E-Newsletter - March 2016

Alliance Presents Novel Data at American Society of Hematology Annual Meeting

The Alliance for Clinical Trials in Oncology presented an array of novel data from many of its hematology studies during the 57th American Society of Hematology (ASH) Annual Meeting and Exposition held in Orlando, FL. Many of these data will help change the delivery of hematologic cancer care or help elucidate the underlying cause and effect relationships seen in this field.

Here is a summary of the Alliance trials.

Alliance A051103
Phase I Study of Rituximab, Lenalidomide, and Ibrutinib in Previously Untreated Follicular Lymphoma (Alliance 051103)
Ujjani C, Jung S, Pitcher B, Martin P, Park SI, Blum KA, Smith SL, Davids MS, Czuczman M, Leonard JP, Cheson BD
Blood 126 (23) 471, 2015
Synopsis: Although protocol-defined dose-limiting toxicity (DLT) was not observed, the combination of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma was associated with a significant incidence of rash, which may have been related to allopurinol, the individual study drugs, or drug interactions. Preliminary overall response rate (ORR) data of the regimen were comparable to prior reports of the lenalidomide and rituximab (R-squared) regimen in this population. Efficacy of the combination, including complete response (CR) rate, may be affected by the reduction in dose intensity. For more trial information, visit https://clinicaltrials.gov/ct2/show/NCT01829568

Alliance A061202
Alliance A061202. A Phase I/II Study of Pomalidomide, Dexamethasone and Ixazomib versus Pomalidomide and Dexamethasone for Patients with Multiple Myeloma Refractory to Lenalidomide and Proteasome Inhibitor Based Therapy: Phase I Results

Voorhees PM, Mulkey F, Hassoun H, Paba-Prada CE, Efebera Y, Hoke E, Aquino G, Carlisle D, Suman V, Richardson PG
Blood 126 (23) 375, 2015
Synposis: In the phase I part of the study, pomalidomide, ixazomib and dexamethasone combination has demonstrated an acceptable toxicity profile thus far with encouraging preliminary efficacy in patients with double-refractory patients multiple myeloid. It also was determined that the observed hematologic toxicities were manageable with close monitoring and supportive care.  For more trial information, visit https://clinicaltrials.gov/ct2/show/NCT02004275

CALGB 10603
The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance])
Stone RM, Mandrekar S, Sanford BL, Geyer S, Bloomfield CD, Dohner K, Thiede C, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Dohner H
Blood 126 (23) 6, 2015
Synopsis: CALGB 10603 demonstrated that a prospective trial in a pre-therapy genetically defined subgroup of patients with acute myeloid leukemia was feasible and that the addition of the multi-kinase inhibitor midostaurin to standard chemotherapy and one-year of maintenance therapy significantly improved event-free survival and overall survival (in both uncensored and censored for transplant analyses) in patients whose blasts had gene aberrations TKD or ITD (low or high FLT3 mutation burden). These findings may lead to improved outcomes through the use of midostaurin as a component of therapy in younger adults with mutant FLT3 AML. For more trial information, visit, https://clinicaltrials.gov/ct2/show/NCT00651261

CALGB 11001
Addition of Sorafenib to Chemotherapy Improves the Overall Survival of Older Adults with FLT3-ITD Mutated AML (Alliance C11001)
Uy GL, Mandrekar S, Laumann K, Sanford B, Marcucci G, Zhao W, Levis M, Klepin HD, Powell BL, Baer MR, Stock W, Byrd J, Stone RM, Larson RA
Blood 126 (23) 319, 2015
Synopsis: This study represents the first prospective clinical trial for older adults with AML targeting a specific mutational profile within the United States cooperative group setting. The study met the primary endpoint demonstrating that the addition of sorafenib to chemotherapy for FLT3-ITD (gene mutation) acute myeloid leukemia improves the survival of older adults more than doubling the one-year overall survival compared to historical controls. For more trial information, visit https://clinicaltrials.gov/ct2/show/NCT01253070

CALGB 50401, CALGB 50402, CALGB 50701, CALGB 50803, CALGB 50901
Interfollicular CD10 Expression and Follicular PD1 Tumor-Infiltrating Lymphocytes as Biologic Risk Factors in Patients with Previously Untreated Follicular Lymphoma Receiving Rituximab-based Biologic Therapy: An Alliance Correlative Science Study (CALGB 50901, 50402, 50701, 50803, 50401)

Sohani AR, Pitcher B, Chadburn A, Said J, Martin P, Czuczman MS, Bartlett NL, Rosenbaum C, Leonard JP, Cheson BD, Hsi ED
Blood 126 (23) 334, 2015
Synopsis: Interfollicular (IF)-CD10 positivity appears to be a poor prognostic biomarker in follicular lymphoma (FL) in the untreated but not relapse setting, while high follicular -PD1 tumor expression appears to be a favorable prognostic feature in patients with untreated FL treated with biologic agents. These are promising biomarkers for risk stratification in FL that warrant further validation in future trials.

CALGB 50403
Bortezomib Maintenance (BM) Versus Consolidation (BC) Following Aggressive Immunochemotherapy and Autologous Stem Cell Transplant (ASCT) For Untreated Mantle Cell Lymphoma (MCL): CALGB 50403
Kaplan LD, Stock W, Jung S, Bartlett NL, Pitcher B, Byrd J, Blum KA, LaCasce AS, His ED, Hurd D, Czuczman M, Leonard JP, Cheson BD
Blood 126 (23) 337, 2015
Synopsis: Induction chemotherapy followed by peripheral blood stem cell autografting (ASCT) and either bortezomib consolidation (BC) versus bortezomib maintenance (BM) was efficacious and tolerable, although BC was associated with more patient withdrawals for toxicity. The comparison between studies CALGB 50403 and CALGB 59909 suggests a progression-free survival (PFS) benefit from the addition of BC or BM. The absence of residual blood cancer (MRD-negativity) following induction chemo-immunotherapy is highly associated with improved PFS and could provide an important tool for designing future trials. For more trial information, visit https://clinicaltrials.gov/ct2/show/NCT00310037

CALGB 50901
Phase II Trial of Ofatumumab (OFA) in Previously Untreated Follicular Non-Hodgkin Lymphoma (NHL): CALGB 50901 (Alliance)
Rosenbaum CA, Pitcher B, Bartlett NL, Smith S, Blum K, His E, Jung S, Leonard JP, Cheson BD
Blood 126 (23) 2741, 2015
Synopsis: Ofatumumab, a monoclonal antibody, when given as a single agent in an extended induction dosing schedule is well tolerated and active as front-line therapy in patients with low-intermediate risk Follicular Lymphoma International Prognostic Index (FLIPI), advanced stage follicular lymphoma in this multi-center study. Activity appears to be in a range comparable to that reported with other anti-CD20 antibodies in this setting, suggesting that significant improvements in efficacy will require novel combinations. For more trial information, visit https://clinicaltrials.gov/ct2/show/NCT01190449

CALGB 50604
Initial Results of US Intergroup Trial of Response-Adapted Chemotherapy or Chemotherapy/Radiation Therapy Based on PET for Non-Bulky Stage I and II Hodgkin Lymphoma (HL) (CALGB/Alliance 50604)
Straus DJ, Pitcher BN, Kostakoglu L, Grecula JC, Hsi ED, Schöder H, Jung S, Popplewell LL, Leonard JP, Friedberg JW, Kahl BS, Cheson BD, Bartlett NL
Blood 126 (23) 578, 2015
Synopsis: These early results confirm interim positron emission tomography (PET) as a potential biomarker for predicting relapse with chemotherapy regimen ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) in patients with non-bulky, stages I/II Hodgkin lymphoma. Importantly, this study demonstrates that defining PET negative as Deauville scores of 1-3 results in only nine percent of patients remaining PET-positive after two ABVD cycles and excellent progression-free survival (PFS) for the PET-negative majority. More intensive treatment with two cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) and involved-field radiation therapy (IF RT) for the nine percent of patients who are interim PET-positive will be unlikely to improve three-year PFS to the level of clinical interest in this trial. Interpretation may be limited by small numbers and lack of a randomized control comparison. Fortunately, exciting new treatment approaches may provide an opportunity to improve outcomes for the minority of patients who are interim PET-positive in the future. For more trial information, visit https://clinicaltrials.gov/ct2/show/NCT01132807

Everolimus Plus R-CHOP-21 is Safe and Highly Effective for New Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Results of the Phase I Trial NCCTG N1085 (Alliance)
Johnston PB, LaPlant BR, McPhail ED, Habermann TM, Inwards DJ, Micallef I, Colgan J,  Nowakowski G, Ansell SM, Witzig TE
Blood: 126 (23) 813, 2015
Synopsis: Everolimus at 10 mg daily in day 1-14 of a standard RCHOP-21 cycle (rituximab and combination chemotherapy) is tolerable with a 96 percent complete response rate in both germinal center B-cell–like (GCB) and non-GCB DLBCL. With a median follow-up of 16.8 months and eight patients out more than 24 months, the lack of disease relapse is encouraging. Longer follow-up and a larger trial will be necessary to confirm the benefits of this novel combination. For more trial information, visit https://clinicaltrials.gov/ct2/show/NCT01334502



For other articles in the March issue of the Alliance E-News newsletter, see below.