naive advanced stage, grade 1-2 FL treated at our center from 2004 to 2014. We included 356 patients treated on clinical trials or standard of care with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP, n = 119); R-CHOP with maintenance (R-CHOP + M, n = 65); bendamustine/rituximab (BR, n = 45); BR with maintenance (BR + M, n = 35); R(2) (n = 94). We compared baseline characteristics, progression-free survival (PFS), overall survival (OS) and analyzed prognostic factors using univariate and multivariate analysis adjusted for treatment.nnnRESULTSnAfter a median follow-up of 4 years (range 0.2-15.0), the 3-year PFS was 60% [95% confidence interval (CI) 51% to 69%] for R-CHOP, 72% (59% to 82%) for R-CHOP + M, 63% (42% to 78%) for BR, 97% (80% to 100%) for BR + M and 87% (78% to 93%) for R(2). Patients treated with R-chemotherapy had more high-risk features than patients treated with R(2) but, by adjusted multivariate analysis, treatment with R(2) [hazard ratio (HR) 0.39 (0.17-0.89), P = 0.02] was associated with a superior PFS. Eastern Cooperative Oncology Group Performance status of one or more predicted inferior OS. Among patients treated with R-chemotherapy, maintenance was associated with the superior PFS [HR 0.38 (95% CI 0.21-0.68)]. By adjusted multivariate analysis, disease progression within 2 years [HR 5.1 (95% CI 1.57-16.83)] and histologic transformation (HT) [HR 11.05 (95% CI 2.84-42.93)] increased risk of death.nnnCONCLUSIONnInduction therapy with R(2) may result in disease control which is comparable with R-chemotherapy. Early disease progression and HT are predictive of inferior survival.

Ultra–low-dose radiotherapy for definitive management of ocular adnexal B-cell lymphoma

The purpose of this study was to report the response to and toxicity of ultra–low‐dose radiotherapy (RT) for B‐cell ocular adnexal lymphoma (OAL).

p53-independent ibrutinib responses in an Eμ-TCL1 mouse model demonstrates efficacy in high-risk CLL.

Deletion of the short-arm of chromosome 17 (17p-) is one of the most critical genetic alterations used in chronic lymphocytic leukemia (CLL) risk stratification. The tumor suppressor TP53 maps to this region, and its loss or mutation accelerates CLL progression, hampers response to chemotherapy and shortens survival. Although florescent in situ hybridization analyses for 17p deletions are routinely performed during clinical diagnoses, p53 mutational status is often unexamined. Given the limited clinical data that exists for frontline treatment of patients with CLL harboring TP53 mutations, there is a need to understand the biology of CLL with TP53 mutations and identify treatment strategies for this subset of patients. Herein, we used a CLL mouse model (Eμ-TCL1) harboring one of the most common TP53 hot-spot mutations observed in CLL (p53R172H, corresponding to p53R175H in humans) to evaluate its impact on disease progression, survival, response to therapy and loss of the remaining wild-type Trp53 allele following ibrutinib treatment. We show that ibrutinib was effective in increasing survival, activating cellular programs outside the p53 pathway and did not place selective pressure on the remaining wild-type Trp53 allele. These data provide evidence that ibrutinib acts as an effective treatment for aggressive forms of CLL with TP53 mutations.

Rituximab with ABVD vs ABVD for advanced stage high-risk classical Hodgkin lymphoma: a randomized phase II study

Based on several randomized studies comparing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with other multi-drug regimens, ABVD is the standard of care for newly diagnosed, advanced stage, classical Hodgkin lymphoma (cHL).[1][1] While the cure rate with ABVD approximates 75% in

Hitting a Moving Target: Successful Management of Diffuse Large B-cell Lymphoma involving the Mesentery with Volumetric Image Guided Intensity Modulated Radiation Therapy

INTRODUCTIONnWe report successful treatment of mesenteric diffuse large B-cell lymphoma (DLBCL) using localized involved site radiation therapy (ISRT), intensity modulated radiation therapy (IMRT), and daily computed tomography (CT)-image guidance.nnnPATIENTS AND METHODSnPatients with mesenteric DLBCL treated with RT between 2011 and 2017 were reviewed. Clinical and treatment characteristics were analyzed for an association with local control, progression-free survival (PFS), and overall survival.nnnRESULTSnTwenty-three patients were eligible. At diagnosis, the median age was 52 years (range, 38-76 years), and 57% (nxa0= 13) had stage I/II DLBCL. All patients received frontline chemotherapy (ChT) (R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone], nxa0= 19; dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin], nxa0= 4) with median 6 cycles. Prior to RT, salvage ChT for refractory DLBCL was given to 43% (nxa0= 10) and autologous stem cell transplantation was administered in 13% (nxa0= 3). At the time of RT, positron emission tomography-CT revealed 5-point scale of 1 to 3 (48%; nxa0= 11), 4 (9%; nxa0= 2), and 5 (44%; nxa0= 10). All patients received IMRT, daily CT imaging, and ISRT. The median RT dose was 40 Gy (range, 16.2-49.4 Gy). Relapse or progression occurred in 22% (nxa0= 5). At a median follow-up of 37 months, the 3-year local control, PFS, and overall survival rates were 80%, 75%, and 96%, respectively. Among patients treated with RT after complete metabolic response to frontline ChT (nxa0= 8), the 3-year PFS was 100%, compared with 61% for patients with a history of chemorefractory DLBCL (nxa0= 15; Pxa0= .055). Four of the 5 relapses occurred in patients with 5-point scale of 5 prior to RT (Pxa0= .127).nnnCONCLUSIONnMesenteric involvement of DLBCL can be successfully targeted with localized ISRT fields using IMRT and daily CT-image guidance.

Phase II Study of Bortezomib in Combination with Cyclophosphamide and Rituximab for Relapsed or Refractory Mantle Cell Lymphoma

BACKGROUNDnRelapsed or refractory mantle cell lymphoma (MCL) has a poor prognosis. The best outcome is achieved in patients who have a partial or complete response to salvage treatment and proceed to allogeneic stem cell transplant.nnnPATIENTS AND METHODSnTwenty-one patients were given a combination regimen of bortezomib, cyclophosphamide, and rituximab at MD Anderson Cancer Center as part of a single-arm, prospective, open-label phase II clinical trial. The median age was 66 years, with a median number of prior treatments of three. Sixty-seven percent had failed intensive chemoimmunotherapy and 43% were intermediate/high risk according to the MCL international prognostic index score, with a median Ki-67 proliferation index of 45% in those who were tested.nnnRESULTSnThe rates of overall and complete response achieved were 74% and 42%, respectively, with median progression-free and overall survivals of 9 months and 36.4 months, respectively. The regimens toxicity profile was acceptable; only 25% of the cycles resulted in grade 3 or 4 neutropenia or thrombocytopenia, and only 3% of cycles produced grade 3-4 fatigue. There were no episodes of grade 3-4 neuropathy.nnnCONCLUSIONnThe combination of bortezomib with cyclophosphamide and rituximab is an effective and well-tolerated regimen in patients with relapsed/refractory MCL. Because of its low toxicity, future combinations of this regimen with other promising drugs that have different mechanisms of action offer a realistic possibility that may improve outcomes for patients who have MCL. The Oncologist 2017;22:549-553 IMPLICATIONS FOR PRACTICE: The combination of bortezomib with cyclophosphamide and rituximab represents an additional effective novel salvage regimen for mantle cell lymphoma. This combination adds to the growing list of treatment options available for patients with mantle cell lymphoma.

LENALIDOMIDE AND OBINUTUZUMAB WITH CHOP FOR NEWLY DIAGNOSED DIFFUSE LARGE B-CELL LYMPHOMA: PHASE I/II RESULTS

CD20 antigen. Bendamustine (Benda) is an active chemotherapy agent in pts with lymphoma. The combination of UTX + TGR‐ 1202 is tolerable and active in pts with rel/ref hematologic malignancies and is under Phase 3 testing for pts with CLL and under Phase 2b testing for pts with DLBCL. This Phase 1 trial evaluates the safety and efficacy of UTX + TGR‐1202 + Benda in pts with advanced diffuse large B‐cell lymphoma (DLBCL) and Follicular Lymphoma (FL). Methods: Eligible pts had rel/ref DLBCL or FL with an ECOG PS ≤ 2 w/ o limit to number of prior therapies. ANC of ≥750 and Platelets ≥50,000 was permitted. Pts refractory to prior PI3Kδ, Benda, or anti‐ CD20 therapy were eligible. UTX was dosed on Days 1, 8, 15 of Cycle 1, Day 1 of Cycle 2–6, followed by Cycle 9 and 12. TGR‐1202 was started at 800 mg QD with a −1 dose reduction cohort at 600 mg if not tolerated in ≥2/6 pts. Benda was dosed at 90 mg/m on Days 1 and 2 of Cycles 1–6 only. Primary endpoints included safety and efficacy (Cheson 2007). Results: Twenty‐three pts were evaluable for safety: 15 diffuse large B‐cell (DLBCL) and 8 follicular (FL). Med age 68 yo (range 31‐81); 12 M/11 F; median prior treatment regimens = 2 (range 1–6); 12 pts (52%) were refractory to their immediate prior treatment and to prior CD20 therapy, and 7 pts had progressed post‐ transplant. ECOG PS 0/1/2 (3/18/2). Initially, 2/4 pts at 800 mg TGR‐1202 experienced AEs in Cycle 1 that led to treatment interruption (rash, neutropenia); thus, the 600 mg dose of TGR‐1202 was explored. No additional Cycle 1 treatment delays were reported at the 600‐mg dose level, which was later expanded, and the 800‐mg TGR‐1202 dose is now being evaluated with stricter eligibility criteria to require an ANC of ≥1.0, and the use of growth factor support in cycle 1 is now encouraged. The most common AEs included diarrhea (39%; G3/4 4%), decreased appetite (35%; G3/4 4%), nausea (30%; G3/4 4%), asthenia (26%; G3/4 4%) and neutropenia (22%). The only Grade 3/4 AE reported in >10% of pts was neutropenia (22%). Two pts had a TGR‐1202 dose reduction. Nineteen pts (11 DLBCL/8 FL) were evaluable for efficacy: ORR amongst all pts was 79% (15/19) with 42% (8/19) achieving a complete response (CR), of which 5 were DLBCL and 3 FL. ORR in the respective groups is as follows:

Improved outcome for patients with relapsed/refractory mantle cell lymphoma (MCL) who stop ibrutinib +/− rituximab for reasons other than progression of disease

Background: Ibrutinib produces a high rate of response in patients with previously treated mantle cell lymphoma (MCL). However, patients who discontinue therapy due to disease progression have a poor overall survival rate (OS; median 8.4 months). The outcome of patients who discontinue ibrutinib due to reasons other than progression has not been well described. Methods: Retrospective review of single institutional patients who received ibrutinib with or without rituximab both on and off protocol for relapsed/refractory MCL. Results: Between 2011 and 2017, 24 patients who received ibrutinib ± rituximab had their treatment discontinued for reasons other than progression after a median of 14 months of therapy (range 2‐57 months), the most common reason being due to infection (see table), and have since been observed without therapy. After a median follow‐up of 13 months from discontinuation of ibrutinib therapy, the median OS is 13 months and likely to improve, since 14 patients are still in CR/PR, with all of them alive except for one. Ten patients have relapsed/progressed and of these, 6 have died (4 from disease). The patients who have not progressed had a mean duration of ibrutinib ± rituximab treatment of 22 months compared to 13 months for those who progressed. Among the 10 patients with progressive disease, the median time to progression was 11 months. Patients who received ibrutinib alone had more frequency of relapse (8/15) than patients who received ibrutinib with rituximab (2/9). Conclusion: Patients who discontinue ibrutinib while responding have better outcomes than patients who discontinue ibrutinib due to disease progression. A longer duration of ibrutinib therapy appears to prolong response duration. Further exploration of outcomes and correlation with pre‐treatment variables will be explored and presented at the symposium. Reasons for Discontinuation of Therapy