Because hematological cancers are rarer than solid tumors, information on treatment practices is somewhat less available, so hematologists are particularly interested in learning what their peers are doing.
Elias Jabbour, MD, of The University of Texas MD Anderson Cancer Center in Houston, says he works at a pace of “200 miles per minute” and always has several dozen research projects going simultaneously.
“People may say, ‘Well, pick one proj-ect and finish it and go to the second.’ I say the opposite. I say pick 10 or 15, because then you can succeed in half of them. If you have one project and you fail, you fail 100%,” said Jabbour, a professor of medicine in the Department of Leukemia.
His drive is demonstrated by the more than 500 research articles he has authored or coauthored and the many leukemia ther-apies he has helped develop. Among them are combinations of chemotherapy and novel agents for patients with acute lymphoblas-tic leukemia (ALL), clofarabine (Clolar) in myeloid malignancies, hypomethylating agents (HMA) in acute myeloid leuke-mia (AML) and myelodysplastic syndromes (MDS), tyrosine kinase inhibitor (TKI) ther-apy in chronic myeloid leukemia (CML), and triplet therapy in AML.
Jabbour has recently led or contributed to studies of regimens that have markedly improved survival in patients with ALL. These include hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus ponatinib (Iclusig) as frontline therapy for adults with Philadelphia chromosome (Ph)–positive ALL and inotuzumab ozogamicin (Besponsa) in combination with the low-inten - sity chemotherapy regimen of mini–hyper-CVD (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone) with or without blinatumomab (Blincyto) for older patients (≥ 60 years) with Ph-negative ALL.1,2
“He has designed a number of clinical trials that incorporate diverse forms of immune therapy and targeted therapies that are really transforming the care of our patients, resulting in very high rates of response and improved survival. They even question the role of allogeneic stem cell trans-plantation [SCT] for some of these patients who, in the past, were considered to have high-risk [disease] and were universally transplanted,” said Guillermo Garcia-Manero, MD, who leads MD Anderson’s MDS program.
Susan M. O’Brien, MD, formerly of MD Anderson and now associate director for clinical science at Chao Family Comprehensive Cancer Center at the University of California, Irvine (UCI), noted Jabbour’s role in bringing inotuzumab ozogamicin and blinatumomab from the lab to the clinic. “He was very involved in the development of the 2 antibodies that we have for relapsed ALL, which have now become standard of care,” she said. “He’s extremely focused on trying to improve outcomes for patients with leukemia, and that’s very clear when you talk to him. He’s really quite dedicated to advancing the field.”Jabbour attributes his productivity to an intense desire to help patients who lack effective treatment options, inspiration from early mentors in his native Lebanon, and the examples set by industrious colleagues such as his friends and frequent collaborators Garcia-Manero, O’Brien, and Hagop M. Kantarjian, MD, a fellow Lebanese American and world leader in leukemia treatment who chairs MD Anderson’s Department of Leukemia. Both O’Brien and Kantarjian are Giants of Cancer Care® award winners in the leukemia category.
“What makes me proud is to be able to help people who come to see me. I have been able to design a trial for them that really improved their survival, and I’m very happy with this,” Jabbour said in a recent interview with OncologyLive®. “When I see people referred to me because I have a treatment that can save a life—that is a huge reward.”
As he contributes to the rapid pace of change in the field, Jabbour is also working to promote the sharing of new findings and best clinical practices with his colleagues across the country and around the world. To that end, he is cochairing the 5th Annual Live Medical Crossfire®: Hematologic Malignancies, an interactive virtual webcast that Physicians’ Education Resource®, LLC (PER®) is hosting on July 17. Experts will present current standards of practice and clinical trials for a range of hematologic malignancies and engage in exchanges with the audience.
Because hematological cancers are rarer than solid tumors, information on treatment practices is somewhat less available, so hematologists are particularly interested in learning what their peers are doing, Jabbour said.
“It’s not a meeting where people will come and listen all day long. It’s more practical: What did I learn today, and how I can treat my patient better tomorrow if I see him in the clinic?” Jabbour said. “For example, Dr A from Brooklyn had seen this patient, and this is what he did for him. Well, Dr B from upstate had a similar patient but did something different. So they learn from each other, and then we learn from them.”
The conference will review developments involving the full gamut of hematological malignancies. Jabbour will lead sessions on AML, ALL, CML, chronic lymphocytic leukemia, and MDS/myeloproliferative neoplasms. Other sessions will cover multiple myeloma, lymphomas, and therapies across malignancies.
In ALL, for example, the speakers will include experts on chimeric antigen receptor (CAR) T-cell therapies, bispecific T-cell engagers, antibody- drug conjugates, and minimal residual disease (MRD) management using next-generation sequencing (NGS) assays, Jabbour said. In the AML session he expects to hear about novel therapies such as FLT3 inhibitors and antibodies and how to integrate them into practice. Additionally, he expects commentary on the new standard of care of HMA plus BCL2 inhibitors such as venetoclax (Venclexta) for the treatment of older adults, and investigational menin inhibitors.
Much of Jabbour’s work focuses on ALL. Relapsed/refractory (R/R) ALL has historically been associated with a poor prognosis, with a cure rate of less than 10% in adult ALL and 30% in pediatric ALL. In adult ALL, the complete remission rate with a standard chemotherapy regimen has been 30% to 40% in the first relapse and 20% to 25% in the second relapse.3 Five-year survival rates across subtypes is 89% for patients younger than 20 years but only 38% for those 20 years and older.4
However, new regimens are revolutionizing the ALL treatment landscape, especially among older patients. Jabbour was principal investigator for a phase 2 trial (NCT01424982) that evaluated the combination of hyper-CVAD plus ponatinib as frontline therapy for patients with previously untreated Ph-positive ALL.1 Ponatinib is a third-generation BCR-ABL inhibitor active against ABL1 T315I mutations, which are believed to confer resistance to imatinib (Gleevec) and other TKIs.5
During the study, patients received 8 cycles of hyper-CVAD alternating with high-dose methotrexate/cytarabine approximately every 21 days. Ponatinib was dosed at 45 mg daily for the first 14 days of cycle 1 and then, as per a protocol amendment, at 30 mg daily for subsequent cycles, with a further reduction to 15 mg daily for those who reached complete molecular response. Patients with CD20 expression of 20% or greater also received rituximab (Rituxan) for the first 4 cycles. Twelve doses of intrathecal chemotherapy were administered to prevent central nervous system (CNS) involvement. Maintenance therapy comprised of monthly vincristine, oral prednisone, and daily ponatinib also was given.1
Overall, 86 patients were treated on the study, according to long-term data. The median age was 46 years (range, 21-80), and 23% of participants were 60 years or older. After a median follow-up of 43 months, the regimen resulted in estimated 5-year continuous rates for complete remission, event-free survival, and overall survival (OS) of 84%, 68%, and 73%, respectively. The 3-year OS rate was 66% among patients who underwent hematopoietic stem cell transplant (HSCT) in f irst remission (n = 18) and 90% for patients who did not undergo HSCT (n = 57; P = .07).5
Kantarjian listed the ponatinib trial among several advances that Jabbour has spearheaded since he became ALL section chief at MD Anderson in 2015. “He has made tremendous discoveries that are changing the way we treat and the way we’re going to treat ALL in the future,” Kantarjian said. “With his endeavors we’re going to be able to cure many more patients, probably 70% or more, with less-intensive chemotherapy and with a shorter course of the whole treatment. Right now it’s about 18 months, but soon we’re going to shrink it down to a year or less.”
Jabbour pointed to other developments that are improving outcomes, including the addition of rituximab to chemotherapy for patients with precursor B-cell ALL, CAR T-cell therapies, and the use of MRD measurements to evaluate response and select treatments.
“We have the tools to cure this disease. I’m saying this with confidence for 2 reasons. No. 1, we have a better understanding of the biology of ALL and therefore we’re able to tailor our therapy strategy based on biology. And second, we have new drugs that, after being tested, have shown promising results,” Jabbour said.
The growing recognition of genetically heterogenous ALL subtypes, the continuing introduction of new therapies, and the proliferation of successful sequencing studies mean there is no standard of care at the moment, he said.
“I don’t have one therapy that fits all, which is good. The future is to better tailor therapy according to biology and to move away from intensive chemotherapy to more of a targeted approach that can improve the outcome without inducing a lot of toxicities,” Jabbour said.
One emerging approach involves moving novel therapies from the salvage setting to the front line to deintensify chemotherapy, avoid relapse due to TKI resistance, and improve survival. In a recent study, Jabbour and colleagues added sequential blinatumomab to hyper-CVAD to treat patients with newly diagnosed Ph-negative pre–Bcell ALL. Early results of the ongoing phase 2 trial (NCT02877303) were reported at the 62nd American Society of Hematology Annual Meeting and Exposition in December 2020 (ASH 2020).6
There were 34 evaluable patients, with a median age of 36 years (range, 17-59). They received hyper-CVAD alternating with highdose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Patients with CD20-positive disease received 8 doses of ofatumumab (Arzerra) or rituximab. Prophylactic intrathecal chemotherapy was administered 8 times in the first 4 cycles. Maintenance therapy involved alternating blocks of POMP chemotherapy (mercaptopurine, vincristine, methotrexate, and prednisone) plus blinatumomab. Starting with the 10th patient, the protocol was amended so that those with high-risk disease features received the blinatumomab after 2 hyper-CVAD cycles to avoid the risk of early relapse.6
With a median follow-up of 22 months (range, 1-40), the 2-year complete remission and OS rates were 79% and 86%, respectively. Five patients (15%) relapsed, 12 (35%) underwent allogeneic SCT in first remission (including 1 additional patient who relapsed post-SCT), and 17 (50%) were in continuous remission and were on treatment or completed maintenance at the time of reporting.6
All relapses occurred in patients with established poor-risk features, including 2 during hyper-CVAD cycles before the protocol was amended. Four patients developed grade 2/3 cytokine release syndrome, which resolved with corticosteroids and interruption of blinatumomab. In all, 14 patients (41%) had a neurological adverse event (AE) of any grade due to blinatumomab. One patient discontinued blinatumomab due to a blinatumomab-related adverse event of grade 2 encephalopathy and dysphasia.6
Investigators at MD Anderson and other centers also are testing ways to maximize the benefits of newer agents in adults with ALL, particularly older patients with poor prognoses who are not suitable for intensive chemotherapy. Jabbour has played a leading role in studies that have demonstrated the efficacy of the mini–hyper-CVD regimen combined with antibody therapies both in frontline and salvage settings in Ph-negative ALL.7,8
In March, Jabbour and colleagues published long-term follow-up data from a single-arm phase 2 study (NCT01371630) evaluating salvage therapy in patients with relapsed or refractory (R/R) Ph-negative ALL using inotuzumab ozogamicin plus mini–hyperCVD with or without blinatumomab. Patients received mini–hyper-CVD alternating with methotrexate/cytarabine plus inotuzumab on day 3 of each of the first 4 courses, with a total of 8 courses every 4 weeks. Participants with CD20-positive expression also received rituximab, and intrathecal therapy was administered as CNS prophylaxis. They also were eligible for POMP maintenance therapy for 3 years.9
Starting with the 68th patient on the study, investigators added 4 courses of blinatumomab to the consolidation phase of therapy and lowered the dose of weekly inotuzumab to reduce the risk of veno—occlusive disease.
In all, 96 patients with a median age of 37 years (range, 17-87) were treated. The overall response rate (ORR) was 80%; 77 patients responded, including 55 (57%) who achieved a complete response (CR). The MRD negativity rate among responders was 83% (62 of 75 patients). Forty-four (46%) patients underwent later allogeneic SCT. Among the 29 patients who received blinatumomab along with inotuzumab, the ORR was 90%, including a CR rate of 52%.9
The estimated 3-year OS rate for the entire population was 33% (95% CI, 23%-43%). Those treated according to the original protocol had a higher 3-year OS rate of 36% (95% CI, 17%-54%) and median OS of 13.9 months compared with 33% (95% CI, 22%-45%) and 13.4 months, respectively, for those who received a lower dose of inotuzumab ozogamicin plus blinatumomab.9
Veno-occlusive disease of any grade occurred in 10 (10%) patients; the rates were 13% with the original schedule and 3% with the use of lower-dose inotuzumab ozogamicin and sequential blinatumomab.
Jabbour said treating patients with ALL without any chemotherapy remains a future goal, but recent studies have had promising results. In the phase 2 GIMEMA trial (NCT02744768) conducted in Italy, 63 adults with newly diagnosed Ph-positive ALL were treated with dasatinib (Sprycel) plus blinatumomab. At a median follow-up of 18 months, OS rate was 95% and disease-free survival rate was 88%. Overall, the regimen was well tolerated, with 21 grade 3 or higher AEs observed, investigators said.10
The Italian group, Gruppo Italiano Malattie EMatologiche dell’Adulto, has announced plans for a phase 3 multicenter study (NCT04722848) of ponatinib plus blinatumomab vs chemotherapy plus imatinib for adults with newly diagnosed Ph-positive ALL. Patients in the control arm who do not achieve a complete hematologic response and/or MRD negativity after the sixth consolidation cycle may cross over to receive blinatumomab, and those who develop an ABL1 mutation will switch to the experimental arm. After 2 cycles of blinatumomab in the experimental arm and after consolidation in the control arm, patients aged 18 to 65 years will be stratified for transplant allocation.11
Other trends Jabbour noted include the reduced need for transplant due to improved survival and cure rates in populations such as adults with Ph-positive ALL and the use of CAR T-cell therapy that may replace transplantation for some patients. Numerous trials are underway to optimize CAR T therapies and minimize toxicities, and CD22-directed and CD19/CD22 bispecific therapies are being developed to circumvent CD19 escape as a cause of relapse. He also highlighted the importance of NGS-based MRD evaluation as an essential tool to gauge response, abandon ineffective regimens, allow shorter courses of treatment, and confirm cure.
“One of the most exciting things in ALL is eventually to be able to shorten therapy, if we’re able to define short-term therapy based on response. If we can assess for MRD with a very deep technique and if I find true responders, then these patients will be spared the need for intensive chemotherapy or prolonged therapy,” he said.
In an article published last year in the American Society of Clinical Oncology Education Book, Jabbour and his coauthors describe MRD data as perhaps the most important predictor of OS. Investigators are now using NGS data to explore individualized or subset-specific treatment algorithms. “It will be crucial to design prospective clinical studies with modular data to evaluate optimal strategies for specific patient subtypes, or ‘personalized’ medicine, testing immunotherapy and combinations of molecularly targeted drugs or drug combinations,” they wrote.12
Treatment of patients with AML has also changed dramatically in recent years, with 11 new drug therapies approved since 2017.13,14 Jabbour’s contributions include leading a phase 2 study (NCT01289457) that tested idarubicin and cytarabine induction chemotherapy in combination with clofarabine (CIA) or fludarabine (FIA) in patients with newly diagnosed AML.15
The therapies had similar efficacy in younger patients (< 50 years), although FIA was associated with a better toxicity profile. In a sensitivity analysis that censored patients at the time of allogeneic SCT, median OS was 18 months and not reached in the CIA and FIA arms, and the 2-year OS rates were 43% and 53%, respectively (P = .17).
Jabbour said he is “fascinated” by the role of BCL2 inhibitors, which have led to new standards of care in AML. He pointed to last year’s landmark phase 3 VIALE-A trial (NCT02993523) of venetoclax plus azacitidine, which showed a sharp reduction in the risk of death compared with azacitidine plus placebo in older adults (median age, 76 years; range, 49-91). At a median follow-up of 20.5 months, the median OS was 14.7 months in the azacytidine/venetoclax group and 9.6 months in the control group (HR for death, 0.66; 95% CI, 0.52-0.85; P < .001).16
“We have a new standard of care, and the question is, can we cure more younger patients?” Jabbour said. “The cure rate is really improving at a very high speed, which is quite, quite good. Of course, for the subset of patients with very bad disease, we urgently need new drugs.”
He noted that venetoclax may improve responses in patients with newly diagnosed AML or R/R AML, when added to the FLAGIDA regimen, which comprises fludarabine, cytarabine, granulocyte colony–stimulating factor, and idarubicin. According to phase 1b/2 results from an MD Anderson study (NCT03214562) presented at ASH 2020, the combination demonstrated robust efficacy across subgroups with an acceptable safety profile in participants with treatment-naïve or R/R AML.17
Among 62 patients who completed at least 1 cycle of therapy prior to analysis, the ORR was 84%. For participants treated with the recommended phase 2 dose, the ORR was 96% in the newly diagnosed cohort (n = 27) and 74% in the R/R setting (n = 19). The composite complete response rates, comprised of the complete plus partial or incomplete hematologic recovery, were 76%, 89%, and 58%, respectively, for the entire population, the treatment-naïve, and the R/R groups.17
Moreover, deep responses were observed as indicated by the MRD-negativity rates among patients with a composite complete response: 83% in the overall population (39 of 47 patients), 96% among those newly diagnosed (23 of 24), and 82% among those with R/R disease (9 of 11).17
Investigators in several trials are adding further targeted therapies to the combination of HMAs and BCL2 inhibitors, Jabbour said. He is also looking forward to more data on menin pathway inhibitors, which are aimed at activity facilitated by MLL/KMT2A rearrangements (MLLr) and NPM1c mutations that occur in 5% to 10% of acute leukemias and are associated with poor outcomes.
In April, Syndax Pharmaceuticals, Inc reported interim results for SNDX5613, a menin inhibitor, for patients with MLLr or NPM1c-mutant R/R AML or ALL treated in its phase 1/2 AUGMENT-101 trial (NCT04065399). Among 31 evaluable patients, the ORR was 48% for the entire cohort, 54% for those with MLLr (13 of 24 patients), and 29% for those with NPM1c mutations (2 of 7 patients). Overall, 67% of respondents (10 of 15 patients) reached MRD negative status.18
Several other menin inhibitors also are in development. Kura Oncology, Inc reported clinical activity with a tolerable safety profile in 6 of 8 evaluable patients with R/R AML who received its agent KO-539. The phase 1/2a KOMET-001 trial (NCT04067336) is ongoing, with genetically defined expansion cohorts.19 Daiichi Sankyo has launched a phase 1/2 trial (NCT04752163) of the menin inhibitor DS-1594b with or without azacitidine, venetoclax, or mini–hyper-CVD in R/R acute leukemias. And in March, Janssen Research & Development initiated a phase 1 study (NCT04811560) of JNJ-75276617, a menin pathway inhibitor, in patients with acute leukemias, including ALL and AML, with KMT2A or NPM1 alterations.
In CML, Jabbour said there is a need for new drugs and combinations that will provide more patients with long-term, deep molecular responses and allow them to stop therapy. He noted that studies are underway to extend use of BCL2 inhibitors and HMAs to CML. He is involved in a number of trials of potential new regimens. These include the third-generation BCR-ABL inhibitor olverembatinib (HQP1351) in a phase 1 study (NCT04260022) in patients with CML or Ph-positive ALL and chemotherapy plus ponatinib in a phase 2 study (NCT01424982) in patients with ALL. In patients with Ph-positive or BCR-ABL–positive R/R ALL, phase 2 studies include evaluations of low-intensity chemotherapy with ponatinib and blinatumomab (NCT03147612) and the combination of blinatumomab, methotrexate, cytarabine, and ponatinib (NCT03263572).
BRILLIANT AND CARING
Jabbour’s passion for medicine began during his childhood. He was deeply inspired by his godfather, a surgeon who treated people injured during Lebanon’s long civil war from the mid-1970s until 1990. As a teenager Jabbour shadowed his godfather in the clinic and sought to emulate him.
“I wanted to become a physician to help people and to pay back to the community,” he said. After medical school he had an internship with Georges Chahine, MD, a hematologist and medical oncologist in Beirut who had previously treated a relative of Jabbour’s. “He had an amazing, human way of caring for patients with cancer. It was like, wow, I want to be like him,” Jabbour recalled.
During a visit to Lebanon, Kantarjian met Jabbour, who vowed to work for him some day. After studying in France, Jabbour had a fellowship at MD Anderson. With Lebanon struggling with war and civil conflict, he canceled plans to return there. “He’s such a brilliant person that I offered him a position as a leukemia researcher,” Kantarjian said. “Since then he has been one of the fastest- rising stars in leukemia at MD Anderson and in the world.” When O’Brien left MD Anderson for UCI, Kantarjian asked Jabbour to succeed her as ALL section chief.
Jabbour says he became an oncologist not only because of his inspiring mentors but also because it allows him to make a big difference in the lives of people who are suffering. “The relationship you establish with your patient— you become like his adviser, his confidant. He will share with you all kinds of stories about his life. There’s nothing in medicine that can forge or create this bond between a physician and his patient...like oncology,” he said.
“I picked oncology because we need to make progress, and I felt the field was evolving dynamically,” he added. “It’s so much fun, not in a way where you laugh, but the fun of working hard to find a cure to help somebody. This is priceless.”
Garcia-Manero said Jabbour not only treats his patients with great compassion and creates life-extending treatments, but also takes the time to offer free advice to patients around the world. He also is a mentor to young oncologists, including many in Lebanon who have gone on to become the country’s top leukemia experts. Before the pandemic, Jabbour was also a world traveler, sharing his knowledge with other oncologists and relishing opportunities to meet and talk with local people in places he visited.
“He is an extremely caring individual, and he’s totally devoted to the care of his patients,” Garcia-Manero said. “He’s one of the busiest clinicians at MD Anderson—not in the department, but at MD Anderson. He’s an extreme collegial individual who basically cannot say no to anything you ask him. I’m very proud to work with him.”