After a long hiatus, I am back! Today, I’m doing a write up on extended half-life Factor VIII products.
On March 16, 2021, Hemophilia published the results of the PROTECT VIII Kids extension study, showing efficacy of Jivi®️ (damoctocog alfa pegol, a PEGylated recombinant Factor VIII product) in previously treated children with severe Hemophilia A (Factor VIII activity <1%) age <12 (Mancuso et al., 2021; 10.1111/hae.14294). 73 patients were enrolled in the main and expansion study and 59 entered the extension study. Jivi®️ was administered intravenously twice weekly (25-60 IU/kg), every 5 days (45-60 IU/kg), or every 7 days (60 IU/kg) according to clinical needs, for 0.4 to 5.9 years (median 5.0 years). 2 patients, both <6 years old, discontinued the trial for non-treatment-related reasons. Median annualized bleeding rate for total bleeds was 1.5 in children <6 years old and 1.9 in children 6-12 years old. Annualized bleeding rate improved with time, and median annualized bleeding rate was 0.0 for spontaneous bleeds in both age groups in the last year of the study. No patients developed anti-PEG or Factor VIII antibodies.
Currently, Jivi®️ is licensed by the FDA to be used in the United States in people age 12 and older. (https://www.jivihcp.com/) The starting prophylactic (prevention of bleeds) dosing regimen is 30-40 IU/kg twice a week, which can be adjusted to 45-60 IU/kg every 5 days, and can be further adjusted (dose or frequency) according to bleeding episodes. Top-up doses are to be given for bleeding episodes (10-20 IU/kg every 24-48 hours to achieve Factor VIII activity 20-40%, 15-30 IU/kg every 24-48 hours to achieve Factor VIII activity 30-60% and 30-50 IU/kg every 8-24 hours to achieve Factor VIII activity 60-100% for minor, moderate and major bleeding respectively, until bleeding is resolved), as well as for perioperative management (beginning pre-operatively, at 15-30 IU/kg every 24 hours to achieve Factor VIII activity 30-60% for at least one day until healing is achieved for minor surgery, and 40-50 IU/kg every 12-24 hours to achieve Factor VIII activity 80-100% until healing is complete followed by a dose achieving 30-60% Factor VIII activity for a further 7 days for major surgery). (https://www.fda.gov/files/vaccines,%20blood%20%26%20biologics/published/Package-Insert-JIVI.pdf)
In children <12 years old, the PROTECT VIII Kids study (main and expansion phases, with 61 and 12 patients enrolled respectively) showed efficacy amongst the 61 patients who completed the study, with median annualized bleeding rate of 2.5 and 2.4 for children <6 years old in the main phase and the expansion phase respectively and 2.9 for children 6-12 years old, for all bleeds, and 0.0, 0.0 and 1.5 respectively for spontaneous bleeds. However, safety concerns were raised. 12 out of the 73 patients discontinued the trial – 1 for perceived inefficacy and 11 for hypersensitivity and/or inefficacy within the first four exposure days (4 moderate hypersensitivity, 1 hypersensitivity; 4 of these patients were <6 years old and 1 was 6-12 years old). All adverse events were transient and did not require intervention. Patients who discontinued the trial successfully resumed their previous Factor VIII product. 7 patients developed anti-BAY 94-9027 (pre-marketing name for Jivi®️) antibodies, which were transient in all 7 patients, 3 patients developed anti-PEG IgE antibodies, which were transient in all 3 patients, and 4 developed anti-PEG IgM antibodies, which persisted in one of the patients. Anti-PEG IgE antibodies were not detected in any of the patients who developed hypersensitivity reactions. No factor VIII inhibitors were reported. (Santagostino et al., 2020; 10.1111/hae.13963) The safety concerns led to children under 12 years to be excluded from licensed use of Jivi®️ by the FDA, stating a greater risk of hypersensitivity reactions as a reason. Since the publication of the results of the extension study, Bayer has not announced any plans for obtaining FDA approval for the use of Jivi®️ in children under 12 years.
Other extended half-life Factor VIII products include Eloctate®️ (efmoroctocogalfa, or rFVIII-Fc), licensed since 2014, (dosed at 50 IU/kg every 4 days for patients 12 years and older, and 50 IU/kg twice a week for patients under 12 years old, to adjust by 25-65 IU/kg at 3-5 day intervals according to response – from https://www.fda.gov/media/88746/download), Adynovate®️ (rurioctocog alfa pegol), licensed by FDA since 2015, (dosed at 40-50 IU/kg twice a week for patients 12 years and older, and 55-70 IU/kg twice a week for patients under 12 years old – from https://www.fda.gov/files/vaccines,%20blood%20&%20biologics/published/Package-Insert—ADYNOVATE.pdf), Afstyla®️ (lonoctocog alfa, or rFVIII-Sc), licensed since 2016, (dosed at 20-50 IU/kg 2 to 3 times a week for patients 12 years and older, and 30-50 IU/kg for patients under 12 years old – from https://www.fda.gov/media/98080/download), and Esperoct®️, (turoctocog alfa pegol), licensed since 2019, (dosed at 50 IU/kg every 4 days for patients 12 years and older and 65 IU/kg twice a week for patients under 12 years old – from https://www.fda.gov/media/120351/download) which have been licensed for use for patients of all ages with Hemophilia A for routine prophylaxis (recommended doses given above), perioperative management and management of bleeding episodes (“on-demand” treatment) . Like Jivi®️, Adynovate®️ and Esperoct®️ are composed of recombinant Factor VIII conjugated with polyethylene glycol (PEG) to extend their plasma half-life by protecting them from proteolytic enzymes. Eloctate®️, however, is fused with the Fc domain (region) of IgG1, allowing it to utilize the neonatal Fc receptor pathway to delay lysosomal degradation and re-enter the circulation. Afstyla®️, on the other hand, is composed of the heavy and light chains of Factor VIII covalently bound together forming a single chain, that has greater affinity to von Willebrand factor that other factor VIII products, which protects it from degradation by prolonging its association to its natural carrier protein that has a critical role in the initiation of the hemostatic process.
How do institutions, providers, patients and their parents choose between these products and standard half-life Factor VIII, and how useful can multiple Factor VIII products in the market be? For patients newly diagnosed with hemophilia, Jivi®️, which has not been licensed for previously untreated patients, is unsuitable unless in the context of a clinical trial. Extended half-life products are potentially less immunogenic (Lieuw 2017; 10.2147/JBM.S103796). However, immune tolerance treatment schedules with these products are not widely available. In some patients, rapid clearance and hence shorter half-lives of Factor VIII may require shorter dosing intervals of extended half-life products, making the higher cost of these products compared to standard half-life products untenable. Finally, even with the availability of long-term (5 years, in the case of Jivi®️) data, consequences to lifelong exposure to polyethylene glycol is unknown. (Wynn and Gumuscu 2016; 10.2147/JBM.S82457). Institutional and provider experience and funding patterns will undoubtedly be the deciding factors amid this plethora of choice for treatment of hemophilia.
Rocks of different shapes, sizes and colors. Alta Vista Trail, Paradise, Mount Rainier National Park, Washington, USA.
Further reading
Aledort L, Mannucci PM, Schramm W, Tarantino M. Factor VIII replacement is still the standard of care in haemophilia A. Blood Transfus. 2019 Nov;17(6):479-486. doi: 10.2450/2019.0211-19. Epub 2019 Dec 11.
After my last blog post, news from the FDA regarding these two drugs being tested for treatment of myeloma have emerged.
First, on February 26, accelerated approval for selinexor in the treatment of relapsed-refractory multiple myeloma was sought based on results of the STORM study Part 2, but the Advisory Committee voted against it. (Onclive article here) In this study, 123 patients with multiple myeloma previously treated with alkylator, bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and steroids and were refractory to one or more proteasome inhibitor, one or more immunomodulatory drug, daratumumab, a steroid and their last line of treatment were given selinexor 80mg and dexmethasone 20mg twice weekly. Of these patients, 84% had previously undergone stem cell transplant and 2 had undergone CAR-T cell therapy.
122 patients were assessed for efficacy. Overall response rate, defined as partial response or better, was 26.2%. Very good partial response or better was seen in 6.5% including 2 patients who had stringent complete response. Median duration of response was 4.4 months. Median progression free survival was 3.7 months and median overall survival was 8 months. 95.9% of patients had discontinued the treatment at the end of the study period, 55.1% owing to disease progression and 32.2% owing to adverse events.
123 patients were included in the safety analysis. Significant adverse effects included thrombocytopenia (67.5%, Grades 3/4 53.7%), anaemia (48%, Grade 3/4 29.3%), fatigue (56.1%, Grade 3/4 18.7%), neutropenia (36.6%, Grade 3/4 18.7%), hyponatremia (30.9%, Grade 3/4 16.3%), nausea (69.1%, grades 3/4 9.8%), anorexia (52%, grades 3/4 3.3%), weight loss (47.2%, grades 3/4 0.8%), vomiting (35%, grades 3/4 3.3%) and diarrhea (33.3%, grades 3/4 6.5%).
The FDA Advisory Committee voted to hold off accelerated approval of selinexor and await the results of the Phase 3 BOSTON trial (bortezomib, dexamethasone with or without selinexor in patients with relapsed-refractory multiple myeloma).
Next, on March 21, the FDA ordered that all clinical trials of venetoclax in treatment of multiple myeloma patients halt enrollment after reviewing the results of the BELLINI trial. Patients who are receiving clinical benefit on these trials may continue after they re-consent.
The BELLINI trial is a randomized Phase 3 trial in which patients with relapsed/refractory multiple myeloma who were sensitive to or naive to proteasome inhibitors were given bortezomib, dexamethasone, and either venetoclax or placebo. At the time of data cutoff on November 26, 2018, 291 patients had been randomized and the median follow up was 17.9 months. (FDA advice here) There were 21.1% deaths in the venetoclax arm and 11.3% deaths in the placebo arm, with a hazard ratio of 2.03 (95% confidence interval 1-04-3.94). The median PFS was 22.4 months in the venetoclax arm and 11.5 months in the placebo arm. The objective response rate was 82% in the venetoclax arm and 68% in the placebo arm.
Based on the 2-fold increased risk of death in the BELLINI trial, the FDA ordered that all clinical trials of venetoclax in multiple myeloma patients are to halt enrollment. Patients taking venetoclax for approved indications (chronic lymphocytic leukaemia and acute myeloid leukaemia) are not affected. Given that the BELLINI data presented so far shows better response rates and progression free survival with venetoclax, bortezomib and dexamethasone than with bortezomib and dexamethasone alone, and similiar rates of grade 3-5 adverse events in the two arms (86.5% venetoclax arm, 87.5% placebo arm), more data regarding the cause of death in the trial subjects would be useful in furthering our understanding of the excess risk of death in patients treated with venetoclax.
Today’s post is about multiple myeloma. I will look at some fairly recent data about available treatment options for newly diagnosed and relapsed-refractory myeloma as well as some agents that are currently under investigation.
For patients with newly diagnosed multiple myeloma, current induction treatment would typically include a proteasome inhibitor such as bortezomib (bortezomib PI link here), a steroid such as dexamethasone, and an immunomodulatory agent such as lenalidomide or an alkylating agent such as cyclophosphamide, followed by autologous stem cell transplant if the patient is eligible. A regimen that added a monoclonal antibody against CD38, daratumumab, to bortezomib, melphalan, and prednisolone (VMP), D-VMP, was tested against VMP in patients with newly diagnosed multiple myeloma who were ineligible for stem cell transplant and the results were published in December 2017. 706 patients were randomized and 700 patients received the assigned treatment. Bortezomib was given subcutaneously at 1.3mg/m2 twice weekly on weeks 1,2,4,5 of cycle 1 and weekly on weeks 1,2,4,5 of cycles 2 to 9. Melphalan was given orally at 9mg/m2 on days 1-4 of each cycle. Prednisolone was given orally at 60mg/m2 on days 1-4 of each cycle. The 346 patients in the daratumumab group were given daratumumab 20mg weekly during cycle 1, 3 weekly during cycles 2 to 9 and 4 weekly thereafter until disease progression or unacceptable toxicity occurs. Dexamethasone was given with daratumumab orally or intravenously to manage infusion reactions and on day 1 of each cycle, prednisolone was substituted by dexamethasone 20mg. Progression-free survival at 18 months was 71.6% in the daratumumab group and 50.2% in the control group. Median progression-free survival in the control group was 18.1 months and not reached in the daratumumab group. Minimal residual disease (MRD) as ascertained by next generation sequencing was 22.3% in the daratumumab group and 6.2% in the control group. Infusion-related reactions occurred in 27.7% of patients receiving daratumumab including 4.9% who had grade 3-4 reactions. The rate of grade 3 to 4 infections was higher in the daratumumab group at 23.1% compared to 14.1% in the control group, but most infections resolved and the rate of discontinuation due to infections did not differ significantly between the two groups (0.9% in the daratumumab group, 1.4% in the control group). (1) link here. The authors reported in an update in December 2018 that progression-free survival at 24 months was 63% in the daratumumab group. After a median follow up of 27.8 months, median progression-free survival was 19.1 months in the control group and was not reached in the daratumumab group. Overall response rate was 90.9% in the D-VMP group and 73.9% in the VMP group. The rate of complete response or better was 45.1% in the D-VMP group and 25.3% in the VMP group. (2) link here
Daratumumab is a human monoclonal antibody against CD38. It is currently FDA approved for treatment of newly diagnosed multiple myeloma in patients ineligible for autologous stem cell transplant in combination with bortezomib, melphalan and prednisolone (due to the positive results of this study), and in combination or as monotherapy in patients with relapsed-refractory multiple myeloma. It is administered by intravenous infusion over several hours at a gradually incremental rate until the maximum rate of 200ml/h is attained, which is then maintained until the dose is completed. Pre-medications (methylprednisolone, acetaminophen, diphenhydramine) are administered 1h prior to infusion. Infusion reactions are managed by interruption of the infusion and resumption at a lower rate in the event of non-life-threatening symptoms that resolve or improve to mild or moderate in severity. A grade 4 reaction or third occurrence of a grade 3 reaction would preclude further use of daratumumab. After the infusion, corticosteroids are administered, which are again administered on the following day. Daratumumab PI link here. Daratumumab costs $5850 per infusion. Source: FiercePharma-link here.
Another regimen, carfilzomib, lenalidomide and dexamethasone, was given to 45 patients in a Phase 2 trial without a comparator arm and results were first reported in 2015. Transplant eligible and ineligible patients were included. Carfilzomib was administered intravenously over 30 minutes at 20mg/m2 on days 1 and 2 of cycle 1 and 36mg/m2 on days 8, 9, 15, 16 on cycle 1 and 36mg/m2 on days 1, 2, 8, 9, 15, 16 every 28 days for cycle 2-8. Dexamethasone was administered intravenously or orally on days 1, 2, 8, 9, 15, 16, 22, 23 at 20mg on cycle 1-4 and 10mg on cycle 5-8. Lenalidomide was administered orally at 25mg on days 2-21 on cycle 1 and days 1-21 on cycles 2-8. After 8 cycles, patients with at least stable disease were continued on lenalidomide for 2 years. The overall response rate was 98%. 62% of patients achieved near complete remission or better, and all of these patients were negative for minimal residual disease (MRD) by multiparametric flow cytometry. Progression-free survival at 18 months was 100% and 63% for patients negative and positive for MRD by flow cytometry respectively, and 92% for the overall group. (3) Link here. In a 2018 update, the authors reported that median duration of action was 65.7 months and median time to progression was 67.3 months. The median duration of MRD negative CR was 52.4 months. Overall survival at 80 months was 84.3%. Achievement of MRD negative CR and time to progression were not affected by age or high-risk cytogenetics. (4) link here.
Carfilzomib is a proteasome inhibitor that has been approved singly or in combination for treatment of relapsed or refractory multiple myeloma. Carfilzomib PI link here. It has not been approved for use in patients with newly diagnosed multiple myeloma, owing to lack of Phase III data. Important side effects include anaemia, thrombocytopenia, diarrhea and hypokalemia. It costs $10000 for each 28 day cycle for a person of average size. Source: AJMC. Link here
What are the options for patients after induction chemotherapy with or without autologous stem transplantation? Maintenance therapy is probably better than observation, and recent data from the United Kingdom supports this. The Myeloma XI study was a phase 3, open-label, adaptive design trial with 3 randomisation stages. The first randomisation stage allocated induction therapy separately for transplant eligible and non-eligible patients, the second allocated induction intensification for patients with a suboptimal response to treatment and the third allocated patients who had completed induction, intensification or autologous stem cell transplantation to maintenance therapy or observation. From Jan 2011 to Sept 2011, patients eligible for maintenance were assigned to lenalidomide 25 mg a day or observation in a 1:1 ratio; from Sept 2011 to June 2013, the protocol was amended to change the randomisation scheme to lenalidomide 10 mg a day on days 1-21 every 28 days, lenalidomide plus vorinostat or observation in a 1:1:1 ratio; finally in June 2013 the protocol was amended to assign patients to lenalidomide 10mg a day on days 1-21 every 28 days or observation in a 2:1 ratio. Maintenance was continued until disease progression or toxicity. Patients assigned to lenalidomide plus vorinostat were excluded in this analysis. 1137 patients were assigned to lenalidomide and 834 to observation. Median follow up was 31 months. Progression-free survival was 39 months in the lenalidomide arm, significantly better than the 20 months in the observation arm. In the subgroup that was transplant eligible, progression free survival was 57 months in the lenalidomide arm and 30 months in the observation arm; in the transplant ineligible subgroup, these were 26 and 11 months respectively. was Overall survival was 61.3% in the lenalidomide arm and 56.6% in the observation arm, which was not statistically significant. Overall survival in the transplant eligible patients were better in the lenalidomide arm than those in the observation arm, being 87.5% compared to 80.2% at 3 years. Serious adverse events were reported in 45% of patients in the lenalidomide arm and 17% in the observation arm, and the overall incidence of second malignancies was 2.4 per 100 patient years in the lenalidomide arm and 1.4 in the observation arm. (5)Link here.
Lenalidomide has long been approved for use in multiple myeloma therapy in combination with dexamethasone and for maintenance after autologous stem cell transplantation. (Lenalidomide PI link here) It currently costs $15000 to $16000 a month (Source: GoodRx. link here).
Another maintenance option, ixazomib, an oral proteasome inhibitor, was explored in the TOURMALINE-MM3 trial. Patients newly diagnosed with multiple myeloma were given stand-of-care induction therapy followed by high dose melphalan and autologous stem cell transplantation, and randomised to oral ixazomib or placebo in a 3:2 ratio for 2 years. Ixazomib was given at 3mg on days 1,8 and 15 every 28 days from cycle 1-4 and 4mg from cycle 5 onwards. 395 patients were assigned ixazomib and 261 to placebo. With a median follow up of 31 months, median progression free survival was 26.5 months in the ixazomib arm and 21.3 months in the placebo arm. Serious adverse events were observed in 27% of patients in the ixazomib group and 20% in the placebo group. Second malignancies occured in 3% of patients in both arms. (6) abstract link here
For relapsed or refractory myeloma, what are the treatment options? One is carfilzomib, lenalidomide and dexamethasone. The randomized ASPIRE trial which had 396 patients in each arm showed that this combination had longer progression-free survival (26.3m vs 17.6m) and better overall (87.1% vs 66.7%) and complete (31.8% vs 9.3%) response rates than lenalidomide and dexamethasone (7) Link here. An update in 2018 confirmed that this led to better median overall survival in the triplet combination at 48.3 months compared to 40.4 months in the doublet combination. (8) Abstract link here
Another option is daratumumab, bortezomib and dexamethasone (D-Vd). In a randomised trial comparing this combination with bortezomib and dexamethasone (Vd), with 251 patients in the D-Vd arm and 247 in the Vd arm, the progression-free survival at 12 months was so much longer in the D-Vd arm than the Vd arm (60.7% compared to 26.9%) that the trial was terminated early. Patients were unblinded and those in the control arm who had progressed were offered daratumumab. (9)Link here Updated results reported in 2018 showed that after a median follow up of 31 months, the median progression-free survival in the daratumumab arm was 16.7 months and in the control arm was 7.1 months, overall response rate (ORR), rate of very good partial response (VGPR) or better, and complete response rates were 85, 63 and 10% in the daratumumab arm and 63, 29 and 10% in the control arm respectively. In patients had who had one previous line of therapy, median PFS was 27 months in the daratumumab arm compared to 7.9 months in the control arm. In patients who had had bortezomib, median PFS was 20.4 months in the daratumumab arm compared to 8.0 months in the control arm; in those who had had lenalidomide, median PFS was 21.2 months compared to 7.0m in the control arm. (10)Link here. Another daratumumab- containing regimen, daratumumab, lenalidomide and dexamethasone, was compared to lenalidomide and dexamethasone in a trial that recruited 286 patients in the daratumumab arm and 283 patients in the control arm. Progression-free survival at 12 months was 83.2% in the daratumumab arm compared with 60.1% in the control arm. ORR, CR and MRD rates were 92.9%, 43.1% and 22.4% in the daratumumab arm and 76.4%, 19.2% and 4.6% in the control arm respectively. Overall survival at 12 months was 92.1% in the daratumumab arm compared to 86.8% in the control arm. (11)Link here Updated results in 2018 showed that after a median follow up of 25 months, median progression-free survival in the daratumumab arm was not reached and was 17.5 months in the control arm. (12)Link here.
Yet another option is the combination of elotuzumab, lenalidomide and dexamethasone. A randomised trial comparing this combination with lenalidomide and dexamethasone with over 320 patients in each arm showed an improvement in progression-free survival at 1 year at 19.4 months in the elotuzumab arm compared to 14.9m in the control arm. (13) Link here. Updated results in 2018 showed that at 5 years, PFS was 18% and overall survival was 39.8% in the elotuzumab arm, compared to 12% and 36% in the control arm. (14)Link here. Patients with disease that had relapsed after or were refractory to lenalidomide and a proteasome inhibitor were recruited in a trial comparing elotuzumab, pomalidomide and dexamethasone with pomalidomide and dexamethasone. With 60 patients in the elotuzumab arm and 57 patients in the pomalidomide arm, the median PFS was 10.3 months in the elotuzumab arm and 4.7 months in the pomalidomide arm. Overall response rates were 53% for the elotuzumab arm and 26% in the pomalidomide arm. (15) Abstract link here.
Elotuzumab is a humanized monoclonal antibody that targets SLAMF7, a protein expressed on myeloma cells and on natural killer cells. It activates natural killer cells and facilitates antibody-dependent cellular cytotoxicity against myeloma cells. It is administered as an intravenous infusion over several hours and premedication with steroids, antihistamines and acetaminophen are necessary. It is FDA-approved for use in patients with relapsed or refractory myeloma in combination with lenalidomide and dexamethasone, or pomalidomide and dexamethasone. (Elotuzumab prescribing information. Link here) Pomalidomide is an immunomodulatory agent that has been FDA-approved for use in combination with dexamethasone in patients with multiple myeloma who have had 2 or more prior lines of therapy including lenalidomide and a proteasome inhibitor. (pomalidomide prescribing information. Link here) Elotuzumab is priced at $15 786 a month (Source: MSKCC. Link here) and pomalidomide at $10 500 a month (Source: FierceBioTech. link here)
Other therapies under investigation include venetoclax, selinexor and adoptive T cell therapies. Venetoclax, an oral BCL2 inhibitor that unblocks apoptosis in tumour cells, showed overall response rates of 21% when used in combination with dexamethasone (16)link here and 68% when in combination with bortezomib and dexamethasone (17)link here in Phase 1 trials of patients with relapsed-refractory multiple myeloma. It is currently approved for use in patients with chronic lymphocytic leukaemia and in patients with acute myeloid leukaemia. (Venetoclax prescribing information. Link here). Selinexor is an oral inhibitor of XPO1, a protein over-expressed in multiple myeloma cells leading to export of tumour suppressor proteins out of the nucleus. A Phase 1 trial in patients with relapsed-refractory multiple myeloma and Waldenstrom macroglobulinemia showed an overall response rate of 50% when selinexor was used in combination with dexamethasone, but the number of patients treated was very small (27 patients). (18)Link here. A variety of chimeric antigen receptor T cell (CAR-T) strategies have been tested and some results are available. A phase 1 study of CAR-T cell therapy targeting B cell maturation antigen (CART-BCMA) reported in 2016 achieved stringent CR in 1 and VGPR in 1 out of 6 patients. Updates of this study were posted in 2017 and 2018. A total of 25 patients had been treated. 9 were given 1-5 x 10(8) CAR-T cells (Cohort 1), 5 given cyclophosphamide 1.5g/m2 and 1-5 x 10(7) CAR-T cells (Cohort 2) and 11 given cyclophosphamide 1.5g/m2 and 1-5 x 10(8) CAR-T cells (Cohort 3). All patients were refractory to immunomodulatory agents and proteasome inhibitors. Median number of prior lines of therapy was 7 for the first 21 patients. Overall response rates were 44%, 20% and 64% for the cohorts 1, 2 and 3 respectively. Of all 25 patients, 3 patients (12%) remain progression free at 11, 14 and 32 months. Of the first 21 patients, amongst those given 1 x 10(8) cells (16 patients), 8 developed cytokine release syndrome (CRS), 3 of whom had grade 3 CRS, 4 of whom received tocilizumab, and 2 developed grade 4 encephalopathy. A higher CD4:CD8 ratio and a greater frequency of CD8 cells with a CD45RO- CD27+ phenotype in the CART-BCMA product were associated with greater in-vivo CART-BCMA expansion and better clinical response. (19 link here, 20 link here, 21 link here) Another product also targeting BCMA, bb2121 anti-BCMA CAR T cells, was tested in a Phase 1 trial reported in 2017. Patients who had received 3 or more previous lines of therapy including a proteasome inhibitor and an immunomodulatory agent and had 50% or more BCMA expression on their malignant cells were recruited. After lymphodepletion with fludarabine 30mg/m2 and cyclophosphamide 300mg/m2 for 3 days, the patients were administered 50, 150, 450, 800, or 1200 x 10(6) of the CAR-T cell product. 21 patients were infused and 18 were patients evaluable for response. 71% of patients developed CRS, 2 patients developed grade 3 CRS, and 4 patients received tocilizumab. The overall response rate was 89%. In an update posted in 2018, no neurotoxicities were reported. Among patients receiving 150 x 10(6) cells or higher, ORR was 94%, CR/unconfirmed was CR 56%, MRD was negative in 9 of 10 evaluable patients, and with a median follow up of 40 weeks, PFS at 9 months was 71% (22 link here, 23 link here). A third CAR-T cell product targeting BCMA, LCAR-B38M, which is directed against 2 distinct BCMA epitopes, was tested in a phase 1 trial in 57 patients and results were reported and updated in 2018. Following lymphodepletion with cyclophosphamide 300mg/m2, patients were administered 0.07 – 2.1 x 10(6) LCAR-B38M T cells. The overall response rate was 88%, complete response rate was 74%, VGPR was 4%, partial response rate was 11% and 68% of patients achieved negative MRD by flow cytometry. The median PFS was 15m; PFS in patients who achieved CR was 24 months. The median OS not reached at a median follow up of 12m. CRS occurred in 90%, and was grade 3 in 7%. Neurotoxicity occurred in 1 patient. (24 link here,25 link here) Finally, CTL019, anti CD19 CAR-T cells were given to 10 patients who had relapsed after autologous stem cell transplant following high-dose melphalan and and a second autologous stem cell transplant. 6 patients achieved VGPR, 2 patients achieved PR. 2 patients exhibited longer PFS compared to PFS after previous ASCT. Both patients progressed with indolent extramedullary plasmacytomas. (26) link here.
In summary, treatment options for multiple myeloma have expanded and institutions and physicians would have their preferred induction regimen. Patients eligible for autologous stem cell transplantation would often proceed for transplantation after induction. Maintenance therapy can help achieve longer progression-free survival after initial treatment. In relapsed or refractory patients, multiple options are available, and in those who have failed multiple lines of therapy, investigative approaches can be attempted in the context of a clinical trial or in a compassionate use program.
References
Mateos MV et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med 2018;378:518-28.
Dimopoulos MA et al. One-Year Update of a Phase 3 Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Patients (Pts) with Transplant-Ineligible Newly Diagnosed Multiple Myeloma (NDMM): Alcyone. ASH 2018 Abstract 156.
Korde N et al. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol 2015;1(6):746-54
Kazandjian D et al. A Phase 2 Study of Carfilzomib, Lenalidomide, and Dexamethasone with Lenalidomide Maintenance (KRd-r) in Newly Diagnosed Multiple Myeloma (NDMM): Sustained Long Term Deep Remissions and Prolonged Progression-Free Duration Regardless of Age or Cytogenetic Risk after 5 Years of Follow up. ASH 2018 Abstract 1957.
Jackson GH et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2019; 20:57–73
Dimopoulos MA et al. Oral ixazomib maintenance following autologous stem cell transplantation(TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet 2019;393(10168):253-264
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Siegel DS et al. Improvement in Overall Survival With Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. J Clin Oncol 2018;36(8):728-734
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Mateos MV et al. Efficacy and Safety of Daratumumab, Bortezomib, and Dexamethasone (D-Vd) Versus Bortezomib and Dexamethasone (Vd) in First Relapse Patients: Two-Year Update of Castor. ASH 2018 Abstract 3270.
Dimopoulos MA et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016;375:1319-31
Dimopoulos MA et al. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Haematologica 2018;103(12):2088-2096
Lonial S et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med 2015;373:621-31
Lonial S et al. Extended 5-y follow-up (FU) of phase 3 ELOQUENT-2 study of elotuzumab + lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM). Journal of Clinical Oncology 2018 36(15_suppl):8040-8040
Dimopoulos et al. Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. N Engl J Med 2018;379:1811-22.
Kumar S et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood 2017;130(22):2401-2409
Moreau P. et al. Venetoclax Combined with Bortezomib and Dexamethasone for Patients with Relapsed/Refractory Multiple Myeloma. Blood 2016;128:975
Chen C et al. Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia. Blood 2018;131(8):855-863
Cohen AD et al. B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) for Multiple Myeloma (MM): Initial Safety and Efficacy from a Phase I Study. Blood 2016;128:1147
Cohen AD et al. Safety and Efficacy of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) with Cyclophosphamide Conditioning for Refractory Multiple Myeloma (MM). Blood 2017;130:505
Cohen AD et al. Predictors of T Cell Expansion and Clinical Responses Following B-Cell Maturation Antigen-Specific Chimeric Antigen Receptor T Cell Therapy (CART-BCMA) for Relapsed/Refractory Multiple Myeloma (MM). ASH 2018 Abstract 1974.
Berdeja JD et al. Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy. Blood 2017;130:740
Raje NS et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study. Journal of Clinical Oncology 2018;36(15_suppl.):8007-8007.
Zhao WH et al. A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. Journal of Hematology and Oncology 2018;11:141
Zhao WH et al. Updated Analysis of a Phase 1, Open-Label Study of LCAR-B38M, a Chimeric Antigen Receptor T Cell Therapy Directed Against B-Cell Maturation Antigen, in Patients with Relapsed/Refractory Multiple Myeloma. ASH 2018 Abstract 955.
Garfall AL et al. Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma. JCI Insight 2018;3(8):e120505.
In today’s post I would like to bring up a few interesting recent or fairly recent findings in the field of acute myeloid leukemia (AML) treatment.
First, are there new options for induction therapy, which is the treatment given upon diagnosis to bring the patient into remission? In Seattle, investigators have tested an induction regimen called CLAG-M, which consists of cladribine, cytarabine, mitoxantrone and G-CSF. 121 patients with newly diagnosed AML (median age of 60) and 60 patients with relapsed or refractory AML (median age of 61) were treated with CLAG-M. A phase 1 study was first conducted in which the dose of mitoxantrone was escalated to determine a dose for the second phase. In the newly diagnosed arm, amongst the 94 patients to whom mitoxantrone was given at 18mg/m2, 86% of the 94 patients achieved complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), with 76.5% achieving negative measurable residual disease (MRD). Early (4 week) mortality was 2%. In the relapsed-refractory arm, amongst the 40 patients given mitoxantrone at 16mg/m2 (18mg/m2 caused 2 dose-limiting toxicities in phase 1), 60% achieved CR/CRi and 47.5% achieved MRD negativity. Early mortality was 5%. (Link here) (1). The high rate of MRD negativity is very promising – many of these patients can be brought to an allogeneic stem cell transplant. Mature results including survival are awaited. A larger study comparing this regime with others such as 3+7 (daunorubicin + cytarabine) and azacitidine would be helpful in elaborating on its benefit.
What about patients for whom intensive induction is contraindicated? Hypomethylating agents have been shown to be useful, but a recent abstract presented in December 2018 explored the use of hypomethylating agents azacitidine or decitabine combined with venetoclax, an oral BCL2 inhibitor in such patients. In the 84 patients (median age 75) treated with azacitidine and venetoclax, 70% achieved CR/CRi, and the median overall survival was 14.9 months. In the 31 patients (median age 72) treated with decitabine and venetoclax, 74% achieved CR/CRi and the median overall survival was 16.2 months. MRD negativity was achieved in 32% of all the patients across both groups. Median time to first response was remarkably short at 1.2 and 1.9 months in the two groups respectively. Early mortality (30 days) were 2% and 7% respectively. (link here) (2). Again, a larger trial comparing hypomethylating agent alone and in combination with venetoclax in patients with AML ineligible for intensive induction, comparing remission rates, survival, adverse effects, quality of life and cost-effectiveness would shed further light on the usefulness of this approach.
Next, how can targeted therapies be utilised in AML? FLT-3 inhibitors can be given to patients with mutations in FLT3-ITD or FLT3-TKD, and IDH1/2 inhibitors to patients with IDH mutation. FLT3-ITD confers either an intermediate or adverse genetic risk profile to patients depending on their NPM1 mutation status. The randomised, controlled RATIFY trial which studied 717 patients demonstrated that midostaurin given in addition to induction and consolidation chemotherapy as well as in the maintenance phase to patients with AML with FLT3-ITD or FLT3-TKD mutations significantly improved median disease-free survival (26.7 months) and overall survival (74.7 months) compared to placebo (15.5 months and 25.6 months respectively), with no significant increase in adverse effects. (Link here). (3). Phase 1 studies of ivosidenib or enasidenib, IDH1/2 inhibitors, combined with chemotherapy in patients with newly diagnosed AML have shown efficacy and safety (link here) (4), and randomized, phase 3 trials are planned. Usage of such targeted therapies as monotherapy in newly diagnosed induction chemotherapy-ineligible or relapsed-refractory patients may also be beneficial, such as was demonstrated by DiNardo et al, who showed that in 125 patients with relapsed-refractory IDH1-mutated AML given ivosidenib monotherapy (500mg orally daily), complete remission or complete remission with partial hematologic recovery was 30.4%, and median overall survival was 8.8 months. Significant adverse effects occurred in 20.7%, with the more unique events being QT prolongation on ECG (7.8%) and IDH differentiation syndrome (3.9%), the latter to be treated with steroids. (Link here). (5).
Allogeneic transplantation is critical in improving long-term survival and relapse-free mortality in many patients with AML, particularly in those without a favourable genetic profile; however it can result in extensive, chronic graft-versus-host-disease (GVHD) that causes morbidity and mortality. How important is this treatment modality in patients with monosomal karyotype, who are classified as having an adverse genetic profile? The EORTC group analyzed data from their AML10 and AML12 trials and showed that amongst the 188 patients with AML age 15-60 with a monosomal karyotype (defined as having two or more autosomal monosomies or having a single monosomy and structural abnormalities), the rate of CR/CRi was 50% and 5-year overall survival was 7.2%, significantly poorer compared to patients without a monosomal karyotype. Different anthracyclines (daunorubicin, mitoxantrone, idarubicin) in combination with standard-dose cytarabine and etoposide and high-dose or standard-dose cytarabine in combination with daunorubicin and etoposide were tested in the AML10 and AML12 trials respectively; in patients with monosomal karyotype, these variables made no difference to their outcomes. Patients with monosomal karyotype who had an HLA-related donor had significantly better 5-year survival from CR/CRi (24.1%) than those without (3.8%). (Link here). (6). Are there any new options for conditioning, the chemotherapy given to patients to ablate remnant leukemic cells before infusion of donor stem cells? A group of investigators from France retrospectively reported their results of adult (age 18 and older) patients who were given reduced-intensity conditioning with clofarabine, busulfan and rabbit anti-thymocyte globulin (ATG), termed CloB2A2/A1 (A2 = ATG for 2 days, A1 = ATG for 1 day) for their allogeneic stem cell transplant. 84 patients were treated; 2 year overall survival was 64.5%, leukemia-free survival was 57.2%, non-relapse mortality was 15.1%, cumulative incidence of acute grade III-IV GVHD at 100 days was 7.1% and cumulative incidence of extensive chronic GVHD at 2 years was 9.6%. Taken together, the 2-year graft-vs-host-disease-relapse-free (GFRS) survival was 43.6%. For patients who were in complete remission at transplant, 2 year overall survival was 74.2%, leukemia free survival was 66.8%, non-relapse mortality was 9.8% and GFRS was 50.9%. Outcomes were similar regardless of number of days of ATG given. In comparison, patients with AML in complete remission treated previously by this group with fludarabine-busulfan-ATG conditioning had 2 year overall survival of 38% and leukemia free survival of 38%. (Link here). (7)
What about maintenance therapy after consolidation or transplantation? The HOVON group randomized 116 patients age 60 or older with AML in CR or CRi after at least 2 cycles of intensive chemotherapy to azacitadine or observation. Disease-free survival at 12 months was significantly better with azacitadine than without at 64% and 42% respectively, though there was no difference in overall survival. (Link here). (8). A German group conducted a Phase 2 trial on the effects of adding midostaurin to induction chemotherapy and in the maintenance phase to patients age 18-70 with AML and FLT3-ITD. 284 patients were treated with intensive chemotherapy and midostaurin and 76.4% achieved CR/CRi. Maintenance therapy was given to 97 patients, 75 after allogeneic stem cell transplant and 22 after consolidation with high-dose cytarabine. 2 year event free survival for patients age 18-60 was 39%; for patients age 61-70 this was 53%. 2 year overall survival for patients age 18-60 was 34%; for patients age 61-70 this was 46%. Compared with historical controls, patients given midostaurin had significantly improved event-free survival and overall survival. (Link here). (9).
New therapeutic strategies for acute myeloid leukemia are being tested, with many showing improved outcomes. Established therapies (daunorubicin based induction, high-dose cytarabine consolidation, allogeneic stem cell transplantation in patients with an intermediate or adverse genetic profile) will likely be the mainstay of treatment for most patients, with the addition of targeted therapies in situations where they are proven beneficial, and alternative induction and conditioning therapies and maintenance therapy to be considered in specific situations. Newer therapeutic agents are being developed and tested and we wait eagerly for further news that signal better outcomes for patients with this disease for which cure still eludes many.
References
Halpern AB, Water RB. CLAG-M with dose-escalated mitoxantrone for adults with acute myeloid leukemia. Oncotarget. 2018;9(93):36543-36544.
Pollyea DA et al. Venetoclax in combination with hypomethylating agents induced rapid, deep and durable responses in patients with AML ineligible for intensive therapy. ASH 2018. Abstract 285.
Stone RM et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017;377:454-64.
Stein EM et al. Ivosidenib or enasidenib combined with induction and consolidation chemotherapy in patients with newly diagnosed AML with an IDH1 or IDH2 mutation is safe, effective, and leads to MRD-negative complete remissions. ASH 2018, abstract 560.
DiNardo et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med 2018;378:2386-98.
Baron F et al. Impact of Induction Regimen and of Allogeneic Hematopoietic Cell Transplantation on Outcome in Younger Adults Patients with Acute Myeloid Leukemia with a Monosomal Karyotype. Haematologica. 2018; 103:xxx.
Bourgeois et al. Clofarabine/busulfan-based reduced intensity conditioning regimens provides very good survivals in acute myeloid leukemia patients in complete remission at transplant: a retrospective study on behalf of the SFGM-TC. Oncotarget, 2018, Vol. 9, (No. 93), pp: 36603-36612
Huls G et al. Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients. Blood 2019:blood-2018-10-879866.
Schlenk et al. Midostaurin added to chemotherapy and continued single agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood 2018: blood-2018-08-869453.
In today’s blog post, I will discuss three issues relevant to patients with Hemophilia. One is about Emicizumab, a Factor VIII mimetic that in November 2016 was approved for patients with Hemophilia A with Factor VIII inhibitors by the FDA. Two is about a successful trial of gene therapy for Hemophilia B, and three is about two successful trials of gene therapy for Hemophilia A.
Emicizumab, formerly known as ACE910, now marketed as Hemlibra by Roche, is a recombinant humanized bispecific antibody that binds to activated factor IX and X, thus continuing the coagulation reaction, even if factor VIII was absent or neutralized by factor VIII antibodies. In 64 healthy volunteers (Uchida et al, Blood 2016; 127(13):1633-1641) no serious adverse events were observed after a single subcutaneous dose. In a non-randomized trial on 18 patients with severe Hemophilia A with or without inhibitors, an initial dose of emicizumab 1mg/kg followed by a weekly dose of 0.3mg/kg resulted in a fall in the median annualised bleeding rate (ABR) from 32.5 to 4.4, while an initial dose of 3mg/kg followed by a weekly dose of 1mg/kg resulted in a fall in the median ABR from 18.3 to 0, and an initial dose of 3mg/kg followed by a weekly dose of 3mg/kg resulted in a fall in the median ABR from 15.2 to 0 (Shima et al. NEJM 2016;374:2044-53). This dose finding Phase 2 study led to HAVEN-1 and HAVEN-2, randomized clinical trials that enrolled large numbers of patients with hemophilia. In HAVEN-1, 53 patients 12 years of age or older with hemophilia A with inhibitors who were previously treated with episodic treatment were randomized 2:1 to emicizumab 3mg/kg weekly subcutaneously for four weeks followed by 1.5mg/kg weekly thereafter or no prophylaxis. The annualized bleeding rate was 2.9 (95% confidence interval 1.7-5.0) in the treatment group versus 23.3 (95% confidence interval 12.3-43.9) in the group without prophylaxis, resulting in an 87% reduction in ABR (p<0.0001). 24 patients who had previously received prophylactic treatment with bypassing agents were prophylactically treated with emicizumab and showed a reduction in ABR by 79% (p<0.001) compared to the rate with previous prophylaxis with bypassing agent. Thrombotic microangiopathy and thrombosis were reported in two participants, both of whom had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. (Oldenburg et al. NEJM 2017;377:809-818) In HAVEN-2, patients 12 years old or younger or 12-17 years old and weighing less than 40kg with hemophilia A and with inhibitors who were previously treated with bypassing agents were treated prophylactically with emicizumab. In the interim analysis, the annualized bleeding rate for treated bleeds in 23 patients was 0.2, and for 13 of these patients, this was a reduction of 99% versus prior treatment. 64.9% of patients had no bleeds and 94.7% of patients had zero treated bleeds. (Young et al, Oral abstract, ASH 2017) This led to approval by the FDA of this drug as prophylaxis for patients with hemophilia A with inhibitors. (FDA approval here; full prescribing information here) A Phase III study on patients with hemophilia A without inhibitors is underway. Emicizumab is priced at $482000 a year for the first year and $448000 a year for subsequent years. (source) Financial assistance is available according to the Hemlibra website.
Even more exciting though, has been the success of gene therapy in seven men with severe hemophilia A who were given a single intravenous dose of adeno-associated virus serotype 5 vector encoding a B-domain deleted human factor VIII. Two other patients who received the same therapy at lower doses had Factor VIII levels at 3IU/dL or less. In the seven patients who received a high dose, factor VIII activity levels exceeded 5IU/dL 2-9 weeks after gene transfer and in six patients, the level exceeded 50IU/dL and was maintained at 1 year. Annualised bleeding rate among participants who had received prophylactic therapy declined from 16 to 1 and by week 22 after gene transfer, factor VIII use for reported bleeding ceased in all participants. The primary adverse event was an elevation in liver enzymes to 1.5 times the upper limit of normal or less. (Rangarajan et al. NEJM;2017:377(26):2519-2530). Phase 3 trials are eagerly awaited.
A similar success was reported in the same month by another group for Hemophilia B (Miesbach et al. Blood 2017;epub-2017-09-804419). Using the same adeno-associated virus 5 (AAV5) vector, with a liver-specific promotor driving expression of a codon-optimized human factor IX gene, a single dose of 5 x 10∧12 and 2 x 10∧13 copies/kg were each administered to five adults with hemophilia B whose factor IX activity levels were 2% or less and had severe bleeding phenotype. Factor IX level rose to 4.4 IU/dL in the low dose cohort and 6.9IU/dL in the higher dose cohort. Annualized spontaneous bleeding rate decreased from 9.8 to 4.6 in the low dose cohort and from 3.0 to 0.9 in the higher dose cohort. There was no reduction in traumatic bleeds. Factor IX prophylaxis was stopped in eight of nine patients who were receiving prophylaxis at time of study entry. Alanine aminotransferase was elevated in three patients, which were asymptomatic, limited and transient and were treated with prednisolone. In another report, (George et al. NEJM 2017;377(23):2215-2227), a single dose of AAV vector with liver-specific promotor and factor IX-Padua transgene at a dose of 5 x 10∧11/kg body weight was infused into ten men with hemophilia B with factor IX activity levels less than or equal to 2%. They were followed for for 28 to 78 weeks. Mean steady-state factor IX activity was 33.7 +/- 18.5% and annualized bleeding rate was reduced from 11.1 before vector administration to 0.4 after vector administration. Factor IX use declined from 2908 iu/kg to 49.3 IU/kg (p< 0.004). 8 patients did not use factor and 9 did not have bleeds after vector administration. An asymptomatic liver-enzyme elevation was noted in two patients and resolved with short term prednisolone treatment. This study is notable for using the Factor IX Padua variant which is a gain-of-function mutation associated with thrombophilia, with individuals carrying the mutation demonstrating 5-10 times the normal factor IX activity.
Thus, in the last three months, significant steps forward have been recorded for patients with hemophilia A and B. For patients with severe hemophilia A with inhibitors who hitherto have had no other options apart from treatment or prophylaxis with expensive bypassing agents, they now have emicizumab, which is more effective and cheaper. For all patients with hemophilia A and B, gene therapy effecting a one-time cure is coming closer to reality.
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