Optimize the Patient to Optimize the Therapy: Role of Prephase Cyclophosphamide in Aggressive Lymphoma

Background: Classical Hodgkin lymphoma (CHL) and aggressive non-Hodgkin lymphomas (NHL) are generally considered curable hematologic malignancies but curative strategies typically implore the use of intensive combination chemotherapy regimens. Unfortunately, patients often present with advanced stage disease, high tumor burden, and end-organ damage. Moreover, the presence of multiple comorbidities further complicates the management and prevents the timely initiation of intensive therapeutic regimens. Although prephase chemotherapy is reported in the literature, there is limited data regarding the use of prephase cyclophosphamide (pCy) in aggressive lymphomas. Here we present our institutional experience of employing pCy for patients ineligible for intensive chemotherapy.

Methods: A retrospective review of the prior year revealed 13 cases using pCy. 11 patients received cyclophosphamide (Cy) 200 mg/m2 IV daily with corticosteroids x 5 doses. 2 patients received alternative Cy dosing: 300 mg/m2 IV daily x 5 doses and 200 mg/m2 IV daily x 3 doses. Corticosteroids included prednisone, methylprednisolone, and dexamethasone at varied doses all given concurrently with Cy. Patients were hospitalized through initiation of treatment and disease specific characteristics, laboratory data, and outcomes recorded.

Results: 13 cases included patients with CHL x2, B-cell NHL (chronic lymphocytic leukemia, diffuse large B-cell lymphoma x3, and high-grade B-cell lymphoma), and T-cell NHL (ALK+ anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, and peripheral T-cell lymphoma, NOS x3). Ages ranged from 18-83 with 9 patients >60 years old all of which had a CIRS-G score >10. All cases were stage III/IV with 11 patients presenting with newly diagnosed disease. Performance status at start of therapy was ≥3 with 85% of patients being ECOG 4. 8 patients had acute kidney injury including 4 patients with CrCl <10 mL/min. 2 patients had a total bilirubin >3 mg/dL. 3 patients required supportive care for tumor lysis syndrome present prior to initiation of treatment. 12 patients completed pCy with improvement in their ECOG performance status (ECOG <2), clinical disease response, and ability to proceed with intensive chemotherapy appropriate for the lymphoma subtype. 7 patients reached a complete response (CR) with subsequent treatment including 3 patients that are proceeding to consolidation with autologous stem cell transplant. 1 patient clinically improved but elected to pursue hospice care and passed away 2 months following treatment. 1 patient failed to respond to 3 subsequent lines of therapy. 1 patient was treated while intubated with septic shock and passed away secondary to streptococcal bacteremia during pCy. The remaining 3 patients have a partial response and are early in their therapy.

Conclusions: pCy represents a reliable method to salvage patients with aggressive lymphomas that are otherwise not a candidate for intensive chemotherapy. Cy has a broad indication across lymphoma subtypes and does not require dose modifications based on renal or liver dysfunction. The side effect profile is limited and allows for prompt initiation of intensive chemotherapy once the patient has clinically improved. pCy has excellent "real world" applicability to clinical practice. Our patients included 3 with renal failure (SCr >3 mg/dL) and 1 with florid liver failure (Tbili >20 mg/dL) that fully recovered. Of note, 4 patients were recommended hospice care and sought a second opinion at our institution; all 4 ultimately reached a CR. Because patients are acutely ill requiring hospitalization, pCy provides a cost effective option and bridge to subsequent outpatient treatments that may include costly immunotherapy or other targeted agents. Likewise, pCy represents a strategy to improve a patient's candidacy for clinical trial enrollment and warrants consideration when designing protocols that would otherwise exclude such candidates having received prior therapy. Advancing diagnostic techniques such as tumor gene sequencing best guide therapeutic decisions however results can delay the initiation of treatment. pCy should also be considered as an approach to bridge patients to optimal therapeutic regimens while awaiting diagnostic results.