Two similar cases for consideration.
1. 44 year old male with HIV diagnosed in 1988 on HAART (atazanavir 150mg/daily, emtricitabine/tenofavir 200/300mg/daily, ritonavir 100mg/daily) obviously quite successfully. Diagnosed in October 2014 with CML-CP, usual Ph-positive and bcr-abl positive. Started on imatinib at 400mg daily. Initially some very transient problems with cytopenias and cholestatic jaundice, now all resolved. Has CHR and about to be checked for 3-month molecular response. Has had significant drop in absolute CD4 and CD8 counts with no change in therapy.
2. 55 year old male with HIV diagnosed in 1993 on HAART (abacavir/lamivudine 600/300mg/daily, nevirapine 400mg/daily) again obviously quite successfully. In 2008 bcr-abl negative, JAK2 negative MPD. No therapy. In 2010 diagnosis of ITP treated with splenectomy. bcr-abl and JAK2 negative again in 2011. In 2014, worsening neutrophilia with left shift and now Ph-positive and bcr-abl positive. Stated on imatinib 400mg daily. Transient issue with cytopenia. Blood counts now stable. Stable 0.33%IS response at 6 and 9 months. Has had a less dramatic drop in absolute CD4 and CD8 counts.

The two questions open for discussion are:
1. Best choice of TKI in these cases
2. What should be the response to the drop in CD4 and CD8 counts.

Answer 1

Speaking with our HIV pharmacy specialist and we came to the following thoughts/insights

Imatinib – the most likely to interact via the CYP system and in both patients they would be at higher risk for hepatic toxicity and would need to be monitored more closely in that regard

Nilotinib – less risk for CYP interaction but at higher risk for Qtc interaction depending on the retroviral agents. Risk for metabolic issues, especially hyperlipidemias, and multiple of the combination HIV agents have a small incidence of pancreatitis which may be something to look more closely for.

Dasatinib – probably the least risk for QTC and CYP interactions, none of the current anti-HIV combos have problems with pulmonary side effects/effusions

Other thoughts
Regimens with zidovudine have increased risk for leukopenias and anemia up front
In all patients once the anti-CML TKI is chosen it would be worth getting an ID consult to see if there is a more modern HAART regimen that might be used as some of the newer HIV agents since as dolutegravir and raltegravir have lower drug interaction profiles and may be able to decrease the overall risk of toxicity as long as their virus is susceptible.

Joseph Bubalo (OHSU Pharmacy)

Answer 2

There is also a published series of six patients showing good outcomes with imatinib and HAART: Chronic myeloid leukemia and HIV-infection.
Schlaberg R, Fisher JG, Flamm MJ, Murty VV, Bhagat G, Alobeid B. Leuk Lymphoma. 2008 Jun;49(6):1155-60.

The limited data with imatinib suggests no change in lymphocytes counts: Immunoprofiling of patients with chronic myeloid leukemia at diagnosis and during tyrosine kinase inhibitor therapy. Rohon P, Porkka K, Mustjoki S. Eur J Haematol. 2010 Nov;85(5):387-98, but some patients, in an older article developed hypogammaglobulinemia: Chronic myeloid leukemia patients resistant to or intolerant of interferon alpha and subsequently treated with imatinib show reduced immunoglobulin levels and hypogammaglobulinemia. Steegmann JL, Moreno G, Aláez C, Osorio S, Granda A, de la Cámara R, Arranz E, Reino FG, Salvanés FR, Fernández-Rañada JM, Muñoz C. Haematologica. 2003 Jul;88(7):762-8

Hope this helps.

Brian Druker

Patient no.1: To take a decision and to guide better treatment I think that it is necessary to monitor BCR-ABL transcript level and CD4 CD8 count with current drug doses. If the pt achieve an MMR, the dose of imatinib can be reduced, with further monitoring. If lymphocyte count drops more, imatinib can be discontinued for a period (one month?) to understand what happens to BCR-ABL and to lymphocyte count.

Patient no. 2: same as patient no. 1

In any case, it is not possible to advise if one does not know the data (BCR-ABL%, CD4 and CD8)) and the changes of the data over time.

Kind regards, Michele Baccarani