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Clinical Conundrums

Source: Clinical Oncology News

Author: Dr. Syed Abutalib

Published: July 11, 2014

Hematology and bone marrow transplant highlights from ASCO—Part I


1. True or False? Diffuse large B-cell lymphoma (DLBCL): Investigators from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource reported to have developed a better cell of origin defining immunohistochemistry (IHC) algorithm than the Hans algorithm to predict overall survival (OS) and event-free survival in patients with DLBCL.

True. The algorithm needs to be further studied in a larger population and compared with the gold standard, gene expression profiling (GEP). Cell of origin is felt to be one of the most important predictors of outcome to therapy, with better outcome in germinal center B cell-like (GCB) subtypes compared with non-GCB. GEP is not widely available. Therefore, IHC algorithms have been developed as a surrogate for GEP in determining cell of origin.

Nadiminti K, Nasr M, Mott SC, et al. A novel immunohistochemistry (IHC) algorithm for assigning cell of origin status in diffuse large B-cell lymphoma (DLBCL) that better predicts survival as compared to the Hans algorithm. J Clin Oncol. 2014;32(5 suppl): abstract e19537.


2. True or False? Refractory Hodgkin lymphoma (HL): In a Phase I/II study, continuous lenalidomide with low-dose protracted bendamustine (LEBEN) was not active in patients with refractory HL.

False. Continuous LEBEN was very active and well tolerated in patients with highly refractory HL. Enrollment continues (NTC01412307), and updated results with correlative data were presented at the 2014 ASCO meeting.

Corazzelli G, Saggese M, Pavone V, et al. A phase 1/2 study of lenalidomide and bendamustine (LEBEN) in chemorefractory Hodgkin lymphoma. J Clin Oncol. 2014;32(5 suppl): abstract 8566.


3. True or False? Cutaneous T-cell lymphoma (CTCL): In a Phase Ib multicenter, double-blind, placebo-controlled randomized trial in patients with stage IA-IIA CTCL, SHP-141, a novel topical skin-restricted histone deacetylase inhibitor (HDAC-i), demonstrated clinical objective response (OR).

 True. No dose-limiting toxicity, early discontinuations, serious adverse events (AEs) or systemic AEs were recorded (NCT01433731). Time to OR was as early as day 7 of therapy. This is the first skin-optimized topical HDAC-i with evidence of early clinical activity and without systemic toxicity. According to the investigators, SHP-141 may address an important unmet medical need in early-stage CTCL by feasibly offering clinical benefits of a HDAC-i without safety concerns.

Kim YH, Krathen M, Duvic M, et al. A Phase 1b study in cutaneous T-cell lymphoma (CTCL) with the novel topically applied skin-restricted histone deacteylase inhibitor (HDAC-i) SHP-141. J Clin Oncol. 2014;32(5 suppl): abstract 8525.


4. True or False? B-cell non-Hodgkin lymphoma (NHL): In a Phase I study, ublituximab (UTX), a novel monoclonal antibody targeting a unique epitope on the CD20 antigen, resulted in an overall response rate (ORR) of 41% in relapsed and refractory B-cell lymphoma patients previously exposed to rituximab.

True. Single-agent therapy with UTX was well tolerated and active in rituximab-exposed patients. Studies are ongoing with UTX in combination with novel targeted agents (PI3K-δ and BTK inhibitors).

O’Connor OA, Deng C, Amengual JE, et al. A phase I trial of ublituximab (TG-1101), a novel glycoengineered anti-CD20 monoclonal antibody (mAb) in B-cell non-Hodgkin lymphoma patients with prior exposure to rituximab. J Clin Oncol. 2014;32(5 suppl): abstract 8524.


5. True or False? Refractory HL: The combination of sirolimus and vorinostat is well tolerated with encouraging activity in very heavily pretreated patients with HL who are refractory to standard therapies.

True. Investigators enrolled 28 patients (median age 34 years, median of 6 prior therapies—including auto-HCT [n=23] and auto- and allogeneic HCT [n=6]) for dose escalation (n=1), a recommended Phase II dose (n=19) or a registered off-label dose (n=8) with the combination of sirolimus and vorinostat. According to Cheson 2007 criteria, the ORR was 57%, with 9 patients showing a complete response (CR; 32%) and 7 a partial response (PR; 25%). At the median follow-up of 5.4 months, the median PFS has not been reached. Also, given successful induction of remissions, 5 patients (18%) were referred for allogeneic stem cell transplant. Major grade 3/4 treatment-related toxicities included grade 3 thrombocytopenia in 9 patients (32%), grade 4 thrombocytopenia in 8 (29%), grade 3 anemia in 4 (14%), and grade 3 transaminitis in 3 (11%).

Janku F, Oki Y, Falchook GS, et al. Activity of the mTOR inhibitor sirolimus and HDAC inhibitor vorinostat in heavily pretreated refractory Hodgkin lymphoma patients. J Clin Oncol. 2014;32(5 suppl): abstract 8508.


6. True or False? Advanced follicular lymphoma (FL): The 5-year update of the FOLL05 study, with mature data on progression-free survival (PFS), confirmed that R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has the best efficacy profile compared with R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) and R-FM (rituximab, fludarabine, and mitoxantrone) for the initial treatment of patients with advanced FL.

True. The final results of FOLL05 study for the initial therapy of advanced stage (II-IV) FL recently were reported, with a median follow-up of 34 months. This trial showed that R-CHOP and R-FM were superior to R-CVP with respect to 3-year time to treatment failure, the primary study end point, and that R-CHOP had a better risk–benefit ratio compared with R-FM. During ASCO 2014, the investigators presented 5-year follow-up analysis of PFS of the 504 patients included in the study.

Luminari S, Dondi A, Marcheselli L, et al. Updated results of the FOLL05 phase III trial from the Fondazione Italiana Linfomi comparing R-CVP, R-CHOP, and R-FM in patients with advanced follicular lymphoma. J Clin Oncol. 2014;32(5 suppl): abstract 8530.


7. True or False? Relapsed and refractory multiple myeloma (MM): Daratumumab (DARA; HuMax-CD38), a human immunoglobulin G1k monoclonal antibody, effectively mediates destruction of CD40-expressing malignant plasma cells.

False. DARA mediates destruction of CD38-expressing malignant plasma cells. Investigators evaluated safety, pharmacokinetics (PK), and efficacy of DARA plus lenalidomide plus dexamethasone (LEN/DEX) in patients with relapsed or refractory MM. The most frequently occurring AEs (>40% patients) were neutropenia and diarrhea; 17 were ≥grade 3 with 70% hematologic (neutropenia, thrombocytopenia, anemia). The maximum tolerated dose was not reached. The PK profile of DARA plus LEN/DEX was similar to that of DARA alone, suggesting that LEN/DEX does not affect the DARA PK profile. Available efficacy data from 11 patients demonstrated marked decrease in M-protein in all patients; 8 of 11 patients achieved a PR or better, 5 of 11 a very good partial response (VGPR), and 2 of 11 had minimal responses. The median time to response was 4.1 weeks (range, 2.1-4.3 weeks).

Plesner T, Arkenau H-T, Lokhorst HM, et al. Safety and efficacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. J Clin Oncol. 2014;32(5 suppl): abstract 8533.

8. True or False? Relapsed and refractory MM: The MM-003 intent-to-treat analysis showed a significant increase in median PFS and OS for high-dose dexamethasone versus pomalidomide plus low-dose dexamethasone.

False. The MM-003 intent-to-treat analysis showed a significant increase in median PFS and OS for pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone. Unadjusted median OS in MM-003 was 12.7 and 8.1 months in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups, respectively. After adjusting for crossover, the difference in median OS in the 2 groups was 7 months (12.7 vs 5.7 months). The median OS in the pomalidomide plus low-dose dexamethasone arm was, therefore, more than double that in the high-dose dexamethasone arm.

Morgan GJ, San Miguel J, Dhanasiri S, et al. Pomalidomide plus low-dose dexamethasone (POM plus LoDEX) versus high-dose dexamethasone (HiDEX) for relapsed or refractory multiple myeloma (RRMM): overall survival (OS) results of MM-003 after adjustment for crossover. J Clin Oncol. 2014;32(5 suppl): abstract 8593.


9. True or False? Autologous hematopoietic cell transplant (auto-HCT) in MM: In an abstract from the University of Texas MD Anderson Cancer Center and Baylor College of Medicine, both in Houston, investigators reported that dialysis-dependent renal failure should not be an exclusion to auto-HCT in patients with MM.

True. Investigators retrospectively reviewed 2,091 patients who underwent auto-HCT from July 2000 to June 2012, and found 24 patients (1.1%) who were dependent on dialysis (21 on hemodialysis and 3 on peritoneal dialysis). Median duration of dialysis before auto-HCT was 235 days (range, 1-1,481 days). Four patients had high-risk cytogenetics. The melphalan dose was 200 mg/m2 in 58% of patients and less than 200 mg/m2 in the remaining 42%. The median collected CD34-positive cell count was 4.35×106/kg. All patients engrafted. Treatment-related mortality at 100 days and 6 months were each 0%. The incidence of grade II/IV nonhematologic toxicity was similar across different melphalan doses. The ORR was 92% (CR, 25%; VGPR, 29.2%; PR, 37.5%). Two patients had stable disease. Only 3 patients (12.5%) became dialysis-independent after transplant. The median follow-up is 6.7 years. At the time of last follow-up, 13 of the 24 patients had died. The median PFS and OS were 1.9 years and 3.8 years, respectively. In univariate analysis, high-risk cytogenetics was a significant predictor of poor PFS (P=0.04) and OS (P<0.009). A multivariate analysis was not performed due to the small sample size.

El Fakih RO, Nieto Y, Fox PS, et al. Autologous stem cell transplantation in dialysis-dependent myeloma patients. J Clin Oncol. 2014;32(5 suppl): abstract 8601.

10. True or False? Primary plasma cell leukemia: (pPCL): Investigators from Mayo Clinic, in Rochester, Minn., analyzed the Surveillance, Epidemiology, and End Results database for trends in survival of patients with pPCL (ICD-O: 9733) over the period from 1973 to 2010, and they found absolutely no survival improvement during this period.

False. Only diagnosis between 2006 and 2010 was associated with a better OS (hazard ratio, 0.65; 95% confidence interval, 0.45-0.94; P=0.0018, with reference to the 1973 to 1995 period). The median OS based on periods of diagnosis of 1973 to 1995, 1996 to 2002, 2003 to 2005, and 2006 to 2010 were 9, 9, 8, and 19 months, respectively (P=0.002). According to the investigators, these results suggest that since 2006, the use of novel agents in the treatment of pPCL has had a positive effect.

Gonsalves WI, Rajkumar V, Go RS, et al. Trends in survival of patients with primary plasma cell leukemia: a population-based analysis from 1973 to 2010. J Clin Oncol. 2014;32(5 suppl): abstract 8608.

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