Combination of Drugs Produces High Rates of Complete Response in Chronic Lymphocytic Leukemia



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Combination of Drugs Produces High Rates of Complete Response in Chronic Lymphocytic Leukemia

AT.LANTA, Georgia – Patients diagnosed with refractory chronic lymphocytic leukemia (CLL) appear to have high rates of complete responses when they are treated with a combination of the targeted agents of ibrutinib and venetoclax, researchers said here at the 59th annual meeting of the American Society of Hematology.

Of 54 patients who had previously been treated for CLL, 38 achieved an objective response – and 15 of those patients achieve a complete response after 6 months of therapy, said Peter Hillmen, MBChB, PhD, professor of experimental hematology, University of Leeds, United Kingdom.

In discussing the preliminary results of the CLARITY trial, Dr. Hillmen said the researchers will treat the patients with a complete response for another 6 months and then take them off medication to see if the response can be maintained without medication. “We cannot detect residual disease that may be lingering so we want to extend therapy another 6 months so we can decrease even this undetectable disease several logs lower to the point that the disease may not ever come back,” he said.

All the patients in the study had been treated with at least one previous line of therapy that failed to control the leukemia – some patients had as many as 6 previous treatments. There were 37 men and 17 women in the study; their median age was 62, but they ranged in age from 31 to 84. About 92% of the patients were in ECOG performance status of 0 or 1.

Patients were first treated with two months of ibrutinib at a dose of 420 mg a day. Then they began 6 months of combined treatment that added 400 mg venetoclax daily. If at the end of this 8 month period the test for minimal residual disease was negative, then treatment with both drugs was extended another 6 months – so at 14 months the decision to go without treatment would be made.

If it took 14 months to achieve a negative minimal residual disease level, then patients would continue on combination treatment for another 12 months. Then if there still was no detectable disease, then that person would stop therapy, Dr. Hillmen explained.

If patients still have detectable disease after 26 months, they would go on ibrutinib monotherapy.

While each drug is effective in treating chronic lymphocytic leukemia on it own, Dr. Hillmen and collagues considered that the two agents which attack aberrant cells in different ways might have a synergistic effect.

Hillmen explained that ibrutinib is an oral BTK-inhibitor affecting antigeninduced proliferation and cell adhesion/ migration while venetoclax is a potent, highly selective, orally bioavailable Bcl-2 inhibitor affecting CLL cell survival. Ibrutninib treatment leads to a rapid nodal response with re-distribution of CLL into the peripheral blood, whereas venetoclax leads to depletion of CLL cells to levels where they cannot be detected in some patients. Ibrutinib leads to reduction of anti-apoptotic molecules such as MCL1, hence theoretically potentiating the effect of venetoclax.

Older folks benefit

In another study, researchers reported that using a screening tool that measures an elderly person’s physical condition to guide therapy for multiple myeloma is feasible and results in a high percentage of patient survival for those both fit and frail.

Of 16 patients who were deemed to be fit by utilizing the Vulnerable Elders Survey (VES-13), all received standard chemotherapy and all had one-year progression-free survival and overall survival, reported Tomonori Nakazato, MD, PhD, of Yokohama Municpal Citizen’s Hospital, Yokohama, Japan.

In a poster presentation, Dr. Nakazato and colleagues reported that 31 patients judged as frail by VES-13 scoring were treated with reduced doses of sequential triplet chemotherapy, and 90% of those patients achieved a one-year progression free survival and a 93.4% one year overall survival.

“Personalized, dose-adjusted sequential triplet therapy based on VES-13 showed high response rates and safety in elderly frail patients with multiple myeloma,” Dr. Nakazato stated. “The use of this geriatric assessment-driven treatment approach may result in optimal outcome in both fit and frail elderly multiple myeloma patients.” The overall response rate was 87.5% in the fit groups and 87.1% in the frail group of patients, he reported.

In the multicenter, prospective Phase II trial, patients diagnosed with multiple myeloma and were deemed transplantation ineligible who were ages 66 to 86, were first assessed using the VES-13, a 13-item self-administered instrument, validated in the elderly population to predict functional decline and mortality. If the patients score 0-2 on the VES-13, they were considered fit; scores of 3-10 placed the patient in the frail category.

The fit patients received a standard dose schedule of 4 cycles of subcutaneous bortezomib, cyclophosphamide and dexamethasome, and that was followed by 4 cycles of subcutaneous bortezomib, thalidomide and dexamthasome. The patients in the frail group were given the some dose of bortezomib, but were given about half the dose of the other drugs in both sequences.

The median age of the fit pateitns was 73 years; the median age of the frail patients was 77. Eight of the 16 fit patients were women; 18 of the 31 frail patients were women. Ten patients in the fit category were in ECOG performance status 0 as were 4 patients in the frail group; 6 patients in the fit group were in performance status 1 as were 4 patients in the frail group. There were 7 patients in the frail goup in performace status 2, and 16 patients in the frail group in performance status 3. The median VES-13 score among the patients in the frail group was 7.

Daratumumab improves outcomes

The addition of the targeted monoclonal antibody daratumumab to rituxtimab markedly improves progression free survival among multiple myeloma patients who are not eligible for stem cell transplantation, researchers said.

In a press conference, Jesus F. San-Miguel, MD, medical director of the Clínica Universidad de Navarra in Pamplona, Spain, said that in the late-breaker study patients treated with bortezomib, melphalan and prednisone (VMP) – a combination favored in Europe and Latin America – achieved a median progression-free survival of 18.1 months but patients who had daratumumab added to the same VMP regimen still have not reached a median progression-free survival (P<.0001). He said that difference translates to a 50% reduction in the risk of having disease progression.

Dr. San-Miguel also said that 91% of the patients treated with the daratumumab achieved an objective response compared with 74% of the patients treated with the regular VMP regimen (P<.0001).

The researchers randomly assigned 356 patients with 9 cycles of VMP – bortezomib 1.3 mg/m2 subcutaneously twice a week for the first cycle and then once weekly for the following 8 cycles; 9 mg/m2 melphalan orally on days 1-4; and prednisone 60 mg/m2 on days 1-4.

Another cohort of 350 patients received the same VMP regimen and daratumumab 16 mg/kg intravenously once for the first week and then ever 3 weeks. Then patients received daratumumab every 4 weeks until disease progression occurred.

To be included in the study, patients had to be ineligible for transplantation for newly diagnosed multiple myelome; had to be in ECOG status 0-2; had to have adequate kidney function and no more than Grade 2 peripheral neuropathy.

The combination also induced deeper responses including a greater than 3-fold higher rate of patients achieving a minimal residual disease-negative rate. Dr. San-Miguel noted that 6% of patients receiving VMP achieved a negative minimal residual disease finding compared with 22% of the patients who were also treated with daratumumab (P<.0001).

He also said the addition of daratumumab was achieved without creating any new safety signal. Infections that occurred more frequently among the patients getting daratumumab resolved. The risk of Grade 3 or Grade 4 neutropenia, thrombocytopenia or anemia was similar in both treatment arms, but there was a higher rate of pneumonia in patients treated with daratumumab – 4% in VMP; 11% in patients with daratumumab.

Combination of Drugs Produces High Rates of Complete Response in Chronic Lymphocytic Leukemia 2

“Our results support that daratumumab in combination with bortezomib, melphalan, and prednisone should become a new standard of care in transplant-ineligible multiple myeloma patients,” said Dr. San-Miguel.

He acknowledged that the VMP regimen is not used throughout the world, but noted that ongoing studies are testing daratumumab with other combinations used elsewhere.

This study was supported by Janssen Research & Development, LLC.

March 2018 Health and Lifestyle

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