NEW YORK—Leukemia researcher Lukas Wartman, MD, has survived two relapses from adult acute lymphoblastic leukemia (ALL) with the help of genomic advances and the financial support of his colleagues at Washington University School of Medicine.
Portrayed in several articles in the media as the leukemia researcher who developed the disease himself, Wartman, a medical oncologist and transplant specialist, described his remarkable journey as a leukemia patient to the Great Debates and Updates in Hematologic Malignancies meeting here. Wartman awed the audience with his very personal talk about integrating novel agents into the current therapeutic platform for adult ALL.
“A lot of things are going on in ALL therapy—for example, learning about the mechanisms of resistance in B cells and T cells,” he said. “Interesting research in ALL treatments involving purine analog metabolism offers a potential route of relapse in a significant number of patients. Using genomics to tailor therapy is also exciting.”
Wartman explained that he was diagnosed with ALL at age 25 when he was a fourth-year medical student at Washington University in 2003. “I presented at an Urgent Care center with six weeks of bone pain, fevers, night sweats, and fatigue. I was pancytopenic. I was diagnosed with standard-risk ALL using chromosomal studies, including routine cytogenetics and FISH, which showed only a 12p deletion involving the ETV6 gene.”
His immunophenotype was typical of precursor B-ALL.
He was treated with a standard chemotherapy regimen of nine drugs over the next two years. “There had not been much progress in ALL treatment then. Doctors were using the same drugs as they had 10 years ago,” he said, noting, though, that he did receive more pediatric-inspired dose levels.
He went into prompt complete remission after the induction chemotherapy. However, he suffered many complications, including a catheter-related bloodstream infection, multiple cerebral spinal fluid leaks that required blood patches, an anaphylactic reaction to L-asparginase, febrile neutropenia, neuropathy, severe bone pain secondary to growth factors, weight gain, and anxiety.
“I completed two years of therapy and, with no adverse prognostic characteristics, I did not opt for a stem cell transplant. Instead, I decided to complete maintenance therapy. There is good five-year event-free survival for those under age 30. I thought I was potentially cured,” he said, noting that survival among adult ALL patients is markedly less than among pediatric ALL patients.
In May 2008 Wartman had his first relapse. He presented with bone pain and fatigue. A bone marrow biopsy confirmed relapsed ALL.
“I was treated again with standard chemotherapy. Luckily, my younger brother was a match for a bone marrow transplant.” On July 31, 2008, Wartman received aggressive myeloablative treatment with hyper-CVAD for four cycles, followed by a matched sibling allogeneic bone marrow transplant with fractionated total body irradiation of 1,320 cGy/VP-16/Cy conditioning.
“I had standard methotrexate and tacrolimus graft-versus-host disease (GvHD) prophylaxis, but I was weaned quickly off tacrolimus to minimize relapse and switched to sirolimus post-transplant based on a retrospective series of pediatric ALL patients,” he said. His transplant course was complicated by mucositis, acute GvHD of the skin, chronic GvHD of the oral mucosa, fatigue, and multiple infections, including H1N1 influenza and herpes zoster.
“It was not a walk in the park, but I did remarkably well. I thought the treatment had wiped out the disease. I was optimistic my disease was cured by the transplant,” he said.
Unfortunately, it was not. Two years later, in July 2011, he had a second relapse. He opted to enter into a clinical trial to make his ALL cells more chemosensitive, using high-dose chemotherapy followed by a donor lymphocyte infusion. But he did not enter remission.
His chemotherapy course was complicated by severe enteritis and fevers. “My chances of a cure or survival appeared to be remote,” Wartman said.
As a leukemia researcher, Wartman knew about basic research in mice that showed that granulocyte colony stimulating factor (G-CSF) induced a pronounced, unexpected reduction in lymphoid cells. It appears that G-CSF causes trophic factors in both mice and people that are not dependent on the G-CSF receptor. “I had a reduced number of B cells in my bone marrow. We hoped G-CSF would have effects on multiple levels of my B cells, and eventually affect mature leukemic cells as well,” he said.
Wartman entered into a pilot trial of G-CSF chemosensitization versus standard chemotherapy in 20 adult relapsed/refractory ALL patients. “My blasts were mobilized, but I was left with residual disease after the high-dose chemotherapy. I was beat up, and not in remission. It didn't work,” he said, adding that 10 patients in the study have been treated to date with no increased hematopoietic toxicity.
G-CSF treatment alone has induced ALL blast cell mobilization and ALL blast apoptosis in the bone marrow. The complete remission rate of 30 percent in this study is comparable to historical controls, he said.
“I was off the grid after my second relapse with no remission, but I had a gamut of exciting treatment options to consider,” he said. These included blinatumomab, a monoclonal antibody that specifically targets the CD19 antigen, and the emerging story of infusing chimeric antigen receptor (CAR) T cells.
“When I had relapsed, a German group had just reported using blinatumomab induction to induce complete remission in three young pediatric B-ALL patients who had relapses after hematopoietic stem cell transplant (HSCT).
“The patients had a remarkably good response,” he continued. “Moreover, the results of a Phase II trial of 20 adult minimal residual disease (MRD)-positive B-ALL patients treated with blinatumomab had just been published. These positive results in MRD-positive ALL were a game-changer. I asked Micromet [the drug's manufacturer] for blinatumomab on a compassionate-use basis, but I was denied. I would have agreed to go to Germany to be treated on a Phase II clinical trial of blinatumomab, but the trial had just closed to enrollment.”
He noted that the German team now has more results in nine patients who have not gone on to transplant: “Six of the nine patients still have remarkable long-term survival in a disease that is 95 percent fatal, in general,” said Wartman, adding that a Phase II trial of blinatumomab in ALL has begun in multiple centers in the United States. “The hope is that this agent will prove to be effective.”
Another new potential treatment had been developed by Carl June, MD, Professor in Immunology at the University of Pennsylvania. June and his colleagues have demonstrated remarkable efficacy of autologous modified T cells that are transfused with CAR, congregating T cells specifically to target CD19+ ALL cells, in pediatric ALL patients. Multiple reports of patients with B-ALL treated with CD19-targeted CARs have now been published.
CD22-targeted CARs and conjugated monoclonal antibodies, such as inotuzumab ozogamicin, are also being developed. Other research in this area uses virus-specific donor T cells, such as Epstein Barr virus, cytomegalovirus, or adenovirus, after HSCT to minimize the risk of GvHD.
“This exciting, ongoing work is focused on moving this emerging field forward,” said Wartman. “There have been no reports of T cell clonal derangements. We can potentially transplant only certain subsets of T cells to minimize the risk of GvHD. It appears to be safe, even with prolonged depletion of T cells.”
Whole Genome Sequencing
Instead of blinatumomab or CAR T-cell infusions, Wartman chose to enter a research study at Washington University School of Medicine that had just opened to use whole genome sequencing in ALL patients. The head of Wartman's lab, Timothy Ley, MD, Professor of Oncology in Medicine at Washington University, offered him a slot in the study.
Researchers at The Genome Institute at Washington University sequenced the DNA and RNA from Wartman's leukemia cells. “I thought this was going to be an academic exercise. We were looking for a magic bullet. Maybe we missed a translocation in BCR-ABL, and then I could get a tyrosine kinase inhibitor to influence my treatment,” Wartman said.
The DNA sequencing results were unremarkable. However, a few days later, RNA sequencing results showed marked FLT3 overexpression. “It was clear that FLT3 was just smoking hot in my leukemic cells,” said Wartman, who received the sequencing results just as he found out that he had refractory disease.
Wartman started taking the FLT3 inhibitor sunitinib, which is FDA-approved for other types of cancer, including metastatic renal cell cancer and imatinib-resistant gastrointestinal stromal tumor. He was also taking low-level standard ALL maintenance therapy with sirolimus, methotrexate, and 6-MP.
“Two weeks later, the treatment was miraculously effective. I was in complete remission,” he said.
But Wartman's insurance carrier would not pay for sunitinib treatments, which are expensive, and Pfizer, the drug's manufacturer, would not provide it to him on a compassionate use basis. As related in an article in the New York Times published last summer that described his journey (7/7/12 issue), the doctors in his division pitched in to buy him a month's supply of the drug.
At that point, he decided to have a second SCT from an unrelated matched donor. “This transplant was much harder to get through. My post-transplant course was complicated by GvHD, and I have been able to take sunitinib only for a short time after the transplant,” he said.
Despite the complications, Wartman is back at work in Ley's lab, continuing his leukemia research.
In reflecting on his decade-long battle with ALL, Wartman noted that “just because something is a late hit doesn't necessarily mean that it is not important to the target.
“FLT3 was not overexpressed when I presented on first relapse. Whatever was driving FLT3 expression was not present in the founding clone. Therapy wiped out that clone, but not the clone that has FLT3 expression. Sunitinib did that.”
He added that ALL is often a complicated mix, a heterogeneous leukemia with different clones, and “you have to hit them all to cure the disease,” he said.
Looking toward future ALL therapies, he said he believes that whole genome sequencing, like his, will provide significant results from patients' leukemic cells.
“We will be able to design a tumor-specific vaccine based on the presence of antigens on tumor cells,” Wartman said. “Normally in my lab I work on a mouse model of leukemia. In my mouse tumors, I can get a specific antigen response.” He noted that multiple trials of vaccination after HCST against the leukemia--associated antigen WT1 have been reported, primarily in patients with AML. There are ongoing trials and a few published reports of WT1 vaccines in patients with ALL as well.
In conclusion, Wartman said, “I feel a tremendous sense of excitement that we are on the verge of understanding the ground rules to improve patient outcomes. I have benefited myself. Words can't express what it means for me to be part of that research team.”