 Case-Based Roundtable event, Haris Ali, MD, associate clinical professor, Department of Hematology and Hematopoietic Cell Transplantation at the City of Hope, discussed a primary myelofibrosis patient case.

: What are the differences among the various prognostic risk models for myelofibrosis?

The International Prognostic Scoring System [IPSS], the Dynamic IPSS [DIPSS], and the DIPSS-plus are all validated prognostic models for primary myelofibrosis. For the IPSS and DIPSS, they use the same parameters [older than 65 years, hemoglobin level lower than 10 g/dL, white blood cell count greater than 25 × 10

/μL, peripheral blood blasts 1% or higher, and the presence of constitutional symptoms]. For DIPSS-plus, however, it’s more comprehensive, as it includes unfavorable karyotype transition, red blood cell transfusion dependency, and low platelet count [less than 100 × 103/μL]. Using these models, the median survival of the risk groups is as follows: low-risk survival is [greater than] 11 years, intermediate-risk-1 survival is 6 to 14 years, intermediate-risk-2 survival is 3 to 4 years, and high-risk survival is 1 to 2 years.

The MIPSS70 model [Mutation-Enhanced IPSS] is a little more recent [2018]. In addition to previously described variables, it also incorporated these variables: bone marrow fibrosis grade of 2 or more, absence of 

type 1 mutation, and presence of high-molecular risk [HMR] mutations, where greater weight is given to the presence of 2 or more mutations. Mutations in the HMR category include 

. Low-risk average survival is [greater than] 2 decades, [whereas] intermediate-risk [average] survival is 7 years, and high-risk [average] survival is 2.3 years.

The most recent model is the MIPSS70-plus version 2.0, in which the authors used the latest categories for cytogenetics. They divided the groups into 5 risk categories: very low, low, intermediate, high, or very high. Median overall survival [OS] ranged from median not reached at very low risk to 1.8 years at very high risk. This was validated in the Mayo Clinic cohort, as well as in an Italian cohort. The very high-risk karyotypes include monosomy 7, isochromosome 17, inversion of chromosome 3, abnormalities of 12p or 11q, and autosomal trisomies not including +8 or +9.

A prognostics scoring system was developed by the Italian group called MYSEC-PM [Myelofibrosis Secondary to PV (polycythemia vera) and ET (essential thrombocytopenia)-Prognostic Model], which uses age, hemoglobin, platelets, circulating blasts, 

, and constitutional symptoms. It was validated for secondary myelofibrosis and survival. For high-risk survival, it’s... close to 2 years and for low risk, median is not reached, and intermediate-1 and intermediate-2 are in-between.

The updated National Comprehensive Cancer Network [NCCN] guidelines recommend checking 1 of the prognostic models for patients: the MIPSS, DIPSS, or MYSEC. They stratify to 2 different risk groups, lower risk or higher risk, depending on the score.

What are the NCCN guidelines for managing high-risk myelofibrosis?

If you look at the NCCN guidelines for high-risk myelofibrosis, the recommendation is to assess the symptom burden using 1 of the symptom assessment forms; MPN-10 is probably the simplest one. It has only 10 questions and is easily scalable. Patients who have low platelets do poorly, so if they are transplant candidates, you proceed to transplant. If they’re not candidates, they can be considered for clinical trials. Patients with platelet counts [greater than] 50,000 mm3, because they’re high risk, can be considered for transplant. If they’re not transplant candidates, the options are JAK inhibitor therapy, clinical trial, and then monitor symptoms and monitor response. If they are responding, continue treatment. If they are not responding, then they can go on an alternative JAK inhibitor or a clinical trial. If the patient progresses to acute myeloid leukemia or advanced myelofibrosis, they’re treated accordingly. Still, if transplant is an option, that can be considered. If a patient is not a transplant candidate and has symptomatic anemia, that can be treated a little bit differently.

Can you describe the response to ruxolitinib in the COMFORT trials?

There were 2 COMFORT trials that led to the approval of ruxolitinib [Jakafi] in 2012, the first drug that came to the market for myelofibrosis. The COMFORT-I trial [NCT00952289] was a United States–based trial, which was a randomized trial between ruxolitinib and placebo.

 The COMFORT-II trial [NCT00934544] was mainly a European trial that compared ruxolitinib with the best available therapy.

In the COMFORT-I trial, 41.9% of patients met the primary end point, which was greater than 35% spleen volume reduction [SVR] vs 0.7% of patients in the placebo group. The majority of the patients on the ruxolitinib had a response; even if they did not reach the primary end point, most of the patients did have reduction in spleen size.

 Similarly, in the COMFORT-II trial, 28% of patients taking ruxolitinib met the same primary end point and the majority of patients had a spleen volume response. Overall, 97% of the patients had a SVR vs 56% of the best available therapy [BAT] arm. A very small percentage of the patients had spleen enlargement on the preterm compared with the BAT.

Looking at the symptom response in COMFORT-1, the secondary end point was more than 50% improvement in the total symptom score. The majority of the patients had more than 50% reduction compared with a very small percentage of patients in the placebo arm. Similarly, there was improvement in the individual symptoms with ruxolitinib vs placebo. If you look at the onset of symptoms, they improved within 4 to 6 weeks. We don’t have this kind of response for the spleen volume, but the symptoms improved dramatically between 4 and 6 weeks.

 For the COMFORT-II trial, they used a different symptom assessment tool, but, again, there were better responses in all the symptoms in the ruxolitinib arm vs the BAT arm.

They also presented survival data. Compared with the control arms, in both the COMFORT trials, patients who were on ruxolitinib had improved survival, and this was significant. [Median OS was 5.3 vs 3.8 years (HR, 0.70; 95% CI, 0.54-0.91; 

There was a retrospective study by Cervantes et al in 2009 that looked at causes of death, including transformation to acute leukemia, primary myelofibrosis progression without acute transformation, thrombotic events, infection, bleeding, portal hypertension, or other causes.1 This included [approximately] 1000 patients. Median survival was 69 months, and there were [approximately] 49% of the patients who died on the analysis.

Looking at the effect of the spleen response on OS, patients who have a spleen response with 35% volume reduction have a longer survival compared with those patients who don’t have that spleen response. Also, patients who have more durable response, their survival is much greater.

 Baseline factors associated with lower response include patients who have a high-risk disease with a very big spleen more than 20 cm below the costal margin, very high white [cell] count, delaying starting ruxolitinib after diagnosis, or keeping it at a lower dose rather than escalating the dose.

They also looked at the various doses and their responses. Patients on a lower dose—for example, less than 10 mg twice daily—had a lower response compared with patients who were on a higher dose, both for symptoms and for spleen volume. At 10 mg twice daily or more, you had a better response. It’s better to avoid starting with the lower dose, but if you start low, you should then escalate quickly to the maximum safe dose. Doses less than 10 mg twice daily may not be very effective for the long term.

Looking at grade 3 to 4 adverse events [AEs] in both the COMFORT-I and COMFORT-II trials, anemia and thrombocytopenia were prominent, which can be explained by the mechanism of action from inhibiting the JAK pathway.

What do you think of the dosing for ruxolitinib?

A study called EXPAND [NCT01317875] was done to assess how high a dose of ruxolitinib could be tolerated in patients with thrombocytopenia. Patients who had moderate thrombocytopenia, with platelet counts of 75 to 99 [× 10

/μL], were started at 5 mg in the morning and 5 mg in the afternoon, and doses were gradually escalated to 15 mg twice daily. Once they saw that there were not too many AEs, they included these doses for the patients with platelet counts of 50 to 74 [× 10

/μL]. A maximum safe dose was established at 10 mg twice daily in both arms. Thrombocytopenia and anemia were still observed in these patients. Even though the platelet count was low, patients still benefited from the treatment, with SVR and improvement in the symptom score.

thiamine [vitamin B1]. That’s why these patients required thiamine to be checked prior to the treatment, replaced, and then monitored during the treatment.

If you look at the high-risk myelofibrosis algorithm [NCCN guidelines], if the patient’s a transplant candidate, they can go to transplant. If they’re not a candidate, assess symptoms. Then depending on the platelet count, if it’s below 50 [× 10

/μL], they’re not candidates for ruxolitinib or fedratinib; they can go on the trials. If it’s over 50 [× 103/μL], then they can go on any other JAK inhibitor. Fedratinib is also added now [because] it was approved. You follow the paradigm of following response and continuing treatment if the patient is responding. If they’re not responding, then consider changing treatment.

Do you use splenectomy in your treatment?

Very few patients will benefit from splenectomy. Occasionally, you will have a patient who has very low-risk disease and has failed a JAK inhibitor where the spleen is still enlarged. Then I would consider doing splenectomy. Most of the time they will be patients who are 

mutation positive. They don’t get the best response to JAK inhibitors. A couple of patients were falling into very low-risk [group] by the MIPSS and DIPSS criteria; they were symptomatic, they had anemia. So I took out the spleen and the platelets improved, the hemoglobin improved, and their lives improved tremendously.

For patients who are transplant candidates and either are not responding to JAK inhibitors or have a low platelet count, would you take them to transplant without a splenectomy?

There’s a recent very good study that came out of Europe [with results that] explained how spleen size and splenectomy...affect transplant. In this patient who had a spleen size of [greater than] than 20 cm, they had a really hard time after transplant with cytopenia. Either you can consider doing a myeloablative regimen if they’re eligible, rather than doing the reduced intensity, or if the patient has otherwise good performance status, you can consider doing a splenectomy. It was a retrospective study, but that means that’s something that they saw; 20 cm was the cutoff point for outcome change.

1. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. 

. 2009;113(13):2895-2901. doi:10.1182/blood-2008-07-170449

2. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International

Articles

Clinical Articles

Haris Ali, MD, discussed a 68-year-old woman who presented to her physician with symptoms of fatigue and abdominal pain lasting 4 months; she also reported increased bruising.

Ali Discusses Treatment Options and Spleen Size in Primary Myelofibrosis

 Case-Based Roundtable, Matt Matasar, MD, discusses treatment options in B-cell lymphomas.  

: What are the treatment options in the second-line setting?

 The NCCN [National Comprehensive Cancer Network] criteria recommend 2 preferred regimens, the first being the R-GemOx [gemcitabine, oxaliplatin (Eloxatin), plus or minus rituximab (Rituxan)] that our patient here received, and the second being the combination of BR/pola [polatuzumab (Polivy), plus or minus bendamustine, plus or minus rituximab].¹ There are a number of other alternative regimens NCCN recommends, most of which are cytotoxic-based with the exception of tafasitamab [Monjuvi] and lenalidomide [Revlimid], which are listed as the last of the “other recs.” Under the category of “useful in certain circumstances,” there are things like brentuximab vedotin [Adcetris] for CD30+ disease; BR without polatuzumab; and then ibrutinib [Imbruvica] or R2, the lenalidomide plus or minus rituximab program for non-GCB [germinal center B-cell] large cell lymphoma.

Which of these regimens are FDA approved? 

The only regimens that are specifically FDA approved are the BR/pola regimen and the tafasitamab plus lenalidomide regimen.

 The BR/pola regimen’s FDA approval is specifically for third-line [therapy] and beyond, but given the data from the clinical trial [NCT02257567] leading to its approval and subsequent updates on those data, it’s NCCN-listed as second-line [therapy] and beyond.

The tafasitamab plus lenalidomide program is simply approved for relapsed/refractory large cell lymphoma, regardless of line of therapy, as long as [patients are] transplant ineligible.

What factors influence decision-making in the thirdline treatment setting? 

In terms of how you follow patients after they’ve gotten their treatment for relapsed/refractory disease, if they’ve either only had a PR [partial response], or relapsed subsequently, or progress on their second-line treatment, then you’re thinking about third-line therapy.

 Third line in NCCN is either CAR [chimeric antigen receptor] T-cell therapy, which has FDA approvals for third line and beyond, or you pick some other second-line program. Or you can give palliative radiotherapy, or just palliative care with considerations for an allogeneic transplant in patients who respond, although that’s a little bit controversial, truthfully. When you look at the third-line subsequent therapy with CAR T cell, there are 3 that are approved: axi-cel [axicabtagene ciloleucel (Yescarta)], tisagen [tisagenlecleucel (Kymriah)], and now liso-cel [lisocabtagene maraleucel (Breyanzi)].

 But NCCN recommends 2 additional drugs: the first is loncastuximab tesirine [Zynlonta], and selinexor [Xpovio], which is approved as third-line [therapy] or beyond.

Challenges with tafasitamab or loncastuximab include that these are both drugs that target CD19. Loncastuximab is a CD19-targeted antibody-drug conjugate and tafasitamab is a naked anti-CD19 antibody.

 There’s a lot of uncertainty in the medical and lymphoma communities about how to sequence CD19-directed therapies. Is it OK to give people loncastuximab or tafasitamab if you’re thinking about a subsequent therapy with a CD19-directed CAR T cell, or are you potentially cutting off your nose to spite your face?

Please discuss the data that led to the approval of axi-cel, tisagen, and liso-cel.

 Axi-cel we think of as maybe the most active, with an ORR [overall response rate] north of 80%, and a CR [complete response] rate approaching 60%.

 Tisagen was a little bit milder, with an ORR of 50%.

 Liso-cel had an ORR of 70%, although some of the mature overall survival [OS] data are around liso-cel, which is helpful.

Toxicity-wise, they do differ, and they seem to track along with the activity. So, [the general theme] the stronger the toxicity has been the general theme. Axi-cel is a little bit stronger than liso-cel, maybe, but definitely more toxic.

Tisagen has much lower rates of neurotoxicity, and so it is more like liso-cel than axi-cel.

 The CRS [(cytokine release syndrome) was determined by a] different scale with tisagen, [they used the University of Pennsylvania grading scale which yielded a score of 23% of patients having a grade 3 or 4 CRS]; but a lot of that would be classified as grade 1-2 by the Lee criteria that the axi-cel and liso-cel data use.

Please discuss some of these data that supports the use of newer therapies in this patient population.

The most recent approval was for loncastuximab tesirine, which was approved [in April 2021 for] the treatment of relapsed/refractory large cell lymphoma.

Loncastuximab’s design is an antibody-drug conjugate, like polatuzumab, in terms of its design, but very different. It targets CD19, as do the CD19-targeting CAR T-cell therapies; and the payload is not MMAE [monomethyl auristatin E], as it is in brentuximab or polatuzumab, but teserine, which is a cytotoxin.

 It’s a PBD [pyrrolobenzodiazepine] payload and it causes cross-links. So, this is a direct cytotoxic agent.

The data behind loncastuximab’s approval come from the LOTIS-2 study [NCT03589469], which was a single arm phase 2 study of loncastuximab in the treatment of relapsed/refractory large cell lymphoma.18 It was designed for third line and beyond. They had to be proven to be CD19 positive if they’d had prior CD19-directed therapy. Bulky diseases were excluded, and that’s based on the phase 1 data, showing that it doesn’t have activity at an adequate level in bulky disease. It did allow for transformed low-grade lymphoma, and high-grade lymphoma, but Burkitt’s lymphoma was excluded; that’s a very different animal along with active central nervous system disease, as well as the other factors.

The way you give loncastuximab [is to administer] a loading dose of 150 µg/kg for the first 2 cycles and after that you decrease to 75 µg/kg.⁹ It’s given as a brief 30-minute infusion every 3 weeks for up to a year of treatment, after which you stop. The ORR was the study’s primary end point and there were a host of secondary clinical end points.

In terms of the patients who were treated with loncastuximab in LOTIS-2, the majority were regular large cell lymphoma, although there was a small percentage of patients who had high-grade lymphoma or primary mediastinal lymphoma.

 A small percentage of patients had a double hit [10%], whereas most patients had advanced-stage disease. The median number of prior lines of therapy was 3, so this is median fourth-line therapy in this study. A minority of patients, but a substantial minority, were primarily refractory to their original anthracycline-based therapy and the majority were refractory to the most recent line of therapy.

What were the efficacy results of LOTIS-2?

In terms of the activity, we see an ORR with loncastuximab monotherapy of 48% [95% CI, 39.9%-56.7%], and a CRR of 24% [95% CI, 17.4%-31.9%].18 Most patients responded early; there were very few late responders. The median time to response was 40 days, and the median number of cycles administered was 4, but some patients did go on to get the full 18 as specified by protocol. When you look at the LOTIS-2 data by subgroup, in that small group of patients who did have double or triple hit, there were responders even in high-grade lymphoma. There were responders in both de novo and transformed disease. There were responders even among the relatively few patients who had a prior transplant.

Even in the small number of patients who had prior CAR T that still had CD19 expression, there was response in that small group. So, the take-home from the subgroup analysis with loncastuximab is that there’s not a prespecified group of patients in whom the drug lacks activity, and that’s important to remember. Although cell of origin may influence decision-making here; for the subset of patients that we had cell of origin, which was not all patients, the activity seemed comparable for GCB and non-GCB, and that makes sense. This is just a cytotoxin; there’s no reason to believe that the B-cell [treatment] differs between GCB and non-CGB.

The duration of response was reasonable, particularly in the CR patients; for those who did achieve a CR, the median duration of response over a year is favorable.18 PRs were relatively few and they tended to drop off quickly, as you’d expect with relapsed aggressive lymphoma.

The median PFS [progression-free survival] was 5 months and the median OS approached 10 months. These are not great survival rates, but for median fourth-line therapy, where the median survival expectancy without active treatment would be measured in weeks and not months, it’s worthwhile contextualizing these results. In terms of subsequent treatment, there were patients who went on to receive CD19-directed CAR T-cell therapy, and those patients did have an adequate response to subsequent CAR T-cell therapy. We don’t know how many patients lose CD19 when they are refractory to loncas-tuximab; that’s an area of ongoing clinical investigation. 

In terms of toxicity, loncastuximab does have some well-characterized toxicity at this point, including hematologic toxicity—particularly thrombocytopenia, although not overwhelmingly so.

 One adverse effect [AE] of loncastuximab that’s unusual, and we think that’s related to the PBD payload because we’ve seen it in other PBD-delivering drugs, is a fluid accumulation issue. This can be peripheral edema and it can also be pleural effusions. This is a clinical pearl: If you ever want to prescribe loncastuximab for patients, be thoughtful about evaluating patients’ weight, look for peripheral edema, listen for effusions, and at the onset of fluid accumulation, start spironolactone [Aldactone] early during treatment.

What are some tips for treatment with loncastuximab?

As I said, you start with a loading dose for 2 cycles and then you continue it for up to a year at a lower dose. Premedicating with steroids is important; you give them ahead of time.

 If you can’t do that, then definitely at least give dexamethasone premedication, and that’s continued through the course of treatment. A little bit of guidance here, particularly regarding the fluids as we’ve just said: If you start getting into trouble despite spironolactone, hold the loncastuximab, dial the dose down if you need to. The same goes for cytopenias, particularly thrombocytopenia. You can also use growth factor support along with loncastuximab if you need to, such as pegfilgrastim.

There’s a lot of work ongoing with developing loncastuximab further. LOTIS-2 was a monotherapy study, and usually we don’t stop at monotherapy. Right now, they’re working on developing LOTIS-5 [NCT04384484], a randomized trial of R-GemOx as an erstwhile standard of care vs loncastuximab plus rituximab.

What data supports tafasitamab’s approval? 

That data that supported tafasitamab’s approval come from the L-MIND study [NCT02399085], it's important to understand the pros and cons of that study.

 This was treatment for second line and beyond large cell lymphoma transplant-ineligible patients with large cell lymphoma, that excluded patients who had primary refractory disease.

That differs from the loncastuximab study, as well as from PBR. [The regimen was] tafasitamab, they get loaded the first month, for 4 weeks in a row, in combination with lenalidomide, and then patients go on to every other week treatment intravenously. After those first 12 cycles, lenalidomide is dropped, and patients stay on tafasitamab maintenance therapy until progression or intolerance.

It was an older patient population, median number of prior lines of therapy was 2, so a little bit less heavily pretreated number of patients.

 Early relapse was only 20%, those with primary refractory disease were excluded. There was a little bit of an amendment process that allowed some patients on who progressed between 3 and 6 months after first-line therapy. So, less heavily pretreated, and less aggressive subset of patients. They all still did have relapsed/refractory large cell lymphoma.

The outcomes show there was good activity in this admittedly select group of patients, with 43% patients achieving a CR, an additional 18% of patients achieving a PR, for an ORR of 60%.

 For those, a median duration of response of almost 2 years and it was quite active in this selected patient population.

At the initial time of reporting, the median PFS was 12 months and OS had not yet been met. This was favorable, compared to what else was available at the time in this patient setting. These data have been updated recently by Dr [Gilles] Salles with a median PFS now estimated at 16 months, and median OS of almost 3 years, an extraordinarily favorable OS.

What is the toxicity profile of tafasitamab? 

In terms of the tolerability, tafasitamab itself seems to add very little toxicity on top of lenalidomide.

 We are all very well acquainted with the toxicity of lenalidomide monotherapy, including some cytopenias. In addition to tafasitamab maintenance, lenalidomide seems to have very little additional toxicity. In terms of nonhematological toxicity, there was maybe a little bit of additional myelosuppression from tafasitamab and most of this we believe is attributable to lenalidomide.

Only 12% of patients came off [of therapy] due to AEs and there were 13% of patients who came off due to death; however, in the opinion of the investigators, none of those were attributable specifically to therapy, and instead were due to progression of disease.

What other studies impact treatment decisions for clinicians?

The GO29365 study [NCT02257567] study was designed to look at both large cell lymphoma and follicular lymphoma, but we’re focusing on the large cell lymphoma part of that study.

It was a small, randomized component after a safety run-in of BR alone vs BR/pola. This was for second line and beyond, transplant-ineligible patients. Primary refractory patients were allowed, however. The median number of prior lines of therapy was 2. The duration of response of the last treatment was less than 12 months, which was most patients, suggesting these were patients who were relatively highly refractory. A substantial fraction of patients had received a prior stem cell transplant, as well.

In terms of the response rates, BR/pola was significantly better than BR alone, with an ORR of 45% compared with only 17% for BR alone.

 The median PFS was 10 months for the BR/pola combination compared with only 4 months for BR alone. Median OS with BR/pola was 12 months compared with 5 months with BR alone.

You may say, “we have a median OS of 12 months for BR/pola, we had a median OS of over 2 years for tafasitamab plus lenalidomide,” and I would caution against that type of cross-trial comparison, given the exclusion of refractory patients. There will be updated data for the BR/pola combination, looking at the patients who would have been eligible for L-MIND, excluding the refractory patients, trying to draw some more cross-trial comparisons that should hopefully shed more light on the activity of BR/pola vs tafasitamab plus lenalidomide in that lower risk patient population.

In terms of AEs, we are all very well familiar with the AEs caused by BR in our patient population, myelosuppression in particular.

 Polatuzumab is an antibody-drug conjugate delivering MMAE, which is an antitubule agent that has wellcharacterized neuropathy. The neuropathy in this study was relatively modest and largely reversible, and polatuzumab does seem to add a little bit on top of the myelosuppression from BR alone.

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4. FDA approves polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. FDA. News release. FDA Drug Approvals and Databases. June 10, 2019. Accessed August 24, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-diffuse-large-b-cell-lymphoma

5. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. FDA Drug Approvals and Databases. August 3, 2020. Accessed August 24, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tafasitamab-cxix-diffuse-large-b-cell-lymphoma

6. Yescarta. Prescribing information. Kite Pharma, Inc; 2021. Accessed August 24, 2021. https://www.gilead.com/-/media/files/pdfs/medicines/oncology/yescarta/yescarta-pi.pdf

7. Kymriah. Prescribing information. Novartis Pharmaceuticals Corp; 2021. Accessed August 24, 2021. https://www.novartis.us/sites/www.novartis.us/files/kymriah.pdf

8. Breyanzi. Prescribing information. Bristol Myers Squibb; 2021. Accessed August 24, 2021. https://packageinserts.bms.com/pi/pi_breyanzi.pdf

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10. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma [ZUMA-1]: a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20[1]:31-42. Accessed August 27, 2021. doi:10.1016/S1470-2045[18]30864-7

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12. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas [TRANSCEND NHL 001]: a multicentre seamless design study. Lancet. 2020;396[10254]:839-852. Accessed August 27, 2021. doi:10.1016/S0140-6736[20]31366-0

13. FDA approves lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma. FDA Drug Approvals and Databases. February 5, 2021. Accessed August 27, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lisocabtagene-maraleucel-relapsed-or-refractory-large-b-cell-lymphoma

14. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017;377[26]:2531-2544. Accessed August 27, 2021. doi:10.1056/NEJMoa1707447

15. Bachanova V, Westin J, Tam C et al. Correlative analyses of cytokine release syndrome and neurological events in tisagenlecleucel-treated relapsed/refractory diffuse large b-cell lymphoma patients. Hemat Oncol. 2019; 37[S20]:308-310. Accessed August 27, 2021. https://doi.org/10.1002/hon.118_2630

16. FDA grants accelerated approval to loncastuximab tesirine-lpyl for large B-cell lymphoma. FDA Drug Approvals and Databases. April 23, 2021. Accessed August 27, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-loncastuximab-tesirine-lpyl-large-b-cell-lymphoma

17. Zammarchi F, Corbett S, Adams L, et al. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. Blood. 2018;131[10]:1094-1105. Accessed August 27, 2021. doi:10.1182/blood-2017-10-813493

18. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma [LOTIS-2]: a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22[6]:790-800. doi:10.1016/S1470-2045[21]00139-X

19. Study to Evaluate Loncastuximab Tesirine With Rituximab Vs Immunochemotherapy in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma [LOTIS 5]. ClinicalTrials.gov. Identifier: NCT04384484. Updated August 23, 2021. Accessed August 27, 2021. https://clinicaltrials.gov/ct2/show/record/NCT04384484?term=NCT04384484&draw=2&rank=1

20. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma [L-MIND]: a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21[7]:978-988. Accessed August 27, 2021. doi:10.1016/S1470-2045[20]30225-4

21. Salles G, Duell J, González Barca E, et al. Long-term outcomes from the phase II L-MIND study of tafasitamab [MOR208] plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Abstract presented at: The 25th European Hematology Association Annual Congress; June 11-21, 2020; Virtual. Accessed August 27, 2021. https://library.ehaweb.org/eha/2020/eha25th/293691/gilles.salles.long-term.outcomes.from.the.phase.ii.l-mind.study.of.tafasitamab.html

22. Zinzani PL, Rodgers T, Marino D, et al. RE-MIND: Comparing tafasitamab + lenalidomide [L-MIND] with a real‑world lenalidomide monotherapy cohort in relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. [online ahead of print] Accessed August 27, 2021. doi:10.1158/1078-0432.CCR-21-1471

23. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2020;38[2]:155-165. Accessed August 27, 2021. doi:10.1200/JCO.19.00172

Matt Matasar, MD, discusses treatment options in B-cell lymphomas.  


Matasar Considers Treatment Options in  B-Cell Lymphoma

During a Targeted Oncology Case-Base Roundtable event, Andrzej Jakubowiak, MD, PhD, led a discussion on new agents for the treatment of multiple myeloma. 

: The patient was diagnosed initially with 17p, which tends to behave more aggressively, sometimes out of proportion to increase in M spike. I think positron emission tomography [PET] imaging would be reasonable. How about repeating the bone marrow biopsy and checking cytogenetic FISH?

 What would be the benefit of a repeat bone marrow biopsy? We already know the patient is high risk; she has 17p deletion, 1 of the highest-risk genetic abnormalities, so I wouldn’t repeat the bone marrow biopsy.

 If you start a new therapy, you want to know whether that new therapy is working. The reason to restage may not be to make sure the patient has progressed—because we know they’ve progressed—but rather to serve as a new baseline because if you give a new therapy, you may need a bone marrow in the future to see how well they’ve responded.

 I personally don’t think I’d trigger [second-line therapy] because of an increase in M protein but more of a trend. If I see a trend, then it’s concerning, and we start worrying about it. I would also do a PET scan to look for something like plasmacytoma that could cause a problem and be easily treated. Sometimes marrow shows more than the blood shows. I will sometimes do the marrow if I’m on the fence about whether to start treatment or not.

If you’re treating someone with an active therapy and their disease meets progression criteria—their M protein has gone up by more than 25%—I would favor changing therapy, even if you don’t have a clinical trial. Drugs have costs and toxicities, so to give someone a therapy while they’re clearly progressing through disease [doesn’t make sense to me].

 There is a trend among some myeloma leaders to start the next-line therapy, for example, with the reappearance of minimal residual disease [MRD] or if the patient was previously in complete remission and has no change in MRD spike, but there is a reappearance of disease in the bone marrow. That is not our practice. I am, with few exceptions, following the rule that at that point intervention is not indicated, but I suspect that will change over time.

 The patient has been on maintenance for 2 years. It’s the rapidity of the rise [of disease] that I look at: Is it a slow rise or rapid rise? I don’t want to burn a bridge; my concern is that we could run out of things to give someone. If somebody is tolerating something really well, you hate to go away from that. Obviously, if there is disease progression.…I do a full workup, including the imaging and the bone marrow, just to see where we are and not just look at the M spike and trends. If it looks like a real progression, obviously go to the next line rather than giving something through which their disease is overtly progressing.

 I have to say that I prefer to have a discussion with a newly diagnosed patient about picking the best therapy rather than a discussion [with a patient about] relapsed/refractory disease. It’s more challenging, and I don’t think we have absolute guidelines.

 Performance status, cytogenetics, time and extent of relapse, and other factors affect what we choose for the patient.

For some of us, including myself, the golden rule in oncology, in the absence of specific guidance based on the cytogenetics or the biology of the disease, is that if the patient’s disease is progressing through the current treatment, [we should] change to 1 or preferably 2 different agents if we can apply them. A lot of data show that a triplet regimen could be even better; of course, we will still look at prior toxicity, the status of the patient, and other factors.

: This patient may be in the initial phase of progression. Is it reasonable to increase the frequency of daratumumab and continue the treatment rather than change it altogether?

 There was a time when we were just starting daratumumab that we were tempted to reintroduce more frequent daratumumab, [and do the same] with lenalidomide maintenance. I think data supports that the more effective way of addressing progression of the disease, regardless of whether we are using optimal dosage or not on a given regimen, is to switch to different agents and different therapy. But nothing is absolutely written in stone.

 It sounds like this patient hasn’t had proteasome inhibitor in a while—or ever. And so that would be a backbone of my next regimen.

I’m not sure I would keep daratumumab, but I would probably use carfilzomib [Kyprolis]- and pomalidomide [Pomalyst]-based therapy.

We’re switching from [lenalidomide to pomalidomide] and adding a proteasome inhibitor. Pomalidomide, in some studies, has been shown to be active in a P53 deleted subset of patients. A lenalidomide and dexamethasone study showed that and a couple of other studies with pomalidomide as well, although not randomized trials. There are a couple of other preferred choices. VPd is very comparable. In fact, in direct comparison, those 2 adjuvant therapies are in the same ballpark of responses and progression-free survival.

 Selinexor is one of the few drugs for which we have proof of a completely different mechanism of action.

 It inhibits exportin, one of the mechanisms of export of oncogenes from the nucleus, and allows the immune system of a patient, especially those with deficient P53, to engage in apoptotic pathways and eliminate more cancer cells. I think that activity of this combination is well supported. Toxicity is usually well managed. Are you comfortable using selinexor in the first and second line of therapy?

 The majority of us who have not had a patient in a clinical trial for the first-line therapy haven’t used daratumumab up front for very long. And so most of our second-line therapy has been daratumumab-based. A lot of us haven’t gotten to a selinexor line because of that. But now that daratumumab has moved up to firstline therapy in so many patients, I think that’s probably going to change.

 I agree. The landscape is changing dramatically. [Comparing older studies to new ones may be unfair because] older studies may not have been able to generate results as impressive as ours. For example, the results of POLLUX were excellent and just beyond anybody’s expectations.

Most of my patients who need secondline therapy are daratumumab naïve. So I tend to use daratumumab with either pomalidomide or carfilzomib, depending on what they had before, with success. I think daratumumab is a great backbone. Lenalidomide has been used first line, for the most part, so daratumumab, pomalidomide, or some combination of that would be my second line for most patients.

 Many patients who have experienced relapse have had a transplant and are on lenalidomide maintenance. They’ve had bortezomib [Velcade], lenalidomide, and dexamethasone as their initial therapy. I usually use daratumumab, pomalidomide, and dexamethasone in that setting.

 I also consider the type of progression. Is it slow progression? Is it more aggressive progression with organ damage? I try to make that distinction. Also, how long has the patient been on the first-line treatment? Is the disease truly refractory, or do we need to reinstitute chemotherapy drugs we used in the earlier line? I look at all that as well.

 How important for you is switching to a different mechanism of action?

 I think it’s important to change to a different mechanism of action in the second or third line. Usually, 2 different drugs or 2 different mechanisms will give us better results.

 The main changes in my practice are using more daratumumab and more pomalidomide. I stopped using elotuzumab [Empliciti] altogether.

 There has been evolution in the regimens that we use. There was a period when carfilzomib, lenalidomide, and dexamethasone was most used. We had too many patients progressing on lenalidomide, and then the pomalidomide combination was approved. Daratumumab, pomalidomide, and dexamethasone was probably the most common regimen for about a year and a half.

In the situation where you have very good long-standing response and a patient’s disease is progressing on lenalidomide, my top 3 choices will be daratumumab, pomalidomide, and dexamethasone; carfilzomib, pomalidomide, and dexamethasone; and isatuximab [Sarclisa], pomalidomide, and dexamethasone. All of these, I would say, may have comparable response rates and duration of response. We have been kind of frustrated that we have to make choices between these 3. We [last presented data on treating this patient population] at the American Society of Hematology 2020 Annual Meeting. There are a small number of patients on the trial, just over 20 patients, but our patient population is rather tough. Over 50% of the patients achieved stringent complete response, which is remarkable, in my opinion and the tolerability is good. This is still an actively enrolling study and with this triplet combination, there is good potential to not miss out on the best choice of drug because we don’t know enough about the biology of the disease.

1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 7.2021. Accessed July 13, 2021. https://bit.ly/36TOWx6 

2. Dimopoulos MA, Moreau P, Terpos E, et al; EHA Guidelines Committee, ESMO Guidelines Committee. Multiple myeloma: EHA-ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(3):309-322. doi:10.1016/j.annonc.2020.11.014 

3. Xpovio. Prescribing information. Karyopharm Therapeutics Inc; 2020. Accessed July 14, 2021. https://bit.ly/3eG0OqV 

4. FDA approves selinexor for refractory or relapsed multiple myeloma. Food and Drug Administration. Updated December 18, 2020. Accessed July 14, 2021. https://bit.ly/2UX4AFq 

5. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi:10.1016/ S0140-6736(20)32292-3 

6. Dimopoulos MA, Oriol A, Nahi H, et al; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331. doi:10.1056/NEJMoa1607751

Roundtable Discussion: Jakubowiak Looks at New Agents for Relapsed/Refractory Multiple Myeloma

We believe that the primary curative mechanism of an allogeneic transplant is an immunologically based graft vs malignancy effect, also called graft vs leukemia or graft vs tumor. The issue, though, is that oftentimes this phenomenon is after allogeneic hematopoietic cell transplantation, and the [further] complication of GVHD has been common over the past few decades. Both acute and chronic GVHD have been a huge area of research for those of us in transplantation and [the disease is] a leading cause of nonrelapse mortality. In acute GVHD, the main organs affected are the patient’s skin, gastrointestinal [GI] tract, and liver; however, chronic GVHD is far more variable, and it can affect almost any organ and the syndrome itself can mimic classic autoimmune disease.

The clinical risk factors traditionally for both acute and chronic GVHD have been quite similar. In fact, if you look at older studies, the occurrence of acute GVHD was thought to be the leading risk factor for chronic disease. That may not be true at this point, though I think large studies may now disagree with each other. With standard methods of prophylaxis, still, about 25% to 50% of patients receiving a conventionally matched transplant will develop some spectrum of acute GVHD that requires some treatment and systemically that remains high-dose steroids. Of those patients who are put on steroids, up to 50% or more will require a second agent because of either failure of a response or an inadequate response.

Acute GVHD starts with damage or inflammation caused by the conditioning regimen, which is often myeloablative at that time, and that created a local environment that was ripe to generate an immunological response. Once donor cells were introduced, and allorecognition happened, donor T-cell activation occurred in secondary lymphoid tissue, and they acquired the trafficking phenotype to go back to those host tissues upon recirculation. Expansion then happened, and those T cells recirculated to the tissue and basically caused damage leading to the clinical manifestations of acute GVHD. This model has been popularized, but I believe we all believe it’s far more complicated at this point and often its specific arms have failed to improve the field.

Every patient after an allogeneic transplant received some form of prevention or prophylaxis against GVHD, not just for acute but also for chronic. The international standard now for a matched transplant has been for the past couple of decades built upon the backbone of a calcineurin inhibitor, which includes either cyclosporin or tacrolimus.

The calcineurin inhibitors were classically paired with short courses of methotrexate after transplant, and recently methotrexate has been substituted for mycophenolate mofetil....Most recently, the newest form of pharmacological prophylaxis includes high doses of cyclophosphamide given on days 3 and 4 after transplant to eliminate alloreactive cells, and ongoing prospect trials are comparing posttransplant cyclophosphamide with our previous standard of calcineurin inhibitor– based prevention.

The other general category for prophylaxis has been called T-cell depletion. This is far less popular because it involves a laboratory expertise and resources, and this involves taking a donor graft and manipulating it either through positive selection of donor stem cells, or negative selection by eliminating a subset of T cells to try and prevent GVHD. Trials have tried to compare T-cell depletion with pharmacological methods and fail to show superior outcomes. In the future, this may change as more trials are done with more sophisticated methods of graft manipulation.

One of our main weaknesses for why we haven’t made progress in GVHD clinical trials is that we treat everybody the same, and when we do a clinical trial, we write it as grade 2 through 4—grade 2 being the most common. We are overwhelmed with low-risk patients, so any intervention we design, we fail to see because it is diluted by a lower-risk population. Now, there have been calls on the national level and international level to how we best risk-stratify patients, and if we’re able to risk-stratify patients, we can then do risk-stratify trials, and have a more homogeneous risk population, higher risk, lower risk, and do different things. There are 2 ways to do this. One is by a clinical score, which is the Minnesota clinical score that they published in about 1800 of their patients with acute GVHD treated over the years.

[Researchers] separated them out into standard risk and high risk, and you can do this when you see your patient; if you can clinically grade their acute GVHD, you can separate them into standard vs high risk. The strength of this criterion is you can do it immediately, but the biggest weakness here is only 16% of patients are high risk and 84% of patients are standard risk. It isn’t really a great delineator into groups, and if you try and do a high-risk trial based on this, you’re going to be doing a trial for a long time, even when only 1 in 6 patients is high risk.

The other model for risk stratification is what we’ve mentioned, which is the biomarkers, that are based on ST2 and Reg3A.3 These are GI-mucosal biomarkers that hint at mucosal injury and track, we think, with GI GVHD in the right setting. So that is another way of how we’re going to biologically restratify patients through the mucosal GI GVHD, biomarkers, and ultimately do trials. I think the discussion on the national level has been if we’re going to make progress, we need to be able to identify high-risk patients and probably do high-risk trials with steroids plus drug X. Then for low-risk patients, if we’re accurately able to restratify, we either do lower-dose steroids or avoid steroids, as has been done in the recent Clinical Trials Network trial, or start steroids and taper really a lot faster.

We have simple approaches; we generally give [1 mg/kg] for skin only. There’s visceral involvement with lower GI and we generally escalate to 2 mg/kg, though you do much less hepatic, and we generally question if this is upper GI infection, but that’s our own issue....We now use clinical criteria, and we reached out to find results based on those.

I think we all understand the downsides to steroids, too. So we’re all afraid to fire away and overtreat patients as well, but I think we can all admit that there are some patients with skin disease that you get to 1 mg/kg and they don’t get better or a week later, they have GI disease and you wonder how that happened.

There are also patients with gut disease that you’re sure they have the disease, you started [treatment], and a week later, they have normal bowel movements, and you wonder how that happened. It does really call into need our lack of tools that better understand the biology of the patients in front of us.

I think many clinicians can agree that if you put the patient on steroids, it may get worse after 3 to 5 days and then we would move on to something else. If we gave them a week, and they didn’t get better, I think we’d all agree to move on to something else. They’re steroid dependent, which involves an initial response, but then once you taper it, the disease flares. I think that’s got shifted to gray because I think tapering below 1 mg/kg is different from tapering below 10 mg a day of prednisone.

Those are different biological populations, but they have often been mixed for the purposes of trials. Then there’s steroid intolerance, which isn’t truly steroid refractory, but that can lead you to go to another agent soon, be it because of things like diabetes, horrible osteoporosis, or manic breaks that may make steroid use unacceptable. [A transplant-oriented] National Comprehensive Cancer Netwrok committee happened in the past 2 years or so [that suggested several treatment options, but] the only one FDA approved is ruxolitinib.

The primary end point [of the phase 2 REACH-1 trial (NCT02953678) was] the day 28 overall response rate [ORR] as has been agreed upon by consensus criteria. There was a 55% ORR and about 73% best ORR at any time. The complete response was 27% at day 28, about half complete responses and half partial responses.

The median duration of response was about a year, which is pretty good, and the time to response was about a week, which tells you this course [of treatment was] quickly released. I think, disappointingly, the nonrelapse mortality rate at 6 months was still high at 44%, but those who obviously responded did a lot better than those who didn’t, as you might expect. REACH1 was the trial that got ruxolitinib FDA approved, and REACH2 [NCT02913261] was the validating trial, and it was a phase 3 trial. We rarely see these in this disease and REACH2 was an international trial that randomized patients with refractory acute GVHD to roughly 10 mg twice a day vs best available therapy [BAT]. The investigator had to specify what they would use as BAT, but I think many people can criticize the BAT as a control. All of us know, there’s no national consensus at that time on the second-line therapy, but this was the best trial that could be done. [The trial compared ruxolitinib with BAT and there was a] big benefit for ruxolitinib of 62% vs 39% ORR and these ORRs did mirror the REACH-1 study.

The durable ORR at 8 weeks was 40% vs 22%. [Without BAT as the] control, I don’t know how else you do a phase 3 trial in this population, and these results can only be viewed as positive progress in the field. Failure-free survival was a key secondary end point from [this study] and was a composite end point that showed a big benefit for ruxolitinib vs control. In terms of adverse events [AEs], there were more cases of thrombocytopenia, and when specifically inhibiting JAK, 2 [cytomegalovirus] infections were about the same, but there weren’t any huge AE signals otherwise.

Patients were randomized between ruxolitinib at 10 mg twice a day vs BAT, with ibrutinib [Imbruvica] added as an option because it became FDA approved. I think you can criticize the BAT control because it’s so heterogeneous, but I think you can see that there is no standard, there’s no consensus [for second-line treatment]. So the only way to do this trial would be in this way, and just like the REACH2 trial, I think this was a massive undertaking and really what needed to be done to move the field forward.

The primary end point here was 6 months’ ORR based on the National Institutes of Health criteria with the key secondary end points of failure-free survival, as well as symptom score. The ORR with ruxolitinib was about 50% compared with BAT at about 25%, so a 2-fold increase in ORR. The trial certainly wasn’t blinded, this is an open-label trial, so investigators and patients knew what they were on, and at 6 months, patients on the BAT arm were allowed to cross over if they had not received ruxolitinib.

Thinking About A Multidisciplinary Approach to GVHD

As a multidisciplinary approach, I think it’s useful to point out all the complications of steroid use. I also think a big push in moving treatment forward is just like in acute GVHD, where we’re trying to stratify patients. I think in chronic disease treatment, we’re trying to do the same thing. I think treating all chronic [GVHD] as 1 patient population is probably going to lead to nonsuccess here, as we’ve had over the past couple of decades.

There has to be a subset of chronic [GVHD] that we have to be very aggressive with and hit harder with steroids and maybe some other drugs up front, and then there have to be some sort of chronic treatment group that you can possibly avoid steroids in and use alternative therapy once we have more access, with ibrutinib and hopefully ruxolitinib.

1. Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute graft-vs-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. 

2. MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-vs-host disease that predicts response to initial therapy, survival, and transplant-related mortality. 

. 2015;21(4):761-767. doi:10.1016/j.bbmt.2015.01.001

3. Choi SW, Reddy P. Current and emerging strategies for the prevention of graft-versus-host disease. 

. 2014;11(9):536-547. doi:10.1038/ nrclinonc.2014.102

4. Schoemans HM, Lee SJ, Ferrara JL, et al. EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment. 

. 2018;53(11):1401-1415. doi:10.1038/ s41409-018-0204-7

5. NCCN. Clinical Practice Guidelines in Oncology. Hepatobiliary cancers, version 2.2021. Accessed September 2, 2021. https://jnccn.org/view/journals/ jnccn/19/5/article-p541.xml

6. Jagasia M, Zeiser R, Arbushites M, Delaite P, Gadbaw B, Bubnoff NV. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. 

. 2018;10(5):391-402. doi:10.2217/imt-2017-0156

7. Jagasia M, Perales MA, Schroeder MA, et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. 

. 2020;135(20):1739-1749. doi:10.1182/blood.2020004823

8. Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. 

. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635

During a Targeted Oncology Case-Base Roundtable event, Yi-Bin A. Chen, MD, discussed options for treating acute and chronic graft versus host disease. 

Case-Based Roundtable Meeting Spotlight September 2021:Hematologic Malignancies | Case-Based Roundtable Meetings Spotlight

Ali Discusses Treatment Options and Spleen Size in Primary Myelofibrosis

Matasar Considers Treatment Options in B-Cell Lymphoma

Roundtable Discussion: Jakubowiak Looks at New Agents for Relapsed/Refractory Multiple Myeloma

Chen Reviews the Best Options in Utilizing Ruxolitinib in Acute and Chronic GVHD

Roundtable Discussions: Barriers in Giving Therapies in Relapsed/ Refractory DLBCL

Usmani Considers Possible Treatments for a Patient With Relapsed/Refractory Multiple Myeloma