Vemurafenib and Obinutuzumab as Frontline Therapy for Hairy Cell Leukemia.

BACKGROUND: Hairy cell leukemia (HCL) is characterized by the underlying genetic lesion of BRAFV600E and responsiveness to BRAF inhibitors. We assessed the safety and activity of the BRAF inhibitor vemurafenib combined with obinutuzumab in patients with previously untreated HCL. METHODS: We conducted a single-arm, multicenter clinical study of vemurafenib plus obinutuzumab. Vemurafenib 960 mg twice daily was administered for four cycles, and obinutuzumab was administered in cycles 2 to 4. The primary end point was complete remission (CR). Secondary end points included assessment of safety, minimal residual disease (MRD), and BRAF allele burden according to digital droplet polymerase chain reaction (ddPCR). RESULTS: Thirty patients were enrolled in the study, and 27 patients completed all four cycles of treatments and achieved CR (90%; 95% confidence interval [CI], 73 to 98). Three patients discontinued the study early because of adverse events and were not evaluable for response. Of the 27 patients who achieved CR, 26 patients (96%; 95% CI, 81 to 99) achieved MRD negativity. BRAFV600E allele was undetectable by ddPCR in all 21 evaluable patients. At a median follow-up of 34.9 months (95% CI, 29.6 to 36.9), no patient experienced disease relapse. The most common vemurafenib-related adverse events were rash and arthralgia. Febrile neutropenia occurred in two patients, and blood or platelet transfusions were required in two patients. CONCLUSIONS: Combined time-limited vemurafenib and obinutuzumab achieved CR in more than 90% of patients with previously untreated HCL. In this small study, acquired vemurafenib resistance or dose-limiting toxicity was not observed. Patients were not observed long enough to reveal secondary malignancies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03410875.)

Long-term outcomes in patients with relapsed or refractory hairy cell leukemia treated with vemurafenib monotherapy.

Vemurafenib, an oral BRAF inhibitor, has demonstrated high response rates in relapsed/refractory (R/R) hairy cell leukemia (HCL). However, little is known about long-term outcomes and response to retreatment. Herein, we report the results of 36 patients with R/R HCL treated with vemurafenib from the United States arm of the phase 2 clinical trial (NCT01711632). The best overall response rate was 86%, including 33% complete response (CR) and 53% partial response (PR). After a median follow-up of 40 months, 21 of 31 responders (68%) experienced relapse with a median relapse-free survival (RFS) of 19 months (range, 12.5-53.9 months). There was no significant difference in the RFS for patients with CR vs PR. Fourteen of 21 (67%) relapsed patients were retreated with vemurafenib, with 86% achieving complete hematologic response. Two patients acquired resistance to vemurafenib with the emergence of new KRAS and CDKN2A mutations, respectively. Six of 12 (50%) responders to vemurafenib retreatment experienced another relapse with a median RFS of 12.7 months. Overall survival (OS) was 82% at 4 years, with a significantly shorter OS in patients who relapsed within 1 year of initial treatment with vemurafenib. Higher cumulative doses or a longer duration of treatment did not lengthen the durability of response. All adverse events in the retreatment cohort were grade 1/2 except for 1 case of a grade 3 rash and 1 grade 3 fever/pneumonia. Our data suggest that vemurafenib retreatment is a safe and effective option for patients with R/R HCL.

Pediatric-inspired chemotherapy incorporating pegaspargase is safe and results in high rates of minimal residual disease negativity in adults up to age 60 with Philadelphia chromosome-negative acute lymphoblastic leukemia.

Administration of pediatric-inspired chemotherapy to adults up to age 60 with acute lymphoblastic leukemia (ALL) is challenging in part due to toxicities of asparaginase as well as myelosuppression. We conducted a multicenter phase II clinical trial (NCT01920737) investigating a pediatric-inspired regimen, based on the augmented arm of the Children's Cancer Group 1882 protocol, incorporating 6 doses of pegaspargase 2000 IU/m2, rationally synchronized to avoid overlapping toxicity with other agents. We treated 39 adults ages 20-60 years (median, 38 years) with newly-diagnosed ALL (n=31) or lymphoblastic lymphoma (n=8). Grade 3-4 hyperbilirubinemia occurred frequently and at higher rates in patients 40-60 (n=18) vs 18-39 (n=21) years (44 vs 10%, p=0.025). However, 8/9 patients re-challenged with pegaspargase did not experience recurrent grade 3-4 hyperbilirubinemia. Grade 3-4 hypertriglyceridemia and hypofibrinogenemia were common (each 59%). Asparaginase activity at 7-days post-infusion reflected levels associated with adequate asparagine depletion, even among those with antibodies to pegaspargase. Complete response (CR)/CR with incomplete hematologic recovery was observed post-induction in 38/39 (97%) patients. Among patients with ALL, rates of MRD negativity by multiparameter flow cytometry were 33% and 83% following Induction Phase I and Phase II, respectively. Event-free and overall survival at 3 years (67.8 and 76.4%) compare favorably to outcomes observed in other series. These results demonstrate pegaspargase can be administered in the context of intensive multi-agent chemotherapy to adults age ≤60 with manageable toxicity. This regimen may serve as an effective backbone into which novel agents may be incorporated in future frontline studies.

Biochemical parameters and 18S rRNA gene sequence analysis amongst green microalgal strains from selected aquatic sites of Eastern India.

In the present study, 24 green microalgae strains were isolated from selected aquatic sites of India. These were microscopically identified as Chlamydomonas sp., Scenedesmus sp., Chlorella sp., Dictyosphaerium sp. and Dunaliella sp. Nannochloropsis sp. (MCC 25), was used as a reference strain. Results showed that Dictyosphaerium sp. (MCC 10 and MCC 12) showed relatively higher nutritive content. The total soluble proteins in the reference strain was 21.4%, whereas it showed carbohydrate content of 17.2% and the lipids were 3.4% on a dry weight basis. Best performing strains were identified by biochemical characterization. Five genera were selected for molecular identification since they were the most representative based upon their area of isolation and their optimum content of total soluble proteins, carbohydrates and lipids. 18S rRNA sequencing authenticated their identification as Scenedesmus sp., Dictyosphaerium sp. and Chlorella sp. The sequences of these have been submitted in NCBI database with accession numbers as KT808247-KT808251. The correlation matrix showed positive correlation between carbohydrates and lipids, while negative correlation was seen between proteins and carbohydrates and between proteins and lipids. This study emphasizes the need for complete compositional analysis of the biomass for the possible applicability in the area of value addition.

Influence of light intensity, temperature and CO2 concentration on growth and lipids in green algae and cyanobacteria.

Effects of the environmental variables such as light intensity (Vmol photons m⁻² S⁻¹), temperature (*C) and CO2 concentration (ppm) on chlorophyll, total soluble proteins and lipids were studied in selected microalgal strains from Chlorophyceae (Chlamydomonas sp., Scenedesmus sp., Chlorella sp., Kirchneriella sp.) and cyanobacteria (Nostoc sp.1, Anabaena sp., Nostoc sp. 2, Cylindrospermum sp.). Cultures were grown under controlled conditions at the National Phytotron Facility, Indian Agricultural Research Institute (IARI), New Delhi. Our results showed that chlorophyll concentration enhanced with increased C02. Chlorella exhibited the highest chlorophyll at 850 ppm CO2 and 28*C; for Chlamydomonas it was at 78 µmol photons m⁻² S⁻¹ light intensity. In Cylindrospernum, total soluble proteins decreased with enhanced C02, and were highest at 18*C. In Anabaena, a light intensity of 65 µmol photons m⁻² S⁻¹ was best for maximum total soluble proteins. In Chlorella, CO2 @ 850 ppm was most suited for maximum lipid accumulation. In Kirchneriella, increase in temperature, from 18*C up to 370C, increased total lipids; the highest was at 28'C. In Chlamydomonas, the light intensity of 78 µmol photons m⁻² S⁻¹ was optimum for lipid accumulation and the maximum total lipids was 30.8 (% dry wt.).

Scope of algae as third generation biofuels.

An initiative has been taken to develop different solid, liquid, and gaseous biofuels as the alternative energy resources. The current research and technology based on the third generation biofuels derived from algal biomass have been considered as the best alternative bioresource that avoids the disadvantages of first and second generation biofuels. Algal biomass has been investigated for the implementation of economic conversion processes producing different biofuels such as biodiesel, bioethanol, biogas, biohydrogen, and other valuable co-products. In the present review, the recent findings and advance developments in algal biomass for improved biofuel production have been explored. This review discusses about the importance of the algal cell contents, various strategies for product formation through various conversion technologies, and its future scope as an energy security.