Valkal Bhatt

Gastroenteropancreatic Neuroendocrine Tumors: Update on Therapeutics

OBJECTIVE: To review the available literature addressing the treatment of pancreatic neuroendocrine tumors (PNETs) and carcinoid tumors. DATA SOURCES: Relevant literature was identified by a PubMed search (January 1977-December 2011) of English-language literature using the terms gastroenteropancreatic neuroendocrine tumor, pancreatic neuroendocrine, carcinoid, and pancreatic islet cell tumor. STUDY SELECTION AND DATA EXTRACTION: All published studies and abstracts, as well as relevant consensus guidelines, evaluating the current literature about PNETs and carcinoid tumors were included. DATA SYNTHESIS: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a genetically diverse group of complex malignancies with varying biological and clinical courses. Historically believed to be rare, recent epidemiologic data suggest their incidence is rising. Two of the most commonly diagnosed GEP-NETs are PNETs and carcinoid tumors. Both subtypes are well-differentiated tumors and present as low or intermediate grade. The systemic manifestations of PNETs and carcinoid tumors are diverse and are related to the secretion of affected hormones and biogenic amines. Surgical resection of localized disease remains the only curative option. However, the utility of this approach is limited because most patients are diagnosed with advanced disease. Recent advances have led to an improvement in outcomes in patients with PNETs and carcinoid tumors. This review describes traditional therapies as well as emerging strategies being investigated to help manage these cancers. Treatment of poorly differentiated GEP-NETs is beyond the scope of this review. CONCLUSIONS: The advent of new therapies for PNETs and carcinoid tumors has introduced a paradigm shift in the management of this heterogeneous malignancy.

The Promising Impact of Ibrutinib, a Bruton's Tyrosine Kinase Inhibitor, for the Management of Lymphoid Malignancies

Lymphoid malignancies comprise a heterogeneous group of disorders originating from clonal proliferation of B or T lymphocytes. Treatment of lymphoid neoplasms has traditionally been pursued with cytotoxic chemotherapy. To improve efficacy and ameliorate the adverse effects associated with classic chemotherapy, molecularly targeted therapy has been developed. At the forefront of clinical development is ibrutinib, an inhibitor of Brutons tyrosine kinase (Btk). Btk is a protein tyrosine kinase that plays an important role in regulating B‐cell signaling. Dysregulated Btk results in uncontrolled B‐lymphocyte proliferation, differentiation, and survival. Ibrutinib is currently being studied in numerous malignancies of lymphoid origin including chronic lymphocytic leukemia, mantle cell lymphoma, non‐Hodgkin lymphoma, follicular lymphoma, and multiple myeloma. Thus far, ibrutinib has demonstrated very promising results in treatment‐naive patients as well as those with relapsed or refractory disease with an acceptable safety profile. In this article, we describe the pharmacology, efficacy, and toxicity profile of ibrutinib and depict the potential role that ibrutinib will play in the treatment paradigm of lymphoid neoplasms.

Robust Vaccine Responses in Adult and Pediatric Cord Blood Transplantation Recipients Treated for Hematologic Malignancies

Because cord blood (CB) lacks memory T and B cells and recent decreases in herd immunity to vaccine-preventable diseases in many developed countries have been documented, vaccine responses in CB transplantation (CBT) survivors are of great interest. We analyzed vaccine responses in double-unit CBT recipients transplanted for hematologic malignancies. In 103 vaccine-eligible patients, graft-versus-host disease (GVHD) most commonly precluded vaccination. Sixty-five patients (63%; engrafting units median HLA-allele match 5/8; range, 2 to 7/8) received protein conjugated vaccines, and 63 patients (median age, 34 years; range, .9 to 64) were evaluated for responses. Median vaccination time was 17 months (range, 7 to 45) post-CBT. GVHD (n = 42) and prior rituximab (n = 13) delayed vaccination. Responses to Prevnar 7 and/or 13 vaccines (serotypes 14, 19F, 23F) were seen in children and adults (60% versus 49%, P = .555). Responses to tetanus, diphtheria, pertussis, Haemophilus influenzae, and polio were observed in children (86% to 100%) and adults (53% to 89%) even if patients had prior GVHD or rituximab. CD4(+)CD45RA(+) and CD19(+) cell recovery significantly influenced tetanus and polio responses. In a smaller cohort responses were seen to measles (65%), mumps (50%), and rubella (100%) vaccines. No vaccine side effects were identified, and all vaccinated patients survived (median follow-up, 57 months). Although GVHD and rituximab can delay vaccination, CBT recipients (including adults and those with prior GVHD) have similar vaccine response rates to adult donor allograft recipients supporting vaccination in CBT recipients.

A Comprehensive Assessment of Toxicities in Patients with Central Nervous System Lymphoma Undergoing Autologous Stem Cell Transplantation Using Thiotepa, Busulfan, and Cyclophosphamide Conditioning

High-dose therapy and autologous stem cell transplantation (ASCT) with thiotepa, busulfan, and cyclophosphamide (TBC) conditioning has emerged as an effective postinduction treatment strategy for patients with primary central nervous system lymphoma (PCNSL) or secondary central nervous system lymphoma (SCNSL), but it is associated with considerable toxicity and transplantation-related mortality (TRM) in the modern era. Forty-three adult patients with chemosensitive PCNSL or SCNSL underwent TBC-conditioned ASCT between 2006 and 2015. Twenty-eight of these patients received pharmacokinetically (PK)-targeted busulfan dosing. The median number of clinically relevant individual grade ≥3 nonhematologic toxicities per patient was 5. We found no association between pretransplantation patient characteristics and the presence of more than 5 grade ≥3 nonhematologic toxicities. Patients with elevated first-dose busulfan area under the curve values did not experience more toxicity. Paradoxically, patients treated with more than 2 regimens before undergoing ASCT had lower first-dose busulfan AUC values. With a median follow-up among survivors of 20 months, 1-year progression-free survival (PFS) and overall survival (OS) from the time of ASCT were 83% and 87%, respectively. Although this study reaffirms the favorable PFS and OS associated with TBC-conditioned ASCT for PCNSL or SCNSL, this treatment strategy carries a large toxicity burden.

Therapeutic Cyclosporine-a (CSA) Levels in the First 7 Days after Cord Blood Transplantation (CBT) Are Critical to Prevent Severe Acute Graft-Versus-Host Disease (aGVHD)

Background: We have investigated CBT after a novel intermediate intensity, reduced toxicity myeloablative cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI regimen with CSA/ MMF (no ATG) with an aim to reduce early organ toxicity while also maximizing engraftment & disease control. Methods: Patient (pt) & graft characteristics associated with TRM, relapse and progression-free survival (PFS) in adult dCBT recipients were analyzed. Eligible pts were first allografts </=65 yrs transplanted for acute leukemia/ MDS/ MPD (</=10% blasts pre-CBT), B-cell NHL or Hodgkin lymphoma. Results: 139 consecutive pts [74 (53%) non-European, 84 (60%) CMV seropositive, median age 51 yrs (range 23-65), median weight 83 kg (range 49-136), 102 acute leukemia, 22 MDS/ MPD, 15 B-cell NHL/ HL] were transplanted 10/2007-12/ 2016. All received double unit grafts [median donor-recipient 8-allele HLA-match 5/8 (range 2-8), median infused CD34+ dose 1.0 x 105/kg/unit (range .2-8.6)]. Haplo-identical CD34+ cells were added as a myeloid bridge in 54 (39%) pts. CB engraftment was 96% (95%CI: 91-99). Day 180 incidences of grades II-IV & III-IV aGVHD were 78% (95%CI: 70-84) & 21% (95%CI: 15-28), respectively. 1-yr cGVHD was 8% (95%CI: 4-14). The incidence of day 180 TRM was 12% (95%CI: 7-17) & 21% (95%CI: 14-29) at 3 yrs. 11% (95%CI: 6-18) of pts relapsed by 3 yrs post-CBT. With a median survivor follow-up of 2.7 yrs (range 6.5 months-9.5 yrs), the 3-yr OS is 71% (95%CI: 6380) & PFS is 67% (95%CI: 59-76). 3-yr PFS in 75 acute leukemia CR1 pts is 66% vs 74% in 27 other disease status pts (P = .574). 3-yr PFS in 23 FLT-3 mutated AML pts is 83%. The 3-yr PFS is 62% in 22 MDS/ MPD pts & 67% in 15 NHL/ HD pts. The revised Disease Risk Index (rDRI) was not associated with TRM, relapse or PFS (Figure 1, Table 1). By contrast, pts with an age-adjusted HCT-Comorbidity index (aaHCT-CI) 0-2 (n = 54) had very low day 180 TRM [4% (95%CI: 1-11)] & high 3-yr PFS [81% (95%CI: 71-94)]. Notably, addition of haploidentical cells, better CB HLA-match, older age (51-65 yrs), CMV sero-positivity, & non-European ancestry had no affect upon PFS. In multivariate analysis of TRM, aaHCT-CI had a HR of 4 (95%CI: 1.4-11.6, P = .01); age alone was not significant [HR 1.9 (95%CI: .8-4.5), P = .12]. In multivariate analysis of PFS, aaHCT-CI HR was 2.4 (95%CI: 1.2-4.7, P = .01); for recent pts (2014-2016) HR was .6 (95%CI: .3-1.2, P = .17). Conclusions: The 3-yr PFS in this intermediate intensity dCBT population (median 51 yrs) is 74% in recent pts suggesting it is an appropriate replacement for high dose ablative or nonmyeloablative regimens in many adult pts. cGVHD & relapse rates are low & rDRI was not associated with TRM, relapse or PFS. Given PFS is 81% in low aaHCT-CI CBT recipients, survival comparisons of intermediate intensity dCBT in this population vs other HSC sources is warranted. CB can also be attractive in high risk pts given its rapid availability.