Future polycythemia vera (PV) treatment plans should be modeled around available criteria and anticipated molecular targets, explained an expert in the field. Additionally, researchers anticipate that interferons or ruxolitinib (Jakafi) will continue to be mainstays in PV treatment due to their demonstrated efficacy in their respective lines.

“Treatment of patients with PV should be, in my opinion, tailored based on the risk,” Francesco Passamonti, MD, said in his presentation at the Society of Hematology Oncology 2021 Annual Conference. “This is quite important. In the future, we will probably have to work more on additional mutations and the role of additional mutations in the prediction of events in PV.”

Until these mutations are found, criteria such as being above 60 years old and history of thrombosis have to be considered according to Passamonti, a professor at Universita dell'Insubria in Varese, Italy.

When managing PV, it’s important to take into account the natural history of the disease. There is a median of 3.3% of people a year who experience thrombosis. The risk of myelofibrosis is 0.9% at 1 year, 5% at 5 years, and 34% at 10 years. Lastly, the risk of blast phase is 0.4% and the incidence stays at this rate over time.

According to the National Comprehensive Cancer Network (NCCN) guidelines, the initial indication for low-risk disease is to monitor for and manage cardiovascular risk factors, give 81 to 100 mg of aspirin per day, and use phlebotomy to maintain a hematocrit level of less than 45%. Passamonti said “the first question is if there is evidence for an alternative to this approach.”

One option comes from phase 2 trial data published in 2021 of ropeginterferon alfa-2b (Besremi; ropegIFN) in low-risk PV (NCT03003325). The study enrolled 127 patients randomized 1:1 to phlebotomy plus aspirin (n = 63) versus phlebotomy, aspirin, and ropegIFN (n = 64). The median follow-up was 12.1 months, and the primary end point was the proportion of responders—patients with median hematocrit level of less than 45% without disease progression—at 1 year of treatment.

More patients in the experimental arm achieved the composite primary end point than the standard arm, with 84% versus 60% responding by 1 year (odds ratio [OR], 3.5; 95% CI, 1.3-10.4; 

= .008). Additionally, 84% of patients receiving ropegIFN had hematocrit control compared with 66% receiving only phlebotomy and aspirin. No patients in the experimental arm had disease progression, however 8% of patients in the standard arm progressed. RopegIFN also demonstrated better symptomology for patients versus the standard of care.

After a patient with low-risk PV experiences symptomatic disease with potential indications for cytoreductive therapy, their disease is considered high risk and they need therapy. In high-risk disease, the NCCN guidelines recommend hydroxyurea or peginterferon alfa-2a in addition to the options suggested for low-risk PV.

Multiple studies have looked into using interferon treatments in PV, including the phase 3 PROUD-PV (2012-005259-18) and CONTINUATION-PV (2014-001357-17) trials. Treatment-naive patients who required cytoreduction were randomized 1:1 to receive ropegIFN (n = 127) versus hydroxyurea (n = 130) for 12 months in PROUD-PV. Twenty-one patients given ropegIFN discontinued treatment and 19 discontinued standard therapy.

In the CONTINUATION-PV trial, patient either continued on ropegIFN (n = 95) or best available therapy (BAT; n = 76). There were 16 patients who discontinued ropegIFN and 7 who discontinued BAT.

Patients treated with ropegIFN achieved complete hematologic response (CHR) at a higher rate than those on the standard arm after 3 years of therapy. The rate of phlebotomy-free patients was higher with ropegIFN, at 79.8% at 4 years compared with 60.0% (

“The most relevant of the responses obtained with interferon was the rate of patients who obtained a molecular response during the 3 years. It was clearly higher with ropegIFN versus hydroxyurea,” Passamonti said. The patients with lower JAK2 AB had a higher number of CHR at 1, 2, and 3 years as well.

The rate of major thromboembolic adverse events (3%) and myelofibrosis (1 case each) was similar between the 2 arms.

If a patient with high-risk PV experiences inadequate response or loss of response, physicians must decide on a second-line treatment. Options include clinical trial or ruxolitinib as preferred regimens, or hydroxyurea or ropegIFN as other recommendations if not previously used.

Peg-interferon-α2a (pegIFN) was investigated in the second line in the phase 2 MPD-RC 111 trial (NCT01259817) of 50 patients with high-risk disease. After 1 year, complete response was achieved in 22% of patients with PV, 46% had a hematocrit level of less than 45%, 37% were phlebotomy independent, 32% had splenomegaly normalization, and 41.3% had more than 20% variant allele frequency reduction. There were 2% of patients with major vascular events at 1 year and 5% at 2 years. Even after discontinuation of pegIFN, data have shown patients can have CHR over time.

“Interferons, either pegIFN or ropegIFN, provided evidence of efficacy in first- and second-line setting within 1- to 3-year follow-up, so the question is: Is 1- to 3-year follow-up enough for me to decide to use ropegIFN in a patient with PV,” Passamonti asked. “Probably not in [all patients], but I think in young patients, interferon is a good option for high risk.”

Currently, the only therapy approved for second-line treatment of high-risk PV is ruxolitinib. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) trials enrolled patient who were resistant or intolerant to hydroxyurea, required phlebotomy every 3 months, had palpable spleen with MRI-confirmed volume of over 450 cm3, and platelet count of less than 100,000. Patients were randomized 1:1 to ruxolitinib at 10 mg twice daily (n = 110) versus BAT (n = 112). There was a primary composite end point of hematocrit control in the absence of phlebotomy and 35% or more spleen volume reduction (SVR35) at week 32 in the RESPONSE trial.

In RESPONSE-2, patients did not have splenomegaly and did not require SVR35 as an end point. The end point in this trial was assessed at week 28.

There were 21% of patients who achieved the primary composite end point in the ruxolitinib arm versus 1% in the BAT arm (OR, 28.64; 95% CI, 4.50-1206; 

< .001). Separately, SVR35 was seen in 38% of patients receiving ruxolitinib and 1 patient receiving BAT; 60% and 20% achieved hematocrit control, respectively.

The RESPONSE-2 trial confirmed data for hematocrit control, with 62.2% of patients given ruxolitinib achieving control compared with 18.7% given BAT (OR, 7.28; 95% CI, 3.43-15.45; 

After 5 years of follow-up for the RESPONSE trial, 83% of patients on the ruxolitinib arm did not require phlebotomies. There were 41% with normalization of leukocytosis and 46% with normalization of thrombocytosis. There was a 67% 5-year probability of maintaining clinic-hematological response and 72% 5-year probability of maintaining SVR35.

In the ruxolitinib arm, the rate of thromboembolic events was 1.2 per 100 patient-years, 8.2 in the BAT arm, and 2.7 in patients who crossed over from BAT to ruxolitinib. Ruxolitinib also improved rates of second malignancies or nonmelanoma skin cancer compared with BAT but did not improve rates of transformation to myelofibrosis and acute myeloid leukemia, according to Passamonti.

Passamonti concluded that he hoped that in the future, new drugs will be able to control thrombosis as well as control the evolution from PV to post-PV myelofibrosis considering that is a more difficult condition to treat.

Mora B, Passamonti F. Polycythemia Vera: Is it Time to Rethink Treatment? Presented at: 62nd American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020. Accessed Sep

Articles

An expert presenting at the Society of Hematology Oncology 2021 Annual Conference shared important updates in polycythemia vera (PV) treatment and weighed in on the direction of future treatment. 

Anticipating the Future of Polycythemia Vera Treatment: Weighing Efficacy and Toxicity

Although there is still an unmet need in treatment for patients with multiple myeloma whose disease progressed after 1-3 prior lines of treatment and are lenalidomide (Revlimid)-refractory, the CAR T-cell therapy ciltacabtagene autoleucel may be able to fill that treatment gap, said Adam D. Cohen.

The CAR T-cell therapy was evaluated in the CARTITUDE-2 study, designed to evaluate its efficacy and safety. Initial results from cohort A of the trial were presented at the 18th International Myeloma Workshop by Coheh, associate professor at the University of Pennsylvania.

“These responses appear to be deepening over time and follow-up is ongoing,” he said. “Of course, what we’re all waiting for is the longer-term follow-up to see if the durability of response is going to be better in this less heavily treated population compared to the more refractory patients treated historically.”

Cohorts B, C, D, and E, for whom data are still under analysis, consist of patients with early relapse after frontline therapy who are progressing after a prior B-cell maturation antigen (BCMA)-targeted therapy, or as consolidation for patients after transplant or induction therapy.

The researchers’ primary objective was minimal residual disease (MRD) negativity of 10-5 sensitivity assessed by next-generation sequencing, with secondary objectives of overall response rate (ORR), duration of response, time and duration of MRD negativity, and incidence and severity of adverse events (AEs).

A single cilta-cel infusion was administered to 20 patients 5 to 7 days after the start of lymphodepletion. With a median follow-up of 5.8 months at data cutoff, ORR was 95%, including 75% of patients who achieved a complete response (CR) or better.

The safety profile was consistent with those observed in previous studies, with the majority of nonhematologic AEs being low grade. The most common grade 3/4 hematologic AEs included neutropenia (90%), thrombocytopenia (35%), anemia (40%), lymphopenia (55%), and leukopenia (55%). Grade 3/4 neutropenia and lymphopenia persisted after 60 days in 25% and 45% of patients, respectively.

Additionally, 85% of patients developed cytokine release syndrome (CRS), with the majority being grade 1 or 2 events. Several patients (15%) experienced typical CAR T-cell–related immune effector cell-associated neurotoxicity syndrome (ICANS).

“A number of mitigation strategies have been implemented in the CAR T program since then, including enhanced bridging therapy to reduce tumor burden prior to infusion early and aggressive treatment of CRS and ICANS, as well as handwriting assessments since microgravity was a presenting feature in some of the patients,” Cohen said.

The implementation of these strategies has significantly reduced the incidence of movement and neurocognitive disorders in the more than 100 additional patients who have been dosed in the time since data cutoff. However, follow-up is still ongoing, Cohen explained.

Cilta-cel continues to be evaluated in a phase 3 study, CARTITUDE-4, in which it is being compared with standard-of-care treatment.

Cohen A, Agha M, Madduri D, et al. Efficacy and safety of ciltacabtagene autoleucel, a BCMA-directed CAR-T cell therapy, in patients with progressive multiple myeloma after 1–3 prior lines of therapy: Initial results from CARTITUDE-2. Presented at: 18th International Myeloma Workshop; September 8-11, 2021; Vienna, Austria.

Patients with progressed multiple myeloma experienced deep and durble responses through CAR T-cell therapy ciltacabtagene autoleucel therapy. 


Cilta-cel CAR T-Cell Therapy May Satisfy Need For Deeper Treatment Responses in Multiple Myeloma 

Whether they are in a premalignant state of monoclonal B lymphocytosis (MBL), treatment naïve and under surveillance, or undergoing active treatment, patients with chronic lymphocytic leukemia (CLL) are at an increased risk for infection, shared Carsten Utoft Niemann, MD, PhD, in a presentation during the 2021 SOHO Annual Meeting.

With the help of the machine learning–based algorithm CLL Treatment-Infection Model (CLL-TIM), Niemann and his colleagues hope to learn whether the natural history of immune dysfunction and infections in CLL can be changed.

Investigators have made great strides in improving survival for patients with CLL, following the advent of chemoimmunotherapy and targeted therapy approaches. Unfortunately, mortality due to infection in these patients has not changed in 4 decades, Niemann explained, and infections are now the leading cause of death among patients with CLL.

“Looking at patients diagnosed with CLL, [they] tend to have a higher risk of having a serious infection within the first 5 years,” said Niemann, an associate professor, head of the CLL Lab, and chair of the Nordic CLL Study Group, in the Department of Hematology, Rigshospitalet, Copenhagen, Denmark. “The 30-day mortality [rate] upon a serious infection for patient diagnosed with CLL is 10%; the 1-year mortality [rate] is only 11% for patients starting treatment for CLL even though 50% of them will have a serious infection after starting treatment. This means that infections are actually more dangerous for patients with CLL who are untreated.”

Niemann is a coinvestigator in the phase 2 PreVent-ACaLL trial (NCT03868722), in which investigators will use the CLL-TIM algorithm to determine whether short-term treatment with the BTK inhibitor acalabrutinib (Calquence) plus the BCL-2 inhibitor venetoclax (Venclexta) can improve immune function and reduce the risk for infection compared with observation in patients with high-risk, newly diagnosed CLL.

“The aim here by this short 3-month treatment is not to 

 CLL,” he said. “The aim is to reduce the CLL clone back into what we consider monoclonal B lymphocytosis and, at the same time, treat the natural history of CLL and immune dysfunction. Thus, we aim to turn back the CLL into a normal immune function, and the outcome here is actually infection-free, treatment-free survival.”

Twenty-five patients will be randomly assigned to the treatment arm, which will be given in 3 cycles of 28 days, and 25 will be assigned to observation. Enrollment has opened in Denmark and is scheduled to open soon in the Netherlands and Sweden. The primary end point is grade 3 or higher infection-free survival in the treatment arm compared with the observation arm after 24 weeks.

CLL-TIM identifies patients at risk for infection or CLL treatment within 2 years of diagnosis as validated on both internal and external cohorts. The ensemble algorithm incorporates 28 machine learning algorithms based on data collected from 4149 patients with CLL. The model is capable of dealing with heterogeneous data, including high rates of missing data to be expected in the real-world setting, with a precision rate of 72% and a recall rate of 75%.

Niemann added that 6 European nations are collaborating in the CLL-CLUE consortium to assess immune dysfunction and drug sensitivity in primary samples collected from patients and clinical trials, and biobanks. Long term, the goal is to better individualize CLL treatment.

Immune Disfunction Starts Long Before Diagnosis

Niemann said that patients with CLL are more likely to be prescribed macro lights, antibiotics, and/or antivirals as much as 20 years before diagnosis. “This indicates that the immune dysfunction, at least, happens decades prior to diagnosis of CLL,” he added.

Going beyond the patient’s CLL and looking at their entire medical history, Niemann said physicians can see the burden of comorbidity in this population. “Almost all types of comorbidities for patients with CLL will increase the overall mortality and also for most of these comorbidities, will increase the CLL-related mortality,” he said.

That said, it appears both treatment and CLL itself play a role in incidence of infection. Niemann noted that lower respiratory tract infections and urinary tract infections are common for the 6 months of treatment with ibrutinib (Imbruvica). “This may indicate that we have an improvement in immune function and lower degree of infections after the first half year on targeted therapy.”

Niemann pointed out that, outside of clinical trials, close to 50% of patients discontinue ibrutinib by 30 months, many due to infections. Physicians must consider that infections might also affect the continuous treatment of patients, he added.

“On the other hand, [there is] no doubt that we may, for patients who are treated, actually improve the immune function over time,” Niemann said. Patients with less disease burden in terms of being treatment-naïve have a lower risk of infections than patients who are relapsed/refractory and would be expected to have had more aggressive or longer duration of CLL.”

Cumulative mean number of infections are lower in patients whose immune globulin levels increase during ibrutinib treatment. However, Niemann said there is no clear correlation between immunoglobulin deficiency and the risk for infections.

“That is what we’ve been working on predicting the risk of infections or risk of needing treatment for CLL,” he said.

To help the patient in the clinic, Niemann said all patients with CLL may have increased infection risk, but investigators need to identify those who at greatest risk for serious infections. Further, patients with CLL are at risk for both increased frequency of infections and also in the distribution of infections, especially for pneumococcal disease.

“Vaccine responses in CLL are impaired due to immune dysfunction. Thus, it should be encouraged to have early vaccination of patients with CLL, and repeat vaccination during treatment and after treatment,” he said. “Immunoglobulin substitution should only be used for patients who both have low IgG [immunoglobulin G] levels and frequent infections as we cannot clearly define these patients just by measuring the IgG levels.”

Niemann CU. Management of infections in patients with CLL. Presented at: the 2021 SOHO Annual Meeting. Virtual. September 8-13, 2021.

Da Cunha-Bang C, Agius R, Kater AP, et al.PreVent-ACaLL short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping. 

. 2019;134(supplement_1):4304. doi:10.1182/blood-2019-121907

Agius R, Brieghel C, Andersen MA, et al. Machine learning can identify newly diagnosed patients with CLL at high risk of infection. 

. 2020;11(1):363. doi:10.1038/s41467-019-14225-8

Patients with chronic lymphocytic leukemia (CLL) are at an increased risk for infection. 

Infection Control a Necessity in Treating CLL

The FDA approved zanubrutinib (Brukinsa) for the treatment of patients with marginal zone lymphoma (MZL) who had with at least 1 prior treatment with an anti-CD20-based therapy.

Zanubrutinib is a next-generation Bruton tyrosine kinase (BTK) inhibitor that was designed to maximize BTK occupancy, and therefore minimize off-target inhabitation of TEC- and EGFR-family kinases. These kinase families are believed to induce atrial fibrillation, thrombocytopenia, and bleeding events, according to a press release.

The regulatory decision was based on findings from 2 single arm trials.

The multicenter, single-arm phase 2 MAGNOLIA (NCT03846427) trial assessed zanubrutinib’s efficacy and safety in 68 adult patients with relapsed/refractory MZL who had received 1 or more lines of prior therapy, including at least 1 CD20-directed therapy.

Zanubrutinib was administered twice a day at a dose of 160mg, until either the disease progressed, or intolerable toxicity was presented. Importantly, the study permitted long-term antiplatelet and anticoagulation agents.

Investigator assessment determined secondary end points, which comprised overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and safety.

An independent review committee and Lugano classification determined ORR for the primary end point of the trial. ORR was 56% (95% CI, 43%-68%) and the complete response (CR) rate was 20%. At 8.3 months, the median DOR had not yet been reached, though 85% of responders were still in remission at 12 months (95% CI, 67-93).

"BTK plays a critical role in B-cell receptor signaling, a driver in the development of marginal zone lymphoma. In the MAGNOLIA trial, Brukinsa demonstrated impressive overall response and complete remission rates, with responses observed in all MZL subtypes,” said Stephen Opat, FRACP, FRCPA, MBBS, director of clinical hematology at Monash Health, Head of Department of Hematology at Monash University, and lead principal investigator of the MAGNOLIA trial. “In addition, this next-generation BTK inhibitor was well-tolerated in these patients, with low rate of discontinuation due to adverse reactions.”

Notable adverse events (AEs) included decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain.

The most common toxicities associated with treatment in the MAGNOLIA trial were reported to be low grade and consisted of diarrhea (19.1%), bruising (17.6), constipation (13.2%), pyrexia (10.3%), upper respiratory tract infection (10.3%), and nausea (10.3%).

Serious AEs presented themselves as thus: 1 case of atrial flutter, 1 case of pyrexia, 1 case of pneumonia, and 1 case of thrombocytopenia. In addition, 1 patient with pre-existing coronary artery disease died due to a myocardial infarction but this is not believed to be associated to the zanubrutinib treatment.

Less serious grade AEs included neutropenia (10.3%, thrombocytopenia (10.3%) and atrial flutter (1.5%).

Throughout the trial, 21 patients discontinued their treatment. Sixteen patients stopped because their disease progressed, 1 withdrew their consent, 2 required prohibited medication, and 2 stopped as a result of their treatment-related AEs.

Previous data from the BGB-3111-AU-003 trial, which examined zanubrutinib in a total of 20 patients with relapsed/refractory MZL, 9 of whom had extranodal subtype, 5 had a nodal subtype, and 6 had s splenic subtype, showed that the BTK inhibitor induced an ORR of 80% at (95% CI, 56%-94%) and the CR rate was 20%. Similarly, the median DOR was not reached. Median follow-up time was 31.4 months, and 72% of responders were in remission at 12 months (95% CI, 40-88).

“The MAGNOLIA trial results provided additional evidence that the selective design of Brukinsa can be translated to improved treatment outcomes for these patients," said Jane Huang, MD, chief medical officer, hematology, BeiGene. "The ongoing evaluation of Brukinsa in its broad global clinical program will enable us to further understand this potentially best-in-class BTK inhibitor and its impact on patients.”

b for the treatment of patients with mantle cell lymphoma (MCL) who have previously received at least 1 therapy. It received the same indication in China the following year, and was also approved to treat chronic lymphocytic leukemia or small lymphocytic lymphoma in patients who had already received 1 line of therapy. In February 2021, the Unites Arab Emirates approved zunubrutinib to treat relapsed or refractory MCL.

Zanubrutinib should be administered at either 160 mg twice a day or 320 mg daily, with or without food. Dosage may be adjusted in response to AEs or certain drug interactions.

US FDA grants BRUKINSA (zanubrutinib) accelerated approval in relapsed or refractory marginal zone lymphoma. News release. BeiGene, Ltd. September 15, 2021. Accessed September 15, 2021. https://ir.beigene.com/news-details/?id=0d5b56bb-d6cd-4606-a9bd-f49e85bb113b.

Opat S, Tedeschi A, Linton K, et al. Efficacy and safety of zanubrutinib in patients with relapsed/refractory marginal zone lymphoma: initial results of the MAGNOLIA (BGB-3111-214) trial. 

. 2020;136(suppl 1):28-30. doi:10.1182/blood-2020-134611

Tedeschi A, Trotman J, Tam C, et al. Phase 1/2 study of single-agent zanubrutinib in patients with relapsed/refractory marginal zone lymphoma. Presented at: 2020 EHA Annual Congress; June 11-21, 2020; Virtual. Abstract EP1165. 

Zanubrutinib received an accelerated approval for the indication of adults with marginal zone lymphoma with at least 1 prior treatment with an anti-CD20-based therapy. 



FDA Approves Zanubrutinib To Treat Patient With Marginal Zone Lymphoma

Although there are no standard treatment options for myeloproliferaive neoplasms in accelerated phase (MPN-AP), it is still necessary for health care providers to understand the disease’s evolution risk factors, current treatment method outcomes, and anticipated targeted therapies in the pipeline, as well as in the blast phase (MPN-BP), explained Olatoyosi Sobulo Odenike, MD, during apresentation at the Society of Hematology Oncology 2021 Annual Conference.

MPN-AP is defined as patients with 10% or more blasts in the peripheral and/or bone marrow, and MPN-BP is 20% or more. After the chronic phase of the Philadelphia chromosome (Ph)-negative MPNs, such as essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), evolves into MPN-AP, the median survival is much shorter.

For ET and PV, overall survival (OS) is generally more than 10 years, and PMF, which also has the highest risk of evolution to MPN-AP, has a median OS of 5 to 6 years. The median survival in MPN-AP is 16 to 17 months for PMF. For patients who evolve to MPN-BP, survival is even worse.

“Of note, even in the chronic phase of the disease, in patients who have 5% to 9% blasts…[have] outcomes that are very similar to those who have 10% or more blasts, arguing that patients who have blasts in this range are also on a continuum towards BP,” Odenike, a professor of medicine at the University of Chicago Medicine, said. “When the disease progresses to the BP, the OS is in the 3- to 5-month range.”

For patients in this setting, risk factors for transformation include receiving cytoreductive agents; increase in blasts, thrombocytopenia, anemia, or other lab parameters; and having PMF, as opposed to ET or PV. According to the Risk Scoring Systems used for MPNs, high-risk features are considered predictive for MPN-AP/BP. These include baseline driver mutations, deleterious mutations, and germline susceptibility.

Identifying patients who are at high risk of progression is crucial, Odenike noted, because the survival rates after transplant are much higher in chronic phase compared with MPN-AP/BP. When approaching treatment in patients with MPN-AP/BP, Odenike posed questions to consider:

whether the patient is fit for intensive induction;

the degree of cytoreduction necessary prior to transplant, if any.

Retrospective data have shown a complete response (CR) rate plus CR with incomplete hematologic recovery (CRi) rate in the 30% to 40% range with intensive chemotherapy and CR rates in the 25% range with hypomethylating agents (HMAs) in patients with MPN-AP. There was no OS advantage to one treatment over the other in the retrospective findings. However, without being able to receive an allogeneic stem cell transplant, there was not as much benefit to intensive chemotherapy. For patients who are transplant ineligible, fewer intensive regimens are preferred.

For patients with Ph-negative MPNs in the chronic phase, JAK inhibition has been a meaningful step forward in treatment. This is especially true for those who are symptomatic or have significant splenomegaly. Now the question has become whether it would be as useful in MPN-AP/BP.

According to Odenike, there is no real benefit to JAK inhibition alone but there is some when it is combined with an HMA. The combination of ruxolitinib (Jakafi) and decitabine in 25 patients demonstrated a median survival of 9.5 months and an overall response rate (ORR) of 44%, 8% of which was CRi and 36% partial response. A similar trial showed a median OS of 8.4 months with the recommended phase 2 dose and an ORR of 45%. Although, it has still not been determined if the JAK inhibitor/HMA combination produces more efficacy than HMA alone for these patients.

The combination of an HMA plus venetoclax (Venclexta) received approval in acute myeloid leukemia, but the trial did not include patients with preexisting MPNs. Therefore, only retrospective data is available for this combination in MPN-AP/BP. A small retrospective series have shown CR/CRi rates of around 43% in the frontline for MPN-BP and a median OS of 7 months with venetoclax and an HMA.

Recently, IDH1/2 inhibitors have been approved in patients with acute myeloid leukemia and 

 mutations, and so these are also being looked at for MPN-AP/BP in retrospective data. There is a potential benefit with IDH inhibitors, which have demonstrated a median survival of 9 months or more in this setting. Of note, some patients have stayed on single-agent therapy for several years after initiating treatment.

To treat patients with MPN-AP/BP, using next-generation sequencing at the beginning of management allows for the detection of 

. Patients with TP53 mutations can have higher chemotherapy-resistance, so Odenike prefers to use HMA-based therapy. “For other mutations, a majority we don’t have any targeted therapies for, I have a relative equipoise between an intensive approach versus HMA-based therapy,” Odenike said. “But I will only use intensive chemotherapy if the patient is also able to then undergo an allogeneic stem cell transplant.”

For this population, participating in clinical trials is also extremely important. In fact, some novel agents that are being investigated in myeloid malignancies include epigenomic modulators, post translational modulators, immune checkpoint inhibitors, and targeted agents.

“The hope is that we will have many more trials that will allow patients with MPN-AP/BP disease to participate in an effort to improve overall outcomes,” Odenike concluded.

Odenike OS. Accelerated Phase of MPN: What Is It and What to Do About It. Presented at the Society of Hematology Oncology 2021 Annual Meeting; September 8-10. Accessed September 9, 2021.

Treating patients with myeloproliferative neoplasms in accelerated phase (MPN-AP) remains an ongoing challenge as there are still no standard therapeutic approaches, says an expert.

Myeloproliferative Neoplasms in Accelerated Phase Continue to Present as Treatment Challenge

Recent findings showed that older patients with newly diagnosed multiple myeloma demonstrated superior overall survival when treated with daratumumab (Darzalex) plus lenalidomide (Revlimid) and dexamethasone, compared with lenalidomide and dexamethasone.

The presentation at the 18th International Myeloma Workshop focused on updated efficacy and safety data of daratumumab plus lenalidomide and dexamethasone compared with lenalidomide and dexamethasone after nearly 5 years of median follow-up in the phase 3 MAIA study (NCT02252172).

“Those results, when looking at [daratumumab plus lenalidomide and dexamethasone], both for PFS and OS and a relatively good safety profile, I would say, are now establishing [daratumumab plus lenalidomide and dexamethasone] as a new standard of care for patients that are not transplant eligible,” said Philippe Moreau, MD, professor of clinical hematology at University Hospital Hôtel-Dieu, in a presentation of the findings.

In particular, researchers analyzed data from 737 patients with newly diagnosed multiple myeloma. These patients were ineligible for high-dose chemotherapy and autologous stem cell transplantation because of their age (older than 65 years) or the presence of comorbidities. Patients were randomly assigned daratumumab plus lenalidomide and dexamethasone (n = 368) or lenalidomide and dexamethasone (n = 369). Patients had a median age of 73 years (range, 45-90).

“One very important point and theory … for elderly patients, we know that many of them are not able to receive 2 or 3 lines of treatment, so this suggests that the most effective treatment should be used upfront and not saved for relapse,” Moreau said.

The primary endpoint was progression-free survival, with key secondary endpoints including overall survival, among others.

After a median follow-up of 56.2 months, patients assigned daratumumab plus lenalidomide and dexamethasone had a 32% reduction in the risk for death compared with those assigned lenalidomide and dexamethasone.

The median overall survival was not reached in either group (HR = 0.68; 95% CI, 0.53-0.86; 

 = .0013). Estimated overall survival at 5 years was 66.3% in the daratumumab plus lenalidomide and dexamethasone group compared with 53.1% in the lenalidomide and dexamethasone group.

The updated median progression-free survival was not reached in patients assigned daratumumab plus lenalidomide and dexamethasone, whereas patients assigned lenalidomide and dexamethasone had a median progression-free survival of 34.4 months (HR = 0.53; 95% CI, 0.43-0.66; 

Longer follow-up did not result in new safety concerns. The most common grade 3/4 treatment-emergent adverse event was neutropenia, occurring in 54.1% of patients in the daratumumab plus lenalidomide and dexamethasone group and 37% in the lenalidomide and dexamethasone group.

Moreau P, Facon T, et al. Overall Survival and Progression-free Survival by Treatment Duration With Datatumumab + Lenalidomide/Dexamethasone in Transplant-ineligible Newly Diagnosed Multiple Myeloma: Phase 3 MAIA Study. Presented at: 18th International Myeloma Workshop; September 8-11, 2021; Vienna, Austria. Oral Abstract Session.

Due to the favorable efficacy and safety profiles of daratumumab plus lenalidomide and dexamethasone, researchers speculate that the combination may become the new standard of care in multiple myeloma treatment. 

Daratumumab-Lenalidomide-Dexamethasone Combination May Become Preferred Treatment for Newly Diagnosed Multiple Myeloma 

Researchers may be able to anticipate outcomes in patients with myeloma based on their minimal residual disease (MRD) status.

Results from the Myeloma XI trial were presented at the 18th International Myeloma Workshop. The trial assessed patients with myeloma who underwent an autologous stem cell transplant and are currently on maintenance therapy with lenalidomide (Revlimid).

“Results support the role of MRD monitoring in assessment of the efficacy of different maintenance/consolidation strategies within clinical trials,” said Ruth de Tute, consultant clinical scientist lead at the Haematological Malignancy Diagnostic Service (HMDS) of St. James Hospital in Leeds, UK.

The phase 3 Myeloma XI trial, “which is the biggest UK myeloma trial to date,” de Tute said, included 1248 patients with myeloma who were eligible for autologous stem cell transplant. After undergoing transplant, patients were randomly assigned either maintenance therapy with (n = 730) or without lenalidomide (n = 518). MRD status was assessed at 3 months after autologous stem cell transplant and 6 months after randomization.

Through this, researchers assessed the potential link between MRD status and both progression-free survival and overall survival. Progression-free survival was defined as the time from either 3 months or 9 months post-transplant to the date of disease progression or all-cause death. Overall survival was defined as the time from either 3 months or 9 months post-transplant to the date of all-cause death.

Of the 750 patients with evaluable samples after autologous stem cell transplantation, 63.3% were MRD-negative. In addition, of the 623 patients with evaluable samples 9 months after transplantation, 65.6% had a negative MRD status.

During a median follow-up of 32.9 months, patients with a positive MRD status had a progression-free survival of 24 months (95% CI, 21-28) compared with 44 months for those with a negative status (HR = 0.47; 95% CI, 0.37-0.58; 

 < .0001). Median overall survival was not reached in either group at the time of the analysis, de Tute said, although at 3 years, it was 78.7% in patients with a positive status to 86.5% in patients with a negative status, leading to a statistically significant difference favoring those with a negative MRD status (HR = 0.59; 95% CI, 0.4-0.85).

Three months after transplantation, compared with patients assigned observation, patients assigned maintenance therapy with lenalidomide had significant improvements in progression-free survival in both the MRD-positive (33 months vs. 18 months; HR = 0.43) and MRD-negative groups (56 months vs. 36 months; HR = 0.62). A similar effect was observed when assessing overall survival, although the median overall survival has not been reached in either group.

When MRD status was assessed 9 months after randomization, patients with a negative status had a significantly longer median progression-free survival compared with those with a positive status (50 months vs. 13 months; HR = 0.2; 95% CI, 0.13-0.31; 

 < .0001). Median overall survival was also not reached in both of these groups at this time point, although the difference between the groups was statistically significant (HR = 0.33; 95% CI, 0.15-0.75; 

Patients assigned lenalidomide, compared with observation, continued to have significant improvements in progression-free survival 9 months after randomization in the MRD-positive (47 months vs. 9 months) and MRD-negative groups (NE vs. 31 months).

The impact of sustained MRD-negative status was assessed in 245 patients. In this analysis, all patients with MRD-negative status 9 months after randomization had equally good outcomes regardless of MRD status at 3 months after transplant. Patients who continued to have an MRD-positive status throughout and those who had a reemergence of disease after originally having a negative status 3 months after transplant had similar outcomes.

Researchers also assessed the impact of MRD status by molecular risk subgroups.

“MRD negativity was predictive of improved progression-free survival in patients with standard risk and high risk or ultra-high-risk disease,” de Tute said during the presentation. “MRD-negative patients with one or more high-risk lesions had a shorter median PFS compared to MRD-negative standard-risk patients, … suggesting achieving MRD negativity is not able to overcome the adverse PFS associated with genetic high risk. This was true for patients defined as high risk with the presence of only one adverse lesion and also those with ultra-high risk with two or more adverse lesions.”

de Tute RM, Pawlyn C, et al. Minimal residual disease following autologous stem cell transplant for myeloma patients in the Myeloma XI trial: prognostic significance and the impact of lenalidomide maintenance and molecular risk. Presented at: 18th International Myeloma Workshop; September 8-11, 2021; Vienna, Austria. Oral Abstract Session.

Patients with myeloma and a negative MRD may be at a reduced risk of mortality and other progression-free survival events. 

Minimal Residual Disease May Anticipate Outcomes in Myeloma Following Stem Cell Transplant

Twenty percent of the patients with malignant pleural mesothelioma at the Vall d’Hebron University Hospitals became infected with COVID-19 during the first year of the pandemic. This led to both a high hospitalization and mortality rate among this population, showed findings from a descriptive study that was presented during the 2021 World Conference on Lung Cancer.

The results showed that 7 patients (18%) were diagnosed with COVID-19 by a reverse transcription polymerase chain reaction test; the median overall survival (OS) of these patients was 17.8 months from cancer diagnosis.

Five of these patients died; reasons for death included COVID-19 (n = 4) and progressive disease (n = 1). The median OS of these patients was 0.4 months since COVID-19 diagnosis.

Patients with thoracic malignancies may be particularly vulnerable to COVID-19, lead study author Susana Cedres, MD, PhD, a medical oncologist in the Thoracic Tumors Unit at the Vall d’Hebron University Hospital and Institute of Oncology in Barcelona, Spain, said in explaining the basis for the study in a virtual presentation of the data.

Although the effect of SARS-CoV-2 infection has previously been evaluated in 200 patients with thoracic malignancies in the TERAVOLT registry, only 8 patients with malignant pleural mesothelioma were included in the assessment.

In the United States, tuberculosis, drug use disorder, hepatitis, HIV/AIDS, cardiomyopathy, diabetes, and malignant pleural mesothelioma has been associated with worse COVID-19 related mortality outcomes.

Therefore, investigators sought to tease out the effect of COVID-19 infection on patients with malignant pleural mesothelioma at Vall d’Hebron University Hospital.

In the study, investigators compiled the medical records of 38 patients with malignant pleural mesothelioma who had visited Vall d’Hebron University Hospital between March 2020 and March 2021.

The data that was collected included information on demographics, comorbidities, oncological background, and course of COVID-19 illness.

Regarding the patient characteristics of those diagnosed with COVID-19, the median age was 62 years (range, 62-87). The study population comprised 4 men (57%) and 4 women (43%). Four patients were non-smokers (57%), and 3 patients were current or former smokers (43%).

All 7 patients (100%) had epithelioid histology. Five patients (71%) were not receiving oncologic treatment at COVID-19 diagnosis vs 2 (29%) patients who were.

Additionally, investigators stratified patients by 6 characteristics at COVID-19 diagnosis: comorbidity, concomitant treatment, clinical onset, laboratory, hospitalization, and respiratory symptoms.

Regarding comorbidities, 4 patients (57%) had a cardiovascular comorbidity, 1 patient (14%) had a respiratory comorbidity, and 1 patient (14%) had a renal comorbidity.

Regarding concomitant treatments, 4 patients (57%) were receiving antiplatelet or anticoagulant therapy, 2 patients (29%) were receiving antidiabetic therapy, and 1 patient (14%) was receiving corticosteroids.

Regarding clinical onset, 4 patients (57%) had symptomatic onset, and 3 patients (43%) had asymptomatic onset.

Regarding laboratory results, 6 patients (85%) had lymphopenia, 4 patients (57%) had high d-dimer, and 4 patients (57%) had high IL-6.

Regarding hospitalization, 6 patients (85%) were hospitalized, and 1 patient (14%) was not.

Regarding respiratory symptoms, 4 patients (57%) had bilateral pneumonia, and 6 patients (85%) had oxygen support.

Cedres S, Assaf JD, Iranzo P, et al. Clinical characteristics and outcomes in patients with malignant pleural mesothelioma (MPM) with COVID-19 infection. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 20

Patients with both COVID-19 and malignant pleural mesothelioma showed high rates of hospitalization and mortality. 

Study Identifies High Mortality Rates in Patients with COVID-19 and Malignant Pleural Mesothelioma 

Survival rates in T-cell acute lymphoblastic leukemia (T-ALL), although formally inferior to survival rates in B-cell acute lymphoblastic leukemia (B-ALL), are now considered similar to B-cell (B-ALL), with a survival rate close to 90%.

The drastic improvement in T-ALL survival rates over the past half-century has been described as one of the great success stories of modern medicine, said David T. Teachey, MD, attending physician and researcher at Children’s Hospital of Philadelphia. Yet, despite these great advancements, researchers are still striving to reach a 100% survival rate.

To reach this goal, Teachey outlined a few encouraging approaches during his presentation, “Novel Approaches to T-ALL,” presented at the Society of Hematologic Oncology 2021 Annual Conference.

“I think introducing targeted therapies and incorporating immunotherapies are the 2 areas where we continue to make improvements in outcomes and survival in these diseases,” Teachey said during his presentation. In addition, methods to improve risk stratification can lead to optimal benefit.

There are several potential new agents under development that are based on the biology of T-ALL, including signal transduction inhibitors, notch pathway inhibitors, CDK4/6 inhibitors, BCL-2 family inhibitors, epigenetic modulators, next-generation chemotherapeutics, and immunotherapies.

“T-ALL is far more biologically complex than B-ALL, so it’s harder to find a one-size-fits-all [treatment] but you can [stratify] patients with T-ALL into different groups who are more likely to respond to different small molecule inhibitors and other novel therapies based on the biology of leukemic blasts,” Teachey said.

In preclinical models, proteasome inhibitors have demonstrated encouraging activity, especially the ability to synergize with chemotherapeutics that can overcome resistance to steroids and other drugs. Further, these agents have shown promise in relapse trials, said Teachey. A number of relapsed trials are ongoing with a focus on proteasome inhibitors, including first-generation proteasome inhibitor bortezomib (Velcade) and second-generation inhibitors, including carfilzomib (Kyprolis).

The phase 3 AALL1231 trial (NCT02112916) randomized patients with T-ALL or T-cell lymphoblastic lymphoma (T-LL) to receive a modified augmented Berlin-Frankfurt-Münster chemotherapy backbone with or without bortezomib during induction and delayed intensification.

 Patients were stratified as standard, intermediate, or very high risk.

Investigators reported a 3-year overall survival (OS) rate for the control group (Arm A) of 85.5% compared with 88.2% for the treatment arm (Arm B). In patients with T-LL, the 3-year OS rate was 78.0% in Arm A and 89.5% in Arm B. The 3-year OS rate for patients with T-ALL was 88.2% in Arm A compared with 87.7% for patients in Arm B. Overall, bortezomib significantly improved event-free survival for these patient populations. “We found that there was a trend towards improved survival in patients who received bortezomib, but it didn’t rise to statistical significance,” Teachey said. “What we found that was interesting, though, was if you broke out patients on this trial who had T-ALL vs T-LL, we found there was no survival benefit.”

JAK/STAT inhibition is another potential pathway to be explored, Teachey said. This pathway is particularly attractive in patients with early T-cell precursor phenotype where JAK/STAT signaling is commonly dysregulated. Teachey noted several trials evaluating JAK inhibitors including ADVL1011 (NCT01164163), which is a phase 1 trial evaluating ruxolitinib (Jakafi) to determine the maximum tolerated or recommended phase 2 dose, dose-limiting toxicities, pharmacokinetics, and pharmacodynamics in children with recurrent/refractory solid tumors;

 and the phase 2 trial AALL1521 (NCT02723994), which is exploring ruxolitinib in combination with a standard multi-agent chemotherapy regimen in CRLF2/JAK-altered ALL.

Other inhibitors that are undergoing evaluation are CDK4/6 inhibitors. Specifically, the AINV18P1 trial (NCT03792256) is exploring palbociclib (Ibrance) in combination with a standard re-induction regimen.

 In the dose-determination portion of the study (part 1; n = 6), palbociclib was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently in combination with 4-drug re-induction chemotherapy. In the ongoing expansion cohort (part 2; n = 2), patients will undergo further assessment for safety and feasibility of combination therapy.

Another target undergoing evaluation is BCL-2. Chonghaile et al

 found that T-ALL cell lines and primary patient samples are dependent upon BCL-XL, except when the cancer has an early T-cell progenitor (ETP) phenotype, in which case the cancer is BCL-2 dependent. The investigators described a change in antiapoptotic protein dependence that is related to the differentiation stage of the leukemic clone. Teachey said their findings demonstrate that BCL-2 is a potential target for therapeutic intervention and that ETP may be sensitive to venetoclax (Venclexta) monotherapy, as demonstrated by Pullarkat et al.

“Pediatric oncologists found [the venetoclax] data exciting because it included 7 relapsed/refractory pediatric patients and a response rate of 86%. I think we need more data and more patients, but this is a promising pathway,” Teachey said.

Turning to immunotherapies, Teachey said that there are several approaches in B-ALL, but that T-ALL poses some challenges. “The field has lagged a little in T-ALL because it’s more difficult to develop chimeric antigen receptors [CARs] against T-ALL for a number of reasons,” Teachey said. He noted that toxicity and CAR T-cell fratricide add to the difficulty in developing CARs in this setting. Despite the challenges, however, Teachey was encouraged because a few T-cell immunotherapy trials are underway that focus on daratumumab (Darzalex), pembrolizumab (Keytruda), nivolumab (Opdivo), and isatuximab-irfc (Sarclisa).

Teachey DT, Devidas M, Wood BL, et al. Cranial radiation can be eliminated in most children with t-cell acute lymphoblastic leukemia (t-all) and bortezomib potentially improves survival in children with t-cell lymphoblastic lymphoma (t-ll): results of children’s oncology group (COG) trial AALL1231. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020. Abstract 266. Accessed September 8, 2021. https://bit.ly/3DXViLp

Loh ML, Tasian SK, Rabin KR, et al. A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: A children’s oncology Group phase 1 consortium study (ADVL1011). 

. 2015;62(10):1717-1724. doi:10.1002/pbc.25575

Raetz EA, Teachey DT, Minard C, et al. Safety of Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: a children’s oncology group pilot study. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020. Abstract 1018. Accessed September 8, 2021. https://bit.ly/3yP1TnG

Chonghaile TN, Roderick JE, Glenfield C, et al. Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. 

. 2014;4(9):1074-1087. doi:10.1158/2159-8290.CD-14-0353

Pullarkat VA, Lacayo NJ, Jabbour E, et al. Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. 

. 2021;11(6):1440-1453. doi:10.1158/2159-8290.CD-20-1465

While survival rates in T-cell acute lymphoblastic leukemia remain around 90%, researchers are optimistic that the use of targeted therapies and immunotherapies will continue to improve treatment options.  

Targeted Therapies Continue to Improve OS in T-Cell Acute Lymphoblastic Leukemia

“Emerging therapies are coming,” shared Stephanie Jackson DNP, MSN, RN, AOCNS, BMTCN, Unit Director, Hematology/Stem Cell Transplantation, UCLA.

Jackson presented on leukemia essentials for the oncology nurse at 

. In an interview with Oncology Nursing News®, Jackson provided a brief introduction to how her presentation would address the 4 different types of leukemias and differentiate between acute myeloid leukemia, acute lymphoblastic leukemia, and the chronic leukemias that are much slower growing, chronic myeloid leukemia and chronic lymphocytic leukemia.

Her presentation highlighted “how [leukemias] are diagnosed, what are the role(s) of the bedside nurses, in terms of the clinical manifestations that are seen, and then how we’re treating them, based on the NCCN guidelines, at the end we’re going to talk about many of the exciting, emerging therapies that are coming, many of which are already FDA approved, and then 1 that we are currently waiting to be FDA approved, which is very exciting.

Stephanie Jackson, DNP, MSN, RN, AOCNS, BMTCN, discusses her recent School of Nursing Oncology presentation. 

Hematology