Conference Update

New Drug Forum 2017: Insights and clinical expertise from HKU hematology team

Haematology
2 months ago, OP Editor

Therapeutics in hematological diseases are developing in an unprecedented pace. It is often difficult for an individual to keep abreast of all advances. The New Drug Forum, hosted by the Division of Hematology of the University of Hong Kong, was held on 7th October. The meeting was a great success and attracted hematologists and oncologists from all over Hong Kong. Clinical experience on the use of novel agents in benign and malignant hematological conditions was reviewed. This is the fourth territory-wide hematology meeting organized by the unit.

Multiple Myeloma: Carfilzomib, Daratumumab, Pomalidomide

Since 2012, medications with distinct mechanisms of actions, such as the second-generation proteasome inhibitor (PI) carfilzomib, monoclonal antibody (mAb) daratumumab, and the third-generation immunomodulatory agents (IMiD) pomalidomide, have been approved for the treatment of relapsed and or refractory multiple myeloma (RRMM).

Which regimen are for first relapse?

As remissions become progressively shorter with subsequent relapses, the choice of regimens is critical, and it would certainly be one of the important clinical questions from the clinicians.1 Prof. Chor-Sang Chim suggested the choice of the optimal regimen would depend on the patient’s characteristics (such as age and comorbidities). In terms of efficacy, “an evaluation of hazard ratios [HRs] among comparable trials would be a reliable method to assess PFS data in the absence of head-to-head trial.” Prof. Chim commented.

For example, to evaluate the choice of regimen for a patient who relapsed 2 years after autologous stem cell transplantation (and had previously received bortezomib/thalidomide/dexamethasone induction with good response), the HRs of four trials, namely ELOQUENT-2, ASPIRE, TOURMALINE-1, and POLLUX could be compared.2-5 “These four trials are comparable in terms of the following reasons: 1) the disease being RRMM, 2) inclusion criteria being 1-3 prior lines of therapy, 3) control arm being Rd [lenalidomide/dexamethasone], and 4) continuous therapy in both control arm and intervention arm,” explained Prof Chim. “While the HRs of around 0.7 from ELOQUENT-2, ASPIRE, and TOURMALINE-1 were already encouraging, the result of daratumumab/lenalidomide/dexamethasone [DRd] in POLLUX is typically impressive, with a HR of 0.37. DRd will thus become the treatment of choice in this case,” he concluded. On the other hand, for patients who relapsed from bortezomib/ lenalidomide/dexamethasone (VRd), Prof. Chim prefers using daratumumab/bortezomib/ dexamethasone (DVd) as salvage therapy, in view of its impressive progression-free survival (PFS) improvement (HR=0.39) in CASTOR study.

Treatment options for refractory MM

Most patients would have received bortezomib and/or lenalidomide-based treatment. Yet, the development of resistance to these agents is now becoming more common. While no randomized study has compared VRd and KRd, carfilzomib may be effective in bortezomib-refractory patients. The result of ENDEAVOUR was clearly in favor of Kd vs. Vd, although the dose of carfilzomib used in this study was higher than the approved one.6 Pomalidomide and daratumumab have been tested in double-refractory patients and also yielded promising results.7,8

What about high-risk MM?

Results of POLLUX and CASTOR trials have generated great enthusiasm with negative minimal residual disease (MRD) being achieved and maintained over longer follow-up with DRd and DVd,9,10 particularly to patients with high-risk cytogenetics,11 which represents a landmark advance in the treatment of MM. Similarly, for carfilzomib, the triplet regimen (KRd) was found to overcome the effects of adverse cytogenetics, and a favourable benefit-risk profile was observed in both high-risk and standard risk RRMM.3 Nevertheless, the use of these potent second-line agents in front-line setting, even in high-risk patients, was not recommended due to the lack of convincing evidence. Given the efficacy of daratumumab, even as a monotherapy, in SIRIUS trial,12 Prof. Chim is positive with the future outcomes of a quadruplet regimen (mAb/PI/IMiD/steroid).

Myeloid Malignancies: Azacitidine, Clofarabine, Decitabine, Ruxolitinib

The place of hypomethylating agents in newly diagnosed high-risk acute myeloid leukemia (AML)

Beyond current indications for myelodysplastic syndromes (MDS) and transplant-ineligible AML, the hypomethylating agents (HMA) azacitidine and decitabine may be considered in transplant-eligible patients with complex karyotype (CK) and TP53 mutations in whom response rates to standard 3+7 regimen (i.e. cytarabine given continuously for 7 days at 100mg/m2 daily together with 3 days of an anthracycline) remain very low.13

Prof. Yok-Lam Kwong explained, “Alterations in TP53, also known as the ‘guardian of genome’, is often associated with a high degree of genomic complexity. Based on our data, TP53 mutation is found to be present in 50% of CK-AML patients, which might partly explain the dismal survival outcomes in this group of patients when treated with conventional apoptosis-based approaches.”

From a mechanistic point of view, HMAs may have the potential of improving therapeutic outcomes in high-risk AMLs by inducing cell cycle exit independent of p53.13,14 Indeed, Welch et al reported similar transplantation and survival outcomes among patients with wild-type or mutated TP53 who have received 10-day courses of decitabine.15

Considering that the clinical response of decitabine is transient,15 Prof. Kwong opined that this drug could offer an opportunity to bridge more patients to hematopoietic stem cell transplantation (HSCT). “This additional 6 months [median survival 12.7 months with decitabine; 4-6 months with chemotherapy] would provide us with more time to come up with an alternative plan, including finding a HLA-matched donor for hematopoietic stem cell transplantation.”

In the absence of a consensus regarding the optimal choice of therapy for CK-AML or those with TP53 mutation, Prof. Kwong’s take home message was: “Adopt trial protocol straightway when you come across these high-risk patients even though they are fit for standard 3+7 induction regimen.”

Potential of HMA in post-remission therapy

In the context of maintenance therapy, Dr. Garret Leung reported a successful use of azacitidine following allogeneic HSCT in patients with CK-AML. While significant differences in relapse-free survival were noted in this 5-year observational study, Dr. Leung cautioned that the results might be confounded by survivor treatment selection bias or immunomodulatory effect of azacitidine that mitigates chronic graft-versus-host disease (cGvHD). Further studies are warranted to clarify azacitidine’s efficacy in post-transplant setting.

Updates of clofarabine in relapsed or refractory AML (r/r AML)

Clofarabine is a second-generation purine analogue that has continued to offer promising clinical benefits within first- and second-line protocols. Among which, clofarabine’s efficacy in combination with high-dose cytarabine (2g/m2/day for 5 days) (CLARA) as salvage therapy, which resulted in a complete remission (CR) rate of 40-50%, and CR/CR with incomplete blood count recovery (CR/CRi) of 40-60%.16-19 However, treatment-related toxicity might potentially limit the use of this regimen (most prominently the grade 3/4 neutropenia, opportunistic infections, and hepatoxicity).

Dr. Harry Gill herein shared his experience of CLAM (clofarabine 30mg/m2 days 1-5; cytarabine 750mg/m2 days 1-5; mitoxantrone 12mg/m2 days 3-5) as first salvage therapy, which is now under an active investigation in Queen Mary Hospital (QMH). The preliminary data are generally encouraging. An improved CR/CRi rate is observed with a lower treatment-related toxicity as compared to CLARA. Although the rate of grade ≥3 leukopenia remains high, infection is quite manageable. “No invasive fungal disease is being reported. All cases were bacterial, and they could be manageable with antibiotics. Up to now, there is zero case of infection-related death.” Dr. Gill said. He concluded that clofarabine-based regimen has undoubtedly opened new potential perspectives to r/r AML patients without specific molecular markers.

Ruxolitinib for the management of myelofibrosis (MF), polycythemia vera (PV), and beyond

Ruxolitinib is a JAK1/JAK2 inhibitor that has been approved for the treatment of intermediate- or high-risk MF, as well as a second-line therapy for patients with hydroxyurea (HU)-resistant or intolerant PV. In the context of MF, reduction in JAK2 mutant allele burden and survival advantage of ruxolitinib was maintained during the 5-year follow-up of COMFORT trials.20,21 However, Dr. Gill noted that the disease-modifying activity is rather modest as assessed by improvement in bone marrow (BM) fibrosis, leading to the speculation that survival benefit may be attributed to improvements in physical fitness from amelioration of splenomegaly and suppression of inflammatory cytokines, rather than to a direct anti-clonal effect or changes in BM histopathology.

Concerning PV, ruxolitinib outperformed best available therapy (BAT) in several parameters, including hematocrit control and complete hematologic response rate, as demonstrated in the RESPONSE trials.22,23 While the experience of hematocrit control in PV patients were inconsistent to the two pivotal trials, Dr. Gill suggested that the effect on platelet count was not as good. “In fact, HU has the best platelet control. For patients with thrombocytosis, I would prefer using HU as first-line to achieve adequate cytocrit reduction, then switch to ruxolitinib for better hemoglobin and hematocrit control.”

Dr. Gill also shared his experiences of using ruxolitinib in MF and essential thrombocytosis (ET). “It is notable that the use of ruxolitinib in MF patients typically led to a drop in hemoglobin at the first 6 months of therapy, which would be a disadvantage to high-risk patients who have a high chance of anemia. Taken into consideration that the drop is transient and that ruxolitinib offers good control in white cell count, there may still be an advantage of using this drug.“ Meanwhile, the use of ruxolitinib in hematological control in ET was not preferred due to the ‘weakness in platelet control’. However, this drug was found useful in managing the symptoms associated with ET.

Aplastic Anemia and PNH: Eculizumab, Eltrombopag, Romiplostim

The evolving role of thrombopoietin (TPO) mimetics in aplastic anemia (AA)

TPO mimetics, such as eltrombopag and romiplostim, were developed to treat patients with immune thrombocytopenia (ITP). Given that the TPO receptor MPL is also expressed on hematopoietic stem and progenitor cells, other roles of TPO mimetics are now being actively explored.

Firstly, eltrombopag has received FDA approval for severe AA (SAA) refractory to immunosuppressive therapy (IST). Recently, promising front-line use of eltrombopag in combination with standard IST was also reported by Townsley et al. In this NIH phase I/II study, an impressive hematologic response at 6 months (OR=92%; CR=54%) was observed in the cohort with longest therapy duration, i.e. receiving eltrombopag from day 1-6 months.24 On the other hand, the phase II/III trials of romiplostim in second-line SAA is still ongoing, and Dr. Carol Cheung was positive with its future development. She noted that romiplostim should be more tolerable than eltrombopag, in terms of the incidence and severity of dyspepsia.

The experience of using TPO mimetics in AA was generally good in QMH. Dr. Joycelyn Sim reported a successful use of eltrombopag-IST regimen in 10 newly diagnosed SAA patients, with a CR of 50% after a median of 61 weeks of treatment. In relapsed/refractory AA, 40% of patients had achieved a trilineage response following a median of 115 weeks of therapy.25 Meanwhile, the data on romiplostim is scarce, as this drug is not commonly prescribed due to financial reasons. Nonetheless, among the two highly refractory SAA patients (failed both IST and high dose eltrombopag), a trilineage response and a bilineage response were observed with romiplostim treatment.

Recent molecular analysis showed that genetic mutations typically associated with myeloid neoplasms were found in up to one-third of patients with AA/SAA,26 leading to the concerns that TPO mimetics might accelerate clonal evolution, and the development of the myelodysplastic syndrome and AML from AA. In this respect, Dr. Sim suggested that data from phase I/II studies in AA and MDS has so far not been associated with disease progression, but remains necessary to elucidate.

Eculizumab and paroxysmal nocturnal hemoglobinuria (PNH)

Eculizumab is an anti-C5 humanized mAb which interrupts the complement cascade at the level of its terminal effector pathway. As the only disease modifying agent for PNH, eculizumab treatment was found to offer survival advantage over simple supportive care, possibly as a result of reducing the risk of thrombosis. While eculizumab may lead to resolution of intravascular hemolysis, Dr. YY Hwang pointed out this drug has one major problem possibly due to its mechanism of actions, “Eculizumab is expected to inhibit the terminal effector complement at the level of C5… thus early complement activation remains uncontrolled on PNH erythrocytes. As a consequence, PNH erythrocytes remain exposed to C3 activation… and C3-mediated extravascular hemolysis could not be prevented.”

B Lymphoid Malignancies: Blinatumomab, Brentuximab vedotin, Ibrutinib, Obinutuzumab, Venetoclax

Updates of blinatumomab in B-cell precursor acute lymphoblastic leukemia (ALL)

Blinatumomab is a first-in-class bispecific T-cell engager (BiTE) antibody with proven efficacy in patients with Philadelphia-chromosome (Ph)-negative, and subsequently Ph+ r/r B-precursor ALL. In Ph- setting, Kantarjian et al. reported an impressive remission rate of 87.9% (CR with full, partial, and incomplete hematologic recovery included) within 12 weeks of blinatumomab treatment.27 Prof. Kwong commented that the trial is well designed, as the total CR in the comparative chemotherapy arm has also achieved 49.3%.27 Nonetheless, this disease is subject to a high relapse rate, with the superiority in OS over chemotherapy could only be maintained for around 12 months,27 suggesting that HSCT is inevitable. In Ph+ setting, blinatumomab monotherapy was also found to provide a transient, yet valuable remission to heavily pre-treated patients,28 which would allow more time for physicians in search of subsequent therapy.

In terms of patient management, Prof. Kwong highlighted the risk of severe immunosuppression during the administration of blinatumomab. “It is well-known that T cell suppression is associated with a higher risk of fungal infection, however, accumulating evidence has now illustrated that potent B cell depleting agent is also associated with such risk” he said. Close monitoring of cytopenic patients with opportunistic infections might be warranted for future use of blinatumomab.

Brentuximab vedotin: The present and future in CD30+ lymphoproliferative diseases

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has demonstrated significant clinical activity in patients with relapsed classical Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL), which has led to its approval for these indications. Conversely, the efficacy in other T cell lymphomas, such as peripheral T cell lymphoma not otherwise specified (PTCL-NOS), is quite disappointing. Referring to the results of a retrospective study conducted in France, the 1-year PFS of PTCL was merely 20%.29 Dr. Karen Tang shared that the experiences of using brentuximab vedotin in CD30+ lymphomas in QMH were generally consistent with the literature. While both brentuximab vedotin and immune checkpoint inhibitors appear to be attractive therapeutic options for r/r HL, Prof. Eric Tse indicated that the former would be his preferred choice for the reason of its having more mature data.

Ibrutinib, obinutuzumab, and venetoclax: Better patient management in chronic lymphocytic leukemia (CLL)

The clinical efficacies of new kids on the block—the BTK inhibitor ibrutinib, the anti-CD20 ofatumumab, and the BCL-2 inhibitor venetoclax, are already quite consolidated as a monotherapy in the context of CLL. Current research is underway to assess a combination approach for further enhancement of treatment response in both relapsed/refractory and upfront setting. Among which, the regimen of venetoclax/obinutuzumab/ibrutinib have yielded an exciting ORR of 100% among relapsed/refractory patients in a phase Ib study.20

While these potent B-cell depleting agents are generally well-tolerated, there are some side effects that merit precautions. For ibrutinib, atrial fibrillation (AF) and bleeding have been the two major concerns. Results from RESONATE-2 showed that AF were generally mild (grade 2) and could be managed with dose adjustments.30 However, if any pharmacological intervention has to be used, Prof. Tse suggested that warfarin should be avoided as warfarin-users were excluded from the pivotal trial. For the use of anti-coagulants, such as aspirin, close monitoring is advised. Acknowledging Prof Kwong’s previous comments that the use of anti-B cell agent is associated with an increased risk of fungal infection and opportunistic infections, Prof. Tse agreed that prophylactic measures are necessary. As for obinutuzumab, Prof. Kwong highlighted that physicians should be aware of first infusion reaction, particularly in elderly patients, as it could lead to serious hematological response, including a dramatic drop in lymphocyte count and platelet count. In view of the immunosuppressive effects, prophylaxis of pneumocystis jiroveci pneumonia (PJP) has been added to the QMH protocol of obinutuzumab.

Immune Check-point Inhibitors: Nivolumab, Pembrolizumab

The introduction of programmed cell death protein 1 (PD-1) inhibitor—nivolumab and pembrolizumab represents an important landmark in the field of oncology. Among their indications for other diseases/malignancies, treatment of classical Hodgkin lymphoma (cHL) who have failed 3 or more lines of therapy is their only approved use in hematological malignancies.

Interestingly, while the response rates were typically <40% in solid tumors with nivolumab, the result in cHL was most striking, with an ORR over 80% and CR of 17% being reported in the pivotal trial. Similar results were noted in pembrolizumab studies. Prof. Kwong speculated that the success in cHL as compared to other hematological malignancies may be attributed to the high levels of PD-1 ligands typically exhibited in cHL, and that the PD-1/PD-L1 pathway serve as its main route of immune escape.

A low dose anti-PD-1 regimen was recently found to be highly efficacious in r/r cHL. Dr. Thomas Chan shared a case in which nivolumab was administered at a dose of 40mg every 2 weeks in a patient with ITP as his last line of therapy. Remarkably, a documented CR as assessed by PET/CT was achieved after 4 cycles of therapy.31 The findings in this case were consistent with other reports by the QMH team that low dose pembrolizumab (median dose 100mg, every 3 weeks) was similarly efficacious as the recommended dose in r/r cHL patients.32

Based on a series of case reports and retrospective analysis, anti-PD-1 regimen also provided clinically meaningful responses in other lymphoma types, such as NK/T cell lymphoma and large B-cell lymphoma (PMBCL),33-35 though a larger prospective trial would be required to clarify the results. According to Prof. Kwong m, it appears that both PD1 inhibitors and brentuximab vedotin serve as effective treatment for HL. Given that gray-zone lymphoma is characterized by having cellular features of both cHL and PMBCL, and clinical data is positive with brentuximab vedotin, my intuition is that the treatment response of this malignancy would have greater similarity towards cHL, and would also respond to anti-PD-1” he said.

As the clinical data of anti-PD-1 has not yet matured, one important question to physicians is when could the treatment be stopped following a remission. Prof. Tse said “So far, there has been no evidence to answer this question, so a continuous treatment would be preferred whenever possible. If treatment has to be discontinued, I would recommend stopping it two years after a documented CR, either in terms of a negative PET/CT scan or a negative circulating Epstein-Barr virus [EBV] DNA.”

 

What was covered in the 2017 New Drug Forum?

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1. Harousseau JL, Attal M. How I treat first relapse of myeloma. Blood. 2017;130:963-73.

2. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375:1319-31.

3. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-52.

4. Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;374:1621-34.

5. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015;373:621-31.

6. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17:27-38.

7. San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:1055-66.

8. Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016;128:37-44.

9. Dimopoulos MA. Efficacy and safety of daratumumab, lenalidomide, and dexamethasone (DRd) versus rd alone in relapsed or refractory multiple myeloma (RRMM): updated analysis of POLLUX. European Hematology Association; 2017. Abstract #P334.

10. Weisel K. Efficacy and safety of daratumumab, bortezomib and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (RRMM): updated analysis of CASTOR. Europena Hematology Association; 2017. Abstract #S459.

11. San Miguel J. Efficacy by cytogenetic risk status for daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone in relapsed or refractory multiple myeloma. Europena Hematology Association; 2017. Abstract #S101.

12. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387:1551-60.

13. Saunthararajah Y. Key clinical observations after 5-azacytidine and decitabine treatment of myelodysplastic syndromes suggest practical solutions for better outcomes. Hematology Am Soc Hematol Educ Program. 2013;2013:511-21.

14. Quintas-Cardama A, Santos FP, Garcia-Manero G. Therapy with azanucleosides for myelodysplastic syndromes. Nat Rev Clin Oncol. 2010;7:433-44.

15. Welch JS, Petti AA, Miller CA, et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med. 2016;375:2023-36.

16. Leung AYH, Tse E, Liu HSY, et al. The Use of Clofarabine and Cytarabine Combination (CLARA) As Salvage Therapy for Relapsed and/or Refractory Acute Myeloid Leukemia (AML). Blood. 2012;120:1518.

17. Becker PS, Kantarjian HM, Appelbaum FR, et al. Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia. Br J Haematol. 2011;155:182-9.

18. Tse E, Leung AY, Sim J, et al. Clofarabine and high-dose cytosine arabinoside in the treatment of refractory or relapsed acute myeloid leukaemia. Ann Hematol. 2011;90:1277-81.

19. Leung AY, Tse E, Hwang YY, et al. Primary treatment of leukemia relapses after allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning second transplantation from the original donor. Am J Hematol. 2013;88:485-91.

20. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30:1701-7.

21. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10:55.

22. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372:426-35.

23. Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol. 2017;18:88-99.

24. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017;376:1540-50.

25. Gill H, Leung GM, Lopes D, et al. The thrombopoietin mimetics eltrombopag and romiplostim in the treatment of refractory aplastic anaemia. Br J Haematol. 2017;176:991-4.

26. Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. N Engl J Med. 2015;373:35-47.

27. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017;376:836-47.

28. Martinelli G, Boissel N, Chevallier P, et al. Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. J Clin Oncol. 2017;35:1795-802.

29. Lamarque M, Bossard C, Contejean A, et al. Brentuximab vedotin in refractory or relapsed peripheral T-cell lymphomas: the French named patient program experience in 56 patients. Haematologica. 2016;101:e103-6.

30. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373:2425-37.

31. Hwang YY, Khong PL, Kwong YL. Low-dose nivolumab induced remission in refractory classical Hodgkin lymphoma. Ann Hematol. 2017;96:1219-20.

32. Chan TS, Luk TH, Lau JS, et al. Low-dose pembrolizumab for relapsed/refractory Hodgkin lymphoma: high efficacy with minimal toxicity. Ann Hemato.l 2017;96:647-51.

33. Kwong YL, Chan TSY, Tan D, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood. 2017;129:2437-42.

34. Chan TSY, Li J, Loong F, et al. PD1 blockade with low-dose nivolumab in NK/T cell lymphoma failing L-asparaginase: efficacy and safety. Ann Hematol. 2017 [Epub ahead of print].

35. Zinzani PL, Ribrag V, Moskowitz CH, et al. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017;130:267-70.

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