Wednesday, December 25, 2013

This year the American Society for Hematology (ASH) took place in New Orleans
and no one participant has left without hearing about CARs
CURRAN et al defines these:
"One promising strategy entails the introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs), which redirect the specificity and function of immune effectors. CAR-modified T cells targeted to the B cell-specific CD19 antigen have demonstrated promising results in multiple early clinical trials, supporting further investigation in patients with B-cell cancers. However, disparities in clinical trial design and CAR structure have complicated the discovery of the optimal application of this technology. Recent preclinical studies support additional genetic modifications of CAR-modified T cells to achieve optimal clinical efficacy using this novel adoptive cellular therapy."
This technology is just another example  of use of our immune system against cancer
It has been made more feasible with the new ability to transfer gene into cells to give them more fighting powers.

"FDA Approval for Sipuleucel-T," was just another example of such manipulation.

* A telomerase inhibitor showed up finally, Imetelsat (geron) at ASH to rock the world of Myelofibrosis, while Obinutuzumab was shaping the CLL world, it could replace Rituxan reportedly.  We know that cd20 expression in CLL is weak, therefore may be a more potent immune based agent is needed in combination with other therapy.  This will be even more important in those cases where Rituxan is used alone!



On November 1, 2013, the Food and Drug Administration (FDA) approved obinutuzumab (Gazyva™ injection, for intravenous use, made by Genentech, Inc.; previously known as GA101) for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).
The approval was based on demonstration of an improvement in progression-free survival (PFS) in a randomized open-label multicenter trial that compared obinutuzumab in combination with chlorambucil (GClb) with chlorambucil (Clb) alone in patients with previously untreated  CD20-positive CLL. The study also compared rituximab in combination with chlorambucil (RClb) with obinutuzumab in combination with chlorambucil (GClb). The results of the comparison of RClb with GClb will be available at a later stage.
Patients randomly assigned to be treated with obinutuzumab in combination with chlorambucil received 1000 mg doses of obinutuzumab intravenously on day 1 (later divided into 100 mg on day 1, followed by 900 mg on day 2), day 8, and day 15 of the first cycle. Chlorambucil, 0.5 mg/kg, was administered on days 1 and 15.  During treatment cycles 2-6, patients received obinutuzumab, 1000 mg intravenously only on day 1 in combination with chlorambucil, 0.5 mg/kg, on days 1 and 15. Patients received pre-medication with a glucocorticoid, acetaminophen, and antihistamine prior to initial obinutuzumab infusions and subsequently as needed. Patients assigned to be treated with single-agent chlorambucil received 0.5 mg/kg on days 1 and 15 of all treatment cycles (cycles 1 to 6). Cycles were repeated every 28 days.
A total of 356 patients were  randomly assigned (2:1) to receive obinutuzumab plus chlorambucil (n=238) or chlorambucil alone (n=118). The median age was 73 years (range 39 years-88 years). The independent review committee-assessed median PFS was 23.0 months for patients treated with obinutuzumab plus chlorambucil and 11.1 months for patients treated with  chloramucil alone [HR 0.16 (95 percent CI: 0.11, 0.24), log-rank p-value <0.0001].
The most common adverse reactions (at least 10 percent) with obinutuzumab plus chlorambucil (with a higher frequency than in the control arm) were infusion-related reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorder. The most common grade 3-4 adverse reactions (at least 10 percent) were infusion-related reactions, neutropenia, and thrombocytopenia.
Infusion reactions occurred in 69 percent of patients receiving obinutuzumab; 21 percent experienced grade 3 or 4 reactions. Symptoms (greater than 10 percent) included dyspnea, hypotension, nausea, vomiting, chills, flushing, and pyrexia.
Obinutuzumab is approved with a BOXED WARNING regarding Hepatitis B virus reactivation and Progressive Multifocal Leukoencephalopathy. Patients should be advised of these risks and assessed for Hepatitis B virus and reactivation risk. Infusion reactions are included in the WARNING and PRECAUTIONS section of the label.
The recommended dose and schedule for the approved regimen is:
Cycle 1: 100 mg intravenously on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15 
Cycles 2-6: 1000 mg administered intravenously every 28 days
0.5 mg/kg orally on days 1 and 15 of each cycle"



*Mylotarg (gemtuzumab ozogamicin): Market Withdrawal, adding Myelotarg to Acute Leukemias seem to prolong disease free survival,calling for an FDA second look!

*Wake up to the Calreticulin gene,

remember when we used to ask for JAK-2 to prove the existence of Myeloproliferative diseases, well now it's not just the JAK-2, but also MPL Mutation, and the latest the CALR gene!

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