Bendamustine therapy associated resolution of anemia and splenomegaly in myelofibrosis
Authors: Ayalew Tefferi, Sonia Cerquozzi, Jenny Liaw
Journal: American Journal of Hematology (2015)

To the Editor: In myelofibrosis (MF), current management includes allogeneic stem cell transplant (ASCT), as a potentially curative treatment modality, and hydroxyurea and ruxolitinib, as palliative drugs 1. In addition, some patients with anemia have shown response to androgen preparations, danazol, thalidomide, prednisone, and lenalidomide whereas those with marked organomegaly have shown response to lenalidomide or cladribine 1. Spleen response has also been demonstrated during clinical trials with other JAK inhibitors 2, 3. Most recently, possibly disease modifying activity was demonstrated for the telomerase inhibitor, imetelstat 4. Unfortunately, the majority of patients with MF are not transplant candidates and drug therapy is often ineffective in inducing responses in both anemia and splenomegaly. A 64-year-old man gave a history of mild anemia and thrombocytosis 20 years prior to his first visit to our institution and outside reports indicated a diagnosis of essential thrombocythemia (ET) at the time. He was initially treated with hydroxyurea for 5 years but has been off treatment for the last 15 years. For several months prior to his initial visit to the Mayo Clinic, he was experiencing profound fatigue, severe night sweats, and weight loss. Diagnostic evaluation elsewhere revealed severe anemia (hemoglobin 8.4 g/dL), palpable splenomegaly, and a bone marrow examination that was reported to be consistent with MF. He was started on hydroxyurea (1.5 g/day) with unremarkable response. Subsequently, the patient was evaluated at the Mayo Clinic in January 2014. Physical examination at the time confirmed a markedly enlarged spleen that crossed the midline abdomen by 3 cm and extended down below the left costal margin by approximately 20 cm. Laboratory tests showed a hemoglobin of 8.6 g/dL, leukocyte count of 4.7 × 10(9)/L, and platelet count of 369,000 × 10(9)/L. Leukoerythroblastosis (LES) was present and lactate dehydrogenase (LDH) was increased to 391 U/L (normal 122–222). Review of the outside bone marrow examination confirmed the diagnosis of MF: markedly hypercellular bone marrow with estimated cellularity of 80%–90%, erythroid precursors quantitatively increased but with normal morphology, granulocyte, and monocyte precursors quantitatively increased but with normal morphology, megakaryocytes quantitatively increased with abnormal morphology showing large hyper-lobated and hyper-chromatic forms with clustering. MDS FISH panel showed no abnormalities and reticulin stain showed grade 2–3+ fibrosis. Driver mutational status was CALR-positive (a 22-bp deletion, exon 9).There was no evidence of lymphoma in the bone marrow and no increase in lymphocytes. Over the ensuing months, treatment with hydroxyurea was continued without any improvement in splenomegaly and with worsening of anemia and persistent constitutional symptoms. In September 2014, patient noticed axillary and cervical lymphadenopathy that revealed follicular lymphoma on biopsy (grade 3a). The immunohistochemical studies showed the lymphoma cells to be B-cell phenotype, CD5 negative, CD10 negative, CD20 positive, CD30 variably positive, CD79A positive, cyclin D1 negative, BCL2 positive, BCL6 positive, PAX5 positive, and c-Myc negative. The Ki-67 proliferation index was 75%. PET/CT showed spleen dimensions of 20.9 cm AP, 13.8 cm transverse, and 33.1 cm craniocaudal. Bone marrow biopsy showed increased B cells with multiple aggregates and focally interstitial and composed of a mixture of small and large cells with irregular nuclear contours. The infiltrate accounted for approximately 10% of the cells, and the flow cytometry showed 2% B cells with lambda predominance. The histologic findings in conjunction with flow cytometry findings and clinical history were felt to be consistent with focal bone marrow involvement by B-cell lymphoma. The patient was initially treated for his follicular lymphoma with Rituxan but experienced a severe infusional reaction to his first dose of the drug (October 2014). Subsequently, he received six cycles of single agent intravenous bendamustine (82 mg/m2 days 1 and 2 every 28 days), starting in November 2014. Prior to starting bendamustine therapy, patient was requiring red cell transfusions (hemoglobin 6.7 g/dL on October 21, 2014), displayed hydroxyurea-resistant massive splenomegaly palpable at 20 cm below the left costal margin and had severe constitutional symptoms. Treatment with bendamustine resulted in complete resolution of his lymphadenopathy, but also of his MF-associated constitutional symptoms, marked splenomegaly, and transfusion-requiring anemia. The salutary effect on the spleen and anemia was noticed within three months of starting bendamustine therapy with hemoglobin level of 11.8 g/dL and palpable spleen size of 12 cm reported in February 2015 and after the third cycle of bendamustine therapy. Our patient was seen for follow-up at the Mayo Clinic in May, 2015. At the time, he had completed his six cycles of bendamustine therapy and denied any constitutional symptoms and his spleen was only tip palpable; laboratory evaluation at the time included hemoglobin 13.1 g/dL, platelets at 592 × 10(9)/L, leukocyte count at 2.5 × 10(9)/L, LDH at 249 U/L, and LES was no longer noted. Subsequently, the patient received two additional cycles of bendamustine therapy with the last dose give in June, 2015. In August 2015, a repeat PET/CT revealed spleen dimensions of 13.4 cm AP, 8.9 cm transverse, and 17.6 cm craniocaudal. In October 2015, the patient was again seen at the Mayo Clinic when he had a relapse of his follicular lymphoma (grade 3a) with cervical lymphadenopathy but he remained in remission from the standpoint of his MF; the spleen was not palpable and hemoglobin was 12.1 g/dL, platelets 678 × 10(9)/L, leukocyte count 6.1 × 10(9)/L and LDH 270 U/L. There was no LES. Screening for CALR mutation revealed no change in allele frequency post bendamustine therapy but the repeat bone marrow examination performed in October 2015 showed improvement in reticulin fibrosis but hypercellularity and abnormal megakaryopoiesis were still evident. Bendamustine is a nitrogen mustard bifunctional molecule with alkylator and antimetabolite properties and is currently approved for use in chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma and has also shown activity in multiple myeloma 5. The current communication suggests a palliative role for bendamustine in MF. This was not totally unexpected since the value of drugs with alkylating and purine-like properties has previously been demonstrated in MF 6, 7. The complete resolution of transfusion-dependent anemia and marked splenomegaly (confirmed by imaging studies) was impressive and durable. It should be noted that severe anemia and marked splenomegaly predated the diagnosis of lymphoma in our patient and it is unlikely that his focal bone marrow involvement by follicular lymphoma contributed to his anemia, his massive splenomegaly or severe constitutional symptoms. Furthermore, the benefit of bendamustine therapy to his MF-related symptoms persisted during relapse of his lymphoma. We believe that further studies looking at the palliative role of bendamustine in MF are warranted. Ayalew Tefferi1*, Sonia Cerquozzi1, Jenny Liaw2 1Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 2Hematologist-Oncologist, Bayside, New York