Jordyn Sava is an assistant editor for Targeted Oncology. 

Jordyn Sava

A 90% complete response rate was demonstrated in patients with orbital indolent B-cell lymphomas when administered an ultra-low dose radiation therapy strategy of 4 Gy in 2 fractions.

Findings come from a phase 2 study led by Chelsea C. Pinnix, MD, PhD, which examined the use of this response-adapted strategy in this patient population. Instead of using higher standard doses, this study evaluated the patients who had a complete response to 4 Gy in 2 fractions, rather than the 24 Gy dose.

The trial included 50 patients with stage I to IV orbital indolent B-cell lymphomas. Patients were treated with 4 Gy in 2 fractions with responses assessed at intervals of 3 months. If patients did not achieve a complete response with the lower dose, an additional 20 Gy was offered to complete the standard dose of 24 Gy of radiation.

Treatment with the ultra-low dose correlated with limited side effects in patients with orbital indolent B-cell lymphomas. Experts believe that this approach has the potential to improve quality of life without limiting efficacy.

“The key takeaway is that this is a paradigm shift, but there is a lot of data before our study to show that 4 Gy in 2 fractions did contribute to excellent responses. There are many retrospective series people can look at to just see the outcome of 4 Gy in 2 fractions in the orbit. While this is a little bit different of an approach, overall, we do have a lot of data endorsing and supporting the high response rates of just 2 fractions” stated Pinnix, associate professor of Radiation Oncology at MD Anderson, in an interview with Targeted OncologyTM.

In the interview, Pinnix discussed the results of this phase 2 study and how these promising results will shift the treatment paradigm of patients with orbital indolent B-cell lymphoma.

Targeted Oncology: What does the current landscape of the indolent B-cell lymphoma look like?

Indolent B-cell lymphoma can impact the orbit and when it does, the most common histology is MALT lymphoma. Other histologies include silica lymphoma, low-grade B-cell lymphoma, unclassifiable, and these are all very slow growing processes. Patients often will present months, sometimes years, after initial symptoms, reinforcing the slow progress of the disease clinically over time. Once the diagnosis is made, if the disease is limited to the orbiter or stage 1 or stage 2, radiation is often regarded as the standard treatment. When there are extra orbital sites and disease involvement, systemic therapy might be pursued alone or in combination with radiation.

Historically, radiation has excellent local control rates, meaning we treat this area, we see regression of lesions and that local control is durable over many years. That is based largely on retrospective studies that have been performed evaluating output patients treated with radiation. With more historic series, higher doses of radiation, we use 30-50 Gy, Gy is our unit of radiation. With that, most patients will never experience a relapse of that disease. It might come back to other places but not in orbit. Ocular side effects are very common with that high dose so subsequently, the dose has been lowered to 24 Gy. That's considered a moderate dose of radiation in general standards, leaving with that moderate dose. Patients can have lifelong dry eyes, and many will experience cataracts.

There's still some side effects with 24 Gy, so our study came out of recognition of a few things. One, those moderate doses can cause problems for patients in terms of [adverse events]. Two, many of our ophthalmologists and other oncologists outside of radiation in our communities were not referring patients when they were initially diagnosed out of concern for those [adverse events]. There have even been studies supporting that type of behavior. If patients didn't have a lot of symptoms, they were just watched and they waited. Out of recognition of those 2 things, we wanted to identify different strategies that may potentially be associated with great efficacy, but not the high ocular morbidity risk.

What were the methods and design of this study?

It was a phase 2, single arm, prospective study and we did something called ultra-low dose response-adapted therapy. In the radiation community, there is recognition that 4 Gy in 2 fractions, which is a low dose of radiation of just 2 treatments, can result in great outcomes for about 70% of patients. This was seen in the FORT trial (NCT00310167) where they compared 24 Gy with 4 Gy for patients with mainly follicular, but also marginal zone and MALT lymphoma.

What they observed with that study was that a lot of 4 Gy did have respectable response rates. The primary outcome of that study was local progression, and it favored the 24 Gy arm and it remained the standard. Since 70% of patients did have a great response, what we wanted to do was identify those patients that 70% that maybe will do great with just 4 Gy alone, and reserve the 24 Gy, the full dose, for the incomplete responders. That's the premise behind the study. In its phase 2, single arm, patients received 4 gray in 2 fractions to the disease in the orbit. If they had bilateral involvement, they would receive radiation to both orbits.

Then at 3 months, we would evaluate them. If they had a complete response, they were observed and if they had stable disease or progressive disease, we wanted to recommend an additional 20 Gy. If they had a partial response or a minimal response defined as more or less than 50% decrease in the tumor volume, then we would continue to watch them in 3 month intervals. At 1-year, if they didn't have a complete response, we gave them the additional 20 Gy to complete this standard course. We're trying to pull out the responders and only give the additional 20 Gy to those that really need it.

We had just over 3 years follow-up and we found that 90% of patients had a complete response to the entire response adopted program, and that included 45 patients total. Forty-four of them only need 4 Gy, only 1 of them received 20 Gy to have a complete response, so that's 90% of the population. We did recommend the 20 Gy to a total of 6 patients, and 2 of them received it. Four of them elected not to have the radiation out of patient or physician preference, which is interesting. They continued to be observed or had systemic therapy. Basically, the control rates among those 45 patients that had a complete response was excellent. None of them had experienced any local relapses in orbit.

Similarly, we had a separate series of 55 patients that we treated the same way, but they were treated off protocol. Among those patients, 98% of them had a complete response to response-adapted therapy with only 2 of them requiring an additional 20 Gy to have a complete response. We have a combined cohort of 105 patients and the vast majority of them responded completely to 4 Gy and a small fraction were eligible for the additional 20 Gy. We are excited that the toxicity was collected prospectively. We only had a handful of cases of dry eye syndrome that represented about 6% of the study population. Toxicity was limited and efficacy was encouraging.

How do you think these results will influence the future of this space?

It's already made a big impact. For our patients with marginal zone lymphoma, this is our standard approach, even for the stage I and stage II patients. There are some concerns that we had initially like, you have a disease, you're taking a potentially curable patient population and giving them what's known to be a substandard dose of radiation, are you worried about higher relapse rates? We looked at a subset of patients that were newly-diagnosed, 22 patients that were treated and had stage I disease, and their local control at 2 years was 91%. We did have 3 distant failures in the contralateral orbit in the mediastinum, but the distant relapse rates were on par with what's seen in older studies that treated patients with higher doses. For us, this has already changed our practice for patients with marginal zone lymphoma. This is also because marginal zone lymphoma is very rarely life threatening.

Follicular lymphoma can be a bit more challenging, requiring more treatments over many years, and in some patients, they can succumb to the disease or to the toxicity from their treatments. I think there is some hesitancy to embrace this for stage I follicular lymphoma patients, but there's a clinical trial that's going to be opening soon that is adopting our response-adapted approach and they're gonna test it in a randomized way. This randomized trial is going to compare our response-adaptive strategy to upfront 24 Gy for patients with limited-stage follicular and marginal zone lymphoma. For patients with stage I follicular lymphoma, I think that the new data that we'll receive from the randomized trial will be helpful, but for us, we're doing this for all of our patients with stage I lymphoma.

Are there any challenges that you are facing with this or anything that might influence this research in the future?

It has a lot to do with how we discuss this treatment option with our patients. It can be anxiety provoking thinking about disease persisting while you're waiting for follow-up. I think the data that we have so far in over 100 patients is really encouraging. That can be something that we can use to encourage patients. It's important for colleges to have that discussion upfront, that this is a slow growing process, this has probably been here in your eye for many months, sometimes years before it was diagnosed. Waiting 3 months to see how you respond, we would not expect to compromise outcomes. If you have patients that you know are not going to follow-up, don't want to follow-up or have a great deal of anxiety behind it, discussing the standard dose is definitely not unreasonable. I think it's really important how we discuss it and our attitudes towards it. Our patients look to us for our opinions, so I think it's important to have those discussions early about the importance of the follow-up and the fact that we don't anticipate losing any efficacy with the delay that comes with awaiting response

Fr community oncologists who want to learn more about this, what are the key takeaways?

The key takeaway is that this is a paradigm shift, but there is a lot of data before our study to show that 4 Gy in 2 fractions did contribute to excellent responses. There are many retrospective series people can look at to just see the outcome of 4 Gy in 2 fractions in the orbit. While this is a little bit different of an approach, overall, we do have a lot of data endorsing and supporting the high response rates of just 2 fractions. For people that will say, I don't have the published data yet to recommend doing this in my practice, I would say that there is enough data out there to endorse shifting to this approach.

This approach provides great efficacy, low toxicity, and also offers decreased cost for the patients. The financial burden decreases. Patients that have disease outside of the orbit that are going to receive chemotherapy or other systemic therapies can get this and then quickly transition to those treatments. This provides a great opportunity, not only for patients with limited stage disease, but also for those with advanced stage disease.

Pinnix CC, Dabaja B, Gunther JR, et al. 3 response adapted ultra low dose radiation therapy for the definitive management of orbital indolent B-cell lymphoma. Presented at ASTRO 2022 Annual Meeting; October 23-26, 2022; San Antonio, TX.

Articles

In an interview with Targeted Oncology, Chelsea C. Pinnix discussed the results of a phase 2 study and how these promising results will shift the treatment paradigm of patients with orbital indolent B-cell lymphoma.

Ultra-Low Dose of Radiation Shows Promise in Orbital Indolent B-Cell Lymphomas

Omidubicel demonstrated long-term graft durability, preserved trilineage hematopoiesis, and immune competence at up to 10 years of follow-up, ultimately improving survival in patients with hematological malignancies receiving allogeneic hematopoietic stem cell transplantation.

Treatment with omidubicel led to no late cases of secondary graft failure beyond the 5 patients reported in the primary analysis and just 1 case (1%) of donor-derived myelodysplastic syndrome (MDS). These data are consistent with previous reports of donor-derived myeloid neoplasms after cord blood transplants (0.6%–2%).

A case of donor-derived acute myeloid leukemia (AML) was also observed in the control arm of the phase 3 trial(NCT02730299).

Omidubicel is an ex vivo expanded stem cell graft derived of umbilical cord blood (UCB). Previously, UBC has demonstrated faster engraftment, fewer infections, and shorter durations of hospitalization in a recent multicenter phase 3 trial. Additionally, the agent has demonstrated early benefits for patients.

In a multi-institutional pooled analysis, the long-term outcomes of omidubicel transplantation from 5 prospective clinical trials were reported and compared. In these 5 trials, patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent hematopoietic stem cell transplantation with omidubicel between 2010-2020 were enrolled. Patients were excluded if they had full engraftment with an unmanipulated UCB.

Across 26 academic transplant centers around the world, 116 patients were enrolled and underwent omidubicel transplantation. Ninety-two patients received omidubicel as a standalone therapy and 24 patients received it along with an unmanipulated UCB.

The median age of patients enrolled was 42 years (range, 2-62). A total of 52% if participants were male, 39% were non-white, and 30% had high or very-high disease risk indices. The most common diseases among patients included AML (41%), ALL (27%), MDS (12%), and sickle cell disease (8%).

Myeloblative conditioning regimens and standard graft vs host disease prophylaxis with a calcineurin inhibitor and mycophenolate mofetil was administered to all patients enrolled.

After engrafting fully with an unmanipulated UCB, 11 patients were excluded from the trial. Among the 105 patients left in the study, 97 (93%) had engrafted fully with omidubicel, 5 (5%) had primary graft failure, 2 (2%) had mixed chimerism between omidubicel and UCB, and 1 patient was deemed unevaluable for engraftment. The overall median follow-up was 22 months (range, 0.3-122.5) and 35.7 months among survivors (range 11.7, 122.5).

The 3-year overall survival was 62.5% (95% CI, 51.8-71.4) and the disease-free survival was 54.0% (95% CI, 43.0-63.7), respectively. Three-year cumulative incidences of chronic GVHD and disease relapse were 36.7% (95% CI, 27.0–46.5) and 24.0% (95% CI, 14.3–31.1), respectively. Most of the chronic GVHD cases were mild (54%). Moderate GVHD was seen in 33% of patients and 13% had severe disease. However, no deaths were attributed to GVHD.

Durable trilineage hematopoiesis was observed for up to 10 years and the median numbers of lymphoid subsets, including CD3+, CD4+, CD8+ T cells, CD19+ B cells, and CD16+/CD56+ NK cells were maintained within normal range for up to 8 years.

While secondary graft failure was noted in 5 patients, 3 of whom underwent a second allogeneic hematopoietic stem cell transplant, there were no late graft failures that occurred beyond what had been previously reported.

For secondary hematologic malignancies, investigators found donor-derived myeloid neoplasm in 1 patient with AML at 40 months post-transplant and post-transplant lymphoproliferative disorder (PTLD) in 2 patients 

17 and 20 months. One death was attributed to PTLD and there was 1 case of donor-derived myeloid neoplasm in the control UCB group of the phase 3 study.

Lin C, Schwarzbach A, Montesinos P, et al. Multicenter long-term follow-up of allogeneic hematopoietic cell transplantation with omidubicel: a pooled analysis of five prospective trials. Presented at: 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022); September 28-October 1, 2022; Houston TX.

Favorable long-term survival rates and manageable rates of graft-vs-host disease were elicited with omidubicel in patients with hematologic malignancies who underwent allogeneic stem cell transplant.

Ten-Year Omidubicel Data Improves Survival in Hematologic Malignancies With HSCT

Treatment with pralsetinib (Gavreto) was safe and produced durable response rates in patients with 

fusion-positive non–small cell lung cancer (NSCLC), according to findings or the phase 1/2 ARROW trial (NCT04222972) published in the 

Among 54 of the 75 treatment-naive patients, their overall response rate (ORR) was 72% (95% CI, 60%-82%) and 59% for 80 of the 130 patients with prior platinum-based chemotherapy (95% CI, 50%-67%).

Tumor shrinkage was observed in all of the treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy. Additionally, the median progression-free survival (PFS) was 13.0 and 16.5 months, respectively.

“In this updated analysis of patients with 

 fusion-positive NSCLC from the ARROW study, pralsetinib administered at a 400 mg [daily] starting dose was generally well tolerated and demonstrated clinical activity in all reported treatment groups, consistent with previous findings,” wrote study authors led by Frank Griesinger Department of Hematology and Oncology, Pius-Hospital, University of Oldenburg, Oldenburg, Germany.

fusion-positive NSCLC were enrolled into the multi-cohort, multicenter, open-label, phase 1/2 ARROW trial between March 17, 2017, the data cut-off date of November 6, 2020. Investigators aimed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of pralsetinib in patients with advanced 

Phase 1 of the trial used a dose-escalation design to evaluate pralsetinib 30-600 mg. The determined recommended phase 2 dose of the study was 400 mg every day. In phase 2, pralsetinib 400 mg daily was evaluated in multiple expansion groups defined by disease type and treatment history.

Pralsetinib was administered at 400 mg daily and patients continued therapy until disease progression, intolerance, consent withdrawal, or investigator’s decision. Dose reductions due to adverse events (AEs) below 100 mg daily were not permitted. Additionally, dose interruptions due to AEs for greater than 28 days were not allowed.

Patients were eligible for enrollment in the study if aged 18 years and older with unresectable, locally advanced or metastatic solid tumors, a pathologically or genetically documented 

 fusion or mutation, an ECOG performance status of 0-2, and baseline measurable disease as per RECIST version 1.1.

 fusion-positive NSCLC cohorts of the study, eligible patients must have had a documented 

 fusion as determined by local testing of tumor or circulating tumor nucleic acid (ctDNA) in blood. Regardless of their eligibility for standard platinum-based chemotherapy, treatment-naive patients with 

 fusion-positive NSCLC were enrolled following a protocol amendment on 11 July 2019.

The median age for all patients enrolled with RET fusion-positive NSCLC (n = 233) was 60 years (range, 26-87). Less than half of the patients were male (n = 111; 48%), 52% were White, 39% were Asian, and the remaining 9% were other/unknown. Thirty-six percent of patients were current or former smokers compared with 62% who had never smoked. Most patients (64%) had an ECOG performance status of 1, 37% had brain metastases, 70% had 

Investigators assessed the co-primary end points of ORR, including complete response (CR) or partial response (PR), in the phase 2 portion of the study. Secondary end points were duration of response (DOR), time from first response until disease progression or death, clinical benefit rate (CBR), disease control rate (DCR), PFS, overall survival, and correlation of RET gene alteration and efficacy.

FIndings showed that in the ITT population, treatment-naive patients with 

 75) had an ORR of 72% (95% CI, 60%-82%) with a median time to first response of 1.8 months (range, 0.9-6.1 months). CR was seen in 4 patients (5%) while 50 (67%) had a PR, 14 (19%) had stable disease, 5 (7%) had progressive disease, and 2 (3%) were not assessable.

For the treatment-naive patients, the median DOR was not reached vs 22.3 months for patients who had received prior platinum-based chemotherapy after a median follow-up of 7.4 months (95% CI, 6.4-9.5 months). However, 84% (95% CI, 73%-95%) and 54% (95% CI, 34%-74%) of patients were responding at 6 months and 12 months, respectively. The DCR was 91% (95% CI, 82%-96%) and the CBR was 80% (95% CI, 69%-88%).

Further, the median PFS was 13.0 vs 16.5 months, respectively, after a median follow-up of 9.2 months (95% CI, 8.6-11.0 months). Seven of the 10 patients with measurable intracranial metastases had intracranial response (95% CI, 35%-93%), and all had received prior systemic treatment.

Regarding safety, the most common grade 3-4 treatment-related adverse events (TRAEs) in the treatment-naive patients with 

 fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n

 116), were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). A total of 7% (20/281) of patients discontinued treatment due to TRAEs.

Currently, the confirmatory phase 3 AcceleRET Lung study (NCT04222972) is ongoing and examining pralsetinib vs standard of care in the first-line setting of this patient population. Experts hope that findings from this trial will further support the use of pralsetinib for patients with 

“In conclusion, we show that orally administered once daily pralsetinib produces a robust ORR, including intracranial activity and durable PFS, in patients with advanced 

fusion-positive NSCLC who are treatment-naive or refractory to standard-of-care chemotherapy. These results show the importance of early comprehensive biomarker testing that includes fusions for all patients with metastatic NSCLC before treatment initiation to inform optimal health care decisions,” concluded the study authors.

Griesinger F, Curigliano G, Thomas M, et al. Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.

. 2022;33(11):1168-1178. doi:10.1016/j.annonc.2022.08.002

Updated analysis from the phase 1/2 ARROW study evaluating pralsetinib in patients with RET fusion-positive non–small cell lung cancer showed the agent to be well tolerated and to elicit clinical activity at a dose of 400 mg daily.

Pralsetinib Shows Positive Phase 1/2 Results in RET Fusion+ NSCLC

Advances have been made in mantle cell lymphoma (MCL) space due to the development and availability of many effective biological agents, including ibrutinib (Imbruvica), acalabrutinib (Calquence), zanubrutinib (Brukinsa), and Bruton tyrosine kinase (BTK) inhibitors.

At the Tenth Annual Meeting of the Society of Hematologic Oncology (SOHO), Jia Ruan, MD, PhD, highlighted the current MCL landscape and the value of chemotherapy-free regimens.

Ruan, associate professor of Clinical Medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine also discussed various phase 2 and 3 clinical trials evaluating regimens of ibrutinib in combination with rituximab (Rituxan), or zanubrutinib in combination with rituximab for patients with MCL.

Further studies will continue evaluating novel therapies and combinations for patients with MCL who have mutations, such as a 

 mutation. More research regarding novel biomarkers, the potential role of bispecific antibodies will continue to shape the treatment landscape for MCL.

, Ruan, discussed the updates in the MCL space, including understanding molecular pathogenesis and risk stratification for this patient population.

Targeted Oncology: Can you give an overview of the available treatment options for mantle cell lymphoma? How have options evolved over the past few years?

In the past several years, significant advances have been made in mantle cell lymphoma, primarily because of the availability of many effective biological agents. They were initially investigated in the relapse setting, but now, we're trying to move them into the frontline initial therapy setting. The most important class of those agents are Bruton's tyrosine kinase inhibitors or BTK inhibitors.

It started with the first generation ibrutinib, and that was approved almost 10 years ago in 2013. Subsequently, we now have second generation BTK inhibitors, and they are represented by acalabrutinib and zanubrutinib. We have maybe 3-5 years of experience of using those BTK inhibitors. The BTK inhibitors are by far the most effective single agent treatment for mantle cell lymphoma. In the relapse setting, we expect overall response rates in the range of 60%-80%. Complete remission rate is also achievable, especially for the second generation BTK inhibitors. With acalabrutinib and zanubrutinib, we're looking at 30%-40% CR rates, so that is quite remarkable. Those are agents that are effective and easy to administer. They come in oral form and patients can take them at ease and convenience at home. They're very suitable for chronic use and their adverse event profiles are quite tolerable.

When we do start prescribing BTK inhibitors to patients, we do discuss adverse event profiles, specifically, those that are specific for this class of agents such as their effect on blood pressures, their effect on cardiac rhythm, atrial fibrillation, their effect on gastrointestinal, and their effect on platelets, bruising, and bleeding. It has transformed the care of mantle cell lymphoma.

What has been discovered recently to help better understand molecular pathogenesis?

In several different levels, our understanding of molecular biology has really helped in terms of designing rational approaches. One of them is to understand that not all mantle cell lymphomas are the same as they have different subtypes. For example, there's this classic mantle cell lymphoma, which is predominant about 70%. They present with no disease, they have a proliferation signature, and they have a lot of genomic characteristics such as instabilities. We also know there's a non-nodal form of mantle cell lymphoma which represents about 30% of mantle cell lymphomas. They tend to be more indolent, they have more peripheral blood and splenic involvement, but not as much as nodal involvement. We do know that they tend to have a lower proliferation index and they also have less of those genomic instability. They have more simple karyotypes when we do pathology evaluation on those cases. That's 1 aspect which are different forms of mantle cell lymphoma. They have a slightly different pace of growth, and we can watch and wait a little bit for a non-nodal form of mantle cell lymphoma as opposed to coming up with a treatment plan more urgently for a more aggressive form of mantle cell lymphoma.

The other aspect of knowing biology is there are recurrent genetic mutations called driver mutations that essentially have risk that determine the aggressiveness or risk category. We know that mutations such as 

 tend to have a more aggressive clinical course and tend to be associated with blastoid mantle cell lymphoma, and more resistance to chemoimmunotherapy. Knowing those biological determinants of mantle cell lymphoma allows us to devise treatment strategies. For example, for patients with high risk 

 mutations, we want to talk to them about if chemoimmunotherapy is optimized for them, can we consider a more novel treatment which may be more effective and with less adverse events, and perhaps we can improve the duration of response. We encourage those patients to participate in clinical trials with novel treatment combinations which may be more sensitive and overcome resistance coming from 

What updates can you give on risk stratification in this space?

Risk stratification is very important, and that's the evaluation that we do when we start initial management for patients with mantle cell lymphoma. Based on the risk stratification, we would come up with a plan on whether those patients can be easily watched and waited vs those patients who require treatment. Within those patients who may be requiring treatment, we try to figure out if they are a good candidate for conventional chemoimmunotherapy vs if they may benefit from addition of novel agents. With those risk stratifications or prognostic factors, we look at the mantle cell international prognostic index [MIPI]. It has 4 clinical parameters, including age, performance status, LDH, and white blood cell counts. It gives us a general assessment of the pace of this condition, in a particular patient. MIPI score is important.

For risk stratification, we also look at Ki-67, which is the proliferation index. We also look at their genetic mutation profiles, and collectively for those patients with high MIPI scores or high Ki-67, and particularly with high-risk mutation profiles, we would consider a treatment plan for those that would overcome treatment resistance.

What options excite you most for the future of this space?

There's a lot of the excitement that's going on, especially in the frontline setting, trying to figure out if chemoimmunotherapy is the most optimal option vs whether we introduce novel agents into the frontline setting. Within that, we would like to find out if the combination of chemoimmunotherapy plus novel agents would improve response rates and survival outcomes vs chemotherapy-free, novel agent combinations. Can they be as good or even better in terms of efficacy and less side effects profile? All of those are being looked at in a number of ongoing randomized clinical trials. Some are comparing chemoimmunotherapy plus novel agents vs the standard chemoimmunotherapy examples of that, including the triangle studies, the ECOG 4181 studies [NCT04115631].

We know that the SHINE study [NCT01776840] has recently been reported as a similar study that's conducted by the combination of ibrutinib plus bendamustine and rituximab and is maturing. The other category would be a direct comparison of chemoimmunotherapy vs a novel agent combination. I think that would be very exciting to see in certain selected patients that we can do away with chemotherapy therapy altogether. There are 2 very important randomized trials ongoing to address this question. One of them is called the ENRICH study [NCT01880567] to compare the ibrutinib plus rituximab combination vs chemotherapy. The second study is looking at zanubrutinib plus rituximab, the next generation BTK inhibitor, and comparing that with bendamustine plus rituximab, which is a form of chemoimmunotherapy. I'm looking forward to knowing more about the study outcomes of those clinical trials.

What should oncologists know about the current MCL space and the current unmet needs?

We're getting more comprehensive reviews of clinical biomarkers and prognostic indexes. We know more about the biology of mantle cell lymphoma and secondly, we are getting a more in-depth analysis of ongoing and also mature data from frontline clinical studies, as well as relapsed/refractory settings. I think there are more options out there and I think this will be informative to recommend for patients to consider participation in clinical trials. Also, it's a more in-depth analysis of published clinical trials and how we can apply the results from those reports in order to serve our patients in a more optimized fashion.

The unmet needs of the mantle cell lymphoma continue to be, how can we move new agents in a rational, designed fashion to the frontline settings, especially for those high-risk patients who have 

 mutations and are resistant to chemotherapy. What are the best combinations out there? I think those would require more clinical trials, combinations with chimeric antigen receptor T cells with bispecific antibodies, and maybe in combination with small molecule inhibitors.

In an interview with Targeted Oncology, Jia Ruan, MD, PhD, discussed the updates in the mantle cell lymphoma space, including understanding molecular pathogenesis and risk stratification for this patient population. 

Understanding Recent Developments in Mantle Cell Lymphoma

For patients with myeloproliferative neoplasms (MPNs), JAK inhibition has become an important therapeutic approach for treatment. Particularly for patients with myelofibrosis (MF), JAK inhibitors have allowed for reduction in symptoms and better outcomes.

The first JAK inhibitor to make its debut in the MPN treatment landscape was ruxolitinib (Jakafi), followed by the FDA approval of fedratinib (Inrebic) in 2019. Since then, experts have continued to make advancements with novel therapeutic strategies.

With now over 10 ongoing phase 3 trials around the world, investigators are combining novel treatments with JAK inhibitors to develop new options to use when treating patients with MPNs, including polycythemia vera (PV), essential thrombocytopenia (ET), and myelofibrosis.

“We are looking first to see whether the combinations that are exploring enhancement of the control of the sign symptoms on top of JAK inhibitors will do that well, well enough to be approved and then considered in everyday practice. We are also looking in the near future to see whether any of these therapies can prolong life,” said Srdan Verstovsek, MD, in an interview with Targeted Oncology

In the interview, Verstovsek, associate professor of medicine in the Leukemia department at the University of Texas MD Anderson Cancer Center, discussed the current MPN treatment landscape and where the field is shifting.

Targeted Oncology: Can you describe the current treatment landscape for essential thrombocytopenia?

 In essential thrombocythemia or ET, we worry about the thrombotic risk and our priority is to decrease it. We define the patients that are at an increased risk of blood clotting by applying certain prognostic factors. A significant change in the prognostication happened several years ago, which is now incorporated in United States based guidance, the NCCN guidelines. This is to say that in addition to historical factors of age over 60, or history of blood clotting, now, we also account for a presence or absence of a 

 mutation, which is present in about 60% of ET patients and it drives the disease process.

Therefore, there is a significant shift in identifying those that are at high risk of blood clotting by adding a 

 mutation presence to age. So, patients that are older than 60 and have a 

 mutation are the high-risk patients or of course, those that have a history of blood clotting. There is also an attempt to improve our management of these patients. Standard practice is to prescribe hydroxyurea, which is chemotherapy by mouth, to decrease the blood cell count. Then anagrelide is a second-line agent which inhibits the growth of the cells in the bone marrow that make platelets, so it lowers the platelets.

There is a phase 3 randomized study underway comparing anagrelide to a new agent that has the potential to be active in ET as it is in PV for which is already approved. I'm talking about ropeginterferon alfa-2b-njft [Besremi]. That study is a global randomized study comparing ropeginterferon to rusfertide, to prove the point that ropeginterferon might be better in controlling the platelets and the white cells that may be elevated sometimes in his patients. Hopefully, we are not going to have only to implement a prognostication and identification of the patients that need to be treated, otherwise, you just give them aspirin, but also more therapies to offer. Right now, it's hydrea. And for interferon if we can get it off label, this will be onlabel as a second-line choice in the near future if the study is successful.

What has recently been seen in the polycythemia vera and myelofibrosis spaces?

Where in essential thrombocythemia we worry about thrombotic risk, we phlebotomize the patients to decrease the hematocrit, which is a measure of the percent of blood made from red blood cells in polycythemia vera and we give patients aspirin to make a blood flow easier. In some patients older than 60 or those that have a history of blood clots, we give them cytoreductive therapy to decrease the red blood cells, white cells, and platelets. Again, we use hydroxyurea for ET. But now ropeginterferon was approved last November for PV. It is a long acting interferon and the guidance now says that one could consider 1 or the other meaning, hydrea or ropeginterferon as a frontline choice. Then in a second-line, we have standard practice drug ruxolitinib, a JAK inhibitor, which is actually approved for hydroxyurea-resistant, -refractory, or -intolerant patients.

In this setting, there is another drug that is being developed in a phase 3 randomized study for possible approval. It's called rusfertide. It's a hepcidin mimetic and hepcidin is an important protein in the blood that modulates the iron metabolism. That medication would mimic what it does and keep the iron inside the liver, for example, or spleen, or a lining of the [gastrointestinal] tract. That's called a radical endothelial system in the body. That would decrease the iron availability for the red blood cells and that would lead to elimination of the need for phlebotomy, which is very important, and people may feel better. At the moment, there is a phase 3 randomized placebo-controlled study in patients that need too many phlebotomies with a goal to approve rusfertide in the near future as another agent for these patients with PV.

Then, myelofibrosis is the most aggressive of MPNs with a shorter life expectancy. Here we have a plethora of different studies underway. The most important part is that in addition to ruxolitinib and fedratinib, this year, we have also pacritinib approved which is another JAK inhibitor and it can be given to patients with low platelets. Then, there is the recent application for possible approval of another JAK inhibitor called momelotinib, which is quite different from the others. It can improve anemia and eliminate the need for transfusions. The phase 3 randomized study of momelotinib vs danazol has completed and the results are good, and an application for approval is in place. By next summer, we may have momelotinib the fourth drug approved from myelofibrosis which will be perfect for patients who have suffered from anemia.

Can you further explain ruxolitinib and its mechanism of action?

Ruxolitinib inhibits JAK1 and JAK2, 2 of 4 members of JAK enzymes that are important in the body for function relative to blood making inflammation in the immune system. In particular, the JAK2 enzyme is associated with the growth factors and mechanisms of cell growth for red blood cells and platelets. JAK1 and JAK2 are also involved heavily in inflammation.Ruxolitinib will inhibit the proliferation and inflammation. People with myelofibrosis, for example, have a smaller spleen because of therapy, and that is why people feel much better, because it's anti-inflammatory. On the other hand, it can lower the platelets through myelosuppression and that's why we need to balance when we can give it. We like to give it as early as possible in the life of the patients and when the patients are not too sick. It's easier to give it, it is a good dose, and the results are much better with earlier intervention.


In polycythemia vera, ruxolitinib is valuable as a second-line choice when things don't go well with hydroxyurea. Patients then have much higher white blood cell counts, may have a big spleen, and of course, require phlebotomy. In that setting, it has been proven in 2 randomized studies that ruxolitinib provides a significant clinical benefit in normalizing blood cell count, improving quality of life, and decreasing spleen in those that have a big spleen. It appears after many years of follow-up that this is very durable, and possibly decreases the risk of early death from the complications of uncontrolled polycythemia vera. We use it often in the second-line setting, and it is a number 1 choice in PV.

What unmet needs still exist regarding MPNs?

In any of these three conditions, ET, PV, or myelofibrosis, we are talking about decreasing thrombotic risk, controlling the blood cell count, improving the quality of life, and decreasing the spleen. We don't really have drugs that would eliminate disease or make it controllable forever. More active drugs that will be much more durable and perhaps that can be achieved by combinations [are needed]. For example, in myelofibrosis, we're witnessing a flurry of phase 3 randomized studies where novel agents are combined with the JAK inhibitor ruxolitinib to make it even better and perhaps longer lasting in controlling signs and symptoms. I would like to see agents like interferon that have a potential that can lower, and perhaps eliminate malignant clones.

What are the future directions in this space?

We are looking first to see whether the combinations that are exploring enhancement of the control of the sign symptoms, on top of JAK inhibitors, will actually do that well or well enough to be approved and considered everyday practice. We are also looking in the very near future to see whether any of these therapies can prolong life. Overall survival is already in 1 study with a possible approval with the drug called imetelstat, which is a telomerase inhibitor, a primary goal. This is a phase 3 randomized study in a second-line setting.

Then to enhance that, perhaps not in a year but in 3-5 years, that effect of the potential targeted agents to bring about the molecular response, and that would mean possibly a complete response and partial response. We are at the beginning of the new phase in developing the drugs, not just to talk about improvement in the number or the size of the spleen or a blood cell count, but also to talk about affecting the malignant clone.

In an interview with Targeted Oncology, Srdan Verstovsek, MD, discussed the current MPN treatment landscape and where the field is shifting. 

Verstovsek Highlights Future Directions for MPN Treatments

oxMIF as a cancer immuno-oncology target shows potential in the treatment of patients with metastatic colorectal cancer (mCRC). The anti-oxMIF antibody ON203 demonstrated direct antitumorigenic effects by blocking the biologic function of oxMIF.

Further, the agent reduced tumor cell proliferation and angiogenesis by immunomodulation of the tumor microenvironment.

The macrophage migration inhibitory factor (MIF) is 1 of the first pleiotropic, proinflammatory cytokines. MIF drives tumor growth, angiogenesis, and metastases, and more recently, it has shown to be a critical driver of innate tumor immunity. Despite significant research efforts, experts like Randolf Kerschbaumer, MD, say that targeting MIF directly has proven elusive.

“Historical efforts to target MIF directly have not been successful since MIF is so abundant in healthy tissues,” said Kerschbaumerm, chief executive officer of OncoOne, in an interview with Targeted OncologyTM. “We simply believe that MIF is most likely inert and undruggable by both small molecules and antibodies, so we created ON203 to target oxMIF, which is only found at the tumor and not in healthy tissues.”

At sites of inflammation, MIF, which is found in abundance in healthy tissues, aggregates and undergoes a change to become oxidized MIF, also known as oxMIF.Optimized monoclonal antibodies were designed to target only oxMIF and reverse pro-tumorigenic cascades driven by MIF.

During the 2022 Society for ImmunoTherapy of Cancer Therapy Congress, research from ON203, a disease-related and druggable isoform of MIF which was tested in tumors derived from patients with mCRC, was shared in a poster presentation.

Preclinical models evaluating ON203 have shown promising data as the agent elicited superior

 efficacy compared with C0008 when used in a prolyphic mouse model of prostate cancer.

To further determine the single agent potential of ON203, investigators assessed the agent’s effect on tumoroids from 5 patients with colorectal cancer. Patients were administered 

With 1 low dose application, ON203 demonstrated single agent activity in tumoroids from 4 of the 5 patients evaluated. However, the tumor cell death that was observed correlated with the activation of key immune effector cells including NKs, NKTs, and macrophages.

“I think the key takeaway from this dataset is that oxMIF is a new immuno-oncology target with significant potential as a standalone therapy for the treatment of patients with colorectal cancer.With tumoroids better predictors of actual clinical outcomes than animal models, these data give the team at OncoOne a great deal of confidence as we prepare to enter clinical trials,” added Kerschbaumer.

ON203 also induced an increase in NK cell numbers in patients whose tumors responded to treatment. The expression of activation marker Granzyme B and the deregulation marker CD107a increased in those who responded to ON203 on NK and NKT cells. The 1 patient who did not respond showed no expression changes.

Also, treatment with ON203 led to a polarization of macrophages towards an anti-tumor phenotype in responders. This was demonstrated by an increase in HLA-DR and FcyRIII CD16 on macrophages which were determined by flow cytometry 24 hours after treatment.

Based on these data, ON203 shows potential as a standalone therapy or in combination with immune checkpoint inhibitors or anti angiogenic agents in patients with solid tumors. OncoOne is now planning to begin a phase 1 trial which will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ON203 in patients with solid tumors, including colorectal cancers. This trial is expected to begin in 2023.

“Looking ahead, MIF has been implicated in practically all solid tumors and even some hematologic malignancies. We feel that the science points solid tumors as the best targets for ON203, especially colorectal, breast, lung, and ovarian cancers.We are hopeful that the single agent activity of ON203 will be mirrored in the clinic, and we certainly believe that ON203 will be combinable with immune checkpoint inhibitors, anti-angiogenic therapies, and chemotherapeutics,” concluded Kerschbaumer.

Maurer B, Mirkina I, Mayer J, et al. ON203: A new antibody targeting the oxidized form of macrophage migration inhibitory factor (oxMIF) exerts antitumorigenic activity and modulate. Presented at Society for Immunotherapy of Cancer 2022 Annual Meeting; November 8-12, 2022; Boston, Massachusetts.

Preclinical data shows the potential of omFIX as a new immuno-oncology target which may be helpful in treating patients with metastatic colorectal cancers