Dexamethasone, Cytarabine and Cisplatin or Oxaliplatin Schedule (DHAP or Ox-DHA) Is Effective and Widely Applicable in Chronic Lymphocytic Leukemia and Waldenström Macroglobulinemia.

Fludarabine alone or in combination is considered the standard treatment for Chronic Lymphocytic Leukemia (CLL). A high response rate is usually observed following fludarabine, particularly if delivered together with rituximab. In spite of the high therapeutic efficacy, most patients subsequently relapse. For these patients there are no defined salvage treatments. Moreover, fludarabine-containing regimens may have some restrictions due to non-negligible side effects. In particular, there are some concerns in employing fludarabine first-line in patients with autoimmune hemolytic anemia (AHA) or with renal function impairment. In addition, fludarabine has been reported to compromise the capacity of progenitor cell mobilization. Thus, novel effective treatment approaches are needed, for the management of patients failing after fludarabine-based regimens and for those unfit to receive fludarabine first-line. A very effective salvage regimen for refractory/relapsed lymphoproliferative disorders is the DHAP combination. DHAP has been widely used in the rescue of both low-grade and high-grade lymphoma. However, its efficacy in CLL has not been verified yet. The main concern with DHAP is the well known renal toxicity of cisplatin. However, the use of the less toxic analog Oxaliplatin, might circumvent this problem. Indeed, recent reports have shown that the inclusion of oxaliplatin into the original DHAP regimen (Ox-DHA) markedly improves the tolerability and widens regimen applicability. Aim: To evaluate retrospectively feasibility and efficacy of the DHAP and Ox-DHA regimens in CLL and in other non-follicular low-grade lymphomas, in particular in Waldenström Macroglobulinemia (WM).

Between 2002 and 2008, 84 low-grade lymphoma patients received DHAP or Ox-DHA; their median age was 60 yrs. (range: 24-84), 58 were male; 70 patients had CLL with advanced stage (65 patients with Binet stage B and C) and 14 had WM. Thirty-eight patients were treated at first relapse, 27 at second or subsequent relapse, whereas 19 received the DHAP or Ox-DHA schedule as first-line treatment, in place of Fludarabine, due to: i. AHA (3 patients), ii. concomitant second malignancy (4 cases), iii. need of initial debulking, before a high-dose program with autograft. The original DHAP schedule requires hospitalization for three to five days; it includes: Cisplatin 100 mg/sqm on day 1, Cytarabine 2 g/sqm/b.i.d. every 12 hrs. on day 2, Dexamethasone 40 mg days 1-4. Ox-DHA can be delivered in the outpatient setting, compared to DHAP, there are two main modifications: Oxaliplatin 100 mg/sqm in two-hr i.v. infusion on day 1, and Cytarabine 2 g/sqm two doses delivered in two consecutive days (day 2 and day 3). Rituximab (375 mg/sqm) was added in 12 DHAP and 28 Ox-DHA courses. Patients aged over 70 yrs had variable dose reductions (25% to 50%).

Ox-DHA had hematological toxicity analogous to that commonly observed with the original DHAP schedule; 11 patients required short hospitalization for severe infectious complications; 7 patients developed fever of unknown origin, 4 showed reversible peripheral neurotoxicity. The program was discontinued in four patients due to disease progression (3 patients) and AHA (1 case). There were no severe liver or renal toxicities. No toxic deaths were recorded. The overall response (OR) rate was 90%; in details, complete remission (CR), or very good partial remission (VGPR), was achieved in 41% of patients receiving DHAP without rituximab and 50% of those receiving DHAP supplemented with rituximab. In the Ox-DHA group, 50% of patients treated without rituximab and 75% of those treated with rituximab reached CR or VGPR. Among patients treated at diagnosis, overall 47% reached CR or VGPR and 42% reached partial remission (PR). The OR rate was unexpectedly high at 91% in patients treated for refractory/relapsed disease, with 66% of them achieving CR/VGPR (74% and 55% for patients at 1st and ≥ 2nd relapse, respectively) and 35% PR. Among 14 WM patients, 1 obtained a CR, 5 a VGPR, 6 a PR and 2 had a stable disease.

Dexamethasone, Cytarabine and Cisplatin or Oxaliplatin schedule is a well tolerated regimen, highly effective both front-line and in the rescue for relapsed/refractory disease in CLL and WM patients. Future clinical trials will define the real efficacy of the DHAP or Ox-DHA regimen in the management of CLL and WM patients.

No relevant conflicts of interest to declare.