Initial therapy of chronic lymphocytic leukemia

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Initial Therapy of Chronic Lymphocytic Leukemia B. Eichhorst, P. Cramer, M. Hallek

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Semin Oncol

Cite this article as: B. Eichhorst, P. Cramer, M. Hallek, Initial Therapy of Chronic Lymphocytic Leukemia, Semin Oncol, http://dx.doi.org/10.1053/j.seminoncol.2016.02.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Initial therapy of chronic lymphocytic leukemia B Eichhorst 1, P Cramer1, M Hallek 1, 2 1

Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne,

Cologne, Germany 2

CECAD - Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated

Diseases

Corresponding author: Barbara Eichhorst, MD, Department I of Internal Medicine and Center of Integrated Oncology Köln Bonn,University of Cologne, Köln, Germany. Email: [email protected]. Phone: 0049-221/478-85255 Disclosures The authors received research funding and honoraria for scientific talks and advisory boards from the following pharmaceutical companies: Celgene, Gilead, GSK, Hofmann LaRoche, Janssen and Mundipharma. MH was supported by the Deutsche Forschungsgemeinschaft, clinical research unit 286 (KFO 286) Abstract Only CLL patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. Prognostic risk factor profile and comorbidity burden are most relevant for the choice of treatment. For physically fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab remains the current standard therapy. For unfit patients, treatment with an anti-CD20 antibody (obinutuzumab or rituximab or ofatumumab) plus milder chemotherapy (chlorambucil)

may be applied. Patients with a del(17p) or TP53 mutation should be treated with the kinase inhibitors ibrutinib or a combination of idelalisib and rituximab. Clinical trials over the next several years will determine, whether kinase inhibitors, other small molecules, immunotherapeutics, or combinations thereof will further improve outcomes for patients with CLL.

Introduction For patients with chronic lymphocytic leukemia (CLL) treatment possibilities and efficacy of various treatment regimens has changed dramatically during the past decades. For a long time, treatment of CLL was a very palliative approach starting with the introduction of the alkylating chlorambucil in 1956 1. Treatment with chlorambucil alone or in combination with steroids showed the first remarkable remissions 2,3. In the 1980ies combination therapies with cyclophosphamide, doxorubicine, vincristine and prednisolone (CHOP) or similar regimen, e.g. COP, were compared to chlorambucil within randomized studies but were not able to show a clear benefit due to a higher toxicity rate 4-6. Hence, chlorambucil was the treatment of choice for decades until a new agent group of chemotherapeutic agents, the purine analogues (including the substances fludarabine, cladribine, pentostatin), was introduced 7,8. Fludarabine monotherapy resulted in a significantly better response rates as well as longer progression-free survival (PFS) in comparison to CHOP 9. Similar results were obtained with fludarabine or cladribine in comparison to chlorambucil 10,11. The combination of purine analogues with cyclophosphamide yielded significantly higher rate of complete remission and furthermore an additional prolongation of relapse-free time. 12-15 With the addition of rituximab to these regimen or to single agent chemotherapeutic agents a treatment standard in previously untreated CLL was defined, the CD20-antibody based chemoimmunotherapy regimen. The new targeted treatment substances, approved mainly for the relapsed and refractory situation and currently investigated in several studies for upfront treatment, will change frontline therapy of CLL

in the near future. The article summarizes current treatment options focusing on chemoimmunotherapy as well as chemotherapy-free regimens.

Indication for treatment initiation In general practice, newly diagnosed patients with asymptomatic early stage disease (Rai 0, Binet A) should be monitored unless they develop symptoms of active and/or progressive disease. Previous studies have shown that early treatment with alkylating agents does not translate into a survival advantage in patients with early stage CLL 16,17. Treatment should be initiated in patients with advanced stage disease (Rai III and IV or Binet C). Patients with intermediate stage (Rai I and II or Binet B) can be monitored until they have symptoms of progression and/or symptomatic disease. According to the IWCLL guidelines the following conditions define active disease: significant B-symptoms, cytopenias not caused by autoimmune phenomena, autoimmune anemia and/or thrombocytopenia poorly responsive to conventional therapy, symptoms or complications from lymphadenopathy, splenomegaly or hepatomegaly as well as lymphocyte doubling time of less than six months (only in patients with more than 30 G lymphoyctes/L) 18. These criteria may also lead to treatment initiation in early stage disease. The absolute lymphocyte count itself should not be used as a sole indicator for treatment initiation, because even patients with very high lymphocyte counts rarely develop symptoms.

General considerations for the choice of initial therapy Because of the broad spectrum of available therapies for CLL, the selection of the optimal initial treatment has become complex. Among those parameters, which have to be considered for treatment recommendation, are the following: 

Clinical stage of the disease



Symptoms



Fitness and comorbidity burden



Genetic risk of the leukemia

As outlined above, treatment should only be administered in patients with advanced and/or symptomatic disease. Because CLL is a disease of elderly patients with a median age of 72 years at diagnosis 19, the evaluation of the patients` fitness and comorbidity burden is very important. For this purpose no ideal fitness stratification tool exists so far. The performance status (Eastern Cooperative Oncology Group (ECOG) status or Karnofsky index) is of limited evidence in CLL and can therefore not be used as single tool for a reliable conclusion for treatment recommendation. Therefore, it is recommended to add another tool for measuring patients´ comorbidity burden. In solid tumors and lymphoma there are several tools available, among these the Cumulative Illness Rating Scale (CIRS)20,21 , Charlson Comorbidity Index (CCI) 23

22

and National Cancer Institute Comorbidity Index

. A comprehensive geriatric assessment measuring additional dimensions of aging beyond

performance status and comorbidities would be beneficial for the best treatment choice 24,25. Based on their physical constitution, comorbidities and estimated life expectancy regardless of the diagnosis of cancer, three groups of elderly cancer patients can be distinguished

26-28

. First,

physically fit patients without or with mild comorbidities that do not adversely impact on the patient´s life expectancy, who should be treated with standard-therapies. Second, patients with relevant comorbidities that have impact on life expectancy, who should receive dose-reduced or modified therapies for disease control and third, patients with a markedly reduced life expectancy due to multiple and/or severe comorbidities or frailty, who should be treated with best supportive care. For these three patient groups different therapeutic goals should be pursued: the aim for the first group is to achieve a long-term remission and a prolongation of survival, whereas for the second and third group disease control and symptom control/palliation should be sought.

Another important factor for the choice of treatment is the genetic risk profile of CLL. The deletion of the short arm of chromosome 17 [del(17p)] or mutation of the TP53 gene is associated with a poor prognosis and resistance to chemotherapeutic agents used for the treatment of CLL 29-33. Therefore, the detection of a del(17p) or a TP53 mutation is crucial for the choice of treatment and a genetic analysis (FISH and molecular testing for IGHV status, del(17p) and TP53 mutation) is strongly recommended before treatment initiation

34

. Because of the possibility of genetic

evolution35-37 testing for specific genetic markers should be repeated before treatment initiation in case the previous testing was done a couple of months or even years ago. The occurrence of a new genetic mutation or deletion should particularly be considered in those patients in whom the clinical course of the disease has changed to a more aggressive form. Besides these most relevant factors driving the treatment decision there are some other factors, which may influence the choice of treatment. Among them is the patients´ expected compliance, which is essential for CLL treatment with oral substances such as kinase inhibitors or the immunomodulatory drug lenalidomide. Moreover, with the new continuous treatments potential interactions with other medications will have to be considered as well. Treatment of fit patients The studies discussed in this section were mostly performed in a patient population not selected according to a strict evaluation of fitness but rather considered by the treating physician as fit enough for more intensive chemoimmunotherapy regimen. However, the patients´ median age in these studies was predominantly in the mid-60s, reflecting the fact that rather young CLL patients were included. Purine analogues based combinations with rituximab After preclinical studies identified a synergy between fludarabine and rituximab fludarabine based chemoimmunotherapy combinations were evaluated in phase II trials

39

38

,

. A

randomized CALGB study compared the efficacy of the concurrent administration of rituximab and

fludarabine (FR) versus fludarabine alone in 104 previously untreated CLL patients

40

. In both arms

induction therapy was followed two months later by four weekly doses of rituximab for consolidation therapy. Overall and complete response rates were higher in the concurrent group (90% and 47% vs. 77% and 28%)

40

. In a retrospective analysis, all patients of the CALGB 9712

protocol treated with fludarabine and rituximab were compared with 178 patients from the previous CALGB 9011 trial receiving fludarabine alone 41. Patients receiving fludarabine and rituximab had a better PFS and overall survival (OS) than patients receiving fludarabine alone. Two-year PFS probabilities were 67% versus 45% and 2-year OS probabilities were 93% versus 81%

41

. After

long-term observation median PFS after FR was 42 months and median OS was 85 months 42. The triple combination of fludarabine, cyclophosphamide and rituximab (FCR) was initially investigated in a monocentric phase II trial performed at the MD Anderson Center in frontline therapy of patients with advanced in CLL

43

. Among the 224 included patients 70% achieved a

complete responses. Long-term follow-up of this study showed a six-year overall and failure-free survival of 77% and 51%, respectively

44

. Median time to progression after frontline FCR therapy

was 80 months. The CLL8 trial of GCLLSG compared the FCR regimen head to head to the FC regimen

45

.

Patients in good physical fitness, defined as CIRS comorbidity score ≤6 and a creatinine clearance >70ml/min were randomly assigned to receive 6 courses of FC or FCR. In 817 patients FCR induced a higher overall response rate than FC (93% versus 85%; p<0.001), more complete responses (44% versus 23%; p<0.001) and a significantly higher proportion of MRD negativity at the end of treatment (63% versus 35%, p< 0.001) FC arm (p<0.01)

45

46

. PFS at 2 years was 77% in the FCR arm and 62% in the

. An update of the CLL8 data after a median observation time of 4.9 years

confirmed the overall survival benefit with FCR first line therapy. 69% of patients treated with FCR remained alive compared to 62% in the FC arm (hazard ratio [HR] = 0.68, 95% Cl 0.535-0.858, p = 0.001) 47. Interestingly, the median PFS was still not reached in FCR-treated patients with a mutated

IGHV status and their Kaplan-Maier PFS curve appeared to level off to a plateau, raising expectations that a subgroup of patients treated with FCR might achieve not only long-term remissions but also a cure from the disease

47

.However, FCR is associated with a high incidence of

adverse events, particularly cytopenias and infections. In the CLL8-trial common toxicity criteria (CTC) grade 3-4 leucopenias and neutropenias occurred in 24% and 34% of patients treated with FCR and 25% experienced CTC grade 3-4 infections

45

. Though neutropenias were significantly

more frequent than with FC the incidence rate of severe infections was similar in both arms. Several studies have investigated the addition of more compounds, such as an additional chemotherapeutic agent or an immunomodulatory drug, to the FCR or FR regimen in order to increase response quality.

A Spanish multicenter phase II trial evaluating the addition of

mitoxantrone to FCR showed no clear benefit when compared to the results reported for FCR 48. The overall response, minimal residual disease (MRD)-negative complete response, MRD-positive complete response and partial response rates were 93%, 46%, 36%, and 11%, respectively. Severe neutropenia developed in 13% of patients. These results do not justify the broad use of this regimen outside of clinical trials. A phase I study evaluating the addition of lenalidomide to fludarabine and rituximab (FRL) first line therapy had to be stopped early because of high toxicity rates in nine included patients 49. Patients received fludarabine 25mg/m² IV for 3-5 days depending on dose level and rituximab (375mg/m² in cycle 1 and 500mg/m² in cycle 2-6), respectively. Lenalidomide was initiated with a dosage of 2.5mg and subsequently increased to a maximum of 25mg. Severe toxicities, particularly prolonged myelotoxicity, as well as tumor flare, myopathy and rash were observed in five patients resulting in dose de-escalations and finally trial termination. However, an Austrian phase II study evaluated a similar treatment schedule consisting of fludarabine 40mg/m² p.o. for three days and rituximab (375mg/m² cycle 1 and 500mg/m² cycle 2-6) in 45 previously untreated patients 50. In contrast to the US study, lenalidomide was started with a

delay of one week on the same dose level of 2.5 mg with planned increase to 25 mg. Maintenance therapy with lenalidomide for 6 months with three additional rituximab infusions was administered after six courses FRL. Severe neutropenia developed in 27% but severe infections developed in only 5% of patients. Due to long lasting neutropenia 46% of the patients receiving maintenance needed lenalidomide dose reduction. Improvement of response from partial remission after induction to complete remission at the end of maintenance was observed in 25%. After a median follow-up of 35 months 89% were still in remission. A recently published smaller study including twenty non-pretreated patients reported the successful treatment with dose reduced FCR (FCR light) regimen in combination with lenalidomide 51

. Fludarabine was given at a dosage of 20mg/m² IV and cyclophosphamide with 150mg/m² IV both

of them for three days. Rituximab was administered biweekly and lenalidomide was slowly dose increased from 5mg to a maximum of 15 mg. Moreover, pegfilgrastim was given routinely with every cycle. The complete remission rate with this regimen is promising with 75%. Severe neutropenia occurred in 52% of the patients, severe infection in 8% and severe rash in 5%. Thus, administration of additional compounds to the FCR or FR regimen may increase toxicity but lenalidomide in combination with a dose reduced chemotherapy regimen may have benefit in selected patients. While a randomized study has been completed to evaluate intensification of FR/FCR with lenalidomide (CALGB 10404), results have yet to be reported. Other purine analogue based combinations substituted fludarabine within the FCR regimen with cladribine (CCR) or pentostatin (PCR). The combination of cladribine plus cyclophosphamide plus rituximab was assessed in patients with relapsed/refractory CLL and had a 78% overall response rate 52. There are no available data of CCR in frontline therapy of CLL. Pentostatin, cyclophosphamide plus rituximab were evaluated in 65 previously untreated CLL patients 53. Overall response and complete response rate were similar to fludarabine based combination therapies with 91% and 41% respectively. Toxicities were mainly hematologic occurring in 58% of the patients. In

a phase III randomized trial comparing FCR to PCR in previously untreated or minimally pretreated CLL patients, there were no statistical differences between treatments in OS or response 54. Moreover, this trial did not demonstrate a lower infection rate with PCR.

Interestingly, a phase II study evaluating the combination of pentostatin and rituximab without cyclophosphamide yielded only a 76% overall response rate and a 27% complete response rate. In addition, relapse free survival was longer with PCR as compared to PR in a historical control, thus the authors concluded that the addition of cyclophosphamide to purine-analogue base chemoimmunotherapy is necessary for a better remission induction. Though no data regarding a head to head comparisons between FCR and FR are yet available, in most countries and regions FCR has become the standard therapy in need of initial therapy. However, as there might be a potentially higher risk for secondary neoplasias after initial therapy with FCR 55, in some areas the FR combination is preferred. 56

Purine analogues based combinations with ofatumumab The fully humanized CD20 antibody ofatumumab was also evaluated in several studies with purine analogue based combinations. An international phase II trial evaluated two different dose levels of ofatumumab combined with fludarabine and cyclophosphamide (FCO) as frontline therapy for CLL. 61 patients were randomized between two different ofatumumab doses (500mg versus 1000mg) 57. The complete response rate as assessed by an independent review committee was 32% for the 500mg- and 50% for the 1000mg cohort; the overall response rate was 77% and 73%, respectively. The most frequent adverse events were neutropenia (48%), thrombocytopenia (15%), anemia (13%), and infection (8%) 57. The lower overall response rate of FCO in comparison to FCR might have been related to the higher-risk profile of included patients. Another phase II study investigated the combination of ofatumumab, pentostatin and cyclophosphamide (PCO) in 48 previously untreated CLL patients 58. The overall response rate was

96% and the complete remission rate was 46%. After median follow-up of 24 months, 21% patients progressed. According to the authors the efficacy and toxicity of the ofatumumab-based chemoimmunotherapy used in this study compared favorably to the historical trials of rituximabbased chemoimmunotherapy using an identical chemotherapy backbone. Thus althoughresponse rates suggest that ofatumumab based chemoimmunotherapy regimen yield similar efficacy as rituximab based therapies longer follow-up is needed in order to evaluate PFS. Purine analogue based combinations with other antibodies Previous studies evaluating combination therapies of fludarabine plus alemtuzumab (antiCD52) have had a high efficacy rate, but also high frequency of toxicity, particularly infections 59,60. The combination of FC plus alemtuzumab (FCA) was assessed in two phase III studies. The phase III trial of the French study group, which compared FCA to FCR in first line therapy was closed prematurely due to the higher toxicity and treatment-related mortality observed in the FCA arm 61. In this trial, alemtuzumab was given subcutaneously. The therapeutic efficacy FCR was clearly superior to FCA with a three-year PFS of 83% with FCR and 72% with FCA 61. Another international phase III study conducted by the HOVON group compared FC versus FCA using alemtuzumab in a significantly lower dose than the French study 62. The study showed that FCA prolonged the primary end point, progression-free survival (three year PFS 53% versus 37%)but did not impact OS 62. Opportunistic infections were more frequent following FCA but without an increase in treatment related mortality. In a phase II study of the MD Anderson Center alemtuzumab was added to FCR (CFAR) on 60 high-risk untreated patients 63. Complete remission was achieved in 70% and partial remission in 22% resulting in an overall response of 92%. Of 14 patients with a del(17p) eight (57%) achieved a complete response. Severe neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median PFS was 38 months and median OS was not reached. Thus CFAR seemed an active frontline regimen for high-risk CLL that might be used for cytoreduction before an

allogeneic stem cell transplant. Due to a strategic financial decision of Sanofi, the marketing license for this drug was withdrawn in August/September 2012. Alemtuzumab is only available now through compassionate use programs. Bendamustine based combinations with CD20 antibodies Bendamustine has been combined with rituximab in 117 patients with previously untreated CLL. 64 Overall response rate was 88% with a complete response rate of 23%. After a median observation time of 27 months, median event-free survival was 34 months and 90% of patients were alive. Grade 3 or 4 severe infections occurred in only 8% of patients. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 20%, 22%, and 20% of patients, respectively 64. Overall, these results compared favorably with the FCR regimen as BR achieved similar response rates, albeit lower CR rates, but induced less neutropenia than FCR.

The CLL10 trial of the GCLLSG therefore prospectively dtermined if the BR-regimen was indeed equally effective and less toxic compared to the current standard treatment FCR for the firstline treatment of physically fit patients. Physically fit patients without del(17p) were randomized to receive up to 6 cycles of either FCR or BR 65. Overall response rates in 564 patients were 98% in both arms, but patients treated with FCR achieved a significantly higher rate of complete remissions (41% versus 31%) and a longer median PFS (54 vs. 43 months, HR=1.589, 95% CI 1.25-2.079, p=0.001). On the other hand significantly more CTC grade 3 and 4 neutropenias and infections occurred with FCR (88% versus 68% and 40% versus 25%), especially in patients >65 years old (48 versus 27%) 65. Taken together, the CLL10 study confirmed that FCR was a standard of therapy in very fit CLL patients, because it yields higher CR rates and longer PFS when compared to BR. However, elderly fit patients and those at high risk of infections might benefit from BR as alternative regimen. The combination of bendamustine plus ofatumumab (BO) was investigated in previously untreated and relapsed CLL within a small phase II study. First results reported that the investigator-

assessed overall and complete response rate was 95% and 43% in the 44 patients included for firstline treatment with BO 66. CTC° grade 3-4 adverse events occurred in 34% and 23% of first-line patients, including 16% and 20% °III/IV neutropenias, 5% CTC grade 3 skin reactions and 11% CTC grade 3-4 infections 66. However, despite these immature results, the combination of BO was approved for the use in CLL; further trials are however needed to define the value of this regimen. In conclusion these data show that BR is inferior to FCR with regard to efficacy, but is better tolerated with the exception of skin reactions. Because of the lower rate of severe infections BR/BO frontline treatment might be considered in those fit CLL patients with a high risk of infectious episodes.

Treatment of less fit patients The minority of clinical trials are focused on elderly and/or less fit CLL patients, the typical group of CLL patients according to the median age at onset. The studies discussed in the section here were performed in a less fit patient population defined by age limit, clinical judgment (“not fit enough for FCR”) or comorbidity assessment. Chlorambucil based combinations In contrast to the progress which has been made in younger CLL patients by intensification of treatment, in elderly/ comorbid patients single agent chlorambucil has still been widely used because of lack of statistically significant differences in OS with other regimens67-69. In order to test the intensification of the chlorambucil regimen several studies evaluated the combination of chlorambucil with different CD20-antibodies. In a first step, two phase II trials assessed the combination of chlorambucil plus rituximab (ClbR) in an elderly patient population 70,71. In the British study 100 patients ineligible for fludarabine-based treatment received 6 cycles of ClbR 70. A complete response was achieved in 10% and overall response in 84% of the patients. The median time to progression was 23.5 months. In the Italian study 85 patients older than 65 years were included 71 and treated with six cycles of ClbR. Afterward, responders were randomized to receive

two years of rituximab maintenance therapy versus observation. As per intention-to-treat analysis 82% of 85 patients had an overall response, 19% a complete response. After a median follow-up of 34.2 months, the median PFS was 34.7 months (95% CI, 33.1-39.5) 71. The combination ClbR was well tolerated in both clinical studies with severe infections occurring in less than 10% of patients. Obinutuzumab is a humanized and glycoengineered CD20 antibody, which showed in vitro higher rates of apoptosis in comparison to rituximab

72,73

. In vitro obinutuzumab showed increased

direct cell killing and antibody-dependent cellular cytotoxicity (ADCC)

74

.

The addition of

rituximab and of obinutuzumab to chlorambucil was tested the CLL11-trial, an international phase III study

75

. Patients with coexisting medical conditions (defined as a CIRS Score >6 and/or

Creatinine-Clearance <70ml/min) were randomized to receive single agent chlorambucil (Clb) or ClbR or obinutuzumab (G-Clb). In 781 patients the incidence of infusion-related reactions (IRR) in general and especially severe IRRs was higher with G-Clb than with ClbR (CTC grade 1-4 and grade 3-4: 66% and 20% vs. 38% and 4%). However, with the introduction of safety precautions for prevention of IRRs, such as adequate premedication, dose-splitting of the first dosage and withholding antihypertensive medications, these were manageable and limited to the first administration of obinutuzumab. Cytopenias, especially neutropenias, were more common with GClb and ClbR compared to single agent chlorambucil (neutropenia CTC grade 3-4: 33% and 28% vs. 10%); but did not lead to a higher rate of infections (infection CTC grade 3-4: 12%, 14% and 14%) 75

. As expected, overall and complete response rate was highest with the combination of

chlorambucil and obinutuzumab (overall response rate 77.3%, inclusive 22.3% complete responses), followed by chlorambucil with rituximab (65.6% and 7.3%) and was worst with single agent chlorambucil (31.4%, no complete responses). With G-Clb a significant proportion of responding patients even achieved MRD negativity in peripheral blood and bone marrow (37.6% and 19.5% of all evaluated patients)

75

. The median PFS was only 11.1 months in patients receiving single agent

chlorambucil and was significantly improved to 16.3 months with the addition of rituximab

(p<0.0001). The combination of G-Clb further improved the median PFS to 26.7 months (p<0.0001) and also improved the median OS in comparison to single agent chlorambucil (p=0.0022). An updated analysis showed that with longer follow-up, OS after ClbR therapy was also significantly improved in comparison to CLB alone (HR 0.60, 95% CI 0.38-0.94, p=0.0242)

76

. However, the

difference in OS between both antibody containing treatment arms was statistically not yet significant (HR 0.70, 95% CI 0.47-1.02, p=0.0632). The combination of chlorambucil and ofatumumab (ClbO) was compared to single agent chlorambucil in a total of 447 treatment-naïve CLL patient, who were considered inappropriate for fludarabine-based therapy due to their age or comorbidities.77 Overall and complete response rate were significantly higher with the addition of ofatumumab compared to chlorambucil alone (82% inclusiding 12% CRs vs. 69% inclusiding 1%, p<0.001), which translated into an improvement in the median PFS of nine months (22.4 vs. 13.1 months, p<0.001). So far, no randomized head-to-head comparison of ofatumumab and with the other anti-CD20 antibodies has been reported. However, based on the data of these two phase III studies chlorambucil-based chemoimmunotherapy combinations are recommended for frontline therapy of elderly/comorbid patients without a high risk profile.

Purine analogues based combinations Because of the high incidence of toxicities associated with full dose FCR in elderly patients with relevant comorbidity, a dose-modified FCR-Lite regimen was designed to maintain the efficacy but decrease the toxicity of the FCR regimen 78,79. This regimen reduced the dose of the two cytostatic agents, (fludarabine to 20 mg/m² and cyclophosphamide to 150 mg/m² for three days) and increased the dose of rituximab (administered on day 1 and day 14). Moreover, maintenance with rituximab at 500 mg/m² was given every 3 months until progression. The complete response rate was 73% for 50 previously untreated CLL patients with an overall response rate of 94%. The median PFS

was 5.8 years. Grade 3-4 neutropenia was documented in only 11% of cycles, which was lower than observed with the usual FCR regimen. Only 6% of the patients developed a severe infection. Notably the median age of patients included in this study was very low (58 years) and therefore not representing an elderly patient population. As mentioned above the addition of lenalidomide to this dose-reduced regimen shortened to four cycles of treatment (FCR²) was feasible and effective in 20 previously untreated patients 51.

Several other studies evaluated different dose-reduced FCR regimens. Mulligan et al. investigated two different dose-reduced FCR regimens and a FR- regimen in 116 fit CLL patients 65 years of age or older 80. The FCR 3 and FCR 5 schedule consisted of either three or five days of fludarabine 24mg/m² and cyclophosphamide 150mg/m² orally administered in combination with rituximab given intravenously (375mg/m² at first cycle and then 500mg/m²). The FR5 regimen (fludarabine 24mg/m² d1-5) was associated with the lowest toxicity but also yielded significantly lower complete remission rates. On the other hand FCR3 and FCR5 resulted in significantly higher complete response rates. However, only 44% of patients receiving FCR5 completed six cycles of therapy. The high incidence of early treatment discontinuation resulted in a shorter PFS with FCR580.

A French study evaluated an orally administered FCR-Lite schedule in fit CLL patients above the age of 65 years 81. Four cycles of dose reduced FC p.o. were combined with intensified six doses of rituximab for induction treatment, similar to the US study by Foon et al. 78. After induction therapy patients achieving at a partial remission were randomized between rituximab maintenance and observation. Also this dose reduced FCR regimen was well tolerated in the elderly and resulted in a promising overall response rate of 96% with 20% complete responses 81. Further results from this study regarding PFS with or without rituximab maintenance therapy are awaited.

The Czech CLL study group initiated an observational study in which 207 CLL patients without determined age or fitness limits were included 82. Patients with a median age of 69 years and a median CIRS score of 5 received FCR-Lite with FC dose reduced to 50% and full dose rituximab. Clinical complete remissions were achieved in 37% of 108 patients but median PFS at 28 months was significantly shorter than with full dose FCR 82. Interestingly, in univariate analysis neither CIRS score nor creatinine clearance were predictive of PFS or OS. Summarizing the results from these studies evaluating dose reduced FCR, the data show that the toxicity of this regimen is acceptable in elderly patients. However, the inferiority of the efficacy might be improved by a more dose dense rituximab administration such as an FCR-Lite regimen.

Bendamustine based combinations Most of the clinical trials evaluating the combination of bendamustine plus rituximab did not focus particularly on elderly or less fit patients. Subgroup analyses of larger studies showed good response rates (overall response rate 84% to 96%; complete response rate 11% to 35%) and median time to progression of 38 to 48 months 64,65. The Mable study investigated BR in randomized phase II in comparison to ClbR in 339 elderly patients ineligible for FCR 83. The interim analysis showed a trend towards a better complete response rate with BR in comparison to ClbR (24% versus 10%; p= 0.033). With regard to toxicities no significant differences in terms of hematotoxicity were observed (32% versus 34% severe neutropenia) but in tendency more pneumonias were observed with BR (7% versus 2%) 83. Non-chemotherapy containing frontline therapy options Rituximab administered either as monotherapy or in combination with steroids for treatment of elderly patients is a frequently used frontline regimen in the US 84. However, data supporting this non-chemotherapy frontline approach from clinical trials are very limited. So far only one single center study investigated rituximab plus high-dose methylprednisolone in first line therapy of 28 patients with CLL 85. Another non-chemotherapy treatment approach in elderly patients is the

immunomodulatory agent lenalidomide. Starting with a low dose and followed by a slow dose increase in lenalidomide was well tolerated and tumor lysis syndrome or tumor flare reaction were rare in a phase II study on 60 patients above the age of 65 years 86. Although the initial overall response was lower than with the chemoimmunotherapy regimen (65% including 10% complete responses), long-term observation showed long lasting remissions > 36 months in 58% of the patients 87. However, a randomized phase III study comparing chlorambucil versus lenalidomide in front line therapy of elderly patients was terminated early due to excess toxicity in the lenalidomide arm. A phase II study evaluated the combination of lenalidomide and rituximab in 69 patients who had not received any previous therapy 88. Patients were assigned to two different strata (age group 45-64 years and age group 65-80 years) with an included median age of 56 and 70 years respectively included. Overall 78% of the 29 elderly patients responded. Eleven percent achieved a complete remission, comparable to lenalidomide alone. After a short median observation time of 17 months the median PFS was 20 months. Novel drugs targeting Bruton’s tyrosine kinase (BTK) in the B-cell receptor signaling pathway showed an excellent PFS and OS in firstline treatment of in a small group of patients 89. Therefore current randomized phase III studies are comparing these new therapeutics versus current chemoimmunotherapy.

Treatment of (very) high risk patients Chemoimmunotherapy Patients with del(17p) or TP53 mutation respond poorly to chemotherapy or have early relapses after frontline therapy. A systematic analysis of prognostic factors including molecular genetics in the CLL8 study of the GCLLSG (FCR versus FC) showed the positive effect of FCR with regard to response applied to most prognostic subgroups including patients with del(17p)

45

However, a more detailed analysis of genetic subgroups showed that FCR did not improve survival

(PFS and OS) of patients with a TP53 mutation. with del(17p) responded to treatment

64

33

With BR frontline therapy only 37% of patients

. Therefore, the FCR regimen was recommended only in

patients with del(17p) or TP53 mutation or for consolidation if an allogeneic stem cell transplantation was performed, the latter feasible only in a minority of patients due to age, physical fitness and comorbidities, or lack of a matching donor.

Kinase inhibitors of the B cell receptor pathway Treatment of patients with CLL and especially patients with del(17p) or TP53 mutation has been markedly improved with the introduction of kinase inhibitors, namely BTK and phosphatidylinositol-3-kinse (PI3K), which act independently of the p53 pathway

90

. Both the BTK-inhibitor

ibrutinib and the PI3K-inhibitor idelalisib were found to induce high response rates and promising progression free and overall survival times both as single agents and in combination with rituximab 91-94

. However, del(17p) and TP53 mutation appeared to retain their adverse prognostic impact as

treatment outcome was inferior with regard to quality and duration of response compared to patients without these genetic abnormalities

95

. Nevertheless, the treatment outcomes achieved with these

drugs are the best ever reported in patients with del(17p)/TP53 mutations. Both ibrutinib and idelalisib were recently approved by the American and European health authorities for the use in patients with relapsed CLL and ibrutinib for patients with a del(17p) or TP53 mutation (including frontline). Allogeneic stem cell transplantation may be considered in patients achieving remission with kinase inhibitors. In this situation long-term treatment with inhibitors could be an alternative option. The decision should be based on transplant- and diseaserisk and patient preferences after a careful discussion of the risks and benefits of an allogeneic transplant 96.

Conclusion

Treatment decision in CLL has become very complex because besides clinical stage, the prognostic risk profile as well comorbidities have to be considered. In general, the most efficacious CLL treatment should be administered initially, because a survival benefit resulted from chemoimmunotherapies (FCR,G-Clb; ClbR) in the first-line setting 45,76,97 (Figure 1). For patients without very high risk genomic alterations, first-line treatment with chemoimmunotherapy has been well studies and has become an established standard of care. FCR is the standard treatment in physically fit with nor or mild comorbidities. Depending on the burden of comorbidities, less intense chemoimmunotherapy regimens based on bendamustine or chlorambucil in combination with CD20 antibodies can be used initially in patients with relevant concomitant diseases. Patients with high risk genomic alterations should be treated with the new targeted drugs whenever access is possible or within clinical studies. Very high risk patients with TP53 deletion or mutation should be treated with a kinase inhibitor initially, whenever possible or included in a clinical trial for patients with very high risk disease. At specialized centers allogeneic stem cell transplantation may be considered depending on quality of response, tolerability of the treatment regimen and donor availability. Clinical trials in coming years will have to determine, whether kinase inhibitors, other small molecules, or combinations thereof can replace chemoimmunotherapies (partially or completely) in the future. Results with hemoimmunotherapies have suggested that only high rates of complete response or MRD negativity result in long-term relapse-free survival and prolongation of overall survival 46,98. A relevant proportion of patients with favorable prognostic factors may benefit from a very long remission after chemoimmunotherapy

47

. However, when using the new drugs achieving

an MRD negative response may become less relevant 99. On the other hand the patient´s adherence to

treatment, medication interactions, or long-term toxicities may be consideratons if these drugs replace chemoimmunotherapy.

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cyclophosphamide

prolongs

progression-free

survival

compared

with

fludarabine

and

cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010;28:1756-65. 98.

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Figure 1: Overview stage, fitness and risk adapted frontline therapy in CLL * Alternatively other purine analogues based chemoimmunotherapy. # Alternatively bendamustine + anti-CD20 antibody

Stage

Fitness

del(17p) p53mut

Therapy

Rai 0II/Binet A-B and inactive

irrelevant

irrelevant

watch & wait

no

Rai 0II/Binet A-B and active

Fit & low comorbidity burden

FCR* (BR possible in fit elderly with previous infections)

yes

Ibrutinib Idelalisib + R discuss allo-SCT

no

CLB + anti-CD20 antibody #

yes

Idelalisib + R Ibrutinib

or Rai III&IV/Binet C

Figure 1

Less fit &/or significant comorbidity burden

Tables Table I. Efficacy of selected purine analogues based chemo immunotherapies in frontline of CLL All agents were given intravenously unless otherwise specified

Reference & Study design

No. patients

Treatment regimen

Clinical response CR

CR + PR

47%

90%

Progression-free survival

Overall survival

67% at 2 years

93% at 2 years

(median 42 mo for both groups)

(median 85 months for both groups)

Fludarabine + Rituximab (FR) Byrd et al., Blood 2003 (CALGB 9712)

51

F 25mg/m² d1-5 iv q 28 d X 6 R 375 mg/m² d1,4 C1 and d1 C2-6

Phase II randomized

R 375 mg/m² x 4 for consolidation

Fludarabine, Cyclophosphamide + Rituximab full dosed (FCR) Keating et al., JCO 2005

224

Phase II

F 25mg/m² d1-3 iv q 28 d x 6

70%

95%

Median 80 mo

77% at 6 years

44%

93%

Median 57 mo

69% at 5 years

Median 68 mo

Not yet reached

C 250mg/m² d1-3 iv q 28d x6 R 375 mg/m² d1 C1 and R 500mg/m² d1 C2-6

Hallek et al., Lancet 2010 (GCLLSG CLL8)

408

F 25mg/m² d1-3 iv q 28 d x 6 C 250mg/m² d1-3 iv q 28d x6

Phase III

R 375 mg/m² d1 C1 and R 500mg/m² d1 C2-6 Fludarabine, Cyclophosphamide + Rituximab dose-reduced (FCR light) Foon et al., JCO 2009 & Blood 2012 Phase II

65

F 20 mg/m² d2-4 C1 and d1-3 q 28d x 6 C2-5 CYC 150 mg/m2 d 2-4 C1 and d1-3 q 28d x 6 C2-5 R 375mg/m² d1 C1 R 500 mg/m² d1+ d14 q

73%

94%

28d C2-6 R maintenance 500mg/m² q3 months Mulligan et al., ASH 2014

41

FCR3

51%

95%

75% at 18 mo

90% at 18 mo

79%

97%

65% at 18 mo

83% at 18 mo

20%

96%

n.a.

n.a.

37%∞

81%

Median 28 mo

75% at 30 mo

41%

91%

Median 33 mo

n.a.

F 24mg/m² p.o. d1-3 q 28d x6

Phase II randomized

CYC 150mg/m² p.o. d1-3 q 28d x 6 R 375mg/m² i.v.d1 C1 R 500 mg/m² i.v.d1 q 28 C2-6

Mulligan et al., ASH 2014

38

FCR5 F 24mg/m² p.o. d1-5 q 28d x6

Phase II randomized

CYC 150mg/m² p.o. d1-5 q 28d x 6 R 375mg/m² i.v. d1 C1 R 500 mg/m² i.v. d1 C2-5 q 28d

Dartigeas et al., ASH 2012

194

Phase III randomized

F 40 mg/m² p.o. d1-3 q 28d x 4 CYC 250 mg/m² p.o. d1-3 q 28d x 4 R 375 mg/m² i.v. d1 C 1 500 mg/m² d14 C1, d1 + 14 C2, d1 C 3&4

Smolej et al., ASH 2014

108

2

F 12 mg/m d1-3 q 28 d x 6 2

Phase II

CYC 150 mg/m d1-3 q 28 dx6 R 375 mg/m² d1 C1 and R 500mg/m² d1 C2-6 Pentostatin, Cyclophosphamide + Rituximab (PCR)

Kay et al., Blood 2007 Phase II

65

P 2 mg/m² d1 q 21 d x 6 CYC 600 mg/m² d1 q 21 d x6 R 375 mg/m² d1 q 21 d x 6

Reynolds et al., Invest New Drugs 2012

92*

P 4 mg/m² d1 q 21 d x 6

7%

49%

63% at 2 years

79% at 2 years

Rando 1: 32%

Rando 1: 77%

Rando 2: 50%

Rando 2: 73%

n.a. (after median observation time of 8 months 70% at 2 years)

n.a. . (after median observation time of 8 months > 90% at 2 years)

n.a.

n.a.

CYC 600 mg/m² d1 q 21 d x6

Phase III

R 375 mg/m² d1 q 21 d x 6

Fludarabine, Cyclophosphamide + Ofatumumab (FCO) Wierda et al., Blood 2011

61

F 25 mg/m² d1-3 q 28 d x 6 CYC 250 mg/m² d 1-3 q 28 dx6

Phase II randomized

O Rando 1: 300mg d1 C1, 500mg i.v d1 C2-C6 q 28d x 6 O Rando 2: 300mg d1 C1, 1000mg i.v d1 C2-C6 q 28d x6

Pentostatin, Cyclophosphamide + Ofatumumab (PCO) Shanafelt et al., Cancer 2013 Phase II

48

P 2 mg/m² d1 q 21 d x 6

46%

96%

CYC 600 mg/m² d1 q 21 d x6 O 300 mg d1 C1 , 1000mg d2 C1 O 1000mg d1 q 21 d x 6

F = fludarabine, CYC = cyclophosphamide, P = pentostatin, R=rituximab, O = ofatumumab d=day, C=cycle, mo=months, n.a.=not available *Including 19 patients with prior chemotherapy ∞ Including CRs non confirmed by bone marrow biopsies

Table II. Efficacy of selected bendamustine-based chemoimmunotherapies in frontline of CLL All agents were given intravenously unless otherwise specified

Reference & Study design

No. patients

Treatment regimen

Clinical response

Progression-free survival

Overall survival

CR

CR + PR

23%

88%

Median 34 mo (event free survival)

At 2 years 90%

31%

98%

Median 43 mo

At 3 years

30%

88%

n.a.

n.a.

43%

95%

n.a.

n.a.

Bendaumstine + Rituximab (BR) Fischer et al., JCO 2012

117

R 375 mg/m² d1 C1 and R 500mg/m² d1 C2-6

Phase II Eichhorst et al., ASH 2014

279

B 90mg/m² d1+2 q 28 x 6 R 375 mg/m² d1 C1 and R 500mg/m² d1 C2-6

Phase III Leblond et al., ASH 2012

B 90mg/m² d1+2 q 28 x 6

40

B 90mg/m² d1+2 q 28 x 6 R 375 mg/m² d1 C1 and R 500mg/m² d1 C2-6

Bendamustine + Ofatumumab (BO) Offner et al., IWCLL abstract 2013

44

B 90mg/m² d1+2 q 28 x 6 O 300 mg d1 C1, 1000mg d8 C1 O 1000mg d1 C2-6

B = bendamustine, R=rituximab, O = ofatumumab d=day, C=cycle, mo=months, n.a.=not available

Table III. Efficacy of selected chlorambucil-based chemoimmunotherapies in frontline of CLL All agents were given intravenously unless otherwise specified Reference & Study design

No. patients

Treatment regimen

Clinical response

Progression-free survival

Overall survival

CR

CR + PR

10%

84%

Median 23.5 mo

At 30 mo 84%

19%

82%

Median 34.7 mo

Median not reached.

7%

66%

Median 15.2 mo

Median not reached

22%

77%

Median 26.7 mo

Median not reached

14%

82%

Median 22.4 mo

At 3 years 85%

Chlorambucil + Rituximab (ClbR) Hillmen et al., JCO 2014

100

CLB 10 mg/m² d 1-7q 28 x 6 (additional 6 cycles CLB

Phase II

mono in patients not in CR) R 375 mg/m2 d 1 C1 and 500 mg/m2 d1 C2-C6

Foa et al., AmJH 2014

85

CLB 8 mg/m² d 1-7 R 375 mg/m² d1 C3 and 500 mg/m² d1 C4-C8.

Phase II randomized

Responders were randomized: R 375 mg/m² q56d x 12 or observation.

Goede et al.NEJM 2014

330

CLB 0.5mg/kg BW d1+15 q28 x 6 R 375 mg/m² d 1 C1 and

Phase III randomized

500 mg/m2 d1 C2-C6

Chlorambucil + Obinutuzumab (G-Clb) Goede et al.NEJM 2014

333

CLB 0.5mg/kg BW d1+15 q28 x 6 Obinutuzumab 1000mg

Phase III randomized

d1,8,15 C1 and 1000mg d1 C2-C6

Chlorambucil + Ofatumumab (ClbO) Hillmen et al., ASH 2013

221

2

Clb 10 mg/m d1-7 q 28 d O C1 d1 300 mg, d8 1000 mg, C 2-12 d1 1000 mg q 28 days

Clb = chlorambucil, R=rituximab, O = ofatumumab, G = GA101= obinutuzumab d=day, C=cycle, mo=months, n.a.=not available