Optimal central nervous system prophylaxis in Philadelphia chromosome-positive acute lymphoblastic leukemia: collateral damage in the imatinib era?

In the current era of tyrosine kinase inhibitors (TKIs), about 40% of adult patients with Philadelphia chromosome-positive acute acute lymphoblastic leukemia (Ph + ALL) are disease-free at 3–5 years [1–3 ]. This is the result of imatinib plus chemotherapy combinations that improve the remission rate and, by reducing the risk of an early relapse, allow significantly more patients to undergo an allogeneic stem cell transplant as a conclusive therapeutic step. Because Ph + ALL prevails in older age groups, many frail patients are excluded from transplant and instead offered TKI-based maintenance, sometimes with beneficial effects [4]. Whatever the policy, it is customary in ALL (and Ph + ALL is no different in this respect) to flank systemic antileukemic therapy with measures apt to prevent a meningeal recurrence, which is otherwise rather common in this type of malignancy and then invariably fatal [5]. This goal is mainly accomplished with intrathecal therapy, which consists of combinations of methotrexate, cytarabine, and steroids. Cranial irradiation and systemic high-dose blocks with methotrexate and cytarabine or asparaginase are often delivered alongside. Neither of these weapons is devoid of toxicity, nor totally effective in preventing central nervous system (CNS) relapse. For intrathecal therapy, a further limitation in aged patients is their poor treatment compliance to repeated intrathecal injections. These are usually 12 or more, scattered over the first treatment year.

In this issue of the journal, Patel and colleagues [6] describe an untoward side effect associated with intrathecal therapy in patients with Ph + ALL: the occurrence of a subdural hematoma (SDH) related to concurrent imatinib administration. The pathogenetic role of the drug is reviewed and appears sufficiently clear; however, the exact clinical relevance and true incidence of the phenomenon are not fully understood, particularly in older patients who are repeatedly exposed to the trauma of a lumbar puncture, become transiently thrombocytopenic because of ongoing chemotherapy, or suffer from any other illness predisposing to bleeding (diabetes, hypertension and anticoagulation, impaired renal function).

This is enough to alert and suggest pre-emptive measures, at least in patients with a first SDH episode who should complete CNS prophylaxis. The imatinib-treated patient having a lumbar puncture should lie supine during and after the procedure, which should be performed by an experienced clinician, avoiding trauma and removing the smallest possible amount of cerebrospinal fluid, and this preferably 1 week apart from the last imatinib dosing (according to protocol spedifications). Anticoagulants must be discontinued in advance and any altered metabolic state or dehydration corrected. It is not known whether intrathecal steroids reduce the risk of SDH, but they are not contraindicated and can exert a general antihemorrhagic effect. The same applies to antifibrinolytic agents given orally or intravenously. As regards platelets, these should be infused to guarantee a count above 50 × 10⁹/L in thrombocytopenic patients, or better the maneuver should be deferred until platelet recovery. The total number of injections should be kept low, especially in older patients. In this regard, liposomal cytarabine (DepoCyte™) with a prolonged half-life of several days in the cerebrospinal fluid may be a suitable alternative to standard intrathecal injections, reducing by 50% the number of applications, without compromising (or even enhancing) efficacy. DepoCyte™ was highly active and tolerable in the management of CNS relapse of adult patients with ALL, including those with Ph + ALL and patients older than 70 years, and is expected to prove effective as a first-line drug [7]. Whether dasatinib, crossing the blood–brain barrier and reaching therapeutic concentrations in the CNS, could be used instead of imatinib and contribute to a safer or better CNS prophylaxis schedule, is worth assessing in a clinical study [8].

All in all, the issue of optimal CNS prophylaxis can be complicated by the ‘collateral damage’ from an effective drug targeting a multitude of biological pathways, not only Ph + cells. This should be considered, following a clever clinical observation.

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