Subcutaneous Rituximab: Coming Soon?

Paola Ghione, MD

Dr. Ghione is a visiting hematology fellow from Torino, Italy who is working with the Weill Cornell Lymphoma Program for six months.

Rituximab is a drug that is used to treat B-cell non-Hodgkin lymphomas. It is a type of immunotherapy called a monoclonal antibody, and it works by targeting CD20, a protein present on the surface of the B-cells.

insulin injectionIn the United States, rituximab is administered by intravenous (IV) infusion, often over several hours. In March 2014, a formulation of rituximab for subcutaneous injection (under the skin rather than directly into the vein) was approved by the European Medicines Agency, and Health Canada approved the subcutaneous formulation in September 2016. At my home institution – the University of Torino — we have been using subcutaneous rituximab routinely. Advantages for patients include the faster administration time, usually less than 10 minutes. Institutions may prefer subcutaneous rituximab because it is administered as a fixed dose, which can reduce the preparation time and waste.

The first study to compare the two formulations was conducted in Europe from 2009 to 2012 in 124 people receiving rituximab maintenance for follicular lymphoma. The purpose of this study was to identify a comparable dose and to compare safety. The second study, called “SABRINA” was conducted in Europe, Canada, and Thailand, with the participation of 127 people with previously untreated follicular lymphoma who were receiving chemotherapy plus rituximab. Patients responded equally to treatment with both formulations (intravenous versus subcutaneous), and no differences were found in terms of safety. In comparing the side effects, IV administration was linked to more gastrointestinal-based events (such as diarrhea and nausea), while skin reactions (usually redness at the injection site) were more common with subcutaneous rituximab.

In another large study, called “MABEASE,” 576 people with diffuse large B-cell lymphoma participated in a clinical trial in which they were randomized to receive CHOP chemotherapy with either subcutaneous or intravenous rituximab. Again, the efficacy of the two formulations was similar and the subcutaneous administration was associated with increased administration-related reactions (mainly rash).

Finally, a clinical trial called “PrefMab” enrolled more than 700 people with diffuse large B-cell lymphoma and follicular lymphoma with the aim of evaluating patient satisfaction using both administration methods. One group of participants started with intravenous infusion and then switched to subcutaneous, and vice-versa for the second group. In general, patients preferred the subcutaneous formulation. Specifically, 80% of the patients preferred the subcutaneous formulation, 10% still preferred the intravenous one and 10% had no preference. This preference was largely due to the reduction of time spent in the hospital and the comfort of the administration.

In addition to efficacy, safety, and patient preference, the financial impact of the new formulation is worth considering. Two groups have conducted economic studies on this subject. The Roche study found that the subcutaneous formulation was associated with reduced costs due to less staff time (nurses, technicians and pharmacists), shorter time in the bed/chair in the infusion center, and a reduction in wasted drug and materials related to the infusion. The Italian study reported an overall saving of 6.057 euros ($6.464 USD) for each rituximab administration. The financial impact might differ in different healthcare systems.

Subcutaneous rituximab is not currently available in the United States, but the Food and Drug Administration (FDA) accepted a Biologics License Application in November 2016. This means that probably the formulation will be soon available in the U.S. market.

Monitoring Minimal Residual Disease in Lymphoma: The Italian Experience

Paola Ghione, MD
Dr. Ghione is a visiting hematology fellow from Torino, Italy who is working with the Weill Cornell Lymphoma Program for six months.

Minimal residual disease (MRD) detection refers to a group of techniques used to find a very small amount of disease, normally undetectable with imaging or clinical exam. Usually, this detection is performed after treatment and, in many cases, is predictive of outcomes such as whether patients will relapse, and how quickly this might happen. Often, the reappearance of MRD can anticipate recurrence of lymphoma before it becomes clinically evident. In other hematologic disorders, such as acute leukemia and chronic myeloid leukemia, MRD is used in standard clinical practice to monitor disease status or to evaluate response to treatment. In the setting of lymphoma, measurement of MRD is still considered experimental, but a lot of research is taking place around the world to find the best way to perform it.

Our laboratory in Torino, Italy, run by Dr. Marco Ladetto and Dr. Simone Ferrero, leads many MRD projects for lymphoma and is part of the EuroMRD Network, an institution born in Europe to standardize MRD techniques. Currently, we look for tumor-specific DNA alterations in the blood before and after treatment using a technique called Allele-Specific Oligonucleotide (ASO)-PCR. Depending on how much tumor DNA is present in the blood, we can figure out the relative amount of tumor left in the body. Unfortunately, ASO-PCR requires an expert laboratory team, and the method is expensive and time-consuming, which makes it hard to use outside of specialized settings. In addition, it seems more reliable if performed directly on bone marrow aspirate (blood from the interior of the bone) than peripheral blood (coming from a normal vein), making it less attractive to clinicians and people with lymphoma.

New techniques that can speed the procedure and reduce the cost are being evaluated. For example, the droplet digital (dd)-PCR is interesting because it is faster and uses less material (i.e., requires less blood for the test). Another interesting method is Next Generation Sequencing (NGS), which allows the detection of several different DNA mutations at once. NGS analysis of cell-free circulating DNA(cfDNA) (the DNA present in circulating blood outside the cells) could give a lot information. Studying cfDNA from the blood could give us a more accurate picture of the lymphoma that in theory could be even better than studying DNA derived from an open biopsy at one site of disease. This is also sometimes referred to as a liquid biopsy. The reason it might be better is that the circulating cfDNA could show us mutations coming from all the sites where the tumor is actively growing, not only the one site from which the open biopsy is taken.

In Italy, although MRD is not yet available in routine clinical practice for treating lymphoma, it is being tested in some innovative clinical trials to guide treatment decisions. In some studies MRD negativity at the end of treatment is the primary goal, while in others reappearance of MRD prompts a preemptive approach. As an example, if MRD reappears when the person is off therapy, we can give a short re-treatment in order to avoid clinical relapse. In one of our clinical trials, evaluation of MRD has been used to rule out the presence of lymphoma in the cells collected prior to autologous stem cell transplantation.

Measurement of MRD has a lot of potential uses, and experience from other diseases proves that it can be practice changing. The challenges provided by more than 50 different lymphoma subtypes as well as the rapid evolution of new laboratory techniques have delayed the adoption of a universal test for MRD. In the near future, however, we expect to see MRD analysis in standard clinical practice everywhere.

FDA Approves First-Ever Targeted Marginal Zone Lymphoma Treatment

On January 19, 2017, the United States Food and Drug Administration (FDA) approved ibrutinib to treat patients that have received at least one line of prior therapy for marginal zone lymphoma (MZL), a type of non-Hodgkin lymphoma (NHL).

MZL is an indolent B-cell lymphoma that accounts for 5-10% of all lymphomas and lacks a standard of care. Current MZL treatments include anti-CD-20 antibody therapy (e.g. rituximab) or chemotherapy. However, ibrutinib is the first-ever treatment to specifically be approved for MZL.

Ibrutinib works by inhibiting Bruton’s tyrosine kinase (BTK), an enzyme responsible for transmitting pro-growth and survival signals from the surface of a cell to its nucleus. In this way, ibrutinib may interfere with chronic stimulation arising from inflammation in the tumor microenvironment; thus slowing the growth of B-cells.

The Weill Cornell Lymphoma Program is proud to have played a role in the phase 2 trial — the largest trial to date for people with previously treated MZL of all subtypes —leading to FDA approval for ibrutinib. Roughly half of all patients had a significant response to ibrutinib, with some degree of tumor shrinkage observed in almost 80% of all patients in the trial. Roughly one-third remained on treatment 18 months after beginning treatment.

The most common side effects included fatigue, diarrhea, and anemia. These side effects were manageable, and consistent with previous research, although some cases required the discontinuation of treatment with ibrutinib.

Results from this study support the use of ibrutinib as an effective well tolerated chemotherapy-free option for the treatment of previously treated MZL. However, some questions remain. MZL is a heterogeneous group of lymphomas, and it is unclear which subtypes might respond best to ibrutinib. With only half of all previously treated MZL patients responding to ibrutinib, improvements might be realized by combining ibrutinib with other drugs and/or using it earlier in the treatment of MZL.

At Weill Cornell, we are currently studying ibrutinib in combination with the immunotherapy drug durvalumab in people with previously treated indolent non-Hodgkin lymphoma, including MZL.