Venu Gopal Bathini

CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer

Any CA19-9 decline at week 8 and radiologic response by week 8 each predicted longer OS in both treatment arms. In the nab-P + Gem arm, the higher proportion of patients with week 8 CA19-9 decrease [82% (206/252); median OS 13.2 months] than a RECIST-defined response [16% (40/252); median OS 13.7 months] suggests that CA19-9 decline is a predictor of OS applicable to a larger population.

Phase-I/II study of bortezomib in combination with carboplatin and bevacizumab as first-line therapy in patients with advanced non-small-cell lung cancer.

Background: This study aimed to establish the maximum tolerated dose (MTD) of weekly bortezomib in combination with fixed standard doses of carboplatin and bevacizumab, and to estimate the efficacy (response rate and progression free survival [PFS]) and safety of combination therapy with carboplatin, bortezomib, and bevacizumab as first-line therapy in patients with advanced non–small-cell lung cancer (NSCLC). Methods: Patients were assigned to three dose levels of weekly bortezomib with the fixed standard doses of carboplatin AUC 6 and bevacizumab (15 mg/kg) every 3 weeks using a standard phase-I design. Bortezomib doses were 1.3 mg/m2, 1.6 mg/m2, and 1.8 mg/m2 weekly on day 1 and day 8 of every 3-week cycle. A maximum of six cycles was administered. Patients with complete, partial response or stable disease were continued on single-agent bevacizumab (15 mg/kg every 3 weeks) as maintenance therapy. In phase II, either level III or MTD was administered to evaluate the efficacy and safety of the combination in first-line treatment of advanced NSCLC. Results: Sixteen patients were enrolled (three, four, and nine patients in dose level I, II, and III, respectively). There was no predefined dose limiting toxicity in cycle 1 in all 16 patients. The recommended phase-II dose is bortezomib 1.8 mg/m2 weekly on day 1 and day 8 in combination with carboplatin AUC 6 and bevacizumab 15 mg/kg on every 21-day cycle. Totally 9 patients were treated at the recommended phase-II dose level. The most common treatment related grade-3/4 toxicities during the subsequent cycles were thrombocytopenia (58%), lymphopenia (25%), neutropenia (12%), and diarrhea (25%). The grade-1/2 neuropathy was seen in 7 out of 16 patients (44%). The response rate, PFS, and overall survival in all patients were 37.5% (95%CI 13.8%–61.2%), 5.0 months (95%CI: 3.1–8.4), 9.9 months (95% CI: 8.2–14.1), and among the 9 patients in phase-II portion are 44% (95%CI 15.3%–77.3%), 5.5 months (95%CI: 3.1–2.2) and 10.9 months (95%CI: 8.0–14.1). Conclusion: The recommended phase-II dose for this combination is: carboplatin AUC 6, bevacizumab 15 mg/kg on day 1 and bortezomib 1.8 mg/m2 on day 1 and day 8 on every 21-day cycle. The regimen was very well tolerated with interesting clinical activity in first-line treatment of NSCLC.

First-line treatment of metastatic pancreatic cancer.

Metastatic pancreatic cancer is an aggressive malignancy that is difficult to treat. Gemcitabine monotherapy has been used first line and many contemporary treatment approaches have focused on gemcitabine plus experimental agents. The 2012 ASCO Gastrointestinal Cancers Symposium Abstract #213 is a study of gemcitabine with IPI-926, a novel hedgehog pathway inhibitor. Abstract #227 is a study of gemcitabine with ⁹⁰Y-hPAM4 radioimmunotherapy with yttrium labeled anti-mucin humanized antibody. Abstract #296 is a study of gemcitabine with temsirolimus, an mTOR inhibitor. Gemcitabine and erlotinib has shown slight advantages to gemcitabine alone. Abstract #253 takes this one step further and evaluates gemcitabine and erlotinib with apricoxib, a COX-2 inhibitor. FOLFIRINOX has shown superiority to gemcitabine; however, doing so at the cost of significantly greater toxicity. Abstract #199, is a study which examines the cost effectiveness of first line FOLFIRINOX approaches. Another cost effective study is portrayed in Abstract #372, a study evaluating the survival of unresectable pancreatic cancer patients treated with gemcitabine and the disease course is followed clinically without radiographic follow-up.

Randomized Phase 2 Trial of Pharmacodynamic Separation of Pemetrexed and Intercalated Erlotinib Versus Pemetrexed Alone for Advanced Nonsquamous, Non–small-cell Lung Cancer

Background: Pharmacodynamic separation of pemetrexed and erlotinib avoids negative cellular interactions and results in antitumor synergy in erlotinib‐resistant non–small‐cell lung cancer (NSCLC) cells, independent of EGFR (epidermal growth factor receptor) genotype. Patients and Methods: Patients with platinum‐treated metastatic nonsquamous NSCLC were randomly assigned 1:2 to pemetrexed alone (500 mg/m2 provided intravenously on day 1) or pemetrexed followed by erlotinib (150 mg provided orally once daily on days 2–17) every 21 days. EGFR genotype was centrally confirmed by Sequenom multiplex oncogenotyping assay. The primary end point was progression‐free survival (PFS), which would be considered promising for future study if median PFS was ≥ 4.5 months. Results: Of 83 patients enrolled, 79 were randomized to either pemetrexed alone (n = 27) or in combination (n = 52). Fifty‐nine (79%) of 75 eligible patients had tumors with confirmed EGFR genotype: 7 with activating mutations and 52 wild type. Median PFS was 4.7 and 2.9 months in the combination and pemetrexed‐alone groups, respectively. In patients with EGFR wild‐type tumors, median PFS was 5.3 and 3.5 months in the combination and pemetrexed‐alone groups, respectively. Objective response rate (29% vs. 10%, P = .17), 6‐month PFS (45% vs. 29%, P = .26), and 12‐month PFS (23% vs. 10%, P = .28) were all higher in the combination arm. Rash (67% vs. 26%, P = .0007) and diarrhea (44% vs. 11%, P = .003) were significantly more common in the combination arm. Conclusion: In patients with unselected or EGFR wild‐type advanced nonsquamous NSCLC, pharmacodynamic separation of pemetrexed and intercalated erlotinib had promising antitumor activity without new safety concerns. The combination merits further evaluation as maintenance or second‐line therapy against new standards in patients with EGFR wild‐type advanced NSCLC. Micro‐Abstract: This randomized phase 2 study demonstrated promising clinical synergism between pemetrexed and intercalated erlotinib in patients with unselected nonsquamous non–small‐cell lung cancer (NSCLC) as second‐line therapy. EGFR (epidermal growth factor receptor) genotyping by Sequenom multiplex oncogenotyping assay was feasible in 79% of eligible patients using tumor DNA from either archival specimens and/or plasma. Because patients with EGFR‐mutant NSCLC respond well to EGFR tyrosine kinase inhibitor monotherapy alone or in combination with bevacizumab, the combination might merit further evaluation as second‐line or maintenance therapy against new standards in patients with EGFR wild‐type advanced NSCLC.

Rare gene fusion rearrangement SPTNB1-PDGFRB in an atypical myeloproliferative neoplasm

The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia recognizes a distinct class of myeloid and lymphoid tumors with eosinophilia-related proliferations associated with specific gene rearrangements, one of which involves rearrangements of platelet-derived growth factor receptor B (PDGFRB) gene. We report a case of a rare PDGFRB rearrangement with SPTNB1 (spectrin beta, nonerythrocytic 1) that presented as atypical myeloproliferative neoplasm.

Large granular lymphocytic leukemia-associated peripheral neuropathy

Dear Editor, Large granular lymphocytic proliferative disorders (LGLPD) are seldom known to be associated with peripheral neuropathy. We report here a case of mononeuritis multiplex associated with T cell LGL leukemia and review the literature concerning to involvement of peripheral nervous system in LGLPD. A 58-year-old right-handed Caucasian male with history of hypertension and GERD presented with chronology of events starting 2 weeks earlier with left foot drop; a few days later, he developed difficulty pronouncing certain syllables (Bp^ as Bf^) and lastly went on to develop insidious left facial numbness and weakness on the day of presentation to emergency department. Pertinent physical examination revealed decreased sensation to pinprick and temperature in the left V2 and V3 territory, although sensation to light touch was preserved. Left nasolabial fold was flattened with a decreased smile on the left, and cheek puff strength was also decreased on the left side. However, eye closure and forehead wrinkle were symmetric and full. Complete blood count and comprehensive metabolic panel were within normal limits. Radiological examination and CSF analysis were within normal limits. Electromyography with nerve conduction study revealed signs of denervation at the left side of the face, left upper extremity, left lower extremity, and right lower extremity which was compatible with a clinical diagnosis of mononeuropathy multiplex. Extensive lab investigations failed to find a cause for the neuropathy. The light chains assay revealed elevated lambda free chains—77.9 mg/L (reference range 5.7–26.3 mg/L)— and kappa free chains—22.9 mg/L (reference range 3.3– 19.4 mg/L)—with a normal ratio of 0.3 (reference range 0.3–1.7). Serum protein electrophoresis revealed no monoclonal protein on immunofixation. Bone marrow biopsy revealed small lymphocytic infiltrates consistent with T cell large granular lymphocytic leukemia. The T cell gene rearrangement studies confirmed it to be a clonal T cell population. A diagnosis of LGL leukemia-related mononeuritis multiplex neuropathy was rendered. The patient refused chemotherapy as he felt his symptoms were not particularly disabling and his clinical symptoms continue to be stable for almost a year without any treatment. LGLPDs arise broadly from two different lineages—CD3 cytotoxic T cells (85%) and CD3 natural killer (NK) cells (15%). The literature search identified 16 other cases of LGL leukemia-associated neuropathy. The clinicopathologic findings of these cases are presented in Table 1 [1–13]. The pathogenetic link between peripheral neuropathy and LGL leukemia remains unclear. In our review, five cases had neuroleukemiosis (leukemic infiltration of the peripheral nervous system) and all of them were of NK cell type. None of the five T cell LGL had clonal leukemic infiltrate in the biopsy specimens. The direct infiltration of NK cells causing neuronal injury has been supported in animal studies where NK cells have been directly implicated in the neuronal injury process [14]. Another important mechanism for neuropathy in LGLPD is believed to be through an abnormal autoimmune response. LGL leukemia is known to be associated with a wide spectrum of autoimmune disorders such as rheumatoid arthritis (RA), Felty syndrome, connective tissue disorders, and vasculitis. The disturbed cytokine network in T-LGL leukemia promotes activation and survival of cytotoxic lymphocytes which is similar to that seen in RA. On the other hand, NKLGL proliferative disorders have been shown to cause abnormal B cell immune dysfunction leading to increased immunoglobulin production with the auto-antibody formation. Our case and literature review highlight, the fact that LGL leukemia should be considered in the differential diagnosis algorithm for peripheral neuropathy and patients may benefit from treatment by lymphocytotoxic therapy. * Neeraj Y Saini, MD lymphomalogy@gmail.com

Anti-VEGF and Anti-EGFR Monoclonal Antibodies in the First-line Therapy for Metastatic Colorectal Cancer - A Meta-Analysis

e15012 Background: Anti-VEGF (VEGFi) and anti-EGFR (EGFRi) Mabs have increased options for patients with metastatic colorectal cancers (mCRC). The optimal class of antibody to combine with chemotherapy (Ctx) in the first-line treatment for mCRC remains less well defined. Results from randomized controlled trials (RCTs) are variable. METHODS Systematic review and meta-analysis were performed on the basis of previously released RCTs results. We searched the MEDLINE, Cochrane registry, proceedings from ASCO, ECCO, ESMO until 12/ 2008 for RCTs of Mabs in first-line mCRC. Summary statistics were pooled hazard ratio (HR) of progression-free survival (PFS), overall survival (OS) and odds ratio (OR) of Response rate (RR) and 60 day mortality (60d-M). Effect of k-ras wild type and mutation were stratified in trials involving EGFRi. RESULTS 7 trials with complete data were identified, including 3 Ctx ± VEGFi (AVF2107g, NO16966, JCO2005.05.122), n=2422; 2 Ctx±EGFRi (CRYSTAL, OPUS), n=1554; 2 Ctx/VEGFi ± EGFRi (PACCE, CAIRO-2), n=1789. Addition of VEGFi to Ctx offered 20-30% risk reduction in disease progression and overall mortality, a 30% higher RR and nonsignificant 60d-M. Benefit of EGFRi in addition to Ctx was seen only in k-ras wild type patients with 36% reduction in disease progression and doubling in RR. However, addition of EGFRi to Ctx+VEGFi caused increased risk of progression and death with no significant increase in RR and 60d-M. CONCLUSIONS Benefit of VEGFi in addition to Ctx in first-line mCRC is well pronounced and persistent. In k-ras wild type patients, addition of EGFRi to Ctx results in significant increase in RR and PFS. Addition of EGFRi to Ctx+VEGFi appeared harmful regardless of k- ras status. [Table: see text] [Table: see text].