Chronic Lymphocytic Leukemia With del(17p13.1): A Distinct Clinical Subtype Requiring Novel Treatment Approaches

Treatment of Younger Patients

Chemoimmunotherapy

FIGURE 2

Treatment Algorithm for Patients at Initial Diagnosis of Del(17p13.1) Chronic Lymphocytic Leukemi

FIGURE 3

Treatment Algorithm for Patients With Relapsed/Refractory Del(17p13.1) Chronic Lymphocytic

As described in the section on epidemiology, above, standard therapy with FCR is not ideal for this group. However, the CLL-8 trial did demonstrate that del(17p13.1) patients who received front-line FCR (n = 21) had a trend towards an improved overall response rate (ORR) (71% vs 46%, P = .08) and improved 3-year PFS (17.9% vs 0%, P = .052), compared with patients who received fludarabine and cyclophosphamide(Drug information on cyclophosphamide) without rituximab(Drug information on rituximab) (n = 16), demonstrating a borderline benefit of rituximab in therapy for these patients.[13] Although the ORR trended towards improvement in this group, the 3-year PFS of only 17.9% indicates that the response to FCR is not durable. FCR can therefore be viewed as a cytoreductive therapy for del(17p13.1) patients that is best followed by consolidation with alloSCT or an alternative investigational therapy. In the relapsed setting, the outcomes with FCR in this population are poor. A large study showed a CR of 0% and an ORR of 35%, with a short median PFS (5 months) and median OS (10.5 months) in this population (n = 20),[18] leading to a recommendation against this regimen in relapsed del(17p13.1) patients. Additional studies have been completed with a fludarabine-and-rituximab-only regimen; however, there are insufficient data available to recommend this regimen in the del(17p13.1) group.

When rituximab and bendamustine (Treanda) were combined for therapy of front-line or relapsed CLL, the outcomes in the del(17p13.1) subset were bleak, with a 43% partial response in the front-line patients (n = 3 of 7)[19] and only one patient (7%) responding, and a median PFS of 6.8 months and median OS of 16.3 months in the relapsed population (n = 14).[20] This regimen should not be recommended in this subgroup.

Oxaliplatin (Eloxatin) and cytarabine(Drug information on cytarabine) have been added to fludarabine and rituximab (OFAR) in an attempt to improve outcomes in the setting of relapsed CLL. A trial using this regimen demonstrated an ORR of 33% in fludarabine-refractory CLL patients. The RR del(17p13.1) patients in this trial (n = 15) also demonstrated an ORR of 33%; however, no further subgroup analysis was completed. For the group as a whole, median response duration was 10 months. The main toxicities were hematologic, with a subset of patients not completing therapy due to these adverse effects.[21]

Rituximab and high-dose corticosteroids. Because the addition of rituximab to chemotherapy improved clinical response, and because previous studies had shown response in the relapsed setting to single-agent high-dose methylprednisolone(Drug information on methylprednisolone) (HDMP),[22] Bowen et al combined rituximab and HDMP for the treatment of relapsed CLL and found an ORR of 56% in patients with del(17p13.1) (n = 9).[23] Subsequently, Castro et al used this regimen in a front-line clinical trial (n = 36); they achieved an ORR of 96% and a median PFS of 30.3 months, with good tolerance of the regimen.[24] Only one patient had del(17p13.1) in this trial, but the HDMP regimen can be used for patients with limited options, who cannot tolerate more aggressive regimens. Patients on this regimen must receive aggressive prophylaxis against opportunistic pathogens, and even with these preventive measures, mortality due to infectious causes is high. Additionally, the metabolic and psychological complications of this regimen can be severe in some patients. Morbidity and mortality are generally more severe in the refractory group of patients receiving this regimen.

Alemtuzumab monotherapy. In light of the success of rituximab, another monoclonal antibody (mAb), alemtuzumab(Drug information on alemtuzumab) (Campath), which targets CD52, has been extensively studied in this high-risk population—and has shown success. The efficacy of alemtuzumab was initially noted when it was used as a single agent in fludarabine-refractory patients with TP53 mutations and deletions.[25] Following their initial case report, Lozanski et al noted in a larger series of patients a 40% response rate and 8-month median duration of survival in this group,[26] results that were confirmed by several other studies.[11,27] The CAM307 trial, which compared alemtuzumab to chlorambucil(Drug information on chlorambucil), is the only study that provides information on the efficacy of alemtuzumab. The small cohort of patients with del(17p13.1) who received alemtuzumab (n = 11) tended to have a superior ORR (64% vs 20%, P = .08) compared with the ORR in the patients who received chlorambucil (n = 10). However, there was no improvement in PFS, with a disappointing median PFS of 10.7 months in the alemtuzumab group (vs 2.2 months in the chlorambucil group, P = .41); moreover, the patients in the alemtuzumab group experienced more neutropenia and cytomegalovirus reactivation.[28] Another notable limitation of this agent, first recognized in the early studies, was that patients with bulky lymph nodes (> 5 cm) were less likely to respond to the antibody.[29]

Alemtuzumab and high-dose corticosteroids. Using the same rationale as was used in the studies with rituximab and HDMP, and building on the fact that HDMP was previously effective in bulky disease, alemtuzumab was combined with HDMP in a pilot study[30] that led to the multicenter recently published CLL-206 trial. The results of this trial describe the outcomes of both previously untreated (n = 17) and treated (n = 22) CLL patients with del(17p13.1). The regimen showed efficacy—more so in the untreated group—with ORR, CR rate, median PFS, and median OS of 88%, 65%, 18.3 months, and 38.9 months, respectively. (In the previously treated group, these results were 17%, 14%, 6.5 months, and 19.5 months, respectively.) The regimen was fairly toxic, especially in patients over the age of 60, with significant grade 3/4 hematologic and glucocorticoid toxicity (67%) and grade 3/4 infection (51%; 68% in patients over age 60). A 5% treatment-related mortality rate was reported.[31] Similarly, the ongoing CLL-20 trial has combined alemtuzumab with oral dexamethasone(Drug information on dexamethasone) (with plans for subsequent maintenance alemtuzumab vs alloSCT) for untreated del(17p13.1), relapsed del(17p13.1), and fludarabine-refractory patients. Preliminary reports have demonstrated ORRs of 100% and 78% and CRs of 23% and 0% in the untreated (n = 31) and relapsed (n = 17) del(17p13.1) patients, respectively. Infection and hematologic toxicity have again been concerns with this regimen.[32]

Multiple additional regimens have been attempts to combine alemtuzumab with various chemoimmunotherapeutic agents (eg, the combination of alemtuzumab with FCR[33, 34]); however, insignificant improvements in response and survival with increased risks of severe infectious toxicity do not allow for recommendation of these therapies in the front-line or relapsed setting.

Ofatumumab. Ofatumumab (Arzerra) is a human mAb to CD20; it is similar to rituximab but binds at a different epitope and causes more potent complement-dependent cytotoxicity than rituximab. Ofatumumab was recently approved in the relapsed population based on a landmark trial in which it was used as a single agent in fludarabine-refractory CLL patients with bulky adenopathy(> 5 cm) (n = 79) and without (n = 59); the resulting ORRs were 47% and 58%, respectively. The del(17p13.1) patients in the group with bulky adenopathy (n = 14) and without (n = 17) had ORRs of 14% and 41%, respectively. No further subgroup analysis was completed; however, PFS for the entire group was slightly less than 6 months. This regimen was very well tolerated, with primarily grade 1 and grade 2 adverse events reported.[35]

Reduced-intensity alloSCT

If a patient is young and otherwise fit and achieves a response with early chemoimmunotherapy regimens, both the NCCN guidelines and the European Group for Blood and Marrow Transplantation consider the presence of del(17p13.1) cytogenetics to be an indication for reduced-intensity alloSCT.[36] A more detailed review on transplantation in this patient group has recently been published.[37] The CLL-3X study indicated that the del(17p13.1) patients (n = 13) who underwent alloSCT demonstrated equivalent outcomes to other cytogenetic groups. The researchers noted a 3-year event-free survival (EFS) of 45% in patients with del(17p13.1), which was consistent with previous studies. Patients with del(17p13.1)who were refractory to chemotherapy at the time of transplant had a significantly shorter EFS (hazard ratio = 2.77; 95% confidence interval = 1.50–5.09).[38] A retrospective study demonstrated a 3-year PFS of 37% for this group (n = 44) and indicated that patients with del(17p13.1) who had had more than three prior therapies had a significantly shorter PFS than those who had received fewer than three prior therapies (19% vs 53%, P = .03).[39]

Although the results of these trials appear promising, it is not clear that the risks of toxicity and transplant-related mortality are balanced by the benefits of prolonged PFS. A prospective trial (Cancer and Leukemia Group B [CALGB] 100701) has been initiated to evaluate this question in previously untreated but symptomatic del(17p13.1) patients. While these trials support the use of transplantation in a young and minimally pretreated population, they cannot be generalized to the typical elderly patient with multiple comorbidities that make pursuit of this modality difficult. All patients with del(17p13.1) who are medically appropriate for reduced-intensity alloSCT should be seen and evaluated by a transplant team early in the course of the disease. For our group, we generally refer such patients at the time we initiate first-line treatment.

Treatment of Elderly Patients

The elderly (> 65 years) subgroup of patients with del(17p13.1) cytogenetics pose a particularly challenging treatment dilemma. Although the median age at diagnosis of CLL is 72 years and ~70% of newly diagnosed patients are older than 65 years,[40] this group has been widely underrepresented in clinical trials, and many of these patients have major medical comorbidities or poor performance status. If an elderly patient has a good performance status, he or she should be enrolled in a clinical trial. If no trial is available, the regimens of alemtuzumab (if no bulky lymph nodes are present) or HDMP + alemtuzumab or HDMP + rituximab could be considered in this group. However, few data exist for alemtuzumab either as monotherapy or in combination with HDMP in the elderly population. A small study (n = 28) using HDMP and rituximab, which included 8 patients over age 70 using this regimen as frontline CLL therapy, demonstrated an ORR of 100% and a CR of 38% in this elderly population; toxicities were minimal. Cytogenetic status was not reported, however.[41] Given the paucity of data in this patient group, clinical studies are needed to better define acceptable and tolerable treatment options. Elderly unfit patients should be referred for palliative care, since there are no therapies for which the benefits outweigh the risks of toxicity.