Latest Developments in Hematological (Blood and Bone Marrow) Cancer Treatment – ASCO 2018

Lymphoma accounts for %1 of cancers. What most distinguishes this hematological (blood and marrow) cancer from solid organ tumors is its excellent treatment response and chance of cure. This brings extra responsibilities for doctors. For example, in metastatic (stage 4) lung, breast and colorectal cancers, complete eradication and no residual tumor on imaging are generally very difficult. Even stable response and reduced tumor burden are successes in stage 4 solid cancers. In lymphoma, regardless of advancement, the goal is always a tumor-free state. Because chemotherapy works so well, high-dose chemotherapy and autologous stem cell transplantationusing the patient’s own cells must be given on schedule, even with poor general condition and low white blood cells or platelets.

- Related topic: What is lymphoma, or lymph cancer? Symptoms and treatment

At the world’s largest cancer congress, ASCO 2018, noteworthy hematological cancer studies:

Follicular lymphomaaccounts for approximately %8 of non-Hodgkin lymphomas and generally occurs at older ages. It causes symptoms such as widespread, large lymph nodes, particularly in the neck, groin and abdomen. Despite these nodes, blood counts are often normal and fever, night sweats and weight loss absent. Although considered indolent (mild, quiet), it has treatments as intensive as aggressive lymphomas. Over the last 10 years, the most important debated questionin a lymphoma sometimes requiring only close observation has been: “If chemotherapy is needed because counts fall or nodes increase in size and number (for example, a node > 6 cm or < 3 cm but at least 3 nodes), can biological drugs with advantages in effects and side effects replace intensive combination chemotherapy?” Another question was: “Since this slow-growing cancer responds less to chemotherapy and has high recurrence risk, can maintenance treatment be given?”

RELEVANCE , a phase-3 clinical trial, answers these 2 questions. Its key point is that, in lymphoma traditionally considered impossible to treat without chemotherapy, it compares 2 smart molecules—oral lenalidomide and the targeted B-cell surface marker CD 20 drug, administered quickly, rituximab—against conventional chemotherapy (adriamycin, vincristine, cyclophosphamide) plus rituximab.

The study enrolled 1030 previously untreated advanced follicular lymphoma patients, men and women with an average age of 50. The chemotherapy-free arm with only 2 smart molecules and rituximab-plus-chemotherapy arm had similar success in 3-year progression-free survival (%77 versus %78). For the more important overall survival measure, over 3 years both 2 treatment groups achieved %94 success .

Patients find chemotherapy harder to accept because of side effects such as hair loss, nausea, vomiting and fatigue. These also occur with smart drugs but less often, preserving quality of life and allowing normal activities without hair loss. This study found febrile neutropenia , potentially life-threatening fever with low white blood cells, less frequent without chemotherapy (%32 versus %50). Achieving equivalent success with a chemotherapy-free regimen for the first time is an excellent development.

Chemotherapy, radiotherapy and smart drugs directly targeting cancer work in our favor, but treatment resistance and recurrence remain possible. Researchers therefore developed immunotherapies, using our natural defenses against tumors instead of external chemotherapy-like agents. T cells normally should recognize tumors and respond fastest, but cancer cells develop resistance, including programmed cell death receptor mechanisms such as PD-L1, putting T cells to sleep.

Hodgkin lymphomahas abundant T cells in its tumor area and is considered ideal for immunotherapy among hematological cancers. First approved by the FDA in 2016, nivolumab (Opdivo) produced responses of %87 in resistant Hodgkin lymphoma, while pembrolizumab (Keytruda) showed responses in Keynote 087 of %74.

This is important: in patients progressing despite multiple lymphoma treatments, infusions taking just half an hour, not causing hair loss and producing fewer side effects without disrupting daily comfort can give response rates around %80. These drugs are also available here and reimbursed by Social Security for selected patients. Are they harmless? No treatment is free of side effects. Rare, even life-threatening endocrine effects involving the thyroid and pituitary, pulmonary edema and colitis can occur.

At this year’s ASCO, Keynote 087 showed pembrolizumab’s effectiveness and acceptable side-effect profile in Hodgkin lymphoma, where nivolumab had previously succeeded. Immunotherapy also treats lung and kidney cancer, melanoma and others, but lymphoma’s chief advantage is very prolonged success. At ASCO these agents were even presented as curing Hodgkin lymphoma. Whereas other cancers require tissue markers (PD-L1) predicting benefit, Hodgkin lymphoma generally responds without such a biomarker , even after prior allogeneic transplantation.

For non-Hodgkin lymphomas, 7 promising posters also suggested nivolumab and pembrolizumab could succeed, though not yet to Hodgkin lymphoma’s degree.

Blood cancers present a seeming contradiction: cell numbers rise but cells cannot function, acting as if deficient. A prime example is multiple myeloma. The cells fighting infections most, remembering bacteria and viruses and responding appropriately, are plasma cells. In myeloma they increase by at least %30 but are nonfunctional. Frequent life-threatening lung, sinus and urinary infections occur, and increased plasma cells deposit on kidneys and bones, causing kidney failure and pathological fractures. Our cells normally undergo programmed death and replacement by new functional cells through apoptosis . In leukemia and lymphoma, molecules such as BCL-2 and MCL-1 block it, enabling uncontrolled cancer proliferation. Venetoclax blocks these 2 harmful molecules and benefits cancer treatment; an excellent study was presented this year.

In resistant multiple myeloma, a study combined the effective agent carfilzomib, the corticosteroid dexamethasone, also effective in myeloma, and venetoclax, achieving response rates up to %87 . Available here as Venclyxto, venetoclax appears an ideal agent for resistant myeloma.

Keynote 183 and 185 were also presented in resistant myeloma, showing longer survival and modest side effects when pembrolizumab was added to standard treatment. However, effective studies are still needed before immunotherapy use in myeloma.

One discovered cancer pathwaycausing uncontrolled blood cell proliferation is Bruton kinase -dependent proliferation. The oral drug ibrutinib blocks this tumor pathway, Bruton kinase, and is used in treatment. Waldenström macroglobulinemia is a rare but potentially fatal disease involving uncontrolled increases of high-molecular-weight proteins, especially immunoglobulin M. Initially treated only with toxic chemotherapy, it has recently been treated successfully with rituximab targeting CD 20 on B-cell lymphocytes. INNOVATE compared rituximab plus ibrutinib with standard rituximab alone in Waldenström patients, obtaining combination response rates of %92 , an excellent result. At 30 months, progression-free survival differed greatly, at %80 versus %22 , but side effects were more frequent with combination than rituximab alone (%43 versus %33).

In conclusion , effective studies of immunotherapies and targeted smart molecules allow hematological cancers to remain several steps ahead of solid tumors in new treatment strategies, maintaining the advantage of fewer side effects and more effective treatment.